Parosmia Is Positively Associated With Problematic Drinking, as Is Phantosmia With Depressive Symptoms.

OBJECTIVES: Alcohol use disorder (AUD) is a global health problem with significant negative consequences, including preventable deaths. Although olfactory dysfunction is associated with chronic alcohol drinking, the relationship among specific types of olfactory deficits, depressive symptoms, and problematic drinking remains to be explored. Here, we examined the prevalence of olfactory distortion (parosmia) and hallucination (phantosmia) and assessed their associations with problematic drinking and depressive symptoms. METHODS: In April-June 2022, 250 participants across the spectrum of AUD were recruited for assessment in the National Institute on Alcohol Abuse and Alcoholism COVID-19 Pandemic Impact on Alcohol study. Surveys covered self-reported olfactory function, depressive symptoms, and problematic drinking, with key measures assessed, including the Alcohol Use Disorders Identification Test and the Patient Health Questionnaire. Predictors in the analysis included parosmia and phantosmia, with covariates comprising age, sex, socioeconomic status, race, ethnicity, COVID-19 infection status, and smoking status. RESULTS: Among 250 individuals, 5.2% experienced parosmia and 4.4% reported phantosmia. Parosmia was associated with higher Alcohol Use Disorders Identification Test scores (ß = 7.14; 95% confidence interval = 3.31, 10.96; P < 0.001), whereas phantosmia was linked to higher Patient Health Questionnaire scores (ß = 3.32; 95% confidence interval = 0.22, 6.42; P = 0.03). These associations persisted in both the full sample and the subset of participants without COVID-19. CONCLUSIONS: Our study highlights strong existing links among olfactory deficits, problem drinking, and depressive symptoms, underscoring the need to assess smell impairments in clinical settings. Future research should explore these connections further to develop new treatments for individuals with AUD and depression.

A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry.

BACKGROUND: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis. METHODS: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239). RESULTS: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis. CONCLUSIONS: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.

Sleep Delta power, age, and sex effects in treatment-resistant depression.

Electroencephalographic (EEG) deficits in slow wave activity or Delta power (0.5-4 Hz) indicate disturbed sleep homeostasis and are hallmarks of depression. Sleep homeostasis is linked to restorative sleep and potential antidepressant response via non-rapid eye movement (NREM) slow wave sleep (SWS) during which neurons undergo essential repair and rejuvenation. Decreased Low Delta power (0.5-2 Hz) was previously reported in individuals with depression. This study investigated power levels in the Low Delta (0.5-<2 Hz), High Delta (2-4 Hz), and Total Delta (0.5-4 Hz) bands and their association with age, sex, and disrupted sleep in treatment-resistant depression (TRD). Mann-Whitney U tests were used to compare the nightly progressions of Total Delta, Low Delta, and High Delta in 100 individuals with TRD and 24 healthy volunteers (HVs). Polysomnographic parameters were also examined, including Total Sleep Time (TST), Sleep Efficiency (SE), and Wake after Sleep Onset (WASO). Individuals with TRD had lower Delta power during the first NREM episode (NREM1) than HVs. The deficiency was observed in the Low Delta band versus High Delta. Females with TRD had higher Delta power than males during the first NREM1 episode, with the most noticeable sex difference observed in Low Delta. In individuals with TRD, Low Delta power correlated with WASO and SE, and High Delta correlated with WASO. Low Delta power deficits in NREM1 were observed in older males with TRD, but not females. These results provide compelling evidence for a link between age, sex, Low Delta power, sleep homeostasis, and non-restorative sleep in TRD.

A patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis.

Only ~20% of heavy drinkers develop alcohol cirrhosis (AC). While differences in metabolism, inflammation, signaling, microbiome signatures and genetic variations have been tied to the pathogenesis of AC, the key underlying mechanisms for this interindividual variability, remain to be fully elucidated. Induced pluripotent stem cell-derived hepatocytes (iHLCs) from patients with AC and healthy controls differ transcriptomically, bioenergetically and histologically. They include a greater number of lipid droplets (LDs) and LD-associated mitochondria compared to control cells. These pre-pathologic indicators are effectively reversed by Aramchol, an inhibitor of stearoyl-CoA desaturase. Bioenergetically, AC iHLCs have lower spare capacity, slower ATP production and their mitochondrial fuel flexibility towards fatty acids and glutamate is weakened. MARC1 and PNPLA3, genes implicated by GWAS in alcohol cirrhosis, show to correlate with lipid droplet-associated and mitochondria-mediated oxidative damage in AC iHLCs. Knockdown of PNPLA3 expression exacerbates mitochondrial deficits and leads to lipid droplets alterations. These findings suggest that differences in mitochondrial bioenergetics and lipid droplet formation are intrinsic to AC hepatocytes and can play a role in its pathogenesis.

Transcriptomic Profiles Associated with Experimental Placebo Effects in Chronic Pain.

Gene expression networks associated with placebo effects are understudied; in this study, we identified transcriptomic profiles associated with placebo responsivity. Participants suffering from chronic pain underwent a verbal suggestion and conditioning paradigm with individually tailored thermal painful stimulations to elicit conditioned placebo effects. Participants reported pain intensity on a visual analog scale (VAS) anchored from zero = no pain to 100 = maximum imaginable pain. RNA was extracted from venous blood and RNA sequencing and validation tests were performed to identify differentially expressed genes (DEGs) associated with placebo effects, controlling for sex and level of pain. Unbiased enrichment analyses were performed to identify biological processes associated with placebo effects. Of the 10,700 protein-coding genes that passed quality control filters, 667 were found to be associated with placebo effects (FDR <0.05). Most genes (97%) upregulated were associated with larger placebo effects. The 17 top transcriptome-wide significant genes were further validated via RT-qPCR in an independent cohort of chronic pain participants. Six of them (CCDC85B, FBXL15, HAGH, PI3, SELENOM, and TNFRSF4) showed positive and significant (P < 0.05) correlation with placebo effects in the cohort. The overall DEGs were highly enriched in regulation of expression of SLITs and ROBOs (R-HSA-9010553, FDR = 1.26e-33), metabolism of RNA (R-HSA-8953854, FDR = 1.34e-30), Huntington's disease (hsa05016, FDR = 9.84e-31), and ribosome biogenesis (GO:0042254, FDR = 2.67e-15); alternations in these pathways might jeopardize the proneness to elicit placebo effects. Future studies are needed to replicate this finding and better understand the unique molecular dynamics of people who are more or less affected by pain and placebo.

Hepatology consultation is associated with decreased early return to alcohol use after discharge from an inpatient alcohol use disorder treatment program.

BACKGROUND: Alcohol cessation is the only intervention that both prevents and halts the progressions of alcohol-associated liver disease. The aim of this study was to assess the relationship between a return to alcohol use and consultation with hepatology in treatment-seeking patients with alcohol use disorder (AUD). METHODS: Two hundred forty-two patients with AUD were enrolled in an inpatient treatment program, with hepatology consultation provided for 143 (59%) patients at the request of the primary team. Patients not seen by hepatology served as controls. The primary outcome was any alcohol use after discharge assessed using AUDIT-C at 26 weeks after discharge. RESULTS: For the primary endpoint, AUDIT at week 26, 61% of the hepatology group and 28% of the controls completed the questionnaire (p=0.07). For the secondary endpoint at week 52, these numbers were 22% and 11% (p = 0.6). At week 26, 39 (45%) patients in the hepatology group versus 31 (70%) controls (p = 0.006) returned to alcohol use. Patients evaluated by hepatology had decreased rates of hazardous alcohol use compared to controls, with 36 (41%) versus 29 (66%) (p = 0.008) of the patients, respectively, reporting hazardous use. There were no significant differences in baseline characteristics between groups and no difference in rates of prescribing AUD therapy. There was no difference in outcomes at 52 weeks. CONCLUSIONS: Patients evaluated by hepatology had significantly lower rates of return to alcohol use and lower rates of hazardous drinking at 26 weeks but not at 52 weeks. These findings suggest that hepatology evaluation during inpatient treatment of AUD may lead to decreased rates of early return to alcohol use.

Sex-dependent responses to high concentration of binge ethanol in spleen of adolescent F344 rats.

BACKGROUND: We previously reported that binge ethanol induces atrophy of the spleen, a key immune organ, in adolescent male F344 rats. Because there are significant sex effects in immune function, we investigated whether binge ethanol exerts sex-dependent effects on the spleen, including producing splenic atrophy. METHODS: We gave F344 rats ethanol (4.8 g/kg/day; 52% w/v; i.g.) on postnatal days [PND] 36 ~ 38 and sacrificed them on PND 39 for spleen collection. We performed immunophenotyping analysis of splenic cells and examined the expression of 158 genes related to alcohol metabolism, epigenetic modification, and immune regulation in the spleens of adolescent (PND 39) male and female rats. We investigated whether binge ethanol exerts sex-dependent effects, including spleen atrophy, in adolescent rats. F344 rats were given ethanol (4.8 g/kg/day; 52% w/v; i.g.) on postnatal days [PND] 36 ~ 38 and sacrificed on PND 39 for spleen collection. We performed immunophenotyping analysis of spleen cells and examined the expression of 158 genes related to alcohol metabolism, epigenetic modification, and immune regulation in spleens of adolescent (PND 39) male and female rats. RESULTS: Following a 3-day ethanol exposure, a loss of body weight, and absolute and relative spleen weight, was seen only in male adolescent rats. Ethanol altered the relative proportions of lymphocyte subtypes in both sexes with different patterns. We also found that 3-day ethanol exposure induced sex-dependent gene expression changes in spleen. Among the 158 genes studied, the expression of only three genes was significantly increased in female rats. However, the expression of 30 genes was significantly increased/decreased in male rats. Female rats had greater expression of alcohol metabolizing enzyme genes in the spleen under physiological conditions and when stimulated by binge ethanol. The genes are involved in epigenetic modification were differentially expressed in a sex-dependent manner. CONCLUSION: We found that male adolescent rats were more sensitive to binge ethanol than female rats. Differential expression of the genes related to alcohol metabolism and epigenetic modification (of DNA methyltransferase and histone deacetylases) between the sexes could account for the observed sex-dependent responses to binge ethanol in adolescent rats.

Completely Plant-Based Diets That Meet Energy Requirements for Resistance Training Can Supply Enough Protein and Leucine to Maximize Hypertrophy and Strength in Male Bodybuilders: A Modeling Study.

Despite increasing awareness of plant-based diets for health and athletic performance, athletes are cautioned that careful dietary monitoring is necessary. Whether commonly consumed plant-based diets are nutritionally adequate for maximal muscular hypertrophy remains unknown. This modeling study assessed the nutrient composition of completely plant-based diets scaled to the caloric demands of maximal muscle mass and strength development in adult male bodybuilders. To model calorie requirements, anthropometric data from bodybuilders were input into the Tinsley resting metabolic rate prediction equation, and an appropriate physical activity factor and calorie surplus were applied. Dietary data from a large cohort following completely plant-based diets were then scaled to meet these needs. Modeled intakes for nutrients of interest were calculated as 1.8 g/kg/day of protein and 2.75 g/meal of leucine, which surpass mean requirements for maximal increases in muscle mass and strength and muscle protein synthesis, respectively. Daily levels for all micronutrients, except vitamin D, also exceeded requirements. Saturated fat levels were aligned with dietary guidelines, although sodium levels exceeded recommended limits. Consumption of larger portions of commonplace plant-based diets, scaled to meet the energy demands of maximal accrual of muscle mass and strength, satisfied protein and leucine requirements without the need for additional planning.

Associations of history of alcohol use disorder with loneliness, social support, and mental health during the COVID-19 pandemic.

This study examined the effects of alcohol use disorder (AUD) and treatment history on changes in loneliness, social support, and mental health symptoms from before to during the pandemic, and tested loneliness and social support as mediators of the AUD-mental health associations. Participants (n = 427) enrolled in the NIAAA COVID-19 Pandemic Impact on Alcohol Study were categorized into three groups: healthy control (62.3%), nontreatment AUD (14.1%), and treatment AUD (23.7%). Multilevel generalized linear models were conducted to examine changes in loneliness, social support, and mental health symptoms by group. Path analyses tested the mediating roles of loneliness and social support. Loneliness increased during the pandemic, especially in the nontreatment AUD group. Social support decreased in the healthy control and AUD treatment group. Anxiety and depressive symptoms increased in the nontreatment AUD group. Individuals with a history of AUD regardless of treatment history reported greater loneliness, which was linked to higher anxiety and depressive symptoms. Loneliness, but not social support, mediated the AUD-mental health associations. Psychosocial interventions aimed at increasing positive social engagement among individuals with AUD may help alleviate feelings of loneliness and mitigate mental health symptoms. Study findings can also help improve preparedness for future public health crises.

Plant-based and Early Time-restricted Eating for Prevention and Treatment of Type 2 Diabetes in Adults: A Narrative Review.

Type 2 diabetes (T2D) is a significant public health challenge for which effective lifestyle interventions are needed. A growing body of evidence supports the use of both plant-based eating patterns and early time-restricted eating (eTRE) for the prevention and treatment of T2D, but research has not yet explored the potential of these dietary strategies in combination. In this narrative review we assessed the evidence by which plant-based diets, in conjunction with eTRE, could support T2D care. The electronic databases MEDLINE and the Web of Science were searched for relevant articles published throughout the last decade. Observational research has shown that healthy plant-based eating patterns and eTRE are associated with reductions in T2D risk. Interventional trials demonstrated that plant-based diets promote improvements in glycated hemoglobin, insulin resistance, glycemic control, and cardiometabolic risk factors. These changes may be mediated, in part, by reductions in oxidative stress, dietary acid load, and hepatocellular and intramyocellular lipids. The eTRE strategies were also shown to improve insulin resistance and glycemic control, and mechanisms of action included enhanced regulation of circadian rhythm and increased metabolic flexibility. Integrating these dietary strategies may produce additive benefits, mediated by reduced visceral adiposity and beneficial shifts in gut microbiota composition. However, potential barriers to concurrent implementation of these interventions may exist, including social challenges, scheduling constraints, and tolerance. Prospective trials are needed to examine their acceptability and clinical effects.

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.

Stress and alcohol-related coping mechanisms linking lifetime suicide ideation and attempt to multidimensional quality of life.

BACKGROUND: Suicide ideation and attempt are linked to adverse mental health outcomes, but few studies have examined their associations with quality of life (QoL). This study examined the impact of lifetime history of suicidal ideation and attempt on four QoL domains via perceived stress and problematic drinking. METHODS: Participants were drawn from the National Institute on Alcohol Abuse and Alcoholism Natural History Protocol (N = 1055), including those with no history of suicidality (78.6 %), suicidal ideation only (15.3 %), and a history of suicide attempt (6.2 %). Structural equation modeling (SEM) was utilized to test perceived stress and drinking as mediational pathways to multidimensional QoL. RESULTS: Individuals with a history of suicide ideation and/or attempt reported higher perceived stress in the past month, more problematic drinking in the past year, and lower QoL domains in the past two weeks. SEM showed significant mediation effects through dimensions of perceived stress (helplessness, lack of self-efficacy) and alcohol problems. When these mediators were considered simultaneously, the mediation effects through alcohol problems were attenuated, while several direct effects of suicidality on physical, psychological, and social QoL were weakened but remained significant. LIMITATIONS: Cross-sectional data with retrospective report of suicidality history. CONCLUSIONS: A lifetime history of suicidality was associated with lower multidimensional QoL. These associations were partially explained by stress and alcohol-related coping mechanisms such as feeling helpless or inadequate when encountering stressors and problematic drinking. Perceived stress and drinking to cope may be important intervention targets to improve QoL among those with a history of suicidality.

Early life stress and body-mass-index modulate brain connectivity in alcohol use disorder.

Early life stress (ELS) significantly increases susceptibility to alcohol use disorder (AUD) by affecting the interplay between the executive and the salience networks (SNs). The link between AUD and higher body-mass index (BMI) is known, but we lack understanding of how BMI impacts the relationship between ELS and brain connectivity in individuals with AUD. To bridge this gap, we investigated the main and interaction effects of ELS and BMI on brain connectivity in individuals with AUD compared to non-AUD participants (n = 77 sex-matched individuals per group). All participants underwent resting-state functional magnetic resonance imaging, revealing intriguing positive functional connectivity between SN seeds and brain regions involved in somatosensory processing, motor coordination and executive control. Examining the relationship of brain connectivity with ELS and BMI, we observed positive associations with the correlations of SN seeds, right anterior insula (RAIns) and supramarginal gyrus (SMG) with clusters in motor [occipital cortex, supplementary motor cortex]; anterior cingulate cortex (ACC) with clusters in frontal, or executive, control regions (middle frontal gyrus; MFG, precentral gyrus) that reportedly are involved in processing of emotionally salient stimuli (all |ß | > 0.001, |p | < 0.05). Interestingly, a negative association of the interaction effect of ELS events and BMI measures with the functional connectivity of SN seeds ACC with decision-making (MFG, precentral gyrus), RAIns and RSMG with visuo-motor control regions (occipital cortex and supplementary motor cortex) (all |ß | = -0.001, |p | < 0.05). These findings emphasize the moderating effect of BMI on ELS-associated SN seed brain connectivity in AUD. Understanding the neural mechanisms linking BMI, ELS and AUD can guide targeted interventions for this population.

The mechanisms underlying alcohol-induced decreased splenic size: A network meta-analysis study.

BACKGROUND: Organ weight change is widely accepted as a measure of toxicologic pathology. We and other groups have shown that excessive alcohol exposure leads to decreased spleen weight in rodents. This study explores the mechanisms underlying alcohol-induced splenic injury through a network meta-analysis. METHODS: QIAGEN Ingenuity Pathway Analysis (IPA) and Mammalian Phenotype (MP) Ontology were used to identify alcohol-related molecules associated with the small spleen phenotype. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and IPA bioinformatics tools were then used to analyze the biologic processes and enriched signaling pathways engaging these molecules. In addition, the "downstream effects analysis" algorithm was used to quantify alcohol's effects. RESULTS: IPA identified 623 molecules affected by alcohol and a Venn diagram revealed that 26 of these molecules overlapped with those associated with the MP Ontology of small spleen. The 26 molecules are TGFB1, CASP8, MTOR, ESR1, CXCR4, CAMK4, NFKBIA, DRD2, BCL2, FAS, PEBP1, TRAF2, ATM, IGHM, EDNRB, MDM2, GLRA1, PRF1, TLR7, IFNG, ALOX5, FOXO1, IL15, APOE, IKBKG, and RORA. Some of the 26 molecules were also associated with the MP Ontology of abnormal white pulp and red pulp morphology of the spleen, abnormal splenic cell ratio, decreased splenocyte number, abnormal spleen physiology, increased splenocyte apoptosis, and reduced splenocyte proliferation. STRING and IPA "Core Analysis" showed that these molecules were mainly involved in pathways related to cell apoptosis, proliferation, migration, and immune responses. IPA's "Molecular Activity Predictor" tool showed that concurrent effects of activation and inhibition of these molecules led to decreased spleen size by modulating apoptosis, proliferation, and migration of splenocytes. CONCLUSIONS: Our network meta-analysis revealed that excessive alcohol exposure can damage the spleen through a variety of molecular mechanisms, thereby affecting immune function and human health. We found that alcohol-mediated splenic atrophy is largely mediated by increased apoptosis signaling, migration of cells, and inhibition of splenocyte proliferation.

Social media addiction as a mediator of the associations between fear of COVID-19, mental health symptoms, and problematic alcohol use.

Background: Fear of COVID-19 is a risk factor for anxiety and depressive symptoms. During the COVID-19 pandemic, drinking to cope with psychological distress has been proposed as a key mechanism leading to problematic drinking. The goal of this study was to test social media addiction as a mediator linking fear of COVID-19 to mental health symptoms and problematic alcohol use. Methods: In between April 6 and July 2 of 2022, 250 participants completed an online survey as part of the National Institute on Alcohol Abuse and Alcoholism COVID-19 Pandemic Impact on Alcohol Study. Path analyses were conducted to test the mediational pathways. Results: Using the polythetic classification scheme, 13.2% (n = 33) of participants were classified as having social media addiction. Compared with participants without social media addiction, participants with social media addiction spent significantly more time on social media platforms and on digital communications with a family member or friend. They also reported greater fear of COVID-19, higher anxiety symptoms, and higher depressive symptoms. Path analyses indicated that social media addiction mediated the associations of fear of COVID-19 with anxiety and depressive symptoms. Furthermore, there were indirect pathways linking fear of COVID-19 to problematic alcohol use through higher social media addiction and higher anxiety and depressive symptoms. Conclusion: Social media addiction may be a maladaptive coping mechanism that individuals with high fear of COVID-19 utilized to deal with uncertainty and perceived risks during the pandemic. Findings underscore the need to examine cognitions related to fear of COVID-19 and address excessive social media use in the context of mental health and alcohol interventions.

Risk factors for Recurrent Clostridioides Difficile Infection in Children.

OBJECTIVE: The aims of this study were to determine the epidemiologic and treatment factors associated with recurrent C. difficile infection in children. METHODS: We conducted a 13-year retrospective review of pediatric C. difficile infections at our institution focusing on the epidemiologic, clinical, and treatment factors associated with recurrent disease. Repeat episodes occurring between 4 weeks and 2 months after initial infection were defined as early recurrences, whereas repeat episodes between 2 and 12 months after initial infection were defined as late recurrences. RESULTS: We identified 303 children with C. difficile infection. Recurrent infections were limited to children with chronic conditions, affecting 27.4% (68 of 248) of this cohort. Early and late recurrences occurred in 36.8 and 63.2% of children, respectively. Among children with a chronic condition, female sex and initial use of metronidazole (as opposed to vancomycin) were associated with recurrent disease in bivariate and multivariate analyses. Overall, there was a high treatment failure rate (34 of 102, 33.3%) once children had developed recurrent disease. CONCLUSIONS: Findings from this study demonstrate the importance of underlying chronic conditions in the development of recurrent C. difficile disease and the shortcomings of current treatment options for recurrent cases. Additionally, our findings indicate that initial treatment selection may impact the likelihood of future disease, with metronidazole usage being associated with higher recurrence rates than vancomycin. These findings highlight the need for additional studies to better understand the implications of C. difficile treatment strategies.

Low Dopamine D2 Receptor Expression Drives Gene Networks Related to GABA, cAMP, Growth and Neuroinflammation in Striatal Indirect Pathway Neurons.

Background: A salient effect of addictive drugs is to hijack the dopamine reward system, an evolutionarily conserved driver of goal-directed behavior and learning. Reduced dopamine type 2 receptor availability in the striatum is an important pathophysiological mechanism for addiction that is both consequential and causal for other molecular, cellular, and neuronal network differences etiologic for this disorder. Here, we sought to identify gene expression changes attributable to innate low expression of the Drd2 gene in the striatum and specific to striatal indirect medium spiny neurons (iMSNs). Methods: Cre-conditional, translating ribosome affinity purification (TRAP) was used to purify and analyze the translatome (ribosome-bound messenger RNA) of iMSNs from mice with low/heterozygous or wild-type Drd2 expression in iMSNs. Complementary electrophysiological recordings and gene expression analysis of postmortem brain tissue from human cocaine users were performed. Results: Innate low expression of Drd2 in iMSNs led to differential expression of genes involved in GABA (gamma-aminobutyric acid) and cAMP (cyclic adenosine monophosphate) signaling, neural growth, lipid metabolism, neural excitability, and inflammation. Creb1 was identified as a likely upstream regulator, among others. In human brain, expression of FXYD2, a modulatory subunit of the Na/K pump, was negatively correlated with DRD2 messenger RNA expression. In iMSN-TRAP-Drd2HET mice, increased Cartpt and reduced S100a10 (p11) expression recapitulated previous observations in cocaine paradigms. Electrophysiology experiments supported a higher GABA tone in iMSN-Drd2HET mice. Conclusions: This study provides strong molecular evidence that, in addiction, inhibition by the indirect pathway is constitutively enhanced through neural growth and increased GABA signaling.

Genomic approaches to explore susceptibility and pathogenesis of alcohol use disorder and alcohol-associated liver disease.

Excessive alcohol use is a major risk factor for the development of an alcohol use disorder (AUD) and contributes to a wide variety of other medical illnesses, including alcohol-associated liver disease (ALD). Both AUD and ALD are complex and causally interrelated diseases, and multiple factors other than alcohol consumption are implicated in the disease pathogenesis. While the underlying pathophysiology of AUD and ALD is complex, there is substantial evidence for a genetic susceptibility of both diseases. Current genome-wide association studies indicate that the genes associated with clinical AUD only poorly overlap with the genes identified for heavy drinking and, in turn, neither overlap with the genes identified for ALD. Uncovering the main genetic factors will enable us to identify molecular drivers underlying the pathogenesis, discover potential targets for therapy, and implement patient care early in disease progression. In this review, we described multiple genomic approaches and their implications to investigate the susceptibility and pathogenesis of both AUD and ALD. We concluded our review with a discussion of the knowledge gaps and future research on genomic studies in these 2 diseases.

Effects of clustering and timing of early life stress exposure on mood problems, ADHD symptoms, and problematic drinking.

OBJECTIVE: Exposure to early life stress (ELS) may lead to long-term health consequences. The Early Life Stress Questionnaire (ELSQ) is a retrospective measure of multiple ELS and their timing. Latent class analysis (LCA) has not been applied to the ELSQ and questions regarding timing are rarely explored. This study examined the effects of clustering and timing of ELS exposure on internalizing and externalizing symptoms. METHOD: Data from 1095 participants in the NIAAA Natural History Protocol were analyzed. LCA was conducted on 18 ELS items. Regression and correlational analyses examined associations of latent classes with sociodemographic variables and clinical outcomes. RESULTS: LCA revealed three classes: Class 1: Minimal ELS (54.2%), Class 2: Moderate ELS (33.2%), and Class 3: Multiple and High ELS (12.6%). Black/African American participants were more likely to be in Class 2, and participants with low household income were more likely to be in Classes 2 and 3. Family history of problematic alcohol use and individual alcohol use disorder diagnosis were linked to Classes with higher ELS exposure. Compared with Class 1, Class 2 reported higher anxiety symptoms, depressive symptoms, ADHD symptoms, and problematic drinking, and Class 3 reported the highest levels across all these outcomes. Regarding timing, earlier exposure to ELS (e.g., sustained family conflict and witnessed domestic violence) was associated with higher psychopathological symptoms. CONCLUSIONS: The ELSQ can effectively capture clustering and timing of exposure to multiple ELS. Greater and earlier exposure to ELS were positively associated with internalizing and externalizing symptoms, underscoring the need for early and well-timed intervention.

Preliminary evidence for changes in frontoparietal network connectivity in the early abstinence period in alcohol use disorder: a longitudinal resting-state functional magnetic resonance imaging study.

The early abstinence period is a crucial phase in alcohol use disorder (AUD) in which patients have to find a new equilibrium and may start recovery, or conversely, relapse. However, the changes in brain functions during this key period are still largely unknown. We set out to study longitudinal changes in large-scale brain networks during the early abstinence period using resting-state scans. We scanned AUD patients twice in a well-controlled inpatient setting, with the first scan taking place shortly after admission and the second scan 4 weeks (±9 days) later near the end of the treatment period. We studied 37 AUD patients (22 males) and 27 healthy controls (16 males). We focused on three networks that are affected in AUD and underly core symptom dimensions in this disorder: the frontoparietal networks (left and right FPN) and default mode network (DMN). Both the whole brain and within network connectivity of these networks were studied using dual regression. Finally, we explored correlations between these brain networks and various neuropsychological and behavioral measures. In contrast to the controls (Z = -1.081, p = 0.280), the AUD patients showed a decrease in within left FPN connectivity (Z = -2.029, p = 0.042). However, these results did not survive a strict Bonferroni correction. The decrease in left FPN connectivity during the early abstinence period in AUD may reflect an initially upregulated FPN, which recovers to a lower resting-state connectivity level during subsequent weeks of abstinence. The AUD patients showed a trend for a positive association between the change in left FPN connectivity and trait anxiety (rs = 0.303, p = 0.068), and a trend for a negative association between the change in left FPN connectivity and delay discounting (rs = -0.283, p = 0.089) (uncorrected for multiple comparisons). This suggests that the FPN might be involved in top-down control of impulsivity and anxiety, which are important risk factors for relapse. Although there were no statistically significant results (after multiple comparison correction), our preliminary findings encourage further research into the dynamic neuroadaptations during the clinically crucial early abstinence period and could inform future study designs.