Pharmacogenetic variants and risk of remdesivir-associated liver enzyme elevations in Million Veteran Program participants hospitalized with COVID-19

Remdesivir is the first US Food and Drug Administration (FDA)-approved drug for the treatment of coronavirus disease 2019 (COVID-19). We conducted a retrospective pharmacogenetic study to examine remdesivir-associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID-19 between March 15, 2020, and June 30, 2021. Pharmacogene phenotypes were assigned using Stargazer. Linear regression was performed on peak log-transformed enzyme values, stratified by population, adjusted for age, sex, baseline liver enzymes, comorbidities, and 10 population-specific principal components. Patients on remdesivir had higher peak alanine aminotransferase (ALT) values following treatment initiation compared with patients not receiving remdesivir. Remdesivir administration was associated with a 33% and 24% higher peak ALT in non-Hispanic White (NHW) and non-Hispanic Black (NHB) participants (p < 0.001), respectively. In a multivariable model, NHW CYP2C19 intermediate/poor metabolizers had a 9% increased peak ALT compared with NHW normal/rapid/ultrarapid metabolizers (p = 0.015); this association was not observed in NHB participants. In summary, remdesivir-associated ALT elevations appear to be multifactorial, and further studies are needed

Happy to help? Exploring the factors associated with variations in rates of volunteering across Europe

The frequency of formal volunteering varies widely across European countries, and rates of formal volunteering are especially low among Eastern European countries. Why are there such large differences in volunteering rates when it is known that volunteering is beneficial for well-being? Using data from the latest round of the European Social Survey, we test three hypotheses to explain these cross-national differences in volunteering. We ask whether people in countries with low frequencies of volunteering spend more of their time on informal volunteering activities; whether they differ on socio-demographic variables which are known to be linked to volunteering rates; or whether they show less well-being benefit from formal volunteering. Contrary to the first hypothesis, we find a positive correlation between formal and informal volunteering. We further conclude that national differences in rates of volunteering cannot be fully explained by differences in the social, psychological or cultural factors associated with volunteering nor the outcome of volunteering. It is likely that contextual factors, such as a country’s historical background or institutions, determine levels of volunteering to a large extent

Time spent on work-related activities, social activities and time pressure as intermediary determinants of health disparities among elderly women and men in 5 European countries: a structural equation model

Background Psychosocial factors shape the health of older adults through complex inter-relating pathways. Besides socioeconomic factors, time use activities may explain gender inequality in self-reported health. This study investigated the role of work-related and social time use activities as determinants of health in old age. Specifically, we analysed whether the impact of stress in terms of time pressure on health mediated the relationship between work-related time use activities (i.e. housework and paid work) on self-reported health. Methods We applied structural equation models and a maximum-likelihood function to estimate the direct and indirect effects of psychosocial factors on health using pooled data from the Multinational Time Use Study on 11,168 men and 14,295 women aged 65+ from Italy, Spain, UK, France and the Netherlands. Results The fit indices for the conceptual model indicated an acceptable fit for both men and women. The results showed that socioeconomic status (SES), demographic factors, stress and work-related time use activities after retirement had a significant direct influence on self-reported health among the elderly, but the magnitude of the effects varied by gender. Social activities had a positive impact on self-reported health but had no significant impact on stress among older men and women. The indirect standardized effects of work-related activities on self-reported health was statistically significant for housework (β = − 0.006; P  0.05 among women), which implied that the paths from paid work and housework on self-reported health via stress (mediator) was very weak because their indirect effects were close to zero. Conclusions Our findings suggest that although stress in terms of time pressure has a direct negative effect on health, it does not indirectly influence the positive effects of work-related time use activities on self-reported health among elderly men and women. The results support the time availability hypothesis that the elderly may not have the same time pressure as younger adults after retirement

One-Step Detection of the 2009 Pandemic Influenza A(H1N1) Virus by the RT-SmartAmp Assay and Its Clinical Validation

<div><h3>Background</h3><p>In 2009, a pandemic (pdm) influenza A(H1N1) virus infection quickly circulated globally resulting in about 18,000 deaths around the world. In Japan, infected patients accounted for 16% of the total population. The possibility of human-to-human transmission of highly pathogenic novel influenza viruses is becoming a fear for human health and society.</p> <h3>Methodology</h3><p>To address the clinical need for rapid diagnosis, we have developed a new method, the “RT-SmartAmp assay”, to rapidly detect the 2009 pandemic influenza A(H1N1) virus from patient swab samples. The RT-SmartAmp assay comprises both reverse transcriptase (RT) and isothermal DNA amplification reactions in one step, where RNA extraction and PCR reaction are not required. We used an exciton-controlled hybridization-sensitive fluorescent primer to specifically detect the HA segment of the 2009 pdm influenza A(H1N1) virus within 40 minutes without cross-reacting with the seasonal A(H1N1), A(H3N2), or B-type (Victoria) viruses.</p> <h3>Results and Conclusions</h3><p>We evaluated the RT-SmartAmp method in clinical research carried out in Japan during a pandemic period of October 2009 to January 2010. A total of 255 swab samples were collected from outpatients with influenza-like illness at three hospitals and eleven clinics located in the Tokyo and Chiba areas in Japan. The 2009 pdm influenza A(H1N1) virus was detected by the RT-SmartAmp assay, and the detection results were subsequently compared with data of current influenza diagnostic tests (lateral flow immuno-chromatographic tests) and viral genome sequence analysis. In conclusion, by the RT-SmartAmp assay we could detect the 2009 pdm influenza A(H1N1) virus in patients' swab samples even in early stages after the initial onset of influenza symptoms. Thus, the RT-SmartAmp assay is considered to provide a simple and practical tool to rapidly detect the 2009 pdm influenza A(H1N1) virus.</p> </div

Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations

Physiological Correlates of Volunteering

We review research on physiological correlates of volunteering, a neglected but promising research field. Some of these correlates seem to be causal factors influencing volunteering. Volunteers tend to have better physical health, both self-reported and expert-assessed, better mental health, and perform better on cognitive tasks. Research thus far has rarely examined neurological, neurochemical, hormonal, and genetic correlates of volunteering to any significant extent, especially controlling for other factors as potential confounds. Evolutionary theory and behavioral genetic research suggest the importance of such physiological factors in humans. Basically, many aspects of social relationships and social activities have effects on health (e.g., Newman and Roberts 2013; Uchino 2004), as the widely used biopsychosocial (BPS) model suggests (Institute of Medicine 2001). Studies of formal volunteering (FV), charitable giving, and altruistic behavior suggest that physiological characteristics are related to volunteering, including specific genes (such as oxytocin receptor [OXTR] genes, Arginine vasopressin receptor [AVPR] genes, dopamine D4 receptor [DRD4] genes, and 5-HTTLPR). We recommend that future research on physiological factors be extended to non-Western populations, focusing specifically on volunteering, and differentiating between different forms and types of volunteering and civic participation

Genetical genomics of growth in a chicken model

Background: The genetics underlying body mass and growth are key to understanding a wide range of topics in biology, both evolutionary and developmental. Body mass and growth traits are affected by many genetic variants of small effect. This complicates genetic mapping of growth and body mass. Experimental intercrosses between individuals from divergent populations allows us to map naturally occurring genetic variants for selected traits, such as body mass by linkage mapping. By simultaneously measuring traits and intermediary molecular phenotypes, such as gene expression, one can use integrative genomics to search for potential causative genes. Results: In this study, we use linkage mapping approach to map growth traits (N = 471) and liver gene expression (N = 130) in an advanced intercross of wild Red Junglefowl and domestic White Leghorn layer chickens. We find 16 loci for growth traits, and 1463 loci for liver gene expression, as measured by microarrays. Of these, the genes TRAK1, OSBPL8, YEATS4, CEP55, and PIP4K2B are identified as strong candidates for growth loci in the chicken. We also show a high degree of sex-specific gene-regulation, with almost every gene expression locus exhibiting sex-interactions. Finally, several trans-regulatory hotspots were found, one of which coincides with a major growth locus. Conclusions: These findings not only serve to identify several strong candidates affecting growth, but also show how sex-specificity and local gene-regulation affect growth regulation in the chicken.Funding Agencies|Carl Tryggers Stiftelse; Swedish Research Council (VR); Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS); Linkoping University Neuro-network; European Research Council [GENEWELL 322206]</p

Identifying Factors Associated With Falls in Postmenopausal Breast Cancer Survivors: A Multi-Disciplinary Approach

Objective—To identify neuromuscular, balance and vision factors that contribute to falls in recently treated breast cancer survivors (BCS) and explore links between fall risk factors and cancer treatment Design—Case-control plus prospective observation Setting—Comprehensive cancer center Participants—BCS within two years chemotherapy completion and/or on adjuvant endocrine therapy (N=59; mean age: 58 yrs) Intervention—not applicable Main outcome measures—Objective measures of postural control, vision and neuromuscular function included 1) a sensory organization test (SOT), 2) a visual assessment battery, 3) muscle mass by DXA, and 4) neuromuscular function with strength by repetition maximum, power by timed stair climb, and gait speed by 4m walk. Falls were self-reported for the past year (retrospective) and monthly for six months (prospective). Results—58% of BCS reported falls in the past year. BCS with a history of falls had lower SOT scores with a vestibular deficit pattern in postural control (