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Functionally oriented analysis of cardiometabolic traits in a trans-ethnic sample.
Petty LE, Highland HM, Gamazon ER, Hu H, Karhade M, Chen HH, de Vries PS, Grove ML, Aguilar D, Bell GI, Huff CD, Hanis CL, Doddapaneni H, Munzy DM, Gibbs RA, Ma J, Parra EJ, Cruz M, Valladares-Salgado A, Arking DE, Barbeira A, Im HK, Morrison AC, Boerwinkle E, Below JE
(2019) Hum Mol Genet 28: 1212-1224
MeSH Terms: Adult, Aged, Blood Pressure, Body Mass Index, Chromosome Mapping, Ethnic Groups, European Continental Ancestry Group, Female, Forecasting, Genetic Association Studies, Genome-Wide Association Study, Humans, Male, Metabolome, Middle Aged, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Transcriptome
Show Abstract · Added February 15, 2019
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.
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19 MeSH Terms
Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.
Giri A, Hellwege JN, Keaton JM, Park J, Qiu C, Warren HR, Torstenson ES, Kovesdy CP, Sun YV, Wilson OD, Robinson-Cohen C, Roumie CL, Chung CP, Birdwell KA, Damrauer SM, DuVall SL, Klarin D, Cho K, Wang Y, Evangelou E, Cabrera CP, Wain LV, Shrestha R, Mautz BS, Akwo EA, Sargurupremraj M, Debette S, Boehnke M, Scott LJ, Luan J, Zhao JH, Willems SM, Thériault S, Shah N, Oldmeadow C, Almgren P, Li-Gao R, Verweij N, Boutin TS, Mangino M, Ntalla I, Feofanova E, Surendran P, Cook JP, Karthikeyan S, Lahrouchi N, Liu C, Sepúlveda N, Richardson TG, Kraja A, Amouyel P, Farrall M, Poulter NR, Understanding Society Scientific Group, International Consortium for Blood Pressure, Blood Pressure-International Consortium of Exome Chip Studies, Laakso M, Zeggini E, Sever P, Scott RA, Langenberg C, Wareham NJ, Conen D, Palmer CNA, Attia J, Chasman DI, Ridker PM, Melander O, Mook-Kanamori DO, Harst PV, Cucca F, Schlessinger D, Hayward C, Spector TD, Jarvelin MR, Hennig BJ, Timpson NJ, Wei WQ, Smith JC, Xu Y, Matheny ME, Siew EE, Lindgren C, Herzig KH, Dedoussis G, Denny JC, Psaty BM, Howson JMM, Munroe PB, Newton-Cheh C, Caulfield MJ, Elliott P, Gaziano JM, Concato J, Wilson PWF, Tsao PS, Velez Edwards DR, Susztak K, Million Veteran Program, O'Donnell CJ, Hung AM, Edwards TL
(2019) Nat Genet 51: 51-62
MeSH Terms: Adolescent, Animals, Blood Pressure, Ethnic Groups, Female, Gene Expression, Genome-Wide Association Study, Humans, Kidney Tubules, Male, Mice, Middle Aged, Polymorphism, Single Nucleotide, Transcriptome, Up-Regulation
Show Abstract · Added January 3, 2019
In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
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15 MeSH Terms
The association between endogenous opioid function and morphine responsiveness: a moderating role for endocannabinoids.
Bruehl S, Burns JW, Morgan A, Koltyn K, Gupta R, Buvanendran A, Edwards D, Chont M, Kingsley PJ, Marnett L, Stone A, Patel S
(2019) Pain 160: 676-687
MeSH Terms: Adult, Analgesics, Opioid, Chronic Pain, Double-Blind Method, Endocannabinoids, Exercise, Female, Humans, Low Back Pain, Male, Middle Aged, Morphine, Naloxone, Opioid Peptides, Pain Measurement, Regression Analysis, Surveys and Questionnaires, Treatment Outcome
Show Abstract · Added April 12, 2019
We sought to replicate previous findings that low endogenous opioid (EO) function predicts greater morphine analgesia and extended these findings by examining whether circulating endocannabinoids and related lipids moderate EO-related predictive effects. Individuals with chronic low-back pain (n = 46) provided blood samples for endocannabinoid analyses, then underwent separate identical laboratory sessions under 3 drug conditions: saline placebo, intravenous (i.v.) naloxone (opioid antagonist; 12-mg total), and i.v. morphine (0.09-mg/kg total). During each session, participants rated low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects 4 times in sequence after incremental drug dosing. Mean morphine effects (morphine-placebo difference) and opioid blockade effects (naloxone-placebo difference; to index EO function) for each primary outcome (low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects) were derived by averaging across the 4 incremental doses. The association between EO function and morphine-induced back pain relief was significantly moderated by endocannabinoids [2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)]. Lower EO function predicted greater morphine analgesia only for those with relatively lower endocannabinoids. Endocannabinoids also significantly moderated EO effects on morphine-related changes in visual analog scale-evoked pain intensity (2-AG), drug liking (AEA and 2-AG), and desire to take again (AEA and 2-AG). In the absence of significant interactions, lower EO function predicted significantly greater morphine analgesia (as in past work) and euphoria. Results indicate that EO effects on analgesic and subjective responses to opioid medications are greatest when endocannabinoid levels are low. These findings may help guide development of mechanism-based predictors for personalized pain medicine algorithms.
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18 MeSH Terms
Antimicrobial exposure and the risk of delirium in critically ill patients.
Grahl JJ, Stollings JL, Rakhit S, Person AK, Wang L, Thompson JL, Pandharipande PP, Ely EW, Patel MB
(2018) Crit Care 22: 337
MeSH Terms: Adult, Aged, Anti-Infective Agents, Cohort Studies, Critical Illness, Cross-Sectional Studies, Delirium, Female, Humans, Intensive Care Units, Length of Stay, Male, Middle Aged, Multivariate Analysis, Retrospective Studies
Show Abstract · Added December 16, 2018
BACKGROUND - Prior retrospective cross-sectional work has associated antimicrobials with a non-specific phrase: encephalopathy without seizures. The purpose of this study is to determine whether different classes of antimicrobials have differential associations with the daily risk of delirium after critical illness is adjusted for.
METHODS - Our study was a nested cohort that enrolled non-neurological critically ill adults from a medical or surgical intensive care unit (ICU) with daily follow-up to 30 days. Our independent variable was exposure to previous-day antimicrobial class: beta-lactams (subclasses: penicillins, first- to third-generation cephalosporins, fourth-generation cephalosporins, and carbapenems), macrolides, fluoroquinolones, and other. We adjusted for baseline covariates (age, comorbidities, cognition scores, sepsis, and mechanical ventilation), previous-day covariates (delirium, doses of analgesics/sedatives, and antipsychotic use), and same-day covariates (illness severity). Our primary outcome of delirium was measured by using the Confusion Assessment Method for the ICU. A daily delirium logistic regression model was used with an ICU time-restricted sensitivity analysis including daily adjustment for sepsis and mechanical ventilation.
RESULTS - Of 418 ICU patients, delirium occurred in 308 (74%) with a median of 3 days (interquartile range 2-6) among those affected and 318 (76%) were exposed to antimicrobials. When covariates and ICU type were adjusted for, only first- to third-generation cephalosporins were associated with delirium (logistic regression model odds ratio (OR) = 2.2, 95% confidence interval (CI) 1.28-3.79, P = 0.004; sensitivity analysis OR = 2.13, 95% CI 1.10-4.10, P = 0.024).
CONCLUSIONS - First-, second-, and third-generation cephalosporins doubled the odds of delirium after baseline co-morbidities, ICU type, the course of critical care, and other competing antimicrobial and psychotropic medication risks were adjusted for. We did not find an association between delirium and cefepime, penicillins, carbapenems, fluoroquinolones, or macrolides.
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15 MeSH Terms
Ventral striatal dopamine transporter availability is associated with lower trait motor impulsivity in healthy adults.
Smith CT, San Juan MD, Dang LC, Katz DT, Perkins SF, Burgess LL, Cowan RL, Manning HC, Nickels ML, Claassen DO, Samanez-Larkin GR, Zald DH
(2018) Transl Psychiatry 8: 269
MeSH Terms: Adult, Aged, Dopamine Plasma Membrane Transport Proteins, Exploratory Behavior, Female, Fluorodeoxyglucose F18, Humans, Impulsive Behavior, Male, Middle Aged, Personality, Personality Inventory, Positron-Emission Tomography, Ventral Striatum, Young Adult
Show Abstract · Added April 15, 2019
Impulsivity is a transdiagnostic feature of a range of externalizing psychiatric disorders. Preclinical work links reduced ventral striatal dopamine transporter (DAT) availability with heightened impulsivity and novelty seeking. However, there is a lack of human data investigating the relationship between DAT availability, particularly in subregions of the striatum, and the personality traits of impulsivity and novelty seeking. Here we collected PET measures of DAT availability (BP) using the tracer F-FE-PE2I in 47 healthy adult subjects and examined relations between BP in striatum, including its subregions: caudate, putamen, and ventral striatum (VS), and trait impulsivity (Barratt Impulsiveness Scale: BIS-11) and novelty seeking (Tridimensional Personality Questionnaire: TPQ-NS), controlling for age and sex. DAT BP in each striatal subregion showed nominal negative associations with total BIS-11 but not TPQ-NS. At the subscale level, VS DAT BP was significantly associated with BIS-11 motor impulsivity (e.g., taking actions without thinking) after correction for multiple comparisons. VS DAT BP explained 13.2% of the variance in motor impulsivity. Our data demonstrate that DAT availability in VS is negatively related to impulsivity and suggest a particular influence of DAT regulation of dopamine signaling in VS on acting without deliberation (BIS motor impulsivity). While needing replication, these data converge with models of ventral striatal functions that emphasize its role as a key interface linking motivation to action.
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Radiation From Kidney-Ureter-Bladder Radiographs Is Not Trivial.
Kuebker J, Shuman J, Hsi RS, Herrell SD, Miller NL
(2019) Urology 125: 46-49
MeSH Terms: Female, Humans, Kidney, Male, Middle Aged, Radiation Dosage, Radiation Exposure, Retrospective Studies, Tomography, X-Ray Computed, Ureter, Urinary Bladder, Urolithiasis
Show Abstract · Added February 26, 2019
OBJECTIVE - To estimate effective dose of kidney-ureter-bladder (KUB) radiographs in a contemporary population of patients with urolithiasis.
METHODS - A retrospective review was performed to identify patients visiting a urology clinic for urolithiasis where a KUB was obtained and whom had a recent computed tomography (CT). Effective dose for KUBs was estimated using a Monte Carlo based simulation program and for CT utilizing the reported dose-length-product. Age, gender, body mass index, and abdominal diameter were analyzed for association with effective dose. KUBs performed at outside facilities in referred patient were compared to those obtained locally when available.
RESULTS - Fifty-four patients were identified meeting criteria. The majority (92.6%) of KUBs contained multiple radiographs. Mean effective dose was 2.15 mSv ± 1.67 mSv. Only 26% of examinations effective dose was under 1 mSv. Body mass index, abdominal thickness, and image count were all associated with an increase in dose (P < .01 each). Similar to local KUBs, 88% of outside examinations contained multiple images.
CONCLUSION - KUB examinations in this contemporary setting are associated with a 2-fold higher effective dose then is often referenced. Increased effective dose is associated with increased patient size and number of images acquired. Nearly 1 in 5 patient's KUB effective dose was similar to a low-dose CT. KUBs role should be re-examined given its limited sensitivity, specificity, associated radiation, and other available imaging options.
Copyright © 2018. Published by Elsevier Inc.
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Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study.
Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, Gobert A, Spano JP, Balko JM, Bonaca MP, Roden DM, Johnson DB, Moslehi JJ
(2018) Lancet Oncol 19: 1579-1589
MeSH Terms: Adult, Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, Bayes Theorem, Cardiotoxicity, Cardiovascular Diseases, Databases, Factual, Female, Humans, Immunotherapy, Male, Middle Aged, Pharmacovigilance, Retrospective Studies, Risk Assessment, Risk Factors, Time Factors
Show Abstract · Added December 13, 2018
BACKGROUND - Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations of different immunotherapies. However, ICIs can also cause severe or fatal immune-related adverse-events (irAEs). We aimed to identify and characterise cardiovascular irAEs that are significantly associated with ICIs.
METHODS - In this observational, retrospective, pharmacovigilance study, we used VigiBase, WHO's global database of individual case safety reports, to compare cardiovascular adverse event reporting in patients who received ICIs (ICI subgroup) with this reporting in the full database. This study included all cardiovascular irAEs classified by group queries according to the Medical Dictionary for Regulatory Activities, between inception on Nov 14, 1967, and Jan 2, 2018. We evaluated the association between ICIs and cardiovascular adverse events using the reporting odds ratio (ROR) and the information component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse events. IC is the lower end of the IC 95% credibility interval, and an IC value of more than zero is deemed significant. This study is registered with ClinicalTrials.gov, number NCT03387540.
FINDINGS - We identified 31 321 adverse events reported in patients who received ICIs and 16 343 451 adverse events reported in patients treated with any drugs (full database) in VigiBase. Compared with the full database, ICI treatment was associated with higher reporting of myocarditis (5515 reports for the full database vs 122 for ICIs, ROR 11·21 [95% CI 9·36-13·43]; IC 3·20), pericardial diseases (12 800 vs 95, 3·80 [3·08-4·62]; IC 1·63), and vasculitis (33 289 vs 82, 1·56 [1·25-1·94]; IC 0·03), including temporal arteritis (696 vs 18, 12·99 [8·12-20·77]; IC 2·59) and polymyalgia rheumatica (1709 vs 16, 5·13 [3·13-8·40]; IC 1·33). Pericardial diseases were reported more often in patients with lung cancer (49 [56%] of 87 patients), whereas myocarditis (42 [41%] of 103 patients) and vasculitis (42 [60%] of 70 patients) were more commonly reported in patients with melanoma (χ test for overall subgroup comparison, p<0·0001). Vision was impaired in five (28%) of 18 patients with temporal arteritis. Cardiovascular irAEs were severe in the majority of cases (>80%), with death occurring in 61 (50%) of 122 myocarditis cases, 20 (21%) of 95 pericardial disease cases, and five (6%) of 82 vasculitis cases (χ test for overall comparison between pericardial diseases, myocarditis, and vasculitis, p<0·0001).
INTERPRETATION - Treatment with ICIs can lead to severe and disabling inflammatory cardiovascular irAEs soon after commencement of therapy. In addition to life-threatening myocarditis, these toxicities include pericardial diseases and temporal arteritis with a risk of blindness. These events should be considered in patient care and in combination clinical trial designs (ie, combinations of different immunotherapies as well as immunotherapies and chemotherapy).
FUNDING - The Cancer Institut Thématique Multi-Organisme of the French National Alliance for Life and Health Sciences (AVIESAN) Plan Cancer 2014-2019; US National Cancer Institute, National Institutes of Health; the James C. Bradford Jr. Melanoma Fund; and the Melanoma Research Foundation.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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19 MeSH Terms
Green tea intake and risk of incident kidney stones: Prospective cohort studies in middle-aged and elderly Chinese individuals.
Shu X, Cai H, Xiang YB, Li H, Lipworth L, Miller NL, Zheng W, Shu XO, Hsi RS
(2019) Int J Urol 26: 241-246
MeSH Terms: Adult, Aged, China, Feeding Behavior, Female, Follow-Up Studies, Humans, Kidney Calculi, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Risk Factors, Self Report, Sex Factors, Tea
Show Abstract · Added February 26, 2019
OBJECTIVES - To investigate the association between green tea intake and incident stones in two large prospective cohorts.
METHODS - We examined self-reported incident kidney stone risk in the Shanghai Men's Health Study (n = 58 054; baseline age 40-74 years) and the Shanghai Women's Health Study (n = 69 166; baseline age 40-70 years). Information on the stone history and tea intake was collected by in-person surveys. Multivariable Cox proportional hazards models were adjusted for baseline demographic variables, medical history and dietary intakes including non-tea oxalate from a validated food frequency questionnaire.
RESULTS - During 319 211 and 696 950 person-years of follow up, respectively, 1202 men and 1451 women reported incident stones. Approximately two-thirds of men and one-quarter of women were tea drinkers at baseline, of whom green tea was the primary type consumed (95% in men, 88% in women). Tea drinkers (men: hazard ratio 0.78, 95% confidence interval 0.69-0.88; women: hazard ratio 0.8, 95% confidence interval 0.77-0.98) and specifically green tea drinkers (men: hazard ratio 0.78, 95% confidence interval 0.69-0.88; women: hazard ratio 0.84, 95% confidence interval 0.74-0.95) had lower incident risk than never/former drinkers. Compared with never/former drinkers, a stronger dose-response trend was observed for the amount of dried tea leaf consumed/month by men (hazard ratio 0.67, 95% confidence interval 0.56-0.80, P  < 0.001) than by women (hazard ratio 0.87, 95% confidence interval 0.70-1.08, P  = 0.041).
CONCLUSIONS - Green tea intake is associated with a lower risk of incident kidney stones, and the benefit is observed more strongly among men.
© 2018 The Japanese Urological Association.
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Frailty and Prognostication in Geriatric Surgery and Trauma.
Maxwell CA, Patel MB, Suarez-Rodriguez LC, Miller RS
(2019) Clin Geriatr Med 35: 13-26
MeSH Terms: Aged, Frailty, Geriatric Assessment, Humans, Mass Screening, Prognosis, Surgical Procedures, Operative, Wounds and Injuries
Show Abstract · Added November 6, 2018
Frailty is a predominant predictor of poor outcomes in older populations. This article presents a review of the concept of frailty and its role for prognostication among geriatric trauma and surgery patients. We discuss models of frailty defined in the scientific literature, emphasizing that frailty is a process of biologic aging. We emphasize the importance of screening, assessment, and inclusion of frailty indices for the development and use of prognostication instruments/tools in the population of interest. Finally, we discuss best practices for the delivery of prognostic information in acute care settings and specific recommendations for trauma and surgical care settings.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Regionally specific volume deficits along the hippocampal long axis in early and chronic psychosis.
McHugo M, Talati P, Woodward ND, Armstrong K, Blackford JU, Heckers S
(2018) Neuroimage Clin 20: 1106-1114
MeSH Terms: Adult, Aged, Bipolar Disorder, Dentate Gyrus, Early Diagnosis, Female, Hippocampus, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Psychotic Disorders
Show Abstract · Added March 26, 2019
Previous studies in psychosis patients have shown hippocampal volume deficits across anterior and posterior regions or across subfields, but subfield specific changes in volume along the hippocampal long axis have not been examined. Here, we tested the hypothesis that volume changes exist across the hippocampus in chronic psychosis but only the anterior CA region is affected in early psychosis patients. We analyzed structural MRI data from 179 patients with a non-affective psychotic disorder (94 chronic psychosis; 85 early psychosis) and 167 heathy individuals demographically matched to the chronic and early psychosis samples respectively (82 matched to chronic patients; 85 matched to early patients). We measured hippocampal volumes using Freesurfer 6-derived automated segmentation of both anterior and posterior regions and the CA, dentate gyrus, and subiculum subfields. We found a hippocampal volume deficit in both anterior and posterior regions in chronic psychosis, but this deficit was limited to the anterior hippocampus in early psychosis patients. This volume change was more pronounced in the anterior CA subfield of early psychosis patients than in the dentate gyrus or subiculum. Our findings support existing models of psychosis implicating initial CA dysfunction with later progression to other hippocampal regions and suggest that the anterior hippocampus may be an important target for early interventions.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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