Bajaj, Jasmohan S

ABSTRACT 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.

Abstract Introduction Biliary fibrosis and inflammation are central to the pathogenesis of cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Inflammatory and fibrogenic stimuli, such as transforming growth factor-β (TGFβ) and lipopolysaccharide (LPS) signaling, drive these processes, but their underlying transcriptional mechanisms in cholangiocytes remain incompletely defined. We investigated the role of Runt-related transcription factor 1 (RUNX1) as a transcriptional co-regulator of fibroinflammatory signaling in cholangiocytes. Methods Human PSC-derived cholangiocytes (PSC-Cs) and mouse large biliary epithelial cells (MLEs) were subjected to RUNX1 knockdown or pharmacologic inhibition (Ro5-3335 or AI-10-104). Cytokine secretion was profiled by Luminex multiplexing; RUNX1 genomic binding and protein interactome were assessed by ChIP-qPCR, ChIP-seq, and LC-MS/MS. In vivo , Mdr2 −/− mice received Ro5-3335, and cholangiocyte-selective Runx1 knockout mice (Krt19-CreERT) were challenged with a DDC diet, followed by evaluation of fibrosis and inflammation. Results RUNX1 expression was significantly increased in cholangiocytes from PSC and PBC patients, and Mdr2 −/− mice. RUNX1 knockdown or inhibition reduced IL6, TNFα, and other proinflammatory cytokines in PSC-Cs and attenuated TGFβ-, LPS-, and TNFα-induced Il6 and Ccl2 expression in MLEs. ChIP-qPCR and ChIP-seq revealed TGFβ-induced RUNX1 binding to the Il6 promoter and 727 additional genomic sites enriched for fibrosis and inflammatory pathways; predicted upstream regulators included TGFβ, TNF, and NFκB signaling. Proteomic analysis identified TGFβ-induced RUNX1 interactions with SMAD2 and NFκB2. In vivo , Ro5-3335 treatment in Mdr2 −/− mice reduced hepatic collagen, ECM gene expression, immune cell infiltration, and serum liver injury markers and bile acids. Similarly, cholangiocyte-specific Runx1 deletion mitigated fibrosis, inflammation, and liver injury in DDC-fed mice. Conclusion RUNX1 is a central transcriptional hub integrating TGFβ and inflammatory signals in cholangiocytes. Its inhibition attenuates biliary fibrosis and inflammation in cholestatic models, supporting RUNX1 as a potential therapeutic target in fibroinflammatory cholangiopathies.

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: Cholestatic liver diseases, including primary sclerosing cholangitis, are characterized by biliary fibroinflammation. TGFβ-activated cholangiocytes release signals that recruit immune cells and activate myofibroblasts, promoting inflammation and extracellular matrix (ECM) deposition. TGFβ also regulates stearoyl-CoA desaturase (SCD), an enzyme involved in lipid signaling. Yet, the role of SCD or its inhibitor, Aramchol, in biliary fibroinflammation had not been studied. Methods and Results: Mdr2 -/- with established biliary fibrosis and 3,5-diethoxycarboncyl-1,4-dihydrocollidine (DDC) diet-fed mice were treated with Aramchol meglumine (12.5 mg/kg/day). Hepatic fibrosis was assessed by qPCR, Picrosirius red staining, immunofluorescence, and hydroxyproline content. Human H69 or murine large cholangiocyte cell lines stimulated with TGFβ, as well as PSC-derived cholangiocytes (PSC-C), were treated with Aramchol or SCD siRNA. RNA-seq, fibroinflammatory marker expression, peroxisome proliferator-activated receptor (PPAR) activity, and targeted fatty acid profiling were performed. Aramchol treatment significantly reduced hepatic ECM gene expression, inflammatory cytokines ( Il6 , Tnfa ), collagen content, and myofibroblast activation (aSMA staining) in both mouse models. In TGFβ-stimulated H69 cells, Aramchol suppressed hepatic fibrosis pathways and enhanced PPAR signaling. Aramchol also reduced the expression of fibrotic markers, myofibroblast-activating mediators ( VEGFA and PDGFB ), and IL6, mirroring the effects of SCD knockdown. In PSC-C, Aramchol significantly downregulated SCD, VEGFA and IL6 . Conversely, PPARα and -γ activity and fatty acid agonist, linoleic acid levels were increased in cholangiocyte cell lines. Conclusions: Aramchol attenuates and prevents biliary fibrosis in mouse models of cholestatic liver disease by inhibiting TGFβ-induced fibroinflammatory mediators and activating PPARa/γ in cholangiocytes. These findings, combined with its favorable clinical safety profile, support the potential of Aramchol as a therapeutic candidate for PSC.

Background and Aims: Reducing avoidable readmissions in cirrhosis is challenging. Enhanced engagement using health information technology (HIT) interventions and caregivers lowered readmissions in an open-label study of the Patient Buddy App (PBA). Aim : Multicenter trial of PBA versus standard of care (SOC) to reduce avoidable readmissions. Approach and Results: An open-label, randomized clinical trial was performed at 3 sites to study the effect of PBA (HIT) versus SOC in cirrhosis inpatients with adult caregivers (dyads). Initial randomization was 1:1:1 between SOC, HIT only, and HIT+ visits. However, due to COVID-19, an unplanned study redesign required a combined HIT versus SOC. Primary outcome : Avoidable readmissions (decided by a blinded monitoring board). Secondary outcomes were all-cause readmission and stakeholder input. PBA focused on medication adherence, cognitive testing, and symptoms, and was remotely monitored by study staff. In all, 464 subjects (232 dyads) were enrolled [Virginia Commonwealth University (VCU): 120, Mayo: 40, Department of Veterans Affairs (VA): 72; 116 dyads/group]. Avoidable readmissions were significantly higher in SOC versus HIT (19.8% vs. 10.3%, p =0.04) with OR of 2.14 (95% CI 1.01–4.54) and remained significant even after removing pre-COVID HIT+ visits patients (19.8% vs. 9.3%, p =0.040) with OR of 2.41 (95% CI 1.02–5.69). All-cause readmissions were higher in SOC versus HIT (48% vs. 30%, p =0.005). App evaluation/engagemen t : 1660 alerts were sent; mostly related to HE. Most dyads were satisfied with the app. Conclusions: In a multicenter randomized clinical trial of 464 cirrhosis inpatients and their CGs across several practice settings, the PBA was associated with lower avoidable readmissions at 30 days post-discharge compared to SOC.

INTRODUCTION: The alfapump system has been shown to be a possible alternative to repeat therapeutic paracentesis (TP) in selected patients with refractory ascites (RA). The objective of this study was to assess the safety and efficacy of alfapump on ascites control and quality of life in these patients. METHODS: Patients with cirrhosis and RA requiring ≥2 TPs 30 days prior were enrolled and followed for 24 months postimplant. Primary efficacy end point assessed at 6 months was reduction in paracentesis requirement; safety end point was device-related adverse events resulting in intervention, explant, or death. RESULTS: Forty patients with RA (mean Model of End-stage Liver Disease-Sodium: 15 ± 4) received an alfapump. TP requirement was decreased from 3.2 ± 1.5 sessions per month preimplant to 0.2 ± 0.6 sessions per month at 6 months postimplant ( P < 0.001), with 77% of patients having ≥50% reduction. Six pumps (15%) were explanted within 6 months due to device-related adverse events, 3 (7.5%) due to pump site skin erosion, and 3 (7.5%) due to bladder discomfort. Twenty-four renal events occurred in the 0–6 month postimplant period; 16 cases were readily reversible stage 1 acute kidney injury. Ascites-related symptoms assessed with an Ascites Q score improved from 51.0 ± 19.3 preimplant to 32.2 ± 21.9 at 6 months postimplant ( P < 0.001). Physical but not mental components of Short Form 36 improved ( P < 0.001). The 5 deaths within 6 months postimplant were not directly related to the device or alfapump therapy. DISCUSSION: The alfapump system effectively controlled ascites, which improved quality of life. It may be considered as an alternative to repeat TP in select patients with RA. Complication rates were similar to those expected in patients with RA.

INTRODUCTION: One of the primary goals of the Liver Cirrhosis Network (LCN) is to develop a cohort study to better understand and predict the risk of hepatic decompensation and other clinical and patient-reported outcomes among patients with Child A cirrhosis. METHODS: The LCN consists of a Scientific Data Coordinating Center and 10 clinical centers whose investigators populate multiple committees. The LCN Definitions and Measurements Committee developed preliminary definitions of cirrhosis and its complications by literature review, expert opinion, and reviewing definition documents developed by other organizations. The Cohort Committee developed the study protocol with the input of the steering committee. RESULTS: The LCN developed a prospective cohort study to describe and predict the rates of incident clinical events pertaining to first decompensation and patient-reported outcomes. The LCN developed a pragmatic definition of compensated cirrhosis incorporating clinical, laboratory, imaging, and histological criteria. Definitions of incident and recompensated ascites, overt hepatic encephalopathy, variceal hemorrhage, bleeding because of portal gastropathy, and hepatocellular carcinoma were also codified. DISCUSSION: The LCN Cohort Study design will inform the natural history of cirrhosis in contemporary patients with compensated cirrhosis. The LCN Definitions and Measures Committee developed criteria for the definition of cirrhosis to standardize entry into this multicenter cohort study and standardized criteria for liver-related outcome measures. This effort has produced definitions intended to be both sensitive and specific as well as easily operationalized by study staff such that outcomes critical to the LCN cohort are identified and reported in an accurate and generalizable fashion. REGISTRATION: NCT05740358.

INTRODUCTION: Management of hepatic encephalopathy relies on self-titration of lactulose. In this feasibility trial, we assess an artificial intelligence–enabled tool to guide lactulose use through a smartphone application. METHODS: Subjects with hepatic encephalopathy on lactulose captured bowel movement pictures during lead-in and intervention phases. During the intervention phase, daily feedback on lactulose titration was delivered through the application. Goals were determined according to number of bowel movement and Bristol Stool Scale reports. RESULTS: Subjects completed the study with more than 80% satisfaction. In the lead-in phase, less compliant subjects achieved Bristol Stool Scale goal on 62/111 (56%) of days compared with 107/136 (79%) in the intervention phase ( P = 0.041), while the most compliant subjects showed no difference. Severe/recurrent hepatic encephalopathy group achieved Bristol Stool Scale goal on 80/104 (77%) days in the lead-in phase and 90/110 (82%) days in the intervention phase ( P = NS), compared with 89/143 (62%) days and 86/127 (68%) days in the stable group. DISCUSSION: Dieta application is a promising tool for objective Bowel Movement/Bristol Stool Scale tracking for hepatic encephalopathy and may potentially be used to assist with lactulose titration.

Lactulose-based hepatic encephalopathy treatment requires bowel movements/day titration, which is improved with Bristol stool scale (BSS) incorporation. Dieta app evaluates artificial intelligence (AI)-based BSS (AI-BSS) with stool images. Initially, controls (N = 13) and cirrhosis patients on lactulose/not on lactulose (n = 33) were trained on the app. They entered self-reported BSS (self-BSS) with AI-BSS communicated. Lactulose dose changes were tracked. A subset (n = 12) was retested with AI communication blocked. Most subjects were comfortable with the app. Self/AI-BSS and lactulose dose/AI-BSS correlation increased with app use. AI-BSS communications improved insight into self-BSS over time. Dieta app to gauge stool AI characteristics was acceptable and increased insight into lactulose dose and BSS in cirrhosis.

Background: App-based technologies could enhance patient and caregiver communication and provide alerts that potentially reducing readmissions. However, the burden of App alerts needs to be optimized to reduce provider burnout. Aim: The purpose of this study was to determine subjective and objective burden of using the Patient Buddy App, a health information technology (HIT) on providers in a randomized multicenter trial, who completed a semi-quantitative Likert scale survey regarding training procedures, data and privacy concerns, follow-up details, and technical support. This randomized multicenter trial recruits cirrhosis inpatients and their caregivers, and randomizes them into standard-of-care, HIT (communication only via App) and HIT+visits (App+phone calls/visits) for 30 days after discharge. The alerts are monitored by providers through a central iPad. The reason(s) and number of alerts were recorded as the objective burden. A total of 1442 messages were sent as alerts from the 103 dyads (patient + caregiver) (n=206) randomized to HIT arms. The most common messages related to Hepatic Encephalopathy (HE) (high or low bowel movement=50% or orientation tests=37%). Twelve providers completed the surveys reflecting the following themes—92% and 100%, felt adequately trained and confident about educating the patients and caregivers before roll out of App and had no concerns related to data and privacy; 70%, felt that appropriate time was spent on pursuing reason for data not being logged; 60% each, had issues with availability of adequate technical support and connectivity. Conclusion: The Patient Buddy App randomized multicenter trial till date shows an overall favorable rating regarding training procedures/education, privacy concerns, and ease of message follow-up, from providers. However, it is important to gauge and address subjective and objective burdens of monitoring human resources in current and future HIT studies to avoid burnout and to ensure successful study completion.