Discovery of Potent Pyrazoline-Based Covalent SARS-CoV-2 Main Protease Inhibitors.

While vaccines and antivirals are now being deployed for the current SARS-CoV-2 pandemic, we require additional antiviral therapeutics to not only effectively combat SARS-CoV-2 and its variants, but also future coronaviruses. All coronaviruses have relatively similar genomes that provide a potential exploitable opening to develop antiviral therapies that will be effective against all coronaviruses. Among the various genes and proteins encoded by all coronaviruses, one particularly "druggable" or relatively easy-to-drug target is the coronavirus Main Protease (3CLpro or Mpro), an enzyme that is involved in cleaving a long peptide translated by the viral genome into its individual protein components that are then assembled into the virus to enable viral replication in the cell. Inhibiting Mpro with a small-molecule antiviral would effectively stop the ability of the virus to replicate, providing therapeutic benefit. In this study, we have utilized activity-based protein profiling (ABPP)-based chemoproteomic approaches to discover and further optimize cysteine-reactive pyrazoline-based covalent inhibitors for the SARS-CoV-2 Mpro. Structure-guided medicinal chemistry and modular synthesis of di- and tri-substituted pyrazolines bearing either chloroacetamide or vinyl sulfonamide cysteine-reactive warheads enabled the expedient exploration of structure-activity relationships (SAR), yielding nanomolar potency inhibitors against Mpro from not only SARS-CoV-2, but across many other coronaviruses. Our studies highlight promising chemical scaffolds that may contribute to future pan-coronavirus inhibitors.

A theory-based model of cumulative activity.

Energy expenditure can be used to examine the health of individuals and the impact of environmental factors on physical activity. One of the more common ways to quantify energy expenditure is to process accelerometer data into some unit of measurement for this expenditure, such as Actigraph activity counts, and bin those measures into physical activity levels. However, accepted thresholds can vary between demographics, and some units of energy measurements do not currently have agreed upon thresholds. We present an approach which computes unique thresholds for each individual, using piecewise exponential functions to model the characteristics of their overall physical activity patterns corresponding to well established sedentary, light, moderate and vigorous activity levels from the literature. Models are fit using existing piecewise fitting techniques and software. Most participants' activity intensity profile is exceptionally well modeled as piecewise exponential decay. Using this model, we find emergent groupings of participant behavior and categorize individuals into non-vigorous, consistent, moderately active, or extremely active activity intensity profiles. In the supplemental materials, we demonstrate that the parameters of the model correlate with demographics of age, household size, and level of education, inform behavior change under COVID lockdown, and are reasonably robust to signal frequency.

Study protocol for CELLAR (COVID-related Eating Limitations and Latent dietary effects in the Atlantic Region): population-based observational study to monitor dietary intakes and purchasing during COVID-19 in four Atlantic Canadian provinces.

INTRODUCTION: Poor diet is a leading preventable risk for the global burden of non-communicable disease. Robust measurement is needed to determine the effect of COVID-19 on dietary intakes and consumer purchasing, given the widespread changes to consumer food environments and economic precarity. The research objectives are as follows: (1) describe dietary intakes of foods, beverages and nutrients of concern during the COVID-19 pandemic; (2) quantify change in diet during COVID-19 as compared with prepandemic, previously captured in the provincial samples of the population-representative 2015 Canadian Community Health Survey-Nutrition and (3) examine how household purchasing practices predict dietary intakes during COVID-19. METHODS AND ANALYSES: Observational study of diet, using a population-based stratified probability sampling strategy allocated via dual-frame (landline and cellphone) calls to random-digit dialled numbers, followed by age-sex group quotas. The base population comprises the four provinces of the Atlantic region of Canada, jurisdictions with an excess burden of pre-existing dietary risk, compared with the rest of Canada. Our aim is n=1000 to obtain reliable estimates at a regional level to describe intakes and compare with prepandemic baseline. Data collection entails 12 weeks participation: (1) enrolment with sociodemographics (key dietary risk predictors such as age, sex, gender, pre-COVID-19 income, employment, household composition, receipt of economic relief, rural residence); (2) two 24hour diet recalls using the online ASA-24 Canada 2018 tool; and (3) online uploads of household food purchase receipts over the 12 weeks enrolled. Participation incentives will be offered. ETHICS AND DISSEMINATION: This research protocol received funding from the Canadian Institutes of Health Research (FRN VR5 172691) and ethics review approval from the Dalhousie University Research Ethics Board. Study protocol and instruments and a de-identified dataset will be made publicly available. We will submit the findings to peer-reviewed journals, as well as conferences geared towards scientific and decision-maker audiences.

Canadian transit agencies response to COVID-19: Understanding strategies, information accessibility and the use of social media.

Over the past few months, transit agencies across Canada have been rushed to implement a range of strategies in response to the COVID-19 pandemic, with no standardized guidelines to direct their efforts. This study explores the initial response of transit agencies serving the 25 most populous Canadian cities by understanding the distinct types of response measures implemented between March 1st and June 1st, 2020. It also explores to what extent information related to these measures was accessible and usable, and how transit agencies used social media to communicate their efforts to the public. To achieve these goals, a detailed review of Canadian transit agencies websites and social media accounts was performed. The findings suggest that larger transit agencies across Canada implemented the most measures to respond to COVID-19, but not necessarily provided the most accessible information regarding the measures. Overall, while all transit agencies reduced the offered service's frequency and capacity and enhanced vehicle cleaning, the implementation of other physical and communication measures varied considerably between agencies. Information related to the number of COVID-19 cases within the workforce was least accessible across agencies. Transit agencies' Twitter platforms were used more by larger agencies. While most of transit agencies tend to employ tweets that include some type of graphics, very few agencies employed videos and animations to communicate important information to the public. This paper provides transit planners and policymakers with comprehensive information regarding the initial response of Canadian transit agencies to maintain operations in such critical times.