Background/Objectives: Heart failure (HF) imposes a significant healthcare burden in aging populations. The COVID-19 pandemic disrupted care, raising concerns about chronic disease management. We analyzed temporal trends in HF hospitalizations in Italy (2008-2022), assessing the influence of demographics, clinical complexity, seasonality, and the pandemic. Methods: Using national discharge records, we strictly identified hospitalizations with a primary HF diagnosis via ICD-9-CM codes. Admissions were stratified by age, sex, season, and clinical severity according to the Elixhauser Comorbidity Index. Temporal trends were analyzed using a Negative Binomial Generalized Linear Mixed Model with the time component modeled through a segmented regression to account for pre-pandemic, pandemic (2020), and late-pandemic dynamics. Results: We identified 3,162,075 primary HF admissions, yielding a crude hospitalization rate of 35.11 per 10,000 person-years. Patients with an intermediate comorbidity burden (Elixhauser 13-20) accounted for 59.3% of the total volume. Multivariable analysis identified male sex (RR = 2.24, p < 0.001 ***), age ≥ 75 years (RR = 95.04 vs. 25-44, p < 0.001 ***), and winter seasonality as strong independent predictors. Trend analysis revealed a structural long-term decline across all severity tiers, driven by a sharp drop in 2020 (RR = 0.80, p < 0.001 ***) coincident with a spike in in-hospital mortality. While patients with low-to-intermediate comorbidity exhibited a partial rebound in 2021-2022 (overall RR = 1.06, p < 0.001 ***), admissions for highly complex patients (score > 20) showed an accelerated late-pandemic decline. Conclusions: HF hospitalizations in Italy remain a substantial burden driven by advanced age and clinical comorbidity. Our 15-year population-level data indicate no sustained, structural late-pandemic surge in HF admissions. The observed fluctuations were likely driven by severe healthcare disruptions and patient care avoidance rather than a true epidemiological shift, highlighting the urgent need for resilient chronic care systems during emergencies.

Background: The rs738409 C>G polymorphism in the PNPLA3 gene (I148M variant) is the strongest genetic risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD). Previous meta-analyses have either focused on cross-sectional associations or included mixed steatotic liver disease populations. The impact of PNPLA3 polymorphisms on longitudinal clinical outcomes specifically in MASLD remains incompletely characterized.Methods: We systematically searched observational cohort studies published up to September 2025, evaluating the impact of PNPLA3 rs738409 polymorphism on clinical outcomes in individuals with MASLD. The primary outcome was liver-related events, while secondary outcomes included hepatocellular carcinoma (HCC), liver-related mortality, cardiovascular events, extrahepatic cancers, and all-cause mortality. We compared outcomes between homozygous risk allele carriers (GG genotype) versus wild-type homozygous individuals (CC genotype), and heterozygous carriers (CG genotype) versus CC genotype. The study was registered on PROSPERO (CRD420251176886).Results: Twenty-one cohort studies involving 232,033 individuals with MASLD were analyzed (132,334 with CC genotype, 84,091 with CG genotype, and 15,608 with GG genotype). Over a median follow-up of 7.2 years, individuals with GG genotype had significantly higher risks of liver-related events (HR 2.87, 95% CI 1.92-4.27, p<0.01; I²=66%) and HCC (HR 2.54, 95% CI 1.86-3.47, p<0.01; I²=0%) compared to those with CC genotype. Heterozygous carriers also demonstrated elevated risk of liver-related events (HR 1.57, 95% CI 1.12-2.19, p<0.01; I²=62%) but not HCC (HR 1.15, 95% CI 0.89-1.48, p=0.53; I²=0%). Conversely, PNPLA3 polymorphisms did not influence cardiovascular events (GG vs CC: HR 0.94, 95% CI 0.74-1.19, p=0.44; CG vs CC: HR 1.02, 95% CI 0.90-1.15, p=0.99), extrahepatic cancers (GG vs CC: HR 0.96, 95% CI 0.67-1.37, p=0.95; CG vs CC: HR 0.83, 95% CI 0.64-1.09, p=0.13), or all-cause mortality (GG vs CC: HR 1.19, 95% CI 0.97-1.45, p=0.78; CG vs CC: HR 1.05, 95% CI 0.90-1.22, p=0.75).Conclusions: PNPLA3 I148M polymorphism confers a substantial, dose-dependent increase in liver-related events and HCC risk in MASLD, with homozygous carriers showing the highest risk. However, this genetic variant does not influence cardiovascular events, extrahepatic cancers, or overall mortality, indicating liver-specific pathogenic effects. These findings support incorporating PNPLA3 genotyping into risk stratification strategies for MASLD management, particularly for identifying individuals who may benefit from enhanced hepatocellular carcinoma surveillance and aggressive treatment to prevent disease progression.

BACKGROUND & AIMS:The availability of new drugs for the treatment of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) underlines the need of early predictors of response to such therapies. This study evaluated the impact of 1-year changes in liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE), controlled attenuation parameters (CAP), and serum alanine aminotransferase (ALT) on liver outcomes in patients with MASLD. METHODS:A large multicenter cohort of MASLD patients with LSM ≥8 kPa and prospective follow-up was enrolled. Liver-related events (LREs), including hepatocellular carcinoma (HCC) and liver decompensation (LD), were evaluated during follow-up. LSM, CAP, ALT, and Fibrosis-4 Index (FIB-4) were assessed at baseline and at 1-year follow-up. Cause-specific Cox regression analyses were performed to correlate 1-year variation in LSM, CAP, ALT, and FIB-4 with the risk of developing LRE, LD, and HCC, in terms of cause-specific hazard ratios (csHRs). RESULTS:We included 1744 patients with LSM ≥8 kPa (median age, 55 years; 52.1% male; 58.3% obese; 55.8% with diabetes) and 989 with LSM ≥10 kPa (median age, 56 years; 50.2% male; 54.7% obese; 51% with diabetes), followed for a median of 28.2 and 32 months, respectively. LREs occurred in 39 patients with LSM ≥8 kPa (26 LD, 22 HCC) and in 35 with LSM ≥10 kPa (25 LD, 19 HCC). A 1-year variation in LSM, but not in CAP, ALT, or FIB-4, was independently associated with LRE in patients with MASLD and LSM ≥8 kPa (csHR, 1.007; 95% confidence interval [CI], 1.001-1.014). Likewise, 1-year LSM variation (csHR, 1.009; 95% CI, 1.000-1.018) independently predicted LD in this population, whereas no 1-year changes in CAP, ALT, or FIB-4 were associated with LD risk. No independent associations were observed between 1-year changes in LSM, CAP, ALT, or FIB-4 and the risk of HCC. All findings were confirmed in patients with LSM ≥10 kPa and in those at high risk of progression with type 2 diabetes. CONCLUSIONS:In patients with MASLD and LSM ≥8 or ≥10 kPa, the % LSM reduction at 1 year was independently associated with lower risk of LRE and LD.

Background & Aims The rs738409C>G polymorphism in the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3 I148M variant) contributes to the largest fraction of metabolic dysfunction-associated steatotic liver disease (MASLD) heritability. However, its prognostic impact on long-term clinical outcomes related to MASLD remains incompletely characterized. We performed a meta-analysis of observational studies to quantify the impact of PNPLA3 polymorphisms on the risk of developing hepatic and extrahepatic outcomes in MASLD. Methods We systematically searched PubMed, Scopus, and Cochrane Central for observational studies evaluating PNPLA3 polymorphisms and clinical outcomes in MASLD. The primary outcome was liver-related events (LREs); secondary outcomes included new-onset hepatocellular carcinoma (HCC), liver-related mortality, cardiovascular events, extrahepatic cancers, and all-cause mortality. We compared homozygous risk-allele carriers (GG) and heterozygous carriers (CG) with wild-type homozygous (CC) individuals using random-effects genotypic models. The study was registered on PROSPERO (CRD#420251176886). Results Twenty-one observational longitudinal studies, including 232,033 adult individuals with MASLD (median follow-up: 7.2 years), were analysed. Individuals with the GG genotype had significantly higher risks of incident LREs (hazard ratio [HR] 2.87, 95% CI 1.92–4.27) and HCC (HR 2.54, 95% CI 1.86-3.47) compared with the CC genotype. CG carriers also had an increased risk of LREs (HR 1.57, 95% CI 1.12–2.19), but not of HCC. PNPLA3 genotypes were not associated with the risk of major cardiovascular events, extrahepatic cancers, or all-cause mortality. Conclusions The PNPLA3 I148M polymorphism confers dose-dependent increases in LRE and HCC risk in MASLD, with liver-specific rather than systemic effects. These findings suggest that PNPLA3 genotyping may inform risk stratification strategies in MASLD, particularly for identifying individuals at higher risk of LREs and HCC who might benefit from closer monitoring. Impact and implications International consensus has prioritised patient education and awareness as a key research domain in MASLD, yet quantitative evidence from patients with an established diagnosis remains scarce, particularly in Europe. In 460 Italian adults with physician-diagnosed MASLD we found pervasive knowledge gaps - including the failure to recognise diabetes as a risk factor and the belief that normal transaminases exclude progressive disease - a wide gap between lifestyle counselling and actual adherence, largely self-prescribed supplement use, partly guideline-discordant pharmacotherapy, and educational attainment as the principal determinant of every cognitive domain. These results are relevant to hepatologists, primary care physicians, patient associations and policymakers, because such misconceptions may delay referral, weaken adherence, and hinder equitable access to newly available therapies such as resmetirom and incretin-based agents. The validated five-domain instrument provides a reproducible tool to profile patients, tailor education to health literacy level and monitor its effect; however, since participants were recruited through a patient association and reported data themselves without fibrosis staging, these estimates probably represent a best-case scenario of awareness and require confirmation in unselected clinical cohorts.

BACKGROUND & AIMS:Accurate staging of liver fibrosis is crucial for risk stratification in patients with metabolic dysfunction-associated steatotic liver disease. We aimed to develop and validate artificial intelligence-based models capable of distinguishing fibrosis stages. METHODS:We developed and validated machine learning models to predict fibrosis stages in more than 3600 biopsy-confirmed patients with metabolic dysfunction-associated steatotic liver disease using 22 clinical features, liver stiffness measurement, and controlled attenuation parameter. Models included Feature Tokenizer Transformer, TabNet variants with distance-aware losses, ordinal Multilayer Perceptron with the COnditional RAnk Logits framework. Three centers were prespecified for geographic external validation. In the remaining centers, we used a stratified 75/25 split into a training pool and an internal random test set, tuned hyperparameters by stratified 10-fold cross-validation on the training pool, and trained 1 model per imputed dataset (M = 5) with an internal 80/20 train-validation split for early stopping and operating-point selection. Performance was pooled across imputations using Rubin's rules and reported for the internal random test set and the held-out centers. RESULTS:Feature Tokenizer Transformer and TabNet achieved the highest performance in binary tasks: area under the receiver operating characteristic curve = 0.860 and 0.855 (F ≥3 vs 0-F2) and area under the receiver operating characteristic curve = 0.800 and 0.788 (F ≥2 vs 0-F1), significantly outperforming the Fibrosis-4 index. For F ≥3, Feature Tokenizer Transformer had significantly higher area under the receiver operating characteristic curve than liver stiffness measurement (P = .014) but only marginally higher than AGILE3+, and, together with TabNet, the highest accuracy and the lowest gray zone (8.2% and 8.4%, respectively). For multiclass staging, ordinal models performed best with Multilayer Perceptron with the Consistent Rank Logits achieving quadratic weighted kappa = 0.616. CONCLUSIONS:Deep learning models with ordinal-aware architectures can accurately predict liver fibrosis stages using routinely available clinical data, offering a scalable alternative to biopsy without requiring specialized biomarkers.

BACKGROUND:Radiomics holds promise for extracting quantitative biomarkers from CT images of hepatocellular carcinoma (HCC), but its clinical translation is hampered by poor reproducibility caused by variations in image acquisition, manual segmentation and feature extraction. This multicenter study assessed the reproducibility of both segmentation and radiomic features in patients with early, intermediate and advanced HCC. METHODS:Forty-five patients (15 per centre; 5 per tumor stage) from three institutions underwent contrast-enhanced CT. Three radiologists independently delineated lesion and perilesion regions on arterial (HAP) and portal venous phases (PVP) using 3D‑Slicer. Segmentation quality was assessed with the Jaccard index; masks with < 25% concordance were manually revised. Using the SlicerRadiomics module, 851 features per phase were extracted, and reproducibility was measured via the generalized concordance correlation coefficient (GCCC) before and after revision. RESULTS:Median Jaccard values were 0,40, 0,56and 0,74, between center 1 and 2, between center 1 and center 3, and between center 2 and 3, respectively. Twenty-seven segmentations underwent manual revision based on Jaccard index. After manual revision Lesion features (mean GCCC 0,65) were more reproducible than perilesional ones (0,52), and PVP produced slightly higher concordance than HAP. Before revision, mean GCCC ranged from 0.45 to 0.68 (median 0.48-0.77); early-stage lesions had the highest reproducibility and advanced-stage the lowest. After revision, lesion mean GCCC improved to 0.71 (HAP) and 0.67 (PVP), with larger gains in intermediate-stage tumours, while perilesional concordance improved modestly. CONCLUSIONS:Radiomic feature reproducibility depends on HCC stage and region. Early HCC lesions yield more reproducible features compared to advanced tumours. Manual revision enhances concordance, particularly for lesion regions, but defining peritumoral tissue remains challenging.

Background and aimsThe rapid advancement of artificial intelligence (AI) is transforming higher education, yet understanding of student perceptions remains limited. This study investigates the structure of student attitudes toward AI and identifies key predictors among Italian university students.MethodsA cross-sectional survey was administered to 864 students at the University of Palermo (May–June 2025). The questionnaire examined demographics, AI experience, and attitudes using 10 Likert-type items. Data were analyzed using exploratory factor analysis and confirmatory factor analysis.ResultsMost students (65.8%) reported superficial AI knowledge, yet 93.6% had used AI applications, predominantly ChatGPT (59.8%). Factor analyses identified two distinct latent constructs: perceived Impact of AI and AI-related Concerns, negatively correlated (r = −0.34, p < 0.001). Perceived Impact was positively predicted by age (β = 0.17), STEM (β = 0.19), Health/Agricultural/Veterinary sciences (β = 0.23), Economics/Law/Social Sciences (β = 0.16), and regular AI use, while negatively predicted by female gender (β = −0.09) and non-use (β = −0.35). AI-related Concerns were positively predicted by female gender (β = 0.21) and non-regular use (never: β = 0.20; occasionally: β = 0.29), and negatively by STEM (β = −0.11) and Health sciences (β = −0.15).ConclusionsStudent attitudes toward AI reflect two distinct dimensions: opportunity recognition and risk awareness, systematically influenced by gender, discipline, and AI experience. Successful implementation requires tailored approaches addressing gender-specific concerns, discipline-specific needs, and promoting direct AI experience.

Background/Objectives: Stroke is a leading cause of mortality and disability worldwide, ranking as the second most common cause of death and the third in disability-adjusted life-years lost. Ischaemic stroke, which constitutes the majority of cases, poses significant public health and economic challenges. This study evaluates trends in ischaemic stroke hospitalisations in Italy from 2008 to 2022, focusing on differences before and after the COVID-19 pandemic. Methods: We analysed ischaemic stroke hospitalisations among individuals admitted through emergency services using Italian hospital discharge records from 2008 to 2022. Poisson Inverse Gaussian regression was employed to assess hospitalisation trends, accounting for age, sex, and geographic variations. Results: Among 1,689,844 ischaemic stroke hospitalisations, there was a marked age-related increase, particularly among individuals aged 74 and older, with males consistently showing higher rates. Hospitalisation trends demonstrated a 20% reduction over 15 years, suggesting improvements in stroke prevention and treatment. However, there was a slight increase in rates during the COVID-19 period, despite the overall declining trend, highlighting the potential healthcare challenges experienced during the pandemic. Multivariable analysis confirmed age and male sex as significant risk factors. Conclusions: This study underscores the age-related increase in stroke hospitalisation rates, emphasising the need for targeted prevention strategies for elderly populations. The overall reduction in stroke hospitalisation rates reflects advancements made in healthcare, although the impact of COVID-19 on access to stroke care is evident. Future policies must address the pandemic’s effects on stroke care continuity and prioritise interventions tailored to age and sex.

PURPOSE:The prognosis of patients with unresectable hepatocellular carcinoma (HCC) and compensated cirrhosis is influenced by cancer progression. Data on the incidence and the prognostic role of clinical hepatic decompensation (CHD) following immune checkpoint inhibitor therapy are lacking. We aimed to assess whether early CHD within 3 months from commencement of systemic therapy affects overall survival (OS) of patients treated with atezolizumab plus bevacizumab or sorafenib. PATIENTS AND METHODS:Individual patient data from the IMbrave150 trial were analyzed. Cumulative incidence of CHD was assessed by competing risk analysis against HCC radiologic progression. Early CHD and HCC radiologic progression were assessed as predictors of OS by the time-dependent Cox model. RESULTS:The 3- and 12-month rates of CHD were 7% and 12%, respectively, whereas the 3- and 12-month rates of HCC radiologic progression were 23% and 52%, respectively. Albumin-bilirubin grade 2 [subdistribution HR (sHR) = 1.79, 95% confidence interval (CI), 1.01-3.19; P = 0.049], INR (sHR = 1.97, 95% CI, 1.64-2.37; P < 0.001), and presence of neoplastic macrovascular invasion (sHR = 2.01, 95% CI, 1.14-3.54; P = 0.020) were independently associated with higher risk of CHD. Early CHD (HR = 7.56, 95% CI, 4.47-12.8) and early HCC radiologic progression (HR = 5.92, 95% CI, 4.03-8.69), as first events, were independently associated with higher mortality. CONCLUSIONS:This study provides robust evidence that early CHD is associated with the highest risk of death in patients with unresectable HCC undergoing systemic treatment. Within well-compensated participants, albumin-bilirubin, INR, and macrovascular invasion identify a population at higher risk of decompensation. Inclusion of clinical decompensation events in future prospective clinical trials may improve characterization of OS from systemic therapy of HCC.

BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction and alcohol-associated steatotic liver disease (MetALD) are two separate entities within the spectrum of steatotic liver disease. We aimed to compare the risks of hepatic and extrahepatic outcomes between individuals with MASLD and MetALD in a comprehensive meta-analysis. METHODS:In this systematic review and meta-analysis, we systematically searched PubMed, Scopus, and the Cochrane Central Register of Controlled Trials for observational cohort studies published up to March 1, 2025, and written in English. We included studies comparing clinical outcomes between adults (>18 years) with MASLD and MetALD, if the studies incorporated appropriate statistical adjustments for known risk factors and potential confounding factors. We excluded studies that did not differentiate between MASLD and MetALD, case reports, case series, commentaries, cross-sectional or case-control studies. We evaluated each study to assess its eligibility and extracted the data. The primary outcome was liver-related events; secondary outcomes included hepatocellular carcinoma, liver-related mortality, cardiovascular events, extrahepatic cancers, and all-cause mortality. We used random-effect models to calculate pooled hazard ratios (HRs) with 95% CIs. The study was registered with PROSPERO (CRD420251003928). FINDINGS:Of 5579 records identified, we included 24 cohort studies involving 11 575 558 individuals in the analysis. 9 801 312 individuals had MASLD (mean age 57·0 years [SD 4·55], ~62% male, and ~38% female) and 1 774 246 had MetALD (mean age 48·6 years [SD 4·91], ~82% male, and ~18% female). Individuals with MetALD had significantly higher risks of liver-related events (HR 1·62, 95% CI 1·16-2·25; p=0·0086), hepatocellular carcinoma (1·33, 1·00-1·77; p=0·048), and extrahepatic cancers (1·03, 1·01-1·06; p<0·0001) compared with those with MASLD. The rates of cardiovascular events (HR 0·96, 95% CI 0·85-1·09; p=0·48), extrahepatic cancer-related mortality (1·44, 0·97-2·15; p=0·065), and all-cause mortality (1·08, 0·97-1·19; p=0·14) did not differ between the two liver conditions. Substantial heterogeneity was observed across most analyses (I2=76-93%), with only extrahepatic cancer incidence showing low heterogeneity (I2=0%). Egger's regression tests suggested that publication bias was unlikely for all outcomes except extrahepatic cancer-related mortality. INTERPRETATION:MetALD might be associated with a higher risk of liver-related events, hepatocellular carcinoma, and extrahepatic cancers than MASLD, whereas all-cause mortality, extrahepatic cancer-related mortality, and cardiovascular events seem similar between the two conditions. These findings emphasise the need for distinct clinical strategies for these related yet different entities within the steatotic liver disease spectrum and highlight the importance of conducting pharmacological clinical trials in this context. FUNDING:The Italian Ministry of Education, University, and Research (MIUR).

Introduction Addressing the shortage of healthcare workers requires a clear understanding of the factors associated with nurses’ intention to leave their current hospital (ITL1), or more critically, to leave the healthcare profession altogether (ITL2). Univariate models, which analyze these outcomes separately, often fail to account for their dependence, resulting in reduced estimation precision and a higher risk of Type II errors. Modelling their joint behavior is essential to improve estimation efficiency and reduce false negatives. Moreover, explicitly capturing the association structure enables the identification of discordant profiles, such as individuals intending to leave the hospital but not the profession, or vice versa. Objectives This paper investigates the determinants of nurses’ intention to leave the hospital and the profession using a bivariate additive ordered logit model, emphasizing its ability to model complex dependence structures in ordinal categorical data. The analysis is implemented using the new R package pblm. Methods The data derive from the METEOR [1] cross-sectional survey conducted in 2022 in eight hospitals across Belgium, the Netherlands, Italy, and Poland. The METEOR Turnover Intention questionnaire (MTI), administered to nurses in these hospitals, was based on the Job Demands–Resources (JD-R) model. It included validated instruments measuring job satisfaction, work engagement, burnout, and turnover intentions (ITL1 and ITL2), both assessed on five-level Likert scales, along with individual and hospital-level covariates. A previous analysis [2] addressed these outcomes separately. In contrast, this study applies a bivariate additive ordered logit model [3] with an association structure governed by a penalty term [4], which constrains the association intercepts (log-global odds ratios, log-gOR) to follow a data-driven polynomial structure. P-splines are used to model non-linear effects of age in both marginal and association equations. The model is fitted using the R package pblm, soon to be released on CRAN. Results The survey collected 1350 complete responses. In the marginal model for ITL1, significant factors included younger age (gOR = 0.95, p < 0.001), having experienced bullying (gOR = 1.31, p = 0.040), emotional exhaustion (gOR = 2.24, p < 0.001), low opportunities for professional development (gOR = 1.80, p = 0.022), low support from supervisors (gOR = 2.10, p < 0.001), low work prospects (gOR = 2.20, p < 0.001), poor physical working conditions (gOR = 1.30, p = 0.038), underuse of professional abilities (gOR = 1.64, p = 0.001), and low salary (gOR = 1.50, p < 0.001). The Netherlands showed the highest country effect (gOR = 1.84, p < 0.001), while Italy showed the lowest (gOR = 0.55, p = 0.005). In the marginal model for ITL2, significant factors included younger age (gOR = 0.96, p < 0.001), experiences of bullying (gOR = 1.31, p = 0.043), emotional exhaustion (gOR = 2.16, p < 0.001), depersonalization (gOR = 2.24, p < 0.001), work-life conflict (gOR = 1.56, p < 0.001), low professional development (gOR = 1.76, p = 0.026), low supervisor support (gOR = 1.56, p = 0.012), low work prospects (gOR = 1.86, p < 0.001), poor physical working conditions (gOR = 1.48, p = 0.002), underuse of professional abilities (gOR = 1.38, p = 0.030), low salary (gOR = 1.62, p < 0.001), and low overall job satisfaction (gOR = 1.56, p = 0.020). Again, the Netherlands exhibited the strongest country effect (gOR = 1.46, p = 0.001), while Italy the weakest (gOR = 0.28, p < 0.001). Regarding the association between ITL1 and ITL2, the strength of association increased significantly with age (relative gOR = 1.046, p < 0.001) and high working pace (relative gOR = 1.622, p < 0.001). Conversely, the association decreased significantly in the presence of health problems (relative gOR = 0.60, p = 0.021), low work prospects (relative gOR = 0.35, p < 0.002), underuse of professional abilities (relative gOR = 0.52, p = 0.025), and when working in the Netherlands (relative gOR = 0.50, p = 0.004). Figure 1 displays the observed and predicted log-gOR structures, along with the partial effects of age (centered at 22 years) estimated using P-splines. These indicate a non-linear increasing effect of age in both marginal and association equations. Conclusions The use of a bivariate additive ordered logit model allowed for the identification of a wider set of significant predictors for nurses’ intention to leave the hospital or the profession, compared to previous univariate analyses [2]. Specifically, five additional factors were identified for ITL1 (bullying, low professional development, low supervisor support, poor physical conditions, and low salary) and six for ITL2 (bullying, high working pace, work-life conflict, low supervisor support, poor physical conditions, and salary). These findings offer more comprehensive insights into the drivers of nurses’ turnover intentions and may support the development of more targeted retention strategies. Furthermore, the association model highlighted the presence of discordant profiles—nurses whose characteristics are associated with a weaker connection between ITL1 and ITL2. These insights may guide the design of future surveys or the refinement of questionnaire items. For instance, among more experienced nurses, the intention to leave the hospital and the profession may reflect a single underlying construct, whereas among younger nurses these outcomes appear more distinct.

BACKGROUND & AIMS:First and further decompensation events mark key transitions in the natural history of cirrhosis and significantly influence mortality risk. We assessed the cumulative incidence of first and further (acute and non-acute) decompensation and evaluated their impact on liver-related death (LR-D) in patients with compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS:We conducted an international, multicenter (17 centers), retrospective study involving 6,061 consecutive patients with cACLD due to MASLD, diagnosed either clinically (liver stiffness measurement >10 kPa) or histologically (F3-F4 fibrosis). Decompensation events were defined according to the Baveno VII criteria. Cumulative incidence functions and cause-specific Cox models (with baseline and time-dependent variables) were used to analyze competing risks. A multistate model was developed to better describe the clinical trajectory of cACLD due to MASLD. RESULTS:The 5-year cumulative incidence of first decompensation was 3.5% (95% CI 3.0-4.1), which was associated with an 18.9-fold increase (95% CI 10.8-32.9) in the cause-specific hazard of LR-D. Among patients who experienced a first decompensation, the 5-year cumulative incidence of further decompensation was 43.9% (95% CI 37.2-50.2), further increasing the hazard of LR-D by 1.52-fold (95% CI 1.02-2.34). Ascites, followed by variceal bleeding, were the most common decompensation events. Hepatocellular carcinoma independently increased the cause-specific hazard of LR-D by 2.95-fold (95% CI 2.02-4.31) in the overall cohort and by 1.43-fold (95% CI 1.03-2.00) in patients who had experienced a first decompensation. CONCLUSIONS:First and subsequent decompensation events are major inflection points in the clinical progression of cACLD due to MASLD, increasing the cause-specific hazard of LR-D by 18.9- and an additional 1.52-fold, respectively. Hepatocellular carcinoma is an independent predictor of LR-D and further exacerbates mortality risk when present alongside decompensation. IMPACT AND IMPLICATIONS:In this large international multicenter cohort of 6,061 patients with compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD), we examined the clinical impact of first and further decompensation events. At 5 years, the cumulative incidences of first and further decompensation were 3.5% and 43.9%, respectively, each significantly increasing the cause-specific hazard of liver-related death (18.9-fold and 1.52-fold). Ascites, more so than variceal bleeding, was the predominant and most impactful event. Both acute and non-acute decompensation similarly contributed to liver-related mortality. Additionally, hepatocellular carcinoma independently increased the hazard of liver-related death, even post-decompensation. Notably, extrahepatic deaths also represented a considerable burden, reflecting the high metabolic risk of MASLD. These findings highlight key prognostic inflection points in MASLD-related cACLD.

Supplementary Figure S1. Early hepatic decompensation identifies patients with hepatocellular carcinoma treated with systemic therapy at highest risk of death. Clinical hepatic decompensation is associated with higher hazard ratio for death, compared to HCC radiological progression. Albumin-bilirubin (ALBI) grade, INR and macrovascular invasion are independent predictors of clinical hepatic decompensation.

Background and AimThe MAESTRO-NASH phase 3 trial reported that a 52-week treatment of Resmetirom is effective in improving fibrosis and metabolic dysfunction-associated steatohepatitis (MASH) in patients with MASH and F2 or F3 fibrosis, while data on the impact on 5-year and long-term clinical outcomes are still lacking. We simulated the transition probabilities of disease progression in MASLD patients with F2 or F3 fibrosis and the effect of Resmetirom treatment on clinical outcomes.MethodsA meta-analysis of literature data formed transition matrices for fibrosis stages and complications, defined as compensated (CC) and decompensated cirrhosis (DC), hepatocellular carcinoma (HCC) and mortality-liver-related mortality (LR-M), cardiovascular mortality (CV-M) and extra-hepatic cancer mortality (EHC-M). Markov model was developed to depict the F2 and F3 fibrosis stage progression towards the complications and to evaluate the effect of Resmetirom treatment on the natural history of MASLD.ResultsWe estimated the 5-year probability of Resmetirom-treated and untreated MASLD patients with baseline F2 fibrosis of developing CC (5.16% vs. 6.82%, respectively), DC (0.25% vs. 0.3%, respectively), HCC (0.25% vs. 0.32%, respectively) and mortality (0.15% vs. 0.16% for LR-M; 1.02% vs. 1.1% for CV-M; 1.07% vs. 1.2% for EHC-M, respectively). Similarly, we estimated the five-year probability of Resmetirom-treated and untreated MASLD patients with baseline F3 fibrosis of developing CC (17.12% vs. 21.34%, respectively), DC(1.1% vs. 1.47%, respectively), HCC (1.21% vs. 1.73%, respectively) and mortality (0.59% vs. 0.91% for LR-M, 1.92% vs. 2.14% for CV-M and 1.04% vs. 1.14% for EHC-M, respectively). Life Years Gained (LYG) of Resmetirom-treated patients were 0.45 and 0.63 in MASLD patients with F2 and F3 fibrosis, respectively, and the model was sensitive to changes in Resmetirom efficacy and transition probabilities.ConclusionsResmetirom decreases the 5-year and lifetime Markov-model estimated risk of CC, DC, HCC and liver-related mortality in patients with MASLD and F2 or F3 fibrosis.

Background & Aim The first and further decompensation mark the natural history and the risk of mortality in patients with cirrhosis. We assessed the cumulative incidence of first and further (acute and non-acute) decompensation and evaluated their impact on both liver-related death (LR-D) in patients with compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD). Methods Consecutive patients with clinical (LSM>10 kPa) or biopsy-proven (F3-F4 fibrosis) diagnosis of cACLD due to MASLD were included. First and further decompensation were defined according to Baveno VII criteria. The acute (AD) and non-acute (NAD)[MOU1] [VW(2] presentation of the decompensation was also evaluated. Competing risk analysis and cumulative incidence functions (CIF) [MOU3] were assessed by Fine and Gray. Cause-specific Cox models with baseline and time-dependent variables were applied. Multistate model was built to better assess the clinical course of cACLD due to MASLD. Results The cumulative incidence of the first decompensation was 3.5% at 5 years, increasing 20-times the risk of LR-D at cause-specific Cox analysis; the cumulative incidence of further decompensation was 44% at 5 years among patients with first decompensation, additionally increasing 1.6-times the risk of LR-D. Ascites, followed by variceal bleeding, were the most common events in both first and further decompensation. The impact of AD and NAD as both first or further event on LR-D was similar[MOU4] . Hepatocellular carcinoma (HCC) further independently increased the risk of LR-D of 3.2-times and 1.6-times, respectively, in the whole cohort of cACLD due to MASLD and in those who experienced first decompensation. Conclusions The first and further decompensations (AD and NAD) represent tipping points in the clinical course of patients with cACLD due to MASLD, increasing 20-times and additionally 1.6-times the risk of LR-D. HCC is an independent predictor of LR-D in patients with cACLD due to MASLD, resulting in an additional risk of LR-D when associated with both first and further decompensation.

IMPORTANCE Multiple immunotherapy-based combinations and tyrosine kinase inhibitors are approved for first-line treatment of unresectable or advanced hepatocellular carcinoma (HCC). While overall survival remains the primary efficacy end point, health-related quality of life (HR-QoL) represents a crucial complementary outcome that has not been comprehensively compared across available treatments. OBJECTIVE To compare the HR-QoL effects associated with different first-line treatments for unresectable or advanced HCC and to integrate treatment-induced survival benefit with impact on patients' HR-QoL. DATA SOURCES The MEDLINE, CENTRAL, and Scopus databases were systematically searched for studies published from inception through November 2024. The search was supplemented with manual reviews of reference lists and abstracts from main oncology conferences from the past 5 years (2020-2024). STUDY SELECTION Phase 3 randomized clinical trials comparing tyrosine kinase inhibitor monotherapy to immune checkpoint inhibitor-based therapies in first-line advanced HCC and reporting HR-QoL deterioration were included. DATA EXTRACTION AND SYNTHESIS Study selection and data extraction were performed by 2 independent reviewers, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Cochrane Collaboration tool was used to assess risk of bias. A bayesian network meta-analysis was performed using sorafenib as the comparator. MAIN OUTCOMES AND MEASURES Time to deterioration of HR-QoL domains were assessed using the European Organization for Research and Treatment of Cancer's Quality-of-Life Questionnaire Core 30 and HCC18. Treatment ranking was calculated using surface under the cumulative ranking (SUCRA) for HR-QoL items. RESULTS Seven HR-QoL items from 9 randomized clinical trials enrolling 6425 patients met inclusion criteria. SUCRA calculations showed that atezolizumab plus bevacizumab had the highest probability of reducing deterioration of global health status and QoL (85%), abdominal swelling (95%), jaundice (89%), and pain (86%). When integrating HR-QoL with overall survival, atezolizumab plus bevacizumab outperformed all other treatments across all items. CONCLUSIONS AND RELEVANCE This network meta-analysis found that atezolizumab plus bevacizumab provides the best balance between QoL preservation and overall survival benefit compared to other systemic therapy options in unresectable or advanced HCC. This integrated assessment of survival and quality of life outcomes offers a more patient-centered approach for treatment selection in clinical practice.