The wellbeing pandemic: Outline of a contested terrain and a proposed research agenda.

Wellbeing has emerged as a central, if not defining, feature of contemporary social life. Yet, despite its global significance spanning the political, social and economic spectrum, there is a remarkable lack of agreement regarding the conceptualization, definition or operationalisation of wellbeing nor any clear evidence of its success as an instrument of policy. This essay explores the contested terrain of wellbeing by examining the concept in relation to emerging politics, complexities and contradictions. More specifically, the essay: (1) briefly describes the historical origins and development of wellbeing; (2) discusses how it has been reconceptualised within the context of neoliberalism; and, (3) outlines a research agenda offering three ways to investigate wellbeing including: (a) as a wicked problem; (b) as part of the process of "wellbeing washing" within state and other institutional structures and policies; and, (c) in relation to alternative futures, which might encourage us to reimagine or jettison the term altogether.

The Value of Sport: Wellbeing Benefits of Sport Participation during Adolescence.

Insight into the unique benefits of sport participation above and beyond those associated with participation in other physical activities among adolescents is limited in Aotearoa New Zealand (NZ). The purpose of this study was to examine the association between wellbeing and organised sport participation among adolescents whilst accounting for demographic characteristics and other recreational physical activity. Demographic characteristics (age, gender, ethnicity, deprivation, (dis)ability status), organized sport, recreational physical activity, and wellbeing were assessed in cohorts of NZ adolescents (11-17 years) between 2017 and 2019. After adjusting for demographics, better wellbeing was associated with participation in any recreational physical activity (OR = 2.49, 95%CI = 1.97-3.13), meeting physical activity recommendations (OR = 1.63, 95%CI = 1.47-1.81), and each additional hour of recreational physical activity (OR = 1.03, 95%CI = 1.02-1.04). After adjusting for demographics and overall recreational physical activity participation, better wellbeing was also associated with participation in any organized sport (OR = 1.66, 95%CI = 1.49-1.86), and each additional hour of organized sport (OR = 1.09, 95%CI = 1.07-1.11). Although participation in recreational physical activity appears to be beneficial for wellbeing, organized sport appears to offer unique additional wellbeing benefits. Positive experiences of organized sport participation may offer additional wellbeing value above and beyond other recreational physical activity types in young people who are active.

"Balance Is Better": The Wellbeing Benefits of Participating in a Breadth of Sports across a Variety of Settings during Adolescence.

The purpose of this study was to examine how wellbeing is associated with the setting in which sport participation takes place and the breadth of sport participation. Demographic characteristics (age, gender, ethnicity, deprivation, (dis)ability status), recreational physical activity, and wellbeing were assessed in cohorts of adolescents (11-17 years) between 2017 and 2019 in Aotearoa, New Zealand. Better wellbeing was associated with participation in any sport vs. none (OR = 1.57, 95% CI = 1.30-1.90). Better wellbeing was also associated with participating in any coached sport training (OR = 1.48, 95% CI = 1.33-1.66), competitive sport (OR = 1.33, 95% CI = 1.18-1.49), social sport (OR = 1.33, 95% CI = 1.18-1.49), and uncoached sport training (OR = 1.16, 95% CI = 1.03-1.31) compared to non-participation in the given setting. Wellbeing was not associated with participation in physical education or solo sport. Participating in sport in three to five different settings (3 settings: OR = 1.21, 95% CI = 1.01-1.44; 4 settings: OR = 1.33, 95% CI = 1.09-1.62; 5 settings: OR = 1.37, 95% CI = 1.07-1.75) or sports (3 sports: OR = 1.25, 95% CI = 1.04-1.51; 4 sports: OR = 1.31, 95% CI = 1.06-1.61; 5 sports: OR = 1.33, 95% CI = 1.05-1.69) was associated with better wellbeing compared to participation in a single setting or sport, respectively. A balanced approach to participating across a variety of sport settings and sports that are facilitated by quality coaches may offer the largest additional wellbeing value.

A high throughput screening assay for inhibitors of SARS-CoV-2 pseudotyped particle entry

Effective small molecule therapies to combat the SARS-CoV-2 infection are still lacking as the COVID-19 pandemic continues globally. High throughput screening assays are needed for lead discovery and optimization of small molecule SARS-CoV-2 inhibitors. In this work, we have applied viral pseudotyping to establish a cell-based SARS-CoV-2 entry assay. Here, the pseudotyped particles (PP) contain SARS-CoV-2 spike in a membrane enveloping both the murine leukemia virus (MLV) gag-pol polyprotein and luciferase reporter RNA. Upon addition of PP to HEK293-ACE2 cells, the SARS-CoV-2 spike protein binds to the ACE2 receptor on the cell surface, resulting in priming by host proteases to trigger endocytosis of these particles, and membrane fusion between the particle envelope and the cell membrane. The internalized luciferase reporter gene is then expressed in cells, resulting in a luminescent readout as a surrogate for spike-mediated entry into cells. This SARS-CoV-2 PP entry assay can be executed in a biosafety level 2 containment lab for high throughput screening. From a collection of 5,158 approved drugs and drug candidates, our screening efforts identified 7 active compounds that inhibited the SARS-CoV-2-S PP entry. Of these seven, six compounds were active against live replicating SARS-CoV-2 virus in a cytopathic effect assay. Our results demonstrated the utility of this assay in the discovery and development of SARS-CoV-2 entry inhibitors as well as the mechanistic study of anti-SARS-CoV-2 compounds. Additionally, particles pseudotyped with spike proteins from SARS-CoV-2 B.1.1.7 and B.1.351 variants were prepared and used to evaluate the therapeutic effects of viral entry inhibitors.

Discovery of Synergistic and Antagonistic Drug Combinations against SARS-CoV-2 In Vitro

COVID-19 is undoubtedly the most impactful viral disease of the current century, afflicting millions worldwide. As yet, there is not an approved vaccine, as well as limited options from existing drugs for treating this disease. We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2. Using in silico approaches, we prioritized 73 combinations of 32 drugs with potential activity against SARS-CoV-2 and then tested them in vitro. Overall, we identified 16 synergistic and 8 antagonistic combinations, 4 of which were both synergistic and antagonistic in a dose-dependent manner. Among the 16 synergistic cases, combinations of nitazoxanide with three other compounds (remdesivir, amodiaquine and umifenovir) were the most notable, all exhibiting significant synergy against SARS-CoV-2. The combination of nitazoxanide, an FDA-approved drug, and remdesivir, FDA emergency use authorization for the treatment of COVID-19, demonstrate a strong synergistic interaction. Notably, the combination of remdesivir and hydroxychloroquine demonstrated strong antagonism. Overall, our results emphasize the importance of both drug repurposing and preclinical testing of drug combinations for potential therapeutic use against SARS-CoV-2 infections.

An OpenData portal to share COVID-19 drug repurposing data in real time

The National Center for Advancing Translational Sciences (NCATS) has developed an online open science data portal for its COVID-19 drug repurposing campaign - named OpenData - with the goal of making data across a range of SARS-CoV-2 related assays available in real-time. The assays developed cover a wide spectrum of the SARS-CoV-2 life cycle, including both viral and human (host) targets. In total, over 10,000 compounds are being tested in full concentration-response ranges from across multiple annotated small molecule libraries, including approved drug, repurposing candidates and experimental therapeutics designed to modulate a wide range of cellular targets. The goal is to support research scientists, clinical investigators and public health officials through open data sharing and analysis tools to expedite the development of SARS-CoV-2 interventions, and to prioritize promising compounds and repurposed drugs for further development in treating COVID-19.

Standardization of enzyme-linked immunosorbent assays for serosurveys of the SARS-CoV-2 pandemic using clinical and at-home blood sampling

The extent of SARS-CoV-2 infection throughout the United States population is currently unknown. High quality serology is a key tool to understanding the spread of infection, immunity against the virus, and correlates of protection. Limited validation and testing of serology assays used for serosurveys can lead to unreliable or misleading data, and clinical testing using such unvalidated assays can lead to medically costly diagnostic errors and improperly informed public health decisions. Estimating prevalence and clinical decision making is highly dependent on specificity. Here, we present an optimized ELISA-based serology protocol from antigen production to data analysis. This protocol defines thresholds for IgG and IgM for determination of seropositivity with estimated specificity well above 99%. Validation was performed using both traditionally collected serum and dried blood on mail-in blood sampling kits, using archival (pre-2019) negative controls and known PCR-diagnosed positive patient controls. Minimal cross-reactivity was observed for the spike proteins of MERS, SARS1, OC43 and HKU1 viruses and no cross reactivity was observed with anti-influenza A H1N1 HAI titer during validation. This strategy is highly specific and is designed to provide good estimates of seroprevalence of SARS-CoV-2 seropositivity in a population, providing specific and reliable data from serosurveys and clinical testing which can be used to better evaluate and understand SARS-CoV-2 immunity and correlates of protection.

The SARS-CoV-2 cytopathic effect is blocked with autophagy modulators

SARS-CoV-2 is a new type of coronavirus capable of rapid transmission and causing severe clinical symptoms; much of which has unknown biological etiology. It has prompted researchers to rapidly mobilize their efforts towards identifying and developing anti-viral therapeutics and vaccines. Discovering and understanding the virus’ pathways of infection, host-protein interactions, and cytopathic effects will greatly aid in the design of new therapeutics to treat COVID-19. While it is known that chloroquine and hydroxychloroquine, extensively explored as clinical agents for COVID-19, have multiple cellular effects including inhibiting autophagy, there are also dose-limiting toxicities in patients that make clearly establishing their potential mechanisms-of-action problematic. Therefore, we evaluated a range of other autophagy modulators to identify an alternative autophagy-based drug repurposing opportunity. In this work, we found that 6 of these compounds blocked the cytopathic effect of SARS-CoV-2 in Vero-E6 cells with EC50 values ranging from 2.0 to 13 µM and selectivity indices ranging from 1.5 to >10-fold. Immunofluorescence staining for LC3B and LysoTracker dye staining assays in several cell lines indicated their potency and efficacy for inhibiting autophagy correlated with the measurements in the SARS-CoV-2 cytopathic effect assay. Our data suggest that autophagy pathways could be targeted to combat SARS-CoV-2 infections and become an important component of drug combination therapies to improve the treatment outcomes for COVID-19.One Sentence Summary Blocking SARS-CoV-2 cytopathic effects with selective autophagy inhibitors underlying the clinical benefits of chloroquine and hydroxychloroquine.Competing Interest StatementThe authors have declared no competing interest.View Full Text