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BACKGROUND - Smokers have lower risk of obesity, which some consider a "beneficial" side effect of smoking. However, some studies suggest that smoking is simultaneously associated with higher central adiposity and, more specifically, ectopic adipose deposition. Little is known about the association of smoking with intermuscular adipose tissue (IMAT), an ectopic adipose depot associated with cardiovascular disease (CVD) risk and a key determinant of muscle quality and function. We tested the hypothesis that smokers have higher abdominal IMAT and lower lean muscle quality than never smokers.
METHODS AND FINDINGS - We measured abdominal muscle total, lean, and adipose volumes (in cubic centimeters) and attenuation (in Hounsfield units [HU]) along with subcutaneous (SAT) and visceral adipose tissue (VAT) volumes using computed tomography (CT) in 3,020 middle-aged Coronary Artery Risk Development in Young Adults (CARDIA) participants (age 42-58, 56.3% women, 52.6% white race) at the year 25 (Y25) visit. The longitudinal CARDIA study was initiated in 1985 with the recruitment of young adult participants (aged 18-30 years) equally balanced by female and male sex and black and white race at 4 field centers located in Birmingham, AL, Chicago, IL, Minneapolis, MN, and Oakland, CA. Multivariable linear models included potential confounders such as physical activity and dietary habits along with traditional CVD risk factors. Current smokers had lower BMI than never smokers. Nevertheless, in the fully adjusted multivariable model with potential confounders, including BMI and CVD risk factors, adjusted mean (95% CI) IMAT volume was 2.66 (2.55-2.76) cm3 in current smokers (n = 524), 2.36 (2.29-2.43) cm3 in former smokers (n = 944), and 2.23 (2.18-2.29) cm3 in never smokers (n = 1,552) (p = 0.007 for comparison of former versus never smoker, and p < 0.001 for comparison of current smoker versus never and former smoker). Moreover, compared to participants who never smoked throughout life (41.6 [41.3-41.9] HU), current smokers (40.4 [39.9-40.9] HU) and former smokers (40.8 [40.5-41.2] HU) had lower lean muscle attenuation suggesting lower muscle quality in the fully adjusted model (p < 0.001 for comparison of never smokers with either of the other two strata). Among participants who had ever smoked, pack-years of smoking exposure were directly associated with IMAT volume (β [95% CI]: 0.017 [0.010-0.025]) (p < 0.001). Despite having less SAT, current smokers also had higher VAT/SAT ratio than never smokers. These findings must be viewed with caution as residual confounding and/or reverse causation may contribute to these associations.
CONCLUSIONS - We found that, compared to those who never smoked, current and former smokers had abdominal muscle composition that was higher in adipose tissue volume, a finding consistent with higher CVD risk and age-related physical deconditioning. These findings challenge the belief that smoking-associated weight loss or maintenance confers a health benefit.

BACKGROUND - The extent to which obesity and genetics determine postoperative complications is incompletely understood.
METHODS - We performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990 and 2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome-wide genotyping data to the Electronic Medical Records and Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease-9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score was constructed from 97 obesity-risk single-nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk of obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components.
RESULTS - Individuals with overweight or obese BMI (≥25 kg/m) had increased risk of incisional hernia (odds ratio [OR] 1.7-5.5, p < 3.1 × 10), and people with obesity (BMI ≥ 30 kg/m) had increased risk of postoperative infection (OR 1.2-2.3, p < 2.5 × 10). In the eMERGE cohort, genetically predicted BMI was associated with incisional hernia (OR 2.1 [95% CI 1.8-2.5], p = 1.4 × 10) and postoperative infection (OR 1.6 [95% CI 1.4-1.9], p = 3.1 × 10). Association findings were similar after limitation of the cohorts to those who underwent abdominal procedures.
CONCLUSIONS - Clinical and Mendelian randomization studies suggest that obesity, as measured by BMI, is associated with the development of postoperative incisional hernia and infection.

BACKGROUND - Cardiovascular disease is the leading cause of death in the United States. Consequently, individuals who are genetically predisposed for high risk of cardiovascular disease would benefit most from prevention and early intervention approaches. Among common health risk factors affecting adult populations, we evaluated 23 cardiovascular disease-related traits, including BMI, glucose levels and lipid profiling to determine their associations with low-frequency recurrent copy number variations (CNV) (population frequency < 5%).
RESULTS - We examined 10,619 unrelated subjects of European ancestry from the Electronic Medical Records and Genomics (eMERGE) Network who were genotyped with 657,366 markers genome-wide on the Illumina Infinium Quad 660 array. We performed CNV calling based on array marker intensity and evaluated data quality, ancestry stratification, and relatedness to ensure unbiased association discovery. Using a segment-based scoring approach, we assessed the association of all CNVs with each trait. In this large genome-wide analysis of low-frequency CNVs, we observed 11 novel genome-wide significant associations of low-frequency CNVs with major cardiovascular disease traits.
CONCLUSION - In one of the largest genome-wide studies for low-frequency recurrent CNVs, we identified 11 loci associated with cardiovascular disease and related traits at the genome-wide significance level that may serve as biomarkers for prevention and early intervention studies in subjects who are at elevated risk. Our study further supports the role of low-frequency recurrent CNVs in the pathogenesis of common complex disease traits.
Copyright © 2019. Published by Elsevier B.V.

Cannabis use is prevalent among HIV-positive persons, but evidence regarding the impact of cannabis in HIV-positive persons is limited. We conducted a retrospective cohort study of HIV-positive adults initiating their first antiretroviral therapy (ART) regimen. A dedicated intake form assessed self-reported cannabis use in the preceding 7 days at each visit. The relationships between time-varying cannabis use and body mass index (BMI), CD4+ T-cell count, and HIV-1 RNA levels were assessed using random effects models adjusted for age, sex, race, and other reported substance use. 4290 patient-visits from 2008 to 2011 were available from 1010 patients. Overall, there were no statistically significant differences in CD4+ T-cell count and BMI across multiple adjusted models using different measures of cannabis use (ever use during the study period, any use, and number of times used in the preceding 7 days). Cannabis use by all three measures was associated with greater odds of having a detectable viral load at a given visit than no reported use (OR 2.02, 1.72, and 1.08, respectively; all adjusted p < 0.05). Self-reported cannabis use was not associated with changes in BMI or CD4+ T-cell count in ART-naïve HIV-positive persons starting treatment. However, reported cannabis use by multiple categories was associated with having a detectable HIV-1 RNA during the study period. Associations between cannabis use, adherence, and HIV-related outcomes merit further study.

Interpretation of genetic association results is difficult because signals often lack biological context. To generate hypotheses of the functional genetic etiology of complex cardiometabolic traits, we estimated the genetically determined component of gene expression from common variants using PrediXcan (1) and determined genes with differential predicted expression by trait. PrediXcan imputes tissue-specific expression levels from genetic variation using variant-level effect on gene expression in transcriptome data. To explore the value of imputed genetically regulated gene expression (GReX) models across different ancestral populations, we evaluated imputed expression levels for predictive accuracy genome-wide in RNA sequence data in samples drawn from European-ancestry and African-ancestry populations and identified substantial predictive power using European-derived models in a non-European target population. We then tested the association of GReX on 15 cardiometabolic traits including blood lipid levels, body mass index, height, blood pressure, fasting glucose and insulin, RR interval, fibrinogen level, factor VII level and white blood cell and platelet counts in 15 755 individuals across three ancestry groups, resulting in 20 novel gene-phenotype associations reaching experiment-wide significance across ancestries. In addition, we identified 18 significant novel gene-phenotype associations in our ancestry-specific analyses. Top associations were assessed for additional support via query of S-PrediXcan (2) results derived from publicly available genome-wide association studies summary data. Collectively, these findings illustrate the utility of transcriptome-based imputation models for discovery of cardiometabolic effect genes in a diverse dataset.
© The Author(s) 2019. Published by Oxford University Press.

Kidney stone formers are at risk for opioid dependence. The aim of this study is to describe opiate exposure and determine predictors of prolonged opiate use among kidney stone formers after surgery. A retrospective review was performed among patients who underwent ureteroscopy for upper tract stone disease. Prescription data were ascertained from a statewide prescribing database. Demographic data and surgical factors were collected from the electronic medical record. Predictors of additional postsurgery prescriptions filled within 30 days and persistent opiate use 60 days after ureteroscopy were determined. Among 208 patients, 127 (61%) had received preoperative opiate prescriptions within 30 days before surgery. Overall, 12% ( = 25) of patients required an additional opiate prescription within 30 days after ureteroscopy, and 7% ( = 14) of patients continued to use opiate medications more than 60 days postoperatively. Patients continuing to use opiates long-term were not chronic opiate users. For both outcomes, preoperative opiate exposure, including number of prescriptions, days prescribed, and unique providers had significant associations (all  < 0.05). Additionally, younger age ( = 0.049) was associated with obtaining an additional opiate prescription within 30 days. Lower BMI ( = 0.02) and higher ASA score ( = 0.03) were predictors of continued opiate use more than 60 days after ureteroscopy. The majority of stone formers have had opiate exposure before surgery, often from multiple providers. Approximately 1 in 8 stone formers who undergo ureteroscopy require additional opiate prescriptions within 30 days. A small but significant population receive opiates beyond the immediate postoperative period.

Although type 2 diabetes (T2D) results from metabolic defects in insulin secretion and insulin sensitivity, most of the genetic risk loci identified to date relates to insulin secretion. We reported that T2D loci influencing insulin sensitivity may be identified through interactions with insulin secretion loci, thereby leading to T2D. Here, we hypothesize that joint testing of variant main effects and interaction effects with an insulin secretion locus increases power to identify genetic interactions leading to T2D. We tested this hypothesis with an intronic MTNR1B SNP, rs10830963, which is associated with acute insulin response to glucose, a dynamic measure of insulin secretion. rs10830963 was tested for interaction and joint (main + interaction) effects with genome-wide data in African Americans (2,452 cases and 3,772 controls) from five cohorts. Genome-wide genotype data (Affymetrix Human Genome 6.0 array) was imputed to a 1000 Genomes Project reference panel. T2D risk was modeled using logistic regression with rs10830963 dosage, age, sex, and principal component as predictors. Joint effects were captured using the Kraft two degrees of freedom test. Genome-wide significant (P < 5 × 10 ) interaction with MTNR1B and joint effects were detected for CMIP intronic SNP rs17197883 (P = 1.43 × 10 ; P = 4.70 × 10 ). CMIP variants have been nominally associated with T2D, fasting glucose, and adiponectin in individuals of East Asian ancestry, with high-density lipoprotein, and with waist-to-hip ratio adjusted for body mass index in Europeans. These data support the hypothesis that additional genetic factors contributing to T2D risk, including insulin sensitivity loci, can be identified through interactions with insulin secretion loci.
© 2018 WILEY PERIODICALS, INC.

BACKGROUND & AIMS - Insulin resistance is a risk marker for non-alcoholic fatty liver disease, and a risk factor for liver disease progression. We assessed temporal trajectories of insulin resistance and β-cell response to serum glucose concentration throughout adulthood and their association with diabetes risk in non-alcoholic fatty liver disease.
METHODS - Three thousand and sixty participants from Coronary Artery Risk Development in Young Adults, a prospective bi-racial cohort of adults age 18-30 years at baseline (1985-1986; Y0) who completed up to 5 exams over 25 years and had fasting insulin and glucose measurement were included. At Y25 (2010-2011), non-alcoholic fatty liver disease was assessed by noncontrast computed tomography after exclusion of other liver fat causes. Latent mixture modelling identified 25-year trajectories in homeostatic model assessment insulin resistance and β-cell response homeostatic model assessment-β.
RESULTS - Three distinct trajectories were identified, separately, for homeostatic model assessment insulin resistance (low-stable [47%]; moderate-increasing [42%]; and high-increasing [12%]) and homeostatic model assessment-β (low-decreasing [16%]; moderate-decreasing [63%]; and high-decreasing [21%]). Y25 non-alcoholic fatty liver disease prevalence was 24.5%. Among non-alcoholic fatty liver disease, high-increasing homeostatic model assessment insulin resistance (referent: low-stable) was associated with greater prevalent (OR 95% CI = 8.0, 2.0-31.9) and incident (OR = 10.5, 2.6-32.8) diabetes after multivariable adjustment including Y0 or Y25 homeostatic model assessment insulin resistance. In contrast, non-alcoholic fatty liver disease participants with low-decreasing homeostatic model assessment-β (referent: high-decreasing) had the highest odds of prevalent (OR = 14.1, 3.9-50.9) and incident (OR = 10.3, 2.7-39.3) diabetes.
CONCLUSION - Trajectories of insulin resistance and β-cell response during young and middle adulthood are robustly associated with diabetes risk in non-alcoholic fatty liver disease. Thus, how persons with non-alcoholic fatty liver disease develop resistance to insulin provides important information about risk of diabetes in midlife above and beyond degree of insulin resistance at the time of non-alcoholic fatty liver disease assessment.
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Background - The obesity-lung cancer association remains controversial. Concerns over confounding by smoking and reverse causation persist. The influence of obesity type and effect modifications by race/ethnicity and tumor histology are largely unexplored.
Methods - We examined associations of body mass index (BMI), waist circumference (WC), and waist-hip ratio (WHR) with lung cancer risk among 1.6 million Americans, Europeans, and Asians. Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for potential confounders. Analyses for WC/WHR were further adjusted for BMI. The joint effect of BMI and WC/WHR was also evaluated.
Results - During an average 12-year follow-up, 23 732 incident lung cancer cases were identified. While BMI was generally associated with a decreased risk, WC and WHR were associated with increased risk after controlling for BMI. These associations were seen 10 years before diagnosis in smokers and never smokers, were strongest among blacks, and varied by histological type. After excluding the first five years of follow-up, hazard ratios per 5 kg/m2 increase in BMI were 0.95 (95% CI = 0.90 to 1.00), 0.92 (95% CI = 0.89 to 0.95), and 0.89 (95% CI = 0.86 to 0.91) in never, former, and current smokers, and 0.86 (95% CI = 0.84 to 0.89), 0.94 (95% CI = 0.90 to 0.99), and 1.09 (95% CI = 1.03 to 1.15) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Hazard ratios per 10 cm increase in WC were 1.09 (95% CI = 1.00 to 1.18), 1.12 (95% CI = 1.07 to 1.17), and 1.11 (95% CI = 1.07 to 1.16) in never, former, and current smokers, and 1.06 (95% CI = 1.01 to 1.12), 1.20 (95% CI = 1.12 to 1.29), and 1.13 (95% CI = 1.04 to 1.23) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Participants with BMIs of less than 25 kg/m2 but high WC had a 40% higher risk (HR = 1.40, 95% CI = 1.26 to 1.56) than those with BMIs of 25 kg/m2 or greater but normal/moderate WC.
Conclusions - The inverse BMI-lung cancer association is not entirely due to smoking and reverse causation. Central obesity, particularly concurrent with low BMI, may help identify high-risk populations for lung cancer.

Objective To determine the factors associated with intra- and postoperative cerebrospinal fluid (CSF) leaks in setting of endoscopic transsphenoidal sellar surgery. Study Design Retrospective cohort. Setting Tertiary referral center. Subjects and Methods This study included 806 patients who underwent endoscopic transsphenoidal sellar surgery between 2004 and 2016. The associations between CSF leaks (intra- and postoperative) and patient demographics, medical history, tumor characteristics, and intraoperative repair techniques were analyzed. Results In sum, 205 (25.4%) patients had a CSF leak: 188 (23.3%) intraoperative leaks and 38 (4.7%) postoperative leaks. Twenty-one (2.6%) patients had postoperative leaks after having repair of an intraoperative leak; 55% of patients with a postoperative leak had an intraoperative leak repaired. On multivariate analysis, body mass index (BMI), hydrocephalus, suprasellar extension, and craniopharyngioma significantly predicted intraoperative CSF leaks, while only BMI and hydrocephalus predicted postoperative CSF leaks. Patients having septal flap repairs of CSF leaks had a higher postoperative leak rate relative to other repair techniques (odds ratio, 6.37; P = .013). Rigid reconstruction did not correlate with leaks. Conclusion For this large cohort of patients undergoing endoscopic transsphenoidal sellar surgery, BMI and hydrocephalus were identified as predictors of postoperative CSF leaks, including those occurring after repair of intraoperative leak. These variables may put stress on the surgical repair of sellar defects, and consideration of these risk factors may help counsel patients and guide perioperative decision making in regard to repair strategies and CSF diversion techniques.