09 April, 2021

First-in-Woman Safety, Tolerability, and Pharmacokinetics of Orally Administered GS-441524: A Broad-Spectrum Antiviral Treatment for COVID-19 -

GS-441524 is a nucleoside analogue with broad-spectrum antiviral activity against RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and feline coronavirus (FCoV). GS-441524 is the main circulating metabolite following intravenous administration of remdesivir (Veklury®), with a plasma half-life of approximately 24 hours. The safety, tolerability, and pharmacokinetics of GS-441524 was evaluated in a healthy human volunteer (N=1) when administered directly as an oral solution (750 mg) once daily for 7 days (Part 1) and 3 times daily for 3 days (Part 2). In Part 1 of the study, the effect of food on the absorption of GS-441524 was also evaluated. GS-441524 appeared rapidly in plasma, with an average time of maximum concentration of 0.5 hours during once-per-day dosing and exhibited an initial half-life phase of approximately 3.3 hours in the fasted state. Negligible accumulation was observed during part 1 of the multiday study. In Part 2 of the study, GS-441524 was administered 3 times daily, every 3 hours. A 2-4-fold accumulation of GS-441524 was observed approximately 3 hours after the third dose was administered, with a time of maximum concentration of 9 hours and a maximum concentration of 12.01 µM, exceeding the concentration reported to eradicate SARS-CoV-2 in vitro. For the duration of the study, GS-441524 was well-tolerated. There were no treatment-related adverse events and no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Taken together, these results demonstrate the safety and viability of orally administered GS-441524 for the treatment of COVID-19 and emerging viral infections.

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Beyond resilience: Promotive and protective traits that facilitate recovery during crisis -

Resilience functions to promote psychological growth and buffer against the effects of negative events. Individual traits that promote optimal mental health beyond resilience, however, remain poorly understood. The current study addresses this gap through a positive psychology perspective. We examine how promotive traits – courage, optimism, hope, and protective traits – nostalgia, wisdom, and spirituality promote well-being and buffer against negative emotional states. We hypothesized that promotive traits will be positively related to well-being while protective traits will be negatively related to negative emotional states. Six-hundred and twenty-six (626) Malaysians responded to an online survey at the end of the country’s second wave of the COVID-19 pandemic (June-September 2020). We conducted a series of regression analyses, controlling for resilience, socio-economic status, age, and perceptions towards government crisis management efforts. Results indicate that courage, optimism and hope positively predicted well-being. The strongest promotive trait contributing to well-being is hope. Results also showed that the only significant protective trait against negative emotional states is spirituality. Interestingly, nostalgia and wisdom positively predicted negative emotional states. Findings indicate that beyond resilience, courage, optimism, hope and spirituality are the strongest predictors of well-being and protect against negative emotional states amidst the COVID-19 pandemic. The findings are of theoretical relevance for resilience and positive psychology research, and practically beneficial in informing mental health interventions.

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Religion Does Not Inhibit Belief in Science, but Non-Religious People Think it Does -

Religion and science are two major sources of knowledge. Some accounts suggest that religious belief inhibits people from trusting scientific information, and encourages conflict between religion and science. We draw from theories of human motivation to challenge this claim, instead suggesting that religious people perceive less conflict between science and religion than non-religious people, that religious—but not non-religious—people use both science and religion when they explain phenomena, and that religious people rely on science more than non-religious people think they do. Five studies support our account. A pilot study uses a large representative sample of Americans to show that religious people perceive less conflict between science and religion than non-religious people. Studies 1-2 show that religious people view religion and science as equally and moderately instrumental for explaining extraordinary events (Study 1) and life’s “big questions” (Study 2), whereas non-religious people view science as highly instrumental and religion as not at all so. Study 3 finds that non-religious people mischaracterize religious people as more reliant on religion and less reliant on science than they really are, and also suggests that religious people view science and religion as orthogonal whereas non-religious people view them as hydraulic. Study 4 applies these findings to the COVID-19 pandemic, showing that faith-based strategies of avoiding infection do not inhibit adoption of science-based strategies. Religious people may be more open to science than many non-religious people think.

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The impact of viral mutations on recognition by SARS-CoV-2 specific T-cells -

We identify amino acid variants within dominant SARS-CoV-2 T-cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T-cells assessed by IFN-{gamma} and cytotoxic killing assays. These data demonstrate the potential for T-cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T-cell as well as humoral immunity.

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Human pulmonary artery endothelial cells upregulate ACE2 expression in response to iron-regulatory elements: potential implications for SARS-CoV-2 infection of vascular endothelial cells. -

Emerging studies from the ongoing covid-19 pandemic have implicated vascular dysfunction and endotheliitis in many patients presenting with severe disease. However, there is limited evidence for the expression of ACE2 (the principal co-receptor for Sars-Cov-2 cellular attachment) in vascular endothelial cells which has prompted the suggestion that the virus does not infect these cell types. However, the studies presented here demonstrate enhanced expression of ACE2 at the level of both mRNA and protein, in human pulmonary artery endothelial cells (PAECs) challenged with either IL-6 or hepcidin. Notably elevated levels both these iron-regulatory elements have been described in Covid-19 patients with severe disease and are further associated with morbidity and mortality. Additionally, levels of both IL-6 and hepcidin are often elevated in the elderly and in chronic disease settings, these populations being at greater risk of adverse outcomes from Sars-Cov-2 infection. A role for IL-6 and hepcidin as modulators of ACE2 expression seems plausible, additional, studies are required to determine if viral infection can be demonstrated in PAECs challenged with either of these iron-regulatory elements.

🖺 Full Text HTML: Human pulmonary artery endothelial cells upregulate ACE2 expression in response to iron-regulatory elements: potential implications for SARS-CoV-2 infection of vascular endothelial cells.

Polymersomes decorated with SARS-CoV-2 spike protein receptor binding domain elicit robust humoral and cellular immunity -

A diverse portfolio of SARS-CoV-2 vaccine candidates is needed to combat the evolving COVID-19 pandemic. Here, we developed a subunit nanovaccine by conjugating SARS-CoV-2 Spike protein receptor binding domain (RBD) to the surface of oxidation-sensitive polymersomes. We evaluated the humoral and cellular responses of mice immunized with these surface-decorated polymersomes (RBDsurf) compared to RBD-encapsulated polymersomes (RBDencap) and unformulated RBD (RBDfree), using monophosphoryl lipid A-encapsulated polymersomes (MPLA PS) as an adjuvant. While all three groups produced high titers of RBD-specific IgG, only RBDsurf elicited a neutralizing antibody response to SARS-CoV-2 comparable to that of human convalescent plasma. Moreover, RBDsurf was the only group to significantly increase the proportion of RBD-specific germinal center B cells in the vaccination-site draining lymph nodes. Both RBDsurf and RBDencap drove similarly robust CD4+ and CD8+ T cell responses that produced multiple Th1-type cytokines. We conclude that multivalent surface display of Spike RBD on polymersomes promotes a potent neutralizing antibody response to SARS-CoV-2, while both antigen formulations promote robust T cell immunity.

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A repurposed drug screen identifies compounds that inhibit the binding of the COVID-19 spike protein to ACE2 -

Repurposed drugs that block the interaction between the SARS-CoV-2 spike protein and its receptor ACE2 could offer a rapid route to novel COVID-19 treatments or prophylactics. Here, we screened 2701 compounds from a commercial library of drugs approved by international regulatory agencies for their ability to inhibit the binding of recombinant, trimeric SARS-CoV-2 spike protein to recombinant human ACE2. We identified 56 compounds that inhibited binding by <90%, measured the EC50 of binding inhibition, and computationally modeled the docking of the best inhibitors to both Spike and ACE2. These results highlight an effective screening approach to identify compounds capable of disrupting the Spike-ACE2 interaction as well as identifying several potential inhibitors that could serve as templates for future drug discovery efforts.

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Seasonal stability of SARS-CoV-2 in biological fluids -

Transmission of SARS-CoV-2 occurs by close contact with infected persons through droplets, the inhalation of infectious aerosols and the exposure to contaminated surface. Previously, we determined the virus stability on different types of surfaces under indoor and seasonal climatic conditions. SARS-CoV-2 survived the longest on surfaces under winter conditions, followed by spring/fall and summer conditions, suggesting the seasonal pattern of stability on surfaces. However, under natural conditions, the virus is secreted in various biological fluids from infected humans. In this respect, it remains unclear how long the virus survives in various types of biological fluids. This study explored the SARS-CoV-2 stability in human biological fluids under different environmental conditions and estimated the half-life. The virus was stable for up to 21 days in nasal mucus, sputum, saliva, tear, urine, blood, and semen; it remained infectious significantly longer under winter and spring/fall conditions than under summer conditions. In contrast, the virus was only stable up to 24 hours in feces and breast milk. These findings demonstrate the potential risk of infectious biological fluids in SARS-CoV-2 transmission and have implications for its seasonality.

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Safe and effective pool testing for SARS-CoV-2 detection -

Background / Objectives: The global spread of SARS-CoV-2 is a serious public health issue. Large-scale surveillance screenings are crucial but can exceed diagnostic test capacities. We set out to optimize test conditions and implemented high throughput pool testing of respiratory swabs into SARS-CoV-2 diagnostics. Study design: In preparation for pool testing, we determined the optimal pooling strategy and pool size. In addition, we measured the impact of vortexing prior to sample processing, compared pipette- and swab-pooling method as well as the sensitivity of three different PCR assays. Results: Using optimized strategies for pooling, we systematically pooled 55,690 samples in a period of 44 weeks resulting in a reduction of 47,369 PCR reactions. In a low prevalence setting, we defined a preferable pool size of ten in a two-stage hierarchical pool testing strategy. Vortexing of the swabs increased cellular yield by a factor of 2.34, and sampling at or shortly after symptom onset was associated with higher viral loads. By comparing different pooling strategies, pipette-pooling was more efficient compared to swab-pooling. Conclusions: For implementing pooling strategies into high throughput diagnostics, we recommend to apply a pipette-pooling method, using pool sizes of ten samples, performing sensitivity validation of the PCR assays used, and vortexing swabs prior to analyses. Our data shows, that pool testing for SARS-CoV-2 detection is feasible and highly effective in a low prevalence setting.

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Taking care with self-care during COVID-19: Affect-behavior associations during early stages of the pandemic -

Although evidence exists for a feedback loop between positive affect and self-care behaviors, it is unclear if findings generalize to the COVID-19 pandemic. A 10-day daily diary was completed by 324 adult participants in the United States during spring 2020 when national stay-at-home orders were in effect. We hypothesized a reciprocal within-person process whereby positive affect increased self-care behaviors (Aim 1) and self-care behaviors increased positive affect (Aim 2). Lagged analyses for Aim 1 indicated that greater negative affect, rather than positive affect, predicted increased self-care behaviors from one day to the next day. For Aim 2, concurrent analyses, but not lagged analyses, indicated self-care behaviors was associated with more positive affect and less negative affect afterwards. We discuss the ways negative affect might function differently than normal during stressful environments and conclude self-care behaviors continue to have only a short-term (within a day) impact on positive and negative affect.

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The Acute and Persisting Impact of COVID-19 on Trajectories of Adolescent Depression: Sex Differences and Social Connectedness -

Background: The COVID-19 era is a time of unprecedented stress, and there is widespread concern regarding its short- and long-term mental health impact. Adolescence is a sensitive period for the emergence of latent psychopathology vulnerabilities, often activated by environmental stressors. The present study examined COVID-19’s impact on adolescent depression and possible influences of different domains of social connectedness (loneliness, social media use, social video game time). Methods: A community sample of 175 adolescents (50.1% boys, mean age=16.01 years) completed questionnaires once before and twice during the COVID-19 pandemic. Piecewise growth modeling examined the acute (7 weeks) and persistent (8 months) effects of COVID-19 on depressive symptoms, and differences across sex and social connectedness. Results: Significant increases in depressive symptoms followed pandemic onset for boys and girls. However, this increase was earlier and more pronounced among girls than boys, whose depression only increased significantly during the persistent period and to a lesser degree. Trajectories of depression were influenced by loneliness and virtual social connections. Limitations: Most participants had economic stability and minimal exposure to the virus. Exacerbation of depressive symptoms may be more severe in higher risk populations. Conclusions: Adolescent depression levels have increased during COVID-19, and are higher for girls and those who are lonely. Enhanced screening and management for adolescent depression and social connectedness could play a critical role in mitigating the negative mental health fallout of COVID-19 and future pandemics within this population.

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Intragroup differences in COVID-19 vaccine attitudes among Black Americans -

COVID-19 vaccine hesitancy among Black Americans threatens to further magnify racial inequities in COVID-19 related health outcomes that emerged in the earliest stages of the pandemic. Here we shed new light on attitudes towards COVID-19 vaccines by considering intragroup variation. Rather than analyzing Blacks as a homogenous group, we examine the relationship between COVID-19 vaccine attitudes and the extent to which participants are aligned with African American versus White culture (i.e., level of “acculturation”). In a sample of N=997 Black Americans, we find that stronger alignment with African American culture predicts substantially more negative attitudes towards COVID-19 vaccination, above and beyond variation explained by age, gender, education, and socioeconomic status. This relationship was substantially attenuated when controlling for suspicion of the healthcare system, but not perceptions that healthcare system treats Blacks unfairly, science knowledge, or cognitive reflection. The intragroup differences among Blacks in COVID-19 vaccine perceptions uncovered here provide insights into designing interventions that provide health information that targets the relevant factors for vaccine hesitancy in differing subgroups.

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Doomscrolling during COVID-19: The negative association between daily social and traditional media consumption and mental health symptoms during the COVID-19 pandemic -

Consumption of traditional and social media markedly increased at the start of the COVID-19 pandemic as new information about the virus and safety guidelines evolved. Much of the information concerned restrictions on daily living activities and the risk posed by the virus. The term ``doomscrolling’’ was used to describe the phenomenon of elevated negative affect after viewing pandemic-related media. The magnitude and duration of this effect, however, is unclear. Furthermore, the effect of doomscrolling likely varies based on prior vulnerabilities for psychopathology such as a history of childhood maltreatment. It was hypothesized that social and traditional media exposure was related to an increase in depression and PTSD and that this increase was moderated by childhood maltreatment severity. Participants completed a baseline assessment for psychopathology and 30 days of daily assessments of depression and PTSD. Using multilevel modeling on 1,117 daily observations, social media access was associated with increased depression and PTSD. This association was stronger for those with more severe maltreatment histories. Furthermore, those with more severe baseline psychopathology used more social media during this period. These results suggest that doomscrolling is associated with increases in psychopathology for those with existing vulnerabilities.

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Both a bioweapon and a hoax: The curious case of contradictory conspiracy theories about COVID-19 -

Amidst the flow of conspiracy theories (CTs) about the coronavirus pandemic, many logically incompatible ones arise. Upon pretesting for familiarity and logical incompatibility, we choose eight pairs of contradictory CTs. Across two studies, we observed a significant portion of respondents (40%-48%) endorsed at least one pair. In Study 1 (N = 290), we showed that conspiracy mentality and doublethink, a general proneness to contradictions, but not preference for consistency, meaningfully relate to endorsement of contradictory COVID-19 CTs; doublethink contributed over and above other predictors. In Study 2 (N = 281), we related the same tendency to different indicators of superficial information processing. Those more prone to endorse contradictory COVID-19 CTs were more intuitive, less rational, more prone to ontological confusions and pseudo-profound bullshit; doublethink again contributed independently of all other predictors. We end by suggesting how the observed psychological profile of endorsers could inform interventions aimed to tackle conspiratorial thinking.

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The impact of the COVID-19 pandemic on gastrointestinal infection trends in England, February - July 2020 -

Objective: To establish the impact of the first six months of the COVID-19 outbreak response of gastrointestinal (GI) infection trends in England. Design: Retrospective ecological study using routinely collected national and regional surveillance data from eight Public Health England coordinated laboratory, outbreak and syndromic surveillance systems using key dates of UK governmental policy change to assign phases for comparison between 2020 and historic data. Results: Decreases in GI illness activity were observed across all surveillance indicators as COVID-19 cases began to peak. Compared to the 5-year average (2015-2019), during the first six months of the COVD-19 response, there was a 52% decrease in GI outbreaks reported (1,544 vs. 3,208 (95% CI: 2,938 - 3,478) and a 34% decrease in laboratory confirmed cases (27,859 vs. 42,495 (95% CI: 40,068 - 44,922). GI indicators began to rise during the first lockdown and lockdown easing, although all remained substantially lower than historic figures. Reductions in laboratory confirmed cases were observed across all age groups and both sexes, with geographical heterogeneity observed in diagnosis trends. Health seeking behaviour changed substantially, with attendances decreasing prior to lockdown across all indicators. Conclusions: There has been a marked change in trends of GI infections in the context of the COVID-19 pandemic. The drivers of this change are likely to be multifactorial; while changes in health seeking behaviour, pressure on diagnostic services and surveillance system ascertainment have undoubtably played a role there has likely been a true decrease in the incidence for some pathogens resulting from the control measures and restrictions implemented. This suggests that if some of these changes in behaviour such as improved hand hygiene were maintained, then we could potentially see sustained reductions in the burden of GI illness.

🖺 Full Text HTML: The impact of the COVID-19 pandemic on gastrointestinal infection trends in England, February - July 2020

Covid-19 Sentry

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