Sleep features in alcohol use disorder: A systematic review and meta-analysis of polysomnographic findings in case-control studies

Background and objectives Alcohol use disorder (AUD) is often linked to sleep problems, but previous studies on sleep abnormalities in AUD have produced inconsistent results. This study aims to provide a comprehensive analysis of objectively measured sleep abnormalities in AUD and determine the impact of related and demographic factors on sleep disturbance. Methods We conducted a comprehensive search of several databases from 1968 to 2023 to identify relevant studies. A total of 12 studies, consisting of 13 datasets, were included in the analysis. We extracted information on sleep microarchitecture, as well as demographic and clinical features, from each study. The GRADE approach was used to assess the reliability and strength of the evidence. Results Patients with AUD exhibited several sleep abnormalities, including longer sleep onset latency, lower sleep efficiency, increased stage 1 sleep, decreased stage 2 sleep, reduced slow wave sleep, and elevated rapid eye movement (REM) sleep density and first REM minute. The sleep patterns in individuals with AUD were also influenced by factors such as ethnicity, age, gender, and abstinence period. Conclusions This study is the largest quantitative assessment of impaired sleep as a diagnostic marker in patients with AUD. Understanding the sleep patterns of individuals with AUD can assist clinicians in developing effective treatment plans for managing sleep-related symptoms associated with AUD. (AU)

Reductions in World Health Organization risk drinking level are associated with improvements in sleep problems among individuals with alcohol use disorder.

AIMS: Among individuals with alcohol use disorder (AUD), sleep disturbances are pervasive and contribute to the etiology and maintenance of AUD. However, despite increased attention toward the relationship between alcohol use and sleep, limited empirical research has systematically examined whether reductions in drinking during treatment for AUD are associated with improvements in sleep problems. METHODS: We used data from a multisite, randomized, controlled trial that compared 6 months of treatment with gabapentin enacarbil extended-release with placebo for adults with moderate-to-severe AUD (N = 346). The Timeline Follow-back was used to assess WHO risk drinking level reductions and the Pittsburgh Sleep Quality Index was used to assess sleep quality over the prior month at baseline and the end of treatment. RESULTS: Sleep problem scores in the active medication and placebo groups improved equally. Fewer sleep problems were noted among individuals who achieved at least a 1-level reduction (B = -0.99, 95% confidence interval (CI) [-1.77, -0.20], P = .014) or at least a 2-level reduction (B = -0.80, 95% CI [-1.47, -0.14], P = .018) in WHO risk drinking levels at the end of treatment. Reductions in drinking, with abstainers excluded from the analysis, also predicted fewer sleep problems at the end of treatment (1-level: B = -1.01, 95% CI [-1.83, -0.20], P = .015; 2-level: B = -0.90, 95% CI [-1.59, -0.22], P = .010). CONCLUSIONS: Drinking reductions, including those short of abstinence, are associated with improvements in sleep problems during treatment for AUD. Additional assessment of the causal relationships between harm-reduction approaches to AUD and improvements in sleep is warranted.

Study on the risk factors of postoperative wound complications in patients with ankle fracture.

Wound complications after surgery for ankle fractures can lead to catastrophic consequences. The purpose of this study was to evaluate the risk factors of postoperative wound complications in patients with ankle fracture and to determine their effects on prognosis. 200 patients with ankle fracture treated in our hospital from October 2021 to December 2023 were analysed retrospectively. The total incidence of postoperative wound complications was 19% (38/200). Type of complications: wound edge necrosis 15 cases (39.47%), dehiscence (reopening of wound) 13 cases (34.21%), delayed healing (>30 days) 10 cases (26.32%); Univariate analysis showed that patients' age, body mass index (BMI), current smoking, alcoholism, diabetes mellitus, injury mechanism, open fracture, wound classification, higher American Society of Anesthesiologists (ASA) score and operation time were all associated with postoperative wound complications. Multivariate Logistic regression model shows: age ≥60 years old OR3.671 (1.875-5.937), BMI OR1.198 (1.143-1.324), current smoking OR2.727 (1.251-5.602), alcoholism OR1.143 (1.034-1.267), complicated with diabetes OR2.763 (1.236-4.852), injury mechanism (high vs. low and medium energy) OR2.437 (1.238-4.786), open fracture OR1.943 (1.8262.139), wound classification (II vs. I) OR4.423 (1.73511.674), ASA score (III-IV vs. I-II) OR1.307 (1.113-2.194) was an independent risk factor for postoperative wound complications in patients with ankle fracture. Further, ROC curves showed that these nine independent influences had high accuracy and validity in predicting postoperative wound complications in patients with ankle fractures. In conclusion, independent risk factors for postoperative complications of ankle fracture were age >60 years, BMI, injury mechanism, open fracture, wound classification (II vs. I), ASA score, current smoking, and alcoholism. The wound classification (II vs. I) has the highest diagnostic value.

Comorbid physical health burden of serious mental health disorders in 32 European countries.

BACKGROUND: Mental health disorders (MHDs) are associated with physical health disparities, but underlying excess risk and health burden have not yet been comprehensively assessed. OBJECTIVE: To assess the burden of comorbid physical health conditions (PHCs) across serious MHDs in Europe. METHODS: We estimated the relative prevalence risk of PHCs associated with alcohol use disorders (AUD), bipolar disorder (BD), depressive disorders (DD) and schizophrenia (SZ) across working-age populations of 32 European countries in 2019 based on a targeted literature review. Excess physical health burden was modelled using population-attributable fractions and country-level prevalence data. FINDINGS: We screened 10 960 studies, of which 41 were deemed eligible, with a total sample size of over 18 million persons. Relative prevalence of PHCs was reported in 54%, 20%, 15%, 5% and 7% of studies, respectively, for SZ, DD, BD, AUD or mixed. Significant relative risk estimates ranged from 1.44 to 3.66 for BD, from 1.43 to 2.21 for DD, from 0.81 to 1.97 for SZ and 3.31 for AUD. Excess physical health burden ranged between 27% and 67% of the total, corresponding to 84 million (AUD), 67 million (BD), 66 million (DD) and 5 million (SZ) PHC diagnoses in Europe. A 1% reduction in excess risk assuming causal inference could result in two million fewer PHCs across investigated MHDs. CONCLUSIONS: This is the first comprehensive study of the physical health burden of serious MHDs in Europe. The methods allow for updates, refinement and extension to other MHDs or geographical areas. CLINICAL IMPLICATIONS: The results indicate potential population health benefits achievable through more integrated mental and physical healthcare and prevention approaches.

Hemochromatosis: Ferroptosis, ROS, Gut Microbiome, and Clinical Challenges with Alcohol as Confounding Variable.

Hemochromatosis represents clinically one of the most important genetic storage diseases of the liver caused by iron overload, which is to be differentiated from hepatic iron overload due to excessive iron release from erythrocytes in patients with genetic hemolytic disorders. This disorder is under recent mechanistic discussion regarding ferroptosis, reactive oxygen species (ROS), the gut microbiome, and alcohol abuse as a risk factor, which are all topics of this review article. Triggered by released intracellular free iron from ferritin via the autophagic process of ferritinophagy, ferroptosis is involved in hemochromatosis as a specific form of iron-dependent regulated cell death. This develops in the course of mitochondrial injury associated with additional iron accumulation, followed by excessive production of ROS and lipid peroxidation. A low fecal iron content during therapeutic iron depletion reduces colonic inflammation and oxidative stress. In clinical terms, iron is an essential trace element required for human health. Humans cannot synthesize iron and must take it up from iron-containing foods and beverages. Under physiological conditions, healthy individuals allow for iron homeostasis by restricting the extent of intestinal iron depending on realistic demand, avoiding uptake of iron in excess. For this condition, the human body has no chance to adequately compensate through removal. In patients with hemochromatosis, the molecular finetuning of intestinal iron uptake is set off due to mutations in the high-FE2+ (HFE) genes that lead to a lack of hepcidin or resistance on the part of ferroportin to hepcidin binding. This is the major mechanism for the increased iron stores in the body. Hepcidin is a liver-derived peptide, which impairs the release of iron from enterocytes and macrophages by interacting with ferroportin. As a result, iron accumulates in various organs including the liver, which is severely injured and causes the clinically important hemochromatosis. This diagnosis is difficult to establish due to uncharacteristic features. Among these are asthenia, joint pain, arthritis, chondrocalcinosis, diabetes mellitus, hypopituitarism, hypogonadotropic hypogonadism, and cardiopathy. Diagnosis is initially suspected by increased serum levels of ferritin, a non-specific parameter also elevated in inflammatory diseases that must be excluded to be on the safer diagnostic side. Diagnosis is facilitated if ferritin is combined with elevated fasting transferrin saturation, genetic testing, and family screening. Various diagnostic attempts were published as algorithms. However, none of these were based on evidence or quantitative results derived from scored key features as opposed to other known complex diseases. Among these are autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). For both diseases, the scored diagnostic algorithms are used in line with artificial intelligence (AI) principles to ascertain the diagnosis. The first-line therapy of hemochromatosis involves regular and life-long phlebotomy to remove iron from the blood, which improves the prognosis and may prevent the development of end-stage liver disease such as cirrhosis and hepatocellular carcinoma. Liver transplantation is rarely performed, confined to acute liver failure. In conclusion, ferroptosis, ROS, the gut microbiome, and concomitant alcohol abuse play a major contributing role in the development and clinical course of genetic hemochromatosis, which requires early diagnosis and therapy initiation through phlebotomy as a first-line treatment.

Elevated liver enzymes and fasting glucose levels correlate with neuropathy in patients diagnosed with alcohol use disorder independently of the blood thiamine levels.

AIMS: Chronic alcohol consumption is well known to cause peripheral neuropathy, affecting both small and large nerve fibers. The aim of this study was to correlate biochemical and neurophysiological findings and investigate possible biomarkers and risk factors for pathogenetic mechanisms of neuropathy in patients diagnosed with alcohol use disorder (AUD). METHODS: Ninety patients diagnosed with AUD were enrolled in this prospective study over a period of 3 years. Serum biochemical parameters, as well as thiamine blood levels, were determined upon admission. Every subject was assessed by clinical neurological examination, followed by Nerve Conduction Studies, Quantitative Sensory Testing, and Sympathetic Skin Response. Fifty age and gender-matched patients without a diagnosis of AUD were used as the control group. RESULTS: Peripheral neuropathy was diagnosed in 54 patients (60%). Among them, pure large fiber neuropathy was found in 18 patients, pure small fiber neuropathy in 12 patients, and both large and small fiber neuropathy was diagnosed in 24 patients. Elevated liver enzymes and fasting glucose levels upon admission were significantly correlated with neuropathy. Lower blood thiamine levels (than reference) were found in seven patients and were not correlated with neuropathy. CONCLUSIONS: Our study suggests that alcohol-related liver dysfunction and hyperglycemia may contribute as risk factors of peripheral neuropathy in patients diagnosed with AUD, while blood thiamine levels do not correlate with neuropathy. Moreover, we suggest that liver enzymes and the De Ritis ratio could be potentially used as biomarkers for the incidence and severity of alcohol-related neuropathy.

Treatment of alcohol use disorder in patients with alcohol-associated liver disease: Innovative approaches and a call to action.

Alcohol-associated liver disease is currently the leading cause of liver transplantation and liver deaths both in Europe and the United States. Efficacious treatments exist for alcohol use disorder, but they are seldomly prescribed for patients who need them. Besides, the presence of liver cirrhosis can complicate pharmacological treatment choices. In this review, we discuss established and innovative treatment strategies to treat unhealthy alcohol use in patients with alcohol-associated liver disease. We also describe the experience of our own institutions, Hospital Universitari Germans Trias i Pujol in Badalona (Spain) and Yale-New Haven Health and Yale Medicine (Connecticut. United States of America).

Sleep-Related Predictors of Risk for Alcohol Use and Related Problems in Adolescents and Young Adults.

PURPOSE: Growing evidence supports sleep and circadian rhythms as influencing alcohol use and the course of alcohol use disorder (AUD). Studying sleep/circadian-alcohol associations during adolescence and young adulthood may be valuable for identifying sleep/circadian-related approaches to preventing and/or treating AUD. This paper reviews current evidence for prospective associations between sleep/circadian factors and alcohol involvement during adolescence and young adulthood with an emphasis on the effects of sleep/circadian factors on alcohol use. SEARCH METHODS: The authors conducted a literature search in PsycInfo, PubMed, and Web of Science using the search terms "sleep" and "alcohol" paired with "adolescent" or "adolescence" or "young adult" or "emerging adult," focusing on the title/abstract fields, and restricting to English-language articles. Next, the search was narrowed to articles with a prospective/longitudinal or experimental design, a sleep-related measure as a predictor, an alcohol-related measure as an outcome, and confirming a primarily adolescent and/or young adult sample. This step was completed by a joint review of candidate article abstracts by two of the authors. SEARCH RESULTS: The initial search resulted in 720 articles. After review of the abstracts, the list was narrowed to 27 articles reporting on observational longitudinal studies and three articles reporting on intervention trials. Noted for potential inclusion were 35 additional articles that reported on studies with alcohol-related predictors and sleep-related outcomes, and/or reported on candidate moderators or mediators of sleep-alcohol associations. Additional articles were identified via review of relevant article reference lists and prior exposure based on the authors' previous work in this area. DISCUSSION AND CONCLUSIONS: Overall, the review supports a range of sleep/circadian characteristics during adolescence and young adulthood predicting the development of alcohol use and/or alcohol-related problems. Although sleep treatment studies in adolescents and young adults engaging in regular and/or heavy drinking show that sleep can be improved in those individuals, as well as potentially reducing alcohol craving and alcohol-related consequences, no studies in any age group have yet demonstrated that improving sleep reduces drinking behavior. Notable limitations include relatively few longitudinal studies and only two experimental studies, insufficient consideration of different assessment timescales (e.g., day-to-day vs. years), insufficient consideration of the multidimensional nature of sleep, a paucity of objective measures of sleep and circadian rhythms, and insufficient consideration of how demographic variables may influence sleep/circadian-alcohol associations. Examining such moderators, particularly those related to minoritized identities, as well as further investigation of putative mechanistic pathways linking sleep/circadian characteristics to alcohol outcomes, are important next steps.

Molecular mechanisms involved in alcohol craving, IRF3, and endoplasmic reticulum stress: a multi-omics study.

Alcohol use disorder (AUD) is the most prevalent substance use disorder worldwide. Acamprosate and naltrexone are anti-craving drugs used in AUD pharmacotherapy. However, molecular mechanisms underlying their anti-craving effect remain unclear. This study utilized a patient-derived induced pluripotent stem cell (iPSC)-based model system and anti-craving drugs that are used to treat AUD as "molecular probes" to identify possible mechanisms associated with alcohol craving. We examined the pathophysiology of craving and anti-craving drugs by performing functional genomics studies using iPSC-derived astrocytes and next-generation sequencing. Specifically, RNA sequencing performed using peripheral blood mononuclear cells from AUD patients with extreme values for alcohol craving intensity prior to treatment showed that inflammation-related pathways were highly associated with alcohol cravings. We then performed a genome-wide assessment of chromatin accessibility and gene expression profiles of induced iPSC-derived astrocytes in response to ethanol or anti-craving drugs. Those experiments identified drug-dependent epigenomic signatures, with IRF3 as the most significantly enriched motif in chromatin accessible regions. Furthermore, the activation of IRF3 was associated with ethanol-induced endoplasmic reticulum (ER) stress which could be attenuated by anti-craving drugs, suggesting that ER stress attenuation might be a target for anti-craving agents. In conclusion, we found that craving intensity was associated with alcohol consumption and treatment outcomes. Our functional genomic studies suggest possible relationships among craving, ER stress, IRF3 and the actions of anti-craving drugs.

Association between smoking and lack of HIV virological suppression in a cross-sectional study of persons with HIV on antiretroviral therapy in Uganda.

BACKGROUND: Smoking and alcohol use frequently co-occur and are the leading causes of preventable death in sub-Saharan Africa (SSA) and are common among people living with HIV (PLWH). While alcohol use has been shown to be associated with reduced adherence to antiretroviral treatment (ART), which may affect HIV viral suppression, the independent effect of smoking on HIV outcomes in SSA is unknown. We aimed to 1) describe the prevalence of current smoking and correlates of smoking; 2) assess the association of smoking with viral suppression, adjusting for level of alcohol use; 3) explore the relationship between smoking and CD4 cell count <350 cells/mm3, among participants who are virally suppressed. METHODS: We analyzed data from the Drinkers Intervention to Prevent Tuberculosis (DIPT) and the Alcohol Drinkers' Exposure to Preventive Therapy for TB (ADEPTT) studies conducted in Southwest Uganda. The studies enrolled PLWH who were on ART for at least 6 months and co-infected with latent tuberculosis and dominated with participants who had unhealthy alcohol use. Current smoking (prior 3 months) was assessed by self-report. Alcohol use was assessed using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C, modified for prior 3 months) and phosphatidylethanol (PEth), an alcohol biomarker. We used logistic regression to estimate the cross-sectional association between smoking and lack of virological suppression (≥40 copies/ml), adjusting for level of alcohol use and other covariates, and to examine the association between smoking and CD4 cell counts among PLWH with viral suppression. RESULTS: Of the 955 participants enrolled from 2017 to 2021 who had viral load (VL) results, 63% were men, median age was 40 years (interquartile range [IQR] 32-47), 63% engaged in high/very high-risk alcohol use (AUDIT-C≥6 or PEth≥200 ng/mL), and 22% reported smoking in the prior 3 months. Among 865 participants (91%) with viral suppression and available CD4 count, 11% had a CD4 cell count <350 cells/mm3. In unadjusted and adjusted analyses, there was no evidence of an association between smoking and lack of virological suppression nor between smoking and CD4 count among those with viral suppression. CONCLUSIONS: The prevalence of smoking was high among a study sample of PLWH in HIV care with latent TB in Southwest Uganda in which the majority of persons engaged in alcohol use. Although there was no evidence of an association between smoking and lack of virological suppression, the co-occurrence of smoking among PLWH who use alcohol underscores the need for targeted and integrated approaches to reduce their co-existence and improve health.

Examining the relationship between the oral microbiome, alcohol intake and alcohol-comorbid neuropsychological disorders: protocol for a scoping review.

INTRODUCTION: Heavy alcohol use and alcohol use disorder (AUD) continues to rise as a public health problem and increases the risk for disease. Elevated rates of anxiety, depression, sleep disruption and stress are associated with alcohol use. Symptoms may progress to diagnosed neurophysiological conditions and increase risk for relapse if abstinence is attempted. Research on mechanisms connecting the gastrointestinal microbiome to neuropsychological disorders through the gut-brain axis is well-established. Less is known how the oral microbiome and oral microbial-associated biomarkers may signal to the brain. Therefore, a synthesis of research studying relationships between alcohol intake, alcohol-associated neurophysiological symptoms and the oral microbiome is needed to understand the state of the current science. In this paper, we outline our protocol to collect, evaluate and synthesise research focused on associations between alcohol intake and AUD-related neuropsychological disorders with the oral microbiome. METHODS AND ANALYSIS: The search strategy was developed and will be executed in collaboration with a medical research librarian. Studies will be screened by two independent investigators according to the aim of the scoping review, along with the outlined exclusion and inclusion criteria. After screening, data will be extracted and synthesised from the included papers according to predefined demographic, clinical and microbiome methodology metrics. ETHICS AND DISSEMINATION: A scoping review of primary sources is needed to synthesise the data on relationships between alcohol use, neuropsychological conditions associated with AUD and the oral microbiome. The proposed scoping review is based on the data from publicly available databases and does not require ethical approval. We expect the results of this synthesis will identify gaps in the growing literature and highlight potential mechanisms linking the oral-brain axis to addiction and other associated neuropsychological conditions. The study findings and results will be disseminated through journals and conferences related to psychology, neuroscience, dentistry and the microbiome.

Review article: Current indications and selection criteria for early liver transplantation in severe alcohol-associated hepatitis.

BACKGROUND: Alcohol-associated hepatitis (AH) is a severe inflammatory form of alcohol-associated liver disease (ALD) that carries a high mortality rate. Early liver transplantation for severe AH is increasingly available. However, specific criteria for referral and selection remain a subject of debate. AIMS: To provide a narrative review of the natural history, diagnostic criteria and indications for referral for early liver transplantation for severe AH. METHODS: We searched PubMed for articles published through August 2023. Key search terms were 'alcoholic hepatitis,' 'alcohol-associated hepatitis,' 'abstinence,' 'alcohol relapse,' and 'liver transplantation.' RESULTS: Previously, a six-month period of alcohol abstinence was required before patients with ALD were considered for liver transplantation. However, studies in recent years have demonstrated that, among carefully selected patients, patients who received early transplants have much higher survival rates than patients with similarly severe disease who did not undergo transplants (77% vs. 23%). Despite these successes, early liver transplantation remains controversial, as these patients have typically not undergone treatment for alcohol use disorder, with the ensuing risk of returning to alcohol use. CONCLUSIONS: While early liver transplantation for AH has survival benefits, many patients would not have received treatment for alcohol use disorder. An integrated approach to evaluating candidacy for early liver transplantation is needed.

Exercising healthy behaviors: A latent class analysis of positive coping during the COVID-19 pandemic and associations with alcohol-related and mental health outcomes.

OBJECTIVE: To identify latent classes of positive coping behaviors during the COVID-19 pandemic and examine associations with alcohol-related and mental health outcomes across participants with and without a history of alcohol use disorder (AUD). METHODS: Baseline data from 463 participants who were enrolled in the NIAAA COVID-19 Pandemic Impact on Alcohol (C19-PIA) Study were analyzed. Latent class analysis (LCA) was applied to five positive coping behaviors during COVID-19: taking media breaks, taking care of their body, engaging in healthy behaviors, making time to relax, and connecting with others. Latent class differences and the moderating role of history of AUD on six alcohol-related and mental health outcomes were examined using multiple regression models. RESULTS: LCA revealed two latent classes: 83.4% High Positive Coping and 16.6% Low Positive Coping. Low Positive Coping was associated with higher levels of perceived stress, anxiety symptoms, and loneliness. A history of AUD was consistently associated with higher levels of alcohol-related and mental health outcomes. Significant interactions between Coping Latent Classes and history of AUD indicated that the associations of Low Positive Coping with problematic alcohol use, depressive symptoms, and drinking to cope motives were either stronger or only significant among individuals with a history of AUD. CONCLUSIONS: Individuals with a history of AUD may be particularly vulnerable to depressive symptoms and alcohol-related outcomes, especially when they do not utilize positive coping strategies. The promotion of positive coping strategies is a promising avenue to address alcohol-related and mental health problems during a public health crisis and warrants future research.

Pain Intensity, Pain-Related Anxiety, and Hazardous Drinking Among Individuals With PTSD.

OBJECTIVE: Evidence suggests that pain intensity may be indirectly linked to hazardous drinking and PTSD symptom severity via pain-related anxiety. The goal of this analysis was to test the hypotheses in a population with PTSD symptoms that pain intensity would be positively and indirectly associated with hazardous drinking, alcohol dependence, alcohol-related problems, and PTSD symptom severity via pain-related anxiety. METHODS: Heavy drinkers with probable PTSD were recruited via Qualtrics panels (N = 371, 53% Female, Mage = 39.68, SD = 10.86). Linear regression and conditional process models were conducted to examine indirect associations between pain intensity and primary outcomes via pain-related anxiety. RESULTS: Pain intensity was found to be indirectly associated with hazardous drinking, alcohol dependence, alcohol-related problems, and PTSD symptom severity via greater pain-related anxiety. CONCLUSION: These initial findings suggest that pain-related anxiety may play an important role in relations between the experience of pain and hazardous patterns of alcohol consumption among individuals with probable PTSD. Future research is needed to determine the temporal nature of these associations and to examine the potential utility of treatments that address pain-related anxiety in the context of comorbid pain, PTSD, and hazardous drinking.

Elevated levels of alcohol dehydrogenase aggravate ethanol-evoked cardiac remodeling and contractile anomalies through FKBP5-yap-mediated regulation of ferroptosis and ER stress.

Alcohol intake provokes severe organ injuries including alcoholic cardiomyopathy with hallmarks of cardiac remodeling and contractile defects. This study examined the toxicity of facilitated ethanol metabolism in alcoholism-evoked changes in myocardial morphology and contractile function, insulin signaling and various cell death domains using cardiac-selective overexpression of alcohol dehydrogenase (ADH). WT and ADH mice were offered an alcohol liquid diet for 12 weeks prior to assessment of cardiac geometry, function, ER stress, apoptosis and ferroptosis. Alcohol intake provoked pronounced glucose intolerance, cardiac remodeling and contractile anomalies with apoptosis, ER stress, and ferroptosis, the effects were accentuated by ADH with the exception of global glucose intolerance. Hearts from alcohol ingesting mice displayed dampened insulin-stimulated phosphorylation of insulin receptor (tyr1146) and IRS-1 (tyrosine) along with elevated IRS-1 serine phosphorylation, the effect was augmented by ADH. Alcohol challenge dampened phosphorylation of Akt and GSK-3ß, and increased phosphorylation of c-Jun and JNK, the effects were accentuated by ADH. Alcohol challenge promoted ER stress, FK506 binding protein 5 (FKBP5), YAP, apoptosis and ferroptosis, the effects were exaggerated by ADH. Using a short-term ethanol challenge model (3 g/kg, i.p., twice in three days), we found that inhibition of FKBP5-YAP signaling or facilitated ethanol detoxification by Alda-1 alleviated ethanol cardiotoxicity. In vitro study revealed that the ethanol metabolite acetaldehyde evoked cardiac contractile anomalies, lipid peroxidation, and apoptosis, the effects of which were mitigated by Alda-1, inhibition of ER stress, FKBP5 and YAP. These data suggest that facilitated ethanol metabolism via ADH exacerbates alcohol-evoked myocardial remodeling, functional defects, and insulin insensitivity possibly through a FKBP5-YAP-associated regulation of ER stress and ferroptosis.

Problematic alcohol use and its impact on liver disease quality of life in a multicenter study of patients with cirrhosis.

BACKGROUND: Management of cirrhosis is challenging and has been complicated by the COVID-19 pandemic due to decreased access to care, increased psychological distress, and alcohol misuse. Recently, The National Institute on Alcohol Abuse and Alcoholism has broadened the definition of recovery from alcohol use disorder to include quality of life (QoL) as an indicator of recovery. This study examined the associations of alcohol-associated cirrhosis etiology and problematic drinking with liver disease QoL (LDQoL). METHODS: Patients with cirrhosis (N=329) were recruited from 3 sites (63% from 2 Veterans Affairs Health Care Systems and 37% from 1 safety net hospital) serving populations that are economically or socially marginalized. Cirrhosis etiology was ascertained by chart review of medical records. Problematic drinking was defined by ≥8 on the Alcohol Use Disorders Identification Test. Multivariable general linear modeling adjusting for age, sex, race/ethnicity, site, pandemic-related stress, and history of anxiety/depressive disorder were conducted. Sensitivity analyses further adjusted for indicators of liver disease severity. RESULTS: Participants were on average 64.6 years old, 17% female, 58% non-White, 44% with alcohol-associated cirrhosis, and 17% with problematic drinking. Problematic drinking was significantly associated with worse LDQoL scores in the overall scale and in the memory/concentration and health distress subscales. These associations remained significant after adjusting for indicators of liver disease severity, including Model for End-Stage Liver Disease-Sodium score and decompensated cirrhosis status. CONCLUSIONS: Among patients with cirrhosis, problematic drinking was associated with worse LDQoL, especially in the domains of memory/concentration and health distress. Assessment and awareness of cognitive deficits and negative emotionality within the context of cirrhosis and problematic drinking may help clinicians provide better integrated care for this population.

Alcohol-related cognitive impairments in patients with and without cirrhosis.

AIMS: up to 80% of patients with alcohol use disorder display cognitive impairments. Some studies have suggested that alcohol-related cognitive impairments could be worsened by hepatic damage. The primary objective of this study was to compare mean scores on the Brief Evaluation of Alcohol-Related Neurocognitive Impairments measure between alcohol use disorder patients with (CIR+) or without cirrhosis (CIR-). METHODS: we conducted a prospective case-control study in a hepatology department of a university hospital. All patients were assessed using the Evaluation of Alcohol-Related Neuropsychological Impairments test. RESULTS: a total of 82 patients (50 CIR+, 32 CIR-) were included in this study. CIR- patients were significantly younger than CIR+ patients (respectively, 45.5 ± 6.8 vs 60.1 ± 9.0; P < .0001). After adjusting for age and educational level, the mean Evaluation of Alcohol-Related Neuropsychological Impairments total scores in the CIR+ group were significantly lower than in the group of CIR- patients (14.1 ± 0.7 vs 7.8 ± 0.4, respectively, P < .0001). The mean subscores on delayed verbal memory, alphabetical ordination, alternating verbal fluency, visuospatial abilities, and ataxia subtests were also significantly lower in the CIR+ than in the CIR- group (respectively, 1.9 ± 0.2 vs 2.8 ± 0.2; 1.8 ± 0.2 vs 2.7 ± 0.2; 2.2 ± 0.2 vs 3.6 ± 0.2; 0.7 ± 0.2 vs 1.6 ± 0.2; 0.7 ± 0.2 vs 3.1 ± 0.2; P < .0001 for all comparisons). CONCLUSIONS: in the present study, alcohol use disorder patients with cirrhosis presented more severe cognitive impairments than those without cirrhosis. Longitudinal studies are needed to investigate how cirrhosis can influence cognitive impairments.

Influence of sleep quality on lapse to alcohol use during a quit attempt.

AIMS: Sleep problems are common among individuals with alcohol use disorder (AUD) and is often associated with a heightened relapse risk. The present study examines the relationship between sleep and alcohol use among individuals with current AUD during a 6-day quit attempt as part of a medication study. METHODS: The current study is a secondary analysis of a medication trial for individuals with AUD. Individuals with AUD (N = 53, 26 females) were randomized to active medication or matched placebo. Randomized participants completed a week-long medication titration (Days 1-7). Following the titration period, participants attended an in-person visit (Day 8) to begin a 6-day quit attempt. During the quit attempt, participants completed daily diary assessments to report on previous day alcohol consumption, sleep quality, and alcohol craving. In the present study, medication condition was controlled for in all models. RESULTS: Baseline global sleep quality was not a significant predictor of drinks per drinking day (P = 0.72) or percent days abstinent (P = 0.16) during the 6-day practice quit attempt. Daily diary analyses found that greater sleep quality was associated with higher next-day drinks per drinking day (b = 0.198, P = 0.029). In contrast, participants reported worse sleep quality following nights of greater alcohol intake, albeit at a trend-level (b = -0.12, P = 0.053). CONCLUSIONS: These results suggest that better sleep quality was a risk factor for drinking during the 6-day quit period, such that better sleep may be associated with increased craving for alcohol and alcohol use the next day. These findings are limited to the early abstinence period and should be considered in studies exploring longer periods of abstinence.

[Qualitative and quantitative characteristics of structures of cerebral cortex structure in young people under conditions of chronic alcohol intoxication]. / Kachestvennaya i kolichestvennaya kharakteristika struktur kory golovnogo mozga u lits molodogo vozrasta v usloviyakh khronicheskoi alkogol'noi intoksikatsii.

OBJECTIVE: To study morphological changes of cerebral cortex in young people under the conditions of chronic alcohol intoxication (CAI). MATERIAL AND METHODS: Morphometric examination of cerebral cortex fragments obtained from 28 persons who died with a CAI diagnosis (average age was 38 years), and 25 subjects who died from other causes, which are not associated with alcohol consumption (average age was 39 years), was carried out. RESULTS: It was shown that neurons of pathological shapes, including hypo- and hyperchromic, pyknotic and «shadow-like¼, were dominant in group of CAI. There was an increase in the glial index and a greater intensity of perivascular and pericellular edema compared to the control group. CONCLUSION: Morphological changes of cerebral cortex under the conditions of CAI are non-specific and largely similar to neurodegenerative alterations in other pathological conditions, senile dementia. Clearer histological criteria for alcoholic encephalopathy are needed, including with the use of immunohistochemical methods.