The risk of COVID-19 transmission upon return to sport: a systematic review.

OBJECTIVES: To evaluate COVID-19 transmission rates in athletes upon return to sport (RTS), as well as the effectiveness of preventive and surveillance measures associated with RTS. METHODS: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the PubMed, Embase, and Cochrane Library databases were searched to identify all articles reporting on RTS during COVID-19. Articles were excluded on the basis of the following criteria: (1) non-English text, (2) only abstract available, (3) population not athlete-specific, (4) outcome not RTS-specific, (5) COVID-19 transmission data not quantified, (6) editorial, or (7) review article or meta-analysis. Study characteristics; athlete demographics; COVID-19 preventive, surveillance, and diagnostic measures; COVID-19 transmission outcomes; and RTS recommendations were collected from each included article and analyzed. RESULTS: 10 studies were included in the final analysis, comprising over 97,000 athletes across a wide variety of sports, levels of play, and RTS settings. Of the 10 studies, eight identified low transmission rates and considered RTS to be safe/low risk. Overall, COVID-19 transmission rates were higher in athletes than in contacts, and more prevalent in the greater community than in athletes specifically. The risk of COVID-19 did not appear to be necessarily higher for athletes who played high-contact team sports, shared common facilities, or lived in communities impacted by high transmission rates, provided that rigorous COVID-19 safety and testing protocols were implemented and followed. Mask wearing and physical distancing during active play presented the greatest challenge to athletes. CONCLUSION: Rigorous preventive and surveillance measures can mitigate the risk of COVID-19 transmission in athletes upon RTS. However, the heterogeneity of RTS playing conditions, availability of COVID-19 resources, rise of unforeseen novel variants, and undetermined long-term impact of vaccination on athletes remain a challenge to safe and effective RTS in the era of COVID-19.

Revealing the structural and molecular interaction landscape of the favipiravir-RTP and SARS-CoV-2 RdRp complex through integrative bioinformatics: Insights for developing potent drugs targeting SARS-CoV-2 and other viruses.

BACKGROUND: The global research community has made considerable progress in therapeutic and vaccine research during the COVID-19 pandemic. Several therapeutics have been repurposed for the treatment of COVID-19. One such compound is, favipiravir, which was approved for the treatment of influenza viruses, including drug-resistant influenza. Despite the limited information on its molecular activity, clinical trials have attempted to determine the effectiveness of favipiravir in patients with mild to moderate COVID-19. Here, we report the structural and molecular interaction landscape of the macromolecular complex of favipiravir-RTP and SARS-CoV-2 RdRp with the RNA chain. METHODS: Integrative bioinformatics was used to reveal the structural and molecular interaction landscapes of two macromolecular complexes retrieved from RCSB PDB. RESULTS: We analyzed the interactive residues, H-bonds, and interaction interfaces to evaluate the structural and molecular interaction landscapes of the two macromolecular complexes. We found seven and six H-bonds in the first and second interaction landscapes, respectively. The maximum bond length is 3.79 Å. In the hydrophobic interactions, five residues (Asp618, Asp760, Thr687, Asp623, and Val557) were associated with the first complex and two residues (Lys73 and Tyr217) were associated with the second complex. The mobilities, collective motion, and B-factor of the two macromolecular complexes were analyzed. Finally, we developed different models, including trees, clusters, and heat maps of antiviral molecules, to evaluate the therapeutic status of favipiravir as an antiviral drug. CONCLUSIONS: The results revealed the structural and molecular interaction landscape of the binding mode of favipiravir with the nsp7-nsp8-nsp12-RNA SARS-CoV-2 RdRp complex. Our findings can help future researchers in understanding the mechanism underlying viral action and guide the design of nucleotide analogs that mimic favipiravir and exhibit greater potency as antiviral drugs against SARS-CoV-2 and other infectious viruses. Thus, our work can help in preparing for future epidemics and pandemics.

Genomic regulatory network of human olfactory neuroepithelial cells infected with novel coronavirus (SARS-COV-2).

Objective To explore the genomic changes of human olfactory neuroepithelial cells after the novel coronavirus (SARS-COV-2) infecting the human body, and establish a protein-protein interaction (PPI) network of differentially expressed genes (DEGs), in order to understand the impact of SARS-COV-2 infection on human olfactory neuroepithelial cells, and provide reference for the prevention and treatment of new coronavirus pneumonia. Methods The public dataset GSE151973 was analyzed by NetworkAnalyst. DEGs were selected by conducting Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway analysis. PPI network, DEGs-microRNA regulatory network, transcription factor-DEGs regulatory network, environmental chemicals-DEGs regulatory network, and drug-DEGs regulatory network were created and visualized by using Cytoscape 3.7.2. Results After SAR-COV-2 invading human olfactory neuroepithelial cells, part of the gene expression profile was significantly up-regulated or down-regulated. A total of 568 DEGs were found, including 550 up-regulated genes (96.8%) and 18 down-regulated genes (3.2%). DEGs were mainly involved in biological processes such as endothelial development and angiogenesis of the olfactory epithelium, and the expression of molecular functions such as the binding of the N-terminal myristylation domain. PPI network suggested that RTP1 and RTP2 were core proteins. MAZ was the most influential transcription factor. Hsa-mir-26b-5p had the most obvious interaction with DEGs regulation. Environmental chemical valproic acid and drug ethanol had the most influence on the regulation of DEG. Conclusion The gene expression of olfactory neuroepithelial cells is significantly up-regulated or down-regulated after infection with SAR-COV-2. SARS-CoV-2 may inhibit the proliferation and differentiation of muscle satellite cells by inhibiting the function of PAX7. RTP1 and RTP2 may resist SARS-CoV-2 by promoting the ability of olfactory receptors to coat the membrane and enhancing the ability of olfactory receptors to respond to odorant ligands. MAZ may regulate DEGs by affecting cell growth and proliferation. Micro RNA, environmental chemicals and drugs also play an important role in the anti-SAR-COV-2 infection process of human olfactory neuroepithelial cells.Copyright © 2022 Editorial Department of Journal of Shanghai Second Medical University. All rights reserved.

Genomic regulatory network of human olfactory neuroepithelial cells infected with novel coronavirus (SARS-COV-2)

Objective To explore the genomic changes of human olfactory neuroepithelial cells after the novel coronavirus (SARS-COV-2) infecting the human body, and establish a protein-protein interaction (PPI) network of differentially expressed genes (DEGs), in order to understand the impact of SARS-COV-2 infection on human olfactory neuroepithelial cells, and provide reference for the prevention and treatment of new coronavirus pneumonia. Methods The public dataset GSE151973 was analyzed by NetworkAnalyst. DEGs were selected by conducting Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway analysis. PPI network, DEGs-microRNA regulatory network, transcription factor-DEGs regulatory network, environmental chemicals-DEGs regulatory network, and drug-DEGs regulatory network were created and visualized by using Cytoscape 3.7.2. Results After SAR-COV-2 invading human olfactory neuroepithelial cells, part of the gene expression profile was significantly up-regulated or down-regulated. A total of 568 DEGs were found, including 550 up-regulated genes (96.8%) and 18 down-regulated genes (3.2%). DEGs were mainly involved in biological processes such as endothelial development and angiogenesis of the olfactory epithelium, and the expression of molecular functions such as the binding of the N-terminal myristylation domain. PPI network suggested that RTP1 and RTP2 were core proteins. MAZ was the most influential transcription factor. Hsa-mir-26b-5p had the most obvious interaction with DEGs regulation. Environmental chemical valproic acid and drug ethanol had the most influence on the regulation of DEG. Conclusion The gene expression of olfactory neuroepithelial cells is significantly up-regulated or down-regulated after infection with SAR-COV-2. SARS-CoV-2 may inhibit the proliferation and differentiation of muscle satellite cells by inhibiting the function of PAX7. RTP1 and RTP2 may resist SARS-CoV-2 by promoting the ability of olfactory receptors to coat the membrane and enhancing the ability of olfactory receptors to respond to odorant ligands. MAZ may regulate DEGs by affecting cell growth and proliferation. Micro RNA, environmental chemicals and drugs also play an important role in the anti-SAR-COV-2 infection process of human olfactory neuroepithelial cells.

Low prevalence of cardiac abnormalities in competitive athletes at return-to-play after COVID-19.

OBJECTIVE: to evaluate the prevalence of cardiac involvement after COVID-19 in competitive athletes at return-to-play (RTP) evaluation, following the recommended Italian protocol including cardiopulmonary exercise test (CPET) and 24-Hour Holter monitoring. DESIGN AND METHODS: this is a single centre observational, cross-sectional study. Since October 2020, all competitive athletes (age ≥ 14 years) evaluated in our Institute after COVID-19, prior RTP were enrolled. The protocol dictated by the Italian governing bodies included: 12­lead ECG, blood test, CPET, 24-h ECG monitoring, spirometry. Cardiovascular Magnetic Resonance (CMR) was performed based on clinical indication. RESULTS: 219 consecutive athletes were examined (59% male), age 23 years (IQR 19-27), 21% asymptomatic, 77% mildly symptomatic, 2% with previous pneumonia. The evaluation was performed after a median of 10 (6-17) days from negative SARS-CoV-2 swab. All athletes showed a good exercise capacity at CPET without cardiovascular and respiratory limitations. Uncommon premature ventricular contractions (PVCs) were found in 9.5% (n = 21) at CPET/Holter ECG monitoring. Two athletes (0.9%) were diagnosed with acute myocarditis (by CMR) and another one with new pericardial effusion. All the three athletes were temporally restricted from sport participation. CONCLUSIONS: Myocarditis in competitive athletes screened after COVID-19 resolution was detected in a low minority of the cases (0.9%). However, a non-negligible prevalence of uncommon PVCs (9%) was observed, either at CPET and/or Holter ECG monitoring, including all athletes with COVID-19 related cardiovascular abnormalities.

Systematic Cardiovascular Screening in Olympic Athletes before and after SARS-CoV-2 Infection.

Conflicting results on the cardiovascular involvement after SARS-CoV-2 infection generated concerns on the safety of return-to-play (RTP) in athletes. The aim of this study was to evaluate the prevalence of cardiac involvement after COVID-19 in Olympic athletes, who had previously been screened in our pre-participation program. Since November 2020, all consecutive Olympic athletes presented to our Institute after COVID-19 prior to RTP were enrolled. The protocol was dictated by the Italian governing bodies and comprised: 12-lead ECG, blood test, cardiopulmonary exercise test (CPET), 24-h ECG monitoring, and spirometry. Cardiovascular Magnetic Resonance (CMR) was also performed. All Athletes were previously screened in our Institute as part of their periodical pre-participation evaluation. Forty-seven Italian Olympic athletes were enrolled: 83% asymptomatic, 13% mildly asymptomatic, and 4% had pneumonia. Uncommon premature ventricular contractions (PVCs) were found in 13% athletes; however, only 6% (n = 3) were newly detected. All newly diagnosed uncommon PVCs were detected by CPET. One of these three athletes had evidence for acute myocarditis by CMR, along with Troponin raise; another had pericardial effusion. No one of the remaining athletes had abnormalities detected by CMR. Cardiac abnormalities in Olympic athletes screened after COVID-19 resolution were detected in a minority, and were associated with new ventricular arrhythmias. Only one had evidence for acute myocarditis (in the presence of symptoms and elevated biomarkers). Our data support the efficacy of the clinical assessment including exercise-ECG to raise suspicion for cardiovascular abnormalities after COVID-19. Instead, the routine use of CMR as a screening tool appears unjustified.

Cardiac involvement in athletes infected by SARS COV-2 disease.

Objectives: The aim of the present study was to conduct a review of the current literature evaluating the available evidence to date in terms of epidemiology, pathophysiology and clinical presentation of COVID-19 in relation to cardiovascular involvement, with a special focus on the myocarditis model, in the population of athletes (professional and recreational) who are preparing to return to competitions, with the ultimate aim of guaranteeing maximum safety for resuming sports activities. News: The COVID-19 pandemic has resulted in the inevitable cancellation of most sports activities, practiced at both a professional and amateur level, in order to minimize the risk of spreading the infection. Since the number of athletes who tested positive was rather high, the potential cardiac involvement in this peculiar population of subjects contracting the disease in a mild (asymptomatic, slightly symptomatic) or moderate form, has recently raised concerns following the observation of cases of recorded myocardial damage, myocarditis, arrhythmias and a first reported case of Sudden Cardiac Death (SCD) in a 27-year-old professional basketball player. Several studies even seem to confirm the possibility of permanent impairment of the cardiorespiratory system following the infection. Medical history, biomarkers, electrocardiographical and cardiac imaging features appear to be crucial in distinguishing cardiovascular alterations related to COVID-19 infection from typical adaptations to exercise related to athletes' heart. Prospects and Projects: Clarifications and prospective data based on long-term follow-ups on larger populations of athletes are still needed to exclude the development of myocardial damage capable of negatively affecting prognosis and increasing cardiovascular risk in athletes recovered from COVID-19 in asymptomatic (simple positivity to SARS-COV-2) or in a mild form. Conclusion: From a clinical point of view extreme caution is necessary when planning the return to sport (Return To Play-RTP) of athletes recovered from a mild or asymptomatic form of COVID-19: a careful preliminary medical-sports evaluation should be carried out in order to assess the potential development of myocardial damage that would increase their cardiovascular risk.

Objectifs: Le but cette étude était de mener une revue de la littérature actuelle évaluant les différents éléments disponibles en termes d'épidémiologie, de physiopathologie et de présentation clinique de l'atteinte cardio-vasculaire du COVID-19. Une attention particulière sera donnée aux lésions myocardiques dans la population des athlètes, à la fois de niveau professionnel et amateur, qui s'apprêtent à reprendre la compétition, dans le but de garantir une sécurité maximale dans la reprise des activités sportives. Actualités: La pandémie de COVID-19 a entraîné l'annulation inévitable de la plupart des activités sportives, pratiquées à la fois à un niveau professionnel et amateur, afin de minimiser le risque de propagation de l'infection. Le nombre d'athlètes testés positifs étant plutôt élevé, les répercussions cardiaques potentielles dans cette population particulière de sujets contractant la maladie sous une forme légère (asymptomatique, légèrement symptomatique) ou modérée, a récemment soulevé des inquiétudes suite à l'observation de cas de lésions myocardiques, de myocardites, d'arythmies et d'un premier cas signalé de mort subite chez un basketteur professionnel de 27 ans. De plus, plusieurs études semblent confirmer la possibilité d'une altération permanente du système cardiorespiratoire suite à l'infection. Les antécédents médicaux, les biomarqueurs, les caractéristiques électrocardiographiques et à l'imagerie cardiaque semblent ainsi être des éléments cruciaux pour pouvoir distinguer les altérations cardiovasculaires liées à l'infection au COVID-19 des adaptations typiques à l'exercice des cœurs d'athlètes. Perspectives et projets: Des précisions et des données prospectives basées sur des suivis à long terme sur des populations plus importantes d'athlètes sont encore nécessaires pour exclure le développement de lésions myocardiques capables d'affecter négativement le pronostic et d'augmenter le risque cardiovasculaire chez les athlètes en rémission d'une infection au COVID-19 asymptomatique (positivité simple au SARS-COV-2) ou sous une forme légère. Conclusion: D'un point de vue clinique, une extrême prudence est nécessaire lors de la planification du retour au sport des athlètes en rémission d'une forme légère ou asymptomatique de COVID-19: une évaluation médico-sportive minutieuse de ces patients doit être effectuée afin d'évaluer le développement potentiel de lésions myocardiques qui augmenteraient leur risque cardiovasculaire.

Transcriptomic characteristics and impaired immune function of patients who retest positive for SARS-CoV-2 RNA.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has become a global public health crisis. Some patients who have recovered from COVID-19 subsequently test positive again for SARS-CoV-2 RNA after discharge from hospital. How such retest-positive (RTP) patients become infected again is not known. In this study, 30 RTP patients, 20 convalescent patients, and 20 healthy controls were enrolled for the analysis of immunological characteristics of their peripheral blood mononuclear cells. We found that absolute numbers of CD4+ T cells, CD8+ T cells, and natural killer cells were not substantially decreased in RTP patients, but the expression of activation markers on these cells was significantly reduced. The percentage of granzyme B-producing T cells was also lower in RTP patients than in convalescent patients. Through transcriptome sequencing, we demonstrated that high expression of inhibitor of differentiation 1 (ID1) and low expression of interferon-induced transmembrane protein 10 (IFITM10) were associated with insufficient activation of immune cells and the occurrence of RTP. These findings provide insight into the impaired immune function associated with COVID-19 and the pathogenesis of RTP, which may contribute to a better understanding of the mechanisms underlying RTP.

Return to Play Following COVID-19 Infection-A Systematic Review of Current Evidence.

CONTEXT: The COVID-19 pandemic has had catastrophic impact on a global scale, affecting people from all walks of life including elite athletes. OBJECTIVES: The purpose of this study was to evaluate the reported rates of return to play (RTP) in conjunction with the expert-derived guidelines previously recommended to enable safe RTP post COVID-19 infection. EVIDENCE ACQUISITION: Two independent reviewers searched the literature based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, utilizing the MEDLINE, Embase, and Scopus databases. Only studies that reported rates of RTP and/or recommended guidelines for safe RTP were included. EVIDENCE SYNTHESIS: Overall, 17 studies (3 level III and 14 level V) were included. A total of 3 studies reported rates of RTP in a total of 1255 athletes and 623 officials; 72 (30 symptomatic) were infected with COVID-19, 100% of whom were able to RTP post COVID-19 infection. Of the 14 studies recommending guidelines for safe RTP, 3 and 9 studies recommended 7 and 14 days of rest in isolation respectively for asymptomatic patients with COVID-19 infection, prior to safe RTP. In contrast, 7 studies recommended 3 to 6 months of rest (following 14 d isolation) in cases of COVID-19-induced myocarditis as a safe timeframe for safe RTP. Of the 11 studies reporting on whether blanket testing prior to RTP was recommended, only 7 studies recommended a negative test result as mandatory prior to RTP for athletes previously infected with COVID-19. CONCLUSIONS: Although excellent rates of RTP have been reported for elite athletes post COVID-19 infection, discrepancies in recommended rest periods, requirement for mandatory negative test results, and the magnitude of screening investigations required continue to exist in the literature, with a need for further standardized international guidelines required in future. LEVEL OF EVIDENCE: Level V; systematic review of all forms of evidence.

Molecular Dynamics Simulations Reveal the Interaction Fingerprint of Remdesivir Triphosphate Pivotal in Allosteric Regulation of SARS-CoV-2 RdRp.

The COVID-19 pandemic has now strengthened its hold on human health and coronavirus' lethal existence does not seem to be going away soon. In this regard, the optimization of reported information for understanding the mechanistic insights that facilitate the discovery towards new therapeutics is an unmet need. Remdesivir (RDV) is established to inhibit RNA-dependent RNA polymerase (RdRp) in distinct viral families including Ebola and SARS-CoV-2. Therefore, its derivatives have the potential to become a broad-spectrum antiviral agent effective against many other RNA viruses. In this study, we performed comparative analysis of RDV, RMP (RDV monophosphate), and RTP (RDV triphosphate) to undermine the inhibition mechanism caused by RTP as it is a metabolically active form of RDV. The MD results indicated that RTP rearranges itself from its initial RMP-pose at the catalytic site towards NTP entry site, however, RMP stays at the catalytic site. The thermodynamic profiling and free-energy analysis revealed that a stable pose of RTP at NTP entrance site seems critical to modulate the inhibition as its binding strength improved more than its initial RMP-pose obtained from docking at the catalytic site. We found that RTP not only occupies the residues K545, R553, and R555, essential to escorting NTP towards the catalytic site, but also interacts with other residues D618, P620, K621, R624, K798, and R836 that contribute significantly to its stability. From the interaction fingerprinting it is revealed that the RTP interact with basic and conserved residues that are detrimental for the RdRp activity, therefore it possibly perturbed the catalytic site and blocked the NTP entrance site considerably. Overall, we are highlighting the RTP binding pose and key residues that render the SARS-CoV-2 RdRp inactive, paving crucial insights towards the discovery of potent inhibitors.

Co-crystallization and structure determination: An effective direction for anti-SARS-CoV-2 drug discovery.

Safer and more-effective drugs are urgently needed to counter infections with the highly pathogenic SARS-CoV-2, cause of the COVID-19 pandemic. Identification of efficient inhibitors to treat and prevent SARS-CoV-2 infection is a predominant focus. Encouragingly, using X-ray crystal structures of therapeutically relevant drug targets (PLpro, Mpro, RdRp, and S glycoprotein) offers a valuable direction for anti-SARS-CoV-2 drug discovery and lead optimization through direct visualization of interactions. Computational analyses based primarily on MMPBSA calculations have also been proposed for assessing the binding stability of biomolecular structures involving the ligand and receptor. In this study, we focused on state-of-the-art X-ray co-crystal structures of the abovementioned targets complexed with newly identified small-molecule inhibitors (natural products, FDA-approved drugs, candidate drugs, and their analogues) with the assistance of computational analyses to support the precision design and screening of anti-SARS-CoV-2 drugs.