Citations

Background: Hepatorenal syndrome–acute kidney injury (HRS-AKI) is associated with high mortality in cirrhosis. Recent FDA approval of terlipressin and updated clinical guidance have expanded management options, but real-world practice patterns remain unknown. Methods: We conducted a nationwide survey of U.S. hepatology providers regarding HRS-AKI management practices. The 33-question survey assessed provider demographics, vasoconstrictor selection, treatment timing, and adherence to guideline recommendations. Results: Among 162 respondents, most were hepatologists (94%) at academic centers (83%). Only 11% obtained a nephrology consultation at AKI detection, with 44% waiting until worsening renal function. Terlipressin was available at 80% of institutions but more commonly at academic centers (84% vs. 53%, p =0.003). Consistent with guideline recommendations, 77% of providers initiate vasoconstrictors only after completing a trial of volume expansion (if no renal improvement), particularly in academic centers (80% vs. 60% non-academic, p =0.03). Terlipressin (49%) and midodrine/octreotide (44%) were preferred first-line treatments, with providers at academic centers more likely to use midodrine/octreotide (46% vs. 30%, p =0.008). Mean arterial pressure was used by 62% of providers to guide vasoconstrictor dosing. Most providers (73%) discontinued vasoconstrictor treatment after 4 days if no improvement. Conclusions: Significant variations exist between guideline recommendations and real-world HRS-AKI management, especially first-line treatment choice, treatment monitoring, and nephrology consultation. These findings highlight opportunities to improve guideline implementation and identify areas where practice patterns might inform provider education and future guidance updates.

The underlying immunopathogenesis of inflammatory arthritis (IA) immune-related adverse event (irAE) remains obscure. Unlike rheumatoid arthritis (RA), where autoantibodies and B cell dysfunction are central features, the contribution of humoral immunity to IA-irAE is unclear. Here, we performed immunophenotyping of peripheral blood from patients with IA-irAE and compared them with patients with seronegative RA, immune checkpoint inhibition–treated patients without irAE, and healthy controls. IA-irAE was marked with increased cytotoxic gene expression and metabolic activation in T cells and reduced CXCR3 and CCR6 expression in CD4 + T cells. Contrary to seronegative RA, patients with IA-irAE displayed no substantial elevation in autoantibody levels or atypical CD11c + CD21 − B cells. IA-irAE was further characterized by elevated levels of interleukin-6 (IL-6), IL-12, and type I interferon, which correlated with the T cell activation phenotypes. Together, our findings define IA-irAE as a disease with certain immunological features distinctive from RA, representing a potentially T cell–driven, autoantibody-independent autoimmunity. These results offer insights into immune tolerance breakdown and therapeutic targeting in irAEs.

Abstract Malignant histiocytic neoplasms (MHNs) are rare tumors derived from the mononuclear phagocyte system (MPS), encompassing histiocytic sarcoma, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, and other high-grade MPS lineage tumors. Despite advances in understanding histiocytic neoplasms, MHNs remain diagnostically challenging and lack standardized treatment algorithms. Current classification systems differ in lineage framing and fail to address mixed or ambiguous phenotypes, contributing to diagnostic uncertainty and inconsistent care. To address these gaps, the Histiocyte Society convened an international working group of pathologists and oncologists, including World Health Organization and International Consensus Classification contributors, to harmonize nomenclature, define minimum diagnostic criteria, and develop pragmatic treatment recommendations. Using a modified Delphi process and case-based review, the group formulated >40 consensus statements spanning classification, pathology, molecular testing, clinical evaluation, and therapeutic strategies. Key recommendations include the adoption of a unified MHN designation, use of a minimum immunophenotypic panel, integration of broad molecular profiling, and the documentation of previous hematopoietic malignancy. Treatment algorithms emphasize surgical resection for unifocal disease and targeted therapy or immune checkpoint inhibition for multifocal disease when actionable mutations or programmed death ligand 1 expression are present. These consensus recommendations aim to reduce diagnostic ambiguity, standardize reporting, and improve outcomes for both pediatric and adult patients. Future priorities include international registries to refine risk stratification and biomarker-driven trials exploring targeted therapy, immunotherapy, and combination approaches.

Abstract Hypoxia constrains cerebral oxygen availability and challenges brain function and stability. Although hypoxia-responsive functional connectivity (HR-FC) reorganizes rapidly with declining arterial oxygen partial pressure, its relationship to local neurovascular activity remains unclear. We examined time-resolved amplitude of low-frequency fluctuations (ALFF) in blood-oxygenation-level dependent (BOLD) fMRI during graded acute hypoxia in healthy adults, performing a continuous cognitive test (Go/No-go task) with concurrent physiological monitoring. Dynamic ALFF and functional connectivity were estimated using a sliding-window approach and analyzed across large-scale brain networks defined by Schaefer’s 17-network parcellation. Severe hypoxia elicited temporally dissociated responses across modalities. Functional connectivity increased monotonically, whereas ALFF exhibited pronounced nonlinear modulation, including phase-dependent divergence across networks. During hypoxic decompensation, the default mode network (DefaultA) showed marked ALFF suppression, whereas a ventral secondary somatosensory-dominant network (SomMotB) exhibited preferential preservation despite similar engagement in HR-FC. Together, these findings indicate that network-level ALFF captures a distinct yet complementary layer of functional dynamics, with a temporal profile distinct from functional connectivity. Spontaneous BOLD dynamics during acute hypoxia reflect structured network-level modulation rather than a uniform suppression attributable solely to reduced oxygen availability. These findings support a conceptual framework of cerebral oxygen budgeting , in which metabolic constraints reshape functional dynamics across brain networks.

Background: Patients with primary sclerosing cholangitis (PSC) are at risk for developing gallbladder neoplasia (GBN) and biliary neoplasia, including cholangiocarcinoma (CCA), because of chronic inflammation and an underlying field effect. However, the risk of CCA after GBN detection in those with PSC remains poorly understood. We aimed to determine if the incidence of CCA is higher in those with GBN. Methods: We conducted a retrospective review of adult patients with large-duct PSC seen at Mayo Clinic between January 1, 1995, and December 31, 2019. Incidence rates for CCA development were calculated. Cox regression analyses were performed to determine features associated with CCA development beginning at the time of PSC diagnosis. Results: Our study included 1,829 patients with PSC. CCA and GBN developed in 334 (18.26%) and 71 individuals (3.88%), respectively. Among those with GBN, 14 (19.72%) developed CCA. The annual incidence of CCA was nearly twofold higher in patients with GBN (4.34% versus 2.21%). GBN was associated with CCA in an unadjusted analysis (hazard ratio 2.14 [95% CI 1.16–3.94]). When adjusting for other predictors of CCA, an association between GBN and CCA may remain. Conclusions: While few patients with PSC develop GBN, this subgroup is more likely to develop CCA. Consequently, once GBN is detected, clinicians should consider more intensive screening for CCA.

Abstract INTRODUCTION Visual perceptual difficulties occur in dementia with Lewy bodies (DLB). Normative data and cut scores for DLB and mild cognitive impairment with Lewy bodies (MCI‐LB) are needed for the 20‐item Noise Pareidolia Task. METHODS Participants included 344 cognitively unimpaired (CU), 112 DLB, and 105 MCI‐LB. Cumulative percentile ranking was used for normative classification. Receiver operating characteristic analyses, convergent validity, and associations with visual hallucinations (VH) were assessed. RESULTS In CU participants, a perfect score was average, one error was low average, and two or more errors fell below average. A cut score of one or more errors optimally distinguished CU participants from DLB (Total score area under the curve [AUC]: 0.82, Noise score AUC: 0.77) and MCI‐LB (Total score AUC: 0.75, Noise score AUC: 0.74). A cut score of two or more errors lowered sensitivity but increased specificity to 94%. Performance was associated with VH in DLB, but not MCI‐LB. DISCUSSION Results establish normative data for the 20‐item Noise Pareidolia Task and support its use in DLB and MCI‐LB.

Variants in TMEM106B and GRN , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN -mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

ABSTRACT Objective To (1) validate GAD65‐ELISA detection and quantification for type 1 diabetes mellitus and autoimmune neurological diagnoses, (2) correlate ELISA results (reference range < 5 IU/mL) with established radioimmunoprecipitation assay (RIA; ≤ 0.02 nmol/L), and (3) define ELISA clinical utility and pitfalls. Methods Serum performance for diabetes (FDA‐cleared, undiluted) was verified, and neurological laboratory‐developed serum and CSF dilution protocols were validated to extend the reportable range beyond > 250 IU/mL. ELISA and RIA values were correlated, including established neurological RIA cut‐offs (serum ≥ 20 nmol/L; CSF any positive). Results ELISA met analytical criteria (precision, accuracy, sensitivity, specificity, reference range) in serum and CSF and was clinically equivalent to RIA for autoimmune diabetes. Neurological ELISA cut‐offs were established at 10,000 IU/mL (serum) and 100 IU/mL (CSF). Precision was better below 10,000 IU/mL (CVs < 20%) than above (CVs 30.8% serum; 26.5% CSF). ELISA–RIA correlation and agreement was stronger below the neurological cut‐off (R 2 = 0.89) than above (R 2 = 0.36). Positive agreement for RIA‐defined neurological disease was 100% in serum and CSF; all serums were > 10,000 IU/mL. Clinical specificity was 97.5% in serum and 100% in CSF, exceeding reported RIA specificity. Screen results > 250 IU/mL spanned a wide range of dilution values; many were below the neurological cut‐off. Most patients with paired serum/CSF positivity showed elevated GAD65 IgG indices. Interpretation GAD65 ELISA and RIA have equivalent sensitivity for autoimmune diabetes and neurological testing, with higher specificity for ELISA. A serum cut‐off of 10,000 IU/mL is informative but requires clinical context, and dilution of screen > 250 IU/mL samples is essential for neurological interpretation.