Pharmacokinetics, Mass Balance, Safety, and Tolerability of Obeldesivir in Healthy Participants.

There is an unmet need for safe and efficacious oral therapies for COVID-19 with low potential for drug-drug interactions. Obeldesivir is an orally administered nucleoside prodrug that has shown antiviral potency in nonclinical studies against SARS-CoV-2 and its circulating variants. Obeldesivir is metabolized to the active nucleoside triphosphate (GS-443902), which acts as an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase, thereby inhibiting viral RNA synthesis. Here, we report the safety, tolerability, and pharmacokinetics from a first-in-human, randomized, placebo-controlled, phase I study following oral administration of obeldesivir and a phase I, open-label absorption, distribution, metabolism, and excretion study following oral administration of [14C]-obeldesivir. Overall, obeldesivir was safe and well tolerated at single and multiple doses between 100 and 1,600 mg, with low potential for QT prolongation as assessed by QT-concentration analysis. The exposures to GS-441524 increased dose proportionally in the 100-900-mg dose range. GS-441524 accumulated by 35% after twice-daily and 12% after once-daily dosing for 5 days. Dose-proportional increases in the intracellular concentration of GS-443902 were also observed in peripheral blood mononuclar cells. Plasma exposure of GS-441524 was not significantly altered by food intake. Following oral administration of [14C]-obeldesivir (500 mg; 100 µCi), the mean cumulative [14C]-dose recovery was 90.7% with 58.5% in urine and 32.2% in feces. GS-441524 was the predominant plasma component (90% of 14C-area under the concentration-time curve) and was primarily eliminated via renal excretion. Collectively, data from these studies support selection of the obeldesivir 350 mg twice-daily dosing regimen for further evaluation in phase III studies for COVID-19.

Universal symptom monitoring to address presenteeism in healthcare workers.

BACKGROUND: The scale of the COVID-19 pandemic has required rapid development of both governmental and institutional policies and protocols to minimize transmission. We describe our institution's implementation of a symptom monitoring program with this goal. METHODS: We developed a symptom monitoring tool based on our return-to-work guidelines using a Qualtrics survey tool. We implemented this for healthcare workers (HCWs) and provided individualized real time guidance and linkage to COVID-19 testing if indicated. RESULTS: During the period from April 2nd to April 17th, 2020, 9446 HCWs had enrolled in the symptom tracking survey, with 5,035 HCWs completing the survey daily at the end of this period. 1,318 HCWs had been identified as being symptomatic with an indication for SARS-CoV-2 testing and were directed to the hotline to have this ordered. Of these, 82% reported not currently staying home from work due to illness or quarantine when first reporting symptoms. DISCUSSION AND CONCLUSIONS: A survey based symptom monitoring tool can be rapidly designed and implemented, and incorporated with a testing strategy. Our results show the potential for quick uptake, and effectiveness in identifying and addressing presenteeism. We report our large academic institution's experience as a model to be adapted for use in this and future pandemics.

Ebola research funding: a systematic analysis, 1997-2015.

BACKGROUND: The latest outbreak of Ebola in West Africa overwhelmed the affected countries, with the impact on health extending far beyond Ebola-related deaths that have exceeded 11 000. The need to promptly mobilise resources to control emerging infections is widely recognized. Yet, data on research funding for emerging infections remains inadequately documented. METHODS: We defined research investment as all funding flows for Ebola and/or Marburg virus from 1997 to April 2015 whose primary purpose was to advance knowledge and new technologies to prevent or cure disease. We sourced data directly from funding organizations and estimated the investment in 2015 US dollars (US$). RESULTS: Funding for Ebola and Marburg virus research in 1997 to 2015 amounted to US$ 1.035 billion, including US$ 435.4 million (42.0%) awarded in 2014 and 2015. Public sources of funding invested US$ 758.8 million (73.1%), philanthropic sources US$ 65.1 million (6.3%), and joint public/private/philanthropic ventures accounted for US$ 213.8 million (20.6%). Prior to the Ebola outbreak in 2014, pre-clinical research dominated research with US$ 443.6 million (73.9%) investment. After the outbreak, however, investment for new product development increased 942.7-fold and that for clinical trials rose 23.5-fold. Investment in new tools to control Ebola and Marburg virus amounted to US$ 399.1 million, with 61.3% awarded for vaccine research, 29.2% for novel therapeutics research such as antivirals and convalescent blood products, and 9.5% for diagnostics research. Research funding and bibliometric output were moderately associated (Spearman's ρ = 0.5232, P = 0.0259), however number of Ebola cases in previous outbreaks and research funding (ρ = 0.1706, P = 0.4985) and Ebola cases in previous outbreaks and research output (ρ = 0.3020, P = 0.0616) were poorly correlated. CONCLUSION: Significant public and philanthropic funds have been invested in Ebola and Marburg virus research in 2014 and 2015, following the outbreak in West Africa. Long term, strategic vision and leadership are needed to invest in infections with pandemic potential early, including innovative financing measures and open access investment data to promote the development of new therapies and technologies.

The Rivas Cohort Study: design and baseline characteristics of a Nicaraguan cohort.

BACKGROUND: A lack of advanced healthcare information systems and validated scientific cohorts in Nicaragua makes it difficult to estimate disease prevalences and other public health statistics. Although there is concern of an "epidemic" of chronic kidney disease (CKD) in this country, statistics regarding its magnitude are derived from only a small number of non-representative studies. Budgetary constraints and the logistical problems of maintaining a study cohort make longitudinal studies difficult. The Rivas Cohort was created to measure disease burden of CKD and other public health priorities in the Department of Rivas, Nicaragua. Using primarily volunteer research students and technologic innovation including GPS, digital photography and point of care biochemical analysis, the ability to establish a longitudinal chronic disease cohort is demonstrated. METHODS: Subjects were recruited from consecutive adjacent households in thirty-two randomly selected communities in the ten municipalities that comprise the Department of Rivas in southern Pacific coastal Nicaragua. The study was conducted in two phases. In the first phase, subjects were enrolled into the cohort and consented for future re-contact. In Phase II, conducted two years later, attempts were made to re-contact 400 of these subjects for additional data collection. Demographic, lifestyle, occupational, exposure and health data was collected for both phases of the study. Blood and urine testing and height, weight and blood pressure measurements were also performed. GPS coordinates of homes were recorded and maps of remote communities created. RESULTS: Of 1397 adults living in 533 households approached for participation a total of 1242 (89 %) were enrolled in the cohort. The median age is 41 years and 43 % are male, demographics in agreement with Nicaraguan census data for the Department of Rivas. During Phase II we attempted to re-contact 400 subjects for a follow-up study of CKD. It was possible to re-contact 84 % of these participants and of those re-contacted 95 % agreed to participate in the follow-up study. Of subjects that were not successfully re-contacted the majority had either moved (32) or were not at home (22) at the time of the study team visits. CONCLUSION: The Rivas Cohort Study enrolled a representative sample of 1242 adults living in the Department of Rivas, Nicaragua. The high re-contact and participation rates at two years suggests that the cohort is suitable for long-term studies and presents opportunities for investigations of disease prevalence, incidence, treatment and other public health matters. GPS coordinates and maps are available for future researchers who wish to use the cohort for additional studies.

Mapping Investments and Published Outputs in Norovirus Research: A Systematic Analysis of Research Funded in the United States and United Kingdom During 1997-2013.

BACKGROUND: Norovirus accounts for a considerable portion of the global disease burden. Mapping national or international investments relating to norovirus research is limited. METHODS: We analyzed the focus and type of norovirus research funding awarded to institutions in the United States and United Kingdom during 1997-2013. Data were obtained from key public and philanthropic funders across both countries, and norovirus-related research was identified from study titles and abstracts. Included studies were further categorized by the type of scientific investigation, and awards related to vaccine, diagnostic, and therapeutic research were identified. Norovirus publication trends are also described using data from Scopus. RESULTS: In total, US and United Kingdom funding investment for norovirus research was £97.6 million across 349 awards; 326 awards (amount, £84.9 million) were received by US institutions, and 23 awards (£12.6 million) were received by United Kingdom institutions. Combined, £81.2 million of the funding (83.2%) was for preclinical research, and £16.4 million (16.8%) was for translational science. Investments increased from £1.7 million in 1997 to £11.8 million in 2013. Publication trends showed a consistent temporal increase from 48 in 1997 to 182 in 2013. CONCLUSIONS: Despite increases over time, trends in US and United Kingdom funding for norovirus research clearly demonstrate insufficient translational research and limited investment in diagnostics, therapeutics, or vaccine research.