Identification of the Molecular Components of Enhancer-Mediated Gene Expression Variation in Multiple Tissues Regulating Blood Pressure.

BACKGROUND: Inter-individual variation in blood pressure (BP) arises in part from sequence variants within enhancers modulating the expression of causal genes. We propose that these genes, active in tissues relevant to BP physiology, can be identified from tissue-level epigenomic data and genotypes of BP-phenotyped individuals. METHODS: We used chromatin accessibility data from the heart, adrenal, kidney, and artery to identify cis-regulatory elements (CREs) in these tissues and estimate the impact of common human single-nucleotide variants within these CREs on gene expression, using machine learning methods. To identify causal genes, we performed a gene-wise association test. We conducted analyses in 2 separate large-scale cohorts: 77 822 individuals from the Genetic Epidemiology Research on Adult Health and Aging and 315 270 individuals from the UK Biobank. RESULTS: We identified 309, 259, 331, and 367 genes (false discovery rate <0.05) for diastolic BP and 191, 184, 204, and 204 genes for systolic BP in the artery, kidney, heart, and adrenal, respectively, in Genetic Epidemiology Research on Adult Health and Aging; 50% to 70% of these genes were replicated in the UK Biobank, significantly higher than the 12% to 15% expected by chance (P<0.0001). These results enabled tissue expression prediction of these 988 to 2875 putative BP genes in individuals of both cohorts to construct an expression polygenic score. This score explained ≈27% of the reported single-nucleotide variant heritability, substantially higher than expected from prior studies. CONCLUSIONS: Our work demonstrates the power of tissue-restricted comprehensive CRE analysis, followed by CRE-based expression prediction, for understanding BP regulation in relevant tissues and provides dual-modality supporting evidence, CRE and expression, for the causality genes.

Sex-specific genetic architecture of blood pressure.

The genetic and genomic basis of sex differences in blood pressure (BP) traits remain unstudied at scale. Here, we conducted sex-stratified and combined-sex genome-wide association studies of BP traits using the UK Biobank resource, identifying 1,346 previously reported and 29 new BP trait-associated loci. Among associated loci, 412 were female-specific (Pfemale ≤ 5 × 10-8; Pmale > 5 × 10-8) and 142 were male-specific (Pmale ≤ 5 × 10-8; Pfemale > 5 × 10-8); these sex-specific loci were enriched for hormone-related transcription factors, in particular, estrogen receptor 1. Analyses of gene-by-sex interactions and sexually dimorphic effects identified four genomic regions, showing female-specific associations with diastolic BP or pulse pressure, including the chromosome 13q34-COL4A1/COL4A2 locus. Notably, female-specific pulse pressure-associated loci exhibited enriched acetylated histone H3 Lys27 modifications in arterial tissues and a female-specific association with fibromuscular dysplasia, a female-biased vascular disease; colocalization signals included Chr13q34: COL4A1/COL4A2, Chr9p21: CDKN2B-AS1 and Chr4q32.1: MAP9 regions. Sex-specific and sex-biased polygenic associations of BP traits were associated with multiple cardiovascular traits. These findings suggest potentially clinically significant and BP sex-specific pleiotropic effects on cardiovascular diseases.

The Relationship Between Barriers to Physical Activity and Depressive Symptoms in Community-Dwelling Women.

Background: Women are less physically active, report greater perceived barriers for exercise, and show higher levels of depressive symptoms. This contributes to high global disability. The relationship between perceived barriers for physical activity and depressive symptoms in women remains largely unexplored. The aims of this cross-sectional analysis were to examine the association between physical activity barriers and depressive symptoms, and identify types of barriers in physically inactive community-dwelling women. Methods: Three hundred eighteen physically inactive women aged 25-65 years completed the Barriers to Being Active Quiz (BBAQ) developed by the Centers for Disease Control and Prevention, and the Center for Epidemiological Studies Depression Scale at the baseline visit of the mobile phone-based physical activity education trial. The BBAQ consists of six subscales (lack of time, social influence, lack of energy, lack of willpower, fear of injury, lack of skill, and lack of resources). We used multivariate regression analyses, correcting for sociodemographics. Results: Higher physical activity barriers were associated with greater depressive symptoms scores (linear effect, estimate = 0.75, 95% confidence interval [CI]: 0.39-1.12, p < 0.001). This effect appeared to taper off for the higher barrier scores (quadratic effect, estimate: -0.02, 95% CI: -0.03 to -0.01, p = 0.002). Exploratory analyses indicated that these associations were most driven by the social influence (p = 0.027) and lack of energy subscales (p = 0.017). Conclusions: Higher depression scores were associated with higher physical activity barriers. Social influence and lack of energy were particularly important barriers. Addressing these barriers may improve the efficacy of physical activity interventions in women with higher depressive symptoms. Future research should assess this in a randomized controlled trial. Trial Registration ClinicalTrialsgov#: NCTO1280812 registered January 21, 2011.

Prenatal exposure to social adversity and infant cortisol in the first year of life.

Exposure to social adversity has been associated with cortisol dysregulation during pregnancy and in later childhood; less is known about how prenatal exposure to social stressors affects postnatal cortisol of infants. In a secondary analysis of data from a longitudinal study, we tested whether a pregnant woman's reports of social adversity during the third trimester were associated with their infant's resting cortisol at 1, 6, and 12 months postnatal. Our hypothesis was that prenatal exposure to social adversity would be associated with elevation of infants' cortisol. Measures included prenatal survey reports of social stressors and economic hardship, and resting cortisol levels determined from infant saliva samples acquired at each postnatal timepoint. Data were analyzed using linear mixed effects models. The final sample included 189 women and their infants (46.56% assigned female sex at birth). Prenatal economic hardship was significantly associated with infant cortisol at 6 months postnatal; reports of social stressors were not significantly associated with cortisol at any time point. Factors associated with hardship, such as psychological distress or nutritional deficiencies, may alter fetal HPA axis development, resulting in elevated infant cortisol levels. Developmental changes unique to 6 months of age may explain effects at this timepoint. More work is needed to better comprehend the complex pre- and post-natal physiologic and behavioral factors that affect infant HPA axis development and function, and the modifying role of environmental exposures.

Genetic risk score for Alzheimer's disease predicts brain volume differences in mid and late life in UK biobank participants.

INTRODUCTION: We estimated the ages when associations between Alzheimer's disease (AD) genes and brain volumes begin among middle-aged and older adults. METHODS: Among 45,616 dementia-free participants aged 45-80, linear regressions tested whether genetic risk score for AD (AD-GRS) had age-dependent associations with 38 regional brain magnetic resonance imaging volumes. Models were adjusted for sex, assessment center, genetic ancestry, and intracranial volume. RESULTS: AD-GRS modified the estimated effect of age (per decade) on the amygdala (-0.41 mm3 [-0.42, -0.40]); hippocampus (-0.45 mm3 [-0.45, -0.44]), nucleus accumbens (-0.55 mm3 [-0.56, -0.54]), thalamus (-0.38 mm3 [-0.39, -0.37]), and medial orbitofrontal cortex (-0.23 mm3 [-0.24, -0.22]). Trends began by age 45 for the nucleus accumbens and thalamus, 48 for the hippocampus, 51 for the amygdala, and 53 for the medial orbitofrontal cortex. An AD-GRS excluding apolipoprotein E (APOE) was additionally associated with entorhinal and middle temporal cortices. DISCUSSION: APOE and other genes that increase AD risk predict lower hippocampal and other brain volumes by middle age.

Association between water insecurity and antiretroviral therapy adherence among pregnant and postpartum women in Greater Accra region of Ghana.

BACKGROUND: Adherence to antiretroviral therapy (ART) can substantially reduce morbidity and mortality among women living with HIV (WLWH) and prevent vertical transmission of HIV. However, in sub-Saharan Africa (SSA), more than 50% of new mothers discontinue ART and HIV care after childbirth. The role of water insecurity (WI) in ART adherence is not well-explored. We examined the relationship between WI and ART adherence among pregnant and postpartum WLWH in Greater Accra region of Ghana. METHODS: Using a cross-sectional survey, we recruited 176 pregnant and postpartum WLWH on ART across 11 health facilities. We examined the association between WI (measured using the Household Water Insecurity Experience Scale, and categorized as moderate and severe WI compard to low WI) and poor ART adherence (defined as scoring a below average observed CASE index score). Bivariate analysis was performed using chi-square test followed by multivariate logistic regression models. We included all variables with p-values less than 0.20 in the multivariate analysis. RESULTS: Most (79.5%) of the pregnant and postpartum WLWH enrolled on ART, were urban residents. Over 2/3 were aged 30 years and older. Overall, 33.5% of respondents had poor ART adherence. Proportion of poor ART adherence was 19.4% among those with low WI, 44.4% in those with moderate WI, and 40.0% among those with high WI. Respondents with moderate household water insecurity had a greater odds of reporting poor ART adherence, as compared to those with low water insecurity (adjusted Odds ratio (aOR) = 2.76, 95%CI: 1.14-6.66, p = 0.024), even after adjusting for food insecurity. Similarly, respondents with high WI had a greater odds of reporting poor ART adherence, as compared to those with low water insecurity (aOR = 1.49, 95%CI: 0.50-4.48, p = 0.479), even after adjusting for food insecurity. CONCLUSION: Water insecurity is prevalent among pregnant and postpartum WLWH and is a significant risk factor for poor ART adherence. Governments and other stakeholders working in HIV care provision should prioritize water security programming for WLWH along the HIV care continuum.

Multi-ancestry genome-wide meta-analysis identifies novel basal cell carcinoma loci and shared genetic effects with squamous cell carcinoma.

Basal cell carcinoma (BCC) is one of the most common malignancies worldwide, yet its genetic determinants are incompletely defined. We perform a European ancestry genome-wide association (GWA) meta-analysis and a Hispanic/Latino ancestry GWA meta-analysis and meta-analyze both in a multi-ancestry GWAS meta-analysis of BCC, totaling 50,531 BCC cases and 762,234 controls from four cohorts (GERA, Mass-General Brigham Biobank, UK Biobank, and 23andMe research cohort). Here we identify 122 BCC-associated loci, of which 36 were novel, and subsequently fine-mapped these associations. We also identify an association of the well-known pigment gene SLC45A2 as well as associations at RCC2 and CLPTM1L with BCC in Hispanic/Latinos. We examine these BCC loci for association with cutaneous squamous cell carcinoma (cSCC) in 16,407 SCC cases and 762,486 controls of European ancestry, and 33 SNPs show evidence of association. Our study findings provide important insights into the genetic basis of BCC and cSCC susceptibility.

"It has changed my life": unconditional cash transfers and personalized infant feeding support- a feasibility intervention trial among women living with HIV in western Kenya.

BACKGROUND: The syndemic effects of poverty, food insecurity and living with HIV are recognized as global health priorities, including through the United Nations Sustainability Goals 1, 2 and 3. Today, women and girls account for 63% of all new HIV infections in eastern and southern Africa, including Kenya. Pregnant and postpartum women living with HIV in this setting face unique challenges including increased financial insecurity as women leave the work force to care for their newborn infants. This contributes to poverty, food scarcity and stress. METHODS: To address financial insecurity, improve infant feeding and reduce stress among mothers living with HIV in this setting, we developed a multilevel intervention, Supporting Healthy Mothers, consisting of 10 monthly unconditional cash transfers (10,000 KES, ~$75 USD/month) and personalized infant feeding support from pregnancy to 7 months postpartum. We conducted a non-randomized feasibility trial of this intervention among women engaged in HIV care in Kisumu, Kenya. From February 23, 2022 to March 23, 2022, we enrolled a total of 40 women who were 20-35 weeks pregnant-20 women to the intervention group at a public clinic, and 20 women to the control group at a similar clinic. Our aim was to assess feasibility, acceptability, and the potential impact of the intervention on food security, infant feeding and maternal mental health. RESULTS: Analyzing data from all 40 participants, we found a significant reduction in food insecurity scores from baseline for the intervention group when compared to the control group at 6 weeks and 6 months postpartum (p = 0.0008 and p < 0.0001, respectively). Qualitative exit interviews with intervention group participants confirmed women felt more financially secure and had newly acquired practical knowledge and skills related to infant feeding. Women found the two intervention components highly acceptable and described an overall positive impact on wellbeing. CONCLUSIONS: The Supporting Healthy Mothers intervention has potential to positively impact women across the perinatal period and beyond by increasing financial security and supporting women to overcome infant feeding challenges and should be assessed in larger trials. TRIAL REGISTRATION: Supporting Healthy Mothers was registered with ClinicalTrials.gov Protocol Registration and Results System, initially published on February 1, 2022. CLINICALTRIALS: gov ID: NCT05219552 Protocol ID: K23MH116807.

Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction.

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.

Agreement of Computerized QT and QTc Interval Measurements Between Both Bedside and Expert Nurses Using Electronic Calipers.

BACKGROUND: In hospitalized patients, QT/QTc (heart rate corrected) prolongation on the electrocardiogram (ECG) increases the risk of torsade de pointes. Manual measurements are time-consuming and often inaccurate. Some bedside monitors automatically and continuously measure QT/QTc; however, the agreement between computerized versus nurse-measured values has not been evaluated. OBJECTIVE: The aim of this study was to examine the agreement between computerized QT/QTc and bedside and expert nurses who used electronic calipers. METHODS: This was a prospective observational study in 3 intensive care units. Up to 2 QT/QTc measurements (milliseconds) per patient were collected. Bland-Altman test was used to analyze measurement agreement. RESULTS: A total of 54 QT/QTc measurements from 34 patients admitted to the ICU were included. The mean difference (bias) for QT comparisons was as follows: computerized versus expert nurses, -11.04 ± 4.45 milliseconds (95% confidence interval [CI], -2.3 to -19.8; P = .016), and computerized versus bedside nurses, -13.72 ± 6.70 (95% CI, -0.70 to -26.8; P = .044). The mean bias for QTc comparisons was as follows: computerized versus expert nurses, -12.46 ± 5.80 (95% CI, -1.1 to -23.8; P = .035), and computerized versus bedside nurses, -18.49 ± 7.90 (95% CI, -3.0 to -33.9; P = .022). CONCLUSION: Computerized QT/QTc measurements calculated by bedside monitor software and measurements performed by nurses were in close agreement; statistically significant differences were found, but differences were less than 20 milliseconds (on-half of a small box), indicating no clinical significance. Computerized measurements may be a suitable alternative to nurse-measured QT/QTc. This could reduce inaccuracies and nurse burden while increasing adherence to practice recommendations. Further research comparing computerized QT/QTc from bedside monitoring to standard 12-lead electrocardiogram in a larger sample, including non-ICU patients, is needed.

Low- and High-Density Lipoprotein Cholesterol and Dementia Risk Over 17 Years of Follow-up Among Members of a Large Health Care Plan.

BACKGROUND AND OBJECTIVES: The associations of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) with dementia risk in later life may be complex, and few studies have sufficient data to model nonlinearities or adequately adjust for statin use. We evaluated the observational associations of HDL-C and LDL-C with incident dementia in a large and well-characterized cohort with linked survey and electronic health record (EHR) data. METHODS: Kaiser Permanente Northern California health plan members aged 55 years and older who completed a health behavior survey between 2002 and 2007, had no history of dementia before the survey, and had laboratory measurements of cholesterol within 2 years after survey completion were followed up through December 2020 for incident dementia (Alzheimer disease-related dementia [ADRD]; Alzheimer disease, vascular dementia, and/or nonspecific dementia) based on ICD-9 or ICD-10 codes in EHRs. We used Cox models for incident dementia with follow-up time beginning 2 years postsurvey (after cholesterol measurement) and censoring at end of membership, death, or end of study period. We evaluated nonlinearities using B-splines, adjusted for demographic, clinical, and survey confounders, and tested for effect modification by baseline age or prior statin use. RESULTS: A total of 184,367 participants [mean age at survey = 69.5 years, mean HDL-C = 53.7 mg/dL (SD = 15.0), mean LDL-C = 108 mg/dL (SD = 30.6)] were included. Higher and lower HDL-C values were associated with elevated ADRD risk compared with the middle quantile: HDL-C in the lowest quintile was associated with an HR of 1.07 (95% CI 1.03-1.11), and HDL-C in the highest quintile was associated with an HR of 1.15 (95% CI 1.11-1.20). LDL-C was not associated with dementia risk overall, but statin use qualitatively modified the association. Higher LDL-C was associated with a slightly greater risk of ADRD for statin users (53% of the sample, HR per 10 mg/dL increase = 1.01, 95% CI 1.01-1.02) and a lower risk for nonusers (HR per 10 mg/dL increase = 0.98; 95% CI 0.97-0.99). There was evidence for effect modification by age with linear HDL-C (p = 0.003) but not LDL-C (p = 0.59). DISCUSSION: Both low and high levels of HDL-C were associated with elevated dementia risk. The association between LDL-C and dementia risk was modest.

Maternal mental health after infant discharge: a quasi-experimental clinical trial of family integrated care versus family-centered care for preterm infants in U.S. NICUs.

BACKGROUND: Involvement in caregiving and tailored support services may reduce the risk of mental health symptoms for mothers after their preterm infant's neonatal intensive care unit (NICU) discharge. We aimed to compare Family-Centered Care (FCC) with mobile-enhanced Family-Integrated Care (mFICare) on post-discharge maternal mental health symptoms. METHOD: This quasi-experimental study enrolled preterm infant (≤ 33 weeks)/parent dyads from three NICUs into sequential cohorts: FCC or mFICare. We analyzed post-discharge symptoms of perinatal post-traumatic stress disorder (PTSD) and depression using intention-to-treat and per protocol approaches. RESULTS: 178 mothers (89 FCC; 89 mFICare) completed measures. We found no main effect of group assignment. We found an interaction between group and stress, indicating fewer PTSD and depression symptoms among mothers who had higher NICU-related stress and received mFICare, compared with mothers who had high stress and received FCC (PTSD: interaction ß=-1.18, 95% CI: -2.10, -0.26; depression: interaction ß=-0.76, 95% CI: -1.53, 0.006). Per protocol analyses of mFICare components suggested fewer PTSD and depression symptoms among mothers who had higher NICU stress scores and participated in clinical team rounds and/or group classes, compared with mothers who had high stress and did not participate in rounds or classes. CONCLUSION: Overall, post-discharge maternal mental health symptoms did not differ between the mFICare and FCC groups. However, for mothers with high levels of stress during the NICU stay, mFICare was associated with fewer post-discharge PTSD and depression symptoms.

Transcriptome-wide association study identifies novel candidate susceptibility genes for migraine.

Genome-wide association studies (GWASs) have identified more than 130 genetic susceptibility loci for migraine; however, how most of these loci impact migraine development is unknown. To identify novel genes associated with migraine and interpret the transcriptional products of those genes, we conducted a transcriptome-wide association study (TWAS). We performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 53 tissues and migraine susceptibility using FUSION software. Meta-analyzed GWAS summary statistics from 26,052 migraine cases and 487,214 controls, all of European ancestry and from two cohorts (the Kaiser Permanente GERA and the UK Biobank), were used. We evaluated the associations for genes after conditioning on variant-level effects from GWAS, and we tested for colocalization of GWAS migraine-associated loci and expression quantitative trait loci (eQTLs). Across tissue-specific and multi-tissue analyses, we identified 53 genes for which genetically predicted gene expression was associated with migraine after correcting for multiple testing. Of these 53 genes, 10 (ATF5, CNTNAP1, KTN1-AS1, NEIL1, NEK4, NNT, PNKP, RUFY2, TUBG2, and VAT1) did not overlap known migraine-associated loci identified from GWAS. Tissue-specific analysis identified 45 gene-tissue pairs and cardiovascular tissues represented the highest proportion of the Bonferroni-significant gene-tissue pairs (n = 22 [49%]), followed by brain tissues (n = 6 [13%]), and gastrointestinal tissues (n = 4 [9%]). Colocalization analyses provided evidence of shared genetic variants underlying eQTL and GWAS signals in 18 of the gene-tissue pairs (40%). Our TWAS reports novel genes for migraine and highlights the important contribution of brain, cardiovascular, and gastrointestinal tissues in migraine susceptibility.

Association of Behavioral and Clinical Risk Factors With Cataract: A Two-Sample Mendelian Randomization Study.

Purpose: To investigate the association of genetically determined primary open-angle glaucoma (POAG), myopic refractive error (RE), type 2 diabetes (T2D), blood pressure (BP), body mass index (BMI), cigarette smoking, and alcohol consumption with the risk of age-related cataract. Methods: To assess potential causal effects of clinical or behavioral factors on cataract risk, we conducted two-sample Mendelian randomization analyses. Genetic instruments, based on common genetic variants associated with risk factors at genome-wide significance (P < 5 × 10-8), were derived from published genome-wide association studies (GWAS). For age-related cataract, we used GWAS summary statistics from our previous GWAS conducted in the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (28,092 cataract cases and 50,487 controls; all non-Hispanic whites) or in the UK Biobank (31,852 cataract cases and 428,084 controls; all European-descent individuals). We used the inverse-variance weighted (IVW) method as our primary source of Mendelian randomization estimates and conducted common sensitivity analyses. Results: We found that genetically determined POAG and mean spherical equivalent RE were significantly associated with cataract risk (IVW model: odds ratio [OR] = 1.04; 95% confidence interval [CI], 1.01-1.08; P = 0.018; per diopter more hyperopic: OR = 0.92; 95% CI, 0.89-0.93; P = 6.51 × 10-13, respectively). In contrast, genetically determined T2D, BP, BMI, cigarette smoking, or alcohol consumption were not associated with cataract risk (P > 0.05). Conclusions: Our results provide evidence that genetic risks for POAG and myopia may be causal risk factors for age-related cataract. These results are consistent with previous observational studies reporting associations of myopia with cataract risk. This information may support population cataract risk stratification and screening strategies.

Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry.

Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS 269 ). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS 269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS 269 constructed with fine-mapping.

Genetically adjusted PSA levels for prostate cancer screening.

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10-8) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGSPSA) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10-14, area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10-12, AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10-4). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.

Influence of depression and interpersonal support on adherence to antiretroviral therapy among people living with HIV.

BACKGROUND: Poor adherence and under-utilization of antiretroviral therapy (ART) services have been major setbacks to achieving 95-95-95 policy goals in Sub-Saharan Africa. Social support and mental health challenges may serve as barriers to accessing and adhering to ART but are under-studied in low-income countries. The purpose of this study was to examine the association of interpersonal support and depression scores with adherence to ART among persons living with HIV (PLWH) in the Volta region of Ghana. METHODS: We conducted a cross-sectional survey among 181 PLWH 18 years or older who receive care at an ART clinic between November 2021 and March 2022. The questionnaire included a 6-item simplified ART adherence scale, the 20-item Center for Epidemiologic Studies Depression Scale (CES-D), and the 12-item Interpersonal Support Evaluation List-12 (ISEL-12). We first used a chi-squared or Fisher's exact test to assess the association between these and additional demographic variables with ART adherence status. We then built a stepwise multivariable logistic regression model to explain ART adherence. RESULTS: ART adherence was 34%. The threshold for depression was met by 23% of participants, but it was not significantly associated with adherence in multivariate analysis(p = 0.25). High social support was reported by 48.1%, and associated with adherence (p = 0.033, aOR = 3.45, 95% CI = 1.09-5.88). Other factors associated with adherence included in the multivariable model included not disclosing HIV status (p = 0.044, aOR = 2.17, 95% CI = 1.03-4.54) and not living in an urban area (p = 0.00037, aOR = 0.24, 95% CI = 0.11-0.52). CONCLUSION: Interpersonal support, rural residence, and not disclosing HIV status were independent predictors of adherence to ART in the study area.

Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry.

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.

Smartphone-Based Cancer and Obesity Prevention Education Program for Chinese Women (SCOPE): A Pilot RCT.

Breast cancer prevalence has increased globally, with 12.2% of breast cancer cases identified in China. Obesity and unhealthy lifestyles are major risk factors for breast cancer. We conducted a randomized control trial to assess the feasibility and evaluate the preliminary effect of the Smartphone-Based Cancer and Obesity Prevention Education (SCOPE) program among adult biological women with a waist circumference greater than 80 cm. The SCOPE program includes tailored and culturally appropriate educational information for obesity and breast cancer prevention delivered by the research team via WeChat. The control group received non-tailored general health information via WeChat. A total of 102 women (52 intervention, 50 control) participated, and 87 (85%) completed 6-month follow-up assessments. For the primary study outcome at 6 months, women using SCOPE significantly reduced waist circumference (Cohen's d = -0.39, p < 0.001). For secondary outcomes at 6 months, women using SCOPE significantly reduced BMI (d = -0.18, p = 0.001) and increased breast cancer-related knowledge (d = 0.48, p = 0.001) and attitude (d = 1.39, p < 0.01). No significant findings were found regarding diet self-efficacy, physical self-efficacy, or breast cancer screening barriers. The results suggest the intervention has great potential to promote the health and wellness of women.

Evaluation of premature ventricular complexes during in-hospital ECG monitoring as a predictor of ventricular tachycardia in an intensive care unit cohort.

In-hospital electrocardiographic (ECG) monitors are typically configured to alarm for premature ventricular complexes (PVCs) due to the potential association of PVCs with ventricular tachycardia (VT). However, no contemporary hospital-based studies have examined the association of PVCs with VT. Hence, the benefit of PVC monitoring in hospitalized patients is largely unknown. This secondary analysis used a large PVC alarm data set to determine whether PVCs identified during continuous ECG monitoring were associated with VT, in-hospital cardiac arrest (IHCA), and/or death in a cohort of adult intensive care unit patients. Six PVC types were examined (i.e., isolated, bigeminy, trigeminy, couplets, R-on-T, and run PVCs) and were compared between patients with and without VT, IHCA, and/or death. Of 445 patients, 48 (10.8%) had VT; 11 (2.5%) had IHCA; and 49 (11%) died. Isolated and run PVC counts were higher in the VT group (p = 0.03 both), but group differences were not seen for the other four PVC types. The regression models showed no significant associations between any of the six PVC types and VT or death, although confidence intervals were wide. Due to the small number of cases, we were unable to test for associations between PVCs and IHCA. Our findings suggest that we should question the clinical relevance of activating PVC alarms as a forewarning of VT, and more work should be done with larger sample sizes. A more precise characterization of clinically relevant PVCs that might be associated with VT is warranted.