diff --git a/citations.tsv b/citations.tsv
index 2bc91a079..b5b9c9d75 100644
--- a/citations.tsv
+++ b/citations.tsv
@@ -1299,13 +1299,18 @@ doi:10.1146/annurev.physiol.67.040403.120816	doi:10.1146/annurev.physiol.67.0404
 doi:10.1073/pnas.1118355109	doi:10.1073/pnas.1118355109	doi:10.1073/pnas.1118355109	BlEZu684
 doi:10.1098/rsif.2017.0387	doi:10.1098/rsif.2017.0387	doi:10.1098/rsif.2017.0387	PZMP42Ak
 url:https://greenelab.github.io/deep-review	url:https://greenelab.github.io/deep-review	url:https://greenelab.github.io/deep-review	heDA5StF
-url:https://github.com/ismms-himc/covid-19_sinai_reviews	url:https://github.com/ismms-himc/covid-19_sinai_reviews	url:https://github.com/ismms-himc/covid-19_sinai_reviews	cYo4O2qX
-doi:10.1038/s41577-020-0319-0	doi:10.1038/s41577-020-0319-0	doi:10.1038/s41577-020-0319-0	YZ4cHNuH
-url:https://www.physicianscientists.org/page/summer-research-pilot-program	url:https://www.physicianscientists.org/page/summer-research-pilot-program	url:https://www.physicianscientists.org/page/summer-research-pilot-program	DGTDsJZy
+doi:10.1053/j.ackd.2020.08.003	doi:10.1053/j.ackd.2020.08.003	doi:10.1053/j.ackd.2020.08.003	7ub6VM4Z
+doi:10/ggpx67	doi:10/ggpx67	doi:10.1016/s0140-6736(20)30461-x	nnfOazAC
+doi:10/d3bmnv	doi:10/d3bmnv	doi:10.1016/s0952-7915(00)00127-8	DfSr1Ohc
 url:https://github.com/greenelab/covid19-review	url:https://github.com/greenelab/covid19-review	url:https://github.com/greenelab/covid19-review	11MwmdOKi
 url:https://greenelab.github.io/covid19-review	url:https://greenelab.github.io/covid19-review	url:https://greenelab.github.io/covid19-review	yTsmmAYC
-doi:10.1109/MCSE.2007.55	doi:10.1109/MCSE.2007.55	doi:10.1109/mcse.2007.55	1026Gxdsi
 doi:10.5014/ajot.60.4.367	doi:10.5014/ajot.60.4.367	doi:10.5014/ajot.60.4.367	17OQtAY4l
+doi:10.1109/MCSE.2007.55	doi:10.1109/MCSE.2007.55	doi:10.1109/mcse.2007.55	1026Gxdsi
+url:https://www.zotero.org	url:https://www.zotero.org	url:https://www.zotero.org	snhvVGmP
+url:https://github.com/ismms-himc/covid-19_sinai_reviews	url:https://github.com/ismms-himc/covid-19_sinai_reviews	url:https://github.com/ismms-himc/covid-19_sinai_reviews	cYo4O2qX
+doi:10.1038/s41577-020-0319-0	doi:10.1038/s41577-020-0319-0	doi:10.1038/s41577-020-0319-0	YZ4cHNuH
+url:https://www.physicianscientists.org/page/summer-research-pilot-program	url:https://www.physicianscientists.org/page/summer-research-pilot-program	url:https://www.physicianscientists.org/page/summer-research-pilot-program	DGTDsJZy
+individual-therapeutics	individual-therapeutics	individual-therapeutics	sbHMb92g
 doi:10.1101/2020.01.28.923011	doi:10.1101/2020.01.28.923011	doi:10.1101/2020.01.28.923011	1HLSeqnY8
 doi:10.1101/2020.02.03.20020206	doi:10.1101/2020.02.03.20020206	doi:10.1101/2020.02.03.20020206	lOQPScZt
 doi:10.1101/2020.02.03.20020289	doi:10.1101/2020.02.03.20020289	doi:10.1101/2020.02.03.20020289	rL9IRhVy
diff --git a/manuscript.html b/manuscript.html
index d71eab68a..6e99afbd8 100644
--- a/manuscript.html
+++ b/manuscript.html
@@ -53,7 +53,7 @@
   <meta name="author" content="Joel D Boerckel" />
   <meta name="author" content="Amruta Naik" />
   <meta name="author" content="Yusha Sun" />
-  <meta name="dcterms.date" content="2021-04-16" />
+  <meta name="dcterms.date" content="2021-04-27" />
   <meta name="keywords" content="covid-19, coronavirus, pandemic, viral infection" />
   <title>SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics</title>
   <style>
@@ -76,8 +76,8 @@
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   <meta property="og:title" content="SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics" />
   <meta property="twitter:title" content="SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics" />
-  <meta name="dc.date" content="2021-04-16" />
-  <meta name="citation_publication_date" content="2021-04-16" />
+  <meta name="dc.date" content="2021-04-27" />
+  <meta name="citation_publication_date" content="2021-04-27" />
   <meta name="dc.language" content="en-US" />
   <meta name="citation_language" content="en-US" />
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@@ -272,13 +272,13 @@
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+  <link rel="alternate" type="text/html" href="https://greenelab.github.io/covid19-review/v/05acaf59cd3a3701df8ce0ad113773e154774d82/" />
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@@ -290,10 +290,10 @@ <h1 class="title">SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and
 </header>
 <p><small><em>
 This manuscript
-(<a href="https://greenelab.github.io/covid19-review/v/89dff08a5bb813c1bbc224275a347891ac8a532d/">permalink</a>)
+(<a href="https://greenelab.github.io/covid19-review/v/05acaf59cd3a3701df8ce0ad113773e154774d82/">permalink</a>)
 was automatically generated
-from <a href="https://github.com/greenelab/covid19-review/tree/89dff08a5bb813c1bbc224275a347891ac8a532d">greenelab/covid19-review@89dff08</a>
-on April 16, 2021.
+from <a href="https://github.com/greenelab/covid19-review/tree/05acaf59cd3a3701df8ce0ad113773e154774d82">greenelab/covid19-review@05acaf5</a>
+on April 27, 2021.
 Snapshots of individual sections are available as preprints <span class="citation" data-cites="r366f5T3 1B22G6dja cifK9B8t">[<a href="#ref-r366f5T3" role="doc-biblioref">1</a>,<a href="#ref-1B22G6dja" role="doc-biblioref">2</a>,<a href="#ref-cifK9B8t" role="doc-biblioref">3</a>]</span>.
 </em></small></p>
 <!-- include the Font Awesome library, per: https://fontawesome.com/start -->
@@ -659,12 +659,12 @@ <h1 class="page_break_before" data-number="1" id="introduction"><span class="hea
 One week later, 4,593 confirmed cases had been identified, spanning not only Asia, but also Australia, North America, and Europe <span class="citation" data-cites="fLTiwToY">[<a href="#ref-fLTiwToY" role="doc-biblioref">5</a>]</span>.
 On March 11, 2020, the WHO formally classified the situation as a pandemic <span class="citation" data-cites="x9975iBK">[<a href="#ref-x9975iBK" role="doc-biblioref">6</a>]</span>.
 On April 4, 2020, the WHO reported that the global number of confirmed cases had surpassed one million <span class="citation" data-cites="1GACP7OZY">[<a href="#ref-1GACP7OZY" role="doc-biblioref">7</a>]</span>.
-<!--2,972,617 COVID-19 deaths had been reported worldwide as of April 14, 2021 (Figure @fig:csse-deaths).
+<!--3,109,247 COVID-19 deaths had been reported worldwide as of April 25, 2021 (Figure @fig:csse-deaths).
 
 ![
 **Cumulative global COVID-19 deaths since January 22, 2020.**
 Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [@https://github.com/CSSEGISandData/COVID-19/tree/master/csse_covid_19_data/csse_covid_19_time_series].
-](https://github.com/greenelab/covid19-review/raw/abc5bb11c3d4338884b50635074611ec7af13001/csse/csse-deaths.png "Global COVID-19 deaths"){#fig:csse-deaths secno=1} --></p>
+](https://github.com/greenelab/covid19-review/raw/af928572d7bcb312c4caa2a6c95e286a10f6814a/csse/csse-deaths.png "Global COVID-19 deaths"){#fig:csse-deaths secno=1} --></p>
 <p>As international attention remains focused on the ongoing public health crisis, the scientific community has responded by mobilizing resources and turning much of its attention to the virus and disease.
 This rapid influx of information is disseminated by traditional publishing mechanisms, preprint servers, and press releases, which provide a venue for scientists to release findings without undergoing the formal publication process.
 While having information available is valuable to efforts to understand and combat COVID-19, many contributions come from researchers across a wide range of fields who have varying degrees of experience working on coronaviruses and related topics.
@@ -1594,42 +1594,42 @@ <h3 data-number="4.5.1" id="sustained-immunity-to-covid-19"><span class="header-
 However, the decline of IgA (15%) activity was less pronounced than that of IgM (53%) or IgG (32%).
 It was noted that higher levels of anti-RBD IgG and anti-N total antibodies were detected in individuals that reported persistent post-acute symptoms at both study visits.<!--To Do: confirm we define N in this paper-->
 Moreover, plasma neutralizing activity decreased five-fold between 1.3 and 6.2 months in an assay of HIV-1 virus pseudotyped with SARS-CoV-2 S protein, and this neutralizing activity was directly correlated with IgG anti-RBD titers <span class="citation" data-cites="iP9vKRvv">[<a href="#ref-iP9vKRvv" role="doc-biblioref">383</a>]</span>.
-These findings are in accordance with other studies that show that the majority of seroconverters have detectable, albeit decreasing, levels of neutralizing antibodies at least 3-6 months post infection <span class="citation" data-cites="19MYPpSCx m1wjdQSV NVgdaNGd">[<a href="#ref-19MYPpSCx" role="doc-biblioref">384</a>,<a href="#ref-m1wjdQSV" role="doc-biblioref">385</a>,<a href="#ref-NVgdaNGd" role="doc-biblioref">386</a>]</span>.
-Determining the potency of anti-RBD antibodies early in the course of an infection may be important moving forward, as their neutralizing potency may be prognostic for disease severity and survival <span class="citation" data-cites="1CZlIiD0p">[<a href="#ref-1CZlIiD0p" role="doc-biblioref">387</a>]</span>.</p>
+These findings are in accordance with other studies that show that the majority of seroconverters have detectable, albeit decreasing, levels of neutralizing antibodies at least 3-6 months post infection <span class="citation" data-cites="doi:10.1126/science.abd7728 m1wjdQSV NVgdaNGd">[<span class="citeproc-not-found" data-reference-id="doi:10.1126/science.abd7728"><strong>???</strong></span>,<a href="#ref-m1wjdQSV" role="doc-biblioref">384</a>,<a href="#ref-NVgdaNGd" role="doc-biblioref">385</a>]</span>.
+Determining the potency of anti-RBD antibodies early in the course of an infection may be important moving forward, as their neutralizing potency may be prognostic for disease severity and survival <span class="citation" data-cites="1CZlIiD0p">[<a href="#ref-1CZlIiD0p" role="doc-biblioref">386</a>]</span>.</p>
 <p>The development of memory B cells and memory T cells has also been assessed in several studies.
 Dan et al. showed that SARS-CoV-2 S-specific memory B cell levels rose steadily over the first 120 days following symptom onset <span class="citation" data-cites="L5l2MrPj">[<a href="#ref-L5l2MrPj" role="doc-biblioref">380</a>]</span>.
-RBD-specific memory B cells had been detected in COVID-19 patients 90 days post-symptom onset in previous studies <span class="citation" data-cites="obrRbBTR 1HNwTvE3S">[<a href="#ref-1HNwTvE3S" role="doc-biblioref">381</a>,<a href="#ref-obrRbBTR" role="doc-biblioref">388</a>]</span>, and this study confirms these finding and shows that levels of these cells increased over the 4-5 months post-symptom onset <span class="citation" data-cites="L5l2MrPj">[<a href="#ref-L5l2MrPj" role="doc-biblioref">380</a>]</span>.
+RBD-specific memory B cells had been detected in COVID-19 patients 90 days post-symptom onset in previous studies <span class="citation" data-cites="obrRbBTR 1HNwTvE3S">[<a href="#ref-1HNwTvE3S" role="doc-biblioref">381</a>,<a href="#ref-obrRbBTR" role="doc-biblioref">387</a>]</span>, and this study confirms these finding and shows that levels of these cells increased over the 4-5 months post-symptom onset <span class="citation" data-cites="L5l2MrPj">[<a href="#ref-L5l2MrPj" role="doc-biblioref">380</a>]</span>.
 Gaebler et al. have shown that memory B cells specific to the RBD remain unaltered and exhibit clonal turnover and antibody sequence evolution 6 months post infection, indicative of prolonged germinal cell reactions <span class="citation" data-cites="iP9vKRvv">[<a href="#ref-iP9vKRvv" role="doc-biblioref">383</a>]</span>.
 The same study showed that antibodies expressed by these memory B cells have resistance to RBD mutations, greater somatic hypermutations, and increased potency, which the authors suggest might be evidence of continued evolution of humoral immunity <span class="citation" data-cites="iP9vKRvv">[<a href="#ref-iP9vKRvv" role="doc-biblioref">383</a>]</span>.
-Indeed, Wheatley et al. showed that S-specific IgG<sup>+</sup> memory B cells consistently increase over time and by 4 months comprise approximately 0.8% of all IgG<sup>+</sup> memory B cells, which may indicate cellular immune memory to even mild-to-moderate COVID-19 infection <span class="citation" data-cites="NVgdaNGd">[<a href="#ref-NVgdaNGd" role="doc-biblioref">386</a>]</span>.
+Indeed, Wheatley et al. showed that S-specific IgG<sup>+</sup> memory B cells consistently increase over time and by 4 months comprise approximately 0.8% of all IgG<sup>+</sup> memory B cells, which may indicate cellular immune memory to even mild-to-moderate COVID-19 infection <span class="citation" data-cites="NVgdaNGd">[<a href="#ref-NVgdaNGd" role="doc-biblioref">385</a>]</span>.
 Dan et al. showed that N-specific memory B cells steadily increased up to 4-5 months post-symptom onset <span class="citation" data-cites="L5l2MrPj">[<a href="#ref-L5l2MrPj" role="doc-biblioref">380</a>]</span>.
-SARS-CoV-2 memory CD8<sup>+</sup> T cells were also detected in 70% of 169 COVID-19 patients after 1 month <span class="citation" data-cites="L5l2MrPj">[<a href="#ref-L5l2MrPj" role="doc-biblioref">380</a>]</span>, which is consistent with previous research <span class="citation" data-cites="CHRiQNCx">[<a href="#ref-CHRiQNCx" role="doc-biblioref">389</a>]</span>.
+SARS-CoV-2 memory CD8<sup>+</sup> T cells were also detected in 70% of 169 COVID-19 patients after 1 month <span class="citation" data-cites="L5l2MrPj">[<a href="#ref-L5l2MrPj" role="doc-biblioref">380</a>]</span>, which is consistent with previous research <span class="citation" data-cites="CHRiQNCx">[<a href="#ref-CHRiQNCx" role="doc-biblioref">388</a>]</span>.
 However, SARS-CoV-2 memory CD8<sup>+</sup> T cells were slightly decreased (50%) 6 months post-symptom onset.
 In this same subset of COVID-19 patients, 93% of subjects had detectable levels of SARS-CoV-2 memory CD4<sup>+</sup> T cells, of which 42% had more than 1% SARS-CoV-2-specific CD4<sup>+</sup> T cells.
 At 6 months, 92% of patients were positive for SARS-CoV-2 memory CD4<sup>+</sup> T cells.
 Indeed, the abundance of S-specific memory CD4<sup>+</sup> T cells over time was similar to that of SARS-CoV-2-specific CD4<sup>+</sup> T cells overall <span class="citation" data-cites="L5l2MrPj">[<a href="#ref-L5l2MrPj" role="doc-biblioref">380</a>]</span>.
-T cell immunity to SARS-CoV-2 at 6 to 8 months following symptom onset has also been confirmed by other studies <span class="citation" data-cites="AKY95Yy3 19p3NXKI5 H7Hdjjfx">[<a href="#ref-H7Hdjjfx" role="doc-biblioref">382</a>,<a href="#ref-AKY95Yy3" role="doc-biblioref">390</a>,<a href="#ref-19p3NXKI5" role="doc-biblioref">391</a>]</span>.
+T cell immunity to SARS-CoV-2 at 6 to 8 months following symptom onset has also been confirmed by other studies <span class="citation" data-cites="AKY95Yy3 19p3NXKI5 H7Hdjjfx">[<a href="#ref-H7Hdjjfx" role="doc-biblioref">382</a>,<a href="#ref-AKY95Yy3" role="doc-biblioref">389</a>,<a href="#ref-19p3NXKI5" role="doc-biblioref">390</a>]</span>.
 In another study, T cell reactivity to SARS-CoV-2 epitopes was also detected in some individuals never been exposed to SARS-CoV-2.
-This finding suggests the potential for cross-reactive T cell recognition between SARS-CoV-2 and pre-existing circulating HCoV that are responsible for the “common cold” <span class="citation" data-cites="CHRiQNCx">[<a href="#ref-CHRiQNCx" role="doc-biblioref">389</a>]</span>, but further research is required.</p>
+This finding suggests the potential for cross-reactive T cell recognition between SARS-CoV-2 and pre-existing circulating HCoV that are responsible for the “common cold” <span class="citation" data-cites="CHRiQNCx">[<a href="#ref-CHRiQNCx" role="doc-biblioref">388</a>]</span>, but further research is required.</p>
 <p>Concerns have also been raised that immunity may wane over time.
-Several reported cases of reinfection have been confirmed via genomic analysis that revealed distinct variants of SARS-CoV-2 within a single patient <span class="citation" data-cites="80JdM9px wAGdediZ 1C3LAVRl0">[<a href="#ref-80JdM9px" role="doc-biblioref">392</a>,<a href="#ref-wAGdediZ" role="doc-biblioref">393</a>,<a href="#ref-1C3LAVRl0" role="doc-biblioref">394</a>]</span>.
+Several reported cases of reinfection have been confirmed via genomic analysis that revealed distinct variants of SARS-CoV-2 within a single patient <span class="citation" data-cites="80JdM9px wAGdediZ 1C3LAVRl0">[<a href="#ref-80JdM9px" role="doc-biblioref">391</a>,<a href="#ref-wAGdediZ" role="doc-biblioref">392</a>,<a href="#ref-1C3LAVRl0" role="doc-biblioref">393</a>]</span>.
 Further research is required to determine the full extent to which sustained immunity can be and is typically achieved following SARS-CoV-2 infection.
-Furthermore, it is unclear whether previous infection may carry repercussions in terms of disease severity for patients <span class="citation" data-cites="5AYUha9Q">[<a href="#ref-5AYUha9Q" role="doc-biblioref">395</a>]</span> and what implications the possibility of reinfection holds for vaccine development and the long-term efficacy of vaccines <span class="citation" data-cites="wFZSnHto up2RNn1W">[<a href="#ref-wFZSnHto" role="doc-biblioref">396</a>,<a href="#ref-up2RNn1W" role="doc-biblioref">397</a>]</span>.
+Furthermore, it is unclear whether previous infection may carry repercussions in terms of disease severity for patients <span class="citation" data-cites="5AYUha9Q">[<a href="#ref-5AYUha9Q" role="doc-biblioref">394</a>]</span> and what implications the possibility of reinfection holds for vaccine development and the long-term efficacy of vaccines <span class="citation" data-cites="wFZSnHto up2RNn1W">[<a href="#ref-wFZSnHto" role="doc-biblioref">395</a>,<a href="#ref-up2RNn1W" role="doc-biblioref">396</a>]</span>.
 <!--To Do: add https://www.nature.com/articles/s41591-020-0965-6#Sec9 and evalute reports of recurrence.--></p>
 <h3 data-number="4.5.2" id="current-approaches"><span class="header-section-number">4.5.2</span> Current Approaches</h3>
 <!-- To Do: Update for 2021-->
-<p>Several countries are now focused on implementing antibody tests, and in the United States, the FDA recently approved a serological test by Cellex for use under emergency conditions <span class="citation" data-cites="n6sKSpIk">[<a href="#ref-n6sKSpIk" role="doc-biblioref">398</a>]</span>.
-Specifically, the Cellex qSARS-CoV-2 IgG/IgM Rapid Test is a chromatographic immunoassay designed to qualitatively detect IgM and IgG antibodies against SARS-CoV-2 in the plasma (from a blood sample) of patients suspected to have developed the SARS-CoV-2 infection <span class="citation" data-cites="n6sKSpIk">[<a href="#ref-n6sKSpIk" role="doc-biblioref">398</a>]</span>.
+<p>Several countries are now focused on implementing antibody tests, and in the United States, the FDA recently approved a serological test by Cellex for use under emergency conditions <span class="citation" data-cites="n6sKSpIk">[<a href="#ref-n6sKSpIk" role="doc-biblioref">397</a>]</span>.
+Specifically, the Cellex qSARS-CoV-2 IgG/IgM Rapid Test is a chromatographic immunoassay designed to qualitatively detect IgM and IgG antibodies against SARS-CoV-2 in the plasma (from a blood sample) of patients suspected to have developed the SARS-CoV-2 infection <span class="citation" data-cites="n6sKSpIk">[<a href="#ref-n6sKSpIk" role="doc-biblioref">397</a>]</span>.
 Such tests illuminate the progression of viral disease, as IgM are the first antibodies produced by the body and indicate that the infection is active.
-Once the body has responded to the infection, IgG are produced and gradually replace IgM, indicating that the body has developed immunogenic memory <span class="citation" data-cites="FFMfMDRN">[<a href="#ref-FFMfMDRN" role="doc-biblioref">399</a>]</span>.
-The Cellex test cassette contains a pad of SARS-CoV-2 antigens and a nitrocellulose strip with lines for each of IgG and IgM, as well as a control (goat IgG) <span class="citation" data-cites="n6sKSpIk">[<a href="#ref-n6sKSpIk" role="doc-biblioref">398</a>]</span>.
-In a specimen that contains antibodies against the SARS-CoV-2 antigen, the antibodies will bind to the strip and be captured by the IgM and/or IgG line(s), resulting in a change of color <span class="citation" data-cites="n6sKSpIk">[<a href="#ref-n6sKSpIk" role="doc-biblioref">398</a>]</span>.
-With this particular assay, results can be read within 15 to 20 minutes <span class="citation" data-cites="n6sKSpIk">[<a href="#ref-n6sKSpIk" role="doc-biblioref">398</a>]</span>.
-Other research groups, such as the Krammer lab of the Icahn School of Medicine at Mount Sinai, proposed an ELISA test that detects IgG and IgM that react against the RBD of the spike proteins (S) of the virus <span class="citation" data-cites="yJW1RVQb">[<a href="#ref-yJW1RVQb" role="doc-biblioref">400</a>]</span>.
-The authors are now working to get the assay into clinical use <span class="citation" data-cites="Gk9WwhYB">[<a href="#ref-Gk9WwhYB" role="doc-biblioref">401</a>]</span>.</p>
+Once the body has responded to the infection, IgG are produced and gradually replace IgM, indicating that the body has developed immunogenic memory <span class="citation" data-cites="FFMfMDRN">[<a href="#ref-FFMfMDRN" role="doc-biblioref">398</a>]</span>.
+The Cellex test cassette contains a pad of SARS-CoV-2 antigens and a nitrocellulose strip with lines for each of IgG and IgM, as well as a control (goat IgG) <span class="citation" data-cites="n6sKSpIk">[<a href="#ref-n6sKSpIk" role="doc-biblioref">397</a>]</span>.
+In a specimen that contains antibodies against the SARS-CoV-2 antigen, the antibodies will bind to the strip and be captured by the IgM and/or IgG line(s), resulting in a change of color <span class="citation" data-cites="n6sKSpIk">[<a href="#ref-n6sKSpIk" role="doc-biblioref">397</a>]</span>.
+With this particular assay, results can be read within 15 to 20 minutes <span class="citation" data-cites="n6sKSpIk">[<a href="#ref-n6sKSpIk" role="doc-biblioref">397</a>]</span>.
+Other research groups, such as the Krammer lab of the Icahn School of Medicine at Mount Sinai, proposed an ELISA test that detects IgG and IgM that react against the RBD of the spike proteins (S) of the virus <span class="citation" data-cites="yJW1RVQb">[<a href="#ref-yJW1RVQb" role="doc-biblioref">399</a>]</span>.
+The authors are now working to get the assay into clinical use <span class="citation" data-cites="Gk9WwhYB">[<a href="#ref-Gk9WwhYB" role="doc-biblioref">400</a>]</span>.</p>
 <h3 data-number="4.5.3" id="limitations-of-serological-tests"><span class="header-section-number">4.5.3</span> Limitations of Serological Tests</h3>
 <p>Like molecular tests, serological tests carry a number of limitations that influence their utility in different situations.
-Importantly, false positives can occur due to cross-reactivity with other antibodies according to the clinical condition of the patient <span class="citation" data-cites="n6sKSpIk">[<a href="#ref-n6sKSpIk" role="doc-biblioref">398</a>]</span>.
+Importantly, false positives can occur due to cross-reactivity with other antibodies according to the clinical condition of the patient <span class="citation" data-cites="n6sKSpIk">[<a href="#ref-n6sKSpIk" role="doc-biblioref">397</a>]</span>.
 Therefore, such tests must be used in combination with RNA detection tests if intended for diagnostic purposes, and while serological tests may be of interest to individuals who wish to confirm they were infected with SARS-CoV-2 in the past, their potential for false positives means that they are not currently recommended for this use.
 <!-- To Do: These are also single-throughput (can't be multiplexed), or can they also be high-throughput??-->
 Due to the long incubation times and delayed immune responses of infected patients, serological tests are insufficiently sensitive for a diagnosis in the early stages of an infection.
@@ -1638,23 +1638,23 @@ <h3 data-number="4.5.3" id="limitations-of-serological-tests"><span class="heade
 <h2 data-number="4.6" id="possible-alternatives-to-current-practices-for-identifying-active-cases"><span class="header-section-number">4.6</span> Possible Alternatives to Current Practices for Identifying Active Cases</h2>
 <p>COVID-19 can present with symptoms similar to other types of pneumonia, and symptoms can vary widely among COVID-19 patients; therefore, clinical presentation is often insufficient as a sole diagnostic criterion.
 In addition, identifying and isolating mild or asymptomatic cases is critical to efforts to manage outbreaks.
-Even among mildly symptomatic patients, a predictive model based on clinical symptoms had a sensitivity of only 56% and a specificity of 91% <span class="citation" data-cites="91dto3z3">[<a href="#ref-91dto3z3" role="doc-biblioref">402</a>]</span>.
+Even among mildly symptomatic patients, a predictive model based on clinical symptoms had a sensitivity of only 56% and a specificity of 91% <span class="citation" data-cites="91dto3z3">[<a href="#ref-91dto3z3" role="doc-biblioref">401</a>]</span>.
 More problematic is that clinical symptom-based tests are only able to identify already symptomatic cases, not presymptomatic or asymptomatic cases.
 They may still be important for clinical practice, and for reducing tests needed for patients deemed unlikely to have COVID-19.</p>
-<p>Similarly, X-ray diagnostics have been reported to have high sensitivity but low specificity in some studies <span class="citation" data-cites="itCGVb5b">[<a href="#ref-itCGVb5b" role="doc-biblioref">403</a>]</span>.
-Other studies have shown that specificity varies between radiologists <span class="citation" data-cites="tkuUFNIX">[<a href="#ref-tkuUFNIX" role="doc-biblioref">404</a>]</span>, though the sensitivity reported here was lower than that published in the previous paper.
-However, preliminary machine-learning results have shown far higher sensitivity and specificity from analyzing chest X-rays than was possible with clinical examination <span class="citation" data-cites="nN9zfzPe">[<a href="#ref-nN9zfzPe" role="doc-biblioref">405</a>]</span>.
+<p>Similarly, X-ray diagnostics have been reported to have high sensitivity but low specificity in some studies <span class="citation" data-cites="itCGVb5b">[<a href="#ref-itCGVb5b" role="doc-biblioref">402</a>]</span>.
+Other studies have shown that specificity varies between radiologists <span class="citation" data-cites="tkuUFNIX">[<a href="#ref-tkuUFNIX" role="doc-biblioref">403</a>]</span>, though the sensitivity reported here was lower than that published in the previous paper.
+However, preliminary machine-learning results have shown far higher sensitivity and specificity from analyzing chest X-rays than was possible with clinical examination <span class="citation" data-cites="nN9zfzPe">[<a href="#ref-nN9zfzPe" role="doc-biblioref">404</a>]</span>.
 X-ray tests with machine learning can potentially detect asymptomatic or presymptomatic infections that show lung manifestations.
 This approach would still not recognize entirely asymptomatic cases.
 Given the above, the widespread use of X-ray tests on otherwise healthy adults is likely inadvisable.</p>
 <h2 data-number="4.7" id="strategies-and-considerations-for-determining-whom-to-test"><span class="header-section-number">4.7</span> Strategies and Considerations for Determining Whom to Test</h2>
-<p>Early in the COVID-19 pandemic, testing was typically limited to individuals considered high risk for developing serious illness <span class="citation" data-cites="OB8BJiwj">[<a href="#ref-OB8BJiwj" role="doc-biblioref">406</a>]</span>.
+<p>Early in the COVID-19 pandemic, testing was typically limited to individuals considered high risk for developing serious illness <span class="citation" data-cites="OB8BJiwj">[<a href="#ref-OB8BJiwj" role="doc-biblioref">405</a>]</span>.
 This approach often involved limiting testing to people with severe symptoms and people showing mild symptoms that had been in contact with a person who had tested positive.
 Individuals who were asymptomatic (i.e., potential spreaders) and individuals who were able to recover at home were therefore often unaware of their status.
 However, this method of testing administration misses a high proportion of infections and does not allow for test-and-trace methods to be used.
 For instance, a recent study from Imperial College estimates that in Italy, the true number of infections was around 5.9 million in a total population ~60 million, compared to the 70,000 detected as of March 28th <span class="citation" data-cites="Frya4XA4">[<a href="#ref-Frya4XA4" role="doc-biblioref">259</a>]</span>.
-Another analysis, which examined New York state, indicated that as of May 2020, approximately 300,000 cases had been reported in a total population of approximately 20 million <span class="citation" data-cites="IldxlHwA">[<a href="#ref-IldxlHwA" role="doc-biblioref">407</a>]</span>.
-This corresponded to ~1.5% of the population, but ~12% of individuals sampled statewide were estimated as positive through antibody tests (along with indications of spatial heterogeneity at higher resolution) <span class="citation" data-cites="IldxlHwA">[<a href="#ref-IldxlHwA" role="doc-biblioref">407</a>]</span>.
+Another analysis, which examined New York state, indicated that as of May 2020, approximately 300,000 cases had been reported in a total population of approximately 20 million <span class="citation" data-cites="IldxlHwA">[<a href="#ref-IldxlHwA" role="doc-biblioref">406</a>]</span>.
+This corresponded to ~1.5% of the population, but ~12% of individuals sampled statewide were estimated as positive through antibody tests (along with indications of spatial heterogeneity at higher resolution) <span class="citation" data-cites="IldxlHwA">[<a href="#ref-IldxlHwA" role="doc-biblioref">406</a>]</span>.
 Technological advancements that facilitate widespread, rapid testing will therefore improve the potential to accurately assess the rate of infection and aid in controlling the virus’ spread.
 <!-- To Do: update this section because there have plenty of efforts to do this in the past 12 months, e.g., countries, universities, etc.--></p>
 <h2 data-number="4.8" id="conclusions-2"><span class="header-section-number">4.8</span> Conclusions</h2>
@@ -1665,11 +1665,11 @@ <h2 data-number="4.8" id="conclusions-2"><span class="header-section-number">4.8
 As of October 2020, a range of diagnostic tests have become available.
 One class of tests uses PCR (RT-PCR or RT-qPCR) to assess the presence of SARS-CoV-2 RNA, while another typically uses ELISA to test for the presence of antibodies to SARS-CoV-2.
 The former approach is useful for identifying active infections, while the latter measures hallmarks of the immune response and therefore can detect either active infections or immunity gained from prior infection.
-Combining these tests leads to extremely accurate detection of SARS-CoV-2 infection (98.6%), but when used alone, PCR-based tests are recommended before 5.5 days after the onset of the illness and antibody tests after 5.5 days <span class="citation" data-cites="CC4sPeuO">[<a href="#ref-CC4sPeuO" role="doc-biblioref">408</a>]</span>.
-Other strategies for testing can also influence the tests’ accuracy, such as the use of nasopharyngeal swabs versus bronchoalveolar lavage fluid <span class="citation" data-cites="CC4sPeuO">[<a href="#ref-CC4sPeuO" role="doc-biblioref">408</a>]</span>, which allow for trade-offs between patient’s comfort and test sensitivity.
+Combining these tests leads to extremely accurate detection of SARS-CoV-2 infection (98.6%), but when used alone, PCR-based tests are recommended before 5.5 days after the onset of the illness and antibody tests after 5.5 days <span class="citation" data-cites="CC4sPeuO">[<a href="#ref-CC4sPeuO" role="doc-biblioref">407</a>]</span>.
+Other strategies for testing can also influence the tests’ accuracy, such as the use of nasopharyngeal swabs versus bronchoalveolar lavage fluid <span class="citation" data-cites="CC4sPeuO">[<a href="#ref-CC4sPeuO" role="doc-biblioref">407</a>]</span>, which allow for trade-offs between patient’s comfort and test sensitivity.
 Additionally, technologies such as digital PCR may allow for scale-up in the throughput of diagnostic testing, facilitating widespread testing.
 One major question that remains is whether people who recover from SARS-CoV-2 develop sustained immunity, and over what period this immunity is expected to last.
-Some reports have suggested that some patients may develop COVID-19 reinfections (e.g., <span class="citation" data-cites="80JdM9px">[<a href="#ref-80JdM9px" role="doc-biblioref">392</a>]</span>), but the rates of reinfection are currently unknown.
+Some reports have suggested that some patients may develop COVID-19 reinfections (e.g., <span class="citation" data-cites="80JdM9px">[<a href="#ref-80JdM9px" role="doc-biblioref">391</a>]</span>), but the rates of reinfection are currently unknown.
 Serologic testing combined with PCR testing will be critical to confirming purported cases of reinfection and to identifying the duration over which immunity is retained and to understanding reinfection risks.</p>
 <h1 data-number="5" id="identification-and-development-of-therapeutics-for-covid-19"><span class="header-section-number">5</span> Identification and Development of Therapeutics for COVID-19</h1>
 <h2 data-number="5.1" id="abstract-4"><span class="header-section-number">5.1</span> Abstract</h2>
@@ -1697,13 +1697,13 @@ <h2 data-number="5.3" id="introduction-4"><span class="header-section-number">5.
 Due to the continued threat of the virus and the severity of the disease, the identification and development of prophylactic and therapeutic interventions have emerged as significant international priorities.
 Both approaches hold valuable potential for controlling the impact of the disease.
 Prophylactics bolster immunity to prevent an individual from contracting a disease, whereas therapeutics treat a disease in individuals who have already been infected.
-While a number of vaccines have recently been developed, approved, or are currently being evaluated by the US Food and Drug Administration and other regional and international bodies, vaccination programs only started being rolled out at the very end of 2020 and beginning of 2021, meaning that treatments that palliate symptoms and prevent the most severe outcomes have been necessary for much of 2020 and will continue to be necessary for the foreseeable future <span class="citation" data-cites="i2CGFwI3">[<a href="#ref-i2CGFwI3" role="doc-biblioref">409</a>]</span>.
+While a number of vaccines have recently been developed, approved, or are currently being evaluated by the US Food and Drug Administration and other regional and international bodies, vaccination programs only started being rolled out at the very end of 2020 and beginning of 2021, meaning that treatments that palliate symptoms and prevent the most severe outcomes have been necessary for much of 2020 and will continue to be necessary for the foreseeable future <span class="citation" data-cites="i2CGFwI3">[<a href="#ref-i2CGFwI3" role="doc-biblioref">408</a>]</span>.
 Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), have provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.</p>
-<p>2,972,617 COVID-19 deaths had been reported worldwide as of April 14, 2021 (Figure <a href="#fig:csse-deaths">2</a>).</p>
+<p>3,109,247 COVID-19 deaths had been reported worldwide as of April 25, 2021 (Figure <a href="#fig:csse-deaths">2</a>).</p>
 <div id="fig:csse-deaths" class="fignos">
 <figure>
-<img src="https://github.com/greenelab/covid19-review/raw/abc5bb11c3d4338884b50635074611ec7af13001/csse/csse-deaths.png" alt="" /><figcaption><span>Figure 2:</span> <strong>Cumulative global COVID-19 deaths since January 22, 2020.</strong>
-Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University <span class="citation" data-cites="MrwDDw9R">[<a href="#ref-MrwDDw9R" role="doc-biblioref">410</a>]</span>.</figcaption>
+<img src="https://github.com/greenelab/covid19-review/raw/af928572d7bcb312c4caa2a6c95e286a10f6814a/csse/csse-deaths.png" alt="" /><figcaption><span>Figure 2:</span> <strong>Cumulative global COVID-19 deaths since January 22, 2020.</strong>
+Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University <span class="citation" data-cites="MrwDDw9R">[<a href="#ref-MrwDDw9R" role="doc-biblioref">409</a>]</span>.</figcaption>
 </figure>
 </div>
 <h3 data-number="5.3.1" id="lessons-from-prior-hcov-outbreaks"><span class="header-section-number">5.3.1</span> Lessons from Prior HCoV Outbreaks</h3>
@@ -1719,7 +1719,7 @@ <h3 data-number="5.3.1" id="lessons-from-prior-hcov-outbreaks"><span class="head
 At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years <span class="citation" data-cites="G5NJrE75">[<a href="#ref-G5NJrE75" role="doc-biblioref">31</a>]</span>.
 The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the World Health Organization (WHO) <span class="citation" data-cites="G5NJrE75">[<a href="#ref-G5NJrE75" role="doc-biblioref">31</a>]</span>.
 In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 <span class="citation" data-cites="Bp847Lfa">[<a href="#ref-Bp847Lfa" role="doc-biblioref">13</a>]</span>, only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19.
-While SARS-CoV-1 belonged to a distinct lineage from the two other HCoVs known at the time of its discovery <span class="citation" data-cites="sP4wQEiM">[<a href="#ref-sP4wQEiM" role="doc-biblioref">33</a>]</span>, SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, <em>Middle East respiratory syndrome-related coronavirus</em> <span class="citation" data-cites="1Fqilxaum 7Ee6Sz9l">[<a href="#ref-1Fqilxaum" role="doc-biblioref">16</a>,<a href="#ref-7Ee6Sz9l" role="doc-biblioref">411</a>]</span>.</p>
+While SARS-CoV-1 belonged to a distinct lineage from the two other HCoVs known at the time of its discovery <span class="citation" data-cites="sP4wQEiM">[<a href="#ref-sP4wQEiM" role="doc-biblioref">33</a>]</span>, SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, <em>Middle East respiratory syndrome-related coronavirus</em> <span class="citation" data-cites="1Fqilxaum 7Ee6Sz9l">[<a href="#ref-1Fqilxaum" role="doc-biblioref">16</a>,<a href="#ref-7Ee6Sz9l" role="doc-biblioref">410</a>]</span>.</p>
 <p>Despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoVs.
 The trajectories of the pandemics associated with each of the viruses have also diverged significantly.
 By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing <span class="citation" data-cites="G5NJrE75">[<a href="#ref-G5NJrE75" role="doc-biblioref">31</a>]</span>.
@@ -1742,7 +1742,7 @@ <h3 data-number="5.3.2" id="overview-of-therapeutic-approaches"><span class="hea
 <p>Therapeutic approaches to the current pandemic can utilize two potential avenues: they can reduce the symptoms that are harmful to COVID-19 patients, or they can directly target the virus to hinder the spread of infection.
 The goal of the former is to reduce the severity and risks of an active infection, while for the latter, it is to inhibit the replication of the virus once an individual is infected.
 A variety of symptom profiles with a range of severity are associated with COVID-19, many of which are not life-threatening.
-A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism <span class="citation" data-cites="xnPm1mx8">[<a href="#ref-xnPm1mx8" role="doc-biblioref">412</a>]</span>.
+A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism <span class="citation" data-cites="xnPm1mx8">[<a href="#ref-xnPm1mx8" role="doc-biblioref">411</a>]</span>.
 Therapeutics that reduce the risks associated with these severe outcomes hold particular potential to reduce the pandemic death toll, while therapeutics that directly target the virus itself would hold the potential to prevent people infected with SARS-CoV-2 from developing potentially damaging symptoms.
 The treatments in this latter category typically fall into the broad category of antivirals.
 Antiviral therapies hinder the spread of a virus within the host, rather than destroying existing copies of the virus, and these drugs can vary in their specificity to a narrow or broad range of viral targets.
@@ -1751,11 +1751,11 @@ <h3 data-number="5.3.2" id="overview-of-therapeutic-approaches"><span class="hea
 The purpose of this review is to critically appraise the literature surrounding a subset of clinical trials and to evaluate a range of approaches to repurpose existing or develop novel approaches to the mitigation and treatment of coronavirus infections.
 The treatments evaluated here are classified according to their biological properties, specifically whether they are biologics (produced from components of organisms) or small molecules.
 Small molecule drugs include drugs targeted at viral particles, drugs targeted at host proteins, and broad spectrum pharmaceuticals, while biologics include antibodies and interferons.
-As we cover vaccines in a separate manuscript <span class="citation" data-cites="i2CGFwI3">[<a href="#ref-i2CGFwI3" role="doc-biblioref">409</a>]</span>, we only consider therapies for the prevention of SARS-CoV-2 infection or COVID-19 in a very limited context here, for example when a drug is studied to see whether it can prevent infection or disease in recently-exposed individuals.
+As we cover vaccines in a separate manuscript <span class="citation" data-cites="i2CGFwI3">[<a href="#ref-i2CGFwI3" role="doc-biblioref">408</a>]</span>, we only consider therapies for the prevention of SARS-CoV-2 infection or COVID-19 in a very limited context here, for example when a drug is studied to see whether it can prevent infection or disease in recently-exposed individuals.
 As results become available from additional clinical trials, we will continue to update this manuscript to keep pace with the current understanding of which therapeutics may be effective against SARS-CoV-2 or COVID-19.</p>
 <div id="fig:ebm-trials" class="fignos">
 <figure>
-<img src="https://github.com/greenelab/covid19-review/raw/abc5bb11c3d4338884b50635074611ec7af13001/ebmdatalab/ebmdatalab-trials.png" alt="" /><figcaption><span>Figure 3:</span> <strong>COVID-19 clinical trials.</strong>
+<img src="https://github.com/greenelab/covid19-review/raw/af928572d7bcb312c4caa2a6c95e286a10f6814a/ebmdatalab/ebmdatalab-trials.png" alt="" /><figcaption><span>Figure 3:</span> <strong>COVID-19 clinical trials.</strong>
 There are 6,417 COVID-19 clinical trials of which 3,706 are interventional.
 The study types include only types used in at least five trials.
 Interventional trials only are analyzed in the figures depicting status, phase, and intervention.
@@ -1763,44 +1763,44 @@ <h3 data-number="5.3.2" id="overview-of-therapeutic-approaches"><span class="hea
 Recruitment status and trial phase are shown only for interventional trials in which the status or phase is recorded.
 The common interventions are all interventions used in at least ten trials.
 Combinations of interventions, such as Hydroxychloroquine + Azithromycin, are tallied separately from the individual interventions.
-Trials data are from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker <span class="citation" data-cites="SSbnPnzT">[<a href="#ref-SSbnPnzT" role="doc-biblioref">413</a>]</span>.</figcaption>
+Trials data are from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker <span class="citation" data-cites="SSbnPnzT">[<a href="#ref-SSbnPnzT" role="doc-biblioref">412</a>]</span>.</figcaption>
 </figure>
 </div>
 <h2 data-number="5.4" id="small-molecule-drugs"><span class="header-section-number">5.4</span> Small Molecule Drugs</h2>
-<p>Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) <span class="citation" data-cites="CcEjS89m">[<a href="#ref-CcEjS89m" role="doc-biblioref">414</a>]</span>.
-Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century <span class="citation" data-cites="ZtfLQJhh">[<a href="#ref-ZtfLQJhh" role="doc-biblioref">415</a>]</span>.
-It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules <span class="citation" data-cites="ZtfLQJhh">[<a href="#ref-ZtfLQJhh" role="doc-biblioref">415</a>]</span>.
+<p>Small molecules are synthesized compounds of low molecular weight, typically less than 1 kilodalton (kDa) <span class="citation" data-cites="CcEjS89m">[<a href="#ref-CcEjS89m" role="doc-biblioref">413</a>]</span>.
+Small-molecule pharmaceutical agents have been a backbone of drug development since the discovery of penicillin in the early twentieth century <span class="citation" data-cites="ZtfLQJhh">[<a href="#ref-ZtfLQJhh" role="doc-biblioref">414</a>]</span>.
+It and other antibiotics have long been among the best known applications of small molecules to therapeutics, but biotechnological developments such as the prediction of protein-protein interactions have facilitated advances in precise targeting of specific structures using small molecules <span class="citation" data-cites="ZtfLQJhh">[<a href="#ref-ZtfLQJhh" role="doc-biblioref">414</a>]</span>.
 Small molecule drugs today encompass a wide range of therapeutics beyond antibiotics, including antivirals, protein inhibitors, and many broad-spectrum pharmaceuticals.</p>
 <h3 data-number="5.4.1" id="small-molecule-antivirals"><span class="header-section-number">5.4.1</span> Small Molecule Antivirals</h3>
 <p>Antiviral drugs against SARS-CoV-2 are designed to inhibit replication of a virus within an epithelial host cell.
-This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps <span class="citation" data-cites="14gthSuhm">[<a href="#ref-14gthSuhm" role="doc-biblioref">416</a>]</span> (Figure <a href="#fig:therapeutics">4</a>).
+This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps <span class="citation" data-cites="14gthSuhm">[<a href="#ref-14gthSuhm" role="doc-biblioref">415</a>]</span> (Figure <a href="#fig:therapeutics">4</a>).
 In the first of these steps, the virus attaches to and enters the host cell through endocytosis.
 Then the virus undergoes uncoating, which is classically defined as the release of viral contents into the host cell.
 Next, the viral genetic material enters the nucleus where it gets replicated during the biosynthesis stage.
 During the assembly stage, viral proteins are translated, allowing new viral particles to be assembled.
 In the final step new viruses are released into the extracellular environment.
 Many antiviral drugs are designed to inhibit the replication of viral genetic material during the biosynthesis step.
-Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication <span class="citation" data-cites="tn6j6IZ0 Sh1FwWps">[<a href="#ref-tn6j6IZ0" role="doc-biblioref">417</a>,<a href="#ref-Sh1FwWps" role="doc-biblioref">418</a>]</span>.
-Targeting the RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin <span class="citation" data-cites="6Qlsbuqr">[<a href="#ref-6Qlsbuqr" role="doc-biblioref">419</a>]</span>.
+Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication <span class="citation" data-cites="tn6j6IZ0 Sh1FwWps">[<a href="#ref-tn6j6IZ0" role="doc-biblioref">416</a>,<a href="#ref-Sh1FwWps" role="doc-biblioref">417</a>]</span>.
+Targeting the RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin <span class="citation" data-cites="6Qlsbuqr">[<a href="#ref-6Qlsbuqr" role="doc-biblioref">418</a>]</span>.
 However, although antivirals are designed to target a virus, they can also impact other processes in the host and may have unintended effects.
 Therefore, these therapeutics must be evaluated for both efficacy and safety.</p>
 <h4 data-number="5.4.1.1" id="nucleoside-and-nucleotide-analogs"><span class="header-section-number">5.4.1.1</span> Nucleoside and Nucleotide Analogs</h4>
 <h5 data-number="5.4.1.1.1" id="favipiravir"><span class="header-section-number">5.4.1.1.1</span> Favipiravir</h5>
-<p>Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. <span class="citation" data-cites="IkAU62Pd">[<a href="#ref-IkAU62Pd" role="doc-biblioref">420</a>]</span>.
-The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as <em>Flaviviridae</em> and <em>Picornaviridae</em>, through a reduction in plaque formation <span class="citation" data-cites="EgoJKtW4">[<a href="#ref-EgoJKtW4" role="doc-biblioref">421</a>]</span> and viral replication in Madin-Darby canine kidney cells <span class="citation" data-cites="rG5RCRdJ">[<a href="#ref-rG5RCRdJ" role="doc-biblioref">422</a>]</span>.
-Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections <span class="citation" data-cites="EgoJKtW4 rG5RCRdJ">[<a href="#ref-EgoJKtW4" role="doc-biblioref">421</a>,<a href="#ref-rG5RCRdJ" role="doc-biblioref">422</a>]</span>.
-In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors <span class="citation" data-cites="14p3btkRH">[<a href="#ref-14p3btkRH" role="doc-biblioref">423</a>]</span>.
-Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses <span class="citation" data-cites="DpdKJbki 9j7NVPJS IYEoCGHy 7d1TnpE3 15kQ4QYbx">[<a href="#ref-DpdKJbki" role="doc-biblioref">424</a>,<a href="#ref-9j7NVPJS" role="doc-biblioref">425</a>,<a href="#ref-IYEoCGHy" role="doc-biblioref">426</a>,<a href="#ref-7d1TnpE3" role="doc-biblioref">427</a>,<a href="#ref-15kQ4QYbx" role="doc-biblioref">428</a>]</span>.
+<p>Favipiravir (Avigan), also known as T-705, was discovered by Toyama Chemical Co., Ltd. <span class="citation" data-cites="IkAU62Pd">[<a href="#ref-IkAU62Pd" role="doc-biblioref">419</a>]</span>.
+The drug was found to be effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as <em>Flaviviridae</em> and <em>Picornaviridae</em>, through a reduction in plaque formation <span class="citation" data-cites="EgoJKtW4">[<a href="#ref-EgoJKtW4" role="doc-biblioref">420</a>]</span> and viral replication in Madin-Darby canine kidney cells <span class="citation" data-cites="rG5RCRdJ">[<a href="#ref-rG5RCRdJ" role="doc-biblioref">421</a>]</span>.
+Furthermore, inoculation of mice with favipiravir was shown to increase survival of influenza infections <span class="citation" data-cites="EgoJKtW4 rG5RCRdJ">[<a href="#ref-EgoJKtW4" role="doc-biblioref">420</a>,<a href="#ref-rG5RCRdJ" role="doc-biblioref">421</a>]</span>.
+In 2014, the drug was approved in Japan for the treatment of influenza that was resistant to conventional treatments like neuraminidase inhibitors <span class="citation" data-cites="14p3btkRH">[<a href="#ref-14p3btkRH" role="doc-biblioref">422</a>]</span>.
+Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including influenza viruses <span class="citation" data-cites="DpdKJbki 9j7NVPJS IYEoCGHy 7d1TnpE3 15kQ4QYbx">[<a href="#ref-DpdKJbki" role="doc-biblioref">423</a>,<a href="#ref-9j7NVPJS" role="doc-biblioref">424</a>,<a href="#ref-IYEoCGHy" role="doc-biblioref">425</a>,<a href="#ref-7d1TnpE3" role="doc-biblioref">426</a>,<a href="#ref-15kQ4QYbx" role="doc-biblioref">427</a>]</span>.
 Nucleotides and nucleosides are the natural building blocks for RNA synthesis.
-Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication <span class="citation" data-cites="MPJdSF1p">[<a href="#ref-MPJdSF1p" role="doc-biblioref">429</a>]</span>.
+Because of this, modifications to nucleotides and nucleosides can disrupt key processes including replication <span class="citation" data-cites="MPJdSF1p">[<a href="#ref-MPJdSF1p" role="doc-biblioref">428</a>]</span>.
 Biochemical experiments showed that favipiravir was recognized as a purine nucleoside analogue and incorporated into the viral RNA template.
-A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis <span class="citation" data-cites="ukZRKllk">[<a href="#ref-ukZRKllk" role="doc-biblioref">430</a>]</span>.
-Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection <span class="citation" data-cites="DpdKJbki 7d1TnpE3 15kQ4QYbx">[<a href="#ref-DpdKJbki" role="doc-biblioref">424</a>,<a href="#ref-7d1TnpE3" role="doc-biblioref">427</a>,<a href="#ref-15kQ4QYbx" role="doc-biblioref">428</a>]</span>.</p>
+A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis <span class="citation" data-cites="ukZRKllk">[<a href="#ref-ukZRKllk" role="doc-biblioref">429</a>]</span>.
+Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of favipiravir in early times post-infection <span class="citation" data-cites="DpdKJbki 7d1TnpE3 15kQ4QYbx">[<a href="#ref-DpdKJbki" role="doc-biblioref">423</a>,<a href="#ref-7d1TnpE3" role="doc-biblioref">426</a>,<a href="#ref-15kQ4QYbx" role="doc-biblioref">427</a>]</span>.</p>
 <p>The effectiveness of favipiravir for treating patients with COVID-19 is currently under investigation.
-An open-label, nonrandomized, before-after controlled study was recently conducted <span class="citation" data-cites="13Oz7yRPx">[<a href="#ref-13Oz7yRPx" role="doc-biblioref">431</a>]</span>.
+An open-label, nonrandomized, before-after controlled study was recently conducted <span class="citation" data-cites="13Oz7yRPx">[<a href="#ref-13Oz7yRPx" role="doc-biblioref">430</a>]</span>.
 The study included 80 COVID-19 patients (35 treated with favipiravir, 45 control) from the isolation ward of the National Clinical Research Center for Infectious Diseases (The Third People’s Hospital of Shenzhen), Shenzhen, China.
 The patients in the control group were treated with other antivirals, such as lopinavir and ritonavir.
-It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed <span class="citation" data-cites="jShm9uhy fTWlYlvp xM0IhxIr">[<a href="#ref-jShm9uhy" role="doc-biblioref">432</a>,<a href="#ref-fTWlYlvp" role="doc-biblioref">433</a>,<a href="#ref-xM0IhxIr" role="doc-biblioref">434</a>]</span>.
+It should be noted that although the control patients received antivirals, two subsequent large-scale analyses, the WHO Solidarity trial and the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, identified no effect of lopinavir or of a lopinavir-ritonavir combination, respectively, on the metrics of COVID-19-related mortality that each assessed <span class="citation" data-cites="jShm9uhy fTWlYlvp xM0IhxIr">[<a href="#ref-jShm9uhy" role="doc-biblioref">431</a>,<a href="#ref-fTWlYlvp" role="doc-biblioref">432</a>,<a href="#ref-xM0IhxIr" role="doc-biblioref">433</a>]</span>.
 Treatment was applied on days 2-14; treatment stopped either when viral clearance was confirmed or at day 14.
 The efficacy of the treatment was measured by, first, the time until viral clearance using Kaplan-Meier survival curves, and, second, the improvement rate of chest computed tomography (CT) scans on day 14 after treatment.
 The study found that favipiravir increased the speed of recovery, measured as viral clearance from the patient by RT-PCR, with patients receiving favipiravir recovering in four days compared to 11 days for patients receiving antivirals such as lopinavir and ritonavir.
@@ -1810,31 +1810,31 @@ <h5 data-number="5.4.1.1.1" id="favipiravir"><span class="header-section-number"
 Despite the study reporting clinical improvement in favipiravir-treated patients, several study design issues are problematic and lower confidence in the overall conclusions.
 For example, the study was neither randomized nor blinded.
 Moreover, the selection of patients did not take into consideration important factors such as previous clinical conditions or sex, and there was no age categorization.
-Additionally, it should be noted that this study was temporarily retracted and then restored without an explanation <span class="citation" data-cites="hfAF6aDr">[<a href="#ref-hfAF6aDr" role="doc-biblioref">435</a>]</span>.</p>
-<p>In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results <span class="citation" data-cites="APU0cUZz 15rGJX7Hl 32n9UEkQ">[<a href="#ref-APU0cUZz" role="doc-biblioref">436</a>,<a href="#ref-15rGJX7Hl" role="doc-biblioref">437</a>,<a href="#ref-32n9UEkQ" role="doc-biblioref">438</a>]</span>.
-The first <span class="citation" data-cites="APU0cUZz">[<a href="#ref-APU0cUZz" role="doc-biblioref">436</a>]</span> used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to standard of care (SOC) alone.
+Additionally, it should be noted that this study was temporarily retracted and then restored without an explanation <span class="citation" data-cites="hfAF6aDr">[<a href="#ref-hfAF6aDr" role="doc-biblioref">434</a>]</span>.</p>
+<p>In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results <span class="citation" data-cites="APU0cUZz 15rGJX7Hl 32n9UEkQ">[<a href="#ref-APU0cUZz" role="doc-biblioref">435</a>,<a href="#ref-15rGJX7Hl" role="doc-biblioref">436</a>,<a href="#ref-32n9UEkQ" role="doc-biblioref">437</a>]</span>.
+The first <span class="citation" data-cites="APU0cUZz">[<a href="#ref-APU0cUZz" role="doc-biblioref">435</a>]</span> used a randomized, controlled, open-label design to compare two drugs, favipiravir and baloxavir marboxil, to standard of care (SOC) alone.
 Here, SOC included antivirals such as lopinavir/ritonavir and was administered to all patients.
 The primary endpoint analyzed was viral clearance at day 14.
 The sample size for this study was very small, with 29 total patients enrolled, and no significant effect of the treatments was found for the primary or any of the secondary outcomes analyzed, which included mortality.
-The second study <span class="citation" data-cites="15rGJX7Hl">[<a href="#ref-15rGJX7Hl" role="doc-biblioref">437</a>]</span> was larger, with 96 patients enrolled, and included only individuals with mild to moderate symptoms who were randomized into two groups: one receiving chloroquine (CQ) in addition to SOC, and the other receiving favipiravir in addition to SOC.
+The second study <span class="citation" data-cites="15rGJX7Hl">[<a href="#ref-15rGJX7Hl" role="doc-biblioref">436</a>]</span> was larger, with 96 patients enrolled, and included only individuals with mild to moderate symptoms who were randomized into two groups: one receiving chloroquine (CQ) in addition to SOC, and the other receiving favipiravir in addition to SOC.
 This study reported a non-significant trend for patients receiving favipiravir to have a shorter hospital stay (13.29 days compared to 15.89 for CQ, <em>p</em> = 0.06) and less likelihood of progressing to mechanical ventilation (<em>p</em> = 0.118) or to an oxygen saturation &lt; 90% (<em>p</em> = 0.129).
 These results, combined with the fact that favipiravir was being compared to CQ, which is now widely understood to be ineffective for treating COVID-19, thus do not suggest that favipiravir was likely to have had a strong effect on these outcomes.
-On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) <span class="citation" data-cites="32n9UEkQ">[<a href="#ref-32n9UEkQ" role="doc-biblioref">438</a>]</span>.
-This study, as well as a prior study of favipiravir <span class="citation" data-cites="qwlYY6jn">[<a href="#ref-qwlYY6jn" role="doc-biblioref">439</a>]</span>, also reported that the drug was generally well-tolerated.
+On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) <span class="citation" data-cites="32n9UEkQ">[<a href="#ref-32n9UEkQ" role="doc-biblioref">437</a>]</span>.
+This study, as well as a prior study of favipiravir <span class="citation" data-cites="qwlYY6jn">[<a href="#ref-qwlYY6jn" role="doc-biblioref">438</a>]</span>, also reported that the drug was generally well-tolerated.
 Thus, in combination, these small studies suggest that the effects of favipiravir as a treatment for COVID-19 cannot be determined based on the available evidence, but additionally, none raise major concerns about the safety profile of the drug.</p>
 <h5 data-number="5.4.1.1.2" id="remdesivir"><span class="header-section-number">5.4.1.1.2</span> Remdesivir</h5>
 <p>Remdesivir (GS-5734) is an intravenous antiviral that was proposed by Gilead Sciences as a possible treatment for Ebola virus disease (EVD).
 At the outset of the COVID-19 pandemic, it did not have any have any FDA-approved use.
-However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients <span class="citation" data-cites="1BYoe0y2H">[<a href="#ref-1BYoe0y2H" role="doc-biblioref">440</a>]</span>.
-The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 <span class="citation" data-cites="yTCAmOyt 1ATTPbCCO DtpdBrgt 16zLDIOyk">[<a href="#ref-yTCAmOyt" role="doc-biblioref">441</a>,<a href="#ref-1ATTPbCCO" role="doc-biblioref">442</a>,<a href="#ref-DtpdBrgt" role="doc-biblioref">443</a>,<a href="#ref-16zLDIOyk" role="doc-biblioref">444</a>]</span>.
-Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination <span class="citation" data-cites="YaxKcqq8 lIko9Imd IhdcvbzC">[<a href="#ref-YaxKcqq8" role="doc-biblioref">445</a>,<a href="#ref-lIko9Imd" role="doc-biblioref">446</a>,<a href="#ref-IhdcvbzC" role="doc-biblioref">447</a>]</span>.
-A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued <span class="citation" data-cites="gnfviuGp">[<a href="#ref-gnfviuGp" role="doc-biblioref">448</a>]</span>.
-Remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s <span class="citation" data-cites="1H0NPTMw9">[<a href="#ref-1H0NPTMw9" role="doc-biblioref">449</a>]</span>.
-It has also been found to inhibit SARS-CoV-2, showing synergy with CQ <em>in vitro</em> <span class="citation" data-cites="IhdcvbzC">[<a href="#ref-IhdcvbzC" role="doc-biblioref">447</a>]</span>.</p>
-<p>Remdesivir was first used on some COVID-19 patients under compassionate use guidelines <span class="citation" data-cites="D4HwvRMd zoLViMNg">[<a href="#ref-D4HwvRMd" role="doc-biblioref">450</a>,<a href="#ref-zoLViMNg" role="doc-biblioref">451</a>]</span>.
+However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients <span class="citation" data-cites="1BYoe0y2H">[<a href="#ref-1BYoe0y2H" role="doc-biblioref">439</a>]</span>.
+The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 <span class="citation" data-cites="yTCAmOyt 1ATTPbCCO DtpdBrgt 16zLDIOyk">[<a href="#ref-yTCAmOyt" role="doc-biblioref">440</a>,<a href="#ref-1ATTPbCCO" role="doc-biblioref">441</a>,<a href="#ref-DtpdBrgt" role="doc-biblioref">442</a>,<a href="#ref-16zLDIOyk" role="doc-biblioref">443</a>]</span>.
+Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination <span class="citation" data-cites="YaxKcqq8 lIko9Imd IhdcvbzC">[<a href="#ref-YaxKcqq8" role="doc-biblioref">444</a>,<a href="#ref-lIko9Imd" role="doc-biblioref">445</a>,<a href="#ref-IhdcvbzC" role="doc-biblioref">446</a>]</span>.
+A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued <span class="citation" data-cites="gnfviuGp">[<a href="#ref-gnfviuGp" role="doc-biblioref">447</a>]</span>.
+Remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s <span class="citation" data-cites="1H0NPTMw9">[<a href="#ref-1H0NPTMw9" role="doc-biblioref">448</a>]</span>.
+It has also been found to inhibit SARS-CoV-2, showing synergy with CQ <em>in vitro</em> <span class="citation" data-cites="IhdcvbzC">[<a href="#ref-IhdcvbzC" role="doc-biblioref">446</a>]</span>.</p>
+<p>Remdesivir was first used on some COVID-19 patients under compassionate use guidelines <span class="citation" data-cites="D4HwvRMd zoLViMNg">[<a href="#ref-D4HwvRMd" role="doc-biblioref">449</a>,<a href="#ref-zoLViMNg" role="doc-biblioref">450</a>]</span>.
 All were in late stages of COVID-19 infection, and initial reports were inconclusive about the drug’s efficacy.
 Gilead Sciences, the maker of remdesivir, led a recent publication that reported outcomes for compassionate use of the drug in 61 patients hospitalized with confirmed COVID-19.
-Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days <span class="citation" data-cites="16zLDIOyk">[<a href="#ref-16zLDIOyk" role="doc-biblioref">444</a>]</span>.
+Here, 200 mg of remdesivir was administered intravenously on day 1, followed by a further 100 mg/day for 9 days <span class="citation" data-cites="16zLDIOyk">[<a href="#ref-16zLDIOyk" role="doc-biblioref">443</a>]</span>.
 There were significant issues with the study design, or lack thereof.
 There was no randomized control group.
 The inclusion criteria were variable: some patients only required low doses of oxygen, while others required ventilation.
@@ -1843,49 +1843,49 @@ <h5 data-number="5.4.1.1.2" id="remdesivir"><span class="header-section-number">
 There was a short follow-up period of investigation.
 Eight patients were excluded from the analysis mainly due to missing post-baseline information; thus, their health was unaccounted for.
 Therefore, even though the study reported clinical improvement in 68% of the 53 patients ultimately evaluated, due to the significant issues with study design, it could not be determined whether treatment with remdesivir had an effect or whether these patients would have recovered regardless of treatment.
-Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control <span class="citation" data-cites="w5y1LWUR">[<a href="#ref-w5y1LWUR" role="doc-biblioref">453</a>]</span>.
+Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control <span class="citation" data-cites="w5y1LWUR">[<a href="#ref-w5y1LWUR" role="doc-biblioref">452</a>]</span>.
 These studies did not alter the understanding of the efficacy of remdesivir in treating COVID-19, but the encouraging results provided motivation for placebo-controlled studies.</p>
-<p>Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States <span class="citation" data-cites="DtpdBrgt 1ATTPbCCO">[<a href="#ref-1ATTPbCCO" role="doc-biblioref">442</a>,<a href="#ref-DtpdBrgt" role="doc-biblioref">443</a>]</span>.
+<p>Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United States <span class="citation" data-cites="DtpdBrgt 1ATTPbCCO">[<a href="#ref-1ATTPbCCO" role="doc-biblioref">441</a>,<a href="#ref-DtpdBrgt" role="doc-biblioref">442</a>]</span>.
 The trial recruited 1,062 patients and randomly assigned them to placebo treatment or treatment with remdesivir.
-Patients were stratified for randomization based on site and the severity of disease presentation at baseline <span class="citation" data-cites="DtpdBrgt">[<a href="#ref-DtpdBrgt" role="doc-biblioref">443</a>]</span>.
+Patients were stratified for randomization based on site and the severity of disease presentation at baseline <span class="citation" data-cites="DtpdBrgt">[<a href="#ref-DtpdBrgt" role="doc-biblioref">442</a>]</span>.
 The treatment was 200 mg on day 1, followed by 100 mg on days 2 through 10.
-Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo <span class="citation" data-cites="DtpdBrgt">[<a href="#ref-DtpdBrgt" role="doc-biblioref">443</a>]</span>.
+Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo <span class="citation" data-cites="DtpdBrgt">[<a href="#ref-DtpdBrgt" role="doc-biblioref">442</a>]</span>.
 The two groups were well matched demographically and clinically at baseline.
 Those who received remdesivir had a median recovery time of 10 days, as compared with 15 days in those who received placebo (rate ratio for recovery, 1.29; 95% confidence interval (CI), 1.12 to 1.49; <em>p</em> &lt; 0.001).
 The Kaplan-Meier estimates of mortality by 14 days were 6.7% with remdesivir and 11.9% with placebo, with a hazard ratio (HR) for death of 0.55 and a 95% CI of 0.36 to 0.83, and at day 29, remdesivir corresponded to 11.4% and the placebo to 15.2% (HR: 0.73; 95% CI, 0.52 to 1.03).
 Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients in the placebo group (31.6%).
-This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization <span class="citation" data-cites="DtpdBrgt">[<a href="#ref-DtpdBrgt" role="doc-biblioref">443</a>]</span>.
-Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older <span class="citation" data-cites="1BYoe0y2H">[<a href="#ref-1BYoe0y2H" role="doc-biblioref">440</a>]</span>.
-Additional clinical trials <span class="citation" data-cites="IhdcvbzC oso9r21L 1q4PmqTm rUTsIlZs JSoOOX98">[<a href="#ref-IhdcvbzC" role="doc-biblioref">447</a>,<a href="#ref-oso9r21L" role="doc-biblioref">454</a>,<a href="#ref-1q4PmqTm" role="doc-biblioref">455</a>,<a href="#ref-rUTsIlZs" role="doc-biblioref">456</a>,<a href="#ref-JSoOOX98" role="doc-biblioref">457</a>]</span> are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure <a href="#fig:ebm-trials">3</a>).
-As of October 22, 2020, remdesivir received FDA approval based on three clinical trials <span class="citation" data-cites="1DTFVDWTn">[<a href="#ref-1DTFVDWTn" role="doc-biblioref">458</a>]</span>.</p>
-<p>However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial <span class="citation" data-cites="jShm9uhy">[<a href="#ref-jShm9uhy" role="doc-biblioref">432</a>]</span>.
-This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world <span class="citation" data-cites="jShm9uhy">[<a href="#ref-jShm9uhy" role="doc-biblioref">432</a>]</span>.
+This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization <span class="citation" data-cites="DtpdBrgt">[<a href="#ref-DtpdBrgt" role="doc-biblioref">442</a>]</span>.
+Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older <span class="citation" data-cites="1BYoe0y2H">[<a href="#ref-1BYoe0y2H" role="doc-biblioref">439</a>]</span>.
+Additional clinical trials <span class="citation" data-cites="IhdcvbzC oso9r21L 1q4PmqTm rUTsIlZs JSoOOX98">[<a href="#ref-IhdcvbzC" role="doc-biblioref">446</a>,<a href="#ref-oso9r21L" role="doc-biblioref">453</a>,<a href="#ref-1q4PmqTm" role="doc-biblioref">454</a>,<a href="#ref-rUTsIlZs" role="doc-biblioref">455</a>,<a href="#ref-JSoOOX98" role="doc-biblioref">456</a>]</span> are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combination with other drugs (Figure <a href="#fig:ebm-trials">3</a>).
+As of October 22, 2020, remdesivir received FDA approval based on three clinical trials <span class="citation" data-cites="1DTFVDWTn">[<a href="#ref-1DTFVDWTn" role="doc-biblioref">457</a>]</span>.</p>
+<p>However, results suggesting no effect of remdesivir on survival were reported by the WHO Solidarity trial <span class="citation" data-cites="jShm9uhy">[<a href="#ref-jShm9uhy" role="doc-biblioref">431</a>]</span>.
+This large-scale, open-label trial enrolled 11,330 adult in-patients at 405 hospitals in 30 countries around the world <span class="citation" data-cites="jShm9uhy">[<a href="#ref-jShm9uhy" role="doc-biblioref">431</a>]</span>.
 Patients were randomized in equal proportions into four experimental conditions and a control condition, corresponding to four candidate treatments for COVID-19 and SOC, respectively; no placebo was administered.
 The 2,750 patients in the remdesivir group were administered 200 mg intravenously on the first day and 100 mg on each subsequent day until day 10 and assessed for in-hospital death (primary endpoint), duration of hospitalization, and progression to mechanical ventilation.
 There were also 2,708 control patients who would have been eligible and able to receive remdesivir were they not assigned to the control group.
 A total of 604 patients among these two cohorts died during initial hospitalization, with 301 in the remdesivir group and 303 in the control group.
 The rate ratio of death between these two groups was therefore not significant (0.95, <em>p</em> = 0.50), suggesting that the administration of remdesivir did not affect survival.
 The two secondary analyses similarly did not find any effect of remdesivir.
-Additionally, the authors compared data from their study with data from three other studies of remdesivir (including <span class="citation" data-cites="DtpdBrgt">[<a href="#ref-DtpdBrgt" role="doc-biblioref">443</a>]</span>) stratified by supplemental oxygen status.
+Additionally, the authors compared data from their study with data from three other studies of remdesivir (including <span class="citation" data-cites="DtpdBrgt">[<a href="#ref-DtpdBrgt" role="doc-biblioref">442</a>]</span>) stratified by supplemental oxygen status.
 A meta-analysis of the four studies yielded an overall rate ratio for death of 0.91 (<em>p</em> = 0.20).
 These results thus do not support the previous findings that remdesivir reduced median recovery time and mortality risk in COVID-19 patients.</p>
-<p>In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of release, the statement had not been peer reviewed <span class="citation" data-cites="zQT9JLP1">[<a href="#ref-zQT9JLP1" role="doc-biblioref">459</a>]</span>; these sentiments have been echoed elsewhere <span class="citation" data-cites="vJVD0Wle">[<a href="#ref-vJVD0Wle" role="doc-biblioref">460</a>]</span>.
-Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases <span class="citation" data-cites="pQkqi9ni xM0IhxIr">[<a href="#ref-xM0IhxIr" role="doc-biblioref">434</a>,<a href="#ref-pQkqi9ni" role="doc-biblioref">461</a>]</span>.
-However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52) <span class="citation" data-cites="DtpdBrgt">[<a href="#ref-DtpdBrgt" role="doc-biblioref">443</a>]</span>.
-Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 <span class="citation" data-cites="6NLZTSS0">[<a href="#ref-6NLZTSS0" role="doc-biblioref">462</a>]</span>.
+<p>In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of release, the statement had not been peer reviewed <span class="citation" data-cites="zQT9JLP1">[<a href="#ref-zQT9JLP1" role="doc-biblioref">458</a>]</span>; these sentiments have been echoed elsewhere <span class="citation" data-cites="vJVD0Wle">[<a href="#ref-vJVD0Wle" role="doc-biblioref">459</a>]</span>.
+Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases <span class="citation" data-cites="pQkqi9ni xM0IhxIr">[<a href="#ref-xM0IhxIr" role="doc-biblioref">433</a>,<a href="#ref-pQkqi9ni" role="doc-biblioref">460</a>]</span>.
+However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52) <span class="citation" data-cites="DtpdBrgt">[<a href="#ref-DtpdBrgt" role="doc-biblioref">442</a>]</span>.
+Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 <span class="citation" data-cites="6NLZTSS0">[<a href="#ref-6NLZTSS0" role="doc-biblioref">461</a>]</span>.
 These results suggest that remdesivir could improve outcomes for patients with moderate COVID-19, but that additional information would be needed to understand the effects of different durations of treatment.
-Therefore, the Solidarity trial may point to limitations in the generalizability of other research on remdesivir, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic <span class="citation" data-cites="xM0IhxIr">[<a href="#ref-xM0IhxIr" role="doc-biblioref">434</a>]</span>.
-On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards <span class="citation" data-cites="jShm9uhy">[<a href="#ref-jShm9uhy" role="doc-biblioref">432</a>]</span>, and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir <span class="citation" data-cites="xM0IhxIr">[<a href="#ref-xM0IhxIr" role="doc-biblioref">434</a>]</span>.
+Therefore, the Solidarity trial may point to limitations in the generalizability of other research on remdesivir, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic <span class="citation" data-cites="xM0IhxIr">[<a href="#ref-xM0IhxIr" role="doc-biblioref">433</a>]</span>.
+On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards <span class="citation" data-cites="jShm9uhy">[<a href="#ref-jShm9uhy" role="doc-biblioref">431</a>]</span>, and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir <span class="citation" data-cites="xM0IhxIr">[<a href="#ref-xM0IhxIr" role="doc-biblioref">433</a>]</span>.
 Despite the findings of the Solidarity trial, remdesivir remains available for the treatment of COVID-19 in many places.
-Remdesivir has also been investigated in combination with other drugs, such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 <span class="citation" data-cites="pDl6Q4UP">[<a href="#ref-pDl6Q4UP" role="doc-biblioref">463</a>]</span>; the FDA has issued an EUA for the combination of remdesivir and baricitinib in adult and pediatric patients <span class="citation" data-cites="1HiXNTn3b">[<a href="#ref-1HiXNTn3b" role="doc-biblioref">464</a>]</span>.
+Remdesivir has also been investigated in combination with other drugs, such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 <span class="citation" data-cites="pDl6Q4UP">[<a href="#ref-pDl6Q4UP" role="doc-biblioref">462</a>]</span>; the FDA has issued an EUA for the combination of remdesivir and baricitinib in adult and pediatric patients <span class="citation" data-cites="1HiXNTn3b">[<a href="#ref-1HiXNTn3b" role="doc-biblioref">463</a>]</span>.
 Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes.</p>
 <p>Similarly, the extent to which the remdesivir dosing regimen could influence outcomes continues to be under consideration.
-A randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days <span class="citation" data-cites="w5y1LWUR yTCAmOyt">[<a href="#ref-yTCAmOyt" role="doc-biblioref">441</a>,<a href="#ref-w5y1LWUR" role="doc-biblioref">453</a>]</span>, complementing the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not <span class="citation" data-cites="6NLZTSS0">[<a href="#ref-6NLZTSS0" role="doc-biblioref">462</a>]</span>.
+A randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days <span class="citation" data-cites="w5y1LWUR yTCAmOyt">[<a href="#ref-yTCAmOyt" role="doc-biblioref">440</a>,<a href="#ref-w5y1LWUR" role="doc-biblioref">452</a>]</span>, complementing the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not <span class="citation" data-cites="6NLZTSS0">[<a href="#ref-6NLZTSS0" role="doc-biblioref">461</a>]</span>.
 Patients in the two groups were administered 200 mg of remdesivir intravenously on the first day, followed by 100 mg on the subsequent four or nine days, respectively.
 The two groups differed significantly in their clinical status, with patients assigned to the 10-day group having more severe illness.
 This study also differed from most because it included not only adults, but also pediatric patients as young as 12 years old.
 It reported no significant differences across several outcomes for patients receiving a 5-day or 10-day course, when correcting for baseline clinical status.
-The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions <span class="citation" data-cites="w5y1LWUR">[<a href="#ref-w5y1LWUR" role="doc-biblioref">453</a>]</span>.
+The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions <span class="citation" data-cites="w5y1LWUR">[<a href="#ref-w5y1LWUR" role="doc-biblioref">452</a>]</span>.
 Thus, additional research is also required to determine whether the dosage and duration of remdesivir administration influences outcomes.</p>
 <p>In summary, remdesivir is the first FDA approved anti-viral against SARS-CoV-2 as well as the first FDA approved COVID-19 treatment.
 Early investigations of this drug established proof of principle that drugs targeting the virus can benefit COVID-19 patients.
@@ -1897,39 +1897,39 @@ <h5 data-number="5.4.1.1.2" id="remdesivir"><span class="header-section-number">
 They are typically combined with protease inhibitors, integrase inhibitors, and even other polymerase inhibitors.
 Additional clinical trials of remdesivir in different patient pools and in combination with other therapies will refine its use in the clinic.</p>
 <h4 data-number="5.4.1.2" id="protease-inhibitors"><span class="header-section-number">5.4.1.2</span> Protease Inhibitors</h4>
-<p>Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors <span class="citation" data-cites="26dpptLw">[<a href="#ref-26dpptLw" role="doc-biblioref">465</a>]</span>.
+<p>Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors <span class="citation" data-cites="26dpptLw">[<a href="#ref-26dpptLw" role="doc-biblioref">464</a>]</span>.
 Several FDA-approved drugs target proteases, including lopinavir and ritonavir for HIV infection and simeprevir for hepatitis C virus infection.
-In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses <span class="citation" data-cites="f7csoyEu">[<a href="#ref-f7csoyEu" role="doc-biblioref">466</a>]</span>.
+In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses <span class="citation" data-cites="f7csoyEu">[<a href="#ref-f7csoyEu" role="doc-biblioref">465</a>]</span>.
 Recently, a study <span class="citation" data-cites="15l3di3Wj">[<a href="#ref-15l3di3Wj" role="doc-biblioref">70</a>]</span> suggested that camostat mesylate, an FDA-approved protease inhibitor could block the entry of SARS-CoV-2 into lung cells <em>in vitro</em>.
 Thus far, investigation of possible protease inhibitors that could work against SARS-CoV-2 has been driven by computational predictions.</p>
 <p>Computer-aided design allowed for the development of a Michael acceptor inhibitor, now known as N3, to target a protease critical to SARS-CoV-2 replication.
-Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">467</a>]</span>.
+Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">466</a>]</span>.
 These polyproteins must undergo proteolytic processing.
 This processing is usually conducted by Mpro, a 33.8-kDa SARS-CoV-2 protease that is therefore fundamental to viral replication and transcription.
-N3 was designed computationally <span class="citation" data-cites="15JYG0AIU">[<a href="#ref-15JYG0AIU" role="doc-biblioref">468</a>]</span> to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses <span class="citation" data-cites="XfOTPQPJ">[<a href="#ref-XfOTPQPJ" role="doc-biblioref">469</a>]</span>, therefore inhibiting proteolytic processing.
-Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">467</a>]</span>, confirming the computational prediction.
-N3 was tested <em>in vitro</em> on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">467</a>]</span>.</p>
+N3 was designed computationally <span class="citation" data-cites="15JYG0AIU">[<a href="#ref-15JYG0AIU" role="doc-biblioref">467</a>]</span> to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses <span class="citation" data-cites="XfOTPQPJ">[<a href="#ref-XfOTPQPJ" role="doc-biblioref">468</a>]</span>, therefore inhibiting proteolytic processing.
+Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">466</a>]</span>, confirming the computational prediction.
+N3 was tested <em>in vitro</em> on SARS-CoV-2-infected Vero cells, which belong to a line of cells established from the kidney epithelial cells of an African green monkey, and was found to inhibit SARS-CoV-2 <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">466</a>]</span>.</p>
 <p>Although N3 is a strong inhibitor of SARS-CoV-2 <em>in vitro</em>, its safety and efficacy still need to be tested in healthy volunteers and patients.
-After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure <span class="citation" data-cites="4Sja6dIz 10NcfBSiT">[<a href="#ref-4Sja6dIz" role="doc-biblioref">467</a>,<a href="#ref-10NcfBSiT" role="doc-biblioref">470</a>]</span>, 10,000 compounds were screened for their <em>in vitro</em> anti-Mpro activity.
+After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro’s structure <span class="citation" data-cites="4Sja6dIz 10NcfBSiT">[<a href="#ref-4Sja6dIz" role="doc-biblioref">466</a>,<a href="#ref-10NcfBSiT" role="doc-biblioref">469</a>]</span>, 10,000 compounds were screened for their <em>in vitro</em> anti-Mpro activity.
 The six leads that were identified were ebselen, disulfiram, tideglusib, carmofur, and PX-12.
-<em>In vitro</em> analysis revealed that ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">467</a>]</span>.
-Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties <span class="citation" data-cites="17EErh01r">[<a href="#ref-17EErh01r" role="doc-biblioref">471</a>]</span>.
-It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease <span class="citation" data-cites="17EErh01r">[<a href="#ref-17EErh01r" role="doc-biblioref">471</a>]</span>, and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety <span class="citation" data-cites="17QBZngoP">[<a href="#ref-17QBZngoP" role="doc-biblioref">472</a>]</span>.
-For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide <span class="citation" data-cites="17EErh01r FBE30Uqz">[<a href="#ref-17EErh01r" role="doc-biblioref">471</a>,<a href="#ref-FBE30Uqz" role="doc-biblioref">473</a>]</span>.
-Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes <span class="citation" data-cites="1355hoYr1 bvMB3ySR 11F21sY2C">[<a href="#ref-1355hoYr1" role="doc-biblioref">474</a>,<a href="#ref-bvMB3ySR" role="doc-biblioref">475</a>,<a href="#ref-11F21sY2C" role="doc-biblioref">476</a>]</span>, possibly indicating that its antioxidative properties are protective <span class="citation" data-cites="FBE30Uqz">[<a href="#ref-FBE30Uqz" role="doc-biblioref">473</a>]</span>.
-On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">467</a>]</span>.
+<em>In vitro</em> analysis revealed that ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">466</a>]</span>.
+Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties <span class="citation" data-cites="17EErh01r">[<a href="#ref-17EErh01r" role="doc-biblioref">470</a>]</span>.
+It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease <span class="citation" data-cites="17EErh01r">[<a href="#ref-17EErh01r" role="doc-biblioref">470</a>]</span>, and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety <span class="citation" data-cites="17QBZngoP">[<a href="#ref-17QBZngoP" role="doc-biblioref">471</a>]</span>.
+For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide <span class="citation" data-cites="17EErh01r FBE30Uqz">[<a href="#ref-17EErh01r" role="doc-biblioref">470</a>,<a href="#ref-FBE30Uqz" role="doc-biblioref">472</a>]</span>.
+Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes <span class="citation" data-cites="1355hoYr1 bvMB3ySR 11F21sY2C">[<a href="#ref-1355hoYr1" role="doc-biblioref">473</a>,<a href="#ref-bvMB3ySR" role="doc-biblioref">474</a>,<a href="#ref-11F21sY2C" role="doc-biblioref">475</a>]</span>, possibly indicating that its antioxidative properties are protective <span class="citation" data-cites="FBE30Uqz">[<a href="#ref-FBE30Uqz" role="doc-biblioref">472</a>]</span>.
+On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">466</a>]</span>.
 While there is clear computational and <em>in vitro</em> support for ebselen’s potential as a COVID-19 therapeutic, results from clinical trials are not yet available for this compound.
-However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen <span class="citation" data-cites="G5cKNGMC">[<a href="#ref-G5cKNGMC" role="doc-biblioref">477</a>]</span>, on 60 adults presenting with each of moderate <span class="citation" data-cites="cUTgHTRj">[<a href="#ref-cUTgHTRj" role="doc-biblioref">478</a>]</span> and severe <span class="citation" data-cites="K13XqU1J">[<a href="#ref-K13XqU1J" role="doc-biblioref">479</a>]</span> COVID-19.</p>
+However, as of July 2020, phase II clinical trials commenced to assess the effects of SPI-1005, an investigational drug from Sound Pharmaceuticals that contains ebselen <span class="citation" data-cites="G5cKNGMC">[<a href="#ref-G5cKNGMC" role="doc-biblioref">476</a>]</span>, on 60 adults presenting with each of moderate <span class="citation" data-cites="cUTgHTRj">[<a href="#ref-cUTgHTRj" role="doc-biblioref">477</a>]</span> and severe <span class="citation" data-cites="K13XqU1J">[<a href="#ref-K13XqU1J" role="doc-biblioref">478</a>]</span> COVID-19.</p>
 <p>In summary, N3 is a computationally designed molecule that inhibits the viral transcription through inhibiting Mpro.
 Ebselen is both a strong Mpro inhibitor and strong inhibitor of viral replication <em>in vitro</em> that was found to reduce SARS-CoV-2 viral load even more effectively than N3.
 Ebselen is a promising compound since its safety has been demonstrated in other indications.
-However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets <span class="citation" data-cites="vXFGEybh">[<a href="#ref-vXFGEybh" role="doc-biblioref">480</a>]</span>.
+However, ebselen may be a false positive, since it is a promiscuous compound that can have many targets <span class="citation" data-cites="vXFGEybh">[<a href="#ref-vXFGEybh" role="doc-biblioref">479</a>]</span>.
 Therefore, the results of ongoing clinical trials are expected to help establish whether compounds with higher specificity are required.</p>
 <h3 data-number="5.4.2" id="broad-spectrum-pharmaceuticals"><span class="header-section-number">5.4.2</span> Broad-Spectrum Pharmaceuticals</h3>
 <p>When a virus enters a host, the host becomes the virus’s environment.
 Therefore, the state of the host can also influence the virus’s ability to replicate and spread.
-Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly <span class="citation" data-cites="FT3Nw9xJ">[<a href="#ref-FT3Nw9xJ" role="doc-biblioref">481</a>]</span>.
-On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate <span class="citation" data-cites="FT3Nw9xJ">[<a href="#ref-FT3Nw9xJ" role="doc-biblioref">481</a>]</span>.
+Traditionally, viral targets have been favored for pharmaceutical interventions because altering host processes is likely to be less specific than targeting the virus directly <span class="citation" data-cites="FT3Nw9xJ">[<a href="#ref-FT3Nw9xJ" role="doc-biblioref">480</a>]</span>.
+On the other hand, targeting the host offers potential for a complementary strategy to antivirals that could broadly limit the ability of viruses to replicate <span class="citation" data-cites="FT3Nw9xJ">[<a href="#ref-FT3Nw9xJ" role="doc-biblioref">480</a>]</span>.
 As a result, therapeutic approaches that target host proteins have become an area of interest for SARS-CoV-2.
 Viral entry receptors in particular have been identified as a potential target.
 Entry of SARS-CoV-2 into the cell depends on binding to angiotensin-converting enzyme 2 (ACE2), which is catalyzed by the enzyme encoded by <em>TMPRSS2</em> <span class="citation" data-cites="15l3di3Wj">[<a href="#ref-15l3di3Wj" role="doc-biblioref">70</a>]</span>.
@@ -1940,82 +1940,82 @@ <h3 data-number="5.4.2" id="broad-spectrum-pharmaceuticals"><span class="header-
 However, the fact that the targets of these agents are non-specific means that the mechanism of action can appear to be relevant to COVID-19 without a therapeutic or prophylactic effect being observed in clinical trials.
 This category of drugs has also received significant attention from the media and general public, often before rigorous testing has been able to determine their effectiveness against SARS-CoV-2.</p>
 <h4 data-number="5.4.2.1" id="ace-inhibitors-and-angiotensin-ii-receptor-blockers"><span class="header-section-number">5.4.2.1</span> ACE Inhibitors and Angiotensin II Receptor Blockers</h4>
-<p>Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among today’s most commonly prescribed medications, often being used to control blood pressure <span class="citation" data-cites="CIeWPFHG pbfxOvnK">[<a href="#ref-CIeWPFHG" role="doc-biblioref">482</a>,<a href="#ref-pbfxOvnK" role="doc-biblioref">483</a>]</span>.
-In the United States, for example, they are prescribed well over 100,000,000 times annually <span class="citation" data-cites="1BVslkmfk">[<a href="#ref-1BVslkmfk" role="doc-biblioref">484</a>]</span>.
-Data from some animal models suggest that several, but not all, ACE inhibitors (ACEIs) and several ARBs increase ACE2 expression in the cells of some organs <span class="citation" data-cites="17xTGqKp2">[<a href="#ref-17xTGqKp2" role="doc-biblioref">485</a>]</span>.
-Clinical studies have not established whether plasma ACE2 expression is increased in humans treated with these medications <span class="citation" data-cites="ZhhV4ztO">[<a href="#ref-ZhhV4ztO" role="doc-biblioref">486</a>]</span>.
+<p>Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among today’s most commonly prescribed medications, often being used to control blood pressure <span class="citation" data-cites="CIeWPFHG pbfxOvnK">[<a href="#ref-CIeWPFHG" role="doc-biblioref">481</a>,<a href="#ref-pbfxOvnK" role="doc-biblioref">482</a>]</span>.
+In the United States, for example, they are prescribed well over 100,000,000 times annually <span class="citation" data-cites="1BVslkmfk">[<a href="#ref-1BVslkmfk" role="doc-biblioref">483</a>]</span>.
+Data from some animal models suggest that several, but not all, ACE inhibitors (ACEIs) and several ARBs increase ACE2 expression in the cells of some organs <span class="citation" data-cites="17xTGqKp2">[<a href="#ref-17xTGqKp2" role="doc-biblioref">484</a>]</span>.
+Clinical studies have not established whether plasma ACE2 expression is increased in humans treated with these medications <span class="citation" data-cites="ZhhV4ztO">[<a href="#ref-ZhhV4ztO" role="doc-biblioref">485</a>]</span>.
 While randomized clinical trials are ongoing, a variety of observational studies have examined the relationship between exposure to ACEIs or ARBs and outcomes in patients with COVID-19.
-An observational study of the association of exposure to ACEIs or ARBs with outcomes in COVID-19 was retracted from the <em>New England Journal of Medicine</em> <span class="citation" data-cites="10q7vcaWw">[<a href="#ref-10q7vcaWw" role="doc-biblioref">487</a>]</span> due to concerns related to data availability <span class="citation" data-cites="3GIXDhwz">[<a href="#ref-3GIXDhwz" role="doc-biblioref">488</a>]</span>.
-Clinical trials are needed because the findings of the various observational studies bearing on this topic cannot be interpreted as indicating a protective effect of the drug <span class="citation" data-cites="19quOF2kK k5xEN3Ke">[<a href="#ref-19quOF2kK" role="doc-biblioref">489</a>,<a href="#ref-k5xEN3Ke" role="doc-biblioref">490</a>]</span>.
-Several clinical trials testing the effects of ACEIs or ARBs on COVID-19 outcomes are ongoing <span class="citation" data-cites="H0oEjZR8 kuUcA1G9 3ccJAyrG NCb9Wq2z 5fkIarR7 c7V9rAFR JP1lU6DV">[<a href="#ref-H0oEjZR8" role="doc-biblioref">491</a>,<a href="#ref-kuUcA1G9" role="doc-biblioref">492</a>,<a href="#ref-3ccJAyrG" role="doc-biblioref">493</a>,<a href="#ref-NCb9Wq2z" role="doc-biblioref">494</a>,<a href="#ref-5fkIarR7" role="doc-biblioref">495</a>,<a href="#ref-c7V9rAFR" role="doc-biblioref">496</a>,<a href="#ref-JP1lU6DV" role="doc-biblioref">497</a>]</span>.</p>
-<p>Two of these analyses <span class="citation" data-cites="H0oEjZR8 JP1lU6DV">[<a href="#ref-H0oEjZR8" role="doc-biblioref">491</a>,<a href="#ref-JP1lU6DV" role="doc-biblioref">497</a>]</span> have reported no effect of continuing or discontinuing ARBs and ACEIs on patients admitted to the hospital for COVID-19.
-The first, known as REPLACE COVID <span class="citation" data-cites="IRuDYZRB">[<a href="#ref-IRuDYZRB" role="doc-biblioref">498</a>]</span>, was a randomized, open-label study that enrolled patients who were admitted to the hospital for COVID-19 and were taking an ACEI at the time of admission.
+An observational study of the association of exposure to ACEIs or ARBs with outcomes in COVID-19 was retracted from the <em>New England Journal of Medicine</em> <span class="citation" data-cites="10q7vcaWw">[<a href="#ref-10q7vcaWw" role="doc-biblioref">486</a>]</span> due to concerns related to data availability <span class="citation" data-cites="3GIXDhwz">[<a href="#ref-3GIXDhwz" role="doc-biblioref">487</a>]</span>.
+Clinical trials are needed because the findings of the various observational studies bearing on this topic cannot be interpreted as indicating a protective effect of the drug <span class="citation" data-cites="19quOF2kK k5xEN3Ke">[<a href="#ref-19quOF2kK" role="doc-biblioref">488</a>,<a href="#ref-k5xEN3Ke" role="doc-biblioref">489</a>]</span>.
+Several clinical trials testing the effects of ACEIs or ARBs on COVID-19 outcomes are ongoing <span class="citation" data-cites="H0oEjZR8 kuUcA1G9 3ccJAyrG NCb9Wq2z 5fkIarR7 c7V9rAFR JP1lU6DV">[<a href="#ref-H0oEjZR8" role="doc-biblioref">490</a>,<a href="#ref-kuUcA1G9" role="doc-biblioref">491</a>,<a href="#ref-3ccJAyrG" role="doc-biblioref">492</a>,<a href="#ref-NCb9Wq2z" role="doc-biblioref">493</a>,<a href="#ref-5fkIarR7" role="doc-biblioref">494</a>,<a href="#ref-c7V9rAFR" role="doc-biblioref">495</a>,<a href="#ref-JP1lU6DV" role="doc-biblioref">496</a>]</span>.</p>
+<p>Two of these analyses <span class="citation" data-cites="H0oEjZR8 JP1lU6DV">[<a href="#ref-H0oEjZR8" role="doc-biblioref">490</a>,<a href="#ref-JP1lU6DV" role="doc-biblioref">496</a>]</span> have reported no effect of continuing or discontinuing ARBs and ACEIs on patients admitted to the hospital for COVID-19.
+The first, known as REPLACE COVID <span class="citation" data-cites="IRuDYZRB">[<a href="#ref-IRuDYZRB" role="doc-biblioref">497</a>]</span>, was a randomized, open-label study that enrolled patients who were admitted to the hospital for COVID-19 and were taking an ACEI at the time of admission.
 They enrolled 152 patients at 20 hospitals across seven countries and randomized them into two arms, continuation (n=75) and discontinuation (n=77).
 The primary outcome evaluated was a global rank score that integrated several dimensions of illness.
 The components of this global rank score, such as time to death and length of mechanical ventilation, were evaluated as secondary endpoints.
 This analysis reported no differences between the two groups in the primary or any of the secondary outcomes.</p>
-<p>Similarly, a second study <span class="citation" data-cites="1DqZPaCtf">[<a href="#ref-1DqZPaCtf" role="doc-biblioref">499</a>]</span> used a randomized, open-label design to examine the effects of continuing versus discontinuing ARBs and ACEIs on patients hospitalized for mild to moderate COVID-19 at 29 hospitals in Brazil.
+<p>Similarly, a second study <span class="citation" data-cites="1DqZPaCtf">[<a href="#ref-1DqZPaCtf" role="doc-biblioref">498</a>]</span> used a randomized, open-label design to examine the effects of continuing versus discontinuing ARBs and ACEIs on patients hospitalized for mild to moderate COVID-19 at 29 hospitals in Brazil.
 This study enrolled 740 patients but had to exclude one trial site from all analyses due to the discovery of violations of Good Clinical Trial practice and data falsification.
 After this exclusion, 659 patients remained, with 334 randomized to discontinuation and 325 to continuation.
 In this study, the primary endpoint analyzed was the number of days that patients were alive and not hospitalized within 30 days of enrollment.
 The secondary outcomes included death (including in-hospital death separately), number of days hospitalized, and specific clinical outcomes such as heart failure or stroke.
 Once again, no significant differences were found between the two groups.
 Initial studies of randomized interventions therefore suggest that ACEIs and ARBs are unlikely to affect COVID-19 outcomes.
-These results are also consistent with findings from observational studies (summarized in <span class="citation" data-cites="IRuDYZRB">[<a href="#ref-IRuDYZRB" role="doc-biblioref">498</a>]</span>).
-Additional information about ACE2, observational studies of ACEIs and ARBs in COVID-19, and clinical trials on this topic have been summarized <span class="citation" data-cites="1Hrsy8Hiq">[<a href="#ref-1Hrsy8Hiq" role="doc-biblioref">500</a>]</span>.
+These results are also consistent with findings from observational studies (summarized in <span class="citation" data-cites="IRuDYZRB">[<a href="#ref-IRuDYZRB" role="doc-biblioref">497</a>]</span>).
+Additional information about ACE2, observational studies of ACEIs and ARBs in COVID-19, and clinical trials on this topic have been summarized <span class="citation" data-cites="1Hrsy8Hiq">[<a href="#ref-1Hrsy8Hiq" role="doc-biblioref">499</a>]</span>.
 Therefore, despite the promising potential mechanism, initial results have not provided support for ACEIs and ARBs as therapies for COVID-19.</p>
 <h4 data-number="5.4.2.2" id="hydroxychloroquine-and-chloroquine"><span class="header-section-number">5.4.2.2</span> Hydroxychloroquine and Chloroquine</h4>
 <p>CQ and hydroxychloroquine (HCQ) are lysosomotropic agents, meaning they are weak bases that can pass through the plasma membrane.
-Both drugs increase cellular pH by accumulating in their protonated form inside lysosomes <span class="citation" data-cites="ggYRK4FU 16IRfGFKb">[<a href="#ref-ggYRK4FU" role="doc-biblioref">501</a>,<a href="#ref-16IRfGFKb" role="doc-biblioref">502</a>]</span>.
-These drugs are used for the treatment and prophylaxis of malaria, as well as the treatment of lupus erythematosus and rheumatoid arthritis in adults <span class="citation" data-cites="1CEGhPPDd">[<a href="#ref-1CEGhPPDd" role="doc-biblioref">503</a>]</span>.
-This shift in pH inhibits the breakdown of proteins and peptides by the lysosomes during the process of proteolysis <span class="citation" data-cites="16IRfGFKb">[<a href="#ref-16IRfGFKb" role="doc-biblioref">502</a>]</span>.
+Both drugs increase cellular pH by accumulating in their protonated form inside lysosomes <span class="citation" data-cites="ggYRK4FU 16IRfGFKb">[<a href="#ref-ggYRK4FU" role="doc-biblioref">500</a>,<a href="#ref-16IRfGFKb" role="doc-biblioref">501</a>]</span>.
+These drugs are used for the treatment and prophylaxis of malaria, as well as the treatment of lupus erythematosus and rheumatoid arthritis in adults <span class="citation" data-cites="1CEGhPPDd">[<a href="#ref-1CEGhPPDd" role="doc-biblioref">502</a>]</span>.
+This shift in pH inhibits the breakdown of proteins and peptides by the lysosomes during the process of proteolysis <span class="citation" data-cites="16IRfGFKb">[<a href="#ref-16IRfGFKb" role="doc-biblioref">501</a>]</span>.
 A number of mechanisms have been proposed through which these drugs could influence the immune response to pathogen challenge.
-For example, CQ/HCQ can interfere with digestion of antigens within the lysosome and inhibit CD4 T-cell stimulation while promoting the stimulation of CD8 T-cells <span class="citation" data-cites="16IRfGFKb">[<a href="#ref-16IRfGFKb" role="doc-biblioref">502</a>]</span>.
-CQ/HCQ can also decrease the production of certain key cytokines involved in the immune response, including interleukin-6 (IL-6), and inhibit the stimulation of Toll-like receptors (TLR) and TLR signaling <span class="citation" data-cites="16IRfGFKb">[<a href="#ref-16IRfGFKb" role="doc-biblioref">502</a>]</span>.
-The drugs also have anti-inflammatory and photoprotective effects and may also affect rates of cell death, blood clotting, glucose tolerance, and cholesterol levels <span class="citation" data-cites="16IRfGFKb">[<a href="#ref-16IRfGFKb" role="doc-biblioref">502</a>]</span>.</p>
+For example, CQ/HCQ can interfere with digestion of antigens within the lysosome and inhibit CD4 T-cell stimulation while promoting the stimulation of CD8 T-cells <span class="citation" data-cites="16IRfGFKb">[<a href="#ref-16IRfGFKb" role="doc-biblioref">501</a>]</span>.
+CQ/HCQ can also decrease the production of certain key cytokines involved in the immune response, including interleukin-6 (IL-6), and inhibit the stimulation of Toll-like receptors (TLR) and TLR signaling <span class="citation" data-cites="16IRfGFKb">[<a href="#ref-16IRfGFKb" role="doc-biblioref">501</a>]</span>.
+The drugs also have anti-inflammatory and photoprotective effects and may also affect rates of cell death, blood clotting, glucose tolerance, and cholesterol levels <span class="citation" data-cites="16IRfGFKb">[<a href="#ref-16IRfGFKb" role="doc-biblioref">501</a>]</span>.</p>
 <p>Interest in CQ and HCQ for treating COVID-19 was catalyzed by a mechanism observed in <em>in vitro</em> studies of both SARS-CoV-1 and SARS-CoV-2.
-In one study, CQ inhibited viral entry of SARS-CoV-1 into Vero E6 cells, a cell line that was derived from Vero cells in 1968, through the elevation of endosomal pH and the terminal glycosylation of ACE2 <span class="citation" data-cites="x6nInyCf">[<a href="#ref-x6nInyCf" role="doc-biblioref">504</a>]</span>.
+In one study, CQ inhibited viral entry of SARS-CoV-1 into Vero E6 cells, a cell line that was derived from Vero cells in 1968, through the elevation of endosomal pH and the terminal glycosylation of ACE2 <span class="citation" data-cites="x6nInyCf">[<a href="#ref-x6nInyCf" role="doc-biblioref">503</a>]</span>.
 Increased pH within the cell, as discussed above, inhibits proteolysis, and terminal glycosylation of ACE2 is thought to interfere with virus-receptor binding.
-An <em>in vitro</em> study of SARS-CoV-2 infection of Vero cells found both HCQ and CQ to be effective in inhibiting viral replication, with HCQ being more potent <span class="citation" data-cites="1GBsnkeLK">[<a href="#ref-1GBsnkeLK" role="doc-biblioref">505</a>]</span>.
+An <em>in vitro</em> study of SARS-CoV-2 infection of Vero cells found both HCQ and CQ to be effective in inhibiting viral replication, with HCQ being more potent <span class="citation" data-cites="1GBsnkeLK">[<a href="#ref-1GBsnkeLK" role="doc-biblioref">504</a>]</span>.
 Additionally, an early case study of three COVID-19 patients reported the presence of antiphospholipid antibodies in all three patients <span class="citation" data-cites="8OnbWuhF">[<a href="#ref-8OnbWuhF" role="doc-biblioref">119</a>]</span>.
-Antiphospholipid antibodies are central to the diagnosis of the antiphospholipid syndrome, a disorder that HCQ has often been used to treat <span class="citation" data-cites="nEaG534R rL8owM5Y 134vCyU3E">[<a href="#ref-nEaG534R" role="doc-biblioref">506</a>,<a href="#ref-rL8owM5Y" role="doc-biblioref">507</a>,<a href="#ref-134vCyU3E" role="doc-biblioref">508</a>]</span>.
-Because the 90% effective concentration (EC<sub>90</sub>) of CQ in Vero E6 cells (6.90 μM) can be achieved in and tolerated by rheumatoid arthritis (RA) patients, it was hypothesized that it might also be possible to achieve the effective concentration in COVID-19 patients <span class="citation" data-cites="WFGcbZhe">[<a href="#ref-WFGcbZhe" role="doc-biblioref">509</a>]</span>.
-Additionally, clinical trials have reported HCQ to be effective in treating HIV <span class="citation" data-cites="hFGjQQN8">[<a href="#ref-hFGjQQN8" role="doc-biblioref">510</a>]</span> and chronic Hepatitis C <span class="citation" data-cites="rQNzKxRd">[<a href="#ref-rQNzKxRd" role="doc-biblioref">511</a>]</span>.
+Antiphospholipid antibodies are central to the diagnosis of the antiphospholipid syndrome, a disorder that HCQ has often been used to treat <span class="citation" data-cites="nEaG534R rL8owM5Y 134vCyU3E">[<a href="#ref-nEaG534R" role="doc-biblioref">505</a>,<a href="#ref-rL8owM5Y" role="doc-biblioref">506</a>,<a href="#ref-134vCyU3E" role="doc-biblioref">507</a>]</span>.
+Because the 90% effective concentration (EC<sub>90</sub>) of CQ in Vero E6 cells (6.90 μM) can be achieved in and tolerated by rheumatoid arthritis (RA) patients, it was hypothesized that it might also be possible to achieve the effective concentration in COVID-19 patients <span class="citation" data-cites="WFGcbZhe">[<a href="#ref-WFGcbZhe" role="doc-biblioref">508</a>]</span>.
+Additionally, clinical trials have reported HCQ to be effective in treating HIV <span class="citation" data-cites="hFGjQQN8">[<a href="#ref-hFGjQQN8" role="doc-biblioref">509</a>]</span> and chronic Hepatitis C <span class="citation" data-cites="rQNzKxRd">[<a href="#ref-rQNzKxRd" role="doc-biblioref">510</a>]</span>.
 Together, these studies triggered initial enthusiasm about the therapeutic potential for HCQ and CQ against COVID-19.
 HCQ/CQ has been proposed both as a treatment for COVID-19 and a prophylaxis against SARS-CoV-2 exposure, and trials often investigated these drugs in combination with azithromycin (AZ) and/or zinc supplementation.
 However, as more evidence has emerged, it has become clear that HCQ/CQ offer no benefits against SARS-CoV-2 or COVID-19.</p>
 <h5 data-number="5.4.2.2.1" id="trials-assessing-therapeutic-administration-of-hcqcq"><span class="header-section-number">5.4.2.2.1</span> Trials Assessing Therapeutic Administration of HCQ/CQ</h5>
-<p>The initial study evaluating HCQ as a treatment for COVID-19 patients was published on March 20, 2020 by Gautret et al. <span class="citation" data-cites="ovHLMvCi">[<a href="#ref-ovHLMvCi" role="doc-biblioref">512</a>]</span>.
+<p>The initial study evaluating HCQ as a treatment for COVID-19 patients was published on March 20, 2020 by Gautret et al. <span class="citation" data-cites="ovHLMvCi">[<a href="#ref-ovHLMvCi" role="doc-biblioref">511</a>]</span>.
 This non-randomized, non-blinded, non-placebo clinical trial compared HCQ to SOC in 42 hospitalized patients in southern France.
 It reported that patients who received HCQ showed higher rates of virological clearance by nasopharyngeal swab on days 3-6 when compared to SOC.
 This study also treated six patients with both HCQ + AZ and found this combination therapy to be more effective than HCQ alone.
 However, the design and analyses used showed weaknesses that severely limit interpretability of results, including the small sample size and the lack of: randomization, blinding, placebo (no “placebo pill” given to SOC group), Intention-To-Treat analysis, correction for sequential multiple comparisons, and trial pre-registration.
-Furthermore, the trial arms were entirely confounded by hospital and there were false negative outcome measurements (see <span class="citation" data-cites="36WPxcLu">[<a href="#ref-36WPxcLu" role="doc-biblioref">513</a>]</span>).
+Furthermore, the trial arms were entirely confounded by hospital and there were false negative outcome measurements (see <span class="citation" data-cites="36WPxcLu">[<a href="#ref-36WPxcLu" role="doc-biblioref">512</a>]</span>).
 Two of these weaknesses are due to inappropriate data analysis and can therefore be corrected <em>post hoc</em> by recalculating the p-values (lack of Intention-To-Treat analysis and multiple comparisons).
 However, all other weaknesses are fundamental design flaws and cannot be corrected for.
 Thus, the conclusions cannot be generalized outside of the study.
-The International Society of Antimicrobial Chemotherapy, the scientific organization that publishes the journal where the article appeared, subsequently announced that the article did not meet its expected standard for publications <span class="citation" data-cites="10J3hBiMo">[<a href="#ref-10J3hBiMo" role="doc-biblioref">514</a>]</span>, although it has not been officially retracted.</p>
+The International Society of Antimicrobial Chemotherapy, the scientific organization that publishes the journal where the article appeared, subsequently announced that the article did not meet its expected standard for publications <span class="citation" data-cites="10J3hBiMo">[<a href="#ref-10J3hBiMo" role="doc-biblioref">513</a>]</span>, although it has not been officially retracted.</p>
 <p>Because of the preliminary data presented in this study, HCQ treatment was subsequently explored by other researchers.
-About one week later, a follow-up case study reported that 11 consecutive patients were treated with HCQ + AZ using the same dosing regimen <span class="citation" data-cites="18KmvBOFr">[<a href="#ref-18KmvBOFr" role="doc-biblioref">515</a>]</span>.
+About one week later, a follow-up case study reported that 11 consecutive patients were treated with HCQ + AZ using the same dosing regimen <span class="citation" data-cites="18KmvBOFr">[<a href="#ref-18KmvBOFr" role="doc-biblioref">514</a>]</span>.
 One patient died, two were transferred to the intensive care unit (ICU), and one developed a prolonged QT interval, leading to discontinuation of HCQ + AZ administration.
 As in the Gautret et al. study, the outcome assessed was virological clearance at day 6 post-treatment, as measured from nasopharyngeal swabs.
 Of the ten living patients on day 6, eight remained positive for SARS-CoV-2 RNA.
 Like in the original study, interpretability was severely limited by the lack of a comparison group and the small sample size.
 However, these results stand in contrast to the claims by Gautret et al. that all six patients treated with HCQ + AZ tested negative for SARS-CoV-2 RNA by day 6 post-treatment.
 This case study illustrated the need for further investigation using robust study design to evaluate the efficacy of HCQ and/or CQ.</p>
-<p>On April 10, 2020, a randomized, non-placebo trial of 62 COVID-19 patients at the Renmin Hospital of Wuhan University was released <span class="citation" data-cites="wzHb7Mj5">[<a href="#ref-wzHb7Mj5" role="doc-biblioref">516</a>]</span>.
-This study investigated whether HCQ decreased time to fever break or time to cough relief when compared to SOC <span class="citation" data-cites="wzHb7Mj5">[<a href="#ref-wzHb7Mj5" role="doc-biblioref">516</a>]</span>.
+<p>On April 10, 2020, a randomized, non-placebo trial of 62 COVID-19 patients at the Renmin Hospital of Wuhan University was released <span class="citation" data-cites="wzHb7Mj5">[<a href="#ref-wzHb7Mj5" role="doc-biblioref">515</a>]</span>.
+This study investigated whether HCQ decreased time to fever break or time to cough relief when compared to SOC <span class="citation" data-cites="wzHb7Mj5">[<a href="#ref-wzHb7Mj5" role="doc-biblioref">515</a>]</span>.
 This trial found HCQ decreased both average time to fever break and average time to cough relief, defined as mild or no cough.
 While this study improved on some of the methodological flaws in Gautret et al. by randomizing patients, it also had several flaws in trial design and data analysis that prevent generalization of the results.
-These weaknesses include the lack of placebo, lack of correction for multiple primary outcomes, inappropriate choice of outcomes, lack of sufficient detail to understand analysis, drastic disparities between pre-registration <span class="citation" data-cites="65ggO2DM">[<a href="#ref-65ggO2DM" role="doc-biblioref">517</a>]</span> and published protocol (including differences in the inclusion and exclusion criteria, the number of experimental groups, the number of patients enrolled, and the outcome analyzed), and small sample size.
+These weaknesses include the lack of placebo, lack of correction for multiple primary outcomes, inappropriate choice of outcomes, lack of sufficient detail to understand analysis, drastic disparities between pre-registration <span class="citation" data-cites="65ggO2DM">[<a href="#ref-65ggO2DM" role="doc-biblioref">516</a>]</span> and published protocol (including differences in the inclusion and exclusion criteria, the number of experimental groups, the number of patients enrolled, and the outcome analyzed), and small sample size.
 The choice of outcomes may be inappropriate as both fevers and cough may break periodically without resolution of illness.
 Additionally, for these outcomes, the authors reported that 23 of 62 patients did not have a fever and 25 of 62 patients did not have a cough at the start of the study, but the authors failed to describe how these patients were included in a study assessing time to fever break and time to cough relief.
 It is important to note here that the authors claimed “neither the research performers nor the patients were aware of the treatment assignments.”
 This blinding seems impossible in a non-placebo trial because at the very least, providers would know whether they were administering a medication or not, and this knowledge could lead to systematic differences in the administration of care.
 Correction for multiple primary outcomes can be adjusted <em>post hoc</em> by recalculating p-values, but all of the other issues were design and statistical weaknesses that cannot be corrected for.
-Additionally, the observation of drastic disparities between pre-registration and published protocol could indicate p-hacking <span class="citation" data-cites="XdCJ4u8O">[<a href="#ref-XdCJ4u8O" role="doc-biblioref">518</a>]</span>.
+Additionally, the observation of drastic disparities between pre-registration and published protocol could indicate p-hacking <span class="citation" data-cites="XdCJ4u8O">[<a href="#ref-XdCJ4u8O" role="doc-biblioref">517</a>]</span>.
 The design limitations mean that the conclusions cannot be generalized outside of the study.</p>
-<p>A second randomized trial, conducted by the Shanghai Public Health Clinical Center, analyzed whether HCQ increased rates of virological clearance at day 7 in respiratory pharyngeal swabs compared to SOC <span class="citation" data-cites="o5gwQA7W">[<a href="#ref-o5gwQA7W" role="doc-biblioref">519</a>]</span>.
+<p>A second randomized trial, conducted by the Shanghai Public Health Clinical Center, analyzed whether HCQ increased rates of virological clearance at day 7 in respiratory pharyngeal swabs compared to SOC <span class="citation" data-cites="o5gwQA7W">[<a href="#ref-o5gwQA7W" role="doc-biblioref">518</a>]</span>.
 This trial was published in Chinese along with an abstract in English, and only the English abstract was read and interpreted for this review.
 The trial found comparable outcomes in virological clearance rate, time to virological clearance, and time to body temperature normalization between the treatment and control groups.
 The small sample size is one weakness, with only 30 patients enrolled and 15 in each arm.
@@ -2024,28 +2024,28 @@ <h5 data-number="5.4.2.2.1" id="trials-assessing-therapeutic-administration-of-h
 Thus, though these studies added randomization to their assessment of HCQ, their conclusions should be interpreted very cautiously.
 These two studies assessed different outcomes and reached differing conclusions about the efficacy of HCQ for treating COVID-19; the designs of both studies, especially with respect to sample size, meant that no general conclusions can be made about the efficacy of the drug.</p>
 <p>Several widely reported studies on HCQ also have issues with data integrity and/or provenance.
-A Letter to the Editor published in <em>BioScience Trends</em> on March 16, 2020 claimed that numerous clinical trials have shown that HCQ is superior to control treatment in inhibiting the exacerbation of COVID-19 pneumonia <span class="citation" data-cites="aiItPxSY">[<a href="#ref-aiItPxSY" role="doc-biblioref">520</a>]</span>.
-This letter has been cited by numerous primary literature, review articles, and media alike <span class="citation" data-cites="1BdQKtXnY z8XnLYWM">[<a href="#ref-1BdQKtXnY" role="doc-biblioref">521</a>,<a href="#ref-z8XnLYWM" role="doc-biblioref">522</a>]</span>.
+A Letter to the Editor published in <em>BioScience Trends</em> on March 16, 2020 claimed that numerous clinical trials have shown that HCQ is superior to control treatment in inhibiting the exacerbation of COVID-19 pneumonia <span class="citation" data-cites="aiItPxSY">[<a href="#ref-aiItPxSY" role="doc-biblioref">519</a>]</span>.
+This letter has been cited by numerous primary literature, review articles, and media alike <span class="citation" data-cites="1BdQKtXnY z8XnLYWM">[<a href="#ref-1BdQKtXnY" role="doc-biblioref">520</a>,<a href="#ref-z8XnLYWM" role="doc-biblioref">521</a>]</span>.
 However, the letter referred to 15 pre-registration identifiers from the Chinese Clinical Trial Registry.
 When these identifiers are followed back to the registry, most trials claim they are not yet recruiting patients or are currently recruiting patients.
 For all of these 15 identifiers, no data uploads or links to publications could be located on the pre-registrations.
 At the very least, the lack of availability of the primary data means the claim that HCQ is efficacious against COVID-19 pneumonia cannot be verified.
-Similarly, a recent multinational registry analysis <span class="citation" data-cites="1BApBNHvd">[<a href="#ref-1BApBNHvd" role="doc-biblioref">523</a>]</span> analyzed the efficacy of CQ and HCQ with and without a macrolide, which is a class of antibiotics that includes Azithromycin, for the treatment of COVID-19.
+Similarly, a recent multinational registry analysis <span class="citation" data-cites="1BApBNHvd">[<a href="#ref-1BApBNHvd" role="doc-biblioref">522</a>]</span> analyzed the efficacy of CQ and HCQ with and without a macrolide, which is a class of antibiotics that includes Azithromycin, for the treatment of COVID-19.
 The study observed 96,032 patients split into a control and four treatment conditions (CQ with and without a macrolide; HCQ with and without a macrolide).
 They concluded that treatment with CQ or HCQ was associated with increased risk of <em>de novo</em> ventricular arrhythmia during hospitalization.
-However, this study has since been retracted by <em>The Lancet</em> due to an inability to validate the data used <span class="citation" data-cites="11FsxWalS">[<a href="#ref-11FsxWalS" role="doc-biblioref">524</a>]</span>.
+However, this study has since been retracted by <em>The Lancet</em> due to an inability to validate the data used <span class="citation" data-cites="11FsxWalS">[<a href="#ref-11FsxWalS" role="doc-biblioref">523</a>]</span>.
 These studies demonstrate that increased skepticism in evaluation of the HCQ/CQ and COVID-19 literature may be warranted, possibly because of the significant attention HCQ and CQ have received as possible treatments for COVID-19 and the politicization of these drugs.</p>
 <p>Despite the fact that the study suggesting that CQ/HCQ increased risk of ventricular arrhythmia in COVID-19 patients has now been retracted, previous studies have identified risks associated with HCQ/CQ.
-A patient with systemic lupus erythematosus developed a prolonged QT interval that was likely exacerbated by use of HCQ in combination with renal failure <span class="citation" data-cites="dY9kXLAS">[<a href="#ref-dY9kXLAS" role="doc-biblioref">525</a>]</span>.
-A prolonged QT interval is associated with ventricular arrhythmia <span class="citation" data-cites="wy3S7Cpa">[<a href="#ref-wy3S7Cpa" role="doc-biblioref">526</a>]</span>.
-Furthermore, a separate study <span class="citation" data-cites="OQ0b31BA">[<a href="#ref-OQ0b31BA" role="doc-biblioref">527</a>]</span> investigated the safety associated with the use of HCQ with and without macrolides between 2000 and 2020.
+A patient with systemic lupus erythematosus developed a prolonged QT interval that was likely exacerbated by use of HCQ in combination with renal failure <span class="citation" data-cites="dY9kXLAS">[<a href="#ref-dY9kXLAS" role="doc-biblioref">524</a>]</span>.
+A prolonged QT interval is associated with ventricular arrhythmia <span class="citation" data-cites="wy3S7Cpa">[<a href="#ref-wy3S7Cpa" role="doc-biblioref">525</a>]</span>.
+Furthermore, a separate study <span class="citation" data-cites="OQ0b31BA">[<a href="#ref-OQ0b31BA" role="doc-biblioref">526</a>]</span> investigated the safety associated with the use of HCQ with and without macrolides between 2000 and 2020.
 The study involved 900,000 cases treated with HCQ and 300,000 cases treated with HCQ + AZ.
 The results indicated that short-term use of HCQ was not associated with additional risk, but that HCQ + AZ was associated with an enhanced risk of cardiovascular complications (such as a 15% increased risk of chest pain, calibrated HR = 1.15, 95% CI, 1.05 to 1.26) and a two-fold increased 30-day risk of cardiovascular mortality (calibrated HR = 2.19; 95% CI, 1.22 to 3.94).
 Therefore, whether studies utilize HCQ alone or HCQ in combination with a macrolide may be an important consideration in assessing risk.
-As results from initial investigations of these drug combinations have emerged, concerns about the efficacy and risks of treating COVID-19 with HCQ and CQ have led to the removal of CQ/HCQ from SOC practices in several countries <span class="citation" data-cites="1CgZR55GZ 1EcscrT32">[<a href="#ref-1CgZR55GZ" role="doc-biblioref">528</a>,<a href="#ref-1EcscrT32" role="doc-biblioref">529</a>]</span>.
-As of May 25, 2020, WHO had suspended administration of HCQ as part of the worldwide Solidarity Trial <span class="citation" data-cites="AMQ5402v">[<a href="#ref-AMQ5402v" role="doc-biblioref">530</a>]</span>, and later the final results of this large-scale trial that compared 947 patients administered HCQ to 906 controls revealed no effect on the primary outcome, mortality during hospitalization (rate ratio: 1.19; <em>p</em> = 0.23)</p>
+As results from initial investigations of these drug combinations have emerged, concerns about the efficacy and risks of treating COVID-19 with HCQ and CQ have led to the removal of CQ/HCQ from SOC practices in several countries <span class="citation" data-cites="1CgZR55GZ 1EcscrT32">[<a href="#ref-1CgZR55GZ" role="doc-biblioref">527</a>,<a href="#ref-1EcscrT32" role="doc-biblioref">528</a>]</span>.
+As of May 25, 2020, WHO had suspended administration of HCQ as part of the worldwide Solidarity Trial <span class="citation" data-cites="AMQ5402v">[<a href="#ref-AMQ5402v" role="doc-biblioref">529</a>]</span>, and later the final results of this large-scale trial that compared 947 patients administered HCQ to 906 controls revealed no effect on the primary outcome, mortality during hospitalization (rate ratio: 1.19; <em>p</em> = 0.23)</p>
 <p>Additional research has emerged largely identifying HCQ/CQ to be ineffective against COVID-19 while simultaneously revealing a number of significant side effects.
-A randomized, open-label, non-placebo trial of 150 COVID-19 patients was conducted in parallel at 16 government-designated COVID-19 centers in China to assess the safety and efficacy of HCQ <span class="citation" data-cites="RXr9BKKT">[<a href="#ref-RXr9BKKT" role="doc-biblioref">531</a>]</span>.
+A randomized, open-label, non-placebo trial of 150 COVID-19 patients was conducted in parallel at 16 government-designated COVID-19 centers in China to assess the safety and efficacy of HCQ <span class="citation" data-cites="RXr9BKKT">[<a href="#ref-RXr9BKKT" role="doc-biblioref">530</a>]</span>.
 The trial compared treatment with HCQ in conjunction with SOC to SOC alone in 150 infected patients who were assigned randomly to the two groups (75 per group).
 The primary endpoint of the study was the negative conversion rate of SARS-CoV-2 in 28 days, and the investigators found no difference in this parameter between the groups (estimated difference between SOC plus HCQ and SOC 4.1%; 95% CI, –10.3% to 18.5%).
 The secondary endpoints were an amelioration of the symptoms of the disease such as axillary temperature ≤36.6°C, SpO2 &gt;94% on room air, and disappearance of symptoms like shortness of breath, cough, and sore throat.
@@ -2060,7 +2060,7 @@ <h5 data-number="5.4.2.2.1" id="trials-assessing-therapeutic-administration-of-h
 The fact that this study was open-label and lacked a placebo limits interpretation, and additional analysis is required to determine whether HCQ reduces inflammatory response.
 Therefore, despite some potential areas of investigation identified in <em>post hoc</em> analysis, this study cannot be interpreted as providing support for HCQ as a therapeutic against COVID-19.
 This study provided no support for HCQ against COVID-19, as there was no difference between the two groups in either negative seroconversion at 28 days or symptom alleviation, and in fact, more severe adverse outcomes were reported in the group receiving HCQ.</p>
-<p>Additional evidence comes from a retrospective analysis <span class="citation" data-cites="MENbRfOl">[<a href="#ref-MENbRfOl" role="doc-biblioref">532</a>]</span> that examined data from 368 COVID-19 patients across all United States Veteran Health Administration medical centers.
+<p>Additional evidence comes from a retrospective analysis <span class="citation" data-cites="MENbRfOl">[<a href="#ref-MENbRfOl" role="doc-biblioref">531</a>]</span> that examined data from 368 COVID-19 patients across all United States Veteran Health Administration medical centers.
 The study retrospectively investigated the effect of the administration of HCQ (n=97), HCQ + AZ (n=113), and no HCQ (n=158) on 368 patients.
 The primary outcomes assessed were death and the need for mechanical ventilation.
 Standard supportive care was rendered to all patients.
@@ -2072,9 +2072,9 @@ <h5 data-number="5.4.2.2.1" id="trials-assessing-therapeutic-administration-of-h
 The study had a few limitations: it was not randomized, and the baseline vital signs, laboratory tests, and prescription drug use were significantly different among the three groups.
 All of these factors could potentially influence treatment outcome.
 Furthermore, the authors acknowledge that the effect of the drugs might be different in females and pediatric subjects, since these subjects were not part of the study.
-The reported result that HCQ + AZ is safer than HCQ contradicts the findings of the previous large-scale analysis of twenty years of records that found HCQ + AZ to be more frequently associated with cardiac arrhythmia than HCQ alone <span class="citation" data-cites="OQ0b31BA">[<a href="#ref-OQ0b31BA" role="doc-biblioref">527</a>]</span>; whether this discrepancy is caused by the pathology of COVID-19, is influenced by age or sex, or is a statistical artifact is not presently known.</p>
+The reported result that HCQ + AZ is safer than HCQ contradicts the findings of the previous large-scale analysis of twenty years of records that found HCQ + AZ to be more frequently associated with cardiac arrhythmia than HCQ alone <span class="citation" data-cites="OQ0b31BA">[<a href="#ref-OQ0b31BA" role="doc-biblioref">526</a>]</span>; whether this discrepancy is caused by the pathology of COVID-19, is influenced by age or sex, or is a statistical artifact is not presently known.</p>
 <p>Finally, findings from the RECOVERY trial were released on October 8, 2020.
-This study used a randomized, open-label design to study the effects of HCQ compared to SOC at 176 hospitals in the United Kingdom <span class="citation" data-cites="KwFZyfFx">[<a href="#ref-KwFZyfFx" role="doc-biblioref">533</a>]</span>.
+This study used a randomized, open-label design to study the effects of HCQ compared to SOC at 176 hospitals in the United Kingdom <span class="citation" data-cites="KwFZyfFx">[<a href="#ref-KwFZyfFx" role="doc-biblioref">532</a>]</span>.
 This large study enrolled 11,197 hospitalized patients whose physicians believed it would not harm them to participate.
 Patients were randomized into either the control group or one of the treatment arms, with twice as many patients enrolled in the control group as any treatment group.
 Of the patients eligible to receive HCQ, 1,561 were randomized into the HCQ arm, and 3,155 were randomized into the control arm.
@@ -2089,14 +2089,14 @@ <h5 data-number="5.4.2.2.1" id="trials-assessing-therapeutic-administration-of-h
 Therefore, though none of the studies have been blinded, examining them together makes it clear that the available evidence points to significant dangers associated with the administration of HCQ to hospitalized COVID-19 patients, without providing any support for its efficacy.</p>
 <h5 data-number="5.4.2.2.2" id="hcq-for-the-treatment-of-mild-cases"><span class="header-section-number">5.4.2.2.2</span> HCQ for the Treatment of Mild Cases</h5>
 <p>One additional possible therapeutic application of HCQ considered was the treatment of mild COVID-19 cases in otherwise healthy individuals.
-This possibility was assessed in a randomized, open-label, multi-center analysis conducted in Catalonia (Spain) <span class="citation" data-cites="V8fkkVZg">[<a href="#ref-V8fkkVZg" role="doc-biblioref">534</a>]</span>.
+This possibility was assessed in a randomized, open-label, multi-center analysis conducted in Catalonia (Spain) <span class="citation" data-cites="V8fkkVZg">[<a href="#ref-V8fkkVZg" role="doc-biblioref">533</a>]</span>.
 This analysis enrolled adults 18 and older who had been experiencing mild symptoms of COVID-19 for fewer than five days.
 Participants were randomized into an HCQ arm (N=136) and a control arm (N=157), and those in the treatment arm were administered 800 mg of HCQ on the first day of treatment followed by 400 mg on each of the subsequent six days.
 The primary outcome assessed was viral clearance at days 3 and 7 following the onset of treatment, and secondary outcomes were clinical progression and time to complete resolution of symptoms.
 No significant differences between the two groups were found: the difference in viral load between the HCQ and control groups was 0.01 (95% CI, -0.28 to 0.29) at day 3 and -0.07 (95% CI -0.44 to 0.29) at day 7, the relative risk of hospitalization was 0.75 (95% CI, 0.32 to 1.77), and the difference in time to complete resolution of symptoms was -2 days (<em>p</em> = 0.38).
 This study thus suggests that HCQ does not improve recovery from COVID-19, even in otherwise healthy adult patients with mild symptoms.</p>
 <h5 data-number="5.4.2.2.3" id="prophylactic-administration-of-hcq"><span class="header-section-number">5.4.2.2.3</span> Prophylactic Administration of HCQ</h5>
-<p>An initial study of the possible prophylactic application of HCQ utilized a randomized, double-blind, placebo-controlled design to analyze the administration of HCQ prophylactically <span class="citation" data-cites="NiVdIN7Z">[<a href="#ref-NiVdIN7Z" role="doc-biblioref">535</a>]</span>.
+<p>An initial study of the possible prophylactic application of HCQ utilized a randomized, double-blind, placebo-controlled design to analyze the administration of HCQ prophylactically <span class="citation" data-cites="NiVdIN7Z">[<a href="#ref-NiVdIN7Z" role="doc-biblioref">534</a>]</span>.
 Asymptomatic adults in the United States and Canada who had been exposed to SARS-CoV-2 within the past four days were enrolled in an online study to evaluate whether administration of HCQ over five days influenced the probability of developing COVID-19 symptoms over a 14-day period.
 Of the participants, 414 received HCQ and 407 received a placebo.
 No significant difference in the rate of symptomatic illness was observed between the two groups (11.8% HCQ, 14.3% placebo, <em>p</em> = 0.35).
@@ -2110,7 +2110,7 @@ <h5 data-number="5.4.2.2.3" id="prophylactic-administration-of-hcq"><span class=
 It is therefore likely that asymptomatic cases were over-represented in this sample, which would not have been detected based on the diagnostic criteria used.
 Therefore, while this study does represent the first effort to conduct a randomized, double-blind, placebo-controlled investigation of HCQ’s effect on COVID-19 prevention after SARS-CoV-2 exposure in a large sample, the lack of PCR tests and several other design flaws significantly impede interpretation of the results.
 However, in line with the results from therapeutic studies, once again no evidence was found suggesting an effect of HCQ against COVID-19.</p>
-<p>A second study <span class="citation" data-cites="oaqFxV4W">[<a href="#ref-oaqFxV4W" role="doc-biblioref">536</a>]</span> examined the effect of administering HCQ to healthcare workers as a pre-exposure prophylactic.
+<p>A second study <span class="citation" data-cites="oaqFxV4W">[<a href="#ref-oaqFxV4W" role="doc-biblioref">535</a>]</span> examined the effect of administering HCQ to healthcare workers as a pre-exposure prophylactic.
 The primary outcome assessed was the conversion from SARS-CoV-2 negative to SARS-CoV-2 positive status over the 8 week study period.
 This study was also randomized, double-blind, and placebo-controlled, and it sought to address some of the limitations of the first prophylactic study.
 The goal was to enroll 200 healthcare workers, preferentially those working with COVID-19 patients, at two hospitals within the University of Pennsylvania hospital system in Philadelphia, PA.
@@ -2121,38 +2121,38 @@ <h5 data-number="5.4.2.2.3" id="prophylactic-administration-of-hcq"><span class=
 As a result, the trial was terminated early, offering additional evidence against the use of HCQ for prophylaxis.</p>
 <h5 data-number="5.4.2.2.4" id="summary-of-hcqcq-research-findings"><span class="header-section-number">5.4.2.2.4</span> Summary of HCQ/CQ Research Findings</h5>
 <p>Early <em>in vitro</em> evidence indicated that HCQ could be an effective therapeutic against SARS-CoV-2 and COVID-19, leading to significant media attention and public interest in its potential as both a therapeutic and prophylactic.
-Initially it was hypothesized that CQ/HCQ might be effective against SARS-CoV-2 in part because CQ and HCQ have both been found to inhibit the expression of CD154 in T-cells and to reduce TLR signaling that leads to the production of pro-inflammatory cytokines <span class="citation" data-cites="j3rGUH1f">[<a href="#ref-j3rGUH1f" role="doc-biblioref">537</a>]</span>.
+Initially it was hypothesized that CQ/HCQ might be effective against SARS-CoV-2 in part because CQ and HCQ have both been found to inhibit the expression of CD154 in T-cells and to reduce TLR signaling that leads to the production of pro-inflammatory cytokines <span class="citation" data-cites="j3rGUH1f">[<a href="#ref-j3rGUH1f" role="doc-biblioref">536</a>]</span>.
 Clinical trials for COVID-19 have more often used HCQ rather than CQ because it offers the advantages of being cheaper and having fewer side effects than CQ.
 However, research has not found support for a positive effect of HCQ on COVID-19 patients.
 Multiple clinical studies have already been carried out to assess HCQ as a therapeutic agent for COVID-19, and many more are in progress.
 To date, none of these studies have used randomized, double-blind, placebo-controlled designs with a large sample size, which would be the gold standard.
 Despite the design limitations (which would be more likely to produce false positives than false negatives), initial optimism about HCQ has largely dissipated.
-The most methodologically rigorous analysis of HCQ as a prophylactic <span class="citation" data-cites="NiVdIN7Z">[<a href="#ref-NiVdIN7Z" role="doc-biblioref">535</a>]</span> found no significant differences between the treatment and control groups, and the WHO’s global Solidarity trial similarly reported no effect of HCQ on mortality <span class="citation" data-cites="jShm9uhy">[<a href="#ref-jShm9uhy" role="doc-biblioref">432</a>]</span>.
+The most methodologically rigorous analysis of HCQ as a prophylactic <span class="citation" data-cites="NiVdIN7Z">[<a href="#ref-NiVdIN7Z" role="doc-biblioref">534</a>]</span> found no significant differences between the treatment and control groups, and the WHO’s global Solidarity trial similarly reported no effect of HCQ on mortality <span class="citation" data-cites="jShm9uhy">[<a href="#ref-jShm9uhy" role="doc-biblioref">431</a>]</span>.
 Thus, HCQ/CQ are not likely to be effective therapeutic or prophylactic agents against COVID-19.
-Additionally, one study identified an increased risk of mortality in older men receiving HCQ, and administration of HCQ and HCQ + AZ did not decrease the use of mechanical ventilation in these patients <span class="citation" data-cites="MENbRfOl">[<a href="#ref-MENbRfOl" role="doc-biblioref">532</a>]</span>.
+Additionally, one study identified an increased risk of mortality in older men receiving HCQ, and administration of HCQ and HCQ + AZ did not decrease the use of mechanical ventilation in these patients <span class="citation" data-cites="MENbRfOl">[<a href="#ref-MENbRfOl" role="doc-biblioref">531</a>]</span>.
 HCQ use for COVID-19 could also lead to shortages for anti-malarial or anti-rheumatic use, where it has documented efficacy.
 Despite significant early attention, these drugs appear to be ineffective against COVID-19.
 Several countries have now removed CQ/HCQ from their SOC for COVID-19 due to the lack of evidence of efficacy and the frequency of adverse effects.</p>
 <h4 data-number="5.4.2.3" id="dexamethasone"><span class="header-section-number">5.4.2.3</span> Dexamethasone</h4>
-<p>Dexamethasone (9α-fluoro-16α-methylprednisolone) is a synthetic corticosteroid that binds to glucocorticoid receptors <span class="citation" data-cites="q0TqfpEr 2M8wLShq">[<a href="#ref-q0TqfpEr" role="doc-biblioref">538</a>,<a href="#ref-2M8wLShq" role="doc-biblioref">539</a>]</span>.
-It was first synthesized in the late 1950s as an anti-inflammatory and has been used to treat RA and other inflammatory conditions <span class="citation" data-cites="KQ7uhAaa bSNVCQbh">[<a href="#ref-KQ7uhAaa" role="doc-biblioref">540</a>,<a href="#ref-bSNVCQbh" role="doc-biblioref">541</a>]</span>, including allergies and asthma <span class="citation" data-cites="17Dq3dNwL">[<a href="#ref-17Dq3dNwL" role="doc-biblioref">542</a>]</span>.
-Steroids such as dexamethasone are widely available and affordable, and they are often used to treat community-acquired pneumonia <span class="citation" data-cites="19dEKfvUE">[<a href="#ref-19dEKfvUE" role="doc-biblioref">543</a>]</span>.
-A clinical trial that began in 2012 recently reported that dexamethasone may improve outcomes for patients with ARDS <span class="citation" data-cites="1DUXbHUEW">[<a href="#ref-1DUXbHUEW" role="doc-biblioref">544</a>]</span>.
-However, a meta-analysis of a small amount of available data about dexamethasone as a treatment for SARS suggested that it may, in fact, be associated with patient harm <span class="citation" data-cites="Ji2fchyS">[<a href="#ref-Ji2fchyS" role="doc-biblioref">545</a>]</span>; these findings may have been biased by the fact that all of the studies examined were observational and a large number of inconclusive studies were not included <span class="citation" data-cites="xndHds7d">[<a href="#ref-xndHds7d" role="doc-biblioref">546</a>]</span>.</p>
-<p>Dexamethasone works as an anti-inflammatory agent by binding to glucocorticoid receptors with higher affinity than endogenous cortisol <span class="citation" data-cites="1ETGa7JyL">[<a href="#ref-1ETGa7JyL" role="doc-biblioref">547</a>]</span>.
+<p>Dexamethasone (9α-fluoro-16α-methylprednisolone) is a synthetic corticosteroid that binds to glucocorticoid receptors <span class="citation" data-cites="q0TqfpEr 2M8wLShq">[<a href="#ref-q0TqfpEr" role="doc-biblioref">537</a>,<a href="#ref-2M8wLShq" role="doc-biblioref">538</a>]</span>.
+It was first synthesized in the late 1950s as an anti-inflammatory and has been used to treat RA and other inflammatory conditions <span class="citation" data-cites="KQ7uhAaa bSNVCQbh">[<a href="#ref-KQ7uhAaa" role="doc-biblioref">539</a>,<a href="#ref-bSNVCQbh" role="doc-biblioref">540</a>]</span>, including allergies and asthma <span class="citation" data-cites="17Dq3dNwL">[<a href="#ref-17Dq3dNwL" role="doc-biblioref">541</a>]</span>.
+Steroids such as dexamethasone are widely available and affordable, and they are often used to treat community-acquired pneumonia <span class="citation" data-cites="19dEKfvUE">[<a href="#ref-19dEKfvUE" role="doc-biblioref">542</a>]</span>.
+A clinical trial that began in 2012 recently reported that dexamethasone may improve outcomes for patients with ARDS <span class="citation" data-cites="1DUXbHUEW">[<a href="#ref-1DUXbHUEW" role="doc-biblioref">543</a>]</span>.
+However, a meta-analysis of a small amount of available data about dexamethasone as a treatment for SARS suggested that it may, in fact, be associated with patient harm <span class="citation" data-cites="Ji2fchyS">[<a href="#ref-Ji2fchyS" role="doc-biblioref">544</a>]</span>; these findings may have been biased by the fact that all of the studies examined were observational and a large number of inconclusive studies were not included <span class="citation" data-cites="xndHds7d">[<a href="#ref-xndHds7d" role="doc-biblioref">545</a>]</span>.</p>
+<p>Dexamethasone works as an anti-inflammatory agent by binding to glucocorticoid receptors with higher affinity than endogenous cortisol <span class="citation" data-cites="1ETGa7JyL">[<a href="#ref-1ETGa7JyL" role="doc-biblioref">546</a>]</span>.
 In order to understand how dexamethasone reduces inflammation, it is necessary to consider the stress response broadly.
-In response to stress, corticotropin‐releasing hormone stimulates the release of neurotransmitters known as catecholamines, such as epinephrine, and steroid hormones known as glucocorticoids, such as cortisol <span class="citation" data-cites="jMzODpwS Riev3em1">[<a href="#ref-jMzODpwS" role="doc-biblioref">548</a>,<a href="#ref-Riev3em1" role="doc-biblioref">549</a>]</span>.
-While catecholamines are often associated with the fight-or-flight response, the specific role that glucocorticoids play is less clear, although they are thought to be important to restoring homeostasis <span class="citation" data-cites="JZyVNRCN">[<a href="#ref-JZyVNRCN" role="doc-biblioref">550</a>]</span>.
+In response to stress, corticotropin‐releasing hormone stimulates the release of neurotransmitters known as catecholamines, such as epinephrine, and steroid hormones known as glucocorticoids, such as cortisol <span class="citation" data-cites="jMzODpwS Riev3em1">[<a href="#ref-jMzODpwS" role="doc-biblioref">547</a>,<a href="#ref-Riev3em1" role="doc-biblioref">548</a>]</span>.
+While catecholamines are often associated with the fight-or-flight response, the specific role that glucocorticoids play is less clear, although they are thought to be important to restoring homeostasis <span class="citation" data-cites="JZyVNRCN">[<a href="#ref-JZyVNRCN" role="doc-biblioref">549</a>]</span>.
 Immune challenge is a stressor that is known to interact closely with the stress response.
-The immune system can therefore interact with the central nervous system; for example, macrophages can both respond to and produce catecholamines <span class="citation" data-cites="jMzODpwS">[<a href="#ref-jMzODpwS" role="doc-biblioref">548</a>]</span>.
-Additionally, the production of both catecholamines and glucocorticoids is associated with inhibition of proinflammatory cytokines such as IL-6, IL-12, and tumor necrosis factor-α (TNF‐α) and the stimulation of anti-inflammatory cytokines such as IL-10, meaning that the stress response can regulate inflammatory immune activity <span class="citation" data-cites="Riev3em1">[<a href="#ref-Riev3em1" role="doc-biblioref">549</a>]</span>.
-Administration of dexamethasone has been found to correspond to dose-dependent inhibition of IL-12 production, but not to affect IL-10 <span class="citation" data-cites="SiXrQUgV">[<a href="#ref-SiXrQUgV" role="doc-biblioref">551</a>]</span>; the fact that this relationship could be disrupted by administration of a glucocorticoid-receptor antagonist suggests that it is regulated by the receptor itself <span class="citation" data-cites="SiXrQUgV">[<a href="#ref-SiXrQUgV" role="doc-biblioref">551</a>]</span>.
+The immune system can therefore interact with the central nervous system; for example, macrophages can both respond to and produce catecholamines <span class="citation" data-cites="jMzODpwS">[<a href="#ref-jMzODpwS" role="doc-biblioref">547</a>]</span>.
+Additionally, the production of both catecholamines and glucocorticoids is associated with inhibition of proinflammatory cytokines such as IL-6, IL-12, and tumor necrosis factor-α (TNF‐α) and the stimulation of anti-inflammatory cytokines such as IL-10, meaning that the stress response can regulate inflammatory immune activity <span class="citation" data-cites="Riev3em1">[<a href="#ref-Riev3em1" role="doc-biblioref">548</a>]</span>.
+Administration of dexamethasone has been found to correspond to dose-dependent inhibition of IL-12 production, but not to affect IL-10 <span class="citation" data-cites="SiXrQUgV">[<a href="#ref-SiXrQUgV" role="doc-biblioref">550</a>]</span>; the fact that this relationship could be disrupted by administration of a glucocorticoid-receptor antagonist suggests that it is regulated by the receptor itself <span class="citation" data-cites="SiXrQUgV">[<a href="#ref-SiXrQUgV" role="doc-biblioref">550</a>]</span>.
 Thus, the administration of dexamethasone for COVID-19 is likely to simulate the release of glucocorticoids endogenously during stress, resulting in binding of the synthetic steroid to the glucocorticoid receptor and the associated inhibition of the production of proinflammatory cytokines.
 In this model, dexamethasone reduces inflammation by stimulating the biological mechanism that reduces inflammation following a threat such as immune challenge.</p>
-<p>Immunosuppressive drugs such as steroids are typically contraindicated in the setting of infection <span class="citation" data-cites="nbiwprc">[<a href="#ref-nbiwprc" role="doc-biblioref">552</a>]</span>, but because COVID-19 results in hyperinflammation that appears to contribute to mortality via lung damage, immunosuppression may be a helpful approach to treatment <span class="citation" data-cites="3HdlV9Vf">[<a href="#ref-3HdlV9Vf" role="doc-biblioref">161</a>]</span>.
-The decision of whether and/or when to counter hyperinflammation with immunosuppression in the setting of COVID-19 was an area of intense debate, as the risks of inhibiting antiviral immunity needed to be weighed against the beneficial anti-inflammatory effects <span class="citation" data-cites="suHq6Qnm">[<a href="#ref-suHq6Qnm" role="doc-biblioref">553</a>]</span>.
-As a result, guidelines early in the pandemic typically recommended avoiding treating COVID-19 patients with corticosteroids such as dexamethasone <span class="citation" data-cites="Ji2fchyS">[<a href="#ref-Ji2fchyS" role="doc-biblioref">545</a>]</span>.</p>
-<p>The application of dexamethasone for the treatment of COVID-19 was evaluated as part of the multi-site RECOVERY trial in the United Kingdom <span class="citation" data-cites="pzQoUwz3">[<a href="#ref-pzQoUwz3" role="doc-biblioref">554</a>]</span>.
+<p>Immunosuppressive drugs such as steroids are typically contraindicated in the setting of infection <span class="citation" data-cites="nbiwprc">[<a href="#ref-nbiwprc" role="doc-biblioref">551</a>]</span>, but because COVID-19 results in hyperinflammation that appears to contribute to mortality via lung damage, immunosuppression may be a helpful approach to treatment <span class="citation" data-cites="3HdlV9Vf">[<a href="#ref-3HdlV9Vf" role="doc-biblioref">161</a>]</span>.
+The decision of whether and/or when to counter hyperinflammation with immunosuppression in the setting of COVID-19 was an area of intense debate, as the risks of inhibiting antiviral immunity needed to be weighed against the beneficial anti-inflammatory effects <span class="citation" data-cites="suHq6Qnm">[<a href="#ref-suHq6Qnm" role="doc-biblioref">552</a>]</span>.
+As a result, guidelines early in the pandemic typically recommended avoiding treating COVID-19 patients with corticosteroids such as dexamethasone <span class="citation" data-cites="Ji2fchyS">[<a href="#ref-Ji2fchyS" role="doc-biblioref">544</a>]</span>.</p>
+<p>The application of dexamethasone for the treatment of COVID-19 was evaluated as part of the multi-site RECOVERY trial in the United Kingdom <span class="citation" data-cites="pzQoUwz3">[<a href="#ref-pzQoUwz3" role="doc-biblioref">553</a>]</span>.
 Over 6,000 hospitalized COVID-19 patients were assigned into the SOC or treatment (dexamethasone) arms of the trial with a 2:1 ratio.
 At the time of randomization, some patients were ventilated (16%), others were on non-invasive oxygen (60%), and others were breathing independently (24%).
 Patients in the treatment arm were administered dexamethasone either orally or intravenously at 6 mg per day for up to 10 days.
@@ -2165,73 +2165,73 @@ <h4 data-number="5.4.2.3" id="dexamethasone"><span class="header-section-number"
 These findings also suggested that dexamethasone may have reduced progression to mechanical ventilation, especially among patients who were receiving oxygen support at randomization.
 Thus, this large, randomized, and multi-site, albeit not placebo-controlled, study suggests that administration of dexamethasone to patients who are unable to breathe independently may significantly improve survival outcomes.
 Additionally, dexamethasone is a widely available and affordable medication, raising the hope that it could be made available to COVID-19 patients globally.</p>
-<p>The results of the RECOVERY trial’s analysis of dexamethasone suggest that this therapeutic is effective primarily in patients who had been experiencing symptoms for at least seven days and patients who were not breathing independently <span class="citation" data-cites="H3C2PalE">[<a href="#ref-H3C2PalE" role="doc-biblioref">555</a>]</span>.
-A meta-analysis that evaluated the results of the RECOVERY trial alongside trials of other corticosteroids, such as hydrocortisone, similarly concluded that corticosteroids may be beneficial to patients with severe COVID-19 who are receiving oxygen supplementation <span class="citation" data-cites="wNXTNffA">[<a href="#ref-wNXTNffA" role="doc-biblioref">556</a>]</span>.
+<p>The results of the RECOVERY trial’s analysis of dexamethasone suggest that this therapeutic is effective primarily in patients who had been experiencing symptoms for at least seven days and patients who were not breathing independently <span class="citation" data-cites="H3C2PalE">[<a href="#ref-H3C2PalE" role="doc-biblioref">554</a>]</span>.
+A meta-analysis that evaluated the results of the RECOVERY trial alongside trials of other corticosteroids, such as hydrocortisone, similarly concluded that corticosteroids may be beneficial to patients with severe COVID-19 who are receiving oxygen supplementation <span class="citation" data-cites="wNXTNffA">[<a href="#ref-wNXTNffA" role="doc-biblioref">555</a>]</span>.
 Thus, it seems likely that dexamethasone is useful for treating inflammation associated with immunopathy or cytokine release syndrome (CRS), which is a condition caused by detrimental overactivation of the immune system <span class="citation" data-cites="r366f5T3">[<a href="#ref-r366f5T3" role="doc-biblioref">1</a>]</span>.
-In fact, corticosteroids such as dexamethasone are sometimes used to treat CRS <span class="citation" data-cites="H70g2GF9">[<a href="#ref-H70g2GF9" role="doc-biblioref">557</a>]</span>.
+In fact, corticosteroids such as dexamethasone are sometimes used to treat CRS <span class="citation" data-cites="H70g2GF9">[<a href="#ref-H70g2GF9" role="doc-biblioref">556</a>]</span>.
 It is not surprising that administration of an immunosuppressant would be most beneficial when the immune system was dysregulated towards inflammation.
 However, it is also unsurprising that care must be taken in administering an immunosuppressant to patients fighting a viral infection.
-In particular, the concern has been raised that treatment with dexamethasone might increase patient susceptibility to concurrent (e.g., nosocomial) infections <span class="citation" data-cites="EgvIETTq">[<a href="#ref-EgvIETTq" role="doc-biblioref">558</a>]</span>.
-Additionally, the drug could potentially slow viral clearance and inhibit patients’ ability to develop antibodies to SARS-CoV-2 <span class="citation" data-cites="EgvIETTq Ji2fchyS">[<a href="#ref-Ji2fchyS" role="doc-biblioref">545</a>,<a href="#ref-EgvIETTq" role="doc-biblioref">558</a>]</span>, with the lack of data about viral clearance being put forward as a major limitation of the RECOVERY trial <span class="citation" data-cites="TytQ90Bl">[<a href="#ref-TytQ90Bl" role="doc-biblioref">559</a>]</span>.
-Furthermore, dexamethasone has been associated with side effects that include psychosis, glucocorticoid-induced diabetes, and avascular necrosis <span class="citation" data-cites="Ji2fchyS">[<a href="#ref-Ji2fchyS" role="doc-biblioref">545</a>]</span>, and the RECOVERY trial did not report outcomes with enough detail to be able to determine whether they observed similar complications.
-The effects of dexamethasone have also been found to differ among populations, especially in high-income versus middle- or low-income countries <span class="citation" data-cites="1E4Qx2UqB">[<a href="#ref-1E4Qx2UqB" role="doc-biblioref">560</a>]</span>.
-However, since the RECOVERY trial’s results were released, strategies have been proposed for administering dexamethasone alongside more targeted treatments to minimize the likelihood of negative side effects <span class="citation" data-cites="EgvIETTq">[<a href="#ref-EgvIETTq" role="doc-biblioref">558</a>]</span>.
+In particular, the concern has been raised that treatment with dexamethasone might increase patient susceptibility to concurrent (e.g., nosocomial) infections <span class="citation" data-cites="EgvIETTq">[<a href="#ref-EgvIETTq" role="doc-biblioref">557</a>]</span>.
+Additionally, the drug could potentially slow viral clearance and inhibit patients’ ability to develop antibodies to SARS-CoV-2 <span class="citation" data-cites="EgvIETTq Ji2fchyS">[<a href="#ref-Ji2fchyS" role="doc-biblioref">544</a>,<a href="#ref-EgvIETTq" role="doc-biblioref">557</a>]</span>, with the lack of data about viral clearance being put forward as a major limitation of the RECOVERY trial <span class="citation" data-cites="TytQ90Bl">[<a href="#ref-TytQ90Bl" role="doc-biblioref">558</a>]</span>.
+Furthermore, dexamethasone has been associated with side effects that include psychosis, glucocorticoid-induced diabetes, and avascular necrosis <span class="citation" data-cites="Ji2fchyS">[<a href="#ref-Ji2fchyS" role="doc-biblioref">544</a>]</span>, and the RECOVERY trial did not report outcomes with enough detail to be able to determine whether they observed similar complications.
+The effects of dexamethasone have also been found to differ among populations, especially in high-income versus middle- or low-income countries <span class="citation" data-cites="1E4Qx2UqB">[<a href="#ref-1E4Qx2UqB" role="doc-biblioref">559</a>]</span>.
+However, since the RECOVERY trial’s results were released, strategies have been proposed for administering dexamethasone alongside more targeted treatments to minimize the likelihood of negative side effects <span class="citation" data-cites="EgvIETTq">[<a href="#ref-EgvIETTq" role="doc-biblioref">557</a>]</span>.
 Given the available evidence, dexamethasone is currently the most promising treatment for severe COVID-19.</p>
 <h2 data-number="5.5" id="biologics"><span class="header-section-number">5.5</span> Biologics</h2>
 <p>Biologics are produced from components of living organisms or viruses.
-They include treatments such as humanized monoclonal antibodies, tocilizumab (TCZ), and neutralizing antibodies (nAbs), and can also include prophylactics such as vaccines <span class="citation" data-cites="i2CGFwI3">[<a href="#ref-i2CGFwI3" role="doc-biblioref">409</a>]</span>.
-Historically produced from animal tissue, biologics have become increasingly feasible to produce as recombinant DNA technologies have advanced <span class="citation" data-cites="1ALDN7rfe">[<a href="#ref-1ALDN7rfe" role="doc-biblioref">561</a>]</span>.
-Often, they are glycoproteins or peptides <span class="citation" data-cites="OgYDNJt3">[<a href="#ref-OgYDNJt3" role="doc-biblioref">562</a>]</span>, but whole viruses can also be used therapeutically or prophylactically, not only for vaccines but also as vectors for gene therapy or therapeutic proteins or for oncolytic virotherapy <span class="citation" data-cites="GO8FwtPx">[<a href="#ref-GO8FwtPx" role="doc-biblioref">563</a>]</span>.
-They are typically catabolized by the body to their amino acid components <span class="citation" data-cites="OgYDNJt3">[<a href="#ref-OgYDNJt3" role="doc-biblioref">562</a>]</span>.
+They include treatments such as humanized monoclonal antibodies, tocilizumab (TCZ), and neutralizing antibodies (nAbs), and can also include prophylactics such as vaccines <span class="citation" data-cites="i2CGFwI3">[<a href="#ref-i2CGFwI3" role="doc-biblioref">408</a>]</span>.
+Historically produced from animal tissue, biologics have become increasingly feasible to produce as recombinant DNA technologies have advanced <span class="citation" data-cites="1ALDN7rfe">[<a href="#ref-1ALDN7rfe" role="doc-biblioref">560</a>]</span>.
+Often, they are glycoproteins or peptides <span class="citation" data-cites="OgYDNJt3">[<a href="#ref-OgYDNJt3" role="doc-biblioref">561</a>]</span>, but whole viruses can also be used therapeutically or prophylactically, not only for vaccines but also as vectors for gene therapy or therapeutic proteins or for oncolytic virotherapy <span class="citation" data-cites="GO8FwtPx">[<a href="#ref-GO8FwtPx" role="doc-biblioref">562</a>]</span>.
+They are typically catabolized by the body to their amino acid components <span class="citation" data-cites="OgYDNJt3">[<a href="#ref-OgYDNJt3" role="doc-biblioref">561</a>]</span>.
 There are many differences on the development side between biologics and synthesized pharmaceuticals, such as small molecule drugs.
-Biologics are typically orders of magnitude larger than small molecule drugs, and their physiochemical properties are often much less understood <span class="citation" data-cites="OgYDNJt3">[<a href="#ref-OgYDNJt3" role="doc-biblioref">562</a>]</span>.
-They are often heat sensitive, and their toxicity can vary, as it is not directly associated with the primary effects of the drug <span class="citation" data-cites="OgYDNJt3">[<a href="#ref-OgYDNJt3" role="doc-biblioref">562</a>]</span>.
+Biologics are typically orders of magnitude larger than small molecule drugs, and their physiochemical properties are often much less understood <span class="citation" data-cites="OgYDNJt3">[<a href="#ref-OgYDNJt3" role="doc-biblioref">561</a>]</span>.
+They are often heat sensitive, and their toxicity can vary, as it is not directly associated with the primary effects of the drug <span class="citation" data-cites="OgYDNJt3">[<a href="#ref-OgYDNJt3" role="doc-biblioref">561</a>]</span>.
 However, this class includes some extremely significant medical breakthroughs, including insulin for the management of diabetes and the smallpox vaccine.
 As a result, biologics are another possible avenue through which the pharmacological management of SARS-CoV-2 infection can be approached.</p>
 <h3 data-number="5.5.1" id="tocilizumab"><span class="header-section-number">5.5.1</span> Tocilizumab</h3>
-<p>TCZ is a receptor antibody that was developed to manage chronic inflammation caused by the continuous synthesis of the cytokine IL-6 <span class="citation" data-cites="NDRyNd61">[<a href="#ref-NDRyNd61" role="doc-biblioref">564</a>]</span>.
+<p>TCZ is a receptor antibody that was developed to manage chronic inflammation caused by the continuous synthesis of the cytokine IL-6 <span class="citation" data-cites="NDRyNd61">[<a href="#ref-NDRyNd61" role="doc-biblioref">563</a>]</span>.
 IL-6 is a pro-inflammatory cytokine belonging to the interleukin family, which is comprised by immune system regulators that are primarily responsible for immune cell differentiation.
-Often used to treat conditions such as RA <span class="citation" data-cites="NDRyNd61">[<a href="#ref-NDRyNd61" role="doc-biblioref">564</a>]</span>, TCZ has become a pharmaceutical of interest for the treatment of COVID-19 because of the role IL-6 plays in this disease.
-It has also been approved to treat CRS caused by CAR-T treatments <span class="citation" data-cites="1636MNwvb">[<a href="#ref-1636MNwvb" role="doc-biblioref">565</a>]</span>.
-While secretion of IL-6 can be associated with chronic conditions, it is a key player in the innate immune response and is secreted by macrophages in response to the detection of pathogen-associated molecular patterns and damage-associated molecular patterns <span class="citation" data-cites="NDRyNd61">[<a href="#ref-NDRyNd61" role="doc-biblioref">564</a>]</span>.
+Often used to treat conditions such as RA <span class="citation" data-cites="NDRyNd61">[<a href="#ref-NDRyNd61" role="doc-biblioref">563</a>]</span>, TCZ has become a pharmaceutical of interest for the treatment of COVID-19 because of the role IL-6 plays in this disease.
+It has also been approved to treat CRS caused by CAR-T treatments <span class="citation" data-cites="1636MNwvb">[<a href="#ref-1636MNwvb" role="doc-biblioref">564</a>]</span>.
+While secretion of IL-6 can be associated with chronic conditions, it is a key player in the innate immune response and is secreted by macrophages in response to the detection of pathogen-associated molecular patterns and damage-associated molecular patterns <span class="citation" data-cites="NDRyNd61">[<a href="#ref-NDRyNd61" role="doc-biblioref">563</a>]</span>.
 An analysis of 191 in-patients at two Wuhan hospitals revealed that blood concentrations of IL-6 differed between patients who did and did not recover from COVID-19.
 Patients who ultimately died had higher IL-6 levels at admission than those who recovered <span class="citation" data-cites="10THxyeCg">[<a href="#ref-10THxyeCg" role="doc-biblioref">38</a>]</span>.
 Additionally, IL-6 levels remained higher throughout the course of hospitalization in the patients who ultimately died <span class="citation" data-cites="10THxyeCg">[<a href="#ref-10THxyeCg" role="doc-biblioref">38</a>]</span>.
 This finding provided some early evidence that COVID-19 deaths may be induced by the hyperactive immune response, often referred to as CRS or cytokine storm syndrome (CSS), as IL-6 plays a key role in this response <span class="citation" data-cites="bZMKqj6e">[<a href="#ref-bZMKqj6e" role="doc-biblioref">148</a>]</span>.
 In this context, the observation of elevated IL-6 in patients who died may reflect an over-production of proinflammatory interleukins, suggesting that TCZ could potentially palliate some of the most severe symptoms of COVID-19 associated with increased cytokine production.</p>
 <p>Human IL-6 is a 26-kDa glycoprotein that consists of 184 amino acids and contains two potential N-glycosylation sites and four cysteine residues.
-It binds to a type I cytokine receptor (IL-6Rα or glycoprotein 80) that exists in both membrane-bound (IL-6Rα) and soluble (sIL-6Rα) forms <span class="citation" data-cites="VXDsRwHC">[<a href="#ref-VXDsRwHC" role="doc-biblioref">566</a>]</span>.
-It is not the binding of IL-6 to the receptor that initiates pro- and/or anti-inflammatory signaling, but rather the binding of the complex to another subunit, known as IL-6Rβ or glycoprotein 130 (gp130) <span class="citation" data-cites="14xZS2Gic VXDsRwHC">[<a href="#ref-VXDsRwHC" role="doc-biblioref">566</a>,<a href="#ref-14xZS2Gic" role="doc-biblioref">567</a>]</span>.
-Unlike membrane-bound IL-6Rα, which is only found on hepatocytes and some types of leukocytes, gp130 is found on most cells <span class="citation" data-cites="LIqxTdN">[<a href="#ref-LIqxTdN" role="doc-biblioref">568</a>]</span>.
-When IL-6 binds to sIL-6Rα, the complex can then bind to a gp130 protein on any cell <span class="citation" data-cites="LIqxTdN">[<a href="#ref-LIqxTdN" role="doc-biblioref">568</a>]</span>.
-The binding of IL-6 to IL-6Rα is termed classical signaling, while its binding to sIL-6Rα is termed trans-signaling <span class="citation" data-cites="1BxkPZYnj 1EEloBjzn LIqxTdN">[<a href="#ref-LIqxTdN" role="doc-biblioref">568</a>,<a href="#ref-1BxkPZYnj" role="doc-biblioref">569</a>,<a href="#ref-1EEloBjzn" role="doc-biblioref">570</a>]</span>.
+It binds to a type I cytokine receptor (IL-6Rα or glycoprotein 80) that exists in both membrane-bound (IL-6Rα) and soluble (sIL-6Rα) forms <span class="citation" data-cites="VXDsRwHC">[<a href="#ref-VXDsRwHC" role="doc-biblioref">565</a>]</span>.
+It is not the binding of IL-6 to the receptor that initiates pro- and/or anti-inflammatory signaling, but rather the binding of the complex to another subunit, known as IL-6Rβ or glycoprotein 130 (gp130) <span class="citation" data-cites="14xZS2Gic VXDsRwHC">[<a href="#ref-VXDsRwHC" role="doc-biblioref">565</a>,<a href="#ref-14xZS2Gic" role="doc-biblioref">566</a>]</span>.
+Unlike membrane-bound IL-6Rα, which is only found on hepatocytes and some types of leukocytes, gp130 is found on most cells <span class="citation" data-cites="LIqxTdN">[<a href="#ref-LIqxTdN" role="doc-biblioref">567</a>]</span>.
+When IL-6 binds to sIL-6Rα, the complex can then bind to a gp130 protein on any cell <span class="citation" data-cites="LIqxTdN">[<a href="#ref-LIqxTdN" role="doc-biblioref">567</a>]</span>.
+The binding of IL-6 to IL-6Rα is termed classical signaling, while its binding to sIL-6Rα is termed trans-signaling <span class="citation" data-cites="1BxkPZYnj 1EEloBjzn LIqxTdN">[<a href="#ref-LIqxTdN" role="doc-biblioref">567</a>,<a href="#ref-1BxkPZYnj" role="doc-biblioref">568</a>,<a href="#ref-1EEloBjzn" role="doc-biblioref">569</a>]</span>.
 These two signaling processes are thought to play different roles in health and illness.
-For example, trans-signaling may play a role in the proliferation of mucosal T-helper TH2 cells associated with asthma, while an earlier step in this proliferation process may be regulated by classical signaling <span class="citation" data-cites="LIqxTdN">[<a href="#ref-LIqxTdN" role="doc-biblioref">568</a>]</span>.
-Similarly, IL-6 is known to play a role in Crohn’s Disease via trans-, but not classical, signaling <span class="citation" data-cites="LIqxTdN">[<a href="#ref-LIqxTdN" role="doc-biblioref">568</a>]</span>.
-Both classical and trans-signaling can occur through three independent pathways: the Janus-activated kinase-STAT3 pathway, the Ras/Mitogen-Activated Protein Kinases pathway and the Phosphoinositol-3 Kinase/Akt pathway <span class="citation" data-cites="VXDsRwHC">[<a href="#ref-VXDsRwHC" role="doc-biblioref">566</a>]</span>.
-These signaling pathways are involved in a variety of different functions, including cell type differentiation, immunoglobulin synthesis, and cellular survival signaling pathways, respectively <span class="citation" data-cites="VXDsRwHC">[<a href="#ref-VXDsRwHC" role="doc-biblioref">566</a>]</span>.
-The ultimate result of the IL-6 cascade is to direct transcriptional activity of various promoters of pro-inflammatory cytokines, such as IL-1, TFN, and even IL-6 itself, through the activity of NF-κB <span class="citation" data-cites="VXDsRwHC">[<a href="#ref-VXDsRwHC" role="doc-biblioref">566</a>]</span>.
-IL-6 synthesis is tightly regulated both transcriptionally and post-transcriptionally, and it has been shown that viral proteins can enhance transcription of the IL-6 gene by strengthening the DNA-binding activity between several transcription factors and IL-6 gene-cis-regulatory elements <span class="citation" data-cites="1H8o8TFtM">[<a href="#ref-1H8o8TFtM" role="doc-biblioref">571</a>]</span>.
+For example, trans-signaling may play a role in the proliferation of mucosal T-helper TH2 cells associated with asthma, while an earlier step in this proliferation process may be regulated by classical signaling <span class="citation" data-cites="LIqxTdN">[<a href="#ref-LIqxTdN" role="doc-biblioref">567</a>]</span>.
+Similarly, IL-6 is known to play a role in Crohn’s Disease via trans-, but not classical, signaling <span class="citation" data-cites="LIqxTdN">[<a href="#ref-LIqxTdN" role="doc-biblioref">567</a>]</span>.
+Both classical and trans-signaling can occur through three independent pathways: the Janus-activated kinase-STAT3 pathway, the Ras/Mitogen-Activated Protein Kinases pathway and the Phosphoinositol-3 Kinase/Akt pathway <span class="citation" data-cites="VXDsRwHC">[<a href="#ref-VXDsRwHC" role="doc-biblioref">565</a>]</span>.
+These signaling pathways are involved in a variety of different functions, including cell type differentiation, immunoglobulin synthesis, and cellular survival signaling pathways, respectively <span class="citation" data-cites="VXDsRwHC">[<a href="#ref-VXDsRwHC" role="doc-biblioref">565</a>]</span>.
+The ultimate result of the IL-6 cascade is to direct transcriptional activity of various promoters of pro-inflammatory cytokines, such as IL-1, TFN, and even IL-6 itself, through the activity of NF-κB <span class="citation" data-cites="VXDsRwHC">[<a href="#ref-VXDsRwHC" role="doc-biblioref">565</a>]</span>.
+IL-6 synthesis is tightly regulated both transcriptionally and post-transcriptionally, and it has been shown that viral proteins can enhance transcription of the IL-6 gene by strengthening the DNA-binding activity between several transcription factors and IL-6 gene-cis-regulatory elements <span class="citation" data-cites="1H8o8TFtM">[<a href="#ref-1H8o8TFtM" role="doc-biblioref">570</a>]</span>.
 Therefore, drugs inhibiting the binding of IL-6 to IL-6Rα or sIL-6Rα are of interest for combating the hyperactive inflammatory response characteristic of CRS/CSS.
 TCZ is a humanized monoclonal antibody that binds both to the insoluble and soluble receptor of IL-6, providing de facto inhibition of the IL-6 immune cascade.</p>
 <p>Tocilizumab is being administered either as an intervention or as concomitant medication in 77 interventional COVID-19 clinical trials (Figure <a href="#fig:ebm-trials">3</a>).
 No randomized, placebo-controlled studies of TCZ have currently released results.
 Therefore, no conclusions can be drawn about its efficacy for the treatment of COVID-19.
-However, early interest in TCZ as a possible treatment for COVID-19 emerged from a very small retrospective study in China that examined 20 patients with severe symptoms in early February 2020 and reported rapid improvement in symptoms following treatment with TCZ <span class="citation" data-cites="bj2feMy4">[<a href="#ref-bj2feMy4" role="doc-biblioref">572</a>]</span>.
+However, early interest in TCZ as a possible treatment for COVID-19 emerged from a very small retrospective study in China that examined 20 patients with severe symptoms in early February 2020 and reported rapid improvement in symptoms following treatment with TCZ <span class="citation" data-cites="bj2feMy4">[<a href="#ref-bj2feMy4" role="doc-biblioref">571</a>]</span>.
 Subsequently, a number of retrospective studies have been conducted in several countries.
 Many studies use a retrospective, observational design, where they compare outcomes for COVID-19 patients who received TCZ to those who did not over a set period of time.
-For example, one of the largest retrospective, observational analyses released to date <span class="citation" data-cites="ayc7zYqi">[<a href="#ref-ayc7zYqi" role="doc-biblioref">573</a>]</span>, consisting of 1,351 patients admitted to several care centers in Italy, compared the rates at which patients who received TCZ died or progressed to invasive medical ventilation over a 14-day period compared to patients receiving only SOC.
+For example, one of the largest retrospective, observational analyses released to date <span class="citation" data-cites="ayc7zYqi">[<a href="#ref-ayc7zYqi" role="doc-biblioref">572</a>]</span>, consisting of 1,351 patients admitted to several care centers in Italy, compared the rates at which patients who received TCZ died or progressed to invasive medical ventilation over a 14-day period compared to patients receiving only SOC.
 Under this definition, SOC could include other drugs such as HCQ, azithromycin, lopinavir-ritonavir or darunavir-cobicistat, or heparin.
 While this study was not randomized, a subset of patients who were eligible to receive TCZ were unable to obtain it due to shortages; however, these groups were not directly compared in the analysis.
 After adjusting for variables such as age, sex, and SOFA (sequential organ failure assessment) score, they found that patients treated with TCZ were less likely to progress to invasive medical ventilation and/or death (adjusted HR = 0.61, CI 0.40-0.92, <em>p</em> = 0.020); analysis of death and ventilation separately suggests that this effect may have been driven by differences in the death rate (20% of control versus 7% of TCZ-treated patients).
 The study reported particular benefits for patients whose PaO<sub>2</sub>/FiO<sub>2</sub> ratio, also known as the Horowitz Index for Lung Function, fell below a 150 mm Hg threshold.
 They found no differences between groups administered subcutaneous versus intravenous TCZ.</p>
-<p>Another retrospective observational analysis of interest examined the charts of patients at a hospital in Connecticut, USA where 64% of all 239 COVID-19 patients in the study period were administered TCZ based on assignment by a standardized algorithm <span class="citation" data-cites="Wt9vgKLY">[<a href="#ref-Wt9vgKLY" role="doc-biblioref">574</a>]</span>.
+<p>Another retrospective observational analysis of interest examined the charts of patients at a hospital in Connecticut, USA where 64% of all 239 COVID-19 patients in the study period were administered TCZ based on assignment by a standardized algorithm <span class="citation" data-cites="Wt9vgKLY">[<a href="#ref-Wt9vgKLY" role="doc-biblioref">573</a>]</span>.
 They found that TCZ administration was associated with more similar rates of survivorship in patients with severe versus nonsevere COVID-19 at intake, defined based on the amount of supplemental oxygen needed.
 They therefore proposed that their algorithm was able to identify patients presenting with or likely to develop CRS as good candidates for TCZ.
 This study also reported higher survivorship in Black and Hispanic patients compared to white patients when adjusted for age.
 The major limitation with interpretation for these studies is that there may be clinical characteristics that influenced medical practitioners decisions to administer TCZ to some patients and not others.
-One interesting example therefore comes from an analysis of patients at a single hospital in Brescia, Italy, where TCZ was not available for a period of time <span class="citation" data-cites="luPHOS0m">[<a href="#ref-luPHOS0m" role="doc-biblioref">575</a>]</span>.
+One interesting example therefore comes from an analysis of patients at a single hospital in Brescia, Italy, where TCZ was not available for a period of time <span class="citation" data-cites="luPHOS0m">[<a href="#ref-luPHOS0m" role="doc-biblioref">574</a>]</span>.
 This study compared COVID-19 patients admitted to the hospital before and after March 13, 2020, when the hospital received TCZ.
 Therefore, patients who would have been eligible for TCZ prior to this arbitrary date did not receive it as treatment, making this retrospective analysis something of a natural experiment.
 Despite this design, demographic factors did not appear to be consistent between the two groups, and the average age of the control group was older than the TCZ group.
@@ -2242,112 +2242,112 @@ <h3 data-number="5.5.1" id="tocilizumab"><span class="header-section-number">5.5
 However, this study also holds a significant limitation: the time delay between the two groups means that knowledge about how to treat the disease likely improved over this timeframe as well.
 All the same, the results of these observational retrospective studies provide support for TCZ as a pharmaceutical of interest for follow-up in clinical trials.</p>
 <p>Other retrospective analyses have utilized a case-control design to match pairs of patients with similar baseline characteristics, only one of whom received TCZ for COVID-19.
-In one such study, TCZ was significantly associated with a reduced risk of progression to ICU admission or death <span class="citation" data-cites="17hgtBpcV">[<a href="#ref-17hgtBpcV" role="doc-biblioref">576</a>]</span>.
+In one such study, TCZ was significantly associated with a reduced risk of progression to ICU admission or death <span class="citation" data-cites="17hgtBpcV">[<a href="#ref-17hgtBpcV" role="doc-biblioref">575</a>]</span>.
 This study examined only 20 patients treated with TCZ (all but one of the patients treated with TCZ in the hospital during the study period) and compared them to 25 patients receiving SOC.
 For the combined primary endpoint of death and/or ICU admission, only 25% of patients receiving TCZ progressed to an endpoint compared to 72% in the SOC group (<em>p</em> = 0.002, presumably based on a chi-square test based on the information provided in the text).
 When the two endpoints were examined separately, progression to invasive medical ventilation remained significant (32% SOC compared to 0% TCZ, <em>p</em> = 0.006) but not for mortality (48% SOC compared to 25% TCZ, <em>p</em> = 0.066).
-In contrast, a study that compared 96 patients treated with TCZ to 97 patients treated with SOC only in New York City found that differences in mortality did not differ between the two groups, but that this difference did become significant when intubated patients were excluded from the analysis <span class="citation" data-cites="WEqfULN1">[<a href="#ref-WEqfULN1" role="doc-biblioref">577</a>]</span>.
+In contrast, a study that compared 96 patients treated with TCZ to 97 patients treated with SOC only in New York City found that differences in mortality did not differ between the two groups, but that this difference did become significant when intubated patients were excluded from the analysis <span class="citation" data-cites="WEqfULN1">[<a href="#ref-WEqfULN1" role="doc-biblioref">576</a>]</span>.
 Taken together, these findings suggest that future clinical trials of TCZ may want to include intubation as an endpoint.
 However, these studies should be approached with caution, not only because of the small number of patients enrolled and the retrospective design, but also because they performed a large number of statistical tests and did not account for multiple hypothesis testing.
 In general, caution must be exercised when interpreting subgroup analyses after a primary combined endpoint analysis.
 These last findings highlight the need to search for a balance between impairing a harmful immune response, such as the one generated during CRS/CSS, and preventing the worsening of the clinical picture of the patients by potential new viral infections.
 Though data about TCZ for COVID-19 is still only just emerging, some meta-analyses and systematic reviews have investigated the available data.
-One meta-analysis <span class="citation" data-cites="3yV2bL9S">[<a href="#ref-3yV2bL9S" role="doc-biblioref">578</a>]</span> evaluated 19 studies published or released as preprints prior to July 1, 2020 and found that the overall trends were supportive of the frequent conclusion that TCZ does improve survivorship, with a significant HR of 0.41 (<em>p</em> &lt; 0.001).
+One meta-analysis <span class="citation" data-cites="3yV2bL9S">[<a href="#ref-3yV2bL9S" role="doc-biblioref">577</a>]</span> evaluated 19 studies published or released as preprints prior to July 1, 2020 and found that the overall trends were supportive of the frequent conclusion that TCZ does improve survivorship, with a significant HR of 0.41 (<em>p</em> &lt; 0.001).
 This trend improved when they excluded studies that administered a steroid alongside TCZ, with a significant HR of 0.04 (<em>p</em> &lt; 0.001).
 They also found some evidence for reduced invasive ventilation or ICU admission, but only when excluding all studies except a small number whose estimates were adjusted for the possible bias introduced by the challenges of stringency during the enrollment process.
-A systematic analysis of sixteen case-control studies of TCZ estimated an odds ratio of mortality of 0.453 (95% CI 0.376–0.547, <em>p</em> &lt; 0.001), suggesting possible benefits associated with TCZ treatment <span class="citation" data-cites="WmK4YTdx">[<a href="#ref-WmK4YTdx" role="doc-biblioref">579</a>]</span>.
+A systematic analysis of sixteen case-control studies of TCZ estimated an odds ratio of mortality of 0.453 (95% CI 0.376–0.547, <em>p</em> &lt; 0.001), suggesting possible benefits associated with TCZ treatment <span class="citation" data-cites="WmK4YTdx">[<a href="#ref-WmK4YTdx" role="doc-biblioref">578</a>]</span>.
 Although these estimates are similar, it is important to note that they are drawing from the same literature and are therefore likely to be affected by the same potential biases in publication.
-A different systematic review of studies investigating TCZ treatment for COVID-19 analyzed 31 studies that had been published or released as pre-prints and reported that none carried a low risk of bias <span class="citation" data-cites="h4reluu">[<a href="#ref-h4reluu" role="doc-biblioref">580</a>]</span>.
+A different systematic review of studies investigating TCZ treatment for COVID-19 analyzed 31 studies that had been published or released as pre-prints and reported that none carried a low risk of bias <span class="citation" data-cites="h4reluu">[<a href="#ref-h4reluu" role="doc-biblioref">579</a>]</span>.
 Therefore, the present evidence is not likely to be sufficient for conclusions about the efficacy of TCZ.</p>
-<p>On February 11, 2021, a preprint describing the first randomized control trial of TCZ was released as part of the RECOVERY trial <span class="citation" data-cites="9wnr4sOS">[<a href="#ref-9wnr4sOS" role="doc-biblioref">581</a>]</span>.
+<p>On February 11, 2021, a preprint describing the first randomized control trial of TCZ was released as part of the RECOVERY trial <span class="citation" data-cites="9wnr4sOS">[<a href="#ref-9wnr4sOS" role="doc-biblioref">580</a>]</span>.
 Of the 21,550 patients enrolled in the RECOVERY trial at the time, 4,116 adults hospitalized with COVID-19 across the 131 sites in the United Kingdom were assigned to the arm of the trial evaluating the effect of TCZ.
 Among them, 2,022 were randomized to receive TCZ and 2,094 were randomized to SOC, with 79% of patients in each group available for analysis at the time that the initial report was released.
 The primary outcome measured was 28-day mortality, and TCZ was found to reduce 28-day mortality from 33% of patients receiving SOC alone to 29% of those receiving TCZ, corresponding to a rate ratio of 0.86 (95% CI 0.77-0.96; <em>p</em> = 0.007).
 TCZ was also significantly associated with the probability of hospital discharge within 28 days for living patients, which was 47% in the SOC group and 54% in the TCZ group (rate ratio 1.22, 95% CI 1.12-1.34, <em>p</em> &lt; 0.0001).
 A potential statistical interaction between TCZ and corticosteroids was observed, with the combination providing greater mortality benefits than TCZ alone, but the authors note that caution is advisable in light of the number of statistical tests conducted.
-Combining the RECOVERY trial data with data from seven smaller randomized control trials indicates that TCZ is associated with a 13% reduction in 28-day mortality (rate ratio 0.87, 95% CI 0.79-0.96, <em>p</em> = 0·005) <span class="citation" data-cites="9wnr4sOS">[<a href="#ref-9wnr4sOS" role="doc-biblioref">581</a>]</span>.
+Combining the RECOVERY trial data with data from seven smaller randomized control trials indicates that TCZ is associated with a 13% reduction in 28-day mortality (rate ratio 0.87, 95% CI 0.79-0.96, <em>p</em> = 0·005) <span class="citation" data-cites="9wnr4sOS">[<a href="#ref-9wnr4sOS" role="doc-biblioref">580</a>]</span>.
 While this initial report did not include the full results expected from the RECOVERY trial, this large-scale, randomized controlled trial therefore offers strong evidence that TCZ may offer benefits for COVID-19 patients, even at this initial stage of analysis.</p>
 <p>There are possible risks associated with the administration of TCZ for COVID-19.
-TCZ has been used for over a decade to treat RA <span class="citation" data-cites="CRriJXDk">[<a href="#ref-CRriJXDk" role="doc-biblioref">582</a>]</span>, and a recent study found the drug to be safe for pregnant and breastfeeding women <span class="citation" data-cites="6xLhs9st">[<a href="#ref-6xLhs9st" role="doc-biblioref">583</a>]</span>.
-However, TCZ may increase the risk of developing infections <span class="citation" data-cites="CRriJXDk">[<a href="#ref-CRriJXDk" role="doc-biblioref">582</a>]</span>, and RA patients with chronic hepatitis B infections had a high risk of hepatitis B virus reactivation when TCZ was administered in combination with other RA drugs <span class="citation" data-cites="IJzmtJOr">[<a href="#ref-IJzmtJOr" role="doc-biblioref">584</a>]</span>.
-As a result, TCZ is contraindicated in patients with active infections such as tuberculosis <span class="citation" data-cites="SiOKIbl3">[<a href="#ref-SiOKIbl3" role="doc-biblioref">585</a>]</span>.
-Previous studies have investigated, with varying results, a possible increased risk of infection in RA patients administered TCZ <span class="citation" data-cites="6Agll71m zRRSvckT">[<a href="#ref-6Agll71m" role="doc-biblioref">586</a>,<a href="#ref-zRRSvckT" role="doc-biblioref">587</a>]</span>, although another study reported that the incidence rate of infections was higher in clinical practice RA patients treated with TCZ than in the rates reported by clinical trials <span class="citation" data-cites="TgV8gb30">[<a href="#ref-TgV8gb30" role="doc-biblioref">588</a>]</span>.
-In the investigation of 544 Italian COVID-19 patients, the group treated with TCZ was found to be more likely to develop secondary infections, with 24% compared to 4% in the control group (<em>p</em> &lt; 0.0001) <span class="citation" data-cites="ayc7zYqi">[<a href="#ref-ayc7zYqi" role="doc-biblioref">573</a>]</span>.
+TCZ has been used for over a decade to treat RA <span class="citation" data-cites="CRriJXDk">[<a href="#ref-CRriJXDk" role="doc-biblioref">581</a>]</span>, and a recent study found the drug to be safe for pregnant and breastfeeding women <span class="citation" data-cites="6xLhs9st">[<a href="#ref-6xLhs9st" role="doc-biblioref">582</a>]</span>.
+However, TCZ may increase the risk of developing infections <span class="citation" data-cites="CRriJXDk">[<a href="#ref-CRriJXDk" role="doc-biblioref">581</a>]</span>, and RA patients with chronic hepatitis B infections had a high risk of hepatitis B virus reactivation when TCZ was administered in combination with other RA drugs <span class="citation" data-cites="IJzmtJOr">[<a href="#ref-IJzmtJOr" role="doc-biblioref">583</a>]</span>.
+As a result, TCZ is contraindicated in patients with active infections such as tuberculosis <span class="citation" data-cites="SiOKIbl3">[<a href="#ref-SiOKIbl3" role="doc-biblioref">584</a>]</span>.
+Previous studies have investigated, with varying results, a possible increased risk of infection in RA patients administered TCZ <span class="citation" data-cites="6Agll71m zRRSvckT">[<a href="#ref-6Agll71m" role="doc-biblioref">585</a>,<a href="#ref-zRRSvckT" role="doc-biblioref">586</a>]</span>, although another study reported that the incidence rate of infections was higher in clinical practice RA patients treated with TCZ than in the rates reported by clinical trials <span class="citation" data-cites="TgV8gb30">[<a href="#ref-TgV8gb30" role="doc-biblioref">587</a>]</span>.
+In the investigation of 544 Italian COVID-19 patients, the group treated with TCZ was found to be more likely to develop secondary infections, with 24% compared to 4% in the control group (<em>p</em> &lt; 0.0001) <span class="citation" data-cites="ayc7zYqi">[<a href="#ref-ayc7zYqi" role="doc-biblioref">572</a>]</span>.
 Reactivation of hepatitis B and herpes simplex virus 1 was also reported in a small number of patients in this study, all of whom were receiving TCZ.
-A July 2020 case report described negative outcomes of two COVID-19 patients after receiving TCZ, including one death; however, both patients were intubated and had entered septic shock prior to receiving TCZ <span class="citation" data-cites="p0tzgJvA">[<a href="#ref-p0tzgJvA" role="doc-biblioref">589</a>]</span>, likely indicating a severe level of cytokine production.
-Additionally, D-dimer and sIL2R levels were reported by one study to increase in patients treated with TCZ, which raised concerns because of the potential association between elevated D-dimer levels and thrombosis and between sIL2R and diseases where T-cell regulation is compromised <span class="citation" data-cites="Wt9vgKLY">[<a href="#ref-Wt9vgKLY" role="doc-biblioref">574</a>]</span>.
-An increased risk of bacterial infection was also identified in a systematic review of the literature, based on the unadjusted estimates reported <span class="citation" data-cites="3yV2bL9S">[<a href="#ref-3yV2bL9S" role="doc-biblioref">578</a>]</span>.
-In the RECOVERY trial, however, only three out of 2,022 participants in the group receiving TCZ developed adverse reactions determined to be associated with the intervention, and no excess deaths were reported <span class="citation" data-cites="9wnr4sOS">[<a href="#ref-9wnr4sOS" role="doc-biblioref">581</a>]</span>.
+A July 2020 case report described negative outcomes of two COVID-19 patients after receiving TCZ, including one death; however, both patients were intubated and had entered septic shock prior to receiving TCZ <span class="citation" data-cites="p0tzgJvA">[<a href="#ref-p0tzgJvA" role="doc-biblioref">588</a>]</span>, likely indicating a severe level of cytokine production.
+Additionally, D-dimer and sIL2R levels were reported by one study to increase in patients treated with TCZ, which raised concerns because of the potential association between elevated D-dimer levels and thrombosis and between sIL2R and diseases where T-cell regulation is compromised <span class="citation" data-cites="Wt9vgKLY">[<a href="#ref-Wt9vgKLY" role="doc-biblioref">573</a>]</span>.
+An increased risk of bacterial infection was also identified in a systematic review of the literature, based on the unadjusted estimates reported <span class="citation" data-cites="3yV2bL9S">[<a href="#ref-3yV2bL9S" role="doc-biblioref">577</a>]</span>.
+In the RECOVERY trial, however, only three out of 2,022 participants in the group receiving TCZ developed adverse reactions determined to be associated with the intervention, and no excess deaths were reported <span class="citation" data-cites="9wnr4sOS">[<a href="#ref-9wnr4sOS" role="doc-biblioref">580</a>]</span>.
 TCZ administration to COVID-19 patients is not without risks and may introduce additional risk of developing secondary infections; however, while caution may be prudent when treating patients who have latent viral infections, the results of the RECOVERY trial indicate that adverse reactions to TCZ are very rare among COVID-19 patients broadly.</p>
-<p>In summary, approximately 33% of hospitalized COVID-19 patients develop ARDS <span class="citation" data-cites="epRQ9yZu">[<a href="#ref-epRQ9yZu" role="doc-biblioref">590</a>]</span>, which is caused by an excessive early response of the immune system which can be a component of CRS/CSS <span class="citation" data-cites="Wt9vgKLY SiOKIbl3">[<a href="#ref-Wt9vgKLY" role="doc-biblioref">574</a>,<a href="#ref-SiOKIbl3" role="doc-biblioref">585</a>]</span>.
+<p>In summary, approximately 33% of hospitalized COVID-19 patients develop ARDS <span class="citation" data-cites="epRQ9yZu">[<a href="#ref-epRQ9yZu" role="doc-biblioref">589</a>]</span>, which is caused by an excessive early response of the immune system which can be a component of CRS/CSS <span class="citation" data-cites="Wt9vgKLY SiOKIbl3">[<a href="#ref-Wt9vgKLY" role="doc-biblioref">573</a>,<a href="#ref-SiOKIbl3" role="doc-biblioref">584</a>]</span>.
 This overwhelming inflammation is triggered by IL-6.
 TCZ is an inhibitor of IL-6 and therefore may neutralize the inflammatory pathway that leads to the cytokine storm.
 While the mechanism suggests TCZ could be beneficial for the treatment of COVID-19 patients experiencing excessive immune activity, no randomized controlled trials are available assessing its effect.
 However, small initial studies have found preliminary indications that TCZ may reduce progression to invasive medical ventilation and/or death.
 It should be noted that SOC varied widely across retrospective studies, with one study administering HCQ, lopinavir-ritonavir, antibiotics, and/or heparin as part of SOC.
-Interest in TCZ as a treatment for COVID-19 was supported by two meta-analyses <span class="citation" data-cites="ZHqWXFcN 3yV2bL9S">[<a href="#ref-3yV2bL9S" role="doc-biblioref">578</a>,<a href="#ref-ZHqWXFcN" role="doc-biblioref">591</a>]</span>, but a third meta-analysis found that all of the available literature carries a risk of bias, with even the largest available TCZ studies to date carrying a moderate risk of bias under the ROBINS-I criteria <span class="citation" data-cites="h4reluu">[<a href="#ref-h4reluu" role="doc-biblioref">580</a>]</span>.
+Interest in TCZ as a treatment for COVID-19 was supported by two meta-analyses <span class="citation" data-cites="ZHqWXFcN 3yV2bL9S">[<a href="#ref-3yV2bL9S" role="doc-biblioref">577</a>,<a href="#ref-ZHqWXFcN" role="doc-biblioref">590</a>]</span>, but a third meta-analysis found that all of the available literature carries a risk of bias, with even the largest available TCZ studies to date carrying a moderate risk of bias under the ROBINS-I criteria <span class="citation" data-cites="h4reluu">[<a href="#ref-h4reluu" role="doc-biblioref">579</a>]</span>.
 Additionally, different studies used different dosages, number of doses, and methods of administration.
-Ongoing research may be needed to optimize administration of TCZ <span class="citation" data-cites="hvOwSJvK">[<a href="#ref-hvOwSJvK" role="doc-biblioref">592</a>]</span>, although similar results were reported by one study for intravenous and subcutaneous administration <span class="citation" data-cites="ayc7zYqi">[<a href="#ref-ayc7zYqi" role="doc-biblioref">573</a>]</span>.
+Ongoing research may be needed to optimize administration of TCZ <span class="citation" data-cites="hvOwSJvK">[<a href="#ref-hvOwSJvK" role="doc-biblioref">591</a>]</span>, although similar results were reported by one study for intravenous and subcutaneous administration <span class="citation" data-cites="ayc7zYqi">[<a href="#ref-ayc7zYqi" role="doc-biblioref">572</a>]</span>.
 Clinical trials that are in progress are likely to provide additional insight into the effectiveness of this drug for the treatment of COVID-19 along with how it should be administered.</p>
 <h3 data-number="5.5.2" id="monoclonal-neutralizing-antibodies"><span class="header-section-number">5.5.2</span> Monoclonal Neutralizing Antibodies</h3>
 <p>Monoclonal antibodies have revolutionized the way we treat human diseases.
-They have become some of the best-selling drugs in the pharmaceutical market in recent years <span class="citation" data-cites="1AKi0FYUB">[<a href="#ref-1AKi0FYUB" role="doc-biblioref">593</a>]</span>.
-There are currently 79 FDA approved mAbs on the market, including antibodies for viral infections (e.g. Ibalizumab for HIV and Palivizumab for RSV) <span class="citation" data-cites="1AKi0FYUB yumBaJ6U">[<a href="#ref-1AKi0FYUB" role="doc-biblioref">593</a>,<a href="#ref-yumBaJ6U" role="doc-biblioref">594</a>]</span>.
-Virus-specific neutralizing antibodies commonly target viral surface glycoproteins or host structures, thereby inhibiting viral entry through receptor binding interference <span class="citation" data-cites="dUnB3gD6 cwbHiM1o">[<a href="#ref-dUnB3gD6" role="doc-biblioref">595</a>,<a href="#ref-cwbHiM1o" role="doc-biblioref">596</a>]</span>.
+They have become some of the best-selling drugs in the pharmaceutical market in recent years <span class="citation" data-cites="1AKi0FYUB">[<a href="#ref-1AKi0FYUB" role="doc-biblioref">592</a>]</span>.
+There are currently 79 FDA approved mAbs on the market, including antibodies for viral infections (e.g. Ibalizumab for HIV and Palivizumab for RSV) <span class="citation" data-cites="1AKi0FYUB yumBaJ6U">[<a href="#ref-1AKi0FYUB" role="doc-biblioref">592</a>,<a href="#ref-yumBaJ6U" role="doc-biblioref">593</a>]</span>.
+Virus-specific neutralizing antibodies commonly target viral surface glycoproteins or host structures, thereby inhibiting viral entry through receptor binding interference <span class="citation" data-cites="dUnB3gD6 cwbHiM1o">[<a href="#ref-dUnB3gD6" role="doc-biblioref">594</a>,<a href="#ref-cwbHiM1o" role="doc-biblioref">595</a>]</span>.
 This is predicted to reduce the viral load, mitigate disease, and reduce overall hospitalization.
-While polyclonal antibodies from convalescent plasma can be used as a treatment for COVID-19, this section focuses on current efforts in developing monoclonal neutralizing antibodies (nAbs) against SARS-CoV-2 (excellent reviews regarding convalescent plasma therapy can be found here <span class="citation" data-cites="f52YwpY3 JPUZjTnq">[<a href="#ref-f52YwpY3" role="doc-biblioref">597</a>,<a href="#ref-JPUZjTnq" role="doc-biblioref">598</a>]</span>).
+While polyclonal antibodies from convalescent plasma can be used as a treatment for COVID-19, this section focuses on current efforts in developing monoclonal neutralizing antibodies (nAbs) against SARS-CoV-2 (excellent reviews regarding convalescent plasma therapy can be found here <span class="citation" data-cites="f52YwpY3 JPUZjTnq">[<a href="#ref-f52YwpY3" role="doc-biblioref">596</a>,<a href="#ref-JPUZjTnq" role="doc-biblioref">597</a>]</span>).
 Specifically, we focus on monoclonal antibodies that have recently been granted emergency use authorization and discuss the challenges in the successful development of monoclonal neutralizing antibodies.</p>
-<p>During the first SARS epidemic in 2002, nAbs were found in SARS-CoV-1-infected patients <span class="citation" data-cites="3gp7t98X KULxo48U">[<a href="#ref-3gp7t98X" role="doc-biblioref">599</a>,<a href="#ref-KULxo48U" role="doc-biblioref">600</a>]</span>.
-Several studies following up on these findings identified various S-glycoprotein epitopes as the major targets of nAbs against SARS-CoV-1 <span class="citation" data-cites="MTcTiS7i">[<a href="#ref-MTcTiS7i" role="doc-biblioref">601</a>]</span>.
+<p>During the first SARS epidemic in 2002, nAbs were found in SARS-CoV-1-infected patients <span class="citation" data-cites="3gp7t98X KULxo48U">[<a href="#ref-3gp7t98X" role="doc-biblioref">598</a>,<a href="#ref-KULxo48U" role="doc-biblioref">599</a>]</span>.
+Several studies following up on these findings identified various S-glycoprotein epitopes as the major targets of nAbs against SARS-CoV-1 <span class="citation" data-cites="MTcTiS7i">[<a href="#ref-MTcTiS7i" role="doc-biblioref">600</a>]</span>.
 Coronaviruses use trimeric spike (S) glycoproteins on their surface to bind to the host cell, allowing for cell entry <span class="citation" data-cites="15l3di3Wj qcVbT0w4">[<a href="#ref-qcVbT0w4" role="doc-biblioref">67</a>,<a href="#ref-15l3di3Wj" role="doc-biblioref">70</a>]</span>.
 Each S glycoprotein protomer is comprised of an S1 domain, also called the RBD, and an S2 domain.
-The S1 domain binds to the host cell while the S2 domain facilitates the fusion between the viral envelope and host cell membranes <span class="citation" data-cites="MTcTiS7i">[<a href="#ref-MTcTiS7i" role="doc-biblioref">601</a>]</span>.
-The genomic identity between the RBD of SARS-CoV-1 and SARS-CoV-2 is around 74% <span class="citation" data-cites="41WAtZmB">[<a href="#ref-41WAtZmB" role="doc-biblioref">602</a>]</span>.
+The S1 domain binds to the host cell while the S2 domain facilitates the fusion between the viral envelope and host cell membranes <span class="citation" data-cites="MTcTiS7i">[<a href="#ref-MTcTiS7i" role="doc-biblioref">600</a>]</span>.
+The genomic identity between the RBD of SARS-CoV-1 and SARS-CoV-2 is around 74% <span class="citation" data-cites="41WAtZmB">[<a href="#ref-41WAtZmB" role="doc-biblioref">601</a>]</span>.
 Due to this high degree of similarity, preexisting antibodies against SARS-CoV-1 were initially considered candidates for neutralizing activity against SARS-CoV-2.
-While some antibodies developed against the SARS-CoV-1 spike protein showed cross-neutralization activity with SARS-CoV-2 <span class="citation" data-cites="19R52ruRw YigWg7xu">[<a href="#ref-19R52ruRw" role="doc-biblioref">603</a>,<a href="#ref-YigWg7xu" role="doc-biblioref">604</a>]</span>, others failed to bind to SARS-CoV-2 spike protein at relevant concentrations <span class="citation" data-cites="CqQVkaqj">[<a href="#ref-CqQVkaqj" role="doc-biblioref">54</a>]</span>.
-Cross-neutralizing activities were dependent on whether the epitope recognized by the antibodies were conserved between SARS-CoV-1 and SARS-CoV-2 <span class="citation" data-cites="19R52ruRw">[<a href="#ref-19R52ruRw" role="doc-biblioref">603</a>]</span>.</p>
-<p>The first human monoclonal neutralizing antibody specifically against the SARS-CoV-2 S glycoprotein was developed using hybridoma technology <span class="citation" data-cites="XcuzhxrJ">[<a href="#ref-XcuzhxrJ" role="doc-biblioref">605</a>]</span>, where antibody-producing B-cells developed by mice are inserted into myeloma cells to produce a hybrid cell line (the hybridoma) that is grown in culture.
+While some antibodies developed against the SARS-CoV-1 spike protein showed cross-neutralization activity with SARS-CoV-2 <span class="citation" data-cites="19R52ruRw YigWg7xu">[<a href="#ref-19R52ruRw" role="doc-biblioref">602</a>,<a href="#ref-YigWg7xu" role="doc-biblioref">603</a>]</span>, others failed to bind to SARS-CoV-2 spike protein at relevant concentrations <span class="citation" data-cites="CqQVkaqj">[<a href="#ref-CqQVkaqj" role="doc-biblioref">54</a>]</span>.
+Cross-neutralizing activities were dependent on whether the epitope recognized by the antibodies were conserved between SARS-CoV-1 and SARS-CoV-2 <span class="citation" data-cites="19R52ruRw">[<a href="#ref-19R52ruRw" role="doc-biblioref">602</a>]</span>.</p>
+<p>The first human monoclonal neutralizing antibody specifically against the SARS-CoV-2 S glycoprotein was developed using hybridoma technology <span class="citation" data-cites="XcuzhxrJ">[<a href="#ref-XcuzhxrJ" role="doc-biblioref">604</a>]</span>, where antibody-producing B-cells developed by mice are inserted into myeloma cells to produce a hybrid cell line (the hybridoma) that is grown in culture.
 The 47D11 antibody clone was able to cross-neutralize SARS-CoV-1 and SARS-CoV-2.
 This antibody (now ABVV-47D11) has recently entered clinical trials in collaboration with AbbVie.
-Since then, an extensive monoclonal neutralizing antibody pipeline has been developed to combat the ongoing pandemic, with over 50 different antibodies in clinical trials <span class="citation" data-cites="hkzKw8NQ">[<a href="#ref-hkzKw8NQ" role="doc-biblioref">606</a>]</span> and two treatments recently receiving emergency use authorization by the FDA.</p>
+Since then, an extensive monoclonal neutralizing antibody pipeline has been developed to combat the ongoing pandemic, with over 50 different antibodies in clinical trials <span class="citation" data-cites="hkzKw8NQ">[<a href="#ref-hkzKw8NQ" role="doc-biblioref">605</a>]</span> and two treatments recently receiving emergency use authorization by the FDA.</p>
 <h4 data-number="5.5.2.1" id="bamlanivimab-ly-cov555-and-etesevimab-ly-cov016"><span class="header-section-number">5.5.2.1</span> Bamlanivimab (LY-CoV555) and Etesevimab (LY-CoV016)</h4>
 <p>Bamlanivimab is a human monoclonal antibody that was derived from convalescent plasma donated by recovered COVID-19 patient, evaluated in research by the National Institute of Allergy and Infectious Diseases (NIAID), and subsequently developed by AbCellera and Eli Lilly.
-The neutralizing activity of bamlanivimab was initially demonstrated <em>in vivo</em> using a nonhuman primate model <span class="citation" data-cites="f44jpdvR">[<a href="#ref-f44jpdvR" role="doc-biblioref">607</a>]</span>.
+The neutralizing activity of bamlanivimab was initially demonstrated <em>in vivo</em> using a nonhuman primate model <span class="citation" data-cites="f44jpdvR">[<a href="#ref-f44jpdvR" role="doc-biblioref">606</a>]</span>.
 In these studies, prophylactic Ly-CoV555 infusions protected rhesus macaques from SARS-CoV-2 infection.
 Based on the positive preclinical data, Eli Lilly initiated the first human clinical trial for a monoclonal antibody against SARS-CoV-2.
-The phase 1 trial, which was conducted in hospitalized COVID-19 patients, was completed in August 2020 <span class="citation" data-cites="4IdGvvyC">[<a href="#ref-4IdGvvyC" role="doc-biblioref">608</a>]</span>.</p>
+The phase 1 trial, which was conducted in hospitalized COVID-19 patients, was completed in August 2020 <span class="citation" data-cites="4IdGvvyC">[<a href="#ref-4IdGvvyC" role="doc-biblioref">607</a>]</span>.</p>
 <p>Estesevimab (LY-CoV016 or JS-016) is also a monoclonal neutralizing antibody against the spike protein of SARS-CoV-2.
 It was initially developed by Junshi Biosciences and later licensed and developed through Eli Lilly.
-A phase 1 clinical trial to assess the safety of etesevimab was completed in October 2020 <span class="citation" data-cites="coZGelVr">[<a href="#ref-coZGelVr" role="doc-biblioref">609</a>]</span>.
-Etesevimab was shown to bind a different epitope on the spike protein than bamlanivimab, suggesting that the two antibodies used as a combination therapy would further enhance their clinical use compared to a monotherapy <span class="citation" data-cites="Gwct8aFG">[<a href="#ref-Gwct8aFG" role="doc-biblioref">610</a>]</span>.</p>
-<p>To assess the efficacy and safety of bamlanivimab alone or in combination with etesevimab for the treatment of COVID-19, a phase 2/3 trial (BLAZE-1) <span class="citation" data-cites="f6m2SeLi">[<a href="#ref-f6m2SeLi" role="doc-biblioref">611</a>]</span> was initiated.
-The interim analysis of the phase 2 portion suggested that bamlanivimab alone was able to reduce accelerate the reduction in viral load <span class="citation" data-cites="Cblh7jlS">[<a href="#ref-Cblh7jlS" role="doc-biblioref">612</a>]</span>.
-However, more recent data suggests that only the bamlanivimab/etesevimab combination therapy is able to reduce viral load in COVID-19 patients <span class="citation" data-cites="Gwct8aFG">[<a href="#ref-Gwct8aFG" role="doc-biblioref">610</a>]</span>.
+A phase 1 clinical trial to assess the safety of etesevimab was completed in October 2020 <span class="citation" data-cites="coZGelVr">[<a href="#ref-coZGelVr" role="doc-biblioref">608</a>]</span>.
+Etesevimab was shown to bind a different epitope on the spike protein than bamlanivimab, suggesting that the two antibodies used as a combination therapy would further enhance their clinical use compared to a monotherapy <span class="citation" data-cites="Gwct8aFG">[<a href="#ref-Gwct8aFG" role="doc-biblioref">609</a>]</span>.</p>
+<p>To assess the efficacy and safety of bamlanivimab alone or in combination with etesevimab for the treatment of COVID-19, a phase 2/3 trial (BLAZE-1) <span class="citation" data-cites="f6m2SeLi">[<a href="#ref-f6m2SeLi" role="doc-biblioref">610</a>]</span> was initiated.
+The interim analysis of the phase 2 portion suggested that bamlanivimab alone was able to reduce accelerate the reduction in viral load <span class="citation" data-cites="Cblh7jlS">[<a href="#ref-Cblh7jlS" role="doc-biblioref">611</a>]</span>.
+However, more recent data suggests that only the bamlanivimab/etesevimab combination therapy is able to reduce viral load in COVID-19 patients <span class="citation" data-cites="Gwct8aFG">[<a href="#ref-Gwct8aFG" role="doc-biblioref">609</a>]</span>.
 Based on this data, the combination therapy received emergency use authorization for COVID-19 from the FDA in February of 2021.</p>
 <h4 data-number="5.5.2.2" id="casirivimab-and-imdevimab-regn-cov2"><span class="header-section-number">5.5.2.2</span> Casirivimab and Imdevimab (REGN-COV2)</h4>
 <p>Casirivimab (REGN10933) and imdevimab (REGN10987) are two monoclonal antibodies against the SARS-CoV-2 spike protein.
-They were both developed by Regeneron in a parallel high-throughput screen to identify neutralizing antibodies from either humanized mice or patient-derived convalescent plasma <span class="citation" data-cites="fom0jw7s">[<a href="#ref-fom0jw7s" role="doc-biblioref">613</a>]</span>.
+They were both developed by Regeneron in a parallel high-throughput screen to identify neutralizing antibodies from either humanized mice or patient-derived convalescent plasma <span class="citation" data-cites="fom0jw7s">[<a href="#ref-fom0jw7s" role="doc-biblioref">612</a>]</span>.
 In these efforts, multiple antibodies were characterized for their ability to bind and neutralize the SARS-CoV-2 spike protein.
 The authors hypothesized that an antibody cocktail, rather than each individual antibody, could increase the therapeutic efficacy while minimizing the risk for virus escape.
 Therefore, the authors tested pairs of individual antibodies for their ability to simultaneously bind the RBD of the spike protein.
-Based on this data, casirivimab and imdevimab were identified as the lead antibody pair, resulting in the initiation of two clinical trials <span class="citation" data-cites="Tn0PkRlx 1stdSBxx">[<a href="#ref-Tn0PkRlx" role="doc-biblioref">614</a>,<a href="#ref-1stdSBxx" role="doc-biblioref">615</a>]</span>.
-Data from this phase 1-3 trial published in the <em>New England Journal of Medicine</em> shows that the REGN-COV2 antibody cocktail reduced viral load, particularly in patients with high viral load or whose endogenous immune response had not yet been initiated <span class="citation" data-cites="Mc2i06U">[<a href="#ref-Mc2i06U" role="doc-biblioref">616</a>]</span>.
+Based on this data, casirivimab and imdevimab were identified as the lead antibody pair, resulting in the initiation of two clinical trials <span class="citation" data-cites="Tn0PkRlx 1stdSBxx">[<a href="#ref-Tn0PkRlx" role="doc-biblioref">613</a>,<a href="#ref-1stdSBxx" role="doc-biblioref">614</a>]</span>.
+Data from this phase 1-3 trial published in the <em>New England Journal of Medicine</em> shows that the REGN-COV2 antibody cocktail reduced viral load, particularly in patients with high viral load or whose endogenous immune response had not yet been initiated <span class="citation" data-cites="Mc2i06U">[<a href="#ref-Mc2i06U" role="doc-biblioref">615</a>]</span>.
 However, in patients who already initiated an immune response, exogenous addition of REGN-COV2 did not improve the endogenous immune response.
 Both doses were well tolerated with no serious events related to the antibody cocktail.
 Based on this data, the FDA granted emergency use authorization for REGN-COV2 in patients with mild to moderate COVID-19 who are at risk to develop severe disease.
-Ongoing efforts are trying to evaluate the efficacy of REGN-COV2 to improve clinical outcomes in hospitalized patients <span class="citation" data-cites="Tn0PkRlx">[<a href="#ref-Tn0PkRlx" role="doc-biblioref">614</a>]</span>.</p>
+Ongoing efforts are trying to evaluate the efficacy of REGN-COV2 to improve clinical outcomes in hospitalized patients <span class="citation" data-cites="Tn0PkRlx">[<a href="#ref-Tn0PkRlx" role="doc-biblioref">613</a>]</span>.</p>
 <h4 data-number="5.5.2.3" id="viral-resistance-to-neutralizing-antibodies"><span class="header-section-number">5.5.2.3</span> Viral Resistance to Neutralizing Antibodies</h4>
 <p>With the ongoing global spread of new SARS-CoV-2 variants, there is a growing concern that mutations in SARS-CoV-2 spike protein could escape antibody neutralization, thereby reducing the efficacy of monoclonal antibody therapeutics and vaccines.
-A comprehensive mutagenesis screen recently identified several amino acid substitutions in the SARS-CoV-2 spike protein that can prevent antibody neutralization <span class="citation" data-cites="1FtcInMeU">[<a href="#ref-1FtcInMeU" role="doc-biblioref">617</a>]</span>.
+A comprehensive mutagenesis screen recently identified several amino acid substitutions in the SARS-CoV-2 spike protein that can prevent antibody neutralization <span class="citation" data-cites="1FtcInMeU">[<a href="#ref-1FtcInMeU" role="doc-biblioref">616</a>]</span>.
 While some mutations result in resistance to only one antibody, others confer broad resistance to multiple monoclonal antibodies as well as polyclonal human sera, suggesting that some amino acids are “hotspots” for antibody resistance.
 However, it was not investigated whether the resistant mutations identified result in a fitness advantage.
-Accordingly, an impact on neutralizing efficiency has been reported for the emerging UK (B.1.1.7) and South Africa (B.1.351) variants <span class="citation" data-cites="g9k7N6ig ZDM0wbnx K18v3qZ">[<a href="#ref-g9k7N6ig" role="doc-biblioref">618</a>,<a href="#ref-ZDM0wbnx" role="doc-biblioref">619</a>,<a href="#ref-K18v3qZ" role="doc-biblioref">620</a>]</span>.
+Accordingly, an impact on neutralizing efficiency has been reported for the emerging UK (B.1.1.7) and South Africa (B.1.351) variants <span class="citation" data-cites="g9k7N6ig ZDM0wbnx K18v3qZ">[<a href="#ref-g9k7N6ig" role="doc-biblioref">617</a>,<a href="#ref-ZDM0wbnx" role="doc-biblioref">618</a>,<a href="#ref-K18v3qZ" role="doc-biblioref">619</a>]</span>.
 While the reported impact on antibody neutralization needs to be confirmed <em>in vivo</em>, it suggests that some adjustments to therapeutic antibody treatments may be necessary to maintain the efficacy that was reported in previous clinical trials.</p>
 <p>Antibody cocktails such as REGN-COV2, CT-P59, and AZD7442 have been developed to overcome the risk for attenuation of neutralizing activity of a single monoclonal antibody.
 These cocktails consist of antibodies that recognize different epitopes on the spike protein, decreasing the likelihood that a single amino acid change can cause resistance to all antibodies in the cocktail.
-However, neutralizing resistance can emerge even against an antibody cocktail if the individual antibodies target subdominant epitopes <span class="citation" data-cites="ZDM0wbnx">[<a href="#ref-ZDM0wbnx" role="doc-biblioref">619</a>]</span>.</p>
-<p>Another strategy is to develop broadly neutralizing antibodies that target structures that are highly conserved, as these are less likely to mutate <span class="citation" data-cites="tnF7yB6H 1Dj5HnmXS">[<a href="#ref-tnF7yB6H" role="doc-biblioref">621</a>,<a href="#ref-1Dj5HnmXS" role="doc-biblioref">622</a>]</span> or to target epitopes that are insensitive to mutations <span class="citation" data-cites="NtlqU5Jy">[<a href="#ref-NtlqU5Jy" role="doc-biblioref">623</a>]</span>.
-One such antibody (ADG-2) has recently been reported <span class="citation" data-cites="B1wzHRpt">[<a href="#ref-B1wzHRpt" role="doc-biblioref">624</a>]</span>.
+However, neutralizing resistance can emerge even against an antibody cocktail if the individual antibodies target subdominant epitopes <span class="citation" data-cites="ZDM0wbnx">[<a href="#ref-ZDM0wbnx" role="doc-biblioref">618</a>]</span>.</p>
+<p>Another strategy is to develop broadly neutralizing antibodies that target structures that are highly conserved, as these are less likely to mutate <span class="citation" data-cites="tnF7yB6H 1Dj5HnmXS">[<a href="#ref-tnF7yB6H" role="doc-biblioref">620</a>,<a href="#ref-1Dj5HnmXS" role="doc-biblioref">621</a>]</span> or to target epitopes that are insensitive to mutations <span class="citation" data-cites="NtlqU5Jy">[<a href="#ref-NtlqU5Jy" role="doc-biblioref">622</a>]</span>.
+One such antibody (ADG-2) has recently been reported <span class="citation" data-cites="B1wzHRpt">[<a href="#ref-B1wzHRpt" role="doc-biblioref">623</a>]</span>.
 This antibody targets a highly conserved epitope that overlaps the hACE2 binding site of all clade 1 sarbecoviruses.
 Prophylactic administration of ADG-2 in an immunocompetent mouse model of COVID-19 resulted in protection against viral replication in the lungs and respiratory burden.
 Since the epitope targeted by ADG-2 represents an Achilles’ heel for clade 1 sarbecoviruses, this antibody might be a promising candidate against all circulating variants as well as emerging SARS-related coronaviruses.</p>
@@ -2360,28 +2360,28 @@ <h4 data-number="5.5.2.3" id="viral-resistance-to-neutralizing-antibodies"><span
 <h3 data-number="5.5.3" id="interferons"><span class="header-section-number">5.5.3</span> Interferons</h3>
 <p>IFNs are a family of cytokines critical to activating the innate immune response against viral infections.
 Interferons are classified into three categories based on their receptor specificity: types I, II and III <span class="citation" data-cites="bZMKqj6e">[<a href="#ref-bZMKqj6e" role="doc-biblioref">148</a>]</span>.
-Specifically, IFNs I (IFN-𝛼 and 𝛽) and II (IFN-𝛾) induce the expression of antiviral proteins <span class="citation" data-cites="LtFtUo2P">[<a href="#ref-LtFtUo2P" role="doc-biblioref">625</a>]</span>.
-Among these IFNs, IFN-𝛽 has already been found to strongly inhibit the replication of other coronaviruses, such as SARS-CoV-1, in cell culture, while IFN-𝛼 and 𝛾 were shown to be less effective in this context <span class="citation" data-cites="LtFtUo2P">[<a href="#ref-LtFtUo2P" role="doc-biblioref">625</a>]</span>.
+Specifically, IFNs I (IFN-𝛼 and 𝛽) and II (IFN-𝛾) induce the expression of antiviral proteins <span class="citation" data-cites="LtFtUo2P">[<a href="#ref-LtFtUo2P" role="doc-biblioref">624</a>]</span>.
+Among these IFNs, IFN-𝛽 has already been found to strongly inhibit the replication of other coronaviruses, such as SARS-CoV-1, in cell culture, while IFN-𝛼 and 𝛾 were shown to be less effective in this context <span class="citation" data-cites="LtFtUo2P">[<a href="#ref-LtFtUo2P" role="doc-biblioref">624</a>]</span>.
 There is evidence that patients with higher susceptibility to ARDS indeed show deficiency in IFN-𝛽.
-For instance, infection with other coronaviruses impairs IFN-𝛽 expression and synthesis, allowing the virus to escape the innate immune response <span class="citation" data-cites="Nfu9kiae">[<a href="#ref-Nfu9kiae" role="doc-biblioref">626</a>]</span>.
-On March 18 2020, Synairgen plc received approval to start a phase II trial for SNG001, an IFN-𝛽-1a formulation to be delivered to the lungs via inhalation <span class="citation" data-cites="5GxCGzrT">[<a href="#ref-5GxCGzrT" role="doc-biblioref">627</a>]</span>.
-SNG001, which contains recombinant interferon beta-1a, was previously shown to be effective in reducing viral load in an <em>in vivo</em> model of swine flu and <em>in vitro</em> models of other coronavirus infections <span class="citation" data-cites="7k9Wp9or">[<a href="#ref-7k9Wp9or" role="doc-biblioref">628</a>]</span>.
-In July, a press release from Synairgen stated that SNG001 reduced progression to ventilation in a double-blind, placebo-controlled, multi-center study of 101 patients with an average age in the late 50s <span class="citation" data-cites="bD1bgfSb">[<a href="#ref-bD1bgfSb" role="doc-biblioref">629</a>]</span>.
-These results were subsequently published in November 2020 <span class="citation" data-cites="qFDbLzcP">[<a href="#ref-qFDbLzcP" role="doc-biblioref">630</a>]</span>.
+For instance, infection with other coronaviruses impairs IFN-𝛽 expression and synthesis, allowing the virus to escape the innate immune response <span class="citation" data-cites="Nfu9kiae">[<a href="#ref-Nfu9kiae" role="doc-biblioref">625</a>]</span>.
+On March 18 2020, Synairgen plc received approval to start a phase II trial for SNG001, an IFN-𝛽-1a formulation to be delivered to the lungs via inhalation <span class="citation" data-cites="5GxCGzrT">[<a href="#ref-5GxCGzrT" role="doc-biblioref">626</a>]</span>.
+SNG001, which contains recombinant interferon beta-1a, was previously shown to be effective in reducing viral load in an <em>in vivo</em> model of swine flu and <em>in vitro</em> models of other coronavirus infections <span class="citation" data-cites="7k9Wp9or">[<a href="#ref-7k9Wp9or" role="doc-biblioref">627</a>]</span>.
+In July, a press release from Synairgen stated that SNG001 reduced progression to ventilation in a double-blind, placebo-controlled, multi-center study of 101 patients with an average age in the late 50s <span class="citation" data-cites="bD1bgfSb">[<a href="#ref-bD1bgfSb" role="doc-biblioref">628</a>]</span>.
+These results were subsequently published in November 2020 <span class="citation" data-cites="qFDbLzcP">[<a href="#ref-qFDbLzcP" role="doc-biblioref">629</a>]</span>.
 The study reports that the participants were assigned at a ratio of 1:1 to receive either SNG001 or a placebo that lacked the active compound, by inhalation for up to 14 days.
 The primary outcome they assessed was the change in patients’ score on the WHO Ordinal Scale for Clinical Improvement (OSCI) at trial day 15 or 16.
 SNG001 was associated with an odds ratio of improvement on the OSCI scale of 2.32 (95% CI 1.07 – 5.04, <em>p</em> = 0.033) in the intention-to-treat analysis and 2.80 (95% CI 1.21 – 6.52, <em>p</em> = 0.017) in the per-protocol analysis, corresponding to significant improvement in the SNG001 group on the OSCI at day 15/16.
 Some of the secondary endpoints analyzed also showed differences: at day 28, the OR for clinical improvement on the OSCI was 3.15 (95% CI 1.39 – 7.14, <em>p</em> = 0.006), and the odds of recovery at day 15/16 and at day 28 were also significant between the two groups.
 Thus, this study suggested that IFN-𝛽1 administered via SNG001 may improve clinical outcomes.</p>
-<p>In contrast, the WHO Solidarity trial reported no significant effect of IFN-𝛽1a on patient survival during hospitalization <span class="citation" data-cites="jShm9uhy">[<a href="#ref-jShm9uhy" role="doc-biblioref">432</a>]</span>.
+<p>In contrast, the WHO Solidarity trial reported no significant effect of IFN-𝛽1a on patient survival during hospitalization <span class="citation" data-cites="jShm9uhy">[<a href="#ref-jShm9uhy" role="doc-biblioref">431</a>]</span>.
 Here, the primary outcome analyzed was in-hospital mortality, and the rate ratio for the two groups was 1.16 (95% CI, 0.96 to 1.39; <em>p</em> = 0.11) administering IFN-𝛽-1a to 2050 patients and comparing their response to 2,050 controls.
 However, there are a few reasons that the different findings of the two trials might not speak to the underlying efficacy of this treatment strategy.
 One important consideration is the stage of COVID-19 infection analyzed in each study.
-The Synairgen trial enrolled only patients who were not receiving invasive ventilation, corresponding to a less severe stage of disease than many patients enrolled in the SOLIDARITY trial, as well as a lower overall rate of mortality <span class="citation" data-cites="11hbhD5Rk">[<a href="#ref-11hbhD5Rk" role="doc-biblioref">631</a>]</span>.
-Additionally, the methods of administration differed between the two trials, with the SOLIDARITY trial administering IFN-𝛽-1a subcutaneously <span class="citation" data-cites="11hbhD5Rk">[<a href="#ref-11hbhD5Rk" role="doc-biblioref">631</a>]</span>.
+The Synairgen trial enrolled only patients who were not receiving invasive ventilation, corresponding to a less severe stage of disease than many patients enrolled in the SOLIDARITY trial, as well as a lower overall rate of mortality <span class="citation" data-cites="11hbhD5Rk">[<a href="#ref-11hbhD5Rk" role="doc-biblioref">630</a>]</span>.
+Additionally, the methods of administration differed between the two trials, with the SOLIDARITY trial administering IFN-𝛽-1a subcutaneously <span class="citation" data-cites="11hbhD5Rk">[<a href="#ref-11hbhD5Rk" role="doc-biblioref">630</a>]</span>.
 The differences in findings between the studies suggests that the method of administration might be relevant to outcomes, with nebulized IFN-𝛽-1a more directly targeting receptors in the lungs.
-A trial that analyzed the effect of subcutaneously administered IFN-β-1a on patients with ARDS between 2015 and 2017 had also reported no effect on 28-day mortality <span class="citation" data-cites="B2urVDo5">[<a href="#ref-B2urVDo5" role="doc-biblioref">632</a>]</span>, while a smaller study analyzing the effect of subcutaneous IFN administration did find a significant improvement in 28-day mortality for COVID-19 <span class="citation" data-cites="xMRJgRES">[<a href="#ref-xMRJgRES" role="doc-biblioref">633</a>]</span>.
-At present, several ongoing clinical trials are investigating the potential effects of IFN-𝛽-1a, including in combination with therapeutics such as remdesivir <span class="citation" data-cites="17so9kzfj">[<a href="#ref-17so9kzfj" role="doc-biblioref">634</a>]</span> and administered via inhalation <span class="citation" data-cites="5GxCGzrT">[<a href="#ref-5GxCGzrT" role="doc-biblioref">627</a>]</span>.
+A trial that analyzed the effect of subcutaneously administered IFN-β-1a on patients with ARDS between 2015 and 2017 had also reported no effect on 28-day mortality <span class="citation" data-cites="B2urVDo5">[<a href="#ref-B2urVDo5" role="doc-biblioref">631</a>]</span>, while a smaller study analyzing the effect of subcutaneous IFN administration did find a significant improvement in 28-day mortality for COVID-19 <span class="citation" data-cites="xMRJgRES">[<a href="#ref-xMRJgRES" role="doc-biblioref">632</a>]</span>.
+At present, several ongoing clinical trials are investigating the potential effects of IFN-𝛽-1a, including in combination with therapeutics such as remdesivir <span class="citation" data-cites="17so9kzfj">[<a href="#ref-17so9kzfj" role="doc-biblioref">633</a>]</span> and administered via inhalation <span class="citation" data-cites="5GxCGzrT">[<a href="#ref-5GxCGzrT" role="doc-biblioref">626</a>]</span>.
 Thus, as additional information becomes available, a more detailed understanding of whether and under which circumstances IFN-𝛽-1a is beneficial to COVID-19 patients should develop.</p>
 <h2 data-number="5.6" id="discussion"><span class="header-section-number">5.6</span> Discussion</h2>
 <p>With the emergence of the COVID-19 pandemic caused by the coronavirus SARS-CoV-2, the development and identification of therapeutic and prophylactic interventions became issues of international urgency.
@@ -2400,47 +2400,47 @@ <h2 data-number="5.6" id="discussion"><span class="header-section-number">5.6</s
 <p>Insights into the pathogenesis of and immune response to SARS-CoV-2 (see <span class="citation" data-cites="r366f5T3">[<a href="#ref-r366f5T3" role="doc-biblioref">1</a>]</span>) have also guided the identification of potential prophylactics and therapeutics.
 As cases have become better characterized, it has become evident that many patients experience an initial immune response to the virus that is typically characterized by fever, cough, dyspnea, and related symptoms.
 However, the most serious concern is CRS, when the body’s immune response becomes dysregulated, resulting in an extreme inflammatory response.
-The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation <span class="citation" data-cites="pzQoUwz3">[<a href="#ref-pzQoUwz3" role="doc-biblioref">554</a>]</span>.
+The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation <span class="citation" data-cites="pzQoUwz3">[<a href="#ref-pzQoUwz3" role="doc-biblioref">553</a>]</span>.
 The results of efforts to identify therapeutic treatments to treat patients early in the course of infection have been more ambiguous.
 Early interest in the drugs HCQ and CQ yielded no promising results from studies with robust experimental designs.
 On the other hand, the experimental drug remdesivir, which was developed as a candidate therapeutic for EVD, has received enough support from early analyses to receive FDA approval, although results have been mixed.
 The potential for other drugs, such as tocilizumab, to reduce recovery time remains unclear, but some early results were promising.</p>
 <p>One additional concern is that the presentation of COVID-19 appears to be heterogeneous across the lifespan.
 Many adult cases, especially in younger adults, present with mild symptoms or even asymptomatically, while others, especially in older adults, can be severe or fatal.
-In children, the SARS-CoV-2 viral infection can present either as a respiratory illness comparable to COVID-19 or as an inflammatory condition, known as multisystem inflammatory syndrome in children, for which presentation is similar to Kawasaki Disease <span class="citation" data-cites="8L30aBV7">[<a href="#ref-8L30aBV7" role="doc-biblioref">635</a>]</span>.
+In children, the SARS-CoV-2 viral infection can present either as a respiratory illness comparable to COVID-19 or as an inflammatory condition, known as multisystem inflammatory syndrome in children, for which presentation is similar to Kawasaki Disease <span class="citation" data-cites="8L30aBV7">[<a href="#ref-8L30aBV7" role="doc-biblioref">634</a>]</span>.
 The therapeutics and prophylactics discussed here were primarily tested in adults, and additional research is needed to identify therapeutics that address the symptoms characteristic of pediatric COVID-19 and MIS-C cases.</p>
 <h3 data-number="5.6.1" id="potential-avenues-of-interest-for-therapeutic-development"><span class="header-section-number">5.6.1</span> Potential Avenues of Interest for Therapeutic Development</h3>
 <p>Given what is currently known about these therapeutics for COVID-19, a number of related therapies beyond those explored above may also prove to be of interest.
 For example, the demonstrated benefit of dexamethasone and the ongoing potential of tocilizumab for treatment of COVID-19 suggests that other anti-inflammatory agents might also hold value for the treatment of COVID-19.
 Current evidence supporting the treatment of severe COVID-19 with dexamethasone suggests that the need to curtail the cytokine storm inflammatory response transcends the risks of immunosuppression, and other anti-inflammatory agents may therefore benefit patients in this phase of the disease.
 While dexamethasone is considered widely available and generally affordable, the high costs of biologics such as tocilizumab therapy may present obstacles to wide-scale distribution of this drug if it proves of value.
-At the doses used for RA patients, the cost for tocilizumab ranges from $179.20 to $896 per dose for the IV form and $355 for the pre-filled syringe <span class="citation" data-cites="7fZ9eyMk">[<a href="#ref-7fZ9eyMk" role="doc-biblioref">636</a>]</span>.
-Several other anti-inflammatory agents used for the treatment of autoimmune diseases may also be able to counter the effects of the cytokine storm induced by the virus, and some of these, such as cyclosporine, are likely to be more cost-effective and readily available than biologics <span class="citation" data-cites="trWLoLFz">[<a href="#ref-trWLoLFz" role="doc-biblioref">637</a>]</span>.
+At the doses used for RA patients, the cost for tocilizumab ranges from $179.20 to $896 per dose for the IV form and $355 for the pre-filled syringe <span class="citation" data-cites="7fZ9eyMk">[<a href="#ref-7fZ9eyMk" role="doc-biblioref">635</a>]</span>.
+Several other anti-inflammatory agents used for the treatment of autoimmune diseases may also be able to counter the effects of the cytokine storm induced by the virus, and some of these, such as cyclosporine, are likely to be more cost-effective and readily available than biologics <span class="citation" data-cites="trWLoLFz">[<a href="#ref-trWLoLFz" role="doc-biblioref">636</a>]</span>.
 While tocilizumab targets IL-6, several other inflammatory markers could be potential targets, including TNF-α.
-Inhibition of TNF-α by a compound such as Etanercept was previously suggested for treatment of SARS-CoV-1 <span class="citation" data-cites="LDQlolY3">[<a href="#ref-LDQlolY3" role="doc-biblioref">638</a>]</span> and may be relevant for SARS-CoV-2 as well.
-Another anti-IL-6 antibody, sarilumab, is also being investigated <span class="citation" data-cites="4DAIEbQF amy3rDsj">[<a href="#ref-4DAIEbQF" role="doc-biblioref">639</a>,<a href="#ref-amy3rDsj" role="doc-biblioref">640</a>]</span>.
-Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections <span class="citation" data-cites="WF7ymA4m">[<a href="#ref-WF7ymA4m" role="doc-biblioref">641</a>]</span>.
-Baricitinib, in particular, may be able to reduce the ability of SARS-CoV-2 to infect lung cells <span class="citation" data-cites="uCns3aFw">[<a href="#ref-uCns3aFw" role="doc-biblioref">642</a>]</span>.
-Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy <span class="citation" data-cites="jKRGxazA JCMhG5r9">[<a href="#ref-jKRGxazA" role="doc-biblioref">643</a>,<a href="#ref-JCMhG5r9" role="doc-biblioref">644</a>]</span>.
+Inhibition of TNF-α by a compound such as Etanercept was previously suggested for treatment of SARS-CoV-1 <span class="citation" data-cites="LDQlolY3">[<a href="#ref-LDQlolY3" role="doc-biblioref">637</a>]</span> and may be relevant for SARS-CoV-2 as well.
+Another anti-IL-6 antibody, sarilumab, is also being investigated <span class="citation" data-cites="4DAIEbQF amy3rDsj">[<a href="#ref-4DAIEbQF" role="doc-biblioref">638</a>,<a href="#ref-amy3rDsj" role="doc-biblioref">639</a>]</span>.
+Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections <span class="citation" data-cites="WF7ymA4m">[<a href="#ref-WF7ymA4m" role="doc-biblioref">640</a>]</span>.
+Baricitinib, in particular, may be able to reduce the ability of SARS-CoV-2 to infect lung cells <span class="citation" data-cites="uCns3aFw">[<a href="#ref-uCns3aFw" role="doc-biblioref">641</a>]</span>.
+Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy <span class="citation" data-cites="jKRGxazA JCMhG5r9">[<a href="#ref-jKRGxazA" role="doc-biblioref">642</a>,<a href="#ref-JCMhG5r9" role="doc-biblioref">643</a>]</span>.
 Identification and targeting of further inflammatory markers that are relevant in SARS-CoV-2 infection may be of value for curtailing the inflammatory response and lung damage.</p>
 <p>In addition to immunosuppressive treatments, which are most beneficial late in disease progression, much research is focused on identifying therapeutics for early-stage patients.
 For example, although studies of HCQ have not supported the early theory-driven interest in this antiviral treatment, alternative compounds with related mechanisms may still have potential.
-Hydroxyferroquine derivatives of HCQ have been described as a class of bioorganometallic compounds that exert antiviral effects with some selectivity for SARS-CoV-1 <em>in vitro</em> <span class="citation" data-cites="Cd5uMaAr">[<a href="#ref-Cd5uMaAr" role="doc-biblioref">645</a>]</span>.
+Hydroxyferroquine derivatives of HCQ have been described as a class of bioorganometallic compounds that exert antiviral effects with some selectivity for SARS-CoV-1 <em>in vitro</em> <span class="citation" data-cites="Cd5uMaAr">[<a href="#ref-Cd5uMaAr" role="doc-biblioref">644</a>]</span>.
 Future work could explore whether such compounds exert antiviral effects against SARS-CoV-2 and whether they would be safer for use in COVID-19.
 Another potential approach is the development of antivirals, which could be broad-spectrum, specific to coronaviruses, or targeted to SARS-CoV-2.
 Development of new antivirals is complicated by the fact that none have yet been approved for human coronaviruses.
 Intriguing new options are emerging, however.
-Beta-D-N4-hydroxycytidine is an orally bioavailable ribonucleotide analog showing broad-spectrum activity against RNA viruses, which may inhibit SARS-CoV-2 replication <em>in vitro</em> and <em>in vivo</em> in mouse models of HCoVs <span class="citation" data-cites="TZleuwHX">[<a href="#ref-TZleuwHX" role="doc-biblioref">646</a>]</span>.
+Beta-D-N4-hydroxycytidine is an orally bioavailable ribonucleotide analog showing broad-spectrum activity against RNA viruses, which may inhibit SARS-CoV-2 replication <em>in vitro</em> and <em>in vivo</em> in mouse models of HCoVs <span class="citation" data-cites="TZleuwHX">[<a href="#ref-TZleuwHX" role="doc-biblioref">645</a>]</span>.
 A range of other antivirals are also in development.
 Development of antivirals will be further facilitated as research reveals more information about the interaction of SARS-CoV-2 with the host cell and host cell genome, mechanisms of viral replication, mechanisms of viral assembly, and mechanisms of viral release to other cells; this can allow researchers to target specific stages and structures of the viral life cycle.
 Finally, antibodies against viruses, also known as antiviral monoclonal antibodies, could be an alternative as well and are described in detail in an above section.
-The goal of antiviral antibodies is to neutralize viruses through either cell-killing activity or blocking of viral replication <span class="citation" data-cites="1FTnvyZlf">[<a href="#ref-1FTnvyZlf" role="doc-biblioref">647</a>]</span>.
+The goal of antiviral antibodies is to neutralize viruses through either cell-killing activity or blocking of viral replication <span class="citation" data-cites="1FTnvyZlf">[<a href="#ref-1FTnvyZlf" role="doc-biblioref">646</a>]</span>.
 They may also engage the host immune response, encouraging the immune system to hone in on the virus.
 Given the cytokine storm that results from immune system activation in response to the virus, which has been implicated in worsening of the disease, an nAb may be preferable.
 Upcoming work may explore the specificity of nAbs for their target, mechanisms by which the nAbs impede the virus, and improvements to antibody structure that may enhance the ability of the antibody to block viral activity.</p>
 <p>Some research is also investigating potential therapeutics and prophylactics that would interact with components of the innate immune response.
 For example, TLRs are pattern recognition receptors that recognize pathogen- and damage-associated molecular patterns and contribute to innate immune recognition and, more generally, promotion of both the innate and adaptive immune responses <span class="citation" data-cites="o6BQnEt7">[<a href="#ref-o6BQnEt7" role="doc-biblioref">144</a>]</span>.
-In mouse models, poly(I:C) and CpG, which are agonists of Toll-like receptors TLR3 and TLR9, respectively, showed protective effects when administered prior to SARS-CoV-1 infection <span class="citation" data-cites="Ull2rQ5L">[<a href="#ref-Ull2rQ5L" role="doc-biblioref">648</a>]</span>.
+In mouse models, poly(I:C) and CpG, which are agonists of Toll-like receptors TLR3 and TLR9, respectively, showed protective effects when administered prior to SARS-CoV-1 infection <span class="citation" data-cites="Ull2rQ5L">[<a href="#ref-Ull2rQ5L" role="doc-biblioref">647</a>]</span>.
 Therefore, TLR agonists hold some potential for broad-spectrum prophylaxis.</p>
 <p>Given that a large number of clinical trials are currently in progress, more information about the potential of these and other therapeutics should become available over time.
 This information, combined with advances in understanding the molecular structure and viral pathogenesis of SARS-CoV-2, may lead to a more complete understanding of how the virus affects the human host and what strategies can improve outcomes.
@@ -2449,7 +2449,7 @@ <h3 data-number="5.6.1" id="potential-avenues-of-interest-for-therapeutic-develo
 However, in the long-term, new drugs specific for treatment of COVID-19 may also enter development.
 Development of novel drugs is likely to be guided by what is known about the pathogenesis and molecular structure of SARS-CoV-2.
 For example, understanding the various structural components of SARS-CoV-2 may allow for the development of small molecule inhibitors of those components.
-Currently, crystal structures of the SARS-CoV-2 main protease have recently been resolved <span class="citation" data-cites="4Sja6dIz AJLaaguT">[<a href="#ref-4Sja6dIz" role="doc-biblioref">467</a>,<a href="#ref-AJLaaguT" role="doc-biblioref">649</a>]</span>, and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">467</a>]</span>.
+Currently, crystal structures of the SARS-CoV-2 main protease have recently been resolved <span class="citation" data-cites="4Sja6dIz AJLaaguT">[<a href="#ref-4Sja6dIz" role="doc-biblioref">466</a>,<a href="#ref-AJLaaguT" role="doc-biblioref">648</a>]</span>, and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">466</a>]</span>.
 Much work remains to be done to determine further crystal structures of other viral components, understand the relative utility of targeting different viral components, perform additional small molecule inhibitor screens, and determine the safety and efficacy of the potential inhibitors.
 While still nascent, work in this area is promising.
 Over the longer term, this approach and others may lead to the development of novel therapeutics specifically for COVID-19 and SARS-CoV-2.<!-- This section could be updated with most recent information on drug discovery efforts --></p>
@@ -2573,25 +2573,25 @@ <h2 data-number="6.2" id="importance-3"><span class="header-section-number">6.2<
 These technologies have revolutionized the timescale at which countries can mount a response to an emerging viral threat and provide potential for mitigating of future threats before their damage reaches the levels caused by SARS-CoV-2.</p>
 <h2 data-number="6.3" id="introduction-5"><span class="header-section-number">6.3</span> Introduction</h2>
 <p>The development of vaccines is widely considered one of the most important medical advances in recent human history.
-Over the past 150 years, the approaches available for the development of vaccines have diversified rapidly <span class="citation" data-cites="YY3x3bBV">[<a href="#ref-YY3x3bBV" role="doc-biblioref">650</a>]</span>.
+Over the past 150 years, the approaches available for the development of vaccines have diversified rapidly <span class="citation" data-cites="YY3x3bBV">[<a href="#ref-YY3x3bBV" role="doc-biblioref">649</a>]</span>.
 Since the turn of the millennium, particular interest has emerged in the potential to develop vaccines as a rapid response to emerging threats.
-Severe acute respiratory syndrome (SARS), “swine flu” (H1N1), Middle East respiratory syndrome (MERS), and Ebola all underscored the importance of a rapid global response to a new infectious virus, but the vaccine development process has historically been slow, and vaccines fail to provide immediate prophylactic protection or treat ongoing infections <span class="citation" data-cites="181QWa7HL">[<a href="#ref-181QWa7HL" role="doc-biblioref">651</a>]</span>.
+Severe acute respiratory syndrome (SARS), “swine flu” (H1N1), Middle East respiratory syndrome (MERS), and Ebola all underscored the importance of a rapid global response to a new infectious virus, but the vaccine development process has historically been slow, and vaccines fail to provide immediate prophylactic protection or treat ongoing infections <span class="citation" data-cites="181QWa7HL">[<a href="#ref-181QWa7HL" role="doc-biblioref">650</a>]</span>.
 However, the <em>Severe acute respiratory syndrome-related coronavirus 2</em> (SARS-CoV-2) pandemic has highlighted a confluence of circumstances that positioned vaccine development as a key player in efforts to control the virus and mitigate its damage.
 Examining the vaccine development programs that emerged in 2020 alongside other 21st century efforts to control emerging viral threats demonstrates the significant biotechnological advances in this field.<!--To Do: awkward phrasing--></p>
 <h2 data-number="6.4" id="historical-vaccine-development"><span class="header-section-number">6.4</span> Historical Vaccine Development</h2>
 <!--To Do: This first paragraph could probably use a little fleshing out since a lot of it is based on one source, but just to give an idea-->
-<p>The first vaccination strategy in human history is widely considered to be the practice of variolation, which makes the history of vaccine development almost 500 years long <span class="citation" data-cites="Q10m9bJ 1Clt2Bek3">[<a href="#ref-Q10m9bJ" role="doc-biblioref">652</a>,<a href="#ref-1Clt2Bek3" role="doc-biblioref">653</a>]</span>.
-Famously employed as a strategy to improve survival of smallpox by, for example, exposing a healthy individual to pus from a smallpox pustule <span class="citation" data-cites="Q10m9bJ 1Clt2Bek3">[<a href="#ref-Q10m9bJ" role="doc-biblioref">652</a>,<a href="#ref-1Clt2Bek3" role="doc-biblioref">653</a>]</span>, variolation provides a mechanism for infecting a healthy individual with a mild case of a disease, allowing them to acquire adaptive immunity, but it also carries a number of risks for the recipient <span class="citation" data-cites="kC2tx3JC">[<a href="#ref-kC2tx3JC" role="doc-biblioref">654</a>]</span>.
-This approach was (debatably) the first example of a live-attenuated virus being used to induce immunity [<span class="citation" data-cites="kC2tx3JC"><a href="#ref-kC2tx3JC" role="doc-biblioref">654</a></span>; 10.1073/pnas.1400472111].
-Many subsequent efforts to develop live-attenuated viral vaccines relied on either the identification of related zoonotic viruses that are less virulent in humans (e.g., cowpox/horsepox or rotavirus vaccines) or efforts to attenuate the virus through culturing it <em>in vitro</em> <span class="citation" data-cites="YY3x3bBV">[<a href="#ref-YY3x3bBV" role="doc-biblioref">650</a>]</span>.
-This approach still carried risks, however <span class="citation" data-cites="YY3x3bBV">[<a href="#ref-YY3x3bBV" role="doc-biblioref">650</a>]</span>.
-Efforts to overcome the limitations of live-virus vaccines led to the development of approaches to inactivate viruses (circa 1900) and to purify proteins from viruses cultured in eggs (circa 1920) <span class="citation" data-cites="YY3x3bBV">[<a href="#ref-YY3x3bBV" role="doc-biblioref">650</a>]</span>.
-Inactivated viral vaccines still raised some concerns, however, including that back-mutations could potentially lead the inactivated vaccines to become virulent or that recombination could occur between the inactivated virus and other viruses in circulation<span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>]</span>.
-For example, errors in the manufacturing process that produced polio vaccines containing live polio virus led to a polio outbreak in the United States <span class="citation" data-cites="AOgZug76">[<a href="#ref-AOgZug76" role="doc-biblioref">656</a>]</span>.
-Additionally, one of the major limitations of inactivated whole virus vaccines is their susceptibility to lose efficacy due to mutations in the epitopes of the circulating virus <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>]</span>.
+<p>The first vaccination strategy in human history is widely considered to be the practice of variolation, which makes the history of vaccine development almost 500 years long <span class="citation" data-cites="Q10m9bJ 1Clt2Bek3">[<a href="#ref-Q10m9bJ" role="doc-biblioref">651</a>,<a href="#ref-1Clt2Bek3" role="doc-biblioref">652</a>]</span>.
+Famously employed as a strategy to improve survival of smallpox by, for example, exposing a healthy individual to pus from a smallpox pustule <span class="citation" data-cites="Q10m9bJ 1Clt2Bek3">[<a href="#ref-Q10m9bJ" role="doc-biblioref">651</a>,<a href="#ref-1Clt2Bek3" role="doc-biblioref">652</a>]</span>, variolation provides a mechanism for infecting a healthy individual with a mild case of a disease, allowing them to acquire adaptive immunity, but it also carries a number of risks for the recipient <span class="citation" data-cites="kC2tx3JC">[<a href="#ref-kC2tx3JC" role="doc-biblioref">653</a>]</span>.
+This approach was (debatably) the first example of a live-attenuated virus being used to induce immunity [<span class="citation" data-cites="kC2tx3JC"><a href="#ref-kC2tx3JC" role="doc-biblioref">653</a></span>; 10.1073/pnas.1400472111].
+Many subsequent efforts to develop live-attenuated viral vaccines relied on either the identification of related zoonotic viruses that are less virulent in humans (e.g., cowpox/horsepox or rotavirus vaccines) or efforts to attenuate the virus through culturing it <em>in vitro</em> <span class="citation" data-cites="YY3x3bBV">[<a href="#ref-YY3x3bBV" role="doc-biblioref">649</a>]</span>.
+This approach still carried risks, however <span class="citation" data-cites="YY3x3bBV">[<a href="#ref-YY3x3bBV" role="doc-biblioref">649</a>]</span>.
+Efforts to overcome the limitations of live-virus vaccines led to the development of approaches to inactivate viruses (circa 1900) and to purify proteins from viruses cultured in eggs (circa 1920) <span class="citation" data-cites="YY3x3bBV">[<a href="#ref-YY3x3bBV" role="doc-biblioref">649</a>]</span>.
+Inactivated viral vaccines still raised some concerns, however, including that back-mutations could potentially lead the inactivated vaccines to become virulent or that recombination could occur between the inactivated virus and other viruses in circulation<span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>]</span>.
+For example, errors in the manufacturing process that produced polio vaccines containing live polio virus led to a polio outbreak in the United States <span class="citation" data-cites="AOgZug76">[<a href="#ref-AOgZug76" role="doc-biblioref">655</a>]</span>.
+Additionally, one of the major limitations of inactivated whole virus vaccines is their susceptibility to lose efficacy due to mutations in the epitopes of the circulating virus <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>]</span>.
 <!--To Do: Add in protein subunit-->
-With the increased feasibility of genetic research in the 1980s came the application of genetic engineering to vaccine development, which allowed for the growth of the gene sequences of specific viral antigens <em>in vitro</em> <span class="citation" data-cites="YY3x3bBV">[<a href="#ref-YY3x3bBV" role="doc-biblioref">650</a>]</span>.
-While vaccine development strategies such as live-attenuation, inactivation, and protein subunit purification<!--To Do: correct?--> remain in use in the 21st century <span class="citation" data-cites="YY3x3bBV">[<a href="#ref-YY3x3bBV" role="doc-biblioref">650</a>]</span>, approaches built off of the principles of genetic engineering offer some of the most dynamic opportunities in the field of modern vaccine development.</p>
+With the increased feasibility of genetic research in the 1980s came the application of genetic engineering to vaccine development, which allowed for the growth of the gene sequences of specific viral antigens <em>in vitro</em> <span class="citation" data-cites="YY3x3bBV">[<a href="#ref-YY3x3bBV" role="doc-biblioref">649</a>]</span>.
+While vaccine development strategies such as live-attenuation, inactivation, and protein subunit purification<!--To Do: correct?--> remain in use in the 21st century <span class="citation" data-cites="YY3x3bBV">[<a href="#ref-YY3x3bBV" role="doc-biblioref">649</a>]</span>, approaches built off of the principles of genetic engineering offer some of the most dynamic opportunities in the field of modern vaccine development.</p>
 <h2 data-number="6.5" id="st-century-approaches-to-vaccine-development"><span class="header-section-number">6.5</span> 21st Century Approaches to Vaccine Development</h2>
 <div id="fig:vaccines" class="fignos">
 <figure>
@@ -2604,53 +2604,53 @@ <h2 data-number="6.5" id="st-century-approaches-to-vaccine-development"><span cl
 <p>While traditional methods of vaccine development such as inactivated whole viruses are still used today (Figure <a href="#fig:vaccines">5</a>), biomedical research in the 21st century has been significantly influenced by the genomic revolution, and vaccine development is no exception.
 <!--To Do: note which methods had produced successful vaccines in the 1900s and which were new in the genomic era.-->
 Building on the advances in vaccine development that came out of genetic engineering, several newer approaches to vaccine development today utilize information available in the DNA sequence of a virus (Figure <a href="#fig:vaccines">5</a>).
-In traditional DNA vaccines, the sequence encoding the antigen(s) against which an immune response is sought can be cultivated in a plasmid and delivered directly to an appropriate tissue <span class="citation" data-cites="XnrBoKVk">[<a href="#ref-XnrBoKVk" role="doc-biblioref">657</a>]</span>.
+In traditional DNA vaccines, the sequence encoding the antigen(s) against which an immune response is sought can be cultivated in a plasmid and delivered directly to an appropriate tissue <span class="citation" data-cites="XnrBoKVk">[<a href="#ref-XnrBoKVk" role="doc-biblioref">656</a>]</span>.
 Plasmids are not the only vector that can be used to deliver sequences associated with viral antigens: genetic material from the target virus can also be delivered using a second virus as a vector.
-Once the plasmid or viral vector brings the DNA sequence to an antigen presenting cell (APC), the host machinery can be used to construct antigen(s) from the transported genetic material, and the body can then synthesize antibodies in response <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>]</span>.
+Once the plasmid or viral vector brings the DNA sequence to an antigen presenting cell (APC), the host machinery can be used to construct antigen(s) from the transported genetic material, and the body can then synthesize antibodies in response <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>]</span>.
 More recently, interest has also emerged the potential for viral RNA to induce an immune response (Figure <a href="#fig:vaccines">5</a>).
 This approach operates one level above the DNA: instead of directly furnishing the gene sequence associated with an antigen to the host, it provides the messenger RNA (mRNA) transcribed from the DNA sequence.
-Some of the potential advantages of mRNA compared to DNA include safety (it cannot be integrated by the host and the half life can be regulated), it avoids any issues of a host immune response against the vector, and it holds the potential to dramatically accelerate vaccine manufacturing and development <span class="citation" data-cites="ENBWnhAh">[<a href="#ref-ENBWnhAh" role="doc-biblioref">659</a>]</span>.
-However, all of these approaches may offer several advantages over vaccination platforms from before genetics became a staple of biomedical research because these vaccines can stimulate both B- and T-cell responses and lack any infectious agent <span class="citation" data-cites="29LxSWHB BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>,<a href="#ref-29LxSWHB" role="doc-biblioref">660</a>]</span>.
+Some of the potential advantages of mRNA compared to DNA include safety (it cannot be integrated by the host and the half life can be regulated), it avoids any issues of a host immune response against the vector, and it holds the potential to dramatically accelerate vaccine manufacturing and development <span class="citation" data-cites="ENBWnhAh">[<a href="#ref-ENBWnhAh" role="doc-biblioref">658</a>]</span>.
+However, all of these approaches may offer several advantages over vaccination platforms from before genetics became a staple of biomedical research because these vaccines can stimulate both B- and T-cell responses and lack any infectious agent <span class="citation" data-cites="29LxSWHB BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>,<a href="#ref-29LxSWHB" role="doc-biblioref">659</a>]</span>.
 These approaches therefore utilize a vector to deliver information needed to produce an antigen to be constructed by the host, triggering an immune response to the antigen without introducing an infectious agent.
 Current methods in vaccine development can therefore be framed in terms of the central dogma of genetics: instead of directly providing the proteins from the infectious agents, vaccines developers are exploring the potential for the delivery of DNA or RNA to induce the cell to produce proteins from the virus that in turn induce a host immune response.</p>
 <p>All of these technologies are fairly new.
 <!--To Do: When did DNA vaccines really hit market? + same for viral vector vaccine, ebola was first-->
-Prior to 2020, no mRNA vaccines had been approved for use in humans<!--To Do: Cite-->, despite significant advances in the development of this technology <span class="citation" data-cites="ENBWnhAh">[<a href="#ref-ENBWnhAh" role="doc-biblioref">659</a>]</span>.
-Vaccine development using mRNA is a recent frontier, with challenges in its execution arising from the instability of mRNA molecules, the design requirements of an efficient delivery system, and the potential for mRNA to elicit a very strong immune response <span class="citation" data-cites="ENBWnhAh">[<a href="#ref-ENBWnhAh" role="doc-biblioref">659</a>]</span>.
+Prior to 2020, no mRNA vaccines had been approved for use in humans<!--To Do: Cite-->, despite significant advances in the development of this technology <span class="citation" data-cites="ENBWnhAh">[<a href="#ref-ENBWnhAh" role="doc-biblioref">658</a>]</span>.
+Vaccine development using mRNA is a recent frontier, with challenges in its execution arising from the instability of mRNA molecules, the design requirements of an efficient delivery system, and the potential for mRNA to elicit a very strong immune response <span class="citation" data-cites="ENBWnhAh">[<a href="#ref-ENBWnhAh" role="doc-biblioref">658</a>]</span>.
 Therefore, while these technologies elegantly capitalize on decades of research in vaccine development as well as the tools of the genomic revolution, it was largely unknown prior to the SARS-CoV-2 pandemic whether this potential could be realized in a real-world crisis.</p>
 <h2 data-number="6.6" id="the-pursuit-of-rapid-scalable-vaccine-development"><span class="header-section-number">6.6</span> The Pursuit of Rapid, Scalable Vaccine Development</h2>
-<p>The requirements for a successful vaccine trial and deployment are complex and may require coordination between government, industry, academia, and philanthropic entities <span class="citation" data-cites="plfPrQP7">[<a href="#ref-plfPrQP7" role="doc-biblioref">661</a>]</span>.
+<p>The requirements for a successful vaccine trial and deployment are complex and may require coordination between government, industry, academia, and philanthropic entities <span class="citation" data-cites="plfPrQP7">[<a href="#ref-plfPrQP7" role="doc-biblioref">660</a>]</span>.
 Flu-like illnesses caused by viruses are a common target of vaccine development programs, and influenza vaccine technology in particular has made many strides.
 Beyond the seasonal flu, however, a number of emergent viral threats over the past 20 years have challenged the vaccine development pipeline to respond more rapidly to previously unknown viruses.
 <!--To Do: SARS-->
 During the H1N1 influenza outbreak, vaccine development was accelerated because of the existing infrastructure, along with the fact that regulatory agencies had already decided that vaccines produced using egg- and cell-based platforms could be licensed under the regulations used for a strain change.
 Critiques of the production and distribution of the H1N1 vaccine have stressed the need for alternative development-and-manufacturing platforms that can be readily adapted to new pathogens.
-Although a monovalent H1N1 vaccine was not available before the pandemic peaked in the United States and Europe, it was available soon afterward as a stand-alone vaccine that was eventually incorporated into commercially available seasonal influenza vaccines <span class="citation" data-cites="HyYY2agc">[<a href="#ref-HyYY2agc" role="doc-biblioref">662</a>]</span>.
+Although a monovalent H1N1 vaccine was not available before the pandemic peaked in the United States and Europe, it was available soon afterward as a stand-alone vaccine that was eventually incorporated into commercially available seasonal influenza vaccines <span class="citation" data-cites="HyYY2agc">[<a href="#ref-HyYY2agc" role="doc-biblioref">661</a>]</span>.
 If H1N1 vaccine development provides any indication, considering developing and manufacturing platforms for promising COVID-19 vaccine trials early could hasten the emergence of an effective prophylactic vaccine against SARS-CoV-2.–&gt;
 <!--To Do: MERS, then Ebola-->
 <!--To Do: add a sentence about adjuvants and link to appendix-->
-The potential for technologies such as DNA and RNA vaccines to benefit the field of oncology has encouraged vaccine developers to invest in next-generation approaches to vaccine development, which have led to the great diversity of vaccine development programs <span class="citation" data-cites="wPl93ATP BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>,<a href="#ref-wPl93ATP" role="doc-biblioref">663</a>]</span>.</p>
+The potential for technologies such as DNA and RNA vaccines to benefit the field of oncology has encouraged vaccine developers to invest in next-generation approaches to vaccine development, which have led to the great diversity of vaccine development programs <span class="citation" data-cites="wPl93ATP BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>,<a href="#ref-wPl93ATP" role="doc-biblioref">662</a>]</span>.</p>
 <h2 data-number="6.7" id="challenges-and-opportunities-in-developing-a-vaccine-against-sars-cov-2"><span class="header-section-number">6.7</span> Challenges and Opportunities in Developing a Vaccine against SARS-CoV-2</h2>
 <p>The emergence of SARS-CoV-2 in late 2019 rapidly induced a global public health crisis.
 This viral threat did not follow the same trajectory as other emergent viruses of recent note, such as SARS-CoV-1, MERS-CoV, and ebola virus, none of which reached the level of pandemic.
 Spread of the SARS-CoV-2 virus has remained out of control in many parts of the world well into 2021.
 While, for various reasons, the outbreak of this virus was not controlled as rapidly as in past epidemics, vaccine development technology had also progressed based on these and other prior viral threats to the point that a rapid international vaccine development response was possible.
-The first critical step towards developing a vaccine against SARS-CoV-2 was characterizing the viral target, which happened extremely early in the COVID-19 outbreak with the sequencing and dissemination of the viral genome by early January 2020 <span class="citation" data-cites="SvOLLYfw">[<a href="#ref-SvOLLYfw" role="doc-biblioref">664</a>]</span> (Figure <a href="#fig:virus">6</a>).
+The first critical step towards developing a vaccine against SARS-CoV-2 was characterizing the viral target, which happened extremely early in the COVID-19 outbreak with the sequencing and dissemination of the viral genome by early January 2020 <span class="citation" data-cites="SvOLLYfw">[<a href="#ref-SvOLLYfw" role="doc-biblioref">663</a>]</span> (Figure <a href="#fig:virus">6</a>).
 <!--To Do: Focus on S protein, anything else being examined?-->
-The <em>S</em> protein is an antigen and induces an immune response <span class="citation" data-cites="Vnbw9o3T 13wCBLnnu">[<a href="#ref-Vnbw9o3T" role="doc-biblioref">665</a>,<a href="#ref-13wCBLnnu" role="doc-biblioref">666</a>]</span>.
+The <em>S</em> protein is an antigen and induces an immune response <span class="citation" data-cites="Vnbw9o3T 13wCBLnnu">[<a href="#ref-Vnbw9o3T" role="doc-biblioref">664</a>,<a href="#ref-13wCBLnnu" role="doc-biblioref">665</a>]</span>.
 &lt;–To Do: insert discussion of pre vs post fusion conformation here-&gt;</p>
 <div id="fig:virus" class="fignos">
 <figure>
 <img src="images/SARS_CoV_2.png" alt="" /><figcaption><span>Figure 6:</span> <strong>Structure of the SARS-CoV-2 virus.</strong>
 The development of vaccines depends on the immune system recognizing the virus.
 Here, the structure of SARS-CoV-2 is represented both in the abstract and against a visualization of the virion.<!--To Do: Add in-line ref-->
-The abstracted visualization was made using BioRender <span class="citation" data-cites="14FBejgLM">[<a href="#ref-14FBejgLM" role="doc-biblioref">667</a>]</span> and the microscopy was done by the National Institute of Allergy and Infectious Diseases <span class="citation" data-cites="Jzj97hJh">[<a href="#ref-Jzj97hJh" role="doc-biblioref">668</a>]</span>.</figcaption>
+The abstracted visualization was made using BioRender <span class="citation" data-cites="14FBejgLM">[<a href="#ref-14FBejgLM" role="doc-biblioref">666</a>]</span> and the microscopy was done by the National Institute of Allergy and Infectious Diseases <span class="citation" data-cites="Jzj97hJh">[<a href="#ref-Jzj97hJh" role="doc-biblioref">667</a>]</span>.</figcaption>
 </figure>
 </div>
 <p>For a highly infectious virus like SARS-CoV-2, a vaccine would hold particular value because it could bolster the immune response to the virus of the population broadly, thereby driving a lower rate of infection and likely significantly reducing fatalities.
 The Coalition for Epidemic Preparedness Innovations (CEPI) is coordinating global health agencies and pharmaceutical companies to develop vaccines against SARS-CoV-2.
-As of September 2020, there were over 180 vaccine candidates against SARS-CoV-2 in development <span class="citation" data-cites="dqpEe5Lz">[<a href="#ref-dqpEe5Lz" role="doc-biblioref">669</a>]</span>.
-While little is currently known about immunity to SARS-CoV-2, vaccine development typically tests for serum neutralizing activity, as this has been established as a biomarker for adaptive immunity in other respiratory illnesses <span class="citation" data-cites="wiGjCZC8">[<a href="#ref-wiGjCZC8" role="doc-biblioref">670</a>]</span>.
+As of September 2020, there were over 180 vaccine candidates against SARS-CoV-2 in development <span class="citation" data-cites="dqpEe5Lz">[<a href="#ref-dqpEe5Lz" role="doc-biblioref">668</a>]</span>.
+While little is currently known about immunity to SARS-CoV-2, vaccine development typically tests for serum neutralizing activity, as this has been established as a biomarker for adaptive immunity in other respiratory illnesses <span class="citation" data-cites="wiGjCZC8">[<a href="#ref-wiGjCZC8" role="doc-biblioref">669</a>]</span>.
 However, unlike in efforts to develop vaccines for prior viral threats, the duration of the COVID-19 pandemic has made it possible to test vaccine in phase III trials, where the effect of the vaccine on a cohort’s likelihood of contracting SARS-CoV-2 can be evaluated.
 Unlike many global vaccine development programs previously, such as with H1N1, the vaccine development landscape for COVID-19 includes vaccines produced by a wide array of technologies.
 These diverse technology platforms include DNA, RNA, virus-like particle, recombinant protein, both replicating and non-replicating viral vectors, live attenuated virus, and inactivated virus approaches (Figure <a href="#fig:vaccines">5</a>).</p>
@@ -2660,90 +2660,90 @@ <h2 data-number="6.8" id="live-attenuated-viruses"><span class="header-section-n
 <h2 data-number="6.9" id="inactivated-whole-virus-vaccines"><span class="header-section-number">6.9</span> Inactivated Whole-Virus Vaccines</h2>
 <p>Another well-established technology, inactivated whole-virus vaccines, is under development against SARS-CoV-2.
 This platform has been a valuable tool in efforts to control many viruses, and some well-known whole virus vaccines targets include influenza viruses, poliovirus, and hepatitis A virus.
-These types of vaccines use full virus particles that have been rendered non-infectious by chemical (i.e. using formaldehyde or β-propiolactone <span class="citation" data-cites="PwjPrwXa">[<a href="#ref-PwjPrwXa" role="doc-biblioref">671</a>]</span>) or physical (i.e. heat) means.
+These types of vaccines use full virus particles that have been rendered non-infectious by chemical (i.e. using formaldehyde or β-propiolactone <span class="citation" data-cites="PwjPrwXa">[<a href="#ref-PwjPrwXa" role="doc-biblioref">670</a>]</span>) or physical (i.e. heat) means.
 Though these virus particles are inactivated, they still have the capacity to prime the immune system.
-The size of the virus particle makes it ideal for uptake by APC, which leads to stimulation of helper T-cells <span class="citation" data-cites="7Knbo28h">[<a href="#ref-7Knbo28h" role="doc-biblioref">672</a>]</span>.
-Additionally, the array of epitopes on the surface of the virus increases antibody binding efficiency <span class="citation" data-cites="7Knbo28h">[<a href="#ref-7Knbo28h" role="doc-biblioref">672</a>]</span>.
+The size of the virus particle makes it ideal for uptake by APC, which leads to stimulation of helper T-cells <span class="citation" data-cites="7Knbo28h">[<a href="#ref-7Knbo28h" role="doc-biblioref">671</a>]</span>.
+Additionally, the array of epitopes on the surface of the virus increases antibody binding efficiency <span class="citation" data-cites="7Knbo28h">[<a href="#ref-7Knbo28h" role="doc-biblioref">671</a>]</span>.
 The native conformation of the surface proteins, which is also important for eliciting an immune response, is preserved using these techniques.
-Membrane proteins, which support B-cell responses to surface proteins, are also included using this method <span class="citation" data-cites="iAa7uWOm">[<a href="#ref-iAa7uWOm" role="doc-biblioref">673</a>]</span>.
+Membrane proteins, which support B-cell responses to surface proteins, are also included using this method <span class="citation" data-cites="iAa7uWOm">[<a href="#ref-iAa7uWOm" role="doc-biblioref">672</a>]</span>.
 Overall, these vaccines are able to mimic the key properties of the virus that stimulate a robust immune response, but the risk of adverse reactions is reduced because the virus is inactivated and thus unable to replicate.</p>
 <!--To Do: Were these investigated for SARS, MERS, ebola, H1N1?-->
 <p>One prominent inactivated whole-virus vaccine against SARS-CoV-2 is being developed by Sinovac, a Beijing-based biopharmaceutical company.
-Their CoronaVac vaccine uses an inactivated whole virus with the addition of an aluminum adjuvant <span class="citation" data-cites="RGPoDfHS">[<a href="#ref-RGPoDfHS" role="doc-biblioref">674</a>]</span> and is currently in Phase III clinical trials in Brazil <span class="citation" data-cites="KewHbkLZ">[<a href="#ref-KewHbkLZ" role="doc-biblioref">675</a>]</span>.
+Their CoronaVac vaccine uses an inactivated whole virus with the addition of an aluminum adjuvant <span class="citation" data-cites="RGPoDfHS">[<a href="#ref-RGPoDfHS" role="doc-biblioref">673</a>]</span> and is currently in Phase III clinical trials in Brazil <span class="citation" data-cites="KewHbkLZ">[<a href="#ref-KewHbkLZ" role="doc-biblioref">674</a>]</span>.
 <!--To Do: Expand slightly (1-2 sentences) on how it is made -- how do they inactivate it?-->
-Phase I and II clinical trials indicated a strong immunogenic response in animal models and the development of neutralizing antibodies in human participants <span class="citation" data-cites="Ozya5HP5 14fILrRWg N1txjPtt">[<a href="#ref-Ozya5HP5" role="doc-biblioref">676</a>,<a href="#ref-14fILrRWg" role="doc-biblioref">677</a>,<a href="#ref-N1txjPtt" role="doc-biblioref">678</a>]</span>.
+Phase I and II clinical trials indicated a strong immunogenic response in animal models and the development of neutralizing antibodies in human participants <span class="citation" data-cites="Ozya5HP5 14fILrRWg N1txjPtt">[<a href="#ref-Ozya5HP5" role="doc-biblioref">675</a>,<a href="#ref-14fILrRWg" role="doc-biblioref">676</a>,<a href="#ref-N1txjPtt" role="doc-biblioref">677</a>]</span>.
 <!--To Do: Check if there are any specifics available about immunogenicity that we can compare across vaccines...-->
 Safety analysis of the vaccine during the phase II trial revealed that most adverse reactions were either mild (grade 1) or moderate (grade 2) in severity.<!--To Do: check this, original text said "all" but that is in conflict with 2 lines below-->
 The most common symptom was pain at the injection site (9%) and fever (3%), and only 2% (n=7) of participants participants reported severe adverse events, though these were determined to be unrelated to the vaccine.
 While data from the phase III study will be required to evaluate the efficacy of the virus under real-world conditions of exposure, the current results suggest that this vaccine is likely to adapt a well-established approach to vaccine development for the prevention of COVID-19.
 <!--To Do: reorganize text from paragraph below, maybe some moves to appendix-->
 India, the biggest producer of vaccines globally, has developed COVAXIN®, which is an indigenous COVID-19 vaccine researched and manufactured by Bharat Biotech International Ltd. in collaboration with the Indian Council of Medical Research (ICMR) - National Institute of Virology (NIV).
-Bharat Biotech reported 80.6% vaccine efficacy for its whole virion inactivated BBV152 (COVAXIN®) vaccine candidate in 25,800 participants in phase III clinical trials <span class="citation" data-cites="Ks3L7qHG DaDKZXdu">[<a href="#ref-Ks3L7qHG" role="doc-biblioref">679</a>,<a href="#ref-DaDKZXdu" role="doc-biblioref">680</a>]</span>.
-It was reported in <em>The Lancet</em> that the BBV152 vaccine candidate adjuvanted with alum and a Toll-like receptor 7/8 (TLR7/8) agonist is safe, immunogenic, and induces Th1-skewed memory T-cell responses upon immunization <span class="citation" data-cites="GxQSMH5l">[<a href="#ref-GxQSMH5l" role="doc-biblioref">681</a>]</span>.
-Importantly, sera from individuals vaccinated with COVAXIN<sup>®</sup> efficiently neutralized the B.1.1.7 variant and the heterologous strain of SARS-CoV-2 <span class="citation" data-cites="VNckMunN">[<a href="#ref-VNckMunN" role="doc-biblioref">682</a>]</span>.
+Bharat Biotech reported 80.6% vaccine efficacy for its whole virion inactivated BBV152 (COVAXIN®) vaccine candidate in 25,800 participants in phase III clinical trials <span class="citation" data-cites="Ks3L7qHG DaDKZXdu">[<a href="#ref-Ks3L7qHG" role="doc-biblioref">678</a>,<a href="#ref-DaDKZXdu" role="doc-biblioref">679</a>]</span>.
+It was reported in <em>The Lancet</em> that the BBV152 vaccine candidate adjuvanted with alum and a Toll-like receptor 7/8 (TLR7/8) agonist is safe, immunogenic, and induces Th1-skewed memory T-cell responses upon immunization <span class="citation" data-cites="GxQSMH5l">[<a href="#ref-GxQSMH5l" role="doc-biblioref">680</a>]</span>.
+Importantly, sera from individuals vaccinated with COVAXIN<sup>®</sup> efficiently neutralized the B.1.1.7 variant and the heterologous strain of SARS-CoV-2 <span class="citation" data-cites="VNckMunN">[<a href="#ref-VNckMunN" role="doc-biblioref">681</a>]</span>.
 U.S.-based Ocugen Inc., a co-development partner of Bharat Biotech, is leading the application for an Emergency Use Authorization (EUA) for COVAXIN™ intended for the U.S. market.
 As of April 1, 2021 COVAXIN® has been approved for emergency use in Iran, Zimbabwe, and Nepal, and Mauritius and Paraguay have received a commercial supply of the vaccine.
 In Asia, China and India are the main COVID-19 vaccination developers and providers.
-Thus far, over 63 million people have been vaccinated against COVID-19 in India <span class="citation" data-cites="5xGlWp9l">[<a href="#ref-5xGlWp9l" role="doc-biblioref">683</a>]</span>.
+Thus far, over 63 million people have been vaccinated against COVID-19 in India <span class="citation" data-cites="5xGlWp9l">[<a href="#ref-5xGlWp9l" role="doc-biblioref">682</a>]</span>.
 A broad range of COVID-19 vaccine candidates are under investigation in order to respond to the COVID-19 pandemic.
-In India, the Covaxin vaccine produced by Bharat Biotech received emergency authorization on January 3rd, 2021, despite the lack of phase III data until March 3rd <span class="citation" data-cites="178GxSdwz Ks3L7qHG">[<a href="#ref-Ks3L7qHG" role="doc-biblioref">679</a>,<a href="#ref-178GxSdwz" role="doc-biblioref">684</a>]</span>.
-Following the release of the phase III data indicating 81% efficacy, Zimbabwe authorized the use of Covaxin <span class="citation" data-cites="13yEnvOyP">[<a href="#ref-13yEnvOyP" role="doc-biblioref">685</a>]</span>.
-In addition to COVAXIN®, Bharat Biotech has also developed an adenovirus vector-based intranasal BBV154 vaccine candidate that induces neutralizing IgG, mucosal IgA, and T cell responses <span class="citation" data-cites="P9mD7Gc9">[<a href="#ref-P9mD7Gc9" role="doc-biblioref">686</a>]</span>.
-In February, 2021, Bharat Biotech received approval from Indian officials to commence a phase I study of this intranasal chimpanzee-adenovirus (ChAd) vectored SARS-CoV-2-S vaccine <span class="citation" data-cites="P9mD7Gc9">[<a href="#ref-P9mD7Gc9" role="doc-biblioref">686</a>]</span>.
-Another Indian pharmaceutical industry, Zydus Cadila is developing India’s first indigenous DNA vaccine candidate ZyCoV-D <span class="citation" data-cites="o5iduzje">[<a href="#ref-o5iduzje" role="doc-biblioref">687</a>]</span> which has completed phase I and II clinical trials and has received approval from Drugs Controller General of India (DCGI) to conduct a phase III clinical trial <span class="citation" data-cites="7f7eGud">[<a href="#ref-7f7eGud" role="doc-biblioref">688</a>]</span>.
-Moreover, Indian-based Biological E.Limited has partnered with U.S.-based biopharmaceutical company Dynavax Technologies Corporation and Baylor College of Medicine, Texas, to initiate a phase I/II clinical trial in India for its COVID-19 subunit vaccine, which consists of the RBD of the spike protein of SARS-CoV-2 <span class="citation" data-cites="7f7eGud">[<a href="#ref-7f7eGud" role="doc-biblioref">688</a>]</span>.
-Notably, Novavax has signed an agreement with the Serum Institute of India allowing them to produce up to 2 billion doses a year <span class="citation" data-cites="e8pnj0O3">[<a href="#ref-e8pnj0O3" role="doc-biblioref">689</a>]</span>.
-Novavax has also signed agreements with the U.K., Canada, Australia, and South Korea <span class="citation" data-cites="X3fVa3P8">[<a href="#ref-X3fVa3P8" role="doc-biblioref">690</a>]</span> and has projected that they will supply 1.1 billion doses to COVAX who will distribute the vaccines to countries with disadvantaged access to vaccine supplies <span class="citation" data-cites="wByD9WaX">[<a href="#ref-wByD9WaX" role="doc-biblioref">691</a>]</span>.
-India has vaccinated approximately 24 million people <span class="citation" data-cites="DQmAgN0V">[<a href="#ref-DQmAgN0V" role="doc-biblioref">692</a>]</span>.
-This has been achieved by mainly using the AstraZeneca-University of Oxford vaccine, known as Covishield in India, which is also produced by the Serum Institute of India, and using India’s own Covaxin vaccine <span class="citation" data-cites="gsNWcXHn">[<a href="#ref-gsNWcXHn" role="doc-biblioref">693</a>]</span>.
-India has also shipped approximately 58 million COVID-19 vaccines to 66 countries <span class="citation" data-cites="QRYET3sK">[<a href="#ref-QRYET3sK" role="doc-biblioref">694</a>]</span>
+In India, the Covaxin vaccine produced by Bharat Biotech received emergency authorization on January 3rd, 2021, despite the lack of phase III data until March 3rd <span class="citation" data-cites="178GxSdwz Ks3L7qHG">[<a href="#ref-Ks3L7qHG" role="doc-biblioref">678</a>,<a href="#ref-178GxSdwz" role="doc-biblioref">683</a>]</span>.
+Following the release of the phase III data indicating 81% efficacy, Zimbabwe authorized the use of Covaxin <span class="citation" data-cites="13yEnvOyP">[<a href="#ref-13yEnvOyP" role="doc-biblioref">684</a>]</span>.
+In addition to COVAXIN®, Bharat Biotech has also developed an adenovirus vector-based intranasal BBV154 vaccine candidate that induces neutralizing IgG, mucosal IgA, and T cell responses <span class="citation" data-cites="P9mD7Gc9">[<a href="#ref-P9mD7Gc9" role="doc-biblioref">685</a>]</span>.
+In February, 2021, Bharat Biotech received approval from Indian officials to commence a phase I study of this intranasal chimpanzee-adenovirus (ChAd) vectored SARS-CoV-2-S vaccine <span class="citation" data-cites="P9mD7Gc9">[<a href="#ref-P9mD7Gc9" role="doc-biblioref">685</a>]</span>.
+Another Indian pharmaceutical industry, Zydus Cadila is developing India’s first indigenous DNA vaccine candidate ZyCoV-D <span class="citation" data-cites="o5iduzje">[<a href="#ref-o5iduzje" role="doc-biblioref">686</a>]</span> which has completed phase I and II clinical trials and has received approval from Drugs Controller General of India (DCGI) to conduct a phase III clinical trial <span class="citation" data-cites="7f7eGud">[<a href="#ref-7f7eGud" role="doc-biblioref">687</a>]</span>.
+Moreover, Indian-based Biological E.Limited has partnered with U.S.-based biopharmaceutical company Dynavax Technologies Corporation and Baylor College of Medicine, Texas, to initiate a phase I/II clinical trial in India for its COVID-19 subunit vaccine, which consists of the RBD of the spike protein of SARS-CoV-2 <span class="citation" data-cites="7f7eGud">[<a href="#ref-7f7eGud" role="doc-biblioref">687</a>]</span>.
+Notably, Novavax has signed an agreement with the Serum Institute of India allowing them to produce up to 2 billion doses a year <span class="citation" data-cites="e8pnj0O3">[<a href="#ref-e8pnj0O3" role="doc-biblioref">688</a>]</span>.
+Novavax has also signed agreements with the U.K., Canada, Australia, and South Korea <span class="citation" data-cites="X3fVa3P8">[<a href="#ref-X3fVa3P8" role="doc-biblioref">689</a>]</span> and has projected that they will supply 1.1 billion doses to COVAX who will distribute the vaccines to countries with disadvantaged access to vaccine supplies <span class="citation" data-cites="wByD9WaX">[<a href="#ref-wByD9WaX" role="doc-biblioref">690</a>]</span>.
+India has vaccinated approximately 24 million people <span class="citation" data-cites="DQmAgN0V">[<a href="#ref-DQmAgN0V" role="doc-biblioref">691</a>]</span>.
+This has been achieved by mainly using the AstraZeneca-University of Oxford vaccine, known as Covishield in India, which is also produced by the Serum Institute of India, and using India’s own Covaxin vaccine <span class="citation" data-cites="gsNWcXHn">[<a href="#ref-gsNWcXHn" role="doc-biblioref">692</a>]</span>.
+India has also shipped approximately 58 million COVID-19 vaccines to 66 countries <span class="citation" data-cites="QRYET3sK">[<a href="#ref-QRYET3sK" role="doc-biblioref">693</a>]</span>
 Considering India produces approximately 60% of the world’s vaccines prior to the pandemic, it is no surprise that several other vaccine candidates are under development.
-These include ZyCov-Di, a DNA vaccine produced by Zydus Cadila, HGCO19, India’s first mRNA vaccine produced by Genova and HDT Biotech Corporation (of the U.S.), and the Bio E subunit vaccine produced by Biological E in collaboration with U.S.-based Dynavax and the Baylor College of Medicine <span class="citation" data-cites="gsNWcXHn">[<a href="#ref-gsNWcXHn" role="doc-biblioref">693</a>]</span>.</p>
-<p>CoronaVac has been approved for use in China and has been granted emergency use in Azerbaijan, Brazil, Cambodia, Chile, Colombia, Ecuador, Hong Kong, Indonesia, Laos, Malaysia, Mexico, Philippines, Thailand, Turkey, Ukraine, and Uruguay <span class="citation" data-cites="ONBMyjqX">[<a href="#ref-ONBMyjqX" role="doc-biblioref">695</a>]</span>.<!--To Do: clean citation-->
-Sinovac has reported that their platform now has the capacity to provide up to a billion doses <span class="citation" data-cites="ONBMyjqX">[<a href="#ref-ONBMyjqX" role="doc-biblioref">695</a>]</span>.<!--To Do: clean citation-->
+These include ZyCov-Di, a DNA vaccine produced by Zydus Cadila, HGCO19, India’s first mRNA vaccine produced by Genova and HDT Biotech Corporation (of the U.S.), and the Bio E subunit vaccine produced by Biological E in collaboration with U.S.-based Dynavax and the Baylor College of Medicine <span class="citation" data-cites="gsNWcXHn">[<a href="#ref-gsNWcXHn" role="doc-biblioref">692</a>]</span>.</p>
+<p>CoronaVac has been approved for use in China and has been granted emergency use in Azerbaijan, Brazil, Cambodia, Chile, Colombia, Ecuador, Hong Kong, Indonesia, Laos, Malaysia, Mexico, Philippines, Thailand, Turkey, Ukraine, and Uruguay <span class="citation" data-cites="ONBMyjqX">[<a href="#ref-ONBMyjqX" role="doc-biblioref">694</a>]</span>.<!--To Do: clean citation-->
+Sinovac has reported that their platform now has the capacity to provide up to a billion doses <span class="citation" data-cites="ONBMyjqX">[<a href="#ref-ONBMyjqX" role="doc-biblioref">694</a>]</span>.<!--To Do: clean citation-->
 <!--To Do: A sentence or two comparing to Sinopharm (2 candidates), https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561304/ BBIBP-CorV; https://pubmed.ncbi.nlm.nih.gov/32778225/ --->
-The Sinopharm-Beijing Institute vaccine is currently approved for use in Bahrain, China, and the United Arab Emirates, but has been granted emergency use in Argentina, Cambodia, Egypt, Guyana, Hungary, Iran, Iraq, Jordan, Nepal, Pakistan, Peru, Venezuela, and Zimbabwe, with limited use in both Serbia and the Seychelles <span class="citation" data-cites="rqDwcy2A">[<a href="#ref-rqDwcy2A" role="doc-biblioref">696</a>]</span>.<!--To do: clean citation-->
-In contrast, the Sinopharm-Wuhan vaccine, which has been approved for use in China since February 25th, 2021, has been distributed almost exclusively within China, with limited supplies distributed to the United Arab Emirates <span class="citation" data-cites="mR6133bK">[<a href="#ref-mR6133bK" role="doc-biblioref">697</a>]</span>.<!--To Do: clean citation-->
+The Sinopharm-Beijing Institute vaccine is currently approved for use in Bahrain, China, and the United Arab Emirates, but has been granted emergency use in Argentina, Cambodia, Egypt, Guyana, Hungary, Iran, Iraq, Jordan, Nepal, Pakistan, Peru, Venezuela, and Zimbabwe, with limited use in both Serbia and the Seychelles <span class="citation" data-cites="rqDwcy2A">[<a href="#ref-rqDwcy2A" role="doc-biblioref">695</a>]</span>.<!--To do: clean citation-->
+In contrast, the Sinopharm-Wuhan vaccine, which has been approved for use in China since February 25th, 2021, has been distributed almost exclusively within China, with limited supplies distributed to the United Arab Emirates <span class="citation" data-cites="mR6133bK">[<a href="#ref-mR6133bK" role="doc-biblioref">696</a>]</span>.<!--To Do: clean citation-->
 <!--To Do: This should be slower to produce, I think? How does this compare to other platforms?-->
-Delays in vaccine distribution have also caused issues, particularly in Turkey where 10 million doses of Sinovac were due to arrive by December 2020, but instead only 3 million were delivered in early January <span class="citation" data-cites="gdTtuj5e">[<a href="#ref-gdTtuj5e" role="doc-biblioref">698</a>]</span>.
-Similar delays and shortages of doses promised have been reported by officials in the Philippines, Egypt, Morocco, and the United Arab Emirates <span class="citation" data-cites="XJmfG8HD 12zVLzkpB">[<a href="#ref-XJmfG8HD" role="doc-biblioref">699</a>,<a href="#ref-12zVLzkpB" role="doc-biblioref">700</a>]</span>.
-This will be concerning to China who have vaccine contracts for millions of doses with Indonesia (&gt;100 million), Brazil (100 million), Chile (60 million), Turkey (50 million), Egypt (40 million) and many others <span class="citation" data-cites="12zVLzkpB">[<a href="#ref-12zVLzkpB" role="doc-biblioref">700</a>]</span>.</p>
+Delays in vaccine distribution have also caused issues, particularly in Turkey where 10 million doses of Sinovac were due to arrive by December 2020, but instead only 3 million were delivered in early January <span class="citation" data-cites="gdTtuj5e">[<a href="#ref-gdTtuj5e" role="doc-biblioref">697</a>]</span>.
+Similar delays and shortages of doses promised have been reported by officials in the Philippines, Egypt, Morocco, and the United Arab Emirates <span class="citation" data-cites="XJmfG8HD 12zVLzkpB">[<a href="#ref-XJmfG8HD" role="doc-biblioref">698</a>,<a href="#ref-12zVLzkpB" role="doc-biblioref">699</a>]</span>.
+This will be concerning to China who have vaccine contracts for millions of doses with Indonesia (&gt;100 million), Brazil (100 million), Chile (60 million), Turkey (50 million), Egypt (40 million) and many others <span class="citation" data-cites="12zVLzkpB">[<a href="#ref-12zVLzkpB" role="doc-biblioref">699</a>]</span>.</p>
 <h2 data-number="6.10" id="protein-subunit-vaccines"><span class="header-section-number">6.10</span> Protein Subunit Vaccines</h2>
 <!--To Do: Add to figure-->
 <p>Compared to the inactivated whole virus vaccines, these protein subunit vaccines isolate a single protein of the virus and use it to stimulate the immune system.
 These proteins, also referred to as antigens, are usually those located on the surface of the viral particle and are therefore key targets of the immune system.
 These proteins are typically grown in yeast and then harvested.
-This vaccine can stimulate antibodies and CD4<sup>+</sup> T-cell response <span class="citation" data-cites="12eGVhH5I">[<a href="#ref-12eGVhH5I" role="doc-biblioref">701</a>]</span>.
-The main advantage of this method is that they are considered very safe because the antigen alone cannot cause an infection; however, the immune response is weaker and an adjuvant is usually needed to boost the response <span class="citation" data-cites="mv42t1HV">[<a href="#ref-mv42t1HV" role="doc-biblioref">702</a>]</span>.
+This vaccine can stimulate antibodies and CD4<sup>+</sup> T-cell response <span class="citation" data-cites="12eGVhH5I">[<a href="#ref-12eGVhH5I" role="doc-biblioref">700</a>]</span>.
+The main advantage of this method is that they are considered very safe because the antigen alone cannot cause an infection; however, the immune response is weaker and an adjuvant is usually needed to boost the response <span class="citation" data-cites="mv42t1HV">[<a href="#ref-mv42t1HV" role="doc-biblioref">701</a>]</span>.
 <!--To Do: Application/advancements in prior 21st century epidemics?--></p>
 <p>NVX-CoV2373, produced by U.S. company Novavax, is a protein nanoparticle vaccine candidate against SARS-CoV-2 that is constructed from a mutated prefusion SARS-CoV-2 spike protein in combination with a specialized adjuvant to elicit an immune response against SARS-CoV-2.
-The spike protein is recombinantly expressed in Sf9 insect cells <span class="citation" data-cites="Qk33ZrIC">[<a href="#ref-Qk33ZrIC" role="doc-biblioref">703</a>]</span>, which have previously been used for several other FDA-approved protein therapeutics <span class="citation" data-cites="RQR2sOmx">[<a href="#ref-RQR2sOmx" role="doc-biblioref">704</a>]</span> and contains mutations in the furin cleavage site (682-RRAR-685 to 682-QQAQ-685) along with two proline substitutions (K986P and V987P) that improve thermostability <span class="citation" data-cites="Qk33ZrIC">[<a href="#ref-Qk33ZrIC" role="doc-biblioref">703</a>]</span>.
-In preclinical mouse models, Novavax-CoV2373 elicited high anti-spike IgG titers 21-28 days post-vaccination that could neutralize the SARS-CoV-2 virus and protect the animals against virus challenge, with particularly strong effects when administered with the proprietary adjuvant Matrix-M<sup>TM</sup> <span class="citation" data-cites="Qk33ZrIC">[<a href="#ref-Qk33ZrIC" role="doc-biblioref">703</a>]</span>.
-In a phase I/II trial, a two-dose regimen of NVX-CoV2373 was found to induce anti-spike IgG levels and neutralizing antibody-titers exceeding those observed in convalescent plasma donated by symptomatic patients <span class="citation" data-cites="dMLXxGAI">[<a href="#ref-dMLXxGAI" role="doc-biblioref">705</a>]</span>.
+The spike protein is recombinantly expressed in Sf9 insect cells <span class="citation" data-cites="Qk33ZrIC">[<a href="#ref-Qk33ZrIC" role="doc-biblioref">702</a>]</span>, which have previously been used for several other FDA-approved protein therapeutics <span class="citation" data-cites="RQR2sOmx">[<a href="#ref-RQR2sOmx" role="doc-biblioref">703</a>]</span> and contains mutations in the furin cleavage site (682-RRAR-685 to 682-QQAQ-685) along with two proline substitutions (K986P and V987P) that improve thermostability <span class="citation" data-cites="Qk33ZrIC">[<a href="#ref-Qk33ZrIC" role="doc-biblioref">702</a>]</span>.
+In preclinical mouse models, Novavax-CoV2373 elicited high anti-spike IgG titers 21-28 days post-vaccination that could neutralize the SARS-CoV-2 virus and protect the animals against virus challenge, with particularly strong effects when administered with the proprietary adjuvant Matrix-M<sup>TM</sup> <span class="citation" data-cites="Qk33ZrIC">[<a href="#ref-Qk33ZrIC" role="doc-biblioref">702</a>]</span>.
+In a phase I/II trial, a two-dose regimen of NVX-CoV2373 was found to induce anti-spike IgG levels and neutralizing antibody-titers exceeding those observed in convalescent plasma donated by symptomatic patients <span class="citation" data-cites="dMLXxGAI">[<a href="#ref-dMLXxGAI" role="doc-biblioref">704</a>]</span>.
 In line with the preclinical studies, the use of Matrix-M adjuvant further increased anti-spike immunoglobulin levels and induced a Th1 response.
-Although the phase III trial data has not been published yet, Novavax announced an efficacy of 89.3% based on their phase III trial in the UK and also noted that 90% of cases occurring in their phase IIb study in South Africa were caused by a variant of concern, B.1.351 <span class="citation" data-cites="YEkrZ5Pz">[<a href="#ref-YEkrZ5Pz" role="doc-biblioref">706</a>]</span>.
-Despite these very preliminary results, Novavax has signed an agreement with the Serum Institute of India allowing them to produce up to 2 billion doses a year <span class="citation" data-cites="e8pnj0O3">[<a href="#ref-e8pnj0O3" role="doc-biblioref">689</a>]</span> and has also signed agreements with the U.K., Canada, Australia, and South Korea <span class="citation" data-cites="X3fVa3P8">[<a href="#ref-X3fVa3P8" role="doc-biblioref">690</a>]</span> as well as projecting that they will supply 1.1 billion doses to COVAX for distribution to countries with limited access to vaccine supplies <span class="citation" data-cites="wByD9WaX">[<a href="#ref-wByD9WaX" role="doc-biblioref">691</a>]</span>.
+Although the phase III trial data has not been published yet, Novavax announced an efficacy of 89.3% based on their phase III trial in the UK and also noted that 90% of cases occurring in their phase IIb study in South Africa were caused by a variant of concern, B.1.351 <span class="citation" data-cites="YEkrZ5Pz">[<a href="#ref-YEkrZ5Pz" role="doc-biblioref">705</a>]</span>.
+Despite these very preliminary results, Novavax has signed an agreement with the Serum Institute of India allowing them to produce up to 2 billion doses a year <span class="citation" data-cites="e8pnj0O3">[<a href="#ref-e8pnj0O3" role="doc-biblioref">688</a>]</span> and has also signed agreements with the U.K., Canada, Australia, and South Korea <span class="citation" data-cites="X3fVa3P8">[<a href="#ref-X3fVa3P8" role="doc-biblioref">689</a>]</span> as well as projecting that they will supply 1.1 billion doses to COVAX for distribution to countries with limited access to vaccine supplies <span class="citation" data-cites="wByD9WaX">[<a href="#ref-wByD9WaX" role="doc-biblioref">690</a>]</span>.
 <!--To Do: closing sentence contextualizing role protein subunit vaccines may play in this pandemic relative to previous ones--></p>
 <h2 data-number="6.11" id="vaccines-delivering-dna"><span class="header-section-number">6.11</span> Vaccines Delivering DNA</h2>
 <p>The delivery and presentation of antigens is fundamental to inducing immunity against a virus such as SARS-CoV-2.
-DNA vaccines offer an approach to delivering foreign substances into the body in a way that induces both a humoral and cellular immune response <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>]</span>.
-Delivering a DNA sequence to host cells allows the host to synthesize an antigen without exposure to a viral threat <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>]</span>.
-Host-synthesized antigens can then be presented in complex with major histocompatibility complex (MHC) I and II, which can activate either T- or B-cells <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>]</span>.
-While these vaccines encode specific proteins, providing many of the benefits of a protein subunit vaccine, they do not carry any risk of DNA being live, replicating, or spreading, and their manufacturing process lends itself to scalability <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>]</span>.
-Many of the safety concerns raised about DNA vaccines were not found to be an issue during preclinical and phase I testing, although antibiotic resistance introduced during the plasmid selection process remained a concern during this initial phase of development <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>]</span>.
-However, the immunogenicity of these vaccines has also not reached expectations <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>]</span>.
+DNA vaccines offer an approach to delivering foreign substances into the body in a way that induces both a humoral and cellular immune response <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>]</span>.
+Delivering a DNA sequence to host cells allows the host to synthesize an antigen without exposure to a viral threat <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>]</span>.
+Host-synthesized antigens can then be presented in complex with major histocompatibility complex (MHC) I and II, which can activate either T- or B-cells <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>]</span>.
+While these vaccines encode specific proteins, providing many of the benefits of a protein subunit vaccine, they do not carry any risk of DNA being live, replicating, or spreading, and their manufacturing process lends itself to scalability <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>]</span>.
+Many of the safety concerns raised about DNA vaccines were not found to be an issue during preclinical and phase I testing, although antibiotic resistance introduced during the plasmid selection process remained a concern during this initial phase of development <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>]</span>.
+However, the immunogenicity of these vaccines has also not reached expectations <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>]</span>.
 <!--To Do: Expand. I have a bunch of papers downloaded about why this such a groundbreaking technology, need to read and summarize--></p>
 <h3 data-number="6.11.1" id="dna-vaccines"><span class="header-section-number">6.11.1</span> DNA Vaccines</h3>
-<p>In the 1990s and 2000s, DNA vaccines delivered via plasmids sparked significant scientific interest, leading to a large number of preclinical trials <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>]</span>.
-Early preclinical trials primarily focused on long-standing disease threats, including viral diseases such as rabies and bacterial diseases such as malaria, and promising results led to phase I testing of the application of this technology to HIV, influenza, malaria, and other diseases of concern during this period <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>]</span>.
-Although they were well-tolerated, these early attempts to develop vaccines were generally not very successful in inducing immunity to the target pathogen, with either limited T-cell or limited neutralizing antibody responses observed <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>]</span>.
+<p>In the 1990s and 2000s, DNA vaccines delivered via plasmids sparked significant scientific interest, leading to a large number of preclinical trials <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>]</span>.
+Early preclinical trials primarily focused on long-standing disease threats, including viral diseases such as rabies and bacterial diseases such as malaria, and promising results led to phase I testing of the application of this technology to HIV, influenza, malaria, and other diseases of concern during this period <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>]</span>.
+Although they were well-tolerated, these early attempts to develop vaccines were generally not very successful in inducing immunity to the target pathogen, with either limited T-cell or limited neutralizing antibody responses observed <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>]</span>.
 <!--To Do: Plasmid DNA vaccines for other 21st century epidemics, and the coming-of-age of this technology in the late 00s--></p>
 <!--To Do: Add background on how the INO-4800 vaccine is designed-->
-<p>Currently, a Phase I safety and immunogenicity clinical trial of INO-4800, a prophylactic vaccine against SARS-CoV-2, is underway <span class="citation" data-cites="xuzLfS0y">[<a href="#ref-xuzLfS0y" role="doc-biblioref">707</a>]</span>.
+<p>Currently, a Phase I safety and immunogenicity clinical trial of INO-4800, a prophylactic vaccine against SARS-CoV-2, is underway <span class="citation" data-cites="xuzLfS0y">[<a href="#ref-xuzLfS0y" role="doc-biblioref">706</a>]</span>.
 The vaccine developer Inovio Pharmaceuticals Technology is overseeing administration of INO-4800 by intradermal injection followed by electroporation with the CELLECTRA® device to healthy volunteers.
 Electroporation is the application of brief electric pulses to tissues in order to permeabilize cell membranes in a transient and reversible manner.
-It has been shown that electroporation can enhance vaccine efficacy by up to 100-fold, as measured by increases in antigen-specific antibody titers <span class="citation" data-cites="H6tWVs5R">[<a href="#ref-H6tWVs5R" role="doc-biblioref">708</a>]</span>.
-The safety of the CELLECTRA® device has been studied for over seven years, and these studies support the further development of electroporation as a safe vaccine delivery method <span class="citation" data-cites="1Hsm2J1sc">[<a href="#ref-1Hsm2J1sc" role="doc-biblioref">709</a>]</span>.
+It has been shown that electroporation can enhance vaccine efficacy by up to 100-fold, as measured by increases in antigen-specific antibody titers <span class="citation" data-cites="H6tWVs5R">[<a href="#ref-H6tWVs5R" role="doc-biblioref">707</a>]</span>.
+The safety of the CELLECTRA® device has been studied for over seven years, and these studies support the further development of electroporation as a safe vaccine delivery method <span class="citation" data-cites="1Hsm2J1sc">[<a href="#ref-1Hsm2J1sc" role="doc-biblioref">708</a>]</span>.
 The temporary formation of pores through electroporation facilitates the successful transportation of macromolecules into cells, allowing cells to robustly take up INO-4800 for the production of an antibody response.
 Approved by the United States (U.S.) FDA on April 6, 2020, the phase I study is enrolling up to 40 healthy adult volunteers in Philadelphia, PA at the Perelman School of Medicine and at the Center for Pharmaceutical Research in Kansas City, MO.
 The trial has two experimental arms corresponding to the two locations.
@@ -2753,48 +2753,48 @@ <h3 data-number="6.11.1" id="dna-vaccines"><span class="header-section-number">6
 The development of a DNA vaccine against SARS-CoV-2 by Inovio could be an important step forward in the world’s search for a COVID-19 vaccine.
 Although exciting, the cost of vaccine manufacturing and electroporation may make scaling the use of this technology for prophylactic use for the general public difficult.</p>
 <h3 data-number="6.11.2" id="viral-vector-dna-vaccines"><span class="header-section-number">6.11.2</span> Viral-Vector DNA Vaccines</h3>
-<p>Viral vectors have emerged as a safe and efficient method to furnish the nucleotide sequences of an antigen to the immune system using a second virus as a vector <span class="citation" data-cites="1Ff2BDzkT">[<a href="#ref-1Ff2BDzkT" role="doc-biblioref">710</a>]</span>.
-The genetic content of the vector virus is often altered to prevent it from replicating, but replication-competent viruses can also be used under certain circumstances <span class="citation" data-cites="1FpZkxdl4">[<a href="#ref-1FpZkxdl4" role="doc-biblioref">711</a>]</span>.
+<p>Viral vectors have emerged as a safe and efficient method to furnish the nucleotide sequences of an antigen to the immune system using a second virus as a vector <span class="citation" data-cites="1Ff2BDzkT">[<a href="#ref-1Ff2BDzkT" role="doc-biblioref">709</a>]</span>.
+The genetic content of the vector virus is often altered to prevent it from replicating, but replication-competent viruses can also be used under certain circumstances <span class="citation" data-cites="1FpZkxdl4">[<a href="#ref-1FpZkxdl4" role="doc-biblioref">710</a>]</span>.
 The vaccine then uses the host machinery to construct antigen(s) from the transported genetic material, for which the body synthesizes antibodies in response.
-One of the early viral vectors explored was adenovirus, with serotype 5 (Ad5) being particularly effective <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>]</span>.
-This technology rose in popularity during the 2000s due to its being more immunogenic in humans and non-human primates than plasmid-vectored DNA vaccines <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>]</span>.
-In the 2000s, interest also arose in utilizing simian adenoviruses as vectors because of the reduced risk that human vaccine recipients would have prior exposure resulting in adaptive immunity <span class="citation" data-cites="BsrTDzJ2 XRmk1S6R">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>,<a href="#ref-XRmk1S6R" role="doc-biblioref">712</a>]</span>, and chimpanzee adenoviruses were explored as a potential vector in the development of a vaccine against <em>Middle East respiratory syndrome-related coronavirus</em> (MERS-CoV) <span class="citation" data-cites="Jkm7jfS8">[<a href="#ref-Jkm7jfS8" role="doc-biblioref">713</a>]</span>.
-Today, various viral-vector platforms including poxviruses <span class="citation" data-cites="8bpbvIro 1AZfAQ5py">[<a href="#ref-8bpbvIro" role="doc-biblioref">714</a>,<a href="#ref-1AZfAQ5py" role="doc-biblioref">715</a>]</span>, adenoviruses <span class="citation" data-cites="zX5UKhti">[<a href="#ref-zX5UKhti" role="doc-biblioref">716</a>]</span>, and vesicular stomatitis viruses <span class="citation" data-cites="SNwg8Qkf lvi4DH2g">[<a href="#ref-SNwg8Qkf" role="doc-biblioref">717</a>,<a href="#ref-lvi4DH2g" role="doc-biblioref">718</a>]</span> are being developed,
-Viral-vector vaccines are able to induce both an antibody and cellular response; however, the response is limited due to the immunogenicity of the viral vector used <span class="citation" data-cites="YRgRziXN zX5UKhti">[<a href="#ref-zX5UKhti" role="doc-biblioref">716</a>,<a href="#ref-YRgRziXN" role="doc-biblioref">719</a>]</span>.
+One of the early viral vectors explored was adenovirus, with serotype 5 (Ad5) being particularly effective <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>]</span>.
+This technology rose in popularity during the 2000s due to its being more immunogenic in humans and non-human primates than plasmid-vectored DNA vaccines <span class="citation" data-cites="BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>]</span>.
+In the 2000s, interest also arose in utilizing simian adenoviruses as vectors because of the reduced risk that human vaccine recipients would have prior exposure resulting in adaptive immunity <span class="citation" data-cites="BsrTDzJ2 XRmk1S6R">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>,<a href="#ref-XRmk1S6R" role="doc-biblioref">711</a>]</span>, and chimpanzee adenoviruses were explored as a potential vector in the development of a vaccine against <em>Middle East respiratory syndrome-related coronavirus</em> (MERS-CoV) <span class="citation" data-cites="Jkm7jfS8">[<a href="#ref-Jkm7jfS8" role="doc-biblioref">712</a>]</span>.
+Today, various viral-vector platforms including poxviruses <span class="citation" data-cites="8bpbvIro 1AZfAQ5py">[<a href="#ref-8bpbvIro" role="doc-biblioref">713</a>,<a href="#ref-1AZfAQ5py" role="doc-biblioref">714</a>]</span>, adenoviruses <span class="citation" data-cites="zX5UKhti">[<a href="#ref-zX5UKhti" role="doc-biblioref">715</a>]</span>, and vesicular stomatitis viruses <span class="citation" data-cites="SNwg8Qkf lvi4DH2g">[<a href="#ref-SNwg8Qkf" role="doc-biblioref">716</a>,<a href="#ref-lvi4DH2g" role="doc-biblioref">717</a>]</span> are being developed,
+Viral-vector vaccines are able to induce both an antibody and cellular response; however, the response is limited due to the immunogenicity of the viral vector used <span class="citation" data-cites="YRgRziXN zX5UKhti">[<a href="#ref-zX5UKhti" role="doc-biblioref">715</a>,<a href="#ref-YRgRziXN" role="doc-biblioref">718</a>]</span>.
 An important consideration in identifying potential vectors is the immune response to the vector.
-Both the innate and adaptive immune responses can potentially respond to the vector, limiting the ability of the vaccine to transfer information to the immune system <span class="citation" data-cites="tbs2wD7F">[<a href="#ref-tbs2wD7F" role="doc-biblioref">720</a>]</span>.
-Different vectors are associated with different levels of reactogenicity; for example, adenoviruses elicit a much stronger innate immune response than replication deficient adeno-associated viruses derived from parvoviruses <span class="citation" data-cites="tbs2wD7F">[<a href="#ref-tbs2wD7F" role="doc-biblioref">720</a>]</span>.
-Additionally, using a virus circulating widely in human populations as a vector presents additional challenges because vaccine recipients may already have developed an immune response to the vector <span class="citation" data-cites="IUplTKEg">[<a href="#ref-IUplTKEg" role="doc-biblioref">721</a>]</span>.</p>
-<p>There are several viral vector vaccines that are available for veterinary use <span class="citation" data-cites="MvKb0qJC BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">658</a>,<a href="#ref-MvKb0qJC" role="doc-biblioref">722</a>]</span>, but prior to the COVID-19 pandemic, only one viral vector vaccine was approved by the FDA for use in humans.
+Both the innate and adaptive immune responses can potentially respond to the vector, limiting the ability of the vaccine to transfer information to the immune system <span class="citation" data-cites="tbs2wD7F">[<a href="#ref-tbs2wD7F" role="doc-biblioref">719</a>]</span>.
+Different vectors are associated with different levels of reactogenicity; for example, adenoviruses elicit a much stronger innate immune response than replication deficient adeno-associated viruses derived from parvoviruses <span class="citation" data-cites="tbs2wD7F">[<a href="#ref-tbs2wD7F" role="doc-biblioref">719</a>]</span>.
+Additionally, using a virus circulating widely in human populations as a vector presents additional challenges because vaccine recipients may already have developed an immune response to the vector <span class="citation" data-cites="IUplTKEg">[<a href="#ref-IUplTKEg" role="doc-biblioref">720</a>]</span>.</p>
+<p>There are several viral vector vaccines that are available for veterinary use <span class="citation" data-cites="MvKb0qJC BsrTDzJ2">[<a href="#ref-BsrTDzJ2" role="doc-biblioref">657</a>,<a href="#ref-MvKb0qJC" role="doc-biblioref">721</a>]</span>, but prior to the COVID-19 pandemic, only one viral vector vaccine was approved by the FDA for use in humans.
 This vaccine is vectored with a recombinant vesicular stomatitis virus and targeted against the ebola virus [doi:10.1016/j.cell.2020.03.011].
-Additionally, several phase I and phase II clinical trials for other vaccines are ongoing <span class="citation" data-cites="1Ff2BDzkT">[<a href="#ref-1Ff2BDzkT" role="doc-biblioref">710</a>]</span>, and the technology is currently being explored for its potential against numerous infectious diseases including malaria <span class="citation" data-cites="OZJWUaDW 3tkGuMXx">[<a href="#ref-OZJWUaDW" role="doc-biblioref">723</a>,<a href="#ref-3tkGuMXx" role="doc-biblioref">724</a>]</span>, ebola <span class="citation" data-cites="AgZwwt5u 9BEMTYn8 PbGQOOI">[<a href="#ref-AgZwwt5u" role="doc-biblioref">725</a>,<a href="#ref-9BEMTYn8" role="doc-biblioref">726</a>,<a href="#ref-PbGQOOI" role="doc-biblioref">727</a>]</span>, and human immunodeficiency virus (HIV) <span class="citation" data-cites="1C8hgfvDF SAIfGNkZ">[<a href="#ref-1C8hgfvDF" role="doc-biblioref">728</a>,<a href="#ref-SAIfGNkZ" role="doc-biblioref">729</a>]</span>.
-The threat of MERS and SARS initiated interest in the application of viral vector vaccines to human coronaviruses <span class="citation" data-cites="Jkm7jfS8">[<a href="#ref-Jkm7jfS8" role="doc-biblioref">713</a>]</span>, but efforts to apply this technology to these pathogens had not yet led to a successful vaccine candidate.
-In the mid-to-late 00s, adenoviral vectored vaccines against SARS were found to induce SARS-CoV-specific IgA in the lungs of mice <span class="citation" data-cites="umEOWDY5">[<a href="#ref-umEOWDY5" role="doc-biblioref">730</a>]</span>, but were later found to offer incomplete protection in ferret models <span class="citation" data-cites="DGTFML2b">[<a href="#ref-DGTFML2b" role="doc-biblioref">731</a>]</span>.
-Gamaleya National Center of Epidemiology and Microbiology in Moscow sought to use an adenovirus platform for the development of vaccines for <em>Middle East respiratory syndrome-related coronavirus</em> and Ebola virus, although neither of the previous vaccines were internationally licensed <span class="citation" data-cites="UCI0TCHy">[<a href="#ref-UCI0TCHy" role="doc-biblioref">732</a>]</span>.</p>
-<p>In 2017, results were published from an initial investigation of two vaccine candidates against MERS-CoV containing the MERS-CoV S gene vectored with chimpanzee adenovirus, Oxford University #1 (ChAdOx1), a replication-deficient chimpanzee adenovirus <span class="citation" data-cites="P94sxWp4">[<a href="#ref-P94sxWp4" role="doc-biblioref">733</a>]</span>.
+Additionally, several phase I and phase II clinical trials for other vaccines are ongoing <span class="citation" data-cites="1Ff2BDzkT">[<a href="#ref-1Ff2BDzkT" role="doc-biblioref">709</a>]</span>, and the technology is currently being explored for its potential against numerous infectious diseases including malaria <span class="citation" data-cites="OZJWUaDW 3tkGuMXx">[<a href="#ref-OZJWUaDW" role="doc-biblioref">722</a>,<a href="#ref-3tkGuMXx" role="doc-biblioref">723</a>]</span>, ebola <span class="citation" data-cites="AgZwwt5u 9BEMTYn8 PbGQOOI">[<a href="#ref-AgZwwt5u" role="doc-biblioref">724</a>,<a href="#ref-9BEMTYn8" role="doc-biblioref">725</a>,<a href="#ref-PbGQOOI" role="doc-biblioref">726</a>]</span>, and human immunodeficiency virus (HIV) <span class="citation" data-cites="1C8hgfvDF SAIfGNkZ">[<a href="#ref-1C8hgfvDF" role="doc-biblioref">727</a>,<a href="#ref-SAIfGNkZ" role="doc-biblioref">728</a>]</span>.
+The threat of MERS and SARS initiated interest in the application of viral vector vaccines to human coronaviruses <span class="citation" data-cites="Jkm7jfS8">[<a href="#ref-Jkm7jfS8" role="doc-biblioref">712</a>]</span>, but efforts to apply this technology to these pathogens had not yet led to a successful vaccine candidate.
+In the mid-to-late 00s, adenoviral vectored vaccines against SARS were found to induce SARS-CoV-specific IgA in the lungs of mice <span class="citation" data-cites="umEOWDY5">[<a href="#ref-umEOWDY5" role="doc-biblioref">729</a>]</span>, but were later found to offer incomplete protection in ferret models <span class="citation" data-cites="DGTFML2b">[<a href="#ref-DGTFML2b" role="doc-biblioref">730</a>]</span>.
+Gamaleya National Center of Epidemiology and Microbiology in Moscow sought to use an adenovirus platform for the development of vaccines for <em>Middle East respiratory syndrome-related coronavirus</em> and Ebola virus, although neither of the previous vaccines were internationally licensed <span class="citation" data-cites="UCI0TCHy">[<a href="#ref-UCI0TCHy" role="doc-biblioref">731</a>]</span>.</p>
+<p>In 2017, results were published from an initial investigation of two vaccine candidates against MERS-CoV containing the MERS-CoV S gene vectored with chimpanzee adenovirus, Oxford University #1 (ChAdOx1), a replication-deficient chimpanzee adenovirus <span class="citation" data-cites="P94sxWp4">[<a href="#ref-P94sxWp4" role="doc-biblioref">732</a>]</span>.
 This study reported that a candidate containing the complete spike protein sequence induced a stronger neutralizing antibody response in mice than candidates vectored with modified vaccinia virus Ankara.
 It was pursued in additional research, and in the summer of 2020 results of two studies were published.
-The first reported that a single dose of ChAdOx1 MERS induced an immune response and inhibited viral replication in macaques <span class="citation" data-cites="3NtMBDMM">[<a href="#ref-3NtMBDMM" role="doc-biblioref">734</a>]</span>.
-The second reported promising results from a phase I trial that administered the vaccine to adults and measured safety/tolerability and immune response (as indicated through immune assays following vaccination) <span class="citation" data-cites="ERfSJf5B">[<a href="#ref-ERfSJf5B" role="doc-biblioref">735</a>]</span>.</p>
+The first reported that a single dose of ChAdOx1 MERS induced an immune response and inhibited viral replication in macaques <span class="citation" data-cites="3NtMBDMM">[<a href="#ref-3NtMBDMM" role="doc-biblioref">733</a>]</span>.
+The second reported promising results from a phase I trial that administered the vaccine to adults and measured safety/tolerability and immune response (as indicated through immune assays following vaccination) <span class="citation" data-cites="ERfSJf5B">[<a href="#ref-ERfSJf5B" role="doc-biblioref">734</a>]</span>.</p>
 <p>While not all of these results were available at the time that vaccine development programs against SARS-CoV-2 began, at least three viral vector vaccines have also been developed against this hCoV.
-First, collaboration between AstraZeneca and researchers at the University of Oxford has successfully applied a viral vector approach to the development of a vaccine against SARS-CoV-2 using the replication-deficient ChAdOx1 vector modified to encode the spike protein of SARS-CoV-2 <span class="citation" data-cites="1037p4Gvs">[<a href="#ref-1037p4Gvs" role="doc-biblioref">736</a>]</span>.
-In phase I and I/II trials, respectively, the immunogenic potential of vaccine candidate ChAdOx1 nCoV-19 was demonstrated through the immune challenge of two animal models, mice and rhesus macaques <span class="citation" data-cites="1037p4Gvs">[<a href="#ref-1037p4Gvs" role="doc-biblioref">736</a>]</span> and patients receiving the ChAdOx1 nCoV-19 vaccine developed antibodies to the SARS-CoV-2 spike protein that peaked by day 28, with these levels remaining stable until a second observation at day 56 <span class="citation" data-cites="2bBVSpM">[<a href="#ref-2bBVSpM" role="doc-biblioref">737</a>]</span>.
-In December 2020, preliminary results of the phase III trial were released detailing randomized control trials conducted in the U.K., Brazil, and South Africa between April and November 2020 <span class="citation" data-cites="Vnbw9o3T">[<a href="#ref-Vnbw9o3T" role="doc-biblioref">665</a>]</span>.
+First, collaboration between AstraZeneca and researchers at the University of Oxford has successfully applied a viral vector approach to the development of a vaccine against SARS-CoV-2 using the replication-deficient ChAdOx1 vector modified to encode the spike protein of SARS-CoV-2 <span class="citation" data-cites="1037p4Gvs">[<a href="#ref-1037p4Gvs" role="doc-biblioref">735</a>]</span>.
+In phase I and I/II trials, respectively, the immunogenic potential of vaccine candidate ChAdOx1 nCoV-19 was demonstrated through the immune challenge of two animal models, mice and rhesus macaques <span class="citation" data-cites="1037p4Gvs">[<a href="#ref-1037p4Gvs" role="doc-biblioref">735</a>]</span> and patients receiving the ChAdOx1 nCoV-19 vaccine developed antibodies to the SARS-CoV-2 spike protein that peaked by day 28, with these levels remaining stable until a second observation at day 56 <span class="citation" data-cites="2bBVSpM">[<a href="#ref-2bBVSpM" role="doc-biblioref">736</a>]</span>.
+In December 2020, preliminary results of the phase III trial were released detailing randomized control trials conducted in the U.K., Brazil, and South Africa between April and November 2020 <span class="citation" data-cites="Vnbw9o3T">[<a href="#ref-Vnbw9o3T" role="doc-biblioref">664</a>]</span>.
 These trials again compared ChAdOx1 nCoV-19 to a control, but the design of each study varied; pooling data across studies indicated an overall efficacy of 70.4%. <!--To Do: symptomatic?-->
-ChAdOx1 nCoV-19 was first approved for emergency use on December 30, 2020 in the United Kingdom <span class="citation" data-cites="1A7PjhDDR">[<a href="#ref-1A7PjhDDR" role="doc-biblioref">738</a>]</span> and has since then been approved for emergency use in several dozen countries, in addition to receiving full approval in Brazil.</p>
+ChAdOx1 nCoV-19 was first approved for emergency use on December 30, 2020 in the United Kingdom <span class="citation" data-cites="1A7PjhDDR">[<a href="#ref-1A7PjhDDR" role="doc-biblioref">737</a>]</span> and has since then been approved for emergency use in several dozen countries, in addition to receiving full approval in Brazil.</p>
 <p>Second, a viral vector approach was also applied by Gamaleya to develop Sputnik V, a replication-deficient recombinant adenovirus (rAd) vaccine that combines two adenovirus vectors, rAd26-S and rAd5-S, that express the full-length SARS-CoV-2 spike glycoprotein.
 The two vectors are administered intramuscularly administered sequentially, following a prime-boost regimen.
-Despite a lack of data from clinical trials, President Vladimir Putin of Russia announced the approval of the Sputnik V vaccines on August 11th, 2020 <span class="citation" data-cites="3KMxmQhV">[<a href="#ref-3KMxmQhV" role="doc-biblioref">739</a>]</span> and it has subsequently been administered in Russia and other countries.
-Subsequently, the phase I/II clinical trial was published and indicated that the vaccine was safe, with the most common adverse events being mild pain at the injection site (58%), hypothermia (50%), headaches (42%), fatigue (28%), and joint and muscle pain (24%), and immunogenic, with seroconversion observed in all participants three weeks after the second dose and with all participants producing antibodies to the SARS-CoV-2 glycoprotein <span class="citation" data-cites="PNZEiId1">[<a href="#ref-PNZEiId1" role="doc-biblioref">740</a>]</span>.
-In February 2021, six months after its approval in Russia, interim results of the phase III trial were released, indicating an overall vaccine efficacy of 91.6% for symptomatic COVID-19 <span class="citation" data-cites="gLAIyAHm">[<a href="#ref-gLAIyAHm" role="doc-biblioref">741</a>]</span>.
-As of early January, Sputnik V had been administered to as many as 1.5 million Russians <span class="citation" data-cites="X5LkVfY6">[<a href="#ref-X5LkVfY6" role="doc-biblioref">742</a>]</span> , and doses of Sputnik V have also been distributed to other parts of Europe, such as Belarus, Bosnia-Herzegovina, Hungary, San Marino, Serbia, and Slovakia <span class="citation" data-cites="16LczMwFO Z0V7NK7Y 16GYKbrOq">[<a href="#ref-16LczMwFO" role="doc-biblioref">743</a>,<a href="#ref-Z0V7NK7Y" role="doc-biblioref">744</a>,<a href="#ref-16GYKbrOq" role="doc-biblioref">745</a>]</span>, with the Czech Republic and Austria also having expressed interest in its procurement <span class="citation" data-cites="125VEHWS7">[<a href="#ref-125VEHWS7" role="doc-biblioref">746</a>]</span>.</p>
-<p>Third, Janssen Pharmaceuticals, Inc., a subsidiary of Johnson &amp; Johnson, also developed a viral vector vaccine in collaboration with and funded by the United States’s “Operation Warp Speed” <span class="citation" data-cites="D3Px25HN 57BTbcko">[<a href="#ref-D3Px25HN" role="doc-biblioref">747</a>,<a href="#ref-57BTbcko" role="doc-biblioref">748</a>]</span>.
-The vaccine candidate JNJ-78436735, formerly known as Ad26.COV2-S, is a monovalent vaccine that is composed of a replication-deficient adenovirus serotype 26 (Ad26) vector expressing the stabilized prefusion S protein of SARS-CoV-2 <span class="citation" data-cites="pWf2T8J8 10UC562ga">[<a href="#ref-pWf2T8J8" role="doc-biblioref">749</a>,<a href="#ref-10UC562ga" role="doc-biblioref">750</a>]</span>.
-Unlike the other two viral vector vaccines available to date, JNJ-78436735 requires only a single dose, a characteristic that is expected to aid in global deployment <span class="citation" data-cites="gOOBv1MD">[<a href="#ref-gOOBv1MD" role="doc-biblioref">751</a>]</span>.
-JNJ-78436735 was selected from among a number of initial candidate designs <span class="citation" data-cites="10UC562ga">[<a href="#ref-10UC562ga" role="doc-biblioref">750</a>]</span> and tested <em>in vivo</em> in Syrian golden hamsters and Rhesus macaques to assess safety and immunogenicity <span class="citation" data-cites="10UC562ga gOOBv1MD HmMIiIv2 EpOXYGt4">[<a href="#ref-10UC562ga" role="doc-biblioref">750</a>,<a href="#ref-gOOBv1MD" role="doc-biblioref">751</a>,<a href="#ref-HmMIiIv2" role="doc-biblioref">752</a>,<a href="#ref-EpOXYGt4" role="doc-biblioref">753</a>]</span>.
-The JNJ-78436735 candidate was selected for its favorable immunogenicity profile and ease of manufacturability <span class="citation" data-cites="10UC562ga gOOBv1MD HmMIiIv2 EpOXYGt4">[<a href="#ref-10UC562ga" role="doc-biblioref">750</a>,<a href="#ref-gOOBv1MD" role="doc-biblioref">751</a>,<a href="#ref-HmMIiIv2" role="doc-biblioref">752</a>,<a href="#ref-EpOXYGt4" role="doc-biblioref">753</a>]</span> and was found to confer protection against SARS-CoV-2 in macaques even after six months <span class="citation" data-cites="HGVDPMLm">[<a href="#ref-HGVDPMLm" role="doc-biblioref">754</a>]</span>.
-The one- versus two-dose regimen was tested in volunteers through a phase I/IIa trial <span class="citation" data-cites="pWf2T8J8">[<a href="#ref-pWf2T8J8" role="doc-biblioref">749</a>]</span>, although these results are not yet available; however, the study did report that the vaccine was well-tolerated and that most participants demonstrated seroconversion in a neutralization assay 29 days after immunization <span class="citation" data-cites="pWf2T8J8">[<a href="#ref-pWf2T8J8" role="doc-biblioref">749</a>]</span>.
-The phase III trial is ongoing across several countries (Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the U.S.), but interim results were reported in a press release on January 29th, 2021 <span class="citation" data-cites="iWMHpTBJ 1FcpboRMm">[<a href="#ref-iWMHpTBJ" role="doc-biblioref">755</a>,<a href="#ref-1FcpboRMm" role="doc-biblioref">756</a>]</span>.
+Despite a lack of data from clinical trials, President Vladimir Putin of Russia announced the approval of the Sputnik V vaccines on August 11th, 2020 <span class="citation" data-cites="3KMxmQhV">[<a href="#ref-3KMxmQhV" role="doc-biblioref">738</a>]</span> and it has subsequently been administered in Russia and other countries.
+Subsequently, the phase I/II clinical trial was published and indicated that the vaccine was safe, with the most common adverse events being mild pain at the injection site (58%), hypothermia (50%), headaches (42%), fatigue (28%), and joint and muscle pain (24%), and immunogenic, with seroconversion observed in all participants three weeks after the second dose and with all participants producing antibodies to the SARS-CoV-2 glycoprotein <span class="citation" data-cites="PNZEiId1">[<a href="#ref-PNZEiId1" role="doc-biblioref">739</a>]</span>.
+In February 2021, six months after its approval in Russia, interim results of the phase III trial were released, indicating an overall vaccine efficacy of 91.6% for symptomatic COVID-19 <span class="citation" data-cites="gLAIyAHm">[<a href="#ref-gLAIyAHm" role="doc-biblioref">740</a>]</span>.
+As of early January, Sputnik V had been administered to as many as 1.5 million Russians <span class="citation" data-cites="X5LkVfY6">[<a href="#ref-X5LkVfY6" role="doc-biblioref">741</a>]</span> , and doses of Sputnik V have also been distributed to other parts of Europe, such as Belarus, Bosnia-Herzegovina, Hungary, San Marino, Serbia, and Slovakia <span class="citation" data-cites="16LczMwFO Z0V7NK7Y 16GYKbrOq">[<a href="#ref-16LczMwFO" role="doc-biblioref">742</a>,<a href="#ref-Z0V7NK7Y" role="doc-biblioref">743</a>,<a href="#ref-16GYKbrOq" role="doc-biblioref">744</a>]</span>, with the Czech Republic and Austria also having expressed interest in its procurement <span class="citation" data-cites="125VEHWS7">[<a href="#ref-125VEHWS7" role="doc-biblioref">745</a>]</span>.</p>
+<p>Third, Janssen Pharmaceuticals, Inc., a subsidiary of Johnson &amp; Johnson, also developed a viral vector vaccine in collaboration with and funded by the United States’s “Operation Warp Speed” <span class="citation" data-cites="D3Px25HN 57BTbcko">[<a href="#ref-D3Px25HN" role="doc-biblioref">746</a>,<a href="#ref-57BTbcko" role="doc-biblioref">747</a>]</span>.
+The vaccine candidate JNJ-78436735, formerly known as Ad26.COV2-S, is a monovalent vaccine that is composed of a replication-deficient adenovirus serotype 26 (Ad26) vector expressing the stabilized prefusion S protein of SARS-CoV-2 <span class="citation" data-cites="pWf2T8J8 10UC562ga">[<a href="#ref-pWf2T8J8" role="doc-biblioref">748</a>,<a href="#ref-10UC562ga" role="doc-biblioref">749</a>]</span>.
+Unlike the other two viral vector vaccines available to date, JNJ-78436735 requires only a single dose, a characteristic that is expected to aid in global deployment <span class="citation" data-cites="gOOBv1MD">[<a href="#ref-gOOBv1MD" role="doc-biblioref">750</a>]</span>.
+JNJ-78436735 was selected from among a number of initial candidate designs <span class="citation" data-cites="10UC562ga">[<a href="#ref-10UC562ga" role="doc-biblioref">749</a>]</span> and tested <em>in vivo</em> in Syrian golden hamsters and Rhesus macaques to assess safety and immunogenicity <span class="citation" data-cites="10UC562ga gOOBv1MD HmMIiIv2 EpOXYGt4">[<a href="#ref-10UC562ga" role="doc-biblioref">749</a>,<a href="#ref-gOOBv1MD" role="doc-biblioref">750</a>,<a href="#ref-HmMIiIv2" role="doc-biblioref">751</a>,<a href="#ref-EpOXYGt4" role="doc-biblioref">752</a>]</span>.
+The JNJ-78436735 candidate was selected for its favorable immunogenicity profile and ease of manufacturability <span class="citation" data-cites="10UC562ga gOOBv1MD HmMIiIv2 EpOXYGt4">[<a href="#ref-10UC562ga" role="doc-biblioref">749</a>,<a href="#ref-gOOBv1MD" role="doc-biblioref">750</a>,<a href="#ref-HmMIiIv2" role="doc-biblioref">751</a>,<a href="#ref-EpOXYGt4" role="doc-biblioref">752</a>]</span> and was found to confer protection against SARS-CoV-2 in macaques even after six months <span class="citation" data-cites="HGVDPMLm">[<a href="#ref-HGVDPMLm" role="doc-biblioref">753</a>]</span>.
+The one- versus two-dose regimen was tested in volunteers through a phase I/IIa trial <span class="citation" data-cites="pWf2T8J8">[<a href="#ref-pWf2T8J8" role="doc-biblioref">748</a>]</span>, although these results are not yet available; however, the study did report that the vaccine was well-tolerated and that most participants demonstrated seroconversion in a neutralization assay 29 days after immunization <span class="citation" data-cites="pWf2T8J8">[<a href="#ref-pWf2T8J8" role="doc-biblioref">748</a>]</span>.
+The phase III trial is ongoing across several countries (Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the U.S.), but interim results were reported in a press release on January 29th, 2021 <span class="citation" data-cites="iWMHpTBJ 1FcpboRMm">[<a href="#ref-iWMHpTBJ" role="doc-biblioref">754</a>,<a href="#ref-1FcpboRMm" role="doc-biblioref">755</a>]</span>.
 The vaccine was well-tolerated, and across all regions studied, it was found to be 66% effective after 28 days for the prevention of moderate to severe COVID-19 and to be 85% effective for the prevention of laboratory-confirmed severe COVID-19 as well as 100% protection against COVID-19-related hospitalization and death.
 However, the reported efficacy ranged from 57% in South Africa to 72% in the United States, suggesting that these observations might be influenced by the prominent viral strains circulating in each country at the time of the trial; at the time, several variants of concern including B.1.351, which was first identified in South Africa <span class="citation" data-cites="sqhvCTIL">[<a href="#ref-sqhvCTIL" role="doc-biblioref">283</a>]</span>, were being monitored.</p>
 <p>The three viral-vector vaccines described above have demonstrated the potential for this technology to facilitate a quick response to an emerging pathogen.
@@ -2805,57 +2805,57 @@ <h3 data-number="6.11.2" id="viral-vector-dna-vaccines"><span class="header-sect
 <h2 data-number="6.12" id="rna-vaccines"><span class="header-section-number">6.12</span> RNA Vaccines</h2>
 <p>Building on DNA Vaccine technology, RNA vaccines are an even more recent advancement for vaccine development.
 RNA vaccines are nucleic-acid based modalities that code for viral antigens against which the human body elicits a humoral and cellular immune response.
-The mRNA technology is transcribed <em>in vitro</em> and delivered to cells via lipid nanoparticles (LNP) <span class="citation" data-cites="HCImhzy8">[<a href="#ref-HCImhzy8" role="doc-biblioref">757</a>]</span>.
-They are recognized by ribosomes <em>in vivo</em> and then translated and modified into functional proteins <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>]</span>.
-The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>]</span>.
+The mRNA technology is transcribed <em>in vitro</em> and delivered to cells via lipid nanoparticles (LNP) <span class="citation" data-cites="HCImhzy8">[<a href="#ref-HCImhzy8" role="doc-biblioref">756</a>]</span>.
+They are recognized by ribosomes <em>in vivo</em> and then translated and modified into functional proteins <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>]</span>.
+The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>]</span>.
 Naturally, mRNA is not very stable and can degrade quickly in the extracellular environment or the cytoplasm.
-The LNP covering protects the mRNA from enzymatic degradation outside of the cell <span class="citation" data-cites="zNKWlCwE">[<a href="#ref-zNKWlCwE" role="doc-biblioref">758</a>]</span>.
+The LNP covering protects the mRNA from enzymatic degradation outside of the cell <span class="citation" data-cites="zNKWlCwE">[<a href="#ref-zNKWlCwE" role="doc-biblioref">757</a>]</span>.
 Codon optimization to prevent secondary structure formation and modifications of the poly-A tail as well as the 5’ untranslated region to promote ribosomal complex binding can increase mRNA expression in cells.
-Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell <span class="citation" data-cites="K0Ltu31S pRoqjur8">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>,<a href="#ref-pRoqjur8" role="doc-biblioref">759</a>]</span>.</p>
-<p>There are three types of RNA vaccines: non-replicating, <em>in vivo</em> self-replicating, and <em>in vitro</em> dendritic cell non-replicating <span class="citation" data-cites="1EM5nGaYd">[<a href="#ref-1EM5nGaYd" role="doc-biblioref">760</a>]</span>.
+Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell <span class="citation" data-cites="K0Ltu31S pRoqjur8">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>,<a href="#ref-pRoqjur8" role="doc-biblioref">758</a>]</span>.</p>
+<p>There are three types of RNA vaccines: non-replicating, <em>in vivo</em> self-replicating, and <em>in vitro</em> dendritic cell non-replicating <span class="citation" data-cites="1EM5nGaYd">[<a href="#ref-1EM5nGaYd" role="doc-biblioref">759</a>]</span>.
 Non-replicating mRNA vaccines consist of a simple open reading frame (ORF) for the viral antigen flanked by the 5’ UTR and 3’ poly-A tail.
-<em>In vivo</em> self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses <span class="citation" data-cites="K0Ltu31S pRoqjur8">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>,<a href="#ref-pRoqjur8" role="doc-biblioref">759</a>]</span>.
+<em>In vivo</em> self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses <span class="citation" data-cites="K0Ltu31S pRoqjur8">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>,<a href="#ref-pRoqjur8" role="doc-biblioref">758</a>]</span>.
 The RNA genome encodes the viral antigen along with proteins of the genome replication machinery, including an RNA polymerase.
-Structural proteins required for viral assembly are not included in the engineered genome <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>]</span>.
-Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response <span class="citation" data-cites="1EM5nGaYd">[<a href="#ref-1EM5nGaYd" role="doc-biblioref">760</a>]</span>.
+Structural proteins required for viral assembly are not included in the engineered genome <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>]</span>.
+Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response <span class="citation" data-cites="1EM5nGaYd">[<a href="#ref-1EM5nGaYd" role="doc-biblioref">759</a>]</span>.
 Finally, <em>in vitro</em> dendritic cell non-replicating RNA vaccines limit transfection to dendritic cells.
 Dendritic cells are potent antigen-presenting immune cells that easily take up mRNA and present fragments of the translated peptide on their MHC proteins, which can then interact with T cell receptors.
-Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus <span class="citation" data-cites="3LMMW7F0">[<a href="#ref-3LMMW7F0" role="doc-biblioref">761</a>]</span>.
-These cells are isolated from the patient, grown and transfected <em>ex vivo</em>, and reintroduced to the patient <span class="citation" data-cites="ENBWnhAh">[<a href="#ref-ENBWnhAh" role="doc-biblioref">659</a>]</span>.</p>
+Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus <span class="citation" data-cites="3LMMW7F0">[<a href="#ref-3LMMW7F0" role="doc-biblioref">760</a>]</span>.
+These cells are isolated from the patient, grown and transfected <em>ex vivo</em>, and reintroduced to the patient <span class="citation" data-cites="ENBWnhAh">[<a href="#ref-ENBWnhAh" role="doc-biblioref">658</a>]</span>.</p>
 <p>Vaccines based on mRNA delivery confer many advantages over traditional viral vectored vaccines and DNA vaccines.
-In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host <span class="citation" data-cites="wYZ6qJMu">[<a href="#ref-wYZ6qJMu" role="doc-biblioref">762</a>]</span>.
-Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>]</span>.
+In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host <span class="citation" data-cites="wYZ6qJMu">[<a href="#ref-wYZ6qJMu" role="doc-biblioref">761</a>]</span>.
+Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>]</span>.
 Furthermore, mRNA vaccines are easily, affordably, and rapidly scalable.
 Although mRNA vaccines have been developed for therapeutic and prophylactic purposes, none have previously been licensed or commercialized.
-Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus <span class="citation" data-cites="3EUiWZdN">[<a href="#ref-3EUiWZdN" role="doc-biblioref">763</a>]</span>.
-Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets <span class="citation" data-cites="6wZy2mn8">[<a href="#ref-6wZy2mn8" role="doc-biblioref">764</a>]</span>.
-Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika <span class="citation" data-cites="pRoqjur8">[<a href="#ref-pRoqjur8" role="doc-biblioref">759</a>]</span>.
-Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm <span class="citation" data-cites="zNKWlCwE">[<a href="#ref-zNKWlCwE" role="doc-biblioref">758</a>]</span>, and facilitate endosomal escape.
-LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels <span class="citation" data-cites="zNKWlCwE Djz8x39x">[<a href="#ref-zNKWlCwE" role="doc-biblioref">758</a>,<a href="#ref-Djz8x39x" role="doc-biblioref">765</a>]</span>.
+Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus <span class="citation" data-cites="3EUiWZdN">[<a href="#ref-3EUiWZdN" role="doc-biblioref">762</a>]</span>.
+Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets <span class="citation" data-cites="6wZy2mn8">[<a href="#ref-6wZy2mn8" role="doc-biblioref">763</a>]</span>.
+Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika <span class="citation" data-cites="pRoqjur8">[<a href="#ref-pRoqjur8" role="doc-biblioref">758</a>]</span>.
+Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm <span class="citation" data-cites="zNKWlCwE">[<a href="#ref-zNKWlCwE" role="doc-biblioref">757</a>]</span>, and facilitate endosomal escape.
+LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels <span class="citation" data-cites="zNKWlCwE Djz8x39x">[<a href="#ref-zNKWlCwE" role="doc-biblioref">757</a>,<a href="#ref-Djz8x39x" role="doc-biblioref">764</a>]</span>.
 Therefore, this technology holds great potential for targeted delivery of modified mRNA.
 <!-- To Do: development of this tech during previous epidemics?--></p>
 <p>Given the potential for this technology to be quickly adapted for a new pathogen, it has held significant interest for the treatment of COVID-19.
 In the vaccines developed under this approach, the mRNA coding for a stabilized prefusion spike protein, which is immunogenic <span class="citation" data-cites="5x25saIz">[<a href="#ref-5x25saIz" role="doc-biblioref">42</a>]</span>, can be furnished to the immune system in order to train its response.
 Two vaccine candidates in this category emerged with promising phase III results at the end of 2020.
 Both require two doses approximately one month apart.
-The first was Pfizer/BioNTech’s BNT162b2, which contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology <span class="citation" data-cites="1CsCQi9wT 10VyxCgQU">[<a href="#ref-1CsCQi9wT" role="doc-biblioref">766</a>,<a href="#ref-10VyxCgQU" role="doc-biblioref">767</a>]</span>.
+The first was Pfizer/BioNTech’s BNT162b2, which contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology <span class="citation" data-cites="1CsCQi9wT 10VyxCgQU">[<a href="#ref-1CsCQi9wT" role="doc-biblioref">765</a>,<a href="#ref-10VyxCgQU" role="doc-biblioref">766</a>]</span>.
 <!--To Do: brief history of phase I & phase II (like 1-2 sentences)-->
 In the phase II/III multinational trial, this vaccine was associated with a 95% efficacy against laboratory-confirmed COVID-19 and with mild-to-moderate local and systemic effects but a low risk of serious adverse effects <span class="citation" data-cites="CWlYjjIV">[<a href="#ref-CWlYjjIV" role="doc-biblioref">334</a>]</span>.
 Similarly, ModernaTX developed mRNA-1273, which, despite being the second mRNA vaccine to release phase III results, was the first mRNA vaccine to enter phase I clinical trials.
-mRNA-1273 is comprised by a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 <span class="citation" data-cites="Biu1CQeQ">[<a href="#ref-Biu1CQeQ" role="doc-biblioref">768</a>]</span>.
-In the phase I trial, neutralizing activity reached similar levels to that observed in convalescent plasma samples by day 7 after the second dose of RNA-1273 <span class="citation" data-cites="wiGjCZC8">[<a href="#ref-wiGjCZC8" role="doc-biblioref">670</a>]</span>.
-A few months later, interim results from the phase III trial indicated 94.5% efficacy of the vaccine in preventing symptomatic COVID-19 in adults who received the vaccine at 99 sites around the United States <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">769</a>]</span>.
-Similar to BNT162b2, the vaccine was associated with mild-to-moderate adverse effects but with a low risk of serious adverse events <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">769</a>]</span>.
-In late 2020, both vaccines both received approval from the United States’s Food and Drug Administration (FDA) under an emergency use authorization <span class="citation" data-cites="cAaN4Te0 13Ou1UUAd">[<a href="#ref-cAaN4Te0" role="doc-biblioref">770</a>,<a href="#ref-13Ou1UUAd" role="doc-biblioref">771</a>]</span>, and these vaccines have been widely distributed, primarily in North America and the European Union <span class="citation" data-cites="wByD9WaX">[<a href="#ref-wByD9WaX" role="doc-biblioref">691</a>]</span>.
+mRNA-1273 is comprised by a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 <span class="citation" data-cites="Biu1CQeQ">[<a href="#ref-Biu1CQeQ" role="doc-biblioref">767</a>]</span>.
+In the phase I trial, neutralizing activity reached similar levels to that observed in convalescent plasma samples by day 7 after the second dose of RNA-1273 <span class="citation" data-cites="wiGjCZC8">[<a href="#ref-wiGjCZC8" role="doc-biblioref">669</a>]</span>.
+A few months later, interim results from the phase III trial indicated 94.5% efficacy of the vaccine in preventing symptomatic COVID-19 in adults who received the vaccine at 99 sites around the United States <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">768</a>]</span>.
+Similar to BNT162b2, the vaccine was associated with mild-to-moderate adverse effects but with a low risk of serious adverse events <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">768</a>]</span>.
+In late 2020, both vaccines both received approval from the United States’s Food and Drug Administration (FDA) under an emergency use authorization <span class="citation" data-cites="cAaN4Te0 13Ou1UUAd">[<a href="#ref-cAaN4Te0" role="doc-biblioref">769</a>,<a href="#ref-13Ou1UUAd" role="doc-biblioref">770</a>]</span>, and these vaccines have been widely distributed, primarily in North America and the European Union <span class="citation" data-cites="wByD9WaX">[<a href="#ref-wByD9WaX" role="doc-biblioref">690</a>]</span>.
 As the first mRNA vaccines to make it to market, these two highly efficacious vaccines demonstrate the power of this emerging technology, which has previously attracted scientific interest because of its potential to be used to treat non-infectious as well as infectious diseases.</p>
 <h2 data-number="6.13" id="discussion-probably-to-be-fleshed-out-into-multiple-sections"><span class="header-section-number">6.13</span> Discussion (Probably to be fleshed out into multiple sections)</h2>
 <p>Given the wide range of vaccines under development, it is possible that some vaccine products may eventually be shown to be more effective in certain subpopulations, such as children, pregnant women, immunocompromised patients, the elderly, etc.
-However, the vaccine development process has historically been slow, and vaccines fail to provide immediate prophylactic protection or treat ongoing infections <span class="citation" data-cites="181QWa7HL">[<a href="#ref-181QWa7HL" role="doc-biblioref">651</a>]</span>.</p>
+However, the vaccine development process has historically been slow, and vaccines fail to provide immediate prophylactic protection or treat ongoing infections <span class="citation" data-cites="181QWa7HL">[<a href="#ref-181QWa7HL" role="doc-biblioref">650</a>]</span>.</p>
 <!--To Do: Add table of different technologies and which vaccines fall under each-->
 <p>Concerns: diversity of volunteer pools, variants, and distribution</p>
 <h1 data-number="7" id="vaccine-development-strategies-for-sars-cov-2-1"><span class="header-section-number">7</span> Vaccine Development Strategies for SARS-CoV-2</h1>
 <h3 data-number="7.0.1" id="appendix-sinovacs-coronavac"><span class="header-section-number">7.0.1</span> Appendix: Sinovac’s CoronaVac</h3>
-<p>Pre-clinical trials were performed using BALB/c mice and rhesus macaques <span class="citation" data-cites="14fILrRWg">[<a href="#ref-14fILrRWg" role="doc-biblioref">677</a>]</span>.
+<p>Pre-clinical trials were performed using BALB/c mice and rhesus macaques <span class="citation" data-cites="14fILrRWg">[<a href="#ref-14fILrRWg" role="doc-biblioref">676</a>]</span>.
 The SARS-CoV-2 strains used in this trial isolated from 11 hospitalized patients (5 from China, 3 from Italy, 1 from the UK, 1 from Spain, 1 from Switzerland).
 A phylogenetic analysis demonstrated that the strains were representative of the current circulating variants.
 One of the strains, CN2, from China was used as the inactivated and purified virus while the other 10 strains were used to challenge.
@@ -2867,7 +2867,7 @@ <h3 data-number="7.0.1" id="appendix-sinovacs-coronavac"><span class="header-sec
 Four macaques were assigned to each of four groups: treatment with 3 μg at day 0, 7 and 14, treatment with a high dose of 6 μg at day 0, 7 and 14, administration of a placebo vaccine, and administration of only the adjuvant.
 All vaccinated macaques induced IgGs and neutralizing antibodies.
 After challenge with SARS-CoV-2 strain CN1, vaccinated macaques were protected compared to control macaques (placebo or adjuvant only) based on histology and viral loads collected from different regions of the lung.</p>
-<p>Phase I/II clinical trials were conducted in adults 18-59 years old <span class="citation" data-cites="N1txjPtt">[<a href="#ref-N1txjPtt" role="doc-biblioref">678</a>]</span> and adults over 60 years old <span class="citation" data-cites="Ozya5HP5">[<a href="#ref-Ozya5HP5" role="doc-biblioref">676</a>]</span> in China.
+<p>Phase I/II clinical trials were conducted in adults 18-59 years old <span class="citation" data-cites="N1txjPtt">[<a href="#ref-N1txjPtt" role="doc-biblioref">677</a>]</span> and adults over 60 years old <span class="citation" data-cites="Ozya5HP5">[<a href="#ref-Ozya5HP5" role="doc-biblioref">675</a>]</span> in China.
 In the case of adults 18-59 years old, a single center, randomized, double-blind, placebo-controlled phase I/II trial was conducted in April 2020.
 Patients in this study were recruited from the community in Suining County of Jiangsu province, China.
 For the phase I trial, 144 (of 185 screened) participants were enrolled, with 72 enrolled in the 14-day interval cohort (i.e., treated on day 0 and day 14) and 72 in the 28-day interval cohort.
@@ -2887,9 +2887,9 @@ <h3 data-number="7.0.1" id="appendix-sinovacs-coronavac"><span class="header-sec
 Most adverse reactions were mild (grade 1) in severity and participants recovered within 48 hours.
 There was a single case, from the 6 μg group, of acute hypersensitivity with manifestation of urticaria 48 hours after the first dose.
 Both the 14-day and 28-day cohorts had a strong neutralizing Ab response.
-The neutralizing Ab response was measured using a micro cytopathogenic effect assay, which assesses the minimum dilution of neutralizing Ab to be 50% protective against structural changes in host cells in response to viral infection <span class="citation" data-cites="1GUVvcQjL">[<a href="#ref-1GUVvcQjL" role="doc-biblioref">772</a>]</span>.
+The neutralizing Ab response was measured using a micro cytopathogenic effect assay, which assesses the minimum dilution of neutralizing Ab to be 50% protective against structural changes in host cells in response to viral infection <span class="citation" data-cites="1GUVvcQjL">[<a href="#ref-1GUVvcQjL" role="doc-biblioref">771</a>]</span>.
 Additionally IgG antibody titers against the receptor binding domain were also measured using ELISA.</p>
-<p>Another phase I/II study was performed with older patients (older than 60 years) <span class="citation" data-cites="Ozya5HP5">[<a href="#ref-Ozya5HP5" role="doc-biblioref">676</a>]</span>.
+<p>Another phase I/II study was performed with older patients (older than 60 years) <span class="citation" data-cites="Ozya5HP5">[<a href="#ref-Ozya5HP5" role="doc-biblioref">675</a>]</span>.
 The study conducted a single-center, randomized, double-blind, placebo-controlled trial.
 The phase I trial looked at dose escalation using 3 dosages: 1.5, 3 and 6 μg.
 The mean age of participants was 65.8 years (std = 4.8).
@@ -2911,103 +2911,103 @@ <h3 data-number="7.0.1" id="appendix-sinovacs-coronavac"><span class="header-sec
 2% (7 participants) reported severe adverse events (4 from the 1.5 μg group, 1 from the 3 μg group, 2 from the 6 μg group), though these were found to be unrelated to the vaccine.</p>
 <p>Overall, the results from the pre-clinical and phase I/II clinical trials are promising.
 It was also very hopeful to see that the immune response was consistent in older adults (&gt; 60 years).
-Currently, phase III trials are being conducted in Brazil <span class="citation" data-cites="KewHbkLZ">[<a href="#ref-KewHbkLZ" role="doc-biblioref">675</a>]</span>.
+Currently, phase III trials are being conducted in Brazil <span class="citation" data-cites="KewHbkLZ">[<a href="#ref-KewHbkLZ" role="doc-biblioref">674</a>]</span>.
 This is a randomized, multicenter, endpoint driven, double-blind, placebo-controlled clinical trial.
 They are expecting 13,060 participants with 11,800 ages 18 to 59 years and 1,260 age 60+.
 Participants will be health care professionals.</p>
 <h2 data-number="7.1" id="rna-vaccines-1"><span class="header-section-number">7.1</span> RNA Vaccines</h2>
 <p>RNA vaccines are nucleic-acid based modalities that code for viral antigens against which the human body elicits a humoral and cellular immune response.
-The mRNA technology is transcribed <em>in vitro</em> and delivered to cells via lipid nanoparticles (LNP) <span class="citation" data-cites="HCImhzy8">[<a href="#ref-HCImhzy8" role="doc-biblioref">757</a>]</span>.
-They are recognized by ribosomes <em>in vivo</em> and then translated and modified into functional proteins <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>]</span>.
-The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>]</span>.
+The mRNA technology is transcribed <em>in vitro</em> and delivered to cells via lipid nanoparticles (LNP) <span class="citation" data-cites="HCImhzy8">[<a href="#ref-HCImhzy8" role="doc-biblioref">756</a>]</span>.
+They are recognized by ribosomes <em>in vivo</em> and then translated and modified into functional proteins <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>]</span>.
+The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>]</span>.
 Naturally, mRNA is not very stable and can degrade quickly in the extracellular environment or the cytoplasm.
-The LNP covering protects the mRNA from enzymatic degradation outside of the cell <span class="citation" data-cites="zNKWlCwE">[<a href="#ref-zNKWlCwE" role="doc-biblioref">758</a>]</span>.
+The LNP covering protects the mRNA from enzymatic degradation outside of the cell <span class="citation" data-cites="zNKWlCwE">[<a href="#ref-zNKWlCwE" role="doc-biblioref">757</a>]</span>.
 Codon optimization to prevent secondary structure formation and modifications of the poly-A tail as well as the 5’ untranslated region to promote ribosomal complex binding can increase mRNA expression in cells.
-Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell <span class="citation" data-cites="K0Ltu31S pRoqjur8">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>,<a href="#ref-pRoqjur8" role="doc-biblioref">759</a>]</span>.
+Furthermore, purifying out double-stranded RNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell <span class="citation" data-cites="K0Ltu31S pRoqjur8">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>,<a href="#ref-pRoqjur8" role="doc-biblioref">758</a>]</span>.
 Vaccines based on mRNA delivery confer many advantages over traditional viral vectored vaccines and DNA vaccines.
-In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host <span class="citation" data-cites="wYZ6qJMu">[<a href="#ref-wYZ6qJMu" role="doc-biblioref">762</a>]</span>.
-Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>]</span>.
+In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host <span class="citation" data-cites="wYZ6qJMu">[<a href="#ref-wYZ6qJMu" role="doc-biblioref">761</a>]</span>.
+Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>]</span>.
 Furthermore, mRNA vaccines are easily, affordably, and rapidly scalable.</p>
 <p>Although mRNA vaccines have been developed for therapeutic and prophylactic purposes, none have previously been licensed or commercialized.
-Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus <span class="citation" data-cites="3EUiWZdN">[<a href="#ref-3EUiWZdN" role="doc-biblioref">763</a>]</span>.
-Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets <span class="citation" data-cites="6wZy2mn8">[<a href="#ref-6wZy2mn8" role="doc-biblioref">764</a>]</span>.
-Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika <span class="citation" data-cites="pRoqjur8">[<a href="#ref-pRoqjur8" role="doc-biblioref">759</a>]</span>.
-Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm <span class="citation" data-cites="zNKWlCwE">[<a href="#ref-zNKWlCwE" role="doc-biblioref">758</a>]</span>, and facilitate endosomal escape.
-LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels <span class="citation" data-cites="zNKWlCwE Djz8x39x">[<a href="#ref-zNKWlCwE" role="doc-biblioref">758</a>,<a href="#ref-Djz8x39x" role="doc-biblioref">765</a>]</span>.
+Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus <span class="citation" data-cites="3EUiWZdN">[<a href="#ref-3EUiWZdN" role="doc-biblioref">762</a>]</span>.
+Preclinical data previously identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets <span class="citation" data-cites="6wZy2mn8">[<a href="#ref-6wZy2mn8" role="doc-biblioref">763</a>]</span>.
+Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika <span class="citation" data-cites="pRoqjur8">[<a href="#ref-pRoqjur8" role="doc-biblioref">758</a>]</span>.
+Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm <span class="citation" data-cites="zNKWlCwE">[<a href="#ref-zNKWlCwE" role="doc-biblioref">757</a>]</span>, and facilitate endosomal escape.
+LNPs can be coated with modalities recognized and engulfed by specific cell types, and LNPs that are 150 nm or less effectively enter into lymphatic vessels <span class="citation" data-cites="zNKWlCwE Djz8x39x">[<a href="#ref-zNKWlCwE" role="doc-biblioref">757</a>,<a href="#ref-Djz8x39x" role="doc-biblioref">764</a>]</span>.
 Therefore, this technology holds great potential for targeted delivery of modified mRNA.</p>
-<p>There are three types of RNA vaccines: non-replicating, <em>in vivo</em> self-replicating, and <em>in vitro</em> dendritic cell non-replicating <span class="citation" data-cites="1EM5nGaYd">[<a href="#ref-1EM5nGaYd" role="doc-biblioref">760</a>]</span>.
+<p>There are three types of RNA vaccines: non-replicating, <em>in vivo</em> self-replicating, and <em>in vitro</em> dendritic cell non-replicating <span class="citation" data-cites="1EM5nGaYd">[<a href="#ref-1EM5nGaYd" role="doc-biblioref">759</a>]</span>.
 Non-replicating mRNA vaccines consist of a simple open reading frame (ORF) for the viral antigen flanked by the 5’ UTR and 3’ poly-A tail.
-<em>In vivo</em> self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses <span class="citation" data-cites="K0Ltu31S pRoqjur8">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>,<a href="#ref-pRoqjur8" role="doc-biblioref">759</a>]</span>.
+<em>In vivo</em> self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses <span class="citation" data-cites="K0Ltu31S pRoqjur8">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>,<a href="#ref-pRoqjur8" role="doc-biblioref">758</a>]</span>.
 The RNA genome encodes the viral antigen along with proteins of the genome replication machinery, including an RNA polymerase.
-Structural proteins required for viral assembly are not included in the engineered genome <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">655</a>]</span>.
-Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response <span class="citation" data-cites="1EM5nGaYd">[<a href="#ref-1EM5nGaYd" role="doc-biblioref">760</a>]</span>.
+Structural proteins required for viral assembly are not included in the engineered genome <span class="citation" data-cites="K0Ltu31S">[<a href="#ref-K0Ltu31S" role="doc-biblioref">654</a>]</span>.
+Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response <span class="citation" data-cites="1EM5nGaYd">[<a href="#ref-1EM5nGaYd" role="doc-biblioref">759</a>]</span>.
 Finally, <em>in vitro</em> dendritic cell non-replicating RNA vaccines limit transfection to dendritic cells.
 Dendritic cells are potent antigen-presenting immune cells that easily take up mRNA and present fragments of the translated peptide on their MHC proteins, which can then interact with T cell receptors.
-Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus <span class="citation" data-cites="3LMMW7F0">[<a href="#ref-3LMMW7F0" role="doc-biblioref">761</a>]</span>.
-These cells are isolated from the patient, grown and transfected <em>ex vivo</em>, and reintroduced to the patient <span class="citation" data-cites="ENBWnhAh">[<a href="#ref-ENBWnhAh" role="doc-biblioref">659</a>]</span>.</p>
+Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus <span class="citation" data-cites="3LMMW7F0">[<a href="#ref-3LMMW7F0" role="doc-biblioref">760</a>]</span>.
+These cells are isolated from the patient, grown and transfected <em>ex vivo</em>, and reintroduced to the patient <span class="citation" data-cites="ENBWnhAh">[<a href="#ref-ENBWnhAh" role="doc-biblioref">658</a>]</span>.</p>
 <p>Given the potential for this technology to be quickly adapted for a new pathogen, it has held significant interest for the treatment of COVID-19.
 In the vaccines developed under this approach, the spike protein, which is immunogenic <span class="citation" data-cites="5x25saIz">[<a href="#ref-5x25saIz" role="doc-biblioref">42</a>]</span>, can be furnished to the immune system in order to train its response.
-The vaccine candidates developed against SARS-CoV-2 using mRNA vectors utilize similar principles and technologies, although there are slight differences in implementation among candidates such as the formulation of the platform and the specific components of the spike protein encapsulated (e.g., the full Spike protein vs. the RBD alone) <span class="citation" data-cites="suRY1e0N">[<a href="#ref-suRY1e0N" role="doc-biblioref">773</a>]</span>.
+The vaccine candidates developed against SARS-CoV-2 using mRNA vectors utilize similar principles and technologies, although there are slight differences in implementation among candidates such as the formulation of the platform and the specific components of the spike protein encapsulated (e.g., the full Spike protein vs. the RBD alone) <span class="citation" data-cites="suRY1e0N">[<a href="#ref-suRY1e0N" role="doc-biblioref">772</a>]</span>.
 The results of the interim analyses of two mRNA vaccine candidates became available at the end of 2020 and provided strong support for this emerging approach to vaccination.
 Below we describe the results available as of February 2021 for two such candidates, mRNA-1273 produced by ModernaTX and BNT162b2 produced by Pfizer, Inc. and BioNTech.</p>
 <h3 data-number="7.1.1" id="modernatx-mrna-vaccine"><span class="header-section-number">7.1.1</span> ModernaTX mRNA Vaccine</h3>
 <p>ModernaTX’s mRNA-1273 vaccine was the first COVID-19 vaccine to enter a phase I clinical trial in the United States.
-In this trial, Moderna spearheaded an investigation on the immunogenicity and reactogenicity of mRNA-1273, a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 <span class="citation" data-cites="Biu1CQeQ">[<a href="#ref-Biu1CQeQ" role="doc-biblioref">768</a>]</span>.
-An initial report described the results of enrolling forty-five participants who were administered intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, with the goal of following patients for the next twelve months <span class="citation" data-cites="wiGjCZC8">[<a href="#ref-wiGjCZC8" role="doc-biblioref">670</a>]</span>.
+In this trial, Moderna spearheaded an investigation on the immunogenicity and reactogenicity of mRNA-1273, a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized S protein for SARS-CoV-2 <span class="citation" data-cites="Biu1CQeQ">[<a href="#ref-Biu1CQeQ" role="doc-biblioref">767</a>]</span>.
+An initial report described the results of enrolling forty-five participants who were administered intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, with the goal of following patients for the next twelve months <span class="citation" data-cites="wiGjCZC8">[<a href="#ref-wiGjCZC8" role="doc-biblioref">669</a>]</span>.
 Healthy males and non-pregnant females aged 18-55 years were recruited for this study and divided into three groups receiving 25, 100, or 250 micrograms (μg) of mRNA-1273.
-IgG ELISA assays on patient serology samples were used to examine the immunogenicity of the vaccine <span class="citation" data-cites="Biu1CQeQ">[<a href="#ref-Biu1CQeQ" role="doc-biblioref">768</a>]</span>.
+IgG ELISA assays on patient serology samples were used to examine the immunogenicity of the vaccine <span class="citation" data-cites="Biu1CQeQ">[<a href="#ref-Biu1CQeQ" role="doc-biblioref">767</a>]</span>.
 Binding antibodies were observed at two weeks after the first dose at all concentrations.
 At the time point one week after the second dose was administered on day 29, the pseudotyped lentivirus reporter single-round-of-infection neutralization assay (PsVNA), which was used to assess neutralizing activity, reached a median level similar to the median observed in convalescent plasma samples.
 Participants reported mild and moderate systemic adverse events after the day 1 injection, and one severe local event was observed in each of the two highest dose levels.
 The second injection led to severe systemic adverse events for three of the participants at the highest dose levels, with one participant in the group being evaluated at an urgent care center on the day after the second dose.
 The reported localized adverse events from the second dose were similar to those from the first.</p>
-<p>Several months later, a press release from ModernaTX described the results of the first interim analysis of the vaccine <span class="citation" data-cites="IMmoqofb">[<a href="#ref-IMmoqofb" role="doc-biblioref">774</a>]</span>.
-On November 16, 2020, a report was released describing the initial results from Phase III testing, corresponding to the first 95 cases of COVID-19 in the 30,000 enrolled participants <span class="citation" data-cites="IMmoqofb">[<a href="#ref-IMmoqofb" role="doc-biblioref">774</a>]</span>, with additional data released to the FDA on December 17, 2020 <span class="citation" data-cites="QEdBZMLe">[<a href="#ref-QEdBZMLe" role="doc-biblioref">775</a>]</span>.
-These results were subsequently published in a peer-reviewed journal (<em>The New England Journal of Medicine</em>) on December 30, 2020 <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">769</a>]</span>.
-The first group of 30,420 study participants were randomized to receive the vaccine or a placebo at a ratio of 1:1 <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">769</a>]</span>.
-Administration occurred at 99 sites within the United States in two sessions, spaced 28 days apart <span class="citation" data-cites="16kGLLlT8 ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">769</a>,<a href="#ref-16kGLLlT8" role="doc-biblioref">776</a>]</span>.
-Patients reporting COVID-19 symptoms upon follow-up were tested for SARS-CoV-2 using a nasopharyngeal swab that was evaluated with RT-PCR <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">776</a>]</span>.
+<p>Several months later, a press release from ModernaTX described the results of the first interim analysis of the vaccine <span class="citation" data-cites="IMmoqofb">[<a href="#ref-IMmoqofb" role="doc-biblioref">773</a>]</span>.
+On November 16, 2020, a report was released describing the initial results from Phase III testing, corresponding to the first 95 cases of COVID-19 in the 30,000 enrolled participants <span class="citation" data-cites="IMmoqofb">[<a href="#ref-IMmoqofb" role="doc-biblioref">773</a>]</span>, with additional data released to the FDA on December 17, 2020 <span class="citation" data-cites="QEdBZMLe">[<a href="#ref-QEdBZMLe" role="doc-biblioref">774</a>]</span>.
+These results were subsequently published in a peer-reviewed journal (<em>The New England Journal of Medicine</em>) on December 30, 2020 <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">768</a>]</span>.
+The first group of 30,420 study participants were randomized to receive the vaccine or a placebo at a ratio of 1:1 <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">768</a>]</span>.
+Administration occurred at 99 sites within the United States in two sessions, spaced 28 days apart <span class="citation" data-cites="16kGLLlT8 ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">768</a>,<a href="#ref-16kGLLlT8" role="doc-biblioref">775</a>]</span>.
+Patients reporting COVID-19 symptoms upon follow-up were tested for SARS-CoV-2 using a nasopharyngeal swab that was evaluated with RT-PCR <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">775</a>]</span>.
 The initial preliminary analysis reported the results of the cases observed up until a cut-off date of November 11, 2020.
-Of these first 95 cases reported, 90 occurred in participants receiving the placebo compared to 5 cases in the group receiving the vaccine <span class="citation" data-cites="IMmoqofb">[<a href="#ref-IMmoqofb" role="doc-biblioref">774</a>]</span>.
+Of these first 95 cases reported, 90 occurred in participants receiving the placebo compared to 5 cases in the group receiving the vaccine <span class="citation" data-cites="IMmoqofb">[<a href="#ref-IMmoqofb" role="doc-biblioref">773</a>]</span>.
 These results suggested the vaccine is 94.5% effective in preventing COVID-19.
 Additionally, eleven severe cases of COVID-19 were observed, and all eleven occurred in participants receiving the placebo.
-The publication reported the results through an extended cut-off date of November 21, 2020, corresponding to 196 cases <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">769</a>]</span>.
+The publication reported the results through an extended cut-off date of November 21, 2020, corresponding to 196 cases <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">768</a>]</span>.
 Of these, 11 occurred in the vaccine group and 185 in the placebo group, corresponding to an efficacy of 94.1%.
 Once again, all of the severe cases of COVID-19 observed (n=30) occurred in the placebo group, including one death.
 Thus, as more cases are reported, the efficacy of the vaccine has remained above 90%, and no cases of severe COVID-19 have yet been reported in participants receiving the vaccine.</p>
 <p>These findings suggest the possibility that the vaccine might bolster immune defenses even for subjects who do still develop a SARS-CoV-2 infection.
-The study was designed with an explicit goal of including individuals at high risk for COVID-19, including older adults, people with underlying health conditions, and people of color <span class="citation" data-cites="vkczroFC">[<a href="#ref-vkczroFC" role="doc-biblioref">777</a>]</span>.
-The Phase III trial population was comprised by approximately 25.3% adults over age 65 in the initial report and 24.8% in the publication <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">776</a>]</span>.
-Among the cases reported by both interim analyses, 16-17% occurred in older adults <span class="citation" data-cites="IMmoqofb ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">769</a>,<a href="#ref-IMmoqofb" role="doc-biblioref">774</a>]</span>..
-Additionally, approximately 10% of participants identified a Black or African-American background and 20% identified Hispanic or Latino ethnicity <span class="citation" data-cites="16kGLLlT8 ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">769</a>,<a href="#ref-16kGLLlT8" role="doc-biblioref">776</a>]</span>.
-Among the first 95 cases, 12.6% occurred in participants identifying a Hispanic or Latino background and 4% in participants reporting a Black or African-American background <span class="citation" data-cites="IMmoqofb">[<a href="#ref-IMmoqofb" role="doc-biblioref">774</a>]</span>; in the publication, they indicated only that 41 of the cases reported in the placebo group and 1 case in the treatment group occurred in “communities of color”, corresponding to 21.4% of all cases <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">769</a>]</span>.
+The study was designed with an explicit goal of including individuals at high risk for COVID-19, including older adults, people with underlying health conditions, and people of color <span class="citation" data-cites="vkczroFC">[<a href="#ref-vkczroFC" role="doc-biblioref">776</a>]</span>.
+The Phase III trial population was comprised by approximately 25.3% adults over age 65 in the initial report and 24.8% in the publication <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">775</a>]</span>.
+Among the cases reported by both interim analyses, 16-17% occurred in older adults <span class="citation" data-cites="IMmoqofb ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">768</a>,<a href="#ref-IMmoqofb" role="doc-biblioref">773</a>]</span>..
+Additionally, approximately 10% of participants identified a Black or African-American background and 20% identified Hispanic or Latino ethnicity <span class="citation" data-cites="16kGLLlT8 ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">768</a>,<a href="#ref-16kGLLlT8" role="doc-biblioref">775</a>]</span>.
+Among the first 95 cases, 12.6% occurred in participants identifying a Hispanic or Latino background and 4% in participants reporting a Black or African-American background <span class="citation" data-cites="IMmoqofb">[<a href="#ref-IMmoqofb" role="doc-biblioref">773</a>]</span>; in the publication, they indicated only that 41 of the cases reported in the placebo group and 1 case in the treatment group occurred in “communities of color”, corresponding to 21.4% of all cases <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">768</a>]</span>.
 While the sample size in both analyses is small relative to the study population of over 30,000, these results suggest that the vaccine is likely to be effective in people from a variety of backgrounds.
 By all indications, this vaccine is likely to be highly useful in mitigating the damage of SARS-CoV-2.</p>
-<p>In-depth safety data was released by ModernaTX as part of their application for an EUA from the FDA and summarized in the associated publication <span class="citation" data-cites="ZYxoabEm 16kGLLlT8">[<a href="#ref-ZYxoabEm" role="doc-biblioref">769</a>,<a href="#ref-16kGLLlT8" role="doc-biblioref">776</a>]</span>.
+<p>In-depth safety data was released by ModernaTX as part of their application for an EUA from the FDA and summarized in the associated publication <span class="citation" data-cites="ZYxoabEm 16kGLLlT8">[<a href="#ref-ZYxoabEm" role="doc-biblioref">768</a>,<a href="#ref-16kGLLlT8" role="doc-biblioref">775</a>]</span>.
 Because the detail provided in the report is greater than that provided in the publication, here we emphasize the results observed at the time of the first analysis.
-Overall, a large percentage of participants reported adverse effects when solicited, and these reports were higher in the vaccine group than in the placebo group (94.5% versus 59.5%, respectively, at the time of the initial analysis) <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">776</a>]</span>.
-Some of these events met the criteria for grade 3 (local or systemic) or grade 4 (systemic only) toxicity <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">776</a>]</span>, but most were grade 1 or grade 2 and lasted 2-3 days <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">769</a>]</span>.
-The most common local adverse reaction was pain at the injection site, reported by 83.7% of participants receiving the first dose of the vaccine and 88.4% upon receiving the second dose, compared to 19.8% and 19.8% and 17.0%, respectively, of patients in the placebo condition <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">776</a>]</span>.
+Overall, a large percentage of participants reported adverse effects when solicited, and these reports were higher in the vaccine group than in the placebo group (94.5% versus 59.5%, respectively, at the time of the initial analysis) <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">775</a>]</span>.
+Some of these events met the criteria for grade 3 (local or systemic) or grade 4 (systemic only) toxicity <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">775</a>]</span>, but most were grade 1 or grade 2 and lasted 2-3 days <span class="citation" data-cites="ZYxoabEm">[<a href="#ref-ZYxoabEm" role="doc-biblioref">768</a>]</span>.
+The most common local adverse reaction was pain at the injection site, reported by 83.7% of participants receiving the first dose of the vaccine and 88.4% upon receiving the second dose, compared to 19.8% and 19.8% and 17.0%, respectively, of patients in the placebo condition <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">775</a>]</span>.
 Fewer than 5% of vaccine recipients reported grade 3 pain at either administration.
-Other frequent local reactions included erythema, swelling, and lymphadenopathy <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">776</a>]</span>.
-For systemic adverse reactions, fatigue was the most common <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">776</a>]</span>.
-Among participants receiving either dose of the vaccine, 68.5% reported fatigue compared to 36.1% participants receiving the placebo <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">776</a>]</span>.
-The level of fatigue experienced was usually fairly mild, with only 9.6% and 1.3% of participants in the vaccine and placebo conditions, respectively, reporting grade 3 fatigue <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">776</a>]</span>, which corresponds to significant interference with daily activity <span class="citation" data-cites="oJWLuU0h">[<a href="#ref-oJWLuU0h" role="doc-biblioref">778</a>]</span>.
-Based on the results of the report, an EUA was issued on December 18, 2020 to allow distribution of this vaccine in the United States <span class="citation" data-cites="13Ou1UUAd">[<a href="#ref-13Ou1UUAd" role="doc-biblioref">771</a>]</span>, and it was shortly followed by an Interim Order authorizing distribution of the vaccine in Canada <span class="citation" data-cites="HwoGQ6DD">[<a href="#ref-HwoGQ6DD" role="doc-biblioref">779</a>]</span> and a conditional marketing authorization by the European Medicines Agency to facilitate distribution in the European Union <span class="citation" data-cites="4hVgIXyi">[<a href="#ref-4hVgIXyi" role="doc-biblioref">780</a>]</span>.</p>
+Other frequent local reactions included erythema, swelling, and lymphadenopathy <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">775</a>]</span>.
+For systemic adverse reactions, fatigue was the most common <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">775</a>]</span>.
+Among participants receiving either dose of the vaccine, 68.5% reported fatigue compared to 36.1% participants receiving the placebo <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">775</a>]</span>.
+The level of fatigue experienced was usually fairly mild, with only 9.6% and 1.3% of participants in the vaccine and placebo conditions, respectively, reporting grade 3 fatigue <span class="citation" data-cites="16kGLLlT8">[<a href="#ref-16kGLLlT8" role="doc-biblioref">775</a>]</span>, which corresponds to significant interference with daily activity <span class="citation" data-cites="oJWLuU0h">[<a href="#ref-oJWLuU0h" role="doc-biblioref">777</a>]</span>.
+Based on the results of the report, an EUA was issued on December 18, 2020 to allow distribution of this vaccine in the United States <span class="citation" data-cites="13Ou1UUAd">[<a href="#ref-13Ou1UUAd" role="doc-biblioref">770</a>]</span>, and it was shortly followed by an Interim Order authorizing distribution of the vaccine in Canada <span class="citation" data-cites="HwoGQ6DD">[<a href="#ref-HwoGQ6DD" role="doc-biblioref">778</a>]</span> and a conditional marketing authorization by the European Medicines Agency to facilitate distribution in the European Union <span class="citation" data-cites="4hVgIXyi">[<a href="#ref-4hVgIXyi" role="doc-biblioref">779</a>]</span>.</p>
 <h3 data-number="7.1.2" id="pfizerbiontech-bnt162b2"><span class="header-section-number">7.1.2</span> Pfizer/BioNTech BNT162b2</h3>
 <p>ModernaTX was, in fact, the second company to release news of a successful interim analysis of an mRNA vaccine and receive an EUA.
-The first report came from Pfizer and BioNTech’s mRNA vaccine BNT162b2 on November 9, 2020 <span class="citation" data-cites="16hlR7Xgi">[<a href="#ref-16hlR7Xgi" role="doc-biblioref">781</a>]</span>, and a preliminary report was published in the <em>New England Journal of Medicine</em> one month later <span class="citation" data-cites="CWlYjjIV">[<a href="#ref-CWlYjjIV" role="doc-biblioref">334</a>]</span>.
-The vaccine candidate is contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology <span class="citation" data-cites="1CsCQi9wT 10VyxCgQU">[<a href="#ref-1CsCQi9wT" role="doc-biblioref">766</a>,<a href="#ref-10VyxCgQU" role="doc-biblioref">767</a>]</span>.
-This vaccine candidate should not be confused with a similar candidate from Pfizer/BioNTech, BNT162b1, that delivered only the RBD of the spike protein <span class="citation" data-cites="dlqAfQ7t T3BkYtz2">[<a href="#ref-dlqAfQ7t" role="doc-biblioref">782</a>,<a href="#ref-T3BkYtz2" role="doc-biblioref">783</a>]</span>, which was not advanced to a stage III trial because of the improved reactogenicity/immunogenicity profile of BNT162b2 <span class="citation" data-cites="MD2K7MYB">[<a href="#ref-MD2K7MYB" role="doc-biblioref">335</a>]</span>.</p>
+The first report came from Pfizer and BioNTech’s mRNA vaccine BNT162b2 on November 9, 2020 <span class="citation" data-cites="16hlR7Xgi">[<a href="#ref-16hlR7Xgi" role="doc-biblioref">780</a>]</span>, and a preliminary report was published in the <em>New England Journal of Medicine</em> one month later <span class="citation" data-cites="CWlYjjIV">[<a href="#ref-CWlYjjIV" role="doc-biblioref">334</a>]</span>.
+The vaccine candidate is contains the full prefusion stabilized, membrane-anchored SARS-CoV-2 spike protein in a vaccine formulation based on modified mRNA (modRNA) technology <span class="citation" data-cites="1CsCQi9wT 10VyxCgQU">[<a href="#ref-1CsCQi9wT" role="doc-biblioref">765</a>,<a href="#ref-10VyxCgQU" role="doc-biblioref">766</a>]</span>.
+This vaccine candidate should not be confused with a similar candidate from Pfizer/BioNTech, BNT162b1, that delivered only the RBD of the spike protein <span class="citation" data-cites="dlqAfQ7t T3BkYtz2">[<a href="#ref-dlqAfQ7t" role="doc-biblioref">781</a>,<a href="#ref-T3BkYtz2" role="doc-biblioref">782</a>]</span>, which was not advanced to a stage III trial because of the improved reactogenicity/immunogenicity profile of BNT162b2 <span class="citation" data-cites="MD2K7MYB">[<a href="#ref-MD2K7MYB" role="doc-biblioref">335</a>]</span>.</p>
 <p>During the Phase III trial of BNT162b2, 43,538 participants were enrolled 1:1 in the placebo and the vaccine candidate and received two 30-μg doses 21 days apart <span class="citation" data-cites="CWlYjjIV">[<a href="#ref-CWlYjjIV" role="doc-biblioref">334</a>]</span>.
 Of these enrolled participants, 21,720 received BNT162b2 and 21,728 received a placebo <span class="citation" data-cites="CWlYjjIV">[<a href="#ref-CWlYjjIV" role="doc-biblioref">334</a>]</span>.
 Recruitment occurred at 135 sites across six countries: Argentina, Brazil, Germany, South Africa, Turkey, and the United States.
-An initial press release described the first 94 cases, which were consistent with 90% efficacy of the vaccine at 7 days following the second dose <span class="citation" data-cites="16hlR7Xgi">[<a href="#ref-16hlR7Xgi" role="doc-biblioref">781</a>]</span>.
+An initial press release described the first 94 cases, which were consistent with 90% efficacy of the vaccine at 7 days following the second dose <span class="citation" data-cites="16hlR7Xgi">[<a href="#ref-16hlR7Xgi" role="doc-biblioref">780</a>]</span>.
 The release of the full trial information covered a longer period and analyzed the first 170 cases occurring at least 7 days after the second dose, 8 of which occurred in patients who had received BNT162b2.
-The press release characterized the study population as diverse, reporting that 42% of the participants worldwide came from non-white backgrounds, including 10% Black and 26% Hispanic or Latino <span class="citation" data-cites="EMWkcH5x">[<a href="#ref-EMWkcH5x" role="doc-biblioref">784</a>]</span>.
-Within the United States, 10% and 13% of participants, respectively, identified themselves as having Black or Hispanic/Latino backgrounds <span class="citation" data-cites="EMWkcH5x">[<a href="#ref-EMWkcH5x" role="doc-biblioref">784</a>]</span>.
-Additionally, 41% of participants worldwide were 56 years of age or older <span class="citation" data-cites="EMWkcH5x">[<a href="#ref-EMWkcH5x" role="doc-biblioref">784</a>]</span>, and they reported that the efficacy of the vaccine in adults over 65 was 94% <span class="citation" data-cites="Ufs4s7hG">[<a href="#ref-Ufs4s7hG" role="doc-biblioref">785</a>]</span>.
-The primary efficacy analysis of the Phase III study was concluded on November 18, 2020 <span class="citation" data-cites="Ufs4s7hG">[<a href="#ref-Ufs4s7hG" role="doc-biblioref">785</a>]</span>, and the final results indicted 94.6% efficacy of the vaccine <span class="citation" data-cites="CWlYjjIV">[<a href="#ref-CWlYjjIV" role="doc-biblioref">334</a>]</span>.</p>
+The press release characterized the study population as diverse, reporting that 42% of the participants worldwide came from non-white backgrounds, including 10% Black and 26% Hispanic or Latino <span class="citation" data-cites="EMWkcH5x">[<a href="#ref-EMWkcH5x" role="doc-biblioref">783</a>]</span>.
+Within the United States, 10% and 13% of participants, respectively, identified themselves as having Black or Hispanic/Latino backgrounds <span class="citation" data-cites="EMWkcH5x">[<a href="#ref-EMWkcH5x" role="doc-biblioref">783</a>]</span>.
+Additionally, 41% of participants worldwide were 56 years of age or older <span class="citation" data-cites="EMWkcH5x">[<a href="#ref-EMWkcH5x" role="doc-biblioref">783</a>]</span>, and they reported that the efficacy of the vaccine in adults over 65 was 94% <span class="citation" data-cites="Ufs4s7hG">[<a href="#ref-Ufs4s7hG" role="doc-biblioref">784</a>]</span>.
+The primary efficacy analysis of the Phase III study was concluded on November 18, 2020 <span class="citation" data-cites="Ufs4s7hG">[<a href="#ref-Ufs4s7hG" role="doc-biblioref">784</a>]</span>, and the final results indicted 94.6% efficacy of the vaccine <span class="citation" data-cites="CWlYjjIV">[<a href="#ref-CWlYjjIV" role="doc-biblioref">334</a>]</span>.</p>
 <p>The safety profile of the vaccine was also assessed <span class="citation" data-cites="CWlYjjIV">[<a href="#ref-CWlYjjIV" role="doc-biblioref">334</a>]</span>.
 A subset of patients were followed for reactogenicity using electronic diaries, with the data collected from these 8,183 participants comprising the solicited safety events analyzed.
 Much like those who received the ModernaTX vaccine candidate, a large proportion of participants reported experiencing site injection pain within 7 days of vaccination.
@@ -3017,14 +3017,14 @@ <h3 data-number="7.1.2" id="pfizerbiontech-bnt162b2"><span class="header-section
 Participants also experienced systemic effects, including fever (in most cases lower than 38.9°C and more common after dose 2), fatigue (25-50% of participants depending on age group and dose), headache (25-50% of participants depending on age group and dose), chills, and muscle or joint pain; more rarely, patients could experience gastrointestinal effects such as vomiting or diarrhea.
 As with the local events, these events were almost always grade I or II.
 While some events were reported by the placebo groups, these events were much rarer than in the treatment group even though compliance was similar.
-Based on the efficacy and safety information released, the vaccine was approved in early December by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency with administration outside of a clinical trial beginning on December 8, 2020 <span class="citation" data-cites="31rsgfCB fhw7l8VO">[<a href="#ref-31rsgfCB" role="doc-biblioref">786</a>,<a href="#ref-fhw7l8VO" role="doc-biblioref">787</a>]</span>.
-As of December 11, 2020, the United States FDA approved this vaccine under an emergency use authorization <span class="citation" data-cites="cAaN4Te0">[<a href="#ref-cAaN4Te0" role="doc-biblioref">770</a>]</span>.</p>
+Based on the efficacy and safety information released, the vaccine was approved in early December by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency with administration outside of a clinical trial beginning on December 8, 2020 <span class="citation" data-cites="31rsgfCB fhw7l8VO">[<a href="#ref-31rsgfCB" role="doc-biblioref">785</a>,<a href="#ref-fhw7l8VO" role="doc-biblioref">786</a>]</span>.
+As of December 11, 2020, the United States FDA approved this vaccine under an emergency use authorization <span class="citation" data-cites="cAaN4Te0">[<a href="#ref-cAaN4Te0" role="doc-biblioref">769</a>]</span>.</p>
 <h2 data-number="7.2" id="viral-vector-vaccines"><span class="header-section-number">7.2</span> Viral Vector Vaccines</h2>
 <h3 data-number="7.2.1" id="chadox1-ncov-19-astrazeneca"><span class="header-section-number">7.2.1</span> ChAdOx1 nCoV-19 (AstraZeneca)</h3>
 <p>As discussed above, prior analyses of viral vector vaccines against hCoV had indicated that this approach showed potential for inducing an immune response, but little information was available about the effect on real-world immunity.
-In the first phase of development, a candidate ChAdOx1 nCoV-19 was evaluated through the immune challenge of two animal models, mice and rhesus macaques <span class="citation" data-cites="1037p4Gvs">[<a href="#ref-1037p4Gvs" role="doc-biblioref">736</a>]</span>.
-Animals in the treatment condition were observed to develop neutralizing antibodies specific to SARS-CoV-2 (both macaques and mice) and to show reduced clinical scores when exposed to SARS-CoV-2 (macaques) <span class="citation" data-cites="1037p4Gvs">[<a href="#ref-1037p4Gvs" role="doc-biblioref">736</a>]</span>.
-Next, a phase I/II trial was undertaken using a single-blind, randomized controlled design <span class="citation" data-cites="2bBVSpM">[<a href="#ref-2bBVSpM" role="doc-biblioref">737</a>]</span>.
+In the first phase of development, a candidate ChAdOx1 nCoV-19 was evaluated through the immune challenge of two animal models, mice and rhesus macaques <span class="citation" data-cites="1037p4Gvs">[<a href="#ref-1037p4Gvs" role="doc-biblioref">735</a>]</span>.
+Animals in the treatment condition were observed to develop neutralizing antibodies specific to SARS-CoV-2 (both macaques and mice) and to show reduced clinical scores when exposed to SARS-CoV-2 (macaques) <span class="citation" data-cites="1037p4Gvs">[<a href="#ref-1037p4Gvs" role="doc-biblioref">735</a>]</span>.
+Next, a phase I/II trial was undertaken using a single-blind, randomized controlled design <span class="citation" data-cites="2bBVSpM">[<a href="#ref-2bBVSpM" role="doc-biblioref">736</a>]</span>.
 ChAdOx1 nCoV-19 and a control, the meningococcal conjugate vaccine MenACWY, were administered intramuscularly to adults ages 18 to 55 at five sites within the United Kingdom (U.K.) at a 1:1 ratio (n=543 and n=534, respectively).
 All but ten participants received a single dose; this small group received a booster 28 days after their first dose of ChAdOx1 nCoV-19.
 Commonly reported local adverse reactions included mild-to-moderate pain and tenderness at the injection site over the course of seven days, while the most common systemic adverse reactions were fatigue and headache; some patients reported severe adverse systemic effects.
@@ -3033,7 +3033,7 @@ <h3 data-number="7.2.1" id="chadox1-ncov-19-astrazeneca"><span class="header-sec
 Analysis of serum indicated that participants developed antibodies to both S and the RBD, and that 100% of them achieved neutralizing titers by day 28.
 By day 35, the neutralization titers of vaccinated patients was comparable to that observed with plasma from convalescents.
 This initial study therefore suggested that the vaccine was likely to confer protection against SARS-CoV-2, although analysis of its efficacy in preventing COVID-19 was not reported.</p>
-<p>In December 2020, preliminary results of the phase III trial were released detailing randomized control trials conducted in the U.K., Brazil, and South Africa between April and November 2020 <span class="citation" data-cites="Vnbw9o3T">[<a href="#ref-Vnbw9o3T" role="doc-biblioref">665</a>]</span>.
+<p>In December 2020, preliminary results of the phase III trial were released detailing randomized control trials conducted in the U.K., Brazil, and South Africa between April and November 2020 <span class="citation" data-cites="Vnbw9o3T">[<a href="#ref-Vnbw9o3T" role="doc-biblioref">664</a>]</span>.
 These trials again compared ChAdOx1 nCoV-19 to a control, but the design of each study varied.
 For example, in South Africa, the trial was double-blinded, whereas in the U.K. and Brazil it was single-blinded, and one of the two trials carried out in the U.K. examined two dosing regimens (low dose or standard dose, both followed by standard dose).
 Some of the trials used MenACWY as a control, while others used saline.
@@ -3043,29 +3043,29 @@ <h3 data-number="7.2.1" id="chadox1-ncov-19-astrazeneca"><span class="header-sec
 However, a higher efficacy was reported in the subgroup of patients who received a low-dose followed by a standard dose (90.0%, 95% CI 67.4 to 97·0).
 A total of ten cases of severe COVID-19 resulting in hospitalization were observed among trial participants, and all of these occurred in patients in the control arm of the study.
 In line with the previously reported safety profiling for this vaccine, serious adverse events were reported to be comparable across the two arms of the study, with only three events identified as potentially associated with the vaccine itself.
-The U.K. Medicines and Healthcare Products Regulatory Agency (MHRA) approved ChAdOx1 nCoV-19 for emergency use on December 30, 2020 <span class="citation" data-cites="1A7PjhDDR">[<a href="#ref-1A7PjhDDR" role="doc-biblioref">738</a>]</span>.
-Additional data about the efficacy of this vaccine became available in a preprint released on March 2, 2021 <span class="citation" data-cites="eV6UplSu">[<a href="#ref-eV6UplSu" role="doc-biblioref">788</a>]</span>.
+The U.K. Medicines and Healthcare Products Regulatory Agency (MHRA) approved ChAdOx1 nCoV-19 for emergency use on December 30, 2020 <span class="citation" data-cites="1A7PjhDDR">[<a href="#ref-1A7PjhDDR" role="doc-biblioref">737</a>]</span>.
+Additional data about the efficacy of this vaccine became available in a preprint released on March 2, 2021 <span class="citation" data-cites="eV6UplSu">[<a href="#ref-eV6UplSu" role="doc-biblioref">787</a>]</span>.
 This report provided data describing the efficacy of ChAdOx1 nCoV-19, along with Pfizer/BioNTech’s BNT162b2, in the U.K. between December 8, 2020 and February 19, 2021 and specifically sought to evaluate the efficacy of the vaccine in the presence of a potentially more contagious variant of concern, B.1.1.7.
 All participants in this study were age 70 or older and the efficacy was estimated to increase from 60% at 28 days after vaccination to 73% at 35 days after vaccination, although the standard error also increased over this time.
 Therefore, preliminary results suggest that in a number of samples, this vaccine confers a high level of protection against SARS-CoV-2.
 <!--To Do: Add discussion of all the drama--></p>
 <h3 data-number="7.2.2" id="sputnik-v-gam-covid-vac-and-gam-covid-vac-lyo"><span class="header-section-number">7.2.2</span> Sputnik-V (Gam-COVID-Vac and Gam-COVID-Vac-Lyo)</h3>
 <p>The vaccine Gam-COVID-Vac, nicknamed Sputnik V in reference to the space race and “V for vaccine”, was developed by the Gamaleya National Center of Epidemiology and Microbiology in Moscow.
-Gamaleya is an organization with prior experience using the adenovirus platform for the development of vaccines for <em>Middle East respiratory syndrome-related coronavirus</em> and Ebola virus, although neither of the previous vaccines were internationally licensed <span class="citation" data-cites="UCI0TCHy">[<a href="#ref-UCI0TCHy" role="doc-biblioref">732</a>]</span>.
-The development of Sputnik V was financed by the Russian Direct Investment Fund (RDIF) <span class="citation" data-cites="3KMxmQhV SxiGicKs">[<a href="#ref-3KMxmQhV" role="doc-biblioref">739</a>,<a href="#ref-SxiGicKs" role="doc-biblioref">789</a>]</span>.
+Gamaleya is an organization with prior experience using the adenovirus platform for the development of vaccines for <em>Middle East respiratory syndrome-related coronavirus</em> and Ebola virus, although neither of the previous vaccines were internationally licensed <span class="citation" data-cites="UCI0TCHy">[<a href="#ref-UCI0TCHy" role="doc-biblioref">731</a>]</span>.
+The development of Sputnik V was financed by the Russian Direct Investment Fund (RDIF) <span class="citation" data-cites="3KMxmQhV SxiGicKs">[<a href="#ref-3KMxmQhV" role="doc-biblioref">738</a>,<a href="#ref-SxiGicKs" role="doc-biblioref">788</a>]</span>.
 Sputnik V is a replication-deficient recombinant adenovirus (rAd) vaccine that combines two adenovirus vectors, rAd26-S and rAd5-S, that express the full-length SARS-CoV-2 spike glycoprotein.
 These vectors are intramuscularly administered individually using two separate vaccines in a prime-boost regimen.
 The rAd26-S is administered first, followed by rAd5-S 21 days later.
 Both vaccines deliver 10<sup>11</sup> viral particles per dose.
-This approach is designed to overcome any potential pre-existing immunity to adenovirus in the population <span class="citation" data-cites="sRAZYY9C">[<a href="#ref-sRAZYY9C" role="doc-biblioref">790</a>]</span>, as some individuals may possess immunity to Ad5 <span class="citation" data-cites="8jwp261S">[<a href="#ref-8jwp261S" role="doc-biblioref">791</a>]</span>.
+This approach is designed to overcome any potential pre-existing immunity to adenovirus in the population <span class="citation" data-cites="sRAZYY9C">[<a href="#ref-sRAZYY9C" role="doc-biblioref">789</a>]</span>, as some individuals may possess immunity to Ad5 <span class="citation" data-cites="8jwp261S">[<a href="#ref-8jwp261S" role="doc-biblioref">790</a>]</span>.
 Sputnik V is the only recombinant adenovirus vaccine to utilize two vectors.
-Other vaccines, such as the Oxford-AstraZeneca vaccine, utilize the chimpanzee adenovirus vector (ChAdOx1 nCoV-19) for both doses <span class="citation" data-cites="LZ8AtMnD">[<a href="#ref-LZ8AtMnD" role="doc-biblioref">792</a>]</span>.
-The Sputnik V vaccines are available in both a lyophilized (Gam-COVID-Vac-Lyo) and frozen form (Gam-COVID-Vac), which are stored at 2-8°C and -18°C respectively <span class="citation" data-cites="PNZEiId1">[<a href="#ref-PNZEiId1" role="doc-biblioref">740</a>]</span>.
-The lyophilized vaccine is convenient for distribution and storage, particularly to remote or disadvantaged areas <span class="citation" data-cites="3KBugyZN">[<a href="#ref-3KBugyZN" role="doc-biblioref">793</a>]</span>.</p>
-<p>In the race to develop vaccines against SARS-CoV-2, President Vladimir Putin of Russia announced the approval of the Sputnik V vaccines on August 11th, 2020 in the absence of clinical evidence <span class="citation" data-cites="3KMxmQhV">[<a href="#ref-3KMxmQhV" role="doc-biblioref">739</a>]</span>.
-Consequently, many international scientific agencies and public health bodies expressed concern that due diligence to the clinical trial process was subverted for the sake of expediency, leading many to question the safety and efficacy of Sputnik V <span class="citation" data-cites="15DiM98Ae x4aIj5Fr 3KMxmQhV">[<a href="#ref-3KMxmQhV" role="doc-biblioref">739</a>,<a href="#ref-15DiM98Ae" role="doc-biblioref">794</a>,<a href="#ref-x4aIj5Fr" role="doc-biblioref">795</a>]</span>.
-Despite regulatory, safety, and efficacy concerns, pre-orders for 1 billion doses of the Sputnik V were reported within days of the vaccine’s approval in Russia <span class="citation" data-cites="3KMxmQhV">[<a href="#ref-3KMxmQhV" role="doc-biblioref">739</a>]</span>.
-Almost a month later, the phase I/II trial data was published <span class="citation" data-cites="PNZEiId1">[<a href="#ref-PNZEiId1" role="doc-biblioref">740</a>]</span>.</p>
+Other vaccines, such as the Oxford-AstraZeneca vaccine, utilize the chimpanzee adenovirus vector (ChAdOx1 nCoV-19) for both doses <span class="citation" data-cites="LZ8AtMnD">[<a href="#ref-LZ8AtMnD" role="doc-biblioref">791</a>]</span>.
+The Sputnik V vaccines are available in both a lyophilized (Gam-COVID-Vac-Lyo) and frozen form (Gam-COVID-Vac), which are stored at 2-8°C and -18°C respectively <span class="citation" data-cites="PNZEiId1">[<a href="#ref-PNZEiId1" role="doc-biblioref">739</a>]</span>.
+The lyophilized vaccine is convenient for distribution and storage, particularly to remote or disadvantaged areas <span class="citation" data-cites="3KBugyZN">[<a href="#ref-3KBugyZN" role="doc-biblioref">792</a>]</span>.</p>
+<p>In the race to develop vaccines against SARS-CoV-2, President Vladimir Putin of Russia announced the approval of the Sputnik V vaccines on August 11th, 2020 in the absence of clinical evidence <span class="citation" data-cites="3KMxmQhV">[<a href="#ref-3KMxmQhV" role="doc-biblioref">738</a>]</span>.
+Consequently, many international scientific agencies and public health bodies expressed concern that due diligence to the clinical trial process was subverted for the sake of expediency, leading many to question the safety and efficacy of Sputnik V <span class="citation" data-cites="15DiM98Ae x4aIj5Fr 3KMxmQhV">[<a href="#ref-3KMxmQhV" role="doc-biblioref">738</a>,<a href="#ref-15DiM98Ae" role="doc-biblioref">793</a>,<a href="#ref-x4aIj5Fr" role="doc-biblioref">794</a>]</span>.
+Despite regulatory, safety, and efficacy concerns, pre-orders for 1 billion doses of the Sputnik V were reported within days of the vaccine’s approval in Russia <span class="citation" data-cites="3KMxmQhV">[<a href="#ref-3KMxmQhV" role="doc-biblioref">738</a>]</span>.
+Almost a month later, the phase I/II trial data was published <span class="citation" data-cites="PNZEiId1">[<a href="#ref-PNZEiId1" role="doc-biblioref">739</a>]</span>.</p>
 <p>In the phase I/II trial study conducted between late June and early August 2020, 76 participants (18-60 years old) were split into two groups of 38 participants, which were non-randomized in two hospitals in Russia.
 In phase I, 9 patients received rAd26 and 9 patients received rAd5-S to assess safety over 28 days.
 In phase II, at least 5 days after the completion of phase I, 20 patients received a prime-boost vaccination of rAd26-S on day 0 and rAd5-S on day 2, which was administered intramuscularly.
@@ -3075,10 +3075,10 @@ <h3 data-number="7.2.2" id="sputnik-v-gam-covid-vac-and-gam-covid-vac-lyo"><span
 RBD-specific IgG levels were high in both the frozen and lyophilized versions of the vaccine (14,703 and 11,143 respectively), indicating a sufficient immune response to both.
 Three weeks post the second vaccination, the virus-neutralizing geometric mean antibody titers were 49.25 and 45.95 from the frozen and lyophilized vaccines, respectively.
 At 28 days, median cell proliferation of 1.3% CD4<sup>+</sup> and 1.1% CD8<sup>+</sup> were reported for the lyophilized vaccine and 2.5% CD4<sup>+</sup> and 1.3% CD8<sup>+</sup> for the vaccine stored frozen.
-These results indicated that both forms of Sputnik V appeared to be safe and induce a humoral and cellular response in human subjects <span class="citation" data-cites="PNZEiId1">[<a href="#ref-PNZEiId1" role="doc-biblioref">740</a>]</span>, which may be robust enough to persist and not wane rapidly <span class="citation" data-cites="sRAZYY9C">[<a href="#ref-sRAZYY9C" role="doc-biblioref">790</a>]</span>.</p>
-<p>A press release on November 11th, 2020 indicated positive results from an interim analysis of the phase III Sputnik V trials, which reported 92% efficacy in 16,000 volunteers <span class="citation" data-cites="JSzDvnk6">[<a href="#ref-JSzDvnk6" role="doc-biblioref">796</a>]</span>.
-However, this release came only two days after both Pfizer and BioNTech reported that their vaccines had an efficacy over 90%, which led to significant skepticism of the Russian findings for a myriad of reasons including the lack of a published protocol and the “reckless” approval of the vaccine in Russia months prior to the publication of the interim results of the phase III trial <span class="citation" data-cites="JSzDvnk6 Yzz3rwqk">[<a href="#ref-JSzDvnk6" role="doc-biblioref">796</a>,<a href="#ref-Yzz3rwqk" role="doc-biblioref">797</a>]</span>.
-In February 2021, the interim results of the phase III randomized, double-blind, placebo-controlled trial were eventually published in <em>The Lancet</em> <span class="citation" data-cites="gLAIyAHm">[<a href="#ref-gLAIyAHm" role="doc-biblioref">741</a>]</span>.
+These results indicated that both forms of Sputnik V appeared to be safe and induce a humoral and cellular response in human subjects <span class="citation" data-cites="PNZEiId1">[<a href="#ref-PNZEiId1" role="doc-biblioref">739</a>]</span>, which may be robust enough to persist and not wane rapidly <span class="citation" data-cites="sRAZYY9C">[<a href="#ref-sRAZYY9C" role="doc-biblioref">789</a>]</span>.</p>
+<p>A press release on November 11th, 2020 indicated positive results from an interim analysis of the phase III Sputnik V trials, which reported 92% efficacy in 16,000 volunteers <span class="citation" data-cites="JSzDvnk6">[<a href="#ref-JSzDvnk6" role="doc-biblioref">795</a>]</span>.
+However, this release came only two days after both Pfizer and BioNTech reported that their vaccines had an efficacy over 90%, which led to significant skepticism of the Russian findings for a myriad of reasons including the lack of a published protocol and the “reckless” approval of the vaccine in Russia months prior to the publication of the interim results of the phase III trial <span class="citation" data-cites="JSzDvnk6 Yzz3rwqk">[<a href="#ref-JSzDvnk6" role="doc-biblioref">795</a>,<a href="#ref-Yzz3rwqk" role="doc-biblioref">796</a>]</span>.
+In February 2021, the interim results of the phase III randomized, double-blind, placebo-controlled trial were eventually published in <em>The Lancet</em> <span class="citation" data-cites="gLAIyAHm">[<a href="#ref-gLAIyAHm" role="doc-biblioref">740</a>]</span>.
 The participants were randomly assigned to receive either a 0.5 mL/dose of vaccine or placebo, which was comprised of the vaccine buffer composition, that was delivered intramuscularly using the same prime-boost regimen as in the phase I/II trials.
 From September 7th to Nov 24th, 19,866 participants completed the trial.
 Of the 14,964 participants who received the vaccine, 16 (0.1%) were confirmed to have COVID-19, whereas 62 of the 4,902 participants (1.3%) in the placebo group were confirmed to have COVID-19.
@@ -3087,45 +3087,45 @@ <h3 data-number="7.2.2" id="sputnik-v-gam-covid-vac-and-gam-covid-vac-lyo"><span
 Therefore, asymptomatic infections were not detected, thus potentially inflating the efficacy estimate.
 Overall, a vaccine efficacy of 91.6% (95% CI 85.6-95.2) was reported, where an efficacy of 91.8% was reported for those over 60 years old and 92.7% for those who were 51-60 years old.
 Indeed, 14 days after the first dose, 87.6% efficacy was achieved and the immunity required to prevent disease occurred within 18 days of vaccination.
-Based on these results, scientists are investigating the potential for a single dose regimen of the rAd26-S sputnik V vaccine <span class="citation" data-cites="wCTVieA3">[<a href="#ref-wCTVieA3" role="doc-biblioref">798</a>]</span>.
+Based on these results, scientists are investigating the potential for a single dose regimen of the rAd26-S sputnik V vaccine <span class="citation" data-cites="wCTVieA3">[<a href="#ref-wCTVieA3" role="doc-biblioref">797</a>]</span>.
 By the end of the trial, 7,485 participants reported adverse events, of which 94% were grade I.
 Of the 68 participants who experienced serious adverse events during the trial, 45 from the vaccine group and 23 from the placebo groups, none were reported to be associated with the vaccination.
-Likewise, 4 deaths occurred during the trial period that were not related to the vaccine <span class="citation" data-cites="gLAIyAHm">[<a href="#ref-gLAIyAHm" role="doc-biblioref">741</a>]</span>.
+Likewise, 4 deaths occurred during the trial period that were not related to the vaccine <span class="citation" data-cites="gLAIyAHm">[<a href="#ref-gLAIyAHm" role="doc-biblioref">740</a>]</span>.
 The interim findings of the phase III trial indicate that the Sputnik V vaccine regimen appears to be safe with 91.6% efficacy.
 Gamaleya had intended to reach a total of 40,000 participants for the completion of their phase III trial.
-However, the trial has stopped enrolling participants and the numbers have been cut to 31,000 as many individuals in the placebo group dropped out of the study to obtain the vaccine <span class="citation" data-cites="15qYogj0H">[<a href="#ref-15qYogj0H" role="doc-biblioref">799</a>]</span>.
-Indeed, other trials involving Sputnik V are currently underway in Belarus, India, the United Arab Emirates, and Venezuela <span class="citation" data-cites="vrzaW9Gb">[<a href="#ref-vrzaW9Gb" role="doc-biblioref">800</a>]</span>.</p>
-<p>Preliminary results of a trial of Argentinian healthcare workers in Buenos Aires who were vaccinated with the Sputnik V rAd26-R vector-based vaccine seems to support the short term safety of the first vaccination <span class="citation" data-cites="vTFvCt1w">[<a href="#ref-vTFvCt1w" role="doc-biblioref">801</a>]</span>.
+However, the trial has stopped enrolling participants and the numbers have been cut to 31,000 as many individuals in the placebo group dropped out of the study to obtain the vaccine <span class="citation" data-cites="15qYogj0H">[<a href="#ref-15qYogj0H" role="doc-biblioref">798</a>]</span>.
+Indeed, other trials involving Sputnik V are currently underway in Belarus, India, the United Arab Emirates, and Venezuela <span class="citation" data-cites="vrzaW9Gb">[<a href="#ref-vrzaW9Gb" role="doc-biblioref">799</a>]</span>.</p>
+<p>Preliminary results of a trial of Argentinian healthcare workers in Buenos Aires who were vaccinated with the Sputnik V rAd26-R vector-based vaccine seems to support the short term safety of the first vaccination <span class="citation" data-cites="vTFvCt1w">[<a href="#ref-vTFvCt1w" role="doc-biblioref">800</a>]</span>.
 Of the 707 vaccinated healthcare workers, 71.3% of the 96.6% of respondents reported at least one adverse event attributed to the vaccine.
 Of these individuals, 68% experienced joint and muscle pain, 54% had injection site pain, 11% reported redness and swelling, 40% had a fever, and 5% reported diarrhea.
 Only 5% of the vaccinated participants experienced serious adverse events that required medical attention, of which one was monitored as an inpatient.</p>
-<p>Additionally, an Independent assessment of Sputnik V in a phase II clinical trial in India found the vaccine to be effective, but the data is not yet publicly available <span class="citation" data-cites="jv875POj">[<a href="#ref-jv875POj" role="doc-biblioref">802</a>]</span>.
-On December 21st, 2020, Gamaleya, AstraZeneca, R-Pharm, and the Russian Direct Investment Fund agreed to assess the safety and immunogenicity of the combined use of components of the AstraZeneca and University of Oxford AZD1222 (ChAdOx1) vaccine and the rAd26-S component of the Sputnik V vaccine in clinical trials <span class="citation" data-cites="150qGOMi9">[<a href="#ref-150qGOMi9" role="doc-biblioref">803</a>]</span>.
+<p>Additionally, an Independent assessment of Sputnik V in a phase II clinical trial in India found the vaccine to be effective, but the data is not yet publicly available <span class="citation" data-cites="jv875POj">[<a href="#ref-jv875POj" role="doc-biblioref">801</a>]</span>.
+On December 21st, 2020, Gamaleya, AstraZeneca, R-Pharm, and the Russian Direct Investment Fund agreed to assess the safety and immunogenicity of the combined use of components of the AstraZeneca and University of Oxford AZD1222 (ChAdOx1) vaccine and the rAd26-S component of the Sputnik V vaccine in clinical trials <span class="citation" data-cites="150qGOMi9">[<a href="#ref-150qGOMi9" role="doc-biblioref">802</a>]</span>.
 This agreement hopes to establish scientific and business relations between the entities with an aim to co-develop a vaccine providing long-term immunization.
 The trial, which will begin enrollment soon, will include 100 participants in a phase II open-label study and is hoped to be complete within 6 months.
 Participants will first receive an intramuscular dose of AZD1222 on day 1, followed by a dose of rAd26 on day 29.
 Participants will be monitored from day 1 for 180 days in total.
 The primary outcomes measured will include incidence of serious adverse events post first dose until the end of the study.
-Secondary outcome measures will include incidence of local and systemic adverse events 7 days post each dose, a time course of antibody responses for the Spike protein and the presence of anti-SARS-CoV-2 neutralizing antibodies <span class="citation" data-cites="1G2ROkAsZ">[<a href="#ref-1G2ROkAsZ" role="doc-biblioref">804</a>]</span>.</p>
+Secondary outcome measures will include incidence of local and systemic adverse events 7 days post each dose, a time course of antibody responses for the Spike protein and the presence of anti-SARS-CoV-2 neutralizing antibodies <span class="citation" data-cites="1G2ROkAsZ">[<a href="#ref-1G2ROkAsZ" role="doc-biblioref">803</a>]</span>.</p>
 <p>Overall, there is hesitancy surrounding the management of the Sputnik V vaccine approval process and concerns over whether the efficacy data may be inflated due to a lack of asymptomatic testing within the trial.
 However, the interim results of the phase III study were promising and further trials are underway, which will likely shed light on the overall efficacy and safety of the Sputnik V vaccine regimen.
 There may be some advantage to the Sputnik V approach including the favorable storage conditions afforded by choice between a frozen and lyophilized vaccine.
-Furthermore, the producers of Gam-COVID-Vac state that they can produce the vaccine at a cost of less than $10 per dose or less than $20 per patient <span class="citation" data-cites="AfkC38Sh">[<a href="#ref-AfkC38Sh" role="doc-biblioref">805</a>]</span>.</p>
+Furthermore, the producers of Gam-COVID-Vac state that they can produce the vaccine at a cost of less than $10 per dose or less than $20 per patient <span class="citation" data-cites="AfkC38Sh">[<a href="#ref-AfkC38Sh" role="doc-biblioref">804</a>]</span>.</p>
 <h3 data-number="7.2.3" id="janssens-jnj-78436735"><span class="header-section-number">7.2.3</span> Janssen’s JNJ-78436735</h3>
-<p>The Johnson &amp; Johnson (J&amp;J) vaccine developed by Janssen Pharmaceuticals, Inc., a subsidiary of J&amp;J, was conducted in collaboration with and funded by “Operation Warp Speed” <span class="citation" data-cites="D3Px25HN 57BTbcko">[<a href="#ref-D3Px25HN" role="doc-biblioref">747</a>,<a href="#ref-57BTbcko" role="doc-biblioref">748</a>]</span>.
-The vaccine candidate JNJ-78436735, formerly known as Ad26.COV2-S, is a monovalent vaccine that is composed of a replication-deficient adenovirus serotype 26 (Ad26) vector expressing the stabilized pre-fusion S protein of SARS-CoV-2 <span class="citation" data-cites="pWf2T8J8 10UC562ga">[<a href="#ref-pWf2T8J8" role="doc-biblioref">749</a>,<a href="#ref-10UC562ga" role="doc-biblioref">750</a>]</span>.
-The vaccine was developed using Janssen’s AdVac<sup>®</sup> and PER.C6 platforms that were previously utilized to develop the European Commission-approved Ebola vaccine (Ad26 ZEBOV and MVN-BN-Filo) and their Zika, respiratory syncytial (RSV), and HIV investigational vaccine candidates <span class="citation" data-cites="10uLoe1rR">[<a href="#ref-10uLoe1rR" role="doc-biblioref">806</a>]</span>.</p>
-<p>The development of a single-dose vaccine was desirable by J&amp;J from the outset, with global deployment being a key priority <span class="citation" data-cites="gOOBv1MD">[<a href="#ref-gOOBv1MD" role="doc-biblioref">751</a>]</span>.
-Using their AdVac<sup>®</sup> technology, the vaccine can remain stable for up to two years between -15℃ and -25℃ and at least three months at 2-8℃ <span class="citation" data-cites="10uLoe1rR">[<a href="#ref-10uLoe1rR" role="doc-biblioref">806</a>]</span>.
+<p>The Johnson &amp; Johnson (J&amp;J) vaccine developed by Janssen Pharmaceuticals, Inc., a subsidiary of J&amp;J, was conducted in collaboration with and funded by “Operation Warp Speed” <span class="citation" data-cites="D3Px25HN 57BTbcko">[<a href="#ref-D3Px25HN" role="doc-biblioref">746</a>,<a href="#ref-57BTbcko" role="doc-biblioref">747</a>]</span>.
+The vaccine candidate JNJ-78436735, formerly known as Ad26.COV2-S, is a monovalent vaccine that is composed of a replication-deficient adenovirus serotype 26 (Ad26) vector expressing the stabilized pre-fusion S protein of SARS-CoV-2 <span class="citation" data-cites="pWf2T8J8 10UC562ga">[<a href="#ref-pWf2T8J8" role="doc-biblioref">748</a>,<a href="#ref-10UC562ga" role="doc-biblioref">749</a>]</span>.
+The vaccine was developed using Janssen’s AdVac<sup>®</sup> and PER.C6 platforms that were previously utilized to develop the European Commission-approved Ebola vaccine (Ad26 ZEBOV and MVN-BN-Filo) and their Zika, respiratory syncytial (RSV), and HIV investigational vaccine candidates <span class="citation" data-cites="10uLoe1rR">[<a href="#ref-10uLoe1rR" role="doc-biblioref">805</a>]</span>.</p>
+<p>The development of a single-dose vaccine was desirable by J&amp;J from the outset, with global deployment being a key priority <span class="citation" data-cites="gOOBv1MD">[<a href="#ref-gOOBv1MD" role="doc-biblioref">750</a>]</span>.
+Using their AdVac<sup>®</sup> technology, the vaccine can remain stable for up to two years between -15℃ and -25℃ and at least three months at 2-8℃ <span class="citation" data-cites="10uLoe1rR">[<a href="#ref-10uLoe1rR" role="doc-biblioref">805</a>]</span>.
 This allows the vaccine to be distributed easily without the requirement for very low temperature storage, unlike many of the other COVID-19 vaccine candidates.
-J&amp;J screened numerous potential vaccine candidates <em>in vitro</em> and in animal models using varying different designs of the S protein, heterologous signal peptides, and prefusion-stabilizing substitutions <span class="citation" data-cites="10UC562ga">[<a href="#ref-10UC562ga" role="doc-biblioref">750</a>]</span>.
-A select few candidates were further investigated as a single dose regimen in Syrian golden hamsters, a single dose regimen in rhesus macaques, and a single- and two-dose regimen in both adult and aged rhesus macaques <span class="citation" data-cites="10UC562ga gOOBv1MD HmMIiIv2 EpOXYGt4">[<a href="#ref-10UC562ga" role="doc-biblioref">750</a>,<a href="#ref-gOOBv1MD" role="doc-biblioref">751</a>,<a href="#ref-HmMIiIv2" role="doc-biblioref">752</a>,<a href="#ref-EpOXYGt4" role="doc-biblioref">753</a>]</span>.
-From these studies, the JNJ-78436735 candidate was selected for its favorable immunogenicity profile and ease of manufacturability <span class="citation" data-cites="10UC562ga gOOBv1MD HmMIiIv2 EpOXYGt4">[<a href="#ref-10UC562ga" role="doc-biblioref">750</a>,<a href="#ref-gOOBv1MD" role="doc-biblioref">751</a>,<a href="#ref-HmMIiIv2" role="doc-biblioref">752</a>,<a href="#ref-EpOXYGt4" role="doc-biblioref">753</a>]</span>.
-A SARS-CoV-2 challenge study in rhesus macaques showed that vaccine doses as low as 2 x 10<sup>9</sup> viral particles/mL was sufficient to induce strong protection in bronchoalveolar lavage but that doses higher than 1.125 x 10<sup>10</sup> were required to close achieve close to complete protection in nasal swabs <span class="citation" data-cites="lVoienSE">[<a href="#ref-lVoienSE" role="doc-biblioref">807</a>]</span>.
-Indeed, six months post-immunization, levels of S-binding and neutralizing antibodies in rhesus macaques indicated that the JNJ-78436735 vaccine conferred durable protection against SARS-CoV-2 <span class="citation" data-cites="HGVDPMLm">[<a href="#ref-HGVDPMLm" role="doc-biblioref">754</a>]</span>.</p>
+J&amp;J screened numerous potential vaccine candidates <em>in vitro</em> and in animal models using varying different designs of the S protein, heterologous signal peptides, and prefusion-stabilizing substitutions <span class="citation" data-cites="10UC562ga">[<a href="#ref-10UC562ga" role="doc-biblioref">749</a>]</span>.
+A select few candidates were further investigated as a single dose regimen in Syrian golden hamsters, a single dose regimen in rhesus macaques, and a single- and two-dose regimen in both adult and aged rhesus macaques <span class="citation" data-cites="10UC562ga gOOBv1MD HmMIiIv2 EpOXYGt4">[<a href="#ref-10UC562ga" role="doc-biblioref">749</a>,<a href="#ref-gOOBv1MD" role="doc-biblioref">750</a>,<a href="#ref-HmMIiIv2" role="doc-biblioref">751</a>,<a href="#ref-EpOXYGt4" role="doc-biblioref">752</a>]</span>.
+From these studies, the JNJ-78436735 candidate was selected for its favorable immunogenicity profile and ease of manufacturability <span class="citation" data-cites="10UC562ga gOOBv1MD HmMIiIv2 EpOXYGt4">[<a href="#ref-10UC562ga" role="doc-biblioref">749</a>,<a href="#ref-gOOBv1MD" role="doc-biblioref">750</a>,<a href="#ref-HmMIiIv2" role="doc-biblioref">751</a>,<a href="#ref-EpOXYGt4" role="doc-biblioref">752</a>]</span>.
+A SARS-CoV-2 challenge study in rhesus macaques showed that vaccine doses as low as 2 x 10<sup>9</sup> viral particles/mL was sufficient to induce strong protection in bronchoalveolar lavage but that doses higher than 1.125 x 10<sup>10</sup> were required to close achieve close to complete protection in nasal swabs <span class="citation" data-cites="lVoienSE">[<a href="#ref-lVoienSE" role="doc-biblioref">806</a>]</span>.
+Indeed, six months post-immunization, levels of S-binding and neutralizing antibodies in rhesus macaques indicated that the JNJ-78436735 vaccine conferred durable protection against SARS-CoV-2 <span class="citation" data-cites="HGVDPMLm">[<a href="#ref-HGVDPMLm" role="doc-biblioref">753</a>]</span>.</p>
 <p>Following selection of the JNJ-78436735 vaccine, J&amp;J began phase I/IIa trials.
-The interim phase I/IIa data was placed on the <em>medRxiv</em> preprint server on September 25th, 2020 <span class="citation" data-cites="14g52GtO3">[<a href="#ref-14g52GtO3" role="doc-biblioref">808</a>]</span> and was later published in the <em>New England Journal of Medicine</em> on January 13th, 2021 <span class="citation" data-cites="pWf2T8J8">[<a href="#ref-pWf2T8J8" role="doc-biblioref">749</a>]</span>.
-The phase I/IIa multi-center, randomized, placebo-controlled trial enrolled 402 healthy participants between 18-55 years old and a further 403 healthy older participants ≥ 65 years old <span class="citation" data-cites="pWf2T8J8">[<a href="#ref-pWf2T8J8" role="doc-biblioref">749</a>]</span>.
+The interim phase I/IIa data was placed on the <em>medRxiv</em> preprint server on September 25th, 2020 <span class="citation" data-cites="14g52GtO3">[<a href="#ref-14g52GtO3" role="doc-biblioref">807</a>]</span> and was later published in the <em>New England Journal of Medicine</em> on January 13th, 2021 <span class="citation" data-cites="pWf2T8J8">[<a href="#ref-pWf2T8J8" role="doc-biblioref">748</a>]</span>.
+The phase I/IIa multi-center, randomized, placebo-controlled trial enrolled 402 healthy participants between 18-55 years old and a further 403 healthy older participants ≥ 65 years old <span class="citation" data-cites="pWf2T8J8">[<a href="#ref-pWf2T8J8" role="doc-biblioref">748</a>]</span>.
 Patients were administered either a placebo, a low dose (5 x 10<sup>10</sup> viral particles per mL), or a high dose (1 X 10<sup>11</sup> viral particles per mL) intramuscularly as part of either a single- or two-dose regimen.
 All patients received injections 56 days apart, but participants in the single-dose condition received the placebo at the second appointment.
 Those who received only one dose of either vaccine received a placebo dose at their second vaccination visit.
@@ -3134,7 +3134,7 @@ <h3 data-number="7.2.3" id="janssens-jnj-78436735"><span class="header-section-n
 Fatigue, headache, myalgia, and pain at the injection site were the most frequent solicited adverse events reported by participants.
 Although less common, particularly for those in the elderly cohort and those on the low dose regimen, the most frequent systemic adverse effect was fever.
 Overall, immunization was well tolerated, particularly at the lower dose concentration.
-In terms of reactogenicity, over 90% of those who received either the low or high dose demonstrated seroconversion in a neutralization assay using wild-type SARS-CoV-2, 29 days after immunization <span class="citation" data-cites="pWf2T8J8">[<a href="#ref-pWf2T8J8" role="doc-biblioref">749</a>]</span>.
+In terms of reactogenicity, over 90% of those who received either the low or high dose demonstrated seroconversion in a neutralization assay using wild-type SARS-CoV-2, 29 days after immunization <span class="citation" data-cites="pWf2T8J8">[<a href="#ref-pWf2T8J8" role="doc-biblioref">748</a>]</span>.
 Neutralizing geometric mean ratio of antibody titers (GMT) between 224-354 were detected regardless of age.
 By day 57, 100% of the 18-55 year old participants had neutralizing GMT (288-488), which remained stable until day 71.
 In the ≥ 65 years old cohort, the incidence of seroconversion for the low- and high-dose was 96% and 88% respectively by day 29.</p>
@@ -3142,18 +3142,18 @@ <h3 data-number="7.2.3" id="janssens-jnj-78436735"><span class="header-section-n
 Seroconversion of the S antibodies was detected in 99% of individuals between 18-55 years old for the low and high doses (GMTs 528 and 695 respectively), with similar findings reported for the ≥ 65 years old.
 Indeed, both dose concentrations also induced robust Th1 cytokine-producing S-specific CD4<sup>+</sup> T cells and CD8<sup>+</sup> T cell responses in both age groups.
 The findings of the phase I/IIa study supported further investigation of a single immunization using the low dose vaccine.
-Therefore, 25 patients were enrolled for a second randomized double-blind, placebo-controlled phase 1 clinical trial currently being conducted in Boston, Massachusetts for 2 years <span class="citation" data-cites="1CBMCD5I2">[<a href="#ref-1CBMCD5I2" role="doc-biblioref">809</a>]</span>.
+Therefore, 25 patients were enrolled for a second randomized double-blind, placebo-controlled phase 1 clinical trial currently being conducted in Boston, Massachusetts for 2 years <span class="citation" data-cites="1CBMCD5I2">[<a href="#ref-1CBMCD5I2" role="doc-biblioref">808</a>]</span>.
 Participants received either a single dose followed by a placebo, or a double dose of either a low dose (5 x 10<sup>10</sup> viral particles/mL) or a high dose (1 x 10<sup>11</sup> viral particles/mL) vaccine administered intramuscularly on day 1 or day 57.
 Placebo-only recipients received a placebo dose on day 1 and 57.
 Interim analyses conducted on day 71 indicated that binding and neutralizing antibodies developed 8 days after administration in 90% and 25% of vaccine recipients, respectively.
 Binding and neutralizing antibodies were detected in 100% of vaccine recipients by day 57 after a single dose immunization.
 Spike-specific antibodies were highly prevalent (GMT 2432 to 5729) as were neutralizing antibodies (GMT 242 to 449) in the vaccinated groups.
-Indeed, CD4<sup>+</sup> and CD8<sup>+</sup> T-cell responses were also induced, which may provide additional protection, particularly if antibodies wane or poorly respond to infection <span class="citation" data-cites="1GRYnvF01">[<a href="#ref-1GRYnvF01" role="doc-biblioref">810</a>]</span>.</p>
-<p>On September 23rd, 2020, J&amp;J launched its phase III trial ENSEMBLE and released the study protocol to the public <span class="citation" data-cites="10uLoe1rR 7n6WEkK8">[<a href="#ref-10uLoe1rR" role="doc-biblioref">806</a>,<a href="#ref-7n6WEkK8" role="doc-biblioref">811</a>]</span>.
-The trial intended to enroll 60,000 volunteers to assess the safety and efficacy of the single vaccine dose versus placebo with primary endpoints of 14 and 28 days post-immunization <span class="citation" data-cites="10uLoe1rR">[<a href="#ref-10uLoe1rR" role="doc-biblioref">806</a>]</span>.
+Indeed, CD4<sup>+</sup> and CD8<sup>+</sup> T-cell responses were also induced, which may provide additional protection, particularly if antibodies wane or poorly respond to infection <span class="citation" data-cites="1GRYnvF01">[<a href="#ref-1GRYnvF01" role="doc-biblioref">809</a>]</span>.</p>
+<p>On September 23rd, 2020, J&amp;J launched its phase III trial ENSEMBLE and released the study protocol to the public <span class="citation" data-cites="10uLoe1rR 7n6WEkK8">[<a href="#ref-10uLoe1rR" role="doc-biblioref">805</a>,<a href="#ref-7n6WEkK8" role="doc-biblioref">810</a>]</span>.
+The trial intended to enroll 60,000 volunteers to assess the safety and efficacy of the single vaccine dose versus placebo with primary endpoints of 14 and 28 days post-immunization <span class="citation" data-cites="10uLoe1rR">[<a href="#ref-10uLoe1rR" role="doc-biblioref">805</a>]</span>.
 The trial was conducted in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the U.S.
-The trial was paused briefly in October 2020 to investigate a “serious medical event”, but resumed shortly after <span class="citation" data-cites="5BTmfe4Y">[<a href="#ref-5BTmfe4Y" role="doc-biblioref">812</a>]</span>.
-An interim analysis was reported via press release on January 29th, 2021 <span class="citation" data-cites="iWMHpTBJ 1FcpboRMm">[<a href="#ref-iWMHpTBJ" role="doc-biblioref">755</a>,<a href="#ref-1FcpboRMm" role="doc-biblioref">756</a>]</span>.
+The trial was paused briefly in October 2020 to investigate a “serious medical event”, but resumed shortly after <span class="citation" data-cites="5BTmfe4Y">[<a href="#ref-5BTmfe4Y" role="doc-biblioref">811</a>]</span>.
+An interim analysis was reported via press release on January 29th, 2021 <span class="citation" data-cites="iWMHpTBJ 1FcpboRMm">[<a href="#ref-iWMHpTBJ" role="doc-biblioref">754</a>,<a href="#ref-1FcpboRMm" role="doc-biblioref">755</a>]</span>.
 The interim data included 43,783 participants who accrued 468 symptomatic cases of COVID-19.
 It was reported that the JNJ-78436735 vaccine was 66% effective across all regions studied for the prevention of moderate to severe COVID-19 28 days post-vaccination in those aged 18 years and older.
 Notably, JNJ-78436735 was 85% effective for the prevention of laboratory-confirmed severe COVID-19 and 100% protection against COVID-19-related hospitalization and death 28 days post-vaccination across all study sites.
@@ -3161,14 +3161,14 @@ <h3 data-number="7.2.3" id="janssens-jnj-78436735"><span class="header-section-n
 The trial also determined that the vaccine candidate has a favorable safety profile as determined by an independent Data and Safety Monitoring Board.
 The vaccine was well tolerated, consistent with previous vaccines produced using the AdVac<sup>®</sup> platform.
 Fever occurred in 9% of vaccine recipients, with grade 3 fever occurring in only 0.2% of recipients.
-Serious adverse events were reportedly higher in the placebo group than the vaccine group, and no anaphylaxis was reported <span class="citation" data-cites="1FcpboRMm">[<a href="#ref-1FcpboRMm" role="doc-biblioref">756</a>]</span>.</p>
+Serious adverse events were reportedly higher in the placebo group than the vaccine group, and no anaphylaxis was reported <span class="citation" data-cites="1FcpboRMm">[<a href="#ref-1FcpboRMm" role="doc-biblioref">755</a>]</span>.</p>
 <p>At the time the phase III trial was being conducted, several concerning variants, including B.1.1.7 <span class="citation" data-cites="m9qtrWft">[<a href="#ref-m9qtrWft" role="doc-biblioref">278</a>]</span> and B.1.351 <span class="citation" data-cites="sqhvCTIL">[<a href="#ref-sqhvCTIL" role="doc-biblioref">283</a>]</span>, were spreading across the globe.
 In particular, B.1.351 was first identified in South Africa, which was one of the JNJ-78436735 vaccine trial sites.
 Therefore, the J&amp;J investigators also analyzed the efficacy of the JNJ-78436735 vaccine associated with their various trial sites to determine any potential risk of reduced efficacy as a result of the novel variants.
 It was determined that JNJ-78436735 was 72% effective in the U.S., 66% effective in Latin America, and 57% effective in South Africa 28 days post-vaccination.
 These findings underpin the importance of monitoring for the emergence of novel SARS-CoV-2 variants and determining their effects on vaccine efficacy.</p>
 <p>Looking forward, Janssen are also running a phase III randomized, double-blind, placebo-controlled clinical trial, Ensemble 2, which aims to assess the efficacy, safety, and immunogenicity of a two-dose regimen of JNJ-78436735 administered 57 days apart.
-This trial will enroll 30,000 participants ≥ 18 years old from Belgium, Colombia, France, Germany, Philippines, South Africa, Spain, U.K., and the U.S. <span class="citation" data-cites="sx7F1ktj">[<a href="#ref-sx7F1ktj" role="doc-biblioref">813</a>]</span>.
+This trial will enroll 30,000 participants ≥ 18 years old from Belgium, Colombia, France, Germany, Philippines, South Africa, Spain, U.K., and the U.S. <span class="citation" data-cites="sx7F1ktj">[<a href="#ref-sx7F1ktj" role="doc-biblioref">812</a>]</span>.
 This trial will also include participants with and without comorbidities associated with an increased risk of COVID-19.</p>
 <h3 data-number="7.2.4" id="overall-status-of-viral-vector-vaccines"><span class="header-section-number">7.2.4</span> Overall Status of Viral-Vector Vaccines</h3>
 <p>The three viral-vector vaccines described above have demonstrated the potential for this technology to facilitate a quick response to an emerging pathogen.
@@ -3178,9 +3178,9 @@ <h3 data-number="7.2.4" id="overall-status-of-viral-vector-vaccines"><span class
 &lt;–To Do: <span class="citation" data-cites="agitter">[<span class="citeproc-not-found" data-reference-id="agitter"><strong>???</strong></span>]</span>’s suggestion to discuss prefusion conformation (J&amp;J) vs not (the other two)–&gt;</p>
 <h2 data-number="7.3" id="sinovacs-coronavac"><span class="header-section-number">7.3</span> Sinovac’s CoronaVac</h2>
 <p>The CoronaVac vaccine is being developed by Sinovac, a Beijing-based biopharmaceutical company.
-The vaccine is using an inactivate whole virus with the addition of an aluminum adjuvant <span class="citation" data-cites="RGPoDfHS">[<a href="#ref-RGPoDfHS" role="doc-biblioref">674</a>]</span>.
+The vaccine is using an inactivate whole virus with the addition of an aluminum adjuvant <span class="citation" data-cites="RGPoDfHS">[<a href="#ref-RGPoDfHS" role="doc-biblioref">673</a>]</span>.
 The vaccine is currently in Phase III clinical trials.</p>
-<p>Pre-clinical trials were performed using BALB/c mice and rhesus macaques <span class="citation" data-cites="14fILrRWg">[<a href="#ref-14fILrRWg" role="doc-biblioref">677</a>]</span>.
+<p>Pre-clinical trials were performed using BALB/c mice and rhesus macaques <span class="citation" data-cites="14fILrRWg">[<a href="#ref-14fILrRWg" role="doc-biblioref">676</a>]</span>.
 The SARS-CoV-2 strains used in this trial isolated from 11 hospitalized patients (5 from China, 3 from Italy, 1 from the UK, 1 from Spain, 1 from Switzerland).
 A phylogenetic analysis demonstrated that the strains were representative of the current circulating variants.
 One of the strains, CN2, from China was used as the inactivated and purified virus while the other 10 strains were used to challenge.
@@ -3192,7 +3192,7 @@ <h2 data-number="7.3" id="sinovacs-coronavac"><span class="header-section-number
 Four macaques were assigned to each of four groups: treatment with 3 μg at day 0, 7 and 14, treatment with a high dose of 6 μg at day 0, 7 and 14, administration of a placebo vaccine, and administration of only the adjuvant.
 All vaccinated macaques induced IgGs and neutralizing antibodies.
 After challenge with SARS-CoV-2 strain CN1, vaccinated macaques were protected compared to control macaques (placebo or adjuvant only) based on histology and viral loads collected from different regions of the lung.</p>
-<p>Phase I/II clinical trials were conducted in adults 18-59 years old <span class="citation" data-cites="N1txjPtt">[<a href="#ref-N1txjPtt" role="doc-biblioref">678</a>]</span> and adults over 60 years old <span class="citation" data-cites="Ozya5HP5">[<a href="#ref-Ozya5HP5" role="doc-biblioref">676</a>]</span> in China.
+<p>Phase I/II clinical trials were conducted in adults 18-59 years old <span class="citation" data-cites="N1txjPtt">[<a href="#ref-N1txjPtt" role="doc-biblioref">677</a>]</span> and adults over 60 years old <span class="citation" data-cites="Ozya5HP5">[<a href="#ref-Ozya5HP5" role="doc-biblioref">675</a>]</span> in China.
 In the case of adults 18-59 years old, a single center, randomized, double-blind, placebo-controlled phase I/II trial was conducted in April 2020.
 Patients in this study were recruited from the community in Suining County of Jiangsu province, China.
 For the phase I trial, 144 (of 185 screened) participants were enrolled, with 72 enrolled in the 14-day interval cohort (i.e., treated on day 0 and day 14) and 72 in the 28-day interval cohort.
@@ -3212,9 +3212,9 @@ <h2 data-number="7.3" id="sinovacs-coronavac"><span class="header-section-number
 Most adverse reactions were mild (grade 1) in severity and participants recovered within 48 hours.
 There was a single case, from the 6 μg group, of acute hypersensitivity with manifestation of urticaria 48 hours after the first dose.
 Both the 14-day and 28-day cohorts had a strong neutralizing Ab response.
-The neutralizing Ab response was measured using a micro cytopathogenic effect assay, which assesses the minimum dilution of neutralizing Ab to be 50% protective against structural changes in host cells in response to viral infection <span class="citation" data-cites="1GUVvcQjL">[<a href="#ref-1GUVvcQjL" role="doc-biblioref">772</a>]</span>.
+The neutralizing Ab response was measured using a micro cytopathogenic effect assay, which assesses the minimum dilution of neutralizing Ab to be 50% protective against structural changes in host cells in response to viral infection <span class="citation" data-cites="1GUVvcQjL">[<a href="#ref-1GUVvcQjL" role="doc-biblioref">771</a>]</span>.
 Additionally IgG antibody titers against the receptor binding domain were also measured using ELISA.</p>
-<p>Another phase I/II study was performed with older patients (older than 60 years) <span class="citation" data-cites="Ozya5HP5">[<a href="#ref-Ozya5HP5" role="doc-biblioref">676</a>]</span>.
+<p>Another phase I/II study was performed with older patients (older than 60 years) <span class="citation" data-cites="Ozya5HP5">[<a href="#ref-Ozya5HP5" role="doc-biblioref">675</a>]</span>.
 The study conducted a single-center, randomized, double-blind, placebo-controlled trial.
 The phase I trial looked at dose escalation using 3 dosages: 1.5, 3 and 6 μg.
 The mean age of participants was 65.8 years (std = 4.8).
@@ -3236,7 +3236,7 @@ <h2 data-number="7.3" id="sinovacs-coronavac"><span class="header-section-number
 2% (7 participants) reported severe adverse events (4 from the 1.5 μg group, 1 from the 3 μg group, 2 from the 6 μg group), though these were found to be unrelated to the vaccine.</p>
 <p>Overall, the results from the pre-clinical and phase I/II clinical trials are promising.
 It was also very hopeful to see that the immune response was consistent in older adults (&gt; 60 years).
-Currently, phase III trials are being conducted in Brazil <span class="citation" data-cites="KewHbkLZ">[<a href="#ref-KewHbkLZ" role="doc-biblioref">675</a>]</span>.
+Currently, phase III trials are being conducted in Brazil <span class="citation" data-cites="KewHbkLZ">[<a href="#ref-KewHbkLZ" role="doc-biblioref">674</a>]</span>.
 This is a randomized, multicenter, endpoint driven, double-blind, placebo-controlled clinical trial.
 They are expecting 13,060 participants with 11,800 ages 18 to 59 years and 1,260 age 60+.
 Participants will be health care professionals.</p>
@@ -3248,24 +3248,24 @@ <h2 data-number="7.4" id="protein-subunit-vaccines-1"><span class="header-sectio
 <p>Compared to the inactivated whole virus vaccines, these protein subunit vaccines isolate a single protein of the virus and use it to stimulate the immune system.
 These proteins, also referred to as antigens, are usually those located on the surface of the viral particle and are therefore key targets of the immune system.
 These proteins are typically grown in yeast and then harvested.
-This vaccine can stimulate antibodies and CD4<sup>+</sup> T-cell response <span class="citation" data-cites="12eGVhH5I">[<a href="#ref-12eGVhH5I" role="doc-biblioref">701</a>]</span>.
-The main advantage of this method is that they are considered very safe because the antigen alone cannot cause an infection; however, the immune response is weaker and an adjuvant is usually needed to boost the response <span class="citation" data-cites="mv42t1HV">[<a href="#ref-mv42t1HV" role="doc-biblioref">702</a>]</span>.</p>
+This vaccine can stimulate antibodies and CD4<sup>+</sup> T-cell response <span class="citation" data-cites="12eGVhH5I">[<a href="#ref-12eGVhH5I" role="doc-biblioref">700</a>]</span>.
+The main advantage of this method is that they are considered very safe because the antigen alone cannot cause an infection; however, the immune response is weaker and an adjuvant is usually needed to boost the response <span class="citation" data-cites="mv42t1HV">[<a href="#ref-mv42t1HV" role="doc-biblioref">701</a>]</span>.</p>
 <h3 data-number="7.4.1" id="novavax-nvx-cov2373"><span class="header-section-number">7.4.1</span> Novavax NVX-CoV2373</h3>
 <p>Novavax-CoV2373 is a protein nanoparticle vaccine candidate against SARS-CoV-2.
 The vaccine is constructed from a mutated SARS-CoV-2 spike protein in combination with a specialized adjuvant to elicit an immune response against SARS-CoV-2.
-The spike protein is recombinantly expressed in Sf9 insect cells <span class="citation" data-cites="Qk33ZrIC">[<a href="#ref-Qk33ZrIC" role="doc-biblioref">703</a>]</span>, which have previously been used for several other FDA-approved protein therapeutics <span class="citation" data-cites="RQR2sOmx">[<a href="#ref-RQR2sOmx" role="doc-biblioref">704</a>]</span>.
-The expressed spike protein contains mutations in the furin cleavage site (682-RRAR-685 to 682-QQAQ-685) to avoid cleavage of the spike protein as well as two proline substitutions (K986P and V987P) to improve thermostability <span class="citation" data-cites="Qk33ZrIC">[<a href="#ref-Qk33ZrIC" role="doc-biblioref">703</a>]</span>.
+The spike protein is recombinantly expressed in Sf9 insect cells <span class="citation" data-cites="Qk33ZrIC">[<a href="#ref-Qk33ZrIC" role="doc-biblioref">702</a>]</span>, which have previously been used for several other FDA-approved protein therapeutics <span class="citation" data-cites="RQR2sOmx">[<a href="#ref-RQR2sOmx" role="doc-biblioref">703</a>]</span>.
+The expressed spike protein contains mutations in the furin cleavage site (682-RRAR-685 to 682-QQAQ-685) to avoid cleavage of the spike protein as well as two proline substitutions (K986P and V987P) to improve thermostability <span class="citation" data-cites="Qk33ZrIC">[<a href="#ref-Qk33ZrIC" role="doc-biblioref">702</a>]</span>.
 The improved stability caused by the proline substitutions is particularly critical to facilitating global distribution, particularly to regions where local refrigerator/freezer capacities are limited.
 Importantly, these amino acid substitutions did not affect the ability of the spike protein to bind the hACE2 receptor (the target receptor of SARS-CoV-2 spike protein).
-The Novavax-CoV2373 vaccine candidate uses a proprietary, saponin-based Matrix-M<sup>TM</sup> adjuvant that contains two different 40nm-sized particles formed by formulating purified saponin with cholesterol and phospholipids <span class="citation" data-cites="1F52Wz7mx">[<a href="#ref-1F52Wz7mx" role="doc-biblioref">814</a>]</span>.
-In preclinical models, the use of the Matrix-M adjuvant potentiated the cellular and humoral immune responses to influenza vaccines <span class="citation" data-cites="scwOT7dw aD5iMC0Q twmXSpc9 1F52Wz7mx">[<a href="#ref-1F52Wz7mx" role="doc-biblioref">814</a>,<a href="#ref-scwOT7dw" role="doc-biblioref">815</a>,<a href="#ref-aD5iMC0Q" role="doc-biblioref">816</a>,<a href="#ref-twmXSpc9" role="doc-biblioref">817</a>]</span>.
-Importantly, Matrix-M adjuvant-containing vaccines have shown acceptable safety profiles in human clinical trials <span class="citation" data-cites="jVCL0201">[<a href="#ref-jVCL0201" role="doc-biblioref">818</a>]</span>.</p>
-<p>In preclinical mouse models, Novavax-CoV2373 elicited high anti-spike IgG titers 21-28 days post-vaccination that could neutralize the SARS-CoV-2 virus and protect the animals against virus challenge <span class="citation" data-cites="Qk33ZrIC">[<a href="#ref-Qk33ZrIC" role="doc-biblioref">703</a>]</span>.
+The Novavax-CoV2373 vaccine candidate uses a proprietary, saponin-based Matrix-M<sup>TM</sup> adjuvant that contains two different 40nm-sized particles formed by formulating purified saponin with cholesterol and phospholipids <span class="citation" data-cites="1F52Wz7mx">[<a href="#ref-1F52Wz7mx" role="doc-biblioref">813</a>]</span>.
+In preclinical models, the use of the Matrix-M adjuvant potentiated the cellular and humoral immune responses to influenza vaccines <span class="citation" data-cites="scwOT7dw aD5iMC0Q twmXSpc9 1F52Wz7mx">[<a href="#ref-1F52Wz7mx" role="doc-biblioref">813</a>,<a href="#ref-scwOT7dw" role="doc-biblioref">814</a>,<a href="#ref-aD5iMC0Q" role="doc-biblioref">815</a>,<a href="#ref-twmXSpc9" role="doc-biblioref">816</a>]</span>.
+Importantly, Matrix-M adjuvant-containing vaccines have shown acceptable safety profiles in human clinical trials <span class="citation" data-cites="jVCL0201">[<a href="#ref-jVCL0201" role="doc-biblioref">817</a>]</span>.</p>
+<p>In preclinical mouse models, Novavax-CoV2373 elicited high anti-spike IgG titers 21-28 days post-vaccination that could neutralize the SARS-CoV-2 virus and protect the animals against virus challenge <span class="citation" data-cites="Qk33ZrIC">[<a href="#ref-Qk33ZrIC" role="doc-biblioref">702</a>]</span>.
 Antibody titers were significantly elevated in groups receiving the vaccine with the Matrix-M adjuvant compared to the groups without adjuvant.
 Novavax-CoV2373 was able to induce a multifunctional CD4/CD8 T-cell responses and generate high frequencies of follicular helper T-cells and B-cell germinal centers after vaccination.
 These findings were subsequently evaluated in a baboon primate model, in which Novavax-CoV2373 also elicited high antibody titers against the SARS-CoV-2 spike protein, as well as an antigen specific T-cell response.
-Based on this data Novavax initiated a Phase 1/2 clinical trial to evaluate the safety and immunogenicity of Novavax-CoV2373 with Matrix-M <span class="citation" data-cites="Nq0cimEs dMLXxGAI">[<a href="#ref-dMLXxGAI" role="doc-biblioref">705</a>,<a href="#ref-Nq0cimEs" role="doc-biblioref">819</a>]</span>.</p>
-<p>The phase I/II trial was a randomized, placebo-controlled study with 131 healthy adult participants in 5 treatment arms <span class="citation" data-cites="dMLXxGAI">[<a href="#ref-dMLXxGAI" role="doc-biblioref">705</a>]</span>.
+Based on this data Novavax initiated a Phase 1/2 clinical trial to evaluate the safety and immunogenicity of Novavax-CoV2373 with Matrix-M <span class="citation" data-cites="Nq0cimEs dMLXxGAI">[<a href="#ref-dMLXxGAI" role="doc-biblioref">704</a>,<a href="#ref-Nq0cimEs" role="doc-biblioref">818</a>]</span>.</p>
+<p>The phase I/II trial was a randomized, placebo-controlled study with 131 healthy adult participants in 5 treatment arms <span class="citation" data-cites="dMLXxGAI">[<a href="#ref-dMLXxGAI" role="doc-biblioref">704</a>]</span>.
 Participants that received the recombinant SARS-CoV-2 vaccine with or without the Matrix-M adjuvant got two injections, 21 days apart.
 Primary outcomes that were assessed include reactogenicity, lab-values (serum chemistry and hematology), and anti-spike IgG levels.
 Secondary outcomes measured included virus neutralization, T-cell responses, and unsolicited adverse events.
@@ -3274,7 +3274,7 @@ <h3 data-number="7.4.1" id="novavax-nvx-cov2373"><span class="header-section-num
 The two-dose vaccine regimen induced anti-spike IgG levels and neutralizing antibody-titers exceeding those in the convalescent plasma of symptomatic patients.
 In line with the preclinical studies, the use of Matrix-M adjuvant further increased anti-spike immunoglobulin levels and induced a Th1 response.
 The outcomes of this trial suggest that Novavax-CoV2373 has an acceptable safety profile and is able to induce a strong immune response with high neutralizing antibody titers.
-The phase II component of this phase I/II trial was recently uploaded to an open-access repository <span class="citation" data-cites="UJnnQNkx">[<a href="#ref-UJnnQNkx" role="doc-biblioref">820</a>]</span>.
+The phase II component of this phase I/II trial was recently uploaded to an open-access repository <span class="citation" data-cites="UJnnQNkx">[<a href="#ref-UJnnQNkx" role="doc-biblioref">819</a>]</span>.
 This part of the trial was designed to identify which dosing regimen should move forward into late phase clinical trials.
 Both younger (18-59 years) and older patients (60-84 years) were randomly assigned to receive either 5 μg or 25 μg Novavax-CoV2373 or placebo in two doses, 21 days apart.<!--To Do: What is placebo?-->
 In line with the phase I data, reactogenicity remained mild to moderate and of short duration.
@@ -3291,154 +3291,154 @@ <h3 data-number="7.6.1" id="adjuvants-for-vaccines"><span class="header-section-
 <p>Adjuvants include a variety of molecules or larger microbial-related products that have an effect on the immune system or an immune response of interest.
 They can either be comprised of or contain immunostimulants or immunomodulators.
 Adjuvants are sometimes included within vaccines, especially vaccines other than live-attenuated and inactivated viruses, in order to enhance the immune response.
-A review on the development of SARS-CoV-2 vaccines <span class="citation" data-cites="ouOXy0wH">[<a href="#ref-ouOXy0wH" role="doc-biblioref">821</a>]</span> also included a brief summary of the potential of adjuvants for these vaccines, including a brief description of some already commonly used adjuvants.
+A review on the development of SARS-CoV-2 vaccines <span class="citation" data-cites="ouOXy0wH">[<a href="#ref-ouOXy0wH" role="doc-biblioref">820</a>]</span> also included a brief summary of the potential of adjuvants for these vaccines, including a brief description of some already commonly used adjuvants.
 Different adjuvants can regulate different types of immune responses, so the type or combination of adjuvants used in a vaccine will depend on both the type of vaccine and concern related to efficacy and safety.
-A variety of possible mechanisms for adjuvants have been researched <span class="citation" data-cites="13bVbfc5h 122h6fIxE uO0uqhxc">[<a href="#ref-13bVbfc5h" role="doc-biblioref">822</a>,<a href="#ref-122h6fIxE" role="doc-biblioref">823</a>,<a href="#ref-uO0uqhxc" role="doc-biblioref">824</a>]</span>, including the following: induction of DAMPs that can be recognized by certain PRRs of the innate immune system; functioning as PAMP that can also be recognized by certain PRRs; and more generally enhancing the humoral or cellular immune responses.
+A variety of possible mechanisms for adjuvants have been researched <span class="citation" data-cites="13bVbfc5h 122h6fIxE uO0uqhxc">[<a href="#ref-13bVbfc5h" role="doc-biblioref">821</a>,<a href="#ref-122h6fIxE" role="doc-biblioref">822</a>,<a href="#ref-uO0uqhxc" role="doc-biblioref">823</a>]</span>, including the following: induction of DAMPs that can be recognized by certain PRRs of the innate immune system; functioning as PAMP that can also be recognized by certain PRRs; and more generally enhancing the humoral or cellular immune responses.
 Selection of one or more adjuvants requires considering how to promote the advantageous effects of the components and/or immune response and, likewise, to inhibit possible deleterious effects.
 There are also considerations related to the method of delivering (or co-delivering) the adjuvant and antigen components of a vaccine.</p>
 <h3 data-number="7.6.2" id="trained-immunity"><span class="header-section-number">7.6.2</span> Trained Immunity</h3>
 <p>Another approach that is being investigated explores the potential for vaccines that are not made from the SARS-CoV-2 virus to confer what has been termed trained immunity.
-In a recent review <span class="citation" data-cites="103fS7Kz2">[<a href="#ref-103fS7Kz2" role="doc-biblioref">825</a>]</span>, trained immunity was defined as forms of memory that are temporary (e.g., months or years) and reversible.
+In a recent review <span class="citation" data-cites="103fS7Kz2">[<a href="#ref-103fS7Kz2" role="doc-biblioref">824</a>]</span>, trained immunity was defined as forms of memory that are temporary (e.g., months or years) and reversible.
 It is induced by exposure to whole-microorganism vaccines or other microbial stimuli that generates heterologous protective effects.
 Trained immunity can be displayed by innate immune cells or innate immune features of other cells, and it is characterized by alterations to immune responsiveness to future immune challenges due to epigenetic and metabolic mechanisms.
 These alterations can take the form of either an increased or decreased response to immune challenge by a pathogen.
-Trained immunity elicited by non-SARS-CoV-2 whole-microorganism vaccines could potentially improve SARS-CoV-2 susceptibility or severity <span class="citation" data-cites="Vu1VILWK">[<a href="#ref-Vu1VILWK" role="doc-biblioref">826</a>]</span>.</p>
+Trained immunity elicited by non-SARS-CoV-2 whole-microorganism vaccines could potentially improve SARS-CoV-2 susceptibility or severity <span class="citation" data-cites="Vu1VILWK">[<a href="#ref-Vu1VILWK" role="doc-biblioref">825</a>]</span>.</p>
 <p>One type of stimulus which research indicates can induce trained immunity is bacillus Calmette-Guerin (BCG) vaccination.
 BCG is an attenuated form of bacteria <em>Mycobacterium bovis</em>.
 The vaccine is most commonly administered for the prevention of tuberculosis in humans.
 Clinical trials in non-SARS-CoV-2-infected adults have been designed to assess whether BCG vaccination could have prophylactic effects against SARS-CoV-2 by reducing susceptibility, preventing infection, or reducing disease severity.
-A number of trials are now evaluating the effects of the BCG vaccine or the related vaccine VPM1002 <span class="citation" data-cites="Vu1VILWK 9m3rP633 y9IYdfM3 xdqxBruc 962rELVS EuwTWcPi dQtUeruv DjXsPR8O 10OE6y3Pv 86OjIybR ITO15LIz VkZGZxLn 13JVjMfQI nk2MVsld 1E2t9tr8h">[<a href="#ref-Vu1VILWK" role="doc-biblioref">826</a>,<a href="#ref-9m3rP633" role="doc-biblioref">827</a>,<a href="#ref-y9IYdfM3" role="doc-biblioref">828</a>,<a href="#ref-xdqxBruc" role="doc-biblioref">829</a>,<a href="#ref-962rELVS" role="doc-biblioref">830</a>,<a href="#ref-EuwTWcPi" role="doc-biblioref">831</a>,<a href="#ref-dQtUeruv" role="doc-biblioref">832</a>,<a href="#ref-DjXsPR8O" role="doc-biblioref">833</a>,<a href="#ref-10OE6y3Pv" role="doc-biblioref">834</a>,<a href="#ref-86OjIybR" role="doc-biblioref">835</a>,<a href="#ref-ITO15LIz" role="doc-biblioref">836</a>,<a href="#ref-VkZGZxLn" role="doc-biblioref">837</a>,<a href="#ref-13JVjMfQI" role="doc-biblioref">838</a>,<a href="#ref-nk2MVsld" role="doc-biblioref">839</a>,<a href="#ref-1E2t9tr8h" role="doc-biblioref">840</a>]</span>.</p>
+A number of trials are now evaluating the effects of the BCG vaccine or the related vaccine VPM1002 <span class="citation" data-cites="Vu1VILWK 9m3rP633 y9IYdfM3 xdqxBruc 962rELVS EuwTWcPi dQtUeruv DjXsPR8O 10OE6y3Pv 86OjIybR ITO15LIz VkZGZxLn 13JVjMfQI nk2MVsld 1E2t9tr8h">[<a href="#ref-Vu1VILWK" role="doc-biblioref">825</a>,<a href="#ref-9m3rP633" role="doc-biblioref">826</a>,<a href="#ref-y9IYdfM3" role="doc-biblioref">827</a>,<a href="#ref-xdqxBruc" role="doc-biblioref">828</a>,<a href="#ref-962rELVS" role="doc-biblioref">829</a>,<a href="#ref-EuwTWcPi" role="doc-biblioref">830</a>,<a href="#ref-dQtUeruv" role="doc-biblioref">831</a>,<a href="#ref-DjXsPR8O" role="doc-biblioref">832</a>,<a href="#ref-10OE6y3Pv" role="doc-biblioref">833</a>,<a href="#ref-86OjIybR" role="doc-biblioref">834</a>,<a href="#ref-ITO15LIz" role="doc-biblioref">835</a>,<a href="#ref-VkZGZxLn" role="doc-biblioref">836</a>,<a href="#ref-13JVjMfQI" role="doc-biblioref">837</a>,<a href="#ref-nk2MVsld" role="doc-biblioref">838</a>,<a href="#ref-1E2t9tr8h" role="doc-biblioref">839</a>]</span>.</p>
 <p>The ongoing trials are using a number of different approaches.
 Some trials enroll healthcare workers, other trials hospitalized elderly adults without immunosuppression who get vaccinated with placebo or BCG at hospital discharge, and yet another set of trials older adults (&gt;50 years) under chronic care for conditions like hypertension and diabetes.
 One set of trials, for example, uses time until first infection as the primary study endpoint; more generally, outcomes measured in some of these trials are related to incidence of disease and disease severity or symptoms.
-Some analyses have suggested a possible correlation at the country level between the frequency of BCG vaccination (or BCG vaccination policies) and the severity of COVID-19 <span class="citation" data-cites="Vu1VILWK">[<a href="#ref-Vu1VILWK" role="doc-biblioref">826</a>]</span>.
+Some analyses have suggested a possible correlation at the country level between the frequency of BCG vaccination (or BCG vaccination policies) and the severity of COVID-19 <span class="citation" data-cites="Vu1VILWK">[<a href="#ref-Vu1VILWK" role="doc-biblioref">825</a>]</span>.
 Currently it is unclear whether this correlation has any connection to trained immunity.
 Many possible confounding factors are also likely to vary among countries, such as age distribution, detection efficiency, stochastic epidemic dynamic effects, differences in healthcare capacity over time in relation to epidemic dynamics, and these have not been adequately accounted for in current analyses. <!-- TO DO: add in study that debunks this-->
 It is unclear whether there is an effect of the timing of BCG vaccination, both during an individual’s life cycle and relative to the COVID-19 pandemic.
-Additionally, given that severe SARS-CoV-2 may be associated with a dysregulated immune response, it is unclear what alterations to the immune response would be most likely to be protective versus pathogenic (e.g., <span class="citation" data-cites="i5k18bpX 1GnFL9zeN Vu1VILWK 1228YjPRv">[<a href="#ref-1GnFL9zeN" role="doc-biblioref">146</a>,<a href="#ref-Vu1VILWK" role="doc-biblioref">826</a>,<a href="#ref-i5k18bpX" role="doc-biblioref">841</a>,<a href="#ref-1228YjPRv" role="doc-biblioref">842</a>]</span>).
-The article <span class="citation" data-cites="Vu1VILWK">[<a href="#ref-Vu1VILWK" role="doc-biblioref">826</a>]</span> proposes that trained immunity might lead to an earlier and stronger response, which could in turn reduce viremia and the risk of later, detrimental immunopathology.
+Additionally, given that severe SARS-CoV-2 may be associated with a dysregulated immune response, it is unclear what alterations to the immune response would be most likely to be protective versus pathogenic (e.g., <span class="citation" data-cites="i5k18bpX 1GnFL9zeN Vu1VILWK 1228YjPRv">[<a href="#ref-1GnFL9zeN" role="doc-biblioref">146</a>,<a href="#ref-Vu1VILWK" role="doc-biblioref">825</a>,<a href="#ref-i5k18bpX" role="doc-biblioref">840</a>,<a href="#ref-1228YjPRv" role="doc-biblioref">841</a>]</span>).
+The article <span class="citation" data-cites="Vu1VILWK">[<a href="#ref-Vu1VILWK" role="doc-biblioref">825</a>]</span> proposes that trained immunity might lead to an earlier and stronger response, which could in turn reduce viremia and the risk of later, detrimental immunopathology.
 While trained immunity is an interesting possible avenue to complement vaccine development efforts through the use of an existing vaccine, additional research is required to assess whether the BCG vaccine is likely to confer trained immunity in the case of SARS-CoV-2.</p>
 <h2 data-number="7.7" id="viral-evolution-and-vaccine-protection"><span class="header-section-number">7.7</span> Viral evolution and vaccine protection</h2>
 <p>With these vaccines in place, one concern is how the virus’s continued evolution will affect their efficacy.
 Since the start of this pandemic, we have already seen multiple variants emerge: B.1.1.7, which emerged in the UK, B.1.351, which emerged in South Africa, and P.1, which emerged in Brazil.</p>
 <p>Viruses evolve or mutate at different rates.
-Mutation rate is measured as the number of substitutions per nucleotide per cell infected (μ<sub>s/n/c</sub>) <span class="citation" data-cites="4sZmtyNk">[<a href="#ref-4sZmtyNk" role="doc-biblioref">843</a>]</span>.
-RNA viruses tend to have mutation rates between 10<sup>-6</sup> to 10<sup>-4</sup> <span class="citation" data-cites="4sZmtyNk">[<a href="#ref-4sZmtyNk" role="doc-biblioref">843</a>]</span>.
-As a reference, influenza A virus has a mutation rate of 10<sup>-5</sup>, whereas the mutation rate of SARS-CoV-2 is lower, with the mutation rate estimated at 10<sup>-6</sup> <span class="citation" data-cites="vESqa6V0">[<a href="#ref-vESqa6V0" role="doc-biblioref">844</a>]</span>.
-The accumulation of mutations allows the virus to escape recognition by the immune system <span class="citation" data-cites="2pzbGZvL">[<a href="#ref-2pzbGZvL" role="doc-biblioref">845</a>]</span>.</p>
+Mutation rate is measured as the number of substitutions per nucleotide per cell infected (μ<sub>s/n/c</sub>) <span class="citation" data-cites="4sZmtyNk">[<a href="#ref-4sZmtyNk" role="doc-biblioref">842</a>]</span>.
+RNA viruses tend to have mutation rates between 10<sup>-6</sup> to 10<sup>-4</sup> <span class="citation" data-cites="4sZmtyNk">[<a href="#ref-4sZmtyNk" role="doc-biblioref">842</a>]</span>.
+As a reference, influenza A virus has a mutation rate of 10<sup>-5</sup>, whereas the mutation rate of SARS-CoV-2 is lower, with the mutation rate estimated at 10<sup>-6</sup> <span class="citation" data-cites="vESqa6V0">[<a href="#ref-vESqa6V0" role="doc-biblioref">843</a>]</span>.
+The accumulation of mutations allows the virus to escape recognition by the immune system <span class="citation" data-cites="2pzbGZvL">[<a href="#ref-2pzbGZvL" role="doc-biblioref">844</a>]</span>.</p>
 <p>The efficacy of vaccines depends on their ability to train the immune system to recognize the virus.
 Therefore, viruses can develop resistance to vaccines through the accumulation of mutations that affect recognition.
 The lower mutation rate of SARS-CoV-2 suggests the possibility of SARS-CoV-2 vaccines having a more long-lasting effect compared to vaccines targeting the influenza A virus.</p>
-<p>The current SARS-CoV-2 vaccines in distribution have been reported to provide similar efficacy against the B.1.1.7 variant compared to the variants common at the time they were developed but reduced efficacy against the B.1.351 variant <span class="citation" data-cites="LxJvckNs">[<a href="#ref-LxJvckNs" role="doc-biblioref">846</a>]</span>.
-Pfizer and Moderna announced that they are working on developing a booster shot to improve efficacy against the B.1.351 variant <span class="citation" data-cites="ZxfNX9xk">[<a href="#ref-ZxfNX9xk" role="doc-biblioref">847</a>]</span>.
-The WHO continues to monitor the emergence of variants and their impact on vaccine efficacy <span class="citation" data-cites="lY0XUlUp">[<a href="#ref-lY0XUlUp" role="doc-biblioref">848</a>]</span>.
-Previous research in the computational prediction of the efficacy of vaccines targeting the influenza A virus might complement efforts to monitor these types of viral outbreaks <span class="citation" data-cites="YlAWEwlx">[<a href="#ref-YlAWEwlx" role="doc-biblioref">849</a>]</span>.
-To adapt, future vaccines may need to account for multiple variants and strains of SARS-CoV-2, and booster shots may be required <span class="citation" data-cites="180UFKjJ2">[<a href="#ref-180UFKjJ2" role="doc-biblioref">850</a>]</span>.</p>
+<p>The current SARS-CoV-2 vaccines in distribution have been reported to provide similar efficacy against the B.1.1.7 variant compared to the variants common at the time they were developed but reduced efficacy against the B.1.351 variant <span class="citation" data-cites="LxJvckNs">[<a href="#ref-LxJvckNs" role="doc-biblioref">845</a>]</span>.
+Pfizer and Moderna announced that they are working on developing a booster shot to improve efficacy against the B.1.351 variant <span class="citation" data-cites="ZxfNX9xk">[<a href="#ref-ZxfNX9xk" role="doc-biblioref">846</a>]</span>.
+The WHO continues to monitor the emergence of variants and their impact on vaccine efficacy <span class="citation" data-cites="lY0XUlUp">[<a href="#ref-lY0XUlUp" role="doc-biblioref">847</a>]</span>.
+Previous research in the computational prediction of the efficacy of vaccines targeting the influenza A virus might complement efforts to monitor these types of viral outbreaks <span class="citation" data-cites="YlAWEwlx">[<a href="#ref-YlAWEwlx" role="doc-biblioref">848</a>]</span>.
+To adapt, future vaccines may need to account for multiple variants and strains of SARS-CoV-2, and booster shots may be required <span class="citation" data-cites="180UFKjJ2">[<a href="#ref-180UFKjJ2" role="doc-biblioref">849</a>]</span>.</p>
 <h2 data-number="7.8" id="global-vaccine-status-and-distribution"><span class="header-section-number">7.8</span> Global Vaccine Status and Distribution</h2>
 <p>The unprecedented development of COVID-19 vaccines in under a year since the beginning of the pandemic now requires rapid global vaccine production and distribution plans.
 The development of vaccines is costly and complicated, but vaccine distribution can be just as challenging.
-Logistical considerations such as transport, storage, equipment (e.g., syringes), the workforce to administer the vaccines, and a continual supply from the manufacturers to meet global demands all must be accounted for and will vary globally due to economic, geographic, and sociopolitical reasons <span class="citation" data-cites="RG0vzlcE 19CWe6pdS d0kUYq5Z">[<a href="#ref-RG0vzlcE" role="doc-biblioref">851</a>,<a href="#ref-19CWe6pdS" role="doc-biblioref">852</a>,<a href="#ref-d0kUYq5Z" role="doc-biblioref">853</a>]</span>.
+Logistical considerations such as transport, storage, equipment (e.g., syringes), the workforce to administer the vaccines, and a continual supply from the manufacturers to meet global demands all must be accounted for and will vary globally due to economic, geographic, and sociopolitical reasons <span class="citation" data-cites="doi:10.1016/j.eclinm.2020.100674 19CWe6pdS d0kUYq5Z">[<span class="citeproc-not-found" data-reference-id="doi:10.1016/j.eclinm.2020.100674"><strong>???</strong></span>,<a href="#ref-19CWe6pdS" role="doc-biblioref">850</a>,<a href="#ref-d0kUYq5Z" role="doc-biblioref">851</a>]</span>.
 Deciding on the prioritization and allocation of the COVID-19 vaccines is also a challenging task due to ethical and operational considerations.
-Various frameworks, models, and methods have been proposed to tackle these issues with many countries, regions or states as is the case in the U.S., devising their own distribution and administration plans <span class="citation" data-cites="S8WhufUV dLbKv1xi jbpdQdOw z5c17nGB s2zZd6pb">[<a href="#ref-S8WhufUV" role="doc-biblioref">854</a>,<a href="#ref-dLbKv1xi" role="doc-biblioref">855</a>,<a href="#ref-jbpdQdOw" role="doc-biblioref">856</a>,<a href="#ref-z5c17nGB" role="doc-biblioref">857</a>,<a href="#ref-s2zZd6pb" role="doc-biblioref">858</a>]</span>.
-The majority of the distribution plans prioritize offering vaccines to key workers such as health care workers, and those who are clinically vulnerable such as the elderly, the immunocompromised, and individuals with comorbidities, before targeting the rest of the population, who are less likely to experience severe outcomes from COVID-19 <span class="citation" data-cites="sEyIoYCS">[<a href="#ref-sEyIoYCS" role="doc-biblioref">859</a>]</span>.
-As of March 6th, 2021, approximately 319 million vaccine doses have been administered in at least 118 countries worldwide using 10 different vaccines <span class="citation" data-cites="dfl5iCJI DQmAgN0V">[<a href="#ref-DQmAgN0V" role="doc-biblioref">692</a>,<a href="#ref-dfl5iCJI" role="doc-biblioref">860</a>]</span>.
-The global vaccination rate is currently ~8.1 million doses per day, which at the current rate would take almost 4 years to vaccinate 75% of the world’s population according to media estimates of a two-dose regimen <span class="citation" data-cites="DQmAgN0V">[<a href="#ref-DQmAgN0V" role="doc-biblioref">692</a>]</span>.
-Vaccine production and distribution varies from region to region and seems to depend on the availability of the vaccines and potentially a country’s resources and wealth <span class="citation" data-cites="kL8PlRJu">[<a href="#ref-kL8PlRJu" role="doc-biblioref">861</a>]</span>.</p>
+Various frameworks, models, and methods have been proposed to tackle these issues with many countries, regions or states as is the case in the U.S., devising their own distribution and administration plans <span class="citation" data-cites="S8WhufUV dLbKv1xi jbpdQdOw z5c17nGB s2zZd6pb">[<a href="#ref-S8WhufUV" role="doc-biblioref">852</a>,<a href="#ref-dLbKv1xi" role="doc-biblioref">853</a>,<a href="#ref-jbpdQdOw" role="doc-biblioref">854</a>,<a href="#ref-z5c17nGB" role="doc-biblioref">855</a>,<a href="#ref-s2zZd6pb" role="doc-biblioref">856</a>]</span>.
+The majority of the distribution plans prioritize offering vaccines to key workers such as health care workers, and those who are clinically vulnerable such as the elderly, the immunocompromised, and individuals with comorbidities, before targeting the rest of the population, who are less likely to experience severe outcomes from COVID-19 <span class="citation" data-cites="sEyIoYCS">[<a href="#ref-sEyIoYCS" role="doc-biblioref">857</a>]</span>.
+As of March 6th, 2021, approximately 319 million vaccine doses have been administered in at least 118 countries worldwide using 10 different vaccines <span class="citation" data-cites="dfl5iCJI DQmAgN0V">[<a href="#ref-DQmAgN0V" role="doc-biblioref">691</a>,<a href="#ref-dfl5iCJI" role="doc-biblioref">858</a>]</span>.
+The global vaccination rate is currently ~8.1 million doses per day, which at the current rate would take almost 4 years to vaccinate 75% of the world’s population according to media estimates of a two-dose regimen <span class="citation" data-cites="DQmAgN0V">[<a href="#ref-DQmAgN0V" role="doc-biblioref">691</a>]</span>.
+Vaccine production and distribution varies from region to region and seems to depend on the availability of the vaccines and potentially a country’s resources and wealth <span class="citation" data-cites="kL8PlRJu">[<a href="#ref-kL8PlRJu" role="doc-biblioref">859</a>]</span>.</p>
 <p>In North America, the majority of vaccines distributed until March 2021 have been produced by Pfizer-BioNTech and Moderna.
 In Canada, the vaccine approval process is conducted by Health Canada, which uses a fast-tracked process whereby vaccine producers can submit data as it becomes available to allow for rapid review.
 An approval may be granted following reviews of the available phase III clinical data.
-This is followed by a period of pharmacovigilance in the population using their post-market surveillance system, which will monitor the long-term safety and efficacy of any vaccines <span class="citation" data-cites="41tJkg7h YPaDf9jp">[<a href="#ref-41tJkg7h" role="doc-biblioref">862</a>,<a href="#ref-YPaDf9jp" role="doc-biblioref">863</a>]</span>.
-Health Canada has authorized the use of the Pfizer (December 9th, 2020), Moderna (December 23rd, 2020), Oxford-AstraZeneca (February 26th, 2021), and the Janssen (March 5th, 2021) vaccines, and the Novavax Inc vaccine is also under consideration <span class="citation" data-cites="15t1ePH1z">[<a href="#ref-15t1ePH1z" role="doc-biblioref">864</a>]</span>.
-While Canada initially projected that by the end of September 2021 a vaccine would be available for all Canadian adults, they now predict that it may be possible earlier as more vaccines have been approved and become available <span class="citation" data-cites="fQM1moSe">[<a href="#ref-fQM1moSe" role="doc-biblioref">865</a>]</span>.</p>
+This is followed by a period of pharmacovigilance in the population using their post-market surveillance system, which will monitor the long-term safety and efficacy of any vaccines <span class="citation" data-cites="41tJkg7h YPaDf9jp">[<a href="#ref-41tJkg7h" role="doc-biblioref">860</a>,<a href="#ref-YPaDf9jp" role="doc-biblioref">861</a>]</span>.
+Health Canada has authorized the use of the Pfizer (December 9th, 2020), Moderna (December 23rd, 2020), Oxford-AstraZeneca (February 26th, 2021), and the Janssen (March 5th, 2021) vaccines, and the Novavax Inc vaccine is also under consideration <span class="citation" data-cites="15t1ePH1z">[<a href="#ref-15t1ePH1z" role="doc-biblioref">862</a>]</span>.
+While Canada initially projected that by the end of September 2021 a vaccine would be available for all Canadian adults, they now predict that it may be possible earlier as more vaccines have been approved and become available <span class="citation" data-cites="fQM1moSe">[<a href="#ref-fQM1moSe" role="doc-biblioref">863</a>]</span>.</p>
 <p>In the U.S., vaccines are required to have demonstrated safety and efficacy in phase III trials before manufacturers apply for an emergency use authorization (EUA) from the FDA.
 If an EUA is granted, an additional evaluation of the safety and efficacy of the vaccines is conducted by the CDC’s Advisory Committee on Immunization Practices (ACIP) who also provide guidance on vaccine prioritization.
-On December 1st, 2020, ACIP provided an interim phase 1a recommendation that healthcare workers and long-term care facility residents should be the first to be offered any vaccine approved <span class="citation" data-cites="18BMz232x">[<a href="#ref-18BMz232x" role="doc-biblioref">866</a>]</span>.
-This was shortly followed by an EUA on December 11th, 2020 for the use of the Pfizer-BioNTech COVID vaccine <span class="citation" data-cites="17wU8KTSP">[<a href="#ref-17wU8KTSP" role="doc-biblioref">867</a>]</span>, which was distributed and administered to the first healthcare workers on December 14th, 2020 <span class="citation" data-cites="ax2zox20">[<a href="#ref-ax2zox20" role="doc-biblioref">868</a>]</span>.
-Shortly thereafter, an EUA for the Moderna vaccine was issue on December 18th, 2020 <span class="citation" data-cites="7yAHeCqZ">[<a href="#ref-7yAHeCqZ" role="doc-biblioref">869</a>]</span>.
-On December 20th, 2020, ACIP updated their initial recommendations to suggest that vaccinations should be offered to people aged 75 years old and older and to non-healthcare frontline workers in phase 1b <span class="citation" data-cites="Y3jvGtR9">[<a href="#ref-Y3jvGtR9" role="doc-biblioref">870</a>]</span>.
-On the same date, it was recommended that phase 1c should include people aged 65-74 years old, individuals between the ages of 16-74 years old at high-risk due to health conditions, and essential workers ineligible in phase 1b <span class="citation" data-cites="Y3jvGtR9">[<a href="#ref-Y3jvGtR9" role="doc-biblioref">870</a>]</span>.
-On the following day, December 21st, 2020, the first Moderna vaccines used outside of clinical trials were administered to American healthcare workers, which was the same day that President-elect Biden and Dr. Biden received their first doses of the Pfizer-BioNTech vaccine live on television to instill confidence in the approval and vaccination process <span class="citation" data-cites="f5yIh2Xp">[<a href="#ref-f5yIh2Xp" role="doc-biblioref">871</a>]</span>.</p>
-<p>On February 27th, 2020, the FDA issued an EUA for the Janssen COVID-19 Vaccine <span class="citation" data-cites="BG7N9ETs">[<a href="#ref-BG7N9ETs" role="doc-biblioref">872</a>]</span>.
-This was followed by an update on recommendations by ACIP for the use of the Janssen COVID-19 vaccine for those over 18 years old <span class="citation" data-cites="yNaiGtW1">[<a href="#ref-yNaiGtW1" role="doc-biblioref">873</a>]</span>.
+On December 1st, 2020, ACIP provided an interim phase 1a recommendation that healthcare workers and long-term care facility residents should be the first to be offered any vaccine approved <span class="citation" data-cites="18BMz232x">[<a href="#ref-18BMz232x" role="doc-biblioref">864</a>]</span>.
+This was shortly followed by an EUA on December 11th, 2020 for the use of the Pfizer-BioNTech COVID vaccine <span class="citation" data-cites="17wU8KTSP">[<a href="#ref-17wU8KTSP" role="doc-biblioref">865</a>]</span>, which was distributed and administered to the first healthcare workers on December 14th, 2020 <span class="citation" data-cites="ax2zox20">[<a href="#ref-ax2zox20" role="doc-biblioref">866</a>]</span>.
+Shortly thereafter, an EUA for the Moderna vaccine was issue on December 18th, 2020 <span class="citation" data-cites="7yAHeCqZ">[<a href="#ref-7yAHeCqZ" role="doc-biblioref">867</a>]</span>.
+On December 20th, 2020, ACIP updated their initial recommendations to suggest that vaccinations should be offered to people aged 75 years old and older and to non-healthcare frontline workers in phase 1b <span class="citation" data-cites="Y3jvGtR9">[<a href="#ref-Y3jvGtR9" role="doc-biblioref">868</a>]</span>.
+On the same date, it was recommended that phase 1c should include people aged 65-74 years old, individuals between the ages of 16-74 years old at high-risk due to health conditions, and essential workers ineligible in phase 1b <span class="citation" data-cites="Y3jvGtR9">[<a href="#ref-Y3jvGtR9" role="doc-biblioref">868</a>]</span>.
+On the following day, December 21st, 2020, the first Moderna vaccines used outside of clinical trials were administered to American healthcare workers, which was the same day that President-elect Biden and Dr. Biden received their first doses of the Pfizer-BioNTech vaccine live on television to instill confidence in the approval and vaccination process <span class="citation" data-cites="f5yIh2Xp">[<a href="#ref-f5yIh2Xp" role="doc-biblioref">869</a>]</span>.</p>
+<p>On February 27th, 2020, the FDA issued an EUA for the Janssen COVID-19 Vaccine <span class="citation" data-cites="BG7N9ETs">[<a href="#ref-BG7N9ETs" role="doc-biblioref">870</a>]</span>.
+This was followed by an update on recommendations by ACIP for the use of the Janssen COVID-19 vaccine for those over 18 years old <span class="citation" data-cites="yNaiGtW1">[<a href="#ref-yNaiGtW1" role="doc-biblioref">871</a>]</span>.
 The Janssen vaccine was first distributed to healthcare facilities on March 1st, 2021.
-On March 12, 2021, the WHO added the Janssen vaccine to the list of safe and effective emergency tools for COVID-19 <span class="citation" data-cites="Vd1wOy6d">[<a href="#ref-Vd1wOy6d" role="doc-biblioref">874</a>]</span>.
-While the CDC’s ACIP can provide recommendations, it is up to the public health authorities of each state, territory, and tribe to interpret the guidance and determine who will be vaccinated first <span class="citation" data-cites="1CcsUnCiw">[<a href="#ref-1CcsUnCiw" role="doc-biblioref">875</a>]</span>.
+On March 12, 2021, the WHO added the Janssen vaccine to the list of safe and effective emergency tools for COVID-19 <span class="citation" data-cites="Vd1wOy6d">[<a href="#ref-Vd1wOy6d" role="doc-biblioref">872</a>]</span>.
+While the CDC’s ACIP can provide recommendations, it is up to the public health authorities of each state, territory, and tribe to interpret the guidance and determine who will be vaccinated first <span class="citation" data-cites="1CcsUnCiw">[<a href="#ref-1CcsUnCiw" role="doc-biblioref">873</a>]</span>.
 Prior to distribution of the Janssen vaccine, over 103 million doses of the Moderna and Pfizer-BioNTech vaccines were delivered across the U.S., with almost 79 million doses administered.
-Of the total population, 15.6% have received at least one dose and 7.9% have received a second dose of either the Moderna (~38.3 million) or the Pfizer-BioNTech (~40.2 million) vaccines by February 28th, 2021 <span class="citation" data-cites="1Bv67ENp2">[<a href="#ref-1Bv67ENp2" role="doc-biblioref">876</a>]</span>.
-President Biden’s administration has predicted that by the end of May 2021 there may be enough vaccine supply available for all adults in the U.S. <span class="citation" data-cites="1H278OmOM 13bndHWdk">[<a href="#ref-1H278OmOM" role="doc-biblioref">877</a>,<a href="#ref-13bndHWdk" role="doc-biblioref">878</a>]</span>.
-However, vaccine production, approval, and distribution was not straightforward in the U.S., as information was initially sparse and the rollout of vaccines was complicated by poor planning and leadership due to political activities prior to the change of administration in January 2021 <span class="citation" data-cites="wDu31Zz8">[<a href="#ref-wDu31Zz8" role="doc-biblioref">879</a>]</span>.
-These political complications highlight the importance of the transparent vaccine approval process conducted by the FDA <span class="citation" data-cites="1Bgnim0gX">[<a href="#ref-1Bgnim0gX" role="doc-biblioref">880</a>]</span>.</p>
-<p>Outside the U.S., the Moderna and Pfizer-BioNTech vaccines have been administered in 29 and 69 other countries, respectively, mainly in Europe and North America <span class="citation" data-cites="dfl5iCJI">[<a href="#ref-dfl5iCJI" role="doc-biblioref">860</a>]</span>.
-The Janssen vaccine has so far only been administered in South Africa and the U.S. <span class="citation" data-cites="dfl5iCJI I0vakLIc">[<a href="#ref-dfl5iCJI" role="doc-biblioref">860</a>,<a href="#ref-I0vakLIc" role="doc-biblioref">881</a>]</span>, but it has also been approved in Bahrain, the European Union (E.U.), Iceland, Liechtenstein, and Norway <span class="citation" data-cites="wByD9WaX">[<a href="#ref-wByD9WaX" role="doc-biblioref">691</a>]</span>.
-On March 11th, 2021, Johnson &amp; Johnson received approval from the European Medicines Agency (EMA) for conditional marketing authorization of their vaccine <span class="citation" data-cites="17BEDzTkD">[<a href="#ref-17BEDzTkD" role="doc-biblioref">882</a>]</span>.
-Notably, on March 2nd, 2021, rivals Johnson &amp; Johnson and Merck announced that they entered an agreement to increase production of the Janssen vaccine to meet global demand <span class="citation" data-cites="hHW8U8rE">[<a href="#ref-hHW8U8rE" role="doc-biblioref">883</a>]</span>.</p>
-<p>The U.K. was the first country to approve use of the Pfizer-BioNTech vaccine on December 2nd, 2020 <span class="citation" data-cites="133HGZMEL">[<a href="#ref-133HGZMEL" role="doc-biblioref">884</a>]</span>, and it was later approved by EMA on December 21st, 2020 <span class="citation" data-cites="G6V3FR6V">[<a href="#ref-G6V3FR6V" role="doc-biblioref">885</a>]</span>.
+Of the total population, 15.6% have received at least one dose and 7.9% have received a second dose of either the Moderna (~38.3 million) or the Pfizer-BioNTech (~40.2 million) vaccines by February 28th, 2021 <span class="citation" data-cites="1Bv67ENp2">[<a href="#ref-1Bv67ENp2" role="doc-biblioref">874</a>]</span>.
+President Biden’s administration has predicted that by the end of May 2021 there may be enough vaccine supply available for all adults in the U.S. <span class="citation" data-cites="1H278OmOM 13bndHWdk">[<a href="#ref-1H278OmOM" role="doc-biblioref">875</a>,<a href="#ref-13bndHWdk" role="doc-biblioref">876</a>]</span>.
+However, vaccine production, approval, and distribution was not straightforward in the U.S., as information was initially sparse and the rollout of vaccines was complicated by poor planning and leadership due to political activities prior to the change of administration in January 2021 <span class="citation" data-cites="wDu31Zz8">[<a href="#ref-wDu31Zz8" role="doc-biblioref">877</a>]</span>.
+These political complications highlight the importance of the transparent vaccine approval process conducted by the FDA <span class="citation" data-cites="1Bgnim0gX">[<a href="#ref-1Bgnim0gX" role="doc-biblioref">878</a>]</span>.</p>
+<p>Outside the U.S., the Moderna and Pfizer-BioNTech vaccines have been administered in 29 and 69 other countries, respectively, mainly in Europe and North America <span class="citation" data-cites="dfl5iCJI">[<a href="#ref-dfl5iCJI" role="doc-biblioref">858</a>]</span>.
+The Janssen vaccine has so far only been administered in South Africa and the U.S. <span class="citation" data-cites="dfl5iCJI I0vakLIc">[<a href="#ref-dfl5iCJI" role="doc-biblioref">858</a>,<a href="#ref-I0vakLIc" role="doc-biblioref">879</a>]</span>, but it has also been approved in Bahrain, the European Union (E.U.), Iceland, Liechtenstein, and Norway <span class="citation" data-cites="wByD9WaX">[<a href="#ref-wByD9WaX" role="doc-biblioref">690</a>]</span>.
+On March 11th, 2021, Johnson &amp; Johnson received approval from the European Medicines Agency (EMA) for conditional marketing authorization of their vaccine <span class="citation" data-cites="17BEDzTkD">[<a href="#ref-17BEDzTkD" role="doc-biblioref">880</a>]</span>.
+Notably, on March 2nd, 2021, rivals Johnson &amp; Johnson and Merck announced that they entered an agreement to increase production of the Janssen vaccine to meet global demand <span class="citation" data-cites="hHW8U8rE">[<a href="#ref-hHW8U8rE" role="doc-biblioref">881</a>]</span>.</p>
+<p>The U.K. was the first country to approve use of the Pfizer-BioNTech vaccine on December 2nd, 2020 <span class="citation" data-cites="133HGZMEL">[<a href="#ref-133HGZMEL" role="doc-biblioref">882</a>]</span>, and it was later approved by EMA on December 21st, 2020 <span class="citation" data-cites="G6V3FR6V">[<a href="#ref-G6V3FR6V" role="doc-biblioref">883</a>]</span>.
 The U.K. was also the first to administer the Pfizer-BioNTech vaccine, making it the first COVID-19 vaccine supported by phase III data to be administered outside of clinical trials on December 8th, 2020.
-The Oxford-AstraZeneca vaccine, was approved by the Medicines and Healthcare Products Regulatory Agency (MHRA) in the U.K. and by EMA in the E.U. on December 30th (2020) <span class="citation" data-cites="1HIxYDTsj">[<a href="#ref-1HIxYDTsj" role="doc-biblioref">886</a>]</span> and January 29th (2021) <span class="citation" data-cites="bbw8sMvc">[<a href="#ref-bbw8sMvc" role="doc-biblioref">887</a>]</span> respectively.
-The Oxford-AstraZeneca vaccine was first administered in the UK on January 4th, 2021 <span class="citation" data-cites="q1Ui5Fm8">[<a href="#ref-q1Ui5Fm8" role="doc-biblioref">888</a>]</span>, and it is now being used in 53 countries in total, including Brazil, India, Pakistan, Mexico, and spanning most of Europe <span class="citation" data-cites="dfl5iCJI">[<a href="#ref-dfl5iCJI" role="doc-biblioref">860</a>]</span>.
-The Moderna vaccine was authorized for use in the E.U. by EMA on January 6th, 2021 <span class="citation" data-cites="JPSLcRBY">[<a href="#ref-JPSLcRBY" role="doc-biblioref">889</a>]</span> and in the U.K. by MHRA on January 8th, 2021 <span class="citation" data-cites="k9X9pXJe">[<a href="#ref-k9X9pXJe" role="doc-biblioref">890</a>]</span>.
-As of March 5th, 2021, 22 million people in the U.K. had received at least one vaccine dose <span class="citation" data-cites="cWMPXfju">[<a href="#ref-cWMPXfju" role="doc-biblioref">891</a>]</span>.</p>
+The Oxford-AstraZeneca vaccine, was approved by the Medicines and Healthcare Products Regulatory Agency (MHRA) in the U.K. and by EMA in the E.U. on December 30th (2020) <span class="citation" data-cites="1HIxYDTsj">[<a href="#ref-1HIxYDTsj" role="doc-biblioref">884</a>]</span> and January 29th (2021) <span class="citation" data-cites="bbw8sMvc">[<a href="#ref-bbw8sMvc" role="doc-biblioref">885</a>]</span> respectively.
+The Oxford-AstraZeneca vaccine was first administered in the UK on January 4th, 2021 <span class="citation" data-cites="q1Ui5Fm8">[<a href="#ref-q1Ui5Fm8" role="doc-biblioref">886</a>]</span>, and it is now being used in 53 countries in total, including Brazil, India, Pakistan, Mexico, and spanning most of Europe <span class="citation" data-cites="dfl5iCJI">[<a href="#ref-dfl5iCJI" role="doc-biblioref">858</a>]</span>.
+The Moderna vaccine was authorized for use in the E.U. by EMA on January 6th, 2021 <span class="citation" data-cites="JPSLcRBY">[<a href="#ref-JPSLcRBY" role="doc-biblioref">887</a>]</span> and in the U.K. by MHRA on January 8th, 2021 <span class="citation" data-cites="k9X9pXJe">[<a href="#ref-k9X9pXJe" role="doc-biblioref">888</a>]</span>.
+As of March 5th, 2021, 22 million people in the U.K. had received at least one vaccine dose <span class="citation" data-cites="cWMPXfju">[<a href="#ref-cWMPXfju" role="doc-biblioref">889</a>]</span>.</p>
 <p>While the Pfizer-BioNTech vaccine was the first to be distributed following phase III clinical trials, the first COVID-19 vaccine to be widely administered to people prior to the completion of phase III clinical trials was Sputnik V.
-Sputnik V was administered to as many as 1.5 million Russians by early January <span class="citation" data-cites="X5LkVfY6">[<a href="#ref-X5LkVfY6" role="doc-biblioref">742</a>]</span> due to the establishment of mass vaccination clinics in December 2020, prior to which only approximately 100,000 Russians had already been vaccinated <span class="citation" data-cites="uvQMgFXB Vwv7l7Hd">[<a href="#ref-uvQMgFXB" role="doc-biblioref">892</a>,<a href="#ref-Vwv7l7Hd" role="doc-biblioref">893</a>]</span>.
-Doses of Sputnik V have also been distributed to other parts of Europe, such as Belarus, Bosnia-Herzegovina, Hungary, San Marino, Serbia, and Slovakia <span class="citation" data-cites="16LczMwFO Z0V7NK7Y 16GYKbrOq">[<a href="#ref-16LczMwFO" role="doc-biblioref">743</a>,<a href="#ref-Z0V7NK7Y" role="doc-biblioref">744</a>,<a href="#ref-16GYKbrOq" role="doc-biblioref">745</a>]</span>, with the Czech Republic and Austria also having expressed interest in its procurement <span class="citation" data-cites="125VEHWS7">[<a href="#ref-125VEHWS7" role="doc-biblioref">746</a>]</span>.
-Hungary was the first E.U. member country to approve and distribute Sputnik V outside of Russia <span class="citation" data-cites="125VEHWS7">[<a href="#ref-125VEHWS7" role="doc-biblioref">746</a>]</span>, despite the EMA stating that they had neither approved nor received a request for approval of Sputnik V <span class="citation" data-cites="P6x0Qy6s">[<a href="#ref-P6x0Qy6s" role="doc-biblioref">894</a>]</span>.
-Hungary is also in talks with China to procure the Sinopharm vaccines, which have been approved by Hungarian health authorities but also have not received approval by EMA in the E.U. <span class="citation" data-cites="125VEHWS7">[<a href="#ref-125VEHWS7" role="doc-biblioref">746</a>]</span>.
-In Latin America, production facilities in both Brazil and Argentina will allow for increased production capacity of Sputnik V and doses have been distributed to Mexico, Argentina, Bolivia, Nicaragua, Paraguay, and Venezuela <span class="citation" data-cites="ID8IywJM">[<a href="#ref-ID8IywJM" role="doc-biblioref">895</a>]</span>.
-Guinea was the first African nation to administer Sputnik V in December 2020, and the Central African Republic, Zimbabwe, and the Ivory Coast have all registered their interest in purchasing doses of the vaccine <span class="citation" data-cites="ID8IywJM">[<a href="#ref-ID8IywJM" role="doc-biblioref">895</a>]</span>.
-In the Middle East, Iran has received its first doses of Sputnik V and the United Arab Emirates is conducting phase III trials <span class="citation" data-cites="ID8IywJM">[<a href="#ref-ID8IywJM" role="doc-biblioref">895</a>]</span>.
-In Asia, while China’s vaccine candidates are favored, the Philippines, Nepal, and Uzbekistan have sought Sputnik V doses <span class="citation" data-cites="160U0Yb7M 160U0Yb7M">[<a href="#ref-160U0Yb7M" role="doc-biblioref">896</a>,<a href="#ref-160U0Yb7M" role="doc-biblioref">896</a>]</span>.
-In total, the RDIF claims to have received orders totalling 1.2 billion doses by over 50 countries worldwide <span class="citation" data-cites="160U0Yb7M">[<a href="#ref-160U0Yb7M" role="doc-biblioref">896</a>]</span> and at least 18 countries are currently administering Sputnik V around the globe <span class="citation" data-cites="dfl5iCJI">[<a href="#ref-dfl5iCJI" role="doc-biblioref">860</a>]</span>.
+Sputnik V was administered to as many as 1.5 million Russians by early January <span class="citation" data-cites="X5LkVfY6">[<a href="#ref-X5LkVfY6" role="doc-biblioref">741</a>]</span> due to the establishment of mass vaccination clinics in December 2020, prior to which only approximately 100,000 Russians had already been vaccinated <span class="citation" data-cites="uvQMgFXB Vwv7l7Hd">[<a href="#ref-uvQMgFXB" role="doc-biblioref">890</a>,<a href="#ref-Vwv7l7Hd" role="doc-biblioref">891</a>]</span>.
+Doses of Sputnik V have also been distributed to other parts of Europe, such as Belarus, Bosnia-Herzegovina, Hungary, San Marino, Serbia, and Slovakia <span class="citation" data-cites="16LczMwFO Z0V7NK7Y 16GYKbrOq">[<a href="#ref-16LczMwFO" role="doc-biblioref">742</a>,<a href="#ref-Z0V7NK7Y" role="doc-biblioref">743</a>,<a href="#ref-16GYKbrOq" role="doc-biblioref">744</a>]</span>, with the Czech Republic and Austria also having expressed interest in its procurement <span class="citation" data-cites="125VEHWS7">[<a href="#ref-125VEHWS7" role="doc-biblioref">745</a>]</span>.
+Hungary was the first E.U. member country to approve and distribute Sputnik V outside of Russia <span class="citation" data-cites="125VEHWS7">[<a href="#ref-125VEHWS7" role="doc-biblioref">745</a>]</span>, despite the EMA stating that they had neither approved nor received a request for approval of Sputnik V <span class="citation" data-cites="P6x0Qy6s">[<a href="#ref-P6x0Qy6s" role="doc-biblioref">892</a>]</span>.
+Hungary is also in talks with China to procure the Sinopharm vaccines, which have been approved by Hungarian health authorities but also have not received approval by EMA in the E.U. <span class="citation" data-cites="125VEHWS7">[<a href="#ref-125VEHWS7" role="doc-biblioref">745</a>]</span>.
+In Latin America, production facilities in both Brazil and Argentina will allow for increased production capacity of Sputnik V and doses have been distributed to Mexico, Argentina, Bolivia, Nicaragua, Paraguay, and Venezuela <span class="citation" data-cites="ID8IywJM">[<a href="#ref-ID8IywJM" role="doc-biblioref">893</a>]</span>.
+Guinea was the first African nation to administer Sputnik V in December 2020, and the Central African Republic, Zimbabwe, and the Ivory Coast have all registered their interest in purchasing doses of the vaccine <span class="citation" data-cites="ID8IywJM">[<a href="#ref-ID8IywJM" role="doc-biblioref">893</a>]</span>.
+In the Middle East, Iran has received its first doses of Sputnik V and the United Arab Emirates is conducting phase III trials <span class="citation" data-cites="ID8IywJM">[<a href="#ref-ID8IywJM" role="doc-biblioref">893</a>]</span>.
+In Asia, while China’s vaccine candidates are favored, the Philippines, Nepal, and Uzbekistan have sought Sputnik V doses <span class="citation" data-cites="160U0Yb7M 160U0Yb7M">[<a href="#ref-160U0Yb7M" role="doc-biblioref">894</a>,<a href="#ref-160U0Yb7M" role="doc-biblioref">894</a>]</span>.
+In total, the RDIF claims to have received orders totalling 1.2 billion doses by over 50 countries worldwide <span class="citation" data-cites="160U0Yb7M">[<a href="#ref-160U0Yb7M" role="doc-biblioref">894</a>]</span> and at least 18 countries are currently administering Sputnik V around the globe <span class="citation" data-cites="dfl5iCJI">[<a href="#ref-dfl5iCJI" role="doc-biblioref">858</a>]</span>.
 Sputnik V has been an attractive vaccine for many countries due to its relatively low price, high efficacy, and its favorable storage conditions.
-For some countries, Russia and China have also been more palatable politically than vaccine suppliers in the West <span class="citation" data-cites="ID8IywJM FAQXPsyc">[<a href="#ref-ID8IywJM" role="doc-biblioref">895</a>,<a href="#ref-FAQXPsyc" role="doc-biblioref">897</a>]</span>.
-For others, the delays in the distribution of the other, more-favored candidates has been a motivating factor for pursuing the Sputnik V and Chinese alternatives <span class="citation" data-cites="FAQXPsyc Z0V7NK7Y">[<a href="#ref-Z0V7NK7Y" role="doc-biblioref">744</a>,<a href="#ref-FAQXPsyc" role="doc-biblioref">897</a>]</span>.
-Additionally, Germany has stated that if Sputnik V were approved by EMA, it would be considered by the E.U. <span class="citation" data-cites="zCPl6A82">[<a href="#ref-zCPl6A82" role="doc-biblioref">898</a>]</span>.
-Russia is developing other vaccine candidates and has approved a third vaccine, CoviVac, which is an inactivated vaccine produced by the Chumakov Centre in Moscow, despite the fact the clinical trials have yet to begin <span class="citation" data-cites="hpScvlYg">[<a href="#ref-hpScvlYg" role="doc-biblioref">899</a>]</span>.</p>
+For some countries, Russia and China have also been more palatable politically than vaccine suppliers in the West <span class="citation" data-cites="ID8IywJM FAQXPsyc">[<a href="#ref-ID8IywJM" role="doc-biblioref">893</a>,<a href="#ref-FAQXPsyc" role="doc-biblioref">895</a>]</span>.
+For others, the delays in the distribution of the other, more-favored candidates has been a motivating factor for pursuing the Sputnik V and Chinese alternatives <span class="citation" data-cites="FAQXPsyc Z0V7NK7Y">[<a href="#ref-Z0V7NK7Y" role="doc-biblioref">743</a>,<a href="#ref-FAQXPsyc" role="doc-biblioref">895</a>]</span>.
+Additionally, Germany has stated that if Sputnik V were approved by EMA, it would be considered by the E.U. <span class="citation" data-cites="zCPl6A82">[<a href="#ref-zCPl6A82" role="doc-biblioref">896</a>]</span>.
+Russia is developing other vaccine candidates and has approved a third vaccine, CoviVac, which is an inactivated vaccine produced by the Chumakov Centre in Moscow, despite the fact the clinical trials have yet to begin <span class="citation" data-cites="hpScvlYg">[<a href="#ref-hpScvlYg" role="doc-biblioref">897</a>]</span>.</p>
 <p>In Asia, China and India are the main COVID-19 vaccination developers and providers.
-In India, the Covaxin vaccine produced by Bharat Biotech received emergency authorization on January 3rd, 2021, despite the lack of phase III data until March 3rd <span class="citation" data-cites="178GxSdwz Ks3L7qHG">[<a href="#ref-Ks3L7qHG" role="doc-biblioref">679</a>,<a href="#ref-178GxSdwz" role="doc-biblioref">684</a>]</span>.
-Following the release of the phase III data indicating 81% efficacy, Zimbabwe authorized the use of Covaxin <span class="citation" data-cites="13yEnvOyP">[<a href="#ref-13yEnvOyP" role="doc-biblioref">685</a>]</span>.
-In February, 2021, Bharat Biotech received approval from Indian officials to commence a phase I study of an intranasal chimpanzee-adenovirus (ChAd) vectored SARS-CoV-2-S vaccine called BBV154 <span class="citation" data-cites="P9mD7Gc9">[<a href="#ref-P9mD7Gc9" role="doc-biblioref">686</a>]</span>.
-Notably, Novavax has signed an agreement with the Serum Institute of India allowing them to produce up to 2 billion doses a year <span class="citation" data-cites="e8pnj0O3">[<a href="#ref-e8pnj0O3" role="doc-biblioref">689</a>]</span>.
-Novavax has also signed agreements with the U.K., Canada, Australia, and South Korea <span class="citation" data-cites="X3fVa3P8">[<a href="#ref-X3fVa3P8" role="doc-biblioref">690</a>]</span> and has projected that they will supply 1.1 billion doses to COVAX who will distribute the vaccines to countries with disadvantaged access to vaccine supplies <span class="citation" data-cites="wByD9WaX">[<a href="#ref-wByD9WaX" role="doc-biblioref">691</a>]</span>.
-India has vaccinated approximately 24 million people <span class="citation" data-cites="DQmAgN0V">[<a href="#ref-DQmAgN0V" role="doc-biblioref">692</a>]</span>.
-This has been achieved by mainly using the AstraZeneca-University of Oxford vaccine, known as Covishield in India, which is also produced by the Serum Institute of India, and using India’s own Covaxin vaccine <span class="citation" data-cites="gsNWcXHn">[<a href="#ref-gsNWcXHn" role="doc-biblioref">693</a>]</span>.
-India has also shipped approximately 58 million COVID-19 vaccines to 66 countries <span class="citation" data-cites="QRYET3sK">[<a href="#ref-QRYET3sK" role="doc-biblioref">694</a>]</span>
+In India, the Covaxin vaccine produced by Bharat Biotech received emergency authorization on January 3rd, 2021, despite the lack of phase III data until March 3rd <span class="citation" data-cites="178GxSdwz Ks3L7qHG">[<a href="#ref-Ks3L7qHG" role="doc-biblioref">678</a>,<a href="#ref-178GxSdwz" role="doc-biblioref">683</a>]</span>.
+Following the release of the phase III data indicating 81% efficacy, Zimbabwe authorized the use of Covaxin <span class="citation" data-cites="13yEnvOyP">[<a href="#ref-13yEnvOyP" role="doc-biblioref">684</a>]</span>.
+In February, 2021, Bharat Biotech received approval from Indian officials to commence a phase I study of an intranasal chimpanzee-adenovirus (ChAd) vectored SARS-CoV-2-S vaccine called BBV154 <span class="citation" data-cites="P9mD7Gc9">[<a href="#ref-P9mD7Gc9" role="doc-biblioref">685</a>]</span>.
+Notably, Novavax has signed an agreement with the Serum Institute of India allowing them to produce up to 2 billion doses a year <span class="citation" data-cites="e8pnj0O3">[<a href="#ref-e8pnj0O3" role="doc-biblioref">688</a>]</span>.
+Novavax has also signed agreements with the U.K., Canada, Australia, and South Korea <span class="citation" data-cites="X3fVa3P8">[<a href="#ref-X3fVa3P8" role="doc-biblioref">689</a>]</span> and has projected that they will supply 1.1 billion doses to COVAX who will distribute the vaccines to countries with disadvantaged access to vaccine supplies <span class="citation" data-cites="wByD9WaX">[<a href="#ref-wByD9WaX" role="doc-biblioref">690</a>]</span>.
+India has vaccinated approximately 24 million people <span class="citation" data-cites="DQmAgN0V">[<a href="#ref-DQmAgN0V" role="doc-biblioref">691</a>]</span>.
+This has been achieved by mainly using the AstraZeneca-University of Oxford vaccine, known as Covishield in India, which is also produced by the Serum Institute of India, and using India’s own Covaxin vaccine <span class="citation" data-cites="gsNWcXHn">[<a href="#ref-gsNWcXHn" role="doc-biblioref">692</a>]</span>.
+India has also shipped approximately 58 million COVID-19 vaccines to 66 countries <span class="citation" data-cites="QRYET3sK">[<a href="#ref-QRYET3sK" role="doc-biblioref">693</a>]</span>
 Considering India produces approximately 60% of the world’s vaccines prior to the pandemic, it is no surprise that several other vaccine candidates are under development.
-These include ZyCov-Di, a DNA vaccine produced by Zydus Cadila, HGCO19, India’s first mRNA vaccine produced by Genova and HDT Biotech Corporation (of the U.S.), and the Bio E subunit vaccine produced by Biological E in collaboration with U.S.-based Dynavax and the Baylor College of Medicine <span class="citation" data-cites="gsNWcXHn">[<a href="#ref-gsNWcXHn" role="doc-biblioref">693</a>]</span>.</p>
+These include ZyCov-Di, a DNA vaccine produced by Zydus Cadila, HGCO19, India’s first mRNA vaccine produced by Genova and HDT Biotech Corporation (of the U.S.), and the Bio E subunit vaccine produced by Biological E in collaboration with U.S.-based Dynavax and the Baylor College of Medicine <span class="citation" data-cites="gsNWcXHn">[<a href="#ref-gsNWcXHn" role="doc-biblioref">692</a>]</span>.</p>
 <p>In China, the Sinopharm-Beijing Institute vaccine, the Sinopharm-Wuhan Institute of Biological Products vaccine, the Sinovac Biotech (CoronaVac) vaccine, and CanSino Biologics vaccine are the main vaccines being distributed.
 The Sinopharm-Beijing vaccine has been distributed to at least 16 countries.
-This vaccine is currently approved for use in Bahrain, China, and the United Arab Emirates, but has been granted emergency use in Argentina, Cambodia, Egypt, Guyana, Hungary, Iran, Iraq, Jordan, Nepal, Pakistan, Peru, Venezuela, and Zimbabwe, with limited use in both Serbia and the Seychelles <span class="citation" data-cites="rqDwcy2A">[<a href="#ref-rqDwcy2A" role="doc-biblioref">696</a>]</span>.<!--To do: clean citation-->
-The Sinovac vaccine, CoronaVac, has been approved for use in China, and has been granted emergency use in Azerbaijan, Brazil, Cambodia, Chile, Colombia, Ecuador, Hong Kong, Indonesia, Laos, Malaysia, Mexico, Philippines, Thailand, Turkey, Ukraine, and Uruguay <span class="citation" data-cites="ONBMyjqX">[<a href="#ref-ONBMyjqX" role="doc-biblioref">695</a>]</span>.<!--To Do: clean citation-->
-Sinovac has reported that their platform now has the capacity to provide up to a billion doses <span class="citation" data-cites="ONBMyjqX">[<a href="#ref-ONBMyjqX" role="doc-biblioref">695</a>]</span>.<!--To Do: clean citation-->
-Indeed, Sinovac and Sinopharm have estimated that they will be able to produce 2 billion doses by the end of 2021, and they have been able to distribute vaccines as aid to the Philippines and Pakistan <span class="citation" data-cites="gdTtuj5e">[<a href="#ref-gdTtuj5e" role="doc-biblioref">698</a>]</span>.
-In contrast, the Sinopharm-Wuhan vaccine, which has been approved for use in China since February 25th, 2021, has been distributed almost exclusively within China, with limited supplies distributed to the United Arab Emirates <span class="citation" data-cites="mR6133bK">[<a href="#ref-mR6133bK" role="doc-biblioref">697</a>]</span>.<!--To Do: clean citation-->
-On the same date, the CanSino vaccine was approved for use in China and has been granted emergency use in Mexico and Pakistan, which were two participating countries in the CanSino phase III trials <span class="citation" data-cites="4PSTgetR">[<a href="#ref-4PSTgetR" role="doc-biblioref">900</a>]</span>.
+This vaccine is currently approved for use in Bahrain, China, and the United Arab Emirates, but has been granted emergency use in Argentina, Cambodia, Egypt, Guyana, Hungary, Iran, Iraq, Jordan, Nepal, Pakistan, Peru, Venezuela, and Zimbabwe, with limited use in both Serbia and the Seychelles <span class="citation" data-cites="rqDwcy2A">[<a href="#ref-rqDwcy2A" role="doc-biblioref">695</a>]</span>.<!--To do: clean citation-->
+The Sinovac vaccine, CoronaVac, has been approved for use in China, and has been granted emergency use in Azerbaijan, Brazil, Cambodia, Chile, Colombia, Ecuador, Hong Kong, Indonesia, Laos, Malaysia, Mexico, Philippines, Thailand, Turkey, Ukraine, and Uruguay <span class="citation" data-cites="ONBMyjqX">[<a href="#ref-ONBMyjqX" role="doc-biblioref">694</a>]</span>.<!--To Do: clean citation-->
+Sinovac has reported that their platform now has the capacity to provide up to a billion doses <span class="citation" data-cites="ONBMyjqX">[<a href="#ref-ONBMyjqX" role="doc-biblioref">694</a>]</span>.<!--To Do: clean citation-->
+Indeed, Sinovac and Sinopharm have estimated that they will be able to produce 2 billion doses by the end of 2021, and they have been able to distribute vaccines as aid to the Philippines and Pakistan <span class="citation" data-cites="gdTtuj5e">[<a href="#ref-gdTtuj5e" role="doc-biblioref">697</a>]</span>.
+In contrast, the Sinopharm-Wuhan vaccine, which has been approved for use in China since February 25th, 2021, has been distributed almost exclusively within China, with limited supplies distributed to the United Arab Emirates <span class="citation" data-cites="mR6133bK">[<a href="#ref-mR6133bK" role="doc-biblioref">696</a>]</span>.<!--To Do: clean citation-->
+On the same date, the CanSino vaccine was approved for use in China and has been granted emergency use in Mexico and Pakistan, which were two participating countries in the CanSino phase III trials <span class="citation" data-cites="4PSTgetR">[<a href="#ref-4PSTgetR" role="doc-biblioref">898</a>]</span>.
 However, the vaccine approval and distribution processes in China have come under increased scrutiny from other nations.
-China was criticized for administering vaccines to thousands of government officials and state-owned businesses in September 2020, prior to the completion of phase III clinical trials <span class="citation" data-cites="1Bgnim0gX">[<a href="#ref-1Bgnim0gX" role="doc-biblioref">880</a>]</span>.
-The behavior of Chinese officials has also come into question due to misinformation campaigns questioning the safety of Western vaccine candidates such as Moderna and Pfizer-BioNTech in a way that is intended to highlight the benefits of their own vaccine candidates <span class="citation" data-cites="gdTtuj5e">[<a href="#ref-gdTtuj5e" role="doc-biblioref">698</a>]</span>.
-Furthermore, delays in vaccine distribution have also caused issues, particularly in Turkey where 10 million doses of Sinovac were due to arrive by December 2020, but instead only 3 million were delivered in early January <span class="citation" data-cites="gdTtuj5e">[<a href="#ref-gdTtuj5e" role="doc-biblioref">698</a>]</span>.
-Similar delays and shortages of doses promised have been reported by officials in the Philippines, Egypt, Morocco, and the United Arab Emirates <span class="citation" data-cites="XJmfG8HD 12zVLzkpB">[<a href="#ref-XJmfG8HD" role="doc-biblioref">699</a>,<a href="#ref-12zVLzkpB" role="doc-biblioref">700</a>]</span>.
-This will be concerning to China who have vaccine contracts for millions of doses with Indonesia (&gt;100 million), Brazil (100 million), Chile (60 million), Turkey (50 million), Egypt (40 million) and many others <span class="citation" data-cites="12zVLzkpB">[<a href="#ref-12zVLzkpB" role="doc-biblioref">700</a>]</span>.</p>
-<p>Globally, North America currently leads the world vaccination rates (13.8 per 100 people) followed by Europe (8.2 per 100), South America (3.1 per 100), Asia (1.9 per 100), Africa (0.3 per 100), and Oceania (0.1 per 100) are trailing behind <span class="citation" data-cites="dfl5iCJI">[<a href="#ref-dfl5iCJI" role="doc-biblioref">860</a>]</span>.
-Considering the wealthy nations of North America and Europe have secured most of the limited COVID-19 vaccine stocks <span class="citation" data-cites="1AvwH3T5y">[<a href="#ref-1AvwH3T5y" role="doc-biblioref">901</a>]</span>, it is likely that low- and middle-income countries will face further competition with Western countries for vaccine availability.
-While South Africa and Zimbabwe have their own vaccination programs, many other African nations will be reliant on the COVID-19 Vaccines Global Access (COVAX) Facility, who have promised 600 million doses to the continent <span class="citation" data-cites="1EnpYQzIq">[<a href="#ref-1EnpYQzIq" role="doc-biblioref">902</a>]</span>.
+China was criticized for administering vaccines to thousands of government officials and state-owned businesses in September 2020, prior to the completion of phase III clinical trials <span class="citation" data-cites="1Bgnim0gX">[<a href="#ref-1Bgnim0gX" role="doc-biblioref">878</a>]</span>.
+The behavior of Chinese officials has also come into question due to misinformation campaigns questioning the safety of Western vaccine candidates such as Moderna and Pfizer-BioNTech in a way that is intended to highlight the benefits of their own vaccine candidates <span class="citation" data-cites="gdTtuj5e">[<a href="#ref-gdTtuj5e" role="doc-biblioref">697</a>]</span>.
+Furthermore, delays in vaccine distribution have also caused issues, particularly in Turkey where 10 million doses of Sinovac were due to arrive by December 2020, but instead only 3 million were delivered in early January <span class="citation" data-cites="gdTtuj5e">[<a href="#ref-gdTtuj5e" role="doc-biblioref">697</a>]</span>.
+Similar delays and shortages of doses promised have been reported by officials in the Philippines, Egypt, Morocco, and the United Arab Emirates <span class="citation" data-cites="XJmfG8HD 12zVLzkpB">[<a href="#ref-XJmfG8HD" role="doc-biblioref">698</a>,<a href="#ref-12zVLzkpB" role="doc-biblioref">699</a>]</span>.
+This will be concerning to China who have vaccine contracts for millions of doses with Indonesia (&gt;100 million), Brazil (100 million), Chile (60 million), Turkey (50 million), Egypt (40 million) and many others <span class="citation" data-cites="12zVLzkpB">[<a href="#ref-12zVLzkpB" role="doc-biblioref">699</a>]</span>.</p>
+<p>Globally, North America currently leads the world vaccination rates (13.8 per 100 people) followed by Europe (8.2 per 100), South America (3.1 per 100), Asia (1.9 per 100), Africa (0.3 per 100), and Oceania (0.1 per 100) are trailing behind <span class="citation" data-cites="dfl5iCJI">[<a href="#ref-dfl5iCJI" role="doc-biblioref">858</a>]</span>.
+Considering the wealthy nations of North America and Europe have secured most of the limited COVID-19 vaccine stocks <span class="citation" data-cites="1AvwH3T5y">[<a href="#ref-1AvwH3T5y" role="doc-biblioref">899</a>]</span>, it is likely that low- and middle-income countries will face further competition with Western countries for vaccine availability.
+While South Africa and Zimbabwe have their own vaccination programs, many other African nations will be reliant on the COVID-19 Vaccines Global Access (COVAX) Facility, who have promised 600 million doses to the continent <span class="citation" data-cites="1EnpYQzIq">[<a href="#ref-1EnpYQzIq" role="doc-biblioref">900</a>]</span>.
 COVAX is a multilateral initiative as part of the Access to COVID-19 Tools (ACT) Accelerator coordinated by the WHO, Gavi The Vaccine Alliance, and the Coalition for Epidemic Preparedness Innovations (CEPI), the latter two of which are supported by the Bill and Melinda Gates Foundation.
-Their intention is to accelerate the development of COVID-19 vaccines, diagnostics, and therapeutics and to ensure the equitable distribution of vaccines to low- and middle-income countries <span class="citation" data-cites="3Gq7ETv7 KzHIbPMY">[<a href="#ref-3Gq7ETv7" role="doc-biblioref">903</a>,<a href="#ref-KzHIbPMY" role="doc-biblioref">904</a>]</span>.
-COVAX invested in several vaccine programs to ensure they would have access to successful vaccine candidates <span class="citation" data-cites="1H0PiQpLz">[<a href="#ref-1H0PiQpLz" role="doc-biblioref">905</a>]</span>.
+Their intention is to accelerate the development of COVID-19 vaccines, diagnostics, and therapeutics and to ensure the equitable distribution of vaccines to low- and middle-income countries <span class="citation" data-cites="3Gq7ETv7 KzHIbPMY">[<a href="#ref-3Gq7ETv7" role="doc-biblioref">901</a>,<a href="#ref-KzHIbPMY" role="doc-biblioref">902</a>]</span>.
+COVAX invested in several vaccine programs to ensure they would have access to successful vaccine candidates <span class="citation" data-cites="1H0PiQpLz">[<a href="#ref-1H0PiQpLz" role="doc-biblioref">903</a>]</span>.
 The COVAX plan ensured that all participating countries would be allocated vaccines in proportion to their population sizes.
 Once each country has received vaccine doses to account for 20% of their population, the country’s risk profile will determine its place in subsequent phases of vaccine distribution.
-However, several limitations of this framework exist, including that the COVAX scheme seems to go against the WHO’s own ethical principles of human well-being, equal respect, and global equity, and that other frameworks might have been more suitable, as is discussed elsewhere <span class="citation" data-cites="12QaZb4si">[<a href="#ref-12QaZb4si" role="doc-biblioref">906</a>]</span>.
-Furthermore, COVAX is supposed to allow poorer countries access to affordable vaccines, but the vaccines are driven by publicly traded companies that are required to make a profit <span class="citation" data-cites="kL8PlRJu">[<a href="#ref-kL8PlRJu" role="doc-biblioref">861</a>]</span>.
+However, several limitations of this framework exist, including that the COVAX scheme seems to go against the WHO’s own ethical principles of human well-being, equal respect, and global equity, and that other frameworks might have been more suitable, as is discussed elsewhere <span class="citation" data-cites="12QaZb4si">[<a href="#ref-12QaZb4si" role="doc-biblioref">904</a>]</span>.
+Furthermore, COVAX is supposed to allow poorer countries access to affordable vaccines, but the vaccines are driven by publicly traded companies that are required to make a profit <span class="citation" data-cites="kL8PlRJu">[<a href="#ref-kL8PlRJu" role="doc-biblioref">859</a>]</span>.
 In any case, COVAX provides access to COVID-19 vaccines that may otherwise have been difficult for some countries to obtain.
-COVAX aims to distribute 2 billion vaccine doses globally by the end of 2021 <span class="citation" data-cites="7dkwQDUf">[<a href="#ref-7dkwQDUf" role="doc-biblioref">907</a>]</span>.
-COVAX may also receive additional donations of doses from Western nations who purchased surplus vaccines in the race to vaccinate their populations, which will be a welcome boost to the vaccination programs of low- and middle-income countries <span class="citation" data-cites="sr5oRBgc">[<a href="#ref-sr5oRBgc" role="doc-biblioref">908</a>]</span>.
-As of March, 2021, 9 African countries have received vaccines and at least 11 other nations have begun vaccinations via COVAX, aid from other countries, or their own agreements with producers <span class="citation" data-cites="1EnpYQzIq 2b6FdDOy">[<a href="#ref-1EnpYQzIq" role="doc-biblioref">902</a>,<a href="#ref-2b6FdDOy" role="doc-biblioref">909</a>]</span>.
-However, much further progress is required when only 0.3 per 100 people have been vaccinated in Africa <span class="citation" data-cites="dfl5iCJI">[<a href="#ref-dfl5iCJI" role="doc-biblioref">860</a>]</span>.</p>
+COVAX aims to distribute 2 billion vaccine doses globally by the end of 2021 <span class="citation" data-cites="7dkwQDUf">[<a href="#ref-7dkwQDUf" role="doc-biblioref">905</a>]</span>.
+COVAX may also receive additional donations of doses from Western nations who purchased surplus vaccines in the race to vaccinate their populations, which will be a welcome boost to the vaccination programs of low- and middle-income countries <span class="citation" data-cites="sr5oRBgc">[<a href="#ref-sr5oRBgc" role="doc-biblioref">906</a>]</span>.
+As of March, 2021, 9 African countries have received vaccines and at least 11 other nations have begun vaccinations via COVAX, aid from other countries, or their own agreements with producers <span class="citation" data-cites="1EnpYQzIq 2b6FdDOy">[<a href="#ref-1EnpYQzIq" role="doc-biblioref">900</a>,<a href="#ref-2b6FdDOy" role="doc-biblioref">907</a>]</span>.
+However, much further progress is required when only 0.3 per 100 people have been vaccinated in Africa <span class="citation" data-cites="dfl5iCJI">[<a href="#ref-dfl5iCJI" role="doc-biblioref">858</a>]</span>.</p>
 <h2 data-number="7.9" id="discussion-1"><span class="header-section-number">7.9</span> Discussion</h2>
 <p>Additionally, major advances in vaccines using mRNA and adenoviruses that have led to three vaccines becoming available or close to becoming available in late 2020 (Figure <a href="#fig:therapeutics">4</a>). <!-- Update depending on where this goes and specify countries etc.--></p>
 <p>Though some concerns remain about the duration of sustained immunity for convalescents, vaccine development efforts are ongoing and show initial promising results.
 <!-- TO DO: Needs to be updated with vaccine info about duration, this is changing rapidly so leaving for now-->
 The Moderna trial, for example, reported that the neutralizing activity in participants who received two doses of the vaccine was similar to that observed in convalescent plasma.</p>
-<p>One of the two mRNA vaccines, Pfizer and BioNTech’s BNT162b2, has been issued an EUA for patients as young as 16 <span class="citation" data-cites="1DETimS2y">[<a href="#ref-1DETimS2y" role="doc-biblioref">910</a>]</span>, while ModernaTX has begun a clinical trial to assess its mRNA vaccine in adolescents ages 12 to 18 <span class="citation" data-cites="eDdKGPvy">[<a href="#ref-eDdKGPvy" role="doc-biblioref">911</a>]</span>.</p>
+<p>One of the two mRNA vaccines, Pfizer and BioNTech’s BNT162b2, has been issued an EUA for patients as young as 16 <span class="citation" data-cites="1DETimS2y">[<a href="#ref-1DETimS2y" role="doc-biblioref">908</a>]</span>, while ModernaTX has begun a clinical trial to assess its mRNA vaccine in adolescents ages 12 to 18 <span class="citation" data-cites="eDdKGPvy">[<a href="#ref-eDdKGPvy" role="doc-biblioref">909</a>]</span>.</p>
 <h1 data-number="8" id="dietary-supplements-and-nutraceuticals-under-investigation-for-covid-19-prevention-and-treatment"><span class="header-section-number">8</span> Dietary Supplements and Nutraceuticals Under Investigation for COVID-19 Prevention and Treatment</h1>
 <h2 data-number="8.1" id="abstract-6"><span class="header-section-number">8.1</span> Abstract</h2>
 <p>Coronavirus disease 2019 (COVID-19) has caused global disruption and a significant loss of life.
@@ -3463,141 +3463,141 @@ <h2 data-number="8.3" id="introduction-6"><span class="header-section-number">8.
 This rapid effort led to the identification of some promising pharmaceutical therapies for hospitalized patients, such as remdesivir and dexamethasone.
 Furthermore, most societies have adopted non-pharmacological preventative measures such as utilizing public health strategies that reduce the transmission of SARS-CoV-2.
 However, during this time, many individuals sought additional protections via the consumption of various dietary supplements and nutraceuticals that they believed to confer beneficial effects.
-While a patient’s nutritional status does seem to play a role in COVID-19 susceptibility and outcomes <span class="citation" data-cites="Lyd8s4Mk UFrQw1gC Hd5V5Usd 1FAOfFx5A 5tHMedSi">[<a href="#ref-Lyd8s4Mk" role="doc-biblioref">912</a>,<a href="#ref-UFrQw1gC" role="doc-biblioref">913</a>,<a href="#ref-Hd5V5Usd" role="doc-biblioref">914</a>,<a href="#ref-1FAOfFx5A" role="doc-biblioref">915</a>,<a href="#ref-5tHMedSi" role="doc-biblioref">916</a>]</span>, the beginning of the pandemic saw sales of vitamins and other supplements soar despite a lack of any evidence supporting their use against COVID-19.
-In the United States, for example, dietary supplement and nutraceutical sales have shown modest annual growth in recent years (approximately 5%, or a $345 million increase in 2019), but during the six-week period preceding April 5, 2020, they increased by 44% ($435 million) relative to the same period in 2019 <span class="citation" data-cites="A225e05z">[<a href="#ref-A225e05z" role="doc-biblioref">917</a>]</span>.
-While growth subsequently leveled off, sales continued to boom, with a further 16% ($151 million) increase during the six weeks preceding May 17, 2020 relative to 2019 <span class="citation" data-cites="A225e05z">[<a href="#ref-A225e05z" role="doc-biblioref">917</a>]</span>.
-In France, New Zealand, India, and China, similar trends in sales were reported <span class="citation" data-cites="LMkJA6Ke puD7Ydak 1FjpTy3Dd 5NJabJny">[<a href="#ref-LMkJA6Ke" role="doc-biblioref">918</a>,<a href="#ref-puD7Ydak" role="doc-biblioref">919</a>,<a href="#ref-1FjpTy3Dd" role="doc-biblioref">920</a>,<a href="#ref-5NJabJny" role="doc-biblioref">921</a>]</span>.
-The increase in sales was driven by a consumer perception that dietary supplements and nutraceuticals would protect consumers from infection and/or mitigate the impact of infection due to the various “immune-boosting” claims of these products <span class="citation" data-cites="10JmgRgZG 18NItmm1M">[<a href="#ref-10JmgRgZG" role="doc-biblioref">922</a>,<a href="#ref-18NItmm1M" role="doc-biblioref">923</a>]</span>.</p>
+While a patient’s nutritional status does seem to play a role in COVID-19 susceptibility and outcomes <span class="citation" data-cites="Lyd8s4Mk UFrQw1gC Hd5V5Usd 1FAOfFx5A 5tHMedSi">[<a href="#ref-Lyd8s4Mk" role="doc-biblioref">910</a>,<a href="#ref-UFrQw1gC" role="doc-biblioref">911</a>,<a href="#ref-Hd5V5Usd" role="doc-biblioref">912</a>,<a href="#ref-1FAOfFx5A" role="doc-biblioref">913</a>,<a href="#ref-5tHMedSi" role="doc-biblioref">914</a>]</span>, the beginning of the pandemic saw sales of vitamins and other supplements soar despite a lack of any evidence supporting their use against COVID-19.
+In the United States, for example, dietary supplement and nutraceutical sales have shown modest annual growth in recent years (approximately 5%, or a $345 million increase in 2019), but during the six-week period preceding April 5, 2020, they increased by 44% ($435 million) relative to the same period in 2019 <span class="citation" data-cites="A225e05z">[<a href="#ref-A225e05z" role="doc-biblioref">915</a>]</span>.
+While growth subsequently leveled off, sales continued to boom, with a further 16% ($151 million) increase during the six weeks preceding May 17, 2020 relative to 2019 <span class="citation" data-cites="A225e05z">[<a href="#ref-A225e05z" role="doc-biblioref">915</a>]</span>.
+In France, New Zealand, India, and China, similar trends in sales were reported <span class="citation" data-cites="LMkJA6Ke puD7Ydak 1FjpTy3Dd 5NJabJny">[<a href="#ref-LMkJA6Ke" role="doc-biblioref">916</a>,<a href="#ref-puD7Ydak" role="doc-biblioref">917</a>,<a href="#ref-1FjpTy3Dd" role="doc-biblioref">918</a>,<a href="#ref-5NJabJny" role="doc-biblioref">919</a>]</span>.
+The increase in sales was driven by a consumer perception that dietary supplements and nutraceuticals would protect consumers from infection and/or mitigate the impact of infection due to the various “immune-boosting” claims of these products <span class="citation" data-cites="10JmgRgZG 18NItmm1M">[<a href="#ref-10JmgRgZG" role="doc-biblioref">920</a>,<a href="#ref-18NItmm1M" role="doc-biblioref">921</a>]</span>.</p>
 <p>Due to the significant interest from the general public in dietary additives, whether and to what extent nutraceuticals or dietary supplements can provide any prophylactic or therapeutic benefit remains a topic of interest for the scientific community.
 Nutraceuticals and dietary supplements are related but distinct non-pharmaceutical products.
-Nutraceuticals are classified as supplements with health benefits beyond their basic nutritional value <span class="citation" data-cites="xLPeszeO 2Us0gNMr">[<a href="#ref-xLPeszeO" role="doc-biblioref">924</a>,<a href="#ref-2Us0gNMr" role="doc-biblioref">925</a>]</span>.
-The key difference between a dietary supplement and a nutraceutical is that nutraceuticals should not only supplement the diet, but also aid in the prophylaxis and/or treatment of a disorder or disease <span class="citation" data-cites="X0jEogv4">[<a href="#ref-X0jEogv4" role="doc-biblioref">926</a>]</span>.
+Nutraceuticals are classified as supplements with health benefits beyond their basic nutritional value <span class="citation" data-cites="xLPeszeO 2Us0gNMr">[<a href="#ref-xLPeszeO" role="doc-biblioref">922</a>,<a href="#ref-2Us0gNMr" role="doc-biblioref">923</a>]</span>.
+The key difference between a dietary supplement and a nutraceutical is that nutraceuticals should not only supplement the diet, but also aid in the prophylaxis and/or treatment of a disorder or disease <span class="citation" data-cites="X0jEogv4">[<a href="#ref-X0jEogv4" role="doc-biblioref">924</a>]</span>.
 However, dietary supplements and nutraceuticals, unlike pharmaceuticals, are not subject to the same regulatory protocols that protect consumers of medicines.
-Indeed, nutraceuticals do not entirely fall under the responsibility of the Food and Drug Administration (FDA), but they are monitored as dietary supplements according to the Dietary Supplement, Health and Education Act 1994 (DSHEA) <span class="citation" data-cites="10Tnnl6nF">[<a href="#ref-10Tnnl6nF" role="doc-biblioref">927</a>]</span> and the Food and Drug Administration Modernization Act 1997 (FDAMA) <span class="citation" data-cites="16eEQf0HM">[<a href="#ref-16eEQf0HM" role="doc-biblioref">928</a>]</span>.
+Indeed, nutraceuticals do not entirely fall under the responsibility of the Food and Drug Administration (FDA), but they are monitored as dietary supplements according to the Dietary Supplement, Health and Education Act 1994 (DSHEA) <span class="citation" data-cites="10Tnnl6nF">[<a href="#ref-10Tnnl6nF" role="doc-biblioref">925</a>]</span> and the Food and Drug Administration Modernization Act 1997 (FDAMA) <span class="citation" data-cites="16eEQf0HM">[<a href="#ref-16eEQf0HM" role="doc-biblioref">926</a>]</span>.
 Due to increases in sales of dietary supplements and nutraceuticals, in 1996 the FDA established the Office of Dietary Supplement Programs (ODSP) to increase surveillance.
 Novel products or nutraceuticals must now submit a new dietary ingredient notification to the ODSP for review.
-There are significant concerns that these legislations do not adequately protect the consumer as they ascribe responsibility to the manufacturers to ensure the safety of the product before manufacturing or marketing <span class="citation" data-cites="5TmtJWVQ">[<a href="#ref-5TmtJWVQ" role="doc-biblioref">929</a>]</span>.
+There are significant concerns that these legislations do not adequately protect the consumer as they ascribe responsibility to the manufacturers to ensure the safety of the product before manufacturing or marketing <span class="citation" data-cites="5TmtJWVQ">[<a href="#ref-5TmtJWVQ" role="doc-biblioref">927</a>]</span>.
 Manufacturers are not required to register or even seek approval from the FDA to produce or sell food supplements or nutraceuticals.
-Health or nutrient content claims for labeling purposes are approved based on an authoritative statement from the Academy of Sciences or relevant federal authorities once the FDA has been notified and on the basis that the information is known to be true and not deceptive <span class="citation" data-cites="5TmtJWVQ">[<a href="#ref-5TmtJWVQ" role="doc-biblioref">929</a>]</span>.
+Health or nutrient content claims for labeling purposes are approved based on an authoritative statement from the Academy of Sciences or relevant federal authorities once the FDA has been notified and on the basis that the information is known to be true and not deceptive <span class="citation" data-cites="5TmtJWVQ">[<a href="#ref-5TmtJWVQ" role="doc-biblioref">927</a>]</span>.
 Therefore, there is often a gap between perceptions by the American public about a nutraceutical or dietary supplement and the actual clinical evidence surrounding its effects.</p>
 <p>Despite differences in regulations, similar challenges exist outside of the United States.
-In Europe, where the safety of supplements is monitored by the European Union (EU) under Directive 2002/46/EC <span class="citation" data-cites="CWdgoTUe">[<a href="#ref-CWdgoTUe" role="doc-biblioref">930</a>]</span>.
+In Europe, where the safety of supplements is monitored by the European Union (EU) under Directive 2002/46/EC <span class="citation" data-cites="CWdgoTUe">[<a href="#ref-CWdgoTUe" role="doc-biblioref">928</a>]</span>.
 However, nutraceuticals are not directly mentioned.
-Consequently, nutraceuticals can be generally described as either a medicinal product under Directive 2004/27/EC <span class="citation" data-cites="G7TnkK6t">[<a href="#ref-G7TnkK6t" role="doc-biblioref">931</a>]</span> or as a ‘foodstuff’ under Directive 2002/46/EC of the European council.
+Consequently, nutraceuticals can be generally described as either a medicinal product under Directive 2004/27/EC <span class="citation" data-cites="G7TnkK6t">[<a href="#ref-G7TnkK6t" role="doc-biblioref">929</a>]</span> or as a ‘foodstuff’ under Directive 2002/46/EC of the European council.
 In order to synchronize the various existing legislations, Regulation EC 1924/2006 on nutrition and health claims was put into effect to assure customers of safety and efficacy of products and to deliver understandable information to consumers.
 However, specific legislation for nutraceuticals is still elusive.
-Health claims are permitted on a product label only following compliance and authorization according to the European Food Safety Authority (EFSA) guidelines on nutrition and health claims <span class="citation" data-cites="dzOveIQY">[<a href="#ref-dzOveIQY" role="doc-biblioref">932</a>]</span>.
-EFSA does not currently distinguish between food supplements and nutraceuticals for health claim applications of new products, as claim authorization is dependent on the availability of clinical data in order to substantiate efficacy <span class="citation" data-cites="MhvDTmeu">[<a href="#ref-MhvDTmeu" role="doc-biblioref">933</a>]</span>.
-These guidelines seem to provide more protection to consumers than the FDA regulations but potentially at the cost of innovation in the sector <span class="citation" data-cites="LBf0kxOm">[<a href="#ref-LBf0kxOm" role="doc-biblioref">934</a>]</span>.
-The situation becomes even more complicated when comparing regulations at a global level, as countries such as China and India have existing regulatory frameworks for traditional medicines and phytomedicines not commonly consumed in Western society <span class="citation" data-cites="jovk0AV9">[<a href="#ref-jovk0AV9" role="doc-biblioref">935</a>]</span>.
-Currently, there is debate among scientists and regulatory authorities surrounding the development of a widespread regulatory framework to deal with the challenges of safety and health claim substantiation for nutraceuticals <span class="citation" data-cites="MhvDTmeu 5TmtJWVQ">[<a href="#ref-5TmtJWVQ" role="doc-biblioref">929</a>,<a href="#ref-MhvDTmeu" role="doc-biblioref">933</a>]</span>, as these products do not necessarily follow the same rigorous clinical trial frameworks used to approve the use of pharmaceuticals.
+Health claims are permitted on a product label only following compliance and authorization according to the European Food Safety Authority (EFSA) guidelines on nutrition and health claims <span class="citation" data-cites="dzOveIQY">[<a href="#ref-dzOveIQY" role="doc-biblioref">930</a>]</span>.
+EFSA does not currently distinguish between food supplements and nutraceuticals for health claim applications of new products, as claim authorization is dependent on the availability of clinical data in order to substantiate efficacy <span class="citation" data-cites="MhvDTmeu">[<a href="#ref-MhvDTmeu" role="doc-biblioref">931</a>]</span>.
+These guidelines seem to provide more protection to consumers than the FDA regulations but potentially at the cost of innovation in the sector <span class="citation" data-cites="LBf0kxOm">[<a href="#ref-LBf0kxOm" role="doc-biblioref">932</a>]</span>.
+The situation becomes even more complicated when comparing regulations at a global level, as countries such as China and India have existing regulatory frameworks for traditional medicines and phytomedicines not commonly consumed in Western society <span class="citation" data-cites="jovk0AV9">[<a href="#ref-jovk0AV9" role="doc-biblioref">933</a>]</span>.
+Currently, there is debate among scientists and regulatory authorities surrounding the development of a widespread regulatory framework to deal with the challenges of safety and health claim substantiation for nutraceuticals <span class="citation" data-cites="MhvDTmeu 5TmtJWVQ">[<a href="#ref-5TmtJWVQ" role="doc-biblioref">927</a>,<a href="#ref-MhvDTmeu" role="doc-biblioref">931</a>]</span>, as these products do not necessarily follow the same rigorous clinical trial frameworks used to approve the use of pharmaceuticals.
 Such regulatory disparities have been highlighted by the pandemic, as many individuals and companies have attempted to profit from the vulnerabilities of others by overstating claims in relation to the treatment of COVID-19 using supplements and nutraceuticals.
-The FDA has written several letters to prevent companies marketing or selling products based on false hyperbolic promises about preventing SARS-CoV-2 infection or treating COVID-19 <span class="citation" data-cites="l2tEuVtb Qo0C93P6 133nfCM4l">[<a href="#ref-l2tEuVtb" role="doc-biblioref">936</a>,<a href="#ref-Qo0C93P6" role="doc-biblioref">937</a>,<a href="#ref-133nfCM4l" role="doc-biblioref">938</a>]</span>.
-These letters came in response to efforts to market nutraceutical prophylactics against COVID-19, some of which charged the consumer as much as $23,000 <span class="citation" data-cites="7B3shLSx">[<a href="#ref-7B3shLSx" role="doc-biblioref">939</a>]</span>.
-There have even been some incidents highlighted in the media because of their potentially life threatening consequences; for example, the use of oleandrin was touted as a potential “cure” by individuals close to the former President of the United States despite its high toxicity <span class="citation" data-cites="Ssmsdskt">[<a href="#ref-Ssmsdskt" role="doc-biblioref">940</a>]</span>.
+The FDA has written several letters to prevent companies marketing or selling products based on false hyperbolic promises about preventing SARS-CoV-2 infection or treating COVID-19 <span class="citation" data-cites="l2tEuVtb Qo0C93P6 133nfCM4l">[<a href="#ref-l2tEuVtb" role="doc-biblioref">934</a>,<a href="#ref-Qo0C93P6" role="doc-biblioref">935</a>,<a href="#ref-133nfCM4l" role="doc-biblioref">936</a>]</span>.
+These letters came in response to efforts to market nutraceutical prophylactics against COVID-19, some of which charged the consumer as much as $23,000 <span class="citation" data-cites="7B3shLSx">[<a href="#ref-7B3shLSx" role="doc-biblioref">937</a>]</span>.
+There have even been some incidents highlighted in the media because of their potentially life threatening consequences; for example, the use of oleandrin was touted as a potential “cure” by individuals close to the former President of the United States despite its high toxicity <span class="citation" data-cites="Ssmsdskt">[<a href="#ref-Ssmsdskt" role="doc-biblioref">938</a>]</span>.
 Thus, heterogeneous and at times relaxed regulatory standards have permitted high-profile cases of the sale of nutraceuticals and dietary supplements that are purported to provide protection against COVID-19, despite a lack of research into these compounds.</p>
 <p>Notwithstanding the issues of poor safety, efficacy, and regulatory oversight, some dietary supplements and nutraceuticals have exhibited therapeutic and prophylactic potential.
-Some have been linked with reduced immunopathology, antiviral and anti-inflammatory activities, or even the prevention of acute respiratory distress syndrome (ARDS) <span class="citation" data-cites="GT7yDBjv 10JmgRgZG EEa0SZCF">[<a href="#ref-10JmgRgZG" role="doc-biblioref">922</a>,<a href="#ref-GT7yDBjv" role="doc-biblioref">941</a>,<a href="#ref-EEa0SZCF" role="doc-biblioref">942</a>]</span>.
+Some have been linked with reduced immunopathology, antiviral and anti-inflammatory activities, or even the prevention of acute respiratory distress syndrome (ARDS) <span class="citation" data-cites="GT7yDBjv 10JmgRgZG EEa0SZCF">[<a href="#ref-10JmgRgZG" role="doc-biblioref">920</a>,<a href="#ref-GT7yDBjv" role="doc-biblioref">939</a>,<a href="#ref-EEa0SZCF" role="doc-biblioref">940</a>]</span>.
 A host of potential candidates have been highlighted in the literature that target various aspects of the COVID-19 viral pathology, while others are thought to prime the host immune system.
-These candidates include vitamins and minerals along with extracts and omega-3 polyunsaturated fatty acids (n-3 PUFA) <span class="citation" data-cites="2hMFPQJR">[<a href="#ref-2hMFPQJR" role="doc-biblioref">943</a>]</span>.
-<em>In vitro</em> and <em>in vivo</em> studies suggest that nutraceuticals containing phycocyanobilin, N-acetylcysteine, glucosamine, selenium or phase 2 inductive nutraceuticals (e.g. ferulic acid, lipoic acid, or sulforaphane) can prevent or modulate RNA virus infections via amplification of the signaling activity of mitochondrial antiviral-signaling protein (MAVS) and activation of Toll-like receptor 7 <span class="citation" data-cites="eyBAUUCl">[<a href="#ref-eyBAUUCl" role="doc-biblioref">944</a>]</span>.
+These candidates include vitamins and minerals along with extracts and omega-3 polyunsaturated fatty acids (n-3 PUFA) <span class="citation" data-cites="2hMFPQJR">[<a href="#ref-2hMFPQJR" role="doc-biblioref">941</a>]</span>.
+<em>In vitro</em> and <em>in vivo</em> studies suggest that nutraceuticals containing phycocyanobilin, N-acetylcysteine, glucosamine, selenium or phase 2 inductive nutraceuticals (e.g. ferulic acid, lipoic acid, or sulforaphane) can prevent or modulate RNA virus infections via amplification of the signaling activity of mitochondrial antiviral-signaling protein (MAVS) and activation of Toll-like receptor 7 <span class="citation" data-cites="eyBAUUCl">[<a href="#ref-eyBAUUCl" role="doc-biblioref">942</a>]</span>.
 Phase 2 inductive molecules used in the production of nutraceuticals are known to activate nuclear factor erythroid 2–related factor 2 (Nrf2), which is a protein regulator of antioxidant enzymes that leads to the induction of several antioxidant enzymes, such as gamma-glutamylcysteine synthetase.
 While promising, further animal and human studies are required to assess the therapeutic potential of these various nutrients and nutraceuticals against COVID-19.
 For the purpose of this review, we have highlighted some of the main dietary supplements and nutraceuticals that are currently under investigation for their potential prophylactic and therapeutic applications.
 These include n-3 PUFA, zinc, vitamins C and D, and probiotics.</p>
 <h2 data-number="8.4" id="n-3-pufa"><span class="header-section-number">8.4</span> n-3 PUFA</h2>
-<p>One category of supplements that has been explored for beneficial effects against various viral infections are the n-3 PUFAs <span class="citation" data-cites="2hMFPQJR">[<a href="#ref-2hMFPQJR" role="doc-biblioref">943</a>]</span>, commonly referred to as omega-3 fatty acids, which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
-EPA and DHA intake can come from a diet high in fish or through dietary supplementation with fish oils or purified oils <span class="citation" data-cites="Ufvsmc3N">[<a href="#ref-Ufvsmc3N" role="doc-biblioref">945</a>]</span>.
-Other, more sustainable sources of EPA and DHA include algae <span class="citation" data-cites="Gzqj7Okm Txn1mlRl">[<a href="#ref-Gzqj7Okm" role="doc-biblioref">946</a>,<a href="#ref-Txn1mlRl" role="doc-biblioref">947</a>]</span>, which can also be exploited for their rich abundance of other bioactive compounds such as angiotensin converting enzyme inhibitor peptides and antiviral agents including phycobiliproteins, sulfated polysaccharides, and calcium-spirulan <span class="citation" data-cites="S1A3WazG">[<a href="#ref-S1A3WazG" role="doc-biblioref">948</a>]</span>.
-n-3 PUFAs have been investigated for many years for their therapeutic potential <span class="citation" data-cites="4xymCvKH">[<a href="#ref-4xymCvKH" role="doc-biblioref">949</a>]</span>.
-Supplementation with fish oils is generally well tolerated <span class="citation" data-cites="4xymCvKH">[<a href="#ref-4xymCvKH" role="doc-biblioref">949</a>]</span>, and intake of n-3 PUFAs through dietary sources or supplementation is specifically encouraged for vulnerable groups such as pregnant and lactating women <span class="citation" data-cites="17CHOdNbe g4dU6DMd">[<a href="#ref-17CHOdNbe" role="doc-biblioref">950</a>,<a href="#ref-g4dU6DMd" role="doc-biblioref">951</a>]</span>.
+<p>One category of supplements that has been explored for beneficial effects against various viral infections are the n-3 PUFAs <span class="citation" data-cites="2hMFPQJR">[<a href="#ref-2hMFPQJR" role="doc-biblioref">941</a>]</span>, commonly referred to as omega-3 fatty acids, which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
+EPA and DHA intake can come from a diet high in fish or through dietary supplementation with fish oils or purified oils <span class="citation" data-cites="Ufvsmc3N">[<a href="#ref-Ufvsmc3N" role="doc-biblioref">943</a>]</span>.
+Other, more sustainable sources of EPA and DHA include algae <span class="citation" data-cites="Gzqj7Okm Txn1mlRl">[<a href="#ref-Gzqj7Okm" role="doc-biblioref">944</a>,<a href="#ref-Txn1mlRl" role="doc-biblioref">945</a>]</span>, which can also be exploited for their rich abundance of other bioactive compounds such as angiotensin converting enzyme inhibitor peptides and antiviral agents including phycobiliproteins, sulfated polysaccharides, and calcium-spirulan <span class="citation" data-cites="S1A3WazG">[<a href="#ref-S1A3WazG" role="doc-biblioref">946</a>]</span>.
+n-3 PUFAs have been investigated for many years for their therapeutic potential <span class="citation" data-cites="4xymCvKH">[<a href="#ref-4xymCvKH" role="doc-biblioref">947</a>]</span>.
+Supplementation with fish oils is generally well tolerated <span class="citation" data-cites="4xymCvKH">[<a href="#ref-4xymCvKH" role="doc-biblioref">947</a>]</span>, and intake of n-3 PUFAs through dietary sources or supplementation is specifically encouraged for vulnerable groups such as pregnant and lactating women <span class="citation" data-cites="17CHOdNbe g4dU6DMd">[<a href="#ref-17CHOdNbe" role="doc-biblioref">948</a>,<a href="#ref-g4dU6DMd" role="doc-biblioref">949</a>]</span>.
 As a result, these well-established compounds have drawn significant interest for their potential immune effects and therapeutic potential.</p>
 <p>Particular interest has arisen in n-3 PUFAs as potential therapeutics against diseases associated with inflammation.
-n-3 PUFAs have been found to modulate inflammation by influencing processes such as leukocyte chemotaxis, adhesion molecule expression, and the production of eicosanoids <span class="citation" data-cites="JNyhLAfe cvX4fl0q">[<a href="#ref-JNyhLAfe" role="doc-biblioref">952</a>,<a href="#ref-cvX4fl0q" role="doc-biblioref">953</a>]</span>.
-This and other evidence indicates that n-3 PUFAs may have the capacity to modulate the adaptive immune response <span class="citation" data-cites="JNyhLAfe Ufvsmc3N 2Us0gNMr">[<a href="#ref-2Us0gNMr" role="doc-biblioref">925</a>,<a href="#ref-Ufvsmc3N" role="doc-biblioref">945</a>,<a href="#ref-JNyhLAfe" role="doc-biblioref">952</a>]</span>; for example, they have been found to influence antigen presentation and the production of CD4(+) Th1 cells, among other relevant effects <span class="citation" data-cites="165UR0Ipw">[<a href="#ref-165UR0Ipw" role="doc-biblioref">954</a>]</span>.
-Certainly, preliminary evidence from banked blood samples from 100 COVID-19 patients suggests that patients with a higher omega-3 index, a measure of the amount of EPA and DHA in red blood cells, had a lower risk of death due to COVID-19 <span class="citation" data-cites="TTfh7mb9">[<a href="#ref-TTfh7mb9" role="doc-biblioref">955</a>]</span>.
-Interest has also arisen as to whether nutritional status related to n-3 PUFAs can also affect inflammation associated with severe disease, such as ARDS or sepsis <span class="citation" data-cites="FtxL59jJ 12vyTsM9W">[<a href="#ref-FtxL59jJ" role="doc-biblioref">956</a>,<a href="#ref-12vyTsM9W" role="doc-biblioref">957</a>]</span>.
-ARDS and sepsis hold particular concern in the treatment of severe COVID-19; an analysis of 82 deceased COVID-19 patients in Wuhan during January to February 2020 reported that respiratory failure (associated with ARDS) was the cause of death in 69.5% of cases, and sepsis or multi-organ failure accounted for 28.0% of deaths <span class="citation" data-cites="16mSlRgM3">[<a href="#ref-16mSlRgM3" role="doc-biblioref">958</a>]</span>.
+n-3 PUFAs have been found to modulate inflammation by influencing processes such as leukocyte chemotaxis, adhesion molecule expression, and the production of eicosanoids <span class="citation" data-cites="JNyhLAfe cvX4fl0q">[<a href="#ref-JNyhLAfe" role="doc-biblioref">950</a>,<a href="#ref-cvX4fl0q" role="doc-biblioref">951</a>]</span>.
+This and other evidence indicates that n-3 PUFAs may have the capacity to modulate the adaptive immune response <span class="citation" data-cites="JNyhLAfe Ufvsmc3N 2Us0gNMr">[<a href="#ref-2Us0gNMr" role="doc-biblioref">923</a>,<a href="#ref-Ufvsmc3N" role="doc-biblioref">943</a>,<a href="#ref-JNyhLAfe" role="doc-biblioref">950</a>]</span>; for example, they have been found to influence antigen presentation and the production of CD4(+) Th1 cells, among other relevant effects <span class="citation" data-cites="165UR0Ipw">[<a href="#ref-165UR0Ipw" role="doc-biblioref">952</a>]</span>.
+Certainly, preliminary evidence from banked blood samples from 100 COVID-19 patients suggests that patients with a higher omega-3 index, a measure of the amount of EPA and DHA in red blood cells, had a lower risk of death due to COVID-19 <span class="citation" data-cites="TTfh7mb9">[<a href="#ref-TTfh7mb9" role="doc-biblioref">953</a>]</span>.
+Interest has also arisen as to whether nutritional status related to n-3 PUFAs can also affect inflammation associated with severe disease, such as ARDS or sepsis <span class="citation" data-cites="FtxL59jJ 12vyTsM9W">[<a href="#ref-FtxL59jJ" role="doc-biblioref">954</a>,<a href="#ref-12vyTsM9W" role="doc-biblioref">955</a>]</span>.
+ARDS and sepsis hold particular concern in the treatment of severe COVID-19; an analysis of 82 deceased COVID-19 patients in Wuhan during January to February 2020 reported that respiratory failure (associated with ARDS) was the cause of death in 69.5% of cases, and sepsis or multi-organ failure accounted for 28.0% of deaths <span class="citation" data-cites="16mSlRgM3">[<a href="#ref-16mSlRgM3" role="doc-biblioref">956</a>]</span>.
 Research in ARDS prior to current pandemic suggests that n-3 PUFAs may hold some therapeutic potential.
-One study randomized 16 consecutive ARDS patients to receive either a fish oil-enriched lipid emulsion or a control lipid emulsion (comprised of 100% long-chain triglycerides) under a double-blinded design <span class="citation" data-cites="LmdFoxGc">[<a href="#ref-LmdFoxGc" role="doc-biblioref">959</a>]</span>.
+One study randomized 16 consecutive ARDS patients to receive either a fish oil-enriched lipid emulsion or a control lipid emulsion (comprised of 100% long-chain triglycerides) under a double-blinded design <span class="citation" data-cites="LmdFoxGc">[<a href="#ref-LmdFoxGc" role="doc-biblioref">957</a>]</span>.
 They reported a statistically significant reduction in leukotriene B4 levels in the group receiving the fish oil-enriched emulsion, suggesting that the fish oil supplementation may have reduced inflammation.
 However, they also reported that most of their tests were not statistically significant, and therefore it seems that additional research using larger sample sizes is required.
-A recent meta-analysis of 10 randomized controlled trials (RCTs) examining the effects of n-3 PUFAs on ARDS patients did not find evidence of any effect on mortality, although the effect on secondary outcomes could not be determined due to a low quality of evidence <span class="citation" data-cites="q9FzffQx">[<a href="#ref-q9FzffQx" role="doc-biblioref">960</a>]</span>.
-However, another meta-analysis that examined 24 RCTs studying the effects of n-3 fatty acids on sepsis, including ARDS-induced sepsis, did find support for an effect on mortality when n-3 fatty acids were administered via enteral nutrition, although a paucity of high-quality evidence again limited conclusions <span class="citation" data-cites="EwajTsK5">[<a href="#ref-EwajTsK5" role="doc-biblioref">961</a>]</span>.
+A recent meta-analysis of 10 randomized controlled trials (RCTs) examining the effects of n-3 PUFAs on ARDS patients did not find evidence of any effect on mortality, although the effect on secondary outcomes could not be determined due to a low quality of evidence <span class="citation" data-cites="q9FzffQx">[<a href="#ref-q9FzffQx" role="doc-biblioref">958</a>]</span>.
+However, another meta-analysis that examined 24 RCTs studying the effects of n-3 fatty acids on sepsis, including ARDS-induced sepsis, did find support for an effect on mortality when n-3 fatty acids were administered via enteral nutrition, although a paucity of high-quality evidence again limited conclusions <span class="citation" data-cites="EwajTsK5">[<a href="#ref-EwajTsK5" role="doc-biblioref">959</a>]</span>.
 Therefore, despite theoretical support for an immunomodulatory effect of n-3 PUFAs in COVID-19, evidence from existing RCTs is insufficient to determine whether supplementation offers an advantage in a clinical setting that would be relevant to COVID-19.</p>
-<p>Another potential mechanism that has led to interest in n-3 PUFAs as protective against viral infections including COVID-19 is its potential as a precursor molecule for the biosynthesis of endogenous specialized proresolving mediators (SPM), such as protectins and resolvins, that actively resolve inflammation and infection <span class="citation" data-cites="BIVORG2X">[<a href="#ref-BIVORG2X" role="doc-biblioref">962</a>]</span>.
-SPM have exhibited beneficial effects against a variety of lung infections, including some caused by RNA viruses <span class="citation" data-cites="uPOTvvjR sxgmhJ68">[<a href="#ref-uPOTvvjR" role="doc-biblioref">963</a>,<a href="#ref-sxgmhJ68" role="doc-biblioref">964</a>]</span>.
-Several mechanisms for SPM have been proposed, including preventing the release of pro-inflammatory cytokines and chemokines or increasing phagocytosis of cellular debris by macrophages <span class="citation" data-cites="OSEnHt6H">[<a href="#ref-OSEnHt6H" role="doc-biblioref">965</a>]</span>.
-In influenza, SPM promote antiviral B lymphocytic activities <span class="citation" data-cites="MK0GQ55y">[<a href="#ref-MK0GQ55y" role="doc-biblioref">966</a>]</span>, and protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery <span class="citation" data-cites="fIo3ESPM">[<a href="#ref-fIo3ESPM" role="doc-biblioref">967</a>]</span>.
-It has thus been hypothesized that SPM could aid in the resolution of the cytokine storm and pulmonary inflammation associated with COVID-19 <span class="citation" data-cites="14LjKv9ZH PRLlghQS">[<a href="#ref-14LjKv9ZH" role="doc-biblioref">968</a>,<a href="#ref-PRLlghQS" role="doc-biblioref">969</a>]</span>.
-Another theory is that some comorbidities, such as obesity, could lead to deficiencies of SPM, which could in turn be related to the occurrence of adverse outcomes for COVID-19 <span class="citation" data-cites="oLunKkIG">[<a href="#ref-oLunKkIG" role="doc-biblioref">970</a>]</span>.
-However, not all studies are in agreement that n-3 PUFAs or their resulting SPM are effective against infections <span class="citation" data-cites="B8toe6Mr">[<a href="#ref-B8toe6Mr" role="doc-biblioref">971</a>]</span>.
-At a minimum, the effectiveness of n-3 PUFAs against infections would be dependent on the dosage, timing, and the specific pathogens responsible <span class="citation" data-cites="3Xht24k3">[<a href="#ref-3Xht24k3" role="doc-biblioref">972</a>]</span>.
-On another level, there is still the question of whether fish oils can raise the levels of SPM levels upon ingestion and in response to acute inflammation in humans <span class="citation" data-cites="Ge00xeR3">[<a href="#ref-Ge00xeR3" role="doc-biblioref">973</a>]</span>.
-Currently, Karolinska University Hospital is running a trial that will measure the levels of SPM as a secondary outcome following intravenous supplementation of n-3 PUFAs in hospitalized COVID-19 patients to determine whether n-3 PUFAs provides therapeutic value <span class="citation" data-cites="n93SvQ2p pIfWCVkv">[<a href="#ref-n93SvQ2p" role="doc-biblioref">974</a>,<a href="#ref-pIfWCVkv" role="doc-biblioref">975</a>]</span>.
+<p>Another potential mechanism that has led to interest in n-3 PUFAs as protective against viral infections including COVID-19 is its potential as a precursor molecule for the biosynthesis of endogenous specialized proresolving mediators (SPM), such as protectins and resolvins, that actively resolve inflammation and infection <span class="citation" data-cites="BIVORG2X">[<a href="#ref-BIVORG2X" role="doc-biblioref">960</a>]</span>.
+SPM have exhibited beneficial effects against a variety of lung infections, including some caused by RNA viruses <span class="citation" data-cites="uPOTvvjR sxgmhJ68">[<a href="#ref-uPOTvvjR" role="doc-biblioref">961</a>,<a href="#ref-sxgmhJ68" role="doc-biblioref">962</a>]</span>.
+Several mechanisms for SPM have been proposed, including preventing the release of pro-inflammatory cytokines and chemokines or increasing phagocytosis of cellular debris by macrophages <span class="citation" data-cites="OSEnHt6H">[<a href="#ref-OSEnHt6H" role="doc-biblioref">963</a>]</span>.
+In influenza, SPM promote antiviral B lymphocytic activities <span class="citation" data-cites="MK0GQ55y">[<a href="#ref-MK0GQ55y" role="doc-biblioref">964</a>]</span>, and protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery <span class="citation" data-cites="fIo3ESPM">[<a href="#ref-fIo3ESPM" role="doc-biblioref">965</a>]</span>.
+It has thus been hypothesized that SPM could aid in the resolution of the cytokine storm and pulmonary inflammation associated with COVID-19 <span class="citation" data-cites="14LjKv9ZH PRLlghQS">[<a href="#ref-14LjKv9ZH" role="doc-biblioref">966</a>,<a href="#ref-PRLlghQS" role="doc-biblioref">967</a>]</span>.
+Another theory is that some comorbidities, such as obesity, could lead to deficiencies of SPM, which could in turn be related to the occurrence of adverse outcomes for COVID-19 <span class="citation" data-cites="oLunKkIG">[<a href="#ref-oLunKkIG" role="doc-biblioref">968</a>]</span>.
+However, not all studies are in agreement that n-3 PUFAs or their resulting SPM are effective against infections <span class="citation" data-cites="B8toe6Mr">[<a href="#ref-B8toe6Mr" role="doc-biblioref">969</a>]</span>.
+At a minimum, the effectiveness of n-3 PUFAs against infections would be dependent on the dosage, timing, and the specific pathogens responsible <span class="citation" data-cites="3Xht24k3">[<a href="#ref-3Xht24k3" role="doc-biblioref">970</a>]</span>.
+On another level, there is still the question of whether fish oils can raise the levels of SPM levels upon ingestion and in response to acute inflammation in humans <span class="citation" data-cites="Ge00xeR3">[<a href="#ref-Ge00xeR3" role="doc-biblioref">971</a>]</span>.
+Currently, Karolinska University Hospital is running a trial that will measure the levels of SPM as a secondary outcome following intravenous supplementation of n-3 PUFAs in hospitalized COVID-19 patients to determine whether n-3 PUFAs provides therapeutic value <span class="citation" data-cites="n93SvQ2p pIfWCVkv">[<a href="#ref-n93SvQ2p" role="doc-biblioref">972</a>,<a href="#ref-pIfWCVkv" role="doc-biblioref">973</a>]</span>.
 Therefore, while this mechanism provides theoretical support for a role for n-3 PUFAs against COVID-19, experimental support is still needed.</p>
-<p>A third possible mechanism by which n-3 PUFAs could benefit COVID-19 patients arises from the fact that some COVID-19 patients, particularly those with comorbidities, are at a significant risk of thrombotic complications including arterial and venous thrombosis <span class="citation" data-cites="17jegDTvF PyKMLraw">[<a href="#ref-PyKMLraw" role="doc-biblioref">124</a>,<a href="#ref-17jegDTvF" role="doc-biblioref">976</a>]</span>.
-Therefore, the use of prophylactic and therapeutic anticoagulants and antithrombotic agents is under consideration <span class="citation" data-cites="SxPCbOB1 rWVL91jq">[<a href="#ref-SxPCbOB1" role="doc-biblioref">977</a>,<a href="#ref-rWVL91jq" role="doc-biblioref">978</a>]</span>.
-Considering that there is significant evidence that n-3 fatty acids and other fish oil-derived lipids possess antithrombotic properties and anti-inflammatory properties <span class="citation" data-cites="umzPtQG7 V9MDMfpj Ufvsmc3N">[<a href="#ref-Ufvsmc3N" role="doc-biblioref">945</a>,<a href="#ref-umzPtQG7" role="doc-biblioref">979</a>,<a href="#ref-V9MDMfpj" role="doc-biblioref">980</a>]</span>, they may have therapeutic value against the prothrombotic complications of COVID-19.
-In particular, concerns have been raised within the medical community about using investigational therapeutics on COVID-19 patients who are already on antiplatelet therapies due to pre-existing comorbidities because the introduction of such therapeutics could lead to issues with dosing and drug choice and/or negative drug-drug interactions <span class="citation" data-cites="SxPCbOB1">[<a href="#ref-SxPCbOB1" role="doc-biblioref">977</a>]</span>.
+<p>A third possible mechanism by which n-3 PUFAs could benefit COVID-19 patients arises from the fact that some COVID-19 patients, particularly those with comorbidities, are at a significant risk of thrombotic complications including arterial and venous thrombosis <span class="citation" data-cites="17jegDTvF PyKMLraw">[<a href="#ref-PyKMLraw" role="doc-biblioref">124</a>,<a href="#ref-17jegDTvF" role="doc-biblioref">974</a>]</span>.
+Therefore, the use of prophylactic and therapeutic anticoagulants and antithrombotic agents is under consideration <span class="citation" data-cites="SxPCbOB1 rWVL91jq">[<a href="#ref-SxPCbOB1" role="doc-biblioref">975</a>,<a href="#ref-rWVL91jq" role="doc-biblioref">976</a>]</span>.
+Considering that there is significant evidence that n-3 fatty acids and other fish oil-derived lipids possess antithrombotic properties and anti-inflammatory properties <span class="citation" data-cites="umzPtQG7 V9MDMfpj Ufvsmc3N">[<a href="#ref-Ufvsmc3N" role="doc-biblioref">943</a>,<a href="#ref-umzPtQG7" role="doc-biblioref">977</a>,<a href="#ref-V9MDMfpj" role="doc-biblioref">978</a>]</span>, they may have therapeutic value against the prothrombotic complications of COVID-19.
+In particular, concerns have been raised within the medical community about using investigational therapeutics on COVID-19 patients who are already on antiplatelet therapies due to pre-existing comorbidities because the introduction of such therapeutics could lead to issues with dosing and drug choice and/or negative drug-drug interactions <span class="citation" data-cites="SxPCbOB1">[<a href="#ref-SxPCbOB1" role="doc-biblioref">975</a>]</span>.
 In such cases, dietary sources of n-3 fatty acids or other nutraceuticals with antiplatelet activities could hold particular value for reducing the risk of thrombotic complications in patients already receiving pharmaceutical antiplatelet therapies.
-A new clinical trial <span class="citation" data-cites="QKHdIx2w">[<a href="#ref-QKHdIx2w" role="doc-biblioref">981</a>]</span> is currently recruiting COVID-19 positive patients to investigate the anti-inflammatory activity of a recently developed, highly purified nutraceutical derivative of EPA known as icosapent ethyl (Vascepa<sup>TM</sup>) <span class="citation" data-cites="12Q4bY0vF">[<a href="#ref-12Q4bY0vF" role="doc-biblioref">982</a>]</span>.
-Other randomized controlled trials that are in the preparatory stages intend to investigate the administration of EPA and other bioactive compounds to COVID-19 positive patients in order to observe whether anti-inflammatory effects or disease state improvements occur <span class="citation" data-cites="8lPjdnE7 1AGVAbQuf">[<a href="#ref-8lPjdnE7" role="doc-biblioref">983</a>,<a href="#ref-1AGVAbQuf" role="doc-biblioref">984</a>]</span>.
-Finally, while there have been studies investigating the therapeutic value of n-3 fatty acids against ARDS in humans, there is still limited evidence of their effectiveness <span class="citation" data-cites="XHtzuR5c">[<a href="#ref-XHtzuR5c" role="doc-biblioref">985</a>]</span>.
+A new clinical trial <span class="citation" data-cites="QKHdIx2w">[<a href="#ref-QKHdIx2w" role="doc-biblioref">979</a>]</span> is currently recruiting COVID-19 positive patients to investigate the anti-inflammatory activity of a recently developed, highly purified nutraceutical derivative of EPA known as icosapent ethyl (Vascepa<sup>TM</sup>) <span class="citation" data-cites="12Q4bY0vF">[<a href="#ref-12Q4bY0vF" role="doc-biblioref">980</a>]</span>.
+Other randomized controlled trials that are in the preparatory stages intend to investigate the administration of EPA and other bioactive compounds to COVID-19 positive patients in order to observe whether anti-inflammatory effects or disease state improvements occur <span class="citation" data-cites="8lPjdnE7 1AGVAbQuf">[<a href="#ref-8lPjdnE7" role="doc-biblioref">981</a>,<a href="#ref-1AGVAbQuf" role="doc-biblioref">982</a>]</span>.
+Finally, while there have been studies investigating the therapeutic value of n-3 fatty acids against ARDS in humans, there is still limited evidence of their effectiveness <span class="citation" data-cites="XHtzuR5c">[<a href="#ref-XHtzuR5c" role="doc-biblioref">983</a>]</span>.
 It should be noted that the overall lack of human studies in this area means there is limited evidence as to whether these supplements could affect COVID-19 infection.
 Consequently, the clinical trials that are underway and those that have been proposed will provide valuable insight into whether the anti-inflammatory potential of n-3 PUFAs and their derivatives can be beneficial to the treatment of COVID-19.
 All the same, while the evidence is not present to draw conclusions about whether n-3 PUFAs will be useful in treating COVID-19, there is likely little harm associated with a diet rich in fish oils, and interest in n-3 PUFA supplementation by the general public is unlikely to have negative effects.</p>
 <h2 data-number="8.5" id="zinc"><span class="header-section-number">8.5</span> Zinc</h2>
 <p>Zinc is nutrient supplement that may exhibit some benefits against RNA viral infections.
-Zinc is a trace metal obtained from dietary sources or supplementation and is important for the maintenance of immune cells involved in adaptive and innate immunity <span class="citation" data-cites="VMI1lOFR">[<a href="#ref-VMI1lOFR" role="doc-biblioref">986</a>]</span>.
+Zinc is a trace metal obtained from dietary sources or supplementation and is important for the maintenance of immune cells involved in adaptive and innate immunity <span class="citation" data-cites="VMI1lOFR">[<a href="#ref-VMI1lOFR" role="doc-biblioref">984</a>]</span>.
 Supplements can be administered orally as a tablet or as a lozenge and are available in many forms, such as zinc picolinate, zinc acetate, and zinc citrate.
 Zinc is also available from dietary sources including meat, seafood, nuts, seeds, legumes, and dairy.
-The role of zinc in immune function has been extensively reviewed <span class="citation" data-cites="VMI1lOFR">[<a href="#ref-VMI1lOFR" role="doc-biblioref">986</a>]</span>.
+The role of zinc in immune function has been extensively reviewed <span class="citation" data-cites="VMI1lOFR">[<a href="#ref-VMI1lOFR" role="doc-biblioref">984</a>]</span>.
 Zinc is an important signaling molecule, and zinc levels can alter host defense systems.
-In inflammatory situations such as an infection, zinc can regulate leukocyte immune responses and modulate the nuclear factor kappa-light-chain-enhancer of activated B cells, thus altering cytokine production <span class="citation" data-cites="Qif5U0Ig 1CEzU1G34">[<a href="#ref-Qif5U0Ig" role="doc-biblioref">987</a>,<a href="#ref-1CEzU1G34" role="doc-biblioref">988</a>]</span>.
-In particular, zinc supplementation can increase natural killer cell levels, which are important cells for host defense against viral infections <span class="citation" data-cites="7ElRN12v VMI1lOFR">[<a href="#ref-VMI1lOFR" role="doc-biblioref">986</a>,<a href="#ref-7ElRN12v" role="doc-biblioref">989</a>]</span>.
+In inflammatory situations such as an infection, zinc can regulate leukocyte immune responses and modulate the nuclear factor kappa-light-chain-enhancer of activated B cells, thus altering cytokine production <span class="citation" data-cites="Qif5U0Ig 1CEzU1G34">[<a href="#ref-Qif5U0Ig" role="doc-biblioref">985</a>,<a href="#ref-1CEzU1G34" role="doc-biblioref">986</a>]</span>.
+In particular, zinc supplementation can increase natural killer cell levels, which are important cells for host defense against viral infections <span class="citation" data-cites="7ElRN12v VMI1lOFR">[<a href="#ref-VMI1lOFR" role="doc-biblioref">984</a>,<a href="#ref-7ElRN12v" role="doc-biblioref">987</a>]</span>.
 As a result of these immune-related functions, zinc is also under consideration for possible benefits against COVID-19.</p>
-<p>Adequate zinc intake has been associated with reduced incidence of infection <span class="citation" data-cites="kxuSwrCI">[<a href="#ref-kxuSwrCI" role="doc-biblioref">990</a>]</span> and antiviral immunity <span class="citation" data-cites="IAOnO0Gj">[<a href="#ref-IAOnO0Gj" role="doc-biblioref">991</a>]</span>.
-A randomized, double-blind, placebo-controlled trial that administered zinc supplementation to elderly subjects over the course of a year found that zinc supplementation decreased susceptibility to infection and that zinc deficiency was associated with increased susceptibility to infection <span class="citation" data-cites="kxuSwrCI">[<a href="#ref-kxuSwrCI" role="doc-biblioref">990</a>]</span>.
-Clinical trial data supports the utility of zinc to diminish the duration and severity of symptoms associated with common colds when it is provided within 24 hours of the onset of symptoms <span class="citation" data-cites="sgr0mlJK lPexOhy6">[<a href="#ref-sgr0mlJK" role="doc-biblioref">992</a>,<a href="#ref-lPexOhy6" role="doc-biblioref">993</a>]</span>.
-An observational study showed that COVID-19 patients had significantly lower zinc levels in comparison to healthy controls and that zinc-deficient COVID-19 patients (those with levels less than 80 μg/dl) tended to have more complications (70.4% vs 30.0%, <em>p</em> = 0.009) and potentially prolonged hospital stays (7.9 vs 5.7 days, <em>p</em> = 0.048) relative to patients who were not zinc deficient <span class="citation" data-cites="1BU6jG2lv">[<a href="#ref-1BU6jG2lv" role="doc-biblioref">994</a>]</span>.
-In coronaviruses specifically, <em>in vitro</em> evidence has demonstrated that the combination of zinc (Zn<sup>2+</sup>) and zinc ionophores (pyrithione) can interrupt the replication mechanisms of SARS-CoV-GFP (a fluorescently tagged SARS-CoV-1) and a variety of other RNA viruses <span class="citation" data-cites="6aOUJdHa NB1udFHF">[<a href="#ref-6aOUJdHa" role="doc-biblioref">995</a>,<a href="#ref-NB1udFHF" role="doc-biblioref">996</a>]</span>.
+<p>Adequate zinc intake has been associated with reduced incidence of infection <span class="citation" data-cites="kxuSwrCI">[<a href="#ref-kxuSwrCI" role="doc-biblioref">988</a>]</span> and antiviral immunity <span class="citation" data-cites="IAOnO0Gj">[<a href="#ref-IAOnO0Gj" role="doc-biblioref">989</a>]</span>.
+A randomized, double-blind, placebo-controlled trial that administered zinc supplementation to elderly subjects over the course of a year found that zinc supplementation decreased susceptibility to infection and that zinc deficiency was associated with increased susceptibility to infection <span class="citation" data-cites="kxuSwrCI">[<a href="#ref-kxuSwrCI" role="doc-biblioref">988</a>]</span>.
+Clinical trial data supports the utility of zinc to diminish the duration and severity of symptoms associated with common colds when it is provided within 24 hours of the onset of symptoms <span class="citation" data-cites="sgr0mlJK lPexOhy6">[<a href="#ref-sgr0mlJK" role="doc-biblioref">990</a>,<a href="#ref-lPexOhy6" role="doc-biblioref">991</a>]</span>.
+An observational study showed that COVID-19 patients had significantly lower zinc levels in comparison to healthy controls and that zinc-deficient COVID-19 patients (those with levels less than 80 μg/dl) tended to have more complications (70.4% vs 30.0%, <em>p</em> = 0.009) and potentially prolonged hospital stays (7.9 vs 5.7 days, <em>p</em> = 0.048) relative to patients who were not zinc deficient <span class="citation" data-cites="1BU6jG2lv">[<a href="#ref-1BU6jG2lv" role="doc-biblioref">992</a>]</span>.
+In coronaviruses specifically, <em>in vitro</em> evidence has demonstrated that the combination of zinc (Zn<sup>2+</sup>) and zinc ionophores (pyrithione) can interrupt the replication mechanisms of SARS-CoV-GFP (a fluorescently tagged SARS-CoV-1) and a variety of other RNA viruses <span class="citation" data-cites="6aOUJdHa NB1udFHF">[<a href="#ref-6aOUJdHa" role="doc-biblioref">993</a>,<a href="#ref-NB1udFHF" role="doc-biblioref">994</a>]</span>.
 Currently, there are over twenty clinical trials registered with the intention to use zinc in a preventative or therapeutic manner for COVID-19.
-However, many of these trials proposed the use of zinc in conjunction with hydroxychloroquine and azithromycin <span class="citation" data-cites="XJrj3MiZ 1EqFW3G4X Hc9mjVB2 T0aXNTIp">[<a href="#ref-XJrj3MiZ" role="doc-biblioref">997</a>,<a href="#ref-1EqFW3G4X" role="doc-biblioref">998</a>,<a href="#ref-Hc9mjVB2" role="doc-biblioref">999</a>,<a href="#ref-T0aXNTIp" role="doc-biblioref">1000</a>]</span>, and it is not known how the lack of evidence supporting the use of hydroxychloroquine will affect investigation of zinc.
+However, many of these trials proposed the use of zinc in conjunction with hydroxychloroquine and azithromycin <span class="citation" data-cites="XJrj3MiZ 1EqFW3G4X Hc9mjVB2 T0aXNTIp">[<a href="#ref-XJrj3MiZ" role="doc-biblioref">995</a>,<a href="#ref-1EqFW3G4X" role="doc-biblioref">996</a>,<a href="#ref-Hc9mjVB2" role="doc-biblioref">997</a>,<a href="#ref-T0aXNTIp" role="doc-biblioref">998</a>]</span>, and it is not known how the lack of evidence supporting the use of hydroxychloroquine will affect investigation of zinc.
 One retrospective observational study of New York University Langone hospitals in New York compared outcomes among hospitalized COVID-19 patients administered hydroxychloroquine and azithromycin with zinc sulfate (n = 411) versus hydroxychloroquine and azithromycin alone (n = 521).
-Notably, zinc is the only treatment that was used in this trial that is still under consideration as a therapeutic agent due to the lack of efficacy and potential adverse events associated with hydroxychloroquine and azithromycin against COVID-19 <span class="citation" data-cites="SmqHOsyB T94OBz6q 1F4wtzwpV">[<a href="#ref-SmqHOsyB" role="doc-biblioref">1001</a>,<a href="#ref-T94OBz6q" role="doc-biblioref">1002</a>,<a href="#ref-1F4wtzwpV" role="doc-biblioref">1003</a>]</span>.
-While the addition of zinc sulfate did not affect the duration of hospitalization, the length of ICU stays or patient ventilation duration, univariate analyses indicated that zinc did increase the frequency of patients discharged and decreased the requirement for ventilation, referrals to the ICU, and mortality <span class="citation" data-cites="Xi9zDqwZ">[<a href="#ref-Xi9zDqwZ" role="doc-biblioref">1004</a>]</span>.
-However, a smaller retrospective study at Hoboken University Medical Center New Jersey failed to find an association between zinc supplementation and survival of hospitalized patients <span class="citation" data-cites="110pLAjkl">[<a href="#ref-110pLAjkl" role="doc-biblioref">1005</a>]</span>.
+Notably, zinc is the only treatment that was used in this trial that is still under consideration as a therapeutic agent due to the lack of efficacy and potential adverse events associated with hydroxychloroquine and azithromycin against COVID-19 <span class="citation" data-cites="SmqHOsyB T94OBz6q 1F4wtzwpV">[<a href="#ref-SmqHOsyB" role="doc-biblioref">999</a>,<a href="#ref-T94OBz6q" role="doc-biblioref">1000</a>,<a href="#ref-1F4wtzwpV" role="doc-biblioref">1001</a>]</span>.
+While the addition of zinc sulfate did not affect the duration of hospitalization, the length of ICU stays or patient ventilation duration, univariate analyses indicated that zinc did increase the frequency of patients discharged and decreased the requirement for ventilation, referrals to the ICU, and mortality <span class="citation" data-cites="Xi9zDqwZ">[<a href="#ref-Xi9zDqwZ" role="doc-biblioref">1002</a>]</span>.
+However, a smaller retrospective study at Hoboken University Medical Center New Jersey failed to find an association between zinc supplementation and survival of hospitalized patients <span class="citation" data-cites="110pLAjkl">[<a href="#ref-110pLAjkl" role="doc-biblioref">1003</a>]</span>.
 Therefore, whether zinc contributes to COVID-19 recovery remains unclear.
-Other trials are now investigating zinc in conjunction with other supplements such as vitamin C or n-3 PUFA <span class="citation" data-cites="1GGbb9IZt 1AGVAbQuf">[<a href="#ref-1AGVAbQuf" role="doc-biblioref">984</a>,<a href="#ref-1GGbb9IZt" role="doc-biblioref">1006</a>]</span>.
+Other trials are now investigating zinc in conjunction with other supplements such as vitamin C or n-3 PUFA <span class="citation" data-cites="1GGbb9IZt 1AGVAbQuf">[<a href="#ref-1AGVAbQuf" role="doc-biblioref">982</a>,<a href="#ref-1GGbb9IZt" role="doc-biblioref">1004</a>]</span>.
 Though there is, overall, encouraging data for zinc supplementation against the common cold and viral infections, there is currently limited evidence to suggest zinc supplementation has any beneficial effects against the current novel COVID-19; thus, the clinical trials that are currently underway will provide vital information on the efficacious use of zinc in COVID-19 prevention and/or treatment.
 However, given the limited risk and the potential association between zinc deficiency and illness, maintaining a healthy diet to ensure an adequate zinc status may be advisable for individuals seeking to reduce their likelihood of infection.</p>
 <h2 data-number="8.6" id="vitamin-c"><span class="header-section-number">8.6</span> Vitamin C</h2>
-<p>Vitamins B, C, D, and E have also been suggested as potential nutrient supplement interventions for COVID-19 <span class="citation" data-cites="2hMFPQJR 3RCeQRRc">[<a href="#ref-2hMFPQJR" role="doc-biblioref">943</a>,<a href="#ref-3RCeQRRc" role="doc-biblioref">1007</a>]</span>.
-In particular vitamin C has been proposed as a potential therapeutic agent against COVID-19 due to its long history of use against the common cold and other respiratory infections <span class="citation" data-cites="190FMJu3y EbAGaMxL">[<a href="#ref-190FMJu3y" role="doc-biblioref">1008</a>,<a href="#ref-EbAGaMxL" role="doc-biblioref">1009</a>]</span>.
+<p>Vitamins B, C, D, and E have also been suggested as potential nutrient supplement interventions for COVID-19 <span class="citation" data-cites="2hMFPQJR 3RCeQRRc">[<a href="#ref-2hMFPQJR" role="doc-biblioref">941</a>,<a href="#ref-3RCeQRRc" role="doc-biblioref">1005</a>]</span>.
+In particular vitamin C has been proposed as a potential therapeutic agent against COVID-19 due to its long history of use against the common cold and other respiratory infections <span class="citation" data-cites="190FMJu3y EbAGaMxL">[<a href="#ref-190FMJu3y" role="doc-biblioref">1006</a>,<a href="#ref-EbAGaMxL" role="doc-biblioref">1007</a>]</span>.
 Vitamin C can be obtained via dietary sources such as fruits and vegetables or via supplementation.
 Vitamin C plays a significant role in promoting immune function due to its effects on various immune cells.
-It affects inflammation by modulating cytokine production, decreasing histamine levels, enhancing the differentiation and proliferation of T- and B-lymphocytes, increasing antibody levels, and protecting against the negative effects of reactive oxygen species, among other effects related to COVID-19 pathology <span class="citation" data-cites="9czQt5cR RjFxOURM 13M3VAfY9">[<a href="#ref-9czQt5cR" role="doc-biblioref">1010</a>,<a href="#ref-RjFxOURM" role="doc-biblioref">1011</a>,<a href="#ref-13M3VAfY9" role="doc-biblioref">1012</a>]</span>.
+It affects inflammation by modulating cytokine production, decreasing histamine levels, enhancing the differentiation and proliferation of T- and B-lymphocytes, increasing antibody levels, and protecting against the negative effects of reactive oxygen species, among other effects related to COVID-19 pathology <span class="citation" data-cites="9czQt5cR RjFxOURM 13M3VAfY9">[<a href="#ref-9czQt5cR" role="doc-biblioref">1008</a>,<a href="#ref-RjFxOURM" role="doc-biblioref">1009</a>,<a href="#ref-13M3VAfY9" role="doc-biblioref">1010</a>]</span>.
 Vitamin C is utilized by the body during viral infections, as evinced by lower concentrations in leukocytes and lower concentrations of urinary vitamin C.
-Post-infection, these levels return to baseline ranges <span class="citation" data-cites="uQFCDDIy 10nBT1HbX 1Bj8VMlSk aEEZ8Pq9 gZRPoTM9">[<a href="#ref-uQFCDDIy" role="doc-biblioref">1013</a>,<a href="#ref-10nBT1HbX" role="doc-biblioref">1014</a>,<a href="#ref-1Bj8VMlSk" role="doc-biblioref">1015</a>,<a href="#ref-aEEZ8Pq9" role="doc-biblioref">1016</a>,<a href="#ref-gZRPoTM9" role="doc-biblioref">1017</a>]</span>.
-It has been shown that as little as 0.1 g/d of vitamin C can maintain normal plasma levels of vitamin C in healthy individuals, but higher doses of at least 1-3 g/d are required for critically ill patients in ICUs <span class="citation" data-cites="DPhRTQw0">[<a href="#ref-DPhRTQw0" role="doc-biblioref">1018</a>]</span>.
-Indeed, vitamin C deficiency appears to be common among COVID-19 patients <span class="citation" data-cites="WEWGGYKl Zrm5dyM1">[<a href="#ref-WEWGGYKl" role="doc-biblioref">1019</a>,<a href="#ref-Zrm5dyM1" role="doc-biblioref">1020</a>]</span>.
-COVID-19 is also associated with the formation of microthrombi and coagulopathy <span class="citation" data-cites="17y6YeJ6R">[<a href="#ref-17y6YeJ6R" role="doc-biblioref">126</a>]</span> that contribute to its characteristic lung pathology <span class="citation" data-cites="19taZjxIT">[<a href="#ref-19taZjxIT" role="doc-biblioref">1021</a>]</span>, but these symptoms can be ameliorated by early infusions of vitamin C to inhibit endothelial surface P-selectin expression and platelet-endothelial adhesion <span class="citation" data-cites="WKBgtN6W">[<a href="#ref-WKBgtN6W" role="doc-biblioref">1022</a>]</span>.
-Intravenous vitamin C also reduced D-dimer levels in a case study of 17 COVID-19 patients <span class="citation" data-cites="d9353XOW">[<a href="#ref-d9353XOW" role="doc-biblioref">1023</a>]</span>.
+Post-infection, these levels return to baseline ranges <span class="citation" data-cites="uQFCDDIy 10nBT1HbX 1Bj8VMlSk aEEZ8Pq9 gZRPoTM9">[<a href="#ref-uQFCDDIy" role="doc-biblioref">1011</a>,<a href="#ref-10nBT1HbX" role="doc-biblioref">1012</a>,<a href="#ref-1Bj8VMlSk" role="doc-biblioref">1013</a>,<a href="#ref-aEEZ8Pq9" role="doc-biblioref">1014</a>,<a href="#ref-gZRPoTM9" role="doc-biblioref">1015</a>]</span>.
+It has been shown that as little as 0.1 g/d of vitamin C can maintain normal plasma levels of vitamin C in healthy individuals, but higher doses of at least 1-3 g/d are required for critically ill patients in ICUs <span class="citation" data-cites="DPhRTQw0">[<a href="#ref-DPhRTQw0" role="doc-biblioref">1016</a>]</span>.
+Indeed, vitamin C deficiency appears to be common among COVID-19 patients <span class="citation" data-cites="WEWGGYKl Zrm5dyM1">[<a href="#ref-WEWGGYKl" role="doc-biblioref">1017</a>,<a href="#ref-Zrm5dyM1" role="doc-biblioref">1018</a>]</span>.
+COVID-19 is also associated with the formation of microthrombi and coagulopathy <span class="citation" data-cites="17y6YeJ6R">[<a href="#ref-17y6YeJ6R" role="doc-biblioref">126</a>]</span> that contribute to its characteristic lung pathology <span class="citation" data-cites="19taZjxIT">[<a href="#ref-19taZjxIT" role="doc-biblioref">1019</a>]</span>, but these symptoms can be ameliorated by early infusions of vitamin C to inhibit endothelial surface P-selectin expression and platelet-endothelial adhesion <span class="citation" data-cites="WKBgtN6W">[<a href="#ref-WKBgtN6W" role="doc-biblioref">1020</a>]</span>.
+Intravenous vitamin C also reduced D-dimer levels in a case study of 17 COVID-19 patients <span class="citation" data-cites="d9353XOW">[<a href="#ref-d9353XOW" role="doc-biblioref">1021</a>]</span>.
 D-dimer levels are an important indicator of thrombus formation and breakdown and are notably elevated in COVID-19 patients <span class="citation" data-cites="18AiyvhO8 v1EIzwfx">[<a href="#ref-v1EIzwfx" role="doc-biblioref">122</a>,<a href="#ref-18AiyvhO8" role="doc-biblioref">123</a>]</span>.
 There is therefore preliminary evidence suggesting that vitamin C status and vitamin C administration may be relevant to COVID-19 outcomes.</p>
 <p>Larger-scale studies of vitamin C, however, have provided mixed results.
-A recent meta-analysis found consistent support for regular vitamin C supplementation reducing the duration of the common cold, but that supplementation with vitamin C (&gt; 200 mg) failed to reduce the incidence of colds <span class="citation" data-cites="Pb5PCH7y">[<a href="#ref-Pb5PCH7y" role="doc-biblioref">1024</a>]</span>.
-Individual studies have found Vitamin C to reduce the susceptibility of patients to lower respiratory tract infections, such as pneumonia <span class="citation" data-cites="JARvpqRw">[<a href="#ref-JARvpqRw" role="doc-biblioref">1025</a>]</span>.
+A recent meta-analysis found consistent support for regular vitamin C supplementation reducing the duration of the common cold, but that supplementation with vitamin C (&gt; 200 mg) failed to reduce the incidence of colds <span class="citation" data-cites="Pb5PCH7y">[<a href="#ref-Pb5PCH7y" role="doc-biblioref">1022</a>]</span>.
+Individual studies have found Vitamin C to reduce the susceptibility of patients to lower respiratory tract infections, such as pneumonia <span class="citation" data-cites="JARvpqRw">[<a href="#ref-JARvpqRw" role="doc-biblioref">1023</a>]</span>.
 Another meta-analysis demonstrated that in twelve trials, vitamin C supplementation reduced the length of stay of patients in intensive care units (ICUs) by 7.8% (95% CI: 4.2% to 11.2%; <em>p</em> = 0.00003).
 Furthermore, high doses (1-3 g/day) significantly reduced the length of an ICU stay by 8.6% in six trials (<em>p</em> = 0.003).
-Vitamin C also shortened the duration of mechanical ventilation by 18.2% in three trials in which patients required intervention for over 24 hours (95% CI 7.7% to 27%; p = 0.001) <span class="citation" data-cites="DPhRTQw0">[<a href="#ref-DPhRTQw0" role="doc-biblioref">1018</a>]</span>.
-Despite these findings, an RCT of 167 patients known as CITRUS ALI failed to show a benefit of a 96-hour infusion of vitamin C to treat ARDS <span class="citation" data-cites="Rt5Aik4p">[<a href="#ref-Rt5Aik4p" role="doc-biblioref">1026</a>]</span>.
-Clinical trials specifically investigating vitamin C in the context of COVID-19 have now begun, as highlighted by Carr et al. <span class="citation" data-cites="EbAGaMxL">[<a href="#ref-EbAGaMxL" role="doc-biblioref">1009</a>]</span>.
+Vitamin C also shortened the duration of mechanical ventilation by 18.2% in three trials in which patients required intervention for over 24 hours (95% CI 7.7% to 27%; p = 0.001) <span class="citation" data-cites="DPhRTQw0">[<a href="#ref-DPhRTQw0" role="doc-biblioref">1016</a>]</span>.
+Despite these findings, an RCT of 167 patients known as CITRUS ALI failed to show a benefit of a 96-hour infusion of vitamin C to treat ARDS <span class="citation" data-cites="Rt5Aik4p">[<a href="#ref-Rt5Aik4p" role="doc-biblioref">1024</a>]</span>.
+Clinical trials specifically investigating vitamin C in the context of COVID-19 have now begun, as highlighted by Carr et al. <span class="citation" data-cites="EbAGaMxL">[<a href="#ref-EbAGaMxL" role="doc-biblioref">1007</a>]</span>.
 These trials intend to investigate the use of intravenous vitamin C in hospitalized COVID-19 patients.
-The first trial to report initial results took place in Wuhan, China <span class="citation" data-cites="nwa7WdNM">[<a href="#ref-nwa7WdNM" role="doc-biblioref">1027</a>]</span>.
-These initial results indicated that the administration of 12 g/12 hr of intravenous vitamin C for 7 days in 56 critically ill COVID-19 patients resulted in a promising reduction of 28-day mortality (<em>p</em> = 0.06) in univariate survival analysis <span class="citation" data-cites="ZX7LDDp0">[<a href="#ref-ZX7LDDp0" role="doc-biblioref">1028</a>]</span>.
-Indeed, the same study reported a significant decrease in IL-6 levels by day 7 of vitamin C infusion (<em>p</em> = 0.04) <span class="citation" data-cites="RM8v7Y7H">[<a href="#ref-RM8v7Y7H" role="doc-biblioref">1029</a>]</span>.
+The first trial to report initial results took place in Wuhan, China <span class="citation" data-cites="nwa7WdNM">[<a href="#ref-nwa7WdNM" role="doc-biblioref">1025</a>]</span>.
+These initial results indicated that the administration of 12 g/12 hr of intravenous vitamin C for 7 days in 56 critically ill COVID-19 patients resulted in a promising reduction of 28-day mortality (<em>p</em> = 0.06) in univariate survival analysis <span class="citation" data-cites="ZX7LDDp0">[<a href="#ref-ZX7LDDp0" role="doc-biblioref">1026</a>]</span>.
+Indeed, the same study reported a significant decrease in IL-6 levels by day 7 of vitamin C infusion (<em>p</em> = 0.04) <span class="citation" data-cites="RM8v7Y7H">[<a href="#ref-RM8v7Y7H" role="doc-biblioref">1027</a>]</span>.
 Additional studies that are being conducted in Canada, China, Iran, and the USA will provide additional insight into whether vitamin C supplementation affects COVID-19 outcomes on a larger scale.</p>
 <p>Even though evidence supporting the use of vitamin C is beginning to emerge, we will not know how effective vitamin C is as a therapeutic for quite some time.
 Currently (as of January 2021) over fifteen trials are registered with clinicaltrials.gov that are either recruiting, active or are currently in preparation.
@@ -3605,169 +3605,169 @@ <h2 data-number="8.6" id="vitamin-c"><span class="header-section-number">8.6</sp
 However, the majority of supplementation studies investigate the intravenous infusion of vitamin C in severe patients.
 Therefore, there is a lack of studies investigating the potential prophylactic administration of vitamin C via oral supplementation for healthy individuals or potentially asymptomatic SARS-CoV-2 positive patients.
 Once again, vitamin C intake is part of a healthy diet and the vitamin likely presents minimal risk, but its potential prophylactic or therapeutic effects against COVID-19 are yet to be determined.
-To maintain vitamin C status, it would be prudent for individuals to ensure that they consume the recommended dietary allowance of vitamin C to maintain a healthy immune system <span class="citation" data-cites="Lyd8s4Mk">[<a href="#ref-Lyd8s4Mk" role="doc-biblioref">912</a>]</span>.
-The recommended dietary allowance according to the FDA is 75-90 mg/d, whereas EFSA recommends 110 mg/d <span class="citation" data-cites="hhf96MB1">[<a href="#ref-hhf96MB1" role="doc-biblioref">1030</a>]</span>.</p>
+To maintain vitamin C status, it would be prudent for individuals to ensure that they consume the recommended dietary allowance of vitamin C to maintain a healthy immune system <span class="citation" data-cites="Lyd8s4Mk">[<a href="#ref-Lyd8s4Mk" role="doc-biblioref">910</a>]</span>.
+The recommended dietary allowance according to the FDA is 75-90 mg/d, whereas EFSA recommends 110 mg/d <span class="citation" data-cites="hhf96MB1">[<a href="#ref-hhf96MB1" role="doc-biblioref">1028</a>]</span>.</p>
 <h2 data-number="8.7" id="vitamin-d"><span class="header-section-number">8.7</span> Vitamin D</h2>
 <p>Of all of the supplements currently under investigation, vitamin D has become a leading prophylactic and therapeutic candidate against SARS-CoV-2.
-Vitamin D can modulate both the adaptive and innate immune system and is associated with various aspects of immune health and antiviral defense <span class="citation" data-cites="3Nyo3kmR SKP7JCfL 15xVUSQRH 15ESVyKi0 npPvtBLw">[<a href="#ref-3Nyo3kmR" role="doc-biblioref">1031</a>,<a href="#ref-SKP7JCfL" role="doc-biblioref">1032</a>,<a href="#ref-15xVUSQRH" role="doc-biblioref">1033</a>,<a href="#ref-15ESVyKi0" role="doc-biblioref">1034</a>,<a href="#ref-npPvtBLw" role="doc-biblioref">1035</a>]</span>.
+Vitamin D can modulate both the adaptive and innate immune system and is associated with various aspects of immune health and antiviral defense <span class="citation" data-cites="3Nyo3kmR SKP7JCfL 15xVUSQRH 15ESVyKi0 npPvtBLw">[<a href="#ref-3Nyo3kmR" role="doc-biblioref">1029</a>,<a href="#ref-SKP7JCfL" role="doc-biblioref">1030</a>,<a href="#ref-15xVUSQRH" role="doc-biblioref">1031</a>,<a href="#ref-15ESVyKi0" role="doc-biblioref">1032</a>,<a href="#ref-npPvtBLw" role="doc-biblioref">1033</a>]</span>.
 Vitamin D can be sourced through diet or supplementation, but it is mainly biosynthesized by the body on exposure to ultraviolet light (UVB) from sunlight.
-Vitamin D deficiency is associated with an increased susceptibility to infection <span class="citation" data-cites="n3v9Thlz">[<a href="#ref-n3v9Thlz" role="doc-biblioref">1036</a>]</span>.
-In particular, vitamin D deficient patients are at risk of developing acute respiratory infections <span class="citation" data-cites="iWLsflrG">[<a href="#ref-iWLsflrG" role="doc-biblioref">1037</a>]</span> and ARDS <span class="citation" data-cites="iWLsflrG">[<a href="#ref-iWLsflrG" role="doc-biblioref">1037</a>]</span>.
+Vitamin D deficiency is associated with an increased susceptibility to infection <span class="citation" data-cites="n3v9Thlz">[<a href="#ref-n3v9Thlz" role="doc-biblioref">1034</a>]</span>.
+In particular, vitamin D deficient patients are at risk of developing acute respiratory infections <span class="citation" data-cites="iWLsflrG">[<a href="#ref-iWLsflrG" role="doc-biblioref">1035</a>]</span> and ARDS <span class="citation" data-cites="iWLsflrG">[<a href="#ref-iWLsflrG" role="doc-biblioref">1035</a>]</span>.
 1,25-dihydroxyvitamin D3 is the active form of vitamin D that is involved in adaptive and innate responses; however, due to its low concentration and a short half life of a few hours, vitamin D levels are typically measured by the longer lasting and more abundant precursor 25-hydroxyvitamin D.
-The vitamin D receptor is expressed in various immune cells, and vitamin D is an immunomodulator of antigen presenting cells, dendritic cells, macrophages, monocytes, and T- and B-lymphocytes <span class="citation" data-cites="n3v9Thlz nwEQBjV4">[<a href="#ref-n3v9Thlz" role="doc-biblioref">1036</a>,<a href="#ref-nwEQBjV4" role="doc-biblioref">1038</a>]</span>.
+The vitamin D receptor is expressed in various immune cells, and vitamin D is an immunomodulator of antigen presenting cells, dendritic cells, macrophages, monocytes, and T- and B-lymphocytes <span class="citation" data-cites="n3v9Thlz nwEQBjV4">[<a href="#ref-n3v9Thlz" role="doc-biblioref">1034</a>,<a href="#ref-nwEQBjV4" role="doc-biblioref">1036</a>]</span>.
 Due to its potential immunomodulating properties, vitamin D supplementation may be advantageous to maintain a healthy immune system.</p>
-<p>Early in the pandemic it was postulated that an individual’s vitamin D status could significantly affect their risk of developing COVID-19 <span class="citation" data-cites="9ac0GYir">[<a href="#ref-9ac0GYir" role="doc-biblioref">1039</a>]</span>.
+<p>Early in the pandemic it was postulated that an individual’s vitamin D status could significantly affect their risk of developing COVID-19 <span class="citation" data-cites="9ac0GYir">[<a href="#ref-9ac0GYir" role="doc-biblioref">1037</a>]</span>.
 This hypothesis was derived from the fact that the current pandemic emerged in Wuhan China during winter, when 25-hydroxyvitamin D concentrations are at their lowest due to a lack of sunlight, whereas in the Southern Hemisphere, where it was nearing the end of the summer and higher 25-hydroxyvitamin D concentrations would be higher, the number of cases was low.
-This led researchers to question whether there was a seasonal component to the SARS-CoV-2 pandemic and whether vitamin D levels might play a role <span class="citation" data-cites="9ac0GYir LpqYmd4C 1EEHgnhPC CS8krfan">[<a href="#ref-9ac0GYir" role="doc-biblioref">1039</a>,<a href="#ref-LpqYmd4C" role="doc-biblioref">1040</a>,<a href="#ref-1EEHgnhPC" role="doc-biblioref">1041</a>,<a href="#ref-CS8krfan" role="doc-biblioref">1042</a>]</span>.
+This led researchers to question whether there was a seasonal component to the SARS-CoV-2 pandemic and whether vitamin D levels might play a role <span class="citation" data-cites="9ac0GYir LpqYmd4C 1EEHgnhPC CS8krfan">[<a href="#ref-9ac0GYir" role="doc-biblioref">1037</a>,<a href="#ref-LpqYmd4C" role="doc-biblioref">1038</a>,<a href="#ref-1EEHgnhPC" role="doc-biblioref">1039</a>,<a href="#ref-CS8krfan" role="doc-biblioref">1040</a>]</span>.
 Though it is assumed that COVID-19 is seasonal, multiple other factors that can affect vitamin D levels should also be considered.
 These factors include an individual’s nutritional status, their age, their occupation, skin pigmentation, potential comorbidities, and the variation of exposure to sunlight due to latitude amongst others.
-Indeed, it has been estimated that each degree of latitude north of 28 degrees corresponded to a 4.4% increase of COVID-19 mortality, indirectly linking a persons vitamin D levels via exposure to UVB light to COVID-19 mortality <span class="citation" data-cites="LpqYmd4C">[<a href="#ref-LpqYmd4C" role="doc-biblioref">1040</a>]</span>.</p>
-<p>As the pandemic has evolved, additional research of varying quality has investigated some of the potential links identified early in the pandemic <span class="citation" data-cites="9ac0GYir">[<a href="#ref-9ac0GYir" role="doc-biblioref">1039</a>]</span> between vitamin D and COVID-19.
+Indeed, it has been estimated that each degree of latitude north of 28 degrees corresponded to a 4.4% increase of COVID-19 mortality, indirectly linking a persons vitamin D levels via exposure to UVB light to COVID-19 mortality <span class="citation" data-cites="LpqYmd4C">[<a href="#ref-LpqYmd4C" role="doc-biblioref">1038</a>]</span>.</p>
+<p>As the pandemic has evolved, additional research of varying quality has investigated some of the potential links identified early in the pandemic <span class="citation" data-cites="9ac0GYir">[<a href="#ref-9ac0GYir" role="doc-biblioref">1037</a>]</span> between vitamin D and COVID-19.
 Indeed, studies are beginning to investigate whether there is any prophylactic and/or therapeutic relationship between vitamin D and COVID-19.
-A study in Switzerland demonstrated that 27 SARS-CoV-2 positive patients exhibited 25-hydroxyvitamin D plasma concentrations that were significantly lower (11.1 ng/ml) than those of SARS-CoV-2 negative patients (24.6 ng/ml; <em>p</em> = 0.004), an association that held when stratifying patients greater than 70 years old <span class="citation" data-cites="1Gy7Svl72">[<a href="#ref-1Gy7Svl72" role="doc-biblioref">1043</a>]</span>.
-These findings seem to be supported by a Belgian observational study of 186 SARS-CoV-2 positive patients exhibiting symptoms of pneumonia, where 25-hydroxyvitamin D plasma concentrations were measured and CT scans of the lungs were obtained upon hospitalization <span class="citation" data-cites="GMAEaWD1">[<a href="#ref-GMAEaWD1" role="doc-biblioref">1044</a>]</span>.
+A study in Switzerland demonstrated that 27 SARS-CoV-2 positive patients exhibited 25-hydroxyvitamin D plasma concentrations that were significantly lower (11.1 ng/ml) than those of SARS-CoV-2 negative patients (24.6 ng/ml; <em>p</em> = 0.004), an association that held when stratifying patients greater than 70 years old <span class="citation" data-cites="1Gy7Svl72">[<a href="#ref-1Gy7Svl72" role="doc-biblioref">1041</a>]</span>.
+These findings seem to be supported by a Belgian observational study of 186 SARS-CoV-2 positive patients exhibiting symptoms of pneumonia, where 25-hydroxyvitamin D plasma concentrations were measured and CT scans of the lungs were obtained upon hospitalization <span class="citation" data-cites="GMAEaWD1">[<a href="#ref-GMAEaWD1" role="doc-biblioref">1042</a>]</span>.
 A significant difference in 25-hydroxyvitamin D levels was observed between the SARS-CoV-2 patients and 2,717 season-matched hospitalized controls.
 It is not clear from the study which diseases caused the control subjects to be admitted at the time of their 25-hydroxyvitamin D measurement, which makes it difficult to assess the observations reported.
 Both female and male patients possessed lower median 25-hydroxyvitamin D concentrations than the control group as a whole (18.6 ng/ml versus 21.5 ng/ml; <em>p</em> = 0.0016) and a higher rate of vitamin D deficiency (58.6% versus 42.5%).
 However, when comparisons were stratified by sex, evidence of sexual dimorphism became apparent, as female patients had equivalent levels of 25-hydroxyvitamin D to females in the control group, whereas male patients were deficient in 25-hydroxyvitamin D relative to male controls (67% versus 49%; <em>p</em> = 0.0006).
 Notably, vitamin D deficiency was progressively lower in males with advancing radiological disease stages (<em>p</em> = 0.001).
-However, these studies are supported by several others that indicate that vitamin D status may be an independent risk factor for the severity of COVID-19 <span class="citation" data-cites="GM9W6HPG kN3eqnZW 5MvUc8IL 18O6t6Jo">[<a href="#ref-GM9W6HPG" role="doc-biblioref">1045</a>,<a href="#ref-kN3eqnZW" role="doc-biblioref">1046</a>,<a href="#ref-5MvUc8IL" role="doc-biblioref">1047</a>,<a href="#ref-18O6t6Jo" role="doc-biblioref">1048</a>]</span> and in COVID-19 patients relative to population-based controls <span class="citation" data-cites="8ZxZKpYS">[<a href="#ref-8ZxZKpYS" role="doc-biblioref">1049</a>]</span>.
-Indeed, serum concentrations of 25-hydroxyvitamin D above 30 ng/ml, which indicate vitamin D sufficiency, seems to be associated with a reduction in serum C-reactive protein, an inflammatory marker, along with increased lymphocyte levels, which suggests that vitamin D levels may modulate the immune response by reducing risk for cytokine storm in response to SARS-CoV-2 infection <span class="citation" data-cites="8ZxZKpYS">[<a href="#ref-8ZxZKpYS" role="doc-biblioref">1049</a>]</span>.
-A study in India determined that COVID-19 fatality was higher in patients with severe COVID-19 and low serum 25-hydroxyvitamin D (mean level 6.2 ng/ml; 97% vitamin D deficient) levels versus asymptomatic non-severe patients with higher levels of vitamin D (mean level 27.9 ng/ml; 33% vitamin D deficient) <span class="citation" data-cites="QAEcHBzN">[<a href="#ref-QAEcHBzN" role="doc-biblioref">1050</a>]</span>.
+However, these studies are supported by several others that indicate that vitamin D status may be an independent risk factor for the severity of COVID-19 <span class="citation" data-cites="GM9W6HPG kN3eqnZW 5MvUc8IL 18O6t6Jo">[<a href="#ref-GM9W6HPG" role="doc-biblioref">1043</a>,<a href="#ref-kN3eqnZW" role="doc-biblioref">1044</a>,<a href="#ref-5MvUc8IL" role="doc-biblioref">1045</a>,<a href="#ref-18O6t6Jo" role="doc-biblioref">1046</a>]</span> and in COVID-19 patients relative to population-based controls <span class="citation" data-cites="8ZxZKpYS">[<a href="#ref-8ZxZKpYS" role="doc-biblioref">1047</a>]</span>.
+Indeed, serum concentrations of 25-hydroxyvitamin D above 30 ng/ml, which indicate vitamin D sufficiency, seems to be associated with a reduction in serum C-reactive protein, an inflammatory marker, along with increased lymphocyte levels, which suggests that vitamin D levels may modulate the immune response by reducing risk for cytokine storm in response to SARS-CoV-2 infection <span class="citation" data-cites="8ZxZKpYS">[<a href="#ref-8ZxZKpYS" role="doc-biblioref">1047</a>]</span>.
+A study in India determined that COVID-19 fatality was higher in patients with severe COVID-19 and low serum 25-hydroxyvitamin D (mean level 6.2 ng/ml; 97% vitamin D deficient) levels versus asymptomatic non-severe patients with higher levels of vitamin D (mean level 27.9 ng/ml; 33% vitamin D deficient) <span class="citation" data-cites="QAEcHBzN">[<a href="#ref-QAEcHBzN" role="doc-biblioref">1048</a>]</span>.
 In the same study, vitamin D deficiency was associated with higher levels of inflammatory markers including IL-6, ferritin, and tumor necrosis factor α.
-Collectively, these studies add to a multitude of observational studies reporting potential associations between low levels of 25-hydroxyvitamin D and COVID-19 incidence and severity <span class="citation" data-cites="1Gy7Svl72 EhakYR7D xv6TOhJg 8ZxZKpYS ZheSCcim pNuUm1NE 5aqg2qxi 18O6t6Jo 10kobTskt Tcc0pGgI">[<a href="#ref-1Gy7Svl72" role="doc-biblioref">1043</a>,<a href="#ref-18O6t6Jo" role="doc-biblioref">1048</a>,<a href="#ref-8ZxZKpYS" role="doc-biblioref">1049</a>,<a href="#ref-EhakYR7D" role="doc-biblioref">1051</a>,<a href="#ref-xv6TOhJg" role="doc-biblioref">1052</a>,<a href="#ref-ZheSCcim" role="doc-biblioref">1053</a>,<a href="#ref-pNuUm1NE" role="doc-biblioref">1054</a>,<a href="#ref-5aqg2qxi" role="doc-biblioref">1055</a>,<a href="#ref-10kobTskt" role="doc-biblioref">1056</a>,<a href="#ref-Tcc0pGgI" role="doc-biblioref">1057</a>]</span>.</p>
-<p>Despite the large number of studies establishing a link between vitamin D status and COVID-19 severity, an examination of data from the UK Biobank did not support this thesis <span class="citation" data-cites="FZ8yXmxQ 7goCwNjQ">[<a href="#ref-FZ8yXmxQ" role="doc-biblioref">1058</a>,<a href="#ref-7goCwNjQ" role="doc-biblioref">1059</a>]</span>.
+Collectively, these studies add to a multitude of observational studies reporting potential associations between low levels of 25-hydroxyvitamin D and COVID-19 incidence and severity <span class="citation" data-cites="1Gy7Svl72 EhakYR7D xv6TOhJg 8ZxZKpYS ZheSCcim pNuUm1NE 5aqg2qxi 18O6t6Jo 10kobTskt Tcc0pGgI">[<a href="#ref-1Gy7Svl72" role="doc-biblioref">1041</a>,<a href="#ref-18O6t6Jo" role="doc-biblioref">1046</a>,<a href="#ref-8ZxZKpYS" role="doc-biblioref">1047</a>,<a href="#ref-EhakYR7D" role="doc-biblioref">1049</a>,<a href="#ref-xv6TOhJg" role="doc-biblioref">1050</a>,<a href="#ref-ZheSCcim" role="doc-biblioref">1051</a>,<a href="#ref-pNuUm1NE" role="doc-biblioref">1052</a>,<a href="#ref-5aqg2qxi" role="doc-biblioref">1053</a>,<a href="#ref-10kobTskt" role="doc-biblioref">1054</a>,<a href="#ref-Tcc0pGgI" role="doc-biblioref">1055</a>]</span>.</p>
+<p>Despite the large number of studies establishing a link between vitamin D status and COVID-19 severity, an examination of data from the UK Biobank did not support this thesis <span class="citation" data-cites="FZ8yXmxQ 7goCwNjQ">[<a href="#ref-FZ8yXmxQ" role="doc-biblioref">1056</a>,<a href="#ref-7goCwNjQ" role="doc-biblioref">1057</a>]</span>.
 These analyses examined 25-hydroxyvitamin D concentrations alongside SARS-CoV-2 positivity and COVID-19 mortality in over 340,000 UK Biobank participants.
-However, these studies have caused considerable debate that will likely be settled following further studies <span class="citation" data-cites="EtCW6lkq ClClnlJb">[<a href="#ref-EtCW6lkq" role="doc-biblioref">1060</a>,<a href="#ref-ClClnlJb" role="doc-biblioref">1061</a>]</span>.
-Overall, while the evidence suggests that there is likely an association between low serum 25-hydroxyvitamin D and COVID-19 incidence, these studies must be interpreted with caution, as there is the potential for reverse causality, bias, and other confounding factors including that vitamin D deficiency is also associated with numerous pre-existing conditions and risk factors that can increase the risk for severe COVID-19 <span class="citation" data-cites="Lyd8s4Mk 1F2cyuTqD LpqYmd4C F4hC9qly">[<a href="#ref-Lyd8s4Mk" role="doc-biblioref">912</a>,<a href="#ref-LpqYmd4C" role="doc-biblioref">1040</a>,<a href="#ref-1F2cyuTqD" role="doc-biblioref">1062</a>,<a href="#ref-F4hC9qly" role="doc-biblioref">1063</a>]</span>.</p>
+However, these studies have caused considerable debate that will likely be settled following further studies <span class="citation" data-cites="EtCW6lkq ClClnlJb">[<a href="#ref-EtCW6lkq" role="doc-biblioref">1058</a>,<a href="#ref-ClClnlJb" role="doc-biblioref">1059</a>]</span>.
+Overall, while the evidence suggests that there is likely an association between low serum 25-hydroxyvitamin D and COVID-19 incidence, these studies must be interpreted with caution, as there is the potential for reverse causality, bias, and other confounding factors including that vitamin D deficiency is also associated with numerous pre-existing conditions and risk factors that can increase the risk for severe COVID-19 <span class="citation" data-cites="Lyd8s4Mk 1F2cyuTqD LpqYmd4C F4hC9qly">[<a href="#ref-Lyd8s4Mk" role="doc-biblioref">910</a>,<a href="#ref-LpqYmd4C" role="doc-biblioref">1038</a>,<a href="#ref-1F2cyuTqD" role="doc-biblioref">1060</a>,<a href="#ref-F4hC9qly" role="doc-biblioref">1061</a>]</span>.</p>
 <p>While these studies inform us of the potential importance of vitamin D sufficiency and the risk of SARS-CoV-2 infection and severe COVID-19, they fail to conclusively determine whether vitamin D supplementation can therapeutically affect the clinical course of COVID-19.
 In one study, 40 vitamin D deficient asymptomatic or mildly symptomatic participants patients were either randomized to receive 60,000 IU of cholecalciferol daily for at least 7 days (n = 16) or a placebo (n = 24) with a target serum 25-hydroxyvitamin D level &gt;50 ng/ml.
 At day 7, 10 patients achieved &gt;50 ng/ml, followed by another 2 by day 14.
-By the end of the study, the treatment group had a greater proportion of vitamin D-deficient participants that tested negative for SARS-CoV-2 RNA, and they had a significantly lower fibrinogen levels, potentially indicating a beneficial effect <span class="citation" data-cites="kurM6Av7">[<a href="#ref-kurM6Av7" role="doc-biblioref">1064</a>]</span>.
-A pilot study in Spain determined that early administration of high dose calcifediol (~21,000 IU days 1-2 and ~11,000 IU days 3-7 of hospital admission) with hydroxychloroquine and azithromycin to 50 hospitalized COVID-19 patients significantly reduced ICU admissions and may have reduced disease severity versus hydroxychloroquine and azithromycin alone <span class="citation" data-cites="rYXmRFCk">[<a href="#ref-rYXmRFCk" role="doc-biblioref">1065</a>]</span>.
-Although this study received significant criticism from the National Institute for Health and Care Excellence (NICE) in the UK <span class="citation" data-cites="OAzFPABw">[<a href="#ref-OAzFPABw" role="doc-biblioref">1066</a>]</span>, an independent follow-up statistical analysis supported the findings of the study with respect to the results of cholecalciferol treatment <span class="citation" data-cites="1FHsBdDVU">[<a href="#ref-1FHsBdDVU" role="doc-biblioref">1067</a>]</span>.
-Another trial of 986 patients hospitalized for COVID-19 in three UK hospitals administered cholecalciferol (≥ 280,000 IU in a time period of 7 weeks) to 151 patients and found an association with a reduced risk of COVID-19 mortality, regardless of baseline 25-hydroxyvitamin D levels <span class="citation" data-cites="UlHOCdfk">[<a href="#ref-UlHOCdfk" role="doc-biblioref">1068</a>]</span>.
+By the end of the study, the treatment group had a greater proportion of vitamin D-deficient participants that tested negative for SARS-CoV-2 RNA, and they had a significantly lower fibrinogen levels, potentially indicating a beneficial effect <span class="citation" data-cites="kurM6Av7">[<a href="#ref-kurM6Av7" role="doc-biblioref">1062</a>]</span>.
+A pilot study in Spain determined that early administration of high dose calcifediol (~21,000 IU days 1-2 and ~11,000 IU days 3-7 of hospital admission) with hydroxychloroquine and azithromycin to 50 hospitalized COVID-19 patients significantly reduced ICU admissions and may have reduced disease severity versus hydroxychloroquine and azithromycin alone <span class="citation" data-cites="rYXmRFCk">[<a href="#ref-rYXmRFCk" role="doc-biblioref">1063</a>]</span>.
+Although this study received significant criticism from the National Institute for Health and Care Excellence (NICE) in the UK <span class="citation" data-cites="OAzFPABw">[<a href="#ref-OAzFPABw" role="doc-biblioref">1064</a>]</span>, an independent follow-up statistical analysis supported the findings of the study with respect to the results of cholecalciferol treatment <span class="citation" data-cites="1FHsBdDVU">[<a href="#ref-1FHsBdDVU" role="doc-biblioref">1065</a>]</span>.
+Another trial of 986 patients hospitalized for COVID-19 in three UK hospitals administered cholecalciferol (≥ 280,000 IU in a time period of 7 weeks) to 151 patients and found an association with a reduced risk of COVID-19 mortality, regardless of baseline 25-hydroxyvitamin D levels <span class="citation" data-cites="UlHOCdfk">[<a href="#ref-UlHOCdfk" role="doc-biblioref">1066</a>]</span>.
 However, a double-blind, randomized, placebo-controlled trial of 240 hospitalized COVID-19 patients in São Paulo, Brazil administered a single 200,000 IU oral dose of vitamin D.
 At the end of the study, there was a 24 ng/mL difference of 25-hydroxyvitamin D levels in the treatment group versus the placebo group (<em>p</em> = 0.001), and 87% of the treatment group were vitamin D sufficient versus ~11% in the placebo group.
 Supplementation was well tolerated.
-However, there was no reduction in the length of hospital stay or mortality, and no change to any other relevant secondary outcomes were reported <span class="citation" data-cites="1GjnSzUKx">[<a href="#ref-1GjnSzUKx" role="doc-biblioref">1069</a>]</span>.
+However, there was no reduction in the length of hospital stay or mortality, and no change to any other relevant secondary outcomes were reported <span class="citation" data-cites="1GjnSzUKx">[<a href="#ref-1GjnSzUKx" role="doc-biblioref">1067</a>]</span>.
 These early findings are thus still inconclusive with regards to the therapeutic value of vitamin D supplementation.
-However, other trials are underway, including one trial that is investigating the utility of vitamin D as an immune-modulating agent by monitoring whether administration of vitamin D precipitates an improvement of health status in non-severe symptomatic COVID-19 patients and whether vitamin D prevents patient deterioration <span class="citation" data-cites="162t7zdGv">[<a href="#ref-162t7zdGv" role="doc-biblioref">1070</a>]</span>.
-Other trials are examining various factors including mortality, symptom recovery, severity of disease, rates of ventilation, inflammatory markers such as C-reactive protein and IL-6, blood cell counts, and the prophylactic capacity of vitamin D administration <span class="citation" data-cites="2K0jV5Bn 162t7zdGv rBiojRHk 6kLoX5qT">[<a href="#ref-162t7zdGv" role="doc-biblioref">1070</a>,<a href="#ref-2K0jV5Bn" role="doc-biblioref">1071</a>,<a href="#ref-rBiojRHk" role="doc-biblioref">1072</a>,<a href="#ref-6kLoX5qT" role="doc-biblioref">1073</a>]</span>.
-Concomitant administration of vitamin D with pharmaceuticals such as aspirin <span class="citation" data-cites="32C2erIe">[<a href="#ref-32C2erIe" role="doc-biblioref">1074</a>]</span> and bioactive molecules such as resveratrol <span class="citation" data-cites="tLVliODQ">[<a href="#ref-tLVliODQ" role="doc-biblioref">1075</a>]</span> is also under investigation.</p>
+However, other trials are underway, including one trial that is investigating the utility of vitamin D as an immune-modulating agent by monitoring whether administration of vitamin D precipitates an improvement of health status in non-severe symptomatic COVID-19 patients and whether vitamin D prevents patient deterioration <span class="citation" data-cites="162t7zdGv">[<a href="#ref-162t7zdGv" role="doc-biblioref">1068</a>]</span>.
+Other trials are examining various factors including mortality, symptom recovery, severity of disease, rates of ventilation, inflammatory markers such as C-reactive protein and IL-6, blood cell counts, and the prophylactic capacity of vitamin D administration <span class="citation" data-cites="2K0jV5Bn 162t7zdGv rBiojRHk 6kLoX5qT">[<a href="#ref-162t7zdGv" role="doc-biblioref">1068</a>,<a href="#ref-2K0jV5Bn" role="doc-biblioref">1069</a>,<a href="#ref-rBiojRHk" role="doc-biblioref">1070</a>,<a href="#ref-6kLoX5qT" role="doc-biblioref">1071</a>]</span>.
+Concomitant administration of vitamin D with pharmaceuticals such as aspirin <span class="citation" data-cites="32C2erIe">[<a href="#ref-32C2erIe" role="doc-biblioref">1072</a>]</span> and bioactive molecules such as resveratrol <span class="citation" data-cites="tLVliODQ">[<a href="#ref-tLVliODQ" role="doc-biblioref">1073</a>]</span> is also under investigation.</p>
 <p>The effectiveness of vitamin D supplementation against COVID-19 remains open for debate.
-All the same, there is no doubt that vitamin D deficiency is a widespread issue and should be addressed not only because of its potential link to SARS-CoV-2 incidence <span class="citation" data-cites="Btt5H6f1">[<a href="#ref-Btt5H6f1" role="doc-biblioref">1076</a>]</span>, but also due to its importance for overall health.
+All the same, there is no doubt that vitamin D deficiency is a widespread issue and should be addressed not only because of its potential link to SARS-CoV-2 incidence <span class="citation" data-cites="Btt5H6f1">[<a href="#ref-Btt5H6f1" role="doc-biblioref">1074</a>]</span>, but also due to its importance for overall health.
 There is a possibility that safe exposure to sunlight could improve endogenous synthesis of vitamin D, potentially strengthening the immune system.
 However, sun exposure is not sufficient on its own, particularly in the winter months.
 Indeed, while the possible link between vitamin D status and COVID-19 is further investigated, preemptive supplementation of vitamin D and encouraging people to maintain a healthy diet for optimum vitamin D status is likely to raise serum levels of 25-hydroxyvitamin D while being unlikely to carry major health risks.
 These principles seem to be the basis of a number of guidelines issued by some countries and scientific organizations that have advised supplementation of vitamin D during the pandemic.
 The Académie Nationale de Médecine in France recommends rapid testing of 25-hydroxyvitamin D for people over 60 years old to identify those most at risk of vitamin D deficiency and advises them to obtain a bolus dose of 50,000 to 100,000 IU vitamin D to limit respiratory complications.
-It has also recommended that those under 60 years old should take 800 to 1,000 IU daily if they receive a SARS-CoV-2 positive test <span class="citation" data-cites="llQ4v7QI">[<a href="#ref-llQ4v7QI" role="doc-biblioref">1077</a>]</span>.
-In Slovenia, doctors have been advised to provide nursing home patients with vitamin D <span class="citation" data-cites="M4v2N83p">[<a href="#ref-M4v2N83p" role="doc-biblioref">1078</a>]</span>.
-Both Public Health England and Public Health Scotland have advised members of the Black, Asian, and minority ethnic communities to supplement for vitamin D in light of evidence that they may be at higher risk for vitamin D deficiency along with other COVID-19 risk factors, a trend that has also been observed in the United States <span class="citation" data-cites="yoAwg53u StktHVeV">[<a href="#ref-yoAwg53u" role="doc-biblioref">1079</a>,<a href="#ref-StktHVeV" role="doc-biblioref">1080</a>]</span>.
+It has also recommended that those under 60 years old should take 800 to 1,000 IU daily if they receive a SARS-CoV-2 positive test <span class="citation" data-cites="llQ4v7QI">[<a href="#ref-llQ4v7QI" role="doc-biblioref">1075</a>]</span>.
+In Slovenia, doctors have been advised to provide nursing home patients with vitamin D <span class="citation" data-cites="M4v2N83p">[<a href="#ref-M4v2N83p" role="doc-biblioref">1076</a>]</span>.
+Both Public Health England and Public Health Scotland have advised members of the Black, Asian, and minority ethnic communities to supplement for vitamin D in light of evidence that they may be at higher risk for vitamin D deficiency along with other COVID-19 risk factors, a trend that has also been observed in the United States <span class="citation" data-cites="yoAwg53u StktHVeV">[<a href="#ref-yoAwg53u" role="doc-biblioref">1077</a>,<a href="#ref-StktHVeV" role="doc-biblioref">1078</a>]</span>.
 However, other UK scientific bodies including the NICE recommend that individuals supplement for vitamin D as per usual UK government advice but warn that people should not supplement for vitamin D solely to prevent COVID-19.
-All the same, the NICE has provided guidelines for research to investigate the supplementation of vitamin D in the context of COVID-19 <span class="citation" data-cites="4DE4ljR9">[<a href="#ref-4DE4ljR9" role="doc-biblioref">1081</a>]</span>.
-Despite vitamin D deficiency being a widespread issue in the United States <span class="citation" data-cites="lhYw2CB">[<a href="#ref-lhYw2CB" role="doc-biblioref">1082</a>]</span>, the National Institutes of Health have stated that there is “insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19” <span class="citation" data-cites="KNwYH6Y4">[<a href="#ref-KNwYH6Y4" role="doc-biblioref">1083</a>]</span>.
+All the same, the NICE has provided guidelines for research to investigate the supplementation of vitamin D in the context of COVID-19 <span class="citation" data-cites="4DE4ljR9">[<a href="#ref-4DE4ljR9" role="doc-biblioref">1079</a>]</span>.
+Despite vitamin D deficiency being a widespread issue in the United States <span class="citation" data-cites="lhYw2CB">[<a href="#ref-lhYw2CB" role="doc-biblioref">1080</a>]</span>, the National Institutes of Health have stated that there is “insufficient data to recommend either for or against the use of vitamin D for the prevention or treatment of COVID-19” <span class="citation" data-cites="KNwYH6Y4">[<a href="#ref-KNwYH6Y4" role="doc-biblioref">1081</a>]</span>.
 These are just some examples of how public health guidance has responded to the emerging evidence regarding vitamin D and COVID-19.
-Outside of official recommendations, there is also evidence that individuals may be paying increased attention to their vitamin D levels, as a survey of Polish consumers showed that 56% of respondents used vitamin D during the pandemic <span class="citation" data-cites="19yy9SHf1">[<a href="#ref-19yy9SHf1" role="doc-biblioref">1084</a>]</span>.
-However, some companies have used the emerging evidence surrounding vitamin D to sell products that claim to prevent and treat COVID-19, which in one incident required a federal court to intervene and issue an injunction barring the sale of vitamin-D-related products due to the lack of clinical data supporting these claims <span class="citation" data-cites="xkewCiC9">[<a href="#ref-xkewCiC9" role="doc-biblioref">1085</a>]</span>.
+Outside of official recommendations, there is also evidence that individuals may be paying increased attention to their vitamin D levels, as a survey of Polish consumers showed that 56% of respondents used vitamin D during the pandemic <span class="citation" data-cites="19yy9SHf1">[<a href="#ref-19yy9SHf1" role="doc-biblioref">1082</a>]</span>.
+However, some companies have used the emerging evidence surrounding vitamin D to sell products that claim to prevent and treat COVID-19, which in one incident required a federal court to intervene and issue an injunction barring the sale of vitamin-D-related products due to the lack of clinical data supporting these claims <span class="citation" data-cites="xkewCiC9">[<a href="#ref-xkewCiC9" role="doc-biblioref">1083</a>]</span>.
 It is clear that further studies and clinical trials are required to conclusively determine the prophylactic and therapeutic potential of vitamin D supplementation against COVID-19.
 Until such time that sufficient evidence emerges, individuals should follow their national guidelines surrounding vitamin D intake to achieve vitamin D sufficiency.</p>
 <h2 data-number="8.8" id="probiotics"><span class="header-section-number">8.8</span> Probiotics</h2>
-<p>Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” <span class="citation" data-cites="1FyHVZ9yx">[<a href="#ref-1FyHVZ9yx" role="doc-biblioref">1086</a>]</span>.
-Some studies suggest that probiotics are beneficial against common viral infections, and there is modest evidence to suggest that they can modulate the immune response <span class="citation" data-cites="pvZU55k9 HKeroTXj">[<a href="#ref-pvZU55k9" role="doc-biblioref">1087</a>,<a href="#ref-HKeroTXj" role="doc-biblioref">1088</a>]</span>.
-As a result, it has been hypothesized that probiotics may have therapeutic value worthy of investigation against SARS-CoV-2 <span class="citation" data-cites="10e8cHDs8">[<a href="#ref-10e8cHDs8" role="doc-biblioref">1089</a>]</span>.
-Probiotics and next-generation probiotics, which are more akin to pharmacological-grade supplements, have been associated with multiple potential beneficial effects for allergies, digestive tract disorders, and even metabolic diseases through their anti-inflammatory and immunomodulatory effects <span class="citation" data-cites="5fU7dexB 1GCrGCp5P">[<a href="#ref-5fU7dexB" role="doc-biblioref">1090</a>,<a href="#ref-1GCrGCp5P" role="doc-biblioref">1091</a>]</span>.
-However, the mechanisms by which probiotics affect these various conditions would likely differ among strains, with the ultimate effect of the probiotic depending on the heterogeneous set of bacteria present <span class="citation" data-cites="1GCrGCp5P">[<a href="#ref-1GCrGCp5P" role="doc-biblioref">1091</a>]</span>.
-Some of the beneficial effects of probiotics include reducing inflammation by promoting the expression of anti-inflammatory mediators, inhibiting Toll-like receptors 2 and 4, competing directly with pathogens, synthesizing antimicrobial substances or other metabolites, improving intestinal barrier function, and/or favorably altering the gut microbiota and the brain-gut axis <span class="citation" data-cites="B2GeSSQo 1GCrGCp5P nmXF8vkS">[<a href="#ref-1GCrGCp5P" role="doc-biblioref">1091</a>,<a href="#ref-B2GeSSQo" role="doc-biblioref">1092</a>,<a href="#ref-nmXF8vkS" role="doc-biblioref">1093</a>]</span>.
-It is also thought that lactobacilli such as <em>Lactobacillus paracasei, Lactobacillus plantarum</em> and <em>Lactobacillus rhamnosus</em> have the capacity to bind to and inactivate some viruses via adsorptive and/or trapping mechanisms <span class="citation" data-cites="sX7GyWpV">[<a href="#ref-sX7GyWpV" role="doc-biblioref">1094</a>]</span>.
-Other probiotic lactobacilli and even non-viable bacterium-like particles have been shown to reduce both viral attachment to host cells and viral titers, along with reducing cytokine synthesis, enhancing the antiviral IFN-α response, and inducing various other antiviral mechanisms <span class="citation" data-cites="IkuChxSp 8gQnAy2v zGORHhOM sX7GyWpV g0qfbA7l DNbZomOZ p9eKMfO2 x46F06Fr uU3GXiaf">[<a href="#ref-sX7GyWpV" role="doc-biblioref">1094</a>,<a href="#ref-IkuChxSp" role="doc-biblioref">1095</a>,<a href="#ref-8gQnAy2v" role="doc-biblioref">1096</a>,<a href="#ref-zGORHhOM" role="doc-biblioref">1097</a>,<a href="#ref-g0qfbA7l" role="doc-biblioref">1098</a>,<a href="#ref-DNbZomOZ" role="doc-biblioref">1099</a>,<a href="#ref-p9eKMfO2" role="doc-biblioref">1100</a>,<a href="#ref-x46F06Fr" role="doc-biblioref">1101</a>,<a href="#ref-uU3GXiaf" role="doc-biblioref">1102</a>]</span>.
-These antiviral and immunobiotic mechanisms and others have been reviewed in detail elsewhere <span class="citation" data-cites="EEa0SZCF Sp05opqA 10e8cHDs8">[<a href="#ref-EEa0SZCF" role="doc-biblioref">942</a>,<a href="#ref-10e8cHDs8" role="doc-biblioref">1089</a>,<a href="#ref-Sp05opqA" role="doc-biblioref">1103</a>]</span>.
-However, there is also a bi-directional relationship between the lungs and gut microbiota known as the gut-lung axis <span class="citation" data-cites="13AWoYvqB">[<a href="#ref-13AWoYvqB" role="doc-biblioref">1104</a>]</span>, whereby gut microbial metabolites and endotoxins may affect the lungs via the circulatory system and the lung microbiota in return may affect the gut <span class="citation" data-cites="Smqu1EYN">[<a href="#ref-Smqu1EYN" role="doc-biblioref">1105</a>]</span>.
-Therefore, the gut-lung axis may play role in our future understanding of COVID-19 pathogenesis and become a target for probiotic treatments <span class="citation" data-cites="d27mQ4kO">[<a href="#ref-d27mQ4kO" role="doc-biblioref">1106</a>]</span>.
-Moreover, as microbial dysbiosis of the respiratory tract and gut may play a role in some viral infections, it has been suggested that SARS-CoV-2 may interact with our commensal microbiota [<span class="citation" data-cites="EEa0SZCF"><a href="#ref-EEa0SZCF" role="doc-biblioref">942</a></span>; <span class="citation" data-cites="HOd4nJPq"><a href="#ref-HOd4nJPq" role="doc-biblioref">1107</a></span>; 10.3389/fmicb.2020.01840] and that the lung microbiome could play a role in developing immunity to viral infections <span class="citation" data-cites="OwqHmSrX">[<a href="#ref-OwqHmSrX" role="doc-biblioref">1108</a>]</span>.
+<p>Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” <span class="citation" data-cites="1FyHVZ9yx">[<a href="#ref-1FyHVZ9yx" role="doc-biblioref">1084</a>]</span>.
+Some studies suggest that probiotics are beneficial against common viral infections, and there is modest evidence to suggest that they can modulate the immune response <span class="citation" data-cites="pvZU55k9 HKeroTXj">[<a href="#ref-pvZU55k9" role="doc-biblioref">1085</a>,<a href="#ref-HKeroTXj" role="doc-biblioref">1086</a>]</span>.
+As a result, it has been hypothesized that probiotics may have therapeutic value worthy of investigation against SARS-CoV-2 <span class="citation" data-cites="10e8cHDs8">[<a href="#ref-10e8cHDs8" role="doc-biblioref">1087</a>]</span>.
+Probiotics and next-generation probiotics, which are more akin to pharmacological-grade supplements, have been associated with multiple potential beneficial effects for allergies, digestive tract disorders, and even metabolic diseases through their anti-inflammatory and immunomodulatory effects <span class="citation" data-cites="5fU7dexB 1GCrGCp5P">[<a href="#ref-5fU7dexB" role="doc-biblioref">1088</a>,<a href="#ref-1GCrGCp5P" role="doc-biblioref">1089</a>]</span>.
+However, the mechanisms by which probiotics affect these various conditions would likely differ among strains, with the ultimate effect of the probiotic depending on the heterogeneous set of bacteria present <span class="citation" data-cites="1GCrGCp5P">[<a href="#ref-1GCrGCp5P" role="doc-biblioref">1089</a>]</span>.
+Some of the beneficial effects of probiotics include reducing inflammation by promoting the expression of anti-inflammatory mediators, inhibiting Toll-like receptors 2 and 4, competing directly with pathogens, synthesizing antimicrobial substances or other metabolites, improving intestinal barrier function, and/or favorably altering the gut microbiota and the brain-gut axis <span class="citation" data-cites="B2GeSSQo 1GCrGCp5P nmXF8vkS">[<a href="#ref-1GCrGCp5P" role="doc-biblioref">1089</a>,<a href="#ref-B2GeSSQo" role="doc-biblioref">1090</a>,<a href="#ref-nmXF8vkS" role="doc-biblioref">1091</a>]</span>.
+It is also thought that lactobacilli such as <em>Lactobacillus paracasei, Lactobacillus plantarum</em> and <em>Lactobacillus rhamnosus</em> have the capacity to bind to and inactivate some viruses via adsorptive and/or trapping mechanisms <span class="citation" data-cites="sX7GyWpV">[<a href="#ref-sX7GyWpV" role="doc-biblioref">1092</a>]</span>.
+Other probiotic lactobacilli and even non-viable bacterium-like particles have been shown to reduce both viral attachment to host cells and viral titers, along with reducing cytokine synthesis, enhancing the antiviral IFN-α response, and inducing various other antiviral mechanisms <span class="citation" data-cites="IkuChxSp 8gQnAy2v zGORHhOM sX7GyWpV g0qfbA7l DNbZomOZ p9eKMfO2 x46F06Fr uU3GXiaf">[<a href="#ref-sX7GyWpV" role="doc-biblioref">1092</a>,<a href="#ref-IkuChxSp" role="doc-biblioref">1093</a>,<a href="#ref-8gQnAy2v" role="doc-biblioref">1094</a>,<a href="#ref-zGORHhOM" role="doc-biblioref">1095</a>,<a href="#ref-g0qfbA7l" role="doc-biblioref">1096</a>,<a href="#ref-DNbZomOZ" role="doc-biblioref">1097</a>,<a href="#ref-p9eKMfO2" role="doc-biblioref">1098</a>,<a href="#ref-x46F06Fr" role="doc-biblioref">1099</a>,<a href="#ref-uU3GXiaf" role="doc-biblioref">1100</a>]</span>.
+These antiviral and immunobiotic mechanisms and others have been reviewed in detail elsewhere <span class="citation" data-cites="EEa0SZCF Sp05opqA 10e8cHDs8">[<a href="#ref-EEa0SZCF" role="doc-biblioref">940</a>,<a href="#ref-10e8cHDs8" role="doc-biblioref">1087</a>,<a href="#ref-Sp05opqA" role="doc-biblioref">1101</a>]</span>.
+However, there is also a bi-directional relationship between the lungs and gut microbiota known as the gut-lung axis <span class="citation" data-cites="13AWoYvqB">[<a href="#ref-13AWoYvqB" role="doc-biblioref">1102</a>]</span>, whereby gut microbial metabolites and endotoxins may affect the lungs via the circulatory system and the lung microbiota in return may affect the gut <span class="citation" data-cites="Smqu1EYN">[<a href="#ref-Smqu1EYN" role="doc-biblioref">1103</a>]</span>.
+Therefore, the gut-lung axis may play role in our future understanding of COVID-19 pathogenesis and become a target for probiotic treatments <span class="citation" data-cites="d27mQ4kO">[<a href="#ref-d27mQ4kO" role="doc-biblioref">1104</a>]</span>.
+Moreover, as microbial dysbiosis of the respiratory tract and gut may play a role in some viral infections, it has been suggested that SARS-CoV-2 may interact with our commensal microbiota [<span class="citation" data-cites="EEa0SZCF"><a href="#ref-EEa0SZCF" role="doc-biblioref">940</a></span>; <span class="citation" data-cites="HOd4nJPq"><a href="#ref-HOd4nJPq" role="doc-biblioref">1105</a></span>; 10.3389/fmicb.2020.01840] and that the lung microbiome could play a role in developing immunity to viral infections <span class="citation" data-cites="OwqHmSrX">[<a href="#ref-OwqHmSrX" role="doc-biblioref">1106</a>]</span>.
 These postulations, if correct, could lead to the development of novel probiotic and prebiotic treatments.
 However, significant research is required to confirm these associations and their relevance to patient care, if any.</p>
 <p>Probiotic therapies and prophylactics may also confer some advantages for managing symptoms of COVID-19 or risks associated with its treatment.
-Probiotics have tentatively been associated with the reduction of risk and duration of viral upper respiratory tract infections <span class="citation" data-cites="1MIGrWIP 58eXvYEV kjavvCzp">[<a href="#ref-1MIGrWIP" role="doc-biblioref">1109</a>,<a href="#ref-58eXvYEV" role="doc-biblioref">1110</a>,<a href="#ref-kjavvCzp" role="doc-biblioref">1111</a>]</span>.
-Some meta-analyses that have assessed the efficacy of probiotics in viral respiratory infections have reported moderate reductions in the incidence and duration of infection <span class="citation" data-cites="58eXvYEV dJIGDt4k">[<a href="#ref-58eXvYEV" role="doc-biblioref">1110</a>,<a href="#ref-dJIGDt4k" role="doc-biblioref">1112</a>]</span>.
-Indeed, randomized controlled trials have shown that administering <em>Bacillus subtilis</em> and <em>Enterococcus faecalis</em> <span class="citation" data-cites="AJav6c61">[<a href="#ref-AJav6c61" role="doc-biblioref">1113</a>]</span>, <em>Lactobacillus rhamnosus GG</em> <span class="citation" data-cites="1E2aDJp4T">[<a href="#ref-1E2aDJp4T" role="doc-biblioref">1114</a>]</span>, or <em>Lactobacillus casei</em> and <em>Bifidobacterium breve</em> with galactooligosaccharides <span class="citation" data-cites="zccFgajh">[<a href="#ref-zccFgajh" role="doc-biblioref">1115</a>]</span> via the nasogastric tube to ventilated patients reduced the occurrence of ventilator-associated pneumonia in comparison to the respective control groups in studies of viral infections and sepsis.
-These findings were also supported by a recent meta-analysis <span class="citation" data-cites="1DI06gFPc">[<a href="#ref-1DI06gFPc" role="doc-biblioref">1116</a>]</span>.
-Additionally, COVID-19 patients carry a significant risk of ventilator-associated bacterial pneumonia <span class="citation" data-cites="164mVBFZx">[<a href="#ref-164mVBFZx" role="doc-biblioref">1117</a>]</span>, but it can be challenging for clinicians to diagnose this infection due to the fact that severe COVID-19 infection presents with the symptoms of pneumonia <span class="citation" data-cites="w2VFo0h1">[<a href="#ref-w2VFo0h1" role="doc-biblioref">1118</a>]</span>.
+Probiotics have tentatively been associated with the reduction of risk and duration of viral upper respiratory tract infections <span class="citation" data-cites="1MIGrWIP 58eXvYEV kjavvCzp">[<a href="#ref-1MIGrWIP" role="doc-biblioref">1107</a>,<a href="#ref-58eXvYEV" role="doc-biblioref">1108</a>,<a href="#ref-kjavvCzp" role="doc-biblioref">1109</a>]</span>.
+Some meta-analyses that have assessed the efficacy of probiotics in viral respiratory infections have reported moderate reductions in the incidence and duration of infection <span class="citation" data-cites="58eXvYEV dJIGDt4k">[<a href="#ref-58eXvYEV" role="doc-biblioref">1108</a>,<a href="#ref-dJIGDt4k" role="doc-biblioref">1110</a>]</span>.
+Indeed, randomized controlled trials have shown that administering <em>Bacillus subtilis</em> and <em>Enterococcus faecalis</em> <span class="citation" data-cites="AJav6c61">[<a href="#ref-AJav6c61" role="doc-biblioref">1111</a>]</span>, <em>Lactobacillus rhamnosus GG</em> <span class="citation" data-cites="1E2aDJp4T">[<a href="#ref-1E2aDJp4T" role="doc-biblioref">1112</a>]</span>, or <em>Lactobacillus casei</em> and <em>Bifidobacterium breve</em> with galactooligosaccharides <span class="citation" data-cites="zccFgajh">[<a href="#ref-zccFgajh" role="doc-biblioref">1113</a>]</span> via the nasogastric tube to ventilated patients reduced the occurrence of ventilator-associated pneumonia in comparison to the respective control groups in studies of viral infections and sepsis.
+These findings were also supported by a recent meta-analysis <span class="citation" data-cites="1DI06gFPc">[<a href="#ref-1DI06gFPc" role="doc-biblioref">1114</a>]</span>.
+Additionally, COVID-19 patients carry a significant risk of ventilator-associated bacterial pneumonia <span class="citation" data-cites="164mVBFZx">[<a href="#ref-164mVBFZx" role="doc-biblioref">1115</a>]</span>, but it can be challenging for clinicians to diagnose this infection due to the fact that severe COVID-19 infection presents with the symptoms of pneumonia <span class="citation" data-cites="w2VFo0h1">[<a href="#ref-w2VFo0h1" role="doc-biblioref">1116</a>]</span>.
 Therefore, an effective prophylactic therapy for ventilator-associated pneumonia in severe COVID-19 patients would carry significant therapeutic value.
-Additionally, in recent years, probiotics have become almost synonymous with the treatment of gastrointestinal issues due to their supposed anti-inflammatory and immunomodulatory effects <span class="citation" data-cites="gcyQ73v7">[<a href="#ref-gcyQ73v7" role="doc-biblioref">1119</a>]</span>.
-Notably, gastrointestinal symptoms commonly occur in COVID-19 patients <span class="citation" data-cites="67ihxDiV">[<a href="#ref-67ihxDiV" role="doc-biblioref">1120</a>]</span>, and angiotensin-converting enzyme 2, the portal by which SARS-CoV-2 enters human cells, is highly expressed in enterocytes of the ileum and colon, suggesting that these organs may be a potential route of infection <span class="citation" data-cites="8Hvgbl3n Nhxoefru">[<a href="#ref-8Hvgbl3n" role="doc-biblioref">1121</a>,<a href="#ref-Nhxoefru" role="doc-biblioref">1122</a>]</span>.
-Indeed, SARS-CoV-2 viral RNA has been detected in human feces <span class="citation" data-cites="TPWaxApy PmE9xedP">[<a href="#ref-PmE9xedP" role="doc-biblioref">105</a>,<a href="#ref-TPWaxApy" role="doc-biblioref">1123</a>]</span>, and fecal-oral transmission of the virus has not yet been ruled out <span class="citation" data-cites="r9HNMqTS">[<a href="#ref-r9HNMqTS" role="doc-biblioref">1124</a>]</span>.
-Rectal swabs of some SARS-CoV-2 positive pediatric patients persistently tested positive for several days despite negative nasopharyngeal tests, indicating the potential for fecal viral shedding <span class="citation" data-cites="eOcc1BUx">[<a href="#ref-eOcc1BUx" role="doc-biblioref">1125</a>]</span>.
-However, there is conflicting evidence for the therapeutic value of various probiotics against the incidence or severity of gastrointestinal symptoms in viral or bacterial infections such as gastroenteritis <span class="citation" data-cites="VwStn9Ps UtAKolza">[<a href="#ref-VwStn9Ps" role="doc-biblioref">1126</a>,<a href="#ref-UtAKolza" role="doc-biblioref">1127</a>]</span>.
-Nevertheless, it has been proposed that the administration of probiotics to COVID-19 patients and healthcare workers may prevent or ameliorate the gastrointestinal symptoms of COVID-19, a hypothesis that several clinical trials are now preparing to investigate <span class="citation" data-cites="1AqF1ESKq 9UYsmETk">[<a href="#ref-1AqF1ESKq" role="doc-biblioref">1128</a>,<a href="#ref-9UYsmETk" role="doc-biblioref">1129</a>]</span>.
-Other studies are investigating whether probiotics may affect patient outcomes following SARS-CoV-2 infection <span class="citation" data-cites="15pDlYtom">[<a href="#ref-15pDlYtom" role="doc-biblioref">1130</a>]</span>.</p>
+Additionally, in recent years, probiotics have become almost synonymous with the treatment of gastrointestinal issues due to their supposed anti-inflammatory and immunomodulatory effects <span class="citation" data-cites="gcyQ73v7">[<a href="#ref-gcyQ73v7" role="doc-biblioref">1117</a>]</span>.
+Notably, gastrointestinal symptoms commonly occur in COVID-19 patients <span class="citation" data-cites="67ihxDiV">[<a href="#ref-67ihxDiV" role="doc-biblioref">1118</a>]</span>, and angiotensin-converting enzyme 2, the portal by which SARS-CoV-2 enters human cells, is highly expressed in enterocytes of the ileum and colon, suggesting that these organs may be a potential route of infection <span class="citation" data-cites="8Hvgbl3n Nhxoefru">[<a href="#ref-8Hvgbl3n" role="doc-biblioref">1119</a>,<a href="#ref-Nhxoefru" role="doc-biblioref">1120</a>]</span>.
+Indeed, SARS-CoV-2 viral RNA has been detected in human feces <span class="citation" data-cites="TPWaxApy PmE9xedP">[<a href="#ref-PmE9xedP" role="doc-biblioref">105</a>,<a href="#ref-TPWaxApy" role="doc-biblioref">1121</a>]</span>, and fecal-oral transmission of the virus has not yet been ruled out <span class="citation" data-cites="r9HNMqTS">[<a href="#ref-r9HNMqTS" role="doc-biblioref">1122</a>]</span>.
+Rectal swabs of some SARS-CoV-2 positive pediatric patients persistently tested positive for several days despite negative nasopharyngeal tests, indicating the potential for fecal viral shedding <span class="citation" data-cites="eOcc1BUx">[<a href="#ref-eOcc1BUx" role="doc-biblioref">1123</a>]</span>.
+However, there is conflicting evidence for the therapeutic value of various probiotics against the incidence or severity of gastrointestinal symptoms in viral or bacterial infections such as gastroenteritis <span class="citation" data-cites="VwStn9Ps UtAKolza">[<a href="#ref-VwStn9Ps" role="doc-biblioref">1124</a>,<a href="#ref-UtAKolza" role="doc-biblioref">1125</a>]</span>.
+Nevertheless, it has been proposed that the administration of probiotics to COVID-19 patients and healthcare workers may prevent or ameliorate the gastrointestinal symptoms of COVID-19, a hypothesis that several clinical trials are now preparing to investigate <span class="citation" data-cites="1AqF1ESKq 9UYsmETk">[<a href="#ref-1AqF1ESKq" role="doc-biblioref">1126</a>,<a href="#ref-9UYsmETk" role="doc-biblioref">1127</a>]</span>.
+Other studies are investigating whether probiotics may affect patient outcomes following SARS-CoV-2 infection <span class="citation" data-cites="15pDlYtom">[<a href="#ref-15pDlYtom" role="doc-biblioref">1128</a>]</span>.</p>
 <p>Generally, the efficacy of probiotic use is a controversial topic among scientists.
-In Europe, EFSA has banned the term probiotics on products labels, which has elicited either criticism for EFSA or support for probiotics from researchers in the field <span class="citation" data-cites="m3SexO9F 5FTOk7ol 1FyHVZ9yx">[<a href="#ref-1FyHVZ9yx" role="doc-biblioref">1086</a>,<a href="#ref-m3SexO9F" role="doc-biblioref">1131</a>,<a href="#ref-5FTOk7ol" role="doc-biblioref">1132</a>]</span>.
+In Europe, EFSA has banned the term probiotics on products labels, which has elicited either criticism for EFSA or support for probiotics from researchers in the field <span class="citation" data-cites="m3SexO9F 5FTOk7ol 1FyHVZ9yx">[<a href="#ref-1FyHVZ9yx" role="doc-biblioref">1084</a>,<a href="#ref-m3SexO9F" role="doc-biblioref">1129</a>,<a href="#ref-5FTOk7ol" role="doc-biblioref">1130</a>]</span>.
 This regulation is due to the hyperbolic claims placed on the labels of various probiotic products, which lack rigorous scientific data to support their efficacy.
-Overall, the data supporting probiotics in the treatment or prevention of many different disorders and diseases is not conclusive, as the quality of the evidence is generally considered low <span class="citation" data-cites="1MIGrWIP">[<a href="#ref-1MIGrWIP" role="doc-biblioref">1109</a>]</span>.
+Overall, the data supporting probiotics in the treatment or prevention of many different disorders and diseases is not conclusive, as the quality of the evidence is generally considered low <span class="citation" data-cites="1MIGrWIP">[<a href="#ref-1MIGrWIP" role="doc-biblioref">1107</a>]</span>.
 However, in the case of probiotics and respiratory infections, the evidence seems to be supportive of their potential therapeutic value.
 Consequently, several investigations are underway to investigate the prophylactic and therapeutic potential of probiotics for COVID-19.
-The blind use of conventional probiotics for COVID-19 is currently cautioned against until the pathogenesis of SARS-CoV-2 can be further established <span class="citation" data-cites="kv94VRLF">[<a href="#ref-kv94VRLF" role="doc-biblioref">1133</a>]</span>.
+The blind use of conventional probiotics for COVID-19 is currently cautioned against until the pathogenesis of SARS-CoV-2 can be further established <span class="citation" data-cites="kv94VRLF">[<a href="#ref-kv94VRLF" role="doc-biblioref">1131</a>]</span>.
 Until clinical trials investigating the prophylactic and therapeutic potential of probiotics for COVID-19 are complete, it is not possible to provide an evidence-based recommendation for their use.
 Despite these concerns, complementary use of probiotics as an adjuvant therapeutic has been proposed by the Chinese National Health Commission and National Administration of Traditional Chinese Medicine <span class="citation" data-cites="3Ak4Mata">[<a href="#ref-3Ak4Mata" role="doc-biblioref">106</a>]</span>.
-While supply issues prevented the probiotics market from showing the same rapid response to the COVID-19 as some other supplements, many suppliers are reporting growth during the pandemic <span class="citation" data-cites="3Hg8dHMg">[<a href="#ref-3Hg8dHMg" role="doc-biblioref">1134</a>]</span>.
+While supply issues prevented the probiotics market from showing the same rapid response to the COVID-19 as some other supplements, many suppliers are reporting growth during the pandemic <span class="citation" data-cites="3Hg8dHMg">[<a href="#ref-3Hg8dHMg" role="doc-biblioref">1132</a>]</span>.
 Therefore, the public response once again seems to have adopted supplements promoted as bolstering the immune response despite a lack of evidence suggesting they are beneficial for preventing or mitigating COVID-19.</p>
 <h2 data-number="8.9" id="discussion-2"><span class="header-section-number">8.9</span> Discussion</h2>
 <p>In this review, we report the findings to date of analyses of several dietary supplements and nutraceuticals.
 While existing evidence suggests potential benefits of n-3 PUFA and probiotic supplementation for COVID-19 treatment and prophylaxis, clinical data is still lacking, although trials are underway.
 Both zinc and vitamin C supplementation in hospitalized patients seem to be associated with positive outcomes; however, further clinical trials are required.
 In any case, vitamin C and zinc intake are part of a healthy diet and likely present minimal risk when supplemented, though their potential prophylactic or therapeutic effects against COVID-19 are yet to be determined.
-On the other hand, mounting evidence from observational studies indicates that there is an association between vitamin D deficiency and COVID-19 incidence has also been supported by meta-analysis <span class="citation" data-cites="sWzpGBil">[<a href="#ref-sWzpGBil" role="doc-biblioref">1135</a>]</span>.
+On the other hand, mounting evidence from observational studies indicates that there is an association between vitamin D deficiency and COVID-19 incidence has also been supported by meta-analysis <span class="citation" data-cites="sWzpGBil">[<a href="#ref-sWzpGBil" role="doc-biblioref">1133</a>]</span>.
 Indeed, scientists are working to confirm these findings and to determine whether a patient’s serum 25-hydroxyvitamin D levels are also associated with COVID-19 severity.
 Clinical trials are required to determine whether preemptive vitamin D supplementation may mitigate against severe COVID-19.
-In terms of the therapeutic potential of vitamin D, initial evidence from clinical trials is conflicting but seems to indicate that vitamin D supplementation may reduce COVID-19 severity <span class="citation" data-cites="rYXmRFCk">[<a href="#ref-rYXmRFCk" role="doc-biblioref">1065</a>]</span>.
+In terms of the therapeutic potential of vitamin D, initial evidence from clinical trials is conflicting but seems to indicate that vitamin D supplementation may reduce COVID-19 severity <span class="citation" data-cites="rYXmRFCk">[<a href="#ref-rYXmRFCk" role="doc-biblioref">1063</a>]</span>.
 The various clinical trials currently underway will be imperative to provide information on the efficacious use of vitamin D supplementation for COVID-19 prevention and/or treatment.</p>
 <p>The purported prophylactic and therapeutic benefits of dietary supplements and nutraceuticals for multiple disorders, diseases, and infections has been the subject of significant research and debate for the last few decades.
 Inevitably, scientists are also investigating the potential for these various products to treat or prevent COVID-19.
 This interest also extends to consumers, which led to a remarkable increase of sales of dietary supplements and nutraceuticals throughout the pandemic due to a desire to obtain additional protections from infection and disease.
 The nutraceuticals discussed in this review, namely vitamin C, vitamin D, n-3 PUFA, zinc, and probiotics, were selected because of potential biological mechanisms that could beneficially affect viral and respiratory infections and because they are currently under clinical investigation.
 Specifically, these compounds have all been found to influence cellular processes related to inflammation.
-Inflammation is particularly relevant to COVID-19 because of the negative outcomes (often death) observed in a large number of patients whose immune response becomes hyperactive in response to SARS-CoV-2, leading to severe outcomes such as ARDS and sepsis <span class="citation" data-cites="nCVMwr28">[<a href="#ref-nCVMwr28" role="doc-biblioref">1136</a>]</span>.
-Additionally, there is a well-established link between diet and inflammation <span class="citation" data-cites="1HHbyV6d">[<a href="#ref-1HHbyV6d" role="doc-biblioref">1137</a>]</span>, potentially mediated in part by the microbiome <span class="citation" data-cites="ViPBMxtf">[<a href="#ref-ViPBMxtf" role="doc-biblioref">1138</a>]</span>.
+Inflammation is particularly relevant to COVID-19 because of the negative outcomes (often death) observed in a large number of patients whose immune response becomes hyperactive in response to SARS-CoV-2, leading to severe outcomes such as ARDS and sepsis <span class="citation" data-cites="nCVMwr28">[<a href="#ref-nCVMwr28" role="doc-biblioref">1134</a>]</span>.
+Additionally, there is a well-established link between diet and inflammation <span class="citation" data-cites="1HHbyV6d">[<a href="#ref-1HHbyV6d" role="doc-biblioref">1135</a>]</span>, potentially mediated in part by the microbiome <span class="citation" data-cites="ViPBMxtf">[<a href="#ref-ViPBMxtf" role="doc-biblioref">1136</a>]</span>.
 Thus, the idea that dietary modifications or supplementation could be used to modify the inflammatory response is tied to a broader view of how diet and the immune system are interconnected.
-The supplements and nutraceuticals discussed here therefore lie in sharp contrast to other alleged nutraceutical or dietary supplements that have attracted during the pandemic, such as colloidal silver <span class="citation" data-cites="wtYA1GbG">[<a href="#ref-wtYA1GbG" role="doc-biblioref">1139</a>]</span>, which have no known nutritional function and can be harmful.
+The supplements and nutraceuticals discussed here therefore lie in sharp contrast to other alleged nutraceutical or dietary supplements that have attracted during the pandemic, such as colloidal silver <span class="citation" data-cites="wtYA1GbG">[<a href="#ref-wtYA1GbG" role="doc-biblioref">1137</a>]</span>, which have no known nutritional function and can be harmful.
 Importantly, while little clinical evidence is available about the effects of any supplements against COVID-19, the risks associated with those discussed above are likely to be low, and in some cases, they can be obtained from dietary sources alone.</p>
 <p>There are various other products and molecules that have garnered scientific interest and could merit further investigation.
-These include polyphenols, lipid extracts, and tomato-based nutraceuticals, all of which have been suggested for the potential prevention of cardiovascular complications of COVID-19 such as thrombosis <span class="citation" data-cites="rWVL91jq EEa0SZCF">[<a href="#ref-EEa0SZCF" role="doc-biblioref">942</a>,<a href="#ref-rWVL91jq" role="doc-biblioref">978</a>]</span>.
-Melatonin is another supplement that has been identified as a potential antiviral agent against SARS-CoV-2 using computational methods <span class="citation" data-cites="TDa7cEUV">[<a href="#ref-TDa7cEUV" role="doc-biblioref">1140</a>]</span>, and it has also been highlighted as a potential therapeutic agent for COVID-19 due to its documented antioxidant, anti-apoptotic, immunomodulatory, and anti-inflammatory effects <span class="citation" data-cites="rWVL91jq GJAYfMR0 2CXoItPz">[<a href="#ref-rWVL91jq" role="doc-biblioref">978</a>,<a href="#ref-GJAYfMR0" role="doc-biblioref">1141</a>,<a href="#ref-2CXoItPz" role="doc-biblioref">1142</a>]</span>.
-Notably, melatonin, vitamin D and zinc have attracted public attention because they were included in the treatment plan of the former President of the United States upon his hospitalization due to COVID-19 <span class="citation" data-cites="MNWnrcz6">[<a href="#ref-MNWnrcz6" role="doc-biblioref">1143</a>]</span>.
+These include polyphenols, lipid extracts, and tomato-based nutraceuticals, all of which have been suggested for the potential prevention of cardiovascular complications of COVID-19 such as thrombosis <span class="citation" data-cites="rWVL91jq EEa0SZCF">[<a href="#ref-EEa0SZCF" role="doc-biblioref">940</a>,<a href="#ref-rWVL91jq" role="doc-biblioref">976</a>]</span>.
+Melatonin is another supplement that has been identified as a potential antiviral agent against SARS-CoV-2 using computational methods <span class="citation" data-cites="TDa7cEUV">[<a href="#ref-TDa7cEUV" role="doc-biblioref">1138</a>]</span>, and it has also been highlighted as a potential therapeutic agent for COVID-19 due to its documented antioxidant, anti-apoptotic, immunomodulatory, and anti-inflammatory effects <span class="citation" data-cites="rWVL91jq GJAYfMR0 2CXoItPz">[<a href="#ref-rWVL91jq" role="doc-biblioref">976</a>,<a href="#ref-GJAYfMR0" role="doc-biblioref">1139</a>,<a href="#ref-2CXoItPz" role="doc-biblioref">1140</a>]</span>.
+Notably, melatonin, vitamin D and zinc have attracted public attention because they were included in the treatment plan of the former President of the United States upon his hospitalization due to COVID-19 <span class="citation" data-cites="MNWnrcz6">[<a href="#ref-MNWnrcz6" role="doc-biblioref">1141</a>]</span>.
 These are just some of the many substances and supplements that are currently under investigation but as of yet lack evidence to support their use for the prevention or treatment of COVID-19.
-While there is plenty of skepticism put forward by physicians and scientists surrounding the use of supplements, these statements have not stopped consumers from purchasing these products, with one study reporting that online searches for dietary supplements in Poland began trending with the start of the pandemic <span class="citation" data-cites="19yy9SHf1">[<a href="#ref-19yy9SHf1" role="doc-biblioref">1084</a>]</span>.
+While there is plenty of skepticism put forward by physicians and scientists surrounding the use of supplements, these statements have not stopped consumers from purchasing these products, with one study reporting that online searches for dietary supplements in Poland began trending with the start of the pandemic <span class="citation" data-cites="19yy9SHf1">[<a href="#ref-19yy9SHf1" role="doc-biblioref">1082</a>]</span>.
 Additionally, supplement usage increased between the first and second wave of the pandemic.
 Participants reported various reasons for their use of supplements, including to improve immunity (60%), to improve overall health (57%), and to fill nutrient gaps in their diet (53%).
 Other efforts to collect large datasets regarding such behavior have also sought to explore a possible association between vitamin or supplement consumption and COVID-19.
-An observational analysis of survey responses from 327,720 users of the COVID Symptom Study App found that the consumption of n-3 PUFA supplements, probiotics, multivitamins, and vitamin D was associated with a lower risk of SARS-CoV-2 infection in women but not men after adjusting for potential confounders <span class="citation" data-cites="RJfF7BYs">[<a href="#ref-RJfF7BYs" role="doc-biblioref">1144</a>]</span>.
-According to the authors, the sexual dimorphism observed may in part be because supplements may better support females due to known differences between the male and female immune systems, or it could be due to behavioral and health consciousness differences between the sexes <span class="citation" data-cites="RJfF7BYs">[<a href="#ref-RJfF7BYs" role="doc-biblioref">1144</a>]</span>.
+An observational analysis of survey responses from 327,720 users of the COVID Symptom Study App found that the consumption of n-3 PUFA supplements, probiotics, multivitamins, and vitamin D was associated with a lower risk of SARS-CoV-2 infection in women but not men after adjusting for potential confounders <span class="citation" data-cites="RJfF7BYs">[<a href="#ref-RJfF7BYs" role="doc-biblioref">1142</a>]</span>.
+According to the authors, the sexual dimorphism observed may in part be because supplements may better support females due to known differences between the male and female immune systems, or it could be due to behavioral and health consciousness differences between the sexes <span class="citation" data-cites="RJfF7BYs">[<a href="#ref-RJfF7BYs" role="doc-biblioref">1142</a>]</span>.
 Certainly, randomized controlled trials are required to investigate these findings further.</p>
-<p>Finally, it is known that a patient’s nutritional status affects health outcomes in various infectious diseases <span class="citation" data-cites="5tHMedSi">[<a href="#ref-5tHMedSi" role="doc-biblioref">916</a>]</span>, and COVID-19 is no different <span class="citation" data-cites="pQxCF4GH Hd5V5Usd d6c8mjAk">[<a href="#ref-Hd5V5Usd" role="doc-biblioref">914</a>,<a href="#ref-pQxCF4GH" role="doc-biblioref">1145</a>,<a href="#ref-d6c8mjAk" role="doc-biblioref">1146</a>]</span>.
-Some of the main risk factors for severe COVID-19, which also happen to be linked to poor nutritional status, include obesity, hypertension, cardiovascular diseases, type II diabetes mellitus, and indeed age-related malnutrition <span class="citation" data-cites="Hd5V5Usd Lyd8s4Mk 1HL90Mz7X">[<a href="#ref-Lyd8s4Mk" role="doc-biblioref">912</a>,<a href="#ref-Hd5V5Usd" role="doc-biblioref">914</a>,<a href="#ref-1HL90Mz7X" role="doc-biblioref">1147</a>]</span>.
+<p>Finally, it is known that a patient’s nutritional status affects health outcomes in various infectious diseases <span class="citation" data-cites="5tHMedSi">[<a href="#ref-5tHMedSi" role="doc-biblioref">914</a>]</span>, and COVID-19 is no different <span class="citation" data-cites="pQxCF4GH Hd5V5Usd d6c8mjAk">[<a href="#ref-Hd5V5Usd" role="doc-biblioref">912</a>,<a href="#ref-pQxCF4GH" role="doc-biblioref">1143</a>,<a href="#ref-d6c8mjAk" role="doc-biblioref">1144</a>]</span>.
+Some of the main risk factors for severe COVID-19, which also happen to be linked to poor nutritional status, include obesity, hypertension, cardiovascular diseases, type II diabetes mellitus, and indeed age-related malnutrition <span class="citation" data-cites="Hd5V5Usd Lyd8s4Mk 1HL90Mz7X">[<a href="#ref-Lyd8s4Mk" role="doc-biblioref">910</a>,<a href="#ref-Hd5V5Usd" role="doc-biblioref">912</a>,<a href="#ref-1HL90Mz7X" role="doc-biblioref">1145</a>]</span>.
 Although not the main focus of this review, it is important to consider the nutritional challenges associated with severe COVID-19 patients.
-Hospitalized COVID-19 patients tend to report an unusually high loss of appetite preceding admission, some suffer diarrhea and gastrointestinal symptoms that result in significantly lower food intake, and patients with poorer nutritional status were more likely to have worse outcomes and require nutrition therapy <span class="citation" data-cites="179QIwE1l">[<a href="#ref-179QIwE1l" role="doc-biblioref">1148</a>]</span>.
-Dysphagia also seems to be a significant problem in pediatric patients that suffered multisystem inflammatory syndrome <span class="citation" data-cites="ARM0HdR3">[<a href="#ref-ARM0HdR3" role="doc-biblioref">1149</a>]</span> and rehabilitating COVID-19 patients, potentially contributing to poor nutritional status <span class="citation" data-cites="1DmkRczqw">[<a href="#ref-1DmkRczqw" role="doc-biblioref">1150</a>]</span>.
-Almost two-thirds of discharged COVID-19 ICU patients exhibit significant weight loss, of which 26% had weight loss greater than 10% <span class="citation" data-cites="d6c8mjAk">[<a href="#ref-d6c8mjAk" role="doc-biblioref">1146</a>]</span>.
-As investigated in this review, hospitalized patients also tend to exhibit vitamin D deficiency or insufficiency, which may be associated with greater disease severity <span class="citation" data-cites="sWzpGBil">[<a href="#ref-sWzpGBil" role="doc-biblioref">1135</a>]</span>.
+Hospitalized COVID-19 patients tend to report an unusually high loss of appetite preceding admission, some suffer diarrhea and gastrointestinal symptoms that result in significantly lower food intake, and patients with poorer nutritional status were more likely to have worse outcomes and require nutrition therapy <span class="citation" data-cites="179QIwE1l">[<a href="#ref-179QIwE1l" role="doc-biblioref">1146</a>]</span>.
+Dysphagia also seems to be a significant problem in pediatric patients that suffered multisystem inflammatory syndrome <span class="citation" data-cites="ARM0HdR3">[<a href="#ref-ARM0HdR3" role="doc-biblioref">1147</a>]</span> and rehabilitating COVID-19 patients, potentially contributing to poor nutritional status <span class="citation" data-cites="1DmkRczqw">[<a href="#ref-1DmkRczqw" role="doc-biblioref">1148</a>]</span>.
+Almost two-thirds of discharged COVID-19 ICU patients exhibit significant weight loss, of which 26% had weight loss greater than 10% <span class="citation" data-cites="d6c8mjAk">[<a href="#ref-d6c8mjAk" role="doc-biblioref">1144</a>]</span>.
+As investigated in this review, hospitalized patients also tend to exhibit vitamin D deficiency or insufficiency, which may be associated with greater disease severity <span class="citation" data-cites="sWzpGBil">[<a href="#ref-sWzpGBil" role="doc-biblioref">1133</a>]</span>.
 Therefore, further research is required to determine how dietary supplements and nutraceuticals may contribute to the treatment of severely ill and rehabilitating patients, who often rely on enteral nutrition.</p>
 <h2 data-number="8.10" id="conclusions-4"><span class="header-section-number">8.10</span> Conclusions</h2>
 <p>Despite all the potential benefits of nutraceutical and dietary supplement interventions presented, currently there is a paucity of clinical evidence to support their use for the prevention or mitigation of COVID-19 infection.
-Nevertheless, optimal nutritional status can prime an individual’s immune system to protect against the effects of acute respiratory viral infections by supporting normal maintenance of the immune system <span class="citation" data-cites="5tHMedSi Lyd8s4Mk">[<a href="#ref-Lyd8s4Mk" role="doc-biblioref">912</a>,<a href="#ref-5tHMedSi" role="doc-biblioref">916</a>]</span>.
-Nutritional strategies can also play a role in the treatment of hospitalized patients, as malnutrition is a risk to COVID-19 patients <span class="citation" data-cites="1DmkRczqw">[<a href="#ref-1DmkRczqw" role="doc-biblioref">1150</a>]</span>.
+Nevertheless, optimal nutritional status can prime an individual’s immune system to protect against the effects of acute respiratory viral infections by supporting normal maintenance of the immune system <span class="citation" data-cites="5tHMedSi Lyd8s4Mk">[<a href="#ref-Lyd8s4Mk" role="doc-biblioref">910</a>,<a href="#ref-5tHMedSi" role="doc-biblioref">914</a>]</span>.
+Nutritional strategies can also play a role in the treatment of hospitalized patients, as malnutrition is a risk to COVID-19 patients <span class="citation" data-cites="1DmkRczqw">[<a href="#ref-1DmkRczqw" role="doc-biblioref">1148</a>]</span>.
 Overall, supplementation of vitamin C, vitamin D, and zinc may be an effective method of ensuring their adequate intake to maintain optimal immune function, which may also convey beneficial effects against viral infections due to their immunomodulatory effects.
 Individuals should pay attention to their nutritional status, particularly their intake of vitamin D, considering that vitamin D deficiency is widespread.
-The prevailing evidence seems to indicate an association between vitamin D deficiency with COVID-19 incidence and, potentially, severity <span class="citation" data-cites="LpqYmd4C">[<a href="#ref-LpqYmd4C" role="doc-biblioref">1040</a>]</span>.
+The prevailing evidence seems to indicate an association between vitamin D deficiency with COVID-19 incidence and, potentially, severity <span class="citation" data-cites="LpqYmd4C">[<a href="#ref-LpqYmd4C" role="doc-biblioref">1038</a>]</span>.
 As a result, some international authorities have advised the general public, particularly those at high risk of infection, to consider vitamin D supplementation.
 However, further well-controlled clinical trials are required to confirm these observations.</p>
-<p>Many supplements and nutraceuticals designed for various ailments that are available in the United States and beyond are not strictly regulated <span class="citation" data-cites="lMhFSIiF">[<a href="#ref-lMhFSIiF" role="doc-biblioref">1151</a>]</span>.
+<p>Many supplements and nutraceuticals designed for various ailments that are available in the United States and beyond are not strictly regulated <span class="citation" data-cites="lMhFSIiF">[<a href="#ref-lMhFSIiF" role="doc-biblioref">1149</a>]</span>.
 Consequently, there can be safety and efficacy concerns associated with many of these products.
 Often, the vulnerable members of society can be exploited in this regard and, unfortunately, the COVID-19 pandemic has proven no different.
-As mentioned above, the FDA has issued warnings to several companies for advertising falsified claims in relation to the preventative and therapeutic capabilities of their products against COVID-19 <span class="citation" data-cites="fez8aZAu">[<a href="#ref-fez8aZAu" role="doc-biblioref">1152</a>]</span>.
+As mentioned above, the FDA has issued warnings to several companies for advertising falsified claims in relation to the preventative and therapeutic capabilities of their products against COVID-19 <span class="citation" data-cites="fez8aZAu">[<a href="#ref-fez8aZAu" role="doc-biblioref">1150</a>]</span>.
 Further intensive investigation is required to establish the effects of these nutraceuticals, if any, against COVID-19.
-Until more effective therapeutics are established, the most effective mitigation strategies consist of encouraging standard public health practices such as regular hand washing with soap, wearing a face mask, and covering a cough with your elbow <span class="citation" data-cites="2Xu90WtD">[<a href="#ref-2Xu90WtD" role="doc-biblioref">1153</a>]</span>, along with following social distancing measures, “stay at home” guidelines, expansive testing, and contact tracing <span class="citation" data-cites="EhbZIMo0 12Met0WvX">[<a href="#ref-EhbZIMo0" role="doc-biblioref">1154</a>,<a href="#ref-12Met0WvX" role="doc-biblioref">1155</a>]</span>.
+Until more effective therapeutics are established, the most effective mitigation strategies consist of encouraging standard public health practices such as regular hand washing with soap, wearing a face mask, and covering a cough with your elbow <span class="citation" data-cites="2Xu90WtD">[<a href="#ref-2Xu90WtD" role="doc-biblioref">1151</a>]</span>, along with following social distancing measures, “stay at home” guidelines, expansive testing, and contact tracing <span class="citation" data-cites="EhbZIMo0 12Met0WvX">[<a href="#ref-EhbZIMo0" role="doc-biblioref">1152</a>,<a href="#ref-12Met0WvX" role="doc-biblioref">1153</a>]</span>.
 Indeed, in light of this review, it would also be pertinent to adopt a healthy diet and lifestyle following national guidelines in order to maintain optimal immune health.
 Because of the broad public appeal of dietary supplements and nutraceuticals, it is important to evaluate the evidence regarding the use of such products.
 We will continue to update this review as more findings become available.</p>
@@ -3776,83 +3776,83 @@ <h2 data-number="9.1" id="social-factors-influencing-covid-19-outcomes"><span cl
 <p>In addition to understanding the fundamental biology of the SARS-CoV-2 virus and COVID-19, it is critical to consider how the broader environment can influence both COVID-19 outcomes and efforts to develop and implement treatments for the disease.
 The evidence clearly indicates that social environmental factors are critical determinants of individuals’ and communities’ risks related to COVID-19.
 There are distinct components to COVID-19 susceptibility, and an individual’s risk can be elevated at one or all stages from exposure to recovery/mortality: an individual may be more likely to be exposed to the virus, more likely to get infected once exposed, more likely to have serious complications once infected, and be less likely to receive adequate care once they are seriously ill.
-The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age <span class="citation" data-cites="hrOv770z">[<a href="#ref-hrOv770z" role="doc-biblioref">1156</a>]</span> underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups.
-Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables <span class="citation" data-cites="hrOv770z">[<a href="#ref-hrOv770z" role="doc-biblioref">1156</a>]</span>.
+The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age <span class="citation" data-cites="hrOv770z">[<a href="#ref-hrOv770z" role="doc-biblioref">1154</a>]</span> underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups.
+Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables <span class="citation" data-cites="hrOv770z">[<a href="#ref-hrOv770z" role="doc-biblioref">1154</a>]</span>.
 Here, we outline a few systemic reasons that may exacerbate the COVID-19 pandemic in communities of color.</p>
 <h2 data-number="9.2" id="factors-observed-to-be-associated-with-susceptibility"><span class="header-section-number">9.2</span> Factors Observed to be Associated with Susceptibility</h2>
 <p>As COVID-19 has spread into communities around the globe, it has become clear that the risks associated with this disease are not equally shared by all individuals or all communities.
 Significant disparities in outcomes have led to interest in the demographic, biomedical, and social factors that influence COVID-19 severity.
 Untangling the factors influencing COVID-19 susceptibility is a complex undertaking.
-Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy <span class="citation" data-cites="15IDA5kX6 11xfoqpEl qlJ8hCUs">[<a href="#ref-15IDA5kX6" role="doc-biblioref">37</a>,<a href="#ref-11xfoqpEl" role="doc-biblioref">1157</a>,<a href="#ref-qlJ8hCUs" role="doc-biblioref">1158</a>]</span>.
-However, hospitalization rates vary by location <span class="citation" data-cites="xZBEFXiG">[<a href="#ref-xZBEFXiG" role="doc-biblioref">1159</a>]</span>.
+Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy <span class="citation" data-cites="15IDA5kX6 11xfoqpEl qlJ8hCUs">[<a href="#ref-15IDA5kX6" role="doc-biblioref">37</a>,<a href="#ref-11xfoqpEl" role="doc-biblioref">1155</a>,<a href="#ref-qlJ8hCUs" role="doc-biblioref">1156</a>]</span>.
+However, hospitalization rates vary by location <span class="citation" data-cites="xZBEFXiG">[<a href="#ref-xZBEFXiG" role="doc-biblioref">1157</a>]</span>.
 This variation may be influenced by demographic (e.g., average age in the area), medical (e.g., the prevalence of comorbid conditions such as diabetes), and social (e.g., income or healthcare availability) factors that vary geographically.
 Additionally, some of the same factors may influence an individual’s probability of exposure to SARS-CoV-2, their risk of developing a more serious case of COVID-19 that would require hospitalization, and their access to medical support.
 As a result, quantifying or comparing susceptibility among individuals, communities, or other groups requires consideration of a number of complex phenomena that intersect across many disciplines of research.
 In this section, the term “risk factor” is used to refer to variables that are statistically associated with more severe COVID-19 outcomes.
 Some are intrinsic characteristics that have been observed to carry an association with variation in outcomes, whereas others may be more functionally linked to the pathophysiology of COVID-19.</p>
 <h3 data-number="9.2.1" id="patient-traits-associated-with-increased-risk"><span class="header-section-number">9.2.1</span> Patient Traits Associated with Increased Risk</h3>
-<p>Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age (typically defined as 60 or older, with the greatest risk among those 85 and older <span class="citation" data-cites="aZlVFn2R">[<a href="#ref-aZlVFn2R" role="doc-biblioref">1160</a>]</span>).
-In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization <span class="citation" data-cites="1D6lVXWbJ Zk5CfYeW">[<a href="#ref-1D6lVXWbJ" role="doc-biblioref">1161</a>,<a href="#ref-Zk5CfYeW" role="doc-biblioref">1162</a>]</span>.
-A retrospective study of hospitalized Chinese patients <span class="citation" data-cites="10THxyeCg">[<a href="#ref-10THxyeCg" role="doc-biblioref">38</a>]</span> found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity <span class="citation" data-cites="BQ4pZGxJ">[<a href="#ref-BQ4pZGxJ" role="doc-biblioref">1163</a>]</span>.
-The CFR for adults over 80 has been estimated upwards of 14% or even 20% <span class="citation" data-cites="1DnayDKc4">[<a href="#ref-1DnayDKc4" role="doc-biblioref">1164</a>]</span>.
-Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death <span class="citation" data-cites="gObtnWSD DqBeNrR5 ConBOYBB">[<a href="#ref-gObtnWSD" role="doc-biblioref">1165</a>,<a href="#ref-DqBeNrR5" role="doc-biblioref">1166</a>,<a href="#ref-ConBOYBB" role="doc-biblioref">1167</a>]</span>.
-Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death <span class="citation" data-cites="DqBeNrR5">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1166</a>]</span>, although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions <span class="citation" data-cites="fH3qecwy">[<a href="#ref-fH3qecwy" role="doc-biblioref">1168</a>]</span>.
-In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio <span class="citation" data-cites="DqBeNrR5">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1166</a>]</span>.
-Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 <span class="citation" data-cites="ConBOYBB">[<a href="#ref-ConBOYBB" role="doc-biblioref">1167</a>]</span>.
-There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort <span class="citation" data-cites="RcYBFjm1">[<a href="#ref-RcYBFjm1" role="doc-biblioref">1169</a>]</span>.</p>
+<p>Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age (typically defined as 60 or older, with the greatest risk among those 85 and older <span class="citation" data-cites="aZlVFn2R">[<a href="#ref-aZlVFn2R" role="doc-biblioref">1158</a>]</span>).
+In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization <span class="citation" data-cites="1D6lVXWbJ Zk5CfYeW">[<a href="#ref-1D6lVXWbJ" role="doc-biblioref">1159</a>,<a href="#ref-Zk5CfYeW" role="doc-biblioref">1160</a>]</span>.
+A retrospective study of hospitalized Chinese patients <span class="citation" data-cites="10THxyeCg">[<a href="#ref-10THxyeCg" role="doc-biblioref">38</a>]</span> found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity <span class="citation" data-cites="BQ4pZGxJ">[<a href="#ref-BQ4pZGxJ" role="doc-biblioref">1161</a>]</span>.
+The CFR for adults over 80 has been estimated upwards of 14% or even 20% <span class="citation" data-cites="1DnayDKc4">[<a href="#ref-1DnayDKc4" role="doc-biblioref">1162</a>]</span>.
+Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death <span class="citation" data-cites="gObtnWSD DqBeNrR5 ConBOYBB">[<a href="#ref-gObtnWSD" role="doc-biblioref">1163</a>,<a href="#ref-DqBeNrR5" role="doc-biblioref">1164</a>,<a href="#ref-ConBOYBB" role="doc-biblioref">1165</a>]</span>.
+Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death <span class="citation" data-cites="DqBeNrR5">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1164</a>]</span>, although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions <span class="citation" data-cites="fH3qecwy">[<a href="#ref-fH3qecwy" role="doc-biblioref">1166</a>]</span>.
+In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio <span class="citation" data-cites="DqBeNrR5">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1164</a>]</span>.
+Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 <span class="citation" data-cites="ConBOYBB">[<a href="#ref-ConBOYBB" role="doc-biblioref">1165</a>]</span>.
+There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort <span class="citation" data-cites="RcYBFjm1">[<a href="#ref-RcYBFjm1" role="doc-biblioref">1167</a>]</span>.</p>
 <p>Both of these risk factors can be approached through the lens of biology.
-The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes <span class="citation" data-cites="1DnayDKc4">[<a href="#ref-1DnayDKc4" role="doc-biblioref">1164</a>]</span>.
+The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes <span class="citation" data-cites="1DnayDKc4">[<a href="#ref-1DnayDKc4" role="doc-biblioref">1162</a>]</span>.
 Several hypotheses have been proposed to account for differences in severity between males and females.
-For example, some evidence suggests that female sex hormones may be protective <span class="citation" data-cites="DqBeNrR5 fH3qecwy">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1166</a>,<a href="#ref-fH3qecwy" role="doc-biblioref">1168</a>]</span>.
-ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol <span class="citation" data-cites="OJvjTsWz fH3qecwy">[<a href="#ref-fH3qecwy" role="doc-biblioref">1168</a>,<a href="#ref-OJvjTsWz" role="doc-biblioref">1170</a>]</span>.
-Other work in mice has shown an inverse association between mortality due to SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone <span class="citation" data-cites="fH3qecwy">[<a href="#ref-fH3qecwy" role="doc-biblioref">1168</a>]</span>.
+For example, some evidence suggests that female sex hormones may be protective <span class="citation" data-cites="DqBeNrR5 fH3qecwy">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1164</a>,<a href="#ref-fH3qecwy" role="doc-biblioref">1166</a>]</span>.
+ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol <span class="citation" data-cites="OJvjTsWz fH3qecwy">[<a href="#ref-fH3qecwy" role="doc-biblioref">1166</a>,<a href="#ref-OJvjTsWz" role="doc-biblioref">1168</a>]</span>.
+Other work in mice has shown an inverse association between mortality due to SARS-CoV-1 and estradiol, suggesting a protective role for the sex hormone <span class="citation" data-cites="fH3qecwy">[<a href="#ref-fH3qecwy" role="doc-biblioref">1166</a>]</span>.
 Similarly, evidence suggests that similar patterns might be found in other tissues.
-A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis showed than female patients, although this pattern was not found in controls <span class="citation" data-cites="DqBeNrR5">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1166</a>]</span>.
-Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the Renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 <span class="citation" data-cites="DqBeNrR5">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1166</a>]</span>.
-Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females <span class="citation" data-cites="fH3qecwy OJvjTsWz">[<a href="#ref-fH3qecwy" role="doc-biblioref">1168</a>,<a href="#ref-OJvjTsWz" role="doc-biblioref">1170</a>]</span>.
-This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males <span class="citation" data-cites="fH3qecwy">[<a href="#ref-fH3qecwy" role="doc-biblioref">1168</a>]</span>.
-Sex steroids can also bind to immune cell receptors to influence cytokine production <span class="citation" data-cites="DqBeNrR5">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1166</a>]</span>.
-Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks <span class="citation" data-cites="ujWsdPdH">[<a href="#ref-ujWsdPdH" role="doc-biblioref">1171</a>]</span>, and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) <span class="citation" data-cites="DqBeNrR5">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1166</a>]</span> among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk <span class="citation" data-cites="agpMLmxt">[<a href="#ref-agpMLmxt" role="doc-biblioref">1172</a>]</span>.)</p>
+A preliminary analysis identified higher levels of ACE2 expression in the myocardium of male patients with aortic valve stenosis showed than female patients, although this pattern was not found in controls <span class="citation" data-cites="DqBeNrR5">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1164</a>]</span>.
+Additionally, research has indicated that females respond to lower doses than males of heart medications that act on the Renin angiotensin aldosterone system (RAAS) pathway, which is shared with ACE2 <span class="citation" data-cites="DqBeNrR5">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1164</a>]</span>.
+Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females <span class="citation" data-cites="fH3qecwy OJvjTsWz">[<a href="#ref-fH3qecwy" role="doc-biblioref">1166</a>,<a href="#ref-OJvjTsWz" role="doc-biblioref">1168</a>]</span>.
+This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males <span class="citation" data-cites="fH3qecwy">[<a href="#ref-fH3qecwy" role="doc-biblioref">1166</a>]</span>.
+Sex steroids can also bind to immune cell receptors to influence cytokine production <span class="citation" data-cites="DqBeNrR5">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1164</a>]</span>.
+Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks <span class="citation" data-cites="ujWsdPdH">[<a href="#ref-ujWsdPdH" role="doc-biblioref">1169</a>]</span>, and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) <span class="citation" data-cites="DqBeNrR5">[<a href="#ref-DqBeNrR5" role="doc-biblioref">1164</a>]</span> among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk <span class="citation" data-cites="agpMLmxt">[<a href="#ref-agpMLmxt" role="doc-biblioref">1170</a>]</span>.)</p>
 <h3 data-number="9.2.2" id="comorbid-health-conditions"><span class="header-section-number">9.2.2</span> Comorbid Health Conditions</h3>
 <p>A number of pre-existing or comorbid conditions have repeatedly been identified as risk factors for more severe COVID-19 outcomes.
-Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease <span class="citation" data-cites="xZBEFXiG">[<a href="#ref-xZBEFXiG" role="doc-biblioref">1159</a>]</span>.
-Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality <span class="citation" data-cites="10THxyeCg">[<a href="#ref-10THxyeCg" role="doc-biblioref">38</a>]</span>, and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex <span class="citation" data-cites="gObtnWSD">[<a href="#ref-gObtnWSD" role="doc-biblioref">1165</a>]</span>.
-Diabetes may increase the risk of lengthy hospitalization <span class="citation" data-cites="9NfXSHjH">[<a href="#ref-9NfXSHjH" role="doc-biblioref">1173</a>]</span> or of death <span class="citation" data-cites="9NfXSHjH 13BpwZaaq">[<a href="#ref-9NfXSHjH" role="doc-biblioref">1173</a>,<a href="#ref-13BpwZaaq" role="doc-biblioref">1174</a>]</span>.
-<span class="citation" data-cites="UkCdtLwF">[<a href="#ref-UkCdtLwF" role="doc-biblioref">1175</a>]</span> and <span class="citation" data-cites="OT5GEOej">[<a href="#ref-OT5GEOej" role="doc-biblioref">1176</a>]</span> discuss possible ways in which COVID-19 and diabetes may interact.
-Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 <span class="citation" data-cites="ZLmNMDrD 2Ahpn6R2">[<a href="#ref-ZLmNMDrD" role="doc-biblioref">1177</a>,<a href="#ref-2Ahpn6R2" role="doc-biblioref">1178</a>]</span>.
-Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear <span class="citation" data-cites="1AmBg80Un">[<a href="#ref-1AmBg80Un" role="doc-biblioref">1179</a>]</span>.
-Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom <span class="citation" data-cites="gObtnWSD">[<a href="#ref-gObtnWSD" role="doc-biblioref">1165</a>]</span>.
-It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally <span class="citation" data-cites="1GakM8xhV">[<a href="#ref-1GakM8xhV" role="doc-biblioref">1180</a>]</span>.
-Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities <span class="citation" data-cites="1DnayDKc4 H6dfv6Wv">[<a href="#ref-1DnayDKc4" role="doc-biblioref">1164</a>,<a href="#ref-H6dfv6Wv" role="doc-biblioref">1181</a>]</span>. <!-- will this url work for Manubot?-->
-Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population <span class="citation" data-cites="1GakM8xhV">[<a href="#ref-1GakM8xhV" role="doc-biblioref">1180</a>]</span>.
-However, other associations may exist, such as patients with sepsis having higher SOFA scores – in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment <span class="citation" data-cites="TuzwDCPt a0h975P6">[<a href="#ref-TuzwDCPt" role="doc-biblioref">1182</a>,<a href="#ref-a0h975P6" role="doc-biblioref">1183</a>]</span>.
+Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease <span class="citation" data-cites="xZBEFXiG">[<a href="#ref-xZBEFXiG" role="doc-biblioref">1157</a>]</span>.
+Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality <span class="citation" data-cites="10THxyeCg">[<a href="#ref-10THxyeCg" role="doc-biblioref">38</a>]</span>, and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex <span class="citation" data-cites="gObtnWSD">[<a href="#ref-gObtnWSD" role="doc-biblioref">1163</a>]</span>.
+Diabetes may increase the risk of lengthy hospitalization <span class="citation" data-cites="9NfXSHjH">[<a href="#ref-9NfXSHjH" role="doc-biblioref">1171</a>]</span> or of death <span class="citation" data-cites="9NfXSHjH 13BpwZaaq">[<a href="#ref-9NfXSHjH" role="doc-biblioref">1171</a>,<a href="#ref-13BpwZaaq" role="doc-biblioref">1172</a>]</span>.
+<span class="citation" data-cites="UkCdtLwF">[<a href="#ref-UkCdtLwF" role="doc-biblioref">1173</a>]</span> and <span class="citation" data-cites="OT5GEOej">[<a href="#ref-OT5GEOej" role="doc-biblioref">1174</a>]</span> discuss possible ways in which COVID-19 and diabetes may interact.
+Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 <span class="citation" data-cites="ZLmNMDrD 2Ahpn6R2">[<a href="#ref-ZLmNMDrD" role="doc-biblioref">1175</a>,<a href="#ref-2Ahpn6R2" role="doc-biblioref">1176</a>]</span>.
+Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear <span class="citation" data-cites="1AmBg80Un">[<a href="#ref-1AmBg80Un" role="doc-biblioref">1177</a>]</span>.
+Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom <span class="citation" data-cites="gObtnWSD">[<a href="#ref-gObtnWSD" role="doc-biblioref">1163</a>]</span>.
+It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally <span class="citation" data-cites="1GakM8xhV">[<a href="#ref-1GakM8xhV" role="doc-biblioref">1178</a>]</span>.
+Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities <span class="citation" data-cites="1DnayDKc4 H6dfv6Wv">[<a href="#ref-1DnayDKc4" role="doc-biblioref">1162</a>,<a href="#ref-H6dfv6Wv" role="doc-biblioref">1179</a>]</span>. <!-- will this url work for Manubot?-->
+Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population <span class="citation" data-cites="1GakM8xhV">[<a href="#ref-1GakM8xhV" role="doc-biblioref">1178</a>]</span>.
+However, other associations may exist, such as patients with sepsis having higher SOFA scores – in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment <span class="citation" data-cites="TuzwDCPt a0h975P6">[<a href="#ref-TuzwDCPt" role="doc-biblioref">1180</a>,<a href="#ref-a0h975P6" role="doc-biblioref">1181</a>]</span>.
 Additionally, certain conditions are likely to be more prevalent under or exacerbated by social conditions, especially poverty, as is discussed further below.</p>
 <h3 data-number="9.2.3" id="ancestry"><span class="header-section-number">9.2.3</span> Ancestry</h3>
 <p>A number of studies have suggested associations between individuals’ racial and ethnic backgrounds and their COVID-19 risk.
-In particular, Black Americans are consistently identified as carrying a higher burden of COVID-19 than white Americans <span class="citation" data-cites="1D6lVXWbJ Zk5CfYeW">[<a href="#ref-1D6lVXWbJ" role="doc-biblioref">1161</a>,<a href="#ref-Zk5CfYeW" role="doc-biblioref">1162</a>]</span>, with differences in the rates of kidney complications from COVID-19 particularly pronounced <span class="citation" data-cites="17hdoiBo9">[<a href="#ref-17hdoiBo9" role="doc-biblioref">110</a>]</span>.
-Statistics from a number of cities indicate significant discrepancies between the proportion of COVID-19 cases and deaths in Black Americans relative to their representation in the general population <span class="citation" data-cites="jKKxa9Yy">[<a href="#ref-jKKxa9Yy" role="doc-biblioref">1184</a>]</span>.
-In addition to Black Americans, disproportionate harm and mortality from COVID-19 has also been noted in Latino/Hispanic Americans and in Native American and Alaskan Native communities, including the Navajo nation <span class="citation" data-cites="yK5bczRb u4MMV8aJ JAo2QxY 12WZObWRf Pp8GWnQm J9T8eR5H">[<a href="#ref-yK5bczRb" role="doc-biblioref">1185</a>,<a href="#ref-u4MMV8aJ" role="doc-biblioref">1186</a>,<a href="#ref-JAo2QxY" role="doc-biblioref">1187</a>,<a href="#ref-12WZObWRf" role="doc-biblioref">1188</a>,<a href="#ref-Pp8GWnQm" role="doc-biblioref">1189</a>,<a href="#ref-J9T8eR5H" role="doc-biblioref">1190</a>]</span>.
-In Brazil, indigenous communities likewise carry an increased burden of COVID-19 <span class="citation" data-cites="ODm1CaEq">[<a href="#ref-ODm1CaEq" role="doc-biblioref">1191</a>]</span>.
-In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 <span class="citation" data-cites="17gnxmOnf">[<a href="#ref-17gnxmOnf" role="doc-biblioref">1192</a>]</span>.</p>
+In particular, Black Americans are consistently identified as carrying a higher burden of COVID-19 than white Americans <span class="citation" data-cites="1D6lVXWbJ Zk5CfYeW">[<a href="#ref-1D6lVXWbJ" role="doc-biblioref">1159</a>,<a href="#ref-Zk5CfYeW" role="doc-biblioref">1160</a>]</span>, with differences in the rates of kidney complications from COVID-19 particularly pronounced <span class="citation" data-cites="17hdoiBo9">[<a href="#ref-17hdoiBo9" role="doc-biblioref">110</a>]</span>.
+Statistics from a number of cities indicate significant discrepancies between the proportion of COVID-19 cases and deaths in Black Americans relative to their representation in the general population <span class="citation" data-cites="jKKxa9Yy">[<a href="#ref-jKKxa9Yy" role="doc-biblioref">1182</a>]</span>.
+In addition to Black Americans, disproportionate harm and mortality from COVID-19 has also been noted in Latino/Hispanic Americans and in Native American and Alaskan Native communities, including the Navajo nation <span class="citation" data-cites="yK5bczRb u4MMV8aJ JAo2QxY 12WZObWRf Pp8GWnQm J9T8eR5H">[<a href="#ref-yK5bczRb" role="doc-biblioref">1183</a>,<a href="#ref-u4MMV8aJ" role="doc-biblioref">1184</a>,<a href="#ref-JAo2QxY" role="doc-biblioref">1185</a>,<a href="#ref-12WZObWRf" role="doc-biblioref">1186</a>,<a href="#ref-Pp8GWnQm" role="doc-biblioref">1187</a>,<a href="#ref-J9T8eR5H" role="doc-biblioref">1188</a>]</span>.
+In Brazil, indigenous communities likewise carry an increased burden of COVID-19 <span class="citation" data-cites="ODm1CaEq">[<a href="#ref-ODm1CaEq" role="doc-biblioref">1189</a>]</span>.
+In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 <span class="citation" data-cites="17gnxmOnf">[<a href="#ref-17gnxmOnf" role="doc-biblioref">1190</a>]</span>.</p>
 <p>From a genetic standpoint, it is highly unlikely that ancestry itself predisposes individuals to contracting COVID-19 or to experiencing severe COVID-19 outcomes.
-Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent <span class="citation" data-cites="pwbrxYv8">[<a href="#ref-pwbrxYv8" role="doc-biblioref">1193</a>]</span>.
-African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans <span class="citation" data-cites="CMAPEmTp">[<a href="#ref-CMAPEmTp" role="doc-biblioref">1194</a>]</span>.
-Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity <span class="citation" data-cites="q4yhes98">[<a href="#ref-q4yhes98" role="doc-biblioref">1195</a>]</span>.
+Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent <span class="citation" data-cites="pwbrxYv8">[<a href="#ref-pwbrxYv8" role="doc-biblioref">1191</a>]</span>.
+African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans <span class="citation" data-cites="CMAPEmTp">[<a href="#ref-CMAPEmTp" role="doc-biblioref">1192</a>]</span>.
+Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity <span class="citation" data-cites="q4yhes98">[<a href="#ref-q4yhes98" role="doc-biblioref">1193</a>]</span>.
 The possibility for genetic variants that confer some risk or some protection remains possible, but has not been widely explored, especially at a global level.
-Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients <span class="citation" data-cites="FbeY1L1s">[<a href="#ref-FbeY1L1s" role="doc-biblioref">1196</a>]</span>.
-Genetic factors may also play a role in the risk of respiratory failure for COVID-19 <span class="citation" data-cites="owevcpwb nn67UTjV I2mIU0wn">[<a href="#ref-owevcpwb" role="doc-biblioref">1197</a>,<a href="#ref-nn67UTjV" role="doc-biblioref">1198</a>,<a href="#ref-I2mIU0wn" role="doc-biblioref">1199</a>]</span>.
+Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients <span class="citation" data-cites="FbeY1L1s">[<a href="#ref-FbeY1L1s" role="doc-biblioref">1194</a>]</span>.
+Genetic factors may also play a role in the risk of respiratory failure for COVID-19 <span class="citation" data-cites="owevcpwb nn67UTjV I2mIU0wn">[<a href="#ref-owevcpwb" role="doc-biblioref">1195</a>,<a href="#ref-nn67UTjV" role="doc-biblioref">1196</a>,<a href="#ref-I2mIU0wn" role="doc-biblioref">1197</a>]</span>.
 However, genetic variants associated with outcomes within ancestral groups are far less surprising than genetic variants explaining outcomes between groups.
-Alleles in <em>ACE2</em> and <em>TMPRSS2</em> have been identified that vary in frequency among ancestral groups <span class="citation" data-cites="KbDdcSgo">[<a href="#ref-KbDdcSgo" role="doc-biblioref">1200</a>]</span>, but whether these variants are associated with COVID-19 susceptibility has not been explored.</p>
+Alleles in <em>ACE2</em> and <em>TMPRSS2</em> have been identified that vary in frequency among ancestral groups <span class="citation" data-cites="KbDdcSgo">[<a href="#ref-KbDdcSgo" role="doc-biblioref">1198</a>]</span>, but whether these variants are associated with COVID-19 susceptibility has not been explored.</p>
 <p>Instead, examining patterns of COVID-19 susceptibility on a global scale that suggest that social factors are of primary importance in predicting mortality.
 Reports from several sub-Saharan African countries have indicated that the effects of the COVID-19 pandemic have been less severe than expected based on the outbreaks in China and Italy.
-In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 <span class="citation" data-cites="4SqaP0Ub">[<a href="#ref-4SqaP0Ub" role="doc-biblioref">1201</a>]</span>.
-This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases <span class="citation" data-cites="4SqaP0Ub">[<a href="#ref-4SqaP0Ub" role="doc-biblioref">1201</a>]</span>.
-Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted <span class="citation" data-cites="eWIOKa0u">[<a href="#ref-eWIOKa0u" role="doc-biblioref">1202</a>]</span>.
-While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places <span class="citation" data-cites="p4AYZss0">[<a href="#ref-p4AYZss0" role="doc-biblioref">1203</a>]</span>, these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent.
-Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location <span class="citation" data-cites="xFKmPg6l">[<a href="#ref-xFKmPg6l" role="doc-biblioref">1204</a>]</span>.
+In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 <span class="citation" data-cites="4SqaP0Ub">[<a href="#ref-4SqaP0Ub" role="doc-biblioref">1199</a>]</span>.
+This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases <span class="citation" data-cites="4SqaP0Ub">[<a href="#ref-4SqaP0Ub" role="doc-biblioref">1199</a>]</span>.
+Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted <span class="citation" data-cites="eWIOKa0u">[<a href="#ref-eWIOKa0u" role="doc-biblioref">1200</a>]</span>.
+While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places <span class="citation" data-cites="p4AYZss0">[<a href="#ref-p4AYZss0" role="doc-biblioref">1201</a>]</span>, these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent.
+Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location <span class="citation" data-cites="xFKmPg6l">[<a href="#ref-xFKmPg6l" role="doc-biblioref">1202</a>]</span>.
 Furthermore, the groups in the United States and United Kingdom that have been identified as carrying elevated COVID-19 burden, namely Black American, indigenous American, and Black and South Asian British, are quite distinct in their position on the human ancestral tree.
 What is shared across these groups is instead a history of disenfranchisement under colonialism and ongoing systematic racism.
-A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients <span class="citation" data-cites="hrOv770z">[<a href="#ref-hrOv770z" role="doc-biblioref">1156</a>]</span>.
+A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients <span class="citation" data-cites="hrOv770z">[<a href="#ref-hrOv770z" role="doc-biblioref">1154</a>]</span>.
 This study reported that when these factors were accounted for, the differences in mortality between Black and white patients were no longer significant.
 Thus, the current evidence suggests that the apparent correlations between ancestry and health outcomes must be examined in the appropriate social context.</p>
 <h2 data-number="9.3" id="environmental-influences-on-susceptibility"><span class="header-section-number">9.3</span> Environmental Influences on Susceptibility</h2>
@@ -3860,83 +3860,83 @@ <h3 data-number="9.3.1" id="exposure-to-covid-19"><span class="header-section-nu
 <p>Social distancing has emerged as one of the main social policies used to manage the COVID-19 epidemic in many countries.
 Many governments issued stay-at-home orders, especially in the initial months of the crisis.
 However, data clearly indicates that these orders impacted different socioeconomic groups differently.
-In U.S. counties with and without stay-at-home orders, smartphone tracking indicated a significant decrease in the general population’s mobility in April relative to February through March of 2020 (-52.3% and -60.8%, respectively) <span class="citation" data-cites="bDNDEYNn">[<a href="#ref-bDNDEYNn" role="doc-biblioref">1205</a>]</span>.
-A linear relationship was observed between counties’ reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors <span class="citation" data-cites="bDNDEYNn">[<a href="#ref-bDNDEYNn" role="doc-biblioref">1205</a>]</span>.
-Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents <span class="citation" data-cites="bDNDEYNn">[<a href="#ref-bDNDEYNn" role="doc-biblioref">1205</a>]</span>.
-Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 <span class="citation" data-cites="RdnghmVU">[<a href="#ref-RdnghmVU" role="doc-biblioref">1206</a>]</span>, as well as in a very large data set from several US cities <span class="citation" data-cites="9OksxLmM">[<a href="#ref-9OksxLmM" role="doc-biblioref">1207</a>]</span>.
+In U.S. counties with and without stay-at-home orders, smartphone tracking indicated a significant decrease in the general population’s mobility in April relative to February through March of 2020 (-52.3% and -60.8%, respectively) <span class="citation" data-cites="bDNDEYNn">[<a href="#ref-bDNDEYNn" role="doc-biblioref">1203</a>]</span>.
+A linear relationship was observed between counties’ reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors <span class="citation" data-cites="bDNDEYNn">[<a href="#ref-bDNDEYNn" role="doc-biblioref">1203</a>]</span>.
+Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents <span class="citation" data-cites="bDNDEYNn">[<a href="#ref-bDNDEYNn" role="doc-biblioref">1203</a>]</span>.
+Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 <span class="citation" data-cites="RdnghmVU">[<a href="#ref-RdnghmVU" role="doc-biblioref">1204</a>]</span>, as well as in a very large data set from several US cities <span class="citation" data-cites="9OksxLmM">[<a href="#ref-9OksxLmM" role="doc-biblioref">1205</a>]</span>.
 These disparities in mobility are likely to be related to the role that essential workers have played during the pandemic.
-Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line <span class="citation" data-cites="15qfRPnUG">[<a href="#ref-15qfRPnUG" role="doc-biblioref">1208</a>]</span>.
-Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible <span class="citation" data-cites="HihYbn6k">[<a href="#ref-HihYbn6k" role="doc-biblioref">1209</a>]</span>.
-Health care work in particular presents an increased risk of exposure to SARS-CoV-2 <span class="citation" data-cites="HihYbn6k F4laSOXM hAYohR8m DOyiuaup 13qkVV6eN">[<a href="#ref-HihYbn6k" role="doc-biblioref">1209</a>,<a href="#ref-F4laSOXM" role="doc-biblioref">1210</a>,<a href="#ref-hAYohR8m" role="doc-biblioref">1211</a>,<a href="#ref-DOyiuaup" role="doc-biblioref">1212</a>,<a href="#ref-13qkVV6eN" role="doc-biblioref">1213</a>]</span>.
-In the United Kingdom, (South) Asians are more likely than their white counterparts to be medical professionals <span class="citation" data-cites="xFKmPg6l">[<a href="#ref-xFKmPg6l" role="doc-biblioref">1204</a>]</span>, although BAME medical professionals are still disproportionately represented in the proportion of National Health Service staff deaths <span class="citation" data-cites="4zjepZ8T">[<a href="#ref-4zjepZ8T" role="doc-biblioref">1214</a>]</span>.
-Similar trends have been reported for nurses, especially nurses of color, in the United States <span class="citation" data-cites="2gxJPENM">[<a href="#ref-2gxJPENM" role="doc-biblioref">1215</a>]</span>.
-Furthermore, beyond the risks associated with work itself, use of public transportation may also impact COVID-19 risk <span class="citation" data-cites="Moc3BREQ">[<a href="#ref-Moc3BREQ" role="doc-biblioref">1216</a>]</span>.
+Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line <span class="citation" data-cites="15qfRPnUG">[<a href="#ref-15qfRPnUG" role="doc-biblioref">1206</a>]</span>.
+Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible <span class="citation" data-cites="HihYbn6k">[<a href="#ref-HihYbn6k" role="doc-biblioref">1207</a>]</span>.
+Health care work in particular presents an increased risk of exposure to SARS-CoV-2 <span class="citation" data-cites="HihYbn6k F4laSOXM hAYohR8m DOyiuaup 13qkVV6eN">[<a href="#ref-HihYbn6k" role="doc-biblioref">1207</a>,<a href="#ref-F4laSOXM" role="doc-biblioref">1208</a>,<a href="#ref-hAYohR8m" role="doc-biblioref">1209</a>,<a href="#ref-DOyiuaup" role="doc-biblioref">1210</a>,<a href="#ref-13qkVV6eN" role="doc-biblioref">1211</a>]</span>.
+In the United Kingdom, (South) Asians are more likely than their white counterparts to be medical professionals <span class="citation" data-cites="xFKmPg6l">[<a href="#ref-xFKmPg6l" role="doc-biblioref">1202</a>]</span>, although BAME medical professionals are still disproportionately represented in the proportion of National Health Service staff deaths <span class="citation" data-cites="4zjepZ8T">[<a href="#ref-4zjepZ8T" role="doc-biblioref">1212</a>]</span>.
+Similar trends have been reported for nurses, especially nurses of color, in the United States <span class="citation" data-cites="2gxJPENM">[<a href="#ref-2gxJPENM" role="doc-biblioref">1213</a>]</span>.
+Furthermore, beyond the risks associated with work itself, use of public transportation may also impact COVID-19 risk <span class="citation" data-cites="Moc3BREQ">[<a href="#ref-Moc3BREQ" role="doc-biblioref">1214</a>]</span>.
 The socioeconomic and racial/ethnic gaps in who is working on the front lines of the pandemic make it clear that socioeconomic privilege is likely to decrease the probability of exposure to SARS-CoV-2.</p>
 <p>Increased risk of exposure can also arise outside the workplace.
-Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks <span class="citation" data-cites="aM2XPE3J">[<a href="#ref-aM2XPE3J" role="doc-biblioref">1217</a>]</span>.
-Prisons and detention centers also confer a high risk of exposure or infection <span class="citation" data-cites="BeedQx3I 2uUcva6Y">[<a href="#ref-BeedQx3I" role="doc-biblioref">1218</a>,<a href="#ref-2uUcva6Y" role="doc-biblioref">1219</a>]</span>.
-Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black <span class="citation" data-cites="zuipD7ZP">[<a href="#ref-zuipD7ZP" role="doc-biblioref">1220</a>]</span>.
-Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds <span class="citation" data-cites="OzhmHOxJ">[<a href="#ref-OzhmHOxJ" role="doc-biblioref">1221</a>]</span>, increasing the risk of exposure for more susceptible family members.
-Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure <span class="citation" data-cites="bDNDEYNn">[<a href="#ref-bDNDEYNn" role="doc-biblioref">1205</a>]</span>, and household crowding is associated with poverty <span class="citation" data-cites="13wfXDXqr">[<a href="#ref-13wfXDXqr" role="doc-biblioref">1222</a>]</span>.
-Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism <span class="citation" data-cites="1Axz3a1Hj 64YOO3yt">[<a href="#ref-1Axz3a1Hj" role="doc-biblioref">1223</a>,<a href="#ref-64YOO3yt" role="doc-biblioref">1224</a>]</span>, would be likely to increase household crowding and other possible sources of exposure.
+Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks <span class="citation" data-cites="aM2XPE3J">[<a href="#ref-aM2XPE3J" role="doc-biblioref">1215</a>]</span>.
+Prisons and detention centers also confer a high risk of exposure or infection <span class="citation" data-cites="BeedQx3I 2uUcva6Y">[<a href="#ref-BeedQx3I" role="doc-biblioref">1216</a>,<a href="#ref-2uUcva6Y" role="doc-biblioref">1217</a>]</span>.
+Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black <span class="citation" data-cites="zuipD7ZP">[<a href="#ref-zuipD7ZP" role="doc-biblioref">1218</a>]</span>.
+Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds <span class="citation" data-cites="OzhmHOxJ">[<a href="#ref-OzhmHOxJ" role="doc-biblioref">1219</a>]</span>, increasing the risk of exposure for more susceptible family members.
+Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure <span class="citation" data-cites="bDNDEYNn">[<a href="#ref-bDNDEYNn" role="doc-biblioref">1203</a>]</span>, and household crowding is associated with poverty <span class="citation" data-cites="13wfXDXqr">[<a href="#ref-13wfXDXqr" role="doc-biblioref">1220</a>]</span>.
+Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism <span class="citation" data-cites="1Axz3a1Hj 64YOO3yt">[<a href="#ref-1Axz3a1Hj" role="doc-biblioref">1221</a>,<a href="#ref-64YOO3yt" role="doc-biblioref">1222</a>]</span>, would be likely to increase household crowding and other possible sources of exposure.
 As a result, facets of systemic inequality such as mass incarceration of Black Americans and poverty are likely to increase the risk of exposure outside of the workplace.</p>
 <h3 data-number="9.3.2" id="severity-of-covid-19-following-exposure"><span class="header-section-number">9.3.2</span> Severity of COVID-19 Following Exposure</h3>
 <p>Following exposure to SARS-CoV-2, the likelihood that an individual develops COVID-19 and the severity of the disease presentation can be influenced by a number of social factors.
 As discussed above, a number of patient characteristics are associated with the likelihood of severe COVID-19 symptoms.
-In some cases, these trends run counter to those expected given rates of exposure: for example, although women are more likely to be exposed, men are more likely to be diagnosed with, hospitalized from, or die from COVID-19 <span class="citation" data-cites="fH3qecwy">[<a href="#ref-fH3qecwy" role="doc-biblioref">1168</a>]</span>.
+In some cases, these trends run counter to those expected given rates of exposure: for example, although women are more likely to be exposed, men are more likely to be diagnosed with, hospitalized from, or die from COVID-19 <span class="citation" data-cites="fH3qecwy">[<a href="#ref-fH3qecwy" role="doc-biblioref">1166</a>]</span>.
 In the case of comorbid conditions and racial/ethnic demographics, however, social factors are highly likely to modulate or at least influence the apparent association between these traits and the increased risk from COVID-19.
 In particular, the comorbidities and racial/ethnic correlates of severe COVID-19 outcomes suggest that poverty confers additional risk for COVID-19.</p>
 <p>In order to explore the relationship between poverty and COVID-19 outcomes, it is necessary to consider how poverty impacts biology.
 In particular, we focus on the United States and the United Kingdom.
-Comorbidities that increase risk for COVID-19, including obesity, type II diabetes, hypertension, and cardiovascular disease, are known to be intercorrelated <span class="citation" data-cites="sRZCzj6j">[<a href="#ref-sRZCzj6j" role="doc-biblioref">1225</a>]</span>.
-Metabolic conditions related to heightened inflammation, like obesity, type II diabetes, and hypertension, are more strongly associated with negative COVID-19 outcomes than other comorbid conditions, such as chronic heart disease <span class="citation" data-cites="JizR1ocj">[<a href="#ref-JizR1ocj" role="doc-biblioref">1226</a>]</span>.
+Comorbidities that increase risk for COVID-19, including obesity, type II diabetes, hypertension, and cardiovascular disease, are known to be intercorrelated <span class="citation" data-cites="sRZCzj6j">[<a href="#ref-sRZCzj6j" role="doc-biblioref">1223</a>]</span>.
+Metabolic conditions related to heightened inflammation, like obesity, type II diabetes, and hypertension, are more strongly associated with negative COVID-19 outcomes than other comorbid conditions, such as chronic heart disease <span class="citation" data-cites="JizR1ocj">[<a href="#ref-JizR1ocj" role="doc-biblioref">1224</a>]</span>.
 As discussed above, dysregulated inflammation characteristic of cytokine release syndrome is one of the greatest concerns for COVID-19-related death.
-Therefore, it is possible that chronic inflammation characteristic of these metabolic conditions predisposes patients to COVID-19-related death <span class="citation" data-cites="JizR1ocj">[<a href="#ref-JizR1ocj" role="doc-biblioref">1226</a>]</span>.
-The association between these diseases and severe COVID-19 outcomes is a concern from a health equity perspective because poverty exposes people to “obesogenic” conditions <span class="citation" data-cites="nYLB9EMw">[<a href="#ref-nYLB9EMw" role="doc-biblioref">1227</a>]</span> and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders <span class="citation" data-cites="h1e9QTlK">[<a href="#ref-h1e9QTlK" role="doc-biblioref">1228</a>]</span>.
-Furthermore, cell phone GPS data suggests that lower socioeconomic status may also be associated with decreased access to healthy food choices during the COVID-19 pandemic <span class="citation" data-cites="94eOAGnA 5G5UozXd">[<a href="#ref-94eOAGnA" role="doc-biblioref">1229</a>,<a href="#ref-5G5UozXd" role="doc-biblioref">1230</a>]</span>, suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues <span class="citation" data-cites="17yfPiYAS">[<a href="#ref-17yfPiYAS" role="doc-biblioref">1231</a>]</span>.
-Chronic inflammation is a known outcome of chronic stress (e.g., <span class="citation" data-cites="Hu7PyNNp P2wUkjrR 109EtOYzw 11oGPv27i">[<a href="#ref-Hu7PyNNp" role="doc-biblioref">1232</a>,<a href="#ref-P2wUkjrR" role="doc-biblioref">1233</a>,<a href="#ref-109EtOYzw" role="doc-biblioref">1234</a>,<a href="#ref-11oGPv27i" role="doc-biblioref">1235</a>]</span>).
-Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in <span class="citation" data-cites="KZSJklnl">[<a href="#ref-KZSJklnl" role="doc-biblioref">1236</a>]</span>) and especially during the stress of the ongoing pandemic.</p>
-<p>A preprint <span class="citation" data-cites="5BMDcXz3">[<a href="#ref-5BMDcXz3" role="doc-biblioref">1237</a>]</span> provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates.
-Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., <span class="citation" data-cites="vImXUPNS">[<a href="#ref-vImXUPNS" role="doc-biblioref">1238</a>]</span>).
-Exposure to air pollution is associated with both poverty (e.g., <span class="citation" data-cites="6ACdDJOV">[<a href="#ref-6ACdDJOV" role="doc-biblioref">1239</a>]</span>) and chronic inflammation <span class="citation" data-cites="11Ift2eIl">[<a href="#ref-11Ift2eIl" role="doc-biblioref">1240</a>]</span>.
-Other outcomes of environmental racism, such as the proximity of abandoned uranium mines to Navajo land, can also cause respiratory illnesses and other health issues <span class="citation" data-cites="J9T8eR5H">[<a href="#ref-J9T8eR5H" role="doc-biblioref">1190</a>]</span>.
-Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency <span class="citation" data-cites="8ZxZKpYS">[<a href="#ref-8ZxZKpYS" role="doc-biblioref">1049</a>]</span>) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism <span class="citation" data-cites="J9T8eR5H aHM6WZzd">[<a href="#ref-J9T8eR5H" role="doc-biblioref">1190</a>,<a href="#ref-aHM6WZzd" role="doc-biblioref">1241</a>]</span>.
+Therefore, it is possible that chronic inflammation characteristic of these metabolic conditions predisposes patients to COVID-19-related death <span class="citation" data-cites="JizR1ocj">[<a href="#ref-JizR1ocj" role="doc-biblioref">1224</a>]</span>.
+The association between these diseases and severe COVID-19 outcomes is a concern from a health equity perspective because poverty exposes people to “obesogenic” conditions <span class="citation" data-cites="nYLB9EMw">[<a href="#ref-nYLB9EMw" role="doc-biblioref">1225</a>]</span> and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders <span class="citation" data-cites="h1e9QTlK">[<a href="#ref-h1e9QTlK" role="doc-biblioref">1226</a>]</span>.
+Furthermore, cell phone GPS data suggests that lower socioeconomic status may also be associated with decreased access to healthy food choices during the COVID-19 pandemic <span class="citation" data-cites="94eOAGnA 5G5UozXd">[<a href="#ref-94eOAGnA" role="doc-biblioref">1227</a>,<a href="#ref-5G5UozXd" role="doc-biblioref">1228</a>]</span>, suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues <span class="citation" data-cites="17yfPiYAS">[<a href="#ref-17yfPiYAS" role="doc-biblioref">1229</a>]</span>.
+Chronic inflammation is a known outcome of chronic stress (e.g., <span class="citation" data-cites="Hu7PyNNp P2wUkjrR 109EtOYzw 11oGPv27i">[<a href="#ref-Hu7PyNNp" role="doc-biblioref">1230</a>,<a href="#ref-P2wUkjrR" role="doc-biblioref">1231</a>,<a href="#ref-109EtOYzw" role="doc-biblioref">1232</a>,<a href="#ref-11oGPv27i" role="doc-biblioref">1233</a>]</span>).
+Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in <span class="citation" data-cites="KZSJklnl">[<a href="#ref-KZSJklnl" role="doc-biblioref">1234</a>]</span>) and especially during the stress of the ongoing pandemic.</p>
+<p>A preprint <span class="citation" data-cites="5BMDcXz3">[<a href="#ref-5BMDcXz3" role="doc-biblioref">1235</a>]</span> provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates.
+Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., <span class="citation" data-cites="vImXUPNS">[<a href="#ref-vImXUPNS" role="doc-biblioref">1236</a>]</span>).
+Exposure to air pollution is associated with both poverty (e.g., <span class="citation" data-cites="6ACdDJOV">[<a href="#ref-6ACdDJOV" role="doc-biblioref">1237</a>]</span>) and chronic inflammation <span class="citation" data-cites="11Ift2eIl">[<a href="#ref-11Ift2eIl" role="doc-biblioref">1238</a>]</span>.
+Other outcomes of environmental racism, such as the proximity of abandoned uranium mines to Navajo land, can also cause respiratory illnesses and other health issues <span class="citation" data-cites="J9T8eR5H">[<a href="#ref-J9T8eR5H" role="doc-biblioref">1188</a>]</span>.
+Similarly, preliminary findings indicate that nutritional status (e.g., vitamin D deficiency <span class="citation" data-cites="8ZxZKpYS">[<a href="#ref-8ZxZKpYS" role="doc-biblioref">1047</a>]</span>) may be associated with COVID-19 outcomes, and reduced access to grocery stores and fresh food often co-occurs with environmental racism <span class="citation" data-cites="J9T8eR5H aHM6WZzd">[<a href="#ref-J9T8eR5H" role="doc-biblioref">1188</a>,<a href="#ref-aHM6WZzd" role="doc-biblioref">1239</a>]</span>.
 Taken together, the evidence suggests that low-income workers who face greater exposure to SARS-CoV-2 due to their home or work conditions are also more likely to face environmental and social stressors associated with increased inflammation, and therefore with increased risk from COVID-19.
 In particular, structural racism can play an important role on disease severity after SARS-CoV-2 exposure, due to consequences of racism which include an increased likelihood of poverty and its associated food and housing instability.
-COVID-19 can thus be considered a “syndemic”, or a synergistic interaction between several epidemics <span class="citation" data-cites="11Ldf3Ch3">[<a href="#ref-11Ldf3Ch3" role="doc-biblioref">1242</a>]</span>.
-As a result, it is not surprising that people from minoritized backgrounds and/or with certain pre-existing conditions are more likely to suffer severe effects of COVID-19, but these “risk factors” are likely to be causally linked to poverty <span class="citation" data-cites="XtKjlYFF">[<a href="#ref-XtKjlYFF" role="doc-biblioref">1243</a>]</span>.</p>
+COVID-19 can thus be considered a “syndemic”, or a synergistic interaction between several epidemics <span class="citation" data-cites="11Ldf3Ch3">[<a href="#ref-11Ldf3Ch3" role="doc-biblioref">1240</a>]</span>.
+As a result, it is not surprising that people from minoritized backgrounds and/or with certain pre-existing conditions are more likely to suffer severe effects of COVID-19, but these “risk factors” are likely to be causally linked to poverty <span class="citation" data-cites="XtKjlYFF">[<a href="#ref-XtKjlYFF" role="doc-biblioref">1241</a>]</span>.</p>
 <h3 data-number="9.3.3" id="access-to-treatment"><span class="header-section-number">9.3.3</span> Access to Treatment</h3>
 <p>Finally, COVID-19 outcomes can be influenced by access to healthcare.
 Receiving care for COVID-19 can, but does not always, include receiving a positive test for the SARS-CoV-2 virus.
-For example, it is common to see treatment guidelines for suspected cases regardless of whether the presence of SARS-CoV-2 has been confirmed (e.g., <span class="citation" data-cites="cSA2h9hO">[<a href="#ref-cSA2h9hO" role="doc-biblioref">1244</a>]</span>).
+For example, it is common to see treatment guidelines for suspected cases regardless of whether the presence of SARS-CoV-2 has been confirmed (e.g., <span class="citation" data-cites="cSA2h9hO">[<a href="#ref-cSA2h9hO" role="doc-biblioref">1242</a>]</span>).
 Whether and where a patient is diagnosed can depend on their access to testing, which can vary both between and within countries.
-In the United States, it is not always clear whether an individual will have access to free testing <span class="citation" data-cites="1Intrlax jc9vc7ws">[<a href="#ref-1Intrlax" role="doc-biblioref">1245</a>,<a href="#ref-jc9vc7ws" role="doc-biblioref">1246</a>]</span>.
-The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States <span class="citation" data-cites="13MGsHBtw">[<a href="#ref-13MGsHBtw" role="doc-biblioref">1247</a>]</span>.
-This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community <span class="citation" data-cites="1D6lVXWbJ">[<a href="#ref-1D6lVXWbJ" role="doc-biblioref">1161</a>]</span>.
-Any delays in treatment are a cause for concern <span class="citation" data-cites="13MGsHBtw">[<a href="#ref-13MGsHBtw" role="doc-biblioref">1247</a>]</span>, which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test <span class="citation" data-cites="P8VNkYTE">[<a href="#ref-P8VNkYTE" role="doc-biblioref">1248</a>]</span>.</p>
+In the United States, it is not always clear whether an individual will have access to free testing <span class="citation" data-cites="1Intrlax jc9vc7ws">[<a href="#ref-1Intrlax" role="doc-biblioref">1243</a>,<a href="#ref-jc9vc7ws" role="doc-biblioref">1244</a>]</span>.
+The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States <span class="citation" data-cites="13MGsHBtw">[<a href="#ref-13MGsHBtw" role="doc-biblioref">1245</a>]</span>.
+This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community <span class="citation" data-cites="1D6lVXWbJ">[<a href="#ref-1D6lVXWbJ" role="doc-biblioref">1159</a>]</span>.
+Any delays in treatment are a cause for concern <span class="citation" data-cites="13MGsHBtw">[<a href="#ref-13MGsHBtw" role="doc-biblioref">1245</a>]</span>, which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test <span class="citation" data-cites="P8VNkYTE">[<a href="#ref-P8VNkYTE" role="doc-biblioref">1246</a>]</span>.</p>
 <p>Another important question is whether patients with moderate to severe cases are able to access hospital facilities and treatments, to the extent that they have been identified.
-Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country <span class="citation" data-cites="tLVYjfMk">[<a href="#ref-tLVYjfMk" role="doc-biblioref">1249</a>]</span>, although reported mortality is generally an estimate of CFR, which is dependent on rates of testing.
-Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources <span class="citation" data-cites="cOQK0zNa">[<a href="#ref-cOQK0zNa" role="doc-biblioref">1250</a>]</span>.
-In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured <span class="citation" data-cites="13MGsHBtw">[<a href="#ref-13MGsHBtw" role="doc-biblioref">1247</a>]</span>.
-As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds <span class="citation" data-cites="gOiB5HDd">[<a href="#ref-gOiB5HDd" role="doc-biblioref">1251</a>]</span>.
+Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country <span class="citation" data-cites="tLVYjfMk">[<a href="#ref-tLVYjfMk" role="doc-biblioref">1247</a>]</span>, although reported mortality is generally an estimate of CFR, which is dependent on rates of testing.
+Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources <span class="citation" data-cites="cOQK0zNa">[<a href="#ref-cOQK0zNa" role="doc-biblioref">1248</a>]</span>.
+In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured <span class="citation" data-cites="13MGsHBtw">[<a href="#ref-13MGsHBtw" role="doc-biblioref">1245</a>]</span>.
+As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds <span class="citation" data-cites="gOiB5HDd">[<a href="#ref-gOiB5HDd" role="doc-biblioref">1249</a>]</span>.
 Therefore, access to diagnostics and care prior to the development of severe COVID-19 is likely to vary depending on socioeconomic and social factors, many of which overlap with the risks of exposure and of developing more severe COVID-19 symptoms.
 This discrepancy ties into concerns about broad infrastructural challenges imposed by COVID-19.
 A major concern in many countries has been the saturation of healthcare systems due to the volume of COVID-19 hospitalizations (e.g., <span class="citation" data-cites="NCcssjLV">[<a href="#ref-NCcssjLV" role="doc-biblioref">260</a>]</span>).
-Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients <span class="citation" data-cites="15Yaf3fc8 1As9kWVvA FaGAJ7AI B3awlFvs">[<a href="#ref-15Yaf3fc8" role="doc-biblioref">1252</a>,<a href="#ref-1As9kWVvA" role="doc-biblioref">1253</a>,<a href="#ref-FaGAJ7AI" role="doc-biblioref">1254</a>,<a href="#ref-B3awlFvs" role="doc-biblioref">1255</a>]</span>.
-Although it is generally considered unethical to consider demographic factors such as age, sex, race, or ethnicity while making such decisions, and ideally this information would not be shared with triage teams tasked with allocating limited resources among patients <span class="citation" data-cites="2i1Y7SYn">[<a href="#ref-2i1Y7SYn" role="doc-biblioref">1256</a>]</span>, there are substantial concerns about implicit and explicit biases against older adults <span class="citation" data-cites="GTL02UT6">[<a href="#ref-GTL02UT6" role="doc-biblioref">1257</a>]</span>, premature infants <span class="citation" data-cites="KQfJ4llw">[<a href="#ref-KQfJ4llw" role="doc-biblioref">1258</a>]</span>, and people with disabilities or comorbidities <span class="citation" data-cites="K6yc6elC 1EaLRFk21 2i1Y7SYn">[<a href="#ref-2i1Y7SYn" role="doc-biblioref">1256</a>,<a href="#ref-K6yc6elC" role="doc-biblioref">1259</a>,<a href="#ref-1EaLRFk21" role="doc-biblioref">1260</a>]</span>.
-Because of the greater burden of chronic disease in populations subjected to systemic racism, algorithms intended to be blind to race and ethnicity could, in fact, reinforce systemic inequalities caused by structural racism <span class="citation" data-cites="cPsuWT7U 1D1FX4zQZ LrqhFVIz">[<a href="#ref-cPsuWT7U" role="doc-biblioref">1261</a>,<a href="#ref-1D1FX4zQZ" role="doc-biblioref">1262</a>,<a href="#ref-LrqhFVIz" role="doc-biblioref">1263</a>]</span>.
-Because of this inequality, it has been argued that groups facing health disparities should be prioritized by these algorithms <span class="citation" data-cites="PFHCN5ep">[<a href="#ref-PFHCN5ep" role="doc-biblioref">1264</a>]</span>.
-This approach would carry its own ethical concerns, including the fact that many resources that need to be distributed do not have well-established risks and benefits <span class="citation" data-cites="PFHCN5ep">[<a href="#ref-PFHCN5ep" role="doc-biblioref">1264</a>]</span>.</p>
-<p>As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest <span class="citation" data-cites="1ExRX1x4C">[<a href="#ref-1ExRX1x4C" role="doc-biblioref">1265</a>]</span>.
-Allocation of interventions that may reduce suffering, including palliative care, has become critically important <span class="citation" data-cites="1ExRX1x4C ztTunmqF">[<a href="#ref-1ExRX1x4C" role="doc-biblioref">1265</a>,<a href="#ref-ztTunmqF" role="doc-biblioref">1266</a>]</span>.
-The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources <span class="citation" data-cites="PFHCN5ep">[<a href="#ref-PFHCN5ep" role="doc-biblioref">1264</a>]</span>.
-For example, remdesivir, discussed above, is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead <span class="citation" data-cites="18et5lcBc 11gslRJJU">[<a href="#ref-18et5lcBc" role="doc-biblioref">1267</a>,<a href="#ref-11gslRJJU" role="doc-biblioref">1268</a>]</span>.
-Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them <span class="citation" data-cites="11gslRJJU">[<a href="#ref-11gslRJJU" role="doc-biblioref">1268</a>]</span>.
-Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial <span class="citation" data-cites="PFHCN5ep">[<a href="#ref-PFHCN5ep" role="doc-biblioref">1264</a>]</span>.
+Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients <span class="citation" data-cites="15Yaf3fc8 1As9kWVvA FaGAJ7AI B3awlFvs">[<a href="#ref-15Yaf3fc8" role="doc-biblioref">1250</a>,<a href="#ref-1As9kWVvA" role="doc-biblioref">1251</a>,<a href="#ref-FaGAJ7AI" role="doc-biblioref">1252</a>,<a href="#ref-B3awlFvs" role="doc-biblioref">1253</a>]</span>.
+Although it is generally considered unethical to consider demographic factors such as age, sex, race, or ethnicity while making such decisions, and ideally this information would not be shared with triage teams tasked with allocating limited resources among patients <span class="citation" data-cites="2i1Y7SYn">[<a href="#ref-2i1Y7SYn" role="doc-biblioref">1254</a>]</span>, there are substantial concerns about implicit and explicit biases against older adults <span class="citation" data-cites="GTL02UT6">[<a href="#ref-GTL02UT6" role="doc-biblioref">1255</a>]</span>, premature infants <span class="citation" data-cites="KQfJ4llw">[<a href="#ref-KQfJ4llw" role="doc-biblioref">1256</a>]</span>, and people with disabilities or comorbidities <span class="citation" data-cites="K6yc6elC 1EaLRFk21 2i1Y7SYn">[<a href="#ref-2i1Y7SYn" role="doc-biblioref">1254</a>,<a href="#ref-K6yc6elC" role="doc-biblioref">1257</a>,<a href="#ref-1EaLRFk21" role="doc-biblioref">1258</a>]</span>.
+Because of the greater burden of chronic disease in populations subjected to systemic racism, algorithms intended to be blind to race and ethnicity could, in fact, reinforce systemic inequalities caused by structural racism <span class="citation" data-cites="cPsuWT7U 1D1FX4zQZ LrqhFVIz">[<a href="#ref-cPsuWT7U" role="doc-biblioref">1259</a>,<a href="#ref-1D1FX4zQZ" role="doc-biblioref">1260</a>,<a href="#ref-LrqhFVIz" role="doc-biblioref">1261</a>]</span>.
+Because of this inequality, it has been argued that groups facing health disparities should be prioritized by these algorithms <span class="citation" data-cites="PFHCN5ep">[<a href="#ref-PFHCN5ep" role="doc-biblioref">1262</a>]</span>.
+This approach would carry its own ethical concerns, including the fact that many resources that need to be distributed do not have well-established risks and benefits <span class="citation" data-cites="PFHCN5ep">[<a href="#ref-PFHCN5ep" role="doc-biblioref">1262</a>]</span>.</p>
+<p>As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest <span class="citation" data-cites="1ExRX1x4C">[<a href="#ref-1ExRX1x4C" role="doc-biblioref">1263</a>]</span>.
+Allocation of interventions that may reduce suffering, including palliative care, has become critically important <span class="citation" data-cites="1ExRX1x4C ztTunmqF">[<a href="#ref-1ExRX1x4C" role="doc-biblioref">1263</a>,<a href="#ref-ztTunmqF" role="doc-biblioref">1264</a>]</span>.
+The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources <span class="citation" data-cites="PFHCN5ep">[<a href="#ref-PFHCN5ep" role="doc-biblioref">1262</a>]</span>.
+For example, remdesivir, discussed above, is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead <span class="citation" data-cites="18et5lcBc 11gslRJJU">[<a href="#ref-18et5lcBc" role="doc-biblioref">1265</a>,<a href="#ref-11gslRJJU" role="doc-biblioref">1266</a>]</span>.
+Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them <span class="citation" data-cites="11gslRJJU">[<a href="#ref-11gslRJJU" role="doc-biblioref">1266</a>]</span>.
+Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial <span class="citation" data-cites="PFHCN5ep">[<a href="#ref-PFHCN5ep" role="doc-biblioref">1262</a>]</span>.
 On the other hand, given that the drug is one of the most promising treatments available for many patients, using a framework that tacitly feeds into structural biases would also be unethical.
-At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that “prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status” <span class="citation" data-cites="ugEOYgfx">[<a href="#ref-ugEOYgfx" role="doc-biblioref">1269</a>]</span>.
-In many cases, experimental therapeutics are made available only through participation in clinical trials <span class="citation" data-cites="1A5E2TkBS">[<a href="#ref-1A5E2TkBS" role="doc-biblioref">1270</a>]</span>.
-However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment <span class="citation" data-cites="1A5E2TkBS">[<a href="#ref-1A5E2TkBS" role="doc-biblioref">1270</a>]</span>.
+At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that “prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status” <span class="citation" data-cites="ugEOYgfx">[<a href="#ref-ugEOYgfx" role="doc-biblioref">1267</a>]</span>.
+In many cases, experimental therapeutics are made available only through participation in clinical trials <span class="citation" data-cites="1A5E2TkBS">[<a href="#ref-1A5E2TkBS" role="doc-biblioref">1268</a>]</span>.
+However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment <span class="citation" data-cites="1A5E2TkBS">[<a href="#ref-1A5E2TkBS" role="doc-biblioref">1268</a>]</span>.
 As a result, the standard practice of requiring enrollment in a clinical trial in order to receive experimental treatment may also reinforce patterns established by systemic racism.
 <!--Risk of comorbid health conditions associated with more severe outcomes may be influenced by long-term damage caused by chronic stress related to traumatic social experiences [@doi:10.1007/s12170-013-0338-5], perhaps mediated by cardiovascular risk factors [@doi:10.1101/2020.05.10.20097253], although the effects of chronic stress have not yet been researched in the specific case of COVID-19 disparities.--></p>
 <h3 data-number="9.3.4" id="access-to-and-representation-in-clinical-trials"><span class="header-section-number">9.3.4</span> Access to and Representation in Clinical Trials</h3>
@@ -3953,55 +3953,55 @@ <h3 data-number="9.3.4" id="access-to-and-representation-in-clinical-trials"><sp
 The advantage to a patient of participation in a clinical trial is that they may receive an experimental treatment they would not have been able to access otherwise.
 The potential downsides of participation include that the efficacy and side effects of such treatments are often poorly characterized and that patients who enroll in clinical trials will in some cases run the risk of being assigned to a placebo condition where they do not receive the treatment but miss out on opportunities to receive other treatments.
 The benefits and burdens of clinical trials therefore need to be weighed carefully to ensure that they don’t reinforce existing health disparities.
-The WHO Director‐General Tedros Adhanom Ghebreyesus stated his condemnation of utilizing low and middle income countries as test subjects for clinical trials, yet having highly developed countries as the majority of clinical trial representation is also not the answer <span class="citation" data-cites="TFKtmAIg">[<a href="#ref-TFKtmAIg" role="doc-biblioref">1271</a>]</span>.
+The WHO Director‐General Tedros Adhanom Ghebreyesus stated his condemnation of utilizing low and middle income countries as test subjects for clinical trials, yet having highly developed countries as the majority of clinical trial representation is also not the answer <span class="citation" data-cites="TFKtmAIg">[<a href="#ref-TFKtmAIg" role="doc-biblioref">1269</a>]</span>.
 Figure <a href="#fig:ebm-map">7</a> showcases two choropleths detailing COVID-19 clinical trial recruitment by country.
 China, the United States, and France are among the countries with the most clinical trial recruiting for trials with single-country enrollment.
 Many countries have little to no clinical trial recruiting, with the continents of Africa and South America much less represented than Asia, Europe, and North America.
 Trials that recruit across multiple countries do appear to broaden geographic representation, but these trials seem to be heavily dominated by the United States and European Union.</p>
 <div id="fig:ebm-map" class="fignos">
 <figure>
-<img src="https://github.com/greenelab/covid19-review/raw/abc5bb11c3d4338884b50635074611ec7af13001/ebmdatalab/ebmdatalab-map.png" alt="" /><figcaption><span>Figure 7:</span> <strong>Geographic distribution of COVID-19 clinical trials.</strong>
+<img src="https://github.com/greenelab/covid19-review/raw/af928572d7bcb312c4caa2a6c95e286a10f6814a/ebmdatalab/ebmdatalab-map.png" alt="" /><figcaption><span>Figure 7:</span> <strong>Geographic distribution of COVID-19 clinical trials.</strong>
 The density of clinical trials is reported at the country level.
-As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker <span class="citation" data-cites="SSbnPnzT">[<a href="#ref-SSbnPnzT" role="doc-biblioref">413</a>]</span>, of which 3,706 are interventional.
+As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker <span class="citation" data-cites="SSbnPnzT">[<a href="#ref-SSbnPnzT" role="doc-biblioref">412</a>]</span>, of which 3,706 are interventional.
 The top figure demonstrates the density of interventional trials recruiting only from a singular country, while the bottom shows the distribution of recruitment for interventional trials that involve more than one country.</figcaption>
 </figure>
 </div>
 <p>A few different concerns arise from this skewed geographic representation in clinical trial recruitment.
 First, treatments such as remdesivir that are promising but primarily available to clinical trial participants are unlikely to be accessible by people in many countries.
 Second, it raises the concern that the findings of clinical trials will be based on participants from many of the wealthiest countries, which may lead to ambiguity in whether the findings can be extrapolated to COVID-19 patients elsewhere.
-Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., <span class="citation" data-cites="MYW3TeXJ">[<a href="#ref-MYW3TeXJ" role="doc-biblioref">1272</a>]</span>, yet data like that shown in Figure <a href="#fig:ebm-map">7</a> demonstrates that accessibility is likely to be a significant issue.
-Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes <span class="citation" data-cites="rh28K8GB">[<a href="#ref-rh28K8GB" role="doc-biblioref">1273</a>]</span>.
-Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll <span class="citation" data-cites="RZiEc6kh">[<a href="#ref-RZiEc6kh" role="doc-biblioref">1274</a>]</span>.
+Especially with the global nature of COVID-19, equitable access to therapeutics and vaccines has been a concern at the forefront of many discussions about policy (e.g., <span class="citation" data-cites="MYW3TeXJ">[<a href="#ref-MYW3TeXJ" role="doc-biblioref">1270</a>]</span>, yet data like that shown in Figure <a href="#fig:ebm-map">7</a> demonstrates that accessibility is likely to be a significant issue.
+Another concern with the heterogeneous international distribution of clinical trials is that the governments of countries leading these clinical trials might prioritize their own populations once vaccines are developed, causing unequal health outcomes <span class="citation" data-cites="rh28K8GB">[<a href="#ref-rh28K8GB" role="doc-biblioref">1271</a>]</span>.
+Additionally, even within a single state in the United States (Maryland), geography was found to influence the likelihood of being recruited into or enrolled in a clinical trial, with patients in under-served rural areas less likely to enroll <span class="citation" data-cites="RZiEc6kh">[<a href="#ref-RZiEc6kh" role="doc-biblioref">1272</a>]</span>.
 Thus, geography both on the global and local levels may influence when treatments and vaccines are available and who is able to access them.
-Efforts such as the African Union’s efforts to coordinate and promote vaccine development <span class="citation" data-cites="BLKtWt4w">[<a href="#ref-BLKtWt4w" role="doc-biblioref">1275</a>]</span> are therefore critical to promoting equity in the COVID-19 response.</p>
+Efforts such as the African Union’s efforts to coordinate and promote vaccine development <span class="citation" data-cites="BLKtWt4w">[<a href="#ref-BLKtWt4w" role="doc-biblioref">1273</a>]</span> are therefore critical to promoting equity in the COVID-19 response.</p>
 <p>Even when patients are located within the geographic recruitment area of clinical trials, however, there can still be demographic inequalities in enrollment.
-When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups <span class="citation" data-cites="FasLN7DR">[<a href="#ref-FasLN7DR" role="doc-biblioref">1276</a>]</span>.
-However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., <span class="citation" data-cites="14jpPBgHd GNMGw3Ff ZdYcndGw QNqutuqe">[<a href="#ref-14jpPBgHd" role="doc-biblioref">1277</a>,<a href="#ref-GNMGw3Ff" role="doc-biblioref">1278</a>,<a href="#ref-ZdYcndGw" role="doc-biblioref">1279</a>,<a href="#ref-QNqutuqe" role="doc-biblioref">1280</a>]</span>).
+When efforts are made to ensure equal opportunity to participate in clinical trials, there is no significant difference in participation among racial/ethnic groups <span class="citation" data-cites="FasLN7DR">[<a href="#ref-FasLN7DR" role="doc-biblioref">1274</a>]</span>.
+However, within the United States, real clinical trial recruitment numbers have indicated for many years that racial minorities, especially African-Americans, tend to be under-represented (e.g., <span class="citation" data-cites="14jpPBgHd GNMGw3Ff ZdYcndGw QNqutuqe">[<a href="#ref-14jpPBgHd" role="doc-biblioref">1275</a>,<a href="#ref-GNMGw3Ff" role="doc-biblioref">1276</a>,<a href="#ref-ZdYcndGw" role="doc-biblioref">1277</a>,<a href="#ref-QNqutuqe" role="doc-biblioref">1278</a>]</span>).
 This trend is especially concerning given the disproportionate impact of COVID-19 on African-Americans.
-Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients <span class="citation" data-cites="2DrMhVAo">[<a href="#ref-2DrMhVAo" role="doc-biblioref">1281</a>]</span>.</p>
+Early evidence suggests that the proportion of Black, Latinx, and Native American participants in clinical trials for drugs such as remdesivir is much lower than the representation of these groups among COVID-19 patients <span class="citation" data-cites="2DrMhVAo">[<a href="#ref-2DrMhVAo" role="doc-biblioref">1279</a>]</span>.</p>
 <p>One proposed explanation for differences among racial and ethnic groups in clinical trial enrollment refers to different experiences in healthcare settings.
-While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance <span class="citation" data-cites="FasLN7DR">[<a href="#ref-FasLN7DR" role="doc-biblioref">1276</a>]</span>, a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare.
-In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., <span class="citation" data-cites="M7sLngTJ">[<a href="#ref-M7sLngTJ" role="doc-biblioref">1282</a>]</span>).
+While some plausible reasons for the disparity in communication between physicians and patients could be a lack of awareness and education, mistrust in healthcare professionals, and a lack of health insurance <span class="citation" data-cites="FasLN7DR">[<a href="#ref-FasLN7DR" role="doc-biblioref">1274</a>]</span>, a major concern is that patients from certain racial and ethnic groups are marginalized even while seeking healthcare.
+In the United States, many patients experience “othering” from physicians and other medical professionals due to their race or other external characteristics such as gender (e.g., <span class="citation" data-cites="M7sLngTJ">[<a href="#ref-M7sLngTJ" role="doc-biblioref">1280</a>]</span>).
 Many studies have sought to characterize implicit biases in healthcare providers and whether they affect their perceptions or treatment of patients.
-A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed <span class="citation" data-cites="sDygnf7I">[<a href="#ref-sDygnf7I" role="doc-biblioref">1283</a>]</span>, with similar findings reported by a second systematic review <span class="citation" data-cites="upbPnFPI">[<a href="#ref-upbPnFPI" role="doc-biblioref">1284</a>]</span>.
-However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises <span class="citation" data-cites="sDygnf7I">[<a href="#ref-sDygnf7I" role="doc-biblioref">1283</a>]</span>, and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient <span class="citation" data-cites="AaFVjNFc">[<a href="#ref-AaFVjNFc" role="doc-biblioref">1285</a>]</span>.
-Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 <span class="citation" data-cites="smVwFlNn">[<a href="#ref-smVwFlNn" role="doc-biblioref">1286</a>]</span>.
+A systematic review that examined 37 such studies reported that most (31) identified racial and/or ethnic biases in healthcare providers in many different roles, although the evidence about whether these biases translated to different attitudes towards patients was mixed <span class="citation" data-cites="sDygnf7I">[<a href="#ref-sDygnf7I" role="doc-biblioref">1281</a>]</span>, with similar findings reported by a second systematic review <span class="citation" data-cites="upbPnFPI">[<a href="#ref-upbPnFPI" role="doc-biblioref">1282</a>]</span>.
+However, data about real-world patient outcomes are very limited, with most studies relying on clinical vignette-based exercises <span class="citation" data-cites="sDygnf7I">[<a href="#ref-sDygnf7I" role="doc-biblioref">1281</a>]</span>, and other analyses suggest that physician implicit bias could impact the patient’s perception of the negativity/positivity of the interaction regardless of the physician’s explicit behavior towards the patient <span class="citation" data-cites="AaFVjNFc">[<a href="#ref-AaFVjNFc" role="doc-biblioref">1283</a>]</span>.
+Because racism is a common factor in both, negative patient experiences with medical professionals are likely to compound other issues of systemic inequality, such as a lack of access to adequate care, a lack of insurance, or increased exposure to SARS-CoV-2 <span class="citation" data-cites="smVwFlNn">[<a href="#ref-smVwFlNn" role="doc-biblioref">1284</a>]</span>.
 Furthermore, the experience of being othered is not only expected to impact patients’ trust in and comfort with their provider, but also may directly impact whether or not the patient is offered the opportunity to participate in a clinical trial at all.
 Some studies suggest communication between physicians and patients impacts whether or not a physician offers a patient participation in a clinical trial.
-For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. <span class="citation" data-cites="FasLN7DR">[<a href="#ref-FasLN7DR" role="doc-biblioref">1276</a>]</span>.
+For example, researchers utilized a linguistic analysis to assess mean word count of phrases related to clinical trial enrollment, such as voluntary participation, clinical trial, etc. <span class="citation" data-cites="FasLN7DR">[<a href="#ref-FasLN7DR" role="doc-biblioref">1274</a>]</span>.
 The data indicated that the mean word count of the entire visit was 1.5 times more for white patients in comparison to Black patients.
-In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients <span class="citation" data-cites="FasLN7DR">[<a href="#ref-FasLN7DR" role="doc-biblioref">1276</a>]</span>.
+In addition, the greatest disparity between white and Black patients’ experience was the discussion of risks, with over 2 times as many risk-related words spoken with white patients than Black patients <span class="citation" data-cites="FasLN7DR">[<a href="#ref-FasLN7DR" role="doc-biblioref">1274</a>]</span>.
 The trends observed for other clinical trials raise the concern that COVID-19 clinical trial information may not be discussed as thoroughly or as often with Black patients compared to white patients.</p>
 <p>These discrepancies are especially concerning given that many COVID-19 treatments are being or are considered being made available to patients prior to FDA approval through Emergency Use Authorizations.
-In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway <span class="citation" data-cites="Vp7KObiA">[<a href="#ref-Vp7KObiA" role="doc-biblioref">1287</a>]</span>.
+In the past, African-Americans have been over-represented relative to national demographics in use of the FDA’s Exception From Informed Consent (EFIC) pathway <span class="citation" data-cites="Vp7KObiA">[<a href="#ref-Vp7KObiA" role="doc-biblioref">1285</a>]</span>.
 Through this pathway, people who are incapacitated can receive an experimental treatment even if they are not able to consent and there is not sufficient time to seek approval from an authorized representative.
-This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments <span class="citation" data-cites="JNha7DEl">[<a href="#ref-JNha7DEl" role="doc-biblioref">1288</a>]</span>.
+This pathway presents concerns, however, when it is considered in the context of a long history of systematic abuses in medical experimentation where informed consent was not obtained from people of color, such as the Tuskegee syphilis experiments <span class="citation" data-cites="JNha7DEl">[<a href="#ref-JNha7DEl" role="doc-biblioref">1286</a>]</span>.
 While the goal of EFIC approval is to provide treatment to patients who urgently need it, the combination of the ongoing legacy of racism in medicine renders this trend concerning.
-With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., <span class="citation" data-cites="i53Z5Ye8">[<a href="#ref-i53Z5Ye8" role="doc-biblioref">1289</a>]</span>), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized.
+With COVID-19, efforts to prioritize people who suffer from systemic racism are often designed with the goal of righting some of these inequalities (e.g., <span class="citation" data-cites="i53Z5Ye8">[<a href="#ref-i53Z5Ye8" role="doc-biblioref">1287</a>]</span>), but particular attention to informed consent will be imperative in ensuring these trials are ethical given that the benefits and risks of emerging treatments are still poorly characterized.
 Making a substantial effort to run inclusive clinical trials is also important because of the possibility that racism could impact how a patient responds to a treatment.
 For example, as discussed above, dexamethasone has been identified as a promising treatment for patients experiencing cytokine release syndrome, but the mechanism of action is tied to the stress response.
-A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug <span class="citation" data-cites="GP85Y1Jo">[<a href="#ref-GP85Y1Jo" role="doc-biblioref">1290</a>]</span>.
-In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids <span class="citation" data-cites="gkEMgdku">[<a href="#ref-gkEMgdku" role="doc-biblioref">1291</a>]</span> and glucocorticoid receptor resistance <span class="citation" data-cites="BlEZu684">[<a href="#ref-BlEZu684" role="doc-biblioref">1292</a>]</span>.
+A study from 2005 reported that Black asthma patients showed reduced responsiveness to dexamethasone in comparison to white patients and suggested Black patients might therefore require higher doses of the drug <span class="citation" data-cites="GP85Y1Jo">[<a href="#ref-GP85Y1Jo" role="doc-biblioref">1288</a>]</span>.
+In the context of chronic stress caused by systemic racism, this result is not surprising: chronic stress is associated with dysregulated production of glucocorticoids <span class="citation" data-cites="gkEMgdku">[<a href="#ref-gkEMgdku" role="doc-biblioref">1289</a>]</span> and glucocorticoid receptor resistance <span class="citation" data-cites="BlEZu684">[<a href="#ref-BlEZu684" role="doc-biblioref">1290</a>]</span>.
 However, it underscores the critical need for treatment guidelines to take into account differences in life experience, which would be facilitated by the recruitment of patients from a wide range of backgrounds.
 Attention to the social aspects of clinical trial enrollment must therefore be an essential component of the medical research community’s response to COVID-19.</p>
 <!--Table for future version: ### Indirect Effects of the Pandemic
@@ -4037,11 +4037,11 @@ <h1 data-number="10" id="discussion-3"><span class="header-section-number">10</s
 As of October 2020, a range of diagnostic tests have become available.
 One class of tests uses PCR (RT-PCR or qRT-PCR) to assess the presence of SARS-CoV-2 RNA, while another typically uses ELISA to test for the presence of antibodies to SARS-CoV-2.
 The former approach is useful for identifying active infections, while the latter measures hallmarks of the immune response and therefore can detect either active infections or immunity gained from prior infection.
-Combining these tests leads to extremely accurate detection of SARS-CoV-2 infection (98.6%), but when used alone, PCR-based tests are recommended before 5.5 days after the onset of the illness and antibody tests after 5.5 days <span class="citation" data-cites="CC4sPeuO">[<a href="#ref-CC4sPeuO" role="doc-biblioref">408</a>]</span>.
-Other strategies for testing can also influence the tests’ accuracy, such as the use of nasopharyngeal swabs versus BALF <span class="citation" data-cites="CC4sPeuO">[<a href="#ref-CC4sPeuO" role="doc-biblioref">408</a>]</span>, which allow for trade-offs between patient’s comfort and test sensitivity.
+Combining these tests leads to extremely accurate detection of SARS-CoV-2 infection (98.6%), but when used alone, PCR-based tests are recommended before 5.5 days after the onset of the illness and antibody tests after 5.5 days <span class="citation" data-cites="CC4sPeuO">[<a href="#ref-CC4sPeuO" role="doc-biblioref">407</a>]</span>.
+Other strategies for testing can also influence the tests’ accuracy, such as the use of nasopharyngeal swabs versus BALF <span class="citation" data-cites="CC4sPeuO">[<a href="#ref-CC4sPeuO" role="doc-biblioref">407</a>]</span>, which allow for trade-offs between patient’s comfort and test sensitivity.
 Additionally, technologies such as digital PCR may allow for scale-up in the throughput of diagnostic testing, facilitating widespread testing.
 One major question that remains is whether people who recover from SARS-CoV-2 develop sustained immunity, and over what period this immunity is expected to last.
-Some reports have suggested that some patients may develop COVID-19 reinfections (e.g., <span class="citation" data-cites="80JdM9px">[<a href="#ref-80JdM9px" role="doc-biblioref">392</a>]</span>), but the rates of reinfection are currently unknown.
+Some reports have suggested that some patients may develop COVID-19 reinfections (e.g., <span class="citation" data-cites="80JdM9px">[<a href="#ref-80JdM9px" role="doc-biblioref">391</a>]</span>), but the rates of reinfection are currently unknown.
 Serologic testing combined with PCR testing will be critical to confirming purported cases of reinfection and to identifying the duration over which immunity is retained and to understanding reinfection risks.</p>
 <p>One of the goals of characterizing the immune response is to identify strategies for the prophylactic enhancements of immunity.
 Though some concerns remain about the duration of sustained immunity for convalescents, vaccine development efforts are ongoing and show initial promising results.
@@ -4050,7 +4050,7 @@ <h1 data-number="10" id="discussion-3"><span class="header-section-number">10</s
 In the meantime, some advances have also been made in the treatment of patients with COVID-19.
 As cases have become better characterized, it has become evident that many patients experience an initial immune response to the virus that is typically characterized by fever, cough, dyspnea, and related symptoms.
 However, the most serious concern is cytokine release syndrome, when the body’s immune response becomes dysregulated, resulting in an extreme inflammatory response.
-The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation <span class="citation" data-cites="pzQoUwz3">[<a href="#ref-pzQoUwz3" role="doc-biblioref">554</a>]</span>.
+The RECOVERY trial, a large-scale, multi-arm trial enrolling about 15% of all COVID-19 patients in the United Kingdom, was the first to identify that the widely available steroid dexamethasone seems to be beneficial for patients suffering from this immune dysregulation <span class="citation" data-cites="pzQoUwz3">[<a href="#ref-pzQoUwz3" role="doc-biblioref">553</a>]</span>.
 Efforts to identify therapeutic treatments to treat patients early in the course of infection have been more ambiguous.
 Early interest in the drugs hydroxychloroquine and chloroquine yielded no promising results from studies with robust experimental designs.
 The experimental drug remdesivir, which was developed for Ebola, has received enough support from early analyses to receive FDA approval, but results have been mixed.
@@ -4060,38 +4060,38 @@ <h2 data-number="10.1" id="additional-therapeutics-of-interest"><span class="hea
 For example, the demonstrated benefit of dexamethasone and the ongoing potential of tocilizumab for treatment of COVID-19 suggests that other anti-inflammatory agents might also hold value for the treatment of COVID-19.
 Given that current evidence about treating COVID-19 with dexamethasone suggests that the need to curtail the cytokine storm inflammatory response to the virus can transcend the risks of immunosuppression, exploration of more anti-inflammatory agents may be warranted.
 While dexamethasone is considered widely available and generally affordable, the high costs of biologics such as tocilizumab therapy may present obstacles to wide-scale distribution of this drug if it proves of value.
-At the doses used for rheumatoid arthritis patients, the cost for tocilizumab ranges from $179.20 to $896 per dose for the IV form and $355 for the pre-filled syringe <span class="citation" data-cites="7fZ9eyMk">[<a href="#ref-7fZ9eyMk" role="doc-biblioref">636</a>]</span>.
-There are several anti-inflammatory agents used for the treatment of autoimmune diseases that may also be able to counter the effects of the cytokine storm induced by the virus, some of which, such as cyclosporine, are likely to be more cost-effective and readily available than biologics <span class="citation" data-cites="trWLoLFz">[<a href="#ref-trWLoLFz" role="doc-biblioref">637</a>]</span>.
+At the doses used for rheumatoid arthritis patients, the cost for tocilizumab ranges from $179.20 to $896 per dose for the IV form and $355 for the pre-filled syringe <span class="citation" data-cites="7fZ9eyMk">[<a href="#ref-7fZ9eyMk" role="doc-biblioref">635</a>]</span>.
+There are several anti-inflammatory agents used for the treatment of autoimmune diseases that may also be able to counter the effects of the cytokine storm induced by the virus, some of which, such as cyclosporine, are likely to be more cost-effective and readily available than biologics <span class="citation" data-cites="trWLoLFz">[<a href="#ref-trWLoLFz" role="doc-biblioref">636</a>]</span>.
 While tocilizumab targets IL-6, several other inflammatory markers could be potential targets, including TNF-alpha.
-Inhibition of TNF-alpha by an inhibitor such as Etanercept has been previously suggested for treatment of SARS-CoV-1 <span class="citation" data-cites="LDQlolY3">[<a href="#ref-LDQlolY3" role="doc-biblioref">638</a>]</span> and may be relevant for SARS-CoV-2 as well.
-Another anti-IL-6 antibody, sarilumab, is also being investigated <span class="citation" data-cites="4DAIEbQF amy3rDsj">[<a href="#ref-4DAIEbQF" role="doc-biblioref">639</a>,<a href="#ref-amy3rDsj" role="doc-biblioref">640</a>]</span>.
-Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections <span class="citation" data-cites="WF7ymA4m">[<a href="#ref-WF7ymA4m" role="doc-biblioref">641</a>]</span>.
-Baricitinib in particular may be able to reduce the ability of SARS-CoV-2 to infect lung cells <span class="citation" data-cites="uCns3aFw">[<a href="#ref-uCns3aFw" role="doc-biblioref">642</a>]</span>.
-Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy <span class="citation" data-cites="jKRGxazA JCMhG5r9">[<a href="#ref-jKRGxazA" role="doc-biblioref">643</a>,<a href="#ref-JCMhG5r9" role="doc-biblioref">644</a>]</span>.
+Inhibition of TNF-alpha by an inhibitor such as Etanercept has been previously suggested for treatment of SARS-CoV-1 <span class="citation" data-cites="LDQlolY3">[<a href="#ref-LDQlolY3" role="doc-biblioref">637</a>]</span> and may be relevant for SARS-CoV-2 as well.
+Another anti-IL-6 antibody, sarilumab, is also being investigated <span class="citation" data-cites="4DAIEbQF amy3rDsj">[<a href="#ref-4DAIEbQF" role="doc-biblioref">638</a>,<a href="#ref-amy3rDsj" role="doc-biblioref">639</a>]</span>.
+Baricitinib and other small molecule inhibitors of the Janus-activated kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections <span class="citation" data-cites="WF7ymA4m">[<a href="#ref-WF7ymA4m" role="doc-biblioref">640</a>]</span>.
+Baricitinib in particular may be able to reduce the ability of SARS-CoV-2 to infect lung cells <span class="citation" data-cites="uCns3aFw">[<a href="#ref-uCns3aFw" role="doc-biblioref">641</a>]</span>.
+Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy <span class="citation" data-cites="jKRGxazA JCMhG5r9">[<a href="#ref-jKRGxazA" role="doc-biblioref">642</a>,<a href="#ref-JCMhG5r9" role="doc-biblioref">643</a>]</span>.
 Identification and targeting of further inflammatory markers that are relevant in SARS-CoV-2 infection may be of value for curtailing the inflammatory response and lung damage.</p>
 <p>In addition to immunosuppressive treatments that are most beneficial late in disease progression, much research is focused on identifying treatments would be likely to benefit early-stage patients.
 For example, although studies of hydroxychloroquine have not supported the early theory-driven interest in this antiviral treatment, alternative compounds with related mechanisms may still have potential.
-Hydroxyferroquine derivatives of HCQ have been described as a class of bioorganometallic compounds that exert antiviral effects with some selectivity for SARS-CoV-1 <em>in vitro</em> <span class="citation" data-cites="Cd5uMaAr">[<a href="#ref-Cd5uMaAr" role="doc-biblioref">645</a>]</span>.
+Hydroxyferroquine derivatives of HCQ have been described as a class of bioorganometallic compounds that exert antiviral effects with some selectivity for SARS-CoV-1 <em>in vitro</em> <span class="citation" data-cites="Cd5uMaAr">[<a href="#ref-Cd5uMaAr" role="doc-biblioref">644</a>]</span>.
 Future work could explore whether such compounds exert antiviral effects against SARS-CoV-2 and whether they would be safer for use in COVID-19.
 Another potential approach is the development of antivirals, which could be broad-spectrum, specific to coronaviruses, or targeted to SARS-CoV-2.
 Development of new antivirals is complicated by the fact that none have yet been approved for human coronaviruses.
 Intriguing new options are emerging, however.
-Beta-D-N4-hydroxycytidine (NHC) is an orally bioavailable ribonucleotide analog showing broad-spectrum activity against RNA viruses, which may inhibit SARS-CoV-2 replication <em>in vitro</em> and <em>in vivo</em> in mouse models of HCoVs <span class="citation" data-cites="TZleuwHX">[<a href="#ref-TZleuwHX" role="doc-biblioref">646</a>]</span>.
+Beta-D-N4-hydroxycytidine (NHC) is an orally bioavailable ribonucleotide analog showing broad-spectrum activity against RNA viruses, which may inhibit SARS-CoV-2 replication <em>in vitro</em> and <em>in vivo</em> in mouse models of HCoVs <span class="citation" data-cites="TZleuwHX">[<a href="#ref-TZleuwHX" role="doc-biblioref">645</a>]</span>.
 A range of other antivirals are also in development.
 Development of antivirals will be further facilitated as research reveals more information about the interaction of SARS-CoV-2 with the host cell and host cell genome, mechanisms of viral replication, mechanisms of viral assembly, and mechanisms of viral release to other cells; this can allow researchers to target specific stages and structures of the viral life cycle.
 Many researchers have also focused their attention to the potential use of dietary supplements and nutraceuticals.
-Indeed, there has been recent interest for the potential use of vitamin D as a prophylactic and therapeutic agent against COVID-19 as several observational studies have linked low vitamin D status to its incidence <span class="citation" data-cites="LpqYmd4C 18O6t6Jo">[<a href="#ref-LpqYmd4C" role="doc-biblioref">1040</a>,<a href="#ref-18O6t6Jo" role="doc-biblioref">1048</a>]</span>.
+Indeed, there has been recent interest for the potential use of vitamin D as a prophylactic and therapeutic agent against COVID-19 as several observational studies have linked low vitamin D status to its incidence <span class="citation" data-cites="LpqYmd4C 18O6t6Jo">[<a href="#ref-LpqYmd4C" role="doc-biblioref">1038</a>,<a href="#ref-18O6t6Jo" role="doc-biblioref">1046</a>]</span>.
 These associations have yet to be confirmed and rigorous trials are required before considering supplementation recommendations.
-However, the nutritional status and general health of a patient can affect their outcomes in various diseases, thus it would be pertinent to advise people to follow a healthy diet and life style to the best of their ability to prevent nutrient deficiencies and insufficiencies and to maintain a healthy immune system <span class="citation" data-cites="Hd5V5Usd">[<a href="#ref-Hd5V5Usd" role="doc-biblioref">914</a>]</span>.
+However, the nutritional status and general health of a patient can affect their outcomes in various diseases, thus it would be pertinent to advise people to follow a healthy diet and life style to the best of their ability to prevent nutrient deficiencies and insufficiencies and to maintain a healthy immune system <span class="citation" data-cites="Hd5V5Usd">[<a href="#ref-Hd5V5Usd" role="doc-biblioref">912</a>]</span>.
 Finally, antibodies against viruses, also known as antiviral monoclonal antibodies, could be an alternative as well and are described in detail in an above section.
-The goal of antiviral antibodies is to neutralize viruses through either cell-killing activity or blocking of viral replication <span class="citation" data-cites="1FTnvyZlf">[<a href="#ref-1FTnvyZlf" role="doc-biblioref">647</a>]</span>.
+The goal of antiviral antibodies is to neutralize viruses through either cell-killing activity or blocking of viral replication <span class="citation" data-cites="1FTnvyZlf">[<a href="#ref-1FTnvyZlf" role="doc-biblioref">646</a>]</span>.
 They may also engage the host immune response, encouraging the immune system to hone in on the virus.
 Given the cytokine storm that results from immune system activation in response to the virus, which has been implicated in worsening of the disease, a neutralizing antibody (nAb) may be preferable.
 Upcoming work may explore the specificity of nAbs for their target, mechanisms by which the nAbs impede the virus, and improvements to antibody structure that may enhance the ability of the antibody to block viral activity.</p>
 <p>Some research is also investigating potential therapeutics and prophylactics that would interact with components of the innate immune response.
 For example, there are a variety of TLRs, PRRs that recognize PAMPs and DAMPs.
 TLRs form a part of innate immune recognition and can more generally contribute to promoting both innate and adaptive responses <span class="citation" data-cites="o6BQnEt7">[<a href="#ref-o6BQnEt7" role="doc-biblioref">144</a>]</span>.
-In mouse models, poly(I:C) and CpG, which are agonists of toll-like receptors TLR3 and TLR9, respectively, showed protective effects when administered prior to SARS-CoV-1 infection <span class="citation" data-cites="Ull2rQ5L">[<a href="#ref-Ull2rQ5L" role="doc-biblioref">648</a>]</span>.
+In mouse models, poly(I:C) and CpG, which are agonists of toll-like receptors TLR3 and TLR9, respectively, showed protective effects when administered prior to SARS-CoV-1 infection <span class="citation" data-cites="Ull2rQ5L">[<a href="#ref-Ull2rQ5L" role="doc-biblioref">647</a>]</span>.
 Therefore, TLR agonists hold some potential for broad-spectrum prophylaxis.</p>
 <p>Given that a large number of clinical trials are currently in progress, more information about the potential of these and other therapeutics should become available over time.
 This information, combined with advances in understanding the molecular structure and viral pathogenesis of SARS-CoV-2, may lead to a more complete understanding of how the virus affects the human host and what strategies can improve outcomes.
@@ -4100,48 +4100,81 @@ <h2 data-number="10.1" id="additional-therapeutics-of-interest"><span class="hea
 However, in the long-term, new drugs specific for treatment of COVID-19 may also enter development.
 Development of novel drugs is likely to be guided by what is known about the pathogenesis and molecular structure of SARS-CoV-2.
 For example, understanding the various structural components of SARS-CoV-2 may allow for the development of small molecule inhibitors of those components.
-Currently, crystal structures of the SARS-CoV-2 main protease have recently been resolved <span class="citation" data-cites="4Sja6dIz AJLaaguT">[<a href="#ref-4Sja6dIz" role="doc-biblioref">467</a>,<a href="#ref-AJLaaguT" role="doc-biblioref">649</a>]</span>, and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">467</a>]</span>.
+Currently, crystal structures of the SARS-CoV-2 main protease have recently been resolved <span class="citation" data-cites="4Sja6dIz AJLaaguT">[<a href="#ref-4Sja6dIz" role="doc-biblioref">466</a>,<a href="#ref-AJLaaguT" role="doc-biblioref">648</a>]</span>, and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits <span class="citation" data-cites="4Sja6dIz">[<a href="#ref-4Sja6dIz" role="doc-biblioref">466</a>]</span>.
 Much work remains to be done to determine further crystal structures of other viral components, understand the relative utility of targeting different viral components, perform additional small molecule inhibitor screens, and determine the safety and efficacy of the potential inhibitors.
 While still nascent, work in this area is promising.
 Over the longer term, this approach and others may lead to the development of novel therapeutics specifically for COVID-19 and SARS-CoV-2.</p>
-<h1 data-number="11" id="application-of-an-open-publishing-framework-to-an-emerging-public-health-crisis"><span class="header-section-number">11</span> Application of an Open Publishing Framework to an Emerging Public health Crisis</h1>
-<h2 data-number="11.1" id="abstract-7"><span class="header-section-number">11.1</span> Abstract</h2>
-<h2 data-number="11.2" id="introduction-7"><span class="header-section-number">11.2</span> Introduction</h2>
-<p>As international attention remains focused on the ongoing public health crisis, the scientific community has responded by mobilizing resources and turning much of its attention to the virus and disease.
-This rapid influx of information is disseminated by traditional publishing mechanisms, preprint servers, and press releases, which provide a venue for scientists to release findings without undergoing the formal publication process.
-While having information available is valuable to efforts to understand and combat COVID-19, many contributions come from researchers across a wide range of fields who have varying degrees of experience working on coronaviruses and related topics.
-The volume of information available, much of which has not gone through rigorous peer review, presents a significant challenge to individual efforts to keep abreast of the state of COVID-19 research <span class="citation" data-cites="1HZeeO4Cs">[<a href="#ref-1HZeeO4Cs" role="doc-biblioref">8</a>]</span>.
-However, research on these topics is proceeding so rapidly that any static review is likely to quickly become dated.
-Our goal as a community is to consolidate information about the virus in the context of related viruses and to synthesize rapidly emerging literature centered on the diagnosis and treatment of COVID-19.
-We used an open publishing framework, Manubot <span class="citation" data-cites="YuJbg3zO">[<a href="#ref-YuJbg3zO" role="doc-biblioref">9</a>]</span>, to manage hundreds of contributions from the community to create a living, scholarly document.
-We designed software to generate figures that automatically update using external data sources. <!-- TODO: replace figure reference with manuscript reference or reference figure conditionally based on template variable [, such as Figure @fig:csse-deaths,] -->
-Our primary goal is to sort and distill informative content out of the overwhelming flood of information <span class="citation" data-cites="1HZeeO4Cs">[<a href="#ref-1HZeeO4Cs" role="doc-biblioref">8</a>]</span> and help the broader scientific community become more conversant on this critical subject.
-Thus, our approach has been to develop a real-time, collaborative effort that welcomes submissions from scientists worldwide into this ongoing effort.
-This document represents the first snapshot, which aims to reflect the state of the field as of October, 2020.
-We plan to refine and expand this document until technologies to mitigate the pandemic are widely available.</p>
-<p>In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews <span class="citation" data-cites="PZMP42Ak heDA5StF">[<a href="#ref-PZMP42Ak" role="doc-biblioref">1293</a>,<a href="#ref-heDA5StF" role="doc-biblioref">1294</a>]</span>.
-Contributors were recruited by word of mouth and on Twitter.
-Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine <span class="citation" data-cites="cYo4O2qX YZ4cHNuH">[<a href="#ref-cYo4O2qX" role="doc-biblioref">1295</a>,<a href="#ref-YZ4cHNuH" role="doc-biblioref">1296</a>]</span>, and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program <span class="citation" data-cites="DGTDsJZy">[<a href="#ref-DGTDsJZy" role="doc-biblioref">1297</a>]</span>.
-The project was managed through GitHub <span class="citation" data-cites="11MwmdOKi">[<a href="#ref-11MwmdOKi" role="doc-biblioref">1298</a>]</span> using Manubot <span class="citation" data-cites="YuJbg3zO">[<a href="#ref-YuJbg3zO" role="doc-biblioref">9</a>]</span> to continuously generate a version of the manuscript online <span class="citation" data-cites="yTsmmAYC">[<a href="#ref-yTsmmAYC" role="doc-biblioref">1299</a>]</span>.
-Contributors developed text that was proposed through GitHub’s pull request system and then reviewed and approved by at least one other author.
-While this document reflects the current version of record, the online version will continue to be developed as information about the pandemic emerges.
-Below, we will describe the processes used to synthesize the literature.</p>
-<h2 data-number="11.3" id="technical-infrastructure"><span class="header-section-number">11.3</span> Technical Infrastructure</h2>
-<h3 data-number="11.3.1" id="collaborative-writing-and-manuscript-generation"><span class="header-section-number">11.3.1</span> Collaborative Writing and Manuscript Generation</h3>
-<p>Manubot <span class="citation" data-cites="YuJbg3zO">[<a href="#ref-YuJbg3zO" role="doc-biblioref">9</a>]</span> is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
-Here, Manubot was used to generate a manuscript from text maintained using GitHub, a popular, online version control interface.
-The GitHub implementation allowed users to contribute either using git on the command line or using the GitHub user interface, and we developed documentation for users with less experience with this platform.
-Manubot also provides a functionality to create a bibliography using digital object identifiers (DOIs), website URLs, or other identifiers such as PubMed identifiers and arXiv IDs.
-Due to the needs of this project, project contributors also implemented new features in Manubot and <a href="https://www.zotero.org/">Zotero</a>, which Manubot uses to extract metadata for some types of citations.
-These features support directly citing clinical trial identifiers such as <code>clinicaltrials:NCT04292899</code> <span class="citation" data-cites="yTCAmOyt">[<a href="#ref-yTCAmOyt" role="doc-biblioref">441</a>]</span> and generating the complete review manuscript along with the individual manuscripts reviewing specific topics. <!-- TODO: reference individual manuscripts -->
-Finally, Manubot and GitHub Actions continuous integration allowed for scripted updates to be run each time the manuscript was generated.
-These scripts were used to check that the manuscript was built correctly, run spellchecking, and cross-reference the manuscripts cited in this review, summarized in Appendix A, and discussed in the project’s issues and pull requests.</p>
-<h3 data-number="11.3.2" id="data-analysis-and-visualization"><span class="header-section-number">11.3.2</span> Data Analysis and Visualization</h3>
-<p>The combination of Manubot and GitHub Actions also made it possible to dynamically update information such as statistics and visualizations in the manuscript.
-Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University <span class="citation" data-cites="MrwDDw9R">[<a href="#ref-MrwDDw9R" role="doc-biblioref">410</a>]</span> were read using a Python script. <!-- TODO: replace figure reference with manuscript reference or reference figure conditionally based on template variable [to generate Figure @fig:csse-deaths.] -->
-Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker <span class="citation" data-cites="SSbnPnzT">[<a href="#ref-SSbnPnzT" role="doc-biblioref">413</a>]</span>. <!-- TODO: replace figure reference with manuscript reference or reference figure conditionally based on template variable [Figure @fig:ebm-trials] -->
-In both cases, frequency data were plotted using Matplotlib <span class="citation" data-cites="1026Gxdsi">[<a href="#ref-1026Gxdsi" role="doc-biblioref">1300</a>]</span> in Python.
-The figure showing the geographic distribution of COVID-19 clinical trials was generated using the countries associated with the trials listed in the COVID-19 TrialsTracker, converting the country names to 3-letter ISO codes using pycountry or manual adjustment when necessary, and visualizing the geographic distribution of trial recruitment using geopandas. <!-- TODO: replace figure reference with manuscript reference or reference figure conditionally based on template variable [Figure @fig:ebm-map] --></p>
+<h1 data-number="11" id="an-open-publishing-response-to-the-covid-19-infodemic"><span class="header-section-number">11</span> An Open-Publishing Response to the COVID-19 Infodemic</h1>
+<h2 data-number="11.1" id="abstract-7"><span class="header-section-number">11.1</span> ABSTRACT</h2>
+<p>In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews <span class="citation" data-cites="PZMP42Ak heDA5StF">[<a href="#ref-PZMP42Ak" role="doc-biblioref">1291</a>,<a href="#ref-heDA5StF" role="doc-biblioref">1292</a>]</span>.</p>
+<h2 data-number="11.2" id="ccs-concepts"><span class="header-section-number">11.2</span> CCS CONCEPTS</h2>
+<!--To Do: @mprobson, do you want to take the lead on this?-->
+<h2 data-number="11.3" id="keywords"><span class="header-section-number">11.3</span> KEYWORDS</h2>
+<h2 data-number="11.4" id="introduction-7"><span class="header-section-number">11.4</span> INTRODUCTION</h2>
+<p>Coronavirus Disease 2019 (COVID-19) has shaped the years 2020 and 2021 by causing a world-wide public health crisis.
+The scientific community has responded by turning significant attention and resources towards COVID-19 and the associated virus, SARS-CoV-2.
+The result has been the rapid release of data, results, and publications related to COVID-19 at a scale never previously seen.
+Over 20,000 articles about COVID-19 were released in the first 4 months of the pandemic <span class="citation" data-cites="7ub6VM4Z">[<a href="#ref-7ub6VM4Z" role="doc-biblioref">1293</a>]</span>.
+The velocity and volume of information being released led to the pandemic being termed as an “infodemic” as well <span class="citation" data-cites="7ub6VM4Z nnfOazAC">[<a href="#ref-7ub6VM4Z" role="doc-biblioref">1293</a>,<a href="#ref-nnfOazAC" role="doc-biblioref">1294</a>]</span>.
+While this influx of information is likely evidence of important work towards understanding the virus and the disease, there are also downsides to the availability of too much information.
+The potential for “excessive publication” has been identified as an issue for over forty years, and was one concern about the move towards electronic, rather than print, publishing at the turn of the millennium <span class="citation" data-cites="DfSr1Ohc">[<a href="#ref-DfSr1Ohc" role="doc-biblioref">1295</a>]</span>.
+<!--To Do: Flesh out above paragraph--></p>
+<!--To Do: Insert CORD-19 data viz here, with breakdown by preprint server versus traditional journal? I think this will really help illustrate the various problems outlined in the intro-->
+<!--To Do: Possible viz of change in clinical trials as well?-->
+<!-- To Do: This is just an outline, formalize this paragraph with citations etc-->
+<p>While some of this information has been disseminated by traditional publishing mechanisms, in other cases, it is made public through preprint servers or even press releases.
+Preprints provide a venue for scientists to release findings rapidly, but have both the advantage and disadvantage of making research available before it has undergone the peer review process.
+Media outlets don’t always report on this accurately.
+Additionally, many papers are being retracted.
+These include both preprints and papers that are published in more traditional venues.
+The large number of retractions may also be influenced by the fact that the time from submission to peer review for papers related to COVID-19 is very low.</p>
+<p>The rate of this proliferation also presents challenges to efforts to summarize and synthesize existing literature, which are necessary given the volume.
+A number of groups have sought to track and review COVID-19 preprints<!--To Do: add refrences-->.
+However, any static review is likely to quickly become dated as new research is released or existing research is retracted or superseded, and the explosive rate of publication made localized efforts to curate new publications increasingly difficult.
+Additionally, the complex nature of COVID-19 means that significant advantages can be gained from examining the virus and disease in a multidisciplinary context.
+Therefore, the COVID-19 publishing climate presented a challenge where curation of the literature by a diverse group of experts in a format that could respond quickly to high-volume, high-velocity information was desirable.</p>
+<p>Recent advances in open publishing have created an infrastructure that facilitates distributed, version-controlled collaboration on manuscripts <span class="citation" data-cites="YuJbg3zO">[<a href="#ref-YuJbg3zO" role="doc-biblioref">9</a>]</span>.<!--To Do: possibly cite some other efforts here-->
+Manubot <span class="citation" data-cites="YuJbg3zO">[<a href="#ref-YuJbg3zO" role="doc-biblioref">9</a>]</span> is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
+With Manubot, manuscripts are managed and maintained using GitHub, a popular, online version control interface that also provides the infrastructure via continuous integration (CI) to incorporate code into the manuscript building process to allow, for example, figures to be continuously updated based on an external data set.
+This open-publishing platform has been used to develop large-scale collaborative efforts such as <!--To Do: brief summary of deep review and one other use case-->.
+However, although synthesis and discussion of the emerging literature by biomedical scientists and clinicians would be expected to provide novel insights into how various areas of COVID-19 research intersect, such tools are not typically associated with biomedical research and the reliance on git can present a significant technical barrier to entry for biomedical scientists.
+The problem of synthesizing the COVID-19 literature lends itself well to a crowd-sourced approach to writing through open collaboration, but in biology, such efforts often rely on WYSIWYG tools such as Google Docs despite the significant limitations of such approaches.<!--To Do: recheck what the Manubot paper says about this and possibly pull some other refs-->
+Therefore, in addition to the unprecedented release of information, COVID-19 presents a unique challenge because most subject matter experts have limited technical training.</p>
+<p>Here, we describe efforts to adapt Manubot to handle the extreme case of the COVID-19 infodemic, with the objective of extending simply reviewing preprints to develop a centralized platform for summarizing and synthesizing a massive amount of preprints, news stories, journal publications, and data.
+Unlike prior collaborations built on Manubot, here most contributors came from a traditional biological or medical background.
+The members of the COVID-19 Review Consortium worked to consolidate information about the virus in the context of related viruses and to synthesize rapidly emerging literature centered on the diagnosis and treatment of COVID-19.
+Manubot provided the infrastructure to manage contributions from the community and create a living, scholarly document that integrated data from multiple sources to respond to the COVID-19 crisis in real time and a back-end that allowed biomedical scientists to sort and distill informative content out of the overwhelming flood of information <span class="citation" data-cites="1HZeeO4Cs">[<a href="#ref-1HZeeO4Cs" role="doc-biblioref">8</a>]</span> in order to provide a resource that would be useful to the broader scientific community.
+This case study demonstrates the value of open collaborative writing tools such as Manubot to emerging challenges and the flexibility of Manubot to be adapted to problems unique to a range of fields.
+By recording the evolution of information over time and assembling a resource that auto-updated in response to the evolving crisis, it revealed the particular value that Manubot holds for managing a rapid changes in scientific thought.</p>
+<h2 data-number="11.5" id="methods"><span class="header-section-number">11.5</span> METHODS</h2>
+<h3 data-number="11.5.1" id="contributor-recruitment"><span class="header-section-number">11.5.1</span> Contributor Recruitment</h3>
+<p>One of the primary goals of this project was to develop Manubot as a platform accessible to researchers with limited computational training, as is common in biology and medicine.<!--To Do: Halie can potentially adapt sources for this from her draft faculty apps-->
+Given the limitations imposed upon scientists by the COVID-19 pandemic and social distancing measures that had most scientists (including students) working from home for much of 2020, community building across disciplines and across career stages was a priority of the project.
+The current project was managed through GitHub <span class="citation" data-cites="11MwmdOKi">[<a href="#ref-11MwmdOKi" role="doc-biblioref">1296</a>]</span> using Manubot <span class="citation" data-cites="YuJbg3zO">[<a href="#ref-YuJbg3zO" role="doc-biblioref">9</a>]</span> to continuously generate a version of the manuscript online <span class="citation" data-cites="yTsmmAYC">[<a href="#ref-yTsmmAYC" role="doc-biblioref">1297</a>]</span>.
+Contributors were recruited by word of mouth and on Twitter, and we sought out opportunities to integrate existing efforts to train early-career researchers (ECRs).
+Few researchers in biological and medical fields are trained in version control tools such as git <!--To Do: Find some sort of reference for this, software carpentry? Pull from citations to 10.1371/journal.pcbi.1004668
+--></p>
+<p>In order to make the project accessible to individuals from a number of backgrounds, we developed resources explaining how to use GitHub’s web interface to develop and edit text and interact with Manubot for individuals with no prior experience working with git or other version control platforms.
+<!--To Do: elaborate on resource development--></p>
+<p>Interested parties were encouraged to contribute in a number of ways.
+One option was to submit articles of interest as issues in the GitHub repository.
+Articles were classified as <em>diagnostic</em>, <em>therapeutic</em>, or <em>other</em>, and a template was developed to guide the review of papers and preprints in each category.
+Following a framework often used for assessing medical literature, the review consisted of examining methods used in each relevant article, assignment (whether the study was observational or randomized), assessment, results, interpretation, and how well the study extrapolates <span class="citation" data-cites="17OQtAY4l">[<a href="#ref-17OQtAY4l" role="doc-biblioref">1298</a>]</span>.
+For examples of each template, please see Appendices B-D.
+Another option was to contribute or edit text using GitHub’s pull request system.
+Each pull request was reviewed and approved by at least one other author.
+Manubot also provides a functionality to create a bibliography using digital object identifiers (DOIs), website URLs, or other identifiers such as PubMed identifiers and arXiv IDs.</p>
+<h3 data-number="11.5.2" id="applying-manubots-existing-capabilities-to-the-challenges-of-covid-19"><span class="header-section-number">11.5.2</span> Applying Manubot’s Existing Capabilities to the Challenges of COVID-19</h3>
+<p>Because of the ever-evolving nature of the COVID-19 crisis, many of the figures and text proposed by subject matter contributors would have quickly become outdated.
+To address this concern, Manubot and GitHub’s continuous integration features were used to create figures and text that could respond to changes in the COVID-19 pandemic over time.
+The combination of Manubot and GitHub Actions also made it possible to dynamically update information such as statistics and visualizations in the manuscript.
+When scientific writers added text that was current only as of a given date, publicly available data sources were identified whenever possible to allow the information to pulled directly into the manuscript in order to keep it up to date.<!--To Do: Add quoted examples-->
+Data was pulled from a number of sources.
+Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University <span class="citation" data-cites="MrwDDw9R">[<a href="#ref-MrwDDw9R" role="doc-biblioref">409</a>]</span> were read using a Python script. <!-- To Do: replace figure reference with manuscript reference or reference figure conditionally based on template variable [to generate Figure @fig:csse-deaths.] -->
+Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker <span class="citation" data-cites="SSbnPnzT">[<a href="#ref-SSbnPnzT" role="doc-biblioref">412</a>]</span>. <!-- TODO: replace figure reference with manuscript reference or reference figure conditionally based on template variable [Figure @fig:ebm-trials] -->
+In both cases, frequency data were plotted using Matplotlib <span class="citation" data-cites="1026Gxdsi">[<a href="#ref-1026Gxdsi" role="doc-biblioref">1299</a>]</span> in Python.
+The figure showing the geographic distribution of COVID-19 clinical trials was generated using the countries associated with the trials listed in the COVID-19 TrialsTracker, converting the country names to 3-letter ISO codes using pycountry or manual adjustment when necessary, and visualizing the geographic distribution of trial recruitment using geopandas. <!-- TODO: replace figure reference with manuscript reference or reference figure conditionally based on template variable [Figure @fig:ebm-map] -->
+<!--To Do: Update with Vaccines--></p>
 <p>GitHub Actions runs a nightly workflow to update these external data and regenerate the statistics and figures for the manuscript.
 The workflow uses the GitHub API to detect and save the latest commit of the external data sources, which are both GitHub repositories.
 It then downloads versioned data from that snapshot of the external repositories and runs bash and Python scripts to calculate the desired statistics and produce the summary figures.
@@ -4150,80 +4183,61 @@ <h3 data-number="11.3.2" id="data-analysis-and-visualization"><span class="heade
 The template variables also include versioned URLs to the dynamically updated figures.
 The JSON files and figures are stored in the <code>external-resources</code> branch of the manuscript’s GitHub repository, which acts as versioned storage.
 The GitHub Actions workflow automatically adds and commits the new JSON files and figures to the <code>external-resources</code> branch every time it runs, and Manubot uses the latest version of these resources when it builds the manuscript.</p>
+<h3 data-number="11.5.3" id="updating-to-manubot-in-response-to-project-demands"><span class="header-section-number">11.5.3</span> Updating to Manubot in Response to Project Demands</h3>
+<p>Due to the needs of this project, project contributors also implemented new features in Manubot.
+<!-- To Do: Detailed description of Ryan's work making it possible to cite clinical trial identifiers-->
+Manubot uses Zotero <span class="citation" data-cites="snhvVGmP">[<a href="#ref-snhvVGmP" role="doc-biblioref">1300</a>]</span> to extract metadata for some types of citations.
+These features support directly citing clinical trial identifiers such as <code>clinicaltrials:NCT04292899</code> <span class="citation" data-cites="yTCAmOyt">[<a href="#ref-yTCAmOyt" role="doc-biblioref">440</a>]</span>.</p>
+<p>Additionally, the fast-moving nature of the infodemic has led to a number of retractions and corrections of COVID-19 literature.
+<!--To Do: Describe integration with scite -- talk to Vince--></p>
+<p>Because in this implementation of Manubot, most collaborators were writing and editing text through the GitHub website rather than in a local text editor, we also needed to add spell-checking functionalities to Manubot.
+<!--To Do: Describe--></p>
+<!-- To Do: Also, if we end up automating anything to do with the Manubot-to-LaTeX or bibtex workflow while trying to submit this paper, we should describe that too, as well as the udpates for the Microsoft Word crowd to generating the complete review manuscript along with the individual manuscripts reviewing specific topics. <!-- To Do: reference individual manuscripts -->
+<h2 data-number="11.6" id="results"><span class="header-section-number">11.6</span> RESULTS</h2>
+<h3 data-number="11.6.1" id="recruitment-and-manuscript-development"><span class="header-section-number">11.6.1</span> Recruitment and Manuscript Development</h3>
+<!--To Do: Add a graph/text describing number of unique contributors & commits over time-->
+<!-- To Do: Word Cloud of #17 to show diversity of interests?-->
+<p>Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine <span class="citation" data-cites="cYo4O2qX YZ4cHNuH">[<a href="#ref-cYo4O2qX" role="doc-biblioref">1301</a>,<a href="#ref-YZ4cHNuH" role="doc-biblioref">1302</a>]</span>, and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program <span class="citation" data-cites="DGTDsJZy">[<a href="#ref-DGTDsJZy" role="doc-biblioref">1303</a>]</span>.
+<!--To Do: Graph of contributions by individual over time and/or by career stage?-->
+<!-- To Do: unique contributors and commits over time like this: https://greenelab.github.io/meta-review/#fig:contrib-->
+<!--To Do: Other possible graphs: plot number of article issues opened over time, distribution of review contents, that is, something showing the number of comments per pull request that was merged, growth of the reference list over time and/or number of clinical trials cited (because we describe that as a necessary enhancement)--></p>
+<!--To Do: Links to documentation-->
+<h3 data-number="11.6.2" id="data-analysis-and-integration"><span class="header-section-number">11.6.2</span> Data Analysis and Integration</h3>
+<!--To Do: Flow chart of data integration? We could have a summary figure showing all of the external data sources that are integrated into the manuscript. We have icons for MSSM reviews, JHU data, etc. at the top. That flows into a GitHub repo, which also takes input from all the contributors. Then the output of the repo is the manuscript and other CI artifacts.-->
+<!-- To Do: example of how the auto-updated figures changed between an early version and most recent version to demonstrate the importance of having current data visualized-->
 <p>The workflow file is available from <a href="https://github.com/greenelab/covid19-review/blob/master/.github/workflows/update-external-resources.yaml" class="uri">https://github.com/greenelab/covid19-review/blob/master/.github/workflows/update-external-resources.yaml</a> and the scripts are available from <a href="https://github.com/greenelab/covid19-review/tree/external-resources" class="uri">https://github.com/greenelab/covid19-review/tree/external-resources</a>.
 The Python package versions are available in <a href="https://github.com/greenelab/covid19-review/blob/external-resources/environment.yml" class="uri">https://github.com/greenelab/covid19-review/blob/external-resources/environment.yml</a>.
-<!-- These files are archived with [Software Heritage](...). --></p>
-<h2 data-number="11.4" id="article-selection-and-evaluation"><span class="header-section-number">11.4</span> Article Selection and Evaluation</h2>
-<p>Relevant articles were identified and submitted as issues on <a href="https://github.com/greenelab/covid19-review">GitHub</a> for review.
-Articles were classified as <em>diagnostic</em>, <em>therapeutic</em>, or <em>other</em>, and a template was developed to guide the review of papers and preprints in each category.
-Following a framework often used for assessing medical literature, the review consisted of examining methods used in each relevant article, assignment (whether the study was observational or randomized), assessment, results, interpretation, and how well the study extrapolates <span class="citation" data-cites="17OQtAY4l">[<a href="#ref-17OQtAY4l" role="doc-biblioref">1301</a>]</span>.
-For examples of each template, please see Appendices B-D.</p>
-<h3 data-number="11.4.1" id="diagnostic-papers"><span class="header-section-number">11.4.1</span> Diagnostic Papers</h3>
-<h4 data-number="11.4.1.1" id="methods"><span class="header-section-number">11.4.1.1</span> Methods</h4>
-<p>Reviewers began by describing the study question(s) being investigated by the article.
-They then described the study population, the sample size, the prevalence of the disease in the study population, countries / regions considered in case of human subjects, demographics of participants, the setting, and any remaining inclusion / exclusion criteria considered.
-They then described the reference test or “gold standard,” if one was utilized.</p>
-<h4 data-number="11.4.1.2" id="assignment"><span class="header-section-number">11.4.1.2</span> Assignment</h4>
-<p>Reviewers described how new and reference tests were assigned, including additional relevant details about the study design.
-For example, reviewers were asked whether the diagnostic test resulted in rigorous assignments of case status or was biased towards sicker or healthier individuals.</p>
-<h4 data-number="11.4.1.3" id="assessment"><span class="header-section-number">11.4.1.3</span> Assessment</h4>
-<p>Reviewers described how the test was performed.
-For example, for both standard and reference tests, reviewers described technical details of assays used, when measurements were taken and by whom.
-Subsequently, they described how individuals were classified as positive or negative cases and whether results were precise and reproducible with repeated tests.
-Reviewers described whether there were any missing data, whether some participants underwent only one test, or whether there were individuals with inconclusive results.</p>
-<h4 data-number="11.4.1.4" id="results"><span class="header-section-number">11.4.1.4</span> Results</h4>
-<p>Reviewers reported the estimated sensitivity, specificity, positive predictive value (PPV), and negative predicted value (NPV), as well as confidence bounds around these measures, if provided.</p>
-<h4 data-number="11.4.1.5" id="interpretation"><span class="header-section-number">11.4.1.5</span> Interpretation</h4>
-<p>Reviewers reported how well the test ruled in or ruled out disease based on the population, if there were identified side effects, and patient adherence.</p>
-<h4 data-number="11.4.1.6" id="extrapolation"><span class="header-section-number">11.4.1.6</span> Extrapolation</h4>
-<p>Reviewers described how well this test will extrapolate outside the measured population.</p>
-<h3 data-number="11.4.2" id="therapeutic-papers"><span class="header-section-number">11.4.2</span> Therapeutic Papers</h3>
-<h4 data-number="11.4.2.1" id="methods-1"><span class="header-section-number">11.4.2.1</span> Methods</h4>
-<p>Reviewers began by describing the study question(s) being investigated by the article.
-They then described the study population, the sample size, the prevalence of the disease in the study population, countries / regions considered in case of human subjects, demographics of participants, the setting, and any remaining inclusion / exclusion criteria considered.</p>
-<h4 data-number="11.4.2.2" id="assignment-1"><span class="header-section-number">11.4.2.2</span> Assignment</h4>
-<p>Reviewers described how the treatment is assigned, whether it was an interventional or observational study, whether randomization took place, etc.</p>
-<h4 data-number="11.4.2.3" id="assessment-1"><span class="header-section-number">11.4.2.3</span> Assessment</h4>
-<h5 data-number="11.4.2.3.1" id="outcome-assessment"><span class="header-section-number">11.4.2.3.1</span> Outcome Assessment</h5>
-<p>Reviewers described the outcome that was assessed and evaluated whether it was appropriate given the underlying study question.
-They described whether there were any missing data such as whether there were individuals lost to follow up.
-They then describe whether there were any potential sources of bias such as lack of blinding in a randomized controlled trial.</p>
-<h5 data-number="11.4.2.3.2" id="statistical-methods-assessment"><span class="header-section-number">11.4.2.3.2</span> Statistical Methods Assessment</h5>
-<p>Reviewers described which statistical methods were used for inference and whether applied methods were appropriate for the study.
-They then described whether adjustments were made for possible confounders.</p>
-<h4 data-number="11.4.2.4" id="results-1"><span class="header-section-number">11.4.2.4</span> Results</h4>
-<p>Reviewers described the estimated association between the treatment and outcome.
-They described measures of confidence or statistical significance, if provided.</p>
-<h4 data-number="11.4.2.5" id="interpretation-1"><span class="header-section-number">11.4.2.5</span> Interpretation</h4>
-<p>Reviewers described whether a causal claim could be made.
-They described whether any side effects or interactions with other drugs were identified, as well as any subgroup findings.</p>
-<h4 data-number="11.4.2.6" id="extrapolation-1"><span class="header-section-number">11.4.2.6</span> Extrapolation</h4>
-<p>Reviewers describe how the study may extrapolate to a different species or population.</p>
-<h2 data-number="11.5" id="conclusions-5"><span class="header-section-number">11.5</span> Conclusions</h2>
-<div id="fig:overview" class="fignos">
-<figure>
-<img src="images/N000-overview.png" alt="" /><figcaption><span>Figure 8:</span> <strong>Summary of the relationships among topics covered in this review.</strong></figcaption>
-</figure>
-</div>
-<p>Several review articles on aspects of COVID-19 have already been published.
-These have included reviews on the disease epidemiology <span class="citation" data-cites="I2EsJmfs">[<a href="#ref-I2EsJmfs" role="doc-biblioref">41</a>]</span>, immunological response <span class="citation" data-cites="5x25saIz">[<a href="#ref-5x25saIz" role="doc-biblioref">42</a>]</span>, diagnostics <span class="citation" data-cites="evtsR3C5">[<a href="#ref-evtsR3C5" role="doc-biblioref">43</a>]</span>, and pharmacological treatments <span class="citation" data-cites="5x25saIz 18eCxyLhx">[<a href="#ref-5x25saIz" role="doc-biblioref">42</a>,<a href="#ref-18eCxyLhx" role="doc-biblioref">44</a>]</span>.
-Others <span class="citation" data-cites="SAE5ME3N xOs5ctsW">[<a href="#ref-SAE5ME3N" role="doc-biblioref">45</a>,<a href="#ref-xOs5ctsW" role="doc-biblioref">46</a>]</span> provide narrative reviews of progress on some important ongoing COVID-19 research questions.
-With the worldwide scientific community uniting during 2020 to investigate SARS-CoV-2 and COVID-19 from a wide range of perspectives, findings from many disciplines are relevant on a rapid timescale to a broad scientific audience.
-Additionally, many findings are published as preprints, which are available prior to going through the peer review process.
-As a result, centralizing, summarizing, and critiquing new literature broadly relevant to COVID-19 can help to expedite the interdisciplinary scientific process that is currently happening at an advanced pace.
-We are particularly interested in providing background to the development of diagnostic, prophylactic, and therapeutic approaches to COVID-19.
-Two major concerns within diagnosis include the detection of current infections in individuals with and without symptoms, and the detection of past exposure without an active infection.
-In the latter category, identifying whether individuals can develop or have developed sustained immunity is also a major consideration.
-The development of high-throughput, affordable methods for detecting active infections and sustained immunity will be critical to understanding and controlling the disease.
-The identification of interventions that can mitigate the effect of the virus on exposed and infected individuals is a significant research priority.
-Some possible approaches include the identification of existing pharmaceuticals that reduce the severity of infection, either by reducing the virus’ virulence (e.g., antivirals) or managing the most severe symptoms of infection.
-Due to the long timeline for the development of novel pharmaceuticals, in most cases, research surrounding possible pharmaceutical interventions focuses on the identification and investigation of existing compounds whose mechanisms may be relevant to COVID-19.
-Other foci of current research include the identification of antibodies produced by survivors of COVID-19 and the development of vaccines.
-Understanding the mechanisms describing host-virus interactions between humans and SARS-CoV-2 is thus critical to identifying candidate therapeutics.
-An overview of the topics covered is visualized in Figure <a href="#fig:overview">8</a>.
-Thus, in this review, we seek to consolidate information about efforts to develop strategies for diagnosis and therapeutics as new information is released by the scientific community.
-We include information from both traditional peer-reviewed scientific literature and from preprints, which typically have not undergone peer review but have been critically evaluated by the scientists involved in this effort.
-The goal of this manuscript is to present preliminary findings within the broader context of COVID-19 research and to identify the broad interpretations of new research, as well as limitations to interpretability.</p>
+<!-- To Do: These files are archived with [Zenodo?](...). --></p>
+<h3 data-number="11.6.3" id="updates-to-manubot"><span class="header-section-number">11.6.3</span> Updates to Manubot</h3>
+<p>The scite integration and spell-checking functionalities have been integrated into the current release of Manubot <!--To Do: Link-->.
+Support for clinical trial identifiers is supported both by Manubot and by Zotero <!--To Do: check this phrasing-->.
+Using CI, Manubot now checks that the manuscript was built correctly, runs spellchecking, and cross-references the manuscripts cited in this review, as summarized in Appendix A and discussed in the project’s issues and pull requests.</p>
+<h2 data-number="11.7" id="discussion-4"><span class="header-section-number">11.7</span> DISCUSSION</h2>
+<p>Working within the Manubot framework allowed for the successful facilitation of a massive collaborative review on an urgent topic.
+Developing Manubot for the specific challenges raised by COVID-19 and expanding on both training resources resulted in seven evolving literature reviews produced by the COVID-19 Review Consortium, all of which are currently available through Manubot and, in some cases, on arXiv <!--To Do: cite individual manuscripts-->.
+As many other efforts have described, the rate of publishing of formal manuscripts and preprints about COVID-19 has been unprecedented <span class="citation" data-cites="7ub6VM4Z">[<a href="#ref-7ub6VM4Z" role="doc-biblioref">1293</a>]</span>.
+The Manubot framework will allow for continuous updating of the manuscripts as the pandemic enters its second year and the landscape shifts with the emergence of promising therapeutics and vaccines <span class="citation" data-cites="individual-therapeutics i2CGFwI3">[<span class="citeproc-not-found" data-reference-id="individual-therapeutics"><strong>???</strong></span>,<a href="#ref-i2CGFwI3" role="doc-biblioref">408</a>]</span>.
+The manuscripts pull data from XX data sources, allowing for information and visualizations to be updated daily using CI.
+This computational approach allows for the information in the manuscripts to be kept up to date automatically.</p>
+<p>Beyond the immediate goal of applying Manubot to the challenges of COVID-19, we have also expanded Manubot to allow for broader participation in open publishing from fields where computational training in tools like version control is uncommon.
+Several review articles on aspects of COVID-19 have already been published, including reviews on the disease epidemiology <span class="citation" data-cites="I2EsJmfs">[<a href="#ref-I2EsJmfs" role="doc-biblioref">41</a>]</span>, immunological response <span class="citation" data-cites="5x25saIz">[<a href="#ref-5x25saIz" role="doc-biblioref">42</a>]</span>, diagnostics <span class="citation" data-cites="evtsR3C5">[<a href="#ref-evtsR3C5" role="doc-biblioref">43</a>]</span>, and pharmacological treatments <span class="citation" data-cites="5x25saIz 18eCxyLhx">[<a href="#ref-5x25saIz" role="doc-biblioref">42</a>,<a href="#ref-18eCxyLhx" role="doc-biblioref">44</a>]</span> and others that provide narrative reviews of progress on some important ongoing COVID-19 research questions <span class="citation" data-cites="SAE5ME3N xOs5ctsW">[<a href="#ref-SAE5ME3N" role="doc-biblioref">45</a>,<a href="#ref-xOs5ctsW" role="doc-biblioref">46</a>]</span>.
+However, the broader topic of COVID-19 intersects with a wide range of fields, including virology, immunology, medicine, pharmacology, evolutionary biology, public health, and more, and any effort to comprehensively document and evaluate this body of literature would require insight from scientists across a number of fields.
+Furthermore, during the initial phase of the COVID-19 pandemic during spring and summer 2020, and much longer in some part of the world, many biological scientists were unable to access their research spaces.
+As a result, early career researchers (ECR) and students were likely to lose out on valuable time for conducting experiments. <!--To Do: look at equity analyses of the effects on the pandemic to see if there is any data on this yet?-->
+Manubot provided a way for all contributors, including ECRs, to join a massive collaborative projects but also demonstrate their individual contributions to the larger work.
+<!--To Do: summary of results of contributor analysis--></p>
+<p>Manubot provides the advantage of allowing a manuscript to be rendered in several formats that serve different purposes, and the current project extended these options.
+For example, beyond building just a PDF, Manubot also renders the manuscript in HTML and docx <!--To Do: And tex?-->
+The HTML manuscript format offers several advantages over a static PDF to harmonize available resources that we were able to apply to specific problems of COVID-19.
+The integration of scite has made the expansive number of references more manageable by visually representing whether their results are contested or whether they have been corrected or retracted.
+Cross-referencing cited preprints with their reviews in the appendix is another.
+Docx is a necessary format for a biological collaboration where authors are typically not working in LaTeX.
+<!--To Do: continue expanding to describe docx updates and possibly LaTeX updates--></p>
+<p>With the worldwide scientific community uniting during 2020 to investigate SARS-CoV-2 and COVID-19 from a wide range of perspectives, findings from many disciplines are relevant on a rapid timescale to a broad scientific audience.
+As a result, centralizing, summarizing, and critiquing data and literature broadly relevant to COVID-19 can help to expedite the interdisciplinary scientific process that is currently happening at an advanced pace.
+The efforts of the COVID-19 Review Consortium illustrate the value of including open source tools, including those focused on open publishing, in these efforts.
+By facilitating the versioning of text, such platforms also allow for documentation of the evolution of thought in an evolving area.
+This application of version control holds the potential to improve scientific publishing in a range of disciplines, including those outside of traditional computational fields.</p>
 <h1 class="page_break_before" data-number="12" id="additional-items"><span class="header-section-number">12</span> Additional Items</h1>
 <h2 data-number="12.1" id="competing-interests"><span class="header-section-number">12.1</span> Competing Interests</h2>
 <table>
@@ -6930,5827 +6944,5846 @@ <h1 class="page_break_before" data-number="13" id="references"><span class="head
 <em>Nature</em> (2021-01-18) <a href="https://doi.org/fq6k">https://doi.org/fq6k</a> <br />
 DOI: <a href="https://doi.org/10.1038/s41586-021-03207-w">10.1038/s41586-021-03207-w</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33461210">33461210</a></p>
 </div>
-<div id="ref-19MYPpSCx">
-<p>384. <strong>Robust neutralizing antibodies to SARS-CoV-2 infection persist for months</strong> <br />
-Ania Wajnberg, Fatima Amanat, Adolfo Firpo, Deena R. Altman, Mark J. Bailey, Mayce Mansour, Meagan McMahon, Philip Meade, Damodara Rao Mendu, Kimberly Muellers, … Carlos Cordon-Cardo<br />
-<em>Science</em> (2020-12-04) <a href="https://doi.org/fgfs">https://doi.org/fgfs</a> <br />
-DOI: <a href="https://doi.org/10.1126/science.abd7728">10.1126/science.abd7728</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33115920">33115920</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810037">PMC7810037</a></p>
-</div>
 <div id="ref-m1wjdQSV">
-<p>385. <strong>Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans</strong> <br />
+<p>384. <strong>Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans</strong> <br />
 Jeffrey Seow, Carl Graham, Blair Merrick, Sam Acors, Suzanne Pickering, Kathryn J. A. Steel, Oliver Hemmings, Aoife O’Byrne, Neophytos Kouphou, Rui Pedro Galao, … Katie J. Doores<br />
 <em>Nature Microbiology</em> (2020-10-26) <a href="https://doi.org/fh7j">https://doi.org/fh7j</a> <br />
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 Mandeep R Mehra, Sapan S Desai, Frank Ruschitzka, Amit N Patel<br />
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 Mayla Gabriela Silva Borba, Fernando Fonseca Almeida Val, Vanderson Souza Sampaio, Marcia Almeida Araújo Alexandre, Gisely Cardoso Melo, Marcelo Brito, Maria Paula Gomes Mourão, José Diego Brito-Sousa, Djane Baía-da-Silva, Marcus Vinitius Farias Guerra, … CloroCovid-19 Team<br />
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 Sophia M. Vrba, Natalie M. Kirk, Morgan E. Brisse, Yuying Liang, Hinh Ly<br />
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 Carly M. Bliss, Abdoulie Drammeh, Georgina Bowyer, Guillaume S. Sanou, Ya Jankey Jagne, Oumarou Ouedraogo, Nick J. Edwards, Casimir Tarama, Nicolas Ouedraogo, Mireille Ouedraogo, … Katie J. Ewer<br />
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 Shengqiang Li, Emily Locke, Joseph Bruder, David Clarke, Denise L. Doolan, Menzo J. E. Havenga, Adrian V. S. Hill, Peter Liljestrom, Thomas P. Monath, Hussein Y. Naim, … Filip Dubovsky<br />
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 Julie E. Ledgerwood, Adam D. DeZure, Daphne A. Stanley, Emily E. Coates, Laura Novik, Mary E. Enama, Nina M. Berkowitz, Zonghui Hu, Gyan Joshi, Aurélie Ploquin, … Barney S. Graham<br />
 <em>New England Journal of Medicine</em> (2017-03-09) <a href="https://doi.org/xdr">https://doi.org/xdr</a> <br />
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 <em>Current Opinion in HIV and AIDS</em> (2013-09) <a href="https://doi.org/f5b5qm">https://doi.org/f5b5qm</a> <br />
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 Shubhanshi Trivedi, Ronald J. Jackson, Charani Ranasinghe<br />
 <em>Virology</em> (2014-11) <a href="https://doi.org/f6ngrk">https://doi.org/f6ngrk</a> <br />
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 Raymond H. See, Alexander N. Zakhartchouk, Martin Petric, David J. Lawrence, Catherine P. Y. Mok, Robert J. Hogan, Thomas Rowe, Lois A. Zitzow, Karuna P. Karunakaran, Mary M. Hitt, … B. Brett Finlay<br />
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 Raymond H. See, Martin Petric, David J. Lawrence, Catherine P. Y. Mok, Thomas Rowe, Lois A. Zitzow, Karuna P. Karunakaran, Thomas G. Voss, Robert C. Brunham, Jack Gauldie, … Rachel L. Roper<br />
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+<p>732. <strong>ChAdOx1 and MVA based vaccine candidates against MERS-CoV elicit neutralising antibodies and cellular immune responses in mice</strong> <br />
 Naif Khalaf Alharbi, Eriko Padron-Regalado, Craig P. Thompson, Alexandra Kupke, Daniel Wells, Megan A. Sloan, Keith Grehan, Nigel Temperton, Teresa Lambe, George Warimwe, … Sarah C. Gilbert<br />
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-<p>734. <strong>A single dose of ChAdOx1 MERS provides protective immunity in rhesus macaques</strong> <br />
+<p>733. <strong>A single dose of ChAdOx1 MERS provides protective immunity in rhesus macaques</strong> <br />
 Neeltje van Doremalen, Elaine Haddock, Friederike Feldmann, Kimberly Meade-White, Trenton Bushmaker, Robert J. Fischer, Atsushi Okumura, Patrick W. Hanley, Greg Saturday, Nick J. Edwards, … Vincent J. Munster<br />
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+<p>734. <strong>Safety and immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored vaccine: a dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial</strong> <br />
 Pedro M Folegatti, Mustapha Bittaye, Amy Flaxman, Fernando Ramos Lopez, Duncan Bellamy, Alexandra Kupke, Catherine Mair, Rebecca Makinson, Jonathan Sheridan, Cornelius Rohde, … Sarah Gilbert<br />
 <em>The Lancet Infectious Diseases</em> (2020-07) <a href="https://doi.org/ggtxgp">https://doi.org/ggtxgp</a> <br />
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+<p>735. <strong>ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques</strong> <br />
 Neeltje van Doremalen, Teresa Lambe, Alexandra Spencer, Sandra Belij-Rammerstorfer, Jyothi N. Purushotham, Julia R. Port, Victoria A. Avanzato, Trenton Bushmaker, Amy Flaxman, Marta Ulaszewska, … Vincent J. Munster<br />
 <em>Nature</em> (2020-07-30) <a href="https://doi.org/gg67jr">https://doi.org/gg67jr</a> <br />
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+<p>736. <strong>Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial</strong> <br />
 Pedro M Folegatti, Katie J Ewer, Parvinder K Aley, Brian Angus, Stephan Becker, Sandra Belij-Rammerstorfer, Duncan Bellamy, Sagida Bibi, Mustapha Bittaye, Elizabeth A Clutterbuck, … Yasmine Yau<br />
 <em>The Lancet</em> (2020-08) <a href="https://doi.org/gg5gwk">https://doi.org/gg5gwk</a> <br />
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-<p>738. <strong>AstraZeneca’s COVID-19 vaccine authorised for emergency supply in the UK</strong> <a href="https://www.astrazeneca.com/media-centre/press-releases/2020/astrazenecas-covid-19-vaccine-authorised-in-uk.html">https://www.astrazeneca.com/media-centre/press-releases/2020/astrazenecas-covid-19-vaccine-authorised-in-uk.html</a></p>
+<p>737. <strong>AstraZeneca’s COVID-19 vaccine authorised for emergency supply in the UK</strong> <a href="https://www.astrazeneca.com/media-centre/press-releases/2020/astrazenecas-covid-19-vaccine-authorised-in-uk.html">https://www.astrazeneca.com/media-centre/press-releases/2020/astrazenecas-covid-19-vaccine-authorised-in-uk.html</a></p>
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-<p>739. <strong>The Russian vaccine for COVID-19</strong> <br />
+<p>738. <strong>The Russian vaccine for COVID-19</strong> <br />
 Talha Khan Burki<br />
 <em>The Lancet Respiratory Medicine</em> (2020-11) <a href="https://doi.org/ft7j">https://doi.org/ft7j</a> <br />
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-<p>740. <strong>Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia</strong> <br />
+<p>739. <strong>Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia</strong> <br />
 Denis Y Logunov, Inna V Dolzhikova, Olga V Zubkova, Amir I Tukhvatulin, Dmitry V Shcheblyakov, Alina S Dzharullaeva, Daria M Grousova, Alina S Erokhova, Anna V Kovyrshina, Andrei G Botikov, … Alexander L Gintsburg<br />
 <em>The Lancet</em> (2020-09) <a href="https://doi.org/gg96hq">https://doi.org/gg96hq</a> <br />
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-<p>741. <strong>Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia</strong> <br />
+<p>740. <strong>Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia</strong> <br />
 Denis Y Logunov, Inna V Dolzhikova, Dmitry V Shcheblyakov, Amir I Tukhvatulin, Olga V Zubkova, Alina S Dzharullaeva, Anna V Kovyrshina, Nadezhda L Lubenets, Daria M Grousova, Alina S Erokhova, … Alexander L Gintsburg<br />
 <em>The Lancet</em> (2021-02) <a href="https://doi.org/ghxj4g">https://doi.org/ghxj4g</a> <br />
 DOI: <a href="https://doi.org/10.1016/s0140-6736(21)00234-8">10.1016/s0140-6736(21)00234-8</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33545094">33545094</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852454">PMC7852454</a></p>
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 <div id="ref-X5LkVfY6">
-<p>742. <strong>1.5 million people have received Sputnik V vaccine, Russia says</strong> <br />
+<p>741. <strong>1.5 million people have received Sputnik V vaccine, Russia says</strong> <br />
 The Brussels Times<br />
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-<p>743. <strong>Hungary becomes first EU country to deploy Russia’s COVID-19 vaccine</strong> <br />
+<p>742. <strong>Hungary becomes first EU country to deploy Russia’s COVID-19 vaccine</strong> <br />
 Michael Daventry<br />
 <em>euronews</em> (2021-02-12) <a href="https://www.euronews.com/2021/02/12/hungary-to-begin-using-russia-s-sputnik-v-vaccine-today">https://www.euronews.com/2021/02/12/hungary-to-begin-using-russia-s-sputnik-v-vaccine-today</a></p>
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 <div id="ref-Z0V7NK7Y">
-<p>744. <strong>San Marino buys Russia’s Sputnik V after EU vaccine delivery delays</strong> <br />
+<p>743. <strong>San Marino buys Russia’s Sputnik V after EU vaccine delivery delays</strong> <br />
 euronews<br />
 (2021-02-24) <a href="https://www.euronews.com/2021/02/24/san-marino-buys-russia-s-sputnik-v-after-eu-vaccine-delivery-delays">https://www.euronews.com/2021/02/24/san-marino-buys-russia-s-sputnik-v-after-eu-vaccine-delivery-delays</a></p>
 </div>
 <div id="ref-16GYKbrOq">
-<p>745. <strong>Belarus Starts Coronavirus Vaccination With Sputnik V</strong> <br />
+<p>744. <strong>Belarus Starts Coronavirus Vaccination With Sputnik V</strong> <br />
 AFP<br />
 <em>The Moscow Times</em> (2020-12-29) <a href="https://www.themoscowtimes.com/2020/12/29/belarus-starts-coronavirus-vaccination-with-sputnik-v-a72512">https://www.themoscowtimes.com/2020/12/29/belarus-starts-coronavirus-vaccination-with-sputnik-v-a72512</a></p>
 </div>
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-<p>746. <strong>Russia’s coronavirus vaccine is alluring for Eastern Europe, creating a headache for the EU</strong> <br />
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 Holly Ellyatt<br />
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 Katherine McMahan, Jingyou Yu, Noe B. Mercado, Carolin Loos, Lisa H. Tostanoski, Abishek Chandrashekar, Jinyan Liu, Lauren Peter, Caroline Atyeo, Alex Zhu, … Dan H. Barouch<br />
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+<p>810. <strong>A Randomized, Double-blind, Placebo-controlled Phase 3 Study to Assess the Efficacy and Safety of Ad26.COV2.S for the Prevention of SARS-CoV-2-mediated COVID-19 in Adults Aged 18 Years and Older</strong> <br />
 Janssen Vaccines &amp; Prevention B.V.<br />
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+<p>811. <strong>Johnson &amp; Johnson Prepares to Resume Phase 3 ENSEMBLE Trial of its Janssen COVID-19 Vaccine Candidate in the U.S. | Johnson &amp; Johnson</strong> <br />
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 Sofia E. Magnusson, Arwen F. Altenburg, Karin Lövgren Bengtsson, Fons Bosman, Rory D. de Vries, Guus F. Rimmelzwaan, Linda Stertman<br />
 <em>Immunologic Research</em> (2018-03-28) <a href="https://doi.org/gdd2fw">https://doi.org/gdd2fw</a> <br />
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+<p>814. <strong>Immune enhancing properties of the novel Matrix-M™ adjuvant leads to potentiated immune responses to an influenza vaccine in mice</strong> <br />
 Sofia E. Magnusson, Jenny M. Reimer, Karin H. Karlsson, Lena Lilja, Karin Lövgren Bengtsson, Linda Stertman<br />
 <em>Vaccine</em> (2013-03) <a href="https://doi.org/f2ntg8">https://doi.org/f2ntg8</a> <br />
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+<p>815. <strong>Intramuscular Matrix-M-adjuvanted virosomal H5N1 vaccine induces high frequencies of multifunctional Th1 CD4+ cells and strong antibody responses in mice</strong> <br />
 Abdullah S. Madhun, Lars R. Haaheim, Mona V. Nilsen, Rebecca J. Cox<br />
 <em>Vaccine</em> (2009-12) <a href="https://doi.org/d6cthn">https://doi.org/d6cthn</a> <br />
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+<p>816. <strong>Matrix-M adjuvanted virosomal H5N1 vaccine confers protection against lethal viral challenge in a murine model</strong> <br />
 Gabriel Pedersen, Diane Major, Sarah Roseby, John Wood, Abdullah S. Madhun, Rebecca J. Cox<br />
 <em>Influenza and Other Respiratory Viruses</em> (2011-11) <a href="https://doi.org/fbkc9w">https://doi.org/fbkc9w</a> <br />
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+<p>817. <strong>Evaluation of a virosomal H5N1 vaccine formulated with Matrix M™ adjuvant in a phase I clinical trial</strong> <br />
 Rebecca J. Cox, Gabriel Pedersen, Abdullah S. Madhun, Signe Svindland, Marianne Sævik, Lucy Breakwell, Katja Hoschler, Marieke Willemsen, Laura Campitelli, Jane Kristin Nøstbakken, … Haakon Sjursen<br />
 <em>Vaccine</em> (2011-10) <a href="https://doi.org/dq7db6">https://doi.org/dq7db6</a> <br />
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+<p>819. <strong>Evaluation of a SARS-CoV-2 Vaccine NVX-CoV2373 in Younger and Older Adults</strong> <br />
 Neil Formica, Raburn Mallory, Gary Albert, Michelle Robinson, Joyce S. Plested, Iksung Cho, Andreana Robertson, Filip Dubovsky, Gregory M. Glenn, for the 2019nCoV-101 Study Group<br />
 <em>Cold Spring Harbor Laboratory</em> (2021-03-01) <a href="https://doi.org/gjh94p">https://doi.org/gjh94p</a> <br />
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 Jinyong Zhang, Hao Zeng, Jiang Gu, Haibo Li, Lixin Zheng, Quanming Zou<br />
 <em>Vaccines</em> (2020-03-29) <a href="https://doi.org/ggq726">https://doi.org/ggq726</a> <br />
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 Philippa Marrack, Amy S. McKee, Michael W. Munks<br />
 <em>Nature Reviews Immunology</em> (2009-04) <a href="https://doi.org/drcwvf">https://doi.org/drcwvf</a> <br />
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+<p>822. <strong>DAMP-Inducing Adjuvant and PAMP Adjuvants Parallelly Enhance Protective Type-2 and Type-1 Immune Responses to Influenza Split Vaccination</strong> <br />
 Tomoya Hayashi, Masatoshi Momota, Etsushi Kuroda, Takato Kusakabe, Shingo Kobari, Kotaro Makisaka, Yoshitaka Ohno, Yusuke Suzuki, Fumika Nakagawa, Michelle S. J. Lee, … Hidetoshi Arima<br />
 <em>Frontiers in Immunology</em> (2018-11-20) <a href="https://doi.org/gfqq89">https://doi.org/gfqq89</a> <br />
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+<p>823. <strong>Better Adjuvants for Better Vaccines: Progress in Adjuvant Delivery Systems, Modifications, and Adjuvant–Antigen Codelivery</strong> <br />
 Zhi-Biao Wang, Jing Xu<br />
 <em>Vaccines</em> (2020-03-13) <a href="https://doi.org/gg35vj">https://doi.org/gg35vj</a> <br />
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+<p>824. <strong>Defining trained immunity and its role in health and disease</strong> <br />
 Mihai G. Netea, Jorge Domínguez-Andrés, Luis B. Barreiro, Triantafyllos Chavakis, Maziar Divangahi, Elaine Fuchs, Leo A. B. Joosten, Jos W. M. van der Meer, Musa M. Mhlanga, Willem J. M. Mulder, … Eicke Latz<br />
 <em>Nature Reviews Immunology</em> (2020-03-04) <a href="https://doi.org/gg28pr">https://doi.org/gg28pr</a> <br />
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+<p>825. <strong>Trained Immunity: a Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection</strong> <br />
 Mihai G. Netea, Evangelos J. Giamarellos-Bourboulis, Jorge Domínguez-Andrés, Nigel Curtis, Reinout van Crevel, Frank L. van de Veerdonk, Marc Bonten<br />
 <em>Cell</em> (2020-05) <a href="https://doi.org/gg2584">https://doi.org/gg2584</a> <br />
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+<p>826. <strong>BCG Vaccination to Protect Healthcare Workers Against COVID-19 - Full Text View - ClinicalTrials.gov</strong> <a href="https://clinicaltrials.gov/ct2/show/NCT04327206">https://clinicaltrials.gov/ct2/show/NCT04327206</a></p>
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+<p>827. <strong>Reducing Health Care Workers Absenteeism in Covid-19 Pandemic Through BCG Vaccine - Full Text View - ClinicalTrials.gov</strong> <a href="https://clinicaltrials.gov/ct2/show/NCT04328441">https://clinicaltrials.gov/ct2/show/NCT04328441</a></p>
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+<p>828. <strong>BCG Vaccine for Health Care Workers as Defense Against COVID 19 - Full Text View - ClinicalTrials.gov</strong> <a href="https://clinicaltrials.gov/ct2/show/NCT04348370">https://clinicaltrials.gov/ct2/show/NCT04348370</a></p>
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-<p>830. <strong>Application of BCG Vaccine for Immune-prophylaxis Among Egyptian Healthcare Workers During the Pandemic of COVID-19</strong> <br />
+<p>829. <strong>Application of BCG Vaccine for Immune-prophylaxis Among Egyptian Healthcare Workers During the Pandemic of COVID-19</strong> <br />
 Adel Khattab<br />
 <em>clinicaltrials.gov</em> (2020-04-17) <a href="https://clinicaltrials.gov/ct2/show/NCT04350931">https://clinicaltrials.gov/ct2/show/NCT04350931</a></p>
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+<p>830. <strong>Performance Evaluation of BCG Vaccination in Healthcare Personnel to Reduce the Severity of SARS-COV-2 Infection in Medellín, Colombia, 2020</strong> <br />
 Universidad de Antioquia<br />
 <em>clinicaltrials.gov</em> (2020-11-24) <a href="https://clinicaltrials.gov/ct2/show/NCT04362124">https://clinicaltrials.gov/ct2/show/NCT04362124</a></p>
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+<p>831. <strong>COVID-19: BCG As Therapeutic Vaccine, Transmission Limitation, and Immunoglobulin Enhancement - Full Text View - ClinicalTrials.gov</strong> <a href="https://clinicaltrials.gov/ct2/show/NCT04369794">https://clinicaltrials.gov/ct2/show/NCT04369794</a></p>
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+<p>832. <strong>Using BCG Vaccine to Protect Health Care Workers in the COVID-19 Pandemic - Full Text View - ClinicalTrials.gov</strong> <a href="https://clinicaltrials.gov/ct2/show/NCT04373291">https://clinicaltrials.gov/ct2/show/NCT04373291</a></p>
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+<p>833. <strong>Reducing Morbidity and Mortality in Health Care Workers Exposed to SARS-CoV-2 by Enhancing Non-specific Immune Responses Through Bacillus Calmette-Guérin Vaccination, a Randomized Controlled Trial</strong> <br />
 TASK Applied Science<br />
 <em>clinicaltrials.gov</em> (2020-05-06) <a href="https://clinicaltrials.gov/ct2/show/NCT04379336">https://clinicaltrials.gov/ct2/show/NCT04379336</a></p>
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+<p>834. <strong>Randomized Controlled Trial Evaluating the Efficacy of Vaccination With Bacillus Calmette and Guérin (BCG) in the Prevention of COVID-19 Via the Strengthening of Innate Immunity in Health Care Workers</strong> <br />
 Assistance Publique - Hôpitaux de Paris<br />
 <em>clinicaltrials.gov</em> (2020-08-17) <a href="https://clinicaltrials.gov/ct2/show/NCT04384549">https://clinicaltrials.gov/ct2/show/NCT04384549</a></p>
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+<p>835. <strong>Study to Assess VPM1002 in Reducing Healthcare Professionals’ Absenteeism in COVID-19 Pandemic - Full Text View - ClinicalTrials.gov</strong> <a href="https://clinicaltrials.gov/ct2/show/NCT04387409">https://clinicaltrials.gov/ct2/show/NCT04387409</a></p>
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+<p>836. <strong>A Randomized Clinical Trial for Enhanced Trained Immune Responses Through Bacillus Calmette-Guérin Vaccination to Prevent Infections by COVID-19: The ACTIVATE II Trial</strong> <br />
 Hellenic Institute for the Study of Sepsis<br />
 <em>clinicaltrials.gov</em> (2020-07-10) <a href="https://clinicaltrials.gov/ct2/show/NCT04414267">https://clinicaltrials.gov/ct2/show/NCT04414267</a></p>
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+<p>837. <strong>Reducing Hospital Admission of Elderly in SARS-CoV-2 Pandemic Via the Induction of Trained Immunity by Bacillus Calmette-Guérin Vaccination, a Randomized Controlled Trial</strong> <br />
 Radboud University<br />
 <em>clinicaltrials.gov</em> (2020-06-03) <a href="https://clinicaltrials.gov/ct2/show/NCT04417335">https://clinicaltrials.gov/ct2/show/NCT04417335</a></p>
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+<p>838. <strong>Study to Assess VPM1002 in Reducing Hospital Admissions and/or Severe Respiratory Infectious Diseases in Elderly in COVID-19 Pandemic - Full Text View - ClinicalTrials.gov</strong> <a href="https://clinicaltrials.gov/ct2/show/NCT04435379">https://clinicaltrials.gov/ct2/show/NCT04435379</a></p>
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-<em>FDA</em> (2021-04-14) <a href="https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/janssen-covid-19-vaccine">https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/janssen-covid-19-vaccine</a></p>
+<em>FDA</em> (2021-04-23) <a href="https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/janssen-covid-19-vaccine">https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/janssen-covid-19-vaccine</a></p>
 </div>
 <div id="ref-yNaiGtW1">
-<p>873. <strong>The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Janssen COVID-19 Vaccine — United States, February 2021</strong> <br />
+<p>871. <strong>The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Janssen COVID-19 Vaccine — United States, February 2021</strong> <br />
 Sara E. Oliver, Julia W. Gargano, Heather Scobie, Megan Wallace, Stephen C. Hadler, Jessica Leung, Amy E. Blain, Nancy McClung, Doug Campos-Outcalt, Rebecca L. Morgan, … Kathleen Dooling<br />
 <em>MMWR. Morbidity and Mortality Weekly Report</em> (2021-03-05) <a href="https://doi.org/gh77cj">https://doi.org/gh77cj</a> <br />
 DOI: <a href="https://doi.org/10.15585/mmwr.mm7009e4">10.15585/mmwr.mm7009e4</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33661860">33661860</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948932">PMC7948932</a></p>
 </div>
 <div id="ref-Vd1wOy6d">
-<p>874. <strong>WHO adds Janssen vaccine to list of safe and effective emergency tools against COVID-19</strong> <a href="https://www.who.int/news/item/12-03-2021-who-adds-janssen-vaccine-to-list-of-safe-and-effective-emergency-tools-against-covid-19">https://www.who.int/news/item/12-03-2021-who-adds-janssen-vaccine-to-list-of-safe-and-effective-emergency-tools-against-covid-19</a></p>
+<p>872. <strong>WHO adds Janssen vaccine to list of safe and effective emergency tools against COVID-19</strong> <a href="https://www.who.int/news/item/12-03-2021-who-adds-janssen-vaccine-to-list-of-safe-and-effective-emergency-tools-against-covid-19">https://www.who.int/news/item/12-03-2021-who-adds-janssen-vaccine-to-list-of-safe-and-effective-emergency-tools-against-covid-19</a></p>
 </div>
 <div id="ref-1CcsUnCiw">
-<p>875. <strong>COVID-19 Vaccine Distribution: The Process</strong> <br />
+<p>873. <strong>COVID-19 Vaccine Distribution: The Process</strong> <br />
 Assistant Secretary for Public Affairs (ASPA)<br />
 <em>HHS.gov</em> (2020-12-16) <a href="https://www.hhs.gov/coronavirus/covid-19-vaccines/distribution/index.html">https://www.hhs.gov/coronavirus/covid-19-vaccines/distribution/index.html</a></p>
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-<p>876. <strong>COVID Data Tracker</strong> <br />
+<p>874. <strong>COVID Data Tracker</strong> <br />
 CDC<br />
 <em>Centers for Disease Control and Prevention</em> (2020-03-28) <a href="https://covid.cdc.gov/covid-data-tracker">https://covid.cdc.gov/covid-data-tracker</a></p>
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-<p>877. <a href="https://www.cnn.com/2021/03/02/politics/biden-merck-johnson">https://www.cnn.com/2021/03/02/politics/biden-merck-johnson</a></p>
+<p>875. <a href="https://www.cnn.com/2021/03/02/politics/biden-merck-johnson">https://www.cnn.com/2021/03/02/politics/biden-merck-johnson</a></p>
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-<p>878. <strong>Covid-19: Was US vaccine rollout a “dismal failure” under Trump?</strong> <br />
+<p>876. <strong>Covid-19: Was US vaccine rollout a “dismal failure” under Trump?</strong> <br />
 BBC News<br />
 (2021-01-26) <a href="https://www.bbc.com/news/world-us-canada-55721437">https://www.bbc.com/news/world-us-canada-55721437</a></p>
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 <div id="ref-wDu31Zz8">
-<p>879. <a href="https://ssrn.com/abstract">https://ssrn.com/abstract</a></p>
+<p>877. <a href="https://ssrn.com/abstract">https://ssrn.com/abstract</a></p>
 </div>
 <div id="ref-1Bgnim0gX">
-<p>880. <strong>The US Regulatory System and COVID-19 Vaccines</strong> <br />
+<p>878. <strong>The US Regulatory System and COVID-19 Vaccines</strong> <br />
 Joshua M. Sharfstein, Jesse L. Goodman, Luciana Borio<br />
 <em>JAMA</em> (2021-03-23) <a href="https://doi.org/gh77b3">https://doi.org/gh77b3</a> <br />
 DOI: <a href="https://doi.org/10.1001/jama.2021.1961">10.1001/jama.2021.1961</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33587124">33587124</a></p>
 </div>
 <div id="ref-I0vakLIc">
-<p>881. <strong>South Africa starts administering Janssen COVID-19 vaccine to health workers</strong> <br />
+<p>879. <strong>South Africa starts administering Janssen COVID-19 vaccine to health workers</strong> <br />
 biopharma-reporter.com<br />
 <em>biopharma-reporter.com</em> <a href="https://www.biopharma-reporter.com/Article/2021/02/18/South-Africa-starts-administering-Janssen-COVID-19-vaccine-to-health-workers">https://www.biopharma-reporter.com/Article/2021/02/18/South-Africa-starts-administering-Janssen-COVID-19-vaccine-to-health-workers</a></p>
 </div>
 <div id="ref-17BEDzTkD">
-<p>882. <strong>EMA receives application for conditional marketing authorisation of COVID-19 Vaccine Janssen</strong> <br />
+<p>880. <strong>EMA receives application for conditional marketing authorisation of COVID-19 Vaccine Janssen</strong> <br />
 Ana Catarina PINHO<br />
 <em>European Medicines Agency</em> (2021-02-16) <a href="https://www.ema.europa.eu/en/news/ema-receives-application-conditional-marketing-authorisation-covid-19-vaccine-janssen">https://www.ema.europa.eu/en/news/ema-receives-application-conditional-marketing-authorisation-covid-19-vaccine-janssen</a></p>
 </div>
 <div id="ref-hHW8U8rE">
-<p>883. <strong>Merck will help make Johnson &amp; Johnson coronavirus vaccine as rivals team up to help Biden accelerate shots</strong> <br />
+<p>881. <strong>Merck will help make Johnson &amp; Johnson coronavirus vaccine as rivals team up to help Biden accelerate shots</strong> <br />
 Christopher Rowland, Laurie McGinley<br />
 <em>Washington Post</em> <a href="https://www.washingtonpost.com/health/2021/03/02/merck-johnson-and-johnson-covid-vaccine-partnership/">https://www.washingtonpost.com/health/2021/03/02/merck-johnson-and-johnson-covid-vaccine-partnership/</a></p>
 </div>
 <div id="ref-133HGZMEL">
-<p>884. <strong>The UK has approved a COVID vaccine — here’s what scientists now want to know</strong> <br />
+<p>882. <strong>The UK has approved a COVID vaccine — here’s what scientists now want to know</strong> <br />
 Heidi Ledford, David Cyranoski, Richard Van Noorden<br />
 <em>Nature</em> (2020-12-03) <a href="https://doi.org/gh4xmm">https://doi.org/gh4xmm</a> <br />
 DOI: <a href="https://doi.org/10.1038/d41586-020-03441-8">10.1038/d41586-020-03441-8</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33288887">33288887</a></p>
 </div>
 <div id="ref-G6V3FR6V">
-<p>885. <strong>EMA recommends first COVID-19 vaccine for authorisation in the EU</strong> <br />
+<p>883. <strong>EMA recommends first COVID-19 vaccine for authorisation in the EU</strong> <br />
 Ana Catarina PINHO<br />
 <em>European Medicines Agency</em> (2020-12-21) <a href="https://www.ema.europa.eu/en/news/ema-recommends-first-covid-19-vaccine-authorisation-eu">https://www.ema.europa.eu/en/news/ema-recommends-first-covid-19-vaccine-authorisation-eu</a></p>
 </div>
 <div id="ref-1HIxYDTsj">
-<p>886. <strong>Regulatory approval of COVID-19 Vaccine AstraZeneca</strong> <br />
+<p>884. <strong>Regulatory approval of COVID-19 Vaccine AstraZeneca</strong> <br />
 GOV.UK<br />
 <a href="https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-astrazeneca">https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-astrazeneca</a></p>
 </div>
 <div id="ref-bbw8sMvc">
-<p>887. <strong>EMA recommends COVID-19 Vaccine AstraZeneca for authorisation in the EU</strong> <br />
+<p>885. <strong>EMA recommends COVID-19 Vaccine AstraZeneca for authorisation in the EU</strong> <br />
 Ana Catarina PINHO<br />
 <em>European Medicines Agency</em> (2021-01-29) <a href="https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-astrazeneca-authorisation-eu">https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-astrazeneca-authorisation-eu</a></p>
 </div>
 <div id="ref-q1Ui5Fm8">
-<p>888. <strong>Covid: Brian Pinker, 82, first to get Oxford-AstraZeneca vaccine</strong> <br />
+<p>886. <strong>Covid: Brian Pinker, 82, first to get Oxford-AstraZeneca vaccine</strong> <br />
 BBC News<br />
 (2021-01-04) <a href="https://www.bbc.com/news/uk-55525542">https://www.bbc.com/news/uk-55525542</a></p>
 </div>
 <div id="ref-JPSLcRBY">
-<p>889. <strong>COVID-19 Vaccine Moderna</strong> <br />
+<p>887. <strong>COVID-19 Vaccine Moderna</strong> <br />
 Dagmara CZARSKA-THORLEY<br />
 <em>European Medicines Agency</em> (2021-01-04) <a href="https://www.ema.europa.eu/en/medicines/human/EPAR/covid-19-vaccine-moderna">https://www.ema.europa.eu/en/medicines/human/EPAR/covid-19-vaccine-moderna</a></p>
 </div>
 <div id="ref-k9X9pXJe">
-<p>890. <strong>Regulatory approval of COVID-19 Vaccine Moderna</strong> <br />
+<p>888. <strong>Regulatory approval of COVID-19 Vaccine Moderna</strong> <br />
 GOV.UK<br />
 <a href="https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-moderna">https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-moderna</a></p>
 </div>
 <div id="ref-cWMPXfju">
-<p>891. <strong>Coronavirus (COVID-19) Vaccinations - Statistics and Research</strong> <br />
+<p>889. <strong>Coronavirus (COVID-19) Vaccinations - Statistics and Research</strong> <br />
 Our World in Data<br />
 <a href="https://ourworldindata.org/covid-vaccinations">https://ourworldindata.org/covid-vaccinations</a></p>
 </div>
 <div id="ref-uvQMgFXB">
-<p>892. <strong>Bloomberg - Are you a robot?</strong> <a href="https://www.bloomberg.com/tosv2.html?vid=&amp;uuid=9b5c7b00-9ec4-11eb-a6f8-b58fbe3ef147&amp;url=L25ld3MvYXJ0aWNsZXMvMjAyMC0xMi0wMi93aXRoaW4taG91cnMtb2YtdS1rLXB1dGluLW9yZGVycy1zdGFydC1vZi1tYXNzLWNvdmlkLTE5LXNob3Rz">https://www.bloomberg.com/tosv2.html?vid=&amp;uuid=9b5c7b00-9ec4-11eb-a6f8-b58fbe3ef147&amp;url=L25ld3MvYXJ0aWNsZXMvMjAyMC0xMi0wMi93aXRoaW4taG91cnMtb2YtdS1rLXB1dGluLW9yZGVycy1zdGFydC1vZi1tYXNzLWNvdmlkLTE5LXNob3Rz</a></p>
+<p>890. <strong>Bloomberg - Are you a robot?</strong> <a href="https://www.bloomberg.com/tosv2.html?vid=&amp;uuid=091df480-a75c-11eb-94ca-b7c1990cdae7&amp;url=L25ld3MvYXJ0aWNsZXMvMjAyMC0xMi0wMi93aXRoaW4taG91cnMtb2YtdS1rLXB1dGluLW9yZGVycy1zdGFydC1vZi1tYXNzLWNvdmlkLTE5LXNob3Rz">https://www.bloomberg.com/tosv2.html?vid=&amp;uuid=091df480-a75c-11eb-94ca-b7c1990cdae7&amp;url=L25ld3MvYXJ0aWNsZXMvMjAyMC0xMi0wMi93aXRoaW4taG91cnMtb2YtdS1rLXB1dGluLW9yZGVycy1zdGFydC1vZi1tYXNzLWNvdmlkLTE5LXNob3Rz</a></p>
 </div>
 <div id="ref-Vwv7l7Hd">
-<p>893. <strong>Facing Record Covid-19 Case Rise, Russia Rolls Out Sputnik V Vaccine</strong> <br />
+<p>891. <strong>Facing Record Covid-19 Case Rise, Russia Rolls Out Sputnik V Vaccine</strong> <br />
 James Rodgers<br />
 <em>Forbes</em> <a href="https://www.forbes.com/sites/jamesrodgerseurope/2020/12/05/facing-record-covid-19-case-rise-russia-rolls-out-sputnik-v-vaccine/">https://www.forbes.com/sites/jamesrodgerseurope/2020/12/05/facing-record-covid-19-case-rise-russia-rolls-out-sputnik-v-vaccine/</a></p>
 </div>
 <div id="ref-P6x0Qy6s">
-<p>894. <strong>Clarification on Sputnik V vaccine in the EU approval process</strong> <br />
+<p>892. <strong>Clarification on Sputnik V vaccine in the EU approval process</strong> <br />
 Ana Catarina PINHO<br />
 <em>European Medicines Agency</em> (2021-02-10) <a href="https://www.ema.europa.eu/en/news/clarification-sputnik-v-vaccine-eu-approval-process">https://www.ema.europa.eu/en/news/clarification-sputnik-v-vaccine-eu-approval-process</a></p>
 </div>
 <div id="ref-ID8IywJM">
-<p>895. <strong>Countries are lining up for Russia’s once-scorned Sputnik vaccine after strong efficacy results</strong> <br />
+<p>893. <strong>Countries are lining up for Russia’s once-scorned Sputnik vaccine after strong efficacy results</strong> <br />
 Fortune<br />
 <a href="https://fortune.com/2021/02/08/international-sputnik-russia-demand/">https://fortune.com/2021/02/08/international-sputnik-russia-demand/</a></p>
 </div>
 <div id="ref-160U0Yb7M">
-<p>896. <strong>Russian Direct Investment Fund</strong> <a href="https://rdif.ru/Eng_fullNews/5858/">https://rdif.ru/Eng_fullNews/5858/</a></p>
+<p>894. <strong>Russian Direct Investment Fund</strong> <a href="https://rdif.ru/Eng_fullNews/5858/">https://rdif.ru/Eng_fullNews/5858/</a></p>
 </div>
 <div id="ref-FAQXPsyc">
-<p>897. <strong>Unable to get U.S. vaccines, world turns to Russia and China</strong> <br />
+<p>895. <strong>Unable to get U.S. vaccines, world turns to Russia and China</strong> <br />
 Ryan Heath<br />
 <em>POLITICO</em> <a href="https://www.politico.com/news/2021/02/25/global-vaccine-public-relations-war-471665">https://www.politico.com/news/2021/02/25/global-vaccine-public-relations-war-471665</a></p>
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 <div id="ref-zCPl6A82">
-<p>898. <strong>Germany moves to bring Russian vaccine into EU orbit</strong> <br />
+<p>896. <strong>Germany moves to bring Russian vaccine into EU orbit</strong> <br />
 France 24<br />
 (2021-02-03) <a href="https://www.france24.com/en/live-news/20210203-germany-moves-to-bring-russian-vaccine-into-eu-orbit">https://www.france24.com/en/live-news/20210203-germany-moves-to-bring-russian-vaccine-into-eu-orbit</a></p>
 </div>
 <div id="ref-hpScvlYg">
-<p>899. <strong>Russia approves its third COVID-19 vaccine, CoviVac</strong> <br />
+<p>897. <strong>Russia approves its third COVID-19 vaccine, CoviVac</strong> <br />
 Polina Ivanova<br />
 <em>Reuters</em> (2021-02-20) <a href="https://www.reuters.com/article/us-health-coronavirus-russia-vaccine-idUSKBN2AK07H">https://www.reuters.com/article/us-health-coronavirus-russia-vaccine-idUSKBN2AK07H</a></p>
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 <div id="ref-4PSTgetR">
-<p>900. <strong>Coronavirus Vaccine Tracker</strong> <br />
+<p>898. <strong>Coronavirus Vaccine Tracker</strong> <br />
 Carl Zimmer, Jonathan Corum, Sui-Lee Wee<br />
 <em>The New York Times</em> <a href="https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html">https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html</a></p>
 </div>
 <div id="ref-1AvwH3T5y">
-<p>901. <strong>With First Dibs on Vaccines, Rich Countries Have “Cleared the Shelves”</strong> <br />
+<p>899. <strong>With First Dibs on Vaccines, Rich Countries Have “Cleared the Shelves”</strong> <br />
 Megan Twohey, Keith Collins, Katie Thomas<br />
 <em>The New York Times</em> (2020-12-15) <a href="https://www.nytimes.com/2020/12/15/us/coronavirus-vaccine-doses-reserved.html">https://www.nytimes.com/2020/12/15/us/coronavirus-vaccine-doses-reserved.html</a></p>
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 <div id="ref-1EnpYQzIq">
-<p>902. <strong>Covid-19 Africa: What is happening with vaccines?</strong> <br />
+<p>900. <strong>Covid-19 Africa: What is happening with vaccines?</strong> <br />
 BBC News<br />
-(2021-04-15) <a href="https://www.bbc.com/news/56100076">https://www.bbc.com/news/56100076</a></p>
+(2021-04-23) <a href="https://www.bbc.com/news/56100076">https://www.bbc.com/news/56100076</a></p>
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 <div id="ref-3Gq7ETv7">
-<p>903. <strong>International Collaboration to Ensure Equitable Access to Vaccines for COVID‐19: The ACT‐Accelerator and the COVAX Facility</strong> <br />
+<p>901. <strong>International Collaboration to Ensure Equitable Access to Vaccines for COVID‐19: The ACT‐Accelerator and the COVAX Facility</strong> <br />
 MARK ECCLESTON‐TURNER, HARRY UPTON<br />
 <em>The Milbank Quarterly</em> (2021-03-02) <a href="https://doi.org/gh77cc">https://doi.org/gh77cc</a> <br />
 DOI: <a href="https://doi.org/10.1111/1468-0009.12503">10.1111/1468-0009.12503</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33650737">33650737</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014072">PMC8014072</a></p>
 </div>
 <div id="ref-KzHIbPMY">
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+<p>902. <strong>Fair allocation mechanism for COVID-19 vaccines through the COVAX Facility</strong> <a href="https://www.who.int/publications/m/item/fair-allocation-mechanism-for-covid-19-vaccines-through-the-covax-facility">https://www.who.int/publications/m/item/fair-allocation-mechanism-for-covid-19-vaccines-through-the-covax-facility</a></p>
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 <div id="ref-1H0PiQpLz">
-<p>905. <strong>Global plan seeks to promote vaccine equity, spread risks</strong> <br />
+<p>903. <strong>Global plan seeks to promote vaccine equity, spread risks</strong> <br />
 Kai Kupferschmidt<br />
 <em>Science</em> (2020-07-30) <a href="https://doi.org/gh77cd">https://doi.org/gh77cd</a> <br />
 DOI: <a href="https://doi.org/10.1126/science.369.6503.489">10.1126/science.369.6503.489</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32732400">32732400</a></p>
 </div>
 <div id="ref-12QaZb4si">
-<p>906. <strong>Covax must go beyond proportional allocation of covid vaccines to ensure fair and equitable access</strong> <br />
+<p>904. <strong>Covax must go beyond proportional allocation of covid vaccines to ensure fair and equitable access</strong> <br />
 Lisa M Herzog, Ole F Norheim, Ezekiel J Emanuel, Matthew S McCoy<br />
 <em>BMJ</em> (2021-01-05) <a href="https://doi.org/gjgqjv">https://doi.org/gjgqjv</a> <br />
 DOI: <a href="https://doi.org/10.1136/bmj.m4853">10.1136/bmj.m4853</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33402340">33402340</a></p>
 </div>
 <div id="ref-7dkwQDUf">
-<p>907. <strong>COVAX</strong> <a href="https://www.who.int/initiatives/act-accelerator/covax">https://www.who.int/initiatives/act-accelerator/covax</a></p>
+<p>905. <strong>COVAX</strong> <a href="https://www.who.int/initiatives/act-accelerator/covax">https://www.who.int/initiatives/act-accelerator/covax</a></p>
 </div>
 <div id="ref-sr5oRBgc">
-<p>908. <strong>Countries now scrambling for COVID-19 vaccines may soon have surpluses to donate</strong> <br />
+<p>906. <strong>Countries now scrambling for COVID-19 vaccines may soon have surpluses to donate</strong> <br />
 Jon Cohen<br />
 <em>Science</em> (2021-03-09) <a href="https://doi.org/gh77cf">https://doi.org/gh77cf</a> <br />
 DOI: <a href="https://doi.org/10.1126/science.abh4476">10.1126/science.abh4476</a></p>
 </div>
 <div id="ref-2b6FdDOy">
-<p>909. <strong>First COVID-19 COVAX vaccine doses administered in Africa</strong> <a href="https://www.who.int/news/item/01-03-2021-first-covid-19-covax-vaccine-doses-administered-in-africa">https://www.who.int/news/item/01-03-2021-first-covid-19-covax-vaccine-doses-administered-in-africa</a></p>
+<p>907. <strong>First COVID-19 COVAX vaccine doses administered in Africa</strong> <a href="https://www.who.int/news/item/01-03-2021-first-covid-19-covax-vaccine-doses-administered-in-africa">https://www.who.int/news/item/01-03-2021-first-covid-19-covax-vaccine-doses-administered-in-africa</a></p>
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+<p>908. <strong>Pfizer and BioNTech to Submit Emergency Use Authorization Request Today to the U.S. FDA for COVID-19 Vaccine | Pfizer</strong> <a href="https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-submit-emergency-use-authorization">https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-submit-emergency-use-authorization</a></p>
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+<p>909. <strong>Moderna Announces First Participants Dosed in Phase 2/3 Study of COVID-19 Vaccine Candidate in Adolescents | Moderna, Inc.</strong> <a href="https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-first-participants-dosed-phase-23-study-covid/">https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-first-participants-dosed-phase-23-study-covid/</a></p>
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-<p>912. <strong>COVID-19: The Inflammation Link and the Role of Nutrition in Potential Mitigation</strong> <br />
+<p>910. <strong>COVID-19: The Inflammation Link and the Role of Nutrition in Potential Mitigation</strong> <br />
 Ioannis Zabetakis, Ronan Lordan, Catherine Norton, Alexandros Tsoupras<br />
 <em>Nutrients</em> (2020-05-19) <a href="https://doi.org/ggxdq3">https://doi.org/ggxdq3</a> <br />
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+<p>911. <strong>Could nutrition modulate COVID-19 susceptibility and severity of disease? A systematic review</strong> <br />
 Philip T. James, Zakari Ali, Andrew E. Armitage, Ana Bonell, Carla Cerami, Hal Drakesmith, Modou Jobe, Kerry S. Jones, Zara Liew, Sophie E. Moore, … Andrew M. Prentice<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-10-21) <a href="https://doi.org/ghr94g">https://doi.org/ghr94g</a> <br />
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-<p>914. <strong>Coronavirus Disease 2019 (COVID-19) and Nutritional Status: The Missing Link?</strong> <br />
+<p>912. <strong>Coronavirus Disease 2019 (COVID-19) and Nutritional Status: The Missing Link?</strong> <br />
 Renata Silverio, Daniela Caetano Gonçalves, Márcia Fábia Andrade, Marilia Seelaender<br />
 <em>Advances in Nutrition</em> (2020-09-25) <a href="https://doi.org/ghhqjd">https://doi.org/ghhqjd</a> <br />
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-<p>915. <strong>Nutritional status of patients with COVID-19</strong> <br />
+<p>913. <strong>Nutritional status of patients with COVID-19</strong> <br />
 Jae Hyoung Im, Young Soo Je, Jihyeon Baek, Moon-Hyun Chung, Hea Yoon Kwon, Jin-Soo Lee<br />
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-<p>916. <strong>Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections</strong> <br />
+<p>914. <strong>Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections</strong> <br />
 Philip Calder, Anitra Carr, Adrian Gombart, Manfred Eggersdorfer<br />
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+<p>915. <strong>Peak dietary supplement sales leveling off during COVID-19 pandemic, but growth still remains strong over last year, market researchers report during webcast</strong> <br />
 Nutritional Outlook<br />
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+<p>916. <strong>Dietary Diversity among Chinese Residents during the COVID-19 Outbreak and Its Associated Factors</strong> <br />
 Ai Zhao, Zhongyu Li, Yalei Ke, Shanshan Huo, Yidi Ma, Yumei Zhang, Jian Zhang, Zhongxia Ren<br />
 <em>Nutrients</em> (2020-06-06) <a href="https://doi.org/ghc6d9">https://doi.org/ghc6d9</a> <br />
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+<p>917. <strong>Lockdown impact: Grocery stores bolstered NZ supplements sales as pharmacies slumped</strong> <br />
 nutraingredients-asia.com<br />
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-<p>920. <strong>COVID-19 temporarily bolsters European interest in supplements</strong> <br />
+<p>918. <strong>COVID-19 temporarily bolsters European interest in supplements</strong> <br />
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+<p>919. <strong>India’s immune health surge: Nation leads APAC in number of new product launches – new data</strong> <br />
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+<p>920. <strong>Food policy, nutrition and nutraceuticals in the prevention and management of COVID-19: Advice for healthcare professionals</strong> <br />
 Yasemin Ipek Ayseli, Nazli Aytekin, Derya Buyukkayhan, Ismail Aslan, Mehmet Turan Ayseli<br />
 <em>Trends in Food Science &amp; Technology</em> (2020-11) <a href="https://doi.org/ghjtcp">https://doi.org/ghjtcp</a> <br />
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+<p>921. <strong>5 Food and Beverage Trends in Europe During COVID-19</strong> <a href="https://kerry.com/insights/kerrydigest/2020/5-food-and-beverage-trends-in-europe-during-covid-19">https://kerry.com/insights/kerrydigest/2020/5-food-and-beverage-trends-in-europe-during-covid-19</a></p>
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+<p>922. <strong>Structural Design Principles for Delivery of Bioactive Components in Nutraceuticals and Functional Foods</strong> <br />
 David Julian McClements, Eric Andrew Decker, Yeonhwa Park, Jochen Weiss<br />
 <em>Critical Reviews in Food Science and Nutrition</em> (2009-06-16) <a href="https://doi.org/dt68m4">https://doi.org/dt68m4</a> <br />
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+<p>923. <strong>Nutraceutical therapies for atherosclerosis</strong> <br />
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+<p>924. <strong>Nutraceutical-definition and introduction</strong> <br />
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 <em>AAPS PharmSci</em> (2015-07-10) <a href="https://doi.org/cg5wc9">https://doi.org/cg5wc9</a> <br />
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+<p>925. <strong>Dietary Supplement Health and Education Act of 1994</strong> <br />
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+<p>927. <strong>Nutraceuticals - shedding light on the grey area between pharmaceuticals and food</strong> <br />
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+<p>928. <a href="https://eur-lex.europa.eu/legal-content/EN/ALL">https://eur-lex.europa.eu/legal-content/EN/ALL</a></p>
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+<p>931. <strong>Nutraceuticals: opening the debate for a regulatory framework</strong> <br />
 Antonello Santini, Silvia Miriam Cammarata, Giacomo Capone, Angela Ianaro, Gian Carlo Tenore, Luca Pani, Ettore Novellino<br />
 <em>British Journal of Clinical Pharmacology</em> (2018-04) <a href="https://doi.org/ggwztm">https://doi.org/ggwztm</a> <br />
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+<p>932. <strong>Reviewing the Nutrition and Health Claims Regulation (EC) No. 1924/2006: What do we know about its challenges and potential impact on innovation?</strong> <br />
 Stefanie Bröring, Sukhada Khedkar, Stefano Ciliberti<br />
 <em>International Journal of Food Sciences and Nutrition</em> (2016-08-02) <a href="https://doi.org/ghr936">https://doi.org/ghr936</a> <br />
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+<p>933. <strong>Dietary Supplements: Regulatory Challenges and Research Resources</strong> <br />
 Johanna Dwyer, Paul Coates, Michael Smith<br />
 <em>Nutrients</em> (2018-01-04) <a href="https://doi.org/ghr949">https://doi.org/ghr949</a> <br />
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+<p>934. <strong>Noetic Nutraceuticals - 607572 - 05/15/2020</strong> <br />
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+<p>936. <strong>Spartan Enterprises Inc. dba Watershed Wellness Center - 610876 - 10/30/2020</strong> <br />
 Center for Drug Evaluation and Research<br />
 <em>Center for Drug Evaluation and Research</em> (2020-11-02) <a href="https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/spartan-enterprises-inc-dba-watershed-wellness-center-610876-10302020">https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/spartan-enterprises-inc-dba-watershed-wellness-center-610876-10302020</a></p>
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+<p>937. <strong>FTC Sues California Marketer of $23,000 COVID-19 “Treatment” Plan</strong> <br />
 Federal Trade Commission<br />
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+<p>938. <a href="https://cen.acs.org/biological-chemistry/natural-products/oleandrin-compound-touted-possible-COVID/98/web/2020/08">https://cen.acs.org/biological-chemistry/natural-products/oleandrin-compound-touted-possible-COVID/98/web/2020/08</a></p>
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+<p>939. <strong>Reducing mortality from 2019-nCoV: host-directed therapies should be an option</strong> <br />
 Alimuddin Zumla, David S Hui, Esam I Azhar, Ziad A Memish, Markus Maeurer<br />
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+<p>940. <strong>Diet Supplementation, Probiotics, and Nutraceuticals in SARS-CoV-2 Infection: A Scoping Review</strong> <br />
 Fabio Infusino, Massimiliano Marazzato, Massimo Mancone, Francesco Fedele, Claudio Maria Mastroianni, Paolo Severino, Giancarlo Ceccarelli, Letizia Santinelli, Elena Cavarretta, Antonino G. M. Marullo, … Gabriella d’Ettorre<br />
 <em>Nutrients</em> (2020-06-08) <a href="https://doi.org/gg8k58">https://doi.org/gg8k58</a> <br />
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+<p>941. <strong>Potential interventions for novel coronavirus in China: A systematic review</strong> <br />
 Lei Zhang, Yunhui Liu<br />
 <em>Journal of Medical Virology</em> (2020-03-03) <a href="https://doi.org/ggpx57">https://doi.org/ggpx57</a> <br />
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 Kimberley Lewis, Dipayan Chaudhuri, Fayez Alshamsi, Laiya Carayannopoulos, Karin Dearness, Zain Chagla, Waleed Alhazzani, for the GUIDE Group<br />
 <em>PLOS ONE</em> (2021-01-06) <a href="https://doi.org/ghsv36">https://doi.org/ghsv36</a> <br />
 DOI: <a href="https://doi.org/10.1371/journal.pone.0244778">10.1371/journal.pone.0244778</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33406138">33406138</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787432">PMC7787432</a></p>
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-<p>1003. <strong>Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis</strong> <br />
+<p>1001. <strong>Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis</strong> <br />
 Thibault Fiolet, Anthony Guihur, Mathieu Edouard Rebeaud, Matthieu Mulot, Nathan Peiffer-Smadja, Yahya Mahamat-Saleh<br />
 <em>Clinical Microbiology and Infection</em> (2021-01) <a href="https://doi.org/gg9jk2">https://doi.org/gg9jk2</a> <br />
 DOI: <a href="https://doi.org/10.1016/j.cmi.2020.08.022">10.1016/j.cmi.2020.08.022</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32860962">32860962</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449662">PMC7449662</a></p>
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-<p>1004. <strong>Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients</strong> <br />
+<p>1002. <strong>Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients</strong> <br />
 Philip M. Carlucci, Tania Ahuja, Christopher Petrilli, Harish Rajagopalan, Simon Jones, Joseph Rahimian<br />
 <em>Journal of Medical Microbiology</em> (2020-10-01) <a href="https://doi.org/ghnws7">https://doi.org/ghnws7</a> <br />
 DOI: <a href="https://doi.org/10.1099/jmm.0.001250">10.1099/jmm.0.001250</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32930657">32930657</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660893">PMC7660893</a></p>
 </div>
 <div id="ref-110pLAjkl">
-<p>1005. <strong>The Minimal Effect of Zinc on the Survival of Hospitalized Patients With COVID-19</strong> <br />
+<p>1003. <strong>The Minimal Effect of Zinc on the Survival of Hospitalized Patients With COVID-19</strong> <br />
 Jasper Seth Yao, Joseph Alexander Paguio, Edward Christopher Dee, Hanna Clementine Tan, Achintya Moulick, Carmelo Milazzo, Jerry Jurado, Nicolás Della Penna, Leo Anthony Celi<br />
 <em>Chest</em> (2021-01) <a href="https://doi.org/gg5w36">https://doi.org/gg5w36</a> <br />
 DOI: <a href="https://doi.org/10.1016/j.chest.2020.06.082">10.1016/j.chest.2020.06.082</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32710890">32710890</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375307">PMC7375307</a></p>
 </div>
 <div id="ref-1GGbb9IZt">
-<p>1006. <strong>Coronavirus Disease 2019- Using Ascorbic Acid and Zinc Supplementation (COVIDAtoZ) Research Study A Randomized, Open Label Single Center Study</strong> <br />
+<p>1004. <strong>Coronavirus Disease 2019- Using Ascorbic Acid and Zinc Supplementation (COVIDAtoZ) Research Study A Randomized, Open Label Single Center Study</strong> <br />
 Milind Desai<br />
 <em>clinicaltrials.gov</em> (2021-01-28) <a href="https://clinicaltrials.gov/ct2/show/NCT04342728">https://clinicaltrials.gov/ct2/show/NCT04342728</a></p>
 </div>
 <div id="ref-3RCeQRRc">
-<p>1007. <strong>Vitamin B12 May Inhibit RNA-Dependent-RNA Polymerase Activity of nsp12 from the COVID-19 Virus</strong> <br />
+<p>1005. <strong>Vitamin B12 May Inhibit RNA-Dependent-RNA Polymerase Activity of nsp12 from the COVID-19 Virus</strong> <br />
 Naveen Narayanan, Deepak T. Nair<br />
 <em>Preprints</em> (2020-03-22) <a href="https://doi.org/ggqmjc">https://doi.org/ggqmjc</a> <br />
 DOI: <a href="https://doi.org/10.20944/preprints202003.0347.v1">10.20944/preprints202003.0347.v1</a></p>
 </div>
 <div id="ref-190FMJu3y">
-<p>1008. <strong>The Long History of Vitamin C: From Prevention of the Common Cold to Potential Aid in the Treatment of COVID-19</strong> <br />
+<p>1006. <strong>The Long History of Vitamin C: From Prevention of the Common Cold to Potential Aid in the Treatment of COVID-19</strong> <br />
 Giuseppe Cerullo, Massimo Negro, Mauro Parimbelli, Michela Pecoraro, Simone Perna, Giorgio Liguori, Mariangela Rondanelli, Hellas Cena, Giuseppe D’Antona<br />
 <em>Frontiers in Immunology</em> (2020-10-28) <a href="https://doi.org/ghr943">https://doi.org/ghr943</a> <br />
 DOI: <a href="https://doi.org/10.3389/fimmu.2020.574029">10.3389/fimmu.2020.574029</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33193359">33193359</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655735">PMC7655735</a></p>
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-<p>1009. <strong>The Emerging Role of Vitamin C in the Prevention and Treatment of COVID-19</strong> <br />
+<p>1007. <strong>The Emerging Role of Vitamin C in the Prevention and Treatment of COVID-19</strong> <br />
 Anitra C. Carr, Sam Rowe<br />
 <em>Nutrients</em> (2020-10-27) <a href="https://doi.org/ghr95c">https://doi.org/ghr95c</a> <br />
 DOI: <a href="https://doi.org/10.3390/nu12113286">10.3390/nu12113286</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33121019">33121019</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693980">PMC7693980</a></p>
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-<p>1010. <strong>Vitamin C Mitigates Oxidative Stress and Tumor Necrosis Factor-Alpha in Severe Community-Acquired Pneumonia and LPS-Induced Macrophages</strong> <br />
+<p>1008. <strong>Vitamin C Mitigates Oxidative Stress and Tumor Necrosis Factor-Alpha in Severe Community-Acquired Pneumonia and LPS-Induced Macrophages</strong> <br />
 Yuanyuan Chen, Guangyan Luo, Jiao Yuan, Yuanyuan Wang, Xiaoqiong Yang, Xiaoyun Wang, Guoping Li, Zhiguang Liu, Nanshan Zhong<br />
 <em>Mediators of Inflammation</em> (2014) <a href="https://doi.org/f6nb5f">https://doi.org/f6nb5f</a> <br />
 DOI: <a href="https://doi.org/10.1155/2014/426740">10.1155/2014/426740</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/25253919">25253919</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165740">PMC4165740</a></p>
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-<p>1011. <strong>Intravenous infusion of ascorbic acid decreases serum histamine concentrations in patients with allergic and non-allergic diseases</strong> <br />
+<p>1009. <strong>Intravenous infusion of ascorbic acid decreases serum histamine concentrations in patients with allergic and non-allergic diseases</strong> <br />
 Alexander F. Hagel, Christian M. Layritz, Wolfgang H. Hagel, Hans-Jürgen Hagel, Edith Hagel, Wolfgang Dauth, Jürgen Kressel, Tanja Regnet, Andreas Rosenberg, Markus F. Neurath, … Martin Raithel<br />
 <em>Naunyn-Schmiedeberg’s Archives of Pharmacology</em> (2013-05-11) <a href="https://doi.org/f48jsb">https://doi.org/f48jsb</a> <br />
 DOI: <a href="https://doi.org/10.1007/s00210-013-0880-1">10.1007/s00210-013-0880-1</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/23666445">23666445</a></p>
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-<p>1012. <strong>Vitamin C and Immune Function</strong> <br />
+<p>1010. <strong>Vitamin C and Immune Function</strong> <br />
 Anitra Carr, Silvia Maggini<br />
 <em>Nutrients</em> (2017-11-03) <a href="https://doi.org/gfzrjs">https://doi.org/gfzrjs</a> <br />
 DOI: <a href="https://doi.org/10.3390/nu9111211">10.3390/nu9111211</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/29099763">29099763</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707683">PMC5707683</a></p>
 </div>
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-<p>1013. <strong>Changes in Leucocyte Ascorbic Acid during the Common Cold</strong> <br />
+<p>1011. <strong>Changes in Leucocyte Ascorbic Acid during the Common Cold</strong> <br />
 R. Hume, Elspeth Weyers<br />
 <em>Scottish Medical Journal</em> (2016-06-25) <a href="https://doi.org/ggqrfj">https://doi.org/ggqrfj</a> <br />
 DOI: <a href="https://doi.org/10.1177/003693307301800102">10.1177/003693307301800102</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/4717661">4717661</a></p>
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-<p>1014. <strong>ASCORBIC ACID FUNCTION AND METABOLISM DURING COLDS</strong> <br />
+<p>1012. <strong>ASCORBIC ACID FUNCTION AND METABOLISM DURING COLDS</strong> <br />
 C. W. M. Wilson<br />
 <em>Annals of the New York Academy of Sciences</em> (1975-09) <a href="https://doi.org/bjfdtb">https://doi.org/bjfdtb</a> <br />
 DOI: <a href="https://doi.org/10.1111/j.1749-6632.1975.tb29312.x">10.1111/j.1749-6632.1975.tb29312.x</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/1106304">1106304</a></p>
 </div>
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-<p>1015. <strong>Metabolism of ascorbic acid (vitamin C) in subjects infected with common cold viruses</strong> <br />
+<p>1013. <strong>Metabolism of ascorbic acid (vitamin C) in subjects infected with common cold viruses</strong> <br />
 J. E. W. Davies, R. E. Hughes, Eleri Jones, Sylvia E. Reed, J. W. Craig, D. A. J. Tyrrell<br />
 <em>Biochemical Medicine</em> (1979-02) <a href="https://doi.org/fd22sv">https://doi.org/fd22sv</a> <br />
 DOI: <a href="https://doi.org/10.1016/0006-2944(79)90058-9">10.1016/0006-2944(79)90058-9</a></p>
 </div>
 <div id="ref-aEEZ8Pq9">
-<p>1016. <strong>Vitamin C and Infections</strong> <br />
+<p>1014. <strong>Vitamin C and Infections</strong> <br />
 Harri Hemilä<br />
 <em>Nutrients</em> (2017-03-29) <a href="https://doi.org/gfkb9n">https://doi.org/gfkb9n</a> <br />
 DOI: <a href="https://doi.org/10.3390/nu9040339">10.3390/nu9040339</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/28353648">28353648</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409678">PMC5409678</a></p>
 </div>
 <div id="ref-gZRPoTM9">
-<p>1017. <strong>Vitamin C and the common cold</strong> <br />
+<p>1015. <strong>Vitamin C and the common cold</strong> <br />
 Harri Hemilä<br />
 <em>British Journal of Nutrition</em> (2007-03-09) <a href="https://doi.org/fszhc6">https://doi.org/fszhc6</a> <br />
 DOI: <a href="https://doi.org/10.1079/bjn19920004">10.1079/bjn19920004</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/1547201">1547201</a></p>
 </div>
 <div id="ref-DPhRTQw0">
-<p>1018. <strong>Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis</strong> <br />
+<p>1016. <strong>Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis</strong> <br />
 Harri Hemilä, Elizabeth Chalker<br />
 <em>Nutrients</em> (2019-03-27) <a href="https://doi.org/gfzscg">https://doi.org/gfzscg</a> <br />
 DOI: <a href="https://doi.org/10.3390/nu11040708">10.3390/nu11040708</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/30934660">30934660</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521194">PMC6521194</a></p>
 </div>
 <div id="ref-WEWGGYKl">
-<p>1019. <strong>Serum Levels of Vitamin C and Vitamin D in a Cohort of Critically Ill COVID-19 Patients of a North American Community Hospital Intensive Care Unit in May 2020: A Pilot Study</strong> <br />
+<p>1017. <strong>Serum Levels of Vitamin C and Vitamin D in a Cohort of Critically Ill COVID-19 Patients of a North American Community Hospital Intensive Care Unit in May 2020: A Pilot Study</strong> <br />
 Cristian Arvinte, Maharaj Singh, Paul E. Marik<br />
 <em>Medicine in Drug Discovery</em> (2020-12) <a href="https://doi.org/ghnwqt">https://doi.org/ghnwqt</a> <br />
 DOI: <a href="https://doi.org/10.1016/j.medidd.2020.100064">10.1016/j.medidd.2020.100064</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32964205">32964205</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499070">PMC7499070</a></p>
 </div>
 <div id="ref-Zrm5dyM1">
-<p>1020. <strong>Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome</strong> <br />
+<p>1018. <strong>Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome</strong> <br />
 Luis Chiscano-Camón, Juan Carlos Ruiz-Rodriguez, Adolf Ruiz-Sanmartin, Oriol Roca, Ricard Ferrer<br />
 <em>Critical Care</em> (2020-08-26) <a href="https://doi.org/ghbr97">https://doi.org/ghbr97</a> <br />
 DOI: <a href="https://doi.org/10.1186/s13054-020-03249-y">10.1186/s13054-020-03249-y</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32847620">32847620</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447967">PMC7447967</a></p>
 </div>
 <div id="ref-19taZjxIT">
-<p>1021. <strong>Targeting coagulation activation in severe COVID-19 pneumonia: lessons from bacterial pneumonia and sepsis</strong> <br />
+<p>1019. <strong>Targeting coagulation activation in severe COVID-19 pneumonia: lessons from bacterial pneumonia and sepsis</strong> <br />
 Ricardo J. José, Andrew Williams, Ari Manuel, Jeremy S. Brown, Rachel C. Chambers<br />
 <em>European Respiratory Review</em> (2020-10-01) <a href="https://doi.org/ghr94s">https://doi.org/ghr94s</a> <br />
 DOI: <a href="https://doi.org/10.1183/16000617.0240-2020">10.1183/16000617.0240-2020</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33004529">33004529</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537941">PMC7537941</a></p>
 </div>
 <div id="ref-WKBgtN6W">
-<p>1022. <strong>Vitamin C and Microvascular Dysfunction in Systemic Inflammation</strong> <br />
+<p>1020. <strong>Vitamin C and Microvascular Dysfunction in Systemic Inflammation</strong> <br />
 Karel Tyml<br />
 <em>Antioxidants</em> (2017-06-29) <a href="https://doi.org/ghr947">https://doi.org/ghr947</a> <br />
 DOI: <a href="https://doi.org/10.3390/antiox6030049">10.3390/antiox6030049</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/28661424">28661424</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618077">PMC5618077</a></p>
 </div>
 <div id="ref-d9353XOW">
-<p>1023. <strong>The use of IV vitamin C for patients with COVID-19: a case series</strong> <br />
+<p>1021. <strong>The use of IV vitamin C for patients with COVID-19: a case series</strong> <br />
 Raul Hiedra, Kevin Bryan Lo, Mohammad Elbashabsheh, Fahad Gul, Robert Matthew Wright, Jeri Albano, Zurab Azmaiparashvili, Gabriel Patarroyo Aponte<br />
 <em>Expert Review of Anti-infective Therapy</em> (2020-08-01) <a href="https://doi.org/ghr938">https://doi.org/ghr938</a> <br />
 DOI: <a href="https://doi.org/10.1080/14787210.2020.1794819">10.1080/14787210.2020.1794819</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32662690">32662690</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441798">PMC7441798</a></p>
 </div>
 <div id="ref-Pb5PCH7y">
-<p>1024. <strong>Vitamin C for preventing and treating the common cold</strong> <br />
+<p>1022. <strong>Vitamin C for preventing and treating the common cold</strong> <br />
 Harri Hemilä, Elizabeth Chalker<br />
 <em>Cochrane Database of Systematic Reviews</em> (2013-01-31) <a href="https://doi.org/xz5">https://doi.org/xz5</a> <br />
 DOI: <a href="https://doi.org/10.1002/14651858.cd000980.pub4">10.1002/14651858.cd000980.pub4</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/23440782">23440782</a></p>
 </div>
 <div id="ref-JARvpqRw">
-<p>1025. <strong>Vitamin C intake and susceptibility to pneumonia</strong> <br />
+<p>1023. <strong>Vitamin C intake and susceptibility to pneumonia</strong> <br />
 HARRI HEMILÄ<br />
 <em>The Pediatric Infectious Disease Journal</em> (1997-09) <a href="https://doi.org/fkvs9d">https://doi.org/fkvs9d</a> <br />
 DOI: <a href="https://doi.org/10.1097/00006454-199709000-00003">10.1097/00006454-199709000-00003</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/9306475">9306475</a></p>
 </div>
 <div id="ref-Rt5Aik4p">
-<p>1026. <strong>Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure</strong> <br />
+<p>1024. <strong>Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure</strong> <br />
 Alpha A. Fowler, Jonathon D. Truwit, R. Duncan Hite, Peter E. Morris, Christine DeWilde, Anna Priday, Bernard Fisher, Leroy R. Thacker, Ramesh Natarajan, Donald F. Brophy, … Matthew Halquist<br />
 <em>JAMA</em> (2019-10-01) <a href="https://doi.org/ggqmh8">https://doi.org/ggqmh8</a> <br />
 DOI: <a href="https://doi.org/10.1001/jama.2019.11825">10.1001/jama.2019.11825</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/31573637">31573637</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777268">PMC6777268</a></p>
 </div>
 <div id="ref-nwa7WdNM">
-<p>1027. <strong>Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial</strong> <br />
+<p>1025. <strong>Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial</strong> <br />
 Fang Liu, Yuan Zhu, Jing Zhang, Yiming Li, Zhiyong Peng<br />
 <em>BMJ Open</em> (2020-07-08) <a href="https://doi.org/gg4sgj">https://doi.org/gg4sgj</a> <br />
 DOI: <a href="https://doi.org/10.1136/bmjopen-2020-039519">10.1136/bmjopen-2020-039519</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32641343">32641343</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348463">PMC7348463</a></p>
 </div>
 <div id="ref-ZX7LDDp0">
-<p>1028. <strong>Pilot Trial of High-dose vitamin C in critically ill COVID-19 patients</strong> <br />
+<p>1026. <strong>Pilot Trial of High-dose vitamin C in critically ill COVID-19 patients</strong> <br />
 Jing Zhang, Xin Rao, Yiming Li, Yuan Zhu, Fang Liu, Guangling Guo, Guoshi Luo, Zhongji Meng, Daniel De Backer, Hui Xiang, Zhi-Yong Peng<br />
 <em>Research Square</em> (2020-08-03) <a href="https://doi.org/ghr94x">https://doi.org/ghr94x</a> <br />
 DOI: <a href="https://doi.org/10.21203/rs.3.rs-52778/v2">10.21203/rs.3.rs-52778/v2</a></p>
 </div>
 <div id="ref-RM8v7Y7H">
-<p>1029. <strong>High-dose vitamin C infusion for the treatment of critically ill COVID-19</strong> <br />
+<p>1027. <strong>High-dose vitamin C infusion for the treatment of critically ill COVID-19</strong> <br />
 Jing Zhang, Xin Rao, Yiming Li, Yuan Zhu, Fang Liu, Guangling Guo, Guoshi Luo, Zhongji Meng, Daniel De Backer, Hui Xiang, Zhi-Yong Peng<br />
 <em>Research Square</em> (2020-08-03) <a href="https://doi.org/ghr94v">https://doi.org/ghr94v</a> <br />
 DOI: <a href="https://doi.org/10.21203/rs.3.rs-52778/v1">10.21203/rs.3.rs-52778/v1</a></p>
 </div>
 <div id="ref-hhf96MB1">
-<p>1030. <strong>Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids</strong> <br />
+<p>1028. <strong>Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids</strong> <br />
 Panel on Dietary Antioxidants and Related Compounds, Subcommittee on Upper Reference Levels of Nutrients, Subcommittee on Interpretation and Uses of Dietary Reference Intakes, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine<br />
 <em>The National Academies Press</em> (2000-07-27) <a href="https://doi.org/ghtvqx">https://doi.org/ghtvqx</a> <br />
 DOI: <a href="https://doi.org/10.17226/9810">10.17226/9810</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/25077263">25077263</a></p>
 </div>
 <div id="ref-3Nyo3kmR">
-<p>1031. <strong>Vitamin D and Infectious Diseases: Simple Bystander or Contributing Factor?</strong> <br />
+<p>1029. <strong>Vitamin D and Infectious Diseases: Simple Bystander or Contributing Factor?</strong> <br />
 Pedro Gois, Daniela Ferreira, Simon Olenski, Antonio Seguro<br />
 <em>Nutrients</em> (2017-06-24) <a href="https://doi.org/ggpcwr">https://doi.org/ggpcwr</a> <br />
 DOI: <a href="https://doi.org/10.3390/nu9070651">10.3390/nu9070651</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/28672783">28672783</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537771">PMC5537771</a></p>
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-<p>1032. <strong>Vitamin D and Influenza—Prevention or Therapy?</strong> <br />
+<p>1030. <strong>Vitamin D and Influenza—Prevention or Therapy?</strong> <br />
 Beata M. Gruber–Bzura<br />
 <em>International Journal of Molecular Sciences</em> (2018-08-16) <a href="https://doi.org/ggndrj">https://doi.org/ggndrj</a> <br />
 DOI: <a href="https://doi.org/10.3390/ijms19082419">10.3390/ijms19082419</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/30115864">30115864</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121423">PMC6121423</a></p>
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-<p>1033. <strong>Immunologic Effects of Vitamin D on Human Health and Disease</strong> <br />
+<p>1031. <strong>Immunologic Effects of Vitamin D on Human Health and Disease</strong> <br />
 Nipith Charoenngam, Michael F. Holick<br />
 <em>Nutrients</em> (2020-07-15) <a href="https://doi.org/gg45fp">https://doi.org/gg45fp</a> <br />
 DOI: <a href="https://doi.org/10.3390/nu12072097">10.3390/nu12072097</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32679784">32679784</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400911">PMC7400911</a></p>
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-<p>1034. <strong>Vitamin D and respiratory health</strong> <br />
+<p>1032. <strong>Vitamin D and respiratory health</strong> <br />
 D. A. Hughes, R. Norton<br />
 <em>Clinical &amp; Experimental Immunology</em> (2009-10) <a href="https://doi.org/b3n6wc">https://doi.org/b3n6wc</a> <br />
 DOI: <a href="https://doi.org/10.1111/j.1365-2249.2009.04001.x">10.1111/j.1365-2249.2009.04001.x</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/19737226">19737226</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759054">PMC2759054</a></p>
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-<p>1035. <strong>Regulation of Immune Function by Vitamin D and Its Use in Diseases of Immunity</strong> <br />
+<p>1033. <strong>Regulation of Immune Function by Vitamin D and Its Use in Diseases of Immunity</strong> <br />
 An-Sofie Vanherwegen, Conny Gysemans, Chantal Mathieu<br />
 <em>Endocrinology and Metabolism Clinics of North America</em> (2017-12) <a href="https://doi.org/gcm7h9">https://doi.org/gcm7h9</a> <br />
 DOI: <a href="https://doi.org/10.1016/j.ecl.2017.07.010">10.1016/j.ecl.2017.07.010</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/29080635">29080635</a></p>
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-<p>1036. <strong>Vitamin D and the Immune System</strong> <br />
+<p>1034. <strong>Vitamin D and the Immune System</strong> <br />
 Cynthia Aranow<br />
 <em>Journal of Investigative Medicine</em> (2015-12-15) <a href="https://doi.org/f3wh87">https://doi.org/f3wh87</a> <br />
 DOI: <a href="https://doi.org/10.2310/jim.0b013e31821b8755">10.2310/jim.0b013e31821b8755</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/21527855">21527855</a></p>
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-<p>1037. <strong>Vitamin D in the prevention of acute respiratory infection: Systematic review of clinical studies</strong> <br />
+<p>1035. <strong>Vitamin D in the prevention of acute respiratory infection: Systematic review of clinical studies</strong> <br />
 David A. Jolliffe, Christopher J. Griffiths, Adrian R. Martineau<br />
 <em>The Journal of Steroid Biochemistry and Molecular Biology</em> (2013-07) <a href="https://doi.org/ggqmh9">https://doi.org/ggqmh9</a> <br />
 DOI: <a href="https://doi.org/10.1016/j.jsbmb.2012.11.017">10.1016/j.jsbmb.2012.11.017</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/23220552">23220552</a></p>
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-<p>1038. <strong>Vitamin D: modulator of the immune system</strong> <br />
+<p>1036. <strong>Vitamin D: modulator of the immune system</strong> <br />
 Femke Baeke, Tatiana Takiishi, Hannelie Korf, Conny Gysemans, Chantal Mathieu<br />
 <em>Current Opinion in Pharmacology</em> (2010-08) <a href="https://doi.org/d43qtf">https://doi.org/d43qtf</a> <br />
 DOI: <a href="https://doi.org/10.1016/j.coph.2010.04.001">10.1016/j.coph.2010.04.001</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/20427238">20427238</a></p>
 </div>
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-<p>1039. <strong>Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths</strong> <br />
+<p>1037. <strong>Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths</strong> <br />
 William B. Grant, Henry Lahore, Sharon L. McDonnell, Carole A. Baggerly, Christine B. French, Jennifer L. Aliano, Harjit P. Bhattoa<br />
 <em>Nutrients</em> (2020-04-02) <a href="https://doi.org/ggr2v5">https://doi.org/ggr2v5</a> <br />
 DOI: <a href="https://doi.org/10.3390/nu12040988">10.3390/nu12040988</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32252338">32252338</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231123">PMC7231123</a></p>
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-<p>1040. <strong>Perspective: Vitamin D deficiency and COVID‐19 severity – plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis</strong> <br />
+<p>1038. <strong>Perspective: Vitamin D deficiency and COVID‐19 severity – plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis</strong> <br />
 J. M. Rhodes, S. Subramanian, E. Laird, G. Griffin, R. A. Kenny<br />
 <em>Journal of Internal Medicine</em> (2020-07-22) <a href="https://doi.org/ghc7dh">https://doi.org/ghc7dh</a> <br />
 DOI: <a href="https://doi.org/10.1111/joim.13149">10.1111/joim.13149</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32613681">32613681</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361294">PMC7361294</a></p>
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-<p>1041. <strong>COVID-19 fatalities, latitude, sunlight, and vitamin D</strong> <br />
+<p>1039. <strong>COVID-19 fatalities, latitude, sunlight, and vitamin D</strong> <br />
 Paul B. Whittemore<br />
 <em>American Journal of Infection Control</em> (2020-09) <a href="https://doi.org/ghr93r">https://doi.org/ghr93r</a> <br />
 DOI: <a href="https://doi.org/10.1016/j.ajic.2020.06.193">10.1016/j.ajic.2020.06.193</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32599103">32599103</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319635">PMC7319635</a></p>
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-<p>1042. <strong>Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity</strong> <br />
+<p>1040. <strong>Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity</strong> <br />
 Jonathan M. Rhodes, Sreedhar Subramanian, Eamon Laird, Rose A. Kenny<br />
 <em>Alimentary Pharmacology &amp; Therapeutics</em> (2020-06) <a href="https://doi.org/ggtw4b">https://doi.org/ggtw4b</a> <br />
 DOI: <a href="https://doi.org/10.1111/apt.15777">10.1111/apt.15777</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32311755">32311755</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264531">PMC7264531</a></p>
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-<p>1043. <strong>25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2</strong> <br />
+<p>1041. <strong>25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2</strong> <br />
 Antonio D’Avolio, Valeria Avataneo, Alessandra Manca, Jessica Cusato, Amedeo De Nicolò, Renzo Lucchini, Franco Keller, Marco Cantù<br />
 <em>Nutrients</em> (2020-05-09) <a href="https://doi.org/ggvv76">https://doi.org/ggvv76</a> <br />
 DOI: <a href="https://doi.org/10.3390/nu12051359">10.3390/nu12051359</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32397511">32397511</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285131">PMC7285131</a></p>
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-<p>1044. <strong>Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics</strong> <br />
+<p>1042. <strong>Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics</strong> <br />
 D. De Smet, K. De Smet, P. Herroelen, S. Gryspeerdt, G. A. Martens<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-05-05) <a href="https://doi.org/ggvv75">https://doi.org/ggvv75</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.05.01.20079376">10.1101/2020.05.01.20079376</a></p>
 </div>
 <div id="ref-GM9W6HPG">
-<p>1045. <strong>Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection</strong> <br />
+<p>1043. <strong>Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection</strong> <br />
 Zhila Maghbooli, Mohammad Ali Sahraian, Mehdi Ebrahimi, Marzieh Pazoki, Samira Kafan, Hedieh Moradi Tabriz, Azar Hadadi, Mahnaz Montazeri, Mehrad Nasiri, Arash Shirvani, Michael F. Holick<br />
 <em>PLOS ONE</em> (2020-09-25) <a href="https://doi.org/ghdzx8">https://doi.org/ghdzx8</a> <br />
 DOI: <a href="https://doi.org/10.1371/journal.pone.0239799">10.1371/journal.pone.0239799</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32976513">32976513</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518605">PMC7518605</a></p>
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 <div id="ref-kN3eqnZW">
-<p>1046. <strong>Role of vitamin D in preventing of COVID-19 infection, progression and severity</strong> <br />
+<p>1044. <strong>Role of vitamin D in preventing of COVID-19 infection, progression and severity</strong> <br />
 Nurshad Ali<br />
 <em>Journal of Infection and Public Health</em> (2020-10) <a href="https://doi.org/ghdzw9">https://doi.org/ghdzw9</a> <br />
 DOI: <a href="https://doi.org/10.1016/j.jiph.2020.06.021">10.1016/j.jiph.2020.06.021</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32605780">32605780</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305922">PMC7305922</a></p>
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 <div id="ref-5MvUc8IL">
-<p>1047. <strong>Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study</strong> <br />
+<p>1045. <strong>Low plasma 25(OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study</strong> <br />
 Eugene Merzon, Dmitry Tworowski, Alessandro Gorohovski, Shlomo Vinker, Avivit Golan Cohen, Ilan Green, Milana Frenkel‐Morgenstern<br />
 <em>The FEBS Journal</em> (2020-08-28) <a href="https://doi.org/gg7b5c">https://doi.org/gg7b5c</a> <br />
 DOI: <a href="https://doi.org/10.1111/febs.15495">10.1111/febs.15495</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32700398">32700398</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404739">PMC7404739</a></p>
 </div>
 <div id="ref-18O6t6Jo">
-<p>1048. <strong>Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results</strong> <br />
+<p>1046. <strong>Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results</strong> <br />
 David O. Meltzer, Thomas J. Best, Hui Zhang, Tamara Vokes, Vineet Arora, Julian Solway<br />
 <em>JAMA Network Open</em> (2020-09-03) <a href="https://doi.org/ghdzw6">https://doi.org/ghdzw6</a> <br />
 DOI: <a href="https://doi.org/10.1001/jamanetworkopen.2020.19722">10.1001/jamanetworkopen.2020.19722</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32880651">32880651</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489852">PMC7489852</a></p>
 </div>
 <div id="ref-8ZxZKpYS">
-<p>1049. <strong>Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection</strong> <br />
+<p>1047. <strong>Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection</strong> <br />
 José L Hernández, Daniel Nan, Marta Fernandez-Ayala, Mayte García-Unzueta, Miguel A Hernández-Hernández, Marcos López-Hoyos, Pedro Muñoz-Cacho, José M Olmos, Manuel Gutiérrez-Cuadra, Juan J Ruiz-Cubillán, … Víctor M Martínez-Taboada<br />
 <em>The Journal of Clinical Endocrinology &amp; Metabolism</em> (2020-10-27) <a href="https://doi.org/ghh737">https://doi.org/ghh737</a> <br />
 DOI: <a href="https://doi.org/10.1210/clinem/dgaa733">10.1210/clinem/dgaa733</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33159440">33159440</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797757">PMC7797757</a></p>
 </div>
 <div id="ref-QAEcHBzN">
-<p>1050. <strong>Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers</strong> <br />
+<p>1048. <strong>Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers</strong> <br />
 Anshul Jain, Rachna Chaurasia, Narendra Singh Sengar, Mayank Singh, Sachin Mahor, Sumit Narain<br />
 <em>Scientific Reports</em> (2020-11-19) <a href="https://doi.org/ghm3zn">https://doi.org/ghm3zn</a> <br />
 DOI: <a href="https://doi.org/10.1038/s41598-020-77093-z">10.1038/s41598-020-77093-z</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33214648">33214648</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677378">PMC7677378</a></p>
 </div>
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-<p>1051. <strong>Low 25-Hydroxyvitamin D Levels on Admission to the Intensive Care Unit May Predispose COVID-19 Pneumonia Patients to a Higher 28-Day Mortality Risk: A Pilot Study on a Greek ICU Cohort</strong> <br />
+<p>1049. <strong>Low 25-Hydroxyvitamin D Levels on Admission to the Intensive Care Unit May Predispose COVID-19 Pneumonia Patients to a Higher 28-Day Mortality Risk: A Pilot Study on a Greek ICU Cohort</strong> <br />
 Alice G. Vassiliou, Edison Jahaj, Maria Pratikaki, Stylianos E. Orfanos, Ioanna Dimopoulou, Anastasia Kotanidou<br />
 <em>Nutrients</em> (2020-12-09) <a href="https://doi.org/ghr95d">https://doi.org/ghr95d</a> <br />
 DOI: <a href="https://doi.org/10.3390/nu12123773">10.3390/nu12123773</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33316914">33316914</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764169">PMC7764169</a></p>
 </div>
 <div id="ref-xv6TOhJg">
-<p>1052. <strong>Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19</strong> <br />
+<p>1050. <strong>Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19</strong> <br />
 G. E. Carpagnano, V. Di Lecce, V. N. Quaranta, A. Zito, E. Buonamico, E. Capozza, A. Palumbo, G. Di Gioia, V. N. Valerio, O. Resta<br />
 <em>Journal of Endocrinological Investigation</em> (2020-08-09) <a href="https://doi.org/gg7kqp">https://doi.org/gg7kqp</a> <br />
 DOI: <a href="https://doi.org/10.1007/s40618-020-01370-x">10.1007/s40618-020-01370-x</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32772324">32772324</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415009">PMC7415009</a></p>
 </div>
 <div id="ref-ZheSCcim">
-<p>1053. <strong>Vitamin D Deficiency and Outcome of COVID-19 Patients</strong> <br />
+<p>1051. <strong>Vitamin D Deficiency and Outcome of COVID-19 Patients</strong> <br />
 Aleksandar Radujkovic, Theresa Hippchen, Shilpa Tiwari-Heckler, Saida Dreher, Monica Boxberger, Uta Merle<br />
 <em>Nutrients</em> (2020-09-10) <a href="https://doi.org/ghgfmp">https://doi.org/ghgfmp</a> <br />
 DOI: <a href="https://doi.org/10.3390/nu12092757">10.3390/nu12092757</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32927735">32927735</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551780">PMC7551780</a></p>
 </div>
 <div id="ref-pNuUm1NE">
-<p>1054. <strong>Impact of Vitamin D Deficiency on COVID-19—A Prospective Analysis from the CovILD Registry</strong> <br />
+<p>1052. <strong>Impact of Vitamin D Deficiency on COVID-19—A Prospective Analysis from the CovILD Registry</strong> <br />
 Alex Pizzini, Magdalena Aichner, Sabina Sahanic, Anna Böhm, Alexander Egger, Gregor Hoermann, Katharina Kurz, Gerlig Widmann, Rosa Bellmann-Weiler, Günter Weiss, … Judith Löffler-Ragg<br />
 <em>Nutrients</em> (2020-09-11) <a href="https://doi.org/ghr95b">https://doi.org/ghr95b</a> <br />
 DOI: <a href="https://doi.org/10.3390/nu12092775">10.3390/nu12092775</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32932831">32932831</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551662">PMC7551662</a></p>
 </div>
 <div id="ref-5aqg2qxi">
-<p>1055. <strong>Does Serum Vitamin D Level Affect COVID-19 Infection and Its Severity?-A Case-Control Study</strong> <br />
+<p>1053. <strong>Does Serum Vitamin D Level Affect COVID-19 Infection and Its Severity?-A Case-Control Study</strong> <br />
 Kun Ye, Fen Tang, Xin Liao, Benjamin A. Shaw, Meiqiu Deng, Guangyi Huang, Zhiqiang Qin, Xiaomei Peng, Hewei Xiao, Chunxia Chen, … Jianrong Yang<br />
 <em>Journal of the American College of Nutrition</em> (2020-10-13) <a href="https://doi.org/ghr935">https://doi.org/ghr935</a> <br />
 DOI: <a href="https://doi.org/10.1080/07315724.2020.1826005">10.1080/07315724.2020.1826005</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33048028">33048028</a></p>
 </div>
 <div id="ref-10kobTskt">
-<p>1056. <strong>Lower levels of vitamin D are associated with SARS-CoV-2 infection and mortality in the Indian population: An observational study</strong> <br />
+<p>1054. <strong>Lower levels of vitamin D are associated with SARS-CoV-2 infection and mortality in the Indian population: An observational study</strong> <br />
 Sunali Padhi, Subham Suvankar, Venketesh K. Panda, Abhijit Pati, Aditya K. Panda<br />
 <em>International Immunopharmacology</em> (2020-11) <a href="https://doi.org/ghr93w">https://doi.org/ghr93w</a> <br />
 DOI: <a href="https://doi.org/10.1016/j.intimp.2020.107001">10.1016/j.intimp.2020.107001</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33182040">33182040</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489890">PMC7489890</a></p>
 </div>
 <div id="ref-Tcc0pGgI">
-<p>1057. <strong>Vitamin D Deficiency Is Associated with COVID-19 Incidence and Disease Severity in Chinese People</strong> <br />
+<p>1055. <strong>Vitamin D Deficiency Is Associated with COVID-19 Incidence and Disease Severity in Chinese People</strong> <br />
 Xia Luo, Qing Liao, Ying Shen, Huijun Li, Liming Cheng<br />
 <em>The Journal of Nutrition</em> (2021-01) <a href="https://doi.org/ghr939">https://doi.org/ghr939</a> <br />
 DOI: <a href="https://doi.org/10.1093/jn/nxaa332">10.1093/jn/nxaa332</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/33188401">33188401</a></p>
 </div>
 <div id="ref-FZ8yXmxQ">
-<p>1058. <strong>Vitamin D concentrations and COVID-19 infection in UK Biobank</strong> <br />
+<p>1056. <strong>Vitamin D concentrations and COVID-19 infection in UK Biobank</strong> <br />
 Claire E. Hastie, Daniel F. Mackay, Frederick Ho, Carlos A. Celis-Morales, Srinivasa Vittal Katikireddi, Claire L. Niedzwiedz, Bhautesh D. Jani, Paul Welsh, Frances S. Mair, Stuart R. Gray, … Jill P. Pell<br />
 <em>Diabetes &amp; Metabolic Syndrome: Clinical Research &amp; Reviews</em> (2020-07) <a href="https://doi.org/ggvv72">https://doi.org/ggvv72</a> <br />
 DOI: <a href="https://doi.org/10.1016/j.dsx.2020.04.050">10.1016/j.dsx.2020.04.050</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32413819">32413819</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204679">PMC7204679</a></p>
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 <div id="ref-7goCwNjQ">
-<p>1059. <strong>Vitamin D and COVID-19 infection and mortality in UK Biobank</strong> <br />
+<p>1057. <strong>Vitamin D and COVID-19 infection and mortality in UK Biobank</strong> <br />
 Claire E. Hastie, Jill P. Pell, Naveed Sattar<br />
 <em>European Journal of Nutrition</em> (2020-08-26) <a href="https://doi.org/ghr93p">https://doi.org/ghr93p</a> <br />
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+<p>1058. <strong>Low serum 25‐hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID‐19 are associated with greater disease severity</strong> <br />
 Grigorios Panagiotou, Su Ann Tee, Yasir Ihsan, Waseem Athar, Gabriella Marchitelli, Donna Kelly, Christopher S. Boot, Nadia Stock, James Macfarlane, Adrian R. Martineau, … Richard Quinton<br />
 <em>Clinical Endocrinology</em> (2020-08-06) <a href="https://doi.org/gg5gbj">https://doi.org/gg5gbj</a> <br />
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+<p>1059. <strong>Letter in response to the article: Vitamin D concentrations and COVID-19 infection in UK biobank (Hastie et al.)</strong> <br />
 W. B. Grant, S. L. McDonnell<br />
 <em>Diabetes &amp; Metabolic Syndrome: Clinical Research &amp; Reviews</em> (2020-09) <a href="https://doi.org/ghc7p4">https://doi.org/ghc7p4</a> <br />
 DOI: <a href="https://doi.org/10.1016/j.dsx.2020.05.046">10.1016/j.dsx.2020.05.046</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32563941">32563941</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293469">PMC7293469</a></p>
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-<p>1062. <strong>Vitamin D deficiency in African Americans is associated with a high risk of severe disease and mortality by SARS-CoV-2</strong> <br />
+<p>1060. <strong>Vitamin D deficiency in African Americans is associated with a high risk of severe disease and mortality by SARS-CoV-2</strong> <br />
 Virna Margarita Martín Giménez, Felipe Inserra, León Ferder, Joxel García, Walter Manucha<br />
 <em>Journal of Human Hypertension</em> (2020-08-13) <a href="https://doi.org/ghr933">https://doi.org/ghr933</a> <br />
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-<p>1063. <strong>Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients</strong> <br />
+<p>1061. <strong>Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients</strong> <br />
 Ali Daneshkhah, Vasundhara Agrawal, Adam Eshein, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman<br />
 <em>Aging Clinical and Experimental Research</em> (2020-09-02) <a href="https://doi.org/ghr93q">https://doi.org/ghr93q</a> <br />
 DOI: <a href="https://doi.org/10.1007/s40520-020-01677-y">10.1007/s40520-020-01677-y</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32876941">32876941</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465887">PMC7465887</a></p>
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+<p>1062. <strong>Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study)</strong> <br />
 Ashu Rastogi, Anil Bhansali, Niranjan Khare, Vikas Suri, Narayana Yaddanapudi, Naresh Sachdeva, GD Puri, Pankaj Malhotra<br />
 <em>Postgraduate Medical Journal</em> (2020-11-12) <a href="https://doi.org/ghnhpq">https://doi.org/ghnhpq</a> <br />
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+<p>1063. <strong>“Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study”</strong> <br />
 Marta Entrenas Castillo, Luis Manuel Entrenas Costa, José Manuel Vaquero Barrios, Juan Francisco Alcalá Díaz, José López Miranda, Roger Bouillon, José Manuel Quesada Gomez<br />
 <em>The Journal of Steroid Biochemistry and Molecular Biology</em> (2020-10) <a href="https://doi.org/ghd79r">https://doi.org/ghd79r</a> <br />
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+<p>1064. <strong>COVID-19 rapid evidence summary: vitamin D for COVID-19 | Advice | NICE</strong> <a href="https://www.nice.org.uk/advice/es28">https://www.nice.org.uk/advice/es28</a></p>
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+<p>1065. <strong>Mathematical analysis of Córdoba calcifediol trial suggests strong role for Vitamin D in reducing ICU admissions of hospitalized COVID-19 patients</strong> <br />
 Irwin Jungreis, Manolis Kellis<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-12-21) <a href="https://doi.org/ghr94h">https://doi.org/ghr94h</a> <br />
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+<p>1066. <strong>High-Dose Cholecalciferol Booster Therapy is Associated with a Reduced Risk of Mortality in Patients with COVID-19: A Cross-Sectional Multi-Centre Observational Study</strong> <br />
 Stephanie F. Ling, Eleanor Broad, Rebecca Murphy, Joseph M. Pappachan, Satveer Pardesi-Newton, Marie-France Kong, Edward B. Jude<br />
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-<p>1069. <strong>Effect of Vitamin D <sub>3</sub> Supplementation vs Placebo on Hospital Length of Stay in Patients with Severe COVID-19: A Multicenter, Double-blind, Randomized Controlled Trial</strong> <br />
+<p>1067. <strong>Effect of Vitamin D <sub>3</sub> Supplementation vs Placebo on Hospital Length of Stay in Patients with Severe COVID-19: A Multicenter, Double-blind, Randomized Controlled Trial</strong> <br />
 Igor H. Murai, Alan L. Fernandes, Lucas P. Sales, Ana J. Pinto, Karla F. Goessler, Camila S. C. Duran, Carla B. R. Silva, André S. Franco, Marina B. Macedo, Henrique H. H. Dalmolin, … Rosa M. R. Pereira<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-11-17) <a href="https://doi.org/ghr94j">https://doi.org/ghr94j</a> <br />
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+<p>1068. <strong>Effect of Vitamin D Administration on Prevention and Treatment of Mild Forms of Suspected Covid-19</strong> <br />
 Manuel Castillo Garzón<br />
 <em>clinicaltrials.gov</em> (2020-04-03) <a href="https://clinicaltrials.gov/ct2/show/NCT04334005">https://clinicaltrials.gov/ct2/show/NCT04334005</a></p>
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+<p>1069. <strong>Improving Vitamin D Status in the Management of COVID-19</strong> <br />
 Aldo Montano-Loza<br />
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+<p>1072. <strong>The LEAD COVID-19 Trial: Low-risk, Early Aspirin and Vitamin D to Reduce COVID-19 Hospitalizations</strong> <br />
 Louisiana State University Health Sciences Center in New Orleans<br />
 <em>clinicaltrials.gov</em> (2020-04-24) <a href="https://clinicaltrials.gov/ct2/show/NCT04363840">https://clinicaltrials.gov/ct2/show/NCT04363840</a></p>
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+<p>1073. <strong>Randomized Double-Blind Placebo-Controlled Proof-of-Concept Trial of a Plant Polyphenol for the Outpatient Treatment of Mild Coronavirus Disease (COVID-19)</strong> <br />
 Marvin McCreary MD<br />
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+<p>1074. <strong>Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society</strong> <br />
 Paul Lips, Kevin D Cashman, Christel Lamberg-Allardt, Heike Annette Bischoff-Ferrari, Barbara Obermayer-Pietsch, Maria Luisa Bianchi, Jan Stepan, Ghada El-Hajj Fuleihan, Roger Bouillon<br />
 <em>European Journal of Endocrinology</em> (2019-04) <a href="https://doi.org/ggr42p">https://doi.org/ggr42p</a> <br />
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 Gareth Iacobucci<br />
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 <em>BMJ</em> (2020-06-19) <a href="https://doi.org/ghr94p">https://doi.org/ghr94p</a> <br />
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 Naveen R Parva, Satish Tadepalli, Pratiksha Singh, Andrew Qian, Rajat Joshi, Hyndavi Kandala, Vinod K Nookala, Pramil Cheriyath<br />
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 Jadwiga Hamulka, Marta Jeruszka-Bielak, Magdalena Górnicka, Małgorzata E. Drywień, Monika A. Zielinska-Pukos<br />
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 Paul W. O’Toole, Julian R. Marchesi, Colin Hill<br />
 <em>Nature Microbiology</em> (2017-04-25) <a href="https://doi.org/ggzggv">https://doi.org/ggzggv</a> <br />
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 Julio Plaza-Diaz, Francisco Javier Ruiz-Ojeda, Mercedes Gil-Campos, Angel Gil<br />
 <em>Advances in Nutrition</em> (2019-01) <a href="https://doi.org/gft8sh">https://doi.org/gft8sh</a> <br />
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 Katrina Halloran, Mark A. Underwood<br />
 <em>Early Human Development</em> (2019-08) <a href="https://doi.org/gg3jc4">https://doi.org/gg3jc4</a> <br />
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 Miriam Bermudez-Brito, Julio Plaza-Díaz, Sergio Muñoz-Quezada, Carolina Gómez-Llorente, Angel Gil<br />
 <em>Annals of Nutrition and Metabolism</em> (2012) <a href="https://doi.org/gg3knb">https://doi.org/gg3knb</a> <br />
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 T BOTIC, T KLINGBERG, H WEINGARTL, A CENCIC<br />
 <em>International Journal of Food Microbiology</em> (2007-04-30) <a href="https://doi.org/fks5cz">https://doi.org/fks5cz</a> <br />
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 N. Waki, N. Yajima, H. Suganuma, B. M. Buddle, D. Luo, A. Heiser, T. Zheng<br />
 <em>Letters in Applied Microbiology</em> (2014-01) <a href="https://doi.org/f5j37w">https://doi.org/f5j37w</a> <br />
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 Paola Mastromarino, Fatima Cacciotti, Alessandra Masci, Luciana Mosca<br />
 <em>Anaerobe</em> (2011-12) <a href="https://doi.org/bcpvm5">https://doi.org/bcpvm5</a> <br />
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 Caroline M. Percopo, Michelle Ma, Todd A. Brenner, Julia O. Krumholz, Timothy J. Break, Karen Laky, Helene F. Rosenberg<br />
 <em>The Journal of Immunology</em> (2019-02-01) <a href="https://doi.org/ghr95h">https://doi.org/ghr95h</a> <br />
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 Biliavska, Pankivska, Povnitsa, Zagorodnya<br />
 <em>Medicina</em> (2019-08-22) <a href="https://doi.org/ghr948">https://doi.org/ghr948</a> <br />
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 Kei Eguchi, Naoki Fujitani, Hisako Nakagawa, Tadaaki Miyazaki<br />
 <em>Scientific Reports</em> (2019-03-18) <a href="https://doi.org/ghr934">https://doi.org/ghr934</a> <br />
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 <em>Beneficial Microbes</em> (2017-04-26) <a href="https://doi.org/f955fh">https://doi.org/f955fh</a> <br />
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 Hortensia Zelaya, Kohichiro Tsukida, Eriko Chiba, Gabriela Marranzino, Susana Alvarez, Haruki Kitazawa, Graciela Agüero, Julio Villena<br />
 <em>International Immunopharmacology</em> (2014-03) <a href="https://doi.org/f5wd93">https://doi.org/f5wd93</a> <br />
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 <em>International Immunopharmacology</em> (2020-01) <a href="https://doi.org/ghr93v">https://doi.org/ghr93v</a> <br />
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+<p>1101. <strong>The potential application of probiotics and prebiotics for the prevention and treatment of COVID-19</strong> <br />
 Amin N. Olaimat, Iman Aolymat, Murad Al-Holy, Mutamed Ayyash, Mahmoud Abu Ghoush, Anas A. Al-Nabulsi, Tareq Osaili, Vasso Apostolopoulos, Shao-Quan Liu, Nagendra P. Shah<br />
 <em>npj Science of Food</em> (2020-10-05) <a href="https://doi.org/ghggq4">https://doi.org/ghggq4</a> <br />
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 <em>Mucosal Immunology</em> (2011-11-16) <a href="https://doi.org/b5knk2">https://doi.org/b5knk2</a> <br />
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 Alexia Dumas, Lucie Bernard, Yannick Poquet, Geanncarlo Lugo-Villarino, Olivier Neyrolles<br />
 <em>Cellular Microbiology</em> (2018-12) <a href="https://doi.org/gfjds9">https://doi.org/gfjds9</a> <br />
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 Debojyoti Dhar, Abhishek Mohanty<br />
 <em>Virus Research</em> (2020-08) <a href="https://doi.org/gg3jc5">https://doi.org/gg3jc5</a> <br />
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 Lirong Bao, Cheng Zhang, Jiajia Dong, Lei Zhao, Yan Li, Jianxun Sun<br />
 <em>Frontiers in Microbiology</em> (2020-07-31) <a href="https://doi.org/ghr944">https://doi.org/ghr944</a> <br />
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 Saroj Khatiwada, Astha Subedi<br />
 <em>Human Microbiome Journal</em> (2020-08) <a href="https://doi.org/gg7m83">https://doi.org/gg7m83</a> <br />
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 L. Lehtoranta, A. Pitkäranta, R. Korpela<br />
 <em>European Journal of Clinical Microbiology &amp; Infectious Diseases</em> (2014-03-18) <a href="https://doi.org/f583jr">https://doi.org/f583jr</a> <br />
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+<p>1108. <strong>Probiotics for preventing acute upper respiratory tract infections</strong> <br />
 Qiukui Hao, Bi Rong Dong, Taixiang Wu<br />
 <em>Cochrane Database of Systematic Reviews</em> (2015-02-03) <a href="https://doi.org/gg3jc3">https://doi.org/gg3jc3</a> <br />
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 Evridiki K. Vouloumanou, Gregory C. Makris, Drosos E. Karageorgopoulos, Matthew E. Falagas<br />
 <em>International Journal of Antimicrobial Agents</em> (2009-09) <a href="https://doi.org/dn8kw8">https://doi.org/dn8kw8</a> <br />
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 Sarah King, Julie Glanville, Mary Ellen Sanders, Anita Fitzgerald, Danielle Varley<br />
 <em>British Journal of Nutrition</em> (2014-04-29) <a href="https://doi.org/f57hq5">https://doi.org/f57hq5</a> <br />
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 Juan Zeng, Chun-Ting Wang, Fu-Shen Zhang, Feng Qi, Shi-Fu Wang, Shuang Ma, Tie-Jun Wu, Hui Tian, Zhao-Tao Tian, Shu-Liu Zhang, … Yu-Ping Wang<br />
 <em>Intensive Care Medicine</em> (2016-04-04) <a href="https://doi.org/f8jnrt">https://doi.org/f8jnrt</a> <br />
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+<p>1112. <strong>Probiotic Prophylaxis of Ventilator-associated Pneumonia</strong> <br />
 Lee E. Morrow, Marin H. Kollef, Thomas B. Casale<br />
 <em>American Journal of Respiratory and Critical Care Medicine</em> (2010-10-15) <a href="https://doi.org/d5hh4t">https://doi.org/d5hh4t</a> <br />
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+<p>1113. <strong>Synbiotics modulate gut microbiota and reduce enteritis and ventilator-associated pneumonia in patients with sepsis: a randomized controlled trial</strong> <br />
 Kentaro Shimizu, Tomoki Yamada, Hiroshi Ogura, Tomoyoshi Mohri, Takeyuki Kiguchi, Satoshi Fujimi, Takashi Asahara, Tomomi Yamada, Masahiro Ojima, Mitsunori Ikeda, Takeshi Shimazu<br />
 <em>Critical Care</em> (2018-09-27) <a href="https://doi.org/gfdggj">https://doi.org/gfdggj</a> <br />
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+<p>1114. <strong>Probiotics for the Prevention of Ventilator-Associated Pneumonia: A Meta-Analysis of Randomized Controlled Trials</strong> <br />
 Minmin Su, Ying Jia, Yan Li, Dianyou Zhou, Jinsheng Jia<br />
 <em>Respiratory Care</em> (2020-05) <a href="https://doi.org/gg3kng">https://doi.org/gg3kng</a> <br />
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 Helvécio Cardoso Corrêa Póvoa, Gabriela Ceccon Chianca, Natalia Lopes Pontes Póvoa Iorio<br />
 <em>Adis Journals</em> (2020) <a href="https://doi.org/gg3knh">https://doi.org/gg3knh</a> <br />
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+<p>1116. <strong>The challenge of ventilator-associated pneumonia diagnosis in COVID-19 patients</strong> <br />
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 <em>The Lancet Gastroenterology &amp; Hepatology</em> (2020-07) <a href="https://doi.org/d2qq">https://doi.org/d2qq</a> <br />
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 Marcos Pereira, Alialdo Dantas Damascena, Laylla Mirella Galvão Azevedo, Tarcio de Almeida Oliveira, Jerusa da Mota Santana<br />
 <em>Critical Reviews in Food Science and Nutrition</em> (2020-11-04) <a href="https://doi.org/ghr937">https://doi.org/ghr937</a> <br />
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 <em>New England Journal of Medicine</em> (2020-12-03) <a href="https://doi.org/ghnhm7">https://doi.org/ghnhm7</a> <br />
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 Prapimpun Wongchitrat, Mayuri Shukla, Ramaswamy Sharma, Piyarat Govitrapong, Russel J. Reiter<br />
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+<p>1149. <strong>The frontier between nutrition and pharma: The international regulatory framework of functional foods, food supplements and nutraceuticals</strong> <br />
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 Nicholet A. Deschine Parkhurst, Kimberly R. Huyser, Aggie J. Yellow Horse<br />
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 Elizabeth J. Williamson, Alex J. Walker, Krishnan Bhaskaran, Seb Bacon, Chris Bates, Caroline E. Morton, Helen J. Curtis, Amir Mehrkar, David Evans, Peter Inglesby, … Ben Goldacre<br />
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 Michael C. Campbell, Sarah A. Tishkoff<br />
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 Michael Yudell, Dorothy Roberts, Rob DeSalle, Sarah Tishkoff, 70 signatories<br />
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 Yonghong Zhang, Ling Qin, Yan Zhao, Ping Zhang, Bin Xu, Kang Li, Lianchun Liang, Chi Zhang, Yanchao Dai, Yingmei Feng, … Ronghua Jin<br />
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 The Severe Covid-19 GWAS Group<br />
 <em>New England Journal of Medicine</em> (2020-10-15) <a href="https://doi.org/gg2pqx">https://doi.org/gg2pqx</a> <br />
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 Chia-Ling Kuo, Luke C Pilling, Janice L Atkins, Jane AH Masoli, João Delgado, George A Kuchel, David Melzer<br />
 <em>The Journals of Gerontology: Series A</em> (2020-11) <a href="https://doi.org/ggx4ng">https://doi.org/ggx4ng</a> <br />
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 Jin Wei, Mia Madel Alfajaro, Ruth E. Hanna, Peter C. DeWeirdt, Madison S. Strine, William J. Lu-Culligan, Shang-Min Zhang, Vincent R. Graziano, Cameron O. Schmitz, Jennifer S. Chen, … Craig B. Wilen<br />
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 Yuan Hou, Junfei Zhao, William Martin, Asha Kallianpur, Mina K. Chung, Lara Jehi, Nima Sharifi, Serpil Erzurum, Charis Eng, Feixiong Cheng<br />
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 <em>Cold Spring Harbor Laboratory</em> (2020-08-01) <a href="https://doi.org/ghcm7q">https://doi.org/ghcm7q</a> <br />
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 Linda Nordling<br />
 <em>Science</em> (2020-08-13) <a href="https://doi.org/ghcm7r">https://doi.org/ghcm7r</a> <br />
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+<p>1202. <strong>Are some ethnic groups more vulnerable to COVID-19 than others?</strong> <a href="https://www.ifs.org.uk/inequality/chapter/are-some-ethnic-groups-more-vulnerable-to-covid-19-than-others/">https://www.ifs.org.uk/inequality/chapter/are-some-ethnic-groups-more-vulnerable-to-covid-19-than-others/</a></p>
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-<p>1205. <strong>Quantifying the social distancing privilege gap: a longitudinal study of smartphone movement</strong> <br />
+<p>1203. <strong>Quantifying the social distancing privilege gap: a longitudinal study of smartphone movement</strong> <br />
 Nabarun Dasgupta, Michele Jonsson Funk, Allison Lazard, Benjamin Eugene White, Stephen W. Marshall<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-05-08) <a href="https://doi.org/gg79qk">https://doi.org/gg79qk</a> <br />
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+<p>1204. <strong>Uncovering socioeconomic gaps in mobility reduction during the COVID-19 pandemic using location data</strong> <br />
 Samuel P. Fraiberger, Pablo Astudillo, Lorenzo Candeago, Alex Chunet, Nicholas K. W. Jones, Maham Faisal Khan, Bruno Lepri, Nancy Lozano Gracia, Lorenzo Lucchini, Emanuele Massaro, Aleister Montfort<br />
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-<p>1207. <strong>Mobility network models of COVID-19 explain inequities and inform reopening</strong> <br />
+<p>1205. <strong>Mobility network models of COVID-19 explain inequities and inform reopening</strong> <br />
 Serina Chang, Emma Pierson, Pang Wei Koh, Jaline Gerardin, Beth Redbird, David Grusky, Jure Leskovec<br />
 <em>Nature</em> (2020-11-10) <a href="https://doi.org/ghjmt2">https://doi.org/ghjmt2</a> <br />
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-<p>1208. <strong>A Basic Demographic Profile of Workers in Frontline Industries</strong> <br />
+<p>1206. <strong>A Basic Demographic Profile of Workers in Frontline Industries</strong> <br />
 Hye Jin Rho;Shawn Fremstad;Hayley Brown<br />
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-<p>1209. <strong>Differential occupational risk for COVID‐19 and other infection exposure according to race and ethnicity</strong> <br />
+<p>1207. <strong>Differential occupational risk for COVID‐19 and other infection exposure according to race and ethnicity</strong> <br />
 Devan Hawkins<br />
 <em>American Journal of Industrial Medicine</em> (2020-06-15) <a href="https://doi.org/gg3rb2">https://doi.org/gg3rb2</a> <br />
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-<p>1210. <strong>Estimating the burden of United States workers exposed to infection or disease: A key factor in containing risk of COVID-19 infection</strong> <br />
+<p>1208. <strong>Estimating the burden of United States workers exposed to infection or disease: A key factor in containing risk of COVID-19 infection</strong> <br />
 Marissa G. Baker, Trevor K. Peckham, Noah S. Seixas<br />
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+<p>1209. <strong>Coronavirus (COVID-19) related deaths by occupation, England and Wales: deaths registered up to and including 20 April 2020</strong> <br />
 Ben Windsor-Shellard, Jasveer Kaur<br />
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-<p>1212. <strong>Which occupations have the highest potential exposure to the coronavirus (COVID-19)?</strong> <br />
+<p>1210. <strong>Which occupations have the highest potential exposure to the coronavirus (COVID-19)?</strong> <br />
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-<p>1213. <strong>Disparities in the risk and outcomes from COVID-19</strong> <br />
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+<p>1212. <strong>Exclusive: deaths of NHS staff from covid-19 analysed</strong> <br />
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+<p>1214. <strong>Racial Disparity in COVID-19 Deaths: Seeking Economic Roots with Census data.</strong> <br />
 John McLaren<br />
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 Michael L. Barnett, Lissy Hu, Thomas Martin, David C. Grabowski<br />
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 Laura Hawks, Steffie Woolhandler, Danny McCormick<br />
 <em>JAMA Internal Medicine</em> (2020-08-01) <a href="https://doi.org/ggtxw6">https://doi.org/ggtxw6</a> <br />
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 Brendan Saloner, Kalind Parish, Julie A. Ward, Grace DiLaura, Sharon Dolovich<br />
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 <em>Sociology Compass</em> (2010-08) <a href="https://doi.org/fsrcr7">https://doi.org/fsrcr7</a> <br />
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 Gary W. Evans, John Eckenrode, Lyscha A. Marcynyszyn<br />
 <em>American Psychological Association (APA)</em> (2010-01-12) <a href="https://doi.org/c76n3g">https://doi.org/c76n3g</a> <br />
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 <em>Clinical Cornerstone</em> (1999-01) <a href="https://doi.org/bpp37d">https://doi.org/bpp37d</a> <br />
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 <em>Journal of The Royal Society Interface</em> (2018-04-04) <a href="https://doi.org/gddkhn">https://doi.org/gddkhn</a> <br />
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 Casey S. Greene, Daniel S. Himmelstein, Daniel C. Elton, Brock C. Christensen, Anthony Gitter, Alexander J. Titus, Joshua J. Levy<br />
 <em>Manubot</em> (2020-11-10) <a href="https://greenelab.github.io/deep-review/">https://greenelab.github.io/deep-review/</a></p>
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 John D. Hunter<br />
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 </div>
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+<p>1304. <strong>Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody</strong> <br />
 Xiaolong Tian, Cheng Li, Ailing Huang, Shuai Xia, Sicong Lu, Zhengli Shi, Lu Lu, Shibo Jiang, Zhenlin Yang, Yanling Wu, Tianlei Ying<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-01-28) <a href="https://doi.org/ggjqfd">https://doi.org/ggjqfd</a> <br />
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+<p>1305. <strong>Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV</strong> <br />
 Xiang He, Lei Zhang, Qin Ran, Junyi Wang, Anying Xiong, Dehong Wu, Feng Chen, Guoping Li<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-05) <a href="https://doi.org/ggrbd8">https://doi.org/ggrbd8</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.03.20020206">10.1101/2020.02.03.20020206</a></p>
 </div>
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-<p>1304. <strong>Diarrhea may be underestimated: a missing link in 2019 novel coronavirus</strong> <br />
+<p>1306. <strong>Diarrhea may be underestimated: a missing link in 2019 novel coronavirus</strong> <br />
 Weicheng Liang, Zhijie Feng, Shitao Rao, Cuicui Xiao, Ze-Xiao Lin, Qi Zhang, Qi Wei<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-17) <a href="https://doi.org/ggrbdw">https://doi.org/ggrbdw</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.03.20020289">10.1101/2020.02.03.20020289</a></p>
 </div>
 <div id="ref-BHQvMYPG">
-<p>1305. <strong>Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection</strong> <br />
+<p>1307. <strong>Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection</strong> <br />
 Xiaoqiang Chai, Longfei Hu, Yan Zhang, Weiyu Han, Zhou Lu, Aiwu Ke, Jian Zhou, Guoming Shi, Nan Fang, Jia Fan, … Fei Lan<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-04) <a href="https://doi.org/ggq626">https://doi.org/ggq626</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.03.931766">10.1101/2020.02.03.931766</a></p>
 </div>
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-<p>1306. <strong>Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids</strong> <br />
+<p>1308. <strong>Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids</strong> <br />
 Bing Zhao, Chao Ni, Ran Gao, Yuyan Wang, Li Yang, Jinsong Wei, Ting Lv, Jianqing Liang, Qisheng Zhang, Wei Xu, … Xinhua Lin<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-17) <a href="https://doi.org/ggq648">https://doi.org/ggq648</a> <br />
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 </div>
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+<p>1309. <strong>ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism</strong> <br />
 Jun Wang, Shanmeizi Zhao, Ming Liu, Zhiyao Zhao, Yiping Xu, Ping Wang, Meng Lin, Yanhui Xu, Bing Huang, Xiaoyu Zuo, … Yuxia Zhang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-07) <a href="https://doi.org/ggrfbx">https://doi.org/ggrfbx</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.05.20020545">10.1101/2020.02.05.20020545</a></p>
 </div>
 <div id="ref-MgLBA5m">
-<p>1308. <strong>The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice</strong> <br />
+<p>1310. <strong>The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice</strong> <br />
 Linlin Bao, Wei Deng, Baoying Huang, Hong Gao, Jiangning Liu, Lili Ren, Qiang Wei, Pin Yu, Yanfeng Xu, Feifei Qi, … Chuan Qin<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-28) <a href="https://doi.org/dph2">https://doi.org/dph2</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.07.939389">10.1101/2020.02.07.939389</a></p>
 </div>
 <div id="ref-1Acv5UMSt">
-<p>1309. <strong>Caution on Kidney Dysfunctions of COVID-19 Patients</strong> <br />
+<p>1311. <strong>Caution on Kidney Dysfunctions of COVID-19 Patients</strong> <br />
 Zhen Li, Ming Wu, Jiwei Yao, Jie Guo, Xiang Liao, Siji Song, Jiali Li, Guangjie Duan, Yuanxiu Zhou, Xiaojun Wu, … Junan Yan<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-27) <a href="https://doi.org/ggq627">https://doi.org/ggq627</a> <br />
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 </div>
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-<p>1310. <strong>Acute renal impairment in coronavirus-associated severe acute respiratory syndrome</strong> <br />
+<p>1312. <strong>Acute renal impairment in coronavirus-associated severe acute respiratory syndrome</strong> <br />
 Kwok Hong Chu, Wai Kay Tsang, Colin S. Tang, Man Fai Lam, Fernand M. Lai, Ka Fai To, Ka Shun Fung, Hon Lok Tang, Wing Wa Yan, Hilda W. H. Chan, … Kar Neng Lai<br />
 <em>Kidney International</em> (2005-02) <a href="https://doi.org/b7tgtx">https://doi.org/b7tgtx</a> <br />
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 </div>
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+<p>1313. <strong>Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection</strong> <br />
 Wei Lin, Longfei Hu, Yan Zhang, Joshua D. Ooi, Ting Meng, Peng Jin, Xiang Ding, Longkai Peng, Lei Song, Zhou Xiao, … Yong Zhong<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-18) <a href="https://doi.org/ggq629">https://doi.org/ggq629</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.08.939892">10.1101/2020.02.08.939892</a></p>
 </div>
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+<p>1314. <strong>The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2</strong> <br />
 James Zhu, Jiwoong Kim, Xue Xiao, Yunguan Wang, Danni Luo, Shuang Jiang, Ran Chen, Lin Xu, He Zhang, Lenny Moise, … Yang Xie<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-09-04) <a href="https://doi.org/ggq628">https://doi.org/ggq628</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.08.939553">10.1101/2020.02.08.939553</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32908981">32908981</a></p>
 </div>
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-<p>1313. <strong>Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection</strong> <br />
+<p>1315. <strong>Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection</strong> <br />
 Yaseen M. Arabi, Ahmed A. Arifi, Hanan H. Balkhy, Hani Najm, Abdulaziz S. Aldawood, Alaa Ghabashi, Hassan Hawa, Adel Alothman, Abdulaziz Khaldi, Basel Al Raiy<br />
 <em>Annals of Internal Medicine</em> (2014-03-18) <a href="https://doi.org/ggptxw">https://doi.org/ggptxw</a> <br />
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 </div>
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-<p>1314. <strong>Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage</strong> <br />
+<p>1316. <strong>Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage</strong> <br />
 Jingyuan Liu, Yao Liu, Pan Xiang, Lin Pu, Haofeng Xiong, Chuansheng Li, Ming Zhang, Jianbo Tan, Yanli Xu, Rui Song, … Xianbo Wang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-12) <a href="https://doi.org/ggrbdx">https://doi.org/ggrbdx</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.10.20021584">10.1101/2020.02.10.20021584</a></p>
 </div>
 <div id="ref-6Y81C4P3">
-<p>1315. <strong>Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China</strong> <br />
+<p>1317. <strong>Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China</strong> <br />
 Chuan Qin, Luoqi Zhou, Ziwei Hu, Shuoqi Zhang, Sheng Yang, Yu Tao, Cuihong Xie, Ke Ma, Ke Shang, Wei Wang, Dai-Shi Tian<br />
 <em>Clinical Infectious Diseases</em> (2020-08-01) <a href="https://doi.org/ggpxcf">https://doi.org/ggpxcf</a> <br />
 DOI: <a href="https://doi.org/10.1093/cid/ciaa248">10.1093/cid/ciaa248</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32161940">32161940</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108125">PMC7108125</a></p>
 </div>
 <div id="ref-P4assQHj">
-<p>1316. <strong>Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)</strong> <br />
+<p>1318. <strong>Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)</strong> <br />
 Suxin Wan, Qingjie Yi, Shibing Fan, Jinglong Lv, Xianxiang Zhang, Lian Guo, Chunhui Lang, Qing Xiao, Kaihu Xiao, Zhengjun Yi, … Yongping Chen<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-12) <a href="https://doi.org/ggq63b">https://doi.org/ggq63b</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.10.20021832">10.1101/2020.02.10.20021832</a></p>
 </div>
 <div id="ref-zskgSnle">
-<p>1317. <strong>Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients</strong> <br />
+<p>1319. <strong>Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients</strong> <br />
 Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Wei Li, Hua Wang, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng<br />
 <em>SSRN Electronic Journal</em> (2020) <a href="https://doi.org/ggq655">https://doi.org/ggq655</a> <br />
 DOI: <a href="https://doi.org/10.2139/ssrn.3539682">10.2139/ssrn.3539682</a></p>
 </div>
 <div id="ref-TXlNzmXd">
-<p>1318. <strong>Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China</strong> <br />
+<p>1320. <strong>Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China</strong> <br />
 Jie Li, Shilin Li, Yurui Cai, Qin Liu, Xue Li, Zhaoping Zeng, Yanpeng Chu, Fangcheng Zhu, Fanxin Zeng<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-12) <a href="https://doi.org/ggq63c">https://doi.org/ggq63c</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.11.20022053">10.1101/2020.02.11.20022053</a></p>
 </div>
 <div id="ref-15K5Ovntj">
-<p>1319. <strong>ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection</strong> <br />
+<p>1321. <strong>ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection</strong> <br />
 Caibin Fan, Kai Li, Yanhong Ding, Wei Lu, Jianqing Wang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-13) <a href="https://doi.org/ggq63d">https://doi.org/ggq63d</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.12.20022418">10.1101/2020.02.12.20022418</a></p>
 </div>
 <div id="ref-Bgo7Cmj3">
-<p>1320. <strong>Aberrant pathogenic GM-CSF <sup>+</sup> T cells and inflammatory CD14 <sup>+</sup> CD16 <sup>+</sup> monocytes in severe pulmonary syndrome patients of a new coronavirus</strong> <br />
+<p>1322. <strong>Aberrant pathogenic GM-CSF <sup>+</sup> T cells and inflammatory CD14 <sup>+</sup> CD16 <sup>+</sup> monocytes in severe pulmonary syndrome patients of a new coronavirus</strong> <br />
 Yonggang Zhou, Binqing Fu, Xiaohu Zheng, Dongsheng Wang, Changcheng Zhao, Yingjie qi, Rui Sun, Zhigang Tian, Xiaoling Xu, Haiming Wei<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-20) <a href="https://doi.org/ggq63f">https://doi.org/ggq63f</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.12.945576">10.1101/2020.02.12.945576</a></p>
 </div>
 <div id="ref-4Z1pEioX">
-<p>1321. <strong>Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia: A Systemic Review and Meta-analysis</strong> <br />
+<p>1323. <strong>Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia: A Systemic Review and Meta-analysis</strong> <br />
 Kai Qian, Yi Deng, Yong-Hang Tai, Jun Peng, Hao Peng, Li-Hong Jiang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-17) <a href="https://doi.org/ggrgbq">https://doi.org/ggrgbq</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.14.20021535">10.1101/2020.02.14.20021535</a></p>
 </div>
 <div id="ref-zTGzuiTI">
-<p>1322. <strong>Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients</strong> <br />
+<p>1324. <strong>Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients</strong> <br />
 Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Hua Wang, Wei Li, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-22) <a href="https://doi.org/ggq63g">https://doi.org/ggq63g</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.16.20023671">10.1101/2020.02.16.20023671</a></p>
 </div>
 <div id="ref-1EIEx8Qe4">
-<p>1323. <strong>Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019</strong> <br />
+<p>1325. <strong>Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019</strong> <br />
 Guang Chen, Di Wu, Wei Guo, Yong Cao, Da Huang, Hongwu Wang, Tao Wang, Xiaoyun Zhang, Huilong Chen, Haijing Yu, … Qin Ning<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-19) <a href="https://doi.org/ggq63h">https://doi.org/ggq63h</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.16.20023903">10.1101/2020.02.16.20023903</a></p>
 </div>
 <div id="ref-NPxs7bbq">
-<p>1324. <strong>Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine</strong> <br />
+<p>1326. <strong>Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine</strong> <br />
 Yiyou Chen, Qiang Wei, Ruobing Li, Hong Gao, Hua Zhu, Wei Deng, Linlin Bao, Wei Tong, Zhe Cong, Hong Jiang, Chuan Qin<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-21) <a href="https://doi.org/ggq63k">https://doi.org/ggq63k</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.17.951939">10.1101/2020.02.17.951939</a></p>
 </div>
 <div id="ref-f50ahNxF">
-<p>1325. <strong>Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)</strong> <br />
+<p>1327. <strong>Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)</strong> <br />
 Bo Diao, Chenhui Wang, Yingjun Tan, Xiewan Chen, Ying Liu, Lifen Ning, Li Chen, Min Li, Yueping Liu, Gang Wang, … Yongwen Chen<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-20) <a href="https://doi.org/ggq63m">https://doi.org/ggq63m</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.18.20024364">10.1101/2020.02.18.20024364</a></p>
 </div>
 <div id="ref-EwNi3WJq">
-<p>1326. <strong>Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China</strong> <br />
+<p>1328. <strong>Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China</strong> <br />
 Xun Li, Luwen Wang, Shaonan Yan, Fan Yang, Longkui Xiang, Jiling Zhu, Bo Shen, Zuojiong Gong<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-25) <a href="https://doi.org/ggq63n">https://doi.org/ggq63n</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.19.20025239">10.1101/2020.02.19.20025239</a></p>
 </div>
 <div id="ref-KG5Lg65z">
-<p>1327. <strong>SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China</strong> <br />
+<p>1329. <strong>SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China</strong> <br />
 Luwen Wang, Xun Li, Hui Chen, Shaonan Yan, Yan Li, Dong Li, Zuojiong Gong<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-23) <a href="https://doi.org/ggq63p">https://doi.org/ggq63p</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.19.20025288">10.1101/2020.02.19.20025288</a></p>
 </div>
 <div id="ref-VRoblZFJ">
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+<p>1330. <strong>Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China</strong> <br />
 Dawei Wang, Bo Hu, Chang Hu, Fangfang Zhu, Xing Liu, Jing Zhang, Binbin Wang, Hui Xiang, Zhenshun Cheng, Yong Xiong, … Zhiyong Peng<br />
 <em>JAMA</em> (2020-03-17) <a href="https://doi.org/ggkh48">https://doi.org/ggkh48</a> <br />
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-<p>1329. <strong>Clinical characteristics of 2019 novel coronavirus infection in China</strong> <br />
+<p>1331. <strong>Clinical characteristics of 2019 novel coronavirus infection in China</strong> <br />
 Wei-jie Guan, Zheng-yi Ni, Yu Hu, Wen-hua Liang, Chun-quan Ou, Jian-xing He, Lei Liu, Hong Shan, Chun-liang Lei, David S. C. Hui, … Nan-shan Zhong<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-09) <a href="https://doi.org/ggkj9s">https://doi.org/ggkj9s</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.06.20020974">10.1101/2020.02.06.20020974</a></p>
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+<p>1332. <strong>Potential T-cell and B-cell Epitopes of 2019-nCoV</strong> <br />
 Ethan Fast, Russ B. Altman, Binbin Chen<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-18) <a href="https://doi.org/ggq63q">https://doi.org/ggq63q</a> <br />
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+<p>1333. <strong>Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein</strong> <br />
 Alexandra C. Walls, Young-Jun Park, M. Alexandra Tortorici, Abigail Wall, Andrew T. McGuire, David Veesler<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-20) <a href="https://doi.org/ggrgbr">https://doi.org/ggrgbr</a> <br />
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+<p>1334. <strong>Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19</strong> <br />
 Irani Thevarajan, Thi HO Nguyen, Marios Koutsakos, Julian Druce, Leon Caly, Carolien E van de Sandt, Xiaoxiao Jia, Suellen Nicholson, Mike Catton, Benjamin Cowie, … Katherine Kedzierska<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-23) <a href="https://doi.org/ggq63r">https://doi.org/ggq63r</a> <br />
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+<p>1335. <strong>The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing</strong> <br />
 Minfeng Liao, Yang Liu, Jin Yuan, Yanling Wen, Gang Xu, Juanjuan Zhao, Lin Chen, Jinxiu Li, Xin Wang, Fuxiang Wang, … Zheng Zhang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-26) <a href="https://doi.org/ggq63s">https://doi.org/ggq63s</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.02.23.20026690">10.1101/2020.02.23.20026690</a></p>
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+<p>1336. <strong>Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells</strong> <br />
 Marlena Scharenberg, Sindhu Vangeti, Eliisa Kekäläinen, Per Bergman, Mamdoh Al-Ameri, Niclas Johansson, Klara Sondén, Sara Falck-Jones, Anna Färnert, Hans-Gustaf Ljunggren, … Nicole Marquardt<br />
 <em>Frontiers in Immunology</em> (2019-05-17) <a href="https://doi.org/ggq656">https://doi.org/ggq656</a> <br />
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+<p>1337. <strong>Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China</strong> <br />
 Chaolin Huang, Yeming Wang, Xingwang Li, Lili Ren, Jianping Zhao, Yi Hu, Li Zhang, Guohui Fan, Jiuyang Xu, Xiaoying Gu, … Bin Cao<br />
 <em>The Lancet</em> (2020-02) <a href="https://doi.org/ggjfnn">https://doi.org/ggjfnn</a> <br />
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+<p>1338. <strong>Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection</strong> <br />
 Benoit Allard, Alice Panariti, James G. Martin<br />
 <em>Frontiers in Immunology</em> (2018-07-31) <a href="https://doi.org/gd3bnz">https://doi.org/gd3bnz</a> <br />
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+<p>1339. <strong>PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection</strong> <br />
 Su Huang, Bibo Zhu, In Su Cheon, Nick P. Goplen, Li Jiang, Ruixuan Zhang, R. Stokes Peebles, Matthias Mack, Mark H. Kaplan, Andrew H. Limper, Jie Sun<br />
 <em>Journal of Virology</em> (2019-04-17) <a href="https://doi.org/ggq652">https://doi.org/ggq652</a> <br />
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+<p>1340. <strong>Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?</strong> <br />
 Yunbao Pan, Guangming Ye, Xiantao Zeng, Guohong Liu, Xiaojiao Zeng, Xianghu Jiang, Jin Zhao, Liangjun Chen, Shuang Guo, Qiaoling Deng, … Xinghuan Wang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-25) <a href="https://doi.org/ggq63t">https://doi.org/ggq63t</a> <br />
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+<p>1341. <strong>Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia</strong> <br />
 Jing Gong, Hui Dong, Qingsong Xia, Zhaoyi Huang, Dingkun Wang, Yan Zhao, Wenhua Liu, Shenghao Tu, Mingmin Zhang, Qi Wang, Fuer Lu<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-26) <a href="https://doi.org/ggq63v">https://doi.org/ggq63v</a> <br />
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+<p>1342. <strong>An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design</strong> <br />
 CV Herst, S Burkholz, J Sidney, A Sette, PE Harris, S Massey, T Brasel, E Cunha-Neto, DS Rosa, WCH Chao, … R Rubsamen<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-04-06) <a href="https://doi.org/ggq63x">https://doi.org/ggq63x</a> <br />
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-<p>1341. <strong>Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2</strong> <br />
+<p>1343. <strong>Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2</strong> <br />
 Lin Li, Ting Sun, Yufei He, Wendong Li, Yubo Fan, Jing Zhang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-27) <a href="https://doi.org/ggnqwt">https://doi.org/ggnqwt</a> <br />
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+<p>1344. <strong>The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis</strong> <br />
 Wang Wenjun, Liu Xiaoqing, Wu Sipei, Lie Puyi, Huang Liyan, Li Yimin, Cheng Linling, Chen Sibei, Nong Lingbo, Lin Yongping, He Jianxing<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-27) <a href="https://doi.org/ggrgbs">https://doi.org/ggrgbs</a> <br />
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+<p>1345. <strong>Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China</strong> <br />
 Ying Huang, Rui Yang, Ying Xu, Ping Gong<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-05) <a href="https://doi.org/ggq63z">https://doi.org/ggq63z</a> <br />
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+<p>1346. <strong>Risk factors related to hepatic injury in patients with corona virus disease 2019</strong> <br />
 Lu Li, Shuang Li, Manman Xu, Pengfei Yu, Sujun Zheng, Zhongping Duan, Jing Liu, Yu Chen, Junfeng Li<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-10) <a href="https://doi.org/ggq632">https://doi.org/ggq632</a> <br />
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+<p>1347. <strong>Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients</strong> <br />
 Xiaohua Chen, Binghong Zhao, Yueming Qu, Yurou Chen, Jie Xiong, Yong Feng, Dong Men, Qianchuan Huang, Ying Liu, Bo Yang, … Feng Li<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-03) <a href="https://doi.org/ggq633">https://doi.org/ggq633</a> <br />
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-<p>1346. <strong>Prognostic factors in the acute respiratory distress syndrome</strong> <br />
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 Wei Chen, Lorraine B Ware<br />
 <em>Clinical and Translational Medicine</em> (2015-07-02) <a href="https://doi.org/ggq653">https://doi.org/ggq653</a> <br />
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 Li Tan, Qi Wang, Duanyang Zhang, Jinya Ding, Qianchuan Huang, Yi-Quan Tang, Qiongshu Wang, Hongming Miao<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-03) <a href="https://doi.org/ggq634">https://doi.org/ggq634</a> <br />
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+<p>1350. <strong>The potential role of IL-6 in monitoring severe case of coronavirus disease 2019</strong> <br />
 Tao Liu, Jieying Zhang, Yuhui Yang, Hong Ma, Zhengyu Li, Jiaoyu Zhang, Ji Cheng, Xiaoyun Zhang, Yanxia Zhao, Zihan Xia, … Jianhua Yi<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-10) <a href="https://doi.org/ggq635">https://doi.org/ggq635</a> <br />
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+<p>1351. <strong>Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China</strong> <br />
 Zonghao Zhao, Jiajia Xie, Ming Yin, Yun Yang, Hongliang He, Tengchuan Jin, Wenting Li, Xiaowu Zhu, Jing Xu, Changcheng Zhao, … Xiaoling Ma<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-06) <a href="https://doi.org/ggq636">https://doi.org/ggq636</a> <br />
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-<p>1350. <strong>Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome</strong> <br />
+<p>1352. <strong>Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome</strong> <br />
 Yang Yang, Chenguang Shen, Jinxiu Li, Jing Yuan, Minghui Yang, Fuxiang Wang, Guobao Li, Yanjie Li, Li Xing, Ling Peng, … Yingxia Liu<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-06) <a href="https://doi.org/ggq637">https://doi.org/ggq637</a> <br />
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-<p>1351. <strong>Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019</strong> <br />
+<p>1353. <strong>Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019</strong> <br />
 Juanjuan Zhao, Quan Yuan, Haiyan Wang, Wei Liu, Xuejiao Liao, Yingying Su, Xin Wang, Jing Yuan, Tingdong Li, Jinxiu Li, … Zheng Zhang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-02) <a href="https://doi.org/ggrbj6">https://doi.org/ggrbj6</a> <br />
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+<p>1354. <strong>Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients</strong> <br />
 Xiaoping Chen, Jiaxin Ling, Pingzheng Mo, Yongxi Zhang, Qunqun Jiang, Zhiyong Ma, Qian Cao, Wenjia Hu, Shi Zou, Liangjun Chen, … Yong Xiong<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-06) <a href="https://doi.org/ggq639">https://doi.org/ggq639</a> <br />
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-<p>1353. <strong>Effects of Systemically Administered Hydrocortisone on the Human Immunome</strong> <br />
+<p>1355. <strong>Effects of Systemically Administered Hydrocortisone on the Human Immunome</strong> <br />
 Matthew J. Olnes, Yuri Kotliarov, Angélique Biancotto, Foo Cheung, Jinguo Chen, Rongye Shi, Huizhi Zhou, Ena Wang, John S. Tsang, Robert Nussenblatt, The CHI Consortium<br />
 <em>Scientific Reports</em> (2016-03-14) <a href="https://doi.org/f8dmvw">https://doi.org/f8dmvw</a> <br />
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+<p>1356. <strong>Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis</strong> <br />
 Giuseppe Lippi, Mario Plebani<br />
 <em>Clinica Chimica Acta</em> (2020-06) <a href="https://doi.org/ggpxp7">https://doi.org/ggpxp7</a> <br />
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+<p>1357. <strong>Clinical findings in critically ill patients infected with SARS-CoV-2 in Guangdong Province, China: a multi-center, retrospective, observational study</strong> <br />
 Yonghao Xu, Zhiheng Xu, Xuesong Liu, Lihua Cai, Haichong Zheng, Yongbo Huang, Lixin Zhou, Linxi Huang, Yun Lin, Liehua Deng, … Yimin Li<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-06) <a href="https://doi.org/ggq64b">https://doi.org/ggq64b</a> <br />
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+<p>1358. <strong>Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus (SARS-CoV-2)</strong> <br />
 Ye Feng, Min Qiu, Liang Liu, Shengmei Zou, Yun Li, Kai Luo, Qianpeng Guo, Ning Han, Yingqiang Sun, Kui Wang, … Fan Mo<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-06-30) <a href="https://doi.org/ggq64c">https://doi.org/ggq64c</a> <br />
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-<p>1357. <strong>Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China</strong> <br />
+<p>1359. <strong>Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China</strong> <br />
 Min Cao, Dandan Zhang, Youhua Wang, Yunfei Lu, Xiangdong Zhu, Ying Li, Honghao Xue, Yunxiao Lin, Min Zhang, Yiguo Sun, … Hongzhou Lu<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-06) <a href="https://doi.org/ggq64d">https://doi.org/ggq64d</a> <br />
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+<p>1360. <strong>Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing</strong> <br />
 Jin Zhang, Jianhua Liu, Na Li, Yong Liu, Rui Ye, Xiaosong Qin, Rui Zheng<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-06) <a href="https://doi.org/ggq64f">https://doi.org/ggq64f</a> <br />
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-<p>1359. <strong>Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection</strong> <br />
+<p>1361. <strong>Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection</strong> <br />
 Bo Diao, Chenhui Wang, Rongshuai Wang, Zeqing Feng, Yingjun Tan, Huiming Wang, Changsong Wang, Liang Liu, Ying Liu, Yueping Liu, … Yongwen Chen<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-04-10) <a href="https://doi.org/ggq64g">https://doi.org/ggq64g</a> <br />
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+<p>1362. <strong>COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients</strong> <br />
 Cong-Ying Song, Jia Xu, Jian-Qin He, Yuan-Qiang Lu<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-08) <a href="https://doi.org/ggq64h">https://doi.org/ggq64h</a> <br />
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 </div>
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-<p>1361. <strong>LY6E impairs coronavirus fusion and confers immune control of viral disease</strong> <br />
+<p>1363. <strong>LY6E impairs coronavirus fusion and confers immune control of viral disease</strong> <br />
 Stephanie Pfaender, Katrina B. Mar, Eleftherios Michailidis, Annika Kratzel, Dagny Hirt, Philip V’kovski, Wenchun Fan, Nadine Ebert, Hanspeter Stalder, Hannah Kleine-Weber, … Volker Thiel<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-07) <a href="https://doi.org/dpvn">https://doi.org/dpvn</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.05.979260">10.1101/2020.03.05.979260</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32511345">32511345</a></p>
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-<p>1362. <strong>A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients</strong> <br />
+<p>1364. <strong>A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients</strong> <br />
 Lei Liu, Wanbing Liu, Yaqiong Zheng, Xiaojing Jiang, Guomei Kou, Jinya Ding, Qiongshu Wang, Qianchuan Huang, Yinjuan Ding, Wenxu Ni, … Shangen Zheng<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-08) <a href="https://doi.org/ggq64j">https://doi.org/ggq64j</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.06.20031856">10.1101/2020.03.06.20031856</a></p>
 </div>
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-<p>1363. <strong>Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2</strong> <br />
+<p>1365. <strong>Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2</strong> <br />
 Zhiqiang Zheng, Vanessa M. Monteil, Sebastian Maurer-Stroh, Chow Wenn Yew, Carol Leong, Nur Khairiah Mohd-Ismail, Suganya Cheyyatraivendran Arularasu, Vincent Tak Kwong Chow, Raymond Lin Tzer Pin, Ali Mirazimi, … Yee-Joo Tan<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-07) <a href="https://doi.org/ggrbj7">https://doi.org/ggrbj7</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.06.980037">10.1101/2020.03.06.980037</a></p>
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-<p>1364. <strong>Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population</strong> <br />
+<p>1366. <strong>Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population</strong> <br />
 Qiang Zeng, Yong-zhe Li, Gang Huang, Wei Wu, Sheng-yong Dong, Yang Xu<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-13) <a href="https://doi.org/ggq64k">https://doi.org/ggq64k</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.08.20031229">10.1101/2020.03.08.20031229</a></p>
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-<p>1365. <strong>Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19</strong> <br />
+<p>1367. <strong>Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19</strong> <br />
 Hua Fan, Lin Zhang, Bin Huang, Muxin Zhu, Yong Zhou, Huan Zhang, Xiaogen Tao, Shaohui Cheng, Wenhu Yu, Liping Zhu, Jian Chen<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-17) <a href="https://doi.org/ggq64n">https://doi.org/ggq64n</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.09.20033068">10.1101/2020.03.09.20033068</a></p>
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-<p>1366. <strong>Relationship between the ABO Blood Group and the COVID-19 Susceptibility</strong> <br />
+<p>1368. <strong>Relationship between the ABO Blood Group and the COVID-19 Susceptibility</strong> <br />
 Jiao Zhao, Yan Yang, Hanping Huang, Dong Li, Dongfeng Gu, Xiangfeng Lu, Zheng Zhang, Lei Liu, Ting Liu, Yukun Liu, … Peng George Wang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-27) <a href="https://doi.org/ggpn3d">https://doi.org/ggpn3d</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.11.20031096">10.1101/2020.03.11.20031096</a></p>
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-<p>1367. <strong>The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15</strong> <br />
+<p>1369. <strong>The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15</strong> <br />
 Shutoku Matsuyama, Miyuki Kawase, Naganori Nao, Kazuya Shirato, Makoto Ujike, Wataru Kamitani, Masayuki Shimojima, Shuetsu Fukushi<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-12) <a href="https://doi.org/ggq64p">https://doi.org/ggq64p</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.11.987016">10.1101/2020.03.11.987016</a></p>
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-<p>1368. <strong>Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19</strong> <br />
+<p>1370. <strong>Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19</strong> <br />
 Bicheng Zhang, Xiaoyang Zhou, Chengliang Zhu, Fan Feng, Yanru Qiu, Jia Feng, Qingzhu Jia, Qibin Song, Bo Zhu, Jun Wang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-16) <a href="https://doi.org/ggq64q">https://doi.org/ggq64q</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.12.20035048">10.1101/2020.03.12.20035048</a></p>
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-<p>1369. <strong>Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2</strong> <br />
+<p>1371. <strong>Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2</strong> <br />
 Linlin Bao, Wei Deng, Hong Gao, Chong Xiao, Jiayi Liu, Jing Xue, Qi Lv, Jiangning Liu, Pin Yu, Yanfeng Xu, … Chuan Qin<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-05-01) <a href="https://doi.org/ggn8r8">https://doi.org/ggn8r8</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.13.990226">10.1101/2020.03.13.990226</a></p>
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-<p>1370. <strong>A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV</strong> <br />
+<p>1372. <strong>A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV</strong> <br />
 Meng Yuan, Nicholas C. Wu, Xueyong Zhu, Chang-Chun D. Lee, Ray T. Y. So, Huibin Lv, Chris K. P. Mok, Ian A. Wilson<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-14) <a href="https://doi.org/ggq64s">https://doi.org/ggq64s</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.13.991570">10.1101/2020.03.13.991570</a></p>
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-<p>1371. <strong>Highly accurate and sensitive diagnostic detection of SARS-CoV-2 by digital PCR</strong> <br />
+<p>1373. <strong>Highly accurate and sensitive diagnostic detection of SARS-CoV-2 by digital PCR</strong> <br />
 Lianhua Dong, Junbo Zhou, Chunyan Niu, Quanyi Wang, Yang Pan, Sitong Sheng, Xia Wang, Yongzhuo Zhang, Jiayi Yang, Manqing Liu, … Xiang Fang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-30) <a href="https://doi.org/ggqnqh">https://doi.org/ggqnqh</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.14.20036129">10.1101/2020.03.14.20036129</a></p>
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-<p>1372. <strong>SARS-CoV-2 invades host cells via a novel route: CD147-spike protein</strong> <br />
+<p>1374. <strong>SARS-CoV-2 invades host cells via a novel route: CD147-spike protein</strong> <br />
 Ke Wang, Wei Chen, Yu-Sen Zhou, Jian-Qi Lian, Zheng Zhang, Peng Du, Li Gong, Yang Zhang, Hong-Yong Cui, Jie-Jie Geng, … Zhi-Nan Chen<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-14) <a href="https://doi.org/ggq64t">https://doi.org/ggq64t</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.14.988345">10.1101/2020.03.14.988345</a></p>
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-<p>1373. <strong>CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint</strong> <br />
+<p>1375. <strong>CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint</strong> <br />
 Tomoki Kosugi, Kayaho Maeda, Waichi Sato, Shoichi Maruyama, Kenji Kadomatsu<br />
 <em>Nephrology Dialysis Transplantation</em> (2015-07) <a href="https://doi.org/ggq624">https://doi.org/ggq624</a> <br />
 DOI: <a href="https://doi.org/10.1093/ndt/gfu302">10.1093/ndt/gfu302</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/25248362">25248362</a></p>
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-<p>1374. <strong>The roles of CyPA and CD147 in cardiac remodelling</strong> <br />
+<p>1376. <strong>The roles of CyPA and CD147 in cardiac remodelling</strong> <br />
 Hongyan Su, Yi Yang<br />
 <em>Experimental and Molecular Pathology</em> (2018-06) <a href="https://doi.org/ggq622">https://doi.org/ggq622</a> <br />
 DOI: <a href="https://doi.org/10.1016/j.yexmp.2018.05.001">10.1016/j.yexmp.2018.05.001</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/29772453">29772453</a></p>
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-<p>1375. <strong>Cancer-related issues of CD147.</strong> <br />
+<p>1377. <strong>Cancer-related issues of CD147.</strong> <br />
 Ulrich H Weidle, Werner Scheuer, Daniela Eggle, Stefan Klostermann, Hannes Stockinger<br />
 <em>Cancer genomics &amp; proteomics</em> <a href="https://www.ncbi.nlm.nih.gov/pubmed/20551248">https://www.ncbi.nlm.nih.gov/pubmed/20551248</a> <br />
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-<p>1376. <strong>Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19</strong> <br />
+<p>1378. <strong>Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19</strong> <br />
 Lulin Huang, Yi Shi, Bo Gong, Li Jiang, Xiaoqi Liu, Jialiang Yang, Juan Tang, Chunfang You, Qi Jiang, Bo Long, … Zhenglin Yang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-17) <a href="https://doi.org/ggq64v">https://doi.org/ggq64v</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.15.20033472">10.1101/2020.03.15.20033472</a></p>
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-<p>1377. <strong>Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections</strong> <br />
+<p>1379. <strong>Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections</strong> <br />
 Huibin Lv, Nicholas C. Wu, Owen Tak-Yin Tsang, Meng Yuan, Ranawaka A. P. M. Perera, Wai Shing Leung, Ray T. Y. So, Jacky Man Chun Chan, Garrick K. Yip, Thomas Shiu Hong Chik, … Chris K. P. Mok<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-17) <a href="https://doi.org/ggq64w">https://doi.org/ggq64w</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.15.993097">10.1101/2020.03.15.993097</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32511317">32511317</a></p>
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-<p>1378. <strong>The feasibility of convalescent plasma therapy in severe COVID- 19 patients: a pilot study</strong> <br />
+<p>1380. <strong>The feasibility of convalescent plasma therapy in severe COVID- 19 patients: a pilot study</strong> <br />
 Kai Duan, Bende Liu, Cesheng Li, Huajun Zhang, Ting Yu, Jieming Qu, Min Zhou, Li Chen, Shengli Meng, Yong Hu, … Xiaoming Yang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-23) <a href="https://doi.org/dqrs">https://doi.org/dqrs</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.16.20036145">10.1101/2020.03.16.20036145</a></p>
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+<p>1381. <strong>Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial</strong> <br />
 Philippe Gautret, Jean-Christophe Lagier, Philippe Parola, Van Thuan Hoang, Line Meddeb, Morgane Mailhe, Barbara Doudier, Johan Courjon, Valérie Giordanengo, Vera Esteves Vieira, … Didier Raoult<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-20) <a href="https://doi.org/dqbv">https://doi.org/dqbv</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.16.20037135">10.1101/2020.03.16.20037135</a></p>
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-<p>1380. <strong>Chloroquine: Modes of action of an undervalued drug</strong> <br />
+<p>1382. <strong>Chloroquine: Modes of action of an undervalued drug</strong> <br />
 Rodolfo Thomé, Stefanie Costa Pinto Lopes, Fabio Trindade Maranhão Costa, Liana Verinaud<br />
 <em>Immunology Letters</em> (2013-06) <a href="https://doi.org/f5b5cr">https://doi.org/f5b5cr</a> <br />
 DOI: <a href="https://doi.org/10.1016/j.imlet.2013.07.004">10.1016/j.imlet.2013.07.004</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/23891850">23891850</a></p>
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-<p>1381. <strong>Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy</strong> <br />
+<p>1383. <strong>Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy</strong> <br />
 B. Lo, K. Zhang, W. Lu, L. Zheng, Q. Zhang, C. Kanellopoulou, Y. Zhang, Z. Liu, J. M. Fritz, R. Marsh, … M. B. Jordan<br />
 <em>Science</em> (2015-07-23) <a href="https://doi.org/f7kc8d">https://doi.org/f7kc8d</a> <br />
 DOI: <a href="https://doi.org/10.1126/science.aaa1663">10.1126/science.aaa1663</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/26206937">26206937</a></p>
 </div>
 <div id="ref-3VPi509z">
-<p>1382. <strong>The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2</strong> <br />
+<p>1384. <strong>The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2</strong> <br />
 Erik Procko<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-05-11) <a href="https://doi.org/ggrbj8">https://doi.org/ggrbj8</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.16.994236">10.1101/2020.03.16.994236</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/32511321">32511321</a></p>
 </div>
 <div id="ref-1EcOLnVXk">
-<p>1383. <strong>Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model</strong> <br />
+<p>1385. <strong>Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model</strong> <br />
 Barry Rockx, Thijs Kuiken, Sander Herfst, Theo Bestebroer, Mart M. Lamers, Dennis de Meulder, Geert van Amerongen, Judith van den Brand, Nisreen M. A. Okba, Debby Schipper, … Bart L. Haagmans<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-17) <a href="https://doi.org/ggq649">https://doi.org/ggq649</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.17.995639">10.1101/2020.03.17.995639</a></p>
 </div>
 <div id="ref-NzFgXYvQ">
-<p>1384. <strong>Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus</strong> <br />
+<p>1386. <strong>Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus</strong> <br />
 Paul B. McCray, Lecia Pewe, Christine Wohlford-Lenane, Melissa Hickey, Lori Manzel, Lei Shi, Jason Netland, Hong Peng Jia, Carmen Halabi, Curt D. Sigmund, … Stanley Perlman<br />
 <em>Journal of Virology</em> (2007-01-15) <a href="https://doi.org/b2dr3s">https://doi.org/b2dr3s</a> <br />
 DOI: <a href="https://doi.org/10.1128/jvi.02012-06">10.1128/jvi.02012-06</a> · PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/17079315">17079315</a> · PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797474">PMC1797474</a></p>
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 <div id="ref-OvFueDLZ">
-<p>1385. <strong>Modeling the Impact of Asymptomatic Carriers on COVID-19 Transmission Dynamics During Lockdown</strong> <br />
+<p>1387. <strong>Modeling the Impact of Asymptomatic Carriers on COVID-19 Transmission Dynamics During Lockdown</strong> <br />
 Jacob B. Aguilar, Jeremy Samuel Faust, Lauren M. Westafer, Juan B. Gutierrez<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-08-11) <a href="https://doi.org/ggqnvp">https://doi.org/ggqnvp</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.18.20037994">10.1101/2020.03.18.20037994</a></p>
 </div>
 <div id="ref-Y9g1sQ1Y">
-<p>1386. <strong>Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice</strong> <br />
+<p>1388. <strong>Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice</strong> <br />
 Quan-xin Long, Hai-jun Deng, Juan Chen, Jie-li Hu, Bei-zhong Liu, Pu Liao, Yong Lin, Li-hua Yu, Zhan Mo, Yin-yin Xu, … Ai-long Huang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-20) <a href="https://doi.org/ggpvz3">https://doi.org/ggpvz3</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.18.20038018">10.1101/2020.03.18.20038018</a></p>
 </div>
 <div id="ref-p1c9Nilh">
-<p>1387. <strong>Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2</strong> <br />
+<p>1389. <strong>Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2</strong> <br />
 Xiumei Hu, Taixue An, Bo Situ, Yuhai Hu, Zihao Ou, Qiang Li, Xiaojing He, Ye Zhang, Peifu Tian, Dehua Sun, … Lei Zheng<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-16) <a href="https://doi.org/ggq646">https://doi.org/ggq646</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.12.20034231">10.1101/2020.03.12.20034231</a></p>
 </div>
 <div id="ref-1BLNvgEao">
-<p>1388. <strong>SARS-CoV-2 specific antibody responses in COVID-19 patients</strong> <br />
+<p>1390. <strong>SARS-CoV-2 specific antibody responses in COVID-19 patients</strong> <br />
 Nisreen M. A. Okba, Marcel A. Müller, Wentao Li, Chunyan Wang, Corine H. GeurtsvanKessel, Victor M. Corman, Mart M. Lamers, Reina S. Sikkema, Erwin de Bruin, Felicity D. Chandler, … Bart L. Haagmans<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-20) <a href="https://doi.org/ggpvz2">https://doi.org/ggpvz2</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.18.20038059">10.1101/2020.03.18.20038059</a></p>
 </div>
 <div id="ref-K41YFM2N">
-<p>1389. <strong>A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19</strong> <br />
+<p>1391. <strong>A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19</strong> <br />
 Drifa Belhadi, Nathan Peiffer-Smadja, François-Xavier Lescure, Yazdan Yazdanpanah, France Mentré, Cédric Laouénan<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-27) <a href="https://doi.org/ggq65b">https://doi.org/ggq65b</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.18.20038190">10.1101/2020.03.18.20038190</a></p>
 </div>
 <div id="ref-eTsOvBVf">
-<p>1390. <strong>ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19</strong> <br />
+<p>1392. <strong>ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19</strong> <br />
 Janice M. Leung, Chen X. Yang, Anthony Tam, Tawimas Shaipanich, Tillie-Louise Hackett, Gurpreet K. Singhera, Delbert R. Dorscheid, Don D. Sin<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-23) <a href="https://doi.org/dqx2">https://doi.org/dqx2</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.18.20038455">10.1101/2020.03.18.20038455</a></p>
 </div>
 <div id="ref-18KZGwJ0J">
-<p>1391. <strong>Dynamic profile of severe or critical COVID-19 cases</strong> <br />
+<p>1393. <strong>Dynamic profile of severe or critical COVID-19 cases</strong> <br />
 Yang Xu<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-20) <a href="https://doi.org/ggrbj9">https://doi.org/ggrbj9</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.18.20038513">10.1101/2020.03.18.20038513</a></p>
 </div>
 <div id="ref-1BJXDZ04c">
-<p>1392. <strong>Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients</strong> <br />
+<p>1394. <strong>Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients</strong> <br />
 Hang Fu, Huayan Xu, Na Zhang, Hong Xu, Zhenlin Li, Huizhu Chen, Rong Xu, Ran Sun, Lingyi Wen, Linjun Xie, … Yingkun Guo<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-23) <a href="https://doi.org/ggq65c">https://doi.org/ggq65c</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.19.20038315">10.1101/2020.03.19.20038315</a></p>
 </div>
 <div id="ref-iMCz5Twj">
-<p>1393. <strong>An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus</strong> <br />
+<p>1395. <strong>An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus</strong> <br />
 Timothy P. Sheahan, Amy C. Sims, Shuntai Zhou, Rachel L. Graham, Collin S. Hill, Sarah R. Leist, Alexandra Schäfer, Kenneth H. Dinnon, Stephanie A. Montgomery, Maria L. Agostini, … Ralph S. Baric<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-20) <a href="https://doi.org/ggrbkb">https://doi.org/ggrbkb</a> <br />
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+<p>1396. <strong>Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs</strong> <br />
 Sangeun Jeon, Meehyun Ko, Jihye Lee, Inhee Choi, Soo Young Byun, Soonju Park, David Shum, Seungtaek Kim<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-28) <a href="https://doi.org/ggq65h">https://doi.org/ggq65h</a> <br />
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+<p>1397. <strong>Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2</strong> <br />
 Vincent J. Munster, Friederike Feldmann, Brandi N. Williamson, Neeltje van Doremalen, Lizzette Pérez-Pérez, Jonathan Schulz, Kimberly Meade-White, Atsushi Okumura, Julie Callison, Beniah Brumbaugh, … Emmie de Wit<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-21) <a href="https://doi.org/ggq65j">https://doi.org/ggq65j</a> <br />
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+<p>1398. <strong>Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in Rhesus macaques</strong> <br />
 Wei Deng, Linlin Bao, Hong Gao, Zhiguang Xiang, Yajin Qu, Zhiqi Song, Shunran Gong, Jiayi Liu, Jiangning Liu, Pin Yu, … Chuan Qin<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-30) <a href="https://doi.org/ggq64r">https://doi.org/ggq64r</a> <br />
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 Bruna G. G. Pinto, Antonio E. R. Oliveira, Youvika Singh, Leandro Jimenez, Andre N A. Gonçalves, Rodrigo L. T. Ogava, Rachel Creighton, Jean Pierre Schatzmann Peron, Helder I. Nakaya<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-27) <a href="https://doi.org/ggq65k">https://doi.org/ggq65k</a> <br />
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 Huijie Bian, Zhao-Hui Zheng, Ding Wei, Zheng Zhang, Wen-Zhen Kang, Chun-Qiu Hao, Ke Dong, Wen Kang, Jie-Lai Xia, Jin-Lin Miao, … Ping Zhu<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-07-15) <a href="https://doi.org/ggq65m">https://doi.org/ggq65m</a> <br />
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+<p>1401. <strong>CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A</strong> <br />
 T. Pushkarsky, G. Zybarth, L. Dubrovsky, V. Yurchenko, H. Tang, H. Guo, B. Toole, B. Sherry, M. Bukrinsky<br />
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+<p>1402. <strong>CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells</strong> <br />
 Akira Watanabe, Misako Yoneda, Fusako Ikeda, Yuri Terao-Muto, Hiroki Sato, Chieko Kai<br />
 <em>Journal of Virology</em> (2010-05-01) <a href="https://doi.org/dpcsqg">https://doi.org/dpcsqg</a> <br />
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+<p>1403. <strong>Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum</strong> <br />
 Cécile Crosnier, Leyla Y. Bustamante, S. Josefin Bartholdson, Amy K. Bei, Michel Theron, Makoto Uchikawa, Souleymane Mboup, Omar Ndir, Dominic P. Kwiatkowski, Manoj T. Duraisingh, … Gavin J. Wright<br />
 <em>Nature</em> (2011-11-09) <a href="https://doi.org/dm59hf">https://doi.org/dm59hf</a> <br />
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+<p>1404. <strong>Function of HAb18G/CD147 in Invasion of Host Cells by Severe Acute Respiratory Syndrome Coronavirus</strong> <br />
 Zhinan Chen, Li Mi, Jing Xu, Jiyun Yu, Xianhui Wang, Jianli Jiang, Jinliang Xing, Peng Shang, Airong Qian, Yu Li, … Ping Zhu<br />
 <em>The Journal of Infectious Diseases</em> (2005-03) <a href="https://doi.org/cd8snd">https://doi.org/cd8snd</a> <br />
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 Christine Yee, Nathan M. Main, Alexandra Terry, Igor Stevanovski, Annette Maczurek, Alison J. Morgan, Sarah Calabro, Alison J. Potter, Tina L. Iemma, David G. Bowen, … Nicholas A. Shackel<br />
 <em>PLOS ONE</em> (2019-07-10) <a href="https://doi.org/ggq654">https://doi.org/ggq654</a> <br />
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+<p>1406. <strong>Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site</strong> <br />
 Andrew D. Davidson, Maia Kavanagh Williamson, Sebastian Lewis, Deborah Shoemark, Miles W. Carroll, Kate Heesom, Maria Zambon, Joanna Ellis, Phillip A. Lewis, Julian A. Hiscox, David A. Matthews<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-24) <a href="https://doi.org/ggq65n">https://doi.org/ggq65n</a> <br />
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+<p>1407. <strong>Modifications to the Hemagglutinin Cleavage Site Control the Virulence of a Neurotropic H1N1 Influenza Virus</strong> <br />
 Xiangjie Sun, Longping V. Tse, A Damon Ferguson, Gary R. Whittaker<br />
 <em>Journal of Virology</em> (2010-09-01) <a href="https://doi.org/drs2zt">https://doi.org/drs2zt</a> <br />
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+<p>1408. <strong>The architecture of SARS-CoV-2 transcriptome</strong> <br />
 Dongwan Kim, Joo-Yeon Lee, Jeong-Sun Yang, Jun Won Kim, V. Narry Kim, Hyeshik Chang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-14) <a href="https://doi.org/ggpx9q">https://doi.org/ggpx9q</a> <br />
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+<p>1409. <strong>First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naïve and Experienced COVID-19 Patients</strong> <br />
 Hongyi Chen, Zhicheng Zhang, Li Wang, Zhihua Huang, Fanghua Gong, Xiaodong Li, Yahong Chen, Jinzi J. Wu<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-24) <a href="https://doi.org/ggrgbt">https://doi.org/ggrgbt</a> <br />
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+<p>1410. <strong>Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)</strong> <br />
 Scott D. Seiwert, Steven W. Andrews, Yutong Jiang, Vladimir Serebryany, Hua Tan, Karl Kossen, P. T. Ravi Rajagopalan, Shawn Misialek, Sarah K. Stevens, Antitsa Stoycheva, … Lawrence M. Blatt<br />
 <em>Antimicrobial Agents and Chemotherapy</em> (2008-12) <a href="https://doi.org/btpg52">https://doi.org/btpg52</a> <br />
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+<p>1411. <strong>Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China</strong> <br />
 Xiaoyuan Xu, Bo Feng, Yujuan Guan, Sujun Zheng, Jifang Sheng, Xingxiang Yang, Yuanji Ma, Yan Huang, Yi Kang, Xiaofeng Wen, … Lai Wei<br />
 <em>Journal of Clinical and Translational Hepatology</em> (2019-09-30) <a href="https://doi.org/ggrbkd">https://doi.org/ggrbkd</a> <br />
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-<p>1410. <strong>Potentially highly potent drugs for 2019-nCoV</strong> <br />
+<p>1412. <strong>Potentially highly potent drugs for 2019-nCoV</strong> <br />
 Duc Duy Nguyen, Kaifu Gao, Jiahui Chen, Rui Wang, Guo-Wei Wei<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-02-13) <a href="https://doi.org/ggrbj5">https://doi.org/ggrbj5</a> <br />
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-<p>1411. <strong>Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset</strong> <br />
+<p>1413. <strong>Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset</strong> <br />
 Bin Lou, Ting-Dong Li, Shu-Fa Zheng, Ying-Ying Su, Zhi-Yong Li, Wei Liu, Fei Yu, Sheng-Xiang Ge, Qian-Da Zou, Quan Yuan, … Yu Chen<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-27) <a href="https://doi.org/ggrbkc">https://doi.org/ggrbkc</a> <br />
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-<p>1412. <strong>SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems</strong> <br />
+<p>1414. <strong>SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems</strong> <br />
 Daniel Blanco-Melo, Benjamin E. Nilsson-Payant, Wen-Chun Liu, Rasmus Møller, Maryline Panis, David Sachs, Randy A. Albrecht, Benjamin R. tenOever<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-24) <a href="https://doi.org/ggq65q">https://doi.org/ggq65q</a> <br />
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-<p>1413. <strong>A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China</strong> <br />
+<p>1415. <strong>A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China</strong> <br />
 Ying Zhou, Zhen Yang, Yanan Guo, Shuang Geng, Shan Gao, Shenglan Ye, Yi Hu, Yafei Wang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-27) <a href="https://doi.org/ggq65r">https://doi.org/ggq65r</a> <br />
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+<p>1416. <strong>Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study</strong> <br />
 Shuke Nie, Xueqing Zhao, Kang Zhao, Zhaohui Zhang, Zhentao Zhang, Zhan Zhang<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-26) <a href="https://doi.org/ggq65s">https://doi.org/ggq65s</a> <br />
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-<p>1415. <strong>Viral Kinetics and Antibody Responses in Patients with COVID-19</strong> <br />
+<p>1417. <strong>Viral Kinetics and Antibody Responses in Patients with COVID-19</strong> <br />
 Wenting Tan, Yanqiu Lu, Juan Zhang, Jing Wang, Yunjie Dan, Zhaoxia Tan, Xiaoqing He, Chunfang Qian, Qiangzhong Sun, Qingli Hu, … Guohong Deng<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-26) <a href="https://doi.org/ggq65t">https://doi.org/ggq65t</a> <br />
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-<p>1416. <strong>Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray</strong> <br />
+<p>1418. <strong>Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray</strong> <br />
 He-wei Jiang, Yang Li, Hai-nan Zhang, Wei Wang, Dong Men, Xiao Yang, Huan Qi, Jie Zhou, Sheng-ce Tao<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-27) <a href="https://doi.org/ggq65g">https://doi.org/ggq65g</a> <br />
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-<p>1417. <strong>Anti–spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection</strong> <br />
+<p>1419. <strong>Anti–spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection</strong> <br />
 Li Liu, Qiang Wei, Qingqing Lin, Jun Fang, Haibo Wang, Hauyee Kwok, Hangying Tang, Kenji Nishiura, Jie Peng, Zhiwu Tan, … Zhiwei Chen<br />
 <em>JCI Insight</em> (2019-02-21) <a href="https://doi.org/ggqbpw">https://doi.org/ggqbpw</a> <br />
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-<p>1418. <strong>COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome</strong> <br />
+<p>1420. <strong>COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome</strong> <br />
 Dan Zhang, Rui Guo, Lei Lei, Hongjuan Liu, Yawen Wang, Yili Wang, Hongbo Qian, Tongxin Dai, Tianxiao Zhang, Yanjun Lai, … Jinsong Hu<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-26) <a href="https://doi.org/ggq65v">https://doi.org/ggq65v</a> <br />
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-<p>1419. <strong>Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study</strong> <br />
+<p>1421. <strong>Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study</strong> <br />
 Aaron Miller, Mac Josh Reandelar, Kimberly Fasciglione, Violeta Roumenova, Yan Li, Gonzalo H. Otazu<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-28) <a href="https://doi.org/ggq65w">https://doi.org/ggq65w</a> <br />
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-<p>1420. <strong>Non-specific effects of BCG vaccine on viral infections</strong> <br />
+<p>1422. <strong>Non-specific effects of BCG vaccine on viral infections</strong> <br />
 S. J. C. F. M. Moorlag, R. J. W. Arts, R. van Crevel, M. G. Netea<br />
 <em>Clinical Microbiology and Infection</em> (2019-12) <a href="https://doi.org/ggq62z">https://doi.org/ggq62z</a> <br />
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-<p>1421. <strong>BCG vaccination to reduce the impact of COVID-19 in healthcare workers (The BRACE Trial)</strong> <br />
+<p>1423. <strong>BCG vaccination to reduce the impact of COVID-19 in healthcare workers (The BRACE Trial)</strong> <br />
 Murdoch Children’s Research Institute<br />
 <a href="https://www.mcri.edu.au/BRACE">https://www.mcri.edu.au/BRACE</a></p>
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+<p>1424. <strong>Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia</strong> <br />
 David H. Brann, Tatsuya Tsukahara, Caleb Weinreb, Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain C. Macaulay, Hsin-jung Chou, Russell Fletcher, … Sandeep Robert Datta<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-05-18) <a href="https://doi.org/ggqr4m">https://doi.org/ggqr4m</a> <br />
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 <div id="ref-t4vofknR">
-<p>1423. <strong>Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract</strong> <br />
+<p>1425. <strong>Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract</strong> <br />
 Joan C. Smith, Erin L. Sausville, Vishruth Girish, Monet Lou Yuan, Kristen M. John, Jason M. Sheltzer<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-04-26) <a href="https://doi.org/ggq65x">https://doi.org/ggq65x</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.28.013672">10.1101/2020.03.28.013672</a></p>
 </div>
 <div id="ref-k1E3DuFN">
-<p>1424. <strong>The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis</strong> <br />
+<p>1426. <strong>The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis</strong> <br />
 Rui Liu, Xinghui Liu, Huan Han, Muhammad Adnan Shereen, Zhili Niu, Dong Li, Fang Liu, Kailang Wu, Zhen Luo, Chengliang Zhu<br />
 <em>Cold Spring Harbor Laboratory</em> (2020-03-30) <a href="https://doi.org/ggqtp5">https://doi.org/ggqtp5</a> <br />
 DOI: <a href="https://doi.org/10.1101/2020.03.28.20045765">10.1101/2020.03.28.20045765</a></p>
@@ -12762,8 +12795,8 @@ <h1 class="page_break_before" data-number="14" id="appendix-a"><span class="head
 <p>This appendix contains reviews produced by the Immunology Institute of the Icahn School of Medicine</p>
 <!-- Appendix source: https://github.com/ismms-himc/covid-19_sinai_reviews/tree/05d387bf10b829dad6bedb4bf313686750b78cc9 -->
 <h2 data-number="14.1" id="potent-binding-of-2019-novel-coronavirus-spike-protein-by-a-sars-coronavirus-specific-human-monoclonal-antibody"><span class="header-section-number">14.1</span> Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody</h2>
-<p>Tian et al. <em>Emerg Microbes Infect 2020</em> <span class="citation" data-cites="1HLSeqnY8">[<a href="#ref-1HLSeqnY8" role="doc-biblioref">1302</a>]</span></p>
-<h3 data-number="14.1.1" id="keywords"><span class="header-section-number">14.1.1</span> Keywords</h3>
+<p>Tian et al. <em>Emerg Microbes Infect 2020</em> <span class="citation" data-cites="1HLSeqnY8">[<a href="#ref-1HLSeqnY8" role="doc-biblioref">1304</a>]</span></p>
+<h3 data-number="14.1.1" id="keywords-1"><span class="header-section-number">14.1.1</span> Keywords</h3>
 <ul>
 <li>Monoclonal antibody</li>
 <li>Cross-reactivity</li>
@@ -12805,8 +12838,8 @@ <h3 data-number="14.1.5" id="credit"><span class="header-section-number">14.1.5<
 at the Immunology Institute of the Icahn School of Medicine, Mount
 Sinai.</em></p>
 <h2 data-number="14.2" id="integrative-bioinformatics-analysis-provides-insight-into-the-molecular-mechanisms-of-2019-ncov"><span class="header-section-number">14.2</span> Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV</h2>
-<p>He et al. <em>medRxiv</em> <span class="citation" data-cites="lOQPScZt">[<a href="#ref-lOQPScZt" role="doc-biblioref">1303</a>]</span></p>
-<h3 data-number="14.2.1" id="keywords-1"><span class="header-section-number">14.2.1</span> Keywords</h3>
+<p>He et al. <em>medRxiv</em> <span class="citation" data-cites="lOQPScZt">[<a href="#ref-lOQPScZt" role="doc-biblioref">1305</a>]</span></p>
+<h3 data-number="14.2.1" id="keywords-2"><span class="header-section-number">14.2.1</span> Keywords</h3>
 <ul>
 <li>ACE2</li>
 <li>lungs</li>
@@ -12890,8 +12923,8 @@ <h3 data-number="14.2.3" id="limitations-1"><span class="header-section-number">
 <h3 data-number="14.2.4" id="credit-1"><span class="header-section-number">14.2.4</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.3" id="diarrhea-may-be-underestimated-a-missing-link-in-2019-novel-coronavirus"><span class="header-section-number">14.3</span> Diarrhea may be underestimated: a missing link in 2019 novel coronavirus</h2>
-<p>Liang et al. <em>medRxiv</em> <span class="citation" data-cites="rL9IRhVy">[<a href="#ref-rL9IRhVy" role="doc-biblioref">1304</a>]</span></p>
-<h3 data-number="14.3.1" id="keywords-2"><span class="header-section-number">14.3.1</span> Keywords</h3>
+<p>Liang et al. <em>medRxiv</em> <span class="citation" data-cites="rL9IRhVy">[<a href="#ref-rL9IRhVy" role="doc-biblioref">1306</a>]</span></p>
+<h3 data-number="14.3.1" id="keywords-3"><span class="header-section-number">14.3.1</span> Keywords</h3>
 <ul>
 <li>SARS-CoV-2</li>
 <li>diarrhea</li>
@@ -12945,8 +12978,8 @@ <h3 data-number="14.3.4" id="significance"><span class="header-section-number">1
 <h3 data-number="14.3.5" id="credit-2"><span class="header-section-number">14.3.5</span> Credit</h3>
 <p><em>Summary generated as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.4" id="specific-ace2-expression-in-cholangiocytes-may-cause-liver-damage-after-2019-ncov-infection"><span class="header-section-number">14.4</span> Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection</h2>
-<p>Chai et al. <em>bioRxiv</em> <span class="citation" data-cites="BHQvMYPG">[<a href="#ref-BHQvMYPG" role="doc-biblioref">1305</a>]</span></p>
-<h3 data-number="14.4.1" id="keywords-3"><span class="header-section-number">14.4.1</span> Keywords</h3>
+<p>Chai et al. <em>bioRxiv</em> <span class="citation" data-cites="BHQvMYPG">[<a href="#ref-BHQvMYPG" role="doc-biblioref">1307</a>]</span></p>
+<h3 data-number="14.4.1" id="keywords-4"><span class="header-section-number">14.4.1</span> Keywords</h3>
 <ul>
 <li>ACE2</li>
 <li>Cholangiocytes</li>
@@ -12980,7 +13013,7 @@ <h3 data-number="14.4.5" id="significance-1"><span class="header-section-number"
 patients is more due to inflammatory cytokines than direct infection of
 the liver. Even if cholangiocytes are infectable by SARS-CoV-2 (which
 was demonstrated by human liver ductal organoid study
-(<span class="citation" data-cites="OuDMtCRl">[<a href="#ref-OuDMtCRl" role="doc-biblioref">1306</a>]</span>),
+(<span class="citation" data-cites="OuDMtCRl">[<a href="#ref-OuDMtCRl" role="doc-biblioref">1308</a>]</span>),
 published clinical data show no significant increase in bile duct injury
 related indexes (i.e. alkaline phosphatase, gamma-glutamyl
 transpeptidase and total bilirubin). In sum, it underscores the
@@ -12990,8 +13023,8 @@ <h3 data-number="14.4.5" id="significance-1"><span class="header-section-number"
 <h3 data-number="14.4.6" id="credit-3"><span class="header-section-number">14.4.6</span> Credit</h3>
 <p><em>Summary generated by Chang Moon as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.5" id="ace2-expression-by-colonic-epithelial-cells-is-associated-with-viral-infection-immunity-and-energy-metabolism"><span class="header-section-number">14.5</span> ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism</h2>
-<p>Wang et al. <em>medRxiv</em>. <span class="citation" data-cites="ViWCb8MJ">[<a href="#ref-ViWCb8MJ" role="doc-biblioref">1307</a>]</span></p>
-<h3 data-number="14.5.1" id="keywords-4"><span class="header-section-number">14.5.1</span> Keywords</h3>
+<p>Wang et al. <em>medRxiv</em>. <span class="citation" data-cites="ViWCb8MJ">[<a href="#ref-ViWCb8MJ" role="doc-biblioref">1309</a>]</span></p>
+<h3 data-number="14.5.1" id="keywords-5"><span class="header-section-number">14.5.1</span> Keywords</h3>
 <ul>
 <li>single cell RNA seq</li>
 <li>ACE2 expression</li>
@@ -13006,8 +13039,8 @@ <h3 data-number="14.5.4" id="significance-2"><span class="header-section-number"
 <h3 data-number="14.5.5" id="credit-4"><span class="header-section-number">14.5.5</span> Credit</h3>
 <p><em>Summary generated as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.6" id="the-pathogenicity-of-2019-novel-coronavirus-in-hace2-transgenic-mice"><span class="header-section-number">14.6</span> The Pathogenicity of 2019 Novel Coronavirus in hACE2 Transgenic Mice</h2>
-<p>Bao et al. <em>bioRxiv</em> <span class="citation" data-cites="MgLBA5m">[<a href="#ref-MgLBA5m" role="doc-biblioref">1308</a>]</span></p>
-<h3 data-number="14.6.1" id="keywords-5"><span class="header-section-number">14.6.1</span> Keywords</h3>
+<p>Bao et al. <em>bioRxiv</em> <span class="citation" data-cites="MgLBA5m">[<a href="#ref-MgLBA5m" role="doc-biblioref">1310</a>]</span></p>
+<h3 data-number="14.6.1" id="keywords-6"><span class="header-section-number">14.6.1</span> Keywords</h3>
 <ul>
 <li>Covid-19 mouse model</li>
 <li>hACE2 mice</li>
@@ -13042,8 +13075,8 @@ <h3 data-number="14.6.5" id="credit-5"><span class="header-section-number">14.6.
 at the Immunology Institute of the Icahn School of Medicine, Mount
 Sinai.</em></p>
 <h2 data-number="14.7" id="caution-on-kidney-dysfunctions-of-2019-ncov-patients"><span class="header-section-number">14.7</span> Caution on Kidney Dysfunctions of 2019-nCoV Patients</h2>
-<p>Li et al. <em>medRxiv</em>. <span class="citation" data-cites="1Acv5UMSt">[<a href="#ref-1Acv5UMSt" role="doc-biblioref">1309</a>]</span></p>
-<h3 data-number="14.7.1" id="keywords-6"><span class="header-section-number">14.7.1</span> Keywords</h3>
+<p>Li et al. <em>medRxiv</em>. <span class="citation" data-cites="1Acv5UMSt">[<a href="#ref-1Acv5UMSt" role="doc-biblioref">1311</a>]</span></p>
+<h3 data-number="14.7.1" id="keywords-7"><span class="header-section-number">14.7.1</span> Keywords</h3>
 <p>CoVID-19, 2019-nCoV, SARS-CoV-2, kidney, clinical, creatinine,
 proteinuria, albuminuria, CT</p>
 <h3 data-number="14.7.2" id="main-findings-6"><span class="header-section-number">14.7.2</span> Main Findings</h3>
@@ -13072,11 +13105,11 @@ <h3 data-number="14.7.4" id="significance-4"><span class="header-section-number"
 <ul>
 <li><p>Multiple lines of evidence along this study’s finding point to the
 idea that renal impairment/injury is a key risk factor in 2019-nCoV
-patients similar to what has been reported for SARS-CoV<span class="citation" data-cites="DMaiZBE1">[<a href="#ref-DMaiZBE1" role="doc-biblioref">1310</a>]</span>; this
+patients similar to what has been reported for SARS-CoV<span class="citation" data-cites="DMaiZBE1">[<a href="#ref-DMaiZBE1" role="doc-biblioref">1312</a>]</span>; this
 may be one of the major causes of virally-induced damage and
 contribute to multiorgan failure.</p></li>
 <li><p>ACE2 expression in kidney proximal tubule epithelia and bladder
-epithelia <span class="citation" data-cites="16Xj27QYj">[<a href="#ref-16Xj27QYj" role="doc-biblioref">1311</a>]</span> support
+epithelia <span class="citation" data-cites="16Xj27QYj">[<a href="#ref-16Xj27QYj" role="doc-biblioref">1313</a>]</span> support
 these clinical findings.</p></li>
 <li><p>Study argues for closely monitoring kidney function, and applying
 potential interventions including continuous renal replacement
@@ -13086,8 +13119,8 @@ <h3 data-number="14.7.4" id="significance-4"><span class="header-section-number"
 <h3 data-number="14.7.5" id="credit-6"><span class="header-section-number">14.7.5</span> Credit</h3>
 <p><em>Review by Samarth Hegde as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.8" id="profiling-the-immune-vulnerability-landscape-of-the-2019-novel-coronavirus"><span class="header-section-number">14.8</span> Profiling the immune vulnerability landscape of the 2019 Novel Coronavirus</h2>
-<p>Zhu et al. <em>bioRxiv</em> <span class="citation" data-cites="QhE5mVCc">[<a href="#ref-QhE5mVCc" role="doc-biblioref">1312</a>]</span></p>
-<h3 data-number="14.8.1" id="keywords-7"><span class="header-section-number">14.8.1</span> Keywords</h3>
+<p>Zhu et al. <em>bioRxiv</em> <span class="citation" data-cites="QhE5mVCc">[<a href="#ref-QhE5mVCc" role="doc-biblioref">1314</a>]</span></p>
+<h3 data-number="14.8.1" id="keywords-8"><span class="header-section-number">14.8.1</span> Keywords</h3>
 <ul>
 <li>epitope prediction</li>
 <li>vaccine development.</li>
@@ -13118,8 +13151,8 @@ <h3 data-number="14.8.4" id="significance-5"><span class="header-section-number"
 <h3 data-number="14.8.5" id="credit-7"><span class="header-section-number">14.8.5</span> Credit</h3>
 <p><em>Summary generated as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.9" id="single-cell-analysis-of-ace2-expression-in-human-kidneys-and-bladders-reveals-a-potential-route-of-2019-ncov-infection"><span class="header-section-number">14.9</span> Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection</h2>
-<p>Lin et al. <em>bioRxiv</em> <span class="citation" data-cites="16Xj27QYj">[<a href="#ref-16Xj27QYj" role="doc-biblioref">1311</a>]</span></p>
-<h3 data-number="14.9.1" id="keywords-8"><span class="header-section-number">14.9.1</span> Keywords</h3>
+<p>Lin et al. <em>bioRxiv</em> <span class="citation" data-cites="16Xj27QYj">[<a href="#ref-16Xj27QYj" role="doc-biblioref">1313</a>]</span></p>
+<h3 data-number="14.9.1" id="keywords-9"><span class="header-section-number">14.9.1</span> Keywords</h3>
 <ul>
 <li>CoVID-19</li>
 <li>2019-nCoV</li>
@@ -13170,22 +13203,22 @@ <h3 data-number="14.9.4" id="significance-6"><span class="header-section-number"
 contact with viral particles are likely to be highly sensitive to
 viral-induced damage.</p></li>
 <li><p>SARS-CoV and MERS-CoV have been shown to be detected in urine of
-patients and associate with higher mortality <span class="citation" data-cites="DMaiZBE1 iObQU2el">[<a href="#ref-DMaiZBE1" role="doc-biblioref">1310</a>,<a href="#ref-iObQU2el" role="doc-biblioref">1313</a>]</span>, thus worth
+patients and associate with higher mortality <span class="citation" data-cites="DMaiZBE1 iObQU2el">[<a href="#ref-DMaiZBE1" role="doc-biblioref">1312</a>,<a href="#ref-iObQU2el" role="doc-biblioref">1315</a>]</span>, thus worth
 understanding kidney damage and resultant immune response in
 SARS-CoV-2 as well.</p></li>
 <li><p>This study argues for a potential mode of viral infectivity and
 resultant inflammatory responses in these tissue in addition to
 reported infectivity in the lung and digestive system, which is
 supported by clinical data showing acute and early kidney
-complications in 2019-nCoV patients <span class="citation" data-cites="1Acv5UMSt">[<a href="#ref-1Acv5UMSt" role="doc-biblioref">1309</a>]</span>.</p></li>
+complications in 2019-nCoV patients <span class="citation" data-cites="1Acv5UMSt">[<a href="#ref-1Acv5UMSt" role="doc-biblioref">1311</a>]</span>.</p></li>
 <li><p>Clinically, thus very important to track urinary CoVID-19 shedding
 as well as study acute kidney injury-related co-morbidities.</p></li>
 </ul>
 <h3 data-number="14.9.5" id="credit-8"><span class="header-section-number">14.9.5</span> Credit</h3>
 <p><em>Review by Samarth Hegde as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.10" id="neutrophil-to-lymphocyte-ratio-predicts-severe-illness-patients-with-2019-novel-coronavirus-in-the-early-stage"><span class="header-section-number">14.10</span> Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage</h2>
-<p>Liu et al. <em>medRxiv</em> <span class="citation" data-cites="gK5e7Yhl">[<a href="#ref-gK5e7Yhl" role="doc-biblioref">1314</a>]</span></p>
-<h3 data-number="14.10.1" id="keywords-9"><span class="header-section-number">14.10.1</span> Keywords</h3>
+<p>Liu et al. <em>medRxiv</em> <span class="citation" data-cites="gK5e7Yhl">[<a href="#ref-gK5e7Yhl" role="doc-biblioref">1316</a>]</span></p>
+<h3 data-number="14.10.1" id="keywords-10"><span class="header-section-number">14.10.1</span> Keywords</h3>
 <ul>
 <li>severe disease</li>
 <li>pneumonia</li>
@@ -13229,12 +13262,12 @@ <h3 data-number="14.10.3" id="limitations-9"><span class="header-section-number"
 patients). Given the small sample size, the proposed NLR and age cut
 offs might not hold for a slightly different set of patients. For
 example, in a study of &gt;400 patients, ‘non-severe’ and ‘severe’ NLR
-were 3.2 and 5.5, respectively <span class="citation" data-cites="6Y81C4P3">[<a href="#ref-6Y81C4P3" role="doc-biblioref">1315</a>]</span>.</p>
+were 3.2 and 5.5, respectively <span class="citation" data-cites="6Y81C4P3">[<a href="#ref-6Y81C4P3" role="doc-biblioref">1317</a>]</span>.</p>
 <h3 data-number="14.10.4" id="credit-9"><span class="header-section-number">14.10.4</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.11" id="characteristics-of-lymphocyte-subsets-and-cytokines-in-peripheral-blood-of-123-hospitalized-patients-with-2019-novel-coronavirus-pneumonia-ncp"><span class="header-section-number">14.11</span> Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)</h2>
-<p>Wan et. al. <em>medRxiv</em> <span class="citation" data-cites="P4assQHj">[<a href="#ref-P4assQHj" role="doc-biblioref">1316</a>]</span></p>
-<h3 data-number="14.11.1" id="keywords-10"><span class="header-section-number">14.11.1</span> Keywords</h3>
+<p>Wan et. al. <em>medRxiv</em> <span class="citation" data-cites="P4assQHj">[<a href="#ref-P4assQHj" role="doc-biblioref">1318</a>]</span></p>
+<h3 data-number="14.11.1" id="keywords-11"><span class="header-section-number">14.11.1</span> Keywords</h3>
 <ul>
 <li>Cytokines</li>
 <li>lymphocyte subsets</li>
@@ -13262,7 +13295,7 @@ <h3 data-number="14.11.3" id="limitations-10"><span class="header-section-number
 individual (Covid-19 Negative) rather used an internal standard value.
 The recently preprint in LANCET shows The degree of lymphopenia and a
 pro-inflammatory cytokine storm is higher in severe COVID-19 patients
-than in mild cases, and is associated with the disease severity <span class="citation" data-cites="zskgSnle">[<a href="#ref-zskgSnle" role="doc-biblioref">1317</a>]</span>.</p>
+than in mild cases, and is associated with the disease severity <span class="citation" data-cites="zskgSnle">[<a href="#ref-zskgSnle" role="doc-biblioref">1319</a>]</span>.</p>
 <h3 data-number="14.11.4" id="significance-7"><span class="header-section-number">14.11.4</span> Significance</h3>
 <p>This translational data identifies key cytokines and lymphopenia
 associated with disease severity although mechanism and key cellular
@@ -13272,8 +13305,8 @@ <h3 data-number="14.11.4" id="significance-7"><span class="header-section-number
 <h3 data-number="14.11.5" id="credit-10"><span class="header-section-number">14.11.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.12" id="epidemiological-and-clinical-characteristics-of-17-hospitalized-patients-with-2019-novel-coronavirus-infections-outside-wuhan-china"><span class="header-section-number">14.12</span> Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China</h2>
-<p>Li et al. <em>medRxiv</em> <span class="citation" data-cites="TXlNzmXd">[<a href="#ref-TXlNzmXd" role="doc-biblioref">1318</a>]</span></p>
-<h3 data-number="14.12.1" id="keywords-11"><span class="header-section-number">14.12.1</span> Keywords</h3>
+<p>Li et al. <em>medRxiv</em> <span class="citation" data-cites="TXlNzmXd">[<a href="#ref-TXlNzmXd" role="doc-biblioref">1320</a>]</span></p>
+<h3 data-number="14.12.1" id="keywords-12"><span class="header-section-number">14.12.1</span> Keywords</h3>
 <ul>
 <li>epidemiology</li>
 <li>clinical characteristics</li>
@@ -13299,8 +13332,8 @@ <h3 data-number="14.12.4" id="significance-8"><span class="header-section-number
 <h3 data-number="14.12.5" id="credit-11"><span class="header-section-number">14.12.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.13" id="ace2-expression-in-kidney-and-testis-may-cause-kidney-and-testis-damage-after-2019-ncov-infection"><span class="header-section-number">14.13</span> ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection</h2>
-<p><span class="citation" data-cites="15K5Ovntj">[<a href="#ref-15K5Ovntj" role="doc-biblioref">1319</a>]</span></p>
-<h3 data-number="14.13.1" id="keywords-12"><span class="header-section-number">14.13.1</span> Keywords</h3>
+<p><span class="citation" data-cites="15K5Ovntj">[<a href="#ref-15K5Ovntj" role="doc-biblioref">1321</a>]</span></p>
+<h3 data-number="14.13.1" id="keywords-13"><span class="header-section-number">14.13.1</span> Keywords</h3>
 <ul>
 <li>CoVID-19</li>
 <li>2019-nCoV</li>
@@ -13337,10 +13370,10 @@ <h3 data-number="14.13.3" id="limitations-12"><span class="header-section-number
 <h3 data-number="14.13.4" id="significance-9"><span class="header-section-number">14.13.4</span> Significance</h3>
 <ul>
 <li><p>Kidney ACE2 result supports other concurrent sequencing studies
-<span class="citation" data-cites="16Xj27QYj">[<a href="#ref-16Xj27QYj" role="doc-biblioref">1311</a>]</span> and clinical reports
+<span class="citation" data-cites="16Xj27QYj">[<a href="#ref-16Xj27QYj" role="doc-biblioref">1313</a>]</span> and clinical reports
 of abnormal renal function or even kidney damage in patients
 infected with 2019-nCoV
-<span class="citation" data-cites="1Acv5UMSt">[<a href="#ref-1Acv5UMSt" role="doc-biblioref">1309</a>]</span>.</p></li>
+<span class="citation" data-cites="1Acv5UMSt">[<a href="#ref-1Acv5UMSt" role="doc-biblioref">1311</a>]</span>.</p></li>
 <li><p>High ACE2 expression in testis suggests potential tropism of the
 virus to testicular tissues and indicates potential risks for male
 fertility. Viral orchitis reported for SARS-CoV previously [1],
@@ -13350,8 +13383,8 @@ <h3 data-number="14.13.4" id="significance-9"><span class="header-section-number
 <h3 data-number="14.13.5" id="credit-12"><span class="header-section-number">14.13.5</span> Credit</h3>
 <p><em>Review by Samarth Hegde as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.14" id="aberrant-pathogenic-gm-csf-t-cells-and-inflammatory-cd14cd16-monocytes-in-severe-pulmonary-syndrome-patients-of-a-new-coronavirus"><span class="header-section-number">14.14</span> Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus</h2>
-<p><span class="citation" data-cites="Bgo7Cmj3">[<a href="#ref-Bgo7Cmj3" role="doc-biblioref">1320</a>]</span></p>
-<h3 data-number="14.14.1" id="keywords-13"><span class="header-section-number">14.14.1</span> Keywords</h3>
+<p><span class="citation" data-cites="Bgo7Cmj3">[<a href="#ref-Bgo7Cmj3" role="doc-biblioref">1322</a>]</span></p>
+<h3 data-number="14.14.1" id="keywords-14"><span class="header-section-number">14.14.1</span> Keywords</h3>
 <ul>
 <li>immunopathology</li>
 <li>Th1</li>
@@ -13430,8 +13463,8 @@ <h3 data-number="14.14.5" id="credit-13"><span class="header-section-number">14.
 <p><em>Review by Gabrielle Lubitz as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.15" id="clinical-characteristics-of-2019-novel-infected-coronavirus-pneumoniaa-systemic-review-and-meta-analysis"><span class="header-section-number">14.15</span> Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia：A Systemic Review and Meta-analysis</h2>
 <p>Qian et al. <em>medRxiv</em>.
-<span class="citation" data-cites="4Z1pEioX">[<a href="#ref-4Z1pEioX" role="doc-biblioref">1321</a>]</span></p>
-<h3 data-number="14.15.1" id="keywords-14"><span class="header-section-number">14.15.1</span> Keywords</h3>
+<span class="citation" data-cites="4Z1pEioX">[<a href="#ref-4Z1pEioX" role="doc-biblioref">1323</a>]</span></p>
+<h3 data-number="14.15.1" id="keywords-15"><span class="header-section-number">14.15.1</span> Keywords</h3>
 <ul>
 <li>White Blood Cells</li>
 <li>Lymphocytes</li>
@@ -13470,8 +13503,8 @@ <h3 data-number="14.15.4" id="significance-11"><span class="header-section-numbe
 <h3 data-number="14.15.5" id="credit-14"><span class="header-section-number">14.15.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.16" id="longitudinal-characteristics-of-lymphocyte-responses-and-cytokine-profiles-in-the-peripheral-blood-of-sars-cov-2-infected-patients"><span class="header-section-number">14.16</span> Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients</h2>
-<p>Liu et al. <em>medRxiv</em> <span class="citation" data-cites="zTGzuiTI">[<a href="#ref-zTGzuiTI" role="doc-biblioref">1322</a>]</span></p>
-<h3 data-number="14.16.1" id="keywords-15"><span class="header-section-number">14.16.1</span> Keywords</h3>
+<p>Liu et al. <em>medRxiv</em> <span class="citation" data-cites="zTGzuiTI">[<a href="#ref-zTGzuiTI" role="doc-biblioref">1324</a>]</span></p>
+<h3 data-number="14.16.1" id="keywords-16"><span class="header-section-number">14.16.1</span> Keywords</h3>
 <ul>
 <li>Lymphopenia</li>
 <li>Neutrophil to CD8 T cell ratio (N8R)</li>
@@ -13520,8 +13553,8 @@ <h3 data-number="14.16.4" id="significance-12"><span class="header-section-numbe
 <h3 data-number="14.16.5" id="credit-15"><span class="header-section-number">14.16.5</span> Credit</h3>
 <p><em>Review by Pauline Hamon as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.17" id="clinical-and-immunologic-features-in-severe-and-moderate-forms-of-coronavirus-disease-2019"><span class="header-section-number">14.17</span> Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019</h2>
-<p>Chen et al. <em>medRxiv</em> <span class="citation" data-cites="1EIEx8Qe4">[<a href="#ref-1EIEx8Qe4" role="doc-biblioref">1323</a>]</span></p>
-<h3 data-number="14.17.1" id="keywords-16"><span class="header-section-number">14.17.1</span> Keywords</h3>
+<p>Chen et al. <em>medRxiv</em> <span class="citation" data-cites="1EIEx8Qe4">[<a href="#ref-1EIEx8Qe4" role="doc-biblioref">1325</a>]</span></p>
+<h3 data-number="14.17.1" id="keywords-17"><span class="header-section-number">14.17.1</span> Keywords</h3>
 <ul>
 <li>severe disease</li>
 <li>lymphocytes</li>
@@ -13571,8 +13604,8 @@ <h3 data-number="14.17.4" id="significance-13"><span class="header-section-numbe
 <h3 data-number="14.17.5" id="credit-16"><span class="header-section-number">14.17.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.18" id="sars-cov-2-and-sars-cov-spike-rbd-structure-and-receptor-binding-comparison-and-potential-implications-on-neutralizing-antibody-and-vaccine-development"><span class="header-section-number">14.18</span> SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development</h2>
-<p>Sun et al. <em>bioRxiv</em> <span class="citation" data-cites="41WAtZmB">[<a href="#ref-41WAtZmB" role="doc-biblioref">602</a>]</span></p>
-<h3 data-number="14.18.1" id="keywords-17"><span class="header-section-number">14.18.1</span> Keywords</h3>
+<p>Sun et al. <em>bioRxiv</em> <span class="citation" data-cites="41WAtZmB">[<a href="#ref-41WAtZmB" role="doc-biblioref">601</a>]</span></p>
+<h3 data-number="14.18.1" id="keywords-18"><span class="header-section-number">14.18.1</span> Keywords</h3>
 <ul>
 <li>SARS-CoV</li>
 <li>SARS-CoV-2</li>
@@ -13628,8 +13661,8 @@ <h3 data-number="14.18.4" id="significance-14"><span class="header-section-numbe
 <h3 data-number="14.18.5" id="credit-17"><span class="header-section-number">14.18.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.19" id="protection-of-rhesus-macaque-from-sars-coronavirus-challenge-by-recombinant-adenovirus-vaccine"><span class="header-section-number">14.19</span> Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine</h2>
-<p>Chen et al. <em>bioRxiv</em> <span class="citation" data-cites="NPxs7bbq">[<a href="#ref-NPxs7bbq" role="doc-biblioref">1324</a>]</span></p>
-<h3 data-number="14.19.1" id="keywords-18"><span class="header-section-number">14.19.1</span> Keywords</h3>
+<p>Chen et al. <em>bioRxiv</em> <span class="citation" data-cites="NPxs7bbq">[<a href="#ref-NPxs7bbq" role="doc-biblioref">1326</a>]</span></p>
+<h3 data-number="14.19.1" id="keywords-19"><span class="header-section-number">14.19.1</span> Keywords</h3>
 <ul>
 <li>SARS-CoV-1</li>
 <li>rhesus macaque</li>
@@ -13667,8 +13700,8 @@ <h3 data-number="14.19.4" id="significance-15"><span class="header-section-numbe
 <h3 data-number="14.19.5" id="credit-18"><span class="header-section-number">14.19.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.20" id="reduction-and-functional-exhaustion-of-t-cells-in-patients-with-coronavirus-disease-2019-covid-19"><span class="header-section-number">14.20</span> Reduction and Functional Exhaustion of T cells in Patients with Coronavirus Disease 2019 (COVID-19)</h2>
-<p><span class="citation" data-cites="f50ahNxF">[<a href="#ref-f50ahNxF" role="doc-biblioref">1325</a>]</span></p>
-<h3 data-number="14.20.1" id="keywords-19"><span class="header-section-number">14.20.1</span> Keywords</h3>
+<p><span class="citation" data-cites="f50ahNxF">[<a href="#ref-f50ahNxF" role="doc-biblioref">1327</a>]</span></p>
+<h3 data-number="14.20.1" id="keywords-20"><span class="header-section-number">14.20.1</span> Keywords</h3>
 <ul>
 <li>T cell exhaustion</li>
 <li>T cell lymphopenia</li>
@@ -13716,8 +13749,8 @@ <h3 data-number="14.20.4" id="significance-16"><span class="header-section-numbe
 <h3 data-number="14.20.5" id="credit-19"><span class="header-section-number">14.20.5</span> Credit</h3>
 <p><em>This review by Chang Moon was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.21" id="clinical-characteristics-of-25-death-cases-infected-with-covid-19-pneumonia-a-retrospective-review-of-medical-records-in-a-single-medical-center-wuhan-china"><span class="header-section-number">14.21</span> Clinical Characteristics of 25 death cases infected with COVID-19 pneumonia: a retrospective review of medical records in a single medical center, Wuhan, China</h2>
-<p><span class="citation" data-cites="EwNi3WJq">[<a href="#ref-EwNi3WJq" role="doc-biblioref">1326</a>]</span></p>
-<h3 data-number="14.21.1" id="keywords-20"><span class="header-section-number">14.21.1</span> Keywords</h3>
+<p><span class="citation" data-cites="EwNi3WJq">[<a href="#ref-EwNi3WJq" role="doc-biblioref">1328</a>]</span></p>
+<h3 data-number="14.21.1" id="keywords-21"><span class="header-section-number">14.21.1</span> Keywords</h3>
 <ul>
 <li>COVID-19</li>
 <li>pneumonia</li>
@@ -13755,8 +13788,8 @@ <h3 data-number="14.21.4" id="significance-17"><span class="header-section-numbe
 <h3 data-number="14.21.5" id="credit-20"><span class="header-section-number">14.21.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.22" id="sars-cov-2-infection-does-not-significantly-cause-acute-renal-injury-an-analysis-of-116-hospitalized-patients-with-covid-19-in-a-single-hospital-wuhan-china"><span class="header-section-number">14.22</span> SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China</h2>
-<p><span class="citation" data-cites="KG5Lg65z">[<a href="#ref-KG5Lg65z" role="doc-biblioref">1327</a>]</span></p>
-<h3 data-number="14.22.1" id="keywords-21"><span class="header-section-number">14.22.1</span> Keywords</h3>
+<p><span class="citation" data-cites="KG5Lg65z">[<a href="#ref-KG5Lg65z" role="doc-biblioref">1329</a>]</span></p>
+<h3 data-number="14.22.1" id="keywords-22"><span class="header-section-number">14.22.1</span> Keywords</h3>
 <ul>
 <li>CoVID-19</li>
 <li>2019-nCoV</li>
@@ -13790,7 +13823,7 @@ <h3 data-number="14.22.3" id="limitations-21"><span class="header-section-number
 be useful to correlate how treatment modality influences kidney
 function (and other parameters).</p></li>
 <li><p>Invokes previous clinical-correlation studies that indicate low
-instances of kidney damage<span class="citation" data-cites="VRoblZFJ bgrzawWp">[<a href="#ref-VRoblZFJ" role="doc-biblioref">1328</a>,<a href="#ref-bgrzawWp" role="doc-biblioref">1329</a>]</span>, but those studies did not track
+instances of kidney damage<span class="citation" data-cites="VRoblZFJ bgrzawWp">[<a href="#ref-VRoblZFJ" role="doc-biblioref">1330</a>,<a href="#ref-bgrzawWp" role="doc-biblioref">1331</a>]</span>, but those studies did not track
 longitudinal urine samples for acute renal injury markers and viral
 shedding.</p></li>
 <li><p>CRRT in patients with CRF is standard therapy irrespective of
@@ -13802,7 +13835,7 @@ <h3 data-number="14.22.4" id="significance-18"><span class="header-section-numbe
 <ul>
 <li><p>This study argues that renal impairment is uncommon in CoVID-19 and
 not associated with high mortaility, in stark contrast with a
-concurrent study <span class="citation" data-cites="1Acv5UMSt">[<a href="#ref-1Acv5UMSt" role="doc-biblioref">1309</a>]</span>.
+concurrent study <span class="citation" data-cites="1Acv5UMSt">[<a href="#ref-1Acv5UMSt" role="doc-biblioref">1311</a>]</span>.
 If supported by further studies, this argues kidney impairment is
 secondary to cytokine storm/inflammation-induced organ failure, and
 not due to direct viral replication.</p></li>
@@ -13813,8 +13846,8 @@ <h3 data-number="14.22.4" id="significance-18"><span class="header-section-numbe
 <h3 data-number="14.22.5" id="credit-21"><span class="header-section-number">14.22.5</span> Credit</h3>
 <p><em>Review by Samarth Hegde as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.23" id="potential-t-cell-and-b-cell-epitopes-of-2019-ncov"><span class="header-section-number">14.23</span> Potential T-cell and B-Cell Epitopes of 2019-nCoV</h2>
-<p><span class="citation" data-cites="hdSafq1o">[<a href="#ref-hdSafq1o" role="doc-biblioref">1330</a>]</span></p>
-<h3 data-number="14.23.1" id="keywords-22"><span class="header-section-number">14.23.1</span> Keywords</h3>
+<p><span class="citation" data-cites="hdSafq1o">[<a href="#ref-hdSafq1o" role="doc-biblioref">1332</a>]</span></p>
+<h3 data-number="14.23.1" id="keywords-23"><span class="header-section-number">14.23.1</span> Keywords</h3>
 <ul>
 <li>COVID-19</li>
 <li>vaccine</li>
@@ -13880,8 +13913,8 @@ <h3 data-number="14.23.4" id="significance-19"><span class="header-section-numbe
 <h3 data-number="14.23.5" id="credit-22"><span class="header-section-number">14.23.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.24" id="structure-function-and-antigenicity-of-the-sarscov-2-spike-glycoprotein"><span class="header-section-number">14.24</span> Structure, Function, and Antigenicity of the SARSCoV-2 Spike Glycoprotein</h2>
-<p>Walls et al. <em>bioRxiv</em>. <span class="citation" data-cites="8xnxgpag">[<a href="#ref-8xnxgpag" role="doc-biblioref">1331</a>]</span> now <span class="citation" data-cites="qcVbT0w4">[<a href="#ref-qcVbT0w4" role="doc-biblioref">67</a>]</span></p>
-<h3 data-number="14.24.1" id="keywords-23"><span class="header-section-number">14.24.1</span> Keywords</h3>
+<p>Walls et al. <em>bioRxiv</em>. <span class="citation" data-cites="8xnxgpag">[<a href="#ref-8xnxgpag" role="doc-biblioref">1333</a>]</span> now <span class="citation" data-cites="qcVbT0w4">[<a href="#ref-qcVbT0w4" role="doc-biblioref">67</a>]</span></p>
+<h3 data-number="14.24.1" id="keywords-24"><span class="header-section-number">14.24.1</span> Keywords</h3>
 <ul>
 <li>binding affinity</li>
 <li>antigenicity</li>
@@ -13918,8 +13951,8 @@ <h3 data-number="14.24.4" id="significance-20"><span class="header-section-numbe
 <h3 data-number="14.24.5" id="credit-23"><span class="header-section-number">14.24.5</span> Credit</h3>
 <p><em>Review by postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.25" id="breadth-of-concomitant-immune-responses-underpinning-viral-clearance-and-patient-recovery-in-a-non-severe-case-of-covid-19"><span class="header-section-number">14.25</span> Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19</h2>
-<p>Thevarajan et al. <em>medRxiv</em> <span class="citation" data-cites="QdimT8mN">[<a href="#ref-QdimT8mN" role="doc-biblioref">1332</a>]</span></p>
-<h3 data-number="14.25.1" id="keywords-24"><span class="header-section-number">14.25.1</span> Keywords</h3>
+<p>Thevarajan et al. <em>medRxiv</em> <span class="citation" data-cites="QdimT8mN">[<a href="#ref-QdimT8mN" role="doc-biblioref">1334</a>]</span></p>
+<h3 data-number="14.25.1" id="keywords-25"><span class="header-section-number">14.25.1</span> Keywords</h3>
 <ul>
 <li>IgG</li>
 <li>IgM</li>
@@ -13951,13 +13984,13 @@ <h3 data-number="14.25.2" id="main-findings-23"><span class="header-section-numb
 <h3 data-number="14.25.3" id="limitations-24"><span class="header-section-number">14.25.3</span> Limitations</h3>
 <p>These results need to be confirmed in additional patients.</p>
 <p>COVID-19 patients have increased infiltration of macrophages in their
-lungs <span class="citation" data-cites="tVkKuIJt">[<a href="#ref-tVkKuIJt" role="doc-biblioref">1333</a>]</span>. Monitoring monocyte proportions in blood earlier in the
+lungs <span class="citation" data-cites="tVkKuIJt">[<a href="#ref-tVkKuIJt" role="doc-biblioref">1335</a>]</span>. Monitoring monocyte proportions in blood earlier in the
 disease might help to evaluate their eventual migration to the lungs.</p>
 <p>The stable concentration of HLA-DR<sup>+</sup> NK cells in blood from day 7 is
 not sufficient to rule out NK cell activation upon SARS-CoV2 infection.
 In response to influenza A virus, NK cells express higher levels of
 activation markers CD69 and CD38, proliferate better and display higher
-cytotoxicity <span class="citation" data-cites="87CJN2CG">[<a href="#ref-87CJN2CG" role="doc-biblioref">1334</a>]</span>. Assessing these parameters in COVID-19 patients is
+cytotoxicity <span class="citation" data-cites="87CJN2CG">[<a href="#ref-87CJN2CG" role="doc-biblioref">1336</a>]</span>. Assessing these parameters in COVID-19 patients is
 required to better understand NK cell role in clearing this infection.</p>
 <p>Neutralization potential of the COVID-19-binding IgG and IgM antibodies
 should be assessed in future studies.</p>
@@ -13969,14 +14002,14 @@ <h3 data-number="14.25.4" id="significance-21"><span class="header-section-numbe
 <p>This study is among the first to describe the appearance of
 COVID-19-binding IgG and IgM antibodies upon infection. The emergence of
 new serological assays might contribute to monitor more precisely the
-seroconversion kinetics of COVID-19 patients <span class="citation" data-cites="yJW1RVQb">[<a href="#ref-yJW1RVQb" role="doc-biblioref">400</a>]</span>. Further association
+seroconversion kinetics of COVID-19 patients <span class="citation" data-cites="yJW1RVQb">[<a href="#ref-yJW1RVQb" role="doc-biblioref">399</a>]</span>. Further association
 studies between IFITM3 SNP-rs12252-C/C variant and clinical data might
 help to refine the COVID-19 outcome prediction tools.</p>
 <h3 data-number="14.25.5" id="credit-24"><span class="header-section-number">14.25.5</span> Credit</h3>
 <p><em>Review by Bérengère Salomé as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.26" id="the-landscape-of-lung-bronchoalveolar-immune-cells-in-covid-19-revealed-by-single-cell-rna-sequencing"><span class="header-section-number">14.26</span> The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing</h2>
-<p>Liao et al. <em>medRxiv</em> <span class="citation" data-cites="tVkKuIJt">[<a href="#ref-tVkKuIJt" role="doc-biblioref">1333</a>]</span></p>
-<h3 data-number="14.26.1" id="keywords-25"><span class="header-section-number">14.26.1</span> Keywords</h3>
+<p>Liao et al. <em>medRxiv</em> <span class="citation" data-cites="tVkKuIJt">[<a href="#ref-tVkKuIJt" role="doc-biblioref">1335</a>]</span></p>
+<h3 data-number="14.26.1" id="keywords-26"><span class="header-section-number">14.26.1</span> Keywords</h3>
 <ul>
 <li>COVID-19</li>
 <li>SARS-CoV-2</li>
@@ -14024,10 +14057,10 @@ <h3 data-number="14.26.3" id="limitations-25"><span class="header-section-number
 healthy and diseased lesions.</p>
 <h3 data-number="14.26.4" id="significance-22"><span class="header-section-number">14.26.4</span> Significance</h3>
 <p>COVID-19 induces a robust inflammatory cytokine storm in patients that
-contributes to severe lung tissue damage and ARDS <span class="citation" data-cites="vasHgjGH">[<a href="#ref-vasHgjGH" role="doc-biblioref">1335</a>]</span>. Accumulation of
+contributes to severe lung tissue damage and ARDS <span class="citation" data-cites="vasHgjGH">[<a href="#ref-vasHgjGH" role="doc-biblioref">1337</a>]</span>. Accumulation of
 monocyte-derived inflammatory macrophages at the expense of Alveolar
 macrophages known to play an anti-inflammatory role following
-respiratory viral infection, in part through the PPARγ pathway <span class="citation" data-cites="9GEyqic3 WBN5f37b">[<a href="#ref-9GEyqic3" role="doc-biblioref">1336</a>,<a href="#ref-WBN5f37b" role="doc-biblioref">1337</a>]</span> are
+respiratory viral infection, in part through the PPARγ pathway <span class="citation" data-cites="9GEyqic3 WBN5f37b">[<a href="#ref-9GEyqic3" role="doc-biblioref">1338</a>,<a href="#ref-WBN5f37b" role="doc-biblioref">1339</a>]</span> are
 likely contributing to lung tissue injuries. These data suggest that
 reduction of monocyte accumulation in the lung tissues could help
 modulate COVID-19-induced inflammation. Further analysis of lymphoid
@@ -14036,8 +14069,8 @@ <h3 data-number="14.26.4" id="significance-22"><span class="header-section-numbe
 <h3 data-number="14.26.5" id="credit-25"><span class="header-section-number">14.26.5</span> Credit</h3>
 <p><em>Review by Bérengère Salomé and Assaf Magen as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.27" id="can-routine-laboratory-tests-discriminate-2019-novel-coronavirus-infected-pneumonia-from-other-community-acquired-pneumonia"><span class="header-section-number">14.27</span> Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?</h2>
-<p>Pan et al. <em>medRxiv</em> <span class="citation" data-cites="FOVDaThy">[<a href="#ref-FOVDaThy" role="doc-biblioref">1338</a>]</span></p>
-<h3 data-number="14.27.1" id="keywords-26"><span class="header-section-number">14.27.1</span> Keywords</h3>
+<p>Pan et al. <em>medRxiv</em> <span class="citation" data-cites="FOVDaThy">[<a href="#ref-FOVDaThy" role="doc-biblioref">1340</a>]</span></p>
+<h3 data-number="14.27.1" id="keywords-27"><span class="header-section-number">14.27.1</span> Keywords</h3>
 <ul>
 <li>Routine laboratory testing</li>
 </ul>
@@ -14071,8 +14104,8 @@ <h3 data-number="14.27.4" id="significance-23"><span class="header-section-numbe
 <h3 data-number="14.27.5" id="credit-26"><span class="header-section-number">14.27.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.28" id="correlation-analysis-between-disease-severity-and-inflammation-related-parameters-in-patients-with-covid-19-pneumonia"><span class="header-section-number">14.28</span> Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia</h2>
-<p><span class="citation" data-cites="1Du40IOOH">[<a href="#ref-1Du40IOOH" role="doc-biblioref">1339</a>]</span></p>
-<h3 data-number="14.28.1" id="keywords-27"><span class="header-section-number">14.28.1</span> Keywords</h3>
+<p><span class="citation" data-cites="1Du40IOOH">[<a href="#ref-1Du40IOOH" role="doc-biblioref">1341</a>]</span></p>
+<h3 data-number="14.28.1" id="keywords-28"><span class="header-section-number">14.28.1</span> Keywords</h3>
 <ul>
 <li>cytokine</li>
 <li>COVID-19 pneumonia</li>
@@ -14122,8 +14155,8 @@ <h3 data-number="14.28.3" id="significance-24"><span class="header-section-numbe
 <h3 data-number="14.28.4" id="credit-27"><span class="header-section-number">14.28.4</span> Credit</h3>
 <p><em>This review by JJF was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.29" id="an-effective-ctl-peptide-vaccine-for-ebola-zaire-based-on-survivors-cd8-targeting-of-a-particular-nucleocapsid-protein-epitope-with-potential-implications-for-covid-19-vaccine-design"><span class="header-section-number">14.29</span> An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design</h2>
-<p>Herst et al. <em>bioRxiv</em> <span class="citation" data-cites="1DTLMIDoM">[<a href="#ref-1DTLMIDoM" role="doc-biblioref">1340</a>]</span></p>
-<h3 data-number="14.29.1" id="keywords-28"><span class="header-section-number">14.29.1</span> Keywords</h3>
+<p>Herst et al. <em>bioRxiv</em> <span class="citation" data-cites="1DTLMIDoM">[<a href="#ref-1DTLMIDoM" role="doc-biblioref">1342</a>]</span></p>
+<h3 data-number="14.29.1" id="keywords-29"><span class="header-section-number">14.29.1</span> Keywords</h3>
 <ul>
 <li>Peptide vaccine</li>
 <li>Ebolavirus</li>
@@ -14182,8 +14215,8 @@ <h3 data-number="14.29.2" id="main-findings-27"><span class="header-section-numb
 <h3 data-number="14.29.3" id="credit-28"><span class="header-section-number">14.29.3</span> Credit</h3>
 <p><em>Review by Andrew M. Leader as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.30" id="epitope-based-peptide-vaccines-predicted-against-novel-coronavirus-disease-caused-by-sars-cov-2"><span class="header-section-number">14.30</span> Epitope-based peptide vaccines predicted against novel coronavirus disease caused by SARS-CoV-2</h2>
-<p>Li et al. <em>bioRxiv</em>. <span class="citation" data-cites="9spK49tt">[<a href="#ref-9spK49tt" role="doc-biblioref">1341</a>]</span></p>
-<h3 data-number="14.30.1" id="keywords-29"><span class="header-section-number">14.30.1</span> Keywords</h3>
+<p>Li et al. <em>bioRxiv</em>. <span class="citation" data-cites="9spK49tt">[<a href="#ref-9spK49tt" role="doc-biblioref">1343</a>]</span></p>
+<h3 data-number="14.30.1" id="keywords-30"><span class="header-section-number">14.30.1</span> Keywords</h3>
 <ul>
 <li>SARS-CoV-2</li>
 <li>immune-informatics</li>
@@ -14235,8 +14268,8 @@ <h3 data-number="14.30.5" id="credit-29"><span class="header-section-number">14.
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.31" id="the-definition-and-risks-of-cytokine-release-syndrome-like-in-11-covid-19-infected-pneumonia-critically-ill-patients-disease-characteristics-and-retrospective-analysis"><span class="header-section-number">14.31</span> The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis</h2>
 <p>Wang Jr. et al. <em>medRxiv</em>.
-<span class="citation" data-cites="qg1bmQng">[<a href="#ref-qg1bmQng" role="doc-biblioref">1342</a>]</span></p>
-<h3 data-number="14.31.1" id="keywords-30"><span class="header-section-number">14.31.1</span> Keywords</h3>
+<span class="citation" data-cites="qg1bmQng">[<a href="#ref-qg1bmQng" role="doc-biblioref">1344</a>]</span></p>
+<h3 data-number="14.31.1" id="keywords-31"><span class="header-section-number">14.31.1</span> Keywords</h3>
 <ul>
 <li>Cytokine release syndrome (CRS)</li>
 <li>biomarkers</li>
@@ -14276,8 +14309,8 @@ <h3 data-number="14.31.4" id="significance-26"><span class="header-section-numbe
 <h3 data-number="14.31.5" id="credit-30"><span class="header-section-number">14.31.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.32" id="clinical-characteristics-of-36-non-survivors-with-covid-19-in-wuhan-china"><span class="header-section-number">14.32</span> Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China</h2>
-<p>Huang et al. <em>medRxiv</em>. <span class="citation" data-cites="YODgfrtM">[<a href="#ref-YODgfrtM" role="doc-biblioref">1343</a>]</span></p>
-<h3 data-number="14.32.1" id="keywords-31"><span class="header-section-number">14.32.1</span> Keywords</h3>
+<p>Huang et al. <em>medRxiv</em>. <span class="citation" data-cites="YODgfrtM">[<a href="#ref-YODgfrtM" role="doc-biblioref">1345</a>]</span></p>
+<h3 data-number="14.32.1" id="keywords-32"><span class="header-section-number">14.32.1</span> Keywords</h3>
 <ul>
 <li>Clinical Characteristics</li>
 <li>Non Survivors</li>
@@ -14307,8 +14340,8 @@ <h3 data-number="14.32.4" id="significance-27"><span class="header-section-numbe
 <h3 data-number="14.32.5" id="credit-31"><span class="header-section-number">14.32.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.33" id="risk-factors-related-to-hepatic-injury-in-patients-with-corona-virus-disease-2019"><span class="header-section-number">14.33</span> Risk Factors Related to Hepatic Injury in Patients with Corona Virus Disease 2019</h2>
-<p><span class="citation" data-cites="5CGbn9Jj">[<a href="#ref-5CGbn9Jj" role="doc-biblioref">1344</a>]</span></p>
-<h3 data-number="14.33.1" id="keywords-32"><span class="header-section-number">14.33.1</span> Keywords</h3>
+<p><span class="citation" data-cites="5CGbn9Jj">[<a href="#ref-5CGbn9Jj" role="doc-biblioref">1346</a>]</span></p>
+<h3 data-number="14.33.1" id="keywords-33"><span class="header-section-number">14.33.1</span> Keywords</h3>
 <ul>
 <li>COVID-related Hepatic Injury</li>
 </ul>
@@ -14343,8 +14376,8 @@ <h3 data-number="14.33.4" id="significance-28"><span class="header-section-numbe
 <h3 data-number="14.33.5" id="credit-32"><span class="header-section-number">14.33.5</span> Credit</h3>
 <p><em>Review by Chang Moon as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.34" id="detectable-serum-sars-cov-2-viral-load-rnaaemia-is-closely-associated-with-drastically-elevated-interleukin-6-il-6-level-in-critically-ill-covid-19-patients"><span class="header-section-number">14.34</span> Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients</h2>
-<p><span class="citation" data-cites="T0BDaXkw">[<a href="#ref-T0BDaXkw" role="doc-biblioref">1345</a>]</span></p>
-<h3 data-number="14.34.1" id="keywords-33"><span class="header-section-number">14.34.1</span> Keywords</h3>
+<p><span class="citation" data-cites="T0BDaXkw">[<a href="#ref-T0BDaXkw" role="doc-biblioref">1347</a>]</span></p>
+<h3 data-number="14.34.1" id="keywords-34"><span class="header-section-number">14.34.1</span> Keywords</h3>
 <ul>
 <li>ARDS</li>
 <li>interleukin-6 (IL-6)</li>
@@ -14381,7 +14414,7 @@ <h3 data-number="14.34.2" id="main-findings-32"><span class="header-section-numb
 marker.</p>
 <h3 data-number="14.34.3" id="limitations-31"><span class="header-section-number">14.34.3</span> Limitations</h3>
 <p>While this group’s report generally confirms some of the major findings
-of a more extensive study, published in early February 2020, <span class="citation" data-cites="vasHgjGH">[<a href="#ref-vasHgjGH" role="doc-biblioref">1335</a>]</span>,
+of a more extensive study, published in early February 2020, <span class="citation" data-cites="vasHgjGH">[<a href="#ref-vasHgjGH" role="doc-biblioref">1337</a>]</span>,
 there are limitations that should be taken into account. First, the
 number of patients enrolled is relatively small; second, interpretation
 of these data would benefit from inclusion of information about study
@@ -14414,12 +14447,12 @@ <h3 data-number="14.34.4" id="significance-29"><span class="header-section-numbe
 (high levels of IL-6, IL-8 and plasma leukotriene were shown to have
 prognostic value at the onset of ARDS ; serum IL-2 and IL-15 have been
 associated with mortality; reviewed by Chen W &amp; Ware L, Clin Transl Med.
-2015 <span class="citation" data-cites="l3CzJ5ni">[<a href="#ref-l3CzJ5ni" role="doc-biblioref">1346</a>]</span>).</p>
+2015 <span class="citation" data-cites="l3CzJ5ni">[<a href="#ref-l3CzJ5ni" role="doc-biblioref">1348</a>]</span>).</p>
 <h3 data-number="14.34.5" id="credit-33"><span class="header-section-number">14.34.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.35" id="lymphopenia-predicts-disease-severity-of-covid-19-a-descriptive-and-predictive-study"><span class="header-section-number">14.35</span> Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study</h2>
-<p><span class="citation" data-cites="uIwTzZkJ">[<a href="#ref-uIwTzZkJ" role="doc-biblioref">1347</a>]</span></p>
-<h3 data-number="14.35.1" id="keywords-34"><span class="header-section-number">14.35.1</span> Keywords</h3>
+<p><span class="citation" data-cites="uIwTzZkJ">[<a href="#ref-uIwTzZkJ" role="doc-biblioref">1349</a>]</span></p>
+<h3 data-number="14.35.1" id="keywords-35"><span class="header-section-number">14.35.1</span> Keywords</h3>
 <ul>
 <li>Lymphopenia</li>
 </ul>
@@ -14452,8 +14485,8 @@ <h3 data-number="14.35.4" id="significance-30"><span class="header-section-numbe
 <h3 data-number="14.35.5" id="credit-34"><span class="header-section-number">14.35.5</span> Credit</h3>
 <p><em>Review by Chang Moon as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.36" id="the-potential-role-of-il-6-in-monitoring-severe-case-of-coronavirus-disease-2019"><span class="header-section-number">14.36</span> The potential role of IL-6 in monitoring severe case of coronavirus disease 2019</h2>
-<p>Liu et al. <em>medRxiv</em>. <span class="citation" data-cites="1GMxHWnxN">[<a href="#ref-1GMxHWnxN" role="doc-biblioref">1348</a>]</span></p>
-<h3 data-number="14.36.1" id="keywords-35"><span class="header-section-number">14.36.1</span> Keywords</h3>
+<p>Liu et al. <em>medRxiv</em>. <span class="citation" data-cites="1GMxHWnxN">[<a href="#ref-1GMxHWnxN" role="doc-biblioref">1350</a>]</span></p>
+<h3 data-number="14.36.1" id="keywords-36"><span class="header-section-number">14.36.1</span> Keywords</h3>
 <ul>
 <li>Cytokine Release Syndrome</li>
 <li>lymphocytopenia</li>
@@ -14493,8 +14526,8 @@ <h3 data-number="14.36.4" id="significance-31"><span class="header-section-numbe
 <h3 data-number="14.36.5" id="credit-35"><span class="header-section-number">14.36.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.37" id="clinical-and-laboratory-profiles-of-75-hospitalized-patients-with-novel-coronavirus-disease-2019-in-hefei-china"><span class="header-section-number">14.37</span> Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China</h2>
-<p>Zhao et al. <em>medRxiv</em>. <span class="citation" data-cites="1B0vBwv1q">[<a href="#ref-1B0vBwv1q" role="doc-biblioref">1349</a>]</span></p>
-<h3 data-number="14.37.1" id="keywords-36"><span class="header-section-number">14.37.1</span> Keywords</h3>
+<p>Zhao et al. <em>medRxiv</em>. <span class="citation" data-cites="1B0vBwv1q">[<a href="#ref-1B0vBwv1q" role="doc-biblioref">1351</a>]</span></p>
+<h3 data-number="14.37.1" id="keywords-37"><span class="header-section-number">14.37.1</span> Keywords</h3>
 <ul>
 <li>Routine laboratory testing</li>
 </ul>
@@ -14529,8 +14562,8 @@ <h3 data-number="14.37.4" id="significance-32"><span class="header-section-numbe
 <h3 data-number="14.37.5" id="credit-36"><span class="header-section-number">14.37.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.38" id="exuberant-elevation-of-ip-10-mcp-3-and-il-1ra-during-sars-cov-2-infection-is-associated-with-disease-severity-and-fatal-outcome"><span class="header-section-number">14.38</span> Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome</h2>
-<p>Yang et al. <em>medRxiv</em> <span class="citation" data-cites="RyXNw87v">[<a href="#ref-RyXNw87v" role="doc-biblioref">1350</a>]</span></p>
-<h3 data-number="14.38.1" id="keywords-37"><span class="header-section-number">14.38.1</span> Keywords</h3>
+<p>Yang et al. <em>medRxiv</em> <span class="citation" data-cites="RyXNw87v">[<a href="#ref-RyXNw87v" role="doc-biblioref">1352</a>]</span></p>
+<h3 data-number="14.38.1" id="keywords-38"><span class="header-section-number">14.38.1</span> Keywords</h3>
 <ul>
 <li>cytokine</li>
 <li>IP-10</li>
@@ -14650,8 +14683,8 @@ <h3 data-number="14.38.6" id="significance-33"><span class="header-section-numbe
 <h3 data-number="14.38.7" id="credit-37"><span class="header-section-number">14.38.7</span> Credit</h3>
 <p><em>Review by Natalie Vaninov as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.39" id="antibody-responses-to-sars-cov-2-in-patients-of-novel-coronavirus-disease-2019"><span class="header-section-number">14.39</span> Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019</h2>
-<p>Zhao Jr. et al. <em>medRxiv</em>. <span class="citation" data-cites="5HXuCa5t">[<a href="#ref-5HXuCa5t" role="doc-biblioref">1351</a>]</span></p>
-<h3 data-number="14.39.1" id="keywords-38"><span class="header-section-number">14.39.1</span> Keywords</h3>
+<p>Zhao Jr. et al. <em>medRxiv</em>. <span class="citation" data-cites="5HXuCa5t">[<a href="#ref-5HXuCa5t" role="doc-biblioref">1353</a>]</span></p>
+<h3 data-number="14.39.1" id="keywords-39"><span class="header-section-number">14.39.1</span> Keywords</h3>
 <ul>
 <li>SARS-CoV-2 IgG</li>
 <li>seroconversion rate</li>
@@ -14717,8 +14750,8 @@ <h3 data-number="14.39.4" id="significance-34"><span class="header-section-numbe
 <h3 data-number="14.39.5" id="credit-38"><span class="header-section-number">14.39.5</span> Credit</h3>
 <p><em>This review was undertaken by Zafar Mahmood and edited by K Alexandropoulos as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.40" id="restoration-of-leukomonocyte-counts-is-associated-with-viral-clearance-in-covid-19-hospitalized-patients"><span class="header-section-number">14.40</span> Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients</h2>
-<p>Chen et al. <em>medRxiv</em> <span class="citation" data-cites="uCyoHtV3">[<a href="#ref-uCyoHtV3" role="doc-biblioref">1352</a>]</span></p>
-<h3 data-number="14.40.1" id="keywords-39"><span class="header-section-number">14.40.1</span> Keywords</h3>
+<p>Chen et al. <em>medRxiv</em> <span class="citation" data-cites="uCyoHtV3">[<a href="#ref-uCyoHtV3" role="doc-biblioref">1354</a>]</span></p>
+<h3 data-number="14.40.1" id="keywords-40"><span class="header-section-number">14.40.1</span> Keywords</h3>
 <ul>
 <li>COVID-19</li>
 <li>T cell</li>
@@ -14750,13 +14783,13 @@ <h3 data-number="14.40.3" id="limitations-37"><span class="header-section-number
 <p>73% of the patients who remained positive for SARS-CoV2 after the 1<sup>st</sup>
 treatment, and 43% of all patients who cleared the virus were treated
 with corticosteroids. Corticosteroids have strong effects on the immune
-compartment in blood <span class="citation" data-cites="L6kwccjn">[<a href="#ref-L6kwccjn" role="doc-biblioref">1353</a>]</span>. The authors should have accounted for
+compartment in blood <span class="citation" data-cites="L6kwccjn">[<a href="#ref-L6kwccjn" role="doc-biblioref">1355</a>]</span>. The authors should have accounted for
 corticosteroid treatment when considering changes in T, NK and B cell
 frequencies.</p>
 <p>Assessing if IL-6 concentrations were back to baseline levels following
 treatment would have provided insights into the COVID-19 cytokine storm
 biology. Patients with higher baseline levels of IL-6 have been reported
-to have lower CD8 and CD4 T cell frequencies <span class="citation" data-cites="1B0vBwv1q">[<a href="#ref-1B0vBwv1q" role="doc-biblioref">1349</a>]</span>. Correlating IL-6 with
+to have lower CD8 and CD4 T cell frequencies <span class="citation" data-cites="1B0vBwv1q">[<a href="#ref-1B0vBwv1q" role="doc-biblioref">1351</a>]</span>. Correlating IL-6 with
 cell counts before and after treatment would thus have also been of
 interest. The report of the laboratory measures in table 2 is incomplete
 and should include the frequencies of patients with increased/decreased
@@ -14769,7 +14802,7 @@ <h3 data-number="14.40.3" id="limitations-37"><span class="header-section-number
 <h3 data-number="14.40.4" id="significance-35"><span class="header-section-number">14.40.4</span> Significance</h3>
 <p>Previous reports suggest an association between disease severity and
 elevated IL-6 or pro-calcitonin concentrations in COVID-19
-patients <span class="citation" data-cites="T0BDaXkw K9G9QT8y">[<a href="#ref-T0BDaXkw" role="doc-biblioref">1345</a>,<a href="#ref-K9G9QT8y" role="doc-biblioref">1354</a>]</span>. IL-6 receptor blockade is also being administered to
+patients <span class="citation" data-cites="T0BDaXkw K9G9QT8y">[<a href="#ref-T0BDaXkw" role="doc-biblioref">1347</a>,<a href="#ref-K9G9QT8y" role="doc-biblioref">1356</a>]</span>. IL-6 receptor blockade is also being administered to
 patients enrolled in clinical trials (NCT04317092). This report thus
 contributes to highlight elevated concentrations of these analytes in
 COVID-19 patients. Mechanisms underlying the association between viral
@@ -14779,8 +14812,8 @@ <h3 data-number="14.40.4" id="significance-35"><span class="header-section-numbe
 <h3 data-number="14.40.5" id="credit-39"><span class="header-section-number">14.40.5</span> Credit</h3>
 <p><em>Review by Bérengère Salomé as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.41" id="clinical-findings-in-critically-ill-patients-infected-with-sars-cov-2-in-guangdong-province-china-a-multi-center-retrospective-observational-study"><span class="header-section-number">14.41</span> Clinical findings in critically ill patients infected with SARS-CoV-2 in Guangdong Province, China: a multi-center, retrospective, observational study</h2>
-<p>Xu et al. <em>medRxiv</em>. <span class="citation" data-cites="USOnp7c0">[<a href="#ref-USOnp7c0" role="doc-biblioref">1355</a>]</span></p>
-<h3 data-number="14.41.1" id="keywords-40"><span class="header-section-number">14.41.1</span> Keywords</h3>
+<p>Xu et al. <em>medRxiv</em>. <span class="citation" data-cites="USOnp7c0">[<a href="#ref-USOnp7c0" role="doc-biblioref">1357</a>]</span></p>
+<h3 data-number="14.41.1" id="keywords-41"><span class="header-section-number">14.41.1</span> Keywords</h3>
 <ul>
 <li>clinical outcomes</li>
 <li>prognosis</li>
@@ -14824,8 +14857,8 @@ <h3 data-number="14.41.4" id="significance-36"><span class="header-section-numbe
 <h3 data-number="14.41.5" id="credit-40"><span class="header-section-number">14.41.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.42" id="immune-multi-epitope-vaccine-design-using-an-immunoinformatics-approach-for-2019-novel-coronavirus-in-china-sars-cov-2"><span class="header-section-number">14.42</span> Immune Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus in China (SARS-CoV-2)</h2>
-<p><span class="citation" data-cites="14OLQIYK0">[<a href="#ref-14OLQIYK0" role="doc-biblioref">1356</a>]</span></p>
-<h3 data-number="14.42.1" id="keywords-41"><span class="header-section-number">14.42.1</span> Keywords</h3>
+<p><span class="citation" data-cites="14OLQIYK0">[<a href="#ref-14OLQIYK0" role="doc-biblioref">1358</a>]</span></p>
+<h3 data-number="14.42.1" id="keywords-42"><span class="header-section-number">14.42.1</span> Keywords</h3>
 <ul>
 <li>Vaccine</li>
 <li>in silico</li>
@@ -14860,8 +14893,8 @@ <h3 data-number="14.42.3" id="limitations-39"><span class="header-section-number
 <h3 data-number="14.42.4" id="credit-41"><span class="header-section-number">14.42.4</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.43" id="clinical-features-of-patients-infected-with-the-2019-novel-coronavirus-covid-19-in-shanghai-china"><span class="header-section-number">14.43</span> Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China</h2>
-<p>Cao et al. <em>medRxiv</em> <span class="citation" data-cites="12ilBRq6I">[<a href="#ref-12ilBRq6I" role="doc-biblioref">1357</a>]</span></p>
-<h3 data-number="14.43.1" id="keywords-42"><span class="header-section-number">14.43.1</span> Keywords</h3>
+<p>Cao et al. <em>medRxiv</em> <span class="citation" data-cites="12ilBRq6I">[<a href="#ref-12ilBRq6I" role="doc-biblioref">1359</a>]</span></p>
+<h3 data-number="14.43.1" id="keywords-43"><span class="header-section-number">14.43.1</span> Keywords</h3>
 <ul>
 <li>Disease severity</li>
 <li>clinical features</li>
@@ -14901,8 +14934,8 @@ <h3 data-number="14.43.5" id="credit-42"><span class="header-section-number">14.
 faculty at the Immunology Institute of the Icahn School of Medicine at
 Mount Sinai.</em></p>
 <h2 data-number="14.44" id="serological-detection-of-2019-ncov-respond-to-the-epidemic-a-useful-complement-to-nucleic-acid-testing"><span class="header-section-number">14.44</span> Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing</h2>
-<p>Zhang et al. <em>medRxiv</em>. <span class="citation" data-cites="IPJURDxi">[<a href="#ref-IPJURDxi" role="doc-biblioref">1358</a>]</span></p>
-<h3 data-number="14.44.1" id="keywords-43"><span class="header-section-number">14.44.1</span> Keywords</h3>
+<p>Zhang et al. <em>medRxiv</em>. <span class="citation" data-cites="IPJURDxi">[<a href="#ref-IPJURDxi" role="doc-biblioref">1360</a>]</span></p>
+<h3 data-number="14.44.1" id="keywords-44"><span class="header-section-number">14.44.1</span> Keywords</h3>
 <ul>
 <li>Immunoassay</li>
 <li>serum IgM and IgG</li>
@@ -14933,8 +14966,8 @@ <h3 data-number="14.44.4" id="significance-38"><span class="header-section-numbe
 <h3 data-number="14.44.5" id="credit-43"><span class="header-section-number">14.44.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.45" id="human-kidney-is-a-target-for-novel-severe-acute-respiratory-syndrome-coronavirus-2-sars-cov-2-infection"><span class="header-section-number">14.45</span> Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection</h2>
-<p><span class="citation" data-cites="H0nvocJz">[<a href="#ref-H0nvocJz" role="doc-biblioref">1359</a>]</span></p>
-<h3 data-number="14.45.1" id="keywords-44"><span class="header-section-number">14.45.1</span> Keywords</h3>
+<p><span class="citation" data-cites="H0nvocJz">[<a href="#ref-H0nvocJz" role="doc-biblioref">1361</a>]</span></p>
+<h3 data-number="14.45.1" id="keywords-45"><span class="header-section-number">14.45.1</span> Keywords</h3>
 <ul>
 <li>Kidney/Renal Failure</li>
 <li>Macrophage Infiltration</li>
@@ -14966,8 +14999,8 @@ <h3 data-number="14.45.4" id="significance-39"><span class="header-section-numbe
 <h3 data-number="14.45.5" id="credit-44"><span class="header-section-number">14.45.5</span> Credit</h3>
 <p><em>Review by Dan Fu Ruan, Evan Cody and Venu Pothula as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine at Mount Sinai.</em></p>
 <h2 data-number="14.46" id="covid-19-early-warning-score-a-multi-parameter-screening-tool-to-identify-highly-suspected-patients"><span class="header-section-number">14.46</span> COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients</h2>
-<p>Song et al. <em>medRxiv</em>. <span class="citation" data-cites="KHNnjP7M">[<a href="#ref-KHNnjP7M" role="doc-biblioref">1360</a>]</span></p>
-<h3 data-number="14.46.1" id="keywords-45"><span class="header-section-number">14.46.1</span> Keywords</h3>
+<p>Song et al. <em>medRxiv</em>. <span class="citation" data-cites="KHNnjP7M">[<a href="#ref-KHNnjP7M" role="doc-biblioref">1362</a>]</span></p>
+<h3 data-number="14.46.1" id="keywords-46"><span class="header-section-number">14.46.1</span> Keywords</h3>
 <ul>
 <li>retrospective</li>
 <li>electronic health records</li>
@@ -15005,8 +15038,8 @@ <h3 data-number="14.46.4" id="significance-40"><span class="header-section-numbe
 <h3 data-number="14.46.5" id="credit-45"><span class="header-section-number">14.46.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.47" id="ly6e-impairs-coronavirus-fusion-and-confers-immune-control-of-viral-disease"><span class="header-section-number">14.47</span> LY6E impairs coronavirus fusion and confers immune control of viral disease</h2>
-<p>Pfaender et al. <em>bioRxiv</em>. <span class="citation" data-cites="19xwRoatu">[<a href="#ref-19xwRoatu" role="doc-biblioref">1361</a>]</span></p>
-<h3 data-number="14.47.1" id="keywords-46"><span class="header-section-number">14.47.1</span> Keywords</h3>
+<p>Pfaender et al. <em>bioRxiv</em>. <span class="citation" data-cites="19xwRoatu">[<a href="#ref-19xwRoatu" role="doc-biblioref">1363</a>]</span></p>
+<h3 data-number="14.47.1" id="keywords-47"><span class="header-section-number">14.47.1</span> Keywords</h3>
 <ul>
 <li>interferon-stimulated genes</li>
 <li>antiviral interferons</li>
@@ -15113,8 +15146,8 @@ <h3 data-number="14.47.4" id="significance-41"><span class="header-section-numbe
 <h3 data-number="14.47.5" id="credit-46"><span class="header-section-number">14.47.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.48" id="a-preliminary-study-on-serological-assay-for-severe-acute-respiratory-syndrome-coronavirus-2-sars-cov-2-in-238-admitted-hospital-patients"><span class="header-section-number">14.48</span> A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients</h2>
-<p>Liu et al. <em>medRxiv</em>. <span class="citation" data-cites="574aSa8C">[<a href="#ref-574aSa8C" role="doc-biblioref">1362</a>]</span></p>
-<h3 data-number="14.48.1" id="keywords-47"><span class="header-section-number">14.48.1</span> Keywords</h3>
+<p>Liu et al. <em>medRxiv</em>. <span class="citation" data-cites="574aSa8C">[<a href="#ref-574aSa8C" role="doc-biblioref">1364</a>]</span></p>
+<h3 data-number="14.48.1" id="keywords-48"><span class="header-section-number">14.48.1</span> Keywords</h3>
 <ul>
 <li>diagnosis</li>
 <li>serological assay</li>
@@ -15147,8 +15180,8 @@ <h3 data-number="14.48.4" id="significance-42"><span class="header-section-numbe
 <h3 data-number="14.48.5" id="credit-47"><span class="header-section-number">14.48.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.49" id="monoclonal-antibodies-for-the-s2-subunit-of-spike-of-sars-cov-cross-react-with-the-newly-emerged-sars-cov-2"><span class="header-section-number">14.49</span> Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2</h2>
-<p><span class="citation" data-cites="NT3T9a8H">[<a href="#ref-NT3T9a8H" role="doc-biblioref">1363</a>]</span></p>
-<h3 data-number="14.49.1" id="keywords-48"><span class="header-section-number">14.49.1</span> Keywords</h3>
+<p><span class="citation" data-cites="NT3T9a8H">[<a href="#ref-NT3T9a8H" role="doc-biblioref">1365</a>]</span></p>
+<h3 data-number="14.49.1" id="keywords-49"><span class="header-section-number">14.49.1</span> Keywords</h3>
 <ul>
 <li>Coronavirus Disease 2019 (COVID-19)</li>
 <li>SARS-CoV-2</li>
@@ -15186,8 +15219,8 @@ <h3 data-number="14.49.4" id="significance-43"><span class="header-section-numbe
 <h3 data-number="14.49.5" id="credit-48"><span class="header-section-number">14.49.5</span> Credit</h3>
 <p><em>This review was undertaken by Tamar Plitt and Katherine Lindblad as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.50" id="mortality-of-covid-19-is-associated-with-cellular-immune-function-compared-to-immune-function-in-chinese-han-population"><span class="header-section-number">14.50</span> Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population</h2>
-<p>Zeng et al. <em>medRxiv</em>. <span class="citation" data-cites="1GEbBtBgh">[<a href="#ref-1GEbBtBgh" role="doc-biblioref">1364</a>]</span></p>
-<h3 data-number="14.50.1" id="keywords-49"><span class="header-section-number">14.50.1</span> Keywords</h3>
+<p>Zeng et al. <em>medRxiv</em>. <span class="citation" data-cites="1GEbBtBgh">[<a href="#ref-1GEbBtBgh" role="doc-biblioref">1366</a>]</span></p>
+<h3 data-number="14.50.1" id="keywords-50"><span class="header-section-number">14.50.1</span> Keywords</h3>
 <ul>
 <li>WBC</li>
 <li>peripheral blood</li>
@@ -15223,8 +15256,8 @@ <h3 data-number="14.50.4" id="significance-44"><span class="header-section-numbe
 <h3 data-number="14.50.5" id="credit-49"><span class="header-section-number">14.50.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.51" id="retrospective-analysis-of-clinical-features-in-101-death-cases-with-covid-19"><span class="header-section-number">14.51</span> Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19</h2>
-<p>Chen et al. <em>medRxiv</em>. <span class="citation" data-cites="WuHcOc9T">[<a href="#ref-WuHcOc9T" role="doc-biblioref">1365</a>]</span></p>
-<h3 data-number="14.51.1" id="keywords-50"><span class="header-section-number">14.51.1</span> Keywords</h3>
+<p>Chen et al. <em>medRxiv</em>. <span class="citation" data-cites="WuHcOc9T">[<a href="#ref-WuHcOc9T" role="doc-biblioref">1367</a>]</span></p>
+<h3 data-number="14.51.1" id="keywords-51"><span class="header-section-number">14.51.1</span> Keywords</h3>
 <ul>
 <li>death biomarkers</li>
 <li>cardiac damage</li>
@@ -15296,8 +15329,8 @@ <h3 data-number="14.51.4" id="significance-45"><span class="header-section-numbe
 <h3 data-number="14.51.5" id="credit-50"><span class="header-section-number">14.51.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.52" id="relationship-between-the-abo-blood-group-and-the-covid-19-susceptibility"><span class="header-section-number">14.52</span> Relationship between the ABO Blood Group and the COVID-19 Susceptibility</h2>
-<p>Zhao et al. <em>medRxiv</em>. <span class="citation" data-cites="1DbV444Pj">[<a href="#ref-1DbV444Pj" role="doc-biblioref">1366</a>]</span></p>
-<h3 data-number="14.52.1" id="keywords-51"><span class="header-section-number">14.52.1</span> Keywords</h3>
+<p>Zhao et al. <em>medRxiv</em>. <span class="citation" data-cites="1DbV444Pj">[<a href="#ref-1DbV444Pj" role="doc-biblioref">1368</a>]</span></p>
+<h3 data-number="14.52.1" id="keywords-52"><span class="header-section-number">14.52.1</span> Keywords</h3>
 <ul>
 <li>ABO blood group</li>
 <li>COVID-19 susceptibility</li>
@@ -15324,8 +15357,8 @@ <h3 data-number="14.52.4" id="significance-46"><span class="header-section-numbe
 <h3 data-number="14.52.5" id="credit-51"><span class="header-section-number">14.52.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.53" id="the-inhaled-corticosteroid-ciclesonide-blocks-coronavirus-rna-replication-by-targeting-viral-nsp15"><span class="header-section-number">14.53</span> The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15</h2>
-<p>Matsuyama et al. <em>bioRxiv</em> <span class="citation" data-cites="JwL9G6bd">[<a href="#ref-JwL9G6bd" role="doc-biblioref">1367</a>]</span></p>
-<h3 data-number="14.53.1" id="keywords-52"><span class="header-section-number">14.53.1</span> Keywords</h3>
+<p>Matsuyama et al. <em>bioRxiv</em> <span class="citation" data-cites="JwL9G6bd">[<a href="#ref-JwL9G6bd" role="doc-biblioref">1369</a>]</span></p>
+<h3 data-number="14.53.1" id="keywords-53"><span class="header-section-number">14.53.1</span> Keywords</h3>
 <ul>
 <li>Corticosteroids</li>
 <li>ciclesonide</li>
@@ -15385,8 +15418,8 @@ <h3 data-number="14.53.4" id="significance-47"><span class="header-section-numbe
 <h3 data-number="14.53.5" id="credit-52"><span class="header-section-number">14.53.5</span> Credit</h3>
 <p><em>This review was undertaken by Alvaro Moreira, MD as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.54" id="a-human-monoclonal-antibody-blocking-sars-cov-2-infection"><span class="header-section-number">14.54</span> A human monoclonal antibody blocking SARS-CoV-2 infection **</h2>
-<p>Wang et al. <em>bioRxiv</em>. <span class="citation" data-cites="XcuzhxrJ">[<a href="#ref-XcuzhxrJ" role="doc-biblioref">605</a>]</span></p>
-<h3 data-number="14.54.1" id="keywords-53"><span class="header-section-number">14.54.1</span> Keywords</h3>
+<p>Wang et al. <em>bioRxiv</em>. <span class="citation" data-cites="XcuzhxrJ">[<a href="#ref-XcuzhxrJ" role="doc-biblioref">604</a>]</span></p>
+<h3 data-number="14.54.1" id="keywords-54"><span class="header-section-number">14.54.1</span> Keywords</h3>
 <ul>
 <li>Monoclonal antibodies</li>
 <li>SARS-CoV2</li>
@@ -15469,8 +15502,8 @@ <h3 data-number="14.54.5" id="credit-53"><span class="header-section-number">14.
 and faculty at the Immunology Institute of the Icahn school of medicine,
 Mount Sinai.</em></p>
 <h2 data-number="14.55" id="immune-phenotyping-based-on-neutrophil-to-lymphocyte-ratio-and-igg-predicts-disease-severity-and-outcome-for-patients-with-covid-19"><span class="header-section-number">14.55</span> Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19</h2>
-<p>Zhang et al. <em>medRxiv</em> <span class="citation" data-cites="1CwCTXPqj">[<a href="#ref-1CwCTXPqj" role="doc-biblioref">1368</a>]</span></p>
-<h3 data-number="14.55.1" id="keywords-54"><span class="header-section-number">14.55.1</span> Keywords</h3>
+<p>Zhang et al. <em>medRxiv</em> <span class="citation" data-cites="1CwCTXPqj">[<a href="#ref-1CwCTXPqj" role="doc-biblioref">1370</a>]</span></p>
+<h3 data-number="14.55.1" id="keywords-55"><span class="header-section-number">14.55.1</span> Keywords</h3>
 <ul>
 <li>Biomarkers</li>
 <li>cytokines</li>
@@ -15514,8 +15547,8 @@ <h3 data-number="14.55.4" id="significance-49"><span class="header-section-numbe
 <h3 data-number="14.55.5" id="credit-54"><span class="header-section-number">14.55.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.56" id="reinfection-could-not-occur-in-sars-2-cov-2-infected-rhesus-macaques"><span class="header-section-number">14.56</span> Reinfection could not occur in SARS-2 CoV-2 infected rhesus macaques</h2>
-<p>Bao et al. <em>bioRxiv</em> <span class="citation" data-cites="3XqFhi8l">[<a href="#ref-3XqFhi8l" role="doc-biblioref">1369</a>]</span></p>
-<h3 data-number="14.56.1" id="keywords-55"><span class="header-section-number">14.56.1</span> Keywords</h3>
+<p>Bao et al. <em>bioRxiv</em> <span class="citation" data-cites="3XqFhi8l">[<a href="#ref-3XqFhi8l" role="doc-biblioref">1371</a>]</span></p>
+<h3 data-number="14.56.1" id="keywords-56"><span class="header-section-number">14.56.1</span> Keywords</h3>
 <ul>
 <li>SARS-CoV-2</li>
 <li>viral load</li>
@@ -15566,8 +15599,8 @@ <h3 data-number="14.56.4" id="significance-50"><span class="header-section-numbe
 <h3 data-number="14.56.5" id="credit-55"><span class="header-section-number">14.56.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.57" id="a-highly-conserved-cryptic-epitope-in-the-receptor-binding-domains-of-sars-cov-2-and-sars-cov"><span class="header-section-number">14.57</span> A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV</h2>
-<p><span class="citation" data-cites="6gQxRkWM">[<a href="#ref-6gQxRkWM" role="doc-biblioref">1370</a>]</span></p>
-<h3 data-number="14.57.1" id="keywords-56"><span class="header-section-number">14.57.1</span> Keywords</h3>
+<p><span class="citation" data-cites="6gQxRkWM">[<a href="#ref-6gQxRkWM" role="doc-biblioref">1372</a>]</span></p>
+<h3 data-number="14.57.1" id="keywords-57"><span class="header-section-number">14.57.1</span> Keywords</h3>
 <ul>
 <li>neutralizing antibody</li>
 <li>cross-reactivity</li>
@@ -15602,8 +15635,8 @@ <h3 data-number="14.57.4" id="significance-51"><span class="header-section-numbe
 <h3 data-number="14.57.5" id="credit-56"><span class="header-section-number">14.57.5</span> Credit</h3>
 <p><em>This review was undertaken by Dan Fu Ruan, Evan Cody and Venu Pothula as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.58" id="highly-accurate-and-sensitive-diagnostic-detection-of-sars-cov-2-by-digital-pcr"><span class="header-section-number">14.58</span> Highly accurate and sensitive diagnostic detection of SARS-CoV-2 by digital PCR</h2>
-<p>Dong et al. <em>medRxiv</em> <span class="citation" data-cites="UYD5T2mp">[<a href="#ref-UYD5T2mp" role="doc-biblioref">1371</a>]</span></p>
-<h3 data-number="14.58.1" id="keywords-57"><span class="header-section-number">14.58.1</span> Keywords</h3>
+<p>Dong et al. <em>medRxiv</em> <span class="citation" data-cites="UYD5T2mp">[<a href="#ref-UYD5T2mp" role="doc-biblioref">1373</a>]</span></p>
+<h3 data-number="14.58.1" id="keywords-58"><span class="header-section-number">14.58.1</span> Keywords</h3>
 <ul>
 <li>Diagnosis</li>
 <li>digital PCR</li>
@@ -15631,8 +15664,8 @@ <h3 data-number="14.58.4" id="significance-52"><span class="header-section-numbe
 <h3 data-number="14.58.5" id="credit-57"><span class="header-section-number">14.58.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.59" id="sars-cov-2-invades-host-cells-via-a-novel-route-cd147-spike-protein"><span class="header-section-number">14.59</span> SARS-CoV-2 invades host cells via a novel route: CD147-spike protein</h2>
-<p>Wang et al. <em>bioRxiv</em> <span class="citation" data-cites="14y8UvAbH">[<a href="#ref-14y8UvAbH" role="doc-biblioref">1372</a>]</span></p>
-<h3 data-number="14.59.1" id="keywords-58"><span class="header-section-number">14.59.1</span> Keywords</h3>
+<p>Wang et al. <em>bioRxiv</em> <span class="citation" data-cites="14y8UvAbH">[<a href="#ref-14y8UvAbH" role="doc-biblioref">1374</a>]</span></p>
+<h3 data-number="14.59.1" id="keywords-59"><span class="header-section-number">14.59.1</span> Keywords</h3>
 <ul>
 <li>spike protein</li>
 <li>viral entry</li>
@@ -15672,18 +15705,18 @@ <h3 data-number="14.59.4" id="significance-53"><span class="header-section-numbe
 <p>It has been shown in various studies that SARS-CoV-2 binds to the cell
 surface protein ACE2 for cell entry, yet ACE2 is highly expressed in
 heart, kidney, and intestinal cells, raising the concern that blocking
-ACE2 would result in harmful side effects <span class="citation" data-cites="BcOf65BE">[<a href="#ref-BcOf65BE" role="doc-biblioref">1373</a>]</span> CD147 on the other hand
+ACE2 would result in harmful side effects <span class="citation" data-cites="BcOf65BE">[<a href="#ref-BcOf65BE" role="doc-biblioref">1375</a>]</span> CD147 on the other hand
 is highly expressed in various tumor types, inflamed tissues, and
 pathogen infected cells, suggesting that the inhibition of CD147 would
-not result in major side effects <span class="citation" data-cites="34nQJalJ KcThTnsm">[<a href="#ref-34nQJalJ" role="doc-biblioref">1374</a>,<a href="#ref-KcThTnsm" role="doc-biblioref">1375</a>]</span> The research in this paper has
+not result in major side effects <span class="citation" data-cites="34nQJalJ KcThTnsm">[<a href="#ref-34nQJalJ" role="doc-biblioref">1376</a>,<a href="#ref-KcThTnsm" role="doc-biblioref">1377</a>]</span> The research in this paper has
 resulted in an ongoing clinical trail in China to test the safety and
 efficacy of anti-CD147 Meplazumab to treat COVID-19. (ClinicalTrails.gov
 identifier NCT04275245).</p>
 <h3 data-number="14.59.5" id="credit-58"><span class="header-section-number">14.59.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.60" id="blood-single-cell-immune-profiling-reveals-that-interferon-mapk-pathway-mediated-adaptive-immune-response-for-covid-19"><span class="header-section-number">14.60</span> Blood single cell immune profiling reveals that interferon-MAPK pathway mediated adaptive immune response for COVID-19</h2>
-<p>Huang et al. <em>medRxiv</em> <span class="citation" data-cites="18l4l0nLX">[<a href="#ref-18l4l0nLX" role="doc-biblioref">1376</a>]</span></p>
-<h3 data-number="14.60.1" id="keywords-59"><span class="header-section-number">14.60.1</span> Keywords</h3>
+<p>Huang et al. <em>medRxiv</em> <span class="citation" data-cites="18l4l0nLX">[<a href="#ref-18l4l0nLX" role="doc-biblioref">1378</a>]</span></p>
+<h3 data-number="14.60.1" id="keywords-60"><span class="header-section-number">14.60.1</span> Keywords</h3>
 <ul>
 <li>COVID-19</li>
 <li>SARS-CoV-2</li>
@@ -15750,8 +15783,8 @@ <h3 data-number="14.60.4" id="significance-54"><span class="header-section-numbe
 <h3 data-number="14.60.5" id="credit-59"><span class="header-section-number">14.60.5</span> Credit</h3>
 <p><em>This review was undertaken by Matthew D. Park as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.61" id="cross-reactive-antibody-response-between-sars-cov-2-and-sars-cov-infection."><span class="header-section-number">14.61</span> Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infection.</h2>
-<p>Lv et al. <em>bioRxiv</em> <span class="citation" data-cites="dM1rOHmH">[<a href="#ref-dM1rOHmH" role="doc-biblioref">1377</a>]</span></p>
-<h3 data-number="14.61.1" id="keywords-60"><span class="header-section-number">14.61.1</span> Keywords</h3>
+<p>Lv et al. <em>bioRxiv</em> <span class="citation" data-cites="dM1rOHmH">[<a href="#ref-dM1rOHmH" role="doc-biblioref">1379</a>]</span></p>
+<h3 data-number="14.61.1" id="keywords-61"><span class="header-section-number">14.61.1</span> Keywords</h3>
 <p>SARS-CoV-2, SARS-CoV, spike protein, RBD, cross-reactivity,
 cross-neutralization, antibody, human patients, mouse</p>
 <h3 data-number="14.61.2" id="main-findings-57"><span class="header-section-number">14.61.2</span> Main Findings</h3>
@@ -15794,8 +15827,8 @@ <h3 data-number="14.61.4" id="significance-55"><span class="header-section-numbe
 <h3 data-number="14.61.5" id="credit-60"><span class="header-section-number">14.61.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.62" id="the-feasibility-of-convalescent-plasma-therapy-in-severe-covid-19-patients-a-pilot-study"><span class="header-section-number">14.62</span> The feasibility of convalescent plasma therapy in severe COVID-19 patients: a pilot study</h2>
-<p>Duan et al. <em>medRxiv</em> <span class="citation" data-cites="UENoLkhz">[<a href="#ref-UENoLkhz" role="doc-biblioref">1378</a>]</span></p>
-<h3 data-number="14.62.1" id="keywords-61"><span class="header-section-number">14.62.1</span> Keywords</h3>
+<p>Duan et al. <em>medRxiv</em> <span class="citation" data-cites="UENoLkhz">[<a href="#ref-UENoLkhz" role="doc-biblioref">1380</a>]</span></p>
+<h3 data-number="14.62.1" id="keywords-62"><span class="header-section-number">14.62.1</span> Keywords</h3>
 <ul>
 <li>COVID-19</li>
 <li>SARS-CoV-2</li>
@@ -15866,8 +15899,8 @@ <h3 data-number="14.62.4" id="significance-56"><span class="header-section-numbe
 <h3 data-number="14.62.5" id="credit-61"><span class="header-section-number">14.62.5</span> Credit</h3>
 <p><em>Review by Matthew D. Park and revised by Alice O. Kamphorst and Maria A. Curotto de Lafaille as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.63" id="hydroxychloroquine-and-azithromycin-as-a-treatment-of-covid-19-results-of-an-open-label-non-randomized-clinical-trial"><span class="header-section-number">14.63</span> Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open label non-randomized clinical trial</h2>
-<p><span class="citation" data-cites="Xbkby2Jr">[<a href="#ref-Xbkby2Jr" role="doc-biblioref">1379</a>]</span></p>
-<h3 data-number="14.63.1" id="keywords-62"><span class="header-section-number">14.63.1</span> Keywords</h3>
+<p><span class="citation" data-cites="Xbkby2Jr">[<a href="#ref-Xbkby2Jr" role="doc-biblioref">1381</a>]</span></p>
+<h3 data-number="14.63.1" id="keywords-63"><span class="header-section-number">14.63.1</span> Keywords</h3>
 <ul>
 <li>hydroxychloroquine</li>
 <li>clearance</li>
@@ -15922,21 +15955,21 @@ <h3 data-number="14.63.3" id="limitations-60"><span class="header-section-number
 <h3 data-number="14.63.4" id="significance-57"><span class="header-section-number">14.63.4</span> Significance</h3>
 <p>Chloroquine is thought to inhibit viral infection,
 including SARS-Cov-2, by increasing pH within endosomes and lysosomes,
-altering the biochemical conditions required for viral fusion <span class="citation" data-cites="IhdcvbzC BIlqPh6M">[<a href="#ref-IhdcvbzC" role="doc-biblioref">447</a>,<a href="#ref-BIlqPh6M" role="doc-biblioref">1380</a>]</span>.
+altering the biochemical conditions required for viral fusion <span class="citation" data-cites="IhdcvbzC BIlqPh6M">[<a href="#ref-IhdcvbzC" role="doc-biblioref">446</a>,<a href="#ref-BIlqPh6M" role="doc-biblioref">1382</a>]</span>.
 However, chloroquine also has immuno-modulatory effects that I think may
 play a role. Chloroquine has been shown to increase CTLA-4 expression at
 the cell surface by decreasing its degradation in the endo-lysosome
 pathway; AP-1 traffics the cytoplasmic tail of CTLA-4 to lysosomes, but
 in conditions of increased pH, the protein machinery required for
-degradation is less functional <span class="citation" data-cites="Q9tXjG1R">[<a href="#ref-Q9tXjG1R" role="doc-biblioref">1381</a>]</span>. As such, more CTLA-4 remains in
+degradation is less functional <span class="citation" data-cites="Q9tXjG1R">[<a href="#ref-Q9tXjG1R" role="doc-biblioref">1383</a>]</span>. As such, more CTLA-4 remains in
 endosomes and is trafficked back to the cell surface. It is possible
 that this may also contribute to patient recovery via reduction of
 cytokine storm, in addition to the direct anti-viral effects of HCQ.</p>
 <h3 data-number="14.63.5" id="credit-62"><span class="header-section-number">14.63.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.64" id="recapitulation-of-sars-cov-2-infection-and-cholangiocyte-damage-with-human-liver-organoids"><span class="header-section-number">14.64</span> Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids</h2>
-<p><span class="citation" data-cites="OuDMtCRl">[<a href="#ref-OuDMtCRl" role="doc-biblioref">1306</a>]</span></p>
-<h3 data-number="14.64.1" id="keywords-63"><span class="header-section-number">14.64.1</span> Keywords</h3>
+<p><span class="citation" data-cites="OuDMtCRl">[<a href="#ref-OuDMtCRl" role="doc-biblioref">1308</a>]</span></p>
+<h3 data-number="14.64.1" id="keywords-64"><span class="header-section-number">14.64.1</span> Keywords</h3>
 <ul>
 <li>CoVID-19</li>
 <li>2019-nCoV</li>
@@ -15982,8 +16015,8 @@ <h3 data-number="14.64.4" id="significance-58"><span class="header-section-numbe
 <h3 data-number="14.64.5" id="credit-63"><span class="header-section-number">14.64.5</span> Credit</h3>
 <p><em>Review by Samarth Hegde as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.65" id="the-sequence-of-human-ace2-is-suboptimal-for-binding-the-s-spike-protein-of-sars-coronavirus-2"><span class="header-section-number">14.65</span> The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2</h2>
-<p><span class="citation" data-cites="3VPi509z">[<a href="#ref-3VPi509z" role="doc-biblioref">1382</a>]</span></p>
-<h3 data-number="14.65.1" id="keywords-64"><span class="header-section-number">14.65.1</span> Keywords</h3>
+<p><span class="citation" data-cites="3VPi509z">[<a href="#ref-3VPi509z" role="doc-biblioref">1384</a>]</span></p>
+<h3 data-number="14.65.1" id="keywords-65"><span class="header-section-number">14.65.1</span> Keywords</h3>
 <ul>
 <li>Coronavirus Disease 2019 (COVID-19)</li>
 <li>SARS-CoV-2</li>
@@ -16072,8 +16105,8 @@ <h3 data-number="14.65.5" id="credit-64"><span class="header-section-number">14.
 in this study represent new tools that can be used for further
 applications, including vaccine development.</p>
 <h2 data-number="14.66" id="comparative-pathogenesis-of-covid-19-mers-and-sars-in-a-non-human-primate-model"><span class="header-section-number">14.66</span> COMPARATIVE PATHOGENESIS OF COVID-19, MERS AND SARS IN A NON-HUMAN PRIMATE MODEL</h2>
-<p><span class="citation" data-cites="1EcOLnVXk">[<a href="#ref-1EcOLnVXk" role="doc-biblioref">1383</a>]</span></p>
-<h3 data-number="14.66.1" id="keywords-65"><span class="header-section-number">14.66.1</span> Keywords</h3>
+<p><span class="citation" data-cites="1EcOLnVXk">[<a href="#ref-1EcOLnVXk" role="doc-biblioref">1385</a>]</span></p>
+<h3 data-number="14.66.1" id="keywords-66"><span class="header-section-number">14.66.1</span> Keywords</h3>
 <ul>
 <li>SARS-CoV2</li>
 <li>cynomolgus macaque</li>
@@ -16110,15 +16143,15 @@ <h3 data-number="14.66.4" id="significance-60"><span class="header-section-numbe
 Cynomolgus macaques offer an environment in which viral replication can
 happen, albeit in a limited way and without translating into clinically
 relevant symptoms. Other groups are contributing to SARS-CoV2 literature
-using this animal model <span class="citation" data-cites="3XqFhi8l">[<a href="#ref-3XqFhi8l" role="doc-biblioref">1369</a>]</span>, potentially showing protection against
+using this animal model <span class="citation" data-cites="3XqFhi8l">[<a href="#ref-3XqFhi8l" role="doc-biblioref">1371</a>]</span>, potentially showing protection against
 reinfection in cured macaques. Therefore, this platform could be used to
 examine SARS-CoV2 pathophysiology while studies in other animal models
-are also underway <span class="citation" data-cites="NzFgXYvQ MgLBA5m">[<a href="#ref-MgLBA5m" role="doc-biblioref">1308</a>,<a href="#ref-NzFgXYvQ" role="doc-biblioref">1384</a>]</span>.</p>
+are also underway <span class="citation" data-cites="NzFgXYvQ MgLBA5m">[<a href="#ref-MgLBA5m" role="doc-biblioref">1310</a>,<a href="#ref-NzFgXYvQ" role="doc-biblioref">1386</a>]</span>.</p>
 <h3 data-number="14.66.5" id="credit-65"><span class="header-section-number">14.66.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.67" id="investigating-the-impact-of-asymptomatic-carriers-on-covid-19-transmission"><span class="header-section-number">14.67</span> Investigating the Impact of Asymptomatic Carriers on COVID-19 Transmission</h2>
-<p><span class="citation" data-cites="OvFueDLZ">[<a href="#ref-OvFueDLZ" role="doc-biblioref">1385</a>]</span></p>
-<h3 data-number="14.67.1" id="keywords-66"><span class="header-section-number">14.67.1</span> Keywords</h3>
+<p><span class="citation" data-cites="OvFueDLZ">[<a href="#ref-OvFueDLZ" role="doc-biblioref">1387</a>]</span></p>
+<h3 data-number="14.67.1" id="keywords-67"><span class="header-section-number">14.67.1</span> Keywords</h3>
 <ul>
 <li>Coronavirus Disease 2019 (COVID-19)</li>
 <li>SARS-CoV-2</li>
@@ -16155,8 +16188,8 @@ <h3 data-number="14.67.4" id="significance-61"><span class="header-section-numbe
 <h3 data-number="14.67.5" id="credit-66"><span class="header-section-number">14.67.5</span> Credit</h3>
 <p><em>This review was undertaken by Tamar Plitt and Katherine Lindblad as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.68" id="antibody-responses-to-sars-cov-2-in-covid-19-patients-the-perspective-application-of-serological-tests-in-clinical-practice"><span class="header-section-number">14.68</span> Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice</h2>
-<p>Long et al. <em>medRxiv</em> <span class="citation" data-cites="Y9g1sQ1Y">[<a href="#ref-Y9g1sQ1Y" role="doc-biblioref">1386</a>]</span></p>
-<h3 data-number="14.68.1" id="keywords-67"><span class="header-section-number">14.68.1</span> Keywords</h3>
+<p>Long et al. <em>medRxiv</em> <span class="citation" data-cites="Y9g1sQ1Y">[<a href="#ref-Y9g1sQ1Y" role="doc-biblioref">1388</a>]</span></p>
+<h3 data-number="14.68.1" id="keywords-68"><span class="header-section-number">14.68.1</span> Keywords</h3>
 <ul>
 <li>Serum antibodies</li>
 <li>IgM</li>
@@ -16204,7 +16237,7 @@ <h3 data-number="14.68.3" id="limitations-65"><span class="header-section-number
 was tested as well as the heat inactivation of serum samples prior to
 testing. It has previously been reported that heat inactivation
 interferes with the level of antibodies to SARS-Cov-2 and their protocol
-may have resulted in diminished quantification of IgM, specifically <span class="citation" data-cites="p1c9Nilh">[<a href="#ref-p1c9Nilh" role="doc-biblioref">1387</a>]</span>.</p>
+may have resulted in diminished quantification of IgM, specifically <span class="citation" data-cites="p1c9Nilh">[<a href="#ref-p1c9Nilh" role="doc-biblioref">1389</a>]</span>.</p>
 <h3 data-number="14.68.4" id="significance-62"><span class="header-section-number">14.68.4</span> Significance</h3>
 <p>Understanding the features of the antibody responses against SARS-CoV is
 useful in the development of a serological test for the diagnosis of
@@ -16219,8 +16252,8 @@ <h3 data-number="14.68.4" id="significance-62"><span class="header-section-numbe
 <h3 data-number="14.68.5" id="credit-67"><span class="header-section-number">14.68.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.69" id="sars-cov-2-specific-antibody-responses-in-covid-19-patients"><span class="header-section-number">14.69</span> SARS-CoV-2 specific antibody responses in COVID-19 patients</h2>
-<p><span class="citation" data-cites="1BLNvgEao">[<a href="#ref-1BLNvgEao" role="doc-biblioref">1388</a>]</span></p>
-<h3 data-number="14.69.1" id="keywords-68"><span class="header-section-number">14.69.1</span> Keywords</h3>
+<p><span class="citation" data-cites="1BLNvgEao">[<a href="#ref-1BLNvgEao" role="doc-biblioref">1390</a>]</span></p>
+<h3 data-number="14.69.1" id="keywords-69"><span class="header-section-number">14.69.1</span> Keywords</h3>
 <ul>
 <li>immunoassay</li>
 <li>antibody specificity</li>
@@ -16234,8 +16267,8 @@ <h3 data-number="14.69.3" id="limitations-66"><span class="header-section-number
 <h3 data-number="14.69.4" id="significance-63"><span class="header-section-number">14.69.4</span> Significance</h3>
 <p>Validated serological tests are urgently needed to map the full spread of SARS-CoV-2 in the population and to determine the kinetics of the antibody response to SARS-CoV-2. Furthermore, clinical trials are ongoing using plasma from patients who have recovered from SARS-CoV-2 as a therapeutic option. An assay such as the one described in this study could be used to screen for strong antibody responses in recovered patients. Furthermore, the assay could be used to screen health care workers for antibody responses to SARS-CoV-2 as personal protective equipment continues to dwindle. The challenge going forward will be to standardize and scale-up the various in-house ELISA’s being developed in independent laboratories across the world.</p>
 <h2 data-number="14.70" id="a-brief-review-of-antiviral-drugs-evaluated-in-registered-clinical-trials-for-covid-19"><span class="header-section-number">14.70</span> A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19</h2>
-<p>Belhadi et al. <span class="citation" data-cites="K41YFM2N">[<a href="#ref-K41YFM2N" role="doc-biblioref">1389</a>]</span></p>
-<h3 data-number="14.70.1" id="keywords-69"><span class="header-section-number">14.70.1</span> Keywords</h3>
+<p>Belhadi et al. <span class="citation" data-cites="K41YFM2N">[<a href="#ref-K41YFM2N" role="doc-biblioref">1391</a>]</span></p>
+<h3 data-number="14.70.1" id="keywords-70"><span class="header-section-number">14.70.1</span> Keywords</h3>
 <ul>
 <li>Clinical trials</li>
 <li>COVID-19</li>
@@ -16287,8 +16320,8 @@ <h3 data-number="14.70.4" id="significance-64"><span class="header-section-numbe
 <h3 data-number="14.70.5" id="credit-68"><span class="header-section-number">14.70.5</span> Credit</h3>
 <p><em>This review was undertaken by K Alexandropoulos as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.71" id="ace-2-expression-in-the-small-airway-epithelia-of-smokers-and-copd-patients-implications-for-covid-19"><span class="header-section-number">14.71</span> ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19</h2>
-<p>Leung et al. <em>medRxiv</em>. <span class="citation" data-cites="eTsOvBVf">[<a href="#ref-eTsOvBVf" role="doc-biblioref">1390</a>]</span></p>
-<h3 data-number="14.71.1" id="keywords-70"><span class="header-section-number">14.71.1</span> Keywords</h3>
+<p>Leung et al. <em>medRxiv</em>. <span class="citation" data-cites="eTsOvBVf">[<a href="#ref-eTsOvBVf" role="doc-biblioref">1392</a>]</span></p>
+<h3 data-number="14.71.1" id="keywords-71"><span class="header-section-number">14.71.1</span> Keywords</h3>
 <ul>
 <li>chronic obstructive pulmonary disease</li>
 <li>COPD</li>
@@ -16331,8 +16364,8 @@ <h3 data-number="14.71.4" id="significance-65"><span class="header-section-numbe
 <h3 data-number="14.71.5" id="credit-69"><span class="header-section-number">14.71.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.72" id="dynamic-profile-of-severe-or-critical-covid-19-cases"><span class="header-section-number">14.72</span> Dynamic profile of severe or critical COVID-19 cases</h2>
-<p><span class="citation" data-cites="18KZGwJ0J">[<a href="#ref-18KZGwJ0J" role="doc-biblioref">1391</a>]</span></p>
-<h3 data-number="14.72.1" id="keywords-71"><span class="header-section-number">14.72.1</span> Keywords</h3>
+<p><span class="citation" data-cites="18KZGwJ0J">[<a href="#ref-18KZGwJ0J" role="doc-biblioref">1393</a>]</span></p>
+<h3 data-number="14.72.1" id="keywords-72"><span class="header-section-number">14.72.1</span> Keywords</h3>
 <ul>
 <li>Coronavirus Disease 2019 (COVID-19)</li>
 <li>SARS-CoV-2</li>
@@ -16367,8 +16400,8 @@ <h3 data-number="14.72.4" id="significance-66"><span class="header-section-numbe
 <h3 data-number="14.72.5" id="credit-70"><span class="header-section-number">14.72.5</span> Credit</h3>
 <p><em>This review was undertaken by Katherine Lindblad and Tamar Plitt as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.73" id="association-between-clinical-laboratory-and-ct-characteristics-and-rt-pcr-results-in-the-follow-up-of-covid-19-patients"><span class="header-section-number">14.73</span> Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients</h2>
-<p>Fu et al. <em>medRxiv</em>. <span class="citation" data-cites="1BJXDZ04c">[<a href="#ref-1BJXDZ04c" role="doc-biblioref">1392</a>]</span></p>
-<h3 data-number="14.73.1" id="keywords-72"><span class="header-section-number">14.73.1</span> Keywords</h3>
+<p>Fu et al. <em>medRxiv</em>. <span class="citation" data-cites="1BJXDZ04c">[<a href="#ref-1BJXDZ04c" role="doc-biblioref">1394</a>]</span></p>
+<h3 data-number="14.73.1" id="keywords-73"><span class="header-section-number">14.73.1</span> Keywords</h3>
 <ul>
 <li>COVID-19</li>
 <li>clinical</li>
@@ -16490,8 +16523,8 @@ <h3 data-number="14.73.6" id="significance-67"><span class="header-section-numbe
 <h3 data-number="14.73.7" id="credit-71"><span class="header-section-number">14.73.7</span> Credit</h3>
 <p><em>This review was undertaken by Natalie Vaninov as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.74" id="an-orally-bioavailable-broad-spectrum-antiviral-inhibits-sars-cov-2-and-multiple-2-endemic-epidemic-and-bat-coronavirus"><span class="header-section-number">14.74</span> An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple 2 endemic, epidemic and bat coronavirus</h2>
-<p>Sheahan et al. <em>bioRxiv</em>. <span class="citation" data-cites="iMCz5Twj">[<a href="#ref-iMCz5Twj" role="doc-biblioref">1393</a>]</span></p>
-<h3 data-number="14.74.1" id="keywords-73"><span class="header-section-number">14.74.1</span> Keywords</h3>
+<p>Sheahan et al. <em>bioRxiv</em>. <span class="citation" data-cites="iMCz5Twj">[<a href="#ref-iMCz5Twj" role="doc-biblioref">1395</a>]</span></p>
+<h3 data-number="14.74.1" id="keywords-74"><span class="header-section-number">14.74.1</span> Keywords</h3>
 <ul>
 <li>Treatment</li>
 <li>Antiviral</li>
@@ -16542,8 +16575,8 @@ <h3 data-number="14.74.4" id="significance-68"><span class="header-section-numbe
 #### Credit</p>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.75" id="identification-of-antiviral-drug-candidates-against-sars-cov-2-from-fda-approved-drugs"><span class="header-section-number">14.75</span> Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs</h2>
-<p>Sangeun Jeon et al. <span class="citation" data-cites="ZDP9vSpg">[<a href="#ref-ZDP9vSpg" role="doc-biblioref">1394</a>]</span></p>
-<h3 data-number="14.75.1" id="keywords-74"><span class="header-section-number">14.75.1</span> Keywords</h3>
+<p>Sangeun Jeon et al. <span class="citation" data-cites="ZDP9vSpg">[<a href="#ref-ZDP9vSpg" role="doc-biblioref">1396</a>]</span></p>
+<h3 data-number="14.75.1" id="keywords-75"><span class="header-section-number">14.75.1</span> Keywords</h3>
 <ul>
 <li>COVID-19</li>
 <li>SARS CoV-2</li>
@@ -16588,8 +16621,8 @@ <h3 data-number="14.75.3" id="limitations-72"><span class="header-section-number
 <h3 data-number="14.75.4" id="credit-72"><span class="header-section-number">14.75.4</span> Credit</h3>
 <p><em>This review was undertaken by K Alexandropoulos as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.76" id="respiratory-disease-and-virus-shedding-in-rhesus-macaques-inoculated-with-sars-cov-2"><span class="header-section-number">14.76</span> Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2</h2>
-<p>Munster et al. <em>bioRxiv</em>. <span class="citation" data-cites="LYFzvlzE">[<a href="#ref-LYFzvlzE" role="doc-biblioref">1395</a>]</span></p>
-<h3 data-number="14.76.1" id="keywords-75"><span class="header-section-number">14.76.1</span> Keywords</h3>
+<p>Munster et al. <em>bioRxiv</em>. <span class="citation" data-cites="LYFzvlzE">[<a href="#ref-LYFzvlzE" role="doc-biblioref">1397</a>]</span></p>
+<h3 data-number="14.76.1" id="keywords-76"><span class="header-section-number">14.76.1</span> Keywords</h3>
 <p>animal model, pulmonary infiltrates, dynamic
 of antibody response, cytokine</p>
 <h3 data-number="14.76.2" id="main-findings-72"><span class="header-section-number">14.76.2</span> Main Findings</h3>
@@ -16630,7 +16663,7 @@ <h3 data-number="14.76.3" id="limitations-73"><span class="header-section-number
 <h3 data-number="14.76.4" id="significance-69"><span class="header-section-number">14.76.4</span> Significance</h3>
 <p>This work confirms that rhesus
 macaques can be a good model to study Covid-19, as it has been shown by
-other groups <span class="citation" data-cites="3XqFhi8l unVgVIfU 1EcOLnVXk">[<a href="#ref-3XqFhi8l" role="doc-biblioref">1369</a>,<a href="#ref-1EcOLnVXk" role="doc-biblioref">1383</a>,<a href="#ref-unVgVIfU" role="doc-biblioref">1396</a>]</span>. While these experiments recapitulate
+other groups <span class="citation" data-cites="3XqFhi8l unVgVIfU 1EcOLnVXk">[<a href="#ref-3XqFhi8l" role="doc-biblioref">1371</a>,<a href="#ref-1EcOLnVXk" role="doc-biblioref">1385</a>,<a href="#ref-unVgVIfU" role="doc-biblioref">1398</a>]</span>. While these experiments recapitulate
 moderate COVID-19 in humans, the mode of inoculation via a combination
 of intratracheal, intranasal, ocular and oral routes, might not
 reproduce how humans get infected and may lead to different dynamics in
@@ -16645,8 +16678,8 @@ <h3 data-number="14.76.4" id="significance-69"><span class="header-section-numbe
 <h3 data-number="14.76.5" id="credit-73"><span class="header-section-number">14.76.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.77" id="ace2-expression-is-increased-in-the-lungs-of-patients-with-comorbidities-associated-with-severe-covid-19"><span class="header-section-number">14.77</span> ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19</h2>
-<p><span class="citation" data-cites="wjtVy2v0">[<a href="#ref-wjtVy2v0" role="doc-biblioref">1397</a>]</span></p>
-<h3 data-number="14.77.1" id="keywords-76"><span class="header-section-number">14.77.1</span> Keywords</h3>
+<p><span class="citation" data-cites="wjtVy2v0">[<a href="#ref-wjtVy2v0" role="doc-biblioref">1399</a>]</span></p>
+<h3 data-number="14.77.1" id="keywords-77"><span class="header-section-number">14.77.1</span> Keywords</h3>
 <ul>
 <li>CoVID-19</li>
 <li>2019-nCoV</li>
@@ -16705,8 +16738,8 @@ <h3 data-number="14.77.4" id="significance-70"><span class="header-section-numbe
 <h3 data-number="14.77.5" id="credit-74"><span class="header-section-number">14.77.5</span> Credit</h3>
 <p><em>Review by Samarth Hegde as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.78" id="meplazumab-treats-covid-19-pneumonia-an-open-labelled-concurrent-controlled-add-on-clinical-trial"><span class="header-section-number">14.78</span> Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial</h2>
-<p>Bian et al. <em>medRxiv</em>. <span class="citation" data-cites="DFhY5nfb">[<a href="#ref-DFhY5nfb" role="doc-biblioref">1398</a>]</span></p>
-<h3 data-number="14.78.1" id="keywords-77"><span class="header-section-number">14.78.1</span> Keywords</h3>
+<p>Bian et al. <em>medRxiv</em>. <span class="citation" data-cites="DFhY5nfb">[<a href="#ref-DFhY5nfb" role="doc-biblioref">1400</a>]</span></p>
+<h3 data-number="14.78.1" id="keywords-78"><span class="header-section-number">14.78.1</span> Keywords</h3>
 <ul>
 <li>Meplazumab</li>
 <li>CD147</li>
@@ -16739,23 +16772,23 @@ <h3 data-number="14.78.3" id="limitations-75"><span class="header-section-number
 <h3 data-number="14.78.4" id="significance-71"><span class="header-section-number">14.78.4</span> Significance</h3>
 <p>These results seem promising as for now there are
 limited treatments for Covid-19 patients, but a larger cohort of patient
-is needed. CD147 has already been described to facilitate HIV <span class="citation" data-cites="yP8TXdq2">[<a href="#ref-yP8TXdq2" role="doc-biblioref">1399</a>]</span>,
-measles virus <span class="citation" data-cites="X8l1n4zY">[<a href="#ref-X8l1n4zY" role="doc-biblioref">1400</a>]</span>, and malaria <span class="citation" data-cites="YcyNaIVC">[<a href="#ref-YcyNaIVC" role="doc-biblioref">1401</a>]</span> entry into host cells. This group was
+is needed. CD147 has already been described to facilitate HIV <span class="citation" data-cites="yP8TXdq2">[<a href="#ref-yP8TXdq2" role="doc-biblioref">1401</a>]</span>,
+measles virus <span class="citation" data-cites="X8l1n4zY">[<a href="#ref-X8l1n4zY" role="doc-biblioref">1402</a>]</span>, and malaria <span class="citation" data-cites="YcyNaIVC">[<a href="#ref-YcyNaIVC" role="doc-biblioref">1403</a>]</span> entry into host cells. This group was
 the first to describe the CD147-spike route of SARS-Cov-2 entry in host
-cells <span class="citation" data-cites="14y8UvAbH">[<a href="#ref-14y8UvAbH" role="doc-biblioref">1372</a>]</span> p147. Indeed, they had previously shown in 2005 that SARS-Cov
-could enter host cells via this transmembrane protein <span class="citation" data-cites="m9yLJ5Da">[<a href="#ref-m9yLJ5Da" role="doc-biblioref">1402</a>]</span>. Further
+cells <span class="citation" data-cites="14y8UvAbH">[<a href="#ref-14y8UvAbH" role="doc-biblioref">1374</a>]</span> p147. Indeed, they had previously shown in 2005 that SARS-Cov
+could enter host cells via this transmembrane protein <span class="citation" data-cites="m9yLJ5Da">[<a href="#ref-m9yLJ5Da" role="doc-biblioref">1404</a>]</span>. Further
 biological understanding of how SARS-CoV-2 can enter host cells and how
 this integrates with ACE2R route of entry is needed. Also, the specific
 cellular targets of the anti-CD147 antibody need to be assessed, as this
 protein can be expressed by many cell types and has been shown to
-involved in leukocytes aggregation <span class="citation" data-cites="J0ibHE3l">[<a href="#ref-J0ibHE3l" role="doc-biblioref">1403</a>]</span>. Lastly, Meplazumab is not a
+involved in leukocytes aggregation <span class="citation" data-cites="J0ibHE3l">[<a href="#ref-J0ibHE3l" role="doc-biblioref">1405</a>]</span>. Lastly, Meplazumab is not a
 commercially-available drug and requires significant health resources to
 generate and administer which might prevent rapid development and use.</p>
 <h3 data-number="14.78.5" id="credit-75"><span class="header-section-number">14.78.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.79" id="potent-human-neutralizing-antibodies-elicited-1-by-sars-cov-2-infection"><span class="header-section-number">14.79</span> Potent human neutralizing antibodies elicited 1 by SARS-CoV-2 infection</h2>
 <p>Ju et al. <em>bioRxiv</em>. <span class="citation" data-cites="GhJYjnft">[<a href="#ref-GhJYjnft" role="doc-biblioref">172</a>]</span></p>
-<h3 data-number="14.79.1" id="keywords-78"><span class="header-section-number">14.79.1</span> Keywords</h3>
+<h3 data-number="14.79.1" id="keywords-79"><span class="header-section-number">14.79.1</span> Keywords</h3>
 <ul>
 <li>monoclonal antibodies</li>
 <li>neutralization</li>
@@ -16831,8 +16864,8 @@ <h3 data-number="14.79.4" id="significance-72"><span class="header-section-numbe
 <h3 data-number="14.79.5" id="credit-76"><span class="header-section-number">14.79.5</span> Credit</h3>
 <p><em>Review by Jovani Catalan-Dibene as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.80" id="characterisation-of-the-transcriptome-and-proteome-of-sars-cov-2-using-direct-rna-sequencing-and-tandem-mass-spectrometry-reveals-evidence-for-a-cell-passage-induced-in-frame-deletion-in-the-spike-glycoprotein-that-removes-the-furin-like-cleavage-site."><span class="header-section-number">14.80</span> Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site.</h2>
-<p>Davidson et al. <span class="citation" data-cites="bCYYaFKM">[<a href="#ref-bCYYaFKM" role="doc-biblioref">1404</a>]</span></p>
-<h3 data-number="14.80.1" id="keywords-79"><span class="header-section-number">14.80.1</span> Keywords</h3>
+<p>Davidson et al. <span class="citation" data-cites="bCYYaFKM">[<a href="#ref-bCYYaFKM" role="doc-biblioref">1406</a>]</span></p>
+<h3 data-number="14.80.1" id="keywords-80"><span class="header-section-number">14.80.1</span> Keywords</h3>
 <ul>
 <li>Transcription</li>
 <li>RNA-seq</li>
@@ -16854,7 +16887,7 @@ <h3 data-number="14.80.2" id="main-findings-76"><span class="header-section-numb
 not SARS-CoV or the closely related bat coronavirus RaTG13, which are
 cleaved at S1 / S2 by other proteases <span class="citation" data-cites="CqQVkaqj">[<a href="#ref-CqQVkaqj" role="doc-biblioref">54</a>]</span>. Furin cleavage sites at
 similar positions in other viruses have been linked to increased
-pathogenicity and greater cell tropism <span class="citation" data-cites="16tHVjVzu">[<a href="#ref-16tHVjVzu" role="doc-biblioref">1405</a>]</span>. Loss of this site in
+pathogenicity and greater cell tropism <span class="citation" data-cites="16tHVjVzu">[<a href="#ref-16tHVjVzu" role="doc-biblioref">1407</a>]</span>. Loss of this site in
 SARS-CoV-2 has also already been shown to increase viral entry into Vero
 but not BHK cells (which are also interferon deficient) <span class="citation" data-cites="qcVbT0w4">[<a href="#ref-qcVbT0w4" role="doc-biblioref">67</a>]</span>. The
 authors therefore make an important contribution in demonstrating that
@@ -16863,7 +16896,7 @@ <h3 data-number="14.80.2" id="main-findings-76"><span class="header-section-numb
 <h3 data-number="14.80.3" id="limitations-77"><span class="header-section-number">14.80.3</span> Limitations</h3>
 <p>As the authors note, a similar study posted earlier by Kim et al., which
 also passaged SARS-CoV-2 in Vero cells, did not identify any loss in the
-S protein furin cleavage site <span class="citation" data-cites="hRVfFbS">[<a href="#ref-hRVfFbS" role="doc-biblioref">1406</a>]</span>. It therefore remains to be
+S protein furin cleavage site <span class="citation" data-cites="hRVfFbS">[<a href="#ref-hRVfFbS" role="doc-biblioref">1408</a>]</span>. It therefore remains to be
 determined how likely it is that this mutation spontaneously arises. A
 quantitative investigation using multiple experimental replicas to
 understand the spontaneous viral mutation rate at this site and
@@ -16902,7 +16935,7 @@ <h3 data-number="14.80.5" id="credit-77"><span class="header-section-number">14.
 <p><em>This review was undertaken by Tim O’Donnell, Maria Kuksin as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.81" id="a-sars-cov-2-human-protein-protein-interaction-map-reveals-drug-targets-and-potential-drug--repurposing"><span class="header-section-number">14.81</span> A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug- Repurposing</h2>
 <p>Gordon et al. <em>bioRxiv</em> <span class="citation" data-cites="phJM8g2Y">[<a href="#ref-phJM8g2Y" role="doc-biblioref">179</a>]</span></p>
-<h3 data-number="14.81.1" id="keywords-80"><span class="header-section-number">14.81.1</span> Keywords</h3>
+<h3 data-number="14.81.1" id="keywords-81"><span class="header-section-number">14.81.1</span> Keywords</h3>
 <ul>
 <li>protein-protein interactions</li>
 <li>mass spectrometry</li>
@@ -16938,8 +16971,8 @@ <h3 data-number="14.81.5" id="credit-78"><span class="header-section-number">14.
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.82" id="first-clinical-study-using-hcv-protease-inhibitor-danoprevir-to-treat-naïve-and-experienced-covid-19-patients"><span class="header-section-number">14.82</span> First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naïve and Experienced COVID-19 Patients</h2>
 <p>Chen et al. <em>medRxiv</em>.
-<span class="citation" data-cites="RTIk8DTo">[<a href="#ref-RTIk8DTo" role="doc-biblioref">1407</a>]</span></p>
-<h3 data-number="14.82.1" id="keywords-81"><span class="header-section-number">14.82.1</span> Keywords</h3>
+<span class="citation" data-cites="RTIk8DTo">[<a href="#ref-RTIk8DTo" role="doc-biblioref">1409</a>]</span></p>
+<h3 data-number="14.82.1" id="keywords-82"><span class="header-section-number">14.82.1</span> Keywords</h3>
 <ul>
 <li>Clinical study</li>
 <li>HCV protease inhibitor</li>
@@ -16949,7 +16982,7 @@ <h3 data-number="14.82.1" id="keywords-81"><span class="header-section-number">1
 </ul>
 <h3 data-number="14.82.2" id="main-findings-78"><span class="header-section-number">14.82.2</span> Main Findings</h3>
 <p>The authors treated 11 Covid-19 patients with Danoprevir, a
-commercialized HCV protease inhibitor <span class="citation" data-cites="YoCPtq6P">[<a href="#ref-YoCPtq6P" role="doc-biblioref">1408</a>]</span><sup>(p4)</sup>, boosted by ritonavir <span class="citation" data-cites="10GnhBctk">[<a href="#ref-10GnhBctk" role="doc-biblioref">1409</a>]</span>, a
+commercialized HCV protease inhibitor <span class="citation" data-cites="YoCPtq6P">[<a href="#ref-YoCPtq6P" role="doc-biblioref">1410</a>]</span><sup>(p4)</sup>, boosted by ritonavir <span class="citation" data-cites="10GnhBctk">[<a href="#ref-10GnhBctk" role="doc-biblioref">1411</a>]</span>, a
 CYP3A4 inhibitor (which enhances the plasma concentration and
 bioavailabilty of Danoprevir). Two patients had never received
 anti-viral therapy before (=naïve), whereas nine patients were on
@@ -16971,10 +17004,10 @@ <h3 data-number="14.82.3" id="limitations-79"><span class="header-section-number
 <h3 data-number="14.82.4" id="significance-75"><span class="header-section-number">14.82.4</span> Significance</h3>
 <p>The authors of the study treated patients with Danoprevir, with the
 rational to that this is an approved and well tolerated drug for HCV
-patients <span class="citation" data-cites="10GnhBctk">[<a href="#ref-10GnhBctk" role="doc-biblioref">1409</a>]</span>, and that it could also target the protease from SARS-CoV-2
+patients <span class="citation" data-cites="10GnhBctk">[<a href="#ref-10GnhBctk" role="doc-biblioref">1411</a>]</span>, and that it could also target the protease from SARS-CoV-2
 (essential for viral replication and transcription). Indeed, homology
 modelling data indicated that HCV protease inhibitors have the highest
-binding affinity to Sars-Cov2 protease among other approved drugs <span class="citation" data-cites="7zBwK1wn">[<a href="#ref-7zBwK1wn" role="doc-biblioref">1410</a>]</span>.</p>
+binding affinity to Sars-Cov2 protease among other approved drugs <span class="citation" data-cites="7zBwK1wn">[<a href="#ref-7zBwK1wn" role="doc-biblioref">1412</a>]</span>.</p>
 <p>While this study shows that the combination of Danoprevir and Ritonavir
 might be beneficial for Covid-19 patients, additional clinical trials
 with more patients and with better methodology (randomization and
@@ -16982,8 +17015,8 @@ <h3 data-number="14.82.4" id="significance-75"><span class="header-section-numbe
 <h3 data-number="14.82.5" id="credit-79"><span class="header-section-number">14.82.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.83" id="efficacy-of-hydroxychloroquine-in-patients-with-covid-19-results-of-a-randomized-clinical-trial"><span class="header-section-number">14.83</span> Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial</h2>
-<p><span class="citation" data-cites="wzHb7Mj5">[<a href="#ref-wzHb7Mj5" role="doc-biblioref">516</a>]</span></p>
-<h3 data-number="14.83.1" id="keywords-82"><span class="header-section-number">14.83.1</span> Keywords</h3>
+<p><span class="citation" data-cites="wzHb7Mj5">[<a href="#ref-wzHb7Mj5" role="doc-biblioref">515</a>]</span></p>
+<h3 data-number="14.83.1" id="keywords-83"><span class="header-section-number">14.83.1</span> Keywords</h3>
 <ul>
 <li>hydroxychloroquine</li>
 </ul>
@@ -17133,8 +17166,8 @@ <h3 data-number="14.83.6" id="credit-80"><span class="header-section-number">14.
 faculty at the Immunology Institute of the Icahn school of medicine,
 Mount Sinai.</em></p>
 <h2 data-number="14.84" id="serology-characteristics-of-sars-cov-2-infection-since-the-exposure-and-post-symptoms-onset"><span class="header-section-number">14.84</span> Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset</h2>
-<p>Lou et al. <em>medRxiv</em>. <span class="citation" data-cites="lnuNSHEW">[<a href="#ref-lnuNSHEW" role="doc-biblioref">1411</a>]</span></p>
-<h3 data-number="14.84.1" id="keywords-83"><span class="header-section-number">14.84.1</span> Keywords</h3>
+<p>Lou et al. <em>medRxiv</em>. <span class="citation" data-cites="lnuNSHEW">[<a href="#ref-lnuNSHEW" role="doc-biblioref">1413</a>]</span></p>
+<h3 data-number="14.84.1" id="keywords-84"><span class="header-section-number">14.84.1</span> Keywords</h3>
 <ul>
 <li>Seroconversion rate</li>
 <li>Total Antibody</li>
@@ -17157,7 +17190,7 @@ <h3 data-number="14.84.2" id="main-findings-80"><span class="header-section-numb
 (d.p.e) or 9, 10- and 12-days post-onset (d.p.o). Seroconversion was
 first detected at day 7d.p.e in 98.9% of the patients. Interestingly
 they found that viral load declined as antibody levels increased. This
-was in contrast to a previous study <span class="citation" data-cites="5HXuCa5t">[<a href="#ref-5HXuCa5t" role="doc-biblioref">1351</a>]</span>, showing that increased antibody
+was in contrast to a previous study <span class="citation" data-cites="5HXuCa5t">[<a href="#ref-5HXuCa5t" role="doc-biblioref">1353</a>]</span>, showing that increased antibody
 titers did not always correlate with RNA clearance (low number of
 patient sample).</p>
 <h3 data-number="14.84.3" id="limitations-82"><span class="header-section-number">14.84.3</span> Limitations</h3>
@@ -17179,8 +17212,8 @@ <h3 data-number="14.84.4" id="significance-76"><span class="header-section-numbe
 <h3 data-number="14.84.5" id="credit-81"><span class="header-section-number">14.84.5</span> Credit</h3>
 <p><em>This review was undertaken and edited by Konstantina A as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.85" id="sars-cov-2-launches-a-unique-transcriptional-signature-from-in-vitro-ex-vivo-and-in-vivo-systems"><span class="header-section-number">14.85</span> SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems</h2>
-<p>Blanco-Melo et al. <em>bioRxiv</em>. <span class="citation" data-cites="aNSdARwe">[<a href="#ref-aNSdARwe" role="doc-biblioref">1412</a>]</span></p>
-<h3 data-number="14.85.1" id="keywords-84"><span class="header-section-number">14.85.1</span> Keywords</h3>
+<p>Blanco-Melo et al. <em>bioRxiv</em>. <span class="citation" data-cites="aNSdARwe">[<a href="#ref-aNSdARwe" role="doc-biblioref">1414</a>]</span></p>
+<h3 data-number="14.85.1" id="keywords-85"><span class="header-section-number">14.85.1</span> Keywords</h3>
 <ul>
 <li>host cellular response</li>
 <li>host-pathogen interaction</li>
@@ -17234,8 +17267,8 @@ <h3 data-number="14.85.5" id="potential-conflicts-of-interest-disclosure"><span
 <h3 data-number="14.85.6" id="credit-82"><span class="header-section-number">14.85.6</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.86" id="a-new-predictor-of-disease-severity-in-patients-with-covid-19-in-wuhan-china"><span class="header-section-number">14.86</span> A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China</h2>
-<p>Zhou et al. <em>bioRxiv</em>. <span class="citation" data-cites="EWZmuLvu">[<a href="#ref-EWZmuLvu" role="doc-biblioref">1413</a>]</span></p>
-<h3 data-number="14.86.1" id="keywords-85"><span class="header-section-number">14.86.1</span> Keywords</h3>
+<p>Zhou et al. <em>bioRxiv</em>. <span class="citation" data-cites="EWZmuLvu">[<a href="#ref-EWZmuLvu" role="doc-biblioref">1415</a>]</span></p>
+<h3 data-number="14.86.1" id="keywords-86"><span class="header-section-number">14.86.1</span> Keywords</h3>
 <ul>
 <li>disease severity</li>
 <li>clinical data</li>
@@ -17270,20 +17303,20 @@ <h3 data-number="14.86.3" id="limitations-84"><span class="header-section-number
 into moderate and mild disease.</p>
 <p>Also, studying different subset of lymphocytes could lead to a more
 specific predictor. Another study showed that the neutrophils to CD8+ T
-cells ratio was a strong predictor of disease severity <span class="citation" data-cites="zTGzuiTI">[<a href="#ref-zTGzuiTI" role="doc-biblioref">1322</a>]</span>. Another more
+cells ratio was a strong predictor of disease severity <span class="citation" data-cites="zTGzuiTI">[<a href="#ref-zTGzuiTI" role="doc-biblioref">1324</a>]</span>. Another more
 precise study showed that the percentage of helper T cells and
 regulatory T cells decrease but the percentage of naïve helper T cells
-increases in severe cases <span class="citation" data-cites="6Y81C4P3">[<a href="#ref-6Y81C4P3" role="doc-biblioref">1315</a>]</span>. Taking these subpopulations into account
+increases in severe cases <span class="citation" data-cites="6Y81C4P3">[<a href="#ref-6Y81C4P3" role="doc-biblioref">1317</a>]</span>. Taking these subpopulations into account
 might make the predictor more powerful.</p>
 <p>Other studies also noted an inverse correlation between disease severity
-and LDH <span class="citation" data-cites="USOnp7c0">[<a href="#ref-USOnp7c0" role="doc-biblioref">1355</a>]</span> or IL6 <span class="citation" data-cites="1GEbBtBgh">[<a href="#ref-1GEbBtBgh" role="doc-biblioref">1364</a>]</span> levels, but the authors here do not discuss LDH nor
+and LDH <span class="citation" data-cites="USOnp7c0">[<a href="#ref-USOnp7c0" role="doc-biblioref">1357</a>]</span> or IL6 <span class="citation" data-cites="1GEbBtBgh">[<a href="#ref-1GEbBtBgh" role="doc-biblioref">1366</a>]</span> levels, but the authors here do not discuss LDH nor
 IL6 levels, although this could help to strengthen the predictor.</p>
 <p>The study is based on the results obtained on the first day of
 admission, studying the dynamic of the changes in patients might also be
 interesting to better predict disease severity.</p>
 <h3 data-number="14.86.4" id="significance-78"><span class="header-section-number">14.86.4</span> Significance</h3>
 <p>This study confirms that the neutrophil to lymphocyte ratio can be a
-predictor of disease severity as shown by many others <span class="citation" data-cites="6Y81C4P3 VRoblZFJ gK5e7Yhl">[<a href="#ref-gK5e7Yhl" role="doc-biblioref">1314</a>,<a href="#ref-6Y81C4P3" role="doc-biblioref">1315</a>,<a href="#ref-VRoblZFJ" role="doc-biblioref">1328</a>]</span>. The
+predictor of disease severity as shown by many others <span class="citation" data-cites="6Y81C4P3 VRoblZFJ gK5e7Yhl">[<a href="#ref-gK5e7Yhl" role="doc-biblioref">1316</a>,<a href="#ref-6Y81C4P3" role="doc-biblioref">1317</a>,<a href="#ref-VRoblZFJ" role="doc-biblioref">1330</a>]</span>. The
 novelty here is that they show that a combination with other markers can
 enhance the specificity and sensibility of the predictor, although the
 study could be improved by taking into account sub-populations of
@@ -17292,8 +17325,8 @@ <h3 data-number="14.86.4" id="significance-78"><span class="header-section-numbe
 <h3 data-number="14.86.5" id="credit-83"><span class="header-section-number">14.86.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.87" id="metabolic-disturbances-and-inflammatory-dysfunction-predict-severity-of-coronavirus-disease-2019-covid-19-a-retrospective-study"><span class="header-section-number">14.87</span> Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study</h2>
-<p>Shuke Nie et al. <em>medRxiv</em>. <span class="citation" data-cites="95sQSGzx">[<a href="#ref-95sQSGzx" role="doc-biblioref">1414</a>]</span></p>
-<h3 data-number="14.87.1" id="keywords-86"><span class="header-section-number">14.87.1</span> Keywords</h3>
+<p>Shuke Nie et al. <em>medRxiv</em>. <span class="citation" data-cites="95sQSGzx">[<a href="#ref-95sQSGzx" role="doc-biblioref">1416</a>]</span></p>
+<h3 data-number="14.87.1" id="keywords-87"><span class="header-section-number">14.87.1</span> Keywords</h3>
 <ul>
 <li>metabolism</li>
 <li>fasting blood glucose</li>
@@ -17346,8 +17379,8 @@ <h3 data-number="14.87.4" id="significance-79"><span class="header-section-numbe
 <h3 data-number="14.87.5" id="credit-84"><span class="header-section-number">14.87.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.88" id="viral-kinetics-and-antibody-responses-in-patients-with-covid-19"><span class="header-section-number">14.88</span> Viral Kinetics and Antibody Responses in Patients with COVID-19</h2>
-<p><span class="citation" data-cites="btVuoX6V">[<a href="#ref-btVuoX6V" role="doc-biblioref">1415</a>]</span></p>
-<h3 data-number="14.88.1" id="keywords-87"><span class="header-section-number">14.88.1</span> Keywords</h3>
+<p><span class="citation" data-cites="btVuoX6V">[<a href="#ref-btVuoX6V" role="doc-biblioref">1417</a>]</span></p>
+<h3 data-number="14.88.1" id="keywords-88"><span class="header-section-number">14.88.1</span> Keywords</h3>
 <ul>
 <li>CoVID-19</li>
 <li>2019-nCoV</li>
@@ -17390,16 +17423,16 @@ <h3 data-number="14.88.4" id="significance-80"><span class="header-section-numbe
 disease progression and kinetics is useful to stratify patients, and
 for future serological tests.</p></li>
 <li><p>Strong spike-IgG levels often correlate with lymphopenia and
-CoVID-19 disease severity <span class="citation" data-cites="LIf5SSUs">[<a href="#ref-LIf5SSUs" role="doc-biblioref">1416</a>]</span>, similar to macaque
-studies in SARS <span class="citation" data-cites="tC5vJmwj">[<a href="#ref-tC5vJmwj" role="doc-biblioref">1417</a>]</span>. It would be critical to see if anti-NP or
+CoVID-19 disease severity <span class="citation" data-cites="LIf5SSUs">[<a href="#ref-LIf5SSUs" role="doc-biblioref">1418</a>]</span>, similar to macaque
+studies in SARS <span class="citation" data-cites="tC5vJmwj">[<a href="#ref-tC5vJmwj" role="doc-biblioref">1419</a>]</span>. It would be critical to see if anti-NP or
 anti-Spike IgG antibodies for SARS-CoV-2 also elicit similar
 detrimental effects before clinical use.</p></li>
 </ul>
 <h3 data-number="14.88.5" id="credit-85"><span class="header-section-number">14.88.5</span> Credit</h3>
 <p><em>Review by Samarth Hegde as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.89" id="covid-19-infection-induces-readily-detectable-morphological-and-inflammation-related-phenotypic-changes-in-peripheral-blood-monocytes-the-severity-of-which-correlate-with-patient-outcome"><span class="header-section-number">14.89</span> COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome</h2>
-<p><span class="citation" data-cites="1FZgghazg">[<a href="#ref-1FZgghazg" role="doc-biblioref">1418</a>]</span></p>
-<h3 data-number="14.89.1" id="keywords-88"><span class="header-section-number">14.89.1</span> Keywords</h3>
+<p><span class="citation" data-cites="1FZgghazg">[<a href="#ref-1FZgghazg" role="doc-biblioref">1420</a>]</span></p>
+<h3 data-number="14.89.1" id="keywords-89"><span class="header-section-number">14.89.1</span> Keywords</h3>
 <ul>
 <li>Monocytes</li>
 <li>FSC-high</li>
@@ -17452,7 +17485,7 @@ <h3 data-number="14.89.3" id="limitations-87"><span class="header-section-number
 <h3 data-number="14.89.4" id="significance-81"><span class="header-section-number">14.89.4</span> Significance</h3>
 <p>Despite the limitations of this study, the discovery of
 a FSC-high monocyte population in COVID-19 patients is of great
-interest. With similar implication, a the recent study by Zhou et al. <span class="citation" data-cites="Bgo7Cmj3">[<a href="#ref-Bgo7Cmj3" role="doc-biblioref">1320</a>]</span>
+interest. With similar implication, a the recent study by Zhou et al. <span class="citation" data-cites="Bgo7Cmj3">[<a href="#ref-Bgo7Cmj3" role="doc-biblioref">1322</a>]</span>
 identified a connection between an inflammatory CD14+CD16+ monocyte
 population and pulmonary immunopathology leading to deleterious clinical
 manifestations and even acute mortality after SARS-CoV-2 infections.
@@ -17462,8 +17495,8 @@ <h3 data-number="14.89.4" id="significance-81"><span class="header-section-numbe
 <h3 data-number="14.89.5" id="credit-86"><span class="header-section-number">14.89.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.90" id="correlation-between-universal-bcg-vaccination-policy-and-reduced-morbidity-and-mortality-for-covid-19-an-epidemiological-study"><span class="header-section-number">14.90</span> Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study</h2>
-<p>Miller et al. <em>medRxiv</em>. <span class="citation" data-cites="15gdkEnfn">[<a href="#ref-15gdkEnfn" role="doc-biblioref">1419</a>]</span></p>
-<h3 data-number="14.90.1" id="keywords-89"><span class="header-section-number">14.90.1</span> Keywords</h3>
+<p>Miller et al. <em>medRxiv</em>. <span class="citation" data-cites="15gdkEnfn">[<a href="#ref-15gdkEnfn" role="doc-biblioref">1421</a>]</span></p>
+<h3 data-number="14.90.1" id="keywords-90"><span class="header-section-number">14.90.1</span> Keywords</h3>
 <ul>
 <li>BCG vaccine</li>
 <li>epidemiology</li>
@@ -17512,17 +17545,17 @@ <h3 data-number="14.90.4" id="significance-82"><span class="header-section-numbe
 <p><strong>This study shows that there is a correlation between BCG vaccination
 policy and reduced mortality for Covid-19</strong>. Indeed, BCG vaccine has
 been shown to protect against several viruses and enhance innate
-immunity <span class="citation" data-cites="16FOT89K5">[<a href="#ref-16FOT89K5" role="doc-biblioref">1420</a>]</span>, which could explain why it could protect against SARS-CoV-2
+immunity <span class="citation" data-cites="16FOT89K5">[<a href="#ref-16FOT89K5" role="doc-biblioref">1422</a>]</span>, which could explain why it could protect against SARS-CoV-2
 infection, but the exact mechanism is still unknown. <strong>Moreover, the
 efficiency of adult/older people vaccination and protection against
 Covid-19 still needs to be assessed.</strong> Regarding this, Australian
 researchers are starting a clinical trial of BCG vaccine for healthcare
-workers <span class="citation" data-cites="MCuIRGFE">[<a href="#ref-MCuIRGFE" role="doc-biblioref">1421</a>]</span>, to assess if it can protect them against Covid-19.</p>
+workers <span class="citation" data-cites="MCuIRGFE">[<a href="#ref-MCuIRGFE" role="doc-biblioref">1423</a>]</span>, to assess if it can protect them against Covid-19.</p>
 <h3 data-number="14.90.5" id="credit-87"><span class="header-section-number">14.90.5</span> Credit</h3>
 <p><em>This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.91" id="non-neural-expression-of-sars-cov-2-entry-genes-in-the-olfactory-epithelium"><span class="header-section-number">14.91</span> Non-neural expression of SARS-CoV-2 entry genes in the olfactory epithelium</h2>
-<p><span class="citation" data-cites="12oDb7aki">[<a href="#ref-12oDb7aki" role="doc-biblioref">1422</a>]</span></p>
-<h3 data-number="14.91.1" id="keywords-90"><span class="header-section-number">14.91.1</span> Keywords</h3>
+<p><span class="citation" data-cites="12oDb7aki">[<a href="#ref-12oDb7aki" role="doc-biblioref">1424</a>]</span></p>
+<h3 data-number="14.91.1" id="keywords-91"><span class="header-section-number">14.91.1</span> Keywords</h3>
 <ul>
 <li>CoVID-19</li>
 <li>2019-nCoV</li>
@@ -17704,8 +17737,8 @@ <h3 data-number="14.91.5" id="credit-88"><span class="header-section-number">14.
 patients infected with SARS-CoV-1 further support the potential
 importance and relevance of this study.</p>
 <h2 data-number="14.92" id="cigarette-smoke-triggers-the-expansion-of-a-subpopulation-of-respiratory-epithelial-cells-that-express-the-sars-cov-2-receptor-ace2"><span class="header-section-number">14.92</span> Cigarette smoke triggers the expansion of a subpopulation of respiratory epithelial cells that express the SARS-CoV-2 receptor ACE2</h2>
-<p><span class="citation" data-cites="t4vofknR">[<a href="#ref-t4vofknR" role="doc-biblioref">1423</a>]</span></p>
-<h3 data-number="14.92.1" id="keywords-91"><span class="header-section-number">14.92.1</span> Keywords</h3>
+<p><span class="citation" data-cites="t4vofknR">[<a href="#ref-t4vofknR" role="doc-biblioref">1425</a>]</span></p>
+<h3 data-number="14.92.1" id="keywords-92"><span class="header-section-number">14.92.1</span> Keywords</h3>
 <ul>
 <li>CoVID-19</li>
 <li>2019-nCoV</li>
@@ -17755,7 +17788,7 @@ <h3 data-number="14.92.4" id="significance-84"><span class="header-section-numbe
 implies CoV-2 susceptibility might be smoking-specific, and not
 fibrosis-specific.</p></li>
 <li><p>Another preprint showed ACE2 expression increases in lung of
-patients with CoV-2 co-morbidities such as hypertension <span class="citation" data-cites="wjtVy2v0">[<a href="#ref-wjtVy2v0" role="doc-biblioref">1397</a>]</span>; these studies
+patients with CoV-2 co-morbidities such as hypertension <span class="citation" data-cites="wjtVy2v0">[<a href="#ref-wjtVy2v0" role="doc-biblioref">1399</a>]</span>; these studies
 collectively paint a better picture of CoV-2 susceptibility before
 actual experiments can be carried out.</p></li>
 </ul>
@@ -17763,8 +17796,8 @@ <h3 data-number="14.92.5" id="credit-89"><span class="header-section-number">14.
 <p><em>Review by Samarth Hegde as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.</em></p>
 <h2 data-number="14.93" id="the-comparative-superiority-of-igm-igg-antibody-test-to-real-time-reverse-transcriptase-pcr-detection-for-sars-cov-2-infection-diagnosis"><span class="header-section-number">14.93</span> The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis</h2>
 <p>Liu et al. <em>medRxiv</em>.
-<span class="citation" data-cites="k1E3DuFN">[<a href="#ref-k1E3DuFN" role="doc-biblioref">1424</a>]</span></p>
-<h3 data-number="14.93.1" id="keywords-92"><span class="header-section-number">14.93.1</span> Keywords</h3>
+<span class="citation" data-cites="k1E3DuFN">[<a href="#ref-k1E3DuFN" role="doc-biblioref">1426</a>]</span></p>
+<h3 data-number="14.93.1" id="keywords-93"><span class="header-section-number">14.93.1</span> Keywords</h3>
 <ul>
 <li>IgM/IgG antibody test</li>
 <li>nucleic acid test</li>
@@ -17902,7 +17935,7 @@ <h3 data-number="14.93.5" id="credit-90"><span class="header-section-number">14.
 <h2 data-number="14.94" id="virus-host-interactome-and-proteomic-survey-of-pmbcs-from-covid-19-patients-reveal-potential-virulence-factors-influencing-sars-cov-2-pathogenesis"><span class="header-section-number">14.94</span> Virus-host interactome and proteomic survey of PMBCs from COVID-19 patients reveal potential virulence factors influencing SARS-CoV-2 pathogenesis</h2>
 <p>Li et al. <em>bioRxiv</em>.
 <span class="citation" data-cites="NLoN4aYj">[<a href="#ref-NLoN4aYj" role="doc-biblioref">181</a>]</span></p>
-<h3 data-number="14.94.1" id="keywords-93"><span class="header-section-number">14.94.1</span> Keywords</h3>
+<h3 data-number="14.94.1" id="keywords-94"><span class="header-section-number">14.94.1</span> Keywords</h3>
 <ul>
 <li>PBMC</li>
 <li>virulence factors
diff --git a/manuscript.md b/manuscript.md
index 4c7493d46..abe982f7c 100644
--- a/manuscript.md
+++ b/manuscript.md
@@ -6,7 +6,7 @@ keywords:
 - pandemic
 - viral infection
 lang: en-US
-date-meta: '2021-04-16'
+date-meta: '2021-04-27'
 author-meta:
 - Halie M. Rando
 - Casey S. Greene
@@ -67,8 +67,8 @@ header-includes: |-
   <meta name="citation_title" content="SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics" />
   <meta property="og:title" content="SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics" />
   <meta property="twitter:title" content="SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics" />
-  <meta name="dc.date" content="2021-04-16" />
-  <meta name="citation_publication_date" content="2021-04-16" />
+  <meta name="dc.date" content="2021-04-27" />
+  <meta name="citation_publication_date" content="2021-04-27" />
   <meta name="dc.language" content="en-US" />
   <meta name="citation_language" content="en-US" />
   <meta name="dc.relation.ispartof" content="Manubot" />
@@ -263,13 +263,13 @@ header-includes: |-
   <meta name="citation_fulltext_html_url" content="https://greenelab.github.io/covid19-review/" />
   <meta name="citation_pdf_url" content="https://greenelab.github.io/covid19-review/manuscript.pdf" />
   <link rel="alternate" type="application/pdf" href="https://greenelab.github.io/covid19-review/manuscript.pdf" />
-  <link rel="alternate" type="text/html" href="https://greenelab.github.io/covid19-review/v/89dff08a5bb813c1bbc224275a347891ac8a532d/" />
-  <meta name="manubot_html_url_versioned" content="https://greenelab.github.io/covid19-review/v/89dff08a5bb813c1bbc224275a347891ac8a532d/" />
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+  <link rel="alternate" type="text/html" href="https://greenelab.github.io/covid19-review/v/05acaf59cd3a3701df8ce0ad113773e154774d82/" />
+  <meta name="manubot_html_url_versioned" content="https://greenelab.github.io/covid19-review/v/05acaf59cd3a3701df8ce0ad113773e154774d82/" />
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   <meta property="og:type" content="article" />
   <meta property="twitter:card" content="summary_large_image" />
-  <meta property="og:image" content="https://github.com/greenelab/covid19-review/raw/89dff08a5bb813c1bbc224275a347891ac8a532d/content/images/thumbnail.png" />
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+  <meta property="og:image" content="https://github.com/greenelab/covid19-review/raw/05acaf59cd3a3701df8ce0ad113773e154774d82/content/images/thumbnail.png" />
+  <meta property="twitter:image" content="https://github.com/greenelab/covid19-review/raw/05acaf59cd3a3701df8ce0ad113773e154774d82/content/images/thumbnail.png" />
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   <meta name="theme-color" content="#ad1457" />
@@ -291,10 +291,10 @@ manubot-clear-requests-cache: false
 
 <small><em>
 This manuscript
-([permalink](https://greenelab.github.io/covid19-review/v/89dff08a5bb813c1bbc224275a347891ac8a532d/))
+([permalink](https://greenelab.github.io/covid19-review/v/05acaf59cd3a3701df8ce0ad113773e154774d82/))
 was automatically generated
-from [greenelab/covid19-review@89dff08](https://github.com/greenelab/covid19-review/tree/89dff08a5bb813c1bbc224275a347891ac8a532d)
-on April 16, 2021.
+from [greenelab/covid19-review@05acaf5](https://github.com/greenelab/covid19-review/tree/05acaf59cd3a3701df8ce0ad113773e154774d82)
+on April 27, 2021.
 Snapshots of individual sections are available as preprints [@individual-pathogenesis; @individual-nutraceuticals; @individual-pharmaceuticals].
 </em></small>
 
@@ -727,12 +727,12 @@ Most of these cases were in China, but one to two exported cases had also been i
 One week later, 4,593 confirmed cases had been identified, spanning not only Asia, but also Australia, North America, and Europe [@url:https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200128-sitrep-8-ncov-cleared.pdf].
 On March 11, 2020, the WHO formally classified the situation as a pandemic [@url:https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200311-sitrep-51-covid-19.pdf].
 On April 4, 2020, the WHO reported that the global number of confirmed cases had surpassed one million [@url:https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200404-sitrep-75-covid-19.pdf].
-<!--2,972,617 COVID-19 deaths had been reported worldwide as of April 14, 2021 (Figure @fig:csse-deaths).
+<!--3,109,247 COVID-19 deaths had been reported worldwide as of April 25, 2021 (Figure @fig:csse-deaths).
 
 ![
 **Cumulative global COVID-19 deaths since January 22, 2020.**
 Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [@https://github.com/CSSEGISandData/COVID-19/tree/master/csse_covid_19_data/csse_covid_19_time_series].
-](https://github.com/greenelab/covid19-review/raw/abc5bb11c3d4338884b50635074611ec7af13001/csse/csse-deaths.png "Global COVID-19 deaths"){#fig:csse-deaths secno=1} -->
+](https://github.com/greenelab/covid19-review/raw/af928572d7bcb312c4caa2a6c95e286a10f6814a/csse/csse-deaths.png "Global COVID-19 deaths"){#fig:csse-deaths secno=1} -->
 
 As international attention remains focused on the ongoing public health crisis, the scientific community has responded by mobilizing resources and turning much of its attention to the virus and disease.
 This rapid influx of information is disseminated by traditional publishing mechanisms, preprint servers, and press releases, which provide a venue for scientists to release findings without undergoing the formal publication process.
@@ -1936,12 +1936,12 @@ Prophylactics bolster immunity to prevent an individual from contracting a disea
 While a number of vaccines have recently been developed, approved, or are currently being evaluated by the US Food and Drug Administration and other regional and international bodies, vaccination programs only started being rolled out at the very end of 2020 and beginning of 2021, meaning that treatments that palliate symptoms and prevent the most severe outcomes have been necessary for much of 2020 and will continue to be necessary for the foreseeable future [@individual-vaccines].
 Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), have provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection.
 
-2,972,617 COVID-19 deaths had been reported worldwide as of April 14, 2021 (Figure @fig:csse-deaths).
+3,109,247 COVID-19 deaths had been reported worldwide as of April 25, 2021 (Figure @fig:csse-deaths).
 
 ![
 **Cumulative global COVID-19 deaths since January 22, 2020.**
 Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [@https://github.com/CSSEGISandData/COVID-19/tree/master/csse_covid_19_data/csse_covid_19_time_series].
-](https://github.com/greenelab/covid19-review/raw/abc5bb11c3d4338884b50635074611ec7af13001/csse/csse-deaths.png "Global COVID-19 deaths"){#fig:csse-deaths secno=1}
+](https://github.com/greenelab/covid19-review/raw/af928572d7bcb312c4caa2a6c95e286a10f6814a/csse/csse-deaths.png "Global COVID-19 deaths"){#fig:csse-deaths secno=1}
 
 #### Lessons from Prior HCoV Outbreaks
 
@@ -2008,7 +2008,7 @@ Recruitment status and trial phase are shown only for interventional trials in w
 The common interventions are all interventions used in at least ten trials.
 Combinations of interventions, such as Hydroxychloroquine + Azithromycin, are tallied separately from the individual interventions.
 Trials data are from the University of Oxford Evidence-Based Medicine Data Lab's COVID-19 TrialsTracker [@doi:10.5281/zenodo.3732709].
-](https://github.com/greenelab/covid19-review/raw/abc5bb11c3d4338884b50635074611ec7af13001/ebmdatalab/ebmdatalab-trials.png "COVID-19 clinical trials"){#fig:ebm-trials secno=1}
+](https://github.com/greenelab/covid19-review/raw/af928572d7bcb312c4caa2a6c95e286a10f6814a/ebmdatalab/ebmdatalab-trials.png "COVID-19 clinical trials"){#fig:ebm-trials secno=1}
 
 ### Small Molecule Drugs
 
@@ -4438,7 +4438,7 @@ Trials that recruit across multiple countries do appear to broaden geographic re
 The density of clinical trials is reported at the country level.
 As of November 9, 2020, there are 6,417 trials in the University of Oxford Evidence-Based Medicine Data Lab's COVID-19 TrialsTracker [@doi:10.5281/zenodo.3732709], of which 3,706 are interventional.
 The top figure demonstrates the density of interventional trials recruiting only from a singular country, while the bottom shows the distribution of recruitment for interventional trials that involve more than one country.
-](https://github.com/greenelab/covid19-review/raw/abc5bb11c3d4338884b50635074611ec7af13001/ebmdatalab/ebmdatalab-map.png "COVID-19 clinical trials"){#fig:ebm-map secno=1}
+](https://github.com/greenelab/covid19-review/raw/af928572d7bcb312c4caa2a6c95e286a10f6814a/ebmdatalab/ebmdatalab-map.png "COVID-19 clinical trials"){#fig:ebm-map secno=1}
 
 A few different concerns arise from this skewed geographic representation in clinical trial recruitment.
 First, treatments such as remdesivir that are promising but primarily available to clinical trial participants are unlikely to be accessible by people in many countries.
@@ -4598,53 +4598,97 @@ Over the longer term, this approach and others may lead to the development of no
 
 
 
-## Application of an Open Publishing Framework to an Emerging Public health Crisis
+## An Open-Publishing Response to the COVID-19 Infodemic
 
-### Abstract
+### ABSTRACT
 
-### Introduction
+In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [@doi:10.1098/rsif.2017.0387; @url:https://greenelab.github.io/deep-review].
 
-As international attention remains focused on the ongoing public health crisis, the scientific community has responded by mobilizing resources and turning much of its attention to the virus and disease.
-This rapid influx of information is disseminated by traditional publishing mechanisms, preprint servers, and press releases, which provide a venue for scientists to release findings without undergoing the formal publication process.
-While having information available is valuable to efforts to understand and combat COVID-19, many contributions come from researchers across a wide range of fields who have varying degrees of experience working on coronaviruses and related topics.
-The volume of information available, much of which has not gone through rigorous peer review, presents a significant challenge to individual efforts to keep abreast of the state of COVID-19 research [@doi:10.1038/s42254-020-0175-7].
-However, research on these topics is proceeding so rapidly that any static review is likely to quickly become dated.
-Our goal as a community is to consolidate information about the virus in the context of related viruses and to synthesize rapidly emerging literature centered on the diagnosis and treatment of COVID-19.
-We used an open publishing framework, Manubot [@doi:10.1371/journal.pcbi.1007128], to manage hundreds of contributions from the community to create a living, scholarly document.
-We designed software to generate figures that automatically update using external data sources. <!-- TODO: replace figure reference with manuscript reference or reference figure conditionally based on template variable [, such as Figure @fig:csse-deaths,] -->
-Our primary goal is to sort and distill informative content out of the overwhelming flood of information [@doi:10.1038/s42254-020-0175-7] and help the broader scientific community become more conversant on this critical subject.
-Thus, our approach has been to develop a real-time, collaborative effort that welcomes submissions from scientists worldwide into this ongoing effort.
-This document represents the first snapshot, which aims to reflect the state of the field as of October, 2020.
-We plan to refine and expand this document until technologies to mitigate the pandemic are widely available.
 
-In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions from the scientific community broadly, similar to previous efforts to develop collaborative reviews [@doi:10.1098/rsif.2017.0387; @url:https://greenelab.github.io/deep-review].
-Contributors were recruited by word of mouth and on Twitter.
-Existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [@url:https://github.com/ismms-himc/covid-19_sinai_reviews; @doi:10.1038/s41577-020-0319-0], and two of the authors were recruited through the American Physician Scientist Association's Virtual Summer Research Program [@url:https://www.physicianscientists.org/page/summer-research-pilot-program].
-The project was managed through GitHub [@url:https://github.com/greenelab/covid19-review] using Manubot [@doi:10.1371/journal.pcbi.1007128] to continuously generate a version of the manuscript online [@url:https://greenelab.github.io/covid19-review].
-Contributors developed text that was proposed through GitHub's pull request system and then reviewed and approved by at least one other author.
-While this document reflects the current version of record, the online version will continue to be developed as information about the pandemic emerges.
-Below, we will describe the processes used to synthesize the literature.
+### CCS CONCEPTS
+
+<!--To Do: @mprobson, do you want to take the lead on this?-->
+
+### KEYWORDS
+
+### INTRODUCTION
 
-### Technical Infrastructure
+Coronavirus Disease 2019 (COVID-19) has shaped the years 2020 and 2021 by causing a world-wide public health crisis.
+The scientific community has responded by turning significant attention and resources towards COVID-19 and the associated virus, SARS-CoV-2.
+The result has been the rapid release of data, results, and publications related to COVID-19 at a scale never previously seen.
+Over 20,000 articles about COVID-19 were released in the first 4 months of the pandemic [@doi:10.1053/j.ackd.2020.08.003].
+The velocity and volume of information being released led to the pandemic being termed as an "infodemic" as well [@doi:10.1053/j.ackd.2020.08.003; @doi:10/ggpx67].
+While this influx of information is likely evidence of important work towards understanding the virus and the disease, there are also downsides to the availability of too much information.
+The potential for "excessive publication" has been identified as an issue for over forty years, and was one concern about the move towards electronic, rather than print, publishing at the turn of the millennium [@doi:10/d3bmnv].
+<!--To Do: Flesh out above paragraph--> 
 
-#### Collaborative Writing and Manuscript Generation
+<!--To Do: Insert CORD-19 data viz here, with breakdown by preprint server versus traditional journal? I think this will really help illustrate the various problems outlined in the intro-->
+<!--To Do: Possible viz of change in clinical trials as well?-->
 
+<!-- To Do: This is just an outline, formalize this paragraph with citations etc-->
+While some of this information has been disseminated by traditional publishing mechanisms, in other cases, it is made public through preprint servers or even press releases.
+Preprints provide a venue for scientists to release findings rapidly, but have both the advantage and disadvantage of making research available before it has undergone the peer review process.
+Media outlets don't always report on this accurately.
+Additionally, many papers are being retracted.
+These include both preprints and papers that are published in more traditional venues.
+The large number of retractions may also be influenced by the fact that the time from submission to peer review for papers related to COVID-19 is very low.
+
+The rate of this proliferation also presents challenges to efforts to summarize and synthesize existing literature, which are necessary given the volume.
+A number of groups have sought to track and review COVID-19 preprints<!--To Do: add refrences-->.
+However, any static review is likely to quickly become dated as new research is released or existing research is retracted or superseded, and the explosive rate of publication made localized efforts to curate new publications increasingly difficult.
+Additionally, the complex nature of COVID-19 means that significant advantages can be gained from examining the virus and disease in a multidisciplinary context.
+Therefore, the COVID-19 publishing climate presented a challenge where curation of the literature by a diverse group of experts in a format that could respond quickly to high-volume, high-velocity information was desirable.
+
+Recent advances in open publishing have created an infrastructure that facilitates distributed, version-controlled collaboration on manuscripts [@doi:10.1371/journal.pcbi.1007128].<!--To Do: possibly cite some other efforts here-->
 Manubot [@doi:10.1371/journal.pcbi.1007128] is a collaborative framework developed to adapt open-source software development techniques and version control for manuscript writing.
-Here, Manubot was used to generate a manuscript from text maintained using GitHub, a popular, online version control interface.
-The GitHub implementation allowed users to contribute either using git on the command line or using the GitHub user interface, and we developed documentation for users with less experience with this platform.
+With Manubot, manuscripts are managed and maintained using GitHub, a popular, online version control interface that also provides the infrastructure via continuous integration (CI) to incorporate code into the manuscript building process to allow, for example, figures to be continuously updated based on an external data set.
+This open-publishing platform has been used to develop large-scale collaborative efforts such as <!--To Do: brief summary of deep review and one other use case-->.
+However, although synthesis and discussion of the emerging literature by biomedical scientists and clinicians would be expected to provide novel insights into how various areas of COVID-19 research intersect, such tools are not typically associated with biomedical research and the reliance on git can present a significant technical barrier to entry for biomedical scientists.
+The problem of synthesizing the COVID-19 literature lends itself well to a crowd-sourced approach to writing through open collaboration, but in biology, such efforts often rely on WYSIWYG tools such as Google Docs despite the significant limitations of such approaches.<!--To Do: recheck what the Manubot paper says about this and possibly pull some other refs-->
+Therefore, in addition to the unprecedented release of information, COVID-19 presents a unique challenge because most subject matter experts have limited technical training.
+
+Here, we describe efforts to adapt Manubot to handle the extreme case of the COVID-19 infodemic, with the objective of extending simply reviewing preprints to develop a centralized platform for summarizing and synthesizing a massive amount of preprints, news stories, journal publications, and data.
+Unlike prior collaborations built on Manubot, here most contributors came from a traditional biological or medical background.
+The members of the COVID-19 Review Consortium worked to consolidate information about the virus in the context of related viruses and to synthesize rapidly emerging literature centered on the diagnosis and treatment of COVID-19.
+Manubot provided the infrastructure to manage contributions from the community and create a living, scholarly document that integrated data from multiple sources to respond to the COVID-19 crisis in real time and a back-end that allowed biomedical scientists to sort and distill informative content out of the overwhelming flood of information [@doi:10.1038/s42254-020-0175-7] in order to provide a resource that would be useful to the broader scientific community.
+This case study demonstrates the value of open collaborative writing tools such as Manubot to emerging challenges and the flexibility of Manubot to be adapted to problems unique to a range of fields.
+By recording the evolution of information over time and assembling a resource that auto-updated in response to the evolving crisis, it revealed the particular value that Manubot holds for managing a rapid changes in scientific thought.
+
+### METHODS
+
+#### Contributor Recruitment
+
+One of the primary goals of this project was to develop Manubot as a platform accessible to researchers with limited computational training, as is common in biology and medicine.<!--To Do: Halie can potentially adapt sources for this from her draft faculty apps-->
+Given the limitations imposed upon scientists by the COVID-19 pandemic and social distancing measures that had most scientists (including students) working from home for much of 2020, community building across disciplines and across career stages was a priority of the project.
+The current project was managed through GitHub [@url:https://github.com/greenelab/covid19-review] using Manubot [@doi:10.1371/journal.pcbi.1007128] to continuously generate a version of the manuscript online [@url:https://greenelab.github.io/covid19-review].
+Contributors were recruited by word of mouth and on Twitter, and we sought out opportunities to integrate existing efforts to train early-career researchers (ECRs).
+Few researchers in biological and medical fields are trained in version control tools such as git <!--To Do: Find some sort of reference for this, software carpentry? Pull from citations to 10.1371/journal.pcbi.1004668
+-->
+
+In order to make the project accessible to individuals from a number of backgrounds, we developed resources explaining how to use GitHub's web interface to develop and edit text and interact with Manubot for individuals with no prior experience working with git or other version control platforms.
+<!--To Do: elaborate on resource development-->
+
+Interested parties were encouraged to contribute in a number of ways.
+One option was to submit articles of interest as issues in the GitHub repository.
+Articles were classified as _diagnostic_, _therapeutic_, or _other_, and a template was developed to guide the review of papers and preprints in each category.
+Following a framework often used for assessing medical literature, the review consisted of examining methods used in each relevant article, assignment (whether the study was observational or randomized), assessment, results, interpretation, and how well the study extrapolates [@doi:10.5014/ajot.60.4.367].
+For examples of each template, please see Appendices B-D.
+Another option was to contribute or edit text using GitHub's pull request system.
+Each pull request was reviewed and approved by at least one other author.
 Manubot also provides a functionality to create a bibliography using digital object identifiers (DOIs), website URLs, or other identifiers such as PubMed identifiers and arXiv IDs.
-Due to the needs of this project, project contributors also implemented new features in Manubot and [Zotero](https://www.zotero.org/), which Manubot uses to extract metadata for some types of citations.
-These features support directly citing clinical trial identifiers such as `clinicaltrials:NCT04292899` [@clinicaltrials:NCT04292899] and generating the complete review manuscript along with the individual manuscripts reviewing specific topics. <!-- TODO: reference individual manuscripts -->
-Finally, Manubot and GitHub Actions continuous integration allowed for scripted updates to be run each time the manuscript was generated.
-These scripts were used to check that the manuscript was built correctly, run spellchecking, and cross-reference the manuscripts cited in this review, summarized in Appendix A, and discussed in the project's issues and pull requests.
 
-#### Data Analysis and Visualization
+#### Applying Manubot's Existing Capabilities to the Challenges of COVID-19 
 
+Because of the ever-evolving nature of the COVID-19 crisis, many of the figures and text proposed by subject matter contributors would have quickly become outdated.
+To address this concern, Manubot and GitHub's continuous integration features were used to create figures and text that could respond to changes in the COVID-19 pandemic over time.
 The combination of Manubot and GitHub Actions also made it possible to dynamically update information such as statistics and visualizations in the manuscript.
-Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [@https://github.com/CSSEGISandData/COVID-19/tree/master/csse_covid_19_data/csse_covid_19_time_series] were read using a Python script. <!-- TODO: replace figure reference with manuscript reference or reference figure conditionally based on template variable [to generate Figure @fig:csse-deaths.] -->
+When scientific writers added text that was current only as of a given date, publicly available data sources were identified whenever possible to allow the information to pulled directly into the manuscript in order to keep it up to date.<!--To Do: Add quoted examples-->
+Data was pulled from a number of sources.
+Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [@https://github.com/CSSEGISandData/COVID-19/tree/master/csse_covid_19_data/csse_covid_19_time_series] were read using a Python script. <!-- To Do: replace figure reference with manuscript reference or reference figure conditionally based on template variable [to generate Figure @fig:csse-deaths.] -->
 Similarly, the clinical trials statistics and figure were generated based on data from the University of Oxford Evidence-Based Medicine Data Lab's COVID-19 TrialsTracker [@doi:10.5281/zenodo.3732709]. <!-- TODO: replace figure reference with manuscript reference or reference figure conditionally based on template variable [Figure @fig:ebm-trials] -->
 In both cases, frequency data were plotted using Matplotlib [@doi:10.1109/MCSE.2007.55] in Python.
 The figure showing the geographic distribution of COVID-19 clinical trials was generated using the countries associated with the trials listed in the COVID-19 TrialsTracker, converting the country names to 3-letter ISO codes using pycountry or manual adjustment when necessary, and visualizing the geographic distribution of trial recruitment using geopandas. <!-- TODO: replace figure reference with manuscript reference or reference figure conditionally based on template variable [Figure @fig:ebm-map] -->
+<!--To Do: Update with Vaccines-->
 
 GitHub Actions runs a nightly workflow to update these external data and regenerate the statistics and figures for the manuscript.
 The workflow uses the GitHub API to detect and save the latest commit of the external data sources, which are both GitHub repositories.
@@ -4655,110 +4699,80 @@ The template variables also include versioned URLs to the dynamically updated fi
 The JSON files and figures are stored in the `external-resources` branch of the manuscript's GitHub repository, which acts as versioned storage.
 The GitHub Actions workflow automatically adds and commits the new JSON files and figures to the `external-resources` branch every time it runs, and Manubot uses the latest version of these resources when it builds the manuscript.
 
-The workflow file is available from <https://github.com/greenelab/covid19-review/blob/master/.github/workflows/update-external-resources.yaml> and the scripts are available from <https://github.com/greenelab/covid19-review/tree/external-resources>.
-The Python package versions are available in <https://github.com/greenelab/covid19-review/blob/external-resources/environment.yml>.
-<!-- These files are archived with [Software Heritage](...). -->
-
-### Article Selection and Evaluation
-
-Relevant articles were identified and submitted as issues on [GitHub](https://github.com/greenelab/covid19-review) for review.
-Articles were classified as _diagnostic_, _therapeutic_, or _other_, and a template was developed to guide the review of papers and preprints in each category.
-Following a framework often used for assessing medical literature, the review consisted of examining methods used in each relevant article, assignment (whether the study was observational or randomized), assessment, results, interpretation, and how well the study extrapolates [@doi:10.5014/ajot.60.4.367].
-For examples of each template, please see Appendices B-D.
-
-#### Diagnostic Papers
-
-##### Methods
-
-Reviewers began by describing the study question(s) being investigated by the article.
-They then described the study population, the sample size, the prevalence of the disease in the study population, countries / regions considered in case of human subjects, demographics of participants, the setting, and any remaining inclusion / exclusion criteria considered.
-They then described the reference test or "gold standard," if one was utilized.
+#### Updating to Manubot in Response to Project Demands
 
-##### Assignment
+Due to the needs of this project, project contributors also implemented new features in Manubot.
+<!-- To Do: Detailed description of Ryan's work making it possible to cite clinical trial identifiers-->
+Manubot uses Zotero [@url:https://www.zotero.org] to extract metadata for some types of citations.
+These features support directly citing clinical trial identifiers such as `clinicaltrials:NCT04292899` [@clinicaltrials:NCT04292899].
 
-Reviewers described how new and reference tests were assigned, including additional relevant details about the study design.
-For example, reviewers were asked whether the diagnostic test resulted in rigorous assignments of case status or was biased towards sicker or healthier individuals.
+Additionally, the fast-moving nature of the infodemic has led to a number of retractions and corrections of COVID-19 literature.
+<!--To Do: Describe integration with scite -- talk to Vince-->  
 
-##### Assessment
+Because in this implementation of Manubot, most collaborators were writing and editing text through the GitHub website rather than in a local text editor, we also needed to add spell-checking functionalities to Manubot.
+<!--To Do: Describe-->
 
-Reviewers described how the test was performed.
-For example, for both standard and reference tests, reviewers described technical details of assays used, when measurements were taken and by whom.
-Subsequently, they described how individuals were classified as positive or negative cases and whether results were precise and reproducible with repeated tests.
-Reviewers described whether there were any missing data, whether some participants underwent only one test, or whether there were individuals with inconclusive results.
+<!-- To Do: Also, if we end up automating anything to do with the Manubot-to-LaTeX or bibtex workflow while trying to submit this paper, we should describe that too, as well as the udpates for the Microsoft Word crowd to generating the complete review manuscript along with the individual manuscripts reviewing specific topics. <!-- To Do: reference individual manuscripts -->
 
-##### Results
+### RESULTS
 
-Reviewers reported the estimated sensitivity, specificity, positive predictive value (PPV), and negative predicted value (NPV), as well as confidence bounds around these measures, if provided.
+#### Recruitment and Manuscript Development
 
-##### Interpretation
+<!--To Do: Add a graph/text describing number of unique contributors & commits over time-->
+<!-- To Do: Word Cloud of #17 to show diversity of interests?-->
+Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [@url:https://github.com/ismms-himc/covid-19_sinai_reviews; @doi:10.1038/s41577-020-0319-0], and two of the authors were recruited through the American Physician Scientist Association's Virtual Summer Research Program [@url:https://www.physicianscientists.org/page/summer-research-pilot-program].
+<!--To Do: Graph of contributions by individual over time and/or by career stage?-->
+<!-- To Do: unique contributors and commits over time like this: https://greenelab.github.io/meta-review/#fig:contrib-->
+<!--To Do: Other possible graphs: plot number of article issues opened over time, distribution of review contents, that is, something showing the number of comments per pull request that was merged, growth of the reference list over time and/or number of clinical trials cited (because we describe that as a necessary enhancement)-->
 
-Reviewers reported how well the test ruled in or ruled out disease based on the population, if there were identified side effects, and patient adherence.
+<!--To Do: Links to documentation-->
 
-##### Extrapolation
+#### Data Analysis and Integration
 
-Reviewers described how well this test will extrapolate outside the measured population.
+<!--To Do: Flow chart of data integration? We could have a summary figure showing all of the external data sources that are integrated into the manuscript. We have icons for MSSM reviews, JHU data, etc. at the top. That flows into a GitHub repo, which also takes input from all the contributors. Then the output of the repo is the manuscript and other CI artifacts.-->
 
-#### Therapeutic Papers
+<!-- To Do: example of how the auto-updated figures changed between an early version and most recent version to demonstrate the importance of having current data visualized-->
 
-##### Methods
-
-Reviewers began by describing the study question(s) being investigated by the article.
-They then described the study population, the sample size, the prevalence of the disease in the study population, countries / regions considered in case of human subjects, demographics of participants, the setting, and any remaining inclusion / exclusion criteria considered.
-
-##### Assignment
-
-Reviewers described how the treatment is assigned, whether it was an interventional or observational study, whether randomization took place, etc.
-
-##### Assessment
-
-###### Outcome Assessment
-
-Reviewers described the outcome that was assessed and evaluated whether it was appropriate given the underlying study question.
-They described whether there were any missing data such as whether there were individuals lost to follow up.
-They then describe whether there were any potential sources of bias such as lack of blinding in a randomized controlled trial.
-
-###### Statistical Methods Assessment
-
-Reviewers described which statistical methods were used for inference and whether applied methods were appropriate for the study.
-They then described whether adjustments were made for possible confounders.
-
-##### Results
-
-Reviewers described the estimated association between the treatment and outcome.
-They described measures of confidence or statistical significance, if provided.
-
-##### Interpretation
-
-Reviewers described whether a causal claim could be made.
-They described whether any side effects or interactions with other drugs were identified, as well as any subgroup findings.
-
-##### Extrapolation
-
-Reviewers describe how the study may extrapolate to a different species or population.
-
-### Conclusions
-
-![**Summary of the relationships among topics covered in this review.**](images/N000-overview.png){#fig:overview secno=1}
+The workflow file is available from <https://github.com/greenelab/covid19-review/blob/master/.github/workflows/update-external-resources.yaml> and the scripts are available from <https://github.com/greenelab/covid19-review/tree/external-resources>.
+The Python package versions are available in <https://github.com/greenelab/covid19-review/blob/external-resources/environment.yml>.
+<!-- To Do: These files are archived with [Zenodo?](...). -->
+
+#### Updates to Manubot
+
+The scite integration and spell-checking functionalities have been integrated into the current release of Manubot <!--To Do: Link-->.
+Support for clinical trial identifiers is supported both by Manubot and by Zotero <!--To Do: check this phrasing-->.
+Using CI, Manubot now checks that the manuscript was built correctly, runs spellchecking, and cross-references the manuscripts cited in this review, as summarized in Appendix A and discussed in the project's issues and pull requests.
+
+### DISCUSSION
+
+Working within the Manubot framework allowed for the successful facilitation of a massive collaborative review on an urgent topic.
+Developing Manubot for the specific challenges raised by COVID-19 and expanding on both training resources resulted in seven evolving literature reviews produced by the COVID-19 Review Consortium, all of which are currently available through Manubot and, in some cases, on arXiv <!--To Do: cite individual manuscripts-->.
+As many other efforts have described, the rate of publishing of formal manuscripts and preprints about COVID-19 has been unprecedented [@doi:10.1053/j.ackd.2020.08.003].
+The Manubot framework will allow for continuous updating of the manuscripts as the pandemic enters its second year and the landscape shifts with the emergence of promising therapeutics and vaccines [@individual-therapeutics; @individual-vaccines].
+The manuscripts pull data from XX data sources, allowing for information and visualizations to be updated daily using CI.
+This computational approach allows for the information in the manuscripts to be kept up to date automatically.
+
+Beyond the immediate goal of applying Manubot to the challenges of COVID-19, we have also expanded Manubot to allow for broader participation in open publishing from fields where computational training in tools like version control is uncommon. 
+Several review articles on aspects of COVID-19 have already been published, including reviews on the disease epidemiology [@doi:10.1016/j.molmed.2020.02.008], immunological response [@doi:10.1016/j.immuni.2020.05.002], diagnostics [@doi:10.1126/scitranslmed.abc1931], and pharmacological treatments [@doi:10.1016/j.immuni.2020.05.002; @doi:10.1001/jama.2020.6019] and others that provide narrative reviews of progress on some important ongoing COVID-19 research questions [@doi:10.1038/d41591-020-00026-w; @doi:10.1001/jama.2020.12839].
+However, the broader topic of COVID-19 intersects with a wide range of fields, including virology, immunology, medicine, pharmacology, evolutionary biology, public health, and more, and any effort to comprehensively document and evaluate this body of literature would require insight from scientists across a number of fields.
+Furthermore, during the initial phase of the COVID-19 pandemic during spring and summer 2020, and much longer in some part of the world, many biological scientists were unable to access their research spaces.
+As a result, early career researchers (ECR) and students were likely to lose out on valuable time for conducting experiments. <!--To Do: look at equity analyses of the effects on the pandemic to see if there is any data on this yet?-->
+Manubot provided a way for all contributors, including ECRs, to join a massive collaborative projects but also demonstrate their individual contributions to the larger work.
+<!--To Do: summary of results of contributor analysis-->
+
+Manubot provides the advantage of allowing a manuscript to be rendered in several formats that serve different purposes, and the current project extended these options.
+For example, beyond building just a PDF, Manubot also renders the manuscript in HTML and docx <!--To Do: And tex?-->
+The HTML manuscript format offers several advantages over a static PDF to harmonize available resources that we were able to apply to specific problems of COVID-19.
+The integration of scite has made the expansive number of references more manageable by visually representing whether their results are contested or whether they have been corrected or retracted.
+Cross-referencing cited preprints with their reviews in the appendix is another.
+Docx is a necessary format for a biological collaboration where authors are typically not working in LaTeX.
+<!--To Do: continue expanding to describe docx updates and possibly LaTeX updates-->
 
-Several review articles on aspects of COVID-19 have already been published.
-These have included reviews on the disease epidemiology [@doi:10.1016/j.molmed.2020.02.008], immunological response [@doi:10.1016/j.immuni.2020.05.002], diagnostics [@doi:10.1126/scitranslmed.abc1931], and pharmacological treatments [@doi:10.1016/j.immuni.2020.05.002; @doi:10.1001/jama.2020.6019].
-Others [@doi:10.1038/d41591-020-00026-w; @doi:10.1001/jama.2020.12839] provide narrative reviews of progress on some important ongoing COVID-19 research questions.
 With the worldwide scientific community uniting during 2020 to investigate SARS-CoV-2 and COVID-19 from a wide range of perspectives, findings from many disciplines are relevant on a rapid timescale to a broad scientific audience.
-Additionally, many findings are published as preprints, which are available prior to going through the peer review process.
-As a result, centralizing, summarizing, and critiquing new literature broadly relevant to COVID-19 can help to expedite the interdisciplinary scientific process that is currently happening at an advanced pace.
-We are particularly interested in providing background to the development of diagnostic, prophylactic, and therapeutic approaches to COVID-19.
-Two major concerns within diagnosis include the detection of current infections in individuals with and without symptoms, and the detection of past exposure without an active infection.
-In the latter category, identifying whether individuals can develop or have developed sustained immunity is also a major consideration.
-The development of high-throughput, affordable methods for detecting active infections and sustained immunity will be critical to understanding and controlling the disease.
-The identification of interventions that can mitigate the effect of the virus on exposed and infected individuals is a significant research priority.
-Some possible approaches include the identification of existing pharmaceuticals that reduce the severity of infection, either by reducing the virus' virulence (e.g., antivirals) or managing the most severe symptoms of infection.
-Due to the long timeline for the development of novel pharmaceuticals, in most cases, research surrounding possible pharmaceutical interventions focuses on the identification and investigation of existing compounds whose mechanisms may be relevant to COVID-19.
-Other foci of current research include the identification of antibodies produced by survivors of COVID-19 and the development of vaccines.
-Understanding the mechanisms describing host-virus interactions between humans and SARS-CoV-2 is thus critical to identifying candidate therapeutics.
-An overview of the topics covered is visualized in Figure @fig:overview.
-Thus, in this review, we seek to consolidate information about efforts to develop strategies for diagnosis and therapeutics as new information is released by the scientific community.
-We include information from both traditional peer-reviewed scientific literature and from preprints, which typically have not undergone peer review but have been critically evaluated by the scientists involved in this effort.
-The goal of this manuscript is to present preliminary findings within the broader context of COVID-19 research and to identify the broad interpretations of new research, as well as limitations to interpretability.
+As a result, centralizing, summarizing, and critiquing data and literature broadly relevant to COVID-19 can help to expedite the interdisciplinary scientific process that is currently happening at an advanced pace.
+The efforts of the COVID-19 Review Consortium illustrate the value of including open source tools, including those focused on open publishing, in these efforts.
+By facilitating the versioning of text, such platforms also allow for documentation of the evolution of thought in an evolving area.
+This application of version control holds the potential to improve scientific publishing in a range of disciplines, including those outside of traditional computational fields.
 
 
 ## Additional Items {.page_break_before} 
diff --git a/manuscript.pdf b/manuscript.pdf
index f1253a9ee..1264f1981 100644
Binary files a/manuscript.pdf and b/manuscript.pdf differ
diff --git a/pathogenesis-manuscript.docx b/pathogenesis-manuscript.docx
index e5fa2c3df..3f21e8579 100644
Binary files a/pathogenesis-manuscript.docx and b/pathogenesis-manuscript.docx differ
diff --git a/references.json b/references.json
index a39e453a8..8a1bbb02a 100644
--- a/references.json
+++ b/references.json
@@ -1163,21 +1163,40 @@
   },
   {
     "id": "JP1lU6DV",
-    "type": "webpage",
-    "title": "Angiotensin Receptor Blockers and Angiotensin-converting Enzyme Inhibitors and Adverse Outcomes in Patients With COVID19 - Full Text View - ClinicalTrials.gov",
-    "abstract": "Angiotensin Receptor Blockers and Angiotensin-converting Enzyme Inhibitors and Adverse Outcomes in Patients With COVID19 - Full Text View.",
+    "type": "report",
+    "title": "Suspension of Angiotensin Receptor Blockers and Angiotensin-converting Enzyme Inhibitors and Adverse Outcomes in Hospitalized Patients With Coronavirus Infection (COVID-19). A Randomized Trial",
+    "publisher": "clinicaltrials.gov",
+    "genre": "Clinical trial registration",
+    "source": "clinicaltrials.gov",
+    "abstract": "Suspension of Angiotensin Receptor Blockers and Angiotensin-converting Enzyme Inhibitors and Adverse Outcomes in Hospitalized Patients With Coronavirus Infection.",
     "URL": "https://clinicaltrials.gov/ct2/show/NCT04364893",
-    "language": "en",
+    "note": "submitted: April 7, 2020\nThis CSL Item was generated by Manubot v0.5.0 from its persistent identifier (standard_id).\nstandard_id: clinicaltrials:NCT04364893",
+    "number": "NCT04364893",
+    "shortTitle": "Angiotensin Receptor Blockers and Angiotensin-converting Enzyme Inhibitors and Adverse Outcomes in Patients With COVID19",
+    "author": [
+      {
+        "family": "D'Or Institute for Research and Education",
+        "given": ""
+      }
+    ],
+    "issued": {
+      "date-parts": [
+        [
+          "2020",
+          7,
+          1
+        ]
+      ]
+    },
     "accessed": {
       "date-parts": [
         [
           "2021",
           4,
-          16
+          25
         ]
       ]
-    },
-    "note": "This CSL Item was generated by Manubot v0.5.0 from its persistent identifier (standard_id).\nstandard_id: clinicaltrials:NCT04364893"
+    }
   },
   {
     "id": "c7V9rAFR",
@@ -1236,21 +1255,40 @@
   },
   {
     "id": "Nq0cimEs",
-    "type": "webpage",
-    "title": "Evaluation of the Safety and Immunogenicity of a SARS-CoV-2 rS Nanoparticle Vaccine With/Without Matrix-M Adjuvant - Full Text View - ClinicalTrials.gov",
-    "abstract": "Evaluation of the Safety and Immunogenicity of a SARS-CoV-2 rS Nanoparticle Vaccine With/Without Matrix-M Adjuvant - Full Text View.",
+    "type": "report",
+    "title": "A 2-Part, Phase 1/2, Randomized, Observer-Blinded Study To Evaluate The Safety And Immunogenicity Of A SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine (SARS-CoV-2 rS) With Or Without MATRIX-M™ Adjuvant In Healthy Subjects",
+    "publisher": "clinicaltrials.gov",
+    "genre": "Clinical trial registration",
+    "source": "clinicaltrials.gov",
+    "abstract": "2019nCoV-101 is a 2-part, randomized, observer-blinded, placebo-controlled, Phase 1/2 trial. Part 1 (Phase 1) of the study is designed to evaluate the safety and immunogenicity of SARS-CoV-2 rS nanoparticle vaccine with or without Matrix-M adjuvant in 131 healthy participants ≥ 18 to 59 (inclusive) years of age at 2 sites in Australia. An interim analysis of Part 1 safety and immunogenicity will be performed prior to optional expansion to Part 2. Part 2 (Phase 2) of the study is designed to evaluate the immunogenicity, safety, and preliminary efficacy of a single construct of SARS-CoV-2 rS nanoparticle vaccine with Matrix-M adjuvant in up to 1,500 healthy participants ≥ 18 to 84 (inclusive) years of age at up to 40 sites across Australia and/or the United States.",
     "URL": "https://clinicaltrials.gov/ct2/show/NCT04368988",
-    "language": "en",
+    "note": "submitted: April 24, 2020\nThis CSL Item was generated by Manubot v0.5.0 from its persistent identifier (standard_id).\nstandard_id: clinicaltrials:NCT04368988",
+    "number": "NCT04368988",
+    "shortTitle": "Evaluation of the Safety and Immunogenicity of a SARS-CoV-2 rS Nanoparticle Vaccine With/Without Matrix-M Adjuvant",
+    "author": [
+      {
+        "family": "Novavax",
+        "given": ""
+      }
+    ],
+    "issued": {
+      "date-parts": [
+        [
+          "2020",
+          10,
+          8
+        ]
+      ]
+    },
     "accessed": {
       "date-parts": [
         [
           "2021",
           4,
-          16
+          25
         ]
       ]
-    },
-    "note": "This CSL Item was generated by Manubot v0.5.0 from its persistent identifier (standard_id).\nstandard_id: clinicaltrials:NCT04368988"
+    }
   },
   {
     "id": "dQtUeruv",
@@ -1469,7 +1507,7 @@
         [
           "2021",
           4,
-          13
+          25
         ]
       ]
     }
@@ -1660,21 +1698,40 @@
   },
   {
     "id": "4IdGvvyC",
-    "type": "webpage",
-    "title": "A Study of LY3819253 (LY-CoV555) in Participants Hospitalized for COVID-19 - Full Text View - ClinicalTrials.gov",
-    "abstract": "A Study of LY3819253 (LY-CoV555) in Participants Hospitalized for COVID-19 - Full Text View.",
+    "type": "report",
+    "title": "A Randomized, Placebo-Controlled, Double-Blind, Sponsor Unblinded, Single Ascending Dose, Phase 1 First in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenous LY3819253 in Participants Hospitalized for COVID-19",
+    "publisher": "clinicaltrials.gov",
+    "genre": "Clinical trial registration",
+    "source": "clinicaltrials.gov",
+    "abstract": "The purpose of this study is to test the safety and tolerability of LY3819253 when it is given by injection into a vein to participants hospitalized with COVID-19. Blood tests will be done to check how much LY3819253 is in the bloodstream and how long the body takes to eliminate it. Participation could last about 8 weeks and may include up to 15 visits in the hospital or the home.",
     "URL": "https://clinicaltrials.gov/ct2/show/NCT04411628",
-    "language": "en",
+    "note": "submitted: May 29, 2020\nThis CSL Item was generated by Manubot v0.5.0 from its persistent identifier (standard_id).\nstandard_id: clinicaltrials:NCT04411628",
+    "number": "NCT04411628",
+    "shortTitle": "A Study of LY3819253 (LY-CoV555) in Participants Hospitalized for COVID-19",
+    "author": [
+      {
+        "family": "Eli Lilly and Company",
+        "given": ""
+      }
+    ],
+    "issued": {
+      "date-parts": [
+        [
+          "2020",
+          10,
+          29
+        ]
+      ]
+    },
     "accessed": {
       "date-parts": [
         [
           "2021",
           4,
-          16
+          25
         ]
       ]
-    },
-    "note": "This CSL Item was generated by Manubot v0.5.0 from its persistent identifier (standard_id).\nstandard_id: clinicaltrials:NCT04411628"
+    }
   },
   {
     "id": "QKHdIx2w",
@@ -1837,7 +1894,7 @@
         [
           "2021",
           4,
-          13
+          25
         ]
       ]
     }
@@ -1874,28 +1931,47 @@
         [
           "2021",
           4,
-          13
+          25
         ]
       ]
     }
   },
   {
     "id": "f6m2SeLi",
-    "type": "webpage",
-    "title": "A Study of LY3819253 (LY-CoV555) and LY3832479 (LY-CoV016) in Participants With Mild to Moderate COVID-19 Illness - Full Text View - ClinicalTrials.gov",
-    "abstract": "A Study of LY3819253 (LY-CoV555) and LY3832479 (LY-CoV016) in Participants With Mild to Moderate COVID-19 Illness - Full Text View.",
+    "type": "report",
+    "title": "A Randomized, Double-blind, Placebo-Controlled, Phase 2/3 Study to Evaluate the Efficacy and Safety of LY3819253 and LY3832479 in Participants With Mild to Moderate COVID-19 Illness",
+    "publisher": "clinicaltrials.gov",
+    "genre": "Clinical trial registration",
+    "source": "clinicaltrials.gov",
+    "abstract": "The purpose of this study is to measure how well LY3819253 and LY3832479 work against the virus that causes COVID-19. LY3819253 and LY3832479 will be given to participants with early symptoms of COVID-19. Samples will be taken from the back of the nose to determine how much virus is in the body at various times during the study. Participation could last about 12 weeks and includes one required visit to the study site, with the remainder of assessments performed in the home or by phone.",
     "URL": "https://clinicaltrials.gov/ct2/show/NCT04427501",
-    "language": "en",
-    "accessed": {
+    "note": "submitted: June 9, 2020\nThis CSL Item was generated by Manubot v0.5.0 from its persistent identifier (standard_id).\nstandard_id: clinicaltrials:NCT04427501",
+    "number": "NCT04427501",
+    "shortTitle": "A Study of LY3819253 (LY-CoV555) and LY3832479 (LY-CoV016) in Participants With Mild to Moderate COVID-19 Illness",
+    "author": [
+      {
+        "family": "Eli Lilly and Company",
+        "given": ""
+      }
+    ],
+    "issued": {
       "date-parts": [
         [
           "2021",
           4,
-          16
+          19
         ]
       ]
     },
-    "note": "This CSL Item was generated by Manubot v0.5.0 from its persistent identifier (standard_id).\nstandard_id: clinicaltrials:NCT04427501"
+    "accessed": {
+      "date-parts": [
+        [
+          "2021",
+          4,
+          25
+        ]
+      ]
+    }
   },
   {
     "id": "nk2MVsld",
@@ -1965,7 +2041,7 @@
         [
           "2021",
           4,
-          13
+          25
         ]
       ]
     }
@@ -2002,7 +2078,7 @@
         [
           "2021",
           4,
-          13
+          25
         ]
       ]
     }
@@ -2039,7 +2115,7 @@
         [
           "2021",
           4,
-          13
+          25
         ]
       ]
     }
@@ -2076,7 +2152,7 @@
         [
           "2021",
           4,
-          13
+          25
         ]
       ]
     }
@@ -2113,7 +2189,7 @@
         [
           "2021",
           4,
-          13
+          25
         ]
       ]
     }
@@ -2157,21 +2233,40 @@
   },
   {
     "id": "1G2ROkAsZ",
-    "type": "webpage",
-    "title": "Study in Adults to Determine the Safety and Immunogenicity of AZD1222, a Non-replicating ChAdOx1 Vector Vaccine, Given in Combination With rAd26-S, Recombinant Adenovirus Type 26 Component of Gam-COVID-Vac Vaccine, for the Prevention of COVID-19. - Full Text View - ClinicalTrials.gov",
-    "abstract": "Study in Adults to Determine the Safety and Immunogenicity of AZD1222, a Non-replicating ChAdOx1 Vector Vaccine, Given in Combination With rAd26-S, Recombinant Adenovirus Type 26 Component of Gam-COVID-Vac Vaccine, for the Prevention of COVID-19. - Full Text View.",
+    "type": "report",
+    "title": "A Phase II Open-label Study in Adults to Determine the Safety and Immunogenicity of AZD1222, a Non-replicating ChAdOx1 Vector Vaccine, Given in Combination With rAd26-S, Recombinant Adenovirus Type 26 Component of Gam-COVID-Vac Vaccine, for the Prevention of COVID 19",
+    "publisher": "clinicaltrials.gov",
+    "genre": "Clinical trial registration",
+    "source": "clinicaltrials.gov",
+    "abstract": "The primary objective of this study is to describe the safety and tolerability of one IM dose of AZD1222 followed by one IM dose of rAd26-S in adults ≥ 18 years of age",
     "URL": "https://clinicaltrials.gov/ct2/show/NCT04686773",
-    "language": "en",
+    "note": "submitted: December 25, 2020\nThis CSL Item was generated by Manubot v0.5.0 from its persistent identifier (standard_id).\nstandard_id: clinicaltrials:NCT04686773",
+    "number": "NCT04686773",
+    "shortTitle": "Study in Adults to Determine the Safety and Immunogenicity of AZD1222, a Non-replicating ChAdOx1 Vector Vaccine, Given in Combination With rAd26-S, Recombinant Adenovirus Type 26 Component of Gam-COVID-Vac Vaccine, for the Prevention of COVID-19.",
+    "author": [
+      {
+        "family": "R-Pharm",
+        "given": ""
+      }
+    ],
+    "issued": {
+      "date-parts": [
+        [
+          "2021",
+          1,
+          12
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     "title": "Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19",
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+    "publisher": "Elsevier BV",
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+    "publisher": "Elsevier BV",
+    "title": "The impact of preprint servers and electronic publishing on biomedical research",
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     "source": "NYTimes.com",
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+    "abstract": "More than 1.04 billion vaccine doses have been administered worldwide, equal to 14 doses for every 100 people.",
     "URL": "https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html",
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     "title": "Covid-19 vaccine effectiveness affected by variants",
-    "URL": "https://www.pharmaceutical-technology.com/comment/covid-19-vaccine-effectiveness-affected-by-variants",
+    "URL": "https://www.pharmaceutical-technology.com/comment/covid-19-vaccine-effectiveness-affected-by-variants/",
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diff --git a/spelling-error-locations.txt b/spelling-error-locations.txt
index 398ad2a94..5a56041bb 100644
--- a/spelling-error-locations.txt
+++ b/spelling-error-locations.txt
@@ -2,3 +2,14 @@ content/09.evolution.md:83:nonsynonymous
 content/09.evolution.md:139:LVNA
 content/23.vaccines-app.md:15:IgGs
 content/23.vaccines-app.md:387:IgGs
+content/60.methods.md:8:CCS
+content/60.methods.md:64:ECRs
+content/60.methods.md:80:Manubot's
+content/60.methods.md:110:scite
+content/60.methods.md:142:scite
+content/60.methods.md:159:ECR
+content/60.methods.md:160:ECRs
+content/60.methods.md:164:docx
+content/60.methods.md:166:scite
+content/60.methods.md:168:Docx
+content/60.methods.md:169:docx
diff --git a/spelling-errors.txt b/spelling-errors.txt
index 1bcf9854f..d8b2fa2e8 100644
--- a/spelling-errors.txt
+++ b/spelling-errors.txt
@@ -1,4 +1,11 @@
+CCS
+Docx
+ECR
+ECRs
+ggpx
 IgGs
 LVNA
+Manubot’s
 nonsynonymous
+scite
 Yusha
diff --git a/vaccines-manuscript.docx b/vaccines-manuscript.docx
index dd253c8d1..97ff46a1e 100644
Binary files a/vaccines-manuscript.docx and b/vaccines-manuscript.docx differ
diff --git a/variables.json b/variables.json
index 83fded729..f19f1e087 100644
--- a/variables.json
+++ b/variables.json
@@ -8,7 +8,7 @@
       "viral infection"
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@@ -60,7 +60,7 @@
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