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Objective To compare the diagnostic accuracy of four available automated electronic medical record (EMR) retrieval methods, including a large language model (LLM)-assisted workflow, against manual chart adjudication for identifying cardiovascular events. Design Retrospective diagnostic accuracy study. Setting Three sites within a single US tertiary health system. Participants Two adult cohorts with previously adjudicated cardiovascular outcomes were included. Cohort 1 included 2258 patients treated with immune checkpoint inhibitors, and Cohort 2 included 1426 patients who underwent transcatheter aortic valve replacement. Primary and secondary outcome measures The reference standard was clinician manual chart adjudication. Outcomes included ischaemic stroke or transient ischaemic attack, myocardial infarction (MI), heart failure (HF) exacerbation or hospitalisation and a composite major adverse cardiovascular events (MACE) outcome. Automated retrieval methods included International Classification of Diseases (ICD) codes, primary diagnosis, problem list and a zero-shot LLM workflow. Area under the (receiver operating characteristic) curve (AUC), sensitivity, specificity and net reclassification improvement were assessed. Results In Cohort 1, the LLM achieved the highest AUC for stroke (0.920; 95% CI 0.881 to 0.958), MI (0.938; 95% CI 0.905 to 0.971) and composite MACE (0.880; 95% CI 0.854 to 0.907), whereas ICD-based retrieval had a higher AUC for HF (0.882; 95% CI 0.845 to 0.918 vs 0.873; 95% CI 0.831 to 0.914). In Cohort 2, the LLM achieved the highest AUC for all evaluated outcomes: stroke (0.915; 95% CI 0.862 to 0.968), MI (0.928; 95% CI 0.839 to 1.000), HF (0.844; 95% CI 0.803 to 0.884) and composite MACE (0.862; 95% CI 0.829 to 0.895). In Cohort 1, differences in AUC between the LLM and ICD methods were not statistically significant across outcomes, whereas in Cohort 2 the LLM showed significantly higher AUC for stroke and composite MACE. Conclusion In this multisite retrospective validation study, the LLM-assisted workflow showed strong but context-dependent performance for identifying cardiovascular events from the EMR. Performance varied by outcome and cohort, and ICD-based retrieval remained competitive for some use cases. These findings support a complementary role for LLM-assisted extraction in retrospective cardiovascular outcomes research.

BACKGROUND: Accurate assessment of left ventricular outflow tract (LVOT) gradients is critical for hypertrophic cardiomyopathy management, yet Doppler-based measurements are technically demanding and require expertise. The objective of this work was to develop a multi-view deep learning model capable of classifying LVOT obstruction (>20 mm Hg) using routine 2-dimensional echocardiographic windows without reliance on Doppler imaging. METHODS: We trained and externally validated a cross-attention-based video-to-video fusion framework that integrated EchoPrime-derived video representations from 3 standard transthoracic echocardiographic views to classify LVOT gradients. RESULTS: Training was performed on a derivation cohort (N=1833) from a tertiary care system in the United States, with model performance evaluated on an internally held-out test set (N=275) and a Korean external validation cohort (N=46). Single-view baselines showed limited discrimination (external area under the receiver operating curves, 0.47–0.70). Conversely, the domain-specific foundational model (EchoPrime) achieved superior single-view performance (area under the receiver operating curves, 0.75–0.80 internal; 0.79–0.83 external), highlighting the importance of echo-specific pretraining and temporal modeling. The proposed multi-view fusion further enhanced predictive performance, with the late fusion model reaching an area under the receiver operating curve of 0.84 on the external cohort with significant population-shift. CONCLUSIONS: These results suggest LVOT physiology is encoded in routine 2-dimensional imaging and can be leveraged for clinically relevant gradient classification without Doppler input. The proposed artificial intelligence-guided strategy demonstrates substantial cost savings compared with the screen-all approach. By integrating complementary spatial-temporal information across multiple views, our approach generalizes robustly across populations and may enable real-time decision support, extend LVOT assessment to portable or resource-limited settings, and complement Doppler-based evaluation for longitudinal hypertrophic cardiomyopathy management.

Abstract Background Vagally mediated syncope and functional bradyarrhythmias can cause recurrent symptoms, injury and a need for permanent pacing, yet standard therapies do not address the underlying autonomic reflex. Cardioneuroablation (CNA) targets this mechanism, but adoption has been limited by uncertainty about patient selection, procedural endpoints and durable outcomes. Methods We studied 95 consecutive patients with vagally mediated syncope (n=78) or functional bradyarrhythmia (n=17) who underwent CNA at a single center by a single lead operator under a uniform, prospectively maintained protocol. Extracardiac vagal stimulation (ECVS) was performed before and after ablation to confirm vagally mediated sinus or atrioventricular (AV) nodal responses and to verify their attenuation. Outcomes through 1 year included clinical recurrence, quality of life, pacing burden and pacemaker extraction. Results Before ablation, ECVS provoked sinus pauses in 95.8% of patients and AV block in 91.6%; after ablation, sinus pauses were abolished in every patient and residual AV block was present in 4.2%. One-year freedom from recurrent syncope and from bradyarrhythmia-related events was 93.8% and 94.1%. Syncope burden fell from a median of 2.7 episodes per year to none, and disease-specific quality of life improved substantially (P<0.001). Among patients with pre-existing devices, atrial pacing burden fell from a median of 22% to 0%. There were no strokes, deaths or myocardial infarctions. Conclusions In this single-center cohort, physiology-guided CNA was associated with durable symptom control, improved quality of life and reduced pacing across vagally mediated bradyarrhythmia syndromes. Multicenter controlled studies are needed to confirm these findings.

Breast cancer is the most common cancer in women, causing more than 600,000 deaths every year. The human microbiome is increasingly recognized as a key regulator of cancer initiation, progression, and therapeutic response. Postbiotics—defined as non-viable microbial cells and/or their structural components and metabolites that confer health benefits—are emerging as promising and safer alternatives to live probiotics in oncology. This review provides a comprehensive mechanistic overview of the potential role of postbiotics against cancer, with a specific focus on breast cancer. Preclinical evidence demonstrates that selected postbiotics exert dose- and time-dependent anticancer effects against multiple breast cancer subtypes by modulating key oncogenic pathways (such as PI3K/AKT and NF-κB) and inducing epigenetic regulation through histone deacetylase inhibition. Beyond direct effects on tumor cell proliferation and apoptosis, postbiotics influence the breast cancer microenvironment by reshaping cytokine networks, suppressing pro-metastatic inflammation, and enhancing antitumor immune responses through the activation of NK cells and T cells. We also provide emerging links between microbiome composition, estrobolome activity, and breast cancer subtype-specific biology. Despite these encouraging findings, the clinical translation of postbiotics in oncology remains limited. Currently, only one registered clinical trial investigates postbiotics in the oncology setting (melanoma), and no clinical trials have specifically evaluated postbiotics in breast cancer patients. This highlights a substantial translational gap between preclinical evidence and clinical application. Accordingly, well-designed, tumor-specific clinical trials are urgently needed to validate the safety, efficacy, and therapeutic potential of postbiotics as novel strategies in personalized breast cancer management.

Background:The development of symptoms or left ventricular dysfunction in severe aortic stenosis (AS) is associated with high morbidity and mortality. While elective transcatheter aortic valve replacement (TAVR) is supported by robust randomized evidence, data on TAVR performed in non-elective settings (urgent, emergent, or salvage) remain limited and heterogeneous. In these settings, outcomes may be influenced more by baseline clinical severity than by procedural factors. This study aimed to systematically evaluate the safety and effectiveness of non-elective TAVR and to compare the associated outcomes with those of elective TAVR.Methods:This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and registered with PROSPERO. The PubMed, Embase, and Scopus databases were searched for studies published after 2002 evaluating urgent, emergent, or salvage TAVR in adult patients with severe AS. Eligible studies were required to include elective TAVR as a comparator. Outcomes included mortality and major procedural complications. Prespecified era-based analyses and sensitivity analyses excluding studies at critical risk of bias were performed. Risk of bias was assessed using the ROBINS-I tool.Results:A total of 17 observational studies published between 2015 and 2025 were included, comprising 215,141 patients. Compared with elective patients, those undergoing non-elective TAVR had more advanced heart failure, higher NYHA class, greater comorbidity burden, and higher surgical risk scores, whereas baseline echocardiographic severity of AS was similar. Pooled outcomes for non-elective TAVR showed in-hospital, 30-day, and 1-year mortality rates of 5.1%, 12.4%, and 26.7%, respectively. Non-elective TAVR was associated with higher mortality at all time points compared with elective procedures; meanwhile, rates of stroke, vascular complications, and permanent pacemaker implantation were similar, while major bleeding and acute kidney injury were more frequent. Era-based analyses showed a stable relative mortality risk over time.Conclusions:Although non-elective TAVR is associated with worse outcomes than elective procedures, these differences appear to be largely driven by baseline clinical severity rather than by the transcatheter intervention. In unstable patients with severe AS, non-elective TAVR remains the most effective definitive treatment option compared with balloon aortic valvuloplasty or conservative management.The PROSPERO Registration:CRD420251239620, https://www.crd.york.ac.uk/PROSPERO/view/CRD420251239620.

Importance Primary hyperparathyroidism (PHPT) is common and contributes to skeletal and kidney end-organ damage. Although parathyroidectomy can mitigate these complications, many patients are managed with observation, and real-world data on the population-based frequency and timing of end-organ damage under usual care are limited. Objective To evaluate the frequency and timing of end-organ damage associated with PHPT. Design, Setting, and Participants This cohort study included a population-based cohort identified from national electronic health record (EHR) and claims data (2010-2023) with follow-up through 2023. Participants were adults with a new biochemical diagnosis of PHPT. Data analysis was performed from August 2025 to April 2026. Exposure A new biochemical diagnosis of PHPT was defined as an elevated PTH (&amp;gt;65 pg/mL) within 1 month after a second elevated calcium level (serum calcium &amp;gt;10.2 mg/dL or ionized calcium &amp;gt;1.3 mmol/L or &amp;gt;5.3 mg/dL). Main Outcomes and Measures PHPT-associated end-organ damage (osteoporosis, atraumatic fractures, kidney stones, stage 3 or worse chronic kidney disease) at or after PHPT diagnosis using EHR or claim codes and laboratory data, in addition to the frequency and timing of parathyroidectomy. Results A total of 43 399 patients with PHPT were identified (mean [SD] age, 67.9 [12.5] years; 33 854 [78%] female and 9545 [22%] male), of whom 22 279 (51.3%) had end-organ damage at diagnosis. Among 21 120 patients without end-organ damage at diagnosis, 6762 (32.0%) progressed to end-organ damage after a median (IQR) 516 (166-1125) days. Only 4442 patients (19.9%) with end-organ damage at diagnosis were treated with parathyroidectomy. Among those who progressed to end-organ damage, 1348 (19.9%) underwent subsequent parathyroidectomy, which occurred a median (IQR) 154 (41-439) days later. Conclusions and Relevance In this national cohort of adults with a biochemical diagnosis of PHPT, 67% had PHPT-associated end-organ damage at diagnosis or on follow-up. Despite this, parathyroidectomy was uncommon. These findings may inform strategies to optimize utilization of parathyroidectomy and mitigate PHPT-associated morbidity.

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.

Background: Noninvasive tests are well validated in metabolic dysfunction–associated steatotic liver disease, but evidence in metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD) is limited. We evaluated noninvasive test–based clinical care pathways for fibrosis risk stratification in MetALD and ALD. Methods: This is a multinational, multicenter, cross-sectional study across 35 centers in 16 countries (2013–2025), including adults with MetALD or ALD. Fibrosis was assessed by liver biopsy and/or vibration-controlled transient elastography (VCTE). In biopsy-proven participants, we analyzed the sequential pathway (Fibrosis-4 [FIB-4] first, followed by VCTE for indeterminate FIB-4) to identify advanced fibrosis (≥F3). Diagnostic accuracy was assessed using the AUC. Results: Among 893 participants (41.3% MetALD and 58.7% ALD), the median age was 52 [43.0–61.0] years, and 79.4% were male. The estimated prevalence of advanced fibrosis was 45% (32.2% in MetALD and 54.0% in ALD). Participants with MetALD had a more dysmetabolic profile but lower fibrosis stages than ALD. Among biopsy-proven participants, FIB-4 AUC was 0.720, and VCTE AUC was 0.833. FIB-4 performed better in MetALD than ALD (AUC 0.773 vs. 0.540), while VCTE accuracy was similar across groups. In the sequential pathways, the false-negative rate for advanced fibrosis (misclassified as low risk) was 6.8% (4.9% MetALD and 11.3% ALD). Conclusions: In biopsy-proven patients, FIB-4 performance was acceptable in MetALD but substantially weaker in ALD. The standard 2-step pathway performed adequately in MetALD but missed a clinically meaningful proportion of advanced fibrosis in ALD.

Abstract Epigenetic inheritance relies on the precise recycling of parental histones during DNA replication. The N-terminal region of Pol1, the catalytic subunit of DNA polymerase α, has previously been implicated in chaperoning parental histone recycling. In this study, we identify a single amino acid mutation in the C-terminal region of Saccharomyces cerevisiae Pol1 (pol1-F1396S) that destabilizes the protein and disrupts the transfer of parental histones to the lagging strand during DNA replication. As a primary consequence, pol1-F1396S cells exhibit decreased chromatin stability. Furthermore, we demonstrate that the cellular abundance—or dosage—of all three DNA polymerases (Pol α, Pol δ, and Pol ε) influences the distribution of parental histones between the leading and lagging strands, revealing a dosage-sensitive mechanism of epigenetic regulation during DNA replication.