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2.
Nat Commun ; 10(1): 4558, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594949

RESUMO

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

3.
Nicotine Tob Res ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31294817

RESUMO

INTRODUCTION: FTND (FagerstrÓ§m test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. METHODS: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. RESULTS: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. CONCLUSIONS: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. IMPLICATIONS: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

4.
Transl Behav Med ; 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31313808

RESUMO

Tobacco smoking is an important risk factor for cancer incidence, an effect modifier for cancer treatment, and a negative prognostic factor for disease outcomes. Inadequate implementation of evidence-based smoking cessation treatment in cancer centers, a consequence of numerous patient-, provider-, and system-level barriers, contributes to tobacco-related morbidity and mortality. This study provides data for a paradigm shift from a frequently used specialist referral model to a point-of-care treatment model for tobacco use assessment and cessation treatment for outpatients at a large cancer center. The point-of-care model is enabled by a low-burden strategy, the Electronic Health Record-Enabled Evidence-Based Smoking Cessation Treatment program, which was implemented in the cancer center clinics on June 2, 2018. Five-month pre- and post-implementation data from the electronic health record (EHR) were analyzed. The percentage of cancer patients assessed for tobacco use significantly increased from 48% to 90% (z = 126.57, p < .001), the percentage of smokers referred for cessation counseling increased from 0.72% to 1.91% (z = 3.81, p < .001), and the percentage of smokers with cessation medication significantly increased from 3% to 17% (z = 17.20, p < .001). EHR functionalities may significantly address barriers to point-of-care treatment delivery, improving its consistent implementation and thereby increasing access to and quality of smoking cessation care for cancer center patients.

5.
Breast Cancer Res Treat ; 178(1): 151-159, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31325073

RESUMO

PURPOSE: Approximately, 10% of breast cancers are hereditary. Identifying women at high risk for hereditary breast and ovarian cancer allows for early detection, prevention, and individualized disease management for those diagnosed with breast cancer. There is limited data about breast cancer genetic risks among African Americans as the majority of the large studies have been conducted in European Americans. We examined the distribution of deleterious genetic mutations in African American breast cancer patients, and evaluated the effectiveness of the National Comprehensive Cancer Network (NCCN) guidelines for identifying African American women at high risk for deleterious genetic mutations. METHODS: African American participants with breast cancer underwent an interview regarding health and family history, and a 30-gene saliva test. Medical records were accessed to determine whether participants had received prior genetic testing as part of usual care, results of previous testing, and cancer characteristics. RESULTS: Two hundred and fifty participants were enrolled between February 2016 and May 2018. Twenty (8.0%) had a deleterious mutation in one of the 30 genes; BRCA2 had the highest frequency (40.0%). 187 (74.8%) met eligibility for testing based on NCCN guidelines. Only 110 (58.8%) of participants eligible for genetic testing, according to guidelines, had received prior testing as part of routine care. Using the 30-gene test, we identified deleterious mutations in 17 of 187 (9.1%) of those who met NCCN criteria for testing, and three of 63 (4.8%) of those who did not meet criteria for testing nonetheless had a deleterious mutation associated with breast cancer. CONCLUSIONS: Our results indicate that a large proportion of African American breast cancer patients who meet criteria for genetic testing do not receive it as part of routine care. Even in women who do not meet testing guidelines, nearly 5% have a known deleterious mutation associated with breast cancer.

6.
BMJ Open ; 9(7): e030066, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31270124

RESUMO

OBJECTIVES: To generate system insights on patient and provider levers and strategies that must be activated to improve hospital-based smoking cessation treatment. DESIGN: Mixed methods study including a series of in-depth group model building sessions, which informed the design of an online survey completed by healthcare providers and a structured interview protocol administered at the bedside to patients who smoke. SETTING: Large, tertiary care hospital in the Midwestern United States. PARTICIPANTS: Group model building: 28 healthcare providers and 22 previously-hospitalised patients; Online survey: 308 healthcare providers; Bedside interviews: 205 hospitalised patients. PRIMARY AND SECONDARY OUTCOME MEASURES: Hypothesis-generating, participatory qualitative methods informed the examination of the following quantitative outcomes: patient interest versus provider perception of patient interest in smoking cessation and treatment; patient-reported receipt versus provider-reported offering of inpatient smoking cessation interventions; and priority ratings of importance and feasibility of strategies to improve treatment. RESULTS: System insights included patients frequently leaving the floor to smoke, which created major workflow disruption. Leverage points included interventions to reduce withdrawal symptoms, and action ideas included nurse-driven protocols for timely administration of nicotine replacement therapy. Quantitative data corroborated system insights; for instance, 80% of providers reported that patients frequently leave the floor to smoke, leading to safety risks, missed assessments and inefficient use of staff time. Patients reported significantly lower rates of receiving any smoking cessation interventions, compared with provider reports (mean difference=17.4%-33.7%, p<0.001). Although 92% of providers cited patient interest as a key barrier, only 4% of patients indicated no interest in quitting or reducing smoking. CONCLUSIONS: Engaging hospital providers and patients in participatory approaches to develop an implementation strategy revealed discrepant perceptions of patient interest and frequency of hospital-based treatment for smoking. These findings spurred adoption of standardised point-of-care treatment for cigarette smoking, which remains highly prevalent yet undertreated among hospitalised patients.

7.
Alcohol Clin Exp Res ; 43(7): 1510-1518, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31135997

RESUMO

BACKGROUND: Although the risks of using central nervous system depressant (CNS-D) medications with alcohol are well documented, little is known about trends in prescribed use of these medications among individuals who regularly consume alcohol (i.e., trends in "concurrent use"). We examined changes in the prevalence of prescribed CNS-D medications among individuals who drank alcohol on 52 or more occasions in the past year ("regular drinking"). CNS-D medications included sedative-hypnotics (subclassified as anxiolytics or sleep medications) and opioids. METHODS: We used 8 cross-sectional cycles of the National Health and Nutrition Examination Survey (1999-2000 to 2013-2014) from participants aged 20 and older (n = 37,709). We used log-binomial regression to examine (i) prevalence trends of prescribed CNS-D medication use, (ii) trend differences by drinking status, and (iii) correlates of CNS-D medication use. RESULTS: Among those who drink regularly, the relative annual increase in prevalence of sedative-hypnotic use was 5.3% (95% CI: 2.7 to 7.9): Anxiolytic and sleep medication use increased annually by 3.7% (95% CI: 0.8 to 6.7) and 11.2% (95% CI: 6.5 to 16.0), respectively. Opioid use trends among those who drink regularly were not statistically significant but were nonlinear. Differences in CNS-D medication trends between those who drink regularly and those who drink infrequently/abstain were not statistically significant. Those who drink regularly were less likely than those who drink infrequently/abstain to use opioids (adjusted relative risk [ARR]: 0.69, 95% CI: 0.60 to 0.78) and anxiolytics (ARR: 0.71, 95% CI: 0.61 to 0.81), but not sleep medications (ARR: 1.04, 95% CI: 0.80 to 1.35). Those aged 40 and older were 2 to 5 times as likely as those aged 20 to 29 to use sedative-hypnotics. CONCLUSIONS: Among those who drink regularly, the prevalence of prescribed sedative-hypnotic use increased and prescribed opioid use remained common. These trends indicate that a substantial portion of the population is at risk of alcohol-related adverse drug reactions-particularly those aged 40 and older.

8.
Addiction ; 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31033084

RESUMO

BACKGROUND AND AIMS: In the United States, the availability of prescription opioids has decreased in recent years. Whether there have been corresponding changes in the likelihood of people with prescription opioid use disorder (POUD) to engage in illegal behaviors related to drug use remains unknown. We examined changes in prevalence of illegal behaviors between people with and without POUD over time, and how transactions for obtaining opioids have changed among people with POUD over time. DESIGN: Temporal trend analysis of repeated cross-sectional data. SETTING: United States household dwelling population from all 50 states and District of Columbia. PARTICIPANTS: Adult subsamples from the 2002-14 National Survey of Drug Use and Health (n = 5393 people with POUD; n = 486 768 people without POUD). MEASUREMENTS: Outcome variables were selected illegal behaviors and sources of opioids used non-medically. POUD was defined using the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria. Time was treated as a continuous variable. The variable of interest for each illegal behavior analysis was the interaction between POUD diagnosis and time. Covariates included age, sex and race/ethnicity. FINDINGS: During the 13-year period examined, the adjusted interaction odds ratio (AIOR) describing the change in association between POUD and selling illicit drugs increased by a factor of 2.41 [95% confidence interval (CI) = 1.56-3.71, P < 0.001]. Similar trends were noted for stealing (AIOR = 2.12, 95% CI = 1.31-3.44, P = 0.002) and for life-time history of arrest (AIOR = 1.53, 95% CI = 1.06-2.19, P = 0.021). People with POUD became less likely to receive opioids for free from friends and family [adjusted odds ratio (AOR) = 0.42, 95% CI = 0.25-0.71, P = 0.001] and more likely to buy them from friends and family (AOR = 3.29, 95% CI = 1.76-6.13, P < 0.001) from 2005 to 2014. CONCLUSIONS: In the United States, against a backdrop of a decreasing prescription opioid supply, rates of some crimes potentially related to drug use increased among people with prescription opioid use disorder compared with those without prescription opioid use disorder from 2002 to 2014.

9.
Nicotine Tob Res ; 2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-30855677

RESUMO

Large segments of the world population use combustible cigarettes, and our society pays a high price for smoking, through increased healthcare expenditures, morbidity and mortality. The development of combustible cigarette smoking requires the initiation of smoking and a subsequent chain of behavioral transitions from experimental use, to established regular use, to the conversion to addiction. Each transition is influenced by both environmental and genetic factors, and our increasing knowledge about genetic contributions to smoking behaviors opens new potential interventions. The large-scale implementation of genetic knowledge to accelerate smoking cessation represents an important clinical challenge for precision medicine. IMPLICATIONSClinical medicine of the future is poised to use an individual's genomic data to predict disease risk and guide clinical care. The treatment of cigarette smoking and tobacco use disorder represents a prime area for genomics implementation. We must prepare for the integration of genomic applications into the clinical care of patients who smoke.

10.
Nicotine Tob Res ; 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30882151

RESUMO

INTRODUCTION: Reducing adverse events from pharmacologic treatment is an important goal of precision medicine and identifying genetic predictors of adverse events is a step towards this goal. In 2012 King et al. reported associations between genetic variants and adverse events in a placebo-controlled smoking cessation trial of varenicline and bupropion. Strong associations were found between gastrointestinal adverse events and 11 variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15, a region repeatedly associated with smoking-related phenotypes. Our goal was to replicate, in an independent sample, the impact of variants in the CHRNA5-CHRNA3-CHRNB4 region on gastrointestinal adverse events, and to extend the analyses to adherence and smoking cessation. METHODS: The University of Wisconsin Transdisciplinary Tobacco Use Research Center (TTURC) conducted a multi-armed, placebo-controlled smoking cessation trial of bupropion and nicotine replacement therapy (NRT) that included 985 genotyped European-ancestry participants. We evaluated relations between our key variables using logistic regression. RESULTS: Gastrointestinal adverse events were experienced by 31.6% of the TTURC participants. Each of the CHRNA5-CHRNA3-CHRNB4 associations from the King study was found in TTURC, with the same direction of effect. Neither these variants nor the gastrointestinal adverse events themselves were associated with adherence to medication or successful smoking cessation. CONCLUSIONS: Variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15 are associated with gastrointestinal adverse events in smoking cessation. Additional independent variants in this region strengthen the association. The consistency between the results of these two independent studies supports the conclusion that these findings reflect biological response to the use of smoking cessation medication. IMPLICATIONS: The fact that our findings from the TTURC smoking cessation trial, support the independent findings of King et al. suggest that associations of variants in the CHRNA5-CHRNA3-CHRNB4 region of chromosome 15 with gastrointestinal adverse events while taking medications for smoking cessation reflect biology. However, although adherence to medication was a strong predictor of successful smoking cessation in TTURC, neither adverse events nor the genetic variants associated with them predicted either adherence or successful cessation in this study. Thus, although we should strive to minimize adverse events during treatment, we should not expect that to increase successful smoking cessation substantially.

11.
Pharmacogenomics ; 19(18): 1383-1394, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30442082

RESUMO

AIM: This study tests whether polygenic risk scores (PRSs) for nicotine metabolism predict smoking behaviors in independent data. MATERIALS & METHODS: Linear regression, logistic regression and survival analyses were used to analyze nicotine metabolism PRSs and nicotine metabolism, smoking quantity and smoking cessation. RESULTS: Nicotine metabolism PRSs based on two genome wide association studies (GWAS) meta-analyses significantly predicted nicotine metabolism biomarkers (R2 range: 9.2-16%; minimum p = 7.6 × 10-8). The GWAS top hit variant rs56113850 significantly predicted nicotine metabolism biomarkers (R2 range: 14-17%; minimum p = 4.4 × 10-8). There was insufficient evidence for these PRSs predicting smoking quantity and smoking cessation. CONCLUSION: Results suggest that nicotine metabolism PRSs based on GWAS meta-analyses predict an individual's nicotine metabolism, so does use of the top hit variant. We anticipate that PRSs will enter clinical medicine, but additional research is needed to develop a more comprehensive genetic score to predict smoking behaviors.

12.
Artigo em Inglês | MEDLINE | ID: mdl-30445639

RESUMO

Background: Digital therapeutic tools (e.g. mobile applications) can be accessible, low-cost interventions that counter misconceptions about medication assisted treatment (MAT) and/or improve deficits in MAT knowledge that are common barriers to treatment entry among individuals with opioid dependence. The purpose of this pilot study was to examine the preliminary effectiveness of a mobile application, 'uMAT-R', that includes health information about OUD recovery supported by science and MAT benefits. Methods: Twenty-six adult participants with OUD recruited via social media completed all modules and pre/post-assessments within uMAT-R. McNemar's test was used to compare interest in treatment before and after completing the app, and paired t tests were used to compare MAT attitude scores before and after completing the modules within uMAT-R. Results: Before viewing uMAT-R, 32% agreed/strongly agreed that they were interested in starting treatment to recover from opioid misuse, compared to 48% after completing uMAT-R. The average scores on the MAT attitudes scale and its Aid to Behavior Change subscale improved from before to after viewing uMAT-R. Among the participants, 88% felt that uMAT-R would be useful to consult when making decisions about recovery. Conclusions: Our encouraging pilot findings support the use of uMAT-R to help address the current opioid epidemic.

13.
J Neuroimmune Pharmacol ; 13(4): 430-437, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30370503

RESUMO

The clinical translation of genetic research on nicotine dependence and treatment response requires acceptance of genetic testing by smokers. This study determines (1) which current smokers are receptive to genetic susceptibility testing for nicotine dependence and (2) to what potential extent smokers motivated to quit desire to take smoking cessation medication when hypothetical genetic results predict their pharmacogenetic medication response. Current smokers from a genetic nicotine dependence study (n = 1306) and an ongoing smoking cessation trial (n = 209) were surveyed on their hypothetical interest in seeing genetic testing results related to risk of nicotine dependence. Most current smokers (84.8%) reported high interest in receiving genetic testing results. Factors associated with high interest included age ≥ 40 years, having a college degree, and a positive medical history (≥1 medical condition). In the ongoing smoking cessation trial, current smokers motivated to quit (n = 474) were surveyed on their desire to take smoking cessation medication given hypothetical below or above average pharmacogenetic responses to the medication. When the hypothetical medication response changed from below to above average, significantly more smokers reported a desire to take medication (from 61.0% to 97.5%, p < .0001). These preliminary findings suggest that genetic testing for personalized smoking cessation treatment is well-received by smokers and that a positive hypothetical pharmacogenetic response increases desire to take smoking cessation medication among current smokers motivated to quit. Graphical abstract ᅟ.

14.
Alcohol Clin Exp Res ; 42(11): 2246-2255, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30281161

RESUMO

BACKGROUND: There is evidence that low-level alcohol use, drinking 1 to 2 drinks on occasion, is protective for cardiovascular disease, but increases the risk of cancer. Synthesizing the overall impact of low-level alcohol use on health is therefore complex. The objective of this paper was to examine the association between frequency of low-level drinking and mortality. METHODS: Two data sets with self-reported alcohol use and mortality follow-up were analyzed: 340,668 individuals from the National Health Interview Survey (NHIS) and 93,653 individuals from the Veterans Health Administration (VA) outpatient medical records. Survival analyses were conducted to evaluate the association between low-level drinking frequency and mortality. RESULTS: The minimum risk drinking frequency among those who drink 1 to 2 drinks per occasion was found to be 3.2 times weekly in the NHIS data, based on a continuous measure of drinking frequency, and 2 to 3 times weekly in the VA data. Relative to these individuals with minimum risk, individuals who drink 7 times weekly had an adjusted hazard ratio (HR) of all-cause mortality of 1.23 (p < 0.0001) in the NHIS data, and individuals who drink 4 to 7 times weekly in the VA data also had an adjusted HR of 1.23 (p = 0.01). Secondary analyses in the NHIS data showed that the minimum risk was drinking 4 times weekly for cardiovascular mortality, and drinking monthly or less for cancer mortality. The associations were consistent in stratified analyses of men, women, and never smokers. CONCLUSIONS: The minimum risk of low-level drinking frequency for all-cause mortality appears to be approximately 3 occasions weekly. The robustness of this finding is highlighted in 2 distinctly different data sets: a large epidemiological data set and a data set of veterans sampled from an outpatient clinic. Daily drinking, even at low levels, is detrimental to one's health.

15.
Nicotine Tob Res ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30304476

RESUMO

Introduction: We examined past-12-month quit attempts and smoking cessation from 2006 to 2016 while accounting for demographic shifts in the US population. In addition, we sought to understand whether the current use of electronic cigarettes was associated with a change in past-12-month quit attempts and successful smoking cessation at the population level. Methods: We analyzed data from 25- to 44-year-olds from the National Health Interview Survey (NHIS) from 2006 to 2016 (N = 26,354) and the Tobacco Use Supplement to the Current Population Survey (TUS-CPS) in 2006-2007, 2010-2011, and 2014-2015 (N = 33,627). Data on e-cigarette use were available in the 2014-2016 NHIS and 2014-2015 TUS-CPS surveys. Results: Past-12-month quit attempts and smoking cessation increased in recent years compared with 2006. Current e-cigarette use was associated with higher quit attempts (adjusted odds ratio [aOR] = 2.29, 95% confidence interval [CI] = 1.87 to 2.81, p < .001) and greater smoking cessation (aOR = 1.64, 95% CI = 1.21 to 2.21, p = .001) in the NHIS. Multivariable logistic regression of the TUS-CPS data showed that current e-cigarette use was similarly significantly associated with increased past-12-month quit attempts and smoking cessation. Significant interactions were found for smoking frequency (everyday and some-day smoking) and current e-cigarette use for both outcomes (p < .0001) with the strongest positive effects seen in everyday smokers. Conclusions: Compared with 2006, past-12-month quit attempts and smoking cessation increased among adults aged 25-44 in recent years. Current e-cigarette use was associated with increased past-12-month quit attempts and successful smoking cessation among established smokers. These findings are relevant to future tobacco policy decisions. Implications: E-cigarettes were introduced into the US market over the past decade. During this period, past-12-month quit attempts and smoking cessation have increased among US adults aged 25-44. These trends are inconsistent with the hypothesis that e-cigarette use is delaying quit attempts and leading to decreased smoking cessation. In contrast, current e-cigarette use was associated with significantly higher past-12-month quit attempts and past-12-month cessation. These findings suggest that e-cigarette use contributes to a reduction in combustible cigarette use among established smokers.

16.
Basic Res Cardiol ; 113(5): 38, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-30097758

RESUMO

The CHRNA5 gene encodes a neurotransmitter receptor subunit involved in multiple processes, including cholinergic autonomic nerve activity and inflammation. Common variants in CHRNA5 have been linked with atherosclerotic cardiovascular disease. Association of variation in CHRNA5 and specific haplotypes with cardiovascular outcomes has not been described. The aim of this study was to examine the association of CHRNA5 haplotypes with gene expression and mortality among patients with acute myocardial infarction (AMI) and explore potential mechanisms of this association. Patients (N = 2054) hospitalized with AMI were genotyped for two common variants in CHRNA5. Proportional hazard models were used to estimate independent association of CHRNA5 haplotype with 1-year mortality. Both individual variants were associated with mortality (p = 0.0096 and 0.0004, respectively) and were in tight LD (D' = 0.99). One haplotype, HAP3, was associated with decreased mortality one year after AMI (adjusted HR = 0.42, 95% CI 0.26, 0.68; p = 0.0004). This association was validated in an independent cohort (N = 637) of post-MI patients (adjusted HR = 0.23, 95% CI 0.07, 0.79; p = 0.019). Differences in CHRNA5 expression by haplotype were investigated in human heart samples (n = 28). Compared with non-carriers, HAP3 carriers had threefold lower cardiac CHRNA5 mRNA expression (p = 0.023). Circulating levels of the inflammatory marker hsCRP were significantly lower in HAP3 carriers versus non-carriers (3.43 ± 4.2 versus 3.91 ± 5.1; p = 0.0379). Activation of the inflammasome, an important inflammatory complex involved in cardiovascular disease that is necessary for release of the pro-inflammatory cytokine IL-1 ß, was assessed in bone marrow-derived macrophages (BMDM) from CHRNA5 knockout mice and wild-type controls. In BMDM from CHRNA5 knockout mice, IL-1ß secretion was reduced by 50% compared to wild-type controls (p = 0.004). Therefore, a common haplotype of CHRNA5 that results in reduced cardiac expression of CHRNA5 and attenuated macrophage inflammasome activation is associated with lower mortality after AMI. These results implicate CHRNA5 and the cholinergic anti-inflammatory pathway in survival following AMI.

17.
Alcohol Clin Exp Res ; 42(10): 1939-1950, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30080258

RESUMO

BACKGROUND: Recent trends in alcoholic liver disease, alcohol-related emergency room admissions, and alcohol use disorder prevalence as measured by general-population surveys have raised concerns about rising alcohol-related morbidity and mortality in the United States. In contrast, upward trends in per capita alcohol consumption have been comparatively modest. METHODS: To resolve these discordant observations, we sought to examine trends in the prevalence of alcohol use and binge drinking from 6 regularly or periodically administered national surveys using a meta-analytic approach. Annual or periodic prevalence estimates for past-12-month or past-30-day alcohol use and binge drinking were estimated for available time points between the years 2000 and 2016. Estimates were combined in a random-effects regression model in which prevalence was modeled as a log-linear function of time to obtain meta-analytic trend estimates for the full population and by sex, race, age, and educational attainment. RESULTS: Meta-analysis-derived estimates of average annual percentage increase in the prevalence of alcohol use and binge drinking were 0.30% per year (95% CI: 0.22%, 0.38%) and 0.72% per year (95% CI: 0.46%, 0.98%), respectively. There was substantial between-survey heterogeneity among trend estimates, although there was notable consistency in the degree to which trends have impacted various demographic groups. For example, most surveys found that the changes in prevalence for alcohol use and binge drinking were large and positive for ages 50 to 64 and 65 and up, and smaller, negative, or nonsignificant for ages 18 to 29. CONCLUSIONS: Significant increases in the prevalence of alcohol use and of binge drinking over the past 10 to 15 years were observed, but not for all demographic groups. However, the increase in binge drinking among middle-aged and older adults is substantial and may be driving increasing rates of alcohol-related morbidity and mortality.

18.
Mol Psychiatry ; 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30131587

RESUMO

Cigarette smoking during pregnancy is a major public health concern. While there are well-described consequences in early child development, there is very little known about the effects of maternal smoking on human cortical biology during prenatal life. We therefore performed a genome-wide differential gene expression analysis using RNA sequencing (RNA-seq) on prenatal (N = 33; 16 smoking-exposed) as well as adult (N = 207; 57 active smokers) human postmortem prefrontal cortices. Smoking exposure during the prenatal period was directly associated with differential expression of 14 genes; in contrast, during adulthood, despite a much larger sample size, only two genes showed significant differential expression (FDR < 10%). Moreover, 1,315 genes showed significantly different exposure effects between maternal smoking during pregnancy and direct exposure in adulthood (FDR < 10%)-these differences were largely driven by prenatal differences that were enriched for pathways previously implicated in addiction and synaptic function. Furthermore, prenatal and age-dependent differentially expressed genes were enriched for genes implicated in non-syndromic autism spectrum disorder (ASD) and were differentially expressed as a set between patients with ASD and controls in postmortem cortical regions. These results underscore the enhanced sensitivity to the biological effect of smoking exposure in the developing brain and offer insight into how maternal smoking during pregnancy affects gene expression in the prenatal human cortex. They also begin to address the relationship between in utero exposure to smoking and the heightened risks for the subsequent development of neuropsychiatric disorders.

19.
Int J Drug Policy ; 59: 67-75, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30029073

RESUMO

BACKGROUND: A number of public health professional organizations support the decriminalization of cannabis due to adverse effects of cannabis-related arrests and legal consequences, particularly on youth. We sought to examine the associations between cannabis decriminalization and both arrests and youth cannabis use in five states that passed decriminalization measures between the years 2008 and 2014: Massachusetts (decriminalized in 2008), Connecticut (2011), Rhode Island (2013), Vermont (2013), and Maryland (2014). METHODS: Data on cannabis possession arrests were obtained from federal crime statistics; data on cannabis use were obtained from state Youth Risk Behavior Survey (YRBS) surveys, years 2007-2015. Using a "difference in difference" regression framework, we contrasted trends in decriminalization states with those from states that did not adopt major policy changes during the observation period. RESULTS: Decriminalization was associated with a 75% reduction in the rate of drug-related arrests for youth (95% CI: 44%, 89%) with similar effects observed for adult arrests. Decriminalization was not associated with any increase in the past-30 day prevalence of cannabis use overall (relative change=-0.2%; 95% CI: -4.5%, 4.3%) or in any of the individual decriminalization states. CONCLUSIONS: Decriminalization of cannabis in Massachusetts, Connecticut, Rhode Island, Vermont, and Maryland resulted in large decreases in cannabis possession arrests for both youth and adults, suggesting that the policy change had its intended consequence. Our analysis did not find any increase in the prevalence of youth cannabis use during the observation period.

20.
Psychiatr Serv ; 69(8): 849-851, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29852824

RESUMO

Patients with serious mental illness have high smoking prevalence and early mortality. Inadequate implementation of evidence-based smoking cessation treatment in community mental health centers (CMHCs) contributes to this disparity. This column describes a study of the effects of quality improvement strategies on treatment and cessation outcomes among patients with serious mental illness at four CMHCs. Two low-burden strategies, decision support and academic detailing with data-driven feedback, were implemented in the CMHCs' clinics from 2014 to 2016. Pre- and postimplementation data from pharmacy and medical records were analyzed. The percentage of patients receiving cessation medication increased from 5% to 18% (p≤.001), and smoking prevalence decreased from 57% to 54% (p≤.001). This quality improvement approach holds great potential for increasing the level of smoking cessation care for patients treated in CMHC settings. Decision support and academic detailing with feedback may be effective strategies to promote best practices.

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