Changes in DNA methylation persist over time in males with severe alcohol use disorder-A longitudinal follow-up study.

Treatment strategies for alcohol use disorder (AUD) aim for abstinence or harm reduction. While deranged biochemical parameters reverse with alcohol abstinence, whether molecular changes at the epigenetic level reverse is not clearly understood. We investigated whether the reduction from high alcohol use reflects DNA methylation at the gene-specific and global level. In subjects seeking treatment for severe AUD, we assessed gene-specific (aldehyde dehydrogenase [ALDH2]/methylene tetrahydrofolate reductase [MTHFR]) and global (long interspersed elements [LINE-1]) methylation across three-time points (baseline, after detoxification and at an early remission period of 3 months), in peripheral blood leukocytes. We observed that both gene-specific and global DNA methylation did not change over time, irrespective of the drinking status at 3 months (52% abstained from alcohol). Further, we also compared DNA methylation in AUD subjects with healthy controls. At baseline, there was a significantly higher gene-specific DNA methylation (ALDH2: p < .001 and MTHFR: p = .001) and a significant lower global methylation (LINE-1: p = .014) in AUD as compared to controls. Our results suggest that epigenetic changes at the DNA methylation level associated with severe AUD persist for at least 3 months of treatment.

Docosahexaenoic acid supplementation in age-related cognitive decline: a systematic review and meta-analysis.

PURPOSE: To investigate the role of DHA supplementation in preventing age-related cognitive decline (ARCD) in individual cognitive domains by conducting systematic review and meta-analysis. METHODS: Relevant clinical trials were systematically searched at Medline, PubMed, Scopus, Cochrane, ProQuest, and Embase databases since inception to June 2018. The PRISMA guidelines were adhered for data abstraction, quality assessment, and validation of included studies. Study details such as participant characteristics, DHA supplementation, and cognitive function outcome measures, i.e., memory, attention, working memory, and executive function, were extracted to perform meta-analysis according to the Cochrane guidelines. Additional meta-regression and subgroup analyses were performed to detect confounding variables and sensitivity of results, respectively. RESULTS: Ten studies including 2327 elderly individuals were part of the final results. Study exhibited minimal or no pooled incremental effects on memory (0.22, 95%CI = - 0.17 to 0.61, I2 = 94.36%), attention (0.1, 95%CI = - 0.04 to 0.25, I2 = 32.25%), working memory (0.01, 95%CI = - 0.10 to 0.12, I2 = 0%), and executive function (0.03, 95%CI = - 0.05 to 0.11, I2 = 78.48%) among the DHA-supplemented group. The results from standard mean difference between the groups, on memory (0.08, 95%CI = - 0.12 to 0.28, I2 = 76.82%), attention (0.04, 95%CI = - 0.09 to 0.23, I2 = 42.63%), working memory (- 0.08, 95%CI = - 0.26 to 0.10, I2 = 37.57%), and executive function (0.17, 95%CI = - 0.01 to 0.36, I2 = 78.48%) were similar to the results of pooled incremental analysis. Lastly, results remained unaffected by sensitivity and sub-group analyses. CONCLUSIONS: Current pieces of evidence do not support the role of DHA supplementation, in preventing/retarding ARCD of memory, executive function, attention, and working memory. Protocol registered at PROSPERO (ID: PROSPERO 2018 CRD42018099401).

Manganese- and 1-methyl-4-phenylpyridinium-induced neurotoxicity display differences in morphological, electrophysiological and genome-wide alterations: implications for idiopathic Parkinson's disease.

Idiopathic Parkinson's disease and manganese-induced atypical parkinsonism are characterized by movement disorder and nigrostriatal pathology. Although clinical features, brain region involved and responsiveness to levodopa distinguish both, differences at the neuronal level are largely unknown. We studied the morphological, neurophysiological and molecular differences in dopaminergic neurons exposed to the Parkinson's disease toxin 1-methyl-4-phenylpyridinium ion (MPP+ ) and manganese (Mn), followed by validation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Mn mouse models. Morphological analysis highlighted loss of neuronal processes in the MPP+ and not the Mn model. Cellular network dynamics of dopaminergic neurons characterized by spike frequency and inter-spike intervals indicated major neuronal population (~ 93%) with slow discharge rates (0-5 Hz). While MPP+ exposure suppressed the firing of these neurons, Mn neither suppressed nor elevated the neuronal activity. High-throughput transcriptomic analysis revealed up-regulation of 694 and 603 genes and down-regulation of 428 and 255 genes in the MPP+ and Mn models respectively. Many differentially expressed genes were unique to either models and contributed to neuroinflammation, metabolic/mitochondrial function, apoptosis and nuclear function, synaptic plasticity, neurotransmission and cytoskeleton. Analysis of the Janus kinase-signal transducer and activator of transcription pathway with implications for neuritogenesis and neuronal proliferation revealed contrasting profile in both models. Genome-wide DNA methylomics revealed differences between both models and substantiated the epigenetic basis of the difference in the Janus kinase-signal transducer and activator of transcription pathway. We conclude that idiopathic Parkinson's disease and atypical parkinsonism have divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and evolution of novel therapeutics. Cover Image for this issue: doi. 10.1111/jnc.13821.

Relation between age at first alcohol drink & adult life drinking patterns in alcohol-dependent patients.

Background & objectives: Age at first drink has its influence on later life drinking patterns. The association between age at first drink and adult alcohol consumption has not been studied in clinical population. This study was aimed to determine the age at first drink and its correlation with adult life drinking patterns in alcohol-dependent patients. Methods: Adult participants with alcohol dependence were included from the inpatient and outpatient wards of a tertiary care de-addiction facility in India. Questionnaires administered were National Institute on Alcohol Abuse and Alcoholism-Quantity Frequency for alcohol and the Fagerstrom Test for Nicotine Dependence for tobacco. Results: Of the 99 participants (92% males) with mean age 37±8.36 yr, mean age at first drink was 21.14±5.33 yr. After controlling for age, satisfaction with life scores and smoking, age at first drink showed a significant negative correlation with drinking days per week (r=-0.259, P=0.012), typical drink per day (r=-0.218, P=0.035) and maximum drinks in the previous month/year (r=-0.233, -0.223 and P=0.024, 0.031, respectively). Interpretation & conclusions: Our study suggested that earlier age of first drink correlated with chronic heavy drinking patterns in later adult life in alcohol-dependent patients. This may have implications for alcohol control policies determining the age for legal consumption.

Assessing Health Seeking Behaviors and Economic Consequences of Morbidity in Indian Construction Workers: A Multicenter Study.

Background: Construction laborers succumb to poor health due to the inherent workplace health hazards and poor socio-economic living conditions. With rising healthcare expenses, the increased risk of poor health may aggravate their economic status, pushing them deeper into poverty. Settings and Design: The current cross-sectional multicenter study comprehensively investigated the determinants of health, health-seeking behavior, and poor economic impact regarding catastrophic health expenditure (CHE) among construction laborers. Methods and Material: We collected details on illnesses among self and family members of the construction laborers that required healthcare visits during the previous year and their approximate expenses. Among the 1110 participants with complete data, 37% reported illness requiring a healthcare visit either for self or a family member. Results: Regression models to ascertain demographic and living condition determinants of perceived illness revealed an increased risk of illness when the kitchen is shared with the living space (OR = 1.87) and use unhygienic smoky cooking fuels (OR = 1.87). More than 25% of those who reported illness incurred CHE. Conclusion: We conclude that the frequency of perceived illness and the economic impact, i.e., CHE is relatively higher among the construction laborers. Our results demonstrate that poor living conditions add to the burden of morbidity in construction workers and families. Providing healthcare coverage for this population and engaging and educating them about affordable healthcare are necessary future steps to prevent the worsening of the economic situation.

High craving is associated with fewer abstinent days and lesser time to relapse during treatment in severe alcohol use disorder.

Background: Craving, an integral aspect of addictive processes, underlies heavy alcohol consumption and alcohol use disorder (AUD). Western studies point out that craving is associated with relapse risks in AUD treatment. The feasibility of assessing and following up with craving dynamicity is not studied in the Indian context. Aim: We aimed to capture craving and explore its association with relapse in an outpatient facility. Methods: Among 264 treatment-seeking male participants (mean [SD] age = 36 [6.7] years) with severe AUD, craving was assessed according to the Penn Alcohol Craving Scale (PACS) at treatment initiation and two follow-up visits (median follow-up: 1, 2 weeks). Days to drink and percentage of days abstinent were acquired during the follow-ups (maximum follow-up days = 355). Those lost to follow-up were censored and considered as having relapsed. Results: High craving was associated with fewer days to drink when considered as a sole predictor (P = 0.030). With covariates including medication at treatment initiation, high craving was marginally associated with fewer days to drink (P = 0.057). Baseline craving was negatively associated with proximal percentage of days abstinent (P = 0.015) and cravings at follow-ups negatively correlated with cross-sectional abstinent days (FU1: P = 0.009, FU2: P = 0.019). Craving reduced significantly over time (P < 0.001), irrespective of the drinking status in follow-ups. Conclusion: Relapse is a real challenge in AUD. The utility of craving assessment in identifying relapse risk in an outpatient facility helps in identifying an at-risk population for future relapse. Thus better-targeted approaches in treating AUD can be developed.

Data Management: The First Step in Reproducible Research.

Reproducibility is a preferred aim in any scientific research, including occupational health research. Datamanagement is an important and essential step in marching towards reproducibility. A good datamanagement helps us stay organized, improve transparency, quality and fosters collaboration. Here we discuss how to organize and prepare for data management, how data management facilitates interoperability and accessibility, followed by storing and dissemination of data. We wrap up by providing pointers on what needs to be included in the data management plans.

Need for workplace smoking cessation program among public transit drivers: Evidence from a cross-sectional study in a metropolitan city of Western India.

Background: Air pollution is a significant contributor to respiratory illness globally, and in India, evidence is scarce on whether smoking exacerbates this problem. Objective and Methods: We aimed at assessing if being a smoker among public transit drivers increased risk for respiratory illnesses and affected performance of pulmonary function tests in a cross-sectional study in a metropolitan city of Gujarat, western state of India. We conducted a cross-sectional study among public transit drivers (those who were smoking and not smoking). Administration staff who were not smoking were considered as control group. We collected socio-demographic and medical history including occupational history (N = 296). We collected details of respiratory symptoms with standard tools and assessed pulmonary function tests (PFT) using spirometry. Group differences and regression analyses were conducted in R software. Results: We found that respiratory symptoms among public transit drivers who smoked were higher than those who did not smoke and healthy controls. In PFT diagnosis, drivers who smoke displayed two times higher prevalence of obstructive pattern compared to drivers who did not smoke. There was a significant reduction in the larger as well as the smaller airway functions, reflected in reduction of FEV1/FVC ratio (p < 0.001) and FEF25-75% (p < 0.001), respectively, among drivers who smoked compared to controls. Our results indicate that being a driver with a smoking history leads to a 3.1% greater decrease in the FEV1/FVC ratio and about half a litre reduction in FEF25-75% compared to the drivers who did not smoke. Conclusion: We suggest there is a high need for smoking cessation programmes for public transit drivers as they are at higher risk for respiratory illnesses and reduced pulmonary functions when smoking is added to the existing vehicular exposure.

The Motivation for Alcohol Reward: Predictors of Progressive-Ratio Intravenous Alcohol Self-Administration in Humans.

The Progressive Ratio (PR) self-administration paradigm is a common pre-clinical method used to examine the motivation for a drug attributed to a craving, reward, or the relief of negative affect. The Computer-assisted Alcohol Infusion System (CAIS) enables intravenous alcohol self-administration behavior in humans. This system provides the investigator with control over the trajectory of each incremental breath alcohol concentration (BrAC) reward and the maximum BrAC allowed in a session. This paradigm allows participants to earn these alcohol rewards using a sequence of button presses specified by the investigator. The system employs a physiologically-based pharmacokinetic model-based algorithm to achieve the same incremental BrAC exposure in every participant. Participants (n = 11) took part in two identical sessions to examine test-retest reliability, and an additional group (n = 73) completed a single session. Sessions began with a 25 min priming phase: participants were instructed to press a button an increasing number of times per reward, accumulating four standardized incremental BrAC trajectories. The second phase comprised an ad-lib, PR paradigm lasting 125 min. Each reward required an increasing number of button presses. Measures of self-administration included: average and peak BrAC, total rewards earned, total grams of ethanol consumed per unit of total body water, the total number of button presses, and the average rate of button pressing. Self-administration measures were highly correlated both between and within sessions, demonstrating test-retest reliability and internal consistency. Recent drinking history was strongly associated with self-administration measures; heavier drinkers chose greater alcohol self-administration. These results indicate the reliability and sensitivity of this progressive-ratio intravenous alcohol self-administration method for assessing the motivational properties of alcohol, with the potential for improved testing of the efficacy of new medications thought to reduce consumption of alcohol. This method can be used to understand the genetic and environmental determinants of alcohol self-administration in humans.

Elevated stearoyl-CoA desaturase 1 activity is associated with alcohol-associated liver disease.

Chronic binge drinking induces hepatic lipid accumulation, but only certain individuals develop alcohol-associated liver disease (ALD). Specific patterns of lipid accumulation are thought to be associated with ALD, but this has not been comprehensively investigated to date. We analyzed plasma fatty acid levels, quantified by gas chromatography-mass spectrometry, in a sample of patients with alcohol use disorder (AUD). Given that elevation in serum alanine transaminase (ALT) levels are strongly associated with ALD, patients were stratified into two groups based on ALT levels: an ALD group (ALT >40 IU/L) and a non-ALD group (ALT ≤40 IU/L). There was a shift toward greater concentrations of monounsaturated fatty acids in the ALD group compared to the non-ALD group. Stearoyl-CoA desaturase (SCD1) activity in the ALD group was then estimated as the ratio of palmitoleic acid (16:1) to palmitic acid (16:0). SCD1 activity was greater in the ALD than the non-ALD group. A series of linear regression models demonstrated that SCD1 activity mediated the association between binge drinking and ALD. These findings provide initial evidence that SCD1 activity may be associated with ALD. If validated prospectively, elevated SCD1 activity could potentially be used as a biomarker to identify individuals at high risk for developing ALD.

Modeling ability to resist alcohol in the human laboratory: A pilot study.

Background: Roughly half of patients with alcohol use disorder prefer non-abstinence based approaches to treatment. However, only individuals who can limit their alcohol use after low-risk consumption are most likely to benefit from these approaches. This pilot study developed a laboratory-based intravenous alcohol self-administration paradigm to determine the characteristics of individuals who could successfully resist consuming alcohol after an initial exposure. Methods: Seventeen non-treatment seeking heavy drinkers completed two versions of an intravenous alcohol self-administration paradigm designed to assess impaired control over alcohol use. In the paradigm, participants received a priming dose of alcohol and then entered a 120-min resist phase, in which they received monetary rewards if they resisted self-administering alcohol. We used Cox proportional hazards regression to determine the impact of craving and Impaired Control Scale scores on rate of lapse. Results: 64.7% of participants across both versions of the paradigm were unable to resist alcohol for the duration of the session. Craving at baseline (HR = 1.07, 95% CI 1.01-1.13, p = 0.02) and following priming (HR = 1.08, 95% CI 1.02-1.15, p = 0.01) were associated with rate of lapse. Individuals who lapsed endorsed greater attempts to control their drinking over the prior six months compared to individuals who resisted. Conclusions: This study provides preliminary evidence that craving may be predictive of risk of lapse in individuals who are trying to limit alcohol intake after consuming a small initial amount of alcohol. Future studies should test this paradigm in a larger and more diverse sample.

The impact of virtual medical student surgical conferences.

BACKGROUND: In recent years, the number of people pursuing a surgical career in the UK has decreased. The COVID-19 pandemic has led to the cancellation of surgical placements for medical students and has affected surgical education. This study evaluates the perceptions and impact of a 1-day virtual surgical conference for medical students considering pursuing a surgical career. METHODS: All delegates of the 2021 Barts and The London International Surgical Conference were invited to participate in two online surveys pre- and post-conference. Data were collected and analysed to evaluate delegates' reasons for attending the conference, and attitudes towards virtual conferences and a surgical career before and after the conference. RESULTS: Out of 132 participants, 106 (80.3%) completed both the pre- and post-conference surveys. Clinical students showed a statistically significant difference in interest in pursuing a surgical career after the conference than before (P=0.03), unlike pre-clinical students (P=0.12). Post-conference, 43 (40.6%) preferred a virtual to a face-to-face conference, which was a slight increase from 40 (37.7%) pre-conference, while 73 (68.9%) and 80 (75.5%) participants favoured virtual talks and presentations respectively. In contrast, only 12 (11.3%) and 21 (19.8%) students preferred workshops and networking virtually. Furthermore, delegates liked the global accessibility and environmentally-friendly nature of virtual conferences but found they can be less engaging and be disrupted by a poor internet connection. CONCLUSIONS: Virtual surgical conferences have many benefits and can help encourage medical students towards a surgical career. They could help bridge the surgical educational gap in medical school during these unprecedented times. Virtual conferences, which have a broader and more inclusive reach, could be an important complement to conventional conferences after the pandemic.

FAAH and CNR1 Polymorphisms in the Endocannabinoid System and Alcohol-Related Sleep Quality.

Sleep disturbances are common among individuals with alcohol use disorder (AUD) and may not resolve completely with short-term abstinence from alcohol, potentially contributing to relapse to drinking. The endocannabinoid system (ECS) is associated with both sleep and alcohol consumption, and genetic variation in the ECS may underlie sleep-related phenotypes among individuals with AUD. In this study, we explored the influence of genetic variants in the ECS (Cannabinoid receptor 1/CNR1: rs806368, rs1049353, rs6454674, rs2180619, and Fatty Acid Amide Hydrolase/FAAH rs324420) on sleep quality in individuals with AUD (N = 497) and controls without AUD (N = 389). We assessed subjective sleep quality (from the Pittsburgh Sleep Quality Index/PSQI) for both groups at baseline and objective sleep efficiency and duration (using actigraphy) in a subset of individuals with AUD at baseline and after 4 weeks of inpatient treatment. We observed a dose-dependent relationship between alcohol consumption and sleep quality in both AUD and control groups. Sleep disturbance, a subscale measure in PSQI, differed significantly among CNR1 rs6454674 genotypes in both AUD (p = 0.015) and controls (p = 0.016). Only among controls, neuroticism personality scores mediated the relationship between genotype and sleep disturbance. Objective sleep measures (sleep efficiency, wake bouts and wake after sleep onset), differed significantly by CNR1 rs806368 genotype, both at baseline (p = 0.023, 0.029, 0.015, respectively) and at follow-up (p = 0.004, p = 0.006, p = 0.007, respectively), and by FAAH genotype for actigraphy recorded sleep duration at follow-up (p = 0.018). These relationships suggest a significant role of the ECS in alcohol-related sleep phenotypes.

Personality Profile and Short-term Treatment Outcome in Patients with Alcohol Dependence: A Study from South India.

BACKGROUND: Studying personality profiles allows researchers to generate important hypotheses in risk factors and correlates of alcohol use/misuse. Studies examining the association between personality traits and treatment outcome are limited in India. We studied the correlation between personality and treatment outcome in patients with alcohol dependence. METHODS: Adult participants with alcohol dependence were recruited from the inpatient and outpatient wards of de-addiction unit of a tertiary care facility in India using a prospective design and followed up after 3 months. Questionnaires administered were revised NEO personality inventory (NEO-PI-R), alcohol use disorders identification test, and advanced warning of alcohol relapse (AWARE). RESULTS: Out of 99 recruited participants (92% males) with mean age of 37 (±8.36) years, 82 (82.8%) patients were followed up to 3 months. E4 (activity) facet of the extraversion domain in the NEO-PI-R significantly correlated with the baseline drinking scores (r = 0.204, P = 0.042, n = 99) and AWARE scores (r = 0.276, P = 0.043, n = 54). There was a significant negative correlation between the E2 (gregariousness) facet and satisfaction with life scores (r = -0.211, P = 0.036, n = 99). Age at first drink was significantly lower among relapsers (P = 0.021). CONCLUSION: Our study suggests that factors related to extraversion, specifically, high activity might be associated with higher drinking as well as higher risk of alcohol relapse. Predicting alcohol relapse by studying the personality traits would help clinicians in improving treatment outcomes.