Identification, Characterization and Drug Discovery for Novel Target Sites for SARS-CoV-2 Proteins

The virus SARS-CoV-2, the cause of the current COVID-19 pandemic, is not well understood. It is critical to understand how the viral proteins function and how their function may be modulated. Inhibitors that target these enzymes serve as potential therapeutic interventions against COVID-19. This work uses artificial intelligence methods developed by us to find sites that other methods may not find and therefore, identify potential exosites, allosteric sites, or other sites of interaction in the structures of viral proteins to serve as new targets for the development of antiviral agents. Large datasets of natural and synthetic compounds are computationally searched for molecules that fit into these alternative sites, and any compounds that fit will be targeted for experimental testing for their ability to inhibit the functions of these viral enzymes. This project uses the unique Partial Order Optimum Likelihood (POOL) machine learning method developed by us to predict multiple types of binding sites in SARS-CoV-2 proteins, including catalytic sites, allosteric sites, and other interaction sites. Molecular dynamics simulations are used to generate conformations for ensemble docking. Compounds from large molecular libraries are computationally docked into the predicted sites to identify potentially strong binding ligands. We have identified approximately 10000 potential ligands for more than 50 SARS-CoV-2 proteins to date. Candidate ligands to selected SARS-CoV-2 proteins are experimentally tested in vitro for binding affinity and the effect of the best-predicted inhibitors on catalytic activities determined by direct biochemical assays. Compound libraries for the study include selected compounds from the ZINC and Enamine databases;Chemical Abstract Service database compounds and COVID-specific libraries from Enamine and Life Chemicals.

Significance of Coagulopathy in Patients with Severe COVID-19 Supported with Veno-Venous Extracorporeal Membrane Oxygenation in United Kingdom - Multicentre Observational Study (preprint)

COVID-19 is a prothrombotic condition and a major focus of attention has been to reduce thrombosis in order to improve outcomes. Extracorporeal membrane oxygenation (ECMO) triggers contact activation of coagulation, platelet dysfunction and systemic anticoagulation which may contribute to both thrombosis and bleeding complications.Methods: Multicentre observational study of mortality, thrombosis, and bleeding complications in 152 consecutive patients (≥18 years) supported with VV ECMO during the first wave of the COVID-19 pandemic (1st of March 2020 to 31st of May 2020) from four nationally commissioned UK ECMO centres.Findings: Of 152 patients, mortality during ECMO up to 120 days was 21.1% (32/152) whilst overall all cause in- hospital mortality up to 143 days from ECMO initiation was 25.7% (39/152). Median duration on ECMO was 17 days (interquartile range [IQR] 11-29.7). On multivariate analysis, mortality increased with age (Hazard ratio [HR] 1.09 [95% CI 1.03 - 1.14]), P=0.002. Rates of major bleeding and thrombosis during ECMO were 25.0% (38/152) and 17.1% (26/152). Presence of major bleeding prior to or at initiation of ECMO and intracranial haemorrhage during ECMO conferred 3.65 ([95% CI 1.16 - 11.48], P=0.027) and 6.92 ([95% CI 2.66 - 18.02], <0.0001) folds risks of death respectively during ECMO. Heparin induced thrombocytopenia was diagnosed in 16/152 (10.52%) of the patients and was independently associated with 4-fold increased risk of developing thrombosis (CI1.78-7.21), P=0.002. Thrombosis, coagulation and laboratory parameters did not predict mortality.Interpretation: Although thrombosis is a major complication in patients with COVID-19, major bleeding was frequent and independently associated with increased mortality. Despite a high incidence of major bleeding and thrombosis, both overall and 120-day mortality in this cohort of patients supported with ECMO were better than reported from international registries.Funding Statement: Bayer plc supported the study by providing the investigator-initiated funding to setup the multicentre database of the study.Declaration of Interests: DJA received funding from Bayer plc to setup the multicentre database of the study as an investigator-initiated funding. Other authors have no conflict of interest to declare.Ethics Approval Statement: The study was approved by the human research authority (HRA) and health and care Research Wales (HCRW) and the local Caldicott Guardian at Scotland (reference number: 20/HRA/1785). All patients lacked capacity, and the need for individual informed consent was waived because of observational nature of the study. Data was collected from patient clinical records by the treating medical team with no breach of privacy or anonymity.

Blueprint for Back to School

From the Executive Summary: Families and communities need schools to be ready to reopen as soon as public health officials signal that it is safe. After all, the nation has recently been reminded just how vital schools really are. Schools connect students with peers and mentors, channel youthful energy into productive pursuits, teach essential academic skills and knowledge, and give overwhelmed parents room to breathe and work. Reopening schools in a manner that is safe and responsive to the needs of families and communities will involve novel challenges. Leaders must begin planning immediately.COVID-19 (Disease);Epidemics;Schools;Social Distancing

Pandemic impacts on healthcare utilisation: a systematic review (preprint)

Objectives: To determine the extent and nature of changes in utilisation of healthcare services during COVID-19 pandemic. Design: Systematic review Eligibility: Eligible studies compared utilisation of services during COVID-19 pandemic to at least one comparable period in prior years. Services included visits, admissions, diagnostics, and therapeutics. Studies were excluded if from single-centres or studied only COVID-19 patients. Data sources: PubMed, Embase, Cochrane COVID-19 Study Register, and pre-prints were searched, without language restrictions, until August 10, using detailed searches with key concepts including COVID-19, health services and impact. Data analysis: Risk of bias was assessed by adapting ROBINS-I and Cochrane Effective Practice and Organization of Care tool. Results were analysed using descriptive statistics, graphical figures, and narrative synthesis. Outcome measures: Primary outcome was change in service utilisation between pre-pandemic and pandemic periods. Secondary outcome was the change in proportions of users of healthcare services with milder or more severe illness (e.g. triage scores). Results: 3097 unique references were identified, and 81 studies across 20 countries included, reporting on >11 million services pre-pandemic and 6.9 million during pandemic. For the primary outcome, there were 143 estimates of changes, with a median 37% reduction in services overall (interquartile range -51% to -20%), comprising median reductions for visits of 42%(-53% to -32%), admissions, 28%(-40% to -17%), diagnostics, 31%(-53% to -24%), and for therapeutics, 30%(-57% to -19%). Among 35 studies reporting secondary outcomes, there were 60 estimates, with 27(45%) reporting larger reductions in utilisation among people with a milder spectrum of illness, and 33 (55%) reporting no change. Conclusions: Healthcare utilisation decreased by about a third during the pandemic, with considerable variation, and with greater reductions among people with less severe illness. While addressing unmet need remains a priority, studies of health impacts of reductions may help health-systems prioritise higher-value care in the post-pandemic recovery. Funding, Study registration: No funding was required. PROSPERO: CRD42020203729