Citations

ABSTRACT Background and Objectives There is increasing use of neoadjuvant treatment (NAT) for patients with pancreatic adenocarcinoma (PDAC). The role of additional adjuvant chemotherapy (AT) is not well‐defined. This study aims to determine the impact of lymphovascular invasion (LVI) and lymph node (LN) involvement on overall survival (OS) in patients with resected PDAC and determine the impact of AT after NAT. Methods This is an observational cohort study of patients with PDAC who underwent NAT and surgical resection. A multivariable model was used to assess for differences in OS. An interaction term between LVI or LN involvement and AT use was utilized to test the benefit of additional AT. Results Seven thousand four hundred and fourteen patients were included; group A (LVI‐, LN‐) had 2787 patients, B (LVI + , LN‐) 652, C (LVI‐, LN + ) 1,712, and D (LVI + , LN + ) 2263. Median OS differed significantly between groups, A had the most favorable survival (34.1 months), followed by B (27.8 months), C (26.3 months), and D (21.2 months, p < 0.001). In patients with persistent LVI or LN involvement after NAT, additional AT was not associated with OS (group A, HR: 0.94, p = 0.4; B and C, HR: 1.0, p = 0.99; D, HR: 0.94, p = 0.32). Conclusions LVI and LN involvement were independently associated with worse OS. After NAT, the use of AT in patients with persistent LVI and LN involvement was not associated with improved OS.

ABSTRACT Background Post‐pancreatectomy exocrine insufficiency is common after resection for pancreatic cancer and requires pancreatic enzyme replacement therapy (PERT). We sought to determine the out‐of‐pocket cost of PERT and the association between PERT and survival. Methods The SEER‐linked Medicare database was queried for patients with pancreatic cancer who underwent pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) from 2010 to 2019. Cumulative out‐of‐pocket costs were calculated and stratified by procedure and radiation. Results 11,854 Medicare beneficiaries with resected pancreatic cancer were identified, 4,653 (39%) required PERT and 7,201 (61%) did not. Median age was 73.0, 50.6% were female and 83.6% White. 25.9% underwent DP and 74.1% underwent PD; 7% received neoadjuvant radiation while 23.5% received adjuvant radiation. Logistic regression demonstrated that female sex (OR 1.25, 95% CI 1.16‐1.35, p < 0.001), neoadjuvant radiation (OR 1.93, 95% CI 1.67‐2.24, p < 0.001), and PD (OR 2.45, 95% CI 2.23‐2.7, p < 0.001) were risk factors for requiring PERT. Patients without subsidies who underwent DP paid a cumulative $4,736 out‐of‐pocket for PERT after 5 years, those who underwent PD paid $5,601 out‐of‐pocket. Conclusions Nearly 40% of Medicare beneficiaries took PERT after resection for pancreatic cancer and paid thousands in out‐of‐pocket costs. While a conservative estimate, these findings highlight the importance of addressing this financial burden to patients.

Importance Breast cancer is the most common cancer diagnosed in women. Therapies for breast cancer are evolving rapidly, and several are associated with cardiovascular adverse effects, can exacerbate cardiovascular risk factors, or can increase the risk of cardiovascular disease. Observations Advances in screening and treatment have led to earlier diagnosis and improved disease-free survival. For long-term survivors of breast cancer, cardiovascular adverse effects can pose a greater threat to overall long-term health than the cancer itself. Additionally, the increasing incidence of breast cancer in younger, premenopausal women has created a distinct demographic with unique medical needs. Conclusions and Relevance Cardiology practitioners need to remain updated on rapidly evolving breast cancer therapies to care for this growing, unique patient population. The field of cardio-oncology has evolved to address the cardiovascular needs of patients and survivors.

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 Mucosal immunization and respiratory IgA offer significant promise in protecting against airborne pathogens, including SARS-CoV-2. However, the conditions and mechanisms that lead to the robust induction of respiratory IgA responses following mucosal vaccination remain poorly understood. Methods In this project, we established SARS-CoV-2 breakthrough infection and mucosal adenovirus-based booster vaccination models. Using genetic mouse models and various in vivo and in vitro blockade or depletion approaches, we further investigated the mechanisms regulating respiratory IgA responses. Results Here we found that a mucosal adenovirus-based booster vaccination in mouse models revealed that respiratory booster immunization elicited markedly stronger and more durable respiratory IgA, T cell response, and protective immunity against SARS-CoV-2, supporting the promise of respiratory mucosal vaccination. Mechanistically, we identified that local CD4+ T cells support respiratory IgA production by promoting IgA+ B cell class switching, proliferation, and survival in situ. This T cell help depended on interactions between local Blimp-1+ T-bet+ Th1 cells and B cells, mediated through ICOS/CD40L/MHC-II engagement and IL-21 signaling. Furthermore, lung macrophages contributed to the mucosal IgA response via TGF-β production. Consequently, mucosal administration of SARS-CoV-2 Spike-encoding mRNA encapsulated in pulmonary surfactant (PS)- incorporated lipid nanoparticles designed to target lung macrophages elicited a stronger mucosal IgA response. Conclusion Our results uncover a local cellular network supporting enhanced mucosal IgA responses, with implications for the development of optimal mucosal immunization strategies against SARS-CoV-2 and other respiratory pathogens such as H5N1 influenza. Funding Source AI147394, AG069264, AI112844, HL170961, AI154598, AI176171 to J.S., AI67986, AI177467 to Hui.H; U54CA260582 to S.L.L; R01AI168684 to G. Z.; S.L.L was also supported by a fund provided by an anonymous private donor to The Ohio State University. Topic Categories Mucosal and Regional Immunology (MUC)

Abstract Body surface gastric mapping (BSGM) enables non-invasive measurement of gastric electrophysiology, but the signals are approximately 100 times weaker than cardiac potentials and overlap spectrally with motion artifacts, necessitating labor-intensive manual review that limits clinical scalability. We present an uncertainty-aware deep learning framework combining a signal reconstruction network with a parallel uncertainty estimation network to automate artifact correction in high-resolution BSGM. Models were trained on 2,398 multihour, 64-channel recordings from 27 international clinical sites using weak supervision, a physiology-aware loss function, and uncertainty-gated quality control. In an independent cohort of 127 patients, the system achieved relative reductions of 39% in signal reconstruction error, 9% in total data removed, and 23% in amplitude–movement correlation compared with the industry-standard Wiener filter. Improved signal fidelity altered automated clinical phenotyping in 7% of patients by recovering previously obscured gastric rhythms. Uncertainty-aware deep learning enables reliable automated artifact correction in body-surface gastric mapping, improving signal fidelity and enabling scalable clinical interpretation. The system is FDA-cleared (510(k) K252504) and deployed in clinical practice, demonstrating that data-driven artifact correction can meet regulatory requirements for medical devices and reduce dependence on specialist manual review.

Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells that repair other damaged kidney cells. This study shows that renovascular disease (RVD) induces site-specific 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications in DNA associated with transcriptional changes and impaired proliferative capacity of swine STCs, which could be mitigated in RVD-STCs treated with an epigenetic modulator. Therefore, our observations may contribute to the development of novel approaches to preserve the reparative capacity of STCs in individuals with RVD.

ABSTRACT Background & Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) is highly prevalent and increasingly recognized as a multisystem cardiometabolic disorder. The global burden, incidence and prognostic implications of coexisting chronic kidney disease (CKD) in MASLD remain uncertain. Methods In this meta‐analysis, we searched MEDLINE and EMBASE from inception through September 25, 2025, for observational studies reporting CKD prevalence and/or incidence among adults (≥ 18 years) with MASLD. The primary outcomes were pooled CKD prevalence, estimated using random‐effects models on the logit scale with the Hartung–Knapp adjustment, and pooled CKD incidence (per 1000 person‐years), estimated using random‐effects models with exact Poisson confidence intervals. Secondary outcomes included all‐cause mortality and cardiovascular, renal and cancer outcomes. Results From 2811 records, 36 observational studies met the inclusion criteria. Twenty‐three studies contributed prevalence estimates (575 615 participants; 56 248 CKD cases) and thirteen studies contributed incidence estimates (27 996 new events). The pooled global CKD prevalence among individuals with MASLD was 15.22% (95% CI 9.69–23.12). The pooled CKD incidence was 22.17 per 1000 person‐years (95% CI 11.44–32.89) in the MASLD population. Hypertension (OR 1.49, 95% CI 1.29–1.72), dyslipidaemia (OR 1.22, 95% CI 1.20–1.24) and diabetes (OR 1.94, 95% CI 1.69–2.22) were associated with higher odds of CKD in the MASLD population. All‐cause mortality rates were 18.28 per 1000 person‐years (95% CI 3.45–33.11) in coexistent MASLD and CKD, more than double those in the MASLD‐only population (7.26 per 1000 person‐years (95% CI 2.97–11.56)). Conclusions Coexistent CKD affects one in seven individuals with MASLD worldwide, conferring a more than two‐fold increased risk of all‐cause mortality compared with individuals with MASLD alone.

Background: Alcohol-associated hepatitis (AH) is a severe inflammatory liver condition driven by dysregulated immune responses. CD8 T cells accumulate in the liver during AH, yet their functional role remains poorly defined. Methods: A murine NIAAA chronic-binge model with lipopolysaccharide (LPS) challenge was used. Single-cell RNA sequencing of liver and blood immune cells defined CD8 T cell subsets, followed by pathway analysis and reanalysis of human AH datasets. Spatial relationships were validated by immunohistochemistry of human AH liver tissue with CD8 T RM and liver sinusoidal endothelial cell (LSEC) co-staining. LSEC–CD8 T cell interactions were examined using in vitro co-culture, and signaling pathways were assessed by bulk RNA sequencing and phospho-protein analyses. IL15 function was evaluated by in vivo neutralization. Results: Single-cell RNA sequencing in the murine AH model revealed a distinct population of CD8 tissue-resident memory T cells (T RM ) with heightened activation and proinflammatory cytokine production. Analysis of human AH liver single-cell RNA sequencing data, along with immunohistochemistry validation, supported CD8 T RM enrichment in diseased tissue. IL15 emerged as a prominent pathway linked to T RM activation, and IL15 blockade reduced T RM abundance and attenuated EtOH/ lipopolysaccharide-induced liver injury. Mechanistically, LSECs not only provided a structural niche for T RM retention but also amplified IL15 signalling. In vitro, coculture experiments demonstrated that LSECs intensified activation in pre-stimulated CD8 T cells in a stimulus-dependent manner: under IL15 stimulation, LSECs boosted effector function without inducing cell death, whereas under T-cell receptor stimulation, LSECs drove hyperactivation and activation-induced cell death. Bulk RNA-seq and phospho-protein analysis identified the PI3K-AKT pathway as a shared pathway enhanced by LSEC coculture in activated CD8 T cells. These findings define a context-dependent mechanism in which LSECs promote IL15-driven signaling through AKT pathway amplification, promoting T RM persistence and inflammatory activity in AH. Conclusions: IL15-associated signaling within the hepatic microenvironment, shaped by LSEC-CD8 T-cell interactions, promotes activation and persistence of CD8 T RM cells in AH. Targeting the IL15-LSEC-AKT axis may disrupt pathogenic T RM niches and represent a promising therapeutic strategy for severe AH.

Abstract The minichromosome maintenance 2-7 (MCM2-7) proteins form a hexameric protein complex that is the structural core of replicative helicase, which is essential for accurate DNA replication. While their role in replication is well-established, the biological functions of excess chromatin-bound MCM2-7 proteins remain unclear. Here, we identify a transcriptional regulatory function of MCM2-7 through its interaction with nuclear factor κB (NF-κB) p65. We demonstrate that MCM2-7 proteins and NF-κB p65 reciprocally recruit each other to target gene promoters. Consequently, MCM2-7 proteins facilitate the localization of RNA Pol II to NF-κB target gene promoters and along the gene body, thereby promoting transcription of NF-κB target genes. These findings reveal MCM2-7 proteins promote NF-κB target gene transcription by facilitating p65 and RNA Pol II recruitment, offering a potential avenue for fine-tuning NF-κB target gene transcription.