Abstract/Text: Importance: The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection.
Observations: No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19.
Conclusions and Relevance: The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.

Abstract/Text: Global sequencing of genomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued to reveal new genetic variants that are the key to unraveling its early evolutionary history and tracking its global spread over time. Here we present the heretofore cryptic mutational history and spatiotemporal dynamics of SARS-CoV-2 from an analysis of thousands of high-quality genomes. We report the likely most recent common ancestor of SARS-CoV-2, reconstructed through a novel application and advancement of computational methods initially developed to infer the mutational history of tumor cells in a patient. This progenitor genome differs from genomes of the first coronaviruses sampled in China by three variants, implying that none of the earliest patients represent the index case or gave rise to all the human infections. However, multiple coronavirus infections in China and the United States harbored the progenitor genetic fingerprint in January 2020 and later, suggesting that the progenitor was spreading worldwide months before and after the first reported cases of COVID-19 in China. Mutations of the progenitor and its offshoots have produced many dominant coronavirus strains that have spread episodically over time. Fingerprinting based on common mutations reveals that the same coronavirus lineage has dominated North America for most of the pandemic in 2020. There have been multiple replacements of predominant coronavirus strains in Europe and Asia as well as continued presence of multiple high-frequency strains in Asia and North America. We have developed a continually updating dashboard of global evolution and spatiotemporal trends of SARS-CoV-2 spread (http://sars2evo.datamonkey.org/).

© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Abstract/Text: BACKGROUND: The SARS-CoV-2 variant of concern, omicron, appears to be less severe than delta. We aim to quantify the differences in symptom prevalence, risk of hospital admission, and symptom duration among the vaccinated population.
METHODS: In this prospective longitudinal observational study, we collected data from participants who were self-reporting test results and symptoms in the ZOE COVID app (previously known as the COVID Symptoms Study App). Eligible participants were aged 16-99 years, based in the UK, with a body-mass index between 15 and 55 kg/m2, had received at least two doses of any SARS-CoV-2 vaccine, were symptomatic, and logged a positive symptomatic PCR or lateral flow result for SARS-CoV-2 during the study period. The primary outcome was the likelihood of developing a given symptom (of the 32 monitored in the app) or hospital admission within 7 days before or after the positive test in participants infected during omicron prevalence compared with those infected during delta prevalence.
FINDINGS: Between June 1, 2021, and Jan 17, 2022, we identified 63 002 participants who tested positive for SARS-CoV-2 and reported symptoms in the ZOE app. These patients were matched 1:1 for age, sex, and vaccination dose, across two periods (June 1 to Nov 27, 2021, delta prevalent at >70%; n=4990, and Dec 20, 2021, to Jan 17, 2022, omicron prevalent at >70%; n=4990). Loss of smell was less common in participants infected during omicron prevalence than during delta prevalence (16·7% vs 52·7%, odds ratio [OR] 0·17; 95% CI 0·16-0·19, p<0·001). Sore throat was more common during omicron prevalence than during delta prevalence (70·5% vs 60·8%, 1·55; 1·43-1·69, p<0·001). There was a lower rate of hospital admission during omicron prevalence than during delta prevalence (1·9% vs 2·6%, OR 0·75; 95% CI 0·57-0·98, p=0·03).
INTERPRETATION: The prevalence of symptoms that characterise an omicron infection differs from those of the delta SARS-CoV-2 variant, apparently with less involvement of the lower respiratory tract and reduced probability of hospital admission. Our data indicate a shorter period of illness and potentially of infectiousness which should impact work-health policies and public health advice.
FUNDING: Wellcome Trust, ZOE, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, and Medical Research Council.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Abstract/Text: UPDATES: This is the thirteenth version (twelfth update) of the living guideline, replacing earlier versions (available as data supplements). New recommendations will be published as updates to this guideline.
CLINICAL QUESTION: What is the role of drugs in the treatment of patients with covid-19?
CONTEXT: The evidence base for therapeutics for covid-19 is evolving with numerous randomised controlled trials (RCTs) recently completed and under way. Emerging SARS-CoV-2 variants (such as omicron) and subvariants are changing the role of therapeutics. This update does not include any changes to the strength or direction of recommendations, but rather concerns i) the use of nirmatrelvir/ritonavir, now considered to be an option also for pregnant and breastfeeding women with non-severe covid-19, and ii) evidence of reduction of in vitro neutralisation activity supporting the strong recommendations against the use of the neutralising monoclonal antibodies sotrovimab and casirivimab-imdevimab.
RECOMMENDATIONS: • Recommended for patients with severe or critical covid-19—strong recommendations for systemic corticosteroids, IL-6 receptor blockers (tocilizumab or sarilumab) in combination with corticosteroids, and baricitinib as an alternative to IL-6 receptor blockers, in combination with corticosteroids. Concerning the concomitant use of IL-6 receptor blockers (tocilizumab and sarilumab), and the JAK inhibitor baricitinib, these drugs may be combined, in addition to corticosteroids. • Recommended for patients with severe covid-19—a conditional recommendation for remdesivir. • Not recommended for patients with critical covid-19—a conditional recommendation against remdesivir. • Recommended for patients with non-severe covid-19 at highest risk of hospitalisation—a strong recommendation for nirmatrelvir/ritonavir; conditional recommendations for molnupiravir and remdesivir. • Not recommended for patients with non-severe covid-19—a conditional recommendation against systemic corticosteroids and colchicine; a strong recommendation against convalescent plasma; a recommendation against fluvoxamine, except in the context of a clinical trial. • Not recommended for patients with non-severe covid-19 at low risk of hospitalisation—a conditional recommendation against nirmatrelvir/ritonavir. • Not recommended for patients with severe or critical covid-19—a recommendation against convalescent plasma except in the context of a clinical trial; a conditional recommendation against the JAK inhibitors ruxolitinib and tofacitinib. • Not recommended, regardless of covid-19 disease severity—strong recommendations against hydroxychloroquine, lopinavir/ritonavir, sotrovimab, and casirivimab-imdevimab; and a recommendation against ivermectin except in the context of a clinical trial.
ABOUT THIS GUIDELINE: This living guideline from the World Health Organization (WHO) incorporates new evidence to dynamically update recommendations for covid-19 therapeutics. The Guideline Development Group (GDG) typically evaluates a therapy when the WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines, making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF, with a summary version here in The BMJ. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact.
FUTURE RECOMMENDATIONS: Recommendations on anticoagulation and updated recommendations on molnupiravir are planned for the next updates to this guideline.

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Abstract/Text: OBJECTIVES: To compare the clinical characteristics and chest CT findings of patients infected with Omicron and Delta variants and the original strain of COVID-19.
METHODS: A total of 503 patients infected with the original strain (245 cases), Delta variant (90 cases), and Omicron variant (168 cases) were retrospectively analyzed. The differences in clinical severity and chest CT findings were analyzed. We also compared the infection severity of patients with different vaccination statuses and quantified pneumonia by a deep-learning approach.
RESULTS: The rate of severe disease decreased significantly from the original strain to the Delta variant and Omicron variant (27% vs. 10% vs. 4.8%, p < 0.001). In the Omicron group, 44% (73/168) of CT scans were categorized as abnormal compared with 81% (73/90) in the Delta group and 96% (235/245, p < 0.05) in the original group. Trends of a gradual decrease in total CT score, lesion volume, and lesion CT value of AI evaluation were observed across the groups (p < 0.001 for all). Omicron patients who received the booster vaccine had less clinical severity (p = 0.015) and lower lung involvement rate than those without the booster vaccine (36% vs. 57%, p = 0.009).
CONCLUSIONS: Compared with the original strain and Delta variant, the Omicron variant had less clinical severity and less lung injury on CT scans.