Alcohol-related Disease Research Articles

Socioeconomic inequalities in avoidable mortality: results from the Italian nationwide cohort

Abstract Background Inequalities in avoidable mortality have been well evaluated in many European countries. We aimed to assess the association between socioeconomic status and avoidable mortality in Italy. Methods The nationwide closed cohort of the 2011 Census of Population and Housing was followed up for 2012- 2019 mortality. Outcomes of preventable and of treatable mortality were evaluated among people aged 30-74. Exposures were education level and residence macro area (North-West, North-East, Center, South-Islands). Adjusted mortality rate ratios (MRRs) were estimated through multivariate quasi-Poisson regression models, by sex and group of causes, taking into account age at death and macro area of residence. Relative index of inequalities (RII) was estimated for preventable, treatable, and non-avoidable mortality and for some specific causes. Results The cohort consisted of 35,708,459 residents (48.8% men, 17.5% aged 65-74), 34% with a high school diploma, 33.5% living in the South-Islands; 1,127,760 deaths were observed, of which 65.2% for avoidable causes (40.4% preventable and 24.9% treatable). Inverse trends between education level and mortality were observed for all causes; comparing the least with the most educated groups, a strong association was observed for preventable (males MRR = 2.39; females MRR = 1.65) and for treatable causes of death (males MRR = 1.93; females MRR = 1.45). Highest RII were observed for HIV/AIDS and alcohol-related diseases (both sexes), drug-related diseases and tuberculosis (males), and diabetes mellitus, cardiovascular diseases, and renal failure (females). Higher risks of preventable and of treatable mortality were found for those living in the South-Islands. Conclusions We documented relevant socioeconomic inequalities in avoidable mortality in Italy, especially in the Southern regions. They represent a possible missed gain in health and suggest a reassessment of priorities and definition of health targets with the lens of equity. Key messages • An inverse socioeconomic gradient in avoidable mortality was observed in Italy, both for preventable and for treatable mortality, with geographical heterogeneity. • Greatest social disparities were found in mortality for causes strongly associated with risk behavior and for which it is possible to identify risk factors on which to intervene.

Alcohol policy and alcohol-attributed disease burden in Finland and the Baltic countries 1995-2019

Abstract Introduction Alcohol remains a significant contributor to mortality and morbidity in Finland and the Baltic countries, particularly among men. This study aimed to assess alcohol policy restrictiveness in this region from 1995 to 2019 using a modified version of the Bridging the Gap (BtG-M) policy scale and examine its association with alcohol-related disease burden. Methods The study utilised national statutory laws to score policy restrictiveness (higher BtG-M scores mean stricter policies) and age-standardised rates of disability-adjusted life years (DALYs), years of life lost (YLLs), years lived with disability (YLDs) and deaths per 100,000 from the 2019 Global Burden of Disease Study (GBD). Spearman correlation tests and panel data regression models were applied to assess the association between policy scores and burden of disease. Results Finland maintained a high BtG-M score, while the Baltic countries experienced recent increases from initially lower scores. Alcohol-related disease burden showed an inverse association with policy changes in these countries. Strongest association was seen between the BtG-M score and DALY rates attributed to injuries. Premature mortality among men constituted the largest proportion of disease burden. Discussion and Conclusions Despite challenges in accessing and comparing policy data over time, we showed a strong association between alcohol policy and alcohol-related harm in Finland and the Baltic countries. This study is one of the first to use the BtG-M scale to monitor changes in alcohol policies over time and their relationship to alcohol-related harm using GBD methodology. The study highlights the effects of national alcohol policies on levels of alcohol-related harm. Key messages • This study stands out due to its longitudinal study design, which quantitatively compares the level of alcohol policy restrictiveness in Finland and the Baltic countries from 1995 to 2019. • Our study suggests that shifts towards more restrictive alcohol policies are linked to reduction in alcohol-related harm in Finland and the Baltic countries.

Alcohol-related diseases: from metabolism to the main effect on the body.

Alcohol consumption can cause, beyond addiction, roughly 200 different diseases and at least fourteen types of cancer. In 2016 the WHO estimated that 29% of alcohol-related deaths were mainly due to oncological diseases, liver cirrhosis (20%), and cardiovascular disorders (19%). The aim of this review was to focus on the absorption and metabolism of ethanol and discuss the main conditions caused by alcohol consumption (i.e., liver and cardiovascular diseases, and tumors). This narrative review is based on a detailed analysis of the scientific literature published before January 31, 2024 (PubMed, Web of Science, Scopus, Google Scholar). Approximately 90% of the absorbed alcohol reaches the liver where it is metabolized to acetaldehyde, a highly reactive and toxic compound. The excessive use of alcohol causes damage to several organs and systems, mainly the liver (e.g., steatosis, steato-hepatitis, fibrosis, and cirrhosis), cardiovascular system (cardiomyopathy, arrythmias, arterial hypertension, and stroke), and significantly contribute to the onset of neoplastic lesions to various organs including the esophagus, liver and breast. Even moderate drinking appears not to reduce mortality risk. Alcohol intake is one of the main risk factors for several pathological conditions and social problems, thus drastically impacting on public health. Proper awareness of the high risk related to alcohol consumption is of crucial importance to reduce the harm to public health.

Age, period, and cohort trends of substance poisoning, alcohol-related disease, and suicide deaths in Australia, 1980-2019.

Deaths due to substance poisoning, alcohol-related disease, and suicide pose a critical public health issue, and have been categorized as "deaths of despair" in the US. Whether these deaths represent a distinct phenomenon requires exploration, particularly in other countries. This retrospective observational study examines age-period-cohort trends of (combined and cause-specific) substance poisoning, alcohol-related disease, and suicide deaths among Australians aged ≥15-years that occurred between 1980 and 2019 and compares trends between males and females. Combined mortality rates were initially (1980-1999) relatively stable, reflecting a reduction in alcohol-related disease deaths offset by an increase in substance poisoning deaths. A decline (2000-2006) and subsequent increase (2007-2019) in combined rates were primarily attributable to corresponding changes in both substance poisoning and suicide deaths among males. Distinct age-period-cohort trends were observed between cause of death sub-types, with net drifts: increasing for male (net drift [95% CI]: 3.33 [2.84, 3.83]) and female (2.58 [2.18, 2.98]) substance poisoning deaths; decreasing among male alcohol-related disease (-1.46 [-1.75, -1.16]) and suicide deaths (-0.52[-0.69, -0.36]); and remaining relatively stable for female alcohol-related disease (-0.28 [-0.66, 0.09]) and suicide deaths (-0.25 [-0.52, 0.01]). Although combined age-specific trends were relatively stable over the study period, different and distinct patterns were observed within cause-specific deaths, challenging the notion that these causes of death represent a distinct epidemiological phenomenon. These data indicate a critical need to review the appropriateness of guidance for clinical practice, prevention strategies, and policy initiatives aimed at preventing future deaths.

Alcohol control policy and alcohol-attributable disease burden in Finland and the Baltic countries: A longitudinal study 1995-2019.

Alcohol remains a significant contributor to mortality and morbidity in Finland and the Baltic countries, particularly among men. This study aimed to assess alcohol policy restrictiveness in this region from 1995 to 2019 using a modified version of the Bridging the Gap (BtG-M) policy scale and examine its association with alcohol-related disease burden. The study utilised national laws to score policy restrictiveness (higher BtG-M scores mean stricter policies) and age-standardised rates of disability-adjusted life years (DALY), years of life lost, years lived with disability and deaths per 100,000 from the 2019 Global Burden of Disease Study (GBD). Spearman correlation tests and panel data regression models were applied to assess the association between policy score and burden of disease. Finland maintained a high BtG-M score, while the Baltic countries experienced recent increases from initially lower scores. Alcohol-related disease burden showed an inverse association with policy changes in these countries. Strongest association was seen between the BtG-M score and DALY rates attributed to injuries. Premature mortality among men constituted the largest proportion of disease burden. Despite challenges in accessing and comparing policy data over time, we showed a strong association between alcohol policy and alcohol-related harm in Finland and the Baltic countries. This study is one of the first to use the BtG-M scale to monitor changes in alcohol policies over time and their relationship to alcohol-related harm using GBD methodology. The study highlights the effects of national alcohol policies on levels of alcohol-related harm.

Inflammation, oxidative stress and gut microbiome perturbation: A narrative review of mechanisms and treatment of the alcohol hangover.

Alcohol is the most widely abused substance in the world, the leading source of mortality in 15-49-year-olds, and a major risk factor for heart disease, liver disease, diabetes, and cancer. Despite this, alcohol is regularly misused in wider society. Consumers of excess alcohol often note a constellation of negative symptoms, known as the alcohol hangover. However, the alcohol hangover is not considered to have long-term clinical significance by clinicians or consumers. We undertook a critical review of the literature to demonstrate the pathophysiological mechanisms of the alcohol hangover. Hereafter, the alcohol hangover is re-defined as a manifestation of sickness behavior secondary to alcohol-induced inflammation, using the Bradford-Hill criteria to demonstrate causation above correlation. Alcohol causes inflammation through oxidative stress and endotoxemia. Alcohol metabolism is oxidative and increased intake causes relative tissue hypoxia and increased free radical generation. Tissue damage ensues through lipid peroxidation and the formation of DNA/protein adducts. Byproducts of alcohol metabolism such as acetaldehyde and congeners, sleep deprivation, and the activation of nonspecific inducible CYP2E1 in alcohol-exposed tissues exacerbate free radical generation. Tissue damage and cell death lead to inflammation, but in the intestine loss of epithelial cells leads to intestinal permeability, allowing the translocation of pathogenic bacteria to the systemic circulation (endotoxemia). This leads to a well-characterized cascade of systemic inflammation, additionally activating toll-like receptor 4 to induce sickness behavior. Considering the evidence, it is suggested that hangover frequency and severity may be predictors of the development of later alcohol-related diseases, meriting formal confirmation in prospective studies. In light of the mechanisms of alcohol-mediated inflammation, research into gut permeability and the gut microbiome may be an exciting future therapeutic avenue to prevent alcohol hangover and other alcohol-related diseases.

Global perspectives on alcohol-related cardiovascular disease

Global perspectives on alcohol-related cardiovascular disease

Midlife diseases of despair and cardiometabolic risk: testing shared origins in adolescent psychopathology.

Rising midlife mortality in the United States is largely attributable to 'deaths of despair' (deaths from suicide, drug poisonings, and alcohol-related diseases) and deaths from cardiometabolic conditions. Although despair- and cardiometabolic-related mortality are increasing concurrently, it is unclear whether they share common developmental origins. We tested adolescent psychopathology as a potential common origin of midlife diseases of despair and cardiometabolic risk. Participants (N = 4578) were from the National Longitudinal Study of Adolescent to Adult Health, a nationally representative cohort followed from adolescence to early midlife. Adolescent psychopathology included depression, anxiety, eating disorders, PTSD, conduct disorder, and ADHD at ages 11-18. Diseases of despair (suicidality, substance misuse, pain, and sleep problems) and cardiometabolic risk (hypertension, hyperlipidemia, high-risk waist circumference, diabetes, and cardiovascular conditions) were multi-modally measured at ages 33-43. At midlife, adolescents who experienced psychopathology exhibited more indicators of despair-related diseases and cardiometabolic risk (IRRs = 1.67 [1.46-1.87] and 1.13 [1.04-1.21], respectively), even after accounting for demographics, adolescent SES, and adolescent cognitive ability. Associations were evident for internalizing and externalizing conditions, and in a dose-response fashion. In mediation analyses, low education explained little of these associations, but early-adult substance use explained 21.5% of psychopathology's association with despair-related diseases. Midlife despair-related diseases and cardiometabolic risk co-occurred within individuals (IRR = 1.12 [1.08-1.16]). Adolescent psychopathology accounted for 8.3% of this co-occurrence, and 16.7% together with adolescent SES and cognitive ability. Adolescent psychopathology precedes both diseases of despair and cardiometabolic risk. Prevention and treatment of psychopathology may mitigate multiple causes of poor midlife health, reducing premature mortality.

Socioeconomic inequalities in avoidable mortality in Italy: results from a nationwide longitudinal cohort

BackgroundDisparities in avoidable mortality have never been evaluated in Italy at the national level. The present study aimed to assess the association between socioeconomic status and avoidable mortality.MethodsThe nationwide closed cohort of the 2011 Census of Population and Housing was followed up for 2012–2019 mortality. Outcomes of preventable and of treatable mortality were separately evaluated among people aged 30–74. Education level (elementary school or less, middle school, high school diploma, university degree or more) and residence macro area (North-West, North-East, Center, South-Islands) were the exposures, for which adjusted mortality rate ratios (MRRs) were calculated through multivariate quasi-Poisson regression models, adjusted for age at death. Relative index of inequalities was estimated for preventable, treatable, and non-avoidable mortality and for some specific causes.ResultsThe cohort consisted of 35,708,459 residents (48.8% men, 17.5% aged 65–74), 34% with a high school diploma, 33.5% living in the South-Islands; 1,127,760 deaths were observed, of which 65.2% for avoidable causes (40.4% preventable and 24.9% treatable). Inverse trends between education level and mortality were observed for all causes; comparing the least with the most educated groups, a strong association was observed for preventable (males MRR = 2.39; females MRR = 1.65) and for treatable causes of death (males MRR = 1.93; females MRR = 1.45). The greatest inequalities were observed for HIV/AIDS and alcohol-related diseases (both sexes), drug-related diseases and tuberculosis (males), and diabetes mellitus, cardiovascular diseases, and renal failure (females). Excess risk of preventable and of treatable mortality were observed for the South-Islands.ConclusionsSocioeconomic inequalities in mortality persist in Italy, with an extremely varied response to policies at the regional level, representing a possible missed gain in health and suggesting a reassessment of priorities and definition of health targets.

77 Emerging strategies for head & neck cancer prevention

Head and neck squamous cell carcinoma (HNSCC) is a group of malignancies mostly involving the oral cavity, oropharynx, hypopharynx, and larynx. All together they represent the seventh most common cancer diagnosis worldwide. With 890,000 new cases and 450,000 deaths annually per GLOBOCAN estimates, HNSCC accounts for roughly 4.5% of cancer diagnoses and deaths. In the developing world, the incidence of HNSCC is growing with increasing consumption of tobacco (smoked or chewed), alcohol, and areca nut (betel quid). Alcohol and tobacco have a synergistic effect, with the heavy consumption of both increasing HNSCC risk 40-fold. In this context, the risk of second primary tumors in the field of cancerization is high. In developed nations, HPV-related HNSCC surpasses tobacco- and alcohol-related disease. HPV-related HNSCC more commonly affects the oropharynx, hypopharynx, and larynx than the oral cavity, and is associated with a significantly longer survival.Based on this epidemiological facts, different strategies involving primary, secondary and tertiary prevention will be discussed. For prevention of HPV-positive HNSCC, emphasis will be given to vaccination strategies and novel diagnostic biomarkers for early detection. HPV-negative HNSCC are mostly represented by oral cavity cancers. In this particular context, a Working Group of international experts was convened by the International Agency for Research on Cancer (IARC) to review and assess all available evidence on the effectiveness of primary and secondary preventive interventions in reducing the incidence of and mortality from oral cancer. Available evidence will be summarized. Finally, we will address the challenge of unmet oral cancer prevention in the context of oral potentially malignant disorders (OPMD) in terms of oral cancer risk assessment and pharmacological interception approachs.In conclusion, a lot remains to be done to improve the prevention of HNSCC but significant opportunities exist that will hopefully allow in the near future to significantly decrease its morbidity, mortality, and profound impact on patient's quality of life.

Deaths from Excessive Alcohol Use - United States, 2016-2021.

Deaths from causes fully attributable to alcohol use have increased during the past 2 decades in the United States, particularly from 2019 to 2020, concurrent with the onset of the COVID-19 pandemic. However, previous studies of trends have not assessed underlying causes of deaths that are partially attributable to alcohol use, such as injuries or certain types of cancer. CDC's Alcohol-Related Disease Impact application was used to estimate the average annual number and age-standardized rate of deaths from excessive alcohol use in the United States based on 58 alcohol-related causes of death during three periods (2016-2017, 2018-2019, and 2020-2021). Average annual number of deaths from excessive alcohol use increased 29.3%, from 137,927 during 2016-2017 to 178,307 during 2020-2021; age-standardized alcohol-related death rates increased from 38.1 to 47.6 per 100,000 population. During this time, deaths from excessive alcohol use among males increased 26.8%, from 94,362 per year to 119,606, and among females increased 34.7%, from 43,565 per year to 58,701. Implementation of evidence-based policies that reduce the availability and accessibility of alcohol and increase its price (e.g., policies that reduce the number and concentration of places selling alcohol and increase alcohol taxes) could reduce excessive alcohol use and alcohol-related deaths.

Substance use-related problems in mild intellectual disability: A Swedish nationwide population-based cohort study with sibling comparison.

Evidence for substance use-related problems in individuals with mild intellectual disability is sparse and mainly limited to selected psychiatric populations. We evaluated the risk of substance use-related problems in individuals with mild intellectual disability compared to the general population. Additionally, we have performed secondary sibling comparison analyses to account for familial confounding. We conducted a population-based cohort study of individuals born in Sweden between 1973 and 2003. A total of 18,307 individuals with mild intellectual disability were compared to 915,350 reference individuals from the general population and 18,996 full siblings of individuals with mild intellectual disability. Information on mild intellectual disability and substance use-related problems was obtained from several Swedish national and regional school and healthcare registers. Substance use-related problems were measured via corresponding diagnostic and legal codes and included alcohol use disorder, drug use disorder, alcohol-related somatic disease, conviction for a substance-related crime, and substance-related death. Individuals with mild intellectual disability had a higher risk of any substance use-related problem compared to the general population (HR, 1.81; 95% CI, 1.72-1.91), both in males (HR, 1.76; 95% CI, 1.65-1.89) and females (HR, 1.89; 95% CI, 1.74-2.05). The risks of substance use-related problems were particularly elevated among individuals with mild intellectual disability and psychiatric comorbidities (HR, 2.21-8.24). The associations were attenuated in the sibling comparison models. Individuals with mild intellectual disability, especially those with psychiatric comorbidity, are at an elevated risk of substance use-related problems. Familial factors shared by full siblings contribute considerably to the association between mild intellectual disability and substance use-related problems.

Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS and impact on esophageal cancer risk in Japanese people.

An East Asian-specific variant on aldehyde dehydrogenase 2 (ALDH2 rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis of alcohol consumption in 175,672 Japanese individuals to explore gene-gene interactions with rs671 behind drinking behavior. The analysis identified three genome-wide significant loci (GCKR, KLB, and ADH1B) in wild-type homozygotes and six (GCKR, ADH1B, ALDH1B1, ALDH1A1, ALDH2, and GOT2) in heterozygotes, with five showing genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Of the discovered loci, four (GCKR, ADH1B, ALDH1A1, and ALDH2) were suggested to interact with rs671 in the risk of esophageal cancer, a representative alcohol-related disease. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.

Disaster-related deaths with alcohol-related diseases after the Fukushima Daiichi nuclear power plant accident: case series.

The health of patients with mental disorders, such as alcohol-related diseases, often deteriorates after disasters. However, the causes of death among those with alcohol-related diseases during and after radiation disasters remain unclear. To minimize and prevent alcohol-related deaths in future radiation disasters, we analyzed and summarized six cases of alcohol-related deaths in Minamisoma City, a municipality near the Fukushima Daiichi nuclear power plant. Patients were generally treated for alcohol-related diseases. In one case, the patient was forced to evacuate because of hospital closure, and his condition worsened as he was repeatedly admitted and discharged from the hospital. In another case, the patient's depression worsened after he returned home because of increased medication and drinking for insomnia and loss of appetite. The overall findings revealed that, in many cases, evacuation caused diseases to deteriorate in the chronic phase, which eventually resulted in death sometime after the disaster. To mitigate loss of life, alcohol-related diseases must be addressed during the chronic phases of future large-scale disasters, including nuclear disasters.

Protective effect of Phyllostachys edulis (Carrière) J. Houz against chronic ethanol-induced cognitive impairment in vivo.

Chronic alcohol consumption causes oxidative stress in the body, which may accumulate excessively and cause a decline in memory; problem-solving, learning, and exercise abilities; and permanent damage to brain structure and function. Consequently, chronic alcohol consumption can cause alcohol-related diseases. In this study, the protective effects of Phyllostachys edulis (Carrière) J. Houz (PE) against alcohol-induced neuroinflammation and cognitive impairment were evaluated using a mouse model. Alcohol (16%, 5 g/kg/day for 6 weeks) and PE (100, 250, and 500 mg/kg/day for 21 days) were administered intragastrically to mice. PE showed a protective effect against memory deficits and cognitive dysfunction caused by alcohol consumption, confirmed through behavioral tests such as the T-maze, object recognition, and Morris water maze tests. Additionally, PE attenuated oxidative stress by reducing lipid oxidation, nitric oxide, and reactive oxygen species levels in the mice's brains, livers, and kidneys. Improvement of neurotrophic factors and downregulation of apoptosis-related proteins were confirmed in the brains of mice fed low and medium concentrations of PE. Additionally, expression of antioxidant enzyme-related proteins GPx-1 and SOD-1 was enhanced in the liver of PE-treated mice, related to their inhibitory effect on oxidative stress. This suggests that PE has both neuroregenerative and antioxidant effects. Collectively, these behavioral and histological results confirmed that PE could improve alcohol-induced cognitive deficits through brain neurotrophic and apoptosis protection and modulation of oxidative stress.

Nrf2 pathway activation promotes the expression of genes related to glutathione metabolism in alcohol-exposed astrocytes.

Oxidative and antioxidant pathways play essential roles in the development of alcohol-induced brain injury. The Nrf2 pathway is an endogenous antioxidant response pathway, but there has been little research on the role of Nrf2 in alcohol-related diseases. Thus, we examined the effects of alcohol and an Nrf2 agonist (TBHQ) on astrocyte function, mRNA expression, and metabolite content to further explore the protective mechanisms of Nrf2 agonists in astrocytes following alcohol exposure. CTX TNA2 astrocytes were cultured with alcohol and TBHQ and then subjected to transcriptome sequencing, LC-MS/MS analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and malondialdehyde (MDA) and superoxide dismutase (SOD) activity assays. Alcohol exposure significantly increased malondialdehyde (MDA) levels while decreasing superoxide dismutase (SOD) levels in astrocytes. Treatment with TBHQ effectively reversed these effects, demonstrating its protective role against oxidative stress induced by alcohol. Transcriptome sequencing and qRT-PCR analysis revealed that TBHQ specifically upregulates genes involved in glutathione metabolism, including a notable increase in the expression of the glutathione S-transferase A5 (GSTA5) gene, which was suppressed by alcohol exposure. Additionally, metabolomic analysis showed that TBHQ regulates key components of ether lipid metabolism in alcohol-exposed astrocytes, with significant reductions in the levels of lysophosphatidylcholine (18:0) (LysoPC (18:0)) and 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine, both of which are critical markers in the ether lipid metabolic pathway. The findings underscore the role of TBHQ as an Nrf2 agonist in mitigating alcohol-induced oxidative damage in astrocytes by modulating glutathione metabolism and ether lipid metabolism. The regulation of GSTA5 gene expression emerges as a key mechanism through which Nrf2 agonists confer neuroprotection against oxidative stress and lipid oxidation. These insights pave the way for potential therapeutic strategies targeting the Nrf2 pathway to protect astrocytes from alcohol-induced damage.

Marchiafava-Bignami Disease: A Rare Section Case Report and a Review of Literature

Marchiafava-Bignami Disease (MBD) is an unusual neurological illness caused by prolonged alcoholism that is distinguished by demyelination of the corpus callosum. Clinicians encounter a wide range of alcohol-related diseases in their practice, and MBD is a rare condition that requires a high clinical suspicion due to its potential to mimic withdrawal symptoms, Wernicke’s-Korsakoff’s Psychosis, and various other neurological conditions, leading to confusion in diagnosis. It is a toxic-demyelinating syndrome that typically affects chronic alcoholics, but it has been described in rare instances in chronically malnourished teetotalers. The symptoms and warning signs are diffuse, and the onset could be abrupt or gradual. This is a case of a 54-year-old chronic alcoholic who presented with neurological symptoms. Magnetic Resonance Imaging (MRI) of the brain revealed typical features of MBD. The patient was treated with high doses of thiamine along with folic acid and other symptomatic treatments, after which significant improvement was observed. This case report reviews past reported cases to shed light on the varied presentation features of the disease. It adds to the limited corpus of MBD literature and highlights the intricate diagnostic process and management complexities associated with this condition. By integrating clinical observations, neuroimaging findings, and treatment outcomes, this report underscores the importance of maintaining a high clinical suspicion in cases involving alcohol abuse and the significance of tailored therapeutic strategies. As MBD continues to present diagnostic challenges, this report contributes valuable insights into its presentation, progression, and potential pathways to recovery. Therefore, it requires a high clinical suspicion for both clinical and radiological diagnosis.

Discovery of 4-Ethoxy-6-chloro-5-azaindazoles as Novel PDE4 Inhibitors for the Treatment of Alcohol Use Disorder and Alcoholic Liver Diseases.

Alcohol use disorder (AUD) results in numerous disabilities and approximately 3 million deaths annually, caused mainly by alcoholic liver disease (ALD). Phosphodiesterase IV (PDE4) has emerged as an attractive molecular target for a new treatment for AUD and ALD. In this study, we describe the identification of 5-azaindazole analogues as PDE4 inhibitors against AUD and ALD. System optimization studies led to the discovery of ZL40 (IC50 = 37.4 nM) with a remarkable oral bioavailability (F = 94%), satisfactory safety, and a lower emetogenic potency than the approved PDE4 inhibitors roflumilast and apremilast. Encouragingly, ZL40 exhibited AUD therapeutic effects by decreasing alcohol intake and improving acute alcohol-induced sedation and motor impairment. Meanwhile, ZL40 displayed the potential to alleviate alcoholic liver injury and attenuate inflammation in the NIAAA mice model. These results showed that ZL40 is a promising compound for future drug development to treat alcohol-related diseases.

Inter- and transgenerational heritability of preconception chronic stress or alcohol exposure: Translational outcomes in brain and behavior

Chronic stress and alcohol (ethanol) use are highly interrelated and can change an individual’s behavior through molecular adaptations that do not change the DNA sequence, but instead change gene expression. A recent wealth of research has found that these nongenomic changes can be transmitted across generations, which could partially account for the “missing heritability” observed in genome-wide association studies of alcohol use disorder and other stress-related neuropsychiatric disorders. In this review, we summarize the molecular and behavioral outcomes of nongenomic inheritance of chronic stress and ethanol exposure and the germline mechanisms that could give rise to this heritability. In doing so, we outline the need for further research to: (1) Investigate individual germline mechanisms of paternal, maternal, and biparental nongenomic chronic stress- and ethanol-related inheritance; (2) Synthesize and dissect cross-generational chronic stress and ethanol exposure; (3) Determine cross-generational molecular outcomes of preconception ethanol exposure that contribute to alcohol-related disease risk, using cancer as an example. A detailed understanding of the cross-generational nongenomic effects of stress and/or ethanol will yield novel insight into the impact of ancestral perturbations on disease risk across generations and uncover actionable targets to improve human health.

Suicides, drug poisonings, and alcohol-related deaths cluster with health and social disadvantage in 4.1 million citizens from two nations.

Deaths from suicides, drug poisonings, and alcohol-related diseases ('deaths of despair') are well-documented among working-age Americans, and have been hypothesized to be largely specific to the U.S. However, support for this assertion-and associated policies to reduce premature mortality-requires tests concerning these deaths in other industrialized countries, with different institutional contexts. We tested whether the concentration and accumulation of health and social disadvantage forecasts deaths of despair, in New Zealand and Denmark. We used nationwide administrative data. Our observation period was 10 years (NZ = July 2006-June 2016, Denmark = January 2007-December 2016). We identified all NZ-born and Danish-born individuals aged 25-64 in the last observation year (NZ = 1 555 902, Denmark = 2 541 758). We ascertained measures of disadvantage (public-hospital stays for physical- and mental-health difficulties, social-welfare benefit-use, and criminal convictions) across the first nine years. We ascertained deaths from suicide, drugs, alcohol, and all other causes in the last year. Deaths of despair clustered within a population segment that disproportionately experienced multiple disadvantages. In both countries, individuals in the top 5% of the population in multiple health- and social-service sectors were at elevated risk for deaths from suicide, drugs, and alcohol, and deaths from other causes. Associations were evident across sex and age. Deaths of despair are a marker of inequalities in countries beyond the U.S. with robust social-safety nets, nationwide healthcare, and strong pharmaceutical regulations. These deaths cluster within a highly disadvantaged population segment identifiable within health- and social-service systems.