The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses.

Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV-related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (Mpro) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease.

The great urban shift: Climate change is predicted to drive mass species turnover in cities.

Human experiences with nature are important for our culture, economy, and health. Anthropogenically-driven climate change is causing widespread shifts in biodiversity and resident urban wildlife are no exception. We modelled over 2,000 animal species to predict how climate change will impact terrestrial wildlife within 60 Canadian and American cities. We found evidence of an impending great urban shift where thousands of species will disappear across the selected cities, being replaced by new species, or not replaced at all. Effects were largely species-specific, with the most negatively impacted taxa being amphibians, canines, and loons. These predicted shifts were consistent across scenarios of greenhouse gas emissions, but our results show that the severity of change will be defined by our action or inaction to mitigate climate change. An impending massive shift in urban wildlife will impact the cultural experiences of human residents, the delivery of ecosystem services, and our relationship with nature.

Oral administration of obeldesivir protects nonhuman primates against Sudan ebolavirus.

Obeldesivir (ODV, GS-5245) is an orally administered prodrug of the parent nucleoside of remdesivir (RDV) and is presently in phase 3 trials for COVID-19 treatment. In this work, we show that ODV and its circulating parent nucleoside metabolite, GS-441524, have similar in vitro antiviral activity against filoviruses, including Marburg virus, Ebola virus, and Sudan virus (SUDV). We also report that once-daily oral ODV treatment of cynomolgus monkeys for 10 days beginning 24 hours after SUDV exposure confers 100% protection against lethal infection. Transcriptomics data show that ODV treatment delayed the onset of inflammation and correlated with antigen presentation and lymphocyte activation. Our results offer promise for the further development of ODV to control outbreaks of filovirus disease more rapidly.

Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys.

Remdesivir 1 is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells, thereby forming the bioactive triphosphate 2-NTP. 2-NTP, an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for 1 have prompted interest in oral approaches to generate 2-NTP. Here, we describe the discovery of a 5'-isobutyryl ester prodrug of 2 (GS-5245, Obeldesivir, 3) that has low cellular cytotoxicity and 3-7-fold improved oral delivery of 2 in monkeys. Prodrug 3 is cleaved presystemically to provide high systemic exposures of 2 that overcome its less efficient metabolism to 2-NTP, leading to strong SARS-CoV-2 antiviral efficacy in an African green monkey infection model. Exposure-based SARS-CoV-2 efficacy relationships resulted in an estimated clinical dose of 350-400 mg twice daily. Importantly, all SARS-CoV-2 variants remain susceptible to 2, which supports development of 3 as a promising COVID-19 treatment.

Efficacy of the oral nucleoside prodrug GS-5245 (Obeldesivir) against SARS-CoV-2 and coronaviruses with pandemic potential.

Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective treatment strategies. Here, we characterize the antiviral activity of GS-5245, Obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-related Bat-CoV RsSHC014, Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (Mpro) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions.

Using smartphone-GPS data to quantify human activity in green spaces.

Cities are growing in density and coverage globally, increasing the value of green spaces for human health and well-being. Understanding the interactions between people and green spaces is also critical for biological conservation and sustainable development. However, quantifying green space use is particularly challenging. We used an activity index of anonymized GPS data from smart devices provided by Mapbox (www.mapbox.com) to characterize human activity in green spaces in the Greater Toronto Area, Canada. The goals of our study were to describe i) a methodological example of how anonymized GPS data could be used for human-nature research and ii) associations between park features and human activity. We describe some of the challenges and solutions with using this activity index, especially in the context of green spaces and biodiversity monitoring. We found the activity index was strongly correlated with visitation records (i.e., park reservations) and that these data are useful to identify high or low-usage areas within green spaces. Parks with a more extensive trail network typically experienced higher visitation rates and a substantial proportion of activity remained on trails. We identified certain land covers that were more frequently associated with human presence, such as rock formations, and find a relationship between human activity and tree composition. Our study demonstrates that anonymized GPS data from smart devices are a powerful tool for spatially quantifying human activity in green spaces. These could help to minimize trade-offs in the management of green spaces for human use and biological conservation will continue to be a significant challenge over the coming decades because of accelerating urbanization coupled with population growth. Importantly, we include a series of recommendations when using activity indexes for managing green spaces that can assist with biomonitoring and supporting sustainable human use.

Therapeutic treatment with an oral prodrug of the remdesivir parental nucleoside is protective against SARS-CoV-2 pathogenesis in mice.

The coronavirus disease 2019 (COVID-19) pandemic remains uncontrolled despite the rapid rollout of safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. In addition, the emergence of SARS-CoV-2 variants of concern, with their potential to escape neutralization by therapeutic monoclonal antibodies, emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parent nucleoside of remdesivir, which targets the highly conserved virus RNA-dependent RNA polymerase. GS-621763 exhibited antiviral activity against SARS-CoV-2 in lung cell lines and two different human primary lung cell culture systems. GS-621763 was also potently antiviral against a genetically unrelated emerging coronavirus, Middle East respiratory syndrome CoV (MERS-CoV). The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 administration reduced viral load and lung pathology; treatment also improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral that has recently received EUA approval, proved both drugs to be similarly efficacious in mice. These data support the exploration of GS-441524 oral prodrugs for the treatment of COVID-19.

The Climate Change-Temperature-Crime Hypothesis: Evidence from a Sample of 15 Large US Cities, 2002 to 2015.

Drawing on prior studies, green criminologists have hypothesized that climate change will both raise the mean temperature and the level of crime. We call this the "climate change-temperature-crime hypothesis" ("CC-T-C"). This hypothesis is an extension of research performed on temperature and crime at the individual level. Other research explores this relationship by testing for the relationship between seasonality and crime within a given period of time (i.e., within years). Climate change, however, produces small changes in temperature over long periods of time, and in this view, the effect of climate change on crime should be assessed across and not within years. In addition, prior CC-T-C studies sometimes employ large geographic aggregations (e.g., the entire whole United States), which masks the CC-T-C association that appears at lower levels of aggregation. Moreover, globally, crime has declined across nations since the early 1990s, during a period of rising mean global temperatures, suggesting that the CC-T-C hypothesis does not fit the general trends in temperature and crime over time. Addressing these issues, the present study assesses the CC-T-C relationship for a sample of 15 large (N = 15) US cities over a 14-year period. Given the CC-T-C hypothesis parameters, we assessed this relationship using correlations between individual crime and temperature trends for each city. Crime trends were measured by both the number and rate of eight Uniform Crime Report (UCR) Part I crimes, so that for each city, there are 16 crime-temperature correlations. Using a liberal p value (p = .10), the temperature-crime correlations were rejected as insignificant in 220 of the 234 tests (94%). We discuss the Implications of this finding and suggest that rather than focusing on the temperature-crime relationship, green criminologists interested in the deleterious effects of climate change draw attention to its larger social, economic, environmental and ecological justice implications.

Therapeutic efficacy of an oral nucleoside analog of remdesivir against SARS-CoV-2 pathogenesis in mice.

The COVID-19 pandemic remains uncontrolled despite the rapid rollout of safe and effective SARS-CoV-2 vaccines, underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. Additionally, the emergence of SARS-CoV-2 variants of concern with their potential to escape therapeutic monoclonal antibodies emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parental nucleoside of remdesivir, which targets the highly conserved RNA-dependent RNA polymerase. GS-621763 exhibited significant antiviral activity in lung cell lines and two different human primary lung cell culture systems. The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 significantly reduced viral load, lung pathology, and improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral currently in human clinical trial, proved both drugs to be similarly efficacious. These data demonstrate that therapy with oral prodrugs of remdesivir can significantly improve outcomes in SARS-CoV-2 infected mice. Thus, GS-621763 supports the exploration of GS-441524 oral prodrugs for the treatment of COVID-19 in humans.

Prodrugs of a 1'-CN-4-Aza-7,9-dideazaadenosine C-Nucleoside Leading to the Discovery of Remdesivir (GS-5734) as a Potent Inhibitor of Respiratory Syncytial Virus with Efficacy in the African Green Monkey Model of RSV.

A discovery program targeting respiratory syncytial virus (RSV) identified C-nucleoside 4 (RSV A2 EC50 = 530 nM) as a phenotypic screening lead targeting the RSV RNA-dependent RNA polymerase (RdRp). Prodrug exploration resulted in the discovery of remdesivir (1, GS-5734) that is >30-fold more potent than 4 against RSV in HEp-2 and NHBE cells. Metabolism studies in vitro confirmed the rapid formation of the active triphosphate metabolite, 1-NTP, and in vivo studies in cynomolgus and African Green monkeys demonstrated a >10-fold higher lung tissue concentration of 1-NTP following molar normalized IV dosing of 1 compared to that of 4. A once daily 10 mg/kg IV administration of 1 in an African Green monkey RSV model demonstrated a >2-log10 reduction in the peak lung viral load. These early data following the discovery of 1 supported its potential as a novel treatment for RSV prior to its development for Ebola and approval for COVID-19 treatment.

Data Collection for Adverse Events Reporting by US Dental Schools.

OBJECTIVES: Accreditation of US dental schools requires a formal system of quality assessment of clinical adverse events (AE). There is no universal system to collect, record, interpret, or release findings or trends pertaining to AEs. The objective of this study was to compare similarities and differences among the AE reporting forms used at US dental schools. METHODS: Sixteen (24%) dental schools responded to a query to provide copies of their AE forms. The forms were analyzed to identify unique AE items. A total of 69 unique AE items were identified, grouped, and ranked according to frequency. Methods of AE data collection were also noted. RESULTS: The forms were different in organization, form, and content. The 69 AE items represented a wide variety of information, with no standardization of the type of information, how it was collected, or by whom. We identified 9 most requested AE items and 4 least requested AE items. The schools differed in how the information was obtained: 2 schools used a menu, 8 schools used free response, and 6 schools used a hybrid of both methods. CONCLUSIONS: We found that dental school clinic AE reporting forms are not standardized in structure, organization, or content. We conclude that a hybrid form containing both guided responses and free responses would ensure that proper information is being reported to fully understand why/how an AE occurred. In addition, dental schools need to develop a standardized method of collecting and assessing AE data which will allow for quality improvement and increased patient safety.

Cross-Network Directory Service: Infrastructure to enable collaborations across distributed research networks.

INTRODUCTION: Existing large-scale distributed health data networks are disconnected even as they address related questions of healthcare research and public policy. This paper describes the design and implementation of a fully functional prototype open-source tool, the Cross-Network Directory Service (CNDS), which addresses much of what keeps distributed networks disconnected from each other. METHODS: The set of services needed to implement a Cross-Directory Service was identified through engagement with stakeholders and workgroup members. CNDS was implemented using PCORnet and Sentinel network instances and tested by participating data partners. RESULTS: Web services that enable the four major functional features of the service (registration, discovery, communication, and governance) were developed and placed into an open-source repository. The services include a robust metadata model that is extensible to accommodate a virtually unlimited inventory of metadata fields, without requiring any further software development. The user interfaces are programmatically generated based on the contents of the metadata model. CONCLUSION: The CNDS pilot project gathered functional requirements from stakeholders and collaborating partners to build a software application to enable cross-network data and resource sharing. The two partners-one from Sentinel and one from PCORnet-tested the software. They successfully entered metadata about their organizations and data sources and then used the Discovery and Communication functionality to find data sources of interest and send a cross-network query. The CNDS software can help integrate disparate health data networks by providing a mechanism for data partners to participate in multiple networks, share resources, and seamlessly send queries across those networks.

Scoping Review: Social Determinants of Young Children's Participation in the United States.

Optimal child development is supported by services, policies, a social determinants of health (SDOH) frame, and meaningful participation (as defined by the International Classification of Functioning, Disability, and Health-Children and Youth [ICF-CY]). This scoping review describes the social determinants that may affect the participation of young children aged 0 to 3 years with developmental disabilities (DD) in the United States. Scoping review of studies including U.S. children with DD aged 0 to 3 years, from 2000 to 2016, were used. 5/979 studies met inclusion criteria. Two researchers independently coded studies to align them with both ICF-CY and SDOH. Studies found determinants of participation stemming from the child (e.g., individual) and multiple contexts: immediate, community, and policy. The emergent literature continues to primarily focus on child determinants but suggests participation of young children with DD is affected by social determinants stemming from the community and policy contexts. The literature underrepresents children from racial/ethnic minority backgrounds.

The Validity of Truant Youths' Marijuana Use and Its Impact on Alcohol Use and Sexual Risk Taking.

Few studies investigating the validity of marijuana use have used samples of truant youth. In the current study, self-reports of marijuana use are compared with urine test results for marijuana to identify marijuana underreporting among adolescents participating in a longitudinal Brief Intervention for drug-involved truant youth. It was hypothesized that marijuana underreporting would be associated with alcohol underreporting and engaging in sexual risk behaviors. The results indicated marijuana underreporting was significantly associated with self-denial of alcohol use, but not associated with sexual risk behavior. Also, there was an age effect in marijuana use underreporting such that younger truant youth were more likely to underreport marijuana use, compared to older truant youth. Implications for policy and future research are discussed.

Regioselective derivatizations of a tribrominated atropisomeric benzamide scaffold.

The enantioselective synthesis of atropisomeric, tribrominated benzamides and subsequent regioselective transformations to afford derivatized, axially chiral molecules is reported. The enantioenriched tribromides were carried through sequential Pd-catalyzed cross-coupling and lithium-halogen exchange with high regioselectivity and enantioretention. A variety of complexity-generation functional group installations were performed to create a library of homochiral benzamides. The potential utility of these molecules is demonstrated by using a phosphino benzamide derivative as an asymmetric ligand in a Pd-catalyzed allylic alkylation.

Brief Intervention for Truant Youth Sexual Risk Behavior and Marijuana Use.

Substance use and sexual risk behaviors are common among adolescents. Although attention has focused primarily on alcohol use, less is known about the relationship between marijuana use and sexual risk behavior among high-risk youth. Since truant youth often experience problems in school, troubled family situations, and other psychosocial problems, they represent an important group of high-risk youth to study. Previous research suggests that truant youth are at considerable risk of continuing their troubled behavior in school and entering the juvenile justice system. It is also likely that truant youth are involved in marijuana use and sexual risk behavior at a higher rate, than the general youth population. Involving them in effective intervention services could reduce these risk behaviors. The current study presents interim findings from a NIDA-funded experimental, brief intervention (BI) study involving truant youths and their parents/guardians. Longitudinal data were analyzed to study: (1) the relationships between the youths' marijuana use and engaging in sexual risk behavior over time, and (2) the effects of a substance use BI on their marijuana use and sexual risk behavior. Analyses examined a growth model for parallel processes in marijuana use and sexual risk behavior, and an assessment of the effect of the intervention on linear and quadratic trends, and on subgroups of youth differing in their sexual risk behavior and marijuana use. Implications of the results for future research and service delivery are considered.

Impact of Brief Intervention Services on Drug Using Truant Youth Arrest Charges over Time.

School truancy is a serious concern in the U.S., with far-reaching negative consequences. Truancy has been positively associated with substance use and delinquent behavior; however, research is limited. Consequently, the Truancy Brief Intervention Project was established to treat and prevent substance use and other risky behaviors among truants. This article examines whether the Brief Intervention program is more effective in preventing future delinquency over a 12-month follow-up period, than the standard truancy program. Results indicate the Brief Intervention was marginally significant in effecting future delinquency among truants, compared to the standard truancy program. Future implications of this study are discussed.

Brief Intervention for Truant Youth Sexual Risk Behavior and Alcohol Use: A Parallel Process Growth Model Analysis.

Truant youths represent a challenging, yet very promising group of at-risk youth to study. In addition to problems in school, they frequently experience troubled family situations, emotional/ psychological problems, involvement in substance use, and delinquency. Given the problems often experienced by truant youth, it is likely they are engaging in alcohol use and sexual risk behavior at a higher rate, than the general youth population. Identification of these youths' problems and early placement into effective intervention services would benefit them, their families, and society. The current study presents interim findings from an ongoing, NIDA-funded experimental, Brief Intervention (BI) study involving truant youths and their parent/guardians. Baseline, 3-month, 6-month, and 12-month follow up data were analyzed to determine whether alcohol use and sexual risk behaviors were longitudinally related, examine the effects of the intervention on longitudinal alcohol use and sexual risk behaviors, identify latent subgroups of youths in the data for alcohol use and sexual risk behaviors, and determine whether the intervention influenced these subgroups. Results indicated alcohol use and sexual risk were longitudinally related. Subgroups of youth were also identified based on alcohol use and sexual risk behavior levels and trends. Further, limited treatment effects were observed for alcohol use. Implications of the results for future research and service delivery are considered.

Spontaneous transfer of chirality in an atropisomerically enriched two-axis system.

One of the most well-recognized stereogenic elements in a chiral molecule is an sp(3)-hybridized carbon atom that is connected to four different substituents. Axes of chirality can also exist about bonds with hindered barriers of rotation; molecules containing such axes are known as atropisomers. Understanding the dynamics of these systems can be useful, for example, in the design of single-atropisomer drugs or molecular switches and motors. For molecules that exhibit a single axis of chirality, rotation about that axis leads to racemization as the system reaches equilibrium. Here we report a two-axis system for which an enantioselective reaction produces four stereoisomers (two enantiomeric pairs): following a catalytic asymmetric transformation, we observe a kinetically controlled product distribution that is perturbed from the system's equilibrium position. As the system undergoes isomerization, one of the diastereomeric pairs drifts spontaneously to a higher enantiomeric ratio. In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases. These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes--one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides. The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium.