Citations

Abstract Background Machine perfusion represents the most significant breakthrough in liver transplantation (LT) since the discovery of cyclosporin. Yet, the optimal perfusion strategy remains unsettled. Randomized trials demonstrate that hypothermic oxygenated perfusion (HOPE) improves graft survival and function and reduces ischemic cholangiopathy, whereas normothermic machine perfusion (NMP) decreases post-transplant injury. Real-world comparisons are lacking and challenging due to heterogeneity in donor-recipient risk profiles and regional differences. Aims To compare real-world outcomes of HOPE and NMP in LT. Methods We analyzed consecutive NMP-preserved LTs from seven North American centers between 2021 and 2024. We compared NMP to the European HOPE-REAL cohort, comprising HOPE-treated LTs from 22 centers between 2012 and 2021. Analyses were stratifyied by graft type and risk category and adjusted for donor age, donor risk index, and balance of risk score using entropy balancing. Results A total of 470 NMP and 1202 HOPE-treated grafts were analyzed, revealing major differences in risk profiles (Figure 1). In NMP, death-censored graft survivals at 1, 2, and 3 years were >95% in donation after brain death (DBD) and >94% in donation after circulatory death (DCD) grafts. Comparable outcomes were observed in the HOPE cohort with >93%, in DBD, and >87% in DCD after up to 3 years, despite significantly higher donor age and longer functional warm ischemia in the HOPE DCD cohort (Figure 2). After risk adjustment, death-censored graft survival remained similar between both modalities (Table 1). Non-anastomotic biliary stricture rates after DCD-LT were comparable (8.5% vs. 12.4%), independent of whether continuous or end-ischemic NMP was performed. Conclusion This first transatlantic real-world report demonstrates excellent outcomes with both NMP and HOPE despite higher graft risk in Europe. Machine perfusion is the new standard of care in LT, while further understanding is needed regarding the distinct benefits of each modality across risk profiles.Figure 1.Graft risk in NMP and HOPE stratified by graft type. Benchmark case was defined as primary transplant with MELD <20 and BAR score <9, extended criteria as either BMI >30kg/m2, donor age >65 years, CIT >12h. DCD grafts were categorized as definedFor image description, please refer to the figure legend and surrounding text. Figure 2.Death-censored graft survival in liver transplantation following NMP and HOPE stratified by graft type. Abbreviations: NMP (Normothermic Machine Perfusion), HOPE (Hypothermic Oxygenated Perfusion), DBD (Donation after Brain Death), DCD (Donation after circulatory death)For image description, please refer to the figure legend and surrounding text. Table 1.Risk-adjusted comparison of death-censored graft survival between NMP and HOPE.For image description, please refer to the figure legend and surrounding text.

ABSTRACT Background : Tirofiban is a GP IIb/IIIa inhibitor, an anti‐platelet drug that is used in ischemic stroke or acute coronary syndromes. The goal of this study is to assess the safety and efficacy of the drug in patients who have suffered an acute ischemic stroke. Methods : A comprehensive search of PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov from inception to December 2025 yielded randomized controlled trials (RCTs) comparing Tirofiban and conventional management in patients with acute ischemic stroke. We assessed the risk of bias using the revised Cochrane “Risk of bias” tool for randomized trials (RoB 2.0). We analyzed the outcomes using RevMan 5.4, with risk ratio (RR) as the effect measure. Results : A total of 9 RCTs with 4210 patients were included in our meta‐analysis. According to our meta‐analysis, the tirofiban group was associated with a statistically significant increase in the patients showing functional independence at 90 days, measured by patients with Modified Rankin Score (mRS) of 0–2 (RR 1.13; CI = 1.06–1.20) and excellent outcome (mRS score 0–1) at 90 days (RR 1.17; CI = 1.05–1.29). We found no statistically significant difference between the two groups regarding mortality (RR 0.94; CI = 0.63–1.40). The tirofiban group had an increased incidence of intracranial hemorrhage (ICH) (RR 1.25; CI = 1.06–1.47) but had a similar incidence of symptomatic ICH as compared to the control group (RR 1.48; CI = 0.98–2.24). Conclusion : This meta‐analysis suggests that tirofiban may improve favorable functional outcomes (mRS 0–2) in acute ischemic stroke, although the certainty of evidence was moderate. While no significant increase in sICH was observed, some analyses showed a higher rate of overall intracranial hemorrhage. These findings should therefore be interpreted cautiously, and further high‐quality randomized trials are needed to confirm the efficacy and safety of tirofiban before routine guideline use.

Post–liver transplant (LT) weight gain and metabolic dysfunction predispose to cardiovascular (CV) morbidity, allograft steatosis, and reduced long-term survival. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) promote weight loss and improve cardiometabolic health, yet evidence in liver transplant recipients (LTRs) is limited. We aimed to evaluate the safety, tolerability, and efficacy of GLP-1 RAs in post-LT weight management. We performed a multicenter retrospective cohort study of adult LTRs treated with GLP-1 RAs across 4 international centers (January 1, 2010–June 30, 2025). Regular GLP-1 RA users were compared with matched non-users by age, sex, obesity, and diabetes status, transplant year, and center. The primary outcome was the change in body weight 1-year post-exposure. Secondary outcomes included glycemic and lipid profiles, kidney and allograft function, immunosuppression effects, major adverse cardiovascular events (MACE), and adverse effects. Longitudinal analyses used linear mixed models with multiple imputation. Among 104 GLP-1 RA users, 68.3% initiated therapy for diabetes; subcutaneous semaglutide was most used at a median dose of 0.82±0.46 mg weekly. Treatment led to significant reductions in body weight (−3.8 kg; −3.9%, p <0.001), body mass index (BMI) (−1.6 kg/m 2 ; −5.0%, p <0.001), and glycated hemoglobin (HbA1c) (−0.48%, p =0.002), with modest lipid improvement. Liver function tests and immunosuppression trough levels remained stable, and no treatment-limiting adverse events occurred. In matched analyses (80 GLP-1 RA users vs. 116 non-users), GLP-1 RAs facilitated greater weight loss (−3.4 kg difference, p =0.009) and HbA1c reduction (−0.43% difference in HbA1c, p =0.042) without increased risk of allograft dysfunction, T-cell–mediated rejection (TCMR), or MACE. This multicenter, international study demonstrates GLP-1 RAs are safe and moderately effective in reducing weight and improving metabolic parameters post-LT, without adverse effects on allograft function or immunosuppression, despite limitations of low dosing. Prospective, randomized trials of GLP-1 RAs in LTRs are thus warranted.

Background Female sex is associated with lower incidence of myocardial infarction, especially at younger ages. However, sex differences in mortality and coronary artery disease patterns among young patients with ST‐segment–elevation myocardial infarction are not well established. This study evaluated sex differences in in‐hospital and 1‐year all‐cause death and in the extent of coronary artery disease in patients aged ≤45 years with ST‐segment–elevation myocardial infarction. Methods A systematic review (December 9, 2025) was conducted using PubMed, Cochrane, Embase, major cardiology conference proceedings, and ClinicalTrials.gov . Studies comparing sexes for outcomes were included. Non‐English publications, abstracts without full text, and studies published before 2010 were excluded. A random‐effects meta‐analysis was performed, with results presented as relative risks (RR) and 95% CIs. Heterogeneity was assessed using τ and I 2 , risk of bias using the Risk of Bias in Nonrandomized Studies of Interventions tool. The study was registered on the International Prospective Register of Systematic Reviews. Results Eleven studies including 738 029 patients with ST‐segment–elevation myocardial infarction (22% women) were analyzed. Female sex was associated with higher unadjusted in‐hospital (RR, 1.56 [95% CI, 1.40–1.74]; τ=0.04; I 2 =0%) and 1‐year mortality rate (RR, 1.78 [95% CI, 1.50–2.12]; τ=0.00; I 2 =0%). Women more frequently had single‐vessel disease (73% versus 60%; RR, 1.13 [95% CI, 1.03–1.23]; τ=0.07; I 2 =67%), while men had 2‐vessel (23% versus 18%; RR, 0.76 [95% CI, 0.68–0.85]; τ=0.00; I 2 =0%;) and 3‐vessel disease (16% versus 9%; RR, 0.49 [95% CI, 0.27–0.86]; τ=0.41; I 2 =33%). Conclusions In young patients with ST‐segment–elevation myocardial infarction, female sex is associated with higher unadjusted in‐hospital and 1‐year death despite less extensive CAD. Further studies adjusting for comorbidities and standardizing CAD definitions are needed.

Abstract Aims Mitral valve prolapse (MVP) is a common valvular disorder associated with ventricular arrhythmias (VAs) in a subgroup of patients, known as arrhythmic MVP (AMVP). Arrhythmic MVP patients with malignant VAs typically receive an implantable cardioverter-defibrillator (ICD) for secondary prevention. However, data regarding the incidence of appropriate ICD therapy and the type of arrhythmia recurrence in this population remain scarce. This study aimed to evaluate the incidence of appropriate ICD therapies and type of arrhythmia recurrence in AMVP patients with an ICD implanted for secondary prevention. Methods and results A systematic literature search was conducted in PubMed/MEDLINE and EMBASE databases until January 2025. Studies reporting the incidence of appropriate ICD therapy in AMVP patients were included. A total of 9 studies met the inclusion criteria, resulting in 166 AMVP patients with ICDs for secondary prevention. The mean age was 41.8 years, with 55.8% of patients being female. Over a weighted mean follow-up of 4.9 ± 3.1 years, 34.9% [95% confidence interval (CI): 28.1–42.5] of the patients experienced recurrence of VA. The pooled incidence of appropriate ICD therapies during follow-up was 8.1 per 100 person-years (95% CI: 5.6–10.5, I2: 11.7%). Regarding the type of arrhythmic recurrence, the majority of arrhythmias (53.8%, 95% CI: 44.3–63.0%) were in the form of ventricular fibrillation or polymorphic ventricular tachycardia (VT), while the remaining arrhythmias were reported as monomorphic VT. Among 67 ventricular arrhythmic episodes reported in 7 studies with available data, 65 required shock therapy, corresponding to a shock proportion of 97.0% (95% CI: 89.6–99.6%). Conclusion Arrhythmic MVP patients with ICDs for secondary prevention exhibit a high risk of recurrent arrhythmias, with recurrences in the form of polymorphic VA occurring in more than half of the cases. PROSPERO registration number: CRD42024588610

INTRODUCTION: Nosocomial infections (NIs) in cirrhosis are associated with high mortality but could be preventable. Logistic regression (LR) models have failed to identify high-risk patients. We aimed to develop machine learning (ML) models to predict NI. METHODS: The CLEARED consortium consists of prospectively enrolled cirrhosis inpatients from >120 centers. Using day-of-admission clinical data, 3 ML approaches (random forest [RF], extreme gradient boosting, and neural networks [NNs]) were used to predict NI. Data were split 80:20 for training and testing stratified by the outcome. Models were compared using area under the receiver operating characteristic curve (AUC). RESULTS: In total, 8,263 patients (55.90 ± 13.34 years; 64.1% men) from 127 centers in 37 countries were included. NI developed in 869 (10.5%), a median of 6 (4–11) days of postadmission. Major NIs were respiratory (29.6%) and urinary tract infection (15.7%), and spontaneous bacterial peritonitis (13.5%). NIs occurred more frequently in patients from low/low-middle income countries and those with severe liver disease, alcohol etiology, and admission infections. NIs were associated with inpatient mortality (31.9% vs 8.1%, P < 0.001) and liver transplantation (4.8% vs 1.9%, P < 0.001). Although the RF model (AUC 0.69) showed good calibration (Brier score 0.09), outperforming extreme gradient boosting, neural network, and LR models (AUC 0.66 for all; LR comparison P = 0.043), no model achieved AUC ≥0.80 for clinical utility. At 10% predicted probability threshold, the RF model demonstrated only 75.4% sensitivity, 52.9% specificity, and 15.9% positive predictive value (PPV). DISCUSSION: NIs cannot be accurately predicted from day-of-admission data using ML models, even in a large, prospective, global cirrhosis cohort. Every hospitalized patient with cirrhosis should receive protocolized infection control measures.

ABSTRACT In 2018, the International Niemann‐Pick Disease Alliance (INPDA) and the International Niemann‐Pick Disease Registry (INPDR) developed and published comprehensive clinical management guidelines to support inclusive and standardized care pathways in Niemann‐Pick disease type C (NPC)—an ultra‐rare, autosomal recessive, neurovisceral lysosomal disorder. Since then, advances in diagnostics, care, and the approval of two novel disease‐modifying agents have underscored the need to revise these guidelines to ensure safe, consistent, and high‐quality care for those affected by NPC. In response, the INPDA and INPDR convened a multidisciplinary Guidelines Development Group (GDG) comprising individuals with NPC expertise from 14 countries across five continents, representing a broad range of specialties, as well as patients and families involved in NPC care. Informed by a comprehensive literature review and two meetings, the GDG systematically reviewed, revised, and updated the 2018 guideline statements, re‐evaluating the level of evidence, strength of recommendations, and expert agreement for each. The resulting 2025 consensus clinical management guidelines constitute a timely, up‐to‐date, and internationally applicable resource for the diagnosis, treatment, and holistic management of individuals with NPC. These guidelines serve as a critical resource for specialist centers, hospital‐based medical teams, staff involved in NPC patient care, family physicians and other primary caregivers, and, importantly, patients and their families.

Background/Aims: Infections with drug-resistant organisms (DROs) are associated with poor outcomes in cirrhosis. Rifaximin, widely used for hepatic encephalopathy (HE), could promote cross-resistance, but data regarding clinical impact are conflicting. Aim: Determine predictors of DROs in a global cirrhosis inpatient cohort focusing on preadmission rifaximin use.Methods: From the global CLEARED consortium, we focused on cirrhosis inpatients with infections on/during admission. Clinical/demographic/medication, especially rifaximin details were recorded. The primary outcome was DRO development. Multivariable regression for DRO including clinical, medications, and country income was performed.Results: 2,949 infected inpatients (55.3 years, 62.9% male) were included. 12.2% of all and 24.4% of culture-positive infections developed DROs; these patients had higher HE (39 vs. 31%, <i>P</i>=0.003), hepatorenal syndrome (25 vs. 19%, <i>P</i>=0.006), lactulose (55 vs. 47%, <i>P</i>=0.008) and rifaximin use (34 vs. 27%, <i>P</i>=0.006) on crude comparisons but country-income distributions were similar. 29.7% were on pre-admission rifaximin, mostly HE-related; they had more advanced cirrhosis and from low/low-middle-income countries. Daptomycin was used in 1.5%, linked with DROs (5.0 vs. 1.0%, <i>P</i><0.0001) without a difference in rifaximin use (1.4 vs.1.7%, <i>P</i>=0.61). On adjusted analysis, MELD-Na (1.03, 95% CI 1.02–1.04, <i>P</i><0.001) increased, whereas male sex (0.73, 95% CI 0.58–0.92, <i>P</i>=0.008) and hepatitis-B (0.65, 95% CI 0.45–0.92, <i>P</i>=0.020) decreased DRO. Rifaximin was not associated with DROs overall (OR 1.07, 95% CI 0.80–1.43, <i>P</i>=0.65) or within income strata (high: 1.07, 95% CI 0.59–1.92, <i>P</i>=0.82, upper-middle: 1.18, 95% CI 0.74–1.85, <i>P</i>=0.49, low/low-middle: 1.04, 95% CI 0.60–1.81, <i>P</i>=0.90) despite sensitivity analyses.Conclusions: In this large global cohort of hospitalized patients with cirrhosis and infections, 12% developed infections involving DROs. 30% had pre-admission rifaximin use which was not linked with daptomycin use or with DRO development on adjusted analysis overall or across country income groups.

Background and importance Emergency tracheal intubation in critically ill adults is associated with a high risk of peri-intubation adverse events, making first-attempt success a key safety target. Objective This study aimed to evaluate whether the use of neuromuscular blocking agents (NMBAs) improves the proportion of first-attempt success and reduces adverse events during emergent intubations outside the operating room. Methods This was a systematic review and meta-analysis of randomized clinical trials or nonrandomized studies comparing sedative-hypnotic plus NMBA versus sedative-hypnotic alone in critically ill adults undergoing emergency endotracheal intubation in nonoperative settings. Animal, cadaveric, manikin/simulation, and pediatric studies were excluded. Articles were screened on 21 August 2025, in Ovid MEDLINE, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection. Main results Of 4736 screened citations, 13 studies (8 cohort; 5 before-after studies) were included in the quantitative analysis, with 14 072 participants. NMBA use was associated with higher first-attempt success, which ranged from 69 to 92% (pooled odds ratio, 2.72; 95% onfidence interval: 1.42–5.21; low-certainty evidence). Secondary outcomes related to adverse events were rated as very low certainty due to sparse data, inconsistent reporting, and serious imprecision. Conclusion NMBA use during emergency intubation was associated with improved first-attempt success, although the certainty of evidence was low.