Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: a pharmacogenomics study from the CHARGE consortium

Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

Greater temperature sensitivity of plant phenology at colder sites: implications for convergence across northern latitudes

Warmer temperatures are accelerating the phenology of organisms around the world. Temperature sensitivity of phenology might be greater in colder, higher latitude sites than in warmer regions, in part because small changes in temperature constitute greater relative changes in thermal balance at colder sites. To test this hypothesis, we examined up to 20 years of phenology data for 47 tundra plant species at 18 high-latitude sites along a climatic gradient. Across all species, the timing of leaf emergence and flowering was more sensitive to a given increase in summer temperature at colder than warmer high-latitude locations. A similar pattern was seen over time for the flowering phenology of a widespread species, Cassiope tetragona. These are among the first results highlighting differential phenological responses of plants across a climatic gradient and suggest the possibility of convergence in flowering times and therefore an increase in gene flow across latitudes as the climate warms

Collegiate Athletic Trainers’ Experiences Planning for Return-to-Sports During COVID-19: A Qualitative Research Study

Purpose: The purpose of this study was to explore the role of intercollegiate head athletic trainers in the process of planning to resume sport, as well as their experiences across the course of the pandemic to identify key strategies, challenges, and future considerations during the Covid-19 pandemic. Method: This exploratory, descriptive qualitative study was conducted via one-on-one semi structured interviews through the Zoom video conference technology. Twenty-four head athletic trainers across NCAA Division I, II, and III institutions participated in the study. Results: Emerging themes included the development of detailed, institution-specific plans with shared elements such as policies for testing and screening, modifications to facilities and cleaning, and incorporation of coach and athlete education. Athletic trainers discussed the processes they used to create their return-to-sport policies, which included professional development and interprofessional collaborations. While participants were confident in their plans, they acknowledged the need to overcome logistical and psychosocial challenges, such as the recognition that the success of their plans relied on numerous variables that could not be completely controlled. Conclusion: It is clear that NCAA ATs have played – and will continue to play – an integral role in overcoming challenges to promote a safe return-to-sports amidst the COVID-19 pandemic via education, policy making, and delivery of healthcare services. The challenges imposed by the accompanying set of circumstances have strained these ATs’ practical tendencies and procedures. ATs have met these challenges through collaboration, information-seeking, and acceptance of the situation. NCAA ATs have embraced the opportunity to lead the way towards safe, successful campus reopening and resumption of competition

Higher Levels of Income and Education are Associated with More Specialized Sport Participation Behaviors: Results from a Representative Sample of Youth Sport Parents from the United States

# Background While previous studies have examined the impact of family socioeconomic characteristics on a child's sport specialization behaviors, this research has been limited to affluent communities with limited sociodemographic diversity. # Hypothesis/Purpose The purpose of this study was to examine associations of parent income and education with child sport specialization behaviors among a nationally representative sample of youth sport parents in the United States. # Study Design Cross-sectional. # Methods Parents of youth athletes in the United States (n=236, age: 39.2±8.1 years, 57.2% female) were recruited to complete an online questionnaire by Qualtrics Online Samples (Qualtrics, Provo, UT) using a combination of actively managed, double-opt-in market research panels. The questionnaire used for this study consisted of: 1) parent demographics (including parent age, race/ethnicity, biological sex, gender identity, household income, and educational status), and 2) child sport participation characteristics and sport specialization behaviors. # Results Parents who reported an annual household income of \$75,001 or more were more likely than parents making less than \$75,000 to report that their child participated on an organized club team (OR $$95$$: 1.94 $$1.15-3.27$$), participated on multiple organized teams at the same time (OR $$95$$: 1.85 $$1.10-3.11$$), or specialized in a single sport (OR $$95$$: 2.45 $$1.45-4.14$$). Parents who reported receiving a Bachelor's degree or higher were more likely than parents who did not to report that their child participated on an organized club team (OR $$95$$: 3.04 $$1.78-5.18$$), participated on multiple organized teams at the same time (OR $$95$$: 2.42 $$1.43-4.10$$), or specialized in a single sport (OR $$95$$: 1.94 $$1.15-3.26$$). # Conclusions Thes results suggest that in the modern youth sport culture, family resources may serve as a major determining factor in the type of experiences available for a youth athlete. # Level of Evidence II

High School Sport Specialization Associated with Missing Time with Friends and Frequent Travel

Purpose: Physical consequences of youth sport specialization have been established, yet the psychosocial demands remain largely unexplored. Hypothesis: Missing time with friends due to sport demands and frequent out-of-state travel is associated with sport specialization classification for each high school grade, and this association remains after stratifying for gender and sport level. Study Design: Cross-sectional. Methods: Six hundred sixty-eight (349 female) Division I and club sport athletes from a large midwestern university completed a retrospective survey assessing sport specialization classification and the travel and social demands of sport participation for each high school grade. To measure the social and travel demands of high school sport participation, participants were asked if they missed time with friends because of sports training and if they regularly traveled out-of-state for any sport, to which they responded “yes” or “no”. Chi-square tests evaluated associations between frequent out-of-state travel and missing time with friends due to sport with sport specialization classification (low, moderate, high). Stratifications such as gender (male or female) and college sport level (club or Division I) were further tested in the analyses. Results: A significant association was found between specialization classification and missing time with friends in each high school grade (p-values \u3c 0.001). Similarly, there was a significant association between specialization classification and frequent out-of-state travel in each high school grade (p-values \u3c 0.001). Significant associations remained after stratifying by gender or college sport level. Conclusions: College athletes who reported themselves as highly specialized athletes in high school were more likely to miss time with friends and frequently travel out-of-state due to the demands of their sport compared to less specialized athletes, regardless of gender or college sport level. Findings from this study may help researchers and clinicians understand additional pressures specialized athletes may face that could lead to burnout and eventual sport drop out. This information can help clinicians encountering young athletes who are considering specialization, or have already specialized in sport, inform them and their parents of the potential consequences

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Association of urine biomarkers of kidney health with subclinical cardiovascular disease among men with and without HIV

ObjectiveThe aim of this study was to determine whether urine biomarkers of kidney health are associated with subclinical cardiovascular disease among men with and without HIV.DesignA cross-sectional study within the Multicenter AIDS Cohort Study (MACS) among 504 men with and without HIV infection who underwent cardiac computed tomography scans and had urine biomarkers measured within the preceding 2 years.MethodsOur primary predictors were four urine biomarkers of endothelial (albuminuria), proximal tubule dysfunction (alpha-1-microglobulin [A1 M] and injury (kidney injury molecule-1 [KIM-1]) and tubulointerstitial fibrosis (pro-collagen-III N-terminal peptide [PIIINP]). These were evaluated for association with coronary artery calcium (CAC) prevalence, CAC extent, total plaque score, and total segment stenosis using multivariable regression.ResultsOf the 504 participants, 384 were men with HIV (MWH) and 120 were men without HIV. In models adjusted for sociodemographic factors, cardiovascular disease risk factors, eGFR, and HIV-related factors, each two-fold higher concentration of albuminuria was associated with a greater extent of CAC (1.35-fold higher, 95% confidence interval 1.11-1.65), and segment stenosis (1.08-fold greater, 95% confidence interval 1.01-1.16). Associations were similar between MWH and men without HIV in stratified analyses. The third quartile of A1 M showed an association with greater CAC extent, total plaque score, and total segment stenosis, compared with the lowest quartile.ConclusionWorse endothelial and proximal tubule dysfunction, as reflected by higher urine albumin and A1 M, were associated with greater CAC extent and coronary artery stenosis

Filling Key Gaps in Population and Community Ecology

We propose research to fill key gaps in the areas of population and community ecology, based on a National Science Foundation workshop identifying funding priorities for the next 5–10 years. Our vision for the near future of ecology focuses on three core areas: predicting the strength and context-dependence of species interactions across multiple scales; identifying the importance of feedbacks from individual interactions to ecosystem dynamics; and linking pattern with process to understand species coexistence. We outline a combination of theory development and explicit, realistic tests of hypotheses needed to advance population and community ecology