Citations

Abstract Objective The aim of this study was to evaluate a large cohort of gallbladder amyloid cases to determine clinical and morphologic features. Methods Cholecystectomy specimens (N = 118) typed using proteomics-based techniques between 2008 and 2023 were identified. Clinical and morphologic features were reviewed. Results Six amyloid types were identified: ATTR (n = 63, 53.4%), AL (n = 46, 39.0%), AA (n = 4, 3.4%), AApoA1 (n = 2, 1.7%), ALECT2 (n = 2, 1.7%), and AEFEMP1 (n = 1, 0.8%). Amyloidogenic mutations were detected in 3 ATTR cases and 2 AApoA1 cases. Morphologic review (n = 26) revealed perimuscular vessel involvement in all cases. Amyloidosis was an unexpected diagnosis first made on the cholecystectomy specimen in half of the patients with clinical information (n = 10). All 9 patients with follow-up had evidence of systemic disease. In 2 patients, cholecystic involvement was initially missed and only retrospectively identified after the diagnosis of cardiac amyloidosis. Conclusions In patients with clinical data, amyloidosis was often unexpected, the gallbladder was commonly the first tissue sampled with amyloidosis, and all patients had systemic disease. Thorough review of cholecystectomy specimens with careful inspection of perimuscular vessels, coupled with a low threshold for ordering Congo red stain in elderly individuals and amyloid typing using a robust method such as proteomics, can prevent a delay in amyloid diagnosis and management.

ABSTRACTBackground and ObjectiveSeladelpar is an oral, once‐daily medication that improves cholestasis through its selective peroxisome proliferator‐activated receptor (PPAR‐δ) agonism. It shows promising efficacy in treating primary biliary cholangitis (PBC) patients.MethodsA systematic review and meta‐analysis synthesizing evidence from randomized controlled trials (RCTs) obtained from PubMed, Cochrane, Scopus, and WOS until July 19th, 2025. Dichotomous outcomes were reported using risk ratio (RR) and continuous outcomes using mean difference (MD), with a 95% confidence interval (CI).ResultsThree RCTs with 499 patients were included. Seladelpar was significantly associated with an increased ALP normalization (RR: 21.12 with 95% CI [4.14, 107.58], p < 0.01), biochemical response (RR: 3.06 with 95% CI [2.00, 4.70], p < 0.01), and decreased pruritus NRS score change (MD: −1.47 with 95% CI [−2.73, −0.21], p = 0.02). Seladelpar was also significantly associated with a decreased incidence of pruritus (RR: 0.54 with 95% CI [0.31, 0.94], p = 0.03) but with an increased incidence of headache (RR: 3.37 with 95% CI [1.11, 10.23], p = 0.03). However, there was no significant difference between seladelpar and placebo regarding the incidence of any adverse events (RR: 0.96 with 95% CI [0.87, 1.06], p = 0.43).ConclusionSeladelpar improved liver biomarkers of cholestasis and reduced pruritus in patients with PBC without significantly increasing the adverse effects. This makes seladelpar a promising addition to the treatments available for PBC.Trial Registration: PROSPERO: CRD42024521208

Abstract Despite significant therapeutic advances in multiple myeloma (MM), outcomes in patients with plasma cell leukemia (PCL) remain dismal. We conducted a multicenter retrospective analysis of patients with PCL who were treated with the B-cell maturation antigen–directed chimeric antigen receptor T-cell (CAR-T) products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). We identified 34 patients; 19 patients received ide-cel and 15 received cilta-cel. With a median follow-up of 11.9 months, the overall median progression-free survival (mPFS) was 9.0 months (95% confidence interval [CI], 4-15) and the median overall survival (mOS) was 13.0 months (95% CI, 8 to not estimable [NE]). The 1-year cumulative incidence of progression or death was 72%, and the 1-year cumulative incidence of death was 47%. Patients who received cilta-cel had a longer mPFS (19.0 months vs 6.0 months) and mOS (&gt;23 months [NE] vs 9.0 months) when compared with those treated with ide-cel. Similarly, the 1-year cumulative incidence of disease progression or death was 37.5% (95% CI, 17.4-68.5) with cilta-cel, whereas all patients treated with ide-cel progressed or died within 12 months of infusion. The rates of hematologic and nonhematologic toxicities were similar between patients treated with cilta-cel and those treated with ide-cel and were consistent with those reported in patients with MM. In this first multicenter study that evaluated patients with PCL who were treated with standard-of-care CAR-T products, we show that CAR-T is safe, feasible, and associated with improved outcomes when compared with historic standards.

IMPORTANCE: Accurate and reliable sedation assessment is crucial to improving patient outcomes in the ICU. OBJECTIVE: To evaluate the inter-rater agreement and reliability of Richmond Agitation Sedation Scale (RASS) assessments between bedside nurses and trained investigators in patients receiving mechanical ventilation in the ICU. DESIGN, SETTING, AND PARTICIPANTS: An assessor triad, comprising an ICU nurse providing direct patient care and two trained investigators, simultaneously performed RASS assessments during 79 encounters with 62 unique patients receiving mechanical ventilation at two ICUs at a tertiary care academic hospital in Colorado. A total of 58 nurses participated in the study. MAIN OUTCOMES AND MEASURES: The inter-rater reliability of RASS assessments was evaluated with the intraclass correlation coefficient (ICC) and weighted kappa (κ), and inter-rater agreement was evaluated with percentage agreement and Bland-Altman analysis. RESULTS: Acute respiratory failure (55%) and altered mental status (21%) were the most common reasons for mechanical ventilation. Most patients were receiving one (interquartile range, 0.5–2) continuous sedative during the assessment. The inter-rater reliability of RASS assessments between the nurses and investigators (ICC, 0.728–0.779; weighted κ, 0.62–0.63) was lower than between the two investigators (ICC, 0.891; weighted κ, 0.80). The assessor triad agreed on the same RASS values in only 35% of observations. The average differences in RASS were greater between the investigators and nurses, ranging from –0.658 to –0.544, compared with 0.114 between the two investigators. Compared with the mean of the two investigators, RASS values recorded by nurses were more likely to be higher (52% of observations), indicating a lighter sedation level. In 16% of observations, at least one assessor commented on uncertainty or ambiguity with the RASS. CONCLUSIONS AND RELEVANCE: The inter-rater reliability of RASS assessments was high. However, we observed variations in the degree of agreement by assessor category. Further studies are necessary to explore how factors such as assessor characteristics, ICU environment, and patient conditions influence the inter-rater agreement of the RASS in contemporary ICU practices.

Abstract Erdheim-Chester disease (ECD) is a rare systemic histiocytic neoplasm, with cardiac morbidities, including cardiovascular (CV) risk factors and cardiac conditions, playing a significant yet poorly understood role in the disease burden. This study evaluated the prevalence, characteristics, and prognosis of ECD in patients with (ECD-C) and without cardiac involvement (ECD-noC) and compared the burden of cardiac morbidities with matched controls. Patients diagnosed with ECD between 1990 and 2021 at a tertiary center were included, with cardiac involvement centrally assessed using radiographic studies. Cardiac morbidities were compared with a control group without ECD, matched for age, sex, body mass index, and smoking history. Among 104 patients with ECD, 39 (37%) had cardiac involvement. Patients with ECD-C had higher rates of hypertension (67% vs 46%), hyperlipidemia (67% vs 40%), heart failure (36% vs 8%), and pericardial effusion (28% vs 2%) than those with ECD-noC. Compared with the matched non-ECD cohort, patients with ECD had higher prevalence of coronary artery disease (20% vs 7%), heart failure (18% vs 4%), and antihypertensive drug use (55% vs 40%). Notably, patients with ECD-C had inferior progression-free survival (PFS) from frontline therapy compared with patients with ECD-noC (5-year PFS, 28.3% vs 70.5%). These findings highlight the burden of CV risk factors and cardiac conditions in ECD, even without a clinical diagnosis of ECD-C. Importantly, this cardiac morbidity burden is substantial for patients with ECD-C compared with ECD-noC. Our findings highlight the need for comprehensive cardiac risk assessment and management strategies to improve patient outcomes.

Abstract Immune thrombocytopenia (ITP) carries an increased risk of thrombosis, which may be further amplified by splenectomy and thrombopoietin receptor agonists (TPO-RAs). Although each intervention has been individually studied for its thrombotic risk, data are lacking on the safety of postsplenectomy TPO-RA use. We conducted a retrospective cohort study of adult patients with ITP who underwent splenectomy between 2011 and 2024. Patients were stratified on the basis of postsplenectomy TPO-RA use. The primary outcome was incidence of thrombosis. Secondary outcomes included bleeding, mortality, and hematologic response. Time-to-event analyses and multivariate Cox regression were performed. Among 88 patients, 37 (42%) patients received TPO-RAs after splenectomy. Thrombosis occurred in 17 patients in the TPO-RA group vs 14 patients in the non–TPO-RA group (P = .07). The 10-year cumulative incidence of thrombosis was numerically higher in the TPO-RA group (57% vs 36%), with clustering of events within the 3 months of postsplenectomy TPO-RA initiation. Venous events predominated; arterial events were rare. No significant differences were observed in bleeding or mortality rates between groups. Platelet counts alone did not independently affect bleeding or thrombosis. TPO-RA use after splenectomy was not significantly associated with increased thrombosis risk. However, early initiation may coincide with a high-risk period, and the sustained numerical difference in cumulative incidence throughout follow-up highlights potential clinical relevance. These findings support the need for individualized thromboprophylaxis and prospective evaluation of TPO-RA safety in this setting.

Our study examined healthy human MASH and MASH-associated hepatocellular carcinoma (MASH-HCC) livers using bulk and scRNA sequencing, spatial transcriptomics, and immunohistochemistry. We found that ACSLs displayed differential and spatially heterogeneous expression. ACSL4 was abundant in tumor tissues, whereas ACSL5 was elevated in noncancerous MASH tissues. ACSL4 was mainly found in immune cells like natural killer cells and natural killer T cells in murine MASH-HCC, suggesting its role in tumor immune microenvironment modulation.

ABSTRACT Hepatopulmonary syndrome (HPS) affects up to one‐third of patients with advanced chronic liver disease (ACLD) and is an independent risk factor for increased mortality. While HPS often improves following liver transplantation, patients with severe or very severe HPS—classified by partial pressure of arterial oxygen (PaO 2 ) <60 mmHg—face higher post‐transplant complications and mortality. However, evidence suggests that even patients with severe HPS may benefit from liver transplantation when performed at high‐volume centers. To assess post‐transplant outcomes in this population, we conducted a retrospective chart review of 20 patients diagnosed with severe or very severe HPS who underwent liver transplantation at Mayo Clinic Hospital in Arizona between 2014 and 2024. The most common post‐transplant complication was persistent hypoxemia, managed on a case‐by‐case basis with various treatments, though no single approach proved consistently superior. All patients who received transplants demonstrated improvement; 84% of patients ultimately discontinued supplemental oxygen, with a mean time of 250 days (range: 0–1113 days). Time was the key factor in recovery. Notably, no deaths in our cohort were directly attributed to HPS. These findings support liver transplantation as a viable treatment option for HPS, even in severe cases, and underscore the importance of experienced transplant centers in optimizing patient outcomes.