Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Population Health
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12218
Peripheral blood signature of vasodilator-responsive pulmonary arterial hypertension
BACKGROUND:Heterogeneity in response to treatment of pulmonary arterial hypertension (PAH) is a major challenge to improving outcome in this disease. Although vasodilator-responsive PAH (VR-PAH) accounts for a minority of cases, VR-PAH has a pronounced response to calcium channel blockers and better survival than vasodilator-nonresponsive PAH (VN-PAH). We hypothesized that VR-PAH has a different molecular cause from VN-PAH that can be detected in the peripheral blood. METHODS AND RESULTS/RESULTS:Microarrays of cultured lymphocytes from VR-PAH and VN-PAH patients followed at Vanderbilt University were performed with quantitative polymerase chain reaction performed on peripheral blood for the 25 most different genes. We developed a decision tree to identify VR-PAH patients on the basis of the results with validation in a second VR-PAH cohort from the University of Chicago. We found broad differences in gene expression patterns on microarray analysis including cell-cell adhesion factors and cytoskeletal and rho-GTPase genes. Thirteen of 25 genes tested in whole blood were significantly different: EPDR1, DSG2, SCD5, P2RY5, MGAT5, RHOQ, UCHL1, ZNF652, RALGPS2, TPD52, MKNL1, RAPGEF2, and PIAS1. Seven decision trees were built with the use of expression levels of 2 genes as the primary genes: DSG2, a desmosomal cadherin involved in Wnt/β-catenin signaling, and RHOQ, which encodes a cytoskeletal protein involved in insulin-mediated signaling. These trees correctly identified 5 of 5 VR-PAH patients in the validation cohort. CONCLUSIONS:VR-PAH and VN-PAH can be differentiated with the use of RNA expression patterns in peripheral blood. These differences may reflect different molecular causes of the 2 PAH phenotypes. This biomarker methodology may identify PAH patients who have a favorable treatment response.
PMCID:4308423
PMID: 25361553
ISSN: 1524-4539
CID: 5161732
HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials
BACKGROUND:Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target. METHODS:We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis. FINDINGS/RESULTS:Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials). INTERPRETATION/CONCLUSIONS:The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition. FUNDING/BACKGROUND:The funding sources are cited at the end of the paper.
PMID: 25262344
ISSN: 1474-547x
CID: 5478212
Beat-to-beat spatiotemporal variability in the T vector is associated with sudden cardiac death in participants without left ventricular hypertrophy: the Atherosclerosis Risk in Communities (ARIC) Study
BACKGROUND:Despite advances in prevention and treatment of cardiovascular disease, sudden cardiac death (SCD) remains a clinical challenge. Risk stratification in the general population is needed. METHODS AND RESULTS/RESULTS:Beat-to-beat spatiotemporal variability in the T vector was measured as the mean angle between consecutive T-wave vectors (mean TT' angle) on standard 12-lead ECGs in 14 024 participants in the Atherosclerosis Risk in Communities (ARIC) study. Subjects with left ventricular hypertrophy, atrial arrhythmias, frequent ectopy, ventricular pacing, or QRS duration ≥120 ms were excluded. The mean spatial TT' angle was 5.21±3.55°. During a median of 14 years of follow-up, 235 SCDs occurred (1.24 per 1000 person-years). After adjustment for demographics, coronary heart disease risk factors, and known ECG markers for SCD, mean TT' angle was independently associated with SCD (hazard ratio 1.089; 95% CI 1.044 to 1.137; P<0.0001). A mean TT' angle >90th percentile (>9.57°) was associated with a 2-fold increase in the hazard for SCD (hazard ratio 2.01; 95% CI 1.28 to 3.16; P=0.002). In a subgroup of patients with T-vector amplitude ≥0.2 mV, the association with SCD was almost twice as strong (hazard ratio 3.92; 95% CI 1.91 to 8.05; P<0.0001). A significant interaction between mean TT' angle and age was found: TT' angle was associated with SCD in participants aged <55 years (hazard ratio 1.096; 95% CI 0.043 to 1.152; P<0.0001) but not in participants aged ≥55 years (P(interaction)=0.009). CONCLUSIONS:In a large, prospective, community-based cohort of left ventricular hypertrophy-free participants, increased beat-to-beat spatiotemporal variability in the T vector, as assessed by increasing TT' angle, was associated with SCD.
PMCID:4330061
PMID: 25600143
ISSN: 2047-9980
CID: 5583642
Translation of EPDS Questionnaire into Kiswahili: Understanding the Cross-Cultural and Translation Issues in Mental Health Research
The need for a suitable tool for assessing postpartum depression in Kenya led to the process of translation of the 10 items Edinburgh Postnatal Scale into Kiswahili. The idea was to seek semantic, conceptual as well as normative equivalence in this translation. The paper discusses issues and the process of translation and provides in depth discussions around translation from the point of view of cross-cultural mental health research and practice. The English version of the EPDS screening tool was finally successfully translated into Kiswahili and the translated version is attached with this paper.
PMCID:4399496
PMID: 25893218
ISSN: 2376-127x
CID: 5831702
Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013
BACKGROUND: Up-to-date evidence on levels and trends for age-sex-specific all-cause and cause-specific mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries. METHODS: We estimated age-sex-specific all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer's disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specific causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum to all-cause mortality based on draws from the uncertainty distributions. FINDINGS: Global life expectancy for both sexes increased from 65.3 years (UI 65.0-65.6) in 1990, to 71.5 years (UI 71.0-71.9) in 2013, while the number of deaths increased from 47.5 million (UI 46.8-48.2) to 54.9 million (UI 53.6-56.3) over the same interval. Global progress masked variation by age and sex: for children, average absolute differences between countries decreased but relative differences increased. For women aged 25-39 years and older than 75 years and for men aged 20-49 years and 65 years and older, both absolute and relative differences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions. HIV/AIDS reduced life expectancy in southern sub-Saharan Africa. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10.7%, from 4.3 million deaths in 1990 to 4.8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than 100,000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias. Diarrhoeal diseases, lower respiratory infections, neonatal causes, and malaria are still in the top five causes of death in children younger than 5 years. The most important pathogens are rotavirus for diarrhoea and pneumococcus for lower respiratory infections. Country-specific probabilities of death over three phases of life were substantially varied between and within regions. INTERPRETATION: For most countries, the general pattern of reductions in age-sex specific mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. Assessing epidemiological convergence across countries depends on whether an absolute or relative measure of inequality is used. Nevertheless, age-standardised death rates for seven substantial causes are increasing, suggesting the potential for reversals in some countries. Important gaps exist in the empirical data for cause of death estimates for some countries; for example, no national data for India are available for the past decade. FUNDING: Bill & Melinda Gates Foundation.
PMCID:4340604
PMID: 25530442
ISSN: 1474-547x
CID: 1514472
Updated Survey of Social Media Use by Members of the American Urological Association
Introduction: We performed a more detailed, updated analysis of social media use by AUA members. Specifically we sought to characterize the frequency of and reason for using different social media platforms as well as barriers to social media use. Methods: From November to December 2013 we sent a 21-item survey on social media use to 16,376 AUA members with a valid email address. A total of 1,114 members (6.8%) completed the survey. Responses were tallied and statistical analysis was performed to evaluate use patterns based on demographic characteristics. Results: Overall 71% of AUA members who responded to the survey currently had a social media account. The most popular social media platform was Facebook (89% of respondents), followed by LinkedIn (59%), YouTubeTM (54%), Twitter (48%) and Google+TM (35%). All platforms except LinkedIn were used primarily for personal reasons. Fewer than a third of respondents had viewed an AUA social media site and 35% of physician respondents participated in a physician-only social media community. Among respondents who did not use social media the most common reasons were no perception of added value and privacy concerns. Conclusions: Although most AUA respondents are involved in social media, they primarily use social media for personal reasons. There remains significant potential for growth and education on the usefulness of social media for urologists in the professional setting
EMBASE:2015886393
ISSN: 2352-0779
CID: 1702712
School readiness and self-regulation: a developmental psychobiological approach
Research on the development of self-regulation in young children provides a unifying framework for the study of school readiness. Self-regulation abilities allow for engagement in learning activities and provide the foundation for adjustment to school. A focus on readiness as self-regulation does not supplant interest in the development of acquired ability, such as early knowledge of letters and numbers; it sets the stage for it. In this article, we review research and theory indicating that self-regulation and consequently school readiness are the product of integrated developmental processes at the biological and behavioral levels that are shaped by the contexts in which development is occurring. In doing so, we illustrate the idea that research on self-regulation powerfully highlights ways in which gaps in school readiness and later achievement are linked to poverty and social and economic inequality and points the way to effective approaches to counteract these conditions.
PMCID:4682347
PMID: 25148852
ISSN: 1545-2085
CID: 1828912
Child care instability from 6 to 36 months and the social adjustment of children in prekindergarten
Most children in the United States experience nonparental child care during early childhood, and many children experience changes in their care during this period. Changes in care, or child care instability, have been argued to disrupt children's emerging relationships with others and may impede children's social-emotional development, particularly when changes occur during infancy and toddlerhood. Data for this study were drawn from the Family Life Project, a longitudinal study representative of families living in rural low-wealth areas. With a sample of 1292 children who were followed from six months to prekindergarten, this study examined the associations between cumulative child provider instability (measured as overall changes or changes across or within settings) from 6 to 36 months and children's social adjustment at prekindergarten. A number of factors were included to control for family selection into child care. Results suggested that more overall child care provider instability was negatively associated with teacher ratings of social adjustment at prekindergarten. This association was driven by provider instability across but not within settings, though effect sizes were small. These findings point to an increased need to understand how early child care instability may be related to children's subsequent development.
SCOPUS:84939971420
ISSN: 0885-2006
CID: 2806502
2014 articles of the year, reviewers of the year, and figure of the year
SCOPUS:84941635214
ISSN: 0002-9262
CID: 3206202
Validation of the substance use brief screen in primary care [Meeting Abstract]
Aims: Implementation of substance use screening in general medical settings is hindered by the lack of a brief yet precise and comprehensive screening tool that is compatible with clinical workflows. To address this need, we developed the Substance Use Brief Screen (SUBS); a 4-item screener for tobacco, alcohol, and drug use (illicit and prescription) that is self-administered and may be easily integrated with electronic health records. Methods: Adult patients were recruited consecutively in the waiting area of an urban safety net primary care clinic. The SUBS was self-administered in English on touchscreen tablet computers. Reference standard measures of unhealthy substance use and substance use disorders were then administered, including self reported measures and saliva drug tests. The SUBS was compared against the reference standards to determine its sensitivity, specificity, and area under the curve (AUC) for each substance class. Results: Among the 390 participants, rates of past year use reported on the SUBS were 37% tobacco, 43% alcohol (4+ drinks/day), 20% illicit drugs, and 12% prescription drugs. Sensitivity and specificity of the SUBS for detecting past year unhealthy use were: tobacco 99% and 91% (AUC = .95); alcohol 94% and 68% (AUC = .81); drugs (illicit or prescription) 84% and 89% (AUC = .86). Sensitivity was lower for prescription drugs (57%) than for illicit drugs (78%). For detecting a substance use disorder, sensitivity and specificity were: tobacco 100% and 73% (AUC = .87); alcohol 93% and 64% (AUC = .79); drugs 85% and 82% (AUC = .84). Conclusions: The SUBS accurately identified unhealthy tobacco, alcohol, and drug use in this primary care sample, and had high sensitivity but lower specificity for identifying substance use disorders. Individuals screening positive on the SUBS should receive further assessment. Our findings support use of the SUBS for substance use screening in primary care, but additional tools may be needed for prescription drugs
EMBASE:71802006
ISSN: 0376-8716
CID: 1514442
