Publications

Neuroinflammation and microglial activation are common features in Alzheimer's disease (AD) and excessive alcohol consumption. Alcohol induces liver damage and inflammation, and altered serum aminotransferases have been reported in patients with AD. Small extracellular vesicles (sEVs) and their cargo are emerging as mediators of intercellular communication in AD and alcohol-induced liver injury. However, the effects of alcohol use on AD progression remain to be elucidated. In this study, we evaluated the effects of repeated binge drinking on the liver and brain in the APP/PS1 mouse model of AD. Alcohol-exposed APP/PS1 mice showed elevated serum alanine aminotransferase levels, indicating liver injury absent in controls, along with increased pro-inflammatory cytokine expression in both liver and brain. Alcohol increased the biogenesis and release of sEVs in AD mice and in mouse hepatocytes. These sEVs were enriched in mature miR-122-5p that is predominant in hepatocytes. In vivo, miR-122-5p was detected in the brain of alcohol-exposed AD mice suggesting EV-mediated miR-122-5p transfer to the brain. Microglial uptake of hepatocyte-derived sEVs was confirmed in vitro. sEVs from alcohol-treated hepatocytes sensitized BV-2 microglia to LPS stimulation, significantly enhancing CCL2, CXCL2, CCL3, and TNF-α production. Transfection of microglia with a miR-122-5p mimic partially recapitulated the pro-inflammatory sensitization by sEVs from alcohol-exposed hepatocytes, which was reversed by miR-122-5p inhibitor delivery. ADAM10, a miR-122-5p target, was reduced in both wild-type and AD brains after alcohol exposure, with cell-specific effects. These results suggest that alcohol-induced hepatocyte-derived sEVs may modulate liver-to-brain signaling via miR-122-5p and contribute to neuroinflammation in AD.

Steatotic liver disease is the most common form of liver disease induced by the metabolic syndrome, excessive alcohol use, or their combination. In progression of steatohepatitis to liver fibrosis, sustained inflammation and activation of innate immune cells plays a critical role. Neutrophils play a critical role in sustaining inflammation as well as in host defense. In this study, we identified neutrophil populations with activated or exhausted phenotypes in alcohol-associated steatohepatitis and discovered induction of neutrophil extracellular traps (NETs) by alcohol in the setting of metabolic dysfunction-associated steatohepatitis (MASH). Mechanistically, we describe how the NLRP3 inflammasome and NLRP3-IL-ß axis is a key component in sustained liver inflammation in MASH, alcohol-induced steatohepatitis, and their combined insult. Finally, using preclinical models, we demonstrate that targeting neutrophils, disruption of NETs, or NLRP3 inflammasome activation are promising directions for new therapeutic approaches in steatohepatitis. Abbreviations: MASH, metabolic dysfunction-associated steatohepatitis; AH, alcohol-associated hepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; ALD, alcohol-associated liver disease; MetALD, metabolic syndrome and alcohol-associated liver disease; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; NLRP3, nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3; DAMPs, damage-associated molecular patterns; PAMPS, pathogen-associated molecular patterns; NETs, neutrophil extracellular traps.

The Kyoto Consensus introduced a key conceptual shift in characterizing acute-on-chronic liver failure (ACLF) patients into Type-A and Type-B phenotypes. A day-long meeting was convened at Istanbul during APASL 2026 to assess the real-world applicability of Type-A and Type-B ACLF across continents. The objective was that physicians could recognize ACLF as a unified disease entity, and quality research and new therapeutic options with defined end-points could be undertaken. Data from APASL ACLF Research Consortium (AARC), EASL-CLIF and NACSELD were assessed and discussed in detail. While the applicability of Type-A and Type-B varied across cohorts, the definition required to be appended. The experts unanimously agreed that 'liver failure' as identified by serum bilirubin of ≥ 5 mg/dl and INR ≥ 1.5 should be the 'core' for both Type-A and Type-B ACLF. Type-A ACLF is considered when "a patient with compensated advanced chronic liver disease or compensated cirrhosis presents with index decompensation as liver failure followed by development of ascites and/or hepatic encephalopathy within 4 weeks." Type-B ACLF is considered when "a patient with prior or concurrent decompensated cirrhosis presents with acute decompensation as liver failure accompanied by one or more extrahepatic organ failures." New definitions of organ dysfunction and failure, as well as endpoints for clinical trials, were also deliberated and finalized. The "Istanbul Report", presents a milestone evidence based consensus document carrying harmonization of various aspects of ACLF, incorporating current evidence, critically analyzed unanimous recommendations, and key areas for future studies.

State-dependent neural dynamics are central to models of large-scale brain regulation in neurodevelopmental and psychotic disorders, but it remains unclear whether autism spectrum disorder (ASD) and schizophrenia (SCH) show altered oscillatory activity across internally and externally oriented cognitive states. This study examined EEG spectral power across resting, interoceptive, and cognitive conditions in adults with ASD, SCH, and matched neurotypical controls. Absolute and relative power were calculated for canonical frequency bands to distinguish overall power differences from spectral redistribution; group and condition effects were analysed while controlling for covariates. Robust condition effects emerged across frequency bands. Absolute delta power decreased during interoception compared to rest and task, while relative delta power was lowest during rest, suggesting spectral reweighting. The most prominent group effect was a condition-invariant elevation of theta power in SCH, suggesting a baseline shift with preserved state-dependent modulation. The ASD group showed modest detectable spectral differences. Condition-dependent modulation patterns were broadly similar across groups. Alpha, beta, and gamma activity were primarily condition-driven with less group differences. Group-by-condition interactions, altered state-dependent oscillatory modulation were not reliably detectable. Absolute and relative EEG power captured partly distinct spectral characteristics across conditions and groups.

INTRODUCTION: Obesity is prevalent in patients with alcohol-associated hepatitis (AH), but its impact on clinical outcomes remains incompletely defined. We aimed to evaluate the association between BMI-defined obesity and 90- and 180-day survival in AH, as well as its association with complications and circulating inflammatory mediators.

METHODS: We analyzed 778 patients with AH enrolled in the NIAAA-supported Alcoholic Hepatitis Network (AlcHepNet) observational cohort and randomized clinical trial. Patients were categorized as normal weight, overweight, or obese by BMI. Multivariable Cox models were used to evaluate survival. Baseline serum cytokines were measured in a randomly selected subset of 168 patients.

RESULTS: Of the 778 patients, 255 (32.8%) were overweight and 310 (39.8%) were obese. Obese patients had higher baseline MELD scores, higher rates of bacterial infection during hospitalization, and higher 90- and 180-day mortality than overweight and normal-weight patients. In multivariable analysis, obesity was associated with reduced 180-day survival (HR 1.50; 95% CI 1.03-2.23, p = 0.041). In adjusted logistic models among severe AH cases, obesity remained associated with infection (OR 1.84; 95% CI 1.15-2.93; p = 0.011) and AKI (OR 2.25; 95% CI 1.42-3.57; p = 0.0005) within 180 days. In the cytokine subset, obese patients showed higher levels of pro-inflammatory cytokines and chemokines and lower levels of growth factors.

CONCLUSIONS: Obesity in AH was associated with more severe disease at presentation, increased risk of complications, and worse survival, supporting obesity as an important adverse factor in AH.

MOTIVATION: Mediation analysis plays a crucial role in understanding how exposure variables influence health outcomes via intermediate variables, or mediators, in environmental studies. When analyzing a large number of environmental exposures, such as chemical mixtures or pollutants, together with multiple potential mediators such as metabolites, advanced methodologies are necessary to accurately separate direct and indirect effects. This paper proposes a novel mediation analysis method based on Sparse Canonical Correlation Analysis (SCCA), designed specifically for settings where both exposures and mediators are high-dimensional. The effectiveness of the proposed method is evaluated through simulation studies and an application to real-world data.

RESULTS: The proposed SCCA-based mediation framework improved identification of relevant mediators and pathways in simulation studies, particularly in high-dimensional and noisy settings. The two-step screening extension further enhanced feature selection while maintaining stable estimation. In the real-data application, the method identified interpretable exposure-metabolite pathways associated with MELD score, with several pathways showing moderate selection stability and robustness to potential unmeasured confounding.

AVAILABILITY: The R code for implementing the proposed method and the simulation studies is available at https://github.com/MaggieLi2001/HDM-SCCA2.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A baseline MAP <80 mmHg is an independent predictor of short- and mid-term mortality in patients with AH. Strategies aimed at restoring hemodynamic stability may improve outcomes in this high-risk population.

Steatotic liver disease (SLD) comprises a heterogeneous group of liver diseases defined by pathological hepatic lipid accumulation with varying degrees of steatohepatitis and progressive fibrosis, which may culminate in cirrhosis and/or hepatocellular carcinoma. SLD encompasses metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called non-alcoholic fatty liver disease (NAFLD); MetALD, describing patients with MASLD consuming moderately high amounts of alcohol; and alcohol-associated/related liver disease (ALD). In addition, SLD encompasses less common aetiologies, including drug-induced and monogenic causes, as well as cryptogenic disease, which lacks metabolic risk factors or an identifiable cause. As the leading cause of chronic liver disease worldwide, MASLD, including metabolic dysfunction-associated steatohepatitis (MASH), is a complex multisystem disorder associated with extrahepatic organ dysfunction. Consequently, MASLD has become a major focus of multidisciplinary research, driving innovation across hepatology, immunology, cardiometabolism, addiction medicine, nutrition, prevention, and beyond. Over the past two decades, a broad array of in vivo, in vitro, and ex vivo experimental models have been developed to recapitulate diverse aspects of SLD pathophysiology, genetics, inflammation, treatment response, and multi-organ crosstalk, substantially advancing mechanistic understanding and therapeutic development. However, the rapid expansion and heterogeneity of available models have also highlighted the need for improved categorisation, standardisation, and harmonisation in line with evolving disease definitions and clinical concepts. In this EASL position paper, we critically review and classify currently available experimental SLD models and propose key criteria required for their appropriate use across distinct SLD subtypes. These criteria encompass systemic and hepatic metabolism, cardiometabolic comorbidities, histopathology, immunopathology, and molecular features relevant to disease stage and aetiology. This position paper aims to guide informed model selection, promote consistent nomenclature, and enhance rigour and translational relevance in preclinical and experimental SLD research.

Alcohol-associated hepatitis (AH) has a high 30-day mortality in patients with a severe AH (sAH). Corticosteroids (CS) are used for patients with sAH but has limitations. There are no biomarkers measured upon hospitalization that predict steroid responsiveness. Signal regulatory protein alpha (SIRPα) is a receptor that regulates inflammation. The role of SIRPAα has not been studied in patients with AH. In a prospective test and validation cohort of sAH patients treated with CS, plasma cytokines and SIRPα levels were measured. Studies with Sirpa-/- mice and in vitro studies were performed to characterize the impact of Sirpa-/- and cleavage. Plasma SIRPα levels were elevated at baseline in CS-NR vs CS-R in both cohorts. Plasma SIRPα levels were also elevated with disease severity and mortality. CS-NR patients had increased pro-inflammatory cytokines. SIRPα cleavage was induced by EtOH and LPS and associated with ADAM10 activity and pro-inflammatory cytokine release. ADAM10 inhibition reduced SIRPα cleavage and pro-inflammatory cytokine release. Sirpa-/- mice developed exacerbated liver injury and inflammation in an experimental model of ALD. Plasma SIRPα is a potential biomarker to predict response to CS and prognosis. Sirpa-/- mice develop a hyper-inflammatory phenotype similar to SIRPα cleavage in humans. Future clinical studies are necessary to validate plasma SIRPα as a predictive biomarker to guide the use of CS in patients with sAH.