The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence

The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case–control analysis (N=908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N=3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA;N=81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N=22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P=0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P=0.033). The 168Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD

Brain volumes in alcohol use disorder : Do females and males differ? A whole-brain magnetic resonance imaging mega-analysis

Emerging evidence suggests distinct neurobiological correlates of alcohol use disorder (AUD) between sexes, which however remain largely unexplored. This work from ENIGMA Addiction Working Group aimed to characterize the sex differences in gray matter (GM) and white matter (WM) correlates of AUD using a whole-brain, voxelbased, multi-tissue mega-analytic approach, thereby extending our recent surfacebased region of interest findings on a nearly matching sample using a complementary methodological approach. T1-weighted magnetic resonance imaging (MRI) data from 653 people with AUD and 326 controls was analyzed using voxel-based morphometry. The effects of group, sex, group-by-sex, and substance use severity in AUD on brain volumes were assessed using General Linear Models. Individuals with AUD relative to controls had lower GM volume in striatal, thalamic, cerebellar, and widespread cortical clusters. Group-by-sex effects were found in cerebellar GM and WM volumes, which were more affected by AUD in females than males. Smaller groupby- sex effects were also found in frontotemporal WM tracts, which were more affected in AUD females, and in temporo-occipital and midcingulate GM volumes, which were more affected in AUD males. AUD females but not males showed a negative association between monthly drinks and precentral GM volume. Our results suggest that AUD is associated with both shared and distinct widespread effects on GM and WM volumes in females and males. This evidence advances our previous region of interest knowledge, supporting the usefulness of adopting an exploratory perspective and the need to include sex as a relevant moderator variable in AUD

Waterpipe smoking among health sciences university students in Iran: perceptions, practices and patterns of use

<p>Abstract</p> <p>Background</p> <p>In recent years waterpipe smoking has become a popular practice amongst young adults in eastern Mediterranean countries, including Iran. The aim of this study was to assess waterpipe smoking perceptions and practices among first-year health sciences university students in Iran and to identify factors associated with the initiation and maintenance of waterpipe use in this population.</p> <p>Results</p> <p>Out of 371 first-year health sciences students surveyed, 358 eight students completed a self-administered questionnaire in the classrooms describing their use and perceptions towards waterpipe smoking. Two hundred and ninety six responders met study inclusion criteria. Waterpipe smoking was common among first-year health sciences university students, with 51% of students indicating they were current waterpipe smokers. Women were smoking waterpipes almost as frequently as men (48% versus 52%, respectively). The majority of waterpipe smokers (75.5%) indicated that the fun and social aspect of waterpipe use was the main motivating factor for them to continue smoking. Of waterpipe smokers, 55.3% were occasional smokers, using waterpipes once a month or less, while 44.7% were frequent smokers, using waterpipes more than once a month. A large number of frequent waterpipe smokers perceived that waterpipe smoking was a healthier way to use tobacco (40.6%) while only 20.6% thought it was addictive. Compared to occasional smokers, significantly more frequent smokers reported waterpipe smoking was relaxing (62.5% vs. 26.2%, <it>p </it>= 0.002), energizing (48.5% vs. 11.4%, <it>p </it>= 0.001), a part of their culture (58.8% vs. 34.1%, <it>p </it>= 0.04), and the healthiest way to use tobacco (40.6% vs. 11.1%, <it>p </it>= 0.005).</p> <p>Conclusions</p> <p>Social and recreational use of waterpipes is widespread among first-year health sciences university students in Iran. Women and men were almost equally likely to be current waterpipe users. Public health initiatives to combat the increasing use of waterpipes among university students in Iran must consider the equal gender distribution and its perception by many waterpipe smokers as being a healthier and non-addictive way to use tobacco.</p

Recalibrating single-study effect sizes using hierarchical Bayesian models

INTRODUCTION: There are growing concerns about commonly inflated effect sizes in small neuroimaging studies, yet no study has addressed recalibrating effect size estimates for small samples. To tackle this issue, we propose a hierarchical Bayesian model to adjust the magnitude of single-study effect sizes while incorporating a tailored estimation of sampling variance.METHODS: We estimated the effect sizes of case-control differences on brain structural features between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis and non-dependent participants for 21 individual studies (Total cases: 903; Total controls: 996). Then, the study-specific effect sizes were modeled using a hierarchical Bayesian approach in which the parameters of the study-specific effect size distributions were sampled from a higher-order overarching distribution. The posterior distribution of the overarching and study-specific parameters was approximated using the Gibbs sampling method.RESULTS: The results showed shrinkage of the posterior distribution of the study-specific estimates toward the overarching estimates given the original effect sizes observed in individual studies. Differences between the original effect sizes (i.e., Cohen's d) and the point estimate of the posterior distribution ranged from 0 to 0.97. The magnitude of adjustment was negatively correlated with the sample size (r = -0.27, p &lt; 0.001) and positively correlated with empirically estimated sampling variance (r = 0.40, p &lt; 0.001), suggesting studies with smaller samples and larger sampling variance tended to have greater adjustments. DISCUSSION: Our findings demonstrate the utility of the hierarchical Bayesian model in recalibrating single-study effect sizes using information from similar studies. This suggests that Bayesian utilization of existing knowledge can be an effective alternative approach to improve the effect size estimation in individual studies, particularly for those with smaller samples.</p

Recalibrating single-study effect sizes using hierarchical Bayesian models

INTRODUCTION: There are growing concerns about commonly inflated effect sizes in small neuroimaging studies, yet no study has addressed recalibrating effect size estimates for small samples. To tackle this issue, we propose a hierarchical Bayesian model to adjust the magnitude of single-study effect sizes while incorporating a tailored estimation of sampling variance.METHODS: We estimated the effect sizes of case-control differences on brain structural features between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis and non-dependent participants for 21 individual studies (Total cases: 903; Total controls: 996). Then, the study-specific effect sizes were modeled using a hierarchical Bayesian approach in which the parameters of the study-specific effect size distributions were sampled from a higher-order overarching distribution. The posterior distribution of the overarching and study-specific parameters was approximated using the Gibbs sampling method.RESULTS: The results showed shrinkage of the posterior distribution of the study-specific estimates toward the overarching estimates given the original effect sizes observed in individual studies. Differences between the original effect sizes (i.e., Cohen's d) and the point estimate of the posterior distribution ranged from 0 to 0.97. The magnitude of adjustment was negatively correlated with the sample size (r = -0.27, p &lt; 0.001) and positively correlated with empirically estimated sampling variance (r = 0.40, p &lt; 0.001), suggesting studies with smaller samples and larger sampling variance tended to have greater adjustments. DISCUSSION: Our findings demonstrate the utility of the hierarchical Bayesian model in recalibrating single-study effect sizes using information from similar studies. This suggests that Bayesian utilization of existing knowledge can be an effective alternative approach to improve the effect size estimation in individual studies, particularly for those with smaller samples.</p

Prevention of non-communicable disease in a population in nutrition transition: Tehran Lipid and Glucose Study phase II

<p>Abstract</p> <p>Background</p> <p>The Tehran Lipid and Glucose Study (TLGS) is a long term integrated community-based program for prevention of non-communicable disorders (NCD) by development of a healthy lifestyle and reduction of NCD risk factors. The study begun in 1999, is ongoing, to be continued for at least 20 years. A primary survey was done to collect baseline data in 15005 individuals, over 3 years of age, selected from cohorts of three medical heath centers. A questionnaire for past medical history and data was completed during interviews; blood pressure, pulse rate, and anthropometrical measurements and a limited physical examination were performed and lipid profiles, fasting blood sugar and 2-hours-postload-glucose challenge were measured. A DNA bank was also collected. For those subjects aged over 30 years, Rose questionnaire was completed and an electrocardiogram was taken. Data collected were directly stored in computers as database software- computer assisted system. The aim of this study is to evaluate the feasibility and effectiveness of lifestyle modification in preventing or postponing the development of NCD risk factors and outcomes in the TLGS population.</p> <p>Design and methods</p> <p>In phase II of the TLGS, lifestyle interventions were implemented in 5630 people and 9375 individuals served as controls. Primary, secondary and tertiary interventions were designed based on specific target groups including schoolchildren, housewives, and high-risk persons. Officials of various sectors such as health, education, municipality, police, media, traders and community leaders were actively engaged as decision makers and collaborators. Interventional strategies were based on lifestyle modifications in diet, smoking and physical activity through face-to-face education, leaflets & brochures, school program alterations, training volunteers as health team and treating patients with NCD risk factors. Collection of demographic, clinical and laboratory data will be repeated every 3 years to assess the effects of different interventions in the intervention group as compared to control group.</p> <p>Conclusion</p> <p>This controlled community intervention will test the possibility of preventing or delaying the onset of non-communicable risk factors and disorders in a population in nutrition transition.</p> <p>Trial registration</p> <p>ISRCTN52588395</p