BACKGROUND:The impact of early administration of active anti-enterococcal empirical therapy (EET) on outcomes of patients with enterococcal bloodstream infections (EBSIs) is unclear. We compared the outcome of patients with EBSIs receiving or not empirical therapy targeting Enterococcus spp. METHODS:A retrospective multicenter study enrolling all hospitalized patients with monomicrobial EBSIs during 2011-2019. The exposure variable was considered receiving EET defined as administration of antibiotic(s) active in vitro against Enterococcus spp isolated from index blood cultures (BCs) ≤48 hours from collection. The primary outcome was 14- and 30-day all-cause mortality from index BC. The impact of EET on mortality was assessed by Kaplan-Meier curves and multivariable Cox regression after adjustment with inverse probability treatment weighting (IPTW). Post hoc analysis explored the effect of EET given ≤24 hours from EBSI onset. RESULTS:Overall, 758 patients (male, 62%; median age, 71 years) had EBSIs and 342 received EET; 14- and 30-day mortality was 24% and 42%, respectively. After IPTW adjustment, a higher number of comorbidities and EBSIs without an identified source but not EET were independent predictors of 14- and 30-day mortality. No significant mortality risk reduction was associated with EET in the real or the IPTW-adjusted analysis. In the subgroup analysis, EET reduced 14-day mortality only in patients with vancomycin-resistant EBSIs. Even among 237 (31%) patients receiving EET <24 hours from EBSI onset, EET did not affect survival. CONCLUSIONS:Early administration of EET may not have a prognostic impact in patients with EBSIs. Delivering EET might affect short-term survival only in patients with vancomycin-resistant EBSIs.

Background Management of E faecium bloodstream infections (BSIs) remains debated, particularly the clinical impact of vancomycin resistance, the role of follow-up cultures, and optimal therapeutic regimens. This study aimed to reach expert consensus on these unresolved clinical domains and identify priorities for future research. Methods We first conducted a systematic review and meta-analysis in January 20, 204 focusing on four predefined areas: mortality in E faecium BSIs compared with other BSIs, mortality in vancomycin-resistant enterococci (VRE)-BSIs compared with vancomycin-susceptible enterococci-BSIs, management of catheter-related E faecium BSIs, and 4) optimal antibiotic therapy for VRE-BSIs. These results informed a three-round Delphi process involving a panel of experts. An iterative approach was adopted: 16 initial questions developed from the systematic review (6-point Likert scale) were refined across rounds based on expert feedback. Consensus was defined as at least 80% agreement or disagreement. Findings 13 statements were generated across three broader domains. Regarding clinical outcomes and diagnostics, experts agreed that mortality is heavily influenced by comorbidities; thus, therapeutic assessment should rely on clinical trends and inflammatory markers, with follow-up blood cultures used to confirm eradication. Catheter-related BSI should be managed with device removal and short-course (<7 days) antibiotics in selected uncomplicated cases. For therapeutic management, teicoplanin is preferred for vanB VRE-BSI. For vanA VRE-BSI, both linezolid and high-dose daptomycin (>9 mg/kg per day) are effective, reserving daptomycin-based combinations for challenging cases (deep-seated infections and/or high Minimum Inhibitory Concentrations). Finally, future trials evaluating the impact of antimicrobial therapy should use Desirability-of-Outcome-Ranking analysis; the in-vitro potential of oritavancin justifies targeted randomized trials to define its clinical efficacy in VRE-BSI. Interpretation This paper delineates current evidence and expert consensus on management of E faecium BSI while identifying crucial knowledge gaps to guide future clinical research. Funding None.

BACKGROUND & AIMS:Resmetirom is the first Food and Drug Administration-approved drug for metabolic dysfunction-associated liver disease (MASLD) in F2 and F3 patients with steatohepatitis. Noninvasive criteria have been proposed for initiating treatment; however, these have not been validated in clinical practice. We validated the proposed criteria and established new guidelines for initiating resmetirom treatment in clinical practice. METHODS:This was a cross-sectional study of 1281 MASLD patients from the HEPAmet registry with biopsy, comorbidity assessment, analytical profile, and elastography. Identification of MASLD with F2 and F3 was the main endpoint. A comprehensive review of international guidelines and expert consensus up to November 2024, focusing on therapeutic indications, was conducted. RESULTS:A total of 38% (n = 486 of 1281) of patients were diagnosed with MASLD F2 and F3 based on biopsy. However, only 39% and 56% of them met treatment eligibility criteria according to the Expert Panel Criteria and the American Association for the Study of Liver Diseases Practice Guidance, respectively. They included 45% of patients with early-stage fibrosis. False positive and false negative rates ranged from 23% to 41% and 44% to 60%, respectively, with area under the receiver-operating characteristic curve values below 0.60.These findings were validated in an external cohort. A two-step strategy, first selecting patients with Fibrosis-4 (FIB-4) ≥1.30, or with diabetes and overweight if FIB-4 <1.30, followed by a liver stiffness between 8 and 25 kPa, demonstrated higher positive (55%) and negative predictive values (77%) and higher area under the receiver-operating characteristic curve (0.67).This approach successfully identified 74% of the target population. CONCLUSIONS:The diagnostic performance and reliability of the proposed noninvasive criteria for initiating resmetirom treatment were suboptimal. About the half of patients with indication would not receive treatment under these criteria. A new strategy, using FIB-4, the presence of diabetes and overweight, and liver stiffness improved the identification of MASLD patients with F2 and F3.

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide. Autoantibodies (Ab), such as antinuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA), are frequently detected in MASLD, but their role in disease progression remains controversial. This study aimed to evaluate the prevalence of positive Ab and the histological features of autoimmune hepatitis (AIH) in MASLD and their association with liver-related outcomes. Methods: We conducted a multicenter, retrospective, longitudinal study of patients with biopsy-proven MASLD from the HEPAmet Registry. Data on ANA (≥1/80), ASMA (≥1/40), and AIH histological features (portal inflammation, interface hepatitis, and plasma cell infiltration) were analyzed for their association with compensated advanced chronic liver disease (cACLD), liver decompensation, and death. Results: Of the 460 patients (49% women, median age 58 years, median BMI 33 kg/m2, and 45% with advanced fibrosis), 17% and 25% tested positive for ANA and ASMA, respectively. Histological features of AIH included interface hepatitis (19%), moderate/severe portal inflammation (12%), and plasma cell clusters (10%). Possible AIH based on histological criteria was present in 8% of patients. The presence of positive Ab was independently associated with cACLD development (odds ratio 2.890, p <0.030), liver decompensation (hazard ratio 3.969, p = 0.001), and death (hazard ratio 2.546, p = 0.036). In contrast, the presence of isolated histologic autoimmune features was not correlated with serological markers and did not affect the prognosis of MASLD. Conclusions: ANA and ASMA are commonly found in patients with MASLD and are associated with poorer liver-related outcomes and reduced survival, whereas isolated histological autoimmune features provide no additional prognostic value. Impact and implications: Metabolic dysfunction-associated steatotic liver disease (MASLD) can coexist with other liver diseases, including autoimmune hepatitis. The role of autoantibodies and histological autoimmune features in MASLD progression remains controversial. Understanding the relationship between autoimmune characteristics and disease progression in MASLD may help physicians identify high-risk populations, enhance risk stratification, and personalize disease treatment.

BACKGROUND AND AIMS:Infections by multidrug resistant (MDR) bacteria are increasing and vary across regions and hospitals. We aimed to assess the epidemiology, prevalence, and outcomes of bacterial infections in patients with decompensated cirrhosis, comparing liver transplant (LT) and non-LT centers in Catalonia. METHODS:This is a multicenter retrospective study including all patients with decompensated cirrhosis and bacterial infections hospitalised between January 2021 and 2022 from 5 university hospitals in the Barcelona metropolitan area. Two of them were LT centres. Clinical, laboratory, microbiological data, and in-hospital mortality were collected. RESULTS:A total of 576 infections were reported in 352 patients. LT centers had more health-related infections, recurrent infections, and septic shock than non-LT centers, while there were no differences in cirrhosis severity, acute-on-chronic liver failure (ACLF) or comorbidities. Although the most commonly isolated microorganisms and types of infection were similar in both centers, LT centers had higher rates of extended-spectrum beta-lactamase (12% vs. 6%), carbapenem (3% vs. 0%) and piperacillin-tazobactam resistant bacteria (14% vs. 7%). MDR rate was also higher in LT centers (38% vs. 25%, p = 0.02) and varied across hospitals (18%-42%, p < 0.05). Furthermore, in-hospital mortality was higher in LT centers (20% vs. 10%; p = 0.01). Independent predictors of in-hospital mortality were septic shock, ACLF, Child-Pugh, age, and leukocyte count. CONCLUSIONS:Our study showed differences in epidemiology, prevalence of MDR infections, and outcomes across university hospitals, particularly between centers with and without LT. Further studies are warranted to unveil the nuances of bacterial infections across different healthcare institutions in Europe and elsewhere.

Despite their high prevalence worldwide, steatotic liver diseases (SLDs) are largely excluded from most non-communicable disease (NCD) guidelines and strategies. We propose policies and strategies to achieve the United Nations Sustainable Development Goal of reducing NCD premature mortality by one-third by 2030. To assess this gap-the exclusion of SLDs from NCD policies-in urban areas, we reviewed Barcelona's strategies for NCD risks (e.g., alcohol, tobacco, healthy food access). We then explored applications of geo-spatial visualisation and whole-of-society approaches (e.g., citizen science engagement) aligned with the World Health Organization (WHO) Best Buys to provide recommendations to address NCDs, generally, and SLDs specifically.

INTRODUCTION:Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly gaining relevance both as a public health issue and a clinical challenge. The development of portal hypertension in MASLD challenges traditional paradigm that it arises only in the context of cirrhosis. AREAS COVERED:This review explores the understanding of portal hypertension in MASLD, addressing recent advances in pathophysiology, diagnosis, and potential therapeutic approaches. Particular attention is given to studies that highlight non-cirrhotic contributors to increased portal pressure. Pathogenic mechanisms, as well as advances in noninvasive diagnostic tools are discussed, focusing on their utility in identifying early hemodynamic changes and stratifying the risk of clinical complications. A comprehensive literature search was conducted using PubMed and major databases, including studies published up to April 2025. EXPERT OPINION:The future of MASLD management lies in early detection, improved noninvasive risk stratification, and personalized treatment strategies. Advances in technology and artificial intelligence will likely enhance diagnostic precision while ongoing research into molecular mechanisms and portal hypertension may enable earlier and effective therapeutic interventions.

This review explores the rationale and available evidence behind incretin-based therapies for metabolic dysfunction-associated steatotic disease (MASLD) and metabolic-associated steatohepatitis (MASH), focusing on glucagon-like peptide 1 (GLP-1) and glucagon (GCG) receptor dual agonists (GLP-1/GCG RA’s). MASLD is the most prevalent chronic liver disease globally, with its more severe form, MASH, emerging as the leading cause of liver transplantation and hepatocellular carcinoma. However, cardiovascular disease remains the primary cause of mortality in this population. While there is no approved treatment for MASLD in Europe yet, incretin-based therapies are rising as promising option acting at both cardiovascular and hepatic level. GLP-1/GCG RA’s have consistently shown a reduction in liver fat content independent of weight loss, positioning them as a promising treatment for MASLD and MASH. However, their approval will depend on histological and clinical outcomes, which rely on the results of ongoing Phase II and III trials.

Background & Aims: Expression of P21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD); however, the underlying mechanisms remain unknown. In the present study, we investigated the function of CDKN1A in SLD. Methods: CDKN1A expression levels were evaluated in different patient cohorts with SLD, fibrosis, and advanced chronic liver disease (ACLD). Cdkn1a-/- and Cdkn1a+/+ mice were fed with either a Western diet (WD), a Lieber-DeCarli (LdC) diet plus multiple EtOH (ethanol) binges, or a DuAL diet (metabolic dysfunction-associated fatty liver disease and alcohol-related liver). Primary hepatocytes were isolated and functional assays performed. Results: A significant increase in CDKN1A expression was observed in patients with steatohepatitis and fibrosis (with a positive correlation with both NAFLD Activity Score and fibrosis staging scores), cirrhosis and ACLD. Cdkn1a+/+ mice, fed a DuAL diet exhibited liver injury and cell death increased reactive oxygen species (ROS), and markers of senescence (γH2AX, β-GAL, Cdkn1a/p53) contributing to steatosis and inflammation. In contrast, Cdkn1a-/- mutant mice showed a significant decrease in senescence-associated markers as well as in markers of liver injury, hepatic steatosis and an increase in fatty acid oxidation and reduction in free fatty acid uptake as well as de novo lipogenesis. Mechanistically, activation of the AMPK-SIRT3 was observed in Cdkn1a-deleted animals. Conclusions: Cdkn1a deletion protected against preclinical SLD by promoting fatty acid oxidation and preventing free fatty acid uptake and de novo lipogenesis via the AMPK-SIRT3 axis. CDKN1A expression was found to be directly correlated with increased severity of NAFLD Activity Score and fibrosis in patients with SLD. CDKN1A could be a potential theragnostic target for the treatment of metabolic dysregulation in patients with SLD, with and without alcohol consumption. Impact and implications:: Expression of p21, encoded by the CDKN1A gene, has been associated with fibrosis progression in steatotic liver disease (SLD), but the molecular mechanisms remain elusive. Interestingly, in this study we found that Cdkn1a deletion protected against preclinical SLD by promoting fatty acid oxidation and preventing free fatty acid uptake and de novo lipogenesis, via the AMPK-SIRT3 axis. Translationally, Cdkn1a expression was found to be directly correlated with increased severity of NAFLD Activity Score (NAS) and fibrosis in SLD patients, and therefore, CDKN1A might be used potential theragnostic target for the treatment of metabolically induced SLD, with and without alcohol consumption.

BACKGROUND & AIMS:Predicting the risk of hepatic decompensation guides prognostication and therapy; however, it is challenging in patients with cirrhosis due to metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to improve a previously developed predictive tool of hepatic decompensation in MASLD cirrhosis (ABIDE) by incorporating liver stiffness measurement (LSM). METHODS:A multi-centre retrospective cohort of patients with compensated cirrhosis due to MASLD was identified, with decompensation incidence assessed using competing risk regression. The prognostic accuracy of a modified ABIDE model incorporating LSM (ABID-LSM) was assessed using time-dependent AUC (tAUC) and compared with other predictive models. RESULTS:Out of 388 patients, 273 (70.4%) had available LSM. Hepatic decompensation occurred in 54 (20%) patients during follow-up (median 31 months, range: 20-60). The predictive accuracy at 5 years of ABID-LSM (tAUC 0.80) was better than ABIDE (tAUC 0.75, p = 0.03) and LSM (tAUC 0.63, p < 0.001). The ABID-LSM model calibrated well (slope 0.99) with excellent overall performance (Integrated Brier Score 0.15). A cut-off of 8.1 separated those at high and low risk of hepatic decompensation at 5 years (24% vs. 5%, respectively, sHR = 4.8, p < 0.001). The ABID-LSM model had better predictive ability at 5 years than ALBI, FIB-4, NAFLD Decompensation Risk Score and ANTICIPATE models (all p < 0.001) as well as hepatic vein pressure gradient measurement (tAUC 0.78 vs. 0.71, p < 0.001, n = 60). CONCLUSIONS:The ABID-LSM model has greater accuracy in predicting hepatic decompensation in patients with cirrhosis due to MASLD than existing predictive models. If externally validated, ABID-LSM may identify those who benefit from pharmacotherapy and close monitoring.

Introduction: The gut–liver axis regulates metabolic homeostasis, with bile acids (BAs) serving as key signalling molecules. BA dysregulation is implicated in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction- and alcohol-associated liver disease (MetALD), yet consistent identification of BA markers and their mechanistic roles across different stages of these diseases remain elusive. Methods: We integrated three complementary studies to examine BA dysregulation: a population-based cohort (1522 females from TwinsUK with serum BA and liver biomarker data), a clinical cohort (30 patients with steatotic liver disease, fibrosis stages F0-F4, and 4 controls), and rodent models (20 rats with MASLD/MetALD vs. 9 controls). BA profiles were quantified via LC–MS. Results: The primary bile acid taurocholate was consistently correlated with liver pathology: in TwinsUK, it associated with ALT (β [95%CI] 1.81 [1.27, 2.36], FDR < 0.05) both overall and when stratifying for age (<65 years, n = 923; ≥65 years, n = 599); in the clinical cohort, it was associated with F3 fibrosis (OR [95%CI] 8.56 × 10−10 [3.80 × 10−13, 1.93 × 10−6], FDR < 0.05); and in rodents, it was associated with MASLD/MetALD (OR [95%CI] 2.86 [1.17, 9.51], FDR < 0.05). The secondary bile acid taurochenodeoxycholate was associated with both early (F0, OR [95%CI] 13.63 [1.04, 179.17], p < 0.05) and advanced stages of disease (rodents, OR [95%CI] 15.41 [2.94, 311.82], FDR < 0.05). Conclusion: Taurocholate and taurochenodeoxycholate emerge as consistent BA markers across liver disease stages, suggesting BA metabolism as potential therapeutic targets. This multi-model study bridges knowledge gaps in BA-driven mechanisms, informing personalised strategies for SLD management.

The current eco-social crisis is driven by an unsustainable socioeconomic model based on continued economic growth that exceeds planetary limits. Groups experiencing disadvantages are being disproportionately affected, further deepening global, regional, and local health inequities. Understanding the simultaneous ecological and social crises through a comprehensive approach across disciplines and sectors-including citizen participation-is essential for driving transformative change and paradigm shifts. Achieving genuine ecological sustainability, social justice, and health equity is critical for transitioning towards a new social-ecological paradigm in research and policy. This requires transformative research and policymaking in key areas-eco-social crisis; democracy, social inclusion and participation; geopolitics; and equitable, sustainable cities-all of which represent pressing challenges within this global crisis, and serve as thematic axes for the European conference Rethinking the Eco-Social Determinants of Health Inequities through the Transdisciplinary and Intersectoral Lens (ESDHI-EU), which will be held in Barcelona, Spain, on May 22-23, 2025, and will explore the root causes of health inequities from a transdisciplinary, intersectoral, and transnational perspective.