Citations

Abstract Purpose To evaluate the test–retest repeatability of a rapid, free‐breathing two‐dimensional (2D) MR elastography (MRE) technique and to assess the reliability of the liver‐stiffness measurements compared with conventional breath‐hold MREs. Methods Fifteen and 115 participants were enrolled in the technical repeatability and measurement equivalence assessment cohorts, respectively. All participants underwent rapid free‐breathing and conventional breath‐hold 2D MRE (twice in repeatability cohort) on 1.5T scanners. Both methods have four phase offsets over one harmonic motion cycle at 60 Hz; one and 10 cycles were collected and processed in breath‐hold and free‐breathing MREs, respectively. The liver stiffness measurements of free‐breathing (LS F ) and breath‐hold MRE (LS B ) were calculated from manually drawn regions of interest. The repeatability coefficients and Spearman correlation were used to assess technical repeatability and measurement agreement between LS F and LS B . Univariable and multivariable linear regressions were performed to identify potential influencing factors, including age, sex, body mass index, and fat fraction, in the measurement agreement between LS B and LS F . Results The repeatability coefficient of free‐breathing 2D MRE is comparable to breath‐hold MRE (LS F : 20.8%, LS B : 20.4%). LS F showed a strong agreement and significant correlation with LS B (LS F = 1.01 × LS B , ρ = 0.94, p < 0.001). The measurement agreement between LS F and LS B was only significantly affected by sex ( p = 0.047) after adjusting for confounding factors of age, body mass index, and fat fraction. Conclusions The nongated, free‐breathing, multislice 2D MRE technique can provide reliable liver stiffness measurements compared with conventional breath‐hold 2D MRE. It could provide a comfortable alternative method with reliable liver stiffness measurements for patients who have difficulty in suspending respiration.

Background and Aims: Clinical hepatology research often faces limited data availability, underrepresentation of minority groups, and complex data-sharing regulations. Synthetic data—artificially generated patient records designed to mirror real-world distributions—offers a potential solution. We hypothesized that diffusion models, a state-of-the-art generative technique, could produce synthetic liver transplant waitlist data from the United Network for Organ Sharing database that maintains statistical fidelity, replicates clinical correlations and survival patterns, and ensures robust privacy protection. Approach and Results: Diffusion models were used to generate synthetic patient cohorts mirroring the United Network for Organ Sharing liver transplant waitlist database between the years 2019 and 2023. Statistical fidelity was assessed using maximum mean discrepancy (MMD) and Wasserstein distance, correlation analysis, and variable-level metrics. Clinical utility was evaluated by comparing transplant-free survival via Kaplan–Meier curves and the MELD score performance. Privacy was quantified using the Distance to Closest Record (DCR) and attribute disclosure risk assessments. The synthetic dataset was nearly indistinguishable from the original dataset (MMD=0.002, standardized Wasserstein distance <1.0), preserving clinically relevant correlations and survival patterns as evidenced by similar median survival times (110 vs. 101 days) and 5-year survival rates (22.2% vs. 22.8%). MELD-based 90-day mortality prediction was maintained (original AUC=0.839 vs. synthetic AUC=0.844). Privacy metrics indicated no identifiable patient matches, and mean DCR values ensured that synthetic individuals were not direct replicas of real patients. Conclusion: Artificial intelligence–generated synthetic data derived from diffusion models can faithfully replicate complex hepatology datasets, maintain key clinical signals, and ensure strong privacy safeguards. This approach can help address data scarcity, enhance model generalizability, foster multi-institutional collaboration, and accelerate progress in hepatology research.

ABSTRACTSeveral dynamic models predict mortality and corticosteroid response in alcohol‐associated hepatitis (AH), yet no consensus exists on the most effective model. This study aimed to assess predictive models for corticosteroid response and short‐term mortality in severe AH within a global cohort. We conducted a multi‐national study of patients with severe AH treated with corticosteroids for at least 7 days, enrolled between 2009 and 2019. Dynamic models—Lille‐4, Lille‐7, trajectory of serum bilirubin (TSB), and neutrophil‐to‐lymphocyte ratio (NLR)—were used to estimate 30‐ and 90‐day mortality. Lille‐7 demonstrated the highest accuracy for both 30‐ and 90‐day mortality.

Background and Aims: Severe alcohol-associated hepatitis (AH) is rising in incidence with a high mortality burden. While corticosteroids are recommended for eligible patients with severe AH, no guidance exists for the timing of steroid initiation, tapering regimens, and surveillance of adverse events. We aim to systematically review these variables and provide evidence-based recommendations for the inpatient and outpatient management of severe AH. Approach and Results: We performed a literature search from inception to May 30, 2024, to include clinical trials published in full form and assessed the quality of evidence using the Cochrane Risk of Bias tool. Data were collected on the timing of initiation, rate, and complications following steroid therapy, and taper regimens in the setting of severe AH. Of 28 studies that fulfilled our inclusion criteria, the median time from admission to steroid initiation was 6.5 days. The most common steroid dosing regimen was prednisolone 40 mg daily for 28 days. Twenty-five studies containing 3196 subjects reported adverse events, with exactly 50% in the steroid arm and the other half in the comparison arm. Infections, gastrointestinal bleeds, and renal impairment were the most frequently reported adverse events. Most infections occurred within the first month of the study. A 2-week steroid taper was the most frequently reported regimen. Conclusions: We recommend taking up to a week to systematically and thoroughly evaluate patients before initiating steroids, and vigilant monitoring in the first month of treatment. We also recommend the lowest possible steroid exposure with a 2-week steroid taper and close outpatient follow-up.

BET bromodomain inhibitors demonstrate significant promise as anti-inflammatory agents targeting a variety of inflammatory disorders. However, clinical data has demonstrated that the administration of non-selective BET bromodomain inhibitors has led to significant dose-limiting toxicity in clinical settings. More selective inhibitors of the second BET bromodomains, referred to as pan-D2 inhibitors, are better tolerated, however their efficacy varies significantly depending on disease indication. Here, we use three orally bioavailable inhibitors, 1–3, that are either selective for the first N-terminal bromodomain of BRD4 (BRD4-D1 selective), or pan-D1 biased, for assessing their cellular and in vivo efficacy and safety profile in two models of inflammatory liver disease. We compare their effects to known pan-D2 and pan-BET inhibitors. Our results show that pan-D1 biased inhibitor, 3, is as efficacious as the pan-BET inhibitor I-BET151 in reducing inflammation from LPS-induced and drug-induced toxicity, whereas pan-D2 inhibitors are less effective. BRD4-D1 selective inhibitors, 1 and 2, are also efficacious; however, new inhibitors with improved cellular target engagement will be necessary to more thoroughly assess their effects. Finally, BRD4-D1 selective inhibitors are better tolerated in a preclinical model of thrombocytopenia than pan-D1 biased inhibitors, while gastrointestinal (GI) toxicity may be a BRD4-driven effect. These results highlight the importance of assessing specific BET protein and bromodomain functions due to their varying roles in diverse disease models.

Abstract Background Outcomes in alcohol‐associated liver disease (ALD) are influenced by several race and ethnic factors, yet its natural history across the continuum of patients in different stages of the disease is unknown. Methods We conducted a retrospective cohort study of U.S. adults from 2011 to 2018, using three nationally representative databases to examine potential disparities in relevant outcomes among racial and ethnic groups. Our analysis included logistic and linear regressions, along with competing risk analysis. Results Black individuals had the highest daily alcohol consumption (12.6 g/day) while Hispanic participants had the largest prevalence of heavy episodic drinking (33.5%). In a multivariable‐adjusted model, Hispanic and Asian participants were independently associated with a higher ALD prevalence compared to Non‐Hispanic White interviewees (OR: 1.4, 95% CI: 1.1–1.8 and OR: 1.5 95% CI:1.1–2.0, respectively), while Blacks participants had a lower ALD prevalence (OR: .7 95% CI: .6–.9), and a lower risk of mortality during hospitalization due to ALD (OR: .83 95% CI: .73–.94). Finally, a multivariate competing‐risk analysis showed that Hispanic ethnicity had a decreased probability of liver transplantation if waitlisted for ALD (SHR: .7, 95% CI: .6–.8) along with female Asian population (HR: .40, 95% CI: .26–.62). Conclusions After accounting for key social and biological health determinants, the Hispanic population showed an increased risk of ALD prevalence, even with lower alcohol consumption. Additionally, Hispanic and Asian female patients had reduced access to liver transplantation compared to other enlisted patients.

Background:Alcohol-associated hepatitis (AH) is associated with significant mortality. Model for End-Stage Liver Disease (MELD) score is used to predict short-term mortality and aid in treatment decisions. MELD is frequently updated in the course of AH. However, once the most updated MELD is known, it is uncertain if previous ones still have prognostic value, which might be relevant for transplant allocation and trial design. We aimed to investigate the predictive performance of updated MELDs in a prospectively collected cohort of patients with AH by the InTeam consortium.Methods:Three hundred seven patients (with 859 MELD values within 60 d of admission) fulfilled the inclusion criteria. The main endpoint was time to death or transplant up to 90 days. We used a joint model approach to assess the predictive value of updated MELDs.Results:Updated MELD measurements had a strong prognostic value for death/transplant (HR: 1.20, 95% CI: 1.14–1.27) (p< 0.0001). Previous MELD values did not add predictive value to the most current MELD. We also showed that MELD at day 28 (MELD28) had a significant predictive value for subsequent mortality/transplant in a landmark analysis (HR: 1.18, 95% CI: 1.12–1.23). We show that the use of an ordinal scale including death, transplant, and MELD28 as a trial outcome could substantially reduce the sample size required to demonstrate short-term benefit of an intervention.Conclusion:We show that updated MELDs during the trajectory of AH predict subsequent mortality or the need for transplant. MELD28 inclusion in an ordinal outcome (together with death or transplant) could increase the efficiency of randomized controlled trials.