A potential interaction between citrate and lactate metabolism may exist in critically ill patients receiving continuous renal replacement therapy (CRRT) with regional citrate anticoagulation (RCA). Although prior studies have investigated the relationships of initial lactate levels and lactate kinetics with citrate accumulation and clinical outcomes, the prognostic significance of lactate kinetics during RCA-CRRT remains inadequately defined. Critically ill patients undergoing CRRT (CRRT cohort) and those receiving RCA (Lactate Kinetics cohort) were identified from the MIMIC-Ⅳ (v3.1) database, as well as from the MIMIC-Ⅲ (v1.4) database (Lactate Kinetics Validation cohort). Propensity score matching, Kaplan-Meier survival curves, and Cox regression models were employed to assess the association between RCA use and 7-day and 28-day all-cause mortality. Latent growth mixture models, receiver operating characteristic curves, and restricted cubic splines were applied to identify lactate kinetics during RCA-CRRT. The association between lactate kinetics and mortality was evaluated using Kaplan-Meier survival curves and Cox regression models. LASSO-logistic regression analysis was applied to identify clinical characteristics associated with lactate kinetics. A total of 1,952, 1,064, and 209 patients were included in the CRRT cohort, Lactate Kinetics cohort, and Lactate Kinetics Validation cohort, respectively. The adjusted 7-day all-cause mortality risk was lower in patients who received RCA compared to those who did not, whereas no significant association was observed for 28-day mortality risk. Four distinct lactate trajectories during RCA-CRRT were identified: Class 1, low lactate with a stable trend; Class 2, high lactate with an improving trend; Classes 3-4, moderate lactate with gradually or rapidly worsening trends. Patients in Classes 3-4 exhibited significantly higher 7-day and 28-day mortality risks compared with Class 1, whereas Classes 2 showed no significant difference. SOFA score, respiratory failure, baseline lactate level, and mean daily citrate consumption were associated with an increased risk of lactate worsening, whereas pH and total carbon dioxide levels were associated with a decreased risk of lactate worsening. Patients with an increase in lactate greater than 1 mmol/L had significantly higher 7-day and 28-day mortality risks compared to those with an increase of less than or equal to 1 mmol/L. Although RCA may not increase overall mortality risk in critically ill patients, lactate worsening during RCA-CRRT has been observed and is strongly associated with adverse outcomes in certain patient populations. Timely clinical evaluation and individualized treatment adjustments are appropriate for these patients.

Liver failure remains a life-threatening syndrome where the available therapeutic options are extremely limited beyond transplantation. This study addresses critical cell source and mechanistic challenges by developing a novel bioartificial liver (BAL) system. We utilized CRISPR/Cas9 technology to knockout the GGTA1 gene in primary porcine hepatocytes to reduce immunogenicity. These hepatocytes were co-cultured with R-spondin1-overexpressing human umbilical vein endothelial cells (R-HUVECs) to form functionally stable liver organoids. In ex vivo study using plasma from patients with acute-on-chronic liver failure (ACLF), the BAL system demonstrated superior detoxification, significantly reducing ammonia and bilirubin levels compared to traditional non-bioartificial liver (NAL) support. Multi-omics analyses revealed that BAL treatment actively restored metabolic homeostasis by promoting branched-chain amino acid (BCAA) metabolism and upregulating lysophosphatidylcholine (LPC) species associated with membrane repair and anti-inflammatory signaling. Significantly, this research demonstrates that unlike the passive physical filtration of NAL, BAL serves as an active biological regulator of systemic metabolism. These findings provide a robust theoretical and practical foundation for the clinical translation of BAL technology, offering a promising strategy to improve outcomes for liver failure patients by modulating systemic metabolism.

Glutathione (GSH) is a key determinant of redox homeostasis and cellular resilience, and its biosynthetic enzyme GshA has been implicated in oxidative stress resistance and virulence in Pseudomonas aeruginosa. However, the mechanistic links between gshA-mediated redox control, nitrogen metabolism, and oxidative-stress-associated pathogenic phenotypes remain unclear. Here, we characterized the enzymatic architecture and metabolic role of GshA. Structure-guided mutagenesis identified a conserved catalytic core required for enzymatic activity. Beyond its canonical antioxidant role, our data support a role for GshA in redox-associated regulation of denitrification-linked nitrogen metabolism and pathogenic phenotypes. Proteomic profiling and RT-qPCR validation showed that gshA deletion was associated with increased abundance and transcriptional induction of nitrate-respiration-associated factors under oxidative stress, whereas nitrate(NO3⁻) and nitrite(NO₂⁻) turnover assays revealed impaired downstream nitrite processing. Succinate supplementation failed to rescue nitrite clearance in ΔgshA, arguing against simple electron donor limitation. In addition, GshA contributed to the H2O2-associated increase in epithelial invasion and in vivo virulence phenotypes. Collectively, these findings support a model in which GshA links glutathione-dependent redox buffering to nitrogen metabolism and virulence-associated phenotypes.

To identify novel antibacterial agents targeting Staphylococcus aureus ClpP (SaClpP), a target-based screening model was established using the fluorogenic substrate Suc-LY-AMC, leading to the identification of a potent hit, Z1, from a proprietary compound library. SDS-PAGE-based protein degradation assays confirmed that Z1 significantly enhances the proteolytic activity of SaClpP. Quantitative analysis demonstrated that the activating potency EC50 of Z1 toward SaClpP is markedly superior to that of the clinical candidate ONC212. Mechanistic investigations revealed that 10 μM Z1 significantly increased the melting temperature (ΔTm) of SaClpP by 18.5 °C, outperforming ONC212 (ΔTm = 15 °C). The intracellular target engagement was further corroborated by the cellular thermal shift assay (CETSA). Isothermal titration calorimetry (ITC) determined a dissociation constant (Kd) of 2.95 μM, indicating an exothermic binding process (ΔH = -14.1 kcal/mol). The binding affinity and interaction mode were further characterized using biolayer interferometry (BLI), three-dimensional fluorescence spectroscopy, and 50 ns molecular dynamics simulations, the latter of which showed a stable root-mean-square deviation (RMSD) within 0.3 nm. Biologically, Z1 exhibited potent antibacterial activity against Methicillin-resistant Staphylococcus aureus (MRSA) ATCC 33591 (MIC = 0.5 μg/mL), outperforming ONC212 (MIC = 1 μg/mL). Notably, Z1 demonstrated a low frequency of resistance (FOR) at the 10-8 level and exhibited significantly lower cytotoxicity against HepG2 cells compared to ONC212. Pharmacokinetic (PK) evaluation in mice revealed a favorable oral bioavailability (F) of 33.50% and an oral half-life (t1/2) of 1.92 h. In a murine skin infection model, Z1 significantly reduced bacterial burden, diminished the infection area, and improved histopathological outcomes. These findings highlight Z1 as a promising ClpP agonist and support the strategy of targeting ClpP for the development of next-generation antibiotics.

Background:Platelet reduction is associated with an increased risk of bleeding in patients with chronic liver disease. However, the association between platelet levels and bleeding events in patients with liver failure treated with an artificial liver support system (ALSS) remains unclear. Methods:This retrospective study included patients with acute-on-chronic liver failure (ACLF) who received ALSS treatment. Logistic and linear regression analyses were employed to assess the association between platelet levels and bleeding events during hospitalization and the relationship between sessions of ALSS treatment and platelet reduction rates. Results:We included 262 patients, of whom 56 (21.4%) experienced bleeding events during hospitalization. Baseline platelet levels in patients with bleeding events were significantly lower than those in patients without bleeding events (59.0 (39.0 ~ 89.3) × 109/L vs. 88.5 (57.0 ~ 121.0) × 109/L; p < 0.001). Baseline platelet levels were negatively associated with bleeding events (adjusted OR, 0.986; 95% CI, 0.976-0.996; p = 0.006), whereas platelet reduction rates and final platelet levels were not significantly associated with bleeding events (all p > 0.05). Compared to patients with baseline platelet grade 0, the risk of bleeding was significantly higher compared to those with baseline platelet grade 1 (adjusted OR: 3.21, 95% CI: 1.20 ~ 8.59, p = 0.002) and grade 2 (adjusted OR: 7.20, 95% CI: 2.28 ~ 21.43, p = 0.001), as well as in the combined group of grades 2 and 3 (adjusted OR: 8.43, 95% CI: 2.96 ~ 23.99, p < 0.001). The number of ALSS treatment sessions was not significantly associated with platelet reduction rates (p > 0.05). Conclusion:Patients with ACLF who underwent ALSS treatment with lower baseline platelet levels were at an increased risk of bleeding during hospitalization, whereas the platelet reduction rate was not independently associated with bleeding risk. These findings underscore the importance of baseline platelet count rather than platelet reduction for early risk stratification in patients with ACLF.

This study investigates the impact of the indirect bilirubin percentage-to-albumin ratio (iBAR) on the prognosis of patients with acute-on-chronic liver failure (ACLF), as defined by the Chinese Group on the Study of Severe Hepatitis B-ACLF (COSSH ACLF) criteria, who were treated with an artificial liver support system (ALSS). In a retrospective cohort of 258 eligible patients, restricted cubic splines, linear regression, and Cox proportional hazards models were used to analyse the association of iBAR with disease severity and 28-day and 90-day outcomes. The 28-day transplant-free and overall survival rates were 76.4% and 82.2%, respectively, while the 90-day rates were 58.5% and 66.3%. The iBAR was significantly lower in 28-day transplant-free survivors compared to those who underwent transplantation or died (6.47 ± 2.95 vs. 8.87 ± 2.49, p < 0.001), with similar findings for 90-day outcomes (6.09 ± 2.75 vs. 8.38 ± 2.88, p < 0.001). A positive association was observed between iBAR and COSSH ACLF score (adjusted β = 0.14, 95% CI: 0.11-0.18, p < 0.001). Furthermore, iBAR was independently associated with higher risks of 28-day transplant-free mortality (adjusted HR = 1.21, 95% CI: 1.10-1.34, p < 0.001), 28-day overall mortality (adjusted HR = 1.26, 95% CI: 1.12-1.42, p < 0.001), 90-day transplant-free mortality (adjusted HR = 1.13, 95% CI: 1.06-1.22, p < 0.001), and 90-day overall mortality (adjusted HR = 1.14, 95% CI: 1.05-1.23, p = 0.002). Patients with an iBAR > 6.13 had significantly poorer 28-day and 90-day prognoses compared to those with iBAR ≤ 6.13 (all adjusted HR > 1, p < 0.05). In conclusion, iBAR is positively associated with disease severity and adverse prognosis in COSSH ACLF patients receiving ALSS therapy, suggesting its potential as a prognostic biomarker that warrants validation in future prospective, multicenter studies.

BACKGROUND AND AIMS:Accurate prediction of hepatitis B surface antigen (HBsAg) seroclearance remains essential for optimising pegylated interferon-α (Peg-IFN-α) therapy in chronic hepatitis B (CHB). While HBsAg is a conventional predictor, HBV RNA and hepatitis B core-related antigen (HBcrAg) have emerged as potential biomarkers. However, whether combining these markers can improve the predictive value of HBsAg seroclearance remains unclear. METHODS:In this study, CHB patients with HBV DNA < 100 IU/mL, HBeAg-negative and HBsAg level ≤ 1500 IU/mL after receiving ≥ 1 year of nucleos(t)ide analogues (NAs) therapy were enrolled and received 48 weeks of Peg-IFN-α add-on therapy. Baseline clinical, biochemical and virological parameters (HBsAg, HBV RNA and HBcrAg) were evaluated for their predictive value of HBsAg seroclearance at week 48. RESULTS:Among 150 patients, 51 (34.0%) achieved HBsAg seroclearance after 48 weeks of Peg-IFN-α add-on therapy. Baseline HBsAg (OR 4.27, p < 0.001), HBV RNA (OR 6.78, p = 0.004) and HBcrAg (OR 2.35, p = 0.044) were independent predictors of HBsAg seroclearance. Combining HBsAg, HBV RNA and HBcrAg improved predictive accuracy over HBsAg alone (AUROC 0.845 vs. 0.785). Patients meeting the criteria of HBsAg < 200 IU/mL, HBV RNA < 130 copies/mL and HBcrAg < 3.5 log10 U/mL had a substantially higher HBsAg seroclearance rate (81.5%) compared with those meeting only one or two criteria (28.1%) or none (7.4%). CONCLUSIONS:Compared to baseline HBsAg alone, the combination of HBsAg, HBV RNA and HBcrAg can better identify NAs-suppressed CHB patients who are likely to achieve HBsAg seroclearance with Peg-IFN-α add-on therapy.

INTRODUCTION:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease, and liver biopsy remains the gold standard for diagnosis. However, a subset of patients diagnosed with MASLD by imaging paradoxically exhibit steatosis grade S0 on liver biopsy, posing a diagnostic challenge. This study investigated the outcomes and causes of steatosis 0. METHODS:Steatosis 0 was defined as imaging-detected MASLD with a biopsy-defined steatosis grade S0. We used global cohorts to evaluate outcomes, histologic progression by paired biopsies, and possible causes. The cause analysis included MRI-proton density fat fraction (MRI-PDFF) for fat distribution, pathologist consistency testing, and comparison of serial biopsy sections. RESULTS:In a follow-up cohort of 3,273 biopsy individuals from 16 centers, 123 (3.8%) exhibited steatosis 0. Of these, 29.3% of them had advanced fibrosis (burnt-out MASLD) and demonstrated a risk of liver-related events, whereas those without advanced fibrosis had no such events. In the paired-biopsy cohort of 1,865 patients, 74 (4.0%) individuals initially showed steatosis grade S0; among them, 93.2% retained no or mild steatosis on follow-up biopsy. MRI-PDFF assessments in 42 MASLD patients revealed heterogeneous hepatic fat distribution, with some segments showing steatosis grade S0 despite elevated average liver fat. Interpathologist variability and discrepancies across consecutive biopsy sections contributed to misclassification of steatosis grade. DISCUSSION:Steatosis 0 represents a potential diagnostic gray zone in MASLD. It may be caused by burnt-out MASLD, uneven liver fat distribution, or variability in pathological assessment. Understanding the causes and implications of steatosis 0 is critical for diagnosis and management.

The impact of neutrophil percentage-to-albumin ratio (NPAR) on the outcome of acute-on-chronic liver failure (ACLF) is scant. A retrospective cohort study was conducted in patients with ACLF treated with artificial liver support system (ALSS). The ACLF was diagnosed according to the Chinese Group on the Study of Severe Hepatitis B-ACLF (COSSH ACLF) criteria. Disease severity was rated according to the COSSH ACLF score. Restricted cubic splines, linear or Cox regression models were used to investigate the relationships of baseline NPAR with disease severity and 90-day prognosis. The 90-day transplant-free and overall survival rates of 258 eligible patients were 58.5% and 66.3%, respectively. The NPAR in transplant-free survivors was lower than that in transplant or death patients (22.8 ± 4.4 vs. 25.3 ± 3.7, P < 0.001). NPAR was positively associated with COSSH ACLF score (adjusted β (95% CI) > 0, P < 0.001), transplant-free survival (adjusted HR (95% CI) for transplant or death: 1.07 (1.02–1.13), P = 0.007), and overall survival (adjusted HR (95% CI) for death: 1.09 (1.03–1.15), P = 0.003). Patients with NPAR ≥ 22.4 had poor 90-day prognosis compared to the rest (all adjusted HR (95% CI) > 1, P < 0.05). NPAR was positively associated with disease severity and poor short-term prognosis in patients with COSSH ACLF who underwent ALSS treatment. Thus, it could be used as a prognostic biomarker for COSSH ACLF.

BACKGROUND & AIMS:Fibrosis-4 Index (FIB-4) is a noninvasive tool for assessing liver fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD). However, its role of dynamic FIB-4 for assessing fibrosis progression and predicting clinical outcomes remains unclear. The aim of this study was to examine the association between changes in FIB-4 and changes in liver stiffness, fibrosis progression, and outcomes in MASLD. METHODS:Three cohorts were analyzed: VCTE-Prognosis cohort (n = 10,203) for stiffness progression, Paired Liver Biopsy cohort (n = 1,145) for fibrosis progression, and Wenzhou Real-World (WRW) cohort (n = 41,105) for clinical outcomes. Stiffness progression was defined as an increase in liver stiffness measurement, and fibrosis progression by a 1-stage increase. Outcomes included all-cause mortality, cardiovascular events, and liver-related events (LREs). FIB-4 was dichotomized into low (<1.3) and high (≥1.3). Increases were defined as ≥20% rise and to ≥1.3 in the low FIB-4 group, and ≥20% rise in the high FIB-4 group. RESULTS:In the VCTE-Prognosis cohort, stiffness progression was more likely with increasing vs stable FIB-4 (adjusted odds ratio [OR], 2.36; P < .001) in those with low baseline FIB-4. In the high FIB-4 group, stiffness progression rates increased from stable to increasing FIB-4 (adjusted OR, 3.42; P < .001). In the Paired Liver Biopsy cohort, fibrosis progression was more frequent with increasing FIB-4 (adjusted OR, 2.20; P = .004 in low FIB-4; adjusted OR, 3.68; P < .001 in high FIB-4). In the WRW cohort, an increase in dynamic FIB-4 was linked to higher risks for all-cause mortality, cardiovascular events, and LREs (all P < .001). CONCLUSIONS:Dynamic FIB-4 monitoring tracks fibrosis and stiffness progression and predicts clinical outcomes in MASLD.

There’s a scarcity of drugs effective against nonalcoholic steatohepatitis (NASH). Exosomes from Human umbilical cord mesenchymal stem cells (huc-MSCs) show potential in managing glycolipid metabolism and the immune response. Therefore, further investigations are required to explore their application in NASH and the underlying mechanisms. C57BL/6J mice were fed with a western diet for 12 weeks to induce NASH, and huc-MSCs exosomes (MSCs-exo) were administered during the feeding period. The effect of MSCs-exo was evaluated by monitoring changes in body weight, fat distribution, blood glucose, and insulin levels, and analyzing pathological alterations in liver tissue. Mechanism investigations were carried out using flow cytometry, immunofluorescence staining, and other experimental techniques. MSCs-exo could reduce liver fat, inflammation, fibrosis, and improved metabolism to alleviate the progression of NASH. Besides, MSCs-exo could decrease macrophage accumulation in the liver, encouraging M2 over M1 macrophage polarization. Furthermore, our study found that MSCs-exo had a high expression of miR-24-3p, which may regulate macrophage polarization by targeting the interferon-stimulated genes (STING) gene in macrophages, with its overexpression amplifying MSCs-exo’s NASH benefits. These findings suggest that the therapeutic effect of MSCs-exo on NASH may be attributed to the regulation of macrophage M2 polarization through miR-24-3p targeting STING. This provides a scientific basis for future clinical application.

To develop new tools integrating host immune response and viral activity to predict Peg-IFNα therapy efficiency in nucleos(t)ide analogs (NUCs)-treated chronic hepatitis B (CHB) patients. This post-hoc study analyzed data from 758 NUCs-experienced, HBeAg-negative CHB patients with baseline HBsAg < 1500 IU/mL and undetectable serum HBV DNA who completed 48 weeks of Peg-IFNα add-on therapy in a prospective study. Clinical and biochemical data were collected every 12 weeks and evaluated for their predictive value of HBsAg seroclearance and seroconversion. Age, qHBsAg, and ALT levels at Week 12 were associated with both HBsAg seroclearance and seroconversion. The ASAP-12 score (ALT/[qHBsAg × Age] at Week 12), demonstrated strong discrimination for both endpoints (AUROCs: 0.802 [cut-off 0.07] and 0.787 [cut-off 0.12], respectively; p < 0.05). Patients with scores above the respective cut-offs had significantly higher cumulative probabilities of HBsAg seroclearance (63.4% vs. 17.8%, Log-rank test p < 0.001) and seroconversion (47.3% vs. 11.0%, Log-rank test p < 0.001). Higher ASAP-12 scores (β = 0.206, p = 0.006) independently correlated with elevated Week 48 HBsAb levels. The ASAP-12 score may serve as a useful tool to predict both HBsAg seroclearance and seroconversion at Week 48 of Peg-IFNα add-on therapy in NUCs-experienced CHB patients, supporting individualized therapeutic decisions.

Patients with liver failure may be accompanied by cerebral edema and elevated intracranial pressure (ICP). The effect of plasma adsorption (PA) and low-volume plasma exchange (PE) on ICP were unclear. A prospective observational cohort study was conducted in patients with acute-on-chronic liver failure (ACLF) receiving PA followed immediately by low-volume PE. ICP was measured by transcranial doppler (TCD) and flash visual evoked potential (FVEP). ICP, mean arterial pressure (MAP) and cerebral perfusion pressure (CPP) were measured repeatedly, and their differences were evaluated by generalized estimation equation. A total of 31 patients with ACLF were enrolled. The median MELD 3.0 was 27.8 (25.7 29.4). Compared with ICP measured by FVEP (ICPFVEP) before PA, the mean (95

Objective: The artificial liver support system (ALSS) has been recruited as an available method for patients with acute-on-chronic liver failure (ACLF), but its impact on the outcome of ACLF remains controversial. This study aimed to investigate the association between ALSS treatment and short-term prognosis of hepatitis B-related ACLF (HBV-ACLF). Methods: This was a retrospective observational cohort study, and data were obtained from the Center of Infectious Diseases, West China Hospital of Sichuan University, between Mar 2015 and December 2021. The primary outcome was 28-day transplant-free mortality and the secondary outcomes were 60- and 90-day transplant-free mortality. Patients were divided into standard medical therapy (SMT) and ALSS groups. Kaplan-Meier survival analysis curves show the 28-day, 60-day and 90-day transplant-free mortality. Based on the feature selection result of univariate logistic, univariate Cox and Boruta algorithm, the univariate and multivariate logistic and COX regression models were used to investigate the association of ALSS with 28-day, 60-day and 90-day outcomes in patients with HBV-ACLF. Subgroup analyses were conducted to test the robustness of the results. Results: A total of 589 hBV-ACLF patients were enrolled in this study (median age, 48.00 years [IQR,44.00-55.00 years]; 70 [11.9%] female). The 28-day, 60-day and 90-day transplant-free mortality rates were 25.6%, 35.8% and 38.9%, respectively. In the univariate and Kaplan-Meier survival analysis, ALSS could significantly reduce 28-day, 60-day and 90-day transplant-free mortality compared to SMT. Furthermore, an in-depth analysis of our study revealed that the therapeutic benefits of the ALSS were observed exclusively within the end-stage (PT-INR >= 2.5) subgroup of HBV-ACLF patients. Conclusion: Compared to SMT, ALSS demonstrated efficacy primarily in enhancing the short- term prognosis of end-stage HBVACLF patients, rather than across the entire spectrum of HBV-ACLF patients.

Although current combination regimens of antibiotics have significantly improved tuberculosis (TB) cure rates, substantial challenges persist in the global effort to end TB. These include poor patient compliance, the emergence of drug-resistant strains due to prolonged treatments, and the persistence of latent TB infections. Host-directed therapies (HDTs) have emerged as a promising complementary strategy, leveraging the modulation of host immune responses to combat Mycobacterium tuberculosis (Mtb). Unlike conventional antibiotics, HDTs can enhance therapeutic outcomes by boosting host defense mechanisms, reducing treatment duration and dosage, and minimizing the risk of resistance development. Notably, several HDTs have shown significant efficacy against multidrug-resistant (MDR) Mtb strains, while also mitigating excessive inflammation and lowering relapse rates-achievements that remain elusive with antibiotic regimens alone. This review provides a comprehensive overview of recent advancements in HDTs, focusing on druggable targets and the mechanisms by which these therapies restore or enhance immune functions disrupted by Mtb. By integrating insights into macrophage polarization, metabolic modulation, autophagy promotion, and cell death regulation, HDTs offer innovative and multifaceted approaches to TB treatment. Furthermore, the potential for HDTs to synergize with existing antibiotics underscores their relevance in overcoming current therapeutic limitations. This synthesis aims to inspire further research and development, with the ultimate goal of advancing HDTs as a transformative solution for TB management.

BACKGROUND:Non-invasive assessment of improvement in fibrotic metabolic dysfunction-associated steatohepatitis (MASH) is an important clinical problem. We aimed to develop and validate the fibrotic MASH resolutionVCTE index, a non-invasive tool for identifying fibrotic MASH resolution and predicting liver-related events (LREs). METHODS:We collected data from 2,017 individuals who had two liver biopsies, separated in time, across 40 centers in the first dataset. This dataset included two independent cohorts, which were used to develop and externally validate the tool (including the baseline and change in acFibroMASH index plus change in serum alanine aminotransferase levels). The second independent dataset, comprising 17,949 patients who underwent vibration-controlled transient elastography (VCTE) at 16 centers, was used to examine associations between the developed index and the risk of incident LREs. FINDINGS:After application of the inclusion and exclusion criteria, 252 and 8,752 patients were included in the first and second datasets, respectively. The fibrotic MASH resolutionVCTE index accurately identified fibrotic MASH resolution with an area under the receiver operating curve (AUROC) of 0.82 (95% CI 0.74-0.90) in the derivation cohort and 0.80 (95% CI 0.72-0.88) in the validation cohort. Patients with a fibrotic MASH resolutionVCTE index >0.61 had a substantially lower risk of incident LREs than those with an index <0.24 (adjusted-hazard ratio 0.043). The index achieved AUROCs of 0.86 and 0.87, respectively, for predicting the 5- and 10-year probability of not developing LREs. CONCLUSIONS:This global multicenter study suggests that the fibrotic MASH resolutionVCTE index may offer a non-invasive approach to estimate fibrotic MASH resolution and stratify long-term risk of LREs. FUNDING:National Natural Science Foundation.

The impact of lactate-to-albumin ratio (LAR) on mortality of critically ill cirrhotic patients with sepsis is scant. Critically ill cirrhotic patients with sepsis were obtained from the MIMIC-IV database (v3.0). Cox regression models alone and in combination with restricted cubic splines, generalized additive models and smoothed curve fitting were used to investigate the relationship between LAR and all-cause mortality. A total of 1864 patients were included. The 30-day, 90-day, and 180-day all-cause mortality rates were 38.0