diff --git a/build/assets/custom-dictionary.txt b/build/assets/custom-dictionary.txt index ff58ead5f..c2a398e46 100644 --- a/build/assets/custom-dictionary.txt +++ b/build/assets/custom-dictionary.txt @@ -875,6 +875,7 @@ Nutraceuticals O’Meara obesogenic OC +ODSP olfaction omics oncolytic diff --git a/content/02.introduction.md b/content/02.introduction.md index 397567282..2813c6a77 100644 --- a/content/02.introduction.md +++ b/content/02.introduction.md @@ -8,8 +8,6 @@ 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]. - -**Global COVID-19 deaths since January 22, 2020.** {{csse_deaths}} COVID-19 deaths had been reported worldwide as of {{csse_date_pretty}} (Figure @fig:csse-deaths). ![ @@ -43,7 +41,7 @@ Public health addresses social and human factors influencing individuals' exposu Strategies from public health and epidemiology for managing the current epidemic have included the promotion of hand hygiene, social distancing, and personal protective equipment such as masks to mitigate spread, as well as containment approaches such as test, trace, and isolate, which depends on widespread testing, contact tracing, and quarantining. An effective public health management strategy involves response coordination, disease surveillance, intervention monitoring, risk communication, and health education (including the containment of “infodemics” of false information) [@isbn:978-92-4-156553-0]. Epidemiology and public health intersect with the topics addressed in this manuscript because they both inform and benefit from relevant biotechnological developments. -For example, the development of accurate and fast diagnostic testing is relevant to test, trace, and isolate strategies for containment, and public education will be critical to deploying vaccines once they become available.. +For example, the development of accurate and fast diagnostic testing is relevant to test, trace, and isolate strategies for containment, and public education will be critical to deploying vaccines once they become available. The present analysis focuses less on human and social factors and more on the basic biology of infection, diagnosis, and recovery, but these areas are inextricable in understanding and responding to the COVID-19 pandemic. ### Initial Characterization of SARS-CoV-2 @@ -127,7 +125,7 @@ The variability of both which symptoms present and their severity makes it diffi 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] and [@doi:10.1001/jama.2020.12839] provide narrative reviews of progress on some important ongoing COVID-19 research questions. +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. @@ -140,7 +138,7 @@ Some possible approaches include the identification of existing pharmaceuticals 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 (Figure @fig:overview). +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. diff --git a/content/07.pathogenesis.md b/content/07.pathogenesis.md index 4da8bc110..f2b9654b3 100644 --- a/content/07.pathogenesis.md +++ b/content/07.pathogenesis.md @@ -238,6 +238,7 @@ Another area of interest is whether SARS-CoV-2 is likely to induce similar chang For example, because of the high level of sequence homology between SARS-CoV-2 and SARS-CoV, it has been hypothesized that sera from convalescent SARS-CoV patients might show some efficacy in cross-neutralizing SARS-CoV-2-S-driven entry [@doi:10.1016/j.cell.2020.02.052]. However, despite the high level of sequence homology, certain protein structures might be immunologically distinct, which would be likely to prohibit effective cross-neutralization across different SARS species [@doi:10.1101/2020.03.21.990770]. Consequently, proteomic analyses of SARS-CoV might also provide some essential information regarding the new pathogen [@doi:10.1073/pnas.0407992101; @doi:10.1016/j.bbrc.2004.02.074]. + Considering the paucity of omics-level big data sets for SARS-CoV-2 currently available, existing data hubs that contain information for other coronaviruses such as UniProt, NCBI Genome Database, The Immune Epitope Database and Analysis Resource (IEDB), and The Virus Pathogen Resource (ViPR) will serve as useful resources for computational and bioinformatics research on SARS-CoV-2. Using such databases, the systems-level reconstruction of the protein-protein interaction (PPI) will enable the generation of hypotheses about the mechanism of action of SARS-CoV-2 and suggest potential drug targets. In an initial study [@doi:10.1101/2020.03.22.002386], 26 of the 29 SARS-CoV-2 proteins were cloned and expressed in HEK293T kidney cells, allowing for the identification of 332 high-confidence human proteins interacting with them. @@ -281,7 +282,7 @@ The SARS-CoV-2 mutation rate is moderate compared to other RNA viruses [@doi:10. Nevertheless, genomic analyses have yielded statistical evidence of ongoing evolution. There are two known variants of the spike protein that differ by a single amino acid at position 614 (G614 and D614), and there is evidence that G614 had become more prevalent than D614 by June 2020 [@doi:10.1016/j.cell.2020.06.043]. While there is a hypothesis that this genomic change increased the SARS-CoV-2 infectivity and virulence, this hypothesis has not yet been tested due to a lack of data [@doi:10.1016/j.cell.2020.06.040]. -Another study [@doi:10.1016/j.meegid.2020.104351] identified 198 recurrent mutations in a dataset of 7666 curated sequences. +Another study [@doi:10.1016/j.meegid.2020.104351] identified 198 recurrent mutations in a dataset of 7,666 curated sequences. This pattern of convergent evolution at some sites could indicate that certain mutations confer an adaptive advantage. While it is evident that SARS-CoV-2 exhibits moderate potential for ongoing and future evolution, the relationship between mutations and pathogenicity is not yet known. Additional data is needed in order to understand patterns of evolutionary change and whether they are likely to affect virulence. diff --git a/content/08.transmission.md b/content/08.transmission.md index 6837693bd..4ab87c305 100644 --- a/content/08.transmission.md +++ b/content/08.transmission.md @@ -215,7 +215,7 @@ While several possible hypotheses for the apparent reduced impact of COVID-19 on 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 [@url:https://www.ifs.org.uk/inequality/chapter/are-some-ethnic-groups-more-vulnerable-to-covid-19-than-others/]. 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 [@doi:10.1001/jamanetworkopen.2020.18039].i +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 [@doi:10.1001/jamanetworkopen.2020.18039]. 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. We explore the role these social factors have played in shaping the COVID-19 pandemic broadly in the Discussion. diff --git a/content/20.treatments.md b/content/20.treatments.md index b41842042..05d7e97d1 100644 --- a/content/20.treatments.md +++ b/content/20.treatments.md @@ -237,7 +237,7 @@ Additionally, for these outcomes, the authors reported that 23 of 62 patients di 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 _post hoc_ 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. +Additionally, the observation of drastic disparities between pre-registration and published protocol could indicate p-hacking [@doi:10.1371/journal.pbio.1002106]. The design limitations mean that the conclusions cannot be generalized outside of the study. 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 standard care [@doi:10/drbx]. This trial was published in Chinese along with an abstract in English, and only the English abstract was read and interpreted for this review. @@ -305,7 +305,7 @@ Finally, findings from the Randomized Evaluation of COVID-19 Therapy (RECOVERY) This study used a randomized, open-label design to study the effects of HCQ compared to standard care at 176 hospitals in the United Kingdom [@doi:10.1056/NEJMoa2022926]. 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, 1561 were randomized into the HCQ arm while 3155 were randomized into the control arm. +Of the patients eligible to receive HCQ, 1,561 were randomized into the HCQ arm while 3,155 were randomized into the control arm. The demographics of the HCQ and control groups were similar in terms of average age (65 years), proportion female (approximately 38%), ethnic make-up (73% versus 76% white), and prevalence of pre-existing conditions (56% versus 57% overall). In the HCQ arm of the study, patients received 800 mg at baseline and again after 6 hours, then 400 mg at 12 hours and every subsequent 12 hours. The primary outcome analyzed was all-cause mortality, and patient vital statistics were reported by physicians upon discharge or death, or else at 28 days following HCQ administration if they remained hospitalized. @@ -430,17 +430,18 @@ Given the current pandemic, scientists and the medical community are scrambling For the general public in particular, whether nutraceuticals or dietary supplements can provide any prophylactic or therapeutic benefit has been a topic of interest. Nutraceuticals are classified as supplements with health benefits beyond their basic nutritional value [@doi:10.1080/10408390902841529; @doi:10.1038/nrcardio.2016.103]. 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 [@doi:10.1208/ps050325]. -Unlike pharmaceuticals, nutraceuticals do not fall under the responsibility of the FDA, but they are monitored as dietary supplements according to the Dietary Supplement, Health and Education Act 1994 (DSHEA) [@url:https://ods.od.nih.gov/About/DSHEA_Wording.aspx] and the Drug Administration Modernization Act 1997 [@url:https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/food-and-drug-administration-modernization-act-fdama-1997]. +Unlike pharmaceuticals, nutraceuticals do not entirely fall under the responsibility of the FDA, but they are monitored as dietary supplements according to the Dietary Supplement, Health and Education Act 1994 (DSHEA) [@url:https://ods.od.nih.gov/About/DSHEA_Wording.aspx] and the Food and Drug Administration Modernization Act 1997 [@url:https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/food-and-drug-administration-modernization-act-fdama-1997]. +Due to the increased sales of dietary supplements and nutraceuticals, the FDA established the Office of Dietary Supplement Programs (ODSP) in 1996 to increase surveillance. However, there is significant concern that these acts do not adequately protect the consumer as they ascribe responsibility on the manufacturers to ensure safety of the product before manufacturing or marketing [@doi:10.1080/17512433.2018.1464911]. Likewise, manufacturers are not required to register or 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 [@doi:10.1080/17512433.2018.1464911]. -In Europe, health claims are permitted on a product label only following authorization according to the European Food Safety Authority (EFSA) guidelines on nutrition and health claims [@url:https://ec.europa.eu/food/safety/labelling_nutrition/claims/register/public]. +In Europe, 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 [@url:https://ec.europa.eu/food/safety/labelling_nutrition/claims/register/public]. 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 [@doi:10.1111/bcp.13496]. These guidelines seem to provide more protection to consumers. Currently, there is a debate among scientists and regulatory authorities over developing a regulatory framework to deal with the challenges of safety and health claim substantiation for nutraceuticals [@doi:10.1111/bcp.13496; @doi:10.1080/17512433.2018.1464911]. -As a result, studies of nutraceuticals do not necessarily follow the same rigorous clinical trial framework used for pharmaceuticals. +As a result, studies of supplements and nutraceuticals do not necessarily follow the same rigorous clinical trial framework used for pharmaceuticals. -Nutraceuticals purported to 'boost' the immune response, reduce immunopathology, exhibit antiviral activities or prevent acute respiratory distress syndrome (ARDS) are being considered for their potential therapeutic value [@doi:10/ggkd3b]. +Nutraceuticals and supplements purported to "boost" the immune response, reduce immunopathology, exhibit antiviral activities, or prevent acute respiratory distress syndrome (ARDS) are being considered for their potential therapeutic value [@doi:10/ggkd3b]. 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) [@doi:10.1002/jmv.25707]. _In vitro_ and _in vivo_ 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 (TLR7) [@doi:10.1016/j.pcad.2020.02.007]. @@ -448,7 +449,7 @@ While promising, further animal and human studies are required to assess the the ##### n-3 PUFA -One nutraceutical that has been explored for beneficial effects against various viral infections is n-3 PUFA [@doi:10.1002/jmv.25707], such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). +One supplement that has been explored for beneficial effects against various viral infections is n-3 PUFA [@doi:10.1002/jmv.25707], such as 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 [@doi:10.1039/c9fo01742a]. They can mediate inflammation and therefore may have the capacity to modulate the adaptive immune response [@doi:10.1111/j.1365-2125.2012.04374.x; @doi:10.1039/c9fo01742a; @doi:10.1038/nrcardio.2016.103]. Another potential mechanism that has led to interest in n-3 PUFA for viral infections 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 [@doi:10.1016/j.immuni.2014.02.009]. @@ -468,13 +469,13 @@ The increased risk of thrombotic complications in COVID-19 infected patients was Considering that there is significant evidence that n-3 fatty acids and other fish oil-derived lipids possess antithrombotic properties and anti-inflammatory properties [@doi:10.1016/j.prostaglandins.2018.09.005; @doi:10.1016/j.blre.2020.100694], they may have therapeutic value against the prothrombotic complications of COVID-19. Based on concern among the medical community that the use of investigational therapeutics on COVID-19 patients already on antiplatelet therapies due to a pre-existing comorbidities may lead to issues with dosing and drug choice, and/or negative drug-drug interactions [@doi:10.1016/j.jacc.2020.04.031], this supplementation holds particular interest for the treatment of patients already receiving pharmaceutical antiplatelet therapies. As a result, the use of other therapeutics, such as dietary sources of n-3 fatty acids or nutraceuticals with antiplatelet activities, may be beneficial and warrant further investigation. -A new clinical trial [@clinicaltrials:NCT04412018] is currently recruiting COVID-19 positive patients to investigate the anti-inflammatory activity of a recently developed, highly purified derivative of EPA known as icosapent ethyl (Vascepa ^TM^) [@doi:10.1056/NEJMoa1812792]. +A new clinical trial [@clinicaltrials:NCT04412018] 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^TM^) [@doi:10.1056/NEJMoa1812792]. Other randomized controlled trials are in the preparatory stages with the intention of investigating the administration of EPA and other bioactive compounds to COVID-19 positive patients to determine whether anti-inflammatory effects or disease state improvements are observed [@clinicaltrials:NCT04335032; @clinicaltrials:NCT04323228]. 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 [@doi:10.3390/ijms21093104]. -It should be noted that the overall lack of human studies in this area means there is limited evidence as to whether these nutraceuticals could affect COVID-19 infection. +It should be noted that the overall lack of human studies in this area means there is limited evidence as to whether these supplements and nutraceuticals could affect COVID-19 infection. Consequently, clinical trials have been proposed and many are in the preparatory stages. These trials will investigate whether the anti-inflammatory potential of n-3 PUFA and their derivatives is beneficial in the treatment of COVID-19. -Therefore, the evidence is not present to draw conclusions about whether n-3 PUFA will be useful in treating COVID-19, but as there is likely little harm associated with a diet rich in fish oils, interest in this nutraceutical by the general public is unlikely to have negative effects. +Therefore, the evidence is not present to draw conclusions about whether n-3 PUFA will be useful in treating COVID-19, but as there is likely little harm associated with a diet rich in fish oils, interest in these products by the general public is unlikely to have negative effects. ##### Zinc @@ -493,7 +494,7 @@ Clinical trial data supports the utility of zinc to diminish the duration and se In coronaviruses specifically, _in vitro_ evidence demonstrates that the combination of zinc (Zn2+) and zinc ionophores (pyrithione) can interrupt the replication mechanisms of SARS-CoV-GFP (a fluorescently tagged SARS-CoV) and a variety of other RNA viruses [@doi:10.1371/journal.ppat.1001176; @doi:10.1016/j.antiviral.2014.12.015]. Currently, there are over twenty clinical trials registered with the intention to use zinc in a preventative or therapeutic manner. However, many of these trials proposed the use of zinc in conjunction with hydroxychloroquine and azithromycin [@clinicaltrials:NCT04370782; @clinicaltrials:NCT04377646; @clinicaltrials:NCT04395768; @clinicaltrials:NCT04373733], and it is not known how the lack of evidence supporting the use of hydroxychloroquine will affect investigation of zinc. -Other trials, however, are investigating zinc in conjunction with other nutrients such as vitamin C or n-3 PUFA [@clinicaltrials:NCT04342728; @clinicaltrials:NCT04323228]. +Other trials, however, are investigating zinc in conjunction with other supplements such as vitamin C or n-3 PUFA [@clinicaltrials:NCT04342728; @clinicaltrials:NCT04323228]. 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, maintaining a healthy diet to ensure an adequate zinc status may be advisable for individuals seeking to reduce their likelihood of infection. @@ -518,7 +519,7 @@ As summarized by Carr [@doi:10.1186/s13054-020-02851-4] the trial will not be co Another trial in Italy [@clinicaltrials:NCT04323514] intends to deliver a 10 g infusion of vitamin C to 500 severe COVID-19 patients with pneumonia to assess in-hospital mortality over a 72 hr period as the primary outcome. The trial is currently recruiting and is due to run until March 2021. We will not know how effective vitamin C is as a therapeutic for quite some time due to the length of both trials. -These are not the only trials investigating the potential value of vitamin C, as there are currently (as of October 2020) over twenty trials registered with clinicaltrials.gov that are either recruiting or are currently in preparation. +These are not the only trials investigating the potential value of vitamin C, as there are currently (as of October 2020) over fifteen trials registered with clinicaltrials.gov that are either recruiting or are currently in preparation. When completed, the trials will provide crucial evidence on the efficacy of vitamin C as a therapeutic for COVID-19 infection. Thus, some evidence suggests that vitamin C supplementation or infusion can shorten the duration of a cold, reduce an individual's susceptibility to infections, and shorten a patient's stay in an ICU when administered at high doses, but we don't yet understand if these findings apply to COVID-19. There are ongoing trials in China and Italy that will inform our understanding of the therapeutic value of vitamin C supplementation for COVID-19. @@ -551,7 +552,7 @@ These studies are supported by several others that indicate that vitamin D statu 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 (CRP), 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. Despite these studies potentially linking vitamin D status with COVID-19 severity, an examination of the UK Biobank did not support this thesis [@doi:10.1016/j.dsx.2020.04.050]. This analysis examined 25-hydroxyvitamin D concentrations in 348,598 UK Biobank participants, of which 449 were SARS-CoV-2 positive. -However, this study has caused considerable debate that will likely be settled following further studies [@doi:10.1111/cen.14276; 10.1016/j.dsx.2020.05.046]. +However, this study has caused considerable debate that will likely be settled following further studies [@doi:10.1111/cen.14276; @doi:10.1016/j.dsx.2020.05.046]. There is significant interest in the link between vitamin D and COVID-19, hence the multitude of studies published in the literature of varying quality and the clinical trials underway. One trial is currently 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 patients infected with COVID-19 or whether vitamin D prevents patient deterioration [@clinicaltrials:NCT04334005]. Other trials are also underway examining various factors including mortality, symptom recovery, severity of disease, rates of ventilation, inflammatory markers such as CRP and IL-6, blood cell counts, and the prophylactic capacity of vitamin D administration [@clinicaltrials:NCT04385940; @clinicaltrials:NCT04334005; @clinicaltrials:NCT04411446; @clinicaltrials:NCT04344041]. @@ -559,7 +560,7 @@ Concomitant administration of vitamin D with pharmaceuticals such as aspirin [@c While there is increasing evidence that vitamin D status is linked to COVID-19 outcomes, the effectiveness of its supplementation remains open for debate. Once again, supplementation of vitamin D and maintaining a healthy diet for optimum vitamin D status is unlikely to carry major health risks while the possible link between vitamin D status and COVID-19 is investigated. -However, pursuing to elevate vitamin D levels through sunlight exposure does carry additional risks, as many densely populated cities around the world are utilizing ‘stay in place’ orders to enforce social distancing guidelines. +However, pursuing to elevate vitamin D levels through sunlight exposure does carry additional risks, as many densely populated cities and countries around the world are sporadically utilizing "shelter in place" orders to enforce social distancing guidelines, especially with cases rising again as winter 2020 approaches. Given the lack of conclusive evidence in support of vitamin D supplementation, it is not clear that these guidelines present additional risk. However, to the extent that people are able to maintain safe exposure to sunlight, there is a possibility that it could improve endogenous synthesis of vitamin D, potentially strengthening the immune system. @@ -597,11 +598,11 @@ Consequently, several investigations are underway to investigate the prophylacti However, blind use of conventional probiotics for COVID-19 is cautioned against until the pathogenesis of SARS-CoV-2 is further established [@doi:10/d2qq]. 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. -##### Nutraceutical Conclusions +##### Nutraceutical and Dietary Supplement Conclusions 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 infections. -Nevertheless, optimal nutritional status will undoubtedly prime an individual’s immune system to protect against the effects of acute respiratory viral infections by supporting normal maintenance of the immune system [@doi:10.3390/nu12041181; @doi:10.3390/nu12051466]. -Nutritional strategies and the use of nutraceuticals will also undoubtedly play a role in the treatment of hospitalized patients, as malnutrition is a risk to COVID-19 patients [@doi:10.1038/s41430-020-0664-x]. +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 [@doi:10.3390/nu12041181; @doi:10.3390/nu12051466]. +Nutritional strategies can also play a role in the treatment of hospitalized patients, as malnutrition is a risk to COVID-19 patients [@doi:10.1038/s41430-020-0664-x]. 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. However, many supplements and nutraceuticals designed for various ailments are available in the United States and beyond that are not strictly regulated [@doi:10.1080/10408398.2019.1592107]. Indeed, there can be safety and efficacy concerns associated with many of these products. @@ -609,7 +610,7 @@ Often, the vulnerable members of society can be exploited in this regard and unf The Food and Drug Administration (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 [@url:https://www.fda.gov/news-events/press-announcements/coronavirus-update-fda-and-ftc-warn-seven-companies-selling-fraudulent-products-claim-treat-or]. In light of these serious occurrences, it is pertinent to clarify that the nutraceuticals discussed in this review have been selected because of their possible relevance to the biological mechanisms that can beneficially affect viral and respiratory infections and because they are currently under clinical investigation. Therefore, further intensive investigation is required to establish the effects of these nutraceuticals, if any, against COVID-19. -Until 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 [@url:https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html], along with following social distancing measures, “stay in place” guidelines, expansive testing, and contact tracing [@doi:10.1101/2020.03.27.20045815; @doi:10.3201/eid2608.201093]. +Until 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 [@url:https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html], along with following social distancing measures, "shelter in place" guidelines, expansive testing, and contact tracing [@doi:10.1101/2020.03.27.20045815; @doi:10.3201/eid2608.201093]. ### Biologics @@ -757,7 +758,7 @@ Several studies following up on these findings identified various S-glycoprotein The passive transfer of immune serum containing nAbs from SARS-CoV-infected mice resulted in protection of naïve mice from viral lower respiratory tract infection upon intranasal challenge [@doi:10.1128/jvi.78.7.3572-3577.2004]. Similarly, a meta-analysis suggested that administration of plasma from recovered SARS-CoV patients reduced mortality upon SARS-CoV infection [@doi:10.1093/infdis/jiu396]. Similar results were observed in MERS-CoV infection during the second coronavirus-related epidemic of the 21st century. -In these cases, neutralizing antibodies were identified against various epitopes of the RBD of the S glycoprotein [@doi:10.1073/pnas.1402074111; doi:10.1128/JVI.00912-14]. +In these cases, neutralizing antibodies were identified against various epitopes of the RBD of the S glycoprotein [@doi:10.1073/pnas.1402074111; @doi:10.1128/JVI.00912-14]. Coronaviruses use trimeric spike (S) glycoproteins on their surface to bind to host cell receptors, such as ACE2, allowing for cell entry [@doi:10.1016/j.cell.2020.02.052; @doi:10.1016/j.cell.2020.02.058]. Each S glycoprotein protomer is comprised of an S1 domain, also called the receptor binding domain (RBD), and an S2 domain. The S1 domain binds to host cell receptors while the S2 domain facilitates the fusion between the viral envelope and host cell membranes [@doi:10.1517/14712590902763755]. @@ -797,7 +798,7 @@ Among these IFNs, IFN-𝛽 has already been found to strongly inhibit the replic 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 [@doi:10.1016/j.virusres.2014.07.024]. 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. -SNG001 was already shown to be effective in reducing viral load in an _in vivo_ model of swine flu and _in vitro_ models of other coronavirus infections [@url:https://www.synairgen.com/wp-content/uploads/2020/03/200318-Synairgen-to-start-trial-of-SNG001-in-COVID-19-imminently-.pdf'. +SNG001 was already shown to be effective in reducing viral load in an _in vivo_ model of swine flu and _in vitro_ models of other coronavirus infections [@synairgen-SNG001]. 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 [@url:https://www.synairgen.com/wp-content/uploads/2020/07/200720-Synairgen-announces-positive-results-from-trial-of-SNG001-in-hospitalised-COVID-19-patients.pdf]. They also reported that patients in the treatment group showed greater recovery and lower breathlessness. However, given that this information was released in a press release rather than in a manuscript and thus cannot be thoroughly reviewed, these findings should be considered preliminary. @@ -814,8 +815,8 @@ If H1N1 vaccine development provides any indication, considering developing and The first critical step towards developing a vaccine against SARS-CoV-2 was characterizing the target, which fortunately happened early in the COVID-19 outbreak with the sequencing and dissemination of the viral genome [@url:https://www.who.int/csr/don/12-january-2020-novel-coronavirus-china/en/]. The Coalition for Epidemic Preparedness Innovations (CEPI) is coordinating global health agencies and pharmaceutical companies to develop vaccines against SARS-CoV-2. -There are over 100 vaccine candidates against SARS-CoV-2 in clinical trials. -Of the 78 active vaccine programs, 73 were in the preclinical or exploratory stage [@doi:10.1038/d41573-020-00073-5]. +As of September 2020, there are over 180 vaccine candidates against SARS-CoV-2 in development [@doi:10.1038/s41586-020-2798-3]. +Of the 78 active vaccine programs in April 2020, 73 were in the preclinical or exploratory stage [@doi:10.1038/d41573-020-00073-5]. 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. Experience in the field of oncology is encouraging COVID-19 vaccine developers to use next-generation approaches to vaccine development, which have led to the great diversity of vaccine development programs [@url:https://www.the-scientist.com/news-opinion/newer-vaccine-technologies-deployed-to-develop-covid-19-shot-67152]. 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 @fig:vaccines). @@ -840,7 +841,7 @@ It has been shown that electroporation can enhance vaccine efficacy by up to 100 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 [@doi:10.4161/hv.24702]. 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 U.S. Food and Drug Administration (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. +Approved by the 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. Participants in Experimental Group 1 will receive one intradermal injection of 1.0 milligram (mg) of INO-4800 followed by electroporation using the CELLECTRA® 2000 device twice, administered at Day 0 and Week 4. Participants in Experimental Group 2 will receive two intradermal injections of 1.0 mg (total 2.0 mg per dosing visit) of INO-4800 followed by electroporation using the CELLECTRA® 2000 device, administered at Day 0 and Week 4. @@ -896,8 +897,8 @@ The second injection led to severe systemic adverse events for three of the part The reported localized adverse events from the second dose were similar to those from the first. In summary, mRNA vaccines are promising tools in the prevention and control of pandemics because they may sidestep many challenges associated with traditional vaccine design and manufacturing. -mRNA-1273 is the only RNA vaccine for SARS-CoV-2 for which preliminary results are available. -This early in the development process, placebo-blinded and randomized results are not yet available, but the initial results are promising. + +As of August 2020, placebo-blinded and randomized results for mRNA vaccines are not yet available, but the initial results are promising. In the dose ranging study, even the lowest dose of 25 μg of mRNA-1273 appeared to be sufficient to induce an immunogenicity profile comparable to that observed in convalescent plasma and appeared to be well tolerated among the population of healthy, non-pregnant participants from 18-55 years of age. Based on the preliminary results from mRNA-1273 [@doi:10.1056/NEJMoa2022483], a new trial aims to enroll 30,000 participants who will be randomized for two injections of 100 μg of mRNA-1273 or placebo, again spaced 28 days apart [@clinicaltrials:NCT04470427]. @@ -953,29 +954,3 @@ At present, a number of promising avenues continue to be explored. Potential therapeutics currently being studied target the SARS-CoV-2 or modify the host environment through many different mechanisms. Here, the relationship between the virus and several therapeutics described above are visualized. ](images/N001-LifeCyclePlusDrugs.png){#fig:therapeutics secno=1} - -##### Trained Immunity - -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 [@doi:10.1038/s41577-020-0285-6], 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 [@doi:10.1016/j.cell.2020.04.042]. - -One type of stimulus which research indicates can induce trained immunity is bacillus Calmette-Guerin (BCG) vaccination. -BCG is an attenuated form of bacteria _Mycobacterium bovis_. -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 [@doi:10.1016/j.cell.2020.04.042; @clinicaltrials:NCT04327206; @clinicaltrials:NCT04328441; @clinicaltrials:NCT04348370; @clinicaltrials:NCT04350931; @clinicaltrials:NCT04362124; @clinicaltrials:NCT04369794; @clinicaltrials:NCT04373291; @clinicaltrials:NCT04379336; @clinicaltrials:NCT04384549; @clinicaltrials:NCT04387409; @clinicaltrials:NCT04414267; @clinicaltrials:NCT04417335; @clinicaltrials:NCT04435379; @clinicaltrials:NCT04439045]. - -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 (>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 [@doi:10.1016/j.cell.2020.04.042]. -Currently it is unclear whether this correlation has any connection to trained immunity. -Many possible confounding factors are also like 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. -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., [@doi:10.1016/j.chom.2020.04.009; @doi:10.1016/j.chom.2020.05.009; @doi:10.1016/j.cell.2020.04.042; @doi:10.1016/j.chom.2020.05.008]). -The article [@doi:10.1016/j.cell.2020.04.042] 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. diff --git a/content/50.discussion.md b/content/50.discussion.md index a566a5ce3..bace218dc 100644 --- a/content/50.discussion.md +++ b/content/50.discussion.md @@ -35,7 +35,7 @@ However, the most serious concern is cytokine release syndrome, when the body's 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 [@doi:10.1101/2020.06.22.20137273]. 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. +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. The potential for other drugs, such as tocilizumab, to reduce recovery time remains unclear, but some early results were promising. ### Additional Therapeutics of Interest @@ -87,7 +87,7 @@ This approach is necessary given the urgency of the situation as well as the ext 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 [@doi:10.1101/2020.02.26.964882; @url:https://www.diamond.ac.uk/covid-19/for-scientists/Main-protease-structure-and-XChem.html], and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits [@doi:10.1101/2020.02.26.964882]. +Currently, crystal structures of the SARS-CoV-2 main protease have recently been resolved [@doi:10.1038/s41586-020-2223-y; @url:https://www.diamond.ac.uk/covid-19/for-scientists/Main-protease-structure-and-XChem.html], and efforts are already in place to perform screens for small molecule inhibitors of the main protease, which have yielded potential hits [@doi:10.1038/s41586-020-2223-y]. 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. @@ -109,7 +109,7 @@ However, data clearly indicates that these orders impacted different socioeconom 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) [@doi:10.1101/2020.05.03.20084624]. 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 [@doi:10.1101/2020.05.03.20084624]. 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 [@doi:10.1101/2020.05.03.20084624]. -Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [@arXiv:2006.15195]. +Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [@arXiv:2006.15195], as well as in a very large data set from several US cities [@doi:10.1038/s41586-020-2923-3]. 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 [@url:https://mronline.org/wp-content/uploads/2020/06/2020-04-Frontline-Workers.pdf]. Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible [@doi:10.1002/ajim.23145]. @@ -145,7 +145,7 @@ Therefore, it is possible that chronic inflammation characteristic of these meta 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 [@doi:10/gddg84] and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders [@doi:10.5604/12321966.1120608]. 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 [@doi:10.1002/oby.22940; @doi:10.1002/oby.22993], suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues [@doi:10.1016/j.pcad.2020.07.002]. Chronic inflammation is a known outcome of chronic stress (e.g., [@doi:10.1067/mai.2000.110163; @doi:10.1037/0278-6133.21.6.531; @doi:10.1037/a0025536; @doi:10.1111/j.1467-8721.2006.00450.x]). -Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in @doi:10.1038/scientificamerican1205-92) and especially during the stress of the ongoing pandemic. +Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in [@doi:10.1038/scientificamerican1205-92]) and especially during the stress of the ongoing pandemic. A preprint [@doi:10.1101/2020.04.05.20054502] 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., [@doi:10.1073/pnas.1803222115]). @@ -185,8 +185,7 @@ This approach would carry its own ethical concerns, including the fact that many 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 [@doi:10.1136/medethics-2020-106460]. Allocation of interventions that may reduce suffering, including palliative care, has become critically important [@doi:10.1136/medethics-2020-106460; @doi:10.1080/15265161.2020.1788663]. 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 [@doi:10.1080/15265161.2020.1795538]. -For example, remdesivir, discussed below, is an antiviral produced by Gilead that has shown some promise for alleviating symptoms and reducing the duration of hospitalization. -Remdesivir 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 [@doi:10.1016/j.mayocp.2020.06.016; @doi:10.1080/15265161.2020.1795529]. +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 [@doi:10.1016/j.mayocp.2020.06.016; @doi:10.1080/15265161.2020.1795529]. Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them [@doi:10.1080/15265161.2020.1795529]. 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 [@doi:10.1080/15265161.2020.1795538]. 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. @@ -266,8 +265,8 @@ Attention to the social aspects of clinical trial enrollment must therefore be a Besides the direct harms caused by infection, many populations are in indirect risk of serious harm due to the social and economic effects of the pandemic and of the efforts needed to fight it. These might include individuals with substance use disorder [@doi:10.7326/M20-1141], victims of natural disasters [@doi:10.1038/s41558-020-0804-2], and victims of human trafficking [@doi:10.1016/j.eclinm.2020.100409]. The pandemic could also delay the fight against other major infectious diseases, such as HIV, malaria and tuberculosis, potentially leading to a further increase of mortality [@doi:10.25561/78670]. -Although they are beyond the scope of this paper, further research is needed in order to prevent these harms. ---> +Although they are beyond the scope of this paper, further research is needed in order to prevent these harms. +[There are already some policy recommendations in literature that we cite - we should probably direct folks there. I think we probably want a stronger synthesis and closing than this] --> ### Conclusions and Future Directions diff --git a/content/70.coi-contribs.md b/content/70.coi-contribs.md index 63162b629..0f3e4ec01 100644 --- a/content/70.coi-contribs.md +++ b/content/70.coi-contribs.md @@ -15,5 +15,5 @@ ### Acknowledgements We thank Nick DeVito for assistance with the Evidence-Based Medicine Data Lab COVID-19 TrialsTracker data. -We thank Yael Evelyn Marshall who contributed writing (original draft) as well as reviewing and editing of pieces of the text but who did not formally approve the manuscript. +We thank Yael Evelyn Marshall who contributed writing (original draft) as well as reviewing and editing of pieces of the text but who did not formally approve the manuscript, as well as Ronnie Russell, who contributed text to and helped develop the structure of the manuscript early in the writing process. We are grateful to the following contributors for reviewing pieces of the text: Nadia Danilova, James Eberwine and Ipsita Krishnan. diff --git a/content/90.back-matter.md b/content/90.back-matter.md index 98c2306dc..28f00b559 100644 --- a/content/90.back-matter.md +++ b/content/90.back-matter.md @@ -5,3 +5,4 @@ [@tag:Park2020_distancing]: url:https://github.com/parksw3/Korea-analysis/blob/master/v1/korea.pdf +[@synairgen-SNG001]: https://www.synairgen.com/wp-content/uploads/2020/03/200318-Synairgen-to-start-trial-of-SNG001-in-COVID-19-imminently-.pdf diff --git a/content/metadata.yaml b/content/metadata.yaml index d65d528c0..9a89d011a 100644 --- a/content/metadata.yaml +++ b/content/metadata.yaml @@ -133,23 +133,24 @@ authors: - Department of Clinical Sciences, Lund University, Lund, Sweden coi: string: Employee and shareholder of SAGA Diagnostics AB. - lastapproved: !!str 2020-11-07 + lastapproved: !!str 2020-11-11 - github: rays1987 - name: Sadipan Ray + name: Sandipan Ray initials: SR orcid: 0000-0002-9960-5768 email: sandipan.ray@pennmedicine.upenn.edu contributions: - Writing - Original Draft + - Writing - Review & Editing code of conduct: - confirmed: No + confirmed: Yes affiliations: - Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA - Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA coi: string: "None" - lastapproved: !!str 2020-03-25 + lastapproved: !!str 2020-11-11 - github: LucyMcGowan name: Lucy D\'Agostino McGowan @@ -191,22 +192,6 @@ authors: lastapproved: !!str 2020-11-10 funders: - John W. and Jeanne M. Rowe Center for Research in Virology - - - github: rmrussell - name: Ronnie M. Russell - initials: RMR - orcid: 0000-0003-1484-4207 - email: russr@pennmedicine.upenn.edu - contributions: - - Writing - Original Draft - - Writing - Review & Editing - code of conduct: - confirmed: No - affiliations: - - Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA - coi: - string: "None" - lastapproved: !!str 2020-04-07 - github: aadattoli name: Anna Ada Dattoli @@ -364,13 +349,13 @@ authors: - Writing - Original Draft - Writing - Review & Editing code of conduct: - confirmed: No + confirmed: Yes affiliations: - Biomedical Science, Midwestern University, Glendale, AZ, United States of America - Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada coi: string: "None" - lastapproved: !!str 2020-04-09 + lastapproved: !!str 2020-11-11 funders: - the American Heart Association (20AIREA35050015) - @@ -383,12 +368,12 @@ authors: - Writing - Original Draft - Writing - Review & Editing code of conduct: - confirmed: No + confirmed: Yes affiliations: - Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America coi: string: "None" - lastapproved: !!str 2020-04-10 + lastapproved: !!str 2020-11-11 - github: jinhui2 name: Jinhui Wang @@ -420,7 +405,7 @@ authors: confirmed: yes coi: string: "None" - lastapproved: !!str 2020-04-14 + lastapproved: !!str 2020-11-11 funders: - NIH Medical Scientist Training Program T32 GM07170 - @@ -439,7 +424,7 @@ authors: confirmed: yes coi: string: "None" - lastapproved: !!str 2020-04-16 + lastapproved: !!str 2020-11-11 funders: - NIH Medical Scientist Training Program T32 GM07170 - @@ -487,12 +472,13 @@ authors: - Writing - Original Draft - Investigation affiliations: + - 1DaySooner, Delaware, United States of America - Risk and Health Communication Research Center, School of Public Health, University of Haifa, Haifa, Israel code of conduct: confirmed: yes coi: string: "None" - lastapproved: !!str 2020-04-28 + lastapproved: !!str 2020-11-11 - github: soumitagh name: Soumita Ghosh @@ -604,6 +590,7 @@ authors: email: dziakj1@gmail.com contributions: - Writing - Original Draft + - Writing - Review & Editing affiliations: - Edna Bennett Pierce Prevention Research Center, The Pennsylvania State University, University Park, PA, United States of America code of conduct: @@ -688,7 +675,7 @@ authors: confirmed: yes coi: string: "None" - lastapproved: !!str 2020-08-03 + lastapproved: !!str 2020-11-11 - github: SystemsResearch name: Dimitri Perrin @@ -722,7 +709,7 @@ authors: confirmed: Yes coi: string: "None" - lastapproved: !!str 2020-08-07 + lastapproved: !!str 2020-11-11 - github: shiktadas name: Shikta Das