In vitro Testing of Trichomonas vaginalis Drug Susceptibility: Evaluation of Minimal Lethal Concentration for Secnidazole that Correlates with Treatment Success.

ABSTRACT: We determined the in vitro minimum lethal concentration (MLC) of secnidazole (SEC) and assessed correlation with clinical susceptibility among T. vaginalis isolates obtained from 71 women, of whom 66 were successfully treated with this medication. An MLC ≤12.5 µg/ml correlated with clinical susceptibility in this study.

Population-average mediation analysis for zero-inflated count outcomes.

Mediation analysis is an increasingly popular statistical method for explaining causal pathways to inform intervention. While methods have increased, there is still a dearth of robust mediation methods for count outcomes with excess zeroes. Current mediation methods addressing this issue are computationally intensive, biased, or challenging to interpret. To overcome these limitations, we propose a new mediation methodology for zero-inflated count outcomes using the marginalized zero-inflated Poisson (MZIP) model and the counterfactual approach to mediation. This novel work gives population-average mediation effects whose variance can be estimated rapidly via delta method. This methodology is extended to cases with exposure-mediator interactions. We apply this novel methodology to explore if diabetes diagnosis can explain BMI differences in healthcare utilization and test model performance via simulations comparing the proposed MZIP method to existing zero-inflated and Poisson methods. We find that our proposed method minimizes bias and computation time compared to alternative approaches while allowing for straight-forward interpretations.

Neighborhood Disadvantage and Parenting in Early Adolescence Predict Epigenetic Aging and Mortality Risk in Adulthood.

Youth who grow up in disadvantaged neighborhoods experience poorer health later in life, but little is known about the biological mechanisms underlying these effects and socioenvironmental factors that may protect youth from the biological embedding of neighborhood adversity. This study tests whether supportive and consistent parenting buffers associations between neighborhood disadvantage in early adolescence and epigenetic aging in adulthood. A community sample from Birmingham, Alabama, USA (N = 343; 57% female; 81% Black, 19% White) was assessed in early adolescence (T1; ages 11 and 13) and adulthood (T2; age 27). At T1, neighborhood poverty was derived from census data and neighborhood disorder was reported by caregivers. Both youth and parents reported on parental discipline and nurturance. At T2, methylation of salivary DNA was used to derive a mortality risk index and Hannum, Horvath, PhenoAge, and GrimAge epigenetic age estimators. Regression analyses revealed that neighborhood disadvantage was associated with accelerated epigenetic aging and/or mortality risk only when combined with high levels of harsh and inconsistent discipline and low child-reported parental nurturance. These findings identify epigenetic aging and mortality risk as relevant mechanisms through which neighborhood adversity experienced in adolescence may affect later health; they also point to the importance of supportive and consistent parenting for reducing the biological embedding of neighborhood adversity in early adolescence.

Mendelian randomization in the multivariate general linear model framework.

Mendelian randomization (MR) is an application of instrumental variable (IV) methods to observational data in which the IV is a genetic variant. MR methods applicable to the general exponential family of distributions are currently not well characterized. We adapt a general linear model framework to the IV setting and propose a general MR method applicable to any full-rank distribution from the exponential family. Empirical bias and coverage are estimated via simulations. The proposed method is compared to several existing MR methods. Real data analyses are performed using data from the REGARDS study to estimate the potential causal effect of smoking frequency on stroke risk in African Americans. In simulations with binary variates and very weak instruments the proposed method had the lowest median [Q1 , Q3 ] bias (0.10 [-3.68 to 3.62]); compared with 2SPS (0.27 [-3.74 to 4.26]) and the Wald method (-0.69 [-1.72 to 0.35]). Low bias was observed throughout other simulation scenarios; as well as more than 90% coverage for the proposed method. In simulations with count variates, the proposed method performed comparably to 2SPS; the Wald method maintained the most consistent low bias; and 2SRI was biased towards the null. Real data analyses find no evidence for a causal effect of smoking frequency on stroke risk. The proposed MR method has low bias and acceptable coverage across a wide range of distributional scenarios and instrument strengths; and provides a more parsimonious framework for asymptotic hypothesis testing compared to existing two-stage procedures.

The pace of biological aging helps explain the association between insomnia and chronic low back pain.

Chronic low back pain (cLBP) is associated with insomnia and advanced age. Emerging evidence suggests that the severity of both sleep disorders (like insomnia) and chronic pain are associated with a faster pace of biological aging. We aimed to determine whether the pace of biological age mediates the relationship between insomnia and the impact of cLBP in a sample of community-dwelling adults ages 19 to 85 years. Participants (49 with no pain, 32 with low-impact pain, and 37 with high-impact pain) completed sociodemographic, pain, insomnia, and short physical performance battery assessments. We calculated the pace of biological aging using DunedinPACE from blood leukocyte DNA. On average, individuals with high-impact cLBP had significantly faster biological aging than those with low-impact and no chronic pain (p < .001). Bivariate associations of DunedinPACE scores with insomnia severity and functional performance were significant at p < .01 (rs = 0.324 and -0.502, respectively). After adjusting for race and sex, the association of insomnia severity and the impact of cLBP was partially mediated by the pace of biological aging (ß = 0.070, p < .001). Also, the association of insomnia severity with functional performance was partially mediated by the pace of biological aging (ß = -0.105, p < .001). Thus, insomnia remains strongly predictive of cLBP outcomes, and the pace of biological aging helps explain this association. Future prospective studies with repeated assessments are needed to uncover the directionality of these complex relationships and ultimately develop interventions to manage cLBP.

Genome-wide DNA methylation analysis implicates enrichment of interferon pathway in African American patients with Systemic Lupus Erythematosus and European Americans with lupus nephritis.

Systemic Lupus Erythematosus (SLE) is a chronic, multisystem, inflammatory autoimmune disease that disproportionately affects women. Trends in SLE prevalence and clinical course differ by ancestry, with those of African American ancestry presenting with more active, severe and rapidly progressive disease than European Americans. Previous research established altered epigenetic signatures in SLE patients compared to controls. However, the contribution of aberrant DNA methylation (DNAm) to the risk of SLE by ancestry and differences among patients with SLE-associated Lupus Nephritis (LN) has not been well described. We evaluated the DNA methylomes of 87 individuals including 41 SLE patients, with and without LN, and 46 controls enrolled in an ancestry diverse, well-characterized cohort study of established SLE (41 SLE patients [20 SLE-LN+, 21 SLE-LN-] and 46 sex-, race- and age-matched controls; 55% African American, 45% European American). Participants were genotyped using the Infinium Global Diversity Array (GDA), and genetic ancestry was estimated using principal components. Genome-wide DNA methylation was initially measured using the Illumina MethylationEPIC 850K Beadchip array followed by methylation-specific qPCR to validate the methylation status at putative loci. Differentially Methylated Positions (DMP) were identified using a case-control approach adjusted for ancestry. We identified a total of 51 DMPs in CpGs among SLE patients compared to controls. Genes proximal to these CpGs were highly enriched for involvement in type I interferon signaling. DMPs among European American SLE patients with LN were similar to African American SLE patients with and without LN. Our findings were validated using an orthogonal, methyl-specific PCR for three SLE-associated DMPs near or proximal to MX1, USP18, and IFITM1. Our study confirms previous reports that DMPs in CpGs associated with SLE are enriched in type I interferon genes. However, we show that European American SLE patients with LN have similar DNAm patterns to African American SLE patients irrespective of LN, suggesting that aberrant DNAm alters activity of type I interferon pathway leading to more severe disease independent of ancestry.

Obesity-Associated Dyslipidemia Is Moderated by Habitual Intake of Marine-Derived n-3 Polyunsaturated Fatty Acids in Yup'ik Alaska Native People: A Cross-Sectional Mediation-Moderation Analysis.

BACKGROUND: Obesity leads to insulin resistance, altered lipoprotein metabolism, dyslipidemia, and cardiovascular disease. The relationship between long-term intake of n-3 polyunsaturated fatty acids (n-3 PUFAs) and prevention of cardiometabolic disease remains unresolved. OBJECTIVES: The aim of this study was to explore direct and indirect pathways between adiposity and dyslipidemia, and the degree to which n-3 PUFAs moderate adiposity-induced dyslipidemia in a population with highly variable n-3 PUFA intake from marine foods. METHODS: In total, 571 Yup'ik Alaska Native adults (18-87 y) were enrolled in this cross-sectional study. The red blood cell (RBC) nitrogen isotope ratio (15N/14N, or NIR) was used as a validated objective measure of n-3 PUFA intake. EPA and DHA were measured in RBCs. Insulin sensitivity and resistance were estimated by the HOMA2 method. Mediation analysis was conducted to evaluate the contribution of the indirect causal path between adiposity and dyslipidemia mediated through insulin resistance. Moderation analysis was used to assess the influence of dietary n-3 PUFAs on the direct and indirect paths between adiposity and dyslipidemia. Outcomes of primary interest included plasma total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), non-HDL-C, and triglycerides (TG). RESULTS: In this Yup'ik study population, we found that up to 21.6% of the total effects of adiposity on plasma TG, HDL-C, and non-HDL-C are mediated through measures of insulin resistance or sensitivity. Moreover, RBC DHA and EPA moderated the positive association between waist circumference (WC) and TC or non-HDL-C, whereas only DHA moderated the positive association between WC and TG. However, the indirect path between WC and plasma lipids was not significantly moderated by dietary n-3 PUFAs. CONCLUSIONS: Intake of n-3 PUFAs may independently reduce dyslipidemia through the direct path resulting from excess adiposity in Yup'ik adults. NIR moderation effects suggest that additional nutrients contained in n-3 PUFA-rich foods may also reduce dyslipidemia.

Non-cigarette tobacco use and stroke among West Africans: evidence from the SIREN study.

INTRODUCTION: Non-cigarette tobacco (NCT) represents a form of tobacco use with a misperceived significance in chronic disease events. Whether NCT use is sufficient to promote stroke events, especially among Africans, is yet to be understood. This study assessed the relationship between NCT use and stroke among indigenous Africans. METHODS: A total of 7,617 respondents (NCT users: 41 vs. non-NCT: 7576) from the Stroke Investigation Research and Educational Network study were included in the current analysis. NCT use was defined as self-reported use of smoked (cigars or piper) or smokeless (snuff or chewed) tobacco in the past year preceding stroke events. Stroke was defined based on clinical presentation and confirmed with a cranial CT/MRI. Multivariable-adjusted logistic regression was applied to estimate the odds ratio (OR) and 95% confidence interval (CI) for the relationship between NCT and stroke at p<0.05. RESULTS: Out of the 41 (0.54%) who reported NCT use, 27 (65.9%) reported using smokeless NCT. NCT users were older than non-smokers (62.8±15.7 vs 57.7±14.8 years). Overall, NCT use was associated with first-ever stroke (OR: 2.08; 95%CI: 1.02, 4.23) in the entire sample. Notably, smokeless NCT use was independently associated with higher odds of stroke (OR: 2.74; 95%CI: 1.15, 6.54), but smoked NCT use (OR: 0.16; 95%CI: 0.02, 1.63) presented a statistically insignificant association after adjusting for hypertension and other covariates. CONCLUSIONS: NCT use was associated with higher odds of stroke, and public health interventions targeting NCT use might be promising in reducing the burden of stroke among indigenous Africans. IMPLICATIONS: A detailed understanding of the relationship between NCT use and stroke will likely inform well-articulated policy guidance to promote evidence-based recommendations for public health prevention and management of stroke on the African continent.

The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders.

The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup'ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup'ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.10 SD (0.02), p = 4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; lean mass, -0.84 (0.19) kg; fat mass and percent, -1.66 (0.33) kg and -1.39 (0.27) %; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p = 0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p = 0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p = 0.0015). In conclusion, we identified a novel variant, where the derived G-allele possibly associated with lower BMI in Arctic populations, and as a consequence also leaner body type, lower insulin resistance, and a favorable lipid profile.

HLA-DQB1*06 and Select Neighboring HLA Variants Predict Chlamydia Reinfection Risk.

Associations of HLA class II alleles with genital chlamydial infection outcomes have been reported, especially HLA DQB1*06. However, the potential role of DQB1*06 in influencing reinfection risk has still not been established. The purpose of this study was to determine whether the association of DQB1*06 with chlamydia reinfection was impacted by any other nearby HLA class II variants that were also associated with reinfection. We used next-generation sequencing to map HLA class II variants spanning the HLA-DQ and -DR loci. DQB1*06 as well as DQB1*04 were confirmed as significant predictors of chlamydia reinfection, when controlling for age and percent African ancestry. SKAT analysis revealed one region each in DRB1, DRB5, DQA2, and three intergenic regions that had variants associated with reinfection. Further analyses of these variants revealed that rs112651494 within DRB5 and an intergenic SNP rs617058 in DRB1:DQA1 were significantly associated with reinfection, but this did not impact the significance of the association of DQB1*06 or DQB1*04 with reinfection.

Are there differences in perceptions, preferences and attitudes towards disclosure of genetic testing for Stroke? A qualitative study among stroke-free SIREN-SIBS genomics study participants.

OBJECTIVE: This study explored perceptions, preferences and attitudes towards disclosure of genetic testing results for stroke among stroke-free controls (and their family members) in the SIREN-SIBS Genomics Study, healthcare providers and policymakers. MATERIALS AND METHODS: We conducted a qualitative thematic analysis of key informant interviews with 61 participants recruited from community advisory boards (30) and health care providers (31) across seven sites in Nigeria and Ghana. RESULTS: Major findings illustrate differences in the knowledge of genetic testing with superior knowledge among health care professionals. Relatives and religious leaders were opined as the best to receive the disclosure as they would be able to break the news to the patient in a culturally sensitive manner to reduce the likely resultant emotional outburst. Poor level of awareness of national guidelines for disclosing genetic results exist. Key facilitating factors for disclosure are education, enabling environment, involvement of religious and community leaders, campaigns, and possible treatment options. Disclosure inhibitors include inadequate information, fear of marital break-up or family displacement, fear of stigmatization, fear of isolation, religious beliefs, health worker attitude, and lack of preparedness to accept results. CONCLUSIONS: These necessitate culturally sensitive interventions for continuing education, increased awareness and sustained engagement to equip all stakeholders in genetic testing disclosure process.

Maternal soybean genistein on prevention of later-life breast cancer through inherited epigenetic regulations.

Breast cancer has strong developmental origins and maternal nutrition composition may influence later-life breast cancer risk in the offspring. Our study focused on a bioactive dietary component, genistein (GE) enriched in soybean products, to investigate specific timing of maternal GE exposure that may influence preventive efficacy of GE on offspring breast cancer later in life, and to explore the potential epigenetic mechanisms. Our results indicate a time-dependent effect of maternal GE exposure on early-life breast cancer development in offspring mice. Through integrated transcriptome and methylome analyses, we identified several candidate genes showing significantly differential gene expression and DNA methylation changes. We further found maternal long-term GE treatment can induce inherited epigenetic landmark changes in a candidate tumor suppressor gene, Trp63, resulting in transcriptional activation of Trp63 and induction of the downstream target genes. Our results suggest that maternal long-term exposure to soybean GE may influence early-life epigenetic reprogramming processes, which may contribute to its temporal preventive effects on breast cancer in the offspring. This study provides important mechanistic insights into an appropriate maternal administration of soybean products on prevention of breast cancer later in offspring life.

A novel Mendelian randomization method with binary risk factor and outcome.

BACKGROUND: Mendelian randomization (MR) applies instrumental variable (IV) methods to observational data using a genetic variant as an IV. Several Monte-Carlo studies investigate the performance of MR methods with binary outcomes, but few consider them in conjunction with binary risk factors. OBJECTIVE: To develop a novel MR estimator for scenarios with a binary risk factor and outcome; and compare to existing MR estimators via simulations and real data analysis. METHODS: A bivariate Bernoulli distribution is adapted to the IV setting. Empirical bias and asymptotic coverage probabilities are estimated via simulations. The proposed method is compared to the Wald method, two-stage predictor substitution (2SPS), two-stage residual inclusion (2SRI), and the generalized method of moments (GMM). An analysis is performed using existing data from the CLEAR study to estimate the potential causal effect of smoking on rheumatoid arthritis risk in African Americans. RESULTS: Bias was low for the proposed method and comparable to 2SPS. The Wald method was often biased towards the null. Coverage was adequate for the proposed method, 2SPS, and 2SRI. Coverage for the Wald and GMM methods was poor in several scenarios. The causal effect of ever smoking on rheumatoid arthritis risk was not statistically significant using a variety of genetic instruments. CONCLUSIONS: Simulations suggest the proposed MR method is sound with binary risk factors and outcomes, and comparable to 2SPS and 2SRI in terms of bias. The proposed method also provides more natural framework for hypothesis testing compared to 2SPS or 2SRI, which require ad-hoc variance adjustments.

Habitual Intake of Marine-Derived n-3 PUFAs is Inversely Associated with a Cardiometabolic Inflammatory Profile in Yup'ik Alaska Native People.

BACKGROUND: The relationship between dietary n-3 PUFAs and the prevention of cardiometabolic diseases, including type 2 diabetes, is unresolved. Examination of the association between n-3 PUFAs and chronic low-grade inflammation in a population where many individuals have had an extremely high intake of marine mammals and fish throughout their lifespan may provide important clues regarding the impact of n-3 PUFAs on health. OBJECTIVES: The aim of this study was to explore associations between concentrations of n-3 PUFAs resulting from habitual intake of natural food sources high in fish and marine mammals with immune biomarkers of metabolic inflammation and parameters of glucose regulation. METHODS: A total of 569 Yup'ik Alaska Native adults (18-87 years old) were enrolled in this cross-sectional study between December 2016 and November 2019. The RBC nitrogen isotope ratio (NIR; 15N/14N) was used as a validated measure of n-3 PUFA intake to select 165 participant samples from the first and fourth quartiles of n-3 PUFA intakes. Outcomes included 38 pro- and anti-inflammatory cytokines and 8 measures of glucose homeostasis associated with type 2 diabetes risks. These outcomes were evaluated for their associations with direct measurements of EPA, DHA, and arachidonic acid in RBCs. ANALYSIS: Linear regression was used to detect significant relationships with cytokines and n-3 PUFAs, adiposity, and glucose-related variables. RESULTS: The DHA concentration in RBC membranes was inversely associated with IL-6 (ß = -0.0066; P < 0.001); EPA was inversely associated with TNFα (ß = -0.4925; P < 0.001); and the NIR was inversely associated with Monocyte chemoattractant protein-1 (MCP-1) (ß = -0.8345; P < 0.001) and IL-10 (ß = -1.2868; P < 0.001). CONCLUSIONS: Habitual intake of marine mammals and fish rich in n-3 PUFAs in this study population of Yup'ik Alaska Native adults is associated with reduced systemic inflammation, which may contribute to the low prevalence of diseases in which inflammation plays an important role.

APOL1 Risk Variants Associated with Serum Albumin in a Population-Based Cohort Study.

INTRODUCTION: The association of apolipoprotein L1 (APOL1) nephropathy risk variants (APOL1), unique to African-ancestry (African-American [AA]) populations, with systemic inflammation, a contributor to chronic kidney disease (CKD) and end-stage kidney disease (ESKD) is ill-defined. This study aimed to describe the role of inflammatory markers in the relationship between APOL1 and incident kidney outcomes using a prospective cohort study. METHODS: APOL1 high-risk status under a recessive genetic model was studied in 10,605 AA adults aged ≥45 years from the Reasons for Geographic and Racial Differences in Stroke study. The primary variables of interest were inflammatory markers: C-reactive protein (mg/dL), white blood cell count (cells/mm3), and serum albumin (sALB) (mg/dL). High inflammation status was defined if at least one of these inflammatory markers exceeded clinical threshold. The association between APOL1 and biomarkers were assessed using regression models adjusting for age, sex, ancestry, hypertension, lipid medications, albumin-to-creatinine ratio, and estimated glomerular filtration rate (eGFR). Models were stratified by diabetes status. We identified incident ESKD using USRDS linkage, and we defined incident CKD as an eGFR <60 mL/min/1.73 m2 and ≥25% decline in the eGFR and normal baseline eGFR and tested for mediation of APOL1 and outcomes by biomarkers using the causal inference approach. RESULTS: Among 7,151 participants with data available on all inflammation markers, 4,479 participants had ≥1 marker meeting the clinical threshold. APOL1 high-risk status was associated with lower adjusted odds of reduced sALB {odds ratio (OR) (95% confidence interval [CI]): 0.59 [0.36, 0.96])}, and this association was significant in people with diabetes (OR [95% CI]: 0.40 [0.18, 0.89]) but not in those without diabetes. There was no association of APOL1 high-risk status with other markers or high inflammation status. APOL1 was independently associated with ESKD (OR [95% CI] = 1.78 [1.28, 2.48]) and CKD (OR [95% CI] = 1.38 [1.00, 1.91]). On mediation analysis, the direct effect between APOL1 and ESKD strengthened after accounting for sALB, but the estimated mediated effect was not statistically significant (OR [95% CI]: 0.98 [0.92, 1.05], p = 0.58). CONCLUSION: APOL1 high-risk variants were associated with sALB. However, sALB did not statistically mediate the association between APOL1 and incident ESKD.

Differential associations between pre-diabetes, diabetes and stroke occurrence among West Africans.

BACKGROUND: There are limited data from Africa on the burden and associations between pre-diabetes (pre-DM), diabetes mellitus (DM) and stroke occurrence in a region experiencing a profound rise in stroke burden. PURPOSE: To characterize the associations between stroke and dysglycemic status among West Africans. METHODS: The Stroke Investigative Research and Educational Network (SIREN) is a multicenter, case-control study involving 15 sites in Ghana and Nigeria. Cases include adults aged ≥18 years with clinical and radiological evidence of an acute stroke. Controls were age-and-gender matched stroke-free adults. Detailed evaluations for vascular factors were performed. Pre-diabetes was defined as HBA1c of 5.7%-6.4% or Fasting blood glucose (FBG) 5.6-7.0 mmol/L and DM as HBA1c >6.5% or FBG>7.0 mmol/L. We used conditional logistic regression to estimate adjusted odds ratios (aOR) with 95% Confidence Interval. RESULTS: Among 2,935 stroke cases the mean age was 60.0 ± 14.2 years with 55.2% being males. By glycemic status, 931 (31.7%) were euglycemic, 633 (21.6%) had Pre-diabetes and 1371 (46.7%) had DM. Of the age- and sex-matched stroke-free controls 69.2% were euglycemic, 13.3% had pre-DM and 17.5% had DM. Pre-DM [aOR (95% CI): 3.68(2.61-5.21)] and DM [4.29 (3.19-5.74)] were independently associated with stroke. The aOR of Pre-DM for ischemic stroke 3.06 (2.01-4.64)] was lower than 4.82 (3.37-6.89) for DM. However, the aOR of Pre-DM for hemorrhagic stroke 6.81 (95% CI: 3.29 - 14.08)] was higher than 3.36 (1.94-5.86) for DM. Furthermore, the aOR of pre-DM for ischemic stroke subtypes were 9.64 (1.30-71.57) for cardio-embolic stroke, 3.64 (1.80-7.34) for small-vessel occlusive disease and 4.63 (0.80-26.65) for large-vessel disease. CONCLUSION: Pre-DM is strongly and independently associated with stroke in Africans. Improving glycemic control through screening, healthy lifestyle and pharmacotherapy at a population level may be strategic in reducing the rising burden of stroke in Africa.

Genetic influences on susceptibility to rheumatoid arthritis in African-Americans.

Large meta-analyses of rheumatoid arthritis (RA) susceptibility in European (EUR) and East Asian (EAS) populations have identified >100 RA risk loci, but genome-wide studies of RA in African-Americans (AAs) are absent. To address this disparity, we performed an analysis of 916 AA RA patients and 1392 controls and aggregated our data with genotyping data from >100 000 EUR and Asian RA patients and controls. We identified two novel risk loci that appear to be specific to AAs: GPC5 and RBFOX1 (PAA < 5 × 10-9). Most RA risk loci are shared across different ethnicities, but among discordant loci, we observed strong enrichment of variants having large effect sizes. We found strong evidence of effect concordance for only 3 of the 21 largest effect index variants in EURs. We used the trans-ethnic fine-mapping algorithm PAINTOR3 to prioritize risk variants in >90 RA risk loci. Addition of AA data to those of EUR and EAS descent enabled identification of seven novel high-confidence candidate pathogenic variants (defined by posterior probability > 0.8). In summary, our trans-ethnic analyses are the first to include AAs, identified several new RA risk loci and point to candidate pathogenic variants that may underlie this common autoimmune disease. These findings may lead to better ways to diagnose or stratify treatment approaches in RA.

Predicting the Probability of Chlamydia Reinfection in African American Women Using Immunologic and Genetic Determinants in a Bayesian Model.

BACKGROUND: African Americans have the highest rates of Chlamydia trachomatis (CT) infection in the United States and also high reinfection rates. The primary objective of this study was to develop a Bayesian model to predict the probability of CT reinfection in African American women using immunogenetic data. METHODS: We analyzed data from a cohort of CT-infected African American women enrolled at the time they returned to a clinic in Birmingham, AL, for the treatment of a positive routine CT test result. We modeled the probability of CT reinfection within 6 months after treatment using logistic regression in a Bayesian framework. Predictors of interest were presence or absence of an HLA-DQB1*06 allele and CT-specific CD4+ IFN-γ response, both of which we had previously reported were independently associated with CT reinfection risk. RESULTS: Among 99 participants evaluated, the probability of reinfection for those with a CT-specific CD4+ IFN-γ response and no HLA-DQB1*06 alleles was 14.1% (95% credible interval [CI], 3.0%-45.0%), whereas the probability of reinfection for those without a CT-specific CD4+ IFN-γ response and at least one HLA-DQB1*06 allele was 61.5% (95% CI, 23.1%-89.7%). CONCLUSIONS: Our model demonstrated that presence or absence of an HLA-DQB1*06 allele and CT-specific CD4+ IFN-γ response can have an impact on the predictive probability of CT reinfection in African American women.

Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension.

Rationale: Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).Objectives: Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Methods: Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis.Measurements and Main Results: After covariate adjustment, self-reported Hispanic patients (n = 290) exhibited significantly reduced mortality versus NHW patients (n = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87]; P = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01]; P = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients (n = 1,524) versus NHW patients (n = 8,829; OR, 0.65 [95% CI, 0.50-0.84]; P = 0.001). An inpatient mortality benefit was observed for Native American patients (n = 185; OR, 0.38 [95% CI, 0.15-0.93]; P = 0.034).Conclusions: This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.

Project SUMS (scaling up of mental health in schools): design and methods for a pragmatic, cluster randomised waitlist-controlled trial on integrated school mental health intervention for adolescents.

BACKGROUND: There is an increasing need for Mental Health Promotion (MHP) among adolescents, especially in developing countries with limited resources and rapid socio-demographic transition. With the growing burden of mental health problems among adolescents (suicide, depression) and their preferences to seek help from their peers, improving Mental Health Literacy (MHL) and behaviours for First Aid in Mental Health (MH-FA) becomes crucial to promote their mental health. METHODS: Schools are ideal settings for reaching the vulnerable adolescents. The proposed study evaluates the effectiveness of a classroom-based teacher-led integrated school mental health intervention called SUMS (MHP + MHL + MH-FA). The study will involve a pragmatic, cluster-randomised waitlist-controlled design to evaluate the effectiveness of SUMS intervention using schools as unit-of-randomisation. The study will be conducted in Srinivaspura taluka (Sub-district) of Kolar district (administrative unit of health) of Karnataka in collaboration with a multi-disciplinary expert team from NIMHANS (National Institute of Mental Health And Neuro Sciences), Bangalore-India and Department of Education, Government of Karnataka, India. A total of 8 schools (400 students studying in 6-8 grade) from Srinivaspura taluka will be randomised into intervention and waitlist control group. The intervention group will receive SUMS intervention through 10-15 h of classroom sessions. The primary outcome is the improvement in positive mental health literacy, as measured by the Mental Health-Promoting Knowledge (MHPK-10) scale. Changes in MH-FA knowledge and intentions, Mental health stigma, help-seeking and resilience are assessed as secondary outcomes. Data will be collected at baseline, 6-weeks, 6-months and 12-months post-intervention. The waitlist-control schools will receive the interventions at the end of the 12-month follow-up assessment in intervention-schools. DISCUSSION: This is the first study to integrate Mental Health Literacy with Mental Health Promotion and behaviours for First Aid in Mental Health to promote mental health well-being among adolescent school children in India. With a need to build a more substantial evidence base on School Mental Health Promotion approaches in developing countries, the study findings will have implications for implementing and operationalising Health and Wellness Ambassador initiative in India. TRIAL REGISTRATION: Clinical Trials Registry - India, CTRI/2019/07/020394. Registered prospectively on 29 July 2019. ( ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=35724&EncHid=&userName=sums ).