The SARS-CoV-2 RNA polymerase is a viral RNA capping enzyme.

SARS-CoV-2 is a positive-sense RNA virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic, which continues to cause significant morbidity, mortality and economic strain. SARS-CoV-2 can cause severe respiratory disease and death in humans, highlighting the need for effective antiviral therapies. The RNA synthesis machinery of SARS-CoV-2 is an ideal drug target and consists of non-structural protein 12 (nsp12), which is directly responsible for RNA synthesis, and numerous co-factors involved in RNA proofreading and 5' capping of viral RNAs. The formation of the 5' 7-methylguanosine (m7G) cap structure is known to require a guanylyltransferase (GTase) as well as a 5' triphosphatase and methyltransferases; however, the mechanism of SARS-CoV-2 RNA capping remains poorly understood. Here we find that SARS-CoV-2 nsp12 is involved in viral RNA capping as a GTase, carrying out the addition of a GTP nucleotide to the 5' end of viral RNA via a 5' to 5' triphosphate linkage. We further show that the nsp12 NiRAN (nidovirus RdRp-associated nucleotidyltransferase) domain performs this reaction, and can be inhibited by remdesivir triphosphate, the active form of the antiviral drug remdesivir. These findings improve understanding of coronavirus RNA synthesis and highlight a new target for novel or repurposed antiviral drugs against SARS-CoV-2.

Predicting attitudinal and behavioral responses to COVID-19 pandemic using machine learning

At the beginning of 2020, COVID-19 became a global problem. Despite all the efforts to emphasize the relevance of preventive measures, not everyone adhered to them. Thus, learning more about the characteristics determining attitudinal and behavioral responses to the pandemic is crucial to improving future interventions. In this study, we applied machine learning on the multinational data collected by the International Collaboration on the Social and Moral Psychology of COVID-19 (N = 51,404) to test the predictive efficacy of constructs from social, moral, cognitive, and personality psychology, as well as socio-demographic factors, in the attitudinal and behavioral responses to the pandemic. The results point to several valuable insights. Internalized moral identity provided the most consistent predictive contribution—individuals perceiving moral traits as central to their self-concept reported higher adherence to preventive measures. Similar results were found for morality as cooperation, symbolized moral identity, self-control, open-mindedness, and collective narcissism, while the inverse relationship was evident for the endorsement of conspiracy theories. However, we also found a non-neglible variability in the explained variance and predictive contributions with respect to macro-level factors such as the pandemic stage or cultural region. Overall, the results underscore the importance of morality-related and contextual factors in understanding adherence to public health recommendations during the pandemic.

Antibiotic prescribing patterns among patients admitted to an academic teaching hospital for COVID-19 during the first wave of the pandemic in Toronto: A retrospective, controlled study.

BACKGROUND: Empirical antibiotics are not recommended for coronavirus disease 2019 (COVID-19). METHODS: In this retrospective study, patients admitted to Toronto General Hospital's general internal medicine from the emergency department for COVID-19 between March 1 and August 31, 2020 were compared with those admitted for community-acquired pneumonia (CAP) in 2020 and 2019 in the same months. The primary outcome was antibiotics use pattern: prevalence and concordance with COVID-19 or CAP guidelines. The secondary outcome was antibiotic consumption in days of therapy (DOT)/100 patient-days. We extracted data from electronic medical records. We used logistic regression to model the association between disease and receipt of antibiotics, linear regression to compare DOT. RESULTS: The COVID-19, CAP 2020, and CAP 2019 groups had 67, 73, and 120 patients, respectively. Median age was 71 years; 58.5% were male. Prevalence of antibiotic use was 70.2%, 97.3%, and 90.8% for COVID-19, CAP 2020, and CAP 2019, respectively. Compared with CAP 2019, the adjusted odds ratio (aOR) for receiving antibiotics was 0.23 (95% CI 0.10 to 0.53, p = 0.001) and 3.42 (95% CI 0.73 to 15.95, p = 0.117) for COVID-19 and CAP 2020, respectively. Among patients receiving antibiotics within 48 hours of admission, compared with CAP 2019, the aOR for guideline-concordant combination regimens was 2.28 (95% CI 1.08 to 4.83, p = 0.031) for COVID-19, and 1.06 (95% CI 0.55 to 2.05, p = 0.856) for CAP 2020. Difference in mean DOT/100 patient-days was -24.29 (p = 0.009) comparing COVID-19 with CAP 2019, and +28.56 (p = 0.003) comparing CAP 2020 with CAP 2019. CONCLUSIONS: There are opportunities for antimicrobial stewardship to address unnecessary antibiotic use.

HISTORIQUE: L'antibiothérapie empirique n'est pas recommandée pour le traitement de la maladie à coronavirus 2019 (COVID-19). MÉTHODOLOGIE: Dans cette étude rétrospective, les chercheurs ont comparé les patients atteints de COVID-19 hospitalisés au département de médecine interne générale du Toronto General Hospital entre le 1er mars et le 31 août 2020 après être passés par l'urgence à ceux hospitalisés à cause d'une pneumonie d'origine communautaire (POC) au cours des mêmes mois en 2020 et 2019 (POC-20 et POC-19). Le résultat primaire était le schéma d'utilisation des antibiotiques, c'est-à-dire la prévalence et le respect des lignes directrices sur la COVID-19 ou la POC. Le résultat secondaire correspondait à la consommation d'antibiotiques pendant les jours de traitement (JdT)/100 jours-patients. Les chercheurs ont puisé les données dans les dossiers médicaux électroniques. Ils se sont servi de la régression logistique pour modéliser l'association entre la maladie et la réception des antibiotiques, et de la régression linéaire pour comparer les JdT. RÉSULTATS: Le groupe COVID-19, le groupe POC-20 et le groupe POC-19 étaient composés de 67, 73 et 120 patients, respectivement. Ils avaient un âge médian de 71 ans, et 58,5 % étaient de sexe masculin. La prévalence d'utilisation d'antibiotiques s'élevait à 70,2 %, 97,3 % et 90,8 % dans les groupes COVID-19, POC-20 et POC-19, respectivement. Par rapport au groupe POC-19, le rapport de cotes rajusté (RCr) relatif à la réception d'antibiotiques s'élevait à 0,23 (IC à 95 %, 0,10 à 0,53, p = 0,001) et 3,42 (IC à 95 %, 0,73 à 15,95, p = 0,117) dans les groupes COVID-19 et POC-20, respectivement. Chez les patients qui avaient reçu des antibiotiques dans les 48 heures suivant leur hospitalisation par rapport au POC-19, le RCr relatif à la posologie d'association conforme aux lignes directrices était de 2,28 (IC à 95 %, 1,08 à 4,83, p = 0,031) et de 1,06 (IC à 95 %, 0,55 à 2,05, p = 0,856) dans le groupe POC-20. La différence quant au nombre moyen de JdT/100 jours-patients correspondait à ­24,29 (p = 0,009) lorsqu'on comparait le groupe COVID-19 au groupe POC-19, et à +28,56 (p = 0,003) lorsqu'on comparait le groupe POC-20 au groupe POC-19. CONCLUSIONS: L'utilisation inutile d'antibiotiques pourrait très bien être prise en charge par la gérance des antimicrobiens.

Longstanding Phenytoin Use as a Cause of Progressive Dyspnea.

CASE PRESENTATION: A 54-year-old South African man with a medical history of type 2 diabetes mellitus, seizure disorder, OSA, and latent TB presented to the ER with gradually progressive dyspnea over months. He also reported occasional dry cough and fatigue at presentation but denied fever, chills, chest pain, leg swelling, palpitations, or lightheadedness. He was treated with a course of levofloxacin for presumed community-acquired pneumonia as an outpatient without improvement and had tested negative for COVID-19. He denied occupational or environmental exposures or sick contacts, though he had traveled back to South Africa 1 year before presentation. He had complex partial seizures for the past 22 years, which had been well controlled on phenytoin (300 mg daily). His other home medications included dulaglutide, sertraline, and atorvastatin and had no recent changes. He quit smoking 30 years ago after smoking one pack per day for 10 years.

Characterization of the SARS-CoV-2 ExoN (nsp14ExoN-nsp10) complex: implications for its role in viral genome stability and inhibitor identification.

The SARS-CoV-2 coronavirus is the causal agent of the current global pandemic. SARS-CoV-2 belongs to an order, Nidovirales, with very large RNA genomes. It is proposed that the fidelity of coronavirus (CoV) genome replication is aided by an RNA nuclease complex, comprising the non-structural proteins 14 and 10 (nsp14-nsp10), an attractive target for antiviral inhibition. Our results validate reports that the SARS-CoV-2 nsp14-nsp10 complex has RNase activity. Detailed functional characterization reveals nsp14-nsp10 is a versatile nuclease capable of digesting a wide variety of RNA structures, including those with a blocked 3'-terminus. Consistent with a role in maintaining viral genome integrity during replication, we find that nsp14-nsp10 activity is enhanced by the viral RNA-dependent RNA polymerase complex (RdRp) consisting of nsp12-nsp7-nsp8 (nsp12-7-8) and demonstrate that this stimulation is mediated by nsp8. We propose that the role of nsp14-nsp10 in maintaining replication fidelity goes beyond classical proofreading by purging the nascent replicating RNA strand of a range of potentially replication-terminating aberrations. Using our developed assays, we identify drug and drug-like molecules that inhibit nsp14-nsp10, including the known SARS-CoV-2 major protease (Mpro) inhibitor ebselen and the HIV integrase inhibitor raltegravir, revealing the potential for multifunctional inhibitors in COVID-19 treatment.

A brief forewarning intervention overcomes negative effects of salient changes in COVID-19 guidance

Keywords: COVID-19, forewarning, health communication, science communication, trust