Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.

OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Differences in perceptions of community stigma towards opioid use disorder between community substance use coalition members and the general public.

INTRODUCTION: To examine differences in perceptions about community stigma towards individuals with opioid use disorder (OUD) between community members involved in the opioid response (i.e., coalition members) and the general public, and how community geography may moderate this relationship. METHODS: This study administered identical cross-sectional surveys about perceived community opioid-related stigma to two distinct populations in 66 communities participating in the HEALing Communities Study prior to the intervention period (i.e., coalition members, November 2019-January 2020; residents, March-April 2020). Linear-mixed models compared survey responses of populations, including the moderating effect of community rural/urban location. RESULTS: A total of 826 coalition members and 1131 residents completed the surveys. The study found no differences between the coalition members and residents for general perceived community opioid-related stigma. In both urban and rural communities, coalition members reported greater perceived community stigma than residents reported towards medication for opioid use disorder (MOUD), naloxone, and drug treatment as an alternative to incarceration. CONCLUSION: Our findings suggest similar perceived community opioid-related stigma between coalition members and residents, yet differences emerge related to evidence-based practices (i.e., MOUD, naloxone, and drug treatment as an alternative to incarceration) to reduce opioid overdose deaths. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04111939.

WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10-9). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD. METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D. RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance (P<5.0×10-8): rs147138607 (intergenic variant between CACNA1E and ZNF648) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, P=3.6×10-9, rs11444867 (intergenic variant near HS3ST1) with HR 1.89, 95% CI 1.52 - 2.35, P=9.9×10-9, and rs335407 (intergenic variant between TFB1M and NOX3) HR 1.25, 95% CI 1.16 - 1.35, P=1.5×10-8. Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with P<0.05, and 5 were significant after Bonferroni correction (P<0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase (P=1.0×10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

A Prediction Model for Severe Maternal Morbidity and Mortality After Delivery Hospitalization.

OBJECTIVE: To develop a risk stratification model for severe maternal morbidity (SMM) or mortality after the delivery hospitalization based on information available at the time of hospital discharge. METHODS: This population-based cohort study included all pregnancies among Ohio residents with Medicaid insurance from 2012 to 2017. Pregnant individuals were identified using linked live birth and fetal death records and Medicaid claims data. Inclusion was restricted to those with continuous postpartum Medicaid enrollment and delivery at 20 or more weeks of gestation. The primary outcome of the study was SMM or mortality after the delivery hospitalization and was assessed up to 42 days postpartum and up to 1 year postpartum separately. Variables considered for the model included patient-, obstetric health care professional-, and system-level data available in vital records or Medicaid claims data. Parsimonious models were created with logistic regression and were internally validated. Receiver operating characteristic curves were used to evaluate model performance, and model calibration was assessed. RESULTS: There were 343,842 pregnant individuals who met inclusion criteria with continuous Medicaid enrollment through 42 days postpartum and 287,513 with continuous enrollment through 1 year. After delivery hospitalization discharge, the incidence of SMM or mortality was 140.5 per 10,000 pregnancies through 42 days of delivery and 330.7 per 10,000 pregnancies through 1 year postpartum. The final model predicting SMM or mortality through 42 days postpartum included maternal prepregnancy body mass index, age, gestational age at delivery, mode of delivery, chorioamnionitis, and maternal diagnosis of cardiac disease, preeclampsia or gestational hypertension, or a mental health condition. Similar variables were included in the model predicting SMM or mortality through 365 days with chronic hypertension, pregestational diabetes, and illicit substance use added and chorioamnionitis removed. Both models demonstrated moderate prediction (area under the curve [AUC] 0.77, 95% CI 0.76-0.78 for 42-day model; AUC 0.72, 95% CI 0.71-0.73 for the 1-year model) and good calibration. CONCLUSION: A prediction model for SMM or mortality up to 1 year postpartum was created and internally validated with information available to health care professionals at the time of hospital discharge. The utility of this model for patient counseling and strategies to optimize postpartum care for high-risk individuals will require further evaluation.

Resiliency Among Women's Health Initiative Women Aged 80 and Older by Race, Ethnicity, and Neighborhood Socioeconomic Status.

OBJECTIVES: A comprehensive examination of resilience by race, ethnicity, and neighborhood socioeconomic status (NSES) among women aged ≥80 is needed, given the aging of the U.S. population, increasing longevity, and growing racial and ethnic diversity. METHODS: Participants were women aged ≥80 enrolled in the Women's Health Initiative. Resilience was assessed with a modified version of the Brief Resilience Scale. Descriptive statistics and multiple linear regression examined the association of demographic, health, and psychosocial variables with resilience by race, ethnicity, and NSES. RESULTS: Participants (n = 29,367, median age = 84.3) were White (91.4%), Black (3.7%), Hispanic (1.9%), and Asian (1.7%) women. There were no significant differences by race and ethnicity on mean resiliency scores (p = .06). Significant differences by NSES were observed regarding mean resiliency scores between those with low NSES (3.94 ± 0.83, out of 5) and high NSES (4.00 ± 0.81). Older age, higher education, higher self-rated health, lower stress, and living alone were significant positive correlates of resilience in the sample. Social support was correlated with resilience among White, Black, and Asian women, but not for Hispanic women. Depression was a significant correlate of lower resilience, except among Asian women. Living alone, smoking, and spirituality were significantly associated with higher resilience among women with moderate NSES. DISCUSSION: Multiple factors were associated with resilience among women aged ≥80 in the Women's Health Initiative. Despite some differing correlates of resilience by race, ethnicity, and NSES, there were many similarities. These results may aid in the design of resilience interventions for the growing, increasingly diverse population of older women.

Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program.

BACKGROUND: Risk for venous thromboembolism has a strong genetic component. Whole genome sequencing from the TOPMed program (Trans-Omics for Precision Medicine) allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. METHODS: The 3793 cases and 7834 controls (11.6% of cases were individuals of African, Hispanic/Latino, or Asian ancestry) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). RESULTS: Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only PROC (odds ratio, 6.2 for carriers of rare variants; P=7.4×10-14) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at PROC (odds ratio, 3.8; P=1.6×10-14), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: PROS1 became significant (minimum P=1.8×10-6 with the secondary filter), while SERPINC1 did not (minimum P=4.4×10-5 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, MS4A1, became significant (P=4.4×10-7 using all missense variants with minor allele frequency <0.0005). CONCLUSIONS: Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel MS4A1 locus and to identify additional rare variation associated with venous thromboembolism.

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

Contribution of Common Genetic Variants to Risk of Early Onset Ischemic Stroke.

BACKGROUND AND OBJECTIVES: Current genome-wide association studies of ischemic stroke have focused primarily on late onset disease. As a complement to these studies, we sought to identifythe contribution of common genetic variants to risk of early onset ischemic stroke. METHODS: We performed a meta-analysis of genome-wide association studies of early onset stroke (EOS), ages 18-59, using individual level data or summary statistics in 16,730 cases and 599,237 non-stroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late onset stroke (LOS) and compared polygenic risk scores for venous thromboembolism between EOS and LOS. RESULTS: We observed genome-wide significant associations of EOS with two variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared to LOS. The odds ratio (OR) for rs529565, tagging O1, 0.88 (95% CI: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared to LOS (p=0.008). DISCUSSION: The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.

Community Coalitions' Perspectives on Engaging with Hospitals in Ohio to Address the Opioid Crisis.

Community coalitions have been leading the multisector response to the opioid epidemic in the Unites States. However, with the medicalization of opioid use disorder and changing health care policies, hospitals have moved to the forefront, becoming more active in collaborating with community coalitions. Little is currently known about how community coalitions view and approach collaborating with hospitals despite its importance for understanding and advancing interorganizational approaches to combating the opioid epidemic. Using data from semistructured interviews (n = 119) conducted from November 2019 to January 2020 as part of the HEALing Communities Study (ClinicalTrials.gov: NCT04111939), the authors examined how community coalition members perceive hospital collaborations and explored the opportunities and challenges of these partnerships. They characterized 3 emergent themes: coalition approaches to collaborating with hospitals, barriers to collaboration, and opportunities for sustainable relationships. This new evidence highlights the value that coalitions place on hospital collaborations, as well as mechanisms that may help support ongoing partnerships.

Analysis of Urine Drug Test Results From Substance Use Disorder Treatment Practices and Overdose Mortality Rates, 2013-2020.

Importance: Drug overdose deaths in the US are currently the highest ever recorded; data collected from public health surveillance sources can help to identify emerging drug use patterns associated with overdose mortality rates, but the time lag in results often limits utility. Urine drug testing (UDT) is one potentially underused source that could augment surveillance efforts through timely data collection. Objective: To evaluate the correlation between real-time UDT results from a proprietary national database and overdose mortality data from the National Vital Statistics System. Design, Setting, and Participants: This retrospective cross-sectional study included 500 000 urine specimens submitted for UDT by substance use disorder (SUD) treatment health care practices and collected between January 1, 2013, and December 31, 2020. Real-time UDT data were obtained from the Millennium Health proprietary national database, and overdose mortality data were obtained from the National Vital Statistics System of the Centers for Disease Control and Prevention (CDC WONDER). Specimens were analyzed for specific drugs in 5 categories (cocaine, heroin, methamphetamine, synthetic opioids, and other opioids) using liquid chromatography-tandem mass spectrometry. Participants were adults aged 18 years and older who provided urine specimens at SUD treatment practices. Exposures: Urine drug testing. Main Outcomes and Measures: The primary outcome was the correlation between UDT positivity rates and overdose mortality rates at national, state, and county levels. Univariate and multivariate regression models were also used to evaluate the association between state- and county-level overdose mortality and standardized UDT positivity rates. Results: Among 500 000 unique patient specimens collected from SUD treatment practices between 2013 and 2020, 288 534 specimens (57.7%) were from men, and the median age of the study population was 34 years (IQR, 17-51 years). On a national level, synthetic opioids and methamphetamine were highly correlated with overdose mortality (Spearman ρ = 0.96 for both). When synthetic opioids were coinvolved, methamphetamine (ρ = 0.98), heroin (ρ = 0.78), cocaine (ρ = 0.94), and other opioids (ρ = 0.83) were also highly correlated with overdose mortality. In the absence of synthetic opioids, all drug categories were highly correlated (ρ = 0.75 for other opioids, 0.81 for heroin, and 0.88 for methamphetamine), with the exception of cocaine (ρ = -0.37). Synthetic opioids (ρ = 0.77) and methamphetamine (ρ = 0.80) had the strongest state-level correlations over time, whereas other opioids had the lowest correlation for both total positivity (ρ = 0.31) and positivity in the absence of synthetic opioids (ρ = 0.23). In Ohio, county-level correlation was strongest for synthetic opioids (ρ = 0.71), followed by heroin (ρ = 0.69) and methamphetamine (ρ = 0.67). At the state level, the multivariate incidence rate ratio (IRR) for synthetic opioids was 1.16 (95% CI, 1.14-1.19; P < .001), and at the county level, the IRR was 1.13 (95% CI, 1.09-1.17; P < .001), suggesting that for every 1-SD increase in the UDT positivity rate, there were 16.2% and 12.8% increases, respectively, in monthly overdose deaths. Both methamphetamine (11.7% increase per 1-SD increase in UDT positivity rate; IRR, 1.12; 95% CI, 1.09-1.14; P < .001) and cocaine (5.1% increase per 1-SD increase in UDT positivity rate; IRR, 1.05; 95% CI, 1.03-1.07; P < .001) also had significant positive associations with mortality rates, but the effect sizes were smaller than that of synthetic opioids (IRR, 1.16). Conclusions and Relevance: In this study, UDT results were highly correlated with mortality rates at national, state, and county levels. These findings suggest that real-time UDT surveillance can help to quickly identify changes in drug use patterns that might inform targeted harm reduction strategies designed to prevent overdose deaths.

Association of Prepregnancy Body Mass Index With Risk of Severe Maternal Morbidity and Mortality Among Medicaid Beneficiaries.

Importance: The association between body mass index (BMI, which is calculated as weight in kilograms divided by height in meters squared) and severe maternal morbidity (SMM) and/or mortality is uncertain, judging from the current evidence. Objective: To examine the association between prepregnancy BMI and SMM and/or mortality through 1 year post partum and to identify both the direct and indirect implications of maternal obesity for SMM and/or mortality by examining hypertensive disorders and pregestational diabetes as potential mediators. Design, Setting, and Participants: This population-based cohort study was conducted from March to October 2021 using the vital records and linked Medicaid claims data in the state of Ohio from January 1, 2012, through December 31, 2017. The cohort comprised pregnant Medicaid beneficiaries who delivered at 20 weeks' gestation or later and had prepregnancy BMI information. Exposures: The primary exposure was maternal prepregnancy BMI, which was categorized as follows: underweight (<18.5), healthy weight (18.5-24.9), overweight (25.0-29.9), class 1 obesity (30.0-34.9), class 2 obesity (35.0-39.9), and class 3 obesity (≥40.0). Main Outcomes and Measures: The primary outcome was a composite of SMM (defined using Centers for Disease Control and Prevention criteria) and/or maternal mortality between 20 weeks' gestation and 1 year post partum. Additional periods were assessed, including 20 weeks' gestation through delivery hospitalization and 20 weeks' gestation through 42 days post partum. Generalized estimating equation models were used to estimate adjusted relative risks (aRRs) for the primary outcome according to BMI category. Maternal hypertensive diseases and pregestational diabetes were assessed as potential meditators. Results: In a cohort of 347 497 pregnancies among 276 691 Medicaid beneficiaries (median [IQR] maternal age at delivery, 25 [21-29] years; 210 470 non-Hispanic White individuals [60.6%]), the prevalence of maternal obesity was 30.5% (n = 106 031). Composite SMM and/or mortality outcome occurred in 5.3% of pregnancies (n = 18 398). Overweight (aRR, 1.07; 95% CI, 1.03-1.11) and obesity (class 1: aRR, 1.19 [95% CI, 1.14-1.24]; class 2: aRR, 1.37 [95% CI, 1.30-1.44]; class 3: aRR, 1.71 [95% CI, 1.63-1.80]) were associated with an elevated risk of SMM and/or mortality during pregnancy to 1 year post partum compared with healthy BMI. Similar findings were observed when the follow-up period was shortened to 42 days post partum or the delivery hospitalization. Hypertension mediated 65.1% (95% CI, 64.6%-65.6%) of the association between obesity and the primary outcome. Conclusions and Relevance: Results of this study showed that maternal prepregnancy obesity was associated with an elevated risk of SMM and/or mortality. Hypertensive disorders appeared to mediate this association, suggesting that improved prevention and management of hypertensive disorders in pregnancy may reduce morbidity and mortality in individuals with obesity.

Association Between Walking for Exercise and Symptomatic and Structural Progression in Individuals With Knee Osteoarthritis: Data From the Osteoarthritis Initiative Cohort.

OBJECTIVE: To assess the relationship between walking for exercise and symptomatic and structural disease progression in individuals with knee osteoarthritis (OA). METHODS: We assessed a nested cohort of participants age 50 years or older within the Osteoarthritis Initiative, a community-based observational study in which subjects were enrolled between 2004 and 2006. We focused on 4 dichotomous outcomes from baseline to the 48-month visit, involving determination of the frequency of knee pain and radiographic severity of knee OA on posteroanterior semiflexed knee radiographs. The outcomes assessed included 1) new frequent knee pain, 2) worsening of radiographic severity of knee OA based on the Kellgren/Lawrence grade, 3) progression of medial joint space narrowing, and 4) improved frequent knee pain. We used a modified version of the Historical Physical Activity Survey Instrument to ascertain those subjects who reported walking for exercise after age 50 years. The survey was administered at the 96-month visit (2012-2014). RESULTS: Of 1,212 participants with knee OA, 45% were male and 73% reported walking for exercise. The mean ± SD age was 63.2 ± 7.9 years, and the mean ± SD body mass index was 29.4 ± 4.6 kg/m2 . The likelihood of new frequent knee pain was reduced in participants with knee OA who walked for exercise as compared to those who were non-walkers (odds ratio [OR] 0.6, 95% confidence interval [95% CI] 0.4-0.8), and progression of medial joint space narrowing was less common in walkers compared to non-walkers (OR 0.8, 95% CI 0.6-1.0). CONCLUSION: In individuals with knee OA who were age 50 years or older, walking for exercise was associated with less frequent development of knee pain. These findings support the notion that walking for exercise should be encouraged for people with knee OA. Furthermore, we offer a proof of concept that walking for exercise could be disease modifying, which warrants further study.

The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations.

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRScommon) with a rare variant PRS (PRSrare) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m2), obesity (BMI ≥ 30 kg/m2), and extreme obesity (BMI ≥ 40 kg/m2). We built PRSscommon and PRSsrare using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRScommon explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRSrare explained 1.49%, and 2.97% and 3.68%, respectively. The PRSrare was associated with an increased risk of obesity and extreme obesity (ORobesity = 1.37 per SDPRS, Pobesity = 1.7x10-85; ORextremeobesity = 1.55 per SDPRS, Pextremeobesity = 3.8x10-40), which was attenuated, after adjusting for PRScommon (ORobesity = 1.08 per SDPRS, Pobesity = 9.8x10-6; ORextremeobesity= 1.09 per SDPRS, Pextremeobesity = 0.02). When PRSrare and PRScommon are combined, the increase in explained variance attributed to PRSrare was small (incremental Nagelkerke R2 = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRSrare to PRScommon provided little improvement to the prediction of obesity (PRSrare AUC = 0.591; PRScommon AUC = 0.708; PRScombined AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRSrare provides limited improvement over PRScommon in the prediction of obesity risk, based on these large populations.

Relationship of Social Connectedness With Decreasing Physical Activity During the COVID-19 Pandemic Among Older Women Participating in the Women's Health Initiative Study.

BACKGROUND: Aging is generally accompanied by decreasing physical activity (PA), which is associated with a decline in many health parameters, leading to recommendations for older adults to increase or at least maintain PA. METHODS: We determined relationships between social connectedness and decreasing or increasing PA levels during the coronavirus disease 2019 pandemic among 41 443 participants of the Women's Health Initiative Extension Study. Outcomes of logistic regression models were decreasing PA activity (reference: maintaining or increasing) and increasing PA activity (reference: maintaining or decreasing). The main predictor was social connectedness as a combined variable: not living alone (reference: living alone) and communicating with others outside the home more than once/week (reference: once/week or less). We adjusted for age, race, ethnicity, body mass index, physical function level, and education. RESULTS: Compared with participants who were not socially connected, socially connected participants had lower odds of decreasing PA (adjusted odds ratio 0.91, 95% confidence interval 0.87-0.95). Odds of increasing PA (vs decreasing or maintaining PA) were not significantly different among socially connected and not socially connected participants. Associations between social connectedness and decreasing PA did not significantly differ by age (<85 vs ≥85 years), race/ethnicity (non-Hispanic White vs other races/ethnicity), education (college vs 75). CONCLUSION: Social connectedness was associated with lower odds of decreasing PA among older women during the pandemic. These findings could inform the development of future interventions to help older women avoid decreasing PA.

KL2 scholars' perceptions of factors contributing to sustained translational science career success.

Introduction: Identifying the most effective ways to support career development of early stage investigators in clinical and translational science should yield benefits for the biomedical research community. Institutions with Clinical and Translational Science Awards (CTSA) offer KL2 programs to facilitate career development; however, the sustained impact has not been widely assessed. Methods: A survey comprised of quantitative and qualitative questions was sent to 2144 individuals that had previously received support through CTSA KL2 mechanisms. The 547 responses were analyzed with identifying information redacted. Results: Respondents held MD (47%), PhD (36%), and MD/PhD (13%) degrees. After KL2 support was completed, physicians' time was divided 50% to research and 30% to patient care, whereas PhD respondents devoted 70% time to research. Funded research effort averaged 60% for the cohort. Respondents were satisfied with their career progression. More than 95% thought their current job was meaningful. Two-thirds felt confident or very confident in their ability to sustain a career in clinical and translational research. Factors cited as contributing to career success included protected time, mentoring, and collaborations. Conclusion: This first large systematic survey of KL2 alumni provides valuable insight into the group's perceptions of the program and outcome information. Former scholars are largely satisfied with their career choice and direction, national recognition of their expertise, and impact of their work. Importantly, they identified training activities that contributed to success. Our results and future analysis of the survey data should inform the framework for developing platforms to launch sustaining careers of translational scientists.

Racket or Bat Sports: No Association With Thumb-Base Osteoarthritis.

CONTEXT: Repetitive joint use is a risk factor for osteoarthritis, which is a leading cause of disability. Sports requiring a racket or bat to perform repetitive high-velocity impacts may increase the risk of thumb-base osteoarthritis. However, this hypothesis remains untested. OBJECTIVE: To determine if a history of participation in racket or bat sports was associated with the prevalence of thumb-base osteoarthritis. DESIGN: Descriptive epidemiologic study. SETTING: Four US clinical sites associated with the Osteoarthritis Initiative. PATIENTS OR OTHER PARTICIPANTS: We recruited 2309 men and women from the community. Eligible participants had dominant-hand radiographic readings, hand symptom assessments, and historical physical activity survey data. MAIN OUTCOME MEASURE(S): A history of exposure to racket or bat sports (badminton, baseball or softball, racketball or squash, table tennis [or ping pong], tennis [doubles], or tennis [singles]) was based on self-reported recall data covering 3 age ranges (12-18, 19-34, and 35-49 years). Prevalent radiographic thumb-base osteoarthritis was defined as Kellgren-Lawrence grade >2 in the first carpometacarpal joint or scaphotrapezoidal joint at the Osteoarthritis Initiative baseline visit. Symptomatic thumb-base osteoarthritis was defined as radiographic osteoarthritis and hand or finger symptoms. RESULTS: Radiographic or symptomatic thumb-base osteoarthritis was present in 355 (34%) and 56 (5%), respectively, of men (total = 1049) and 535 (42%) and 170 (13%), respectively, of women (total = 1260). After adjusting for age, race, and education level, we found no significant associations between a history of any racket or bat sport participation and thumb-base osteoarthritis (radiographic or symptomatic; odds ratios ranged from 0.82 to 1.34). CONCLUSIONS: In a community-based cohort, a self-reported history of participation in racket or bat sports was not associated with increased odds of having radiographic or symptomatic thumb-base osteoarthritis in the dominant hand.

Exploring perspectives on changing opioid prescribing practices: A qualitative study of community stakeholders in the HEALing Communities Study.

BACKGROUND: Community-based perspectives are needed to more broadly inform policy-makers, public health practitioners, prescribers, and pharmacists about community-led and broader efforts to reduce opioid overprescribing, and ultimately reduce prescription opioid use disorder, overdoses and fatalities. The aim of this study is to explore community-based perspectives on efforts to change opioid prescribing practices in their communities. METHODS: Semi-structured interviews were conducted with 388 community stakeholders across four states (Kentucky, Massachusetts, New York, Ohio) from November 2019 to January 2020 about community approaches and goals of community-led responses to the opioid crisis. Data analysis combined deductive and inductive approaches to identify themes and sub-themes related to improving opioid prescribing practices. RESULTS: Three major themes and different subthemes were characterized: (1) acknowledging progress (i.e., healthcare providers being part of the solution, provider education, and prescription drug monitoring programs); (2) emergent challenges (i.e., physician nonadherence with safer opioid prescribing guidelines, difficulty identifying appropriate use of opioids, and concerns about accelerating the progression from opioid misuse to drug abuse); and (3) opportunities for change (i.e., educating patients about safer use and proper disposal of opioids, expanding prescriber and pharmacist education, changing unrealistic expectations around eliminating pain, expanding and increasing insurance coverage for alternative treatment options). CONCLUSIONS: Community stakeholders appeared to support specific opportunities to reduce prescription opioid misuse and improve safer prescribing. The opportunities included culture change around pain expectations, awareness of safe disposal, additional provider education, and increased coverage and acceptability of non-opioid treatments.