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Competing risks data are commonly encountered in randomized clinical trials and observational studies. This paper considers the situation where the ending statuses of competing events have different clinical interpretations and/or are of simultaneous interest. In clinical trials, often more than one competing event has meaningful clinical interpretations even though the trial effects of different events could be different or even opposite to each other. In this paper, we develop estimation procedures and inferential properties for the joint use of multiple cumulative incidence functions (CIFs). Additionally, by incorporating longitudinal marker information, we develop estimation and inference procedures for weighted CIFs and related metrics. The proposed methods are applied to a COVID‐19 in‐patient treatment clinical trial, where the outcomes of COVID‐19 hospitalization are either death or discharge from the hospital, two competing events with completely different clinical implications. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic, caused by the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created an unprecedented threat to public health. The pandemic has been sweeping the globe, impacting more than 200 countries, with more outbreaks still lurking on the horizon. At the time of the writing, no approved drugs or vaccines are available to treat COVID-19 patients, prompting an urgent need to decipher mechanisms underlying the pathogenesis and develop curative treatments. To fight COVID-19, researchers around the world have provided specific tools and molecular information for SARS-CoV-2. These pieces of information can be integrated to aid computational investigations and facilitate clinical research. This paper reviews current knowledge, the current status of drug development and various resources for key steps toward effective treatment of COVID-19, including the phylogenetic characteristics, genomic conservation and interaction data. The final goal of this paper is to provide information that may be utilized in bioinformatics approaches and aid target prioritization and drug repurposing. Several SARS-CoV-2-related tools/databases were reviewed, and a web-portal named OverCOVID (http://bis.zju.edu.cn/overcovid/) is constructed to provide a detailed interpretation of SARS-CoV-2 basics and share a collection of resources that may contribute to therapeutic advances. These information could improve researchers' understanding of SARS-CoV-2 and help to accelerate the development of new antiviral treatments. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic saw unprecedented resources and funds driven into research for the development, and subsequent rapid distribution, of vaccines, diagnostics and directly acting antivirals (DAAs). DAAs have undeniably prevented progression and life-threatening conditions in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, there are concerns of antimicrobial resistance (AMR), antiviral resistance specifically, for DAAs. To preserve activity of DAAs for COVID-19 therapy, as well as detect possible mutations conferring resistance, antimicrobial stewardship and surveillance were rapidly implemented in England. This paper expands on the ubiquitous ongoing public health activities carried out in England, including epidemiologic, virologic and genomic surveillance, to support the stewardship of DAAs and assess the deployment, safety, effectiveness and resistance potential of these novel and repurposed therapeutics. [ABSTRACT FROM AUTHOR]

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic led to rapid vaccine development and large global vaccination schemes. However, patients with immune-mediated kidney disease, chronic kidney diseases and kidney transplant recipients show high non-response rates to vaccination despite more than three vaccinations and, consequently, reduced viral clearance capacity when infected while receiving certain immunosuppressants, carrying an elevated risk for coronavirus disease 2019 (COVID-19)-related morbidity and mortality. SARS-CoV-2 evolution has been characterized by the emergence of novel variants and spike mutations contributing to waning efficacy of neutralizing antibodies. To this end, the therapeutic field expands from vaccination towards a combined approach of immunization, pre-exposure prophylaxis and early post-exposure treatment using direct-acting antivirals and neutralizing monoclonal antibodies to treat early in the disease course and avoid hospitalization. This expert opinion paper from the Immunonephrology Working Group of the European Renal Association (ERA-IWG) summarizes available prophylactic and/or early treatment options (i.e. neutralizing monoclonal antibodies and direct-acting antivirals) of SARS-CoV-2-infected patients with immune-mediated kidney disease, chronic kidney disease and kidney transplant recipients. [ABSTRACT FROM AUTHOR]

I noticed a recently published paper named 'Is acupuncture effective in the treatment of COVID-19 related symptoms? Based on bioinformatics/network topology strategy' with great interest. I am inspired and also have some doubts, which are mainly about the active compounds of acupuncture treating COVID-19. The authors choose only two active compounds, which remains to be elucidated clearly with some criteria description. The 11 300 disease targets of COVID-19 were screened using the terms like the related symptoms, which might be other diseases' manifestations. So the better legends of Figures and Tables should be the terms like COVID-19-related symptoms, instead of COVID-19. [ABSTRACT FROM AUTHOR]

Acupuncture is an important part of Chinese medicine that has been widely used in the treatment of inflammatory diseases. During the coronavirus disease 2019 (COVID-19) epidemic, acupuncture has been used as a complementary treatment for COVID-19 in China. However, the underlying mechanism of acupuncture treatment of COVID-19 remains unclear. Based on bioinformatics/topology, this paper systematically revealed the multi-target mechanisms of acupuncture therapy for COVID-19 through text mining, bioinformatics, network topology, etc. Two active compounds produced after acupuncture and 180 protein targets were identified. A total of 522 Gene Ontology terms related to acupuncture for COVID-19 were identified, and 61 pathways were screened based on the Kyoto Encyclopedia of Genes and Genomes. Our findings suggested that acupuncture treatment of COVID-19 was associated with suppression of inflammatory stress, improving immunity and regulating nervous system function, including activation of neuroactive ligand–receptor interaction, calcium signaling pathway, cancer pathway, viral carcinogenesis, Staphylococcus aureus infection, etc. The study also found that acupuncture may have additional benefits for COVID-19 patients with cancer, cardiovascular disease and obesity. Our study revealed for the first time the multiple synergistic mechanisms of acupuncture on COVID-19. Acupuncture may play an active role in the treatment of COVID-19 and deserves further promotion and application. These results may help to solve this pressing problem currently facing the world. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) has spread rapidly throughout the globe. The spectrum of disease is broad but among hospitalized patients with COVID-19, respiratory failure from acute respiratory distress syndrome is the leading cause of mortality. There is an urgent need for an effective treatment. The current focus has been developing novel therapeutics, including antivirals, protease inhibitors, vaccines and targeting the overactive cytokine response with anti-cytokine therapy. The overproduction of early response proinflammatory cytokines results in what has been described as a "cytokine storm" is leading eventually to death when the cells fail to terminate the inflammatory response. Accumulating evidence shows that inflammatory cytokines induce selectin ligands that play a crucial role in the pathogenesis of inflammatory diseases by mediating leukocyte migration from the blood into the tissue. Thus, the selectins and selectin ligands represent a promising therapeutic target for the treatment of COVID-19. In this paper, potential pan-selectin inhibitors were identified employing a virtual screening using a docking procedure. For this purpose, the Asinex and ZINC databases of ligands, including approved drugs, biogenic compounds and glycomimetics, altogether 923,602 compounds, were screened against the P-, L- and E-selectin. At first, the experimentally confirmed inhibitors were docked into all three selectins' carbohydrate recognition domains to assess the suitability of the screening procedure. Finally, based on the evaluation of ligands binding, we propose 10 purchasable pan-selectin inhibitors to develop COVID-19 therapeutics. [ABSTRACT FROM AUTHOR]

Rejoinder: Improving precision and power in randomized trials for COVID-19 treatments using covariate adjustment, for binary, ordinal, and time-to-event outcomes An alternative estimator to consider for time-to-event outcomes is the augmented, inverse probability weighted estimator from Díaz I et al i . M. Zhang and B. Zhang describe a general approach for constructing covariate adjusted estimators that applies to many estimands. [Extracted from the article]

Benkeser et al. present a very informative paper evaluating the efficiency gains of covariate adjustment in settings with binary, ordinal, and time‐to‐event outcomes. The adjustment method focuses on estimating the marginal treatment effect averaged over the covariate distribution in both arms combined. The authors show that covariate adjustment can achieve power gains that could find answers more quickly. The suggested approach is an important weapon in the armamentarium against epidemics like COVID‐19. I recommend evaluating the procedure against more traditional approaches for conditional analyses (e.g., logistic regression) and against blinded methods of building prediction models followed by randomization‐based inference. [ABSTRACT FROM AUTHOR]

Dear Editor, We would like to thank Dr Kounis and his colleagues for taking interest in our paper and providing their valuable opinion.[1] In his letter, Dr Kounis highlights the possible use of corticosteroids in mild COVID-19. Google Scholar Crossref Search ADS PubMed WorldCat 6 Sarda R, Swain S, Ray A, Wig N. COVID-19 associated mucormycosis and evolving evidence. [Extracted from the article]

5 Saville, B. R., Koch, G. G. (2013) Estimating covariate-adjusted log hazard ratios in randomized clinical trials using Cox proportional hazards models and non-parametric randomization based analysis of covariance. Noteworthy is the fact that the FDA guidance remains silent on the use of covariate adjustments to correct for imbalances between treatment groups for purposes of producing unbiased estimates of the drug's effects. The advantages of covariate adjustment in the much simpler linear model context have been known for a while, and the method is popular with clinical trialists for its ability to improve the precision of treatment effect estimates with minimal assumptions. [Extracted from the article]

Objectives Immunocompromised patients have an increased risk of severe or prolonged COVID-19. Currently available drugs are registered to treat COVID-19 during the first 5 to 7 days after symptom onset. Data on the effectivity in immunocompromised patients with chronic non-resolving COVID-19 are urgently needed. Here, we report the outcome of patients treated with nirmatrelvir/ritonavir together with high-titer convalescent plasma (CP) in six immunocompromised patients with non-resolving COVID-19. Methods Immunocompromised patients with persisting COVID-19 (positive PCR with Ct values <30 for ≥20 days) received off-label therapy with nirmatrelvir/ritonavir. It was combined with CP containing BA.5 neutralizing titers of ≥1/640 whenever available. Follow-up was done by PCR and sequencing on nasopharyngeal swabs on a weekly basis until viral genome was undetectable consecutively. Results Five immunocompromised patients were treated with high-titer CP and 5 days of nirmatrelvir/ritonavir. One patient received nirmatrelvir/ritonavir monotherapy. Median duration of SARS-CoV-2 PCR positivity was 70 (range 20–231) days before nirmatrelvir/ritonavir treatment. In four patients receiving combination therapy, no viral genome of SARS-CoV-2 was detected on day 7 and 14 after treatment while the patient receiving nirmatrelvir/ritonavir monotherapy, the day 7 Ct value increased to 34 and viral genome was undetectable thereafter. Treatment was unsuccessful in one patient. In this patient, sequencing after nirmatrelvir/ritonavir treatment did not show protease gene mutations. Conclusions In immunocompromised patients with non-resolving COVID-19, the combination of nirmatrelvir/ritonavir and CP may be an effective treatment. Larger prospective studies are needed to confirm these preliminary results and should compare different treatment durations. [ABSTRACT FROM AUTHOR]

In many randomized clinical trials of therapeutics for COVID‐19, the primary outcome is an ordinal categorical variable, and interest focuses on the odds ratio (OR; active agent vs control) under the assumption of a proportional odds model. Although at the final analysis the outcome will be determined for all subjects, at an interim analysis, the status of some participants may not yet be determined, for example, because ascertainment of the outcome may not be possible until some prespecified follow‐up time. Accordingly, the outcome from these subjects can be viewed as censored. A valid interim analysis can be based on data only from those subjects with full follow‐up; however, this approach is inefficient, as it does not exploit additional information that may be available on those for whom the outcome is not yet available at the time of the interim analysis. Appealing to the theory of semiparametrics, we propose an estimator for the OR in a proportional odds model with censored, time‐lagged categorical outcome that incorporates additional baseline and time‐dependent covariate information and demonstrate that it can result in considerable gains in efficiency relative to simpler approaches. A byproduct of the approach is a covariate‐adjusted estimator for the OR based on the full data that would be available at a final analysis. [ABSTRACT FROM AUTHOR]

Ordinal endpoints are common in clinical studies. For example, many clinical trials for evaluating COVID-19 infection therapies have adopted an ordinal scale as recommended by the World Health Organization. Despite their importance in clinical studies, design methods for ordinal endpoints are limited; in practice, a dichotomized approach is often used for simplicity. Here, we introduce a Bayesian group sequential scheme to assess ordinal endpoints, which considers a proportional-odds (PO) model, a nonproportional-odds (NPO) model, and a PO/NPO-switch model to handle various scenarios. Extensive simulations are conducted to demonstrate desirable performance, and the R package BayesOrdDesign has been made publicly available. [ABSTRACT FROM AUTHOR]

Background The efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection. Methods This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection. Results In total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P =.49) and COVID-19 (26.3 vs 25.9 days; P =.35) was similar for both groups. Conclusions Administration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection. Clinical Trials Registration NCT04323800. [ABSTRACT FROM AUTHOR]

Background: The families of healthcare professionals are one of the most vulnerable groups whose lives have been severely damaged by the COVID-19 pandemic. So far, the experiences and perceptions of these individuals have not been explored. The present study aims to investigate the experiences and perceptions of the family members of the healthcare professionals during COVID-19.Methods: The present study is a qualitative research with a phenomenological design. The participants were 25 family members of healthcare professionals which were selected from the medical centres in Iran via purposeful sampling from August 2021 to October 2021. The sampling was kept on until the data became saturated. To collect data, individual semi-structured interviews were conducted online. The Colaizzi approach was used to analyse the data collected.Results: The findings of the study emerged as two main themes: psychological tension with five categories (indescribable fear and worry, longing to see their loved ones, patient stone, bitter farewell, fear of the future) and dignity with four categories (acclamation, appreciation, feeling proud, spiritual growth).Conclusion: During the COVID-19 pandemic, the family members of healthcare professionals have experienced dignity combined with the degrees of psychological tension which were beyond the experiences of the majority of people in the society, but similar to the psychological tension experienced by the families of COVID-19 victims. The families of healthcare workers are continuously anxious about the safety of their loved ones who are responsible to obtain the treatment of COVID-19 patients, which potentially jeopardizes their physical and psychological well-being. Therefore, the appreciation and support of people in the community of the family members of healthcare professionals have increased their tolerance. Healthcare providers can successfully promote the health of healthcare professionals' families by providing comprehensive assistance to healthcare personnel and their families. [ABSTRACT FROM AUTHOR]

The elevated levels of inflammatory cytokines have attracted much attention during the treatment of COVID-19 patients. The conclusions of current observational studies are often controversial in terms of the causal effects of COVID-19 on various cytokines because of the confounding factors involving underlying diseases. To resolve this problem, we conducted a Mendelian randomization analysis by integrating the GWAS data of COVID-19 and 41 cytokines. As a result, the levels of 2 cytokines were identified to be promoted by COVID-19 and had unsignificant pleiotropy. In comparison, the levels of 10 cytokines were found to be inhibited and had unsignificant pleiotropy. Among down-regulated cytokines, CCL2, CCL3 and CCL7 were members of CC chemokine family. We then explored the potential molecular mechanism for a significant causal association at a single cell resolution based on single-cell RNA data, and discovered the suppression of CCL3 and the inhibition of CCL3-CCR1 interaction in classical monocytes (CMs) of COVID-19 patients. Our findings may indicate that the capability of COVID-19 in decreasing the chemotaxis of lymphocytes by inhibiting the CCL3-CCR1 interaction in CMs. [ABSTRACT FROM AUTHOR]

Background Coronavirus disease 2019 (COVID-19) has spurred a boom in uncovering repurposable existing drugs. Drug repurposing is a strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication. Motivation Current works of drug repurposing for s evere a cute r espiratory s yndrome c or o na v irus 2 (SARS-CoV-2) are mostly limited to only focusing on chemical medicines, analysis of single drug targeting single SARS-CoV-2 protein, one-size-fits-all strategy using the same treatment (same drug) for different infected stages of SARS-CoV-2. To dilute these issues, we initially set the research focusing on herbal medicines. We then proposed a heterogeneous graph embedding method to signaled candidate repurposing herbs for each SARS-CoV-2 protein, and employed the variational graph convolutional network approach to recommend the precision herb combinations as the potential candidate treatments against the specific infected stage. Method We initially employed the virtual screening method to construct the 'Herb-Compound' and 'Compound-Protein' docking graph based on 480 herbal medicines, 12,735 associated chemical compounds and 24 SARS-CoV-2 proteins. Sequentially, the 'Herb-Compound-Protein' heterogeneous network was constructed by means of the metapath-based embedding approach. We then proposed the heterogeneous-information-network-based graph embedding method to generate the candidate ranking lists of herbs that target structural, nonstructural and accessory SARS-CoV-2 proteins, individually. To obtain precision synthetic effective treatments forvarious COVID-19 infected stages, we employed the variational graph convolutional network method to generate candidate herb combinations as the recommended therapeutic therapies. Results There were 24 ranking lists, each containing top-10 herbs, targeting 24 SARS-CoV-2 proteins correspondingly, and 20 herb combinations were generated as the candidate-specific treatment to target the four infected stages. The code and supplementary materials are freely available at https://github.com/fanyang-AI/TCM-COVID19. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a global pandemic and there is an urgent need to discover the therapy for COVID-19. In our original article, we first obtained the target proteins of acupuncture and related target genes of COVID-19 by searching English and Chinese databases, then Gene Ontology biological processes and enrichment analysis were performed on the overlapping targets of acupuncture with COVID-19. Moreover, the compound-target and compound-disease-target network was constructed. This is an innovative attempt to predict the potential benefits of acupuncture treatment for COVID-19. In this letter, we answered reader Zheng's comments. [ABSTRACT FROM AUTHOR]

Background Severely ill people with coronavirus disease 2019 (COVID-19) are at risk of acute kidney injury treated with renal replacement therapy (AKI-RRT). The understanding of the risk factors and outcomes for AKI-RRT is incomplete. Methods We prospectively collected data on the incidence, demographics, area of residence, time course, outcomes and associated risk factors for all COVID-19 AKI-RRT cases during the first two waves of the pandemic in Ontario, Canada. Results There were 271 people with AKI-RRT, representing 0.1% of all diagnosed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases. These included 10% of SARS-CoV-2 admissions to intensive care units (ICU). Median age was 65 years, with 11% <50 years, 76% were male, 47% non-White and 48% had diabetes. Overall, 59% resided in the quintile of Ontario neighborhoods with the greatest ethnocultural composition and 51% in the two lowest income quintile neighborhoods. Mortality was 58% at 30 days after RRT initiation, and 64% at 90 days. By 90 days, 20% of survivors remained RRT-dependent and 31% were still hospitalized. On multivariable analysis, people aged >70 years had higher mortality (odds ratio 2.4, 95% confidence interval 1.3, 4.6). Cases from the second versus the first COVID-19 wave were older, had more baseline comorbidity and were more likely to initiate RRT  >2 weeks after SARS-CoV-2 diagnosis (34% versus 14%; P < 0.001). Conclusions AKI-RRT is common in COVID-19 ICU admissions. Residency in areas with high ethnocultural composition and lower socioeconomic status are strong risk factors. Late-onset AKI-RRT was more common in the second wave. Mortality is high and 90-day survivors have persisting high morbidity. [ABSTRACT FROM AUTHOR]

Background: Azithromycin has been widely used in the management of COVID-19. However, the evidence on its actual effects remains disperse and difficult to apply in clinical settings. This systematic review and meta-analysis summarizes the available evidence to date on the beneficial and adverse effects of azithromycin in patients with COVID-19.Methods: The PRISMA 2020 statement criteria were followed. Randomized controlled trials (RCTs) and observational studies comparing clinical outcomes of patients treated with and without azithromycin, indexed until 5 July 2021, were searched in PubMed, Embase, The Web of Science, Scopus, The Cochrane Central Register of Controlled Trials and MedRXivs. We used random-effects models to estimate pooled effect size from aggregate data.Results: The initial search produced 4950 results. Finally, 16 studies, 5 RCTs and 11 with an observational design, with a total of 22 984 patients, were included. The meta-analysis showed no difference in mortality for those treated with or without azithromycin, in observational studies [OR: 0.90 (0.66-1.24)], RCTs [OR: 0.97 (0.87-1.08)] and also when both types of studies were pooled together [with an overall OR: 0.95 (0.79-1.13)]. Different individual studies also reported no significant difference for those treated with or without azithromycin in need for hospital admission or time to admission from ambulatory settings, clinical severity, need for intensive care, or adverse effects.Conclusions: The results presented in this systematic review do not support the use of azithromycin in the management of COVID-19. Future research on treatment for patients with COVID-19 may need to focus on other drugs. [ABSTRACT FROM AUTHOR]

Often HT ht is linear in I Y i . Suppose one postulates a model, likely misspecified, for HT ht , where HT ht is a vector of known basis functions. It is also equivalent to fitting HT ht using OLS. When HT ht , strategy (iii) has a very slight advantage. [Extracted from the article]

Time is of the essence in evaluating potential drugs and biologics for the treatment and prevention of COVID‐19. There are currently 876 randomized clinical trials (phase 2 and 3) of treatments for COVID‐19 registered on clinicaltrials.gov. Covariate adjustment is a statistical analysis method with potential to improve precision and reduce the required sample size for a substantial number of these trials. Though covariate adjustment is recommended by the U.S. Food and Drug Administration and the European Medicines Agency, it is underutilized, especially for the types of outcomes (binary, ordinal, and time‐to‐event) that are common in COVID‐19 trials. To demonstrate the potential value added by covariate adjustment in this context, we simulated two‐arm, randomized trials comparing a hypothetical COVID‐19 treatment versus standard of care, where the primary outcome is binary, ordinal, or time‐to‐event. Our simulated distributions are derived from two sources: longitudinal data on over 500 patients hospitalized at Weill Cornell Medicine New York Presbyterian Hospital and a Centers for Disease Control and Prevention preliminary description of 2449 cases. In simulated trials with sample sizes ranging from 100 to 1000 participants, we found substantial precision gains from using covariate adjustment–equivalent to 4–18% reductions in the required sample size to achieve a desired power. This was the case for a variety of estimands (targets of inference). From these simulations, we conclude that covariate adjustment is a low‐risk, high‐reward approach to streamlining COVID‐19 treatment trials. We provide an R package and practical recommendations for implementation. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the causative agent of coronavirus disease‐2019 (COVID‐19), a respiratory disease that varies in severity from mild to severe/fatal. Several risk factors for severe disease have been identified, notably age, male sex, and pre‐existing conditions such as diabetes, obesity, and hypertension. Several advancements in clinical care have been achieved over the past year, including the use of corticosteroids (e.g., corticosteroids) and other immune‐modulatory treatments that have now become standard of care for patients with acute severe COVID‐19. While the understanding of the mechanisms that underlie increased disease severity with age has improved over the past few months, it remains incomplete. Furthermore, the molecular impact of corticosteroid treatment on host response to acute SARS‐CoV‐2 infection has not been investigated. In this study, a cross‐sectional and longitudinal analysis of Ab, soluble immune mediators, and transcriptional responses in young (65 ≤ years) and aged (≥ 65 years) diabetic males with obesity hospitalized with acute severe COVID‐19 was conducted. Additionally, the transcriptional profiles in samples obtained before and after corticosteroids became standard of care were compared. The analysis indicates that severe COVID‐19 is characterized by robust Ab responses, heightened systemic inflammation, increased expression of genes related to inflammatory and pro‐apoptotic processes, and reduced expression of those important for adaptive immunity regardless of age. In contrast, COVID‐19 patients receiving steroids did not show high levels of systemic immune mediators and lacked transcriptional indicators of heightened inflammatory and apoptotic responses. Overall, these data suggest that inflammation and cell death are key drivers of severe COVID‐19 pathogenesis in the absence of corticosteroid therapy. [ABSTRACT FROM AUTHOR]

To describe the restructuring of services by British radiologists in response to evolving national guidelines and highlight the impact of the COVID-19 pandemic on the treatment of musculoskeletal (MSK) conditions. An online anonymised survey was distributed via the British Society of Skeletal Radiology (BSSR) members forum in November 2020. Responses were collated using a standardised Google form including 21 questions. 135 members of the BSSR completed the survey. 85% of respondents stopped performing corticosteroid injections (CSI) during the initial lockdown of the pandemic. This was primarily influenced by national guidelines. The majority of respondents initially abstained from offered CSI procedures, then by November 2020, 69% of respondents were providing CSI for high and low risk patients, 23% were only providing CSI for low-risk patients with 8% still not performing any CSI. 40% of respondents reported routinely obtaining specific written consent regarding the risk of COVID-19. Approximately, 11,000 CSI were performed by respondents between March and November 2020 with no reported significant COVID-19-related complications. Over 80% of BSSR members reported that the number of CSI procedures that they performed dropped by more than 80% compared to usual. 73% of respondents reported an increased backlog of patients awaiting treatment. The average waiting time for routine outpatient CSI treatment was > 12 weeks in 53% of responses, compared to 34% the previous year. The COVID-19 pandemic has had a significant impact on the clinical practices of MSK radiologists in the UK. Our survey highlights the rapid response of BSSR members as national guidelines evolved. Currently, the majority of respondents are performing CSI for musculoskeletal conditions when clinically indicated, with enhanced consent. However, the pandemic has resulted in increased waiting times – delaying the treatment of patients who may be suffering with significant pain and disability. Further research is warranted to provide guidance around both service recovery and provision of CSI around COVID-19 vaccination schedules. BSSR members responded rapidly to changing guidelines during the COVID-19 pandemic. The majority of respondents are currently performing CSI when clinically indicated. The pandemic has resulted in a significant increase in waiting times which will have a significant impact on UK musculoskeletal services. [ABSTRACT FROM AUTHOR]

The World Health Organization (WHO) has declared coronavirus disease 2019 (COVID-19) as pandemic in March 2020. Currently there is no specific effective treatment for COVID-19. The major cause of death in COVID-19 is severe pneumonia leading to respiratory failure. Radiation in low doses (<100 cGy) has been known for its anti-inflammatory effect and therefore, low dose radiation therapy (LDRT) to lungs can potentially mitigate the severity of pneumonia and reduce mortality. We conducted a pilot trial to study the feasibility and clinical efficacy of LDRT to lungs in the management of patients with COVID-19. From June to Aug 2020, we enrolled 10 patients with COVID-19 having moderate to severe risk disease [National Early Warning Score (NEWS) of ≥5]. Patients were treated as per the standard COVID-19 management guidelines along with LDRT to both lungs with a dose of 70cGy in single fraction. Response assessment was done based on the clinical parameters using the NEWS. All patients completed the prescribed treatment. Nine patients had complete clinical recovery mostly within a period ranging from 3 to 7 days. One patient, who was a known hypertensive, showed clinical deterioration and died 24 days after LDRT. No patients showed the signs of acute radiation toxicity. The results of our pilot study suggest that LDRT is feasible in COVID-19 patients having moderate to severe disease. Its clinical efficacy may be tested by conducting randomized controlled trials. LDRT has shown promising results in COVID-19 pneumonia and should be researched further through randomized controlled trials. [ABSTRACT FROM AUTHOR]

COVID-19 has been a threat throughout the world since December 2019. In attempts to discover an urgent treatment regime for COVID-19, hydroxychloroquine (HCQ) and chloroquine (CQ) have been on solidarity clinical trial. However, many countries have pulled HCQ and CQ from their COVID-19 treatment regimens recently, some countries still continue using them for patients who have previously started HCQ and CQ and they may complete their course under the supervision of a doctor. HCQ and CQ are 4-aminoquinoline drugs and it is safe to use them for autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus and malaria as well. Determination of CQ, HCQ and their metabolites in biologic fluids and in pharmaceuticals has great importance, especially for pharmacokinetics, pharmacodynamics and epidemiological studies. In this review, liquid chromatographic methods developed in the last 10 years were summarized focusing on sample preparation and detection methods for HCQ and CQ determination in biological fluids and pharmaceutical preparations. It is hoped that this article could be helpful to facilitate the use of these drugs in clinical trials or drug research studies as it provides comprehensive information on the reported analytical methods. [ABSTRACT FROM AUTHOR]

Motivation A global effort is underway to identify compounds for the treatment of COVID-19. Since de novo compound design is an extremely long, time-consuming and expensive process, efforts are underway to discover existing compounds that can be repurposed for COVID-19 and new viral diseases. We propose a machine learning representation framework that uses deep learning induced vector embeddings of compounds and viral proteins as features to predict compound-viral protein activity. The prediction model in-turn uses a consensus framework to rank approved compounds against viral proteins of interest. Results Our consensus framework achieves a high mean Pearson correlation of 0.916, mean R2 of 0.840 and a low mean squared error of 0.313 for the task of compound-viral protein activity prediction on an independent test set. As a use case, we identify a ranked list of 47 compounds common to three main proteins of SARS-COV-2 virus (PL-PRO, 3CL-PRO and Spike protein) as potential targets including 21 antivirals, 15 anticancer, 5 antibiotics and 6 other investigational human compounds. We perform additional molecular docking simulations to demonstrate that majority of these compounds have low binding energies and thus high binding affinity with the potential to be effective against the SARS-COV-2 virus. Availability and implementation All the source code and data is available at: https://github.com/raghvendra5688/Drug-Repurposing and https://dx.doi.org/10.17632/8rrwnbcgmx.3. We also implemented a web-server at: https://machinelearning-protein.qcri.org/index.html. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

This article provides a brief overview of drug resistance to antiviral therapy as well as known and emergent variability in key SARS-CoV-2 viral sequences. The purpose is to stimulate deliberation about the need to consider drug resistance prior to widespread roll-out of antivirals for SARS-CoV-2. Many existing candidate agents have mechanisms of action involving drug targets likely to be critical for future drug development. Resistance emerged quickly with monotherapies deployed for other pulmonary viruses such as influenza virus, and in HIV mutations in key drug targets compromised efficacy of multiple drugs within a class. The potential for drug resistance in SARS-CoV-2 has not yet been rigorously debated or assessed, and we call for more academic and industry research on this potentially important future threat prior to widespread roll-out of monotherapies for COVID-19 treatment and prevention. [ABSTRACT FROM AUTHOR]

Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. The majority of patients experience asymptomatic to mild self-limited disease, but some cases progress to respiratory and multi-organ failure. However, so far, no approved antiviral therapy has been available for treatment of COVID-19. Sofosbuvir/velpatasvir (SOF/VEL) is an approved anti-HCV drug that is capable of suppressing other families of positive-sense RNA viruses with conserved polymerase and may be effective against SARS-CoV-2. This study was conducted to evaluate the efficacy of the SOF/VEL combination in addition to the national standard of care versus the national standard of care alone (hydroxychloroquine and lopinavir/ritonavir as well as supportive care) in patients with moderate to severe COVID-19 infection.Methods: This single-centre, randomized, open-labelled, prospective clinical trial was done in patients with moderate to severe COVID-19 admitted to Farabi Hospital in Kermanshah Province, Iran. Eligible patients were randomly assigned in a 1:1 ratio to the SOF/VEL arm (SOF/VEL plus the national standard of care) or the control arm (the national standard of care alone). The main outcome of the study was the mortality on Day 28 after randomization. Secondary outcomes were time from the start of medication to clinical improvement, hospital length of stay, need for mechanical ventilation, duration of mechanical ventilation and conversion of RT-PCR results from positive to negative from the time of randomization to discharge. Adverse events were evaluated in all patients who started their assigned treatment.Results: Between 11 April and 8 June 2020, 80 patients were recruited and randomly assigned into the SOF/VEL (n = 40) and control (n = 40) arms. The primary outcome was not significantly different between the two arms (P = 1.00). Secondary outcomes, including time to clinical improvement, hospital length of stay, need for mechanical ventilation, duration of mechanical ventilation and RT-PCR conversion, were not significantly different between arms either (P > 0.05). SOF/VEL treatment and the national standard of care were tolerated similarly.Conclusions: Although treatment with SOF/VEL was safe, adding SOF/VEL to the standard of care did not improve the clinical status or reduce mortality in patients with moderate to severe COVID-19. However, larger randomized clinical trials including more parameters are needed for accurate estimation of the efficacy of SOF/VEL. [ABSTRACT FROM AUTHOR]

Background Monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a promising treatment for limiting the progression of coronavirus disease 2019 (COVID-19) and decreasing strain on hospitals. Their use, however, remains limited, particularly in disadvantaged populations. Methods Electronic health records were reviewed from SARS-CoV-2 patients at a single medical center in the United States that initiated mAb infusions in January 2021 with the support of the US Department of Health and Human Services' National Disaster Medical System. Patients who received mAbs were compared with untreated patients from the time period before mAb availability who met eligibility criteria for mAb treatment. We used logistic regression to measure the effect of mAb treatment on the risk of hospitalization or emergency department (ED) visit within 30 days of laboratory-confirmed COVID-19. Results Of 598 COVID-19 patients, 270 (45%) received bamlanivimab and 328 (55%) were untreated. Two hundred thirty-one patients (39%) were Hispanic. Among treated patients, 5/270 (1.9%) presented to the ED or required hospitalization within 30 days of a positive SARS-CoV-2 test, compared with 39/328 (12%) untreated patients (P  < .001). After adjusting for age, gender, and comorbidities, the risk of ED visit or hospitalization was 82% lower in mAb-treated patients compared with untreated patients (95% CI, 56%–94%). Conclusions In this diverse, real-world COVID-19 patient population, mAb treatment significantly decreased the risk of subsequent ED visit or hospitalization. Broader treatment with mAbs, including in disadvantaged patient populations, can decrease the burden on hospitals and should be facilitated in all populations in the United States to ensure health equity. [ABSTRACT FROM AUTHOR]

Background Interleukin-6 inhibitors showed promising results in observational trials of patients with coronavirus disease 2019 (COVID-19). Aim To evaluate whether interleukin-6 inhibitor tocilizumab (TCZ) reduces mortality among hospitalized COVID-19 patients. Design A systematic review and meta-analysis. Methods Systematic review and meta-analysis of randomized controlled trials (RCTs) comparing TCZ vs. placebo/control, for treatment of adults with COVID-19. Primary outcome was 28–30 days all-cause mortality. Search was conducted up to 1 April 2021. Two independent reviewers screened citations, extracted data and assessed risk of bias. Relative risk (RR) with 95% confidence intervals (CI) were pooled. We performed subgroup analysis for patients with critical illness and sensitivity analyses. Results Eight RCTs were included, assessing 6481 patients with mostly severe non-critical COVID-19 infection. TCZ was associated with a reduction in all-cause 28–30-day mortality compared to placebo/control (RR = 0.89, 95% CI 0.82–0.96). Among the subgroup of critically ill patients no reduced mortality was demonstrated (RR = 0.94, 95% CI 0.74–1.19). No mortality benefit with TCZ was demonstrated in trials that used steroids for >80% of patients. TCZ was associated with significantly reduced risk for mechanical ventilation (MV); for combined endpoint of death or MV and for intensive care unit (ICU) admission. No significant difference in adverse events was demonstrated. Risk of serious superinfection was significantly lower with TCZ (RR = 0.57, 95% CI 0.35–0.93). Conclusion The treatment with TCZ reduces 28–30 days all-cause mortality, ICU admission, superinfections, MV and the combined endpoint of death or MV. Among critically ill patients, and when steroids were used for most patients, no mortality benefit was demonstrated. Additional research should further define sub-groups that would benefit most and preferred timing of administration of TCZ in severe COVID-19. [ABSTRACT FROM AUTHOR]

Emergency authorized coronavirus disease 2019 (COVID-19)–neutralizing monoclonal antibodies can aid outpatients with mild to moderate COVID-19 infection. Many report barriers to adequate distribution and uptake. We present our model for distribution in a large health system as well as early lessons learned. [ABSTRACT FROM AUTHOR]

Objective: We aimed to evaluate the characteristics and outcomes of critically ill children managed in an intensive care unit because of coronavirus disease (COVID-19) pneumonia with respiratory support requirements.Methods: We performed a single-center retrospective observational study in a pediatric intensive care unit (PICU) with 32 beds in Ankara City Hospital, Ankara, Turkey, from 13 March 2020 to 31 December 2020. Patients who needed positive-pressure ventilation (PPV) therapy for COVID-19 pneumonia were included in the study. Demographic, clinical and laboratory data were extracted from the patients' electronic medical records. As outcomes, the hospitalization rate of all pediatric patients diagnosed as having with COVID-19 by Polymerase Chaın Reactıon(PCR), PICU admission rate for COVID-19 pneumonia among all hospitalized patients, PPV support rate, intensive care hospitalization duration (days), total hospitalization duration (days), survival rate and tracheotomy requirement were evaluated.Results: During the study period, 7033 children tested positive for COVID-19 in PCR tests. Of these patients, 1219 were hospitalized for COVID-19. Seventeen patients needed PPV support because of COVID-19 pneumonia. High proportion (65%) of patients admitted to the PICU had comorbid diseases. Noninvasive ventilation was applied in 15 patients (88%). The hospitalization rate among the children with COVID-19 was 17%, of whom 1.6% were admitted to the PICU. Mortality rates were 0.056% of all the cases and 0.32% of the hospitalized patients in our hospital.Conclusion: The presence of a comorbid disease could be a sign of severe disease in children with higher lethality. Very few children required PPV support because of severe COVID-19 pneumonia. [ABSTRACT FROM AUTHOR]

Objectives Viral outbreaks are a frequent concern for humans. A great variety of drugs has been used to treat viral diseases, which are not always safe and effective and may induce adverse effects, indicating the need for new antiviral drugs extracted from natural sources. Propolis is a beemade product exhibiting many biological properties. An overview of viruses, antiviral immunity, propolis safety and its immunomodulatory and antiviral action is reported, as well as perspectives for coronavirus disease 2019 (COVID-19) treatment. PubMed platform was used for data collection, searching for the keywords "propolis", "virus", "antiviral", "antimicrobial" and "coronavirus". Key findings Propolis is safe and exerts antiviral and immunomodulatory activity; however, clinical trials should investigate its effects on individuals with viral diseases, in combination or not with antiviral drugs or vaccines. Summary Regarding COVID-19, the effects of propolis should be investigated directly on the virus in vitro or on infected individuals alone or in combination with antiviral drugs, due to its immunomodulatory and anti-inflammatory action. Propolis administration simultaneously with vaccines should be analyzed, due to its adjuvant properties, to enhance the individuals' immune response. The search for therapeutic targets may be useful to find out how propolis can help to control COVID-19. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel virus of the family Coronaviridae. The virus causes the infectious disease COVID-19. The biology of coronaviruses has been studied for many years. However, bioinformatics tools designed explicitly for SARS-CoV-2 have only recently been developed as a rapid reaction to the need for fast detection, understanding and treatment of COVID-19. To control the ongoing COVID-19 pandemic, it is of utmost importance to get insight into the evolution and pathogenesis of the virus. In this review, we cover bioinformatics workflows and tools for the routine detection of SARS-CoV-2 infection, the reliable analysis of sequencing data, the tracking of the COVID-19 pandemic and evaluation of containment measures, the study of coronavirus evolution, the discovery of potential drug targets and development of therapeutic strategies. For each tool, we briefly describe its use case and how it advances research specifically for SARS-CoV-2. All tools are free to use and available online, either through web applications or public code repositories. Contact: evbc@unj-jena.de [ABSTRACT FROM AUTHOR]

Objective Coronavirus disease 2019 (COVID-19) is a fatal and fast-spreading viral infection. To date, the number of COVID-19 patients worldwide has crossed over six million with over three hundred and seventy thousand deaths (according to the data from World Health Organization; updated on 2 June 2020). Although COVID-19 can be rapidly diagnosed, efficient clinical treatment of COVID-19 remains unavailable, resulting in high fatality. Some clinical trials have identified vitamin C (VC) as a potent compound pneumonia management. In addition, glycyrrhizic acid (GA) is clinically as an anti-inflammatory medicine against pneumonia-induced inflammatory stress. We hypothesized that the combination of VC and GA is a potential option for treating COVID-19. Methods The aim of this study was to determine pharmacological targets and molecular mechanisms of VC + GA treatment for COVID-19, using bioinformational network pharmacology. Results We uncovered optimal targets, biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of VC + GA against COVID-19. Our findings suggested that combinatorial VC and GA treatment for COVID-19 was associated with elevation of immunity and suppression of inflammatory stress, including activation of the T cell receptor signaling pathway, regulation of Fc gamma R-mediated phagocytosis, ErbB signaling pathway and vascular endothelial growth factor signaling pathway. We also identified 17 core targets of VC + GA, which suggest as antimicrobial function. Conclusions For the first time, our study uncovered the pharmacological mechanism underlying combined VC and GA treatment for COVID-19. These results should benefit efforts to address the most pressing problem currently facing the world. [ABSTRACT FROM AUTHOR]

Background Chronic kidney disease (CKD) and immunosuppression, such as in renal transplantation (RT), stand as one of the established potential risk factors for severe coronavirus disease 2019 (COVID-19). Case morbidity and mortality rates for any type of infection have always been much higher in CKD, haemodialysis (HD) and RT patients than in the general population. A large study comparing COVID-19 outcome in moderate to advanced CKD (Stages 3–5), HD and RT patients with a control group of patients is still lacking. Methods We conducted a multicentre, retrospective, observational study, involving hospitalized adult patients with COVID-19 from 47 centres in Turkey. Patients with CKD Stages 3–5, chronic HD and RT were compared with patients who had COVID-19 but no kidney disease. Demographics, comorbidities, medications, laboratory tests, COVID-19 treatments and outcome [in-hospital mortality and combined in-hospital outcome mortality or admission to the intensive care unit (ICU)] were compared. Results A total of 1210 patients were included [median age, 61 (quartile 1–quartile 3 48–71) years, female 551 (45.5%)] composed of four groups: control (n = 450), HD (n = 390), RT (n = 81) and CKD (n = 289). The ICU admission rate was 266/1210 (22.0%). A total of 172/1210 (14.2%) patients died. The ICU admission and in-hospital mortality rates in the CKD group [114/289 (39.4%); 95% confidence interval (CI) 33.9–45.2; and 82/289 (28.4%); 95% CI 23.9–34.5)] were significantly higher than the other groups: HD = 99/390 (25.4%; 95% CI 21.3–29.9; P < 0.001) and 63/390 (16.2%; 95% CI 13.0–20.4; P < 0.001); RT = 17/81 (21.0%; 95% CI 13.2–30.8; P = 0.002) and 9/81 (11.1%; 95% CI 5.7–19.5; P = 0.001); and control = 36/450 (8.0%; 95% CI 5.8–10.8; P < 0.001) and 18/450 (4%; 95% CI 2.5–6.2; P < 0.001). Adjusted mortality and adjusted combined outcomes in CKD group and HD groups were significantly higher than the control group [hazard ratio (HR) (95% CI) CKD: 2.88 (1.52–5.44); P = 0.001; 2.44 (1.35–4.40); P = 0.003; HD: 2.32 (1.21–4.46); P = 0.011; 2.25 (1.23–4.12); P = 0.008), respectively], but these were not significantly different in the RT from in the control group [HR (95% CI) 1.89 (0.76–4.72); P = 0.169; 1.87 (0.81–4.28); P = 0.138, respectively]. Conclusions Hospitalized COVID-19 patients with CKDs, including Stages 3–5 CKD, HD and RT, have significantly higher mortality than patients without kidney disease. Stages 3–5 CKD patients have an in-hospital mortality rate as much as HD patients, which may be in part because of similar age and comorbidity burden. We were unable to assess if RT patients were or were not at increased risk for in-hospital mortality because of the relatively small sample size of the RT patients in this study. [ABSTRACT FROM AUTHOR]

Response to: "Corticosteroid Therapy in COVID-19 Associated With In-hospital Mortality in Geriatric Patients: A Propensity Matched Cohort Study" To the Editor, In a propensity-matched cohort study, Lidou-Renault et al. documented a 2-fold increment of in-hospital mortality when using corticosteroids in a geriatric cohort (median 85 years) of COVID-19 patients ([1]). Corticosteroid therapy in COVID-19 associated with in-hospital mortality in geriatric patients: a propensity matched cohort study. [Extracted from the article]

In this article, we explain why profit-driven models for developing treatments for epidemic pathogens produce sub-optimal and sometimes negative public health outcomes. Using the example of the drug remdesivir, we demonstrate how the divergence of private incentives from public health needs has led to such outcomes during the COVID-19 pandemic. We conclude that policy responses to this and future pandemics ought to be conceived and designed in ways that narrow the divergence of private interests from public health needs, including through greater public-sector involvement in pharmaceutical R&D. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) public health emergency has amplified both the potential value and the challenges with healthcare providers deploying telehealth solutions. As people across the country find ways to stay at home, telehealth preserves an opportunity to obtain necessary healthcare services. Further, telehealth can help individuals avoid COVID-19 infection, free up hospital beds and other resources for those patients most in need, and prevent infected individuals from spreading that infection. Federal and state regulators have recognized this potential of telehealth and have quickly changed a variety of laws and regulations to enable healthcare providers to deploy solutions quickly. These changes can provide lasting benefits for the use of telehealth well after the current crisis. However, to best realize telehealth's benefits, further legal and regulatory actions are necessary. Specifically, lawmakers and regulators should focus on six areas: reimbursement, privacy/cybersecurity, liability, licensure, technology access, and artificial intelligence. [ABSTRACT FROM AUTHOR]

Although additional experiments and clinical studies are required to confirm this hypothesis, we hope that hydrogen therapy would provide an emerging and good option for the currently limited prevention and treatment strategy of COVID-19. High IL-6 level had also been found closely correlated with the incidence of detectable serum severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and the vital signs of coronavirus disease 2019 (COVID-19) patients. 7,8 We hypothesize that hydrogen therapy may be as an effective and novel adjuvant treatment against COVID-19, and exhibit the beneficial potential to prevent COVID-19-associated cytokine storm and multiple organ damage through following multiple mechanisms. [Extracted from the article]

Linked Article: Cho et al. Br J Dermatol 2021; 184:296–303. [ABSTRACT FROM AUTHOR]