Citations

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)

Background/Objectives: To develop and evaluate a deep learning-based quality control system for Lumbar Spinal Digital Radiographs (LSDR), designed to automate and improve their evaluation and reduce reliance on manual reviews. Methods: This retrospective study utilized a deep learning workflow comprising image segmentation, feature extraction, and a classification model. The dataset, including anteroposterior (AP) and lateral (LAT) X-ray images, was expanded through data augmentation techniques. Four U-Net-based models were assessed: standard U-Net, Swin-UNet, Attention U-Net, and Attention U-Net with the weight map, with the latter selected for its superior performance. Extracted features, such as brightness, contrast, and anatomical positioning, were used in an XGBoost classifier, which was evaluated using mean intersection over union (mIoU), accuracy, sensitivity, specificity, and AUC. Results: The Attention U-Net with weighted attention outperformed the other models, achieving high mIoU scores in both AP and LAT views. The XGBoost classifier achieved the best performance in classifying images as “qualified” or “unqualified,” with an AUC of approximately 0.9, high accuracy, and balanced sensitivity and specificity. This approach effectively addressed class imbalances and improved model accuracy compared to traditional machine learning models such as MLP and SVM. Conclusions: The developed automated quality control system demonstrated potential for enhancing image quality, enhancing diagnostic reliability, and optimizing clinical workflow efficiency.

Key Points Alanyl-transfer RNA synthetase 1 (AARS1) was upregulated and promoted cyst growth in autosomal dominant polycystic kidney disease. AARS1 promoted lysine lactylation of signal transducer and activator of transcription 3 (K140) and NF-κB p65 (K310), enhancing their phosphorylation, interaction, and transcriptional activity. AARS1 transcriptionally repressed its novel targets, Atg5 and Dusp4, to impair autophagy but activate polycystic kidney disease signaling pathways. Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, characterized by metabolic reprogramming with enhanced glycolysis and lactate accumulation. However, the enzyme that senses lactate and uses it as a substrate for protein lactylation in ADPKD remains unknown. Alanyl-transfer RNA synthetase 1 (AARS1) is a lactate-responsive enzyme with lactyltransferase activity, while its role and mechanisms in ADPKD have not been defined. Methods To investigate the role of AARS1, we generated Pkd1 and Aars1 double conditional knockout Pkd1 fl/fl :Aars1 fl/fl :Ksp-Cre mice and evaluated the effect of AARS1 inhibitor β -alanine in two ADPKD mouse models. Coimmunoprecipitation and Cleavage Under Targets and Tagmentation analyses were performed to identify novel AARS1 substrates and downstream target genes involved in cystogenesis. Results AARS1 was elevated in Pkd1 mutant renal epithelial cells and kidneys, and genetic deletion of Aars1 significantly delayed cyst growth, preserved kidney function, and reduced renal lactylation in Pkd1 mutant mice. Mechanistically, AARS1 promoted lactylation-dependent activation of signal transducer and activator of transcription 3 (STAT3) and NF-κB (p65), specifically at STAT3 K140 and p65 K310, thereby amplifying pro-proliferative and proinflammatory transcriptional programs. AARS1 also associated with promoter regions and mediated histone H3 lysine 14 lactylation, thereby repressing the transcription of Atg5 to impair autophagy and suppressing the transcription of Dusp4 to sustain phosphorylation of cAMP response element–binding protein and retinoblastoma protein. Cytokine signaling through IL-6 and TNF- α further reinforced AARS1 expression through STAT3- and NF-κB–dependent feed-forward loops. Importantly, inhibition of AARS1 with β -alanine markedly slowed cyst progression in Pkd1 mutant mouse models. Conclusions Our study identified AARS1 as a central metabolic sensor linking lactate-driven lysine lactylation to transcriptional, epigenetic, and signaling pathways that drive ADPKD progression.

BACKGROUND: Cardiac computed tomography (CT) acquired during the acute stroke imaging protocol is an emerging modality to detect cardiac thrombi. We determined its yield in patients with acute ischemic stroke. METHODS: We performed a 1-stage individual patient data meta-analysis of 4 prospective observational cohorts (AIS of HEARTS [Acute Ischemic Stroke of Heart-Related Embolic Sources Detected on Acute Cardiac CT Scans]), including patients with acute ischemic stroke who underwent ECG-gated or non–ECG-gated cardiac CT between May 2018 and June 2024. We excluded patients with transient ischemic attack or stroke mimics. The primary outcome was the proportion of patients with a thrombus on cardiac CT. Secondary outcomes were additional scan time, radiation dose, comparison with echocardiography, and 90-day outcomes. We performed logistic regression analyses to compare 90-day outcomes between patients with and without thrombus, adjusting for age, sex, history of atrial fibrillation, ischemic heart disease, chronic heart failure, stroke or transient ischemic attack, anticoagulant use, prestroke modified Rankin Scale score, National Institutes of Health Stroke Scale score, large vessel occlusions, and intravenous thrombolysis, as appropriate for each outcome. RESULTS: We included 3919 patients (median age, 74 [interquartile range (IQR), 63–82], 58% male, median National Institutes of Health Stroke Scale score 6 [IQR, 3–12]). Cardiac CT detected a thrombus in 243 (6.2%) patients. Among 1323 patients that underwent both cardiac CT and transthoracic echocardiography, cardiac CT had a higher yield than transthoracic echocardiography (odds ratio, 7.4 [95% CI, 4.0–15.1]; P <0.001). Median additional scan time was 6 minutes (IQR, 5–7) for ECG-gated and 13 seconds (IQR, 12–61) for non–ECG-gated cardiac CT. Median additional radiation dose was 2.9 mSv (IQR, 1.6–4.1). Patients with thrombi had higher 90-day mortality (33% versus 15%, adjusted odds ratio, 1.6 [95% CI, 1.1–2.3]) and worse modified Rankin Scale scores (median modified Rankin Scale score 3 versus 2, adjusted odds ratio, 1.6 [95% CI, 1.2–2.0]), but similar recurrent stroke rates (5% versus 4%, adjusted odds ratio, 1.4 [95% CI, 0.7–2.5]). CONCLUSIONS: Implementing cardiac CT into the acute stroke imaging protocol is feasible, detects thrombi in ≈6% of patients, and has a higher yield than transthoracic echocardiography. Cardiac thrombi were associated with higher mortality, but not higher stroke recurrence. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT07165093.

1042 Background: The primary analysis of the phase 3 HER2CLIMB-05 study (NCT05132582) showed the addition of TUC to 1L maintenance HP yielded a statistically significant improvement in progression-free survival (per investigator) versus control treatment (hazard ratio: 0.641, P < 0.0001) in patients with HER2+ MBC. Here we report our findings from an in-depth safety analysis of HER2CLIMB-05. Methods: Patients with centrally confirmed HER2+ MBC without evidence of progression following chemotherapy-based induction treatment (taxane + HP) were randomly assigned 1:1 to TUC (300 mg) or placebo (PBO) BID, both in combination with HP. The safety analysis set included all randomly assigned patients who received ≥1 dose of any study treatment. Treatment-emergent adverse events (TEAEs), laboratory values, and TUC/PBO dose modifications and discontinuations were examined. Results: Among patients in the safety analysis set (TUC arm = 326; PBO arm = 324), median treatment durations of TUC and PBO were 17.1 months (range: 0.4–36.5) and 15.5 months (range: 0.5–41.3), respectively. Grade (G) ≥3 TEAEs occurred in 42.3% of patients in the TUC arm and 24.4% in the PBO arm; the most frequent G ≥3 TEAEs in the TUC arm were elevated alanine aminotransferase (ALT; 13.5%) and aspartate aminotransferase (AST; 7.1%). TUC was discontinued in 13.5% of patients due to a TEAE. Cardiac TEAEs were similar between TUC and PBO arms (4.3% vs 6.2%). TEAEs of hepatic events (43.6% vs 15.7%) and diarrhea (72.7% vs 51.2%) occurred at higher incidence in the TUC arm versus the PBO arm (Table). In the TUC arm, increased ALT (28.2%) and AST (25.8%) accounted for the majority of hepatic TEAEs. Most hepatic and diarrhea TEAEs were managed with TUC dose modifications and/or discontinuation; 7.7% of patients discontinued TUC due to hepatic TEAEs and 1.5% discontinued due to diarrhea (Table). Among the patients with a TEAE of diarrhea, 57.7% and 29.9%, respectively, in the TUC and PBO arms used antidiarrheals; the most used medication was loperamide. Further details of the in-depth safety analysis will be presented. Conclusions: TUC addition to 1L HP maintenance therapy may be an effective option for HER2+ MBC with a clinically manageable safety profile. Clinical trial information: NCT05132582 . TEAEs* Any Any hepatic Increased ALT/AST Diarrhea Arm TUC PBO TUC PBO TUC PBO TUC PBO Any G, % 99.1 96.6 43.6 15.7 28.2/25.8 7.1/9.0 72.7 51.2 G ≥3 42.3 24.4 18.1 1.2 13.5/7.1 0.6/0.6 6.1 4.0 Any G: Median time to onset (days) 34.5 85.0 11.0 32.0 Median time to resolution (days) 25.0 22.0 2.0 5.0 Any G: TUC/PBO dose hold, % 49.4 25.3 19.3 2.5 12.6/4.0 0.6/0.6 8.6 3.4 TUC/PBO dose reduction, % 29.1 11.1 16.3 0.9 11.7/2.8 0.3/0.6 6.4 3.1 TUC/PBO discontinuation, % 13.5 2.2 7.7 0 4.0/0.3 0/0 1.5 0.9 *As of data cutoff, Sep 5, 2025.

ABSTRACT Background Uremic toxins are a growing area of research in nephrology, with significant implications in the progression and treatment of chronic kidney disease (CKD) and the management of end‐stage kidney disease (ESKD). This bibliometric analysis aims to evaluate the global research trends, key contributors, and the impact of publications in the field of uremic toxins from 1991 to 2024. Methods The data were retrieved from the Science Citation Index Expanded (SCI‐EXPANDED) database. The study analyzed 2210 articles using various bibliometric indicators, including total publications ( TP ), average number of citations per publication ( CPP 2024 ), and the Y ‐index for author contributions. Publication trends were examined across countries, institutions, and authors. The analysis included document types, languages, Web of Science categories, and journals. Results The study revealed a steady increase in uremic toxin research publications. Japan, the USA, and China remained the most productive countries, with Japan maintaining the highest output, while Belgium achieved the highest citation impact. Citations of uremic toxin‐related research peaked 2 years following publication and plateaued after approximately 6 years. The research foci evolved, with CKD, ESKD, indoxyl sulfate, protein‐bound solutes, and gut microbiota gaining prominence. Studies on oxidative stress, inflammation, metabolomics, and advanced adsorption‐based toxin removal strategies increased markedly. International collaboration and interdisciplinary integration across nephrology, microbiology, and biochemistry correlated with higher citation performance and research visibility. Conclusion This bibliometric study provides an in‐depth analysis of uremic toxin research trends, identifies major contributors, and suggests future research priorities. The findings can inform future research directions, guide funding allocation, and strengthen global collaborative efforts towards improved management of toxin‐related kidney disease.

Abstract Background and aims Cardiac CT is increasingly used in the acute diagnostic work-up of acute ischemic stroke (AIS), but commonly used scan protocols do not allow assessment of left ventricular ejection fraction (LVEF), a known predictor of functional outcome. We aimed to develop a prediction model for reduced LVEF using clinical and imaging data. Methods This post-hoc analysis of the Mind the Heart study included AIS patients who underwent acute cardiac CT (acquired during diastole) and routine diagnostic work-up, including transthoracic echocardiography (TTE), which served as the reference standard for LVEF. Multivariable logistic regression models incorporating baseline variables, arterial input function (AIF) derived from CT-perfusion, and left atrial and ventricular cardiac CT volumes were developed using the training set (80%) to predict reduced LVEF (&lt;50%). Performance was evaluated on the testing set (20%) using receiver operating characteristic analysis, reporting the area under the curve (AUC), sensitivity, and specificity. Non-linear associations were modeled using restricted cubic splines, and Least Absolute Shrinkage and Selection Operator regression was used for variable selection. We evaluated whether cardiac CT information improved model fit. Results We included 298 AIS patients (61% male, median age 71 [IQR 61-79] years), of whom 87 (29%) had reduced LVEF. The final model showed moderate discrimination (AUC 0.71), sensitivity (0.67) and specificity (0.70). Including cardiac CT volumes in addition to baseline and AIF variables improved model fit (p=0.04). Conclusions Our model may aid risk stratification for reduced LVEF in AIS patients undergoing acute cardiac CT and could support identification of patients in whom additional TTE is warranted. Conflict of interest MMW received the Arthur Fonville Award for Stroke Research in 2025 for this work. SSN received travel grants from the Cultuurfondsbeurs, Remmert Adriaan Laan Fonds, CONTRAST consortium and Dr. Jan Meerwaldt Stichting outside the submitted work, JMC reports grants from Medtronic, Siemens, AstraZeneca and Bayer outside the submitted work (all paid to institution). JMC is shareholder and co-founder of TrianecT. CBM reports grants from Stryker and Boeringher-Ingelheim outside the submitted work (paid to institution) and is shareholder of Nicolab (minority interest). LAR was supported by a personal Dekker Junior Clinical Scientist Grant from the Dutch Heart Foundation.The other authors have no financial conflicts of interest.

ABSTRACT Background Fall risk screening and prevention interventions initiated from the Emergency Department (ED) are endorsed by current national guidelines. We aimed to evaluate the effectiveness of ED‐based multi‐factorial and multi‐component interventions to prevent falls. Methods We conducted a systematic review and meta‐analysis of interventions for fall prevention initiated in the ED for older patients (age ≥ 60 years). Multi‐component and multi‐factorial interventions were included. We excluded studies without a control or comparison group. The published literature was searched from 2019 to May 2024. Risk of bias was assessed with the Newcastle Ottawa tool for observation studies and the Cochrane Risk of Bias v2 for randomized trials. A meta‐analysis was completed for the outcomes with multiple studies. Results The search resulted in 6312 abstracts with 2571 duplicates, for 3741 unique citations. A total of 18 studies were included in the systematic review; 5 were rated as high risk of bias/low quality. The articles were heterogenous in the intervention type (8 multi‐factorial and 8 multi‐component), setting (ED focused vs. outpatient), intervention components (i.e., nurses, physicians, therapists), and size (103–1435 participants). The interventions did not decrease risk of falls at 3 months (risk difference 0.05 95% CI [0.00; 0.09]), 6 months (0.07 [−0.04; 0.18]) or 12 months (−0.02 [−0.11; 0.07]). ED revisits at 1 month (−0.01 [−0.03; 0.00]), 3 months (−0.04 [−0.14; 0.06]), and 12 months (0.02 [−0.05; 0.25]) were also unchanged. Mortality and hospitalization rates were also unaffected. Improvement in functional status was noted in 4 of 5 studies reporting this outcome. Conclusions Multi‐factorial and multi‐component fall prevention interventions initiated from the ED did not decrease falls or recurrent healthcare use. These interventions may improve functional status in older adults at fall risk. Comparisons are limited by the heterogeneity in types of interventions, intervention compliance, and timing of outcomes.