ABSTRACT
Vaccines and first-generation antiviral therapeutics have provided important protection against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PLpro) is one of two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease (Mpro) have demonstrated clinical efficacy, known PLpro inhibitors have to date lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PLpro translates to in vivo efficacy in a preclinical setting. Herein, we report the machine learning-driven discovery of potent, selective, and orally available SARS-CoV-2 PLpro inhibitors, with lead compound PF-07957472 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.
Subject(s)
COVID-19 , Coronavirus InfectionsABSTRACT
Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. In 2020, the COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized hundreds of thousands of specific predictions from more than 50 different academic, industry, and independent research groups. This manuscript systematically evaluates 23 models that regularly submitted forecasts of reported weekly incident COVID-19 mortality counts in the US at the state and national level. One of these models was a multi-model ensemble that combined all available forecasts each week. The performance of individual models showed high variability across time, geospatial units, and forecast horizons. Half of the models evaluated showed better accuracy than a naive baseline model. In combining the forecasts from all teams, the ensemble showed the best overall probabilistic accuracy of any model. Forecast accuracy degraded as models made predictions farther into the future, with probabilistic accuracy at a 20-week horizon more than 5 times worse than when predicting at a 1-week horizon. This project underscores the role that collaboration and active coordination between governmental public health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks. f
Subject(s)
COVID-19ABSTRACT
Since its emergence in late 2019, COVID-19 has caused significant global morbidity and mortality, overwhelming health systems. Considerable attention has been paid to the burden COVID-19 has put on acute care hospitals, with numerous models projecting hospitalizations and ICU needs for the duration of the pandemic. However, less attention has been paid to where these patients may go if they require additional care following hospital discharge. As COVID-19 patients recover from severe infections, many of them require additional care. Yet with post-acute care facilities averaging 85\% capacity prior to the pandemic and the significant potential for outbreaks, consideration of the downstream effects of the surge of hospitalized COVID-19 patients is critical. Here, we present a method for projecting COVID-19 post-acute care needs. Our model is designed to take the output from any of the numerous epidemiological models (hospital discharges) and estimate the flow of patients to post-acute care services, thus providing a similar surge planning model for post-acute care services. Using data from the University of Utah Hospital, we find that for those who require specialized post-acute care, the majority require either home health care or skilled nursing facilities. Likewise, we find the expected peak in post-acute care occurs about two weeks after the expected peak for acute care hospitalizations, a result of the duration of hospitalization. This short delay between acute care and post-acute care surges highlights the importance of considering the organization necessary to accommodate the influx of recovering COVID patients and protect non-COVID patients prior to the peak in acute care hospitalizations. We developed this model to guide policymakers in addressing the "aftershocks" of discharged patients requiring further supportive care; while we only show the outcomes for discharges based on preliminary data from the University of Utah Hospital, we suggest alternative uses for our model including adapting it to explore potential alternative strategies for addressing the surge in acute care facilities during future pandemic waves.
Subject(s)
COVID-19ABSTRACT
Coronavirus disease 2019 (COVID-19) has caused strain on health systems worldwide due to its high mortality rate and the large portion of cases requiring critical care and mechanical ventilation. During these uncertain times, public health decision makers, from city health departments to federal agencies, sought the use of epidemiological models for decision support in allocating resources, developing non-pharmaceutical interventions, and characterizing the dynamics of COVID-19 in their jurisdictions. In response, we developed a flexible scenario modeling pipeline that could quickly tailor models for decision makers seeking to compare projections of epidemic trajectories and healthcare impacts from multiple intervention scenarios in different locations. Here, we present the components and configurable features of the COVID Scenario Pipeline, with a vignette detailing its current use. We also present model limitations and active areas of development to meet ever-changing decision maker needs.