Citations

Single-cell studies have defined immune states in inflammatory bowel disease (IBD), but how adaptive receptor histories organize circulating immunity remains unclear. We generated a single-cell transcriptomic atlas of peripheral blood from 249 participants with Crohn's disease, ulcerative colitis, or non-IBD control status, including 182 with productive TCR and BCR recovery. Expanded TCR clonotypes marked inflammatory-memory and cytotoxic states, while distinct but similar paired TCRs shared inflammatory programs across participants. BCR lineage maturation linked IgA-associated mucosal and plasma B cell programs to somatic mutation and class switching, distinguishing maturation-associated biology from clonal expansion. Helper, regulatory, and cytotoxic T-cell programs covaried with B-cell states, and inferred interactions nominated reciprocal antigen-presentation and helper pathways. Repertoire-based machine learning distinguished diagnosis, inflammation, and contemporaneous six-month treatment-response status. Together, this atlas connects receptor architecture to coordinated systemic immune remodeling, establishes a foundation for repertoire-informed patient stratification, and prioritizes candidate mechanisms of IBD pathogenesis.

Abstract Background Online hemodiafiltration (HDF) enhances the removal of middle molecules, including large-middle molecules, through the combined action of diffusion and convection. Randomized controlled trials (RCTs) and individual participant data (IPD) meta-analyses demonstrate improved cardiovascular outcomes and, importantly, a reduction in all-cause mortality when HDF is delivered with sufficiently high convective volumes in post-dilution mode. These findings underscore that an adequate convective dose is a critical determinant of clinical benefits compared to high-flux hemodialysis (HD). However, translation into consistent clinical practice remains heterogeneous. Therefore, the Italian Society of Nephrology convened an international, multidisciplinary panel to synthesize randomized evidence comparing online post-dilution HDF with high-flux HD in adults receiving maintenance hemodialysis. Methods The critical outcomes included all-cause and cardiovascular mortality, whereas the important outcomes included selected patient-reported health domains, including physical function, patient-perceived cognitive function, pain interference, social participation, and health-related quality of life. The certainty of the evidence was appraised using the GRADE methodology. Structured guidance recommendations and best practice statements were developed through a consensus. Sensitivity analyses were performed to assess the robustness of the observed mortality effect. Results High-volume post-dilution HDF reduces all-cause mortality (hazard ratio 0.84; 95% CI 0 74–0.95; moderate-certainty evidence) and cardiovascular mortality (hazard ratio 0.78, 95% CI 0.64–0.96; moderate-certainty evidence; data from an individual participant data analysis of trials of high volume HDF versus high-flux HD). Emerging evidence suggests slower deterioration in selected patient-reported domains, including physical function, patient-perceived cognitive function, pain interference, and social participation (low-certainty evidence). Safety with on-line post-dilution HDF has been demonstrated to be similar to that of high-flux HD. Conclusions Online post-dilution HDF should be regarded as a dose-dependent therapy. We recommend its use to reduce cardiovascular mortality and suggest high-volume HDF to reduce all-cause mortality and slow deterioration in selected patient-reported health domains. Effective implementation in clinical practice requires a targeted and individualized approach with careful optimization and monitoring of convective volume, along with appropriate treatment time, blood-flow rate, supporting infrastructure, and consideration of patient preferences. This guidance provides evidence-based recommendations and best practice statements for its use.

Introduction: Co-stimulatory proteins are master regulators of the immune system. We identified the co-stimulatory CD40-CD40L dyad as a key driver of inflammation during atherosclerosis and have shown that CD40 and CD40L exert cell-type divergent functions. Hypothesis: CD40 is abundantly expressed on endothelial cells (EC) undergoing endothelial mesenchymal transition (EndMT). We hypothesize that EC CD40 drives atherosclerosis via EndMT. Methods: We analyzed scRNAseq data from human carotid plaques, performed multiplex IHC, and used human aortic endothelial cells (HAECs) for in vitro studies. A tamoxifen-inducible EC specific CD40 deficient atherosclerotic mouse model (cadherin5 (cdh5)ERT2-CD40 flfl -ApoE -/- ) was generated. Results: Besides its presence on immune cells, CD40 is expressed on endothelial cells in both human and mouse atherosclerotic plaques. Analysis of scRNAseq data of human carotid atherosclerotic plaques showed that CD40 is highly expressed in COL1A2/FN1 expressing endothelial cells (ECs), a subset undergoing EndMT. Multiplex staining revealed that CD40 colocalized with the EndMT markers αSMA, NOTCH3, TWIST and VCAM1 in human plaques. In vitro , stimulation of human arterial endothelial cells (HAECs) with CD40L resulted in an increase in the EndMT markers markers fibronectin, vimentin, sm22α, FSP1 and snail. Using phosphoproteomics, CD40L was found to decrease phosphorylation of the junctional integrity proteins CTNNA1 [S652; S655] and ARHGAP21 [S1383]. To investigate the endothelial-specific effects of CD40 in atherosclerosis, 8-week-old cdh5ERT2-CD40 flfl -ApoE -/- mice and their CD40 flfl -ApoE -/- littermate controls were treated with tamoxifen and fed a high cholesterol diet for 10 wks. Deletion of EC-CD40 resulted in a significant reduction in plaque size. This reduction was accompanied by a shift from fibrous cap atheromas (FCA) towards intimal xanthoma (IX) and pathological intimal thickening (PIT). Flow cytometry analysis of the spleen showed that CD40 deletion in ECs results in a significant decrease in CD8 and CD4 effector T cells. This decrease in CD8 and CD4 effector T cells was accompanied by a diminished activation status, shown by a decrease in CD69 + CD8 + CD62 - CD44 + T cells, CD40L + CD8 + CD62 - CD44 + T cells and CD40L + CD4 + CD62 - CD44 + T cells. These findings demonstrate that endothelial CD40 drives atherosclerosis by inducing EndMT-driven plaque inflammation.

Introduction: V-domain Immunoglobulin Suppressor of T-cell Activation (VISTA), a co-inhibitory immune checkpoint protein, is known for regulating adaptive immune responses. Here, we investigated the role of VISTA in atherosclerosis. Hypothesis: VISTA is constitutively expressed on hematopoietic cells, particularly T cells. VISTA functions as both a ligand and receptor to maintain T cell quiescence. We hypothesize that VISTA expression is protective against plaque formation by inhibiting CD4 + T cell activation. Methods: Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) was performed on aortic CD45 + cells of HCD fed ApoE-/- mice. Spatial transcriptomics (VISIUM) was performed on carotid plaques from patients with either asymptomatic or symptomatic cerebrovascular disease. Plaque burden, characterization, and flow cytometry of blood and lymphoid organs were performed on VISTA -/- ApoE -/- (VISTA KO) and VISTA +/+ ApoE -/- (WT) mice that were fed a HCD for 10 weeks. ApoE -/- mice treated with VISTA agonist 8G8 or IgG control (200ug, intra-peritoneal, 3 times per week for the last 6/10 weeks of HCD feeding). In vitro proliferation, migration, and functional T cell assays were performed. Results: We found that VISTA is expressed on plaque T cell populations, particularly regulatory T cells, gamma-delta T cells, and naïve T cells. In humans, individuals with symptomatic CVD have significantly reduced VISTA gene expression in carotid plaques. VISTA KO mice have increased total plaque area and necrotic core area compared to littermate WT controls. VISTA KO mice have increased peripheral CD4 + and CD8 + effector memory T (T EM ) cells with a corresponding decrease in CD4 + and CD8 + naïve T (T N ) cells and CD4 + regulatory T (T reg ) cells. Further, VISTA KO mice have a higher frequency of CD4 + T H 1 (T-bet + IFNy + ) cells and lower frequencies of IL-10 + CD4 + T cells and CD4 + T H 2 (GATA-3 + IL-13 + ) cells. In vitro assays showed that VISTA suppresses CD4 + T cell proliferation, IFNγ production, and migration. Finally, VISTA agonist treatment significantly decreased plaque and necrotic core areas in atherosclerotic mice. Conclusion: Our data reveals a novel role for VISTA in reducing plaque development and in suppressing T cell activation, proliferation, and migration. Further characterization of T-cell specific VISTA-deficient mouse models and mechanistic insights into how VISTA modulates T cells are currently being investigated.

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 Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used. Objective To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads. Data Sources PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025). Study Selection Studies were included if they provided Centiloids, radiotracer, age, and sex. Data Extraction and Synthesis Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis. Main Outcomes and Measures Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen κ) with the binary visual reads when available. Results This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49 227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n = 48 786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I 2 = 97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I 2 = 95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I 2 = 95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n = 35 045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen κ, 0.86; 95% CI, 0.83-0.89; I 2 = 96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I 2 = 80%). Conclusions and Relevance In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.

Abstract Background The Charlson comorbidity index (CCI) is a validated weighted measure of comorbidity burden, but has an unclear role in heart failure (HF). Objectives To characterize age-adjusted CCI (ACCI) in HF, its association with the use of guideline-directed medical therapy (GDMT) and with outcomes. Methods In the Swedish HF registry, patients were divided into 3 groups based on ACCI scores (low 1-3, intermediate 4-6, and high ≥7). We studied its association with clinical characteristics and GDMT use. Multivariable multinominal and Cox regressions were used to analyze ACCI and its association with ejection fraction (EF) category (reduced [HFrEF], mildly reduced [HFmrEF], preserved [HFpEF]), and with outcomes up to 3 years. Results Among 117,419 patients (age 75 [66-82], 36% women, 53% HFrEF, 24% HFmrEF, 23% HFpEF, median ACCI was 5, 6 and 6 respectively. ACCI ≥7 was present in 31% with HFrEF, 35% with HFmrEF and 42% with HFpEF. A higher ACCI score was associated with higher EF category, NYHA class, serum NT-proBNP, diuretic use, and lower quality of life and GDMT use (p<0.05 for all). The risk of composite CV mortality/first HF hospitalization was higher with intermediate (adjusted HR 1.34, 95% CI 1.29-1.39) and high vs low ACCI (1.76, 1.69-1.83). High ACCI category (vs low) was significantly associated with non-CV (adjusted HR 6.36, 95% CI 5.75-7.04), but also, CV mortality (4.35, 3.99-4.74), and total hospitalizations (adjusted IRR 2.16, 2.11-2.22) but also HF hospitalizations 1.23 (1.17-1.28) Conclusion The ACCI discriminates well in HF, with higher ACCI being associated with greater severity of HF, lesser GDMT use and worse quality of life. Higher ACCI was more strongly associated with death than hospitalization. Higher ACCI was more strongly associated with non-CV outcomes but also with CV and HF outcomes.

Abstract Background Spinocerebellar ataxia type 3 (SCA3), the most common autosomal dominant ataxia, is driven by the accumulation of polyglutamine‐expanded (polyQ) ATXN3 proteins. While promising as biomarkers, their longitudinal trajectories across multiple biofluids remain poorly defined. Objectives To quantify polyQ ATXN3 levels in cerebrospinal fluid (CSF), plasma, and urine within a comprehensive cohort, utilizing serial measurements to map protein dynamics. Methods We employed a validated immunoassay to quantify polyQ ATXN3 in 97 symptomatic and 13 presymptomatic SCA3 patients, correlating levels with clinical features, ancestry, disease status, and longitudinal progression. Results Asian participants exhibited lower plasma but elevated urinary polyQ ATXN3 levels relative to other ancestries. While CSF levels were higher in symptomatic patients at baseline, they showed a significant longitudinal decline. Conclusions PolyQ ATXN3 is a viable multi‐biofluid biomarker. Declining CSF levels likely reflect neurodegeneration, supporting its role in tracking progression and emphasizing the need for ancestry‐based adjustment in trials. © 2026 International Parkinson and Movement Disorder Society.