INTRODUCTION:Nosocomial infections (NIs) in cirrhosis are associated with high mortality but could be preventable. Logistic regression (LR) models have failed to identify high-risk patients. We aimed to develop machine learning (ML) models to predict NI. METHODS:The CLEARED consortium consists of prospectively enrolled cirrhosis inpatients from >120 centers. Using day-of-admission clinical data, 3 ML approaches (random forest [RF], extreme gradient boosting, and neural networks [NNs]) were used to predict NI. Data were split 80:20 for training and testing stratified by the outcome. Models were compared using area under the receiver operating characteristic curve (AUC). RESULTS:In total, 8,263 patients (55.90 ± 13.34 years; 64.1% men) from 127 centers in 37 countries were included. NI developed in 869 (10.5%), a median of 6 (4-11) days of postadmission. Major NIs were respiratory (29.6%) and urinary tract infection (15.7%), and spontaneous bacterial peritonitis (13.5%). NIs occurred more frequently in patients from low/low-middle income countries and those with severe liver disease, alcohol etiology, and admission infections. NIs were associated with inpatient mortality (31.9% vs 8.1%, P < 0.001) and liver transplantation (4.8% vs 1.9%, P < 0.001). Although the RF model (AUC 0.69) showed good calibration (Brier score 0.09), outperforming extreme gradient boosting, neural network, and LR models (AUC 0.66 for all; LR comparison P = 0.043), no model achieved AUC ≥0.80 for clinical utility. At 10% predicted probability threshold, the RF model demonstrated only 75.4% sensitivity, 52.9% specificity, and 15.9% positive predictive value (PPV). DISCUSSION:NIs cannot be accurately predicted from day-of-admission data using ML models, even in a large, prospective, global cirrhosis cohort. Every hospitalized patient with cirrhosis should receive protocolized infection control measures.

Background: Prognostic models for alcohol-associated hepatitis (AH) are typically single-centre and generalise poorly, yet the data sharing needed to improve them is limited by privacy regulation. We assessed whether diffusion-generated synthetic data can reproduce the structure, clinical associations, and predictive utility of pooled multi-site AH data while limiting disclosure risk, enabling collaborative modelling without exchanging real patient records. Methods: We assembled four geographically and sociodemographically distinct Mayo Clinic severe AH cohorts (Rochester, Arizona, Florida, and the Mayo Clinic Health System; 2016–2024; N=1477). Pooled real training data (n=1032) trained a tabular denoising diffusion probabilistic model (TabDDPM), generating 10 000 synthetic patients. We evaluated fidelity, survival associations, privacy, and predictive utility; four algorithms trained on synthetic versus real data were tested on a common held-out real set (n=445) for 30-day and 90-day death or liver transplantation. Non-inferiority was prespecified as the upper 95% CI bound of the AUC difference (real minus synthetic) below 0·05. Findings: Baseline characteristics differed across sites (eg, 30-day composite event rate 12·0–21·1%; all p<0·05). Synthetic data reproduced every marginal distribution (p=0·54–1·00) and the correlation structure (Pearson r=0·998), and preserved survival stratification across five risk factors (p≤0·001). Synthetic-trained models were non-inferior to real-trained models for all four algorithms at both horizons in the combined cohort (AUC difference −0·007 to +0·024). Site-level non-inferiority was met in 13/20 and 12/20 comparisons (small per-site samples). Calibration was comparable and empirical disclosure risk was low (membership-inference AUC 0·499; no exact matches). Interpretation: Diffusion-generated synthetic data preserved the structure, clinical associations, and predictive utility of multi-site AH cohorts with low empirical disclosure risk, substituting for—not merely resembling—the real data. Such surrogates are a reusable complement to federated learning, pending validation across independent institutions.

OBJECTIVES:The Fontan pathway (inferior vena cava-pulmonary artery connection) regulates forward flow and backward pressure, but its optimal size remains uncertain. This study aimed to evaluate the relationship between Fontan pathway diameter, hemodynamics, exercise capacity, and liver disease markers. METHODS:A retrospective review of 67 adults with extracardiac conduit (EC) or lateral tunnel (LT) Fontan procedures who underwent exercise cardiac catheterization was conducted. Minimal pathway diameter was measured via angiography or computed tomography. Exercise capacity was assessed by percent predicted peak oxygen consumption. Liver disease markers included aspartate aminotransferase-to-platelet ratio, fibrosis-4, and Model for End-Stage Liver Disease excluding international normalized ratio scores. RESULTS:The mean age at catheterization was 30.4 ± 7.9 years. Minimal pathway diameter was 17.5 ± 6.0 mm. Larger diameter was associated with reduced augmentation of pulmonary and systemic blood flow during exercise (pulmonary flow, -2.3% per mm; 95% CI, -3.9 to -0.7; P = .005; systemic flow, -2.2% per mm; 95% CI, -4.1 to -0.2; P = .03), and lower percent predicted peak oxygen consumption (-0.8% per mm; 95% CI, -1.4 to -0.2; P = .009), independent of exercise mean pulmonary artery and pulmonary artery wedge pressures, and peak heart rate. No consistent association was observed between pathway diameter and markers of liver disease. Notably, the pressure gradient on the liver imposed by the pathway contributed minimally to inferior vena cava pressure at rest (0; interquartile range, 0-7.1%) or during exercise (6.4%; interquartile range, 0.5%-14.3%). CONCLUSIONS:Larger Fontan pathway diameter was paradoxically associated with impaired flow augmentation during exercise, which may contribute to reduced exercise capacity.

BACKGROUND AND AIMS:It remains unclear whether different factors influence 30- and 90-day readmission rates. We identified predictors of 90-day mortality in a global cohort of hospitalised patients with cirrhosis. METHODS:Variables associated with 30- and 90-day post-discharge readmission, liver transplantation (LT), and mortality were compared in prospectively enrolled, non-electively hospitalised adult patients with cirrhosis. RESULTS:We enrolled 4208 patients from 125 centres across 37 countries. Alcohol-related liver disease was the most common aetiology of cirrhosis (40%), followed by hepatitis B virus infection (21%); 47% were readmitted, 8% received liver transplantation (LT), and 23% died within 90 days post-discharge. In multivariable analysis, country income was significantly associated with both 30- and 90-day readmission rates, the receipt of LT, and mortality within 30 and 90 days post-discharge (all p-values < 0.001). Independent predictors of higher rates of 30- and 90-day readmissions, respectively, were disease severity (p < 0.001, p = 0.003), prior ascites (p = 0.025, p = 0.016), prior hospitalisation (p < 0.001), hyponatremia (p < 0.001, p = 0.008), and in-hospital vasopressor use (p = 0.002, p = 0.011). Prior variceal bleeding independently predicted higher 90-day readmission rates, whereas age, disease severity, mechanical ventilation, and in-hospital vasopressor use (all, p < 0.001) increased odds of 30- and 90-day post-discharge death. Additionally, admission (p = 0.011) and nosocomial (p = 0.022) infections increased the odds of 90-day post-discharge death. CONCLUSION:In a global cohort of hospitalised patients with cirrhosis, patients in high-income countries exhibited the highest rates of 30- and 90-day readmission, alongside lower mortality rates and a higher incidence of LT. Variables that predict 30-day readmission also predicted 90-day readmission. Understanding these disparities is essential for achieving health equity.

BACKGROUND & AIMS:Alcohol is a leading global risk factor for more than 200 diseases, premature death, and disability. We aimed at updating the Alcohol Preparedness Index (API) to map global and regional policy trends between 2010 and 2019. METHODS:We compiled policy data from 141 countries from the World Health Organization Global Information System on Alcohol and Health and scored five domains: national policy frameworks; production, pricing, and taxation; marketing and availability; drink-driving countermeasures; and monitoring and surveillance. The primary endpoint was the percentage change in API between 2010 and 2019. We summarized trends by region and explored potential variables that explain these trends with an adjusted regression model. RESULTS:By 2019, fewer than 25% of countries had a strong national alcohol plan (defined as a written national policy accompanied by a formal action plan for its implementation), whereas 40% had none. Production, pricing, and taxation showed the clearest increase (27% in 2010 and 78% in 2019). Monitoring and surveillance reached strong levels at 47.5%. The median API increased from 57.0 (39.0-82.0) in 2010 to 74.8 (58.3-83.5) in 2016, remaining above baseline in 2019 at 67.8 (51.2-83.8). Larger population size negatively correlated with API change (β = -19.1, p <0.05). Human Development Index and alcohol per capita consumption were not significantly associated with API change. CONCLUSIONS:From 2010 to 2019, preparedness on alcohol policy increased globally, though progress remained uneven across domains and regions. These findings highlight persistent policy gaps and support the prioritization of evidence-based interventions aligned with the SAFER framework. Future efforts should focus on translating policy presence into implementation, with particular attention to domains most strongly linked to alcohol-associated liver disease outcomes. IMPACT AND IMPLICATIONS:Despite the well-established harms of alcohol, global trends in alcohol policy preparedness remain poorly characterized. Using the validated Alcohol Preparedness Index across 141 countries, we demonstrate meaningful but uneven global progress between 2010 and 2019, with gains concentrated in taxation and monitoring domains, whereas national planning and marketing controls lagged, particularly in low-income regions. These findings are directly relevant to policymakers and public health authorities, as stronger alcohol policy environments have previously been linked to lower rates of alcohol-associated liver disease, hepatocellular carcinoma, and cardiovascular mortality. Within the limitations of an ecological study design, this work provides a practical roadmap for identifying policy gaps and prioritizing interventions aligned with the WHO SAFER framework to reduce the global burden of alcohol-related disease.

BACKGROUND AND AIMS:Although the role of cardiometabolic risk factors (CMRFs) has been characterized in steatotic liver disease, their role in the severity of alcohol-associated hepatitis (AH) remains unclear. We aimed to evaluate the impact of CMRFs on mortality. APPROACH AND RESULTS:Multinational prospective cohort study (2015-2024) including hospitalized patients with AH across 32 centers in 14 countries. Diagnosis of AH was made using the National Institute on Alcohol Abuse and Alcoholism criteria. Analyses included adjusted competing-risk models by age, sex, ethnicity, history of cirrhosis, CMRF, corticosteroid use, MELD, and acute-on-chronic liver failure grade, with liver transplantation as a competing risk. Nine hundred thirty-six participants were included; the mean age was 48±11.2 years, and 88.9% were male. At least 1 CMRF was present in 46.6%; median body mass index was 24.2 kg/m 2 [IQR: 22.8-28.2], prevalence of diabetes 17.6%, hypertension 16.5%, and dyslipidemia 5.8%. Median MELD was 24.4 (19.3-31.4), 86.7% had severe AH, and 180-day survival was 72.9%. Survival did not differ by CMRF status (log-rank p =0.453). In adjusted competing-risk models, higher age (subdistribution hazard ratio [sHR] 1.03; 95% CI: 1.01-1.04), greater alcohol intake (per g/day; sHR: 1.001; 95% CI: 1.000-1.002), MELD (sHR: 1.04; 95% CI: 1.01-1.06), and acute-on-chronic liver failure grade 2-3 (sHR: 2.34 and 4.34) predicted mortality. However, no individual CMRF independently increased mortality. A prespecified nonlinear body mass index analysis showed modestly lower mortality between 25 and 40 kg/m², with a higher risk above 40 kg/m². CONCLUSIONS:Among patients with severe AH, metabolic dysfunction was not associated with increased mortality. Although a higher body mass index was associated with slightly lower mortality in AH, this may reflect better nutritional status rather than a true protective effect.

INTRODUCTION:Alcohol-associated hepatitis (AH) is a severe condition with high short-term mortality. Identifying key predictors of poor outcomes is critical for guiding therapeutic strategies. Mean arterial pressure (MAP), a key determinant of tissue perfusion and systemic hemodynamics, may play a pivotal role in prognosis. METHODS:We analyzed a multicenter, prospective cohort of 323 patients hospitalized with AH, with validation in an independent cohort of 290 patients. Survival was evaluated using Kaplan-Meier curves and compared with the log-rank (Mantel-Cox) test. Cox proportional hazards models were used to estimate hazard ratios for mortality, adjusted for Model for end stage liver disease score. Mechanistic insights were explored through assessment of cardiovascular biomarkers. RESULTS:A baseline MAP <80 mm Hg was associated with significantly higher mortality at both 28 days (27.3% vs 8.0%) and 90 days (40.3% vs 15.6%; P < 0.001 for both). This association persisted after adjusting for Model for end stage liver disease score, age, and baseline hepatic encephalopathy. The incidence of infections during follow-up was similar across MAP groups (27.6% vs 22.8%), but acute kidney injury occurred more frequently in the MAP <80 mm Hg group (62% vs 38%, P < 0.001). In the validation cohort, patients with MAP <80 mm Hg also demonstrated significantly lower 28-day transplant-free survival. Although B-type natriuretic peptide and plasma renin levels were altered in patients with AH, they did not correlate with MAP values. DISCUSSION:A baseline MAP <80 mm Hg is an independent predictor of short-term and mid-term mortality in patients with AH. Strategies aimed at restoring hemodynamic stability may improve outcomes in this high-risk population.

Karvellas, Constantine J.; Bajaj, Jasmohan S.; Kamath, Patrick S.; Napolitano, Lena; O’Leary, Jacqueline G.; Solà, Elsa; Subramanian, Ram; Wong, Florence; Asrani, Sumeet K. Author Information

BACKGROUND & AIMS:Frailty predicts mortality in liver transplant candidates, but its impact on hospitalizations in general hepatology outpatients-and whether related components such as functional capacity provide additional prognostic value- remains unclear. METHODS:We analyzed data from the North American Consortium for the Study of End-Stage Liver Disease (NACSELD), a multicenter prospective ambulatory cirrhosis cohort. Frailty was assessed using the Liver Frailty Index, categorized as robust (≤3.2), prefrail (3.2-4.4), and frail (≥4.4), and the Duke Activity Status Index. The primary outcome was hospitalization at 6 months. RESULTS:Among 1007 patients, at enrollment, 12.9% were robust, 70.6% were prefrail, and 16.5% were frail. Twenty-four percent of the cohort was hospitalized within 6 months, and hospitalization rates increased with frailty at 3 months (5%, 12%, and 21%, respectively; P = .001) and almost doubled by 6 months (11%, 21%, and 31%, respectively; P = .002). In multivariable modeling, the Liver Frailty Index (odds ratio, 1.6; P = .03) or the Duke Activity Status Index (odds ratio, 0.99; P = .04), after controlling for Model for End-stage Liver Disease 3.0, Charlson Comorbidity Index, cirrhosis etiology, diabetes, prior cirrhosis complications, admission medications, and Child-Turcotte-Pugh score remained independently associated with 6-month hospitalization risk. The Liver Frailty Index and the Duke Activity Status Index were inversely correlated (Pearson -0.37; P < .001); with every 0.1 unit increase in the Liver Frailty Index, the Duke Activity Status Index decreased by 0.95 units. Low 6-month mortality underpowered the association of the Liver Frailty Index with mortality. CONCLUSION:Measures of frailty (by Liver Frailty Index) and functional capacity (by Duke Activity Status Index) independently predict 6-month hospitalization in ambulatory patients with cirrhosis. One-third of frail patients and almost one-quarter of prefrail patients with a median Model for End-stage Liver Disease 3.0 of 11 required hospitalization by 6 months. Routine assessment with the Liver Frailty Index may improve risk stratification and guide interventions to reduce health care utilization.