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Individual inflammation biomarkers are associated with incident coronary heart disease (CHD) events. However, there is limited research on whether the risk for incident CHD is progressively higher with a higher number of inflammation biomarkers in abnormal levels.We used data from 15,758 Reasons for Geographic and Racial Differences in Stroke (REGARDS) study participants aged ≥45 years without a history of CHD at baseline in 2003-2007. Abnormal levels of baseline high-sensitivity C-reactive protein, leukocyte count and serum albumin were defined as ≥3.8 mg/L (3rd tertile), ≥6.3 x 10Overall, 38.9% (n = 6,123) had 0, 36.6% (n = 5,774) had 1, 19.8% (n = 3,113) had 2 and 4.7% (n = 748) had 3 biomarkers of inflammation in abnormal levels. Over a median follow-up of 11.4 years, 954 (6.1%) participants had incident CHD. The rate of incident CHD per 1000 person-years for individuals with 0, 1, 2, and 3 biomarkers of inflammation in abnormal levels was 4.4 (95% confidence interval [CI]: 3.9-5.0), 6.3 (95% CI: 5.6-6.9), 8.8 (95% CI: 7.8-9.9), and 10.6 (95% CI: 8.1-13.1), respectively. Multi-variable adjusted hazard ratios for incident CHD associated with 1, 2 and 3 versus no inflammation biomarker in abnormal levels were 1.26 (95% CI: 1.07-1.49), 1.72 (95% CI: 1.43-2.07), and 1.84 (95% CI: 1.37-2.47), respectively (P-trend.001).The number of inflammation markers in abnormal levels was associated with increased risk of incident CHD after multi-variable adjustment.

Background & Aims: A genome-wide significant association between anti–Helicobacter pylori (H pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigated this association in an updated genome-wide association study (GWAS) meta-analysis for populations with low gastric cancer incidence, address potential causes of cohort heterogeneity, and explore functional implications of genetic variation at the TLR1/6/10 locus. Methods: The dichotomous GWAS (25% individuals exhibiting highest anti–H pylori IgG titers vs remaining 75%) included discovery and replication sampls of, respectively, n = 15,685 and n = 9676, all of European ancestry. Longitudinal analysis of serologic data was performed on H pylori–eradicated subjects (n = 132) and patients under surveillance for premalignant gastric lesions (n = 107). TLR1/6/10 surface expression, TLR1 mRNA, and cytokine levels were measured in leukocyte subsets of healthy subjects (n = 26) genotyped for TLR1/6/10 variants. Results: The association of the TLR1/6/10 locus with anti–H pylori IgG titers (rs12233670; β = −0.267 ± SE 0.034; P = 4.42 × 10−15) presented with high heterogeneity and failed replication. Anti–H pylori IgG titers declined within 2–4 years after eradication treatment (P = 0.004), and decreased over time in patients with premalignant gastric lesions (P < 0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1 surface expression on monocytes (P = 0.016) and neutrophils (P = 0.030), but not mRNA levels. Conclusions: The association between anti–H pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly owing to dependency of anti–H pylori IgG titers on therapy, clearance, and antibody decay. H pylori–mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.

Consistent with previous cross-sectional studies, in the Southern Community Cohort Study, the largest cohort for Black Americans conducted in a predominantly low-income population with 81,694 participants, we found that moderate alcohol drinking was associated with a significantly increased risk of mortality due to liver disease in Black Americans (hazard ratio = 2.06; 95% confidence interval: 1.08-3.94) but not in White Americans (hazard ratio = 0.87; 95% confidence interval: 0.52-1.44). We found that heavy drinking was significantly associated with an increased risk of mortality due to liver disease in both Black and White Americans. Future studies are warranted to understand the mechanism involving such racial disparity.

Background Following the high morbidity and mortality due to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections in New Orleans, Louisiana, we sought to assess progress toward herd immunity. Methods Ochsner Health employees and patients who volunteered for Abbott SARS-CoV-2 immunoglobulin G (IgG) antibody test between March 1 and May 1, 2020 were included. We estimated IgG prevalence and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for variables associated with IgG test status. Results Of the 13,343 participants with IgG test results, 78.6% were women, 70.6% were non-Hispanic White, 21.1% non-Hispanic Black, 2.9% Hispanic Americans and 5.4% belonged to other races. Overall, 7.99% (95% CI: 7.53-8.45%) of the participants tested IgG positive. In age-, sex- and body mass index (BMI)-adjusted analyses, non-Hispanic Blacks were 2.7-times more likely to test positive than non-Hispanic Whites (OR=2.72; 95% CI: 2.33-3.19). Corresponding ORs (95% CIs) were 1.29 (0.84-1.99) for Hispanic Americans and 1.22 (0.85-1.75) for Other race/ethnicities. Compared to participants in administrative occupations, physician assistants (OR=7.14; 95% CI: 1.72-29.6) and therapists (OR=4.74; 95% CI: 1.49-15.03) were significantly more likely to have IgG antibodies while the association among nurses was not significant (OR=2.35; 95% CI: 0.96-5.77). Relative to 1.40, the test threshold for positivity, our measurements indicate a strong immune response (5.38±1.69), especially among those with a higher BMI. Conclusions SARS-COV-2 IgG antibodies were prevalent only in 8% of the participants. IgG prevalence was highest among non-Hispanic Blacks and participants with higher BMI but was lower among older participants.

Introduction The Southern Community Cohort Study is a prospective study of low socioeconomic status (SES) blacks and whites from the southeastern US, where the burden of end-stage renal disease (ESRD) and its risk factors are high. We tested whether the 2.4-fold elevated risk of ESRD we previously observed in blacks compared to whites was explained by differences in baseline kidney function. Methods We conducted a case-cohort study of incident ESRD cases (n = 737) with stored blood and a probability sampled subcohort (n = 4238) and calculated estimated glomerular filtration rate (eGFR) from serum creatinine. 86% of participants were enrolled from community health centers in medically underserved areas and 14% from the general population in 12 states in the southeastern United States. Incident ESRD after entry into the cohort was ascertained by linkage of the cohort with the US Renal Data System (USRDS). Results Median (25th, 75th percentile) eGFR at baseline was 63.3 (36.0, 98.2) ml/min/1.73m2 for ESRD cases and 103.2 (86.0, 117.9) for subcohort. Black ESRD cases had higher median (25th, 75th) eGFR [63.3 (35.9, 95.9)] compared to whites [59.1 (39.4, 99.2)]. In multivariable Cox models accounting for sampling weights, baseline eGFR was a strong predictor of ESRD risk, and an interaction with race was detected (P = 0.029). The higher ESRD risk among blacks relative to whites persisted (hazard ratio: 2.58; 95% confidence interval: 1.65, 4.03) after adjustment for eGFR. Conclusion In this predominantly lower SES cohort, the racial disparity in ESRD risk is not explained by differences in baseline kidney function. Electronic supplementary material The online version of this article (10.1186/s12882-019-1502-z) contains supplementary material, which is available to authorized users.

BACKGROUND AND AIMS: Data on the relation of egg consumption with risk of type 2 diabetes (T2D) and coronary heart disease (CHD) are limited and inconsistent. Few studies have controlled for overall dietary patterns in egg-T2D or egg-CHD analyses, and it is unclear whether any observed elevated risks of T2D and CHD with frequent egg consumption is real or due to confounding by dietary habits. We tested the hypothesis that frequent egg consumption is associated with a higher risk of T2D and CHD risk after adjustment for overall dietary patterns among adults. DESIGN: We used prospective cohort design to complete time-to-event analyses. METHODS: We pooled de novo, harmonized, individual-level analyses from nine US cohorts (n=103,811). Cox regression was used to estimate hazard ratios separately in each cohort adjusting for age, ethnicity, body mass index (BMI), exercise, smoking, alcohol intake, and dietary patterns. We pooled cohort-specific results using an inverse-variance weighted method to estimate summary relative risks. RESULTS: Median age ranged from 25 to 72 years. Median egg consumption was 1 egg per week in most of the cohorts. While egg consumption up to one per week was not associated with T2D risk, consumption of ≥2 eggs per week was associated with elevated risk [27% elevated risk of T2D comparing 7+ eggs/week with none (95% CI: 16% to 37%)]. There was little evidence for heterogeneity across cohorts and we observed similar conclusions when stratified by BMI. Overall, egg consumption was not associated with the risk of CHD. However, in a sensitivity analysis, there was a 30% higher risk of CHD (95% CI: 3%-56%) restricted to older adults consuming 5-6 eggs/week. CONCLUSIONS: Our data showed an elevated risk of T2D with egg consumption of ≥2 eggs per week but not with

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

Background Copy number variation (CNV) in the salivary amylase gene (AMY1) modulates salivary α-amylase levels and is associated with postprandial glycemic traits. Whether AMY1-CNV plays a role in age-mediated change in insulin resistance (IR) is uncertain. Methods We measured AMY1-CNV using duplex quantitative real-time polymerase chain reaction in two studies, the Boston Puerto Rican Health Study (BPRHS, n = 749) and the Genetics of Lipid-Lowering Drug and Diet Network study (GOLDN, n = 980), and plasma metabolomic profiles in the BPRHS. We examined the interaction between AMY1-CNV and age by assessing the relationship between age with glycemic traits and type 2 diabetes (T2D) according to high or low copy numbers of the AMY1 gene. Furthermore, we investigated associations between metabolites and interacting effects of AMY1-CNV and age on T2D risk. Results We found positive associations of IR with age among subjects with low AMY1-copy-numbers in both studies. T2D was marginally correlated with age in participants with low AMY1-copy-numbers but not with high AMY1-copy-numbers in the BPRHS. Metabolic pathway enrichment analysis identified the pentose metabolic pathway based on metabolites that were associated with both IR and the interactions between AMY1-CNV and age. Moreover, in older participants, high AMY1-copy-numbers tended to be associated with lower levels of ribonic acid, erythronic acid, and arabinonic acid, all of which were positively associated with IR. Conclusions We found evidence supporting a role of AMY1-CNV in modifying the relationship between age and IR. Individuals with low AMY1-copy-numbers tend to have increased IR with advancing age.

ObjectiveObesity and insulin resistance play important roles in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Mg intake is linked to a reduced risk of metabolic syndrome and insulin resistance; people with NAFLD or alcoholic liver disease are at high risk of Mg deficiency. The present study aimed to investigate whether Mg and Ca intakes were associated with risk of fatty liver disease and prediabetes by alcohol drinking status.DesignWe analysed the association between Ca or Mg intake and fatty liver disease, prediabetes or both prediabetes and fatty liver disease in cross-sectional analyses.SettingThird National Health and Nutrition Examination Survey (NHANES III) follow-up cohort of US adults.SubjectsNationally representative sample of US adults in NHANES (n 13 489).ResultsAfter adjusting for potential confounders, Mg intake was associated with approximately 30 % reduced odds of fatty liver disease and prediabetes, comparing the highest intake quartile v. the lowest. Mg intake may only be related to reduced odds of fatty liver disease and prediabetes in those whose Ca intake is less than 1200 mg/d. Mg intake may also only be associated with reduced odds of fatty liver disease among alcohol drinkers.ConclusionsThe study suggests that high intake of Mg may be associated with reduced risks of fatty liver disease and prediabetes. Further large studies, particularly prospective cohort studies, are warranted to confirm the findings.

Background and objectives Prognostic uncertainty is one barrier that impedes providers in engaging patients with CKD in shared decision making and advance care planning. The surprise question has been shown to identify patients at increased risk of dying. Design, setting, participants, & measurements In our prospective observational study, 488 patients ≥60 years of age with CKD stage 4 or 5 were enrolled. Binary surprise question (i.e., “Would you be surprised if this patient died in the next 12 months?”) responses were recorded, and dialysis planning preferences, presence of advance care planning documentation, and care preceding death were abstracted. Results The median patient age was 71 (65–77) years old. Providers responded no and yes to the surprise question for 171 (35%) and 317 (65%) patients, respectively. Median follow-up was 1.9 (1.5–2.1) years, during which 18% of patients died (33% of surprise question no, 10% of surprise question yes; P Conclusions Nephrologists’ prognostic perceptions were associated with modest changes in care, highlighting a critical gap in conservative management discussions, advance care planning, and end of life care among older adults with CKD stages 4 and 5 and high-risk clinical characteristics. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_09_18_CJASNPodcast_17_11.mp3

The SLC8A1 (solute carrier family 8, member 1) gene, encoding Na+/Ca2+ exchanger, is essential in regulating calcium reabsorption and homeostasis. Calcium homeostasis plays a key role in cell proliferation and apoptosis. We hypothesized that polymorphisms in five calcium-regulating genes (SLC8A1, ATP2B1, CALB1, CALB2, and CABP1) interact with calcium intake in relation to the risk of colorectal neoplasia. A two-phase (discovery and replication) study was conducted within the Tennessee Colorectal Polyp Study, including a total of 1275 cases and 2811 controls. In Phase I, we identified six out of 135 SNPs that significantly interacted with calcium intake in relation to adenoma risk. In Phase II, the calcium intake by rs4952490 (SLC8A1) interaction was replicated (P interaction = 0.048). We found an inverse association between calcium intake (1000-2000 mg/day) and colorectal adenomas, particularly for multiple/advanced adenomas, among the G-allele carriers but not among homozygous carriers of the common variant (A) in rs4952490. In the joint analysis of SLC8A1, KCNJ1 and SLC12A1 SNPs, carriers of variant alleles in at least two genes and with calcium intake above the DRI (1000 mg/day) were approximately 30-57% less likely to have adenomas than those whose calcium intake was below the DRI. The association was stronger for multiple/advanced adenomas. No association was found among those who did not carry any variant alleles in these genes when calcium intake was below 2500 mg per day. These findings, if confirmed, may provide a new avenue for the personalized prevention of colorectal adenoma and cancer. This article is protected by copyright. All rights reserved

Objectives This study examines the relationship between alcohol consumption and incident stroke among older adults and tests whether alcohol consumption contributes to observed race and sex differences in stroke. Method Data are from a U.S. national cohort of black and white adults aged 45 and older, the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Current and past drinking levels were reported at baseline (2003-2007). Participants who had never had a stroke were followed for adjudicated stroke events through September 2015 (n = 27,265). We calculated Cox proportional hazard models for stroke, adjusting for demographic, socioeconomic, behavioral, and health characteristics. Results Participants, mean age 64.7 years, consumed on average 2.2 drinks/week and experienced 1,140 first-time stroke events over median 9.1 years follow-up. Nondrinkers had a 12% higher risk of stroke than current drinkers; the risk of stroke among nondrinkers largely reflected high risks among past drinkers; these differences were explained by socioeconomic characteristics. Among current drinkers, light drinkers had significantly lower stroke risks than moderate drinkers after accounting for demographic, socioeconomic, behavioral, and health characteristics. Implications of alcohol did not differ between blacks and whites but did differ by sex: Especially among women, nondrinkers, and specifically past drinkers, had higher risks; these differences were largely explained by health characteristics and behaviors. Alcohol did not explain race and sex differences in stroke incidence. Discussion Among older adults, those who used to, but no longer, drink had higher risks of stroke, especially among women; current light drinkers had the lowest risk of stroke.

ObjectiveTo examine whether lifestyle factors, including sedentary time and physical activity, could independently contribute to risk of end-stage renal disease (ESRD).Study designCase-cohort study.SettingSouth-eastern USA.ParticipantsThe Southern Community Cohort Study recruited ~86 000 black and white participants from 2002 to 2009. We assembled a case cohort of 692 incident ESRD cases and a probability sample of 4113 participants.PredictorsSedentary time was calculated as hours/day from daily sitting activities. Physical activity was calculated as metabolic equivalent (MET)-hours/day from engagement in light, moderate and vigorous activities.OutcomesIncident ESRD.ResultsAt baseline, among the subcohort, mean (SD) age was 52 (8.6) years, and median (25th, 75th centile) estimated glomerular filtration rate (eGFR) was 102.8 (85.9–117.9) mL/min/1.73 m2. Medians (25th–75th centile) for sedentary time and physical activity were 8.0 (5.5–12.0) hours/day and 17.2 (8.7–31.9) MET-hours/day, respectively. Median follow-up was 9.4 years. We observed significant interactions between eGFR and both physical activity and sedentary behaviour (p2. The inverse association is most pronounced at physical activity levels >27 MET-hours/day. High levels of sitting time were associated with increased ESRD risk only among those with reduced kidney function (eGFR ≤30 mL/min/1.73 m2); this association was attenuated after excluding the first 2 years of follow-up.ConclusionsIn a population with a high prevalence of chronic kidney disease risk factors such as hypertension and diabetes, physical activity appears to be associated with reduced risk of ESRD among those with preserved kidney function. A positive association between sitting time and ESRD observed among those with advanced kidney disease is likely due to reverse causation.

People with fatty liver disease are at high risk of magnesium deficiency. Meanwhile, low magnesium status is linked to both chronic inflammation and insulin resistance. However, no study has investigated the association between intake of magnesium and risk of mortality due to liver diseases. We evaluated the association between total magnesium intake and mortality due to liver diseases in the Third National Health and Nutrition Examination Study (NHANES III) cohort, which included 13,504 participants who completed liver ultrasound examination for hepatic steatosis. Overall magnesium intake was associated with a reduced risk of mortality due to liver disease at borderline significance (P = 0.05). In fully-adjusted analyses, every 100 mg increase in intake of magnesium was associated with a 49% reduction in the risk for mortality due to liver diseases. Although interactions between magnesium intake and alcohol use and hepatic steatosis at baseline were not significant (P 0.05), inverse associations between magnesium intake and liver disease mortality were stronger among alcohol drinkers and those with hepatic steatosis. Our findings suggest higher intakes of magnesium may be associated with a reduced risk of mortality due to liver disease particularly among alcohol drinkers and those with hepatic steatosis. Further studies are warranted to confirm the findings.

Impaired hematologic status (IHS) was investigated as a determinant of immune function defined as cluster of differentiation 4 (CD4) T-helper cell count, quality of life (QOL) weight and hospitalization/mortality over 18-months among 398 adult persons living with HIV/AIDS (PLWHA) on anti-retroviral therapy. IHS was defined as having anemia at baseline (Hemoglobin: 200 μg/L for men and >150 μg/L for women) ferritin levels at baseline. Months-to-hospitalization/death or study-end (if no event) was calculated from enrollment. Multivariable linear-mixed models quantified associations between IHS and changes in CD4 cell-count, weight gain and QOL. Cox proportional hazards models calculated hazard ratios (HR) and corresponding 95% confidence intervals (CI) for IHS-related differences in time-to-hospitalization/death. The prevalences of anemia and high and low ferritin levels at baseline were 48.7% (n = 194), 40.5% (n = 161) and 17% (n = 68), respectively. Most patients (63.4%, n = 123) remained anemic during follow-up. Weight gained (ferritin-time interaction, p < 0.01) and QOL (anemia-time interaction, p = 0.05; ferritin-time interaction, p = 0.01) were lower for PLWHA with versus without IHS. Relative to anemia-free/normal ferritin, the risk of hospitalization/death was elevated for PLWHA with anemia (HR = 2.0; 95% CI: 1.2–3.6), low or high ferritin (HR: 1.8–1.9, 95% CI: 0.9–4.1) and those that developed new/persistent/progressive anemia (HR: 2.3–6.7, 95% CI: 1.0–12.7). Among PLWHA, IHS predicted deficits in QOL, low weight gain and a high risk of hospitalization/death. Intervention to mitigate persistent IHS may be warranted among PLWHA on long-term highly active antiretroviral therapy (HAART) to improve health outcomes.

Objective To investigate race-sex associations with risk among whites and blacks in the southeastern United States. The relationship between race, sex, and kidney stone risk is poorly understood. Methods Participants were 42,136 black and white adults enrolled in the Southern Community Cohort Study between 2002 and 2009, with no history of kidney stones and receiving Medicare or Medicaid services. Incident kidney stone diagnoses through December 2014 were determined via linkage with Centers for Medicare and Medicaid Services research files. Hazard ratios (HRs) for associations with race and sex were computed from multivariable Cox proportional hazards models adjusting for baseline characteristics, comorbid diseases, and dietary intakes. Results During 116,931 and 270,917 person-years of follow-up for whites and blacks, respectively, age-adjusted incidence rates (95% confidence interval [CI]) were 5.98 (4.73-7.23) and 4.50 (3.86-5.14) per 1000 person-years for white men and women, respectively, while corresponding rates among blacks were 2.19 (1.71-2.67) and 2.47 (2.19-2.75) per 1000 person-years. Risk was higher among whites compared to blacks (HR = 2.23, 95% CI 1.97-2.53). Male sex was significantly associated with risk among whites (HR = 1.45, 95% CI 1.20-1.75), but not among blacks (HR = 0.90, 95% CI 0.75-1.07). Formal tests of interaction by race and sex were statistically significant for all models (P = .01 for fully adjusted model). Conclusion The association of incident kidney stones with sex differs between whites and blacks. White men have the highest risk, while no difference in risk is observed between black men and women.

Background Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established. Objective To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA. Design We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European descent. We also investigated relationships between specific single nucleotide polymorphisms (SNPs) in the lactase (LCT) gene, associated with adult-onset lactase intolerance, with circulating levels of dairy-derived OCSFA, and evaluated associations of candidate sphingolipid genes with C23:0 levels. Results We found no genome-wide significant evidence that common genetic variation is associated with circulating levels of C15:0 or C23:0. In two cohorts with available data, we identified one intronic SNP (rs13361131) in myosin X gene (MYO10) associated with C17:0 level (P = 1.37×10−8), and two intronic SNP (rs12874278 and rs17363566) in deleted in lymphocytic leukemia 1 (DLEU1) region associated with C19:0 level (P = 7.07×10−9). In contrast, when using a candidate-gene approach, we found evidence that three SNPs in LCT (rs11884924, rs16832067, and rs3816088) are associated with circulating C17:0 level (adjusted P = 4×10−2). In addition, nine SNPs in the ceramide synthase 4 (CERS4) region were associated with circulating C23:0 levels (adjusted P

AMH is associated with menopausal timing in several studies. In contrast to prior studies that were restricted to women with regular cycles, our objective was to examine this association in women with either regular or irregular menstrual cycles.CARDIA is a longitudinal, population-based study that recruited adults ages 18-30 when it began in 1985-1986. AMH was measured in serum stored in 2002-2003. Natural menopause was assessed by survey in 2005-2006 and 2010-2011.Among 716 premenopausal women, median [25th, 75th] AMH was 0.77 [0.22-2.02]ng/dL at a median age of 42 [39-45] years. Twenty-nine percent of the women (n=207) reported natural menopause during 9 years of follow up. In fully adjusted discrete-time hazard models, a 0.5 ng/dL AMH decrement was associated with higher risk of menopause (p0.001). Hazard ratios varied with time since AMH measurement. The HR (95% CI) for menopause was 8.1 (2.5-26.1) within 0-3 years and 2.3 (1.7-3.3) and 1.6 (1.3-2.1) for 3-6 and 6-9 years, respectively. When restricted to women with regular menses, results were similar (e.g., HR=6.1; 95% CI: 1.9-20.0 for 0-3 years).AMH is independently associated with natural menopause. AMH appears most useful in identifying women at risk of menopause in the near future (within 3 years of AMH measurement).

Background— Type 2 diabetes mellitus (T2D) and cardiovascular disease share risk factors and subclinical atherosclerosis (SCA) predicts events in those with and without diabetes mellitus. T2D genetic risk may predict both T2D and SCA. We hypothesized that greater T2D genetic risk is associated with higher extent of SCA. Methods and Results— In a cross-sectional analysis, including ≤9210 European Americans, 3773 African Americans, 1446 Hispanic Americans, and 773 Chinese Americans without known cardiovascular disease and enrolled in the Framingham Heart Study, Coronary Artery Risk Development in Young Adults, Multi-Ethnic Study of Atherosclerosis, and Genetic Epidemiology Network of Arteriopathy studies, we tested a 62 T2D-loci genetic risk score for association with measures of SCA, including coronary artery or abdominal aortic calcium score, common and internal carotid artery intima-media thickness, and ankle-brachial index. We used ancestry-stratified linear regression models, with random effects accounting for family relatedness when appropriate, applying a genetic-only (adjusted for sex) and a full SCA risk factors–adjusted model (significance, P P =0.004) and with common carotid artery intima-media thickness in the Framingham Heart Study ( P =0.009) was not confirmed in other study cohorts, either separately or in meta-analysis. Secondary analyses showed no consistent associations with β-cell and insulin resistance genetic risk sub-scores in the Framingham Heart Study and in the Coronary Artery Risk Development in Young Adults. Conclusions— SCA does not have a major genetic component linked to a burden of 62 T2D loci identified by large genome-wide association studies. A shared T2D-SCA genetic basis, if any, might become apparent from better functional information about both T2D and cardiovascular disease risk loci.

Circulating trans fatty acids (TFAs), which cannot be synthesized by humans, are linked to adverse health outcomes. Although TFAs are obtained from diet, little is known about subsequent influences (e.g., relating to incorporation, metabolism, or intercompetition with other fatty acids) that could alter circulating concentrations and possibly modulate or mediate impacts on health.The objective was to elucidate novel biologic pathways that may influence circulating TFAs by evaluating associations between common genetic variation and TFA biomarkers.We performed meta-analyses using 7 cohorts of European-ancestry participants (n = 8013) having measured genome-wide variation in single-nucleotide polymorphisms (SNPs) and circulating TFA biomarkers (erythrocyte or plasma phospholipids), including trans-16:1n-7, total trans-18:1, trans/cis-18:2, cis/trans-18:2, and trans/trans-18:2. We further evaluated SNPs with genome-wide significant associations among African Americans (n = 1082), Chinese Americans (n = 669), and Hispanic Americans (n = 657) from 2 of these cohorts.Among European-ancestry participants, 31 SNPs in or near the fatty acid desaturase (FADS) 1 and 2 cluster were associated with cis/trans-18:2; a top hit was rs174548 (β = 0.0035, P = 4.90 × 10(-15)), an SNP previously associated with circulating n-3 and n-6 polyunsaturated fatty acid concentrations. No significant association was identified for other TFAs. rs174548 in FADS1/2 was also associated with cis/trans-18:2 in Hispanic Americans (β = 0.0053, P = 1.05 × 10(-6)) and Chinese Americans (β = 0.0028, P = 0.002) but not African Americans (β = 0.0009, P = 0.34); however, in African Americans, fine mapping identified a top hit in FADS2 associated with cis/trans-18:2 (rs174579: β = 0.0118, P = 4.05 × 10(-5)). The association between rs174548 and cis/trans-18:2 remained significant after further adjustment for individual circulating n-3 and n-6 fatty acids, except arachidonic acid. After adjustment for arachidonic acid concentrations, the association between rs174548 and cis/trans-18:2 was nearly eliminated in European-ancestry participants (β-coefficient reduced by 86%), with similar reductions in Hispanic Americans and Chinese Americans.Our findings provide novel evidence for genetic regulation of cis/trans-18:2 by the FADS1/2 cluster and suggest that this regulation may be influenced/mediated by concentrations of arachidonic acid, an n-6 polyunsaturated fat.

Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10(-26)) and lignoceric acid (P = 3.20 × 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.

BACKGROUND/OBJECTIVES To identify factors associated with plasma polyunsaturated fatty acid (PUFA) levels among 3-month-old Tanzanian infants. SUBJECTS/METHODS Infants (n = 238) and mothers (n = 193) randomly selected from participants in the neonatal vitamin A supplementation randomized controlled trial. A cross-sectional study of maternal-infant pairs at 3 months postpartum. RESULTS All infant total, n-3, n-6, and individual PUFA levels were correlated with maternal levels. Infant plasma n-3 PUFA levels were higher when maternal n-3 PUFA levels were higher (mean difference in infant % fatty acid per unit increase in maternal levels ± standard error: 0.79 ± 0.08; P

Objective Dietary protein intake could have deleterious renal effects in populations at risk for chronic kidney disease. Here, we examined whether higher protein intake (≥80th percentile of energy from protein) is associated with decline in kidney function and whether this decline varies by diabetes status. Design Observational cohort study. Subjects and Settings Participants were African-Americans (n = 5,301), who enrolled in the Jackson Heart Study between 2000 and 2004. Methods Dietary intake was assessed using a validated food-frequency questionnaire at baseline, and serum creatinine was measured at baseline (visit 1) and 8 years later (visit 3). Estimated glomerular filtration rates (eGFRs) at baseline and follow-up were computed using the chronic kidney disease epidemiology collaboration equation. Main Outcome Measure The change in eGFR was computed by subtracting eGFR at visit 1 from that at visit 3. Results Of 3,165 participants with complete data, 64% were women, 57% had hypertension, and 19% had diabetes. The median (25th, 75th percentile) percent energy intake from protein was 14.3 (12.4, 16.4), comparable to that reported for the general US population (15% of energy). During a median (25th, 75th percentile) follow-up of 8.0 (7.4, 8.3) years, eGFR declined by 10.5% from a mean (SD) of 97.4 (17.5) to 86.9 (21.3) mL/min/1.73 m 2 . In the fully adjusted model, consumption of protein as percent of energy intake in lowest and highest quintiles was associated with decline in eGFR among diabetic subjects. The analysis of variance with a robust variance estimator was used to determine whether long-term change in eGFR significantly varies by protein intake. Conclusions Our results show that, among African-Americans with diabetes, higher protein intake as a percent of total energy intake is positively associated with greater decline in eGFR in analyses that accounted for risk factors for kidney disease.

Intubation is an essential component of intensive care, yet it does have potential complications. Posterior glottic stenosis (PGS) is among the most severe sequela. Risk factors are poorly understood. One hypothesis is that large endotracheal tubes (ETTs) in smaller airways may increase risk. Because tracheal diameter is proportional to height, we designed a case-control study to evaluate the association between intensive care unit (ICU)-patient height (proxy for tracheal diameter) and their risk of postintubation PGS.Retrospective case-control study METHODS: Among patients who underwent intubation in an ICU at a single tertiary care medical center between 2001 and 2015, a convenience sample of all patients with confirmed PGS (cases) were enrolled. Cases were matched 1:1 by age, sex, and race with intubated non-PGS controls chosen from the same population of ventilated patients. Data on height, weight, comorbidities, size of ETT, and duration of intubation were abstracted from the medical record. Multivariate models were used to test the association between patient height and risk of PGS development.In all, 106 PGS cases (mean age 48.9 years, 50.7% female, 79.2% Caucasian) were identified; 77 met inclusion criteria. Compared to matched controls, cases were significantly shorter (mean 166 cm vs. 173 cm, P = .001). Height and PGS showed an inverse relationship in multivariate models. Specifically, odds of PGS decreased 9% (95% confidence interval: 0.01%-16%) for each centimeter increase in height.Shorter height is independently associated with increased odds of having PGS. Further work should consider whether height should be incorporated into ETT selection algorithms.3b Laryngoscope, 128:2811-2814, 2018.

Background Recent data suggest that neighborhood socioeconomic environment predicts heart failure (HF) hospital readmissions. We investigated whether neighborhood deprivation predicts risk of incident HF beyond individual socioeconomic status in a low-income population. Methods and Results Participants were 27 078 whites and blacks recruited during 2002 to 2009 in the SCCS (Southern Community Cohort Study), who had no history of HF and were using Centers for Medicare or Medicaid Services. Incident HF diagnoses through December 31, 2010, were ascertained using International Classification of Diseases , Ninth Revision, codes 428.x via linkage with Centers for Medicare or Medicaid Services research files. Participant residential information was geocoded and census tract determined by a spatial join to the US Census Bureau TIGER/Line Shapefiles. The neighborhood deprivation index was constructed using principal components analysis based on census tract-level socioeconomic variables. Cox models with Huber–White cluster sandwich estimator of variance were used to investigate the association between neighborhood deprivation index and HF risk. The study sample was predominantly middle aged (mean, 55.5 years), black (69%), female (63%), low income (70% earned 50% of participants lived in the most deprived neighborhoods (third neighborhood deprivation index tertile). Over median follow-up of 5.2 years, 4300 participants were diagnosed with HF. After adjustment for demographic, lifestyle, and clinical factors, a 1 interquartile increase in neighborhood deprivation index was associated with a 12% increase in risk of HF (hazard ratio, 1.12; 95% confidence interval, 1.07–1.18), and 4.8% of the variance in HF risk (intraclass correlation coefficient, 4.8; 95% confidence interval, 3.6–6.4) was explained by neighborhood deprivation. Conclusions In this low-income population, scant neighborhood resources compound the risk of HF above and beyond individual socioeconomic status and traditional cardiovascular risk factors. Improvements in community resources may be a significant axis for curbing the burden of HF.

To compare presenting characteristics of patients with adductor spasmodic dysphonia (ADSD), ADSD with laryngeal tremor (ADSD + LT), and laryngeal tremor without ADSD (LT).Cross-sectional analysis.Patients treated for laryngeal movement disorders (1990-2016) were included. Analysis of variance and chi square tests measured differences in patient characteristics across the three disease groups. Using ADSD as the referent, multivariable logistic regression models were used to determine whether potential risk factors including patient demographics, family history, presence of potential inciting events prior to disease onset, and coprevalent movement disorders were associated with ADSD + LT or LT.In all, 652 patients with ADSD (n = 377), ADSD + LT (n = 98), and LT (n = 177) were included. ADSD patients were significantly younger than those with ADSD + LT and LT (52.5 ± 13.4, 63.9 ± 11.3, and 69.3 ± 10.5 years, respectively; P 0.001). Coprevalent movement disorders were more common in ADSD + LT (38.7%) and LT (57.1%) groups than in the ADSD group (11.5%; P 0.001). Compared to ADSD, patients with ADSD + LT and LT were more likely to develop an additional movement disorder during follow-up. In multivariable analyses, increasing age, female gender, and having a movement disorder at presentation were associated with significantly greater odds of having ADSD + LT or LT when compared to ADSD.ADSD + LT patients demonstrate intermediate gender composition and age distributions between those with ADSD and LT. These findings suggest that ADSD + LT may be a distinct phenotype in the spectrum of laryngeal movement disorders.4 Laryngoscope, 129:170-176, 2019.

Background— There is a paucity of data on heart failure (HF) incidence among low-income and minority populations. Our objective was to investigate HF incidence and post-HF survival by race and sex among low-income adults in the southeastern United States. Methods and Results— Participants were 27 078 white and black men and women enrolled during 2002 to 2009 in the SCCS (Southern Community Cohort Study) who had no history of HF and were receiving Centers for Medicare and Medicaid Services. Incident HF diagnoses through December 31, 2010 were ascertained using International Classification of Diseases 9th Revision codes 428.x via linkage with Centers for Medicare and Medicaid Services research files. Most participants were black (68.8%), women (62.6%), and earned Conclusions— In this low-income population, HF incidence was higher for all race–sex groups than previously reported in other cohorts. The SCCS is a unique resource to investigate determinants of HF risk in a segment of the population underrepresented in other existing cohorts.

MUFAs are unsaturated FAs with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels are associated with cardiometabolic disorders, including CVD, T2D, and metabolic syndrome (MS). Previous genome-wide association studies (GWASs) have identified seven loci for plasma and erythrocyte palmitoleic and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential functional variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in more than 15,000 participants of Chinese and European ancestry. We identified novel genome-wide significant associations for vaccenic acid at FADS1/2 and PKD2L1 [log(10)(Bayes factor). >= 8.07] and for gondoic acid at FADS1/2 and GCKR [log(10)(Bayes factor) >= 6.22], and also observed improved fine-mapping resolutions at FADS1/2 and GCKR loci. The greatest improvement was observed at GCKR, where the number of variants in the 99\% credible set was reduced from 16 (covering 94.8 kb) to 5 (covering 19.6 kb, including a missense variant rs1260326) after trans-ethnic meta-analysis. We also confirmed the previously reported associations of PKD2L1, FADS1/2, GCKR, and HIF1AN with palmitoleic acid and of FADS1/2 and LPCAT3 with oleic acid in the Chinese-specific GWAS and the trans-ethnic meta-analyses. Pathway-based analyses suggested that the identified loci were in unsaturated FA metabolism and signaling pathways.(jl) Our findings provide novel insight into the genetic basis relevant to MUFA metabolism and biology. Infrastructure for the CHARGE Consortium was supported in part by the National Heart, Lung, and Blood Institute grant HL105756. The NHAPC study was supported by the major project of the Ministry of Science and Technology of China (2016YFC1304903) and the National Natural Science Foundation of China (81471013, 30930081, 81170734, and 81321062). The ARIC Study was carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C and grants R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by grant UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The CARDIA study was conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging. Genotyping of the CARDIA participants was supported by National Human Genome Research Institute grants U01-HG-004729, U01-HG-004446, and U01-HG-004424. Statistical analyses and FA measures were funded by National Heart, Lung, and Blood Institute grant R01-HL-084099 (M.F.). The CHS was supported by National Heart, Lung, and Blood Institute contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086; and National Heart, Lung, and Blood Institute grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL085710, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through National Institute on Aging grant R01AG023629. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences CTSI grant UL1TR000124 and the National Institute of Diabetes and Digestive and Kidney Diseases Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The HPFS and NHS were supported by National Institutes of Health research grants UM1 CA186107, R01 HL034594, UM1 CA167552, R01 HL35464, HL60712, and CA055075; National Heart, Lung, and Blood Institute career development award R00HL098459; American Diabetes Association research grant 1-12-JF-13; and American Heart Association grant 11SDG7380016. The MESA study and MESA SHARe were supported by National Heart, Lung, and Blood Institute contracts N01-HC-95159 through N01-HC-95169 and RR-024156. Funding for MESA SHARe genotyping was provided by National Heart, Lung, and Blood Institute contract N02HL64278. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences CTSI grant UL1TR000124 and the National Institute of Diabetes and Digestive and Kidney Diseases Diabetes Research Center grant DK063491 (Southern California Diabetes Endocrinology Research Center).; The GOLDN study was funded by National Heart, Lung, and Blood Institute grants U01HL072524 and HL54776. The InCHIANTI baseline (1998-2000) was supported as a ``targeted project (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by National Institute on Aging contracts 263 MD 9164 and 263 MD 821336. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Sí

Background and aims Adiponectin is an adipose-secreted protein that has been linked to changes in insulin sensitivity, high-density lipoprotein cholesterol levels, and inflammatory patterns. Although fenofibrate therapy can raise adiponectin levels, treatment response is heterogeneous and heritable, suggesting a role for genetic mediators. This is the first genome-wide association study of fenofibrate effects on circulating adiponectin. Methods and results Plasma adiponectin was measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network ( n = 793) before and after a 3-week daily treatment with 160 mg of fenofibrate. Associations between variants on the Affymetrix Genome-Wide Human SNP Array 6.0 and adiponectin were assessed using mixed linear models, adjusted for age, sex, site, and family. We observed a statistically significant ( P = 5 × 10 −8 ) association between rs2384207 in 12q24, a region previously linked to several metabolic traits, and the fenofibrate-induced change in circulating adiponectin. Additionally, our genome-wide analysis of baseline adiponectin levels replicated the previously reported association with CDH13 and suggested novel associations with markers near the PCK1, ZBP1, TMEM18, and SCUBE1 genes. The findings from the single marker tests were corroborated in gene-based analyses. Biological pathway analyses suggested a borderline significant association between the EGF receptor signaling pathway and baseline adiponectin levels. Conclusions We present preliminary evidence linking several biologically relevant genetic variants to adiponectin levels at baseline and in response to fenofibrate therapy. Our findings provide support for fine-mapping of the 12q24 region to investigate the shared biological mechanisms underlying levels of circulating adiponectin and susceptibility to metabolic disease.

Background: A high intake of trans fatty acids decreases HDL cholesterol and is associated with increased LDL cholesterol, inflammation, diabetes, cancer, and mortality from cardiovascular disease. The relation between trans fat intake and all-cause mortality has not been established. Objective: The aim of this study was to determine the relation between trans fat intake and all-cause mortality. Design: We used data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study—a prospective cohort study of white and black men and women residing in the continental United States. Energy-adjusted trans fat intake was categorized into quintiles, and Cox-regression was used to evaluate the association between trans fat intake and all-cause mortality. Results: During 7 y of follow-up, there were 1572 deaths in 18,513 participants included in REGARDS. From the first to the fifth quintile of trans fat intake, the mortality rates per 1000 person-years of follow-up (95% CIs) were 12.8 (11.3, 14.5), 14.3 (12.7, 16.2), 14.6 (13.0, 16.5), 19.0 (17.1, 21.1), and 23.6 (21.5, 25.9), respectively. After adjustment for demographic factors, education, and risk factors for mortality, the HRs (95% CIs) for all-cause mortality were 1.00, 1.03 (0.86, 1.23), 0.98 (0.82, 1.17), 1.25 (1.05, 1.48), and 1.24 (1.05, 1.48), respectively (P-trend = 0.004). The population attributable risk due to trans fat intake was 7% (95% CI: 5%, 8%). Conclusion: Higher trans fat intake is associated with an increased risk of all-cause mortality. Am J Clin Nutr doi: 10.3945/ajcn. 112.049064.

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

Cardiovascular disease (CVD) biomarkers were examined in a cohort of HIV-infected and HIV-uninfected adolescents who participated in Adolescent Trials Network study 083 utilizing samples from the Reaching for Excellence in Adolescent Care cohort, a longitudinal study of youth infected through adult risk behavior. Nonfasting blood samples from 97 HIV-infected and 81 HIV-uninfected adolescents infected by adult risk behaviors were analyzed for total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), triglycerides, apolipoprotein A-I, high-sensitivity C-reactive protein (hsCRP), soluble vascular adhesion molecule-1 (sVCAM-1), myeloperoxidase, and neopterin at baseline and 18 months later. Results were analyzed using ANOVA, Wilcoxon signed-rank, and paired t tests. Among infected subjects 67 received antiretroviral therapy and 30 were treatment naive. The HIV-infected and HIV-uninfected subjects were similar in gender, ethnicity, and cardiovascular risk factors such as smoking and obesity. In all groups lipid parameters were within accepted guidelines for cardiovascular risk. Among HIV-infected youth on antiretroviral therapy (ART), HDL and apoprotein A-I were significantly lower when compared to uninfected youth. hsCRP was not elevated and thus not predictive for risk in any group. sVCAM-1 levels were significantly elevated in both HIV-infected groups: 1,435 ng/ml and 1,492 ng/ml in untreated and treated subjects, respectively, and 1,064 ng/ml in the uninfected group (p

Sunlight may be related to cognitive function through vitamin D metabolism or circadian rhythm regulation. The analysis presented here sought to test whether ground and satellite measures of solar radiation are associated with cognitive decline. The study used a 15-year residential history merged with satellite and ground monitor data to determine sunlight (solar radiation) and air temperature exposure for a cohort of 19,896 cognitively intact black and white participants aged 45+ from the 48 contiguous United States. Exposures of 15, 10, 5, 2, and 1-year were used to predict cognitive status at the most recent assessment in logistic regression models; 1-year insolation and maximum temperatures were chosen as exposure measures. Solar radiation interacted with temperature, age, and gender in its relationships with incident cognitive impairment. After adjustment for covariates, the odds ratio (OR) of cognitive decline for solar radiation exposure below the median vs above the median in the 3rd tertile of maximum temperatures was 1.88 (95 % CI: 1.24, 2.85), that in the 2nd tertile was 1.33 (95 % CI: 1.09, 1.62), and that in the 1st tertile was 1.22 (95 % CI: 0.92, 1.60). We also found that participants under 60 years old had an OR = 1.63 (95 % CI: 1.20, 2.22), those 60-80 years old had an OR = 1.18 (95 % CI: 1.02, 1.36), and those over 80 years old had an OR = 1.05 (0.80, 1.37). Lastly, we found that males had an OR = 1.43 (95 % CI: 1.22, 1.69), and females had an OR = 1.02 (0.87, 1.20). We found that lower levels of solar radiation were associated with increased odds of incident cognitive impairment.

Background Fatty acids, including n-6 series, modulate immune function, but their effect on CD4 cell counts, death, or hospitalization in HIV-infected patients on antiretroviral therapy is unknown. Methods In a randomized trial for effects of multivitamins in HIV-infected patients in Uganda, we used gas chromatography to measure plasma n-6 fatty acids at baseline; determined CD4 counts at baseline, 3, 6, 12, and 18 months; and recorded hospitalization or death events. The associations of fatty acids with CD4 counts and events were analyzed using repeated-measures analysis of variance and Cox regression, respectively. Results Among 297 patients with fatty acids measurements, 16 patients died and 69 were hospitalized within 18 months. Except for linoleic acid, n-6 fatty acids levels were positively associated with CD4 counts at baseline but not during follow-up. In models that included all 5 major n-6 fatty acids, age; sex; body mass index; anemia status; use of antiretroviral therapy, multivitamin supplements, and alcohol; and the risk of death or hospitalization decreased significantly with an increase in linoleic acid and gamma-linolenic acid levels, whereas associations for dihomo-gamma-linolenic acid, arachidonic acid, and aolrenic acid were null. The hazard ratios (95% confidence intervals) per 1 SD increase in linoleic acid and gamma-linolenic acid were 0.73 (0.56-0.94) and 0.51 (0.36-0.72), respectively. Gamma-linolenic acid remained significant (hazard ratio = 0.51; 95% confidence interval: 0.35 to 0.68) after further adjustment for other plasma fatty acids. Conclusions Lower levels of gamma-linolenic acid are associated with lower CD4 counts and an increased risk of death or hospitalization. These results suggest a potential for using n-6 fatty acids to improve outcomes from antiretroviral therapy.

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and have been linked to acute kidney injury (AKI), chronic kidney disease (CKD) and cardiovascular disease (CVD). Patients who survive an AKI episode are at risk for future adverse kidney and cardiovascular outcomes. The objective of our study was to examine the prevalence and predictors of NSAID use among AKI survivors. Methods The Southern Community Cohort Study is a prospective study of low-income adults aged 40–79 in the southeastern US. Through linkage with Centers for Medicare and Medicaid Services, 826 participants with an AKI diagnosis (ICD-9 584.5-584.9) at any age prior to cohort enrollment were identified. At baseline, data were collected on regular use of prescription and over-the-counter NSAIDs, as well as demographic, medical and other characteristics. Additional comorbidities were ascertained via linkage with CMS or the US Renal Data System. Results One hundred fifty-four AKI survivors (19%) reported regular NSAID use at cohort enrollment (52 prescription, 81 OTC, 21 both) and the percentage of NSAID users did not vary by time since AKI event. Over 58% of users were taking NSAIDS regularly both before and after their AKI event. Hypertension (83%), arthritis (71%), heart failure (44%), CKD (36%) and diabetes (35%) were prevalent among NSAID users. In a multivariable model, history of arthritis (OR: 3.00; 95% CI: 1.92, 4.68) and acetaminophen use (OR: 2.43; 95% CI: 1.50, 3.93) were significantly associated with NSAID use, while prevalent CKD (OR: 0.63; 95% CI: 0.41, 0.98) and diabetes (OR: 0.44; 95% CI: 0.29, 0.69) were significantly inversely associated. Conclusions NSAID use among AKI survivors is common and highlights the need to understand physician and patient decision-making around NSAIDs and to develop effective strategies to reduce NSAID use in this vulnerable population. Electronic supplementary material The online version of this article (doi:10.1186/s12882-016-0411-7) contains supplementary material, which is available to authorized users.

BACKGROUND/OBJECTIVE Studies based on food frequency questionnaires suggest that folate and vitamin B12 intake could protect against hearing loss. We investigated whether erythrocyte folate and serum vitamin B12 levels are independently associated with hearing loss in humans. METHODS Participants in the 2003–2004 US National Health and Nutrition Examination Survey who had data on hearing, folate, and vitamin B12 levels were included. Pure-tone average (PTA) at 0.5, 1.0, 2.0 and 4.0 kHz was computed for each ear. We used weighted logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relation between quartiles of folate and vitamin B12, and hearing loss (present if PTA >25 dB in either ear and absent if PTA ≤25 dB in both ears). RESULTS Participants (n=1,149) were 20 to 69 (mean 42) years old and 16.4% had hearing loss in at least one ear. Our data suggest a U-shaped relationship between folate and hearing loss. Compared to the 1st quartile, the ORs (95% CIs) for hearing loss were 0.87 (0.49–1.53), 0.70 (0.49–1.00) and 1.08 (0.61–1.94) for the 2nd, 3rd and 4th quartile of erythrocyte folate in analyses adjusted for age, sex, vitamin B12, smoking, alcohol use, body mass index, race/ethnicity, exposure to noise, income and education. Although we observed inverse associations between vitamin B12 and hearing loss, the associations were not statistically significant (P>0.05). CONCLUSION Our data show a U-shaped relationship between erythrocyte folate levels and hearing loss, suggesting a need to evaluate whether optimizing blood folate levels could prevent hearing loss.

Background Whether polyunsaturated fatty acids (PUFA) are associated with end-stage renal disease (ESRD) in populations with a high burden of risk factors for kidney disease is unknown. We sought to determine whether PUFA intake is associated with ESRD. Methods We conducted a nested case–control study of ESRD within the Southern Community Cohort Study (SCCS), a prospective cohort of low-income blacks and whites in the southeastern US (2002–2009). Through 2012, 1,074 incident ESRD cases were identified by linkage with the United States Renal Data System and matched to 3,230 controls by age, sex and race. Dietary intake of total, n-3 or n-6 PUFA was assessed from a validated food frequency questionnaire administered at baseline. Odds ratios (ORs) and 95 % confidence intervals (CIs) were computed from logistic regression models that included matching variables, body mass index, smoking, diabetes, hypertension, education, income, total energy intake and percent energy from protein and saturated fat. Results The mean (SD) age of participants was 55 (9) years. Most participants were women (55 %), black (87 %), with hypertension (67 %) and on average obtained 8 % of their energy from PUFA. Higher PUFA intake was marginally associated with a lower risk of ESRD in adjusted analyses. The adjusted odds ratios (95 % confidence intervals) for ESRD for the 5th vs. 1st quintile of PUFA were 0.79 (0.60–1.05; P trend = 0.06) for total PUFA, 0.81 (0.61–1.06; P trend = 0.04) for n-6 PUFA and 0.93 (0.71–1.21; P trend = 0.45) for n-3 PUFA. Conclusions We observed a marginally significant inverse trend between dietary PUFA intake and ESRD incidence, mainly driven by n-6 fatty acid intake. Our findings require replication but suggest that a diet rich in n-6 PUFA may prevent ESRD development in a population with a high burden of kidney disease risk factors.

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. Video Abstract [Figure presented] Keywords: type 2 diabetes (T2D); genetics; disease mechanism; SLC16A11; MCT11; solute carrier (SLC); monocarboxylates; fatty acid metabolism; lipid metabolism; precision medicine

To characterize the risk and predictors of growth during observation of vestibular schwannomas (VS).Retrospective case series.Single academic, tertiary care center.Five hundred sixty-four consecutive VS patients who underwent at least two magnetic resonance imaging (MRI) studies before intervention.Serial MRI studies.Tumor growth, defined as a ≥2 mm increase in the maximum tumor diameter between consecutive MRI studies, or between the first and last study.A total of 1296 patients (1995-2015) with VS were identified. Of those, 564 patients (median age 59.2 years; 53.5% female) were initially observed and underwent multiple MRI studies (median follow-up 22.9 months, interquartile range [IQR] 11.7-42.7). The median maximum tumor diameter at presentation was 1.00 cm (IQR 0.6-1.51 cm). In all, 40.8% of tumors demonstrated growth and 32.1% underwent intervention (21.5% microsurgery, 10.5% radiation) during the surveillance period. Multivariable Cox regression analysis showed that for each tumor, the risk of growth or intervention was significantly increased for larger initial VS diameters (HR = 2.22; 95% CI: 1.90-2.61) and when disequilibrium was a presenting symptom (HR = 1.70; 95% CI: 1.30-2.23). Patient age, sex, aspirin use, and presenting symptoms of asymmetric hearing loss, tinnitus, and vertigo were not associated with tumor growth.To date, this is the largest series of observed VS reported in the literature. Risk of VS growth is significantly increased among patients who present with larger tumors and who have concomitant disequilibrium.IRB:: 151481.No cohort with this sample size has assessed vestibular schwannoma growth rates in conjunction with this number of variables.To characterize vestibular schwannoma growth rates and predictors of growth.

BACKGROUND: The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100,000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.METHODS: We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990-2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values.FINDINGS: 292,982 (95% UI 261,017-327,792) maternal deaths occurred in 2013, compared with 376,034 (343,483-407,574) in 1990. The global annual rate of change in the MMR was -0·3% (-1·1 to 0·6) from 1990 to 2003, and -2·7% (-3·9 to -1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290-2866) maternal deaths were related to HIV in 2013, 0·4% (0·2-0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1-1262·8) in South Sudan to 2·4 (1·6-3·6) in Iceland.INTERPRETATION: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.FUNDING: Bill & Melinda Gates Foundation.

Background In 2010, overweight and obesity were estimated to cause 3·4 million deaths, 3·9% of years of life lost, and 3·8% of disability-adjusted life-years (DALYs) worldwide. The rise in obesity has led to widespread calls for regular monitoring of changes in overweight and obesity prevalence in all populations. Comparable, up-to-date information about levels and trends is essential to quantify population health effects and to prompt decision makers to prioritise action. We estimate the global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013. Methods We systematically identified surveys, reports, and published studies (n=1769) that included data for height and weight, both through physical measurements and self-reports. We used mixed effects linear regression to correct for bias in self-reports. We obtained data for prevalence of obesity and overweight by age, sex, country, and year (n=19 244) with a spatiotemporal Gaussian process regression model to estimate prevalence with 95% uncertainty intervals (UIs). Findings Worldwide, the proportion of adults with a body-mass index (BMI) of 25 kg/m2 or greater increased between 1980 and 2013 from 28·8% (95% UI 28·4-29·3) to 36·9% (36·3-37·4) in men, and from 29·8% (29·3- 30·2) to 38·0% (37·5-38·5) in women. Prevalence has increased substantially in children and adolescents in developed countries; 23·8% (22·9-24·7) of boys and 22·6% (21·7-23·6) of girls were overweight or obese in 2013. The prevalence of overweight and obesity has also increased in children and adolescents in developing countries, from 8·1% (7·7-8·6) to 12·9% (12·3-13·5) in 2013 for boys and from 8·4% (8·1-8·8) to 13·4% (13·0-13·9) in girls. In adults, estimated prevalence of obesity exceeded 50% in men in Tonga and in women in Kuwait, Kiribati, Federated States of Micronesia, Libya, Qatar, Tonga, and Samoa. Since 2006, the increase in adult obesity in developed countries has slowed down. Interpretation Because of the established health risks and substantial increases in prevalence, obesity has become a major global health challenge. Not only is obesity increasing, but no national success stories have been reported in the past 33 years. Urgent global action and leadership is needed to help countries to more effectively intervene. Funding Bill and Melinda Gates Foundation. © 2014 Elsevier Ltd.

Diabetes, a risk factor for end-stage renal disease (ESRD), is associated with impaired protein metabolism. We investigated whether protein intake is associated with ESRD and whether the risk is higher among blacks with diabetes.We conducted a nested case-control study of ESRD within the Southern Community Cohort Study, a prospective study of low-income blacks and whites in the southeastern US (2002-2009). Through 2012, 1057 incident ESRD cases were identified by linkage with the United States Renal Data System and matched to 3198 controls by age, sex, and race. Dietary intakes were assessed from a validated food frequency questionnaire at baseline. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed from logistic regression models that included matching variables, BMI, education, income, hypertension, total energy intake, and percent energy from saturated and polyunsaturated fatty acids. Mean (±SD) daily energy intake from protein was higher among ESRD cases than controls (15.7 ± 3.3 vs. 15.1 ± 3.1%, P 0.0001). For a 1% increase in percent energy intake from protein, the adjusted ORs (95% CIs) for ESRD were 1.06 (1.02-1.10) for blacks with diabetes, 1.02 (0.98-1.06) for blacks without diabetes, 0.99 (0.90-1.09) for whites with diabetes and 0.94 (0.84-1.06) for whites without diabetes. Protein intake in g/kg/day was also associated with ESRD (4th vs. 1st quartile OR = 1.76; 95% CI: 1.17-2.65).Our results raise the possibility that among blacks with diabetes, increased dietary protein is associated with increased incidence of ESRD. Studies on how protein intake and metabolism affect ESRD are needed.

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

Despite the evidence in support of the anti-inflammatory and triglyceride-lowering effects of fenofibrate, little is known about genetic determinants of the observed heterogeneity in treatment response. This study provides the first genome-wide examination of fenofibrate effects on systemic inflammation.Biomarkers of inflammation were measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n=1092) before and after a 3-week daily treatment with 160 mg of fenofibrate. Two inflammatory patterns [high-sensitivity C-reactive protein-interleukin-6 and monocyte chemoattractant protein-1-tumor necrosis factor (MCP1-TNF-α)] were derived using principal component analysis. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and phenotypes were assessed using mixed linear models, adjusted for age, sex, study center, and ancestry as fixed effects and pedigree as a random effect.Before fenofibrate treatment, the strongest evidence for association was observed for polymorphisms near or within the IL2RA gene with the high-sensitivity C-reactive protein-interleukin-6 (IL6) pattern (rs7911500, P=5×10 and rs12722605, P=5×10). Associations of the MCP1-TNF-α pattern with loci in several biologically plausible genes [CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485)] approached genome-wide significance (P=3×10, 5×10, 6×10, and 7×10, respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-α pattern (P=3×10). The analyses of individual biomarker response to fenofibrate did not yield genome-wide significant results, but the rs6517147 locus near the immunologically relevant IFNAR2 gene was suggestively associated with IL6 (P=7×10).We have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment.

There is a paucity of research examining the relationships between dietary patterns and risk of developing precancerous lesions as well as biomarkers associated with such dietary patterns. The purpose of the current study was to identify dietary patterns that are associated with higher grades of cervical intraepithelial neoplasia (CIN 2+) and to determine whether these dietary patterns are associated with the degree of DNA methylation in the long interspersed nucleotide elements (L1s) of peripheral blood mononuclear cells (PBMCs), a biomarker associated with risk of developing CIN 2+. Study population consisted of 319 child-bearing age women. Dietary patterns were derived by factor analysis. The degree of PBMC L1 methylation was assessed by pyrosequencing. Logistic regression models were used to evaluate the associations between dietary patterns and CIN 2+. Similar models were used to evaluate the associations between dietary patterns and degree of PBMC L1 methylation in women free of CIN 2+. Women with the unhealthiest dietary pattern were 3.5 times more likely to be diagnosed with CIN 2+ than women with the healthiest dietary pattern [OR = 3.5; 95% confidence interval (CI), 1.2–10.1; P = 0.02]. Women at risk for developing CIN 2+ with the healthiest dietary pattern were 3.3 times more likely to have higher PBMC L1 methylation than women with the unhealthiest dietary pattern (OR = 3.3; 95% CI, 1.0–10.6; P = 0.04). Our findings suggest that human papilloma virus associated risk of developing CIN 2+ may be reduced by improving dietary patterns. The degree of PBMC L1 methylation may serve as a biomarker for monitoring the effectiveness of dietary modifications needed for reducing the risk of CIN 2+. Cancer Prev Res; 5(3); 385–92. ©2012 AACR.

The US Head Start program serves low-income preschoolers and their caregivers and provides an opportunity for assessment and intervention on obesity. We sought to determine the prevalence of obesity among children and their caregivers and to identify variables that are associated with child body mass index (BMI) z scores and caregiver BMI.Cross-sectional data on diet and BMI from 770 caregiver-child dyads recruited from 57 Head Start centers in Alabama and Texas.Height and weight of each caregiver and child were measured using standardized protocols. Dietary intakes of caregiver-child dyads were collected using three 24-hour dietary recalls and Block food frequency questionnaires. Data were collected between September 2004 and November 2005. The larger Food Pyramid categories were divided into 17 food consumption groups and tested for their association with child BMI z scores. Analysis of variance was used to test if food groups were significantly associated with child BMI z score.The prevalence of obesity among children was 18.4%, 24.3%, and 37.3% among black, Hispanic, and white children, respectively (P0.0001), whereas it was 58.3%, 41.4%, and 41.6% among black, Hispanic, and white caregivers, respectively (P0.0001). Child BMI z scores and caregiver BMIs were correlated (r=0.16, P0.0001). In multivariable models, children were 1.90 (95% confidence interval 1.31-2.74) times more likely to have BMI ≥95th percentile if their caregiver was obese. Five variables (fruits, unsweetened beverages, low-fat dairy, race, and caregiver's BMI) were significantly associated with child BMI z scores. Fruits were inversely related, whereas unsweetened beverages, low-fat dairy, and caregiver's BMI were positively associated with child BMI z score (P0.03). Compared to whites, black and Hispanic children had lower BMI z scores (P0.05).The high prevalence of obesity in this population together with the observed inverse association between fruit consumption and BMI, if replicated in other studies, suggests that interventions that promote fruit consumption could have beneficial effects on child BMI.

Alcohol intake has been shown to have a J-shaped association with blood pressure (BP). However, this association has not been examined in mixed race populations or in people with diabetes where tighter blood pressure control is recommended. Participants in the REGARDS study who were 45 years or older (n = 30,239) were included. Medical history (including self-reported alcohol intake) was collected by telephone while blood collection and clinical measurements were done during an in-home visit. We defined diabetes as use of medications and/or fasting glucose ≥ 126 mg/dL and hypertension as use of blood pressure lowering medications and/or BP ≥ 140/90 mmHg or BP ≥ 130/80 mmHg in people with diabetes. After adjustment for confounders, heavy drinking was associated with an increased odds of hypertension (OR = 1.59, 95% CI = 1.37, 1.87). Diabetes and gender significantly modified (interaction P < 0.05 for both) the association between alcohol use and hypertension, although heavy drinking remained associated with increased odds of hypertension in sub-group analyses. We did not observe the previously described J-shaped relationship in any sub-group except white females. These data suggest heavy alcohol consumption is associated with poor BP control and that heavy drinkers may want to consider limiting alcohol intake in order to manage hypertension.

Background The statistical power of cluster randomized trials depends on two sample size components, the number of clusters per group and the numbers of individuals within clusters (cluster size). Variable cluster sizes are common and this variation alone may have significant impact on study power. Previous approaches have taken this into account by either adjusting total sample size using a designated design effect or adjusting the number of clusters according to an assessment of the relative efficiency of unequal versus equal cluster sizes. Purpose This article defines a relative efficiency of unequal versus equal cluster sizes using noncentrality parameters, investigates properties of this measure, and proposes an approach for adjusting the required sample size accordingly. Methods We focus on comparing two groups with normally distributed outcomes using t-test, and use the noncentrality parameter to define the relative efficiency of unequal versus equal cluster sizes and show that statistical power depends only on this parameter for a given number of clusters. We calculate the sample size required for an unequal cluster sizes trial to have the same power as one with equal cluster sizes. Results Relative efficiency based on the noncentrality parameter is straightforward to calculate and easy to interpret. It connects the required mean cluster size directly to the required sample size with equal cluster sizes. Consequently, our approach first determines the sample size requirements with equal cluster sizes for a pre-specified study power and then calculates the required mean cluster size while keeping the number of clusters unchanged. Our approach allows adjustment in mean cluster size alone or simultaneous adjustment in mean cluster size and number of clusters, and is a flexible alternative to and a useful complement to existing methods. Comparison indicated that we have defined a relative efficiency that is greater than the relative efficiency in the literature under some conditions. Limitations Our measure of relative efficiency might be less than the measure in the literature under some conditions, underestimating the relative efficiency. Conclusions The relative efficiency of unequal versus equal cluster sizes defined using the noncentrality parameter suggests a sample size approach that is a flexible alternative and a useful complement to existing methods.

Several clinical studies report increased risk of diabetes mellitus (DM) with pharmacologic treatment for hypertension (HTN). HTN genes may modify glycemic response to antihypertensive treatment. The current study examined the association of 24 single nucleotide polymorphisms (SNPs) in 11 HTN candidate genes with fasting glucose measured at 2, 4, and 6 years after treatment initiation. The study sample included participants free of diabetes at baseline in the Genetics of Hypertension Associated Treatment (GenHAT) study (N=9,309). GenHAT participants were randomized to receive treatment with a diuretic (chlorthalidone), calcium channel blocker (amlodipine), or ACE inhibitor (lisinopril). Mixed models for repeated measures were employed to test for gene and pharmacogenetic associations with fasting glucose during follow-up. Fasting glucose at year 2 increased on average 6.8 mg/dL, 4.8 mg/dL and 3.0 mg/dL from baseline in the chlorthalidone, amlodipine and lisinopril groups, respectively. Carrying the I allele (rs1799752) of the angiotensin-converting enzyme (ACE) I/D polymorphism was associated with lower fasting glucose levels (P=0.02). Additionally, an ACE promoter polymorphism (−262, rs4291) was associated with lower fasting glucose for the model AA/AT vs. TT which remained significant after correction for multiple testing (P=0.001). Finally, a SNP in the α-subunit of the amiloride-sensitive epithelial sodium channel (SCNN1A, rs2228576) modified the association of amlodipine versus chlorthalidone treatment with fasting glucose (P

Importance The relative outcomes of onabotulinum toxin A injections for treatment of adductor spasmodic dysphonia (ADSD), ADSD with lateral laryngeal tremor (ADSD+LT), and lateral LT without ADSD are unclear. Objective To compare the outcomes of onabotulinum toxin A treatment on ADSD, ADSD+LT, and lateral LT without ADSD. Design, Setting, and Participants A retrospective cohort study was conducted from January 1, 1990, to September 30, 2016, at a tertiary referral voice center. Participants included 817 patients treated with onabotulinum toxin A injections for diagnosis of ADSD, ADSD+LT, and lateral LT without ADSD. Exposure Injection of onabotulinum toxin A into the thyroarytenoid/lateral cricoarytenoid muscle complex. Main Outcomes and Measures Data from patient diaries were used to evaluate patient-perceived effectiveness of onabotulinum toxin A injection. Primary outcomes were (1) patient-reported good voice days (voice breaks or tremor minimized to patient satisfaction) and (2) percentage of injections in which maximal voice quality was reached (significant or complete reduction in vocal tremor or spasms during a treatment cycle). Multivariate analysis of variance tests compared differences in outcomes between groups. Subanalysis was performed to compare outcomes in patients with isolated LT with those who had mixed tremor (lateral with concomitant anterior-posterior and/or vertical components). Results Of 817 patients treated with onabotulinum toxin A injections for laryngeal movement disorders, 548 patients (12 771 injection sessions) met inclusion criteria (ADSD: n = 328, ADSD+LT: n = 77, lateral LT without ADSD: n = 143). Of these, 408 (80.8%) were women; mean (SD) age was 57.2 (13.7) years. Among patients with tremor, those with isolated LT had better outcomes than those with mixed tremor. In adjusted analysis, good voice days in patients with ADSD, ADSD+LT, and lateral LT without ADSD were 81.1, 75.4, and 71.3 days, respectively (partial η2, 0.05; 95% CI, 0.01-0.09). The percentage of maximally beneficial injections was 88.1% for ADSD, 83.4% for ADSD+LT, and 70.4% for LT without ADSD (partial η2, 0.12; 95% CI, 0.06-0.17). Conclusions and Relevance Onabotulinum toxin A injections into the thyroarytenoid/lateral cricoarytenoid muscle complex are an effective treatment for ADSD, ADSD+LT, and LT without ADSD; however, the greatest effectiveness was observed among patients with ADSD. Defining tremor directionality may help to prognosticate the effectiveness of onabotulinum toxin A injection among patients presenting with tremor components.