Citations

Background: Neurological diseases share overlapping systemic and molecular features, but the specificity and interpretation of cross-disease metabolomic signatures remain uncertain. Methods: We analyzed summary-level Nightingale NMR metabolomic and genetic data from 274,241 UK Biobank participants across eight neurological endpoints. The disease rankings used here were derived from baseline plasma metabolites predicting future incident disease rather than from contemporaneous diagnostic case–control contrasts. Results: Among 57 priority metabolites with genome-wide significant instruments (2472 SNPs; mean F = 162.4), nine ranked in the top 30 for at least seven of the eight endpoints, defining a shared pre-diagnostic neurological signature confirmed as non-random cross-endpoint convergence by permutation testing (p < 0.0001). Because we did not perform a quantitative non-neurological disease control analysis, this signature should not be interpreted as neurologically specific and may partly reflect systemic morbidity, renal function, body composition, or frailty-related physiology. Forward Mendelian randomization across 45 metabolite–disease pairs found no Bonferroni-significant causal effects; three nominal protective associations are consistent with the number of false-positive findings expected under multiple testing and require replication. Conclusions: These results support a shared systemic, pre-diagnostic metabolic signature across the neurological disease spectrum, while the null MR findings and specificity limitations favor interpretation as a biomarker or prodromal downstream signal rather than a proven causal mechanism. External prospective validation is essential.

Abstract Lupus nephritis (LN) requires long-term immunosuppressive therapy, which is often associated with severe systemic side effects. Therefore, new therapeutic strategies that maintain high efficacy while minimizing adverse effects are essential. Although nanomedicine has advanced systemic and kidney-targeted drug delivery, a reliable method for glomerulus-specific delivery is lacking. Collagen IV (Col4)-alpha 3, located in the glomerular basement membrane at the blood–tissue interface through fenestrated capillary endothelium, represents an ideal target for glomeruli delivery. Herein, we developed a novel liposomal nanoparticle conjugated with a Col4-alpha 3-binding peptide (Col4-α3-NPs) for selective glomerular targeting. Prednisolone-loaded Col4-α3-NPs were administered to lupus-prone mice twice weekly for 8 weeks. Kidney injury and function were evaluated biweekly, and renal immune cell populations were analyzed by flow cytometry at study completion. The results show that rhodamine-labeled NPs predominantly accumulate in kidney glomeruli 48 h after intravenous injection. The Col4-NP system demonstrated stable and prolonged release of the encapsulated drug for over 48 h. Lupus-prone mice treated with prednisolone-loaded Col4-NPs showed significantly improved renal function and histology, including a 30% increase in glomerular filtration rate, a 56% reduction in proteinuria, and decreased IgG deposition and fibrosis. Notably, treatment also enhanced renal regulatory T cell populations. These findings suggest that glomerulus-targeted Col4-α3-NPs hold significant translational promise. This platform may offer an effective, site-specific treatment for LN while minimizing systemic side effects and could be adapted for other glomerular diseases requiring targeted therapy.

Importance Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective To evaluate the combination of anti−programmed cell death 1 protein (PD-1) cemiplimab and anti−lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2 -negative early-stage, high-risk breast cancer. Design, Setting, and Participants The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2 -negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2 , 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2 -negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance In this randomized clinical trial, the combination of PD-1 and anti−LAG-3 inhibition with standard NAC was effective in early-stage ERBB2 -negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration ClinicalTrials.gov Identifier: NCT01042379

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Introduction Alzheimer’s disease (AD) is characterized by pathologies including amyloid, tau, neurodegeneration reflected in established blood biomarkers and track with clinical changes. However, the association between peripheral cell-specific signatures and AD-related phenotypes remain poorly characterized. Methods We analyzed bulk blood transcriptome data from the Mayo Clinic Study of Aging (MCSA) and Emory University Vascular study. We used BayesPrism, CIBERSORTx, and an in-house pipeline CNNreg to deconvolute these data and obtain peripheral cell proportions. Cell type specific transcripts were estimated with BayesPrism. We compared cell proportions between cases (AD/MCI) and controls. Association analysis was performed between cell type specific transcripts and AD-related phenotypes including diagnosis and cognition. Meta-analysis of transcripts associations and gene ontology analysis were conducted to assess the enriched pathways for significant genes. Results In MCSA, B and CD4+ T cells proportions are significantly lower while that of myeloid cells higher in cases. The Emory cohort had similar trends. We identified transcripts associated with AD-related phenotypes in CD4+ T and CD8+ T cells. In CD4+ T cells, transcripts downregulated in case are enriched in response to stimulus pathway, whereas those upregulated in negative regulation of immune response. Downregulation of CD4+ T genes enriched in extracellular matrix disassembly and epigenetic regulation and upregulation of those in protein localization associate with better cognition. In CD8+T cells, genes pertinent to vascular development were downregulated while those to metabolic processes were upregulated in cases. Downregulation of CD8+T genes involved in lipid transportation and upregulation of those in mitochondria associate with better cognition. Conclusion We identified peripheral cellular transcriptional changes associated with AD/MCI phenotypes and involved in important biological pathways, revealing potential disease mechanisms in AD. Funding Source RF1 AG051504 Topic Categories Neuroimmunology (NEUR)

Abstract Immune checkpoint inhibitors (ICIs) can produce durable tumor control, yet many patients experience primary or acquired resistance, mixed lesion-level responses, or immune-related adverse events. Tissue and blood biomarkers provide biologically informative but spatially incomplete views of a heterogeneous and time-varying tumor–host system. Radiologic imaging complements these assays by repeatedly measuring whole-body tumor burden, organ-specific disease patterns, lesion-level heterogeneity, and treatment-related change. This critical narrative review evaluates imaging-centered artificial intelligence (AI) for precision cancer immunotherapy, including baseline and serial CT, MRI, and PET; radiomics and learned image representations; lesion-level and whole-body heterogeneity; toxicity assessment; and integration with pathology, genomics, circulating tumor DNA, laboratory measurements, and electronic health records. Representative cohorts range from early radiogenomic studies of approximately 100–200 patients to externally validated and longitudinal models involving hundreds or thousands of patients. Rather than treating all reported performance estimates as equally actionable, we appraise the clinical question, cohort design, endpoint, validation strategy, calibration, and intended clinical action. Current evidence supports noninvasive immune phenotyping, risk stratification, longitudinal monitoring, and multimodal biomarker integration. However, most models predict outcomes among patients already receiving ICIs and therefore remain prognostic under treatment rather than predictive of differential treatment benefit. Radiotherapy (RT) combined with ICI serves as a focused imaging use case because lesion identity, dose distribution, fractionation, sequence, and thoracic and normal-tissue exposure must be linked to defined actions. Existing patient-level AI studies estimate efficacy or toxicity after treatment selection; none has prospectively shown that an AI-selected RT strategy improves patient outcomes. Translation will require patient-level leakage control, calibration, geographic and temporal validation, robustness to missing modalities, and prospective evaluation of prespecified model-guided decisions.

Abstract Background aneurysmal subarachnoid hemorrhage (aSAH) is neurological emergency associated with substantial mortality and disability. Current grading systems such as the modified Fisher Scale (mFS) and World Federation of Neurological Societies (WFNS) score, rely on semiquantitative and examination based assessments. Hence, they demonstrate limited predictive precision. The enhanced subarachnoid hemorrhage (eSAH) score is a simplified quantitative model integrating age, Glasgow Coma Scale (GCS), and cisternal subarachnoid hemorrhage volume (SAHV) to predict clinical outcomes after aSAH. Methods We performed a retrospective multicenter cohort study that included 1088 patients across three tertiary-care centers the United States. Predictive performance for unfavorable functional outcome, in-hospital mortality and delayed cerebral ischemia (DCI) was evaluated using receiver operating characteristic (ROC) analysis and area under the curve (AUC). Comparative analyses were performed and compared to the WFNS and mFS grading systems. Results the eSAH score demonstrated excellent discrimination for unfavorable functional outcome at discharge ( AUC 0.89 ) and in-hospital mortality (AUC 0.87). The DCI subscore demonstrated good discriminatory performance for predicting DCI (AUC 0.77). Compared with conventional grading systems, this was superior to both the WFNS (AUC 0.75) and the mFS ( AUC 0.70). increasing eSAH scores were additionally associated with progressively higher rates of mortality and unfavorable functional outcomes. Conclusion the eSAH score demonstrates strong external validity, reproducibility and superior predictive performance compared with conventional grading systems in a large multicenter cohort. These findings support the clinical utility of quantitative hemorrhage burden integration for early risk stratification in patients with aSAH.

ABSTRACT Lupus nephritis requires long-term immunosuppressive therapy, which is often associated with severe systemic side effects. Therefore, new therapeutic strategies that maintain high efficacy while minimizing adverse effects is essential. Although nanomedicine has advanced systemic and kidney-targeted drug delivery, a reliable method for glomerulus-specific delivery is lacking. Collagen IV (Col4)-alpha 3, located in the glomerular basement membrane (GBM) at the blood–tissue interface through fenestrated capillary endothelium, represents an ideal target for glomeruli delivery. Herein, we developed a novel liposomal nanoparticle conjugated with a Col4-alpha 3 binding peptide (Col4-α3-NPs) for selective glomerular targeting. Prednisolone-loaded Col4-α3-NPs were administered to lupus-prone mice twice weekly for 8 weeks. Kidney injury and function were evaluated biweekly, and renal immune cell populations were analyzed by flow cytometry at study completion. The results show that rhodamine-labeled NPs predominantly accumulate in kidney glomeruli 48 hours after intravenous injection. The Col4-NP system demonstrated stable and prolonged release of the encapsulated drug for over 48 hours. Lupus-prone mice treated with prednisolone-loaded Col4-NPs showed significantly improved renal function and histology, including a 30% increase in glomerular filtration rate (GFR), a 56% reduction in proteinuria, and decreased IgG deposition and fibrosis. Notably, treatment also enhanced renal regulatory T cell (Treg) populations. These findings suggest that glomerulus-targeted Col4-α3-NPs hold significant translational promise. This platform may offer an effective, site-specific treatment for lupus nephritis while minimizing systemic side effects and could be adapted for other glomerular diseases requiring targeted therapy.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.