Citations

Objective: Review the current literature for available treatments for acute cholecystitis (AC) in nonsurgical candidates and provide guidelines for the management of these patients. Background: Cholecystectomy is the gold-standard treatment modality for AC. A considerable number of patients who are not eligible for surgery are managed by percutaneous and endoscopic techniques. There is recent data regarding endoscopic ultrasound-guided gallbladder drainage and emerging percutaneous approaches to address cholelithiasis and remove drains. Methods: An expert panel of surgeons, gastroenterologists, and interventional radiologists reviewed the current literature and provided recommendations for AC management in nonsurgical candidates. Recommendations were based on relevant evidence, with quality and strength assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Results: Percutaneous cholecystostomy is advised for patients ineligible for lumen-apposing metal stent (LAMS) or with reversible conditions, aiming to bridge to cholecystectomy. The optimal timing of cholecystectomy after percutaneous cholecystostomy remains unclear. In cases where surgery is not feasible, potential definitive treatments such as percutaneous cholecystolithotripsy/lithectomy and cholecystoduodenal stenting should be considered. For calculous AC, endoscopic ultrasound-guided gallbladder drainage with LAMS is recommended as a therapy for never-surgical candidates if they are eligible for monitored anesthesia care or general anesthesia and there is institutional expertise and minimal intervening ascites. Conclusions: The management of AC in nonsurgical candidates remains a challenge, with institutional protocols varying based on physician preferences and expertise. The proposed protocol integrates percutaneous and endoscopic approaches and emphasizes the need for multidisciplinary collaboration. Further research is required to evaluate these evolving management techniques, as the current literature is limited.

Background Severe alcohol-associated hepatitis (sAH) is a life-threatening condition with high mortality, where corticosteroid use is the only treatment that has shown short-term benefits. Pentoxifylline, an anti-tumour necrosis factor-alpha agent, has been proposed for its potential to improve outcomes, especially in patients with acute kidney injury (AKI). We aimed to evaluate the impact of pentoxifylline on mortality in patients with sAH and AKI in a well-characterised global cohort. Methods We conducted a retrospective, registry-based study including patients meeting the National Institute on Alcohol Abuse and Alcoholism clinical criteria for sAH and AKI. Mortality was the primary endpoint, with liver transplantation as a competing risk. Statistical analysis included Cox regression and Kaplan-Meier survival estimates. Results We included 525 patients from 20 centres across eight countries. The median age was 48 years, with 26.1% females, and 76.9% had a history of cirrhosis. Multivariable Cox regression models showed that pentoxifylline use was not associated with survival (HR 1.20, 95% CI 0.85 to 1.69, p=0.291). Factors associated with mortality included age (HR 1.23, 95% CI 1.10 to 1.36, p<0.001), Model for End-Stage Liver Disease score at admission (HR 1.06, 95% CI 1.04 to 1.08, p<0.001) and renal replacement therapy use (HR 1.39, 95% CI 1.05 to 1.84, p=0.019). The main causes of death were multiple organ failure (42%), infections (10%), oesophageal varices bleeding (7%) and renal failure (6%). Conclusion Pentoxifylline showed no significant benefit on mortality in patients with sAH and AKI. Further studies are needed to refine treatment strategies for this high-risk group.

Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)–autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.

Abstract Tau aggregation in early affected regions in the asymptomatic stage of Alzheimer’s disease marks a transitional phase between stable asymptomatic amyloid positivity and the clinically manifest stage. How this early region tau aggregation covertly affects brain function during this asymptomatic stage remains unclear. In this study, 83 participants underwent a 128 electrodes resting-state EEG, a dynamic 100 min tau PET scan (18F-MK6240), an amyloid PET scan, a structural T1 MRI scan and neuropsychological assessment. Tau PET data quality control led to a final sample of 66 subjects. Based on the clinical and cognitive status, amyloid and tau PET biomarkers, the group was composed of 37 cognitively unimpaired amyloid negative subjects, 14 cognitively unimpaired amyloid positive subjects and 15 patients with prodromal Alzheimer’s disease. We calculated the average undirected weighted Phase Lag Index in the alpha frequency band with eyes closed and used this as weights for the graph and analysed the global clustering coefficient and characteristic path length in sensor space. As a primary objective, we assessed how these global graph measures correlated with tau PET values, in an a priori defined early metaVOI, comprised of the entorhinal and perirhinal cortex, hippocampus, parahippocampus and fusiform cortex. As secondary analyses, we investigated which specific brain regions were mainly implicated, what the contribution was of amyloid, the effect of electrode density and the relation to cognitive performance. In the overall group and within the cognitively unimpaired amyloid positive subgroup, tau aggregation was associated with a decrease in global clustering coefficient and an increase in characteristic path length. These changes reflect the initial disintegration of the small-world brain network during the transitional phase, even before clinical symptoms are apparent. The correlations are most prominent in the perirhinal cortex, indicating that global deterioration of the network is already present early in the Alzheimer’s disease pathology. We obtained similar results with only taking 64 electrodes into account. To conclude, we found that in the asymptomatic stage of Alzheimer’s disease, tau PET load in medial temporal cortex is associated with global electrophysiological measures of network disintegration. The study demonstrates the potential value of high-density EEG in the era of biologically defined Alzheimer’s disease for characterizing brain function in the asymptomatic stage.

Abstract INTRODUCTION β‐synuclein is a promising blood marker to track synaptic degeneration in Alzheimer's disease (AD) but changes in preclinical AD are unclear. METHODS We investigated serum β‐synuclein in 69 cognitively unimpaired mutation non‐carriers, 78 cognitively unimpaired AD mutation carriers (asymptomatic AD), and 31 symptomatic mutation carriers from the Dominantly Inherited Alzheimer Network. RESULTS β‐synuclein levels were already higher in asymptomatic AD mutation carriers compared to non‐carriers and highest in symptomatic carriers. Longitudinal trajectories and correlation analyses indicated that β‐synuclein levels start to rise after amyloid deposition preceding axonal degeneration, brain atrophy and hypometabolism, and cognitive decline. β‐synuclein levels were associated with cognitive impairment and gradually increased with declining cognition. DISCUSSION Our study supports the use of blood β‐synuclein to track synaptic changes in preclinical AD and as a surrogate marker for cognitive impairment which might be used in early diagnosis and to support patient selection and monitoring of treatment effects in clinical trials. Highlights Blood β‐synuclein levels were already higher in asymptomatic Alzheimer's disease (AD) mutation carriers. Blood β‐synuclein levels were highest in symptomatic AD mutation carriers. Blood β‐synuclein levels start to rise 11 years before symptom onset. Rise of β‐synuclein precedes axonal degeneration, brain atrophy, and cognitive decline. β‐synuclein levels gradually increased with declining cognition.

Pregnancy induces significant physiologic changes that impact the cardiovascular system, potentially exacerbating pre-existing cardiac conditions or precipitating new illnesses. Pregnant patients with cardiac emergencies pose unique challenges, as standard interventions may pose risks to the developing fetus. This article aims to enhance emergency physicians’ confidence in managing pregnancy-related cardiac emergencies by providing a structured approach to initial evaluation and stabilization. We review eight common categories of pregnancy-associated cardiac illness: gestational hypertension and pre-eclampsia, cardiomyopathy, arrhythmias, valvular disease, aortopathies, congenital heart disease and pulmonary hypertension, coronary disease, and anticoagulation-related complications. For each condition, we summarize relevant pregnancy-specific pathophysiology and outline evidence-based, personalized emergency management strategies.