Search Results (305)

Background/Objectives: Sex differences in ethanol consumption have been reported in both humans and laboratory rodents, but the independent/dependent contributions of genetic and hormonal sex biasing mechanisms to these phenotypes have not yet been fully explored. Methods: To examine the contributions of sex-chromosome complement (SCC) and gonadal sex (GS) to ethanol consumption, we studied adolescent (28–32 days old) four core genotypes (FCG) mice on a C57BL/6J background, a model which allows for independent assortment of GS and SCC. A modified drinking-in-the-dark (DID) procedure was employed, in which mice were offered concurrent access to 20%, 10% and 0% ethanol (in water) in four daily 2 h sessions. Consumption at the level of individual bouts was recorded. Results: Overall ethanol intake differed substantially by group and was driven almost entirely by differences in consumption of the 20% ethanol solution; all groups preferred the 20% solution over the 10% and 0% solutions, but consumed similar amounts of the 10% and 0% solutions. Intake of the 20% ethanol solution followed the rank order XXM > XYM > XYF > XXF. This pattern reflects an interaction between SCC and GS, such that SCC effects were greatest in gonadal females (XY > XX), whereas GS effects were greatest in XX mice (gonadal males > gonadal females). Moreover, the magnitude of these effects varied both across and within drinking sessions. The behavioral microstructure of ethanol consumption (i.e., parameterization of within-session discriminable drinking bouts) support the validity of our three-bottle modification of the DID procedure as a model of binge-like consumption, because (1) the consumption rate of the 20% ethanol solution was ~80 g EtOH/kg/h within a bout (~12 s/bout, ~three bouts/session), (2) most of this ethanol consumption was completed in a single bout and (3) within-session ethanol consumption was greater earlier than later, indicating “front loading.” Conclusions: These results suggest that the effects of GS on binge-like ethanol consumption are observed in early adolescence and moderated by SCC in adolescent FCG mice, with GS effects most pronounced in XX mice and SCC effects evident mainly in gonadal females. Full article

Background and Objectives: Sleep is a vital psychological function for health and well-being in all age groups, from children to adolescents, to adults and the elderly, and impacts quality of life. This study evaluated temporal changes in sleep quality and lifestyle behaviors among medical students in North-Western Romania (Transylvania) between the COVID-19 pandemic and the post-pandemic period. Materials and Methods: A cross-sectional design was employed involving 709 medical students assessed during the first pandemic wave (2020) and the 2023–2024 academic year. Online questionnaires collected data on demographics, body mass index (BMI), substance use, and physical activity. Sleep quality was measured using the validated Athens Insomnia Scale (AIS), and multiple linear regression was performed to identify predictors of sleep outcomes. Results: Post-pandemic data revealed a significant decline in sleep quality, with female gender and lower academic performance identified as significant predictors of insomnia symptoms (R² of 0.258, p < 0.05). While physical activity levels improved significantly in 2024 compared to the confinement period, this was accompanied by increased fast-food consumption and a rise in overweight and obesity rates. Conversely, illicit drug use decreased, and alcohol consumption patterns shifted, characterized by reduced weekly frequency among females but persistent binge drinking episodes. Conclusions: The transition to post-pandemic education yielded mixed health outcomes; while physical activity rebounded, sleep quality and nutritional status deteriorated. These findings highlight the necessity for university-based interventions focusing on sleep hygiene, nutrition, and stress management to support the well-being of medical students. Full article

This observational study examined the association between binge drinking and a binary measure of participation in physical activity (PPA) in veterans and nonveterans using pooled 2021–2023 Behavioral Risk Factor Surveillance System data (n = 107,498). Multivariable survey-weighted logistic regression models were stratified by veteran status and adjusted for sociodemographic and health characteristics. Veterans were older than nonveterans (mean age: 60.8 vs. 51.4 years) and slightly less likely to report PPA (80.8% vs. 83.4%). Among veterans, binge drinking days were inversely associated with PPA (aOR = 0.98, p = 0.01), indicating lower odds of physical activity with increasing binge drinking days. A similar but stronger association was observed among nonveterans (aOR = 0.98, p < 0.001). These findings suggest that binge drinking is associated with reduced PPA among veterans and nonveterans. Full article

Alcoholic liver disease (ALD), secondary to chronic alcohol abuse, encompasses a spectrum of liver disorders that progress from steatosis and hepatitis to fibrosis, cirrhosis, and acute-on-chronic liver failure. It poses a considerable global health burden due to its elevated rates of associated morbidity and mortality. The rising prevalence of ALD, coupled with the lack of approved pharmacotherapies, presents considerable unmet clinical needs. In this study, long-chain acyl-CoA synthetase 4 (ACSL4) was identified as a pathogenic driver in the context of chronic alcohol consumption. Hepatocyte Acsl4 ablation mitigated key pathological manifestations in Gao-Binge model mice, as evidenced by reduced inflammatory cell infiltration and attenuated lipid accumulation. Mechanistically, ACSL4 inhibition augmented cellular antioxidant defence through elevating gamma-glutamylcysteine (γ-GC) levels. In addition, γ-GC bound to and suppressed the expression of protein tyrosine phosphatase type IVA member 1 (PTP4A1). Both genetic silencing and pharmacological inhibition of PTP4A1 attenuated the activation of the downstream MAPK-NF-κB inflammatory cascade. Dronedarone, identified as a novel compound targeting ACSL4, demonstrated efficacy in ameliorating the progression of ALD. Overall, these findings elucidate a novel mechanism wherein ACSL4 modulates antioxidant responses via a small bioactive peptide, highlighting ACSL4 as a potential therapeutic target for ALD. Full article

Atrial septal defect (ASD) affects 1:11.3 children in some US states; however, the antecedents of these trends are yet to be identified. A total of 1882 ASD rates (ASDRs) for 2003–2020 were sourced from the National Birth Defects Prevention Network reports. A total of 406,893 ASDs are reported. Substance (cigarettes, binge alcohol, cannabis, cannabinoids, analgesics, cocaine) exposure data were taken from the National Survey of Drug Use and Health. Income and ethnicity data were derived from the US Census. Adjustment was performed by mixed effects, survey and generalized additive regression. Causal analysis was by inverse probability weighting and E-values. Data were analyzed in RStudio. The highest ASDR of 884/10,000 live births was amongst Non-Hispanic Asians and Pacific Islanders in Nevada in 2016–2020. The 2005–2018 median ASDR rose >12-fold in Nevada and New Mexico, >6-fold in New York, and 4.2-fold nationally 1989–2020; it doubled in NY from 2012–2016 to 2016–2020. The average state ASDR rose supra-exponentially (p = 0.0075) and was associated with higher cannabis use states (p = Zero, Cohen’s D = 1.24), apparently driven by cannabis legalization (p = Zero). Estimated exposures to Δ9THC, cannabidiol and cannabigerol were implicated (from p = 2.67 × 10^–68). Cannabis-legal states were compared with others (mean ASDR (C.I.) 178.15 (131.68, 224.62) vs. 74.28 (70.60, 77.96), p = Zero; O.R. 1.82 (1.81, 1.84), E-values 3.04 (lower C.I. 3.02), Cohen’s D 1.29 (0.96, 1.62)). Overall, 29/39 (74.4%) E-value estimates were >4; 39/39 (100%) were >1.25. Cannabis, cannabinoids and cannabis legalization are strong candidates for driving the US ASDR supra-exponentially. Estimates of many cannabinoids, including cannabidiol, Δ9THC, and cannabigerol, are implicated. The results are consistent with other large epidemiological studies. The importance of the results is magnified by the increasing legalization and penetration of cannabinoids into the US population. Since therapeutic abortion is not practiced for ASD, it may be used as a bellwether index of heritable transgenerational cannabinoid genotoxicity and epigenotoxicity associated with cannabinoid exposure. Full article

Background: Alcohol is associated with increased mortality and morbidity globally. Pulmonary infections with opportunistic pathogens can occur in healthy humans; however, binge alcohol intoxication (≥0.08% BAC) is a major risk factor. We have previously shown that a single dose of alcohol comparable to binge alcohol intoxication increases infection by reducing alveolar macrophage function in vivo. Sulforaphane (SFN), a phytonutrient, is a potent inducer of antioxidant production through the induction of nuclear factor erythroid 2-related factor 2 (Nrf2) and inhibition of the nuclear factor kappa-light-chain-enhancer (NF-kB) pathway. The aim of this study was to test the therapeutic potential of SFN given as a pretreatment to prevent alcohol-induced phagocytic dysfunction. Methods: Intracellular phagocytic killing was measured via colony-forming units (CFU) and cytokine expression via ELISA. G. mellonella survival was used to determine the therapeutic potential of SFN in vivo. Results: Dose–response curves indicated that SFN concentrations of less than 20 µM were not cytotoxic in either MH-S (murine) or THP-1 (human) cells. Live infection assay results showed that MH-S and THP-1 cells pretreated with SFN (5 µM) and challenged with 0.2% (v/v) alcohol for 3 or 8 h prior to live B. thailandensis or S. epidermidis infection improved intracellular pathogen killing between 12- and 20-fold compared to macrophages treated with alcohol alone. ELISA analysis indicated that SFN significantly reduced levels of Tumor necrosis factor-alpha (TNF-α) expression at 3 and 8 h compared to controls. Additionally, a Galleria mellonella larvae model demonstrated greater survivability in the prophylaxis group compared to larvae exposed to either Gram-positive or Gram-negative pathogens, as well as in groups that received alcohol prior to pathogen inoculation. Conclusions: Taken together, SFN-induced cytoprotection was extended beyond in vitro cell culture to include an in vivo G. mellonella model demonstrating protection against Gram-positive and negative opportunistic pathogens. These data demonstrate that SFN may be an effective pretreatment option to prevent alcohol-mediated innate immune dysfunction and restore macrophage phagocytic killing. Full article

Excessive alcohol consumption promotes clinical myopathy and injury-related immobilization. Because both alcohol and disuse jeopardize muscle health, their combined effects may synergistically accelerate fiber type-dependent muscle wasting. Ten-week-old male C57BL/6J mice were fed a control or 5% alcohol-diet for 3 weeks (NIAAA-model), with or without 1 week of unilateral hindlimb immobilization, generating four sets of limb muscles (n = 9/grp): control (CO), with immobilization (CI), alcohol (AL), with immobilization (AI). Gastrocnemius and soleus muscles were atrophied by CI, AL, and AI, whereas quadriceps atrophy was induced by CI and AI only (all p < 0.05). In soleus, CI, AL, and AL decreased p-mTOR (~40–60%, p < 0.01) and p-p70S6K (~50–87%, p < 0.05), indicating suppressed anabolic signaling. In contrast, in the quadriceps, alcohol increased p-4EBP1 by ~200% (p < 0.01), while p-Akt was elevated by ~180%, only in AI (p < 0.01). Myogenesis signaling was inhibited by alcohol and immobilization. For protein degradation, immobilization increased MAFbx by >50% in both muscles (p < 0.01). Quadriceps exhibited increased p-PERK (+53%) under AI (p < 0.05), whereas several markers of ER stress were reduced by all interventions in soleus (p < 0.05). These findings suggest that alcohol consumption does not exacerbate immobilization-induced atrophy; however, alcohol suppresses anabolic signaling in soleus, suggesting greater susceptibility to myopathy. Full article

Firefighters face elevated risks of alcohol misuse due to occupational stress, trauma exposure, and cultural norms within the fire service. This beta test study evaluated the feasibility, acceptability, and preliminary outcomes of From Bottle to Nozzle, a digitally delivered alcohol awareness and prevention intervention tailored for firefighters. Fifty fire service personnel were invited to participate; 46 consented and completed baseline questionnaires, and 22 completed the full program. The intervention consisted of five self-paced online modules incorporating multimedia content, quizzes, and self-assessments that addressed alcohol history, fire service culture, risk-reduction strategies, communication, and health effects. Pre- and post-intervention assessments measured changes in alcohol-related knowledge, alcohol use, motivation to reduce drinking, and usability. Reinforcement messages were delivered via text and email. Alcohol-related knowledge improved significantly post-intervention, particularly in the general and total knowledge domains. Moderate drinkers showed reductions in drinking days and AUDIT scores. Among heavy drinkers, overall consumption declined slightly, though binge-drinking episodes increased. Changes in motivation to reduce drinking were mixed. Usability ratings were high, with an 80% module completion rate and favorable feedback on program brevity and format, though navigation and video length were noted as challenges. From Bottle to Nozzle demonstrated strong feasibility and acceptability. While knowledge gains were robust, behavioral outcomes were mixed, highlighting the need for larger controlled studies with extended follow-up. Full article

Nicotine vaping has surged in recent years, particularly among young adults, and is strongly linked with concurrent alcohol use. Separately, chronic excessive alcohol use drives hypertension and cardiomyopathy, while nicotine vaping is linked to a modest rise in cardiovascular disease incidence and mortality. However, little is known about how concurrent use interacts to affect protein expression in the cardiovascular system. The aim of this study was to determine differential cardiac protein expression in mice exposed to concurrent chronic-plus-binge alcohol and nicotine vaping use. Male C57BL6/J mice received a 20-day 5% ethanol diet with 5 g/kg ethanol binges on days 10 and 20, alongside isocaloric controls. During this period, they were also exposed nightly to either 5% nicotine salt vapor, vegetable glycerin/propylene glycol vehicle vapor, or room air. The left ventricular free wall was collected and analyzed using discovery-based proteomics and subsequent Ingenuity Pathway Analysis. A total of 3144 proteins were identified across all groups. Compared to air-exposed, control-fed mice, 201 proteins were significantly altered by ethanol, 101 proteins by nicotine vaping, and 159 proteins by combined exposure. Both ethanol and nicotine vaping influenced pathways involved in lipid homeostasis, extracellular matrix remodeling, and mitochondrial bioenergetics; however, these alterations did not uniformly manifest in the dual-use group. This pattern highlights the nonadditive and potentially interaction-dependent nature of alcohol and nicotine vaping effects on cardiovascular protein expression patterns that may contribute to a distinct functional phenotype. Full article

Substance use, a significant public health concern, may be associated with worsening social connections and feelings of loneliness among adult populations. This study examined the associations between substance use (i.e., binge alcohol, e-cigarette, and traditional cigarette use) and loneliness among adults aged ≥50 years residing in the US. We conducted a secondary analysis of cross-sectional data from the 2023 Behavioral Risk Factor Surveillance System Social Determinant of Health Equity module. The sample included 138,614 adults aged ≥50 years, representing approximately 55.4 million individuals in this age group. Substance use was the key independent variable and categorized into two groups: no substance use and substance use—participants who reported current use of ≥1 of three substances (i.e., binge alcohol, e-cigarette, and traditional cigarette use). Overall, 19.0% of participants reported using ≥1 substance use, 21.0% reported feeling lonely sometimes, and 5.1% feeling lonely always/usually. Participants who reported using ≥1 substance had a 17.0% higher relative risk of feeling lonely always/usually (compared to feeling never/rarely lonely) than adults who did not report substance use, after adjusting for all covariates (RRR 1.17; 95% CI 1.10–1.35; p = 0.029). These findings underscore the strong link between substance use and loneliness among midlife and older adults. Full article

Background: Alcohol use disorder (AUD) is associated with chronic heavy or repeated binge alcohol abuse, which can cause alcohol-related brain damage (ARBD) marked by neurobehavioral, cognitive, and motor deficits. The anterior frontal lobe and cerebellar vermis are two of the major targets of ARBD in humans with AUD and in experimental alcohol exposed models. Alcohol’s neurotoxic and neurodegenerative effects include impairments in signaling through insulin and insulin-like growth factor (IGF) pathways that regulate energy metabolism. This human AUD study was inspired by a recent report suggesting that dysfunction of the frontal lobe incretin network in experimental ARBD is linked to known impairments in brain insulin/IGF signaling. Objective: The overarching goal was to investigate whether AUD is associated with dysfunction of the brain’s incretin network, focusing on the cerebellum and frontal lobe. Methods: Fresh frozen postmortem cerebellar vermis and anterior frontal lobe tissues from adult male AUD (n = 6) and control (n = 6) donors were processed for protein extraction. Duplex enzyme-linked immunosorbent assays (ELISAs) were used to assess immunoreactivity to neurofilament light chain (NfL) as a marker of neurodegeneration. A multiplex ELISA was used to measure immunoreactivity to a panel of gut hormones, including incretin polypeptides. Results: AUD was associated with significantly increased NfL immunoreactivity in both the cerebellar vermis and anterior frontal lobe. However, the patterns of AUD-related alterations in gut hormone immunoreactivity differed regionally. AUD reduced pancreatic polypeptide immunoreactivity in the cerebellar vermis, and GIP, GLP-1, leptin, and ghrelin in the frontal lobe. Conclusions: (1) Increased NfL may serve as a useful biomarker of neurodegeneration in AUD. (2) AUD’s adverse effects on neuroendocrine signaling networks differ in the cerebellar vermis and anterior frontal region, although both are significant targets of ARBD. (3) The finding of AUD-associated reductions in frontal lobe GIP and GLP-1 suggests that therapeutic targeting with incretin receptor agonists may help restore energy metabolism and neurobehavioral and cognitive functions linked to their networks. Full article

Background: Due to variability in patterns of consumption as well as well-known difficulties in obtaining valid self-report from heavy drinkers, quantifying the effects of heavy alcohol consumption on mortality is challenging. Using a DNA methylation biomarker of chronic heavy alcohol consumption (HAC) named the alcohol T-score (ATS), we previously showed that chronic HAC was a strong predictor of mortality. However, whether there is a similar effect when measures of shorter-term heavy alcohol use, i.e., recent “binge” drinking, were used to predict mortality was not examined. This is a critical issue because most biomarkers of HAC assess only short-term HAC. Methods: Therefore, we examined the prediction of all-cause mortality from a DNA methylation biomarker of smoking (cg05575921), the ATS and a short-term biomarker of recent heavy alcohol use (cg07375256) in 708 subjects from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial using Cox Proportional Hazards Regression Modeling. Models were compared using Akaike’s Information Criterion. Results: The ATS was the best single predictor among three-variable models that included controls for sex and age. Of the possible four variable models, the model consisting of age, sex, cg05575921 methylation and ATS best predicted mortality. The addition of cg07375256 methylation did not improve model performance. In sensitivity analyses using only participants who provided alcohol SR (n = 639), the importance of the ATS and cg05575921 was replicated. We also found that ATS values were higher among those who declined to provide self-report alcohol use, indicating that missing self-report data about alcohol intake are not missing at random, and sometimes reflects elevated alcohol consumption. Finally, cg05575921 methylation was strongly associated with ATS values but only weakly with alcohol SR and not at all with cg07375256 methylation. Conclusions: Accordingly, this study indicates a strong effect of chronic HAC, but not short-term HAC, on mortality, further highlights the limitations of self-reported alcohol use in the prediction of all-cause mortality and indicates the value of assessing HAC in addition to smoking. Full article

Background/Objectives: Since 1988, the IARC has classified alcohol as a type 1 carcinogen, causally linked to seven types of cancer (oral cavity, pharynx, larynx, esophagus, colorectum, liver and breast carcinomas). Several agencies, such as the WHO and the IARC, hold that there is a direct monotonic association between any gram of alcohol consumed and the risk of cancer, regardless of the drinking pattern. On the other hand, an expanding body of evidence indicates that drinking pattern may substantially modify the effect of alcohol consumption. The Mediterranean alcohol-drinking pattern (MADP) includes different aspects of alcohol consumption, such as preference for red wine, moderate alcohol consumption with meals, spreading consumption over the week and avoiding binge drinking. Conformity to this pattern has shown inverse associations with all-cause mortality, cardiovascular disease and diabetes. However, its relationship with cancer incidence has not been studied yet. Our objective was to assess how alcohol consumption patterns, with particular emphasis on the MADP, relate to the incidence of the seven alcohol-related cancers. This information is needed to support cancer prevention recommendations that may go beyond the amount of alcohol consumed to also include the drinking pattern. Methods: We prospectively followed 19,541 participants in the SUN (“Seguimiento Universidad de Navarra”) cohort for a median of 13.8 years. We classified participants into four groups, namely, abstainers and three further groups according to their adherence to the MADP score (low, moderate and high). Results: A substantial reduction in the risk of alcohol-related cancer incidence was observed only in men for high versus low adherence to the MADP, with an adjusted hazard ratio (HR) of 0.44 (95% confidence intervals (CIs) (0.21–0.92)). The category of moderate adherence to the MADP showed a lower risk of cancer incidence with a tendency towards statistical significance (HR = 0.56, 95% CI, 0.30–1.06). For women, no result reached statistical significance. Conclusions: Based on the available evidence, separate messages by sex should be delivered. In men, the association between alcohol and cancer goes beyond the amount of alcohol consumed, and a Mediterranean drinking pattern may be beneficial even for alcohol-related cancers. Men should, therefore, receive an additional message: among alcohol consumers, greater adherence to the MADP may help lower their risk of developing alcohol-related cancers. No benefit is supported for the MADP against alcohol-related cancers in women. Full article

Adolescence is a critical period during which alcohol is the most commonly used substance worldwide, and such use has detrimental effects on neurobiological, psychosocial, and physiological development. Despite substantial international evidence, little is known about the concurrent influence of drinking motives and internalizing symptoms on adolescent alcohol use, particularly in the Croatian context, where adolescent drinking rates remain high. A cross-sectional study using a survey questionnaire was conducted in 2024 in Split-Dalmatia County, Croatia. The final stratified cluster sample comprised 925 students (58.8% of the planned sample), with a mean age of 15.41 years. Using hierarchical regression analysis, the results showed that the final model, which included both drinking motives and mental health indicators, explained 39.6% of the variance in alcohol use, 37.2% of the variance in binge drinking, and 31.8% of the variance in alcohol intoxication. Male sex was consistently associated with all three outcomes, whereas age was positively associated with alcohol use and binge drinking. Drinking motives contributed the largest proportion of the explained variance. Furthermore, lower levels of loneliness and higher levels of anxiety were associated with more frequent alcohol use, while lower stress and higher anxiety were associated with more frequent intoxication. Drinking motives are stronger predictors of adolescent alcohol use and risky drinking patterns than internalizing symptoms whose predictive strength was generally small. Prevention programs should address aspects of drinking motives in addition to promoting mental health. Full article

Background: The use of electronic cigarettes (ECs) has become a significant public health problem, especially among young people. EC use has been associated with increased nicotine exposure and other toxic substances, increasing the risk of early addiction and health problems. Recently, attention has focused on understanding the interplay between psychosocial stressors, exposure to violence, psychological distress, and an increased propensity to experiment with nicotine. Hence, the aim of this study was to estimate the prevalence of EC use in the previous month and its associated factors. Methods: This is a cross-sectional study based on secondary data analysis of a nationwide survey conducted to monitor risk and protective factors for the health of school-aged adolescents (52.89% males; 55.97% aged up to 15 years old). Specifically, we analyzed data from adolescents aged 13–17 years who answered questions on EC use (n = 36,659). Results: The results show that the prevalence of EC use in this sample was 11.23% (IC95%: 11.23, 11.87). Logistic regression revealed several factors that increased the likelihood of EC use, such as alcohol use by friends, alcohol use in the past month, gender (male), intentional binge drinking, higher mental health symptoms, living in urban areas, experience of abuse at home, report of other drug use, and smoking friends, with the latter exerting a higher influence. Conclusion: Findings show the interplay of peers, family and environmental influences on youth risk behavior. Prevention strategies should therefore include school- and family-based interventions, trauma-informed approaches and anti-marketing campaigns to dispel misconceptions regarding EC. Full article