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BACKGROUND In the United States, hypertension disproportionately afflicts over half of African American adults, many of whom also experience racial discrimination. Understanding gene × discrimination effects may help explain racial disparities in hypertension. METHODS We tested for the main effects and interactive effects of 5 candidate single nucleotide polymorphisms (SNPs: rs2116737, rs11190458, rs2445762, rs2597955, and rs2416545) and experiences of discrimination on blood pressure (BP) in African Americans not taking antihypertensive medications in the Jackson Heart Study from Mississippi (n = 2,933). Multiple linear regression models assumed an additive genetic model and adjusted for ancestry, age, sex, body mass index, education, and relatedness. We additionally tested recessive and dominant genetic models. RESULTS Discrimination was significantly associated with higher diastolic BP (P = 0.003). In contrast, there were no main effects of any SNP on BP. When analyzing SNPs and discrimination together, SGCD (Sarcoglycan Delta; rs2116737) demonstrated a gene × environment interaction. Specifically, an SGCD × Discrimination interaction was associated with systolic BP (β =1.95, P = 0.00028) in a recessive model. Participants carrying a T allele, regardless of discrimination experiences, and participants with a GG genotype and high experiences of discrimination had higher systolic BP than participants with a GG genotype and low experiences of discrimination. This finding suggests the SGCD GG genotype may have a protective effect on systolic BP, but only in a setting of low discrimination. CONCLUSIONS The inclusion of culturally relevant stressors, like discrimination, may be important to understand the gene-environment interplay likely underlying complex diseases with racial health inequities.

Single nucleotide polymorphisms (SNPs) have been associated with differential beta-blocker (BB) effects on heart rate, blood pressure, and left ventricular ejection fraction in various patient populations. This study aimed to determine if SNPs previously associated with BB response are also associated with differential survival in heart failure (HF) patients receiving BBs. HF patient data were derived from electronic health records and the Social Security Death Index. Associations and interactions between BB dose, SNP genotype, and the outcome of death were assessed using a Cox proportional-hazard model adjusting for covariates known to be associated with differential survival in HF patients. Two SNPs, ADRB1 Arg389Gly and ADRB2 Glu27Gln, displayed significant interactions (Pint = 0.043 and Pint = 0.017, respectively) with BB dose and their association with mortality. Our study suggests that ADRB2 27Glu and ADRB1 389Arg may confer a larger survival benefit with higher BB doses in patients with HF.

STUDY OBJECTIVE This study aimed to determine if variants in NR3C2, which codes the target protein of spironolactone, or CYP11B2, which is involved in aldosterone synthesis, were associated with spironolactone response, focused on the primary end point of diastolic function (E/e'), in Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) participants. DESIGN Post-hoc genetic analysis. DATA SOURCE Data and samples were derived from the multi-center, randomized, double-blind, placebo-controlled Aldo-DHF trial. PATIENTS Aldo-DHF participants treated with spironolactone (n = 184) or placebo (n = 178) were included. INTERVENTION Participants were genotyped for NR3C2 rs5522, NR3C2 rs2070951 and CYP11B2 rs1799998 via pyrosequencing. MEASUREMENTS In the placebo and spironolactone arms, separate multivariable linear regression analyses were performed for change in E/e' with each single nucleotide polymorphism (SNP), adjusted for age, sex, and baseline E/e'. To discern potential mechanisms of a genotype effect, associated SNPs were further examined for their association with change in blood pressure, circulating procollagen type III N-terminal peptide (PIIINP), and left atrial area. MAIN RESULTS Carriers of the rs5522 G allele in the placebo arm had a greater increase in E/e' over the 12-month course of the trial compared to noncarriers (β = 1.10; 95% confidence interval [CI]: 0.05-2.16; p = 0.04). No corresponding E/e' worsening by rs5522 genotype was observed in the spironolactone arm. None of the other genotypes were associated with change in E/e'. Compared to noncarriers, rs5522 G carriers also had a greater increase in left atrial area with placebo (β = 0.83; 95% CI: 0.17-1.48; p = 0.01) and a greater reduction in diastolic blood pressure with spironolactone (β = -3.56; 95% CI: -6.73 to -0.39; p = 0.03). Serum PIIINP levels were similar across rs5522 genotypes. CONCLUSIONS Our results suggest that spironolactone attenuates progression of diastolic dysfunction associated with the NR3C2 rs5522 G allele. Validation of our findings is needed.

Background: Multiple clinical trials have evaluated the efficacy and safety of aldosterone receptor antagonist (ARA) use in heart failure (HF). They indicate that not all HF patients have the same level of hyperkalemia risk or morbidity risk reduction on ARAs. Identification of clinical predictors of patient response to ARAs would allow for treatment better tailored to the potential risks and benefits of each individual patient. The study’s objective was to identify a clinical predictive model for both hyperkalemia and all-cause mortality or HF-related hospitalization in ARA-prescribed patients with HF. Methods: This retrospective analysis used an anonymized EHR dataset of 8742 adult patients with a diagnosis of HF and an ARA prescription from the University of Florida health system. A list of potential clinical predictors identified from the literature was refined via feature selection using the least absolute shrinkage and selection operator (LASSO) technique. With the variables selected via LASSO, a logistic regression model for hyperkalemia and a Cox proportional hazards regression model for death or HF hospitalizations were used to identify the most significant predictors. Results: A model of 25 significant predictors for hyperkalemia in ARA-prescribed HF patients was identified (AUC = 0.70), including an ACE inhibitor/angiotensin receptor blocker (ARB) prescription, type 2 diabetes diagnosis, and chronic kidney disease diagnosis as predictors (Table 1). For death or HF hospitalizations, a predictive model of 20 significant predictors included a loop diuretic prescription, pulmonary hypertension diagnosis, and arrhythmia diagnosis (C-statistic = 0.76; Table 1). Conclusions: We developed an EHR-based model to predict hyperkalemia and morbidity and mortality in ARA-prescribed HF patients. Once validated, these findings should assist clinicians in providing more individualized and effective ARA therapy. Table 1: Significant Predictors in Model for Hyperkalemia and Death or HF Hospitalizations

Introduction: Few genome-wide association studies (GWAS) of heart failure (HF) mortality have been published, with most focused on incidence or surrogate endpoints. Our aim was to identify genomic predictors of HF mortality in a racially diverse population. Hypothesis: Both ancestry-specific and trans-ancestry variants are associated with survival in HF patients. Methods: HF patients with preserved or reduced ejection fraction from the University of Illinois Chicago cardiology clinics were prospectively enrolled and followed until 11/2015. Whole blood was collected. Clinical data were retrospectively acquired through medical records. Genotyping was performed via Affymetrix Axiom Pan-African Array and imputed via TOPMed Imputation Server. Genetic ancestry (African/non-African) was assigned by principal component (PC) analysis. Within each ancestral population, associations between genetic variants and all-cause mortality were assessed by Cox regression model, adjusted for age, sex, NYHA class, HF medication regimen, and PCs. A trans-ancestry fixed-effect meta-analysis was then conducted. P < 5.0 x 10 -8 was considered statistically significant. Results: The cohort included 319 HF patients (age 63 ± 13 yrs, 51% men, median follow-up 33 mos), comprised of 237 African ancestry (AA) (134 deaths) and 82 non-AA subjects (41 deaths). In the AA GWAS, 5 loci reached genome-wide significance. The top single nucleotide polymorphism (SNP), rs142008984 on chromosome 1 ( P = 5.21 x 10 -10 , HR = 8.55, 95%CI 4.34 - 16.82), resides in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene. No SNPs in the non-AA GWAS reached the defined significance level, and the AA-associated NOS1AP SNPs were not present in non-AA. Meta-analysis revealed 2 additional significant loci, among which was the top SNP on chromosome 6, rs79027708 ( P = 1.43 x 10 -9 , HR = 0.15, 95% CI 0.08 - 0.28), in the phosphodiesterase 10A ( PDE10A) gene. Conclusions: This study identified novel loci associated with all-cause mortality in a racially diverse HF population. NOS1AP and PDE10A have previously been associated with sudden cardiac death, cardiac hypertrophy, and fibrosis risk. Risk variants specific to AA were also identified, which may contribute to the lower survival in this population.

Junctional ectopic tachycardia (JET) is a potentially life-threatening postoperative arrhythmia in children with specific congenital heart defects and can contribute significantly to postoperative morbidity for at-risk populations. In adults, β1-adrenergic receptor (ADRB1) and β2-adrenergic receptor (ADRB2) genotypes have been associated with increased risk for arrhythmias. However, their association with arrhythmia risk in children is unknown. We aimed to test associations between ADRB1 and ADRB2 genotypes and postoperative JET in patients with congenital heart defects. Children who underwent cardiac surgery were genotyped for the ADRB1 p.Ser49Gly (rs1801252; c.145A>G), p.Arg389Gly (rs1801253; c.1165C>G), ADRB2 p.Arg16Gly (rs1042713; c.46A>G), and p.Glu27Gln (rs1042714; c.79G>C) polymorphisms. The occurrence of postoperative JET was assessed via cardiologist-interpreted electrocardiograms. Genotype associations with JET were analyzed via logistic regression, adjusted for clinical variables associated with JET, with separate analysis in patients not on a β-blocker. Of the 343 children included (median age 8 months, 53% boys, 69% European ancestry), 45 (13%) developed JET. The Arg389Arg genotype was not significantly associated with JET in the overall population (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 0.96-4.03, p = 0.064), but was nominally associated in patients not taking a β-blocker (n = 324, OR = 2.25, 95% CI = 1.05-4.80. p = 0.034). None of the other variants were associated with JET. These data suggest that the ADRB1 Arg389Arg genotype may predict risk for JET following cardiac surgery in pediatric patients in the absence of β-blockade. Whether treatment with a β-blocker ameliorates this association requires further research.

Abnormal uterine bleeding (AUB) is a common presentation that can occur in all age groups. AUB is an umbrella term for any uterine bleeding that occurs outside a woman’s normal pattern in volume, regularity, and/or timing. AUB is described by using frequency, regularity, duration, and volume or by using PALM-COEIN (Polyp, Adenomyosis, Leiomyoma, Malignancy and premalignant conditions; Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, Not yet classified). Workup for AUB comprises a history (with a detailed menstrual history), physical examination (including a pelvic and bimanual examination), lab tests, and imaging (primarily transvaginal ultrasonography). For treatment, medical therapies should be considered before surgical therapies, especially when fertility is desired. The decisions for treatment are based on etiology, fertility concerns, contraindications, or patient preference. Of the medical therapies, there are hormonal and nonhormonal therapies. The most common treatments for AUB are levonorgestrel intrauterine device, tranexamic acid, oral contraceptives, and nonsteroidal anti-inflammatory drugs. The most common surgical treatments are myomectomy, endometrial ablation, uterine artery embolization, and hysterectomy. This review contains 7 figures, 10 tables and 45 references Key words: abnormal uterine bleeding, adenomyosis, contraceptives, endometrial, fibroids, hysterectomy, menorrhagia

BACKGROUND Obesity has been associated with attenuated vaccine responses and an increased risk of contracting pneumococcal pneumonia, but no study to our knowledge has assessed the impact of obesity and genetics on 23-valent pneumococcal vaccine (PPSV23) efficacy. We assessed the relationship of obesity (primary analysis) and stimulator of interferon genes (STING1) genotype (secondary analysis) on PPSV23 efficacy. METHODS Nonobese (BMI 22–25 kg/m2) and obese participants (BMI ≥30 kg/m2) were given a single dose of PPSV23. Blood was drawn immediately prior to and 4–6 weeks after vaccination. Serum samples were used to assess PPSV23-specific antibodies. STING1 genotypes were identified using PCR on DNA extracted from peripheral blood samples. RESULTS Forty-six participants were categorized as nonobese (n = 23; 56.5% women; mean BMI 23.3 kg/m2) or obese (n = 23; 65.2% women; mean BMI 36.3 kg/m2). Obese participants had an elevated fold change in vaccine-specific responses compared with nonobese participants (P < 0.0001). The WT STING1 group (R232/R232) had a significantly higher PPSV23 response than individuals with a single copy of HAQ-STING1 regardless of BMI (P = 0.0025). When WT was assessed alone, obese participants had a higher fold serotype-specific response compared with nonobese participants (P < 0.0001), but no difference was observed between obese and nonobese individuals with 1 HAQ allele (P = 0.693). CONCLUSIONS These observations demonstrate a positive association between obesity and PPSV23 efficacy specifically in participants with the WT STING1 genotype. TRIAL REGISTRATION ClinicalTrials.gov NCT02471014. FUNDING This research was supported by the NIH and the University of Florida MD-PhD Training Program., Obesity and a WT STING1 genotype are positively associated with efficacy of the 23-valent pneumococcal vaccine in a small cohort of subjects.

Objective: Health literacy and health insurance literacy affect healthcare utilization. The purpose of this study was to determine the relation between health insurance knowledge, self-efficacy, and student healthcare utilization in the past year. Participants: A random sample of 1,450 respondents, over the age of 18, attending a public university in the southeastern United States completed a survey in March 2017. Methods: A model was constructed to test the effect of health insurance self-efficacy on the relation between knowledge and healthcare utilization in the past year. Results: Health insurance knowledge (M = 5.8, range 0-10) and self-efficacy (M = 2.48, range 1-4) were low. Self-efficacy was a significant moderator when explaining healthcare utilization in the past year. Conclusions: College students have low knowledge and self-efficacy regarding health insurance. These findings can be used for developing policies and self-efficacy-based health education programs that may increase student healthcare utilization.

Introduction: Previous anthropological studies have demonstrated the utility of integrating genetic and psychosocial data, such as discrimination, to understand complex phenotypes such as blood pressure (BP). In these studies, including both single nucleotide polymorphisms (SNP) and psychosocial measures in the model only revealed significant SNPs after accounting for gene by social environment interactions. Methods: We sought to externally validate SNPs associated with BP in African Americans (AAs) identified in a study by Quinlan et al. in 2016 that incorporated novel measures of unfair treatment/discrimination and revealed new genes and biological pathways relevant to BP variation. Our validation was done using a larger cohort study of AAs, the Jackson Heart Study (JHS). Systolic and diastolic BP were measured twice in the same visit using a random-zero mercury sphygmomanometer and averaged. During this visit, perceived discrimination was assessed as lifetime occurrence of unfair treatment in nine social domains using the JHS discrimination instrument. Using available GWAS data, 28 significant SNPs were imputed from 1000 Genomes Project Phase 1 (version 3). Our analysis was conducted separately on participants who reported use of BP medications (n= 1532) and those who did not (n=1407). We similarly tested for associations of SNPs with BP using 3 linear regression models adjusting for global ancestry, sex, age, education, BMI, and relatedness. Model 1 tested only the SNPs, model 2 tested the SNPs and discrimination, and model 3 tested an interaction between SNPs and discrimination. Results: JHS participants were 62% female, with a mean age of 55 years, mean BMI of 32, mean systolic BP of 127 and mean diastolic BP of 76. Participants on average experienced unfair treatment in three domains in their lifetime. In participants not on BP medications, we found that rs2116737, in the gene SGCD , achieved Bonferroni-corrected significance (p < 0.004) with systolic BP in a recessive genotype model (β= 11.92; p =2.00х10 -4 ) and was only identified through model 3, the gene-discrimination interaction model. No significant findings were seen in patients using BP medications. Conclusions: rs2116737 was validated in the JHS for a gene-discrimination interaction. rs2116737 is an intronic variant in SGCD , a gene that is highly expressed in arterial tissue, suggesting vascular regulation as a possible mechanism behind the interaction. In conclusion, the findings suggest accounting for a gene by social environment interaction can identify new SNPs that deserve further investigation in understanding BP variation.

Pathologic vascular adaptation following local injury is the primary driver for accelerated intimal hyperplasia and an occlusive phenotype. Smooth muscle cell (SMC) proliferation within the wall, and migration into the developing intima, is a major component of this remodeling response. The primary objective in the current study was to investigate the effect of the local biomechanical forces on early vein graft adaptation, specifically focusing on the spatial and temporal response SMC proliferation and their conversion from a contractile to synthetic architecture. Taking advantage of the differential adaptation that occurs during exposure to divergent flow environments, vein grafts were implanted in rabbits to create two distinct flow environments and harvested at times ranging from 2 hours to 28 days. Using an algorithm for the virtual reconstruction of unfixed, histologic specimens, immunohistochemical tracking of DNA synthesis, and high-throughput transcriptional analysis, the spatial and temporal changes in graft morphology, cell proliferation, and SMC phenotype were catalogued. Notable findings include a burst of cell proliferation at 7 days post-implantation, which was significantly augmented by exposure to a reduced flow environment. Compared to the adjacent media, proliferation rates were 3-fold greater in the intima, and a specific spatial distribution of these proliferating cells was identified, with a major peak in the sub-endothelial region and a second peak centering on the internal elastic lamina. Genomic markers of a contractile SMC phenotype were reduced as early as 2 hours post-implantation and reached a nadir at 7 days. Network analysis of upstream regulatory pathways identified GATA6 and KLF5 as important transcription factors that regulate this shift in SMC phenotype.

OBJECTIVES/SPECIFIC AIMS: The study aims to determine the current clinical research training interventions of MD-PhD programs and how effective they are in promoting clinical research self-efficacy. METHODS/STUDY POPULATION: A national survey of MD-PhD trainees was conducted in 2018 to identify clinical research training methods and self-efficacy for clinical research skills. MD-PhD program directors and coordinators from 108 institutions were asked to distribute the survey to their students. Responses were received from 61 institutions (56.5%). Responses were obtained from 647 MD-PhD students in all years of training, representing 17.9% of the 3613 possible participants at the 61 medical schools represented. No compensation was provided for this study. RESULTS/ANTICIPATED RESULTS: The primary methods of clinical research training reported by students included didactics, mentored clinical research, didactics plus mentored clinical research, didactics plus clinical research practicum, and didactics plus mentored clinical research plus clinical research practicum. A quarter of all participants reported having no clinical research training. Clinical research self-efficacy was then correlated with the amount of clinical research training. Students exposed to no clinical research had the lowest self-efficacy in clinical research skills and students experiencing didactics plus mentored clinical research plus clinical research practicum had the highest perceived self-efficacy in clinical research domains. DISCUSSION/SIGNIFICANCE OF IMPACT: This is one of the first studies assessing clinical research training methods for MD-PhD students and assessing their efficacy. We found that of all students questioned, 25% mentioned had not received any type of clinical research training. The remaining students identified 5 research training methods that institutions currently use. This work highlights the importance of clinical research experience students need to improve their self-efficacy, a major influence on research career outcomes.