BACKGROUND:Both all-cause and alcohol mortality follow a social gradient. Studies have provided evidence of interaction between socioeconomic status (SES) and alcohol use in predicting alcohol-attributable mortality. It is unclear whether this holds true for all-cause mortality. This study examines interaction effects and investigates the role of biomarkers in all-cause mortality. METHODS:We included data from 4307 participants of the baseline survey (1997-2001) of SHIP (Study of Health in Pomerania)-START and a mortality follow-up from baseline until January 2023. All-cause mortality was the outcome; exposure variables were income or education as SES proxies, alcohol use, and biomarkers related to chronic alcohol consumption. Confounders were age, sex, marital status, smoking, and Body Mass Index (BMI). We used Cox proportional hazards regression (CPHR) in main analyses and CPHR and Aalen additive hazards regression (AAHR) in interaction analyses. RESULTS:Our final samples (either with income or education) consisted of 3771/3939 individuals of whom 981 (26.0%) and 1047 (28.6%) died during the follow-up period. Adjusting for confounders, individuals with low income (HR = 1.31, CI = 1.11, 1.56; compared to high income) and both current abstainers that formerly consumed alcohol (HR = 1.56, CI = 1.27, 1.92) and individuals with high alcohol intake (HR = 1.31, CI = 1.03, 1.66; compared to individuals with low alcohol intake) showed increased mortality. Biomarkers were positively associated with mortality. There was evidence of statistical interaction effects, for example, increased risks in low-income current abstainers as well as individuals with moderate or high alcohol use. CONCLUSIONS:We found a social gradient in all-cause mortality that was attenuated, but not fully explained, by risk factors. There was some evidence of statistical interaction effects between alcohol use and SES, but small subgroup counts limit the certainty of related conclusions.
BACKGROUND:Longitudinal excessive alcohol consumption has adverse effects on brain structure and functions. The immediate effects of alcohol consumption on the activity and functioning of different circuits in the brain are less known. This exploratory study aimed to examine the effects of acute alcohol exposure on cortical activity in healthy adults. METHODS:The study included 34 adults, aged 29-36 years, who took part in the Youth and Alcohol Project's (YAP) alcohol exposure test. The participants' alcohol consumption was measured with the shortened version of the Alcohol Use Disorders Identification Test (AUDIT-C). Cortical functioning was investigated at baseline (BL) before alcohol intoxication, and 30 min (T2) and 120 min (T3) after alcohol intoxication using navigated transcranial magnetic stimulation combined with electroencephalography (TMS-EEG), focusing on TMS-evoked EEG potential (TEP) peaks P30, N45, P60, N100, and P180. The blood alcohol level was monitored using an alcohol breathalyzer. RESULTS:During alcohol intoxication, there were changes in the global mean field power (GMFP) and TEP magnitudes compared to BL. After alcohol consumption, the global mean field power (GMFP) amplitude decreased from approximately 80 ms poststimulus onward. For P30, N45, P60, and P180, the mean amplitude decreased in T2 compared to BL and recovered in T3. For N100, the mean amplitude decreased in T2 and in T3. Differences in TEP peaks between BL and T2 or BL and T3 were emphasized in frontal and central brain regions. CONCLUSIONS:The results suggest time-dependent and region-specific modulation of cortical excitability during acute alcohol intoxication. Alcohol's effects are dynamic, regionally heterogeneous, and not limited to simple global suppression. TMS-EEG offers a promising tool for assessing alcohol-related changes in cortical functions.
BACKGROUND:Alcohol use disorder (AUD) is often comorbid with depressive disorders such as major depressive disorder (MDD). These comorbidities are often modeled by allowing C57BL/6 (B6) mice to drink alcohol and testing for depressive- and anxiety-like phenotypes 2-3 weeks into abstinence; however, it should be noted that B6 mice are both inbred, which may limit external validity, and show modest intakes compared to humans with AUD. We have created a new selectively bred line of high alcohol-preferring mice, the crossed High Alcohol Preferring X High Drinking-in-the-Dark mice (cHAPxHDIDs). The cHAPxHDID mice have not been explored as a model of AUD + MDD comorbidity, nor has their drinking propensity been characterized in any publication to date. METHODS:We used male and female cHAPxHDID mice and a home cage 2-bottle choice (2BC) paradigm (water/water v. 10% ethanol/water) for 5 weeks across three experiments. We characterized the cHAPxHDIDs' 2BC drinking by measuring intake over a day, along with blood ethanol concentrations (BECs). Additionally, we ran behavioral tests for negative affect at different timepoints in abstinence. Finally, we also probed for the emergence and sustenance of anhedonia during the drinking period with a modified 1% sucrose preference test (SPT). RESULTS:We found that cHAPxHDID mice drink excessively, especially at the onset of the dark cycle, and achieve average BECs higher than 300 mg/dL. Ethanol drinkers showed increased latency in the novelty-suppressed feeding test (NSFT) at 6 days into abstinence. Alcohol-drinking mice reduced their sucrose intake during the drinking period beginning in Week 2, which normalizes at 48 h into abstinence. CONCLUSIONS:The cHAPxHDIDs show some evidence of depressive symptomatology after and during drinking. They drink excessive amounts of alcohol voluntarily, reaching high and sustained BECs. Taken together, our data suggest that the cHAPxHDIDs may be a promising model for excessive drinking and its mood-related comorbidities.
BACKGROUND:The field's conventional understanding of how genetic factors impact risk for alcohol use disorder (AUD) typically focuses on direct genetic effects, or how an individual's own genetic predispositions are associated with the likelihood of experiencing clinically significant alcohol problems. More recently, studies of behavioral health outcomes in preclinical and human studies have demonstrated the potential importance of social genetic effects or the influence of a social partner's genotype on substance use and related outcomes. In this study, we sought to characterize social genetic effects for AUD, specifically in the context of marriage. METHODS:The sample included 660 opposite-sex spousal dyads from the Collaborative Study on the Genetics of Alcoholism, restricted to individuals who were genetically similar to European reference panels. Measured and latent indicators of genetic risk included polygenic scores of problematic alcohol use (PGSPAU) and parental history of AUD (PHAUD), respectively. The outcome was Diaganostic and Statistical Manual (DSM)-5 alcohol use disorder criterion count (AUDcrit) during marriage. Multilevel models accounted for the non-independence of partners' data, including correlations between partners' genetic risk and residual covariance in AUDcrit. RESULTS:After accounting for direct genetic effects (i.e., the influence of one's own genetic predispositions) and the correlations between partners' genetic predispositions, we found that having a spouse with higher PGSPAU was associated with higher AUDcrit (B = 0.084, 95% CI [0.035, 0.132]). This social genetic effect was robust after adjusting for both partners' educational attainment. Spousal PHAUD was not associated with AUDcrit. Exploratory analyses indicated that the social genetic effect of spousal PGSPAU was stronger among male target individuals. CONCLUSIONS:Findings highlight the potential importance of social genetic effects for understanding the pathways from genotype to alcohol use disorder and the need for further investigation of latent measures of genetic predispositions in studies of social genetic effects.
BACKGROUND:Histone deacetylase 6 (HDAC6) inhibition can alleviate depression- and anxiety-like behaviors. Accordingly, HDAC6 may be a promising target to mitigate negative reinforcement in alcohol use disorder (AUD). We previously reported reduced α-tubulin acetylation in mice withdrawn from chronic intermittent ethanol (CIE) vapor inhalation, suggesting potential HDAC6 hyperactivity in this mouse model of AUD. The present study aimed to probe the behavioral significance of this acetylation deficit by testing whether HDAC6 inhibition can reverse ethanol drinking escalation in CIE-exposed mice. METHODS:Male C57BL/6J mice were subjected to limited-access ethanol drinking sessions (two-bottle choice, 2BC) combined with CIE to escalate voluntary ethanol intake relative to air-exposed counterparts (Air). Ethanol and saccharin intake during 2BC was measured after acute and subchronic administration of bavarostat, a brain-penetrant HDAC6 inhibitor. Acetyl-lysine and acetyl-α-tubulin levels were quantified via immunoblotting. RESULTS:Acute administration of bavarostat at 100 mg/kg, but not lower doses, significantly reduced ethanol intake in both Air and CIE mice. Ethanol intake during subchronic administration of 100 mg/kg bavarostat was reduced on the first day in both Air and CIE mice compared to vehicle-treated counterparts, but this effect was lost on subsequent days. CIE mice also consumed more saccharin than Air controls. Bavarostat did not impact saccharin intake in either group. When saccharin was offered along with ethanol, CIE mice consumed significantly more ethanol and less saccharin than Air counterparts, indicating intact taste discrimination. Bavarostat administered prior to brain collection significantly increased acetyl-lysine and acetyl-α-tubulin levels in the frontal cortex, confirming reduced HDAC6 activity. These levels did not differ between Air and CIE mice. CONCLUSIONS:Systemic administration of bavarostat reduces voluntary ethanol drinking in mice. This effect is dose-dependent, selective for ethanol, independent of ethanol dependence, and transient. These findings support HDAC6 as a viable target to acutely reduce the drive to consume ethanol.
BACKGROUND:Alcohol consumption and aging are factors promoting osteopenia and osteoporosis. How these factors interact is poorly understood. To investigate this relationship, a binge ethanol exposure model in mice was used to determine how aging affects skeletal responses to binge ethanol. METHODS:Dmp1-Cre TdTomato mice with the fluorescent marker TdTomato expressed in osteoblasts and osteocytes, and control mice without Cre expression were used. Mice of both sexes at 12 weeks and 78 weeks of age were gavaged for four consecutive days with 3, 3, 4, and 4.5 g of ethanol/kg of body weight or with PBS (control). Skeletal responses were determined by serum bone turnover markers using ELISA and by gene expression and protein measurement in the femoral shaft and lumbar vertebrae using qRT-PCR and western blots. RESULTS:Ethanol and aging both significantly decreased serum levels of Procollagen Type I (P1NP) and osteocalcin, indicating reduced bone formation. Serum levels of C-terminal telopeptide of type I collagen (CTX-1) increased significantly with ethanol exposure in the aging mice, reflecting enhanced bone resorption. In the femoral shaft, ethanol and aging increased the expression of genes involved in osteoclast activation, Calcitonin receptor (Calcr) and RANKL, with a significantly larger induction of receptor activator of nuclear factor-κB ligand (RANKL) mRNA in 78-week-old than 12-week-old mice. Expression of osteoblast-associated genes, Collagen Type I Alpha 1 Chain (Col1a1), Collagen Type I Alpha 2 Chain (Col1a2), and Sphingomyelin phosphodiesterase 3 (Smpd3), was downregulated by ethanol, with stronger ethanol-mediated reduction in the 78-week-old than 12-week-old mice. Aging did not decrease the expression of TdTomato mRNA or TdTomato protein, indicating no overall loss of osteoblasts and osteocytes. CONCLUSIONS:Binge ethanol exposure and aging independently and synergistically disrupt bone remodeling by inhibiting bone formation and enhancing bone resorption.
BACKGROUND:Alcohol-associated hepatitis (AH) has high short-term mortality, whereas current prognostic models mainly reflect liver and renal dysfunction. The Metabolic Vulnerability Index (MVX) is a nuclear magnetic resonance-derived score comprising the Inflammation Vulnerability Index (IVX; small high-density lipoprotein particles [S-HDL-P] and GlycA) and the Metabolic Malnutrition Index (MMX). We evaluated whether MVX, IVX, and IVX components improve 90-day mortality prediction beyond Model for End-Stage Liver Disease (MELD) in AH. METHODS:Serum samples from 196 patients with AH, 169 heavy-drinking controls, and 351 healthy controls were analyzed by nuclear magnetic resonance spectroscopy. The primary outcome was 90-day AH-related mortality. Biomarkers were modeled continuously after standardization within the AH cohort; S-HDL-P was modeled per 1 SD decrease. Cox models were adjusted for MELD, age, sex, white blood cell count, and baseline antibiotic or corticosteroid use. Model performance was assessed using Akaike information criterion (AIC), likelihood-ratio testing, and Harrell's C-statistic. RESULTS:Among patients with AH, 30 AH-related deaths occurred within 90 days (15.3%). IVX and MVX were highest in AH cases and increased with AH severity, whereas MMX did not consistently differentiate severity. Lower S-HDL-P was independently associated with 90-day mortality in fully adjusted models (HR, 1.84; 95% CI, 1.01-3.35; p = 0.045), whereas GlycA was not (HR, 0.86; 95% CI, 0.54-1.37; p = 0.527). Adding S-HDL-P improved fully adjusted MELD-based model fit (AIC, 298.97 vs. 301.46; LR p = 0.034; C-statistic, 0.741 vs. 0.729). IVX showed supportive improvement in model fit and discrimination (AIC, 299.81; LR p = 0.056; C-statistic, 0.749). Continuous MELD interaction analyses supported risk separation for S-HDL-P (LR χ2 = 6.20; p = 0.045) and IVX (LR χ2 = 6.64; p = 0.036). CONCLUSIONS:Lower S-HDL-P appears to be the principal short-term prognostic component within the IVX domain in AH. S-HDL-P and IVX may refine MELD-based 90-day risk stratification, pending external validation.
BACKGROUND:The objective of this study was to characterize facial dysmorphology in a self-identified African-American cohort of children with prenatal alcohol exposure (PAE) and to evaluate the utility of computer vision-based methods for quantitative assessment and screening of facial form. METHODS:A total of 307 self-identified African-American individuals were evaluated by expert dysmorphologists and classified according to PAE status as unexposed controls (controls), individuals with prenatal alcohol exposed without fetal alcohol syndrome (FAS)-associated physical features (AE), or individuals with prenatal alcohol exposed with FAS-associated physical features (AE-FAS). Three-dimensional (3D) facial images were analyzed using volumetric and measurement-based approaches. Statistical shape modeling was applied to support surface-based analysis, cluster identification, and group discrimination testing. RESULTS:(i) Facial growth in the AE-FAS group was significantly reduced. (ii) We observed a subgroup of AE clinically without FAS-associated physical features who displayed an affinity to the AE-FAS group in the unscaled models. (iii) Sex-stratified analyses revealed alcohol-associated alterations in sexual dimorphism of facial morphology, with a substantially stronger association between PAE and reduced facial growth in females than in males. (iv) Unique patterns of facial dysmorphology were exhibited in the AE group, showing underdevelopment of the zygomatic arch. (v) Using closest mean, support vector machine, and linear discriminant analysis, discrimination between AE-FAS and controls was moderate. CONCLUSIONS:3D facial analysis facilitates recognition of potential sex-related differences in facial morphology associated with PAE in African-American children, a population underrepresented in the clinical literature. The distinct patterns of dysmorphology observed may contribute to improved phenotypic characterization and diagnostic support.
BACKGROUND:Most people with alcohol use disorder (AUD) do not receive treatment. Few digital evidence-based treatments have been tested among community-based samples of people with AUD. The present trial of Computer-Based Training for Cognitive Behavioral Therapy (CBT4CBT) (1) assessed CBT4CBT usability and acceptability and (2) explored alcohol-related outcomes by study condition in a non-treatment sample of people with AUD. METHODS:For the current two-arm clinical trial, a non-treatment sample of people with lifetime AUD and current heavy drinking was recruited using ResearchMatch.org and randomized (3:1) to the CBT4CBT program or an assessment-only control, stratified by sex (N = 160 total; CBT: n = 109; Co: n = 51). Study assessments included post-intervention acceptability ratings and self-reported alcohol-related measures administered at baseline, post-intervention, and 1-month follow-up. RESULTS:Participants were 68.1% female and 31.9% male, in their early forties (M = 42.6, SD = 15.7, range 19-76 years). Most participants identified as white (65.0%) or Black (27.5%) and non-Latinx (89.4%). Acceptability ratings and usability measures for CBT4CBT were favorable and comparable to studies among clinical treatment samples. Participants in the CBT4CBT group demonstrated faster reductions in the percentage of drinking days and were significantly less likely to report any heavy drinking days than those in the control condition at 1-month follow-up. The CBT4CBT group reported higher recovery scores than the control group. CONCLUSIONS:The present study provides benchmark data on the use of CBT4CBT in a sample of people with AUD not receiving treatment. Findings have important clinical and research implications for expanding the reach of evidence-based addiction treatment beyond traditional treatment settings.
BACKGROUND:Liver-brain communication is increasingly recognized as a potential contributor to vulnerability to alcohol use disorder (AUD). However, the behavioral consequences of early alcohol-associated liver disease (ALD) remain underexplored. This study aimed to determine whether alcohol-induced hepatic injury influences subsequent alcohol consumption and cognitive outcomes. METHODS:Female C57BL/6J mice were fed a Lieber-DeCarli (LDC) ethanol diet to induce early-stage ALD-like pathology, followed by a voluntary two-bottle choice (TBC) paradigm measuring alcohol consumption. Behavioral assessments included novel object recognition, T-maze with spontaneous alternation, and elevated plus maze. Hepatic steatosis was measured by histology and triglyceride quantification; inflammatory gene expression was evaluated by RT-qPCR, and hippocampal BDNF/TrkB signaling was investigated by western blot. RESULTS:LDC mice on an ethanol diet developed hepatic steatosis and hepatomegaly compared with controls. These mice also consumed significantly more alcohol during initial TBC testing, with intake positively correlated with the degree of steatosis. Hepatic steatosis was transient, recovering by the end of TBC period with accompanied upregulation of inflammatory markers and evidence suggestive of neutrophilic infiltration in ethanol-exposed mice. These mice also exhibited impaired spatial working memory without significant differences in long-term recognition or anxiety-like behavior in the elevated plus maze. In addition, ethanol exposure was associated with reduced hippocampal expression of BDNF and its receptor TrkB. CONCLUSION:These findings suggest that alcohol-induced early hepatic injury may contribute to increased alcohol consumption and impaired spatial working memory performance paralleling sustained hepatic inflammation and dysfunction in neurotrophic signaling. Further investigation is warranted to elucidate the mechanisms underlying liver-brain communication in the context of AUD and ALD progression.
BACKGROUND:Prenatal exposure to alcohol (PAE) and/or tobacco (PTE) may impact neurobiological and cognitive development years after such exposures have occurred. While such effects on cortical gray matter and cognition are widely researched, there is less research on the effects of PAE and PTE on white-matter development and cognition, particularly in non-clinical, community samples. METHODS:We analyzed white-matter microstructure and its cognitive correlates in four hundred and sixty five 8-12-year-olds in the urban Cape Town region of South Africa: 192 were prenatally exposed to alcohol and tobacco (PAE + PTE), 73 to tobacco only (PTE), 102 to alcohol only (PAE), and 98 to neither tobacco nor alcohol (CON). White-matter microstructure was quantified via neurite orientation and dendrite dispersion imaging (NODDI). The outcome variables were fractional anisotropy (FA), the neurite density index (NDI), and neurite orientation dispersion index (ODI) for 52 white-matter tracts. Cognition was measured using the Wechsler Intelligence Scale for Children-Fifth Edition (WISC-V). RESULTS:PAE (but not PTE) was associated with NDI in 35 of 52 white-matter tracts analyzed. There were no false-discovery-rate (FDR) corrected main effects of PAE or PTE on FA or ODI. For 17 of the 35 tracts affected by PAE, the corresponding NDIs were positively associated with scores on the WISC-V Processing Speed Index. CONCLUSIONS:Our previous research of neuroanatomical structure in this cohort suggested that there are stronger effects of PTE on cortical gray matter. In contrast, the present data suggest that PAE may have stronger associations with white-matter microstructure, with such effects potentially manifesting as downstream deficits in processing speed.
BACKGROUND:Ghrelin, a stomach-derived orexigenic peptide, typically rises during fasting to stimulate food intake. Chronic alcohol consumption elevates circulating ghrelin, which induces alcohol craving and increases intake in clinical and preclinical models. By increasing alcohol drive, ghrelin contributes to alcohol use disorder (AUD) and accelerates alcohol-associated liver disease (ALD) by inhibiting insulin secretion and promoting adipose lipolysis. However, the cellular mechanisms by which ethanol dysregulates ghrelin secretion remain unclear. This study investigated how ethanol modulates ghrelin production and disrupts nutrient sensing in ghrelin-secreting cells. METHODS:Stomach (SG-1) and pancreatic (PG-1) ghrelinoma cells were treated with 25 mM or 50 mM ethanol for 48 h, after which ghrelin synthesis and secretion were measured. Further, the interaction between ethanol and other physiological regulators (glucose [10 mM], insulin [20 mM], and palmitic acid [400 μM]) of ghrelin secretion was evaluated. Intracellular glycolytic rate was characterized using Seahorse-XFe analysis. RESULTS:Chronic ethanol exposure (48 h) significantly increased ghrelin secretion and the mRNA encoding for ghrelin and ghrelin O-acyltransferase (GOAT), an enzyme that activates ghrelin. Under normal conditions, high glucose effectively suppressed ghrelin secretion; however, ethanol pretreatment blunted this inhibitory effect. While palmitic acid alone had no effect, its combination with ethanol synergistically enhanced ghrelin secretion. Mechanistically, ethanol-pretreated cells exhibited a metabolic impairment characterized by increased glucose uptake but significantly reduced basal glycolysis, proton efflux rate (PER), and compensatory glycolytic capacity. This metabolic failure was linked to the profound downregulation of the rate-limiting enzymes glucokinase, hexokinase, and pyruvate kinase. CONCLUSIONS:Ethanol drives increased ghrelin by disrupting the glucose-sensing machinery within ghrelin-secreting cells. By suppressing key glycolytic enzymes, ethanol uncouples the cell from glucose, mimicking a state of starvation despite nutrient availability. Targeting these metabolic pathways may provide a novel therapeutic strategy for the interconnected pathologies of AUD and ALD.
BACKGROUND:Alcohol drinking is a major risk factor for oropharyngeal cancer, yet the nature of risk differences across drinking patterns remains unclear. METHODS:We leveraged data from large-scale genome-wide association studies to conduct Mendelian randomization analyses, assessing the effects of alcohol intake with meals, intake frequency, maximum habitual intake, and drinks per week on risks of oral cavity cancer, pharyngeal cancer, stomatitis, lichen planus, and oral leucoplakia. Multiple Mendelian randomization methods were applied to model pleiotropic effects, and multivariable analysis was performed to evaluate the interplay between alcohol consumption and household income. RESULTS:Alcohol intake frequency was associated with increased risk of oral and pharyngeal cancer. In contrast, alcohol intake with meals showed an apparent protective association with these outcomes, which was nullified after adjusting for household income in the multivariable analysis-indicating that the observed benefit was explained by higher socioeconomic status. The frequency-risk relationship remained significant after adjustment, highlighting intake frequency as an independent risk factor under MR assumptions. The number of drinks per week was linked to increased stomatitis risk, and this association remained significant after accounting for household income, suggesting an independent effect of alcohol consumption on stomatitis risk under MR assumptions. CONCLUSION:Cancer prevention strategies should target harmful alcohol consumption patterns with attention to drinking frequency and socioeconomic context, rather than treating alcohol exposure as monolithic.
BACKGROUND:Brief Interventions (BIs) in primary care are an effective, evidence-based tool for reducing the cost and harm associated with unhealthy alcohol use. However, little is known about the impact of alcohol BIs on the utilization of acute healthcare services over time. This study aims to examine the association between receiving a BI in the outpatient setting and Emergency Department (ED) and inpatient utilization over 2 years among adults screening positive for unhealthy alcohol use. METHODS:This population-based, retrospective observational study utilized electronic health record (EHR) data collected between January 1, 2013 and June 30, 2019 of 254,190 adult primary care patients who screened positive for unhealthy alcohol use. Patients were grouped by whether or not they received a BI for unhealthy alcohol use from their primary physician at the index date. ED and inpatient utilization was assessed for each 6-month interval following the index screening up to 24 months. Separate generalized estimating equation (GEE) logistic models with inverse probability treatment weighting (IPTW) were fit to examine the associations between BI receipt and ED and inpatient utilization over the 2-year follow-up period. RESULTS:IPTW GEE models indicated that receiving BI was associated with significantly lower odds of ED (aOR [95% CI] = 0.96 [0.94-0.98]) and inpatient utilization (aOR [95% CI] = 0.96 [0.93-1.00]) over the 2-year follow-up period. However, the association between BI and ED utilization attenuated over time, and receiving a BI was only significantly associated with lower inpatient utilization in the first 6 months following index. CONCLUSION:The observed reductions in ED and inpatient utilization contribute novel insight into the duration of BI's harm-reduction effects. Ultimately, our findings support widespread implementation of BI programs in primary care settings as a means of reducing acute healthcare utilization.
BACKGROUND:Despite strong links between emotion regulation (ER) difficulties and problem drinking, few studies have directly addressed whether interventions that target ER positively impact drinking outcomes. In a prior Stage 1a/1b behavioral therapies development study, we developed an Emotion Regulation Treatment (ERT) for alcohol use disorder (AUD) that included strategies addressing prolonged direct experiencing of emotion, mindfulness, and coping and distress tolerance. Results demonstrated the feasibility and initial efficacy of ERT as a supplement to cognitive behavioral therapy (CBT) for AUD. Based on this initial success, the current study reports on a fully powered stage II randomized clinical efficacy trial to compare CBT plus ERT (CBT + ERT) to CBT plus an active health and lifestyles (HLS) control (CBT + HLS) and explore potential mechanisms of action. METHODS:Adults (n = 194) with moderate-to-severe AUD were enrolled in 12 week outpatient treatment and randomized to either the CBT + ERT or CBT + HLS treatment condition. Analyses evaluated (1) the impact of treatment condition on percent days abstinent (PDA) and percent heavy drinking days (PHDD) at end of treatment (EOT) and 3, 6, and 12 months posttreatment, and (2) whether change trajectories of negative affect, craving, mindfulness, cognitive reappraisal, or adaptive alcohol coping, assessed daily or weekly during treatment, partially accounted for associations between treatment condition and EOT alcohol outcomes. RESULTS:The CBT + ERT group had greater PDA at all posttreatment follow-ups relative to the CBT + HLS group. There were no group differences in PHDD. Levels of PDA and PHDD did not change across posttreatment follow-ups for either group. The CBT + ERT group exhibited greater adaptive alcohol coping across the first week of treatment, which in turn was associated with higher PDA and lower PHDD at EOT. No other mediation effects were detected. CONCLUSIONS:CBT + ERT was associated with greater PDA at EOT relative to CBT + HLS, an association that was partially explained by greater adaptive coping early in treatment.
BACKGROUND:Individuals with disabilities have a right to live independently, be included within their communities, and have adequate standards of living and social protections. However, individuals with fetal alcohol spectrum disorder (FASD) experience elevated obstacles to obtaining and maintaining housing. In addition to brain-based differences that can create barriers to successful navigation of daily demands, many individuals with FASD experience mental health concerns, substance use, or trauma, and the experience of being houseless is, in itself, traumatic. These factors often compound, leaving individuals with FASD disproportionately affected by the ongoing housing and cost of living crisis. METHODS:This study brought together 47 Canadian housing providers, youth with FASD, caregivers, researchers, and policy makers to understand the challenges and opportunities for housing options for individuals with FASD. Reflexive thematic analysis was conducted to explore the aim of the research: individuals' living experiences, perspectives, and recommendations on what safe and stable housing for individuals with FASD could look like. RESULTS:Four themes were generated describing how housing experiences for individuals with FASD could be improved: (1) being able to access all that is needed for housing; (2) embracing individuality and the pitfalls of blanket approaches; (3) working as a team to foster interdependency; and (4) the need for greater understanding of FASD across all sectors. CONCLUSIONS:The results of this study provide vital insights on the needs of individuals with FASD in the context of housing and suggest ways forward to reduce the disproportionate impact of the Canadian housing crisis on individuals with FASD and their families.
BACKGROUND:Several alcohol-specific parenting behaviors are associated with adolescent alcohol use. An important next step in the literature is integrating these behaviors into unified risk pathways, which have the potential to inform preventive interventions and public health messaging. Youth involvement in family drinking (i.e., asking children to fetch, pour, and open drinks) reflects parental-approved contact with alcohol, which may present the opportunity for sipping/tasting alcohol with parental permission. In turn, sipping/tasting alcohol with parental permission may increase adolescents' perceived parental approval of underage drinking, a known risk factor for alcohol use later in adolescence and young adulthood. This indirect pathway was tested and sensation seeking was posited as a moderator of the association between youth involvement in family drinking and sipping/tasting alcohol with parental permission. METHODS:The community sample included 260 parent-teen dyads (adolescents aged 11-12 years; 60.85% White, 28.9% Black or African American, 2.33% Asian, 1.16% American Indian or Alaska Native, and 7.36% identified as "more than one race"). Hypotheses were tested using path modeling. RESULTS:Youth involvement in family drinking was positively associated with sipping/tasting with parental permission and perceived parental approval of underage alcohol use. Sipping/tasting with parental permission was not associated with perceived parental approval of underage alcohol use. Moderation was not supported. CONCLUSIONS:Youth involvement in family drinking may be the start of an early risk pathway that facilitates sipping/tasting with parental permission and directly shapes adolescent perceptions of parental approval of underage alcohol use. Lack of moderation may suggest that progression to sipping/tasting is driven more strongly by a family environment that approves of alcohol exposure rather than adolescent temperament. Findings highlight the utility of considering different alcohol-specific parenting practices mechanistically in risk models.
BACKGROUND:The neurocognitive dysfunction observed in Alcohol Use Disorder (AUD) is related to a complex interplay between genetic, neurobiological, and environmental factors. The μ-opioid receptor (MOR), encoded by the OPRM1 gene, modulates reward processing, stress responsivity, and excitatory-inhibitory activity within prefrontal-limbic and hippocampal circuits implicated in neurocognition. The common A118G (Asn40Asp, rs1799971) polymorphism alters MOR expression and signaling, but its contribution to domain-specific cognitive functioning in AUD, particularly among Veterans, has received limited investigation. METHODS:Veterans (n = 127) in residential treatment for AUD completed a neurocognitive battery assessing the following domains of functioning: auditory-verbal and visuospatial learning and memory, executive function, and working memory. Participants were genotyped for OPRM1 A118G, and A homozygotes and G-allele carriers (AG/GG) were compared on the above measures, using bootstrapped generalized linear models, adjusted for age, education, biological sex, race, pre-study alcohol consumption, and brain-derived neurotrophic factor (BDNF) (rs6265) and catechol-O-methyltransferase (COMT) (rs4680) genotypes, which have been previously shown to be associated with neurocognition. RESULTS:G-allele carriers demonstrated significantly worse performance than A homozygotes on measures of auditory-verbal learning and memory, cognitive flexibility/set shifting, auditory working memory, and on a composite average of all measures. BDNF or COMT genotypes were not associated with any measure, and there were no significant interactions among OPRM1, BDNF, and COMT genotypes. CONCLUSIONS:Findings suggest that altered MOR signaling in G-allele carriers may be associated with differences in prefrontal network efficiency, potentially justifying future studies investigating the relationship between OPRM1 and glutamatergic plasticity. The results highlight a potential genetically influenced contributor to the neurocognitive heterogeneity in AUD and underscore the possible value of integrating MOR-related biological markers into neurocognitive assessment of individuals with AUD.
BACKGROUND:Prenatal alcohol exposure (PAE) can result in fetal alcohol spectrum disorder (FASD), a permanent, heterogeneous condition characterized by severe neurodevelopmental impairments with or without microcephaly, characteristic facial dysmorphology, and congenital anomalies. Clinical and pre-clinical studies suggest that genetic factors, in the mother or fetus, influence the phenotypic outcomes following PAE. The objectives of this study were to evaluate the prevalence and types of DNA copy number variants (CNVs) in children (0-18 years) diagnosed with FASD and to identify genes known to be associated with neurodevelopmental disorders. METHODS:Chromosomal microarray (CMA) was performed in children diagnosed with FASD in the NSW CICADA FASD Service-a state-wide multidisciplinary diagnostic clinic in Australia. We performed a retrospective chart review of 175 patients diagnosed with FASD between 2015 and 2022 to obtain data on medical and family history, phenotype, and genotype. All CMA results were reviewed by a clinical geneticist. RESULTS:A rare CNV was identified in 38 of 157 (24.2%) patients who had CMA testing and 40 unique CNVs were identified. In four patients, a neurodevelopmental susceptibility syndrome was identified including Xq28 microduplication syndrome, 16p12.2 microdeletion syndrome, 17q11.2 microduplication syndrome, and an atypical variant of 22q11.2 deletion syndrome. Two children had incidental pathogenic variants. In 32 of 38 (84.2%) cases with a rare CNV, 34 variants of unknown significance (VOUS) were identified, of which 13 encoded a total of 14 genes associated with common neurodevelopmental disorders. Three variants of uncertain significance (VOUS) encoded different subunits of the voltage-dependent calcium channel complex protein (CACNB2, CACNA1A, CACNA2D3). CONCLUSION:These novel results suggest that approximately one in four children diagnosed with FASD may harbor a rare CNV, of which 85.0% are currently of uncertain clinical significance. Genetic testing can support the FASD diagnostic process and may reveal additional diagnoses or sources of genetic vulnerability to FASD.
