Citations

Abstract Background Primary aldosteronism (PA) is a common treatable cause of hypertension. When caused by unilateral adrenal disease, it is potentially curable by adrenalectomy. However, specialized tests and other factors may delay definitive treatment. We assessed the time to adrenalectomy (TTA) for patients worldwide. Methods We conducted an international, multicentre retrospective study involving 39 centres from 15 countries to determine the total time taken from the first presentation to adrenalectomy and the intervals between each stage (screening, confirmatory, subtyping, and adrenalectomy). We included patients with PA who underwent adrenalectomy from January 1, 2018, to October 30, 2022. Post-adrenalectomy outcomes were evaluated using the Primary Aldosteronism Surgery Outcome criteria. We performed multivariable quantile and linear regression to identify characteristics associated with longer TTA. Results We included 861 patients, mean age 49.3 ± 11.1 years, and 44.5% were women. Overall median TTA was 13.5 months, IQR: 6.6-24.5. Median intervals were 0.1 months (screening), 1.0 months (confirmatory), 4.1 months (subtyping), and 4.3 months (adrenalectomy). On multivariable analysis, median TTA was increased by 5.4 months for each additional adrenal vein sampling (AVS) procedure. Other factors associated with longer TTA included adrenalectomy post-COVID-19, younger age, and additional screening tests. Compared with countries with routine AVS, those without AVS had a shorter TTA (6.1 vs 15.1 months, P < .001), but greater likelihood of absent/partial biochemical success post-adrenalectomy (27.4% vs 12.4%, P < .001). Conclusion Primary aldosteronism management is time-consuming worldwide, especially for subtyping tests and adrenalectomy. While omitting AVS reduces overall time, patients are less likely to achieve biochemical cure post-adrenalectomy.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

We performed a retrospective review of patients with lichen planus pemphigoides (LPP) over almost a 23-year period to gather clinical, histopathological, immunological and treatment-related information and to compare idiopathic LPP with drug-induced LPP. This study represents the largest single-institution case series of LPP to date and includes novel findings related to mucosal involvement, autoantibody profiles and the value of monitoring bullous pemphigoid (BP) autoantibodies in predicting treatment response. This study also includes characteristic histopathological findings that can aid in the diagnosis and differentiation of LPP from BP, in addition to comparisons between idiopathic LPP and drug-induced LPP.

Objective: To develop and validate a risk score for predicting post-transplant recurrence in perihilar cholangiocarcinoma (pCCA) patients. Background: pCCA is an aggressive malignancy with a poor prognosis. Although neoadjuvant chemoradiation (CRT) followed by liver transplantation (LT) offers a potential cure for patients with unresectable, early-stage de novo or primary sclerosing cholangitis (PSC)-associated pCCA, post-transplant recurrence negatively impacts survival. Currently, no risk stratification tools exist. Methods: This retrospective study included consecutive patients with unresectable de novo or PSC-associated pCCA who underwent neoadjuvant CRT followed by LT at Mayo Clinic (1993–2024). Predictors of post-transplant recurrence were identified using multivariable Cox regression with LASSO variable selection. The Perihilar Cholangiocarcinoma Risk Estimation of Tumor Recurrence after Transplant (PRETREAT) risk score was created by assigning points from model coefficients. Score performance was evaluated by discrimination (c-statistic), internally validated with 10-fold cross-validation, and externally validated in a separate cohort. Survival outcomes were compared across 3 PRETREAT risk groups and between 2 time periods. Results: This study included 399 patients (development: 301; validation: 98). The 5-year cumulative incidence of post-transplant recurrence was 29.7% in the development cohort and 27.6% in the validation cohort. Multivariable analysis identified 4 independent predictors: macroscopic residual tumor on explant [hazard ratio (HR): 12.4], vascular encasement (HR: 2.18), lymphovascular invasion (HR: 2.04), and radial tumor diameter (HR: 1.02/mm). The PRETREAT score (0–22), based on these factors, demonstrated excellent performance in both internal and external validation (C-index 0.83 and 0.85, respectively). Patients were stratified into low-risk (0–7), moderate-risk (8–15), and high-risk (16–22) groups. The 5-year recurrence-free survival rates significantly differed across low-risk, moderate-risk, and high-risk groups (89.0%, 38.3%, and 15.4%, respectively; P<0.001). Over the last decade, overall survival improved significantly only in moderate-risk patients (70.4% vs 46.9%, P=0.024), without significant improvement in recurrence-free survival. Conclusions: The PRETREAT score provides a valuable tool for guiding post-transplant management of pCCA, enabling risk-stratified surveillance, and laying the foundation for future clinical trials.

Abstract P2x purinoreceptor 7 (P2RX7), an ATP-gated ion channel, is known to play pivotal roles in the progression of Alzheimer’s disease (AD), although its cell type-specific pathological mechanisms have yet to be elucidated. Here, we show that genetic deletion of P2rx7 mitigates brain atrophy, tau accumulation and cognitive impairment in PS19 tauopathy mice. Specific deletion of P2rx7 in microglia, but not astrocytes, significantly suppresses tau propagation from the entorhinal cortex to CA1 in the hippocampus, an early event in AD pathology. Single-cell (sc)-RNA sequencing of mouse brains revealed specific P2rx7 expression in microglia, inducing inflammatory changes accompanied by elevated extracellular vesicles (EVs) secretion in PS19 mice. Brain-derived EVs (BDEVs) proteome demonstrated that P2RX7 increases EV cargo loading of tau and mitochondrial molecules in BDEVs from PS19 mice, which was further validated by single-molecule super-resolution. Notably, following the injection of BDEVs isolated from PS19 mice with or without P2rx7 deficiency, the microglial transcriptome of recipient mice revealed enriched DNA-sensing and type II interferon signaling in response to BDEVs from PS19 mice, which was diminished in the group injected with P2rx7-deficient BDEVs. Thus, our results indicate that P2RX7 regulates EV-mediated tau and mitochondrial transfer and inflammatory activation in microglia with increased EV secretion, thereby contributing to tauopathy and neurodegeneration, highlighting the therapeutic potential of targeting the P2RX7-EV axis in AD.

ABSTRACT Background In healthy controls, higher gastric accommodation (GA) was associated with slower gastric emptying (GE) of solids. Aims In patients with gastroparesis: (1) To investigate the association between GA and GE of solids. (2) To assess the prevalence of abnormally high GA. Methods An electronic medical records (EMR) review (2010–2024) was conducted on 745 adult patients with measured GA following 300 kcal Ensure using SPECT, and scintigraphy‐based GE of solids (320 kcal, 30% fat, egg meal). Among these patients, 284 had gastroparesis (GE < 25% emptied at 2 h or < 75% emptied at 4 h). Spearman correlation analysis examined associations between GA volume or ratio and GE at 1, 2, and 4 h, and GE T 1/2 . Results Weak positive correlations were observed between GA volume and GE of solids % at 1 and 2 h (respectively R s = 0.148, p = 0.0234, and R s = 0.121, p = 0.042). In addition, there was a correlation between GA ratio and GE of solids % at 2 h ( R s = 0.143, p = 0.0160). However, there were no significant correlations of GA with GE % at 4 h or GE T 1/2 . Among the 284 patients with gastroparesis, we had documented increased GA, assessed by postprandial minus preprandial gastric volume (> 640 mL), in 7.75%, and increased GA by GA ratio > 3.85 in 22.9%. Conclusions Among patients with gastroparesis, higher GA is associated with accelerated GE of solids in the first 2 h, though the effect size is small. There is no significant effect on delayed GE at 4 h or GE T 1/2 .

Abstract Single‐molecule immunoassay is a reliable technique for the detection and quantification of low‐abundance blood biomarkers, which are essential for early disease diagnosis and biomedical research. However, current single‐molecule methods predominantly rely on endpoint detection and necessitate signal amplification via labeling, which brings a variety of unwanted effects, like matrix effect and autofluorescence interference. This study introduces a real‐time mass imaging‐based label‐free single‐molecule immunoassay (LFSMiA). Featuring plasmonic scattering microscopy‐based mass imaging, a 2‐step sandwich assay format enables background reduction, minimization of matrix effect by dynamic tracking of single binding events, and fully leveraging real‐time data for improved measurement precision through a Bayesian Gaussian process model, the LFSMiA enables ultra‐sensitive and direct protein detection at the single‐molecule level in neat blood sample matrices. LFSMiA measurement is demonstrated for interleukin‐6 and prostate‐specific antigen in buffer, undiluted serum, and whole blood with sub‐femtomolar detection limits and eight logs of dynamic ranges. Moreover, comparable performance is achieved with an inexpensive miniaturized setup. To show its translational potential to clinical settings and point‐of‐care diagnostics, N‐terminal pro‐B‐type natriuretic peptide is examined in patient whole blood samples using the LFSMiA and results in a strong linear correlation (r > 0.99) with standard clinical lab results.

Background/Objectives: Accurate assessment of spinal bone density is essential for evaluating bone health, particularly in preoperative planning. Conventional manual methods for Hounsfield unit (HU) measurements rely on single-slice measurements within the region of interest, limiting their precision and reproducibility in patients with severe vertebral deformities. We hypothesize that a novel deep-reasoning and learning model (DR-AI) can fully automate spinal bone density assessment volumetrically, with high correlations to spinal bone mineral density (BMD) obtained from dual-energy X-ray absorptiometry (DXA), as well as to the T- and Z-scores. Methods: A cross-sectional study was conducted on patients who had BMD assessment of their lumbar spine and lumbar CT scans within 1 year. The fully-automated DR model was utilized to analyze the soft-tissue window of the lumbar vertebrae CT scans. Spearman correlation coefficients were calculated to assess the strength of relationships between the computed volumetric HUs and the BMD, T-, and Z-scores from each vertebra. Results: 84 patients (67 females, mean age 74.1 ± 10.3 years; 17 males, mean age 68.1 ± 12.4 years) meeting inclusion criteria. Correlation analyses for L1 to L4 showed significant positive relationships (p < 0.0001), with the strongest correlation at L2 between HU and BMD (ρ = 0.75). Conclusions: the DR model for automated assessment of volumetric HUs offers a highly reliable, efficient, and precise alternative to DXA measurements.