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OBJECTIVE: The association between alcohol use and erectile dysfunction (ED) has not been explored adequately. The aim of this study is (i) to determine the prevalence of ED in patients with Alcohol use disorder (AUD), (ii) the association of ED with sociodemographic and clinical variables, (iii) the association between severity of drinking and sociodemographic and clinical variables, and (iv) the assess the change in ED after one month of abstinence from alcohol. METHODS: 203 consecutive patients were recruited into the study after taking written informed consent. Sociodemographic data was collected using a proforma and ED was assessed using International Index of Erectile Function-5 (IIEF-5). The patients were also followed up after 1 month of abstinence to assess the change in erectile function. RESULTS: The prevalence of ED was 68.5%. Out of the 203 subjects, 28.1% had mild ED, 24.1% had mild to moderate ED, 9.9% had moderate ED and 6.4% had severe ED. Significant association were seen between ED and age, marital status, diabetes mellitus, hypertension, total duration, and severity of drinking. A significant association was seen between severity of drinking and age, diabetes mellitus, hypertension, alcoholic liver disease, tobacco use and duration of drinking. The improvement in ED after 1 month abstinence was found to be significant. CONCLUSIONS: ED is a common problem in patients with AUD. Routine assessment of sexual functioning is warranted in patients with AUD and the information that ED improves with abstinence can provide an impetus to change.

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OBJECTIVE: Stemming from historical traumas and changes in the Inuit way of life, substance use and its intertwined problems are a major cause of concern for Nunavimmiut. This study's objective is to investigate sociocultural determinants of substance use and misuse to inform culturally appropriate public health programs. METHODS: The 2017 Qanuilirpitaa? survey was conducted among a sample intended to be representative of Nunavimmiut aged 16 and over (total n = 1326). Sociocultural factors included cultural identity, land-based activities, involvement in community activities, social support, and family and community cohesion. The frequency of binge drinking (5 or more drinks on one occasion), cannabis use, and problematic substance use (CAGE and DAST-10) were documented. Data were analyzed using weighted multivariate logistic regressions. Inuit partners were involved from the planning of analyses to the co-interpretation of results. RESULTS: Nearly a third of Nunavimmiut aged 16 and over reported binge drinking at least once a week (29.3%), and 68.6% of drinkers were at risk of potential drinking problems. Forty-five percent (45%) reported using cannabis at least once a week, and 30% of drug users were at risk of potential drug abuse problems. Volunteering and participation in community activities were associated with lower odds of cannabis use, as was frequently going on the land with weekly binge drinking, potential drinking problems, and weekly cannabis use. Social support and community cohesion were associated with higher odds of weekly binge drinking, as was cultural identity (centrality scale) with potential drinking problems. CONCLUSION: Key determinants of substance use relevant to Inuit culture were identified. Results are in line with our Inuit partners' experience in their communities and are coherent with current land-based interventions implemented in Nunavik. A thorough understanding of substance use contexts and related stressors should guide the content and implementation of substance use programs in Nunavik.

RéSUMé: OBJECTIF: Suite aux traumas historiques et changements au mode de vie, l'usage de substance et les problèmes associés sont une source d'inquiétude majeure pour les Nunavimmiut. L'objectif de cette étude est d'investiguer les déterminants socioculturels de l'usage de substances pour adapter les programmes de santé publique à la culture Inuit. MéTHODES: L'enquête Qanuilirpitaa? 2017 repose sur un échantillon sélectionné pour être représentatif des Nunavimmiut (16 ans et plus; n = 1 326). Les déterminants socioculturels incluent : identité culturelle, activités sur le territoire, activités communautaires, support social, cohésion familiale et communautaire. La fréquence de consommation excessive d'alcool (5 consommations ou plus), l'usage du cannabis et l'usage problématique (CAGE et DAST-10) ont été documentés. Données analysées par régression multiple pondérée. Nos partenaires Inuit ont été impliqués de la planification des analyses à la co-interprétation des résultats. RéSULTATS: Près du tiers des Nunavimmiut de 16 ans et plus ont rapporté une consommation hebdomadaire excessive d'alcool (29,3 %) et 68,6 % de ceux consommant de l'alcool étaient potentiellement à risque de consommation problématique. Quarante-cinq pourcent (45 %) ont rapporté consommer du cannabis au moins une fois par semaine et 30 % des consommateurs de drogue étaient à risque de consommation potentiellement problématique. Le bénévolat et la participation aux activités communautaires étaient associés à une cote plus faible d'usage de cannabis, tout comme la pratique fréquente d'activités sur le territoire avec la consommation hebdomadaire excessive d'alcool, d'usage potentiellement problématique d'alcool et d'usage hebdomadaire de cannabis. Le support social et la cohésion communautaire étaient associés à une cote plus élevée de consommation excessive hebdomadaire d'alcool, tout comme l'identité culturelle (centralité) avec l'usage potentiellement problématique d'alcool. CONCLUSION: Des déterminants clés de l'usage de substance spécifiques aux Inuit ont été identifiés. Les résultats concordent avec le vécu de nos partenaires dans leurs communautés et le cadre théorique d'interventions déjà implémentées impliquant des activités sur le territoire et de guérison. Les contextes de consommation et les stresseurs associés devraient guider l'élaboration des programmes au Nunavik.

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Over 25% of patients with rheumatoid arthritis (RA) are expected to undergo a joint replacement during their lifetime. Current practice guidelines recommend withholding biologic therapy 1 week prior to total hip arthroplasty, given its immunosuppressive effects. Most patients are on a regimen including biologic and nonbiologic therapy; however, the individual influences of these therapies are not well understood in the setting of total knee arthroplasty (TKA). Therefore, we sought to compare biologic, nonbiologic, and recipients of both types of therapy in patients with RA undergoing TKA. We specifically assessed (1) medical complications at 90 days; (2) surgical complications up to 1 year; and (3) independent risk factors for prosthetic joint infections (PJIs).A retrospective review was conducted using a national, all-payer database for patients undergoing primary TKA from January 2010 to April 2020 (n = 1.97 million). Patients diagnosed with RA were then separated into at least 1-year users of biologic (n = 3,092), nonbiologic (28,299), or dual (n = 10,949) therapy. Bivariate analyses were utilized to assess for 90-day medical and up to 1-year surgical outcomes. Additionally, multivariate regression models were utilized to assess for independent risk factors.The incidence and odds ratio for medical/surgical outcomes were equivocal among the biologic, nonbiologic, and recipients receiving both types of therapy (p > 0.061). No differences were observed between the type of therapy as additional risk factors for infection (p > 0.505). However, glucocorticoids at 90 days and alcohol abuse, diabetes mellitus, obesity, as well as tobacco use were identified as additional risk factors for PJI(p < 0.036).No appreciable differences in medical or surgical outcomes were associated with the independent use of biologic, nonbiologic, or recipients of both types of therapy in patients with RA. Additionally, alcohol abuse, diabetes mellitus, glucocorticoids, obesity, and tobacco use conferred an increased risk of PJI. These results can serve as an adjunct to current practice guidelines.

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BACKGROUND: To clarify, in a national sample, associations between risk for seven psychiatric and substance use disorders and five key transitions in Sweden's public educational system. METHODS: Swedish-born individuals (1972-1995, N = 1 997 910) were followed through 12-31-2018, at mean age 34.9. We predicted, from these educational transitions, risk for major depression (MD), obsessive-compulsive disorder (OCD), bipolar disorder (BD), schizophrenia (SZ), anorexia nervosa (AN), alcohol use disorder (AUD), and drug use disorder (DUD), assessed from Swedish national registers, by Cox regression, censoring individuals with onsets ⩽17. We also predicted risk from the deviation of grades from family-genetic expectations (deviation 1) and from changes in grades from ages 16 to 19 (deviation 2). RESULTS: We observed four major risk patterns across transitions in our disorders: (i) MD and BD, (ii) OCD and SZ, (iii) AUD and DUD, and (iv) AN. Failing early educational transitions had the greatest impact on risk for OCD and SZ while for other disorders, not progressing from basic to upper high school had the largest effect. Completing vocational v. college-prep upper high school was strongly associated with risk for AUD and DUD, had little relation with MD, OCD, BD, and SZ risk, and was protective for AN. Deviation 1 predicted risk most strongly for SZ, AN, and MD. Deviation 2 predicted risk most strongly for SZ, AUD, and DUD. CONCLUSIONS: The pattern of educational transitions and within family and within person development deviations are strongly and relatively specifically associated with future risk for seven psychiatric and substance-use disorders.

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Everyone experiences the natural ebb and flow of task-unrelated thoughts. Given how common the fluctuations in these thoughts are, surprisingly, we know very little about how they shape individuals' responses to alcohol use. Here, we investigated if mind wandering is associated with a risk of developing problematic alcohol use. We undertook an online survey among the general population in China (N = 1123) and Germany (N = 1018) from December 2021 to February 2022 and examined the subjective experience of mind wandering and problematic alcohol use through the Mind Wandering Questionnaire (MWQ) and the Alcohol Use Disorders Identification Test (AUDIT). We compared mind wandering and problematic alcohol use between two countries and investigated the association between MWQ scores with AUDIT scores. We found higher scores on the MWQ and a high percentage of problematic alcohol use (i.e., AUDIT score ≥ 8) in Germany (22.5%) as compared to in China (14.5%). Higher self-reported mind wandering was associated with higher AUDIT scores. AUDIT scores were increased mostly in male, elder, and high-mind wandering people. Our findings highlight that mind wandering and problematic alcohol use enhanced in Germany as compared to in China. Our study sheds light on the relationship between mind wandering and problematic alcohol use that may help to further investigate causal effects of interventions.

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Adolescence is a critical phase for the development of substance use disorders (SUDs). For Europe and Germany, there are limited data on problematic substance use from representative youth samples. Trait mindfulness is relevant in buffering against substance use-related problems and associated deficits in self-regulatory control. The objective of this study is to estimate 12-month prevalence rates for SUDs in a representative sample of adolescents in Germany and to examine associations with mindfulness and related factors such as stress, impulsivity, sensation seeking and symptoms of psychopathology. A sample of 4001 adolescents aged 12-18 years from Germany was surveyed based on DSM-IV diagnostic criteria for SUDs. Logistic regression analyses were used to examine associations with mindfulness-related variables. Criteria of at least one of the assessed SUDs were endorsed by 11.2% of the adolescents. Alcohol use disorders had the highest prevalence rate (10.1%) followed by cannabis use disorders (2.6%). For both substances, the criteria for abuse were met about twice as often as those for dependence. The prevalence of cigarette dependence was 1.7%, while the prevalence for e-cigarette dependence was only 0.1%. Prevalence rates were higher for male youth and increasing with age. SUD prevalence was also related to mindfulness, impulsivity and sensation seeking and externalizing symptoms of psychopathology. The statistically significant associations varied across different SUDs. SUDs appear highly prevalent among German adolescents. The results have public health implications with regard to treatment needs and prevention measures in the youth population in Germany.

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PURPOSE: Although the trajectory of mental disorders can be improved with timely treatment, many people defer treatment-seeking. This study aimed to examine the prevalence and correlates of treatment delays for mental disorders in Singapore, as well as perceived effectiveness of treatment received. METHODS: A total of 6126 respondents, aged 18 and above, participated in the Singapore Mental Health Study 2016-a cross-sectional, nationwide study conducted in Singapore from 2016 to 2018. Lifetime treatment contact for mood, anxiety, and alcohol use disorders (AUD) was assessed using the World Mental Health-Composite International Diagnostic Interview (Version 3.0). Multivariable logistic regression was conducted to examine correlates of delayed treatment. RESULTS: A total of 137 participants had made lifetime treatment contact for a mental disorder. The proportion of respondents who received delayed treatment (i.e., at least one year after onset of disorder) was 60.8% for any disorder, 59.5% for mood disorders, 56.3% for anxiety disorders, and 92.7% for AUD. The median delay was 5 years for mood disorders, one year for anxiety disorders, and 4 years for AUD. Treatment delay was significantly associated with older age, higher educational qualification, lifetime AUD, and earlier age of onset of disorder. 58.4% of respondents with lifetime treatment contact had received treatment that they considered effective. CONCLUSION: The high prevalence and long durations of treatment delay underscore the need to encourage help-seeking for mental disorders, especially since treatment is generally perceived to be helpful. Our findings also highlight several population groups more susceptible to receiving delayed treatment.

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OBJECTIVE: The prevalence of research conducted online in the addiction field has increased rapidly over the past decade. However, little focus has been given to careless responding in these online studies, despite the issues it may cause for statistical inference and generalizability. Our aim was to examine whether alcohol use is associated with careless responses. METHOD: Raw data were requested from online studies examining alcohol use and related problems which also addressed careless responding. We obtained 13 data sets of 12,237 participants (Mage = 42.16, SD = 15.65, 50.5% female). The sample had an average Alcohol Use Disorders Identification Test (AUDIT) score of 10.88 (SD = 7.77). Predictors included demographic information (age, gender) and AUDIT total scores. The primary outcome was whether an individual was classed as a careless responder, for example, by failing an explicit attention check question. RESULTS: AUDIT total scores were associated with careless responding (OR = 1.07, 95% CI [1.06, 1.08], p < .001). Hazardous drinking or worse was associated with 2.21 greater odds (OR = 2.21, 95% CI [1.81, 2.71] of careless responding, whereas harmful drinking or worse was associated with 3.43 greater odds (OR = 3.43, 95% CI [2.83, 4.17]) and probable dependence was associated with 3.63 greater odds (OR = 3.63, 95% CI [2.95, 4.48]). CONCLUSIONS: Alcohol use and related problems are positively associated with careless responding in online research. Removal of individuals identified as careless responders may lead to issues of generalizability, and more care should be taken to identify and handle careless responder data. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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The aim was the comparison between the Society of Hair Testing (SoHT) consensus for the use of alcohol markers which powdering hair for the extraction of ethylglucuronide (EtG) in water and extraction using the patented M3 Reagent Test kit on cut hair. Hair samples were cut into small segments and washed twice with methanol and diethyl ether. The SoHT-Consensus entails the extraction of pulverised hair in water. This is obtained by incubation of 25 mg of hair at room temperature overnight and 2 h sonication, even if the overnight incubation is not mandatory. The M3 method entails incubation of 25 mg of cut hair with the M3-Reagent at 100°C for 60 min. After centrifugation, the supernatant is injected into a liquid chromatography-tandem mass spectrometry (LC-MS/MS). Samples (191) were collected in the APSS laboratory in Trento, Italy, between 2021 and 2022. The limit of quantification (LOQ) was set at 5 pg/mg for the pulverised and M3-Reagent methods. Assays showed good linearity above the range of LOQ-300 pg/mg. Precision (within 20%) values were also obtained using both methods. In the Passing-Bablock linear regression, the final regression curve between M3 (y) and the pulverising method (x) showed good agreement; the Bland-Altman analysis did not show any significant bias between the two methods. The M3-Reagent method, due to cut hair use, is easy to perform, saves time and allows for a smaller sample quantity loss with use of nondisposable grinding jars for the ball mill to obtain the extraction of EtG.

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BACKGROUND: Relapse remains the major challenge in treatment of alcohol use disorder (AUD). Aberrant decision-making has been found as important cognitive mechanism underlying relapse, but factors associated with relapse vulnerability are unclear. Here, we aim to identify potential computational markers of relapse vulnerability by investigating risky decision-making in individuals with AUD. METHODS: Forty-six healthy controls and fifty-two individuals with AUD were recruited for this study. The risk-taking propensity of these subjects was investigated using the balloon analog risk task (BART). After completion of clinical treatment, all individuals with AUD were followed up and divided into a non-relapse AUD group and a relapse AUD group according to their drinking status. RESULTS: The risk-taking propensity differed significantly among healthy controls, the non-relapse AUD group, and the relapse AUD group, and was negatively associated with the duration of abstinence in individuals with AUD. Logistic regression models showed that risk-taking propensity, as measured by the computational model, was a valid predictor of alcohol relapse, and higher risk-taking propensity was associated with greater risk of relapse to drink. CONCLUSION: Our study presents new insights into risk-taking measurement and identifies computational markers that provide prospective information for relapse to drink in individuals with AUD.

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OBJECTIVE: Most alcohol consumption takes place in social contexts, and the belief that alcohol enhances social interactions has been identified as among the more robust predictors of alcohol use disorder (AUD) development. Yet, we know little of how alcohol affects mental representations of others-what we share and do not share-nor the extent to which intoxication might impact the development of shared understanding (i.e., common ground) between interaction partners. Employing a randomized experimental design and objective linguistic outcome measures, we present two studies examining the impact of alcohol consumption on the development and use of common ground. METHOD: In Study 1, groups of strangers or friends were administered either alcohol (target Breath Alcohol Content = .08%) or a control beverage, following which they completed a task requiring them to develop a shared language to describe ambiguous images and then describe those images to either a knowledgeable or a naïve partner. The same procedures were completed in Study 2 using a within-subjects alcohol administration design and all-stranger groups. RESULTS: Study 1 findings did not reach significance but suggested that alcohol may facilitate common ground development selectively among stranger groups. This effect emerged as significant in the context of the within-subjects design of Study 2, b = -0.19, p = .007, with participants demonstrating greater facility in establishing common ground during alcohol versus control sessions. CONCLUSIONS: Results suggest that alcohol facilitates the development of shared linguistic understanding in novel social spaces, indicating common ground as one potential mechanism to consider in our broader examination of alcohol reinforcement and AUD etiology. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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Topiramate (TPM), a GABA/glutamate modulator, has shown positive results for treating alcohol use disorder (AUD), but causes significant cognitive adverse effects. TPM causes cognitive side effects by reducing glutathione levels in the frontal lobe. N-acetyl cysteine (NAC) increases level of intracellular glutathione. We hypothesized that combining NAC with TPM may mitigate the possible cognitive side effects of TPM, as well as working synergistically in reducing alcohol consumption more efficaciously than using TPM alone. A 12-week, double-blind randomized trial assessing the effects of combining NAC (1200 mg/day) with TPM (200 mg/day) vs TPM alone (i) cognitive side effects caused by TPM, (ii) percentage of heavy drinking days (PHDD) and percentage of days abstinent (PDA) using weekly calendar, and (iii) craving outcomes using the obsessive-compulsive drinking scale. Seventeen participants were randomized into the study (nine received TPM + NAC and eight matching TPM + Placebo). Cognitive adverse events were not significantly different between the treatment arms (P = 0.581). There was no difference in PHDD (P = 0.536) and in PDA over the entire study period (P = 0.892). However, both treatment groups at study end, compared with the baseline, significantly reduced their PHDD and increased their PDA. As for cravings: TPM + NAC group has shown higher level in automaticity of drinking (P = 0.029) and interference due to drinking (P = 0.014) subscales compared with the TPM + Placebo group. No difference was observed between groups in terms of Drinking Obsessions and Alcohol Consumption subscales. This pilot study indicates that combining NAC with TPM is overall safe, but the addition of NAC has no significant benefit over placebo in the incidence of TPM-related cognitive impairment, and alcohol drinking. Furthermore, craving outcomes may become worse with the addition of NAC.

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BACKGROUND: Benzodiazepines are the gold standard for treatment of alcohol withdrawal, yet the selection of a preferred benzodiazepine is limited due to a lack of comparative studies. OBJECTIVES: The primary objective of this study was to compare the efficacy and safety of injectable lorazepam (LZP) and diazepam (DZP) in the treatment of severe alcohol withdrawal syndrome (AWS). METHODS: Retrospective cohort study of adult patients admitted to an intensive care unit with a primary diagnosis of AWS. Subjects who received at least 12 LZP equivalent units (LEU) of injectable DZP or LZP within 24 hours of initiation of the severe AWS protocol were included. The primary outcome was time with Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) scores at goal over the first 24 hours of treatment. RESULTS: A total of 191 patients were included (DZP n = 89, LZP n = 102). Time with CIWA-Ar scores at goal during the first 24 hours was similar between groups (DZP 12 hours [interquartile range, IQR, = 9-15] vs LZP 14 hours [IQR = 10-17]), P = 0.06). At 24 hours, LEU requirement was similar (DZP 40 [IQR = 22-78] vs LZP 32 [IQR = 18-56], P = 0.05). Drug cost at 24 hours was higher in the DZP group ($204.6 [IQR = 112.53-398.97] vs $8 [IQR = 4.5-14], P < 0.01). CONCLUSION AND RELEVANCE: DZP or LZP are equally efficacious for the treatment of severe AWS. LZP may be preferred due to cost but both medications can be used interchangeably based on availability.

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Maintaining abstinence and preventing relapse are key to the successful recovery from alcohol use disorder. There are two main ways individuals with alcohol use disorder abstain from alcohol use: forced (e.g., incarceration) and voluntary. Voluntary abstinence is often evoked due to the negative consequences associated with excessive alcohol consumption. This study investigated relapse-like behavior to alcohol seeking following acute, forced, and voluntary abstinence. Male rats had increased operant self-administration responding throughout training compared to females; however, females consumed greater amounts of alcohol in g/kg. Both male and female rats achieved voluntary abstinence, which was induced using an electric barrier on the operant chamber floor with alcohol readily available during this period. Interestingly, male rats that underwent voluntary abstinence displayed reduced alcohol seeking compared to males in the acute and forced abstinence groups. This difference in alcohol seeking behavior across abstinence groups was not observed in female rats. Quantification of neuronal activation (Fos protein) revealed numerous brain regions (e.g., ventral subiculum and lateral habenula) to be associated with the reduced reinstatement propensity seen in male rats that underwent voluntary abstinence. Additionally, hierarchical clustering found enhanced functional connectivity and coordination in the male voluntary abstinence group compared to the male forced abstinence group. Collectively, these data implicate a sexual dimorphism in the effect that voluntary abstinence, at least in the model employed here, has on relapse-like behavior. This maybe driven by reduced neuronal activation at a network level and enhanced functional connectivity and integration. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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Alcohol Use Disorder (AUD) is a relapsing brain disorder that involves perturbations of brain dopamine (DA) systems, and combined treatment with varenicline + bupropion produces additive effects on accumbal DA output and abolishes the alcohol deprivation effect (ADE) in rats. Also, direct and indirect glycine receptor (GlyR) agonists raise basal DA, attenuate alcohol-induced DA release in the nucleus Accumbens (nAc) and reduce alcohol consumption in rats. This study in rats examines whether the GlyT1-inhibitor Org 24598, an indirect GlyR agonist, enhances the ADE-reducing and DA elevating action of the combined administration of varenicline + bupropion in lower doses than previously applied. Effects on voluntary alcohol consumption, the ADE and extracellular levels of glycine and DA in nAc were examined following treatment with Org 24598 6 and 9 mg/kg i.p., bupropion 3.75 mg/kg i.p. and varenicline 1.5 mg/kg s.c., in monotherapy or combined, using a two-bottle, free-choice alcohol consumption paradigm with an ADE paradigm, and in vivo microdialysis in male Wistar rats. Notably, all treatment regimens appeared to abolish the ADE but only the effect produced by the triple combination (Org24598 + varenicline + bupropion) was significant compared to vehicle. Hence, addition of Org 24598 may enhance the ADE-reducing action of varenicline + bupropion and appears to allow for a dose reduction of bupropion. Treatment with Org 24598 raised accumbal glycine levels but did not significantly alter DA output in monotherapy. Varenicline + bupropion produced a substantial elevation in accumbal DA output that was slightly enhanced following addition of Org 24598. Conceivably, the blockade of the ADE is achieved by the triple combination enhancing accumbal DA transmission in complementary ways, thereby alleviating a hypothesized hypodopaminergia and negative reinforcement to drink. Ultimately, combining an indirect or direct GlyR agonist with varenicline + bupropion may constitute a new pharmacological treatment principle for AUD, although further refinement in dosing and evaluation of other glycinergic compounds are warranted.

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The genetic architectures underlying symptoms of conduct problems and depression have largely been examined separately and without incorporating temperament, despite evidence for their genetic overlap. We examined how symptoms and temperament dimensions were transmitted together in families to identify highly heritable composite phenotypes, and how these composite phenotypes predicted alcohol outcomes in young adulthood. Participants (N = 486) were drawn from the third generation of families oversampled for alcohol use disorder in the first generation. Conduct problems, depression, and temperament were reported at 11-19 years old and alcohol outcomes at 18-26 years old. Using principal components of heritability analysis, we found seven highly heritable composite phenotypes, five of which predicted alcohol outcomes: three characterized by co-occurring conduct problems and depression and two by conduct problems. Novel composite phenotypes that were characterized by both conduct problems and depression showed different types of symptoms, temperament features, and genetic underpinnings. Children manifesting differing composite phenotypes might benefit from distinct treatments based on their unique etiologies.

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RATIONALE: Alcohol use disorder (AUD) is a debilitating physiological and psychiatric disorder which affects individuals globally. The current pharmacological interventions to treat AUD are limited, and hence there is an urgent need for a novel pharmacological therapy which can be effective and safe across the population. OBJECTIVE: We aimed to investigate a novel neutral cannabinoid receptor-1 (CB1R) antagonist, AM6527, in several preclinical models of ethanol consumption using male and female C57BL6/J mice. METHODS: Independent groups of male and female mice were subjected to repeated cycles of drinking in the dark (DID), or intermittent access to alcohol (IAA) procedures. Twenty minutes prior to ethanol access in each procedure, animals were treated with intraperitoneal injections of either 1, 3, and 10 mg/kg of AM6527 or its respective vehicle. Acamprosate (100, 200, 300, and 400 mg/kg) or its respective vehicle was used as a positive control. Separate groups of male mice were subjected to a chain schedule of ethanol reinforcement to gain access to ethanol wherein completion of a fixed interval (FI; 5 min) schedule (link 1: "Seeking") was reinforced with continuous access to ethanol (fixed ratio; FR1) for up to 1.8 g/kg (link 2: "consumption"). All the animals were treated with 1, 3, and 10 mg/kg of AM6527 or its respective vehicle 20 mins prior to the start of the FI chain of the procedure. Separately, AM6527 was also evaluated in male and female mice undergoing acute ethanol withdrawal following 8 weeks of intermittent or continuous access to 20% ethanol drinking. RESULTS: In both DID and IAA procedures, AM6527 reduced ethanol consumption in a dose-related manner in both male and female mice. AM6527 produced no tolerance in the DID procedure; mice treated with 3 mg/kg of AM6527 for 3 weeks continuously drank significantly smaller amounts of ethanol as compared to vehicle-treated mice over a period of three DID cycles. Moreover, in the IAA procedure, AM6527 caused an increase in water intake over the 24-h period. Acamprosate transiently reduced ethanol intake in male mice in both the DID and the IAA procedures but failed to produce any significant effect in female mice. AM6527 also produced a decrease in the FI responding ("ethanol seeking") in animals trained to self-administer ethanol. Lastly, AM6527 mitigated neurological withdrawal signs, i.e., handling induced convulsions (HIC) in mice undergoing acute ethanol withdrawal. CONCLUSIONS: Current findings support previous studies with CB1R neutral antagonist in reducing voluntary ethanol intake and seeking behavior. Based on results shown in this work, AM6527 can be developed as a first in class CB1R neutral antagonist to treat AUD in both males and females.

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BACKGROUND: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 2019 (COVID-19) is most well-known for causing pulmonary injury, a significant proportion of patients experience hepatic dysfunction. The mechanism by which SARS-CoV2 causes liver injury is not fully understood. The goal of this study was to describe the hepatic pathology in a large cohort of deceased patients with COVID-19 as compared to a control group of deceased patients without COVID-19. METHODS: Consented autopsy cases at two institutions were searched for documentation of COVID-19 as a contributing cause of death. A group of consecutive consented autopsy cases during the same period, negative for SARS-CoV-2 infection, was used as a control group. The autopsy report and electronic medical records were reviewed for relevant clinicopathologic information. H&E-stained liver sections from both groups were examined for pertinent histologic features. Select cases underwent immunohistochemical staining for CD 68 and ACE2 and droplet digital polymerase chain reaction (ddPCR) assay for evaluation of SARS-CoV2 RNA. RESULTS: 48 COVID-19 positive patients (median age 73, M:F 3:1) and 40 COVID-19 negative control patients (median age 67.5, M:F 1.4:1) were included in the study. The COVID-19 positive group was significantly older and had a lower rate of alcoholism and malignancy, but there was no difference in other comorbidities. The COVID-19 positive group was more likely to have received steroids (75.6 % vs. 36.1 %, p < 0.001). Hepatic vascular changes were seen in a minority (10.6 %) of COVID-19 positive cases. When all patients were included, there were no significant histopathologic differences between groups, but when patients with chronic alcoholism were excluded, the COVID-19 positive group was significantly more likely to have steatosis (80.9 % vs. 50.0 %, p = 0.004) and lobular inflammation (45.7 % vs. 20.7 %, p = 0.03). Testing for viral RNA by ddPCR identified 2 of the 18 (11.1 %) COVID-19 positive cases to have SARS-CoV-2 RNA detected within the liver FFPE tissue. CONCLUSIONS: The most significant findings in the liver of COVID-19 positive patients were mild lobular inflammation and steatosis. The high rate of steroid therapy in this population may be a possible source of steatosis. Hepatic vascular alterations were only identified in a minority of patients and did not appear to play a predominant role in COVID-19 mediated hepatic injury. Low incidence of SARS-CoV-2 RNA positivity in liver tissue in our cohort suggests hepatic injury in the setting of COVID-19 may be secondary in nature.

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INTRODUCTION: Theory of Mind (ToM) is the ability to ascribe thoughts (cognitive ToM) and feelings (affective ToM) to others. Ample evidence exists for impairments of affective and cognitive ToM in individuals with alcohol use disorder (AUD); however, evidence regarding changes of these impairments during AUD treatment and their possible relationship to comorbid symptoms is ambiguous. The current study analyzed changes in ToM during treatment and tested associations with comorbid symptoms of depression, anxiety, somatization, and social functioning. METHODS: We analyzed data from 175 individuals with AUD. The study assessed ToM and comorbid symptoms of depression, anxiety, somatization, and social functioning at the time of admission and at the time of discharge from an approximately 60 days long abstinence-oriented inpatient treatment. We assessed affective and cognitive ToM using the Movie for the Assessment of Social Cognition, a measure with high ecological validity. RESULTS: All symptoms, total and cognitive ToM improved following treatment; however, affective ToM did not improve. Moreover, cognitive ToM at the beginning of treatment was associated with improved symptoms of depression and somatization, while affective ToM was not. CONCLUSIONS: Our study shows improvements in total and cognitive ToM as well as symptoms of depression, anxiety, somatization, and social functioning following long-term treatment. Furthermore, cognitive ToM was related to improvements in comorbid symptoms. This finding suggests that ToM may be an important treatment target in patients with AUD.

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BACKGROUND & AIMS: The long-term impact of alcohol-related public health policies (PHPs) on disease burden is unclear. We aimed to assess the association between alcohol-related PHPs and alcohol-related health consequences. METHODS: We conducted an ecological multi-national study including 169 countries. We collected data on alcohol-related PHPs from the WHO Global Information System of Alcohol and Health 2010. Data on alcohol-related health consequences between 2010-2019 were obtained from the Global Burden of Disease database. We classified PHPs into five items, including criteria for low, moderate, and strong PHP establishment. We estimated an alcohol preparedness index (API) using multiple correspondence analysis (0 lowest and 100 highest establishment). We estimated an incidence rate ratio (IRR) for outcomes according to API using adjusted multilevel generalized linear models with a Poisson family distribution. RESULTS: The median API in the 169 countries was 54 [IQR 34.9-76.8]. The API was inversely associated with alcohol use disorder (AUD) prevalence (IRR 0.13; 95% CI 0.03-0.60; p = 0.010), alcohol-associated liver disease (ALD) mortality (IRR 0.14; 95% CI 0.03-0.79; p = 0.025), mortality due to neoplasms (IRR 0.09; 95% CI 0.02-0.40; p = 0.002), alcohol-attributable hepatocellular carcinoma (HCC) (IRR 0.13; 95% CI 0.02-0.65; p = 0.014), and cardiovascular diseases (IRR 0.09; 95% CI 0.02-0.41; p = 0.002). The highest associations were observed in the Americas, Africa, and Europe. These associations became stronger over time, and AUD prevalence was significantly lower after 2 years, while ALD mortality and alcohol-attributable HCC incidence decreased after 4 and 8 years from baseline API assessment, respectively (p <0.05). CONCLUSIONS: The API is a valuable instrument to quantify the robustness of alcohol-related PHP establishment. Lower AUD prevalence and lower mortality related to ALD, neoplasms, alcohol-attributable HCC, and cardiovascular diseases were observed in countries with a higher API. Our results encourage the development and strengthening of alcohol-related policies worldwide. IMPACT AND IMPLICATIONS: We first developed an alcohol preparedness index, an instrument to assess the existence of alcohol-related public policies for each country. We then evaluated the long-term association of the country's alcohol preparedness index in 2010 with the burden of chronic liver disease, hepatocellular carcinoma, other neoplasms, and cardiovascular disease. The strengthening of alcohol-related public health policies could impact long-term mortality rates from cardiovascular disease, neoplasms, and liver disease. These conditions are the main contributors to the global burden of disease related to alcohol use. Over time, this association has not only persisted but also grown stronger. Our results expand the preliminary evidence regarding the importance of public health policies in controlling alcohol-related health consequences.

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