Citations

Objective Magnetic resonance imaging (MRI)‐visible enlarged perivascular spaces (PVS) are markers of cerebral small vessel disease (SVD) and aging, processes implicated in both neurodegenerative and cerebrovascular pathologies. However, longitudinal positron emission tomography (PET) studies examining PVS as a mechanism underlying Alzheimer's disease (AD) pathophysiological progression are lacking. Our overall objective was to investigate the associations of baseline PVS burden with white matter hyperintensity (WMH) volume, amyloid‐PET, and tau‐PET, both cross‐sectionally and longitudinally. Methods We examined 2,229 participants across the aging‐AD spectrum from the Mayo Clinic Study of Aging (MCSA) and the Mayo Alzheimer's Disease Research Center (ADRC) (mean age = 68.59 ± 12.70 and 48.94% women). PVS and WMH were quantified using a novel in‐house algorithm. Amyloid on [ 11 C]Pittsburgh Compound B (PiB)‐PET and tau on AV1451‐PET were measured. Cross‐sectional regional and global associations were examined using canonical correlation analysis (CCA). Longitudinal associations were examined using age‐ and sex‐adjusted linear mixed effect (LME) models with natural splines and subject‐wise 10‐fold cross‐validation. Result Three distinct associations were observed: (1) PVS in the basal ganglia (PVS‐BG) was associated with greater WMH volume both cross‐sectionally and longitudinally; (2) PVS‐BG covaried with higher PiB standardized uptake value ratio (SUVR) cross‐sectionally, with longitudinal trajectory associations limited to amyloid‐negative individuals; (3) PVS in the centrum semiovale (PVS‐CSO) was not associated with amyloid or tau, but was associated with occipital WMH, a pattern characteristic of CAA. Interpretation Findings lend support for PVS‐BG as an early indicator of small vessel dysfunction and WMH pathogenesis. Individuals with higher PVS‐BG burden exhibited higher WMH burden and faster WMH progression, suggesting that PVS‐BG may identify individuals at increased risk of progressive SVD. Evidence linking PVS to downstream AD biomarker progression was weaker. Findings support the relevance of PVS‐CSO to CAA, suggesting that they may reflect changes occurring early in the disease process. ANN NEUROL 2026

Context.— One objective of the College of American Pathologists/American College of Medical Genetics Cytogenetics Committee is to ensure the accurate detection and clinical interpretation of abnormalities observed by fluorescence in situ hybridization (FISH) analysis when evaluating hematologic neoplasms. Objective.— To report a 20-year performance summary (2005–2024) of FISH challenges focusing on hematologic neoplasms. Design.— A retrospective review was performed from 2005 through 2024 to identify FISH challenges specifically addressing hematologic neoplasms. The overall performance of participants was evaluated to identify potential recurring errors of clinical relevance. Results.— A total of 124 hematologic neoplasm FISH challenges from 2005 to 2024 were provided to participating laboratories, including 45 paper challenges (results and/or images were provided for interpretation purposes), 43 liquid challenges (bone marrow aspirate or peripheral blood), and 36 formalin-fixed paraffin-embedded (FFPE) tissue challenges. Of the 124 challenges, 120 (97%) exceeded the required 80% consensus for grading purposes. Of the 4 failed challenges (3%), 2 (1 liquid, 1 paper) involved the interpretation of atypical FISH signal patterns; 1 (paper) involved the interpretation of FISH signal patterns correlating involvement by myeloid versus lymphoid interphase nuclei; and 1 (liquid) likely involved a specimen processing or handling error that resulted in discordant participant responses. All 36 FFPE tissue challenges exceeded the 80% consensus for grading purposes. Conclusions.— This 20-year retrospective review demonstrates that clinical cytogenomic laboratories have been and continue to be highly proficient in the detection and interpretation of FISH abnormalities associated with hematologic neoplasms.

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after neoadjuvant therapy (NT) and curative-intent resection. Although major pathologic response predicts favorable outcomes, most patients achieve only minor response with a heterogeneous recurrence risk. We asked whether the spatial organization of residual PDAC encodes clinically relevant biology beyond residual tumor burden. Experimental Design: In a retrospective cohort of 203 patients with resected PDAC treated with NT and restricted to minor pathologic response, routine hematoxylin and eosin (H&E) whole-slide images were segmented into cancer and stroma using an artificial intelligence–enabled pipeline. Spatial composition (patch density, edge density) and configuration (compactness/complexity, intermixing) were quantified and tested for associations with disease-free survival (DFS) using multivariable models adjusted for standard clinicopathologic factors. Results: Shorter DFS was associated with a fragmented, interface-rich tumor–stroma ecology featuring higher edge density and diversity and reduced homotypic aggregation, independent of clinicopathologic variables. Two spatial risk models were independently prognostic: (i) cancer mean shape index plus stromal shape index variability [adjusted hazard ratio (HR), 1.71; P = 0.003] and (ii) mean stromal patch area plus edge density (adjusted HR, 2.19; P = 0.002). Both models stratified outcomes in which pathologic response grading and residual cancer area did not. High-risk configurations were further associated with reduced intratumoral tumor-infiltrating lymphocyte (TIL) density and infiltration ratio, with relative TIL accumulation at the cancer periphery and within the stroma, consistent with an immune-excluded phenotype. Conclusions: Residual cancer–stroma topology quantified from standard H&E slides yields independent prognostic signals after NT in PDAC, provides a cellular immune correlate for spatial risk, and motivates prospective validation and spatially informed adjuvant strategies.

Abstract Polygenic risk scores (PRSs), which quantify inherited susceptibility to complex traits and diseases, have emerged as valuable tools for risk stratification and precision medicine. Despite their promise, PRS developed on European cohorts often demonstrate substantially reduced predictive accuracy in non-European populations, due to differences in genetic architecture. The disproportionate representation of European ancestry cohorts in genome-wide association studies (GWAS) leads to inequitable deployment of PRS technologies across diverse populations. Here, we introduce PRANA (Polygenic Risk Adaptation via Neural-network Architecture), a deep learning framework that adapts an existing PRS developed on one population to other ancestries. Unlike methods that require large-scale GWAS in the target population, PRANA leverages pre-trained PRS models derived from European cohorts and adapts them using modestly sized cohorts from the target population. We evaluated PRANA on seven complex traits in South Asian, East Asian and Ashkenazi Jewish populations, as well as in selected smaller East Asian subpopulations where the scarcity of training data poses a particular challenge. PRANA mostly improved predictive performance of the baseline PRS models by 5%-20% in terms of effect size (β) and Nagelkerke’s R², and, in most cases, outperformed existing cross-ancestry multi-PRS approaches. These results highlight PRANA as a scalable and practical strategy to reduce disparities in genomic risk prediction and advance the equitable application of PRS in diverse populations.

Importance Ischemic heart disease (IHD), the leading cause of death in the US, is predominantly due to modifiable risk factors. Estimates of IHD mortality attributable to risk factors provide evidence for health policy decision-making. Objective To estimate the burden of IHD death attributable to risk factors in the US from 1990-2023. Design, Setting, and Participants The Global Burden of Disease Study 2023 (GBD 2023) used vital records and a broad set of epidemiologic data to estimate IHD death rates, risk factor exposure, and relative risk curves for risk-outcome pairs for 1990-2023 for the general population. Data analysis was performed from October 2024 to December 2025. Exposure Twelve metabolic, behavioral, and environmental risk factors. Main Outcomes and Measures The primary outcomes were IHD death rates per 100 000 persons, counts, and attributable risks from 1990-2023 by age, sex, and US state. Estimates include 95% uncertainty intervals (UI). IHD death rates were estimated using ensemble modeling methods. Risk exposures were estimated using bayesian meta-regression methods. Relative risks were estimated following the Burden of Proof framework. Results In 2023, there were 473 000 IHD deaths (95% UI, 414 000-510 000) in the US, a decrease of 58.7% (95% UI, 56.8%-61.0%) in age-standardized rate since 1990. Between 2010 and 2023, there was a 19.0% decrease (95% UI, 15.0%-22.9%) for males and a 24.5% decrease (95% UI, 20.3%-29.7%) for females in IHD death rates. High systolic blood pressure (SBP), dietary risks, and high low-density lipoprotein cholesterol (LDL-C) were the leading risk factors for IHD deaths in 2023, accounting for 47.2% (95% UI, 36.4%-57.0%), 38.6% (95% UI, 17.2%-56.8%), and 28.5% (95% UI, 19.3%-39.6%) of IHD deaths, respectively. Increased exposure to several risk factors substantially increased their attributable burden for IHD deaths in 2023, with high fasting plasma glucose (FPG) increasing 38.8% (95% UI, 11.5%-81.1%) and high body mass index (BMI) increasing 54.5% (95% UI, 41.8%-66.3%) since 1990. Smoking and particulate matter pollution had the greatest decrease in attributable IHD mortality since 1990, at 33.3% (95% UI, 23.6%-41.7%) and 74.9% (95% UI, 46.7%-88.8%), respectively. Conclusion and Relevance Per the results of this systematic analysis of GBD 2023, a total of 88.7% (95% UI, 83.4%-92.5%) of IHD deaths were attributable to modifiable risk factors in the US in 2023, with high SBP, dietary risks, and high LDL-C being the greatest contributors. High BMI and high FPG showed the largest attribution increases, while exposure to other risks did not increase significantly for the population.

Background Genes that enhance T-cell function represent promising targets for improving engineered T-cell therapies for cancer. While extensive CRISPR knockout screens have identified key genes enhancing T-cell persistence, employing Sleeping Beauty ( SB ) insertional mutagenesis, which induces both gain-of-function (GOF) and loss-of-function (LOF) mutations via the generation of fusion transcripts with endogenous genes, may uncover additional critical factors that previous approaches have overlooked. Methods We developed transgenic mice carrying D oxycycline (Dox)- i nducible SB mutag e nesis s y stem (DiSBey) in primary T cells. Using DiSBey, we conducted screens for genetic alterations enhancing T-cell persistence under chronic antigen exposure. Specifically, CD8 + T cells from Dox-fed DiSBey mice were subjected to repeated anti-CD3 stimulation over 18 days to mimic chronic antigenic stimulation. We then identified SB transposon genomic insertion sites and corresponding fusion transcripts from the persistent DiSBey CD8 + T cells using enhanced-specificity tagmentation sequencing and RNA sequencing, respectively. Results Under chronic stimulation, SB -mutagenized CD8 + T cells exhibited improved persistence and reduced terminal exhaustion phenotype. Across six independent screens, we identified 38 genes that were recurrently targeted by the SB transposon T2/Onc2 and differentially expressed under chronic anti-CD3 stimulation. T2/Onc2 insertions into Bach2 and Elmo1 were recurrently identified at the genomic level and were associated with altered nascent transcript expression. Bach2 , known as a key regulator of T-cell memory formation and resistance to chronic viral infection-induced exhaustion but less characterized in engineered T cells for cancer therapy, was found to counteract exhaustion in vitro and enhance in vivo tumor persistence in the B16-Ova tumor model. Further, we showed that ectopic Bach2 expression levels influence engineered T-cell differentiation lineage, as low Bach2 overexpression retained more functional progenitor exhausted T cells and exhibited improved therapeutic efficacy. Finally, in human CART19-28ζ cells, BACH2 overexpression enhanced cytotoxicity and tumor control following chronic cancer stimulation. Conclusions Controllable SB mutagenesis using DiSBey mice provides a novel platform for functional screening of genes that improve T-cell phenotypes important for their use as therapies. Our findings highlight a dose-dependent role of BACH2 in enhancing the function of engineered T cells under conditions of chronic antigenic stimulation.

Background Lewy body disease (LBD) is a progressive neurodegenerative a-synucleinopathy, whereas isolated REM sleep behavior disorder (iRBD) is recognized as a prodromal stage of LBD. Although growing evidence implicates the gut–brain axis in neurodegeneration, the taxonomic and functional roles of the gut microbiome across the prodromal-to-symptomatic LBD continuum remain poorly defined. Methods Here, we performed shotgun metagenomic sequencing on stool samples from 25 patients with LBD (10 mild cognitive impairment due to LBD [MCI-LB] and 15 dementia with Lewy bodies [DLB]), 10 individuals with iRBD, and their household matched cohabitant controls to characterize disease-associated microbial alterations while minimizing environmental confounding. Results Despite no significant differences in global microbial diversity, we identified convergent shifts in microbial taxa, metabolic pathways, and gene families across disease stages. Both LBD and iRBD showed increased abundance of microbial taxa potentially associated with gut barrier disruption, as well as higher abundance of functional pathways related to lipopolysaccharide biosynthesis. LBD showed lower abundance of pathways related to complex carbohydrate fermentation, and both groups showed lower abundance of pathways associated with neurotransmitter-related metabolism. In particular, pathways and gene families associated with starch degradation were reduced in LBD, and those associated with histidine-to-glutamate/ GABA metabolism were reduced in both groups. Discussion These exploratory findings represent the first high-resolution, shotgun metagenomic characterization of gut microbiome alterations across the LBD continuum, highlighting functional patterns that may serve as candidate markers of disease progression in future longitudinal and mechanistic studies.

OBJECTIVE Endovascular thrombectomy (EVT) for acute large-vessel occlusion stroke is well established, yet its role in patients presenting with minor stroke symptoms (National Institutes of Health Stroke Scale [NIHSS] score < 6) remains unclear. Prior studies have not accounted for intraprocedural factors that may influence outcomes in this subgroup. METHODS The authors analyzed 5693 patients from the STAR (Stroke and Thrombectomy and Aneurysm Registry), including 398 with low NIHSS scores, to evaluate the association between procedure time (PT) and outcomes. Among patients with low NIHSS scores, propensity score matching was used to compare outcomes between those with PT ≤ 35 versus > 35 minutes, a cutoff defined using receiver operating characteristic curve analysis. The authors performed a meta-analysis of studies reporting best medical management (BMM) outcomes in patients with low NIHSS scores. To compare these with EVT-treated patients, a matched BMM comparator cohort using stratification on pooled baseline characteristics was constructed. Outcomes included 90-day functional independence (modified Rankin Scale [mRS] scores 0–2), intracranial hemorrhage, and mortality. RESULTS PT had a stronger negative effect on outcomes in patients with low NIHSS scores compared with those with high scores, with a steeper decline in functional independence per minute of PT (slope: –0.45% vs –0.21%; p = 0.03 for interaction). Among patients with low scores, PT ≤ 35 minutes was associated with higher 90-day functional independence compared with the propensity score–matching cohort with PT > 35 minutes (82.6% vs 59.0%, p < 0.001). When benchmarked against BMM (75.2% mRS scores 0–2), patients undergoing EVT within 35 minutes had superior outcomes (85.1%, p = 0.047). In contrast, EVT with PT > 35 minutes resulted in worse outcomes than BMM (mRS scores 0–2: 59.8%, p = 0.008). The number needed to treat for PT ≤ 35 minutes was 10, whereas PT > 35 minutes yielded a number needed to harm of 6. CONCLUSIONS PT critically modulates the benefit of EVT in minor stroke. While efficient EVT yields better outcomes than BMM, prolonged procedures are associated with harm. These findings may explain prior inconsistent evidence on EVT in patients with low NIHSS scores and underscore the need to individualize procedural thresholds in this population.

Abstract Clinical empathy is essential for patient care, but physicians need continually balance emotional warmth with factual precision under the cognitive and emotional constraints of clinical practice. This study investigates how large language models (LLMs) can function as empathy editors, refining physicians’ written responses to enhance empathetic tone while preserving underlying medical information. More importantly, we introduce novel quantitative metrics, an Empathy Ranking Score and a MedFactChecking Score to systematically assess both emotional and factual quality of the responses. Experimental results show that LLM-edited responses significantly increase perceived empathy while preserving factual accuracy compared with fully LLM-generated outputs. These findings suggest that using LLMs as editorial assistants, rather than autonomous generators , offers a safer, more effective pathway to empathetic and trustworthy AI-assisted healthcare communication.

Abstract Background The Movement Disorder Society (MDS) research criteria for possible prodromal multiple system atrophy (PP‐MSA) have not been prospectively validated. Objective To evaluate the diagnostic performance of the PP‐MSA criteria in a longitudinal cohort of patients with pure autonomic failure (PAF) and to assess whether additional clinical features improve their predictive value. Methods Seventy‐six patients with PAF enrolled across eight centers in the Natural History Study of the Synucleinopathies were followed for ≥6 years or until phenoconversion. Participants were classified according to MDS PP‐MSA criteria and followed for development of MSA, Parkinson's disease, or dementia with Lewy bodies. Diagnostic performance was assessed longitudinally. Analyses were repeated using a stricter olfactory threshold (University of Pennsylvania Smell Identification Test [UPSIT]≤28) as an exclusion criterion. Results Thirty‐eight participants met PP‐MSA criteria, of whom 12 phenoconverted to MSA within 6 years. Sensitivity was 100% at year 1 and 92% at year 6, whereas specificity ranged from 56% to 67%. Positive predictive value (PPV) ranged from 21% to 34%. Applying a stricter olfactory threshold improved specificity (90%–97%) and PPV (53%–83%), with a modest reduction in sensitivity (to 83%). Participants who phenoconverted to MSA were younger, had more severe urinary dysfunction, and greater orthostatic heart rate responses. Conclusions The PP‐MSA criteria demonstrate high sensitivity but limited specificity in patients with PAF. A stricter olfactory threshold improves diagnostic performance and may enhance cohort enrichment for clinical trials. © 2026 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.