Alcohol-Associated Tissue Injury: Current Views on Pathophysiological Mechanisms.

At-risk alcohol use is a major contributor to the global health care burden and leads to preventable deaths and diseases including alcohol addiction, alcoholic liver disease, cardiovascular disease, diabetes, traumatic injuries, gastrointestinal diseases, cancers, and fetal alcohol syndrome. Excessive and frequent alcohol consumption has increasingly been linked to alcohol-associated tissue injury and pathophysiology, which have significant adverse effects on multiple organ systems. Extensive research in animal and in vitro models has elucidated the salient mechanisms involved in alcohol-induced tissue and organ injury. In some cases, these pathophysiological mechanisms are shared across organ systems. The major alcohol- and alcohol metabolite-mediated mechanisms include oxidative stress, inflammation and immunometabolic dysregulation, gut leak and dysbiosis, cell death, extracellular matrix remodeling, endoplasmic reticulum stress, mitochondrial dysfunction, and epigenomic modifications. These mechanisms are complex and interrelated, and determining the interplay among them will make it possible to identify how they synergistically or additively interact to cause alcohol-mediated multiorgan injury. In this article, we review the current understanding of pathophysiological mechanisms involved in alcohol-induced tissue injury.

Electrochemical and Spectroscopic Studies Performed for Indomethacin and 1-Naphthol Incorporated in 1-Butyl-3-methyl-imidazolium Bis(2-ethylhexyl) Sulfosuccinate Vesicles to Investigate Them as a Potentially pH-Sensitive Nanocarrier.

Characterization studies of 1-butyl-3-methyl-imidazolium bis(2-ethylhexyl) sulfosuccinate vesicles at different pH values have been carried out by using liquid surface tension, transmission electron microscopy, and dynamic light scattering. The results show that there are no vesicle changes in its size and negative Z potential at pH 3, 6, and 10. Furthermore, indomethacin and 1-naphthol, both pH-dependent, electroactive, and fluorescence probes, were used to further characterize the bilayer employing electrochemical and emission techniques. The partition of indomethacin and 1-naphthol between the water and bilayer pseudophases only occurs for the neutral species and does not happen for the anionic species because the highly negative Z bilayer potential prevents incorporation due to negative repulsion. For the neutral species, the partition constant values were evaluated by square wave voltammetry and emission spectroscopy. Finally, for the indomethacin incorporated into the vesicle bilayer at pH 3, the release profile was monitored over time at pH 6. It was found that a change in the pH values causes the complete release of indomethacin after 25 min, which led us to think that the vesicles presented in this work can be used as a pH-sensitive nanocarrier for neutral pH-sensitive drugs.

The Impact of Childhood Adversity on Life Course Alcohol Use Patterns and Health Status Among People Living with HIV.

Adverse childhood experiences (ACEs) and financial hardship are associated with increased likelihood of heavier alcohol use and health challenges in adulthood among persons living with HIV (PWH). We examined whether retrospectively captured lifetime drinking trajectories are a pathway through which childhood hardships affect current health in a sample of 365 adult PWH. Childhood economic hardship and ACEs were used as main predictors. Measures of alcohol use included age at first drink and lifetime drinking trajectories. Health indicators included health-related quality of life, frailty, number of comorbidities, and symptoms of anxiety, depression, and post-traumatic stress disorder (PTSD). Structural equation modeling (SEM) was applied to estimate both direct and indirect pathways between childhood hardship and physical and mental health. Participants were mostly male; Black (84%); and averaged 48 years of age. SEM results supported both direct and indirect pathways between childhood experiences and adult health. ACEs were connected to physical health directly and mental health both directly and indirectly through age at first drink and drinking heaviness during ages 10-20. Childhood economic hardship related to mental health indirectly through higher drinking levels during ages 10-20. Childhood adverse experiences, economic hardship, and early drinking patterns appear to accumulate, resulting in later life physical and mental health concerns for PWH. Findings support taking a life course approach to health. This includes considering individual trauma histories in HIV care engagement and taking preventative approaches which support the economic and social well-being of vulnerable children to improve health in subsequent decades.

Alcohol Impairs Bioenergetics and Differentiation Capacity of Myoblasts from Simian Immunodeficiency Virus-Infected Female Macaques.

Alcohol misuse and HIV independently induce myopathy. We previously showed that chronic binge alcohol (CBA) administration, with or without simian immunodeficiency virus (SIV), decreases differentiation capacity of male rhesus macaque myoblasts. We hypothesized that short-term alcohol and CBA/SIV would synergistically decrease differentiation capacity and impair bioenergetic parameters in female macaque myoblasts. Myoblasts from naïve (CBA-/SIV-), vehicle [VEH]/SIV, and CBA/SIV (N = 4-6/group) groups were proliferated (3 days) and differentiated (5 days) with 0 or 50 mM ethanol (short-term). CBA/SIV decreased differentiation and increased non-mitochondrial oxygen consumption rate (OCR) versus naïve and/or VEH/SIV. Short-term alcohol decreased differentiation; increased maximal and non-mitochondrial OCR, mitochondrial reactive oxygen species (ROS) production, and aldolase activity; and decreased glycolytic measures, ATP production, mitochondrial membrane potential (ΔΨm), and pyruvate kinase activity. Mitochondrial ROS production was closely associated with mitochondrial network volume, and differentiation indices were closely associated with key bioenergetic health and function parameters. Results indicate that short-term alcohol and CBA non-synergistically decrease myoblast differentiation capacity. Short-term alcohol impaired myoblast glycolytic function, driving the bioenergetic deficit. Results suggest potentially differing mechanisms underlying decreased differentiation capacity with short-term alcohol and CBA, highlighting the need to elucidate the impact of different alcohol use patterns on myopathy.

An aerobic exercise intervention to improve metabolic health among people living with HIV with at-risk alcohol use: the ALIVE-Ex research study protocol.

BACKGROUND: Effective antiretroviral therapy (ART) in people living with HIV (PLWH) has improved life expectancy and increased risk of age-associated cardiometabolic comorbidities. At-risk alcohol use is more frequent among PLWH and increases the risk of health challenges. PLWH with at-risk alcohol use are more likely to meet criteria for prediabetes/diabetes and this is associated with impaired whole-body glucose-insulin dynamics. METHODS: The Alcohol & Metabolic Comorbidities in PLWH: Evidence Driven Interventions Study (ALIVE-Ex Study, NCT03299205) is a longitudinal, prospective, interventional study to determine the effects of an aerobic exercise protocol on improving dysglycemia among PLWH with at-risk alcohol use. The intervention is a moderate intensity aerobic exercise protocol implemented 3 days per week for 10 weeks at the Louisiana State University Health Sciences Center-New Orleans. Participants who have a fasting blood glucose level between 94 and 125 mg/dl will be enrolled in the study. Oral glucose tolerance tests, fitness assessments, and skeletal muscle biopsies will be performed pre- and post-exercise intervention. The primary outcome is to determine whether the exercise protocol improves measures of whole-body glucose-insulin dynamics, cardiorespiratory fitness, and skeletal muscle metabolic and bioenergetic function. Secondary outcomes are to determine whether the exercise intervention improves cognitive function and overall quality of life. Results generated will demonstrate the effect of exercise on glycemic measures in PLWH with subclinical dysglycemia and at-risk alcohol use. CONCLUSIONS: The proposed intervention will also have the potential to be scalable to promote lifestyle changes among PLWH, particularly in underserved communities.

Interprofessional education as a potential foundation for future team-based prevention of alcohol use disorder.

BACKGROUND: Effective screening of alcohol use and prevention of alcohol use disorder (AUD) requires the continuous preparation of educated and confident providers across all health professions who will ideally work in close collaboration in their future practices. As one mechanism for achieving this goal, the development and provision of interprofessional education (IPE) training modules for health care students may cultivate beneficial interactions among future health providers early in their formative education. METHODS: In the present study, we assessed attitudes about alcohol and confidence in screening and AUD prevention in 459 students at our health sciences center. Students represented ten different health professions (audiology, cardiovascular sonography, dental hygiene, dentistry, medicine, nursing, physical therapy, public health, respiratory therapy, and speech language pathology programs). For purposes of this exercise, students were divided into small, professionally diverse teams. Responses to ten survey questions (Likert scale) were collected via a web-based platform. These assessments were collected before and after a case-based exercise that provided information to students on the risks of excessive alcohol use as well as the effective screening and team-based management of individuals susceptible to AUD. RESULTS: Wilcoxon signed-rank analyses revealed that the exercise led to significant decreases in stigma toward individuals engaging in at-risk alcohol use. We also discovered significant increases in self-reported knowledge and confidence in personal qualifications needed to initiate brief interventions to reduce alcohol use. Focused analyses of students from individual health programs uncovered unique improvements according to question theme and health profession. CONCLUSION: Our findings demonstrate the utility and effectiveness of single, focused IPE-based exercises to impact personal attitudes and confidence in young health professions learners. While additional longitudinal cohort follow-up studies are needed, these results may translate into more effective and collaborative AUD treatment in future clinical settings.

Mitochondrial Dysfunction: At the Nexus between Alcohol-Associated Immunometabolic Dysregulation and Tissue Injury.

Alcohol misuse, directly or indirectly as a result of its metabolism, negatively impacts most tissues, including four with critical roles in energy metabolism regulation: the liver, pancreas, adipose, and skeletal muscle. Mitochondria have long been studied for their biosynthetic roles, such as ATP synthesis and initiation of apoptosis. However, current research has provided evidence that mitochondria participate in myriad cellular processes, including immune activation, nutrient sensing in pancreatic ß-cells, and skeletal muscle stem and progenitor cell differentiation. The literature indicates that alcohol impairs mitochondrial respiratory capacity, promoting reactive oxygen species (ROS) generation and disrupting mitochondrial dynamics, leading to dysfunctional mitochondria accumulation. As discussed in this review, mitochondrial dyshomeostasis emerges at a nexus between alcohol-disrupted cellular energy metabolism and tissue injury. Here, we highlight this link and focus on alcohol-mediated disruption of immunometabolism, which refers to two distinct, yet interrelated processes. Extrinsic immunometabolism involves processes whereby immune cells and their products influence cellular and/or tissue metabolism. Intrinsic immunometabolism describes immune cell fuel utilization and bioenergetics that affect intracellular processes. Alcohol-induced mitochondrial dysregulation negatively impacts immunometabolism in immune cells, contributing to tissue injury. This review will present the current state of literature, describing alcohol-mediated metabolic and immunometabolic dysregulation from a mitochondrial perspective.

Unique circulating microRNA associations with dysglycemia in people living with HIV and alcohol use.

People living with HIV (PLWH) have increased prevalence of comorbid conditions including insulin resistance and at-risk alcohol use. Circulating microRNAs (miRs) may serve as minimally invasive indicators of pathophysiological states. We aimed to identify whether alcohol modulates circulating miR associations with measures of glucose/insulin dynamics in PLWH. PLWH (n = 96; 69.8% males) enrolled in the Alcohol & Metabolic Comorbidities in PLWH: Evidence-Driven Interventions (ALIVE-Ex) study were stratified into negative phosphatidylethanol (PEth < 8 ng/mL, n = 42) and positive PEth (PEth ≥ 8 ng/mL, n = 54) groups. An oral glucose tolerance test (OGTT) was administered, and total RNA was isolated from fasting plasma to determine absolute miR expression. Circulating miRs were selected based on their role in skeletal muscle (miR-133a and miR-206), pancreatic ß-cell (miR-375), liver (miR-20a), and adipose tissue (miR-let-7b, miR-146a, and miR-221) function. Correlation and multiple regression analyses between miR expression and adiponectin, 2 h glucose, insulin, and C-peptide values were performed adjusting for body mass index (BMI) category, age, sex, and viral load. miR-133a was negatively associated with adiponectin (P = 0.002) in the negative PEth group, and miR-20a was positively associated with 2 h glucose (P = 0.013) in the positive PEth group. Regression analyses combining miRs demonstrated that miR-133a (P < 0.001) and miR-221 (P = 0.010) together predicted adiponectin in the negative PEth group. miR-20a (P < 0.001) and miR-375 (P = 0.002) together predicted 2 h glucose in the positive PEth group. Our results indicate that associations between miRs and measures of glucose/insulin dynamics differed between PEth groups, suggesting that the pathophysiological mechanisms contributing to altered glucose homeostasis in PLWH are potentially modulated by alcohol use.

Alcohol use, physical activity, and muscle strength moderate the relationship between body composition and frailty risk among people living with HIV.

BACKGROUND: Antiretroviral therapy has improved life expectancy among people living with HIV (PLWH). Despite increased longevity, PLWH are at increased risk of age-related comorbidities, including frailty. We examined the relationship between body composition and frailty among PLWH, and moderation of this relationship by substance use, physical activity (PA), and physical function. METHODS: Participants (n = 341; 71% male, 48 ± 10 years, body mass index (BMI) = 27.3 ± 7.0 kg/m2 ) enrolled in the New Orleans Alcohol Use in HIV (NOAH) study underwent measures of body composition, muscle strength, and gait speed. Whole blood phosphatidylethanol (PEth) was measured, and substance use and PA were self-reported. Frailty risk measures included the 58-Item Deficit Index (DI58) and the Veterans Aging Cohort Study (VACS) Index 1.0, where higher scores indicate greater frailty risk. RESULTS: Multivariable linear regression adjusted for age, sex, and race showed that higher fat-free mass index (FFMI), body fat (%), waist-to-hip ratio, and body mass index (BMI) ≥ 25.0 kg/m2 vs. < 25.0 kg/m2 were significantly (p < 0.05) associated with decreased frailty risk measured by the VACS Index, whereas adjusted analyses showed no association between body composition variables and the DI58 score. Recent alcohol use, muscle strength, and PA, but not lifetime alcohol use or gait speed, significantly moderated associations between body composition variables and frailty risk with medium-to-large effect sizes. Subgroup analyses revealed a negative relationship between DI58 and FFMI among people with PEth > 8 ng/ml and negative relationships of VACS Index with FFMI and WHR in people with lower muscle strength. Overweight or obese BMI categories were positively associated with DI58 in people with lower muscle strength or higher PA level but negatively associated in those with higher muscle strength. CONCLUSIONS: Our findings indicate that body composition has significant modulatory effects on frailty risk in PLWH, where obesity increases the risk of frailty and greater muscle mass may be protective, even in individuals who use alcohol. These results highlight the importance of considering body composition, physical activity, and physical function in assessing frailty risk in PLWH, particularly among individuals who use alcohol. Moreover, they support the implementation of physical activity interventions to ameliorate the risk of frailty in aging PLWH.

A review of alcohol-pathogen interactions: New insights into combined disease pathomechanisms.

Progression of chronic infections to end-stage diseases and poor treatment results are frequently associated with alcohol abuse. Alcohol metabolism suppresses innate and adaptive immunity leading to increased viral load and its spread. In case of hepatotropic infections, viruses accelerate alcohol-induced hepatitis and liver fibrosis, thereby promoting end-stage outcomes, including cirrhosis and hepatocellular carcinoma (HCC). In this review, we concentrate on several unexplored aspects of these phenomena, which illustrate the combined effects of viral/bacterial infections and alcohol in disease development. We review alcohol-induced alterations implicated in immunometabolism as a central mechanism impacting metabolic homeostasis and viral pathogenesis in Simian immunodeficiency virus/human immunodeficiency virus infection. Furthermore, in hepatocytes, both HIV infection and alcohol activate oxidative stress to cause lysosomal dysfunction and leakage and apoptotic cell death, thereby increasing hepatotoxicity. In addition, we discuss the mechanisms of hepatocellular carcinoma and tumor signaling in hepatitis C virus infection. Finally, we analyze studies that review and describe the immune derangements in hepatotropic viral infections focusing on the development of novel targets and strategies to restore effective immunocompetency in alcohol-associated liver disease. In conclusion, alcohol exacerbates the pathogenesis of viral infections, contributing to a chronic course and poor outcomes, but the mechanisms behind these events are virus specific and depend on virus-alcohol interactions, which differ among the various infections.

Sociodemographic and behavioural factors of adherence to the no-screen guideline for toddlers among parents from the French nationwide Elfe birth cohort.

BACKGROUND: Excessive screen time in infancy and childhood has been associated with consequences on children's development and health. International guidelines call for no screen time before age 2 years, whereas in France, the most prominent guidelines recommend no screen before age 3 years. However, data are lacking on parental adherence to the no-screen guideline for toddlers and factors of adherence in France. Using data from the French nationwide Elfe birth cohort, we estimated adherence to the no-screen guideline at age 2 years and examined related factors, including sociodemographic characteristics, parental leisure activities and screen time. METHODS: In 2011, 18,329 newborns and their parents were enrolled in 349 randomly selected maternity units across mainland France. At age 2 years, screen exposure of 13,117 toddlers was reported by parents in phone interviews. Data on sociodemographic characteristics, parental leisure activities and screen time were collected from both parents. Three patterns of parental leisure activities were derived by principal component analysis: literate (e.g.,reading), screen-based, and physical/artistic activities. Multivariable logistic regression models were used to examine the associations of sociodemographic characteristics, parental leisure activities and parental screen time with adherence to the no-screen guideline for toddlers. RESULTS: Overall, 1809/13,117 (13.5%) families adhered to the no-screen guideline for toddlers. Adherence was reduced with maternal age < 40 years, low parental education, single-parent household and parental migration status. After adjusting for sociodemographic characteristics, adherence to the guideline was positively associated with a parental literate activity pattern (mothers: odds ratio [95% confidence interval]: 1.15 [1.08, 1.22]); fathers: 1.15 [1.07, 1.23]) and negatively with a screen-based activity pattern (mothers: 0.73 [0.69, 0.77]; fathers: 0.81 [0.76, 0.87]). With each additional hour of parental screen time, mothers and fathers were less likely to adhere to the guideline (mothers: adjusted odds ratio 0.80 [0.77, 0.83]; fathers: 0.88 [0.85, 0.91]). CONCLUSIONS: Adherence to the no-screen guideline for toddlers in France was low. Parental leisure activities and parental screen time are major factors of adherence to the no-screen guideline and could be considered in targeted public health interventions.

Family-focused contextual factors associated with lifestyle patterns in young children from two mother-offspring cohorts: GUSTO and EDEN.

BACKGROUND: Integrated patterns of energy balance-related behaviours of preschool children in Asia are sparse, with few comparative analyses. PURPOSE: Using cohorts in Singapore (GUSTO) and France (EDEN), we characterized lifestyle patterns of children and investigated their associations with family-focused contextual factors. METHODS: Ten behavioural variables related to child's diet, walking, outdoor play and screen time were ascertained by parental questionnaires at age 5-6 years. Using principal component analysis, sex-specific lifestyle patterns were derived independently for 630 GUSTO and 989 EDEN children. Contextual variables were organised into distal (family socio-economics, demographics), intermediate (parental health, lifestyle habits) and proximal (parent-child interaction factors) levels of influence and analysed with hierarchical linear regression. RESULTS: Three broadly similar lifestyle patterns were identified in both cohorts: "discretionary consumption and high screen time", "fruit, vegetables, and low screen time" and "high outdoor playtime and walking". The latter two patterns showed small differences between cohorts and sexes. The "discretionary consumption and high screen time" pattern was consistently similar in both cohorts; distal associated factors were lower maternal education (EDEN boys), no younger siblings (GUSTO boys) and Malay/Indian ethnicity (GUSTO), while intermediate and proximal associated factors in both cohorts and sexes were poor maternal diets during pregnancy, parents allowing high child control over food intake, snacking between meals and having television on while eating. CONCLUSIONS: Three similar lifestyle patterns were observed among preschool children in Singapore and France. There were more common associated proximal factors than distal ones. Cohort specific family-focused contextual factors likely reflect differences in social and cultural settings. Findings will aid development of strategies to improve child health.

Associations of Binge Drinking and Heavy Alcohol Use on Sugar and Fat Intake in a Cohort of Southern People Living with HIV.

AIMS: To assess whether binge drinking and heavy alcohol use are associated with increased sugar and fat consumption among a Southern cohort of people living with HIV (PWH). METHODS: This was a cross-sectional analysis of PWH enrolled in the New Orleans Alcohol use in HIV (NOAH) Study (n = 215). Binge and heavy drinking were identified through a 30-day Alcohol Timeline-Followback and dietary intake was assessed through a 24-hour dietary recall. RESULTS: Participants were 65.4% male, 83.3% Black, with a mean age of 49.2 ± 9.9. Heavy drinkers consumed more total calories than abstainers (P = 0.035) and low-to-moderate drinkers (P = 0.024), and binge drinkers consumed more calories than non-binge drinkers (P = 0.025). Binge and heavy drinkers had significantly higher intake of total and saturated fat in grams. However, substantially increased caloric intake among these participants led to non-significant associations for alcohol use with high total and saturated fat intake as a percent of total energy intake (%TEI). Binge drinkers had lower odds of consuming high sugar as a %TEI (odds ratio: 0.31 [0.14, 0.68]). Additionally, sugar intake predicted total and saturated fat intake, and this association was slightly higher among binge drinkers (total fat P-value: 0.12). CONCLUSIONS: In this population of PWH, while binge and heavy drinking predicted higher caloric and fat intake in grams, binge drinkers were less likely to consume a high-sugar diet. This analysis suggests that interventions focused on reduced alcohol use may be especially beneficial in reducing metabolic disease burden in PWH if supplemented with information on incorporating lower energy-dense foods with reduced fat.

Patterns of Eating Associated with Sleep Characteristics: A Pilot Study among Individuals of Mexican Descent at the US-Mexico Border.

Introduction: Previous studies have linked sleep to risk of diabetes and obesity, at least partially via alterations in food intake. Diabetes and obesity are common among Hispanics/Latinos, and studies are needed to better clarify the role of sleep in health among this group. Utilizing the revised TFEQ-R-18, this study will examine whether eating behaviors such as cognitive restraint, emotional eating and uncontrolled eating are related to self-reported sleep experiences. Specifically, we hypothesized that poor eating habits would be associated with (1) more insomnia symptoms, (2) overall worse sleep quality, (3) increased daytime sleepiness, and (4) shorter sleep duration.Methods: Data were collected from N = 100 adults (age 18-60, 47% female) of Mexican descent in the city of Nogales, AZ (34% not born in the US). Surveys were presented in English or Spanish. Eating Patterns were assessed with the Three-Factor Eating Questionnaire (TFEQ), which resulted in a total score and subscales for "cognitive restraint," "uncontrolled eating," and "emotional eating." Insomnia was assessed with the use of the Insomnia Severity Index (ISI), Sleepiness with the use of the Epworth Sleepiness Scale (ESS), Sleep quality with the use of the Pittsburgh Sleep Quality Index (PSQI), and weekday and weekend sleep duration with the use of the Sleep Timing Questionnaire (STQ). Covariates included age, sex, Body Mass Index (BMI), education and immigrant status.Results: Overall TFEQ score (problematic eating) was positively associated with greater insomnia, poorer sleep quality, more sleepiness, and less weekend (but not weekday) sleep. Mean TFEQ score in the sample was 18.7 (range 0-51). In adjusted analyses, every point on the TFEQ was associated with 0.6 ISI points, 0.8 PSQI points, 0.5 ESS points, and 1.1 minutes of less weekend sleep duration. Regarding subscale scores, relationships were generally seenbetween sleep and emotional eating and unrestricted eating, and not cognitive restraint.Conclusions: Greater insomnia, poorer sleep quality, increased daytime sleepiness and decreased weekend sleep duration were associated with eating patterns at the US-Mexico border, particularly in the area of unrestricted eating and emotional eating. This suggests possible mechanisms linking sleep and obesity in Hispanic/Latinos.

Alcohol Use Is Associated With Intestinal Dysbiosis and Dysfunctional CD8+ T-Cell Phenotypes in Persons With Human Immunodeficiency Virus.

BACKGROUND: Inflammation persists among persons with human immunodeficiency virus (PWH) despite effective antiretroviral therapy and may contribute to T-cell dysfunction. Alcohol use is prevalent among PWH and promotes intestinal leak, dysbiosis, and a proinflammatory milieu. Whether alcohol use is associated with T-cell late differentiation remains to be investigated. METHODS: Data and samples from PWH (N = 359 of 365) enrolled in the New Orleans Alcohol Use in HIV Study were used. Alcohol use was assessed by self-report (Alcohol Use Disorders Identification Test; lifetime alcohol exposure; 30-day Alcohol Timeline Followback) and phosphatidylethanol (PEth) quantitation. In a subset of participants, fecal bacterial content was assessed by ribosomal 16S marker gene deep sequencing and quantitative polymerase chain reaction. Intestinal leak was assessed by fecal-to-plasma α-1-antitrypsin (A1AT) enzyme-linked immunosorbent assay ratio. Peripheral T-cell populations were quantified by flow cytometry. RESULTS: Alcohol Use Disorder Identification Test scores were positively associated with activated-senescent, exhausted, and terminal effector memory CD45RA+CD8+ but not CD4+ T cells (cells/µL) after confounder adjustment (P < .050). Phosphatidylethanol was positively associated with A1AT (P < .050). The PEth and activated-senescent CD8+ were associated with bacterial ß-diversity (P < .050) and positively associated with the relative abundance of coabundant Prevotellaceae members (q < .100). CONCLUSIONS: Alcohol use among PWH is associated with CD8+ T-cell late differentiation, intestinal leak, and dysbiosis. Alcohol-associated dysbiosis is implicated in CD8+ T-cell senescence.

Alcohol Use Disorder and Hepatitis C Prevention and Care in People Who Inject Drugs: The State of Play.

Safe and effective treatment with direct-acting antivirals (DAAs) has ushered in an era in which hepatitis C virus (HCV) elimination, as set out by the World Health Organization, is possible. However, alcohol use disorder (AUD) has the potential to reduce the benefits of prevention interventions and reduce access to and continuity of HCV care in at-risk populations, such as people who inject drugs (PWID). We review the literature on the consequences of AUD on the effectiveness of HCV prevention and the cascade of care in PWID and provide recommendations for future research in the field of alcohol use and HCV.

Ethanol-induced lymphatic endothelial cell permeability via MAP-kinase regulation.

Chronic alcohol alters the immune system enhancing the susceptibility to inflammation, bacterial, and viral infections in alcohol users. We have shown that alcohol causes increased permeability of mesenteric lymphatic vessels in alcohol-fed rats. The mechanisms of alcohol-induced lymphatic leakage are unknown. Endothelial cell monolayer permeability is controlled by junctional proteins complexes called tight junctions (TJ) and adherens junctions (AJ), and each can be regulated by MAPK activation. We hypothesize that ethanol induces lymphatic endothelial cell (LEC) permeability via disruption of LEC TJ through MAPK activation. An in vitro model of rat LECs was used. Ethanol-supplemented medium was added at concentrations of 0, 25, and 50 mM to confluent cells. Resistance-based barrier function, transwell permeability, cell viability, TJ, AJ, and MAPK protein activity, TJ and AJ gene expressions, and the role of p38 MAPK in barrier function regulation were measured. Ethanol increased the permeability of LECs compared to controls that was not associated with decreased cell viability. LECs treated with 50 mM ethanol showed an increase in phosphorylated levels of p38. No significant changes in TJ and AJ gene or protein expressions were observed after ethanol treatment. p38 inhibition prevented ethanol-induced increases in permeability. These findings suggest that p38 may play a role in the regulation of ethanol-induced LEC permeability, but altered permeability may not be associated with decreased TJ or AJ protein expression. Further investigation into junctional protein localization is needed to better understand the effects of ethanol on lymphatic endothelial cell-to-cell contacts and hyperpermeability.

Chronic binge alcohol and ovariectomy dysregulate omental adipose tissue metaboproteome in simian immunodeficiency virus-infected female macaques.

Effective antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH), and the prevalence of at-risk alcohol use is higher among PLWH. Increased survival and aging of PLWH is associated with increased prevalence of metabolic comorbidities especially among menopausal women, and adipose tissue metabolic dysregulation may be a significant contributing factor. We examined the differential effects of chronic binge alcohol (CBA) administration and ovariectomy (OVX) on the omental adipose tissue (OmAT) proteome in a subset of simian immunodeficiency virus (SIV)-infected macaques of a longitudinal parent study. Quantitative discovery-based proteomics identified 1,429 differentially expressed proteins. Ingenuity Pathway Analysis (IPA) was used to calculate z-scores, or activation predictions, for functional pathways and diseases. Results revealed that protein changes associated with functional pathways centered around the "OmAT metaboproteome profile." Based on z-scores, CBA did not affect functional pathways of metabolic disease but dysregulated proteins involved in adenosine monophosphate-activated protein kinase (AMPK) signaling and lipid metabolism. OVX-mediated proteome changes were predicted to promote pathways involved in glucose- and lipid-associated metabolic disease. Proteins involved in apoptosis, necrosis, and reactive oxygen species (ROS) pathways were also predicted to be activated by OVX and these were predicted to be inhibited by CBA. These results provide evidence for the role of ovarian hormone loss in mediating OmAT metaboproteome dysregulation in SIV and suggest that CBA modifies OVX-associated changes. In the context of OVX, CBA administration produced larger metabolic and cellular effects, which we speculate may reflect a protective role of estrogen against CBA-mediated adipose tissue injury in female SIV-infected macaques.

Whole-Genome Analysis Surveillance of Influenza A Virus Resistance to Polymerase Complex Inhibitors in Eastern Spain from 2016 to 2019.

Molecular surveillance by whole-genome sequencing was used to monitor the susceptibility of circulating influenza A viruses to three polymerase complex inhibitors. A total of 12 resistance substitutions were found among 285 genomes analyzed, but none were associated with high levels of resistance. Natural resistance to these influenza A antivirals is currently uncommon.

Skeletal muscle bioenergetic health and function in people living with HIV: association with glucose tolerance and alcohol use.

At-risk alcohol use is prevalent and increases dysglycemia among people living with human immunodeficiency virus (PLWH). Skeletal muscle (SKM) bioenergetic dysregulation is implicated in dysglycemia and type 2 diabetes. The objective of this study was to determine the relationship between at-risk alcohol, glucose tolerance, and SKM bioenergetic function in PLWH. Thirty-five PLWH (11 females, 24 males, age: 53 ± 9 yr, body mass index: 29.0 ± 6.6 kg/m2) with elevated fasting glucose enrolled in the ALIVE-Ex study provided medical history and alcohol use information [Alcohol Use Disorders Identification Test (AUDIT)], then underwent an oral glucose tolerance test (OGTT) and SKM biopsy. Bioenergetic health and function and mitochondrial volume were measured in isolated myoblasts. Mitochondrial gene expression was measured in SKM. Linear regression adjusting for age, sex, and smoking was performed to examine the relationship between glucose tolerance (2-h glucose post-OGTT), AUDIT, and their interaction with each outcome measure. Negative indicators of bioenergetic health were significantly (P < 0.05) greater with higher 2-h glucose (proton leak) and AUDIT (proton leak, nonmitochondrial oxygen consumption, and bioenergetic health index). Mitochondrial volume was increased with the interaction of higher 2-h glucose and AUDIT. Mitochondrial gene expression decreased with higher 2-h glucose (TFAM, PGC1B, PPARG, MFN1), AUDIT (MFN1, DRP1, MFF), and their interaction (PPARG, PPARD, MFF). Decreased expression of mitochondrial genes were coupled with increased mitochondrial volume and decreased bioenergetic health in SKM of PLWH with higher AUDIT and 2-h glucose. We hypothesize these mechanisms reflect poorer mitochondrial health and may precede overt SKM bioenergetic dysregulation observed in type 2 diabetes.