DNA methylation is a widely studied epigenetic mark and a powerful biomarker of cell type, age, environmental exposures, and disease. Whole-genome sequencing following selective conversion of unmethylated cytosines into thymines via bisulfite treatment or enzymatic methods remains the reference method for DNA methylation profiling genome-wide. While numerous software tools facilitate processing of DNA methylation sequencing reads, a comprehensive benchmarking study has been lacking. In this study, we systematically compared complete computational workflows for processing DNA methylation sequencing data using a dedicated benchmarking dataset generated with five whole-genome profiling protocols. As an evaluation reference, we employed accurate locus-specific measurements from our previous benchmark of targeted DNA methylation assays. Based on this experimental gold-standard assessment and multiple performance metrics, we identified workflows that consistently demonstrated superior performance and revealed major workflow development trends. To ensure the long-term utility of our benchmark, we implemented an interactive workflow execution and data presentation platform, adaptable to user-defined criteria and readily expandable to future software.

While disability progression in multiple sclerosis (MS) is age-dependent, the exact timing of neuroaxonal degeneration throughout the patient lifespan remains unclear.

To investigate the influence of age on retinal neurodegeneration after the first unilateral episode of optic neuritis (ON).

We measured peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell inner plexiform layer (mGCIPL) absolute thickness and intereye differences (IEDs) in 61 MS patients with a single unilateral ON 6-24 months prior (MS-ON) and 61 MS patients without ON history (MS-NON). Participants were 1:1 matched based on age, sex, and Expanded Disability Status Scale (EDSS). Statistical significance was evaluated using mixed linear effects models.

Age and ON status of eyes significantly interacted in predicting absolute pRNFL and mGCIPL thickness (pRNFL: B = 0.28, 95% confidence interval (CI) = [0.03, 0.54], p = 0.03, mGCIPL: B = 0.24, 95% CI = [0.01, 0.46], p = 0.04).

Our data show evidence of increased relapse-associated neuroaxonal damage in older individuals. This suggests less neuronal resilience following attacks and implicates age-effects beyond insidious progression. The growing population of older people with MS (pwMS) may be at increased risk of neurodegeneration and permanent disability worsening after acute MS attacks. Longitudinal studies should confirm this.

Our study aimed to estimate the cost-effectiveness of non-statin lipid-lowering therapies (LLTs) in patients with very-high cardiovascular risk, based on their relative efficacy and current yearly treatment costs in the Spanish setting.

We generated a cohort of patients in secondary prevention with low-density lipoprotein cholesterol (LDL-C) levels >100 mg/dL using a Monte Carlo simulation. Based on the relative LDL-C reductions described in the literature for each studied non-statin LLTs, we estimated the percentages of cohort patients that would achieve the 2019/2025 European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) dyslipidemia guidelines treatment targets (LDL-C levels <55 mg/dL and ≥50% reduction from baseline; defined as effectively treated patients). Derived, the annual costs per effectively treated patient were calculated.

Evolocumab 140 mg every two weeks (Q2W), followed by alirocumab 150 mg Q2W were modeled to be the most efficacious non-statin regimens, with 80% and 70% of effectively treated patients, respectively. The results for inclisiran and the other studied doses of alirocumab were modeled to be more modest (20% to 33%). The mean annual cost per patient effectively treated with evolocumab 140 mg Q2W was 6,200.1€, compared with 7,126.5€ for alirocumab 150 mg Q2W, 15,159.1€ with alirocumab 75 mg Q2W and 19,254.9€ with alirocumab 300 mg every month. Inclisiran resulted in higher costs both during the first year (31,329.1€) and the subsequent time scenarios (26,107.6€ and 22,974.7€ during average first two and five years, respectively).

No head-to-head clinical trials comparing non-statin LLTs are available. We only considered the published direct pharmacological costs in the Spanish setting.

In our simulation study, evolocumab 140 mg Q2W resulted in similar (versus alirocumab 150 mg Q2W) or better cost-effectiveness in achieving 2019/2025 ESC/EAS LDL-C targets for secondary prevention patients compared to other LLTs.

Multimodal large language models (LLMs) offer new potential for enhancing cardiovascular decision support, particularly in interpreting echocardiographic data. This study systematically evaluates and benchmarks foundation models from diverse domains on echocardiogram-based tasks to assess their effectiveness, limitations and potential in clinical cardiovascular applications.

We curated three cardiovascular imaging datasets-EchoNet-Dynamic, TMED2, and an expert-annotated echocardiogram (TTE) dataset-to evaluate performance on four critical tasks: (1) cardiac function evaluation through ejection fraction (EF) prediction, (2) cardiac view classification, (3) aortic stenosis (AS) severity assessment, and (4) cardiovascular disease classification. We evaluated six multimodal LLMs: EchoClip (cardiovascular-specific), BiomedGPT and LLaVA-Med (medical-domain), and MiniCPM-V 2.6, LLaMA-3-Vision-Alpha, and Gemini-1.5 (general-domain). Models were assessed using zero-shot, few-shot, and fine-tuning strategies, where applicable. Performance was measured using mean absolute error (MAE) and root mean squared error (RMSE) for EF prediction, and accuracy, precision, recall, and F1 score for classification tasks.

Domain-specific models such as EchoClip demonstrated the strongest zero-shot performance in EF prediction, achieving an MAE of 10.34. General-domain models showed limited effectiveness without adaptation, with MiniCPM-V 2.6 reporting an MAE of 251.92. Fine-tuning significantly improved outcomes; for example, MiniCPM-V 2.6's MAE decreased to 31.93, and view classification accuracy increased from 20 % to 63.05 %. In classification tasks, EchoClip achieved F1 scores of 0.2716 for AS severity and 0.4919 for disease classification but exhibited limited performance in view classification (F1 = 0.1457). Few-shot learning yielded modest gains but was generally less effective than fine-tuning.

This evaluation and benchmarking study demonstrated the importance of domain-specific pretraining and model adaptation in cardiovascular decision support tasks. Cardiovascular-focused models and fine-tuned general-domain models achieved superior performance, especially for complex assessments such as EF estimation. These findings offer critical insights into the current capabilities and future directions for clinically meaningful AI integration in cardiovascular medicine.

In Japan, the CHADS₂ score has long been recommended as a Class I indication for risk stratification in patients with nonvalvular atrial fibrillation. However, the recent Japanese Circulation Society guidelines have proposed the HELT-E₂S₂ score as a Class IIa recommendation, which is a novel risk stratification system developed using the pooled data from five registries in Japan. In Europe, the CHA₂DS₂-VASc score has been adopted as a Class I recommendation over the past decade. However, the 2024 European Society of Cardiology guidelines have newly recommended the CHA₂DS₂-VA score as a Class I indication, excluding the sex category from the original CHA₂DS₂-VASc score. This review will first present the background and rationale for the development of the HELT-E₂S₂ score, followed by a summary of the current status of its clinical validation and the remaining challenges that need to be addressed. In addition, a focused discussion will be provided on the comparison between the recently highlighted CHA₂DS₂-VA score and the widely used CHA₂DS₂-VASc score, emphasizing their similarities, differences, and potential implications for risk stratification.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for type 2 diabetes and obesity, delivering robust metabolic and cardiovascular benefits. However, their potential impact on tumorigenesis remains debated. Preclinical findings in rodents have suggested that GLP-1R activation may influence thyroid C-cells and pancreatic ducts, while human studies have yielded inconsistent cancer risk signals. This review synthesizes current evidence on GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling in cancer biology, emphasizing the role of biased agonism and context-dependent effects. GLP-1R activation, predominantly via cAMP/PKA signaling, has shown antiproliferative effects in gastrointestinal adenocarcinomas and pancreatic ductal adenocarcinoma models, whereas GIPR activation frequently engages PI3K/Akt (PI3K, phosphoinositide 3-kinase; Akt, protein kinase B) and ERK/MAPK cascades (ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase), enhancing proliferation in colorectal and neuroendocrine tumors. Conversely, GLP-1R stimulation can promote growth in GLP-1R-high neuroendocrine tumors, reflecting ligand- and tissue-specific signaling biases. Beyond direct tumor cell effects, GLP-1RAs modulate the tumor microenvironment by reducing NF-κB-driven inflammation, altering stromal activity, and potentially enhancing immune surveillance. Current clinical evidence does not support a generalized increase in cancer risk with GLP-1RA therapy; benefits in metabolic control may even reduce obesity-related cancer incidence. Nonetheless, caution is advised in patients with medullary thyroid carcinoma, MEN2, or GLP-1R-high neuroendocrine tumors. The emerging paradigm suggests precision approaches, integrating receptor profiling, biased agonist design, and risk stratification, will be key to safely leveraging incretin-based therapies in oncology.

Clonal hematopoiesis of indeterminate potential (CHIP) is a condition associated with increased risk of hematologic malignancies and cardiovascular diseases. While radiation therapy has been identified as a risk factor for CHIP, specific radiation factors that influence the development of CHIP remain unclear.

We identified 489 cancer patients who underwent radiation therapy (RT) at least 6 months prior to blood samples deposited in an institutional biorepository. Patients with prior hematologic malignancy diagnosis or cytotoxic chemotherapy exposure were excluded. Targeted DNA sequencing of the blood samples was performed to detect mutations in CHIP-associated genes. CHIP prevalence was compared with a control cohort of 854 cancer patients without exposure to RT or chemotherapy. RT parameters, including dose, technique, and irradiated site, were characterized and examined for association with CHIP prevalence.

CHIP was detected in 23% of patients who received RT. The probability of CHIP was increased in patients who received RT compared to the patients who did not (odds ratio 1.49, 95% confidence interval 1.08-2.05), after adjusting for age, sex, race, smoking status, and metastatic disease status. The risk of CHIP positively correlated with the biologically equivalent dose (Pearson correlation coefficient r=0.64, p<0.001). CHIP was associated with stereotactic technique (OR 2.56, 95% CI 1.01-6.34) and more prevalent in patients with primary lung cancer and patients who received radiation to spine. We observed five cases of subsequent myelodysplastic syndrome and one case of subsequent acute myeloid leukemia in the RT cohort with a median interval of 6.3 years between RT and diagnosis, and one case of myelodysplastic syndrome in the control cohort, 7.5 years after blood sample collection.

In this cohort study, prior radiation therapy was associated with an increased risk of clonal hematopoiesis, particularly among patients receiving higher biologically equivalent radiation doses, stereotactic techniques, or treatment to the spine.

Heterozygous familial hypercholesterolaemia is a common, autosomal semi-dominant condition characterised by elevation of LDL cholesterol from birth and early onset of atherosclerotic cardiovascular disease. With major advances in knowledge about the disease, familial hypercholesterolaemia has become an exemplar for the practice of precision and personalised medicine. Beyond genetics, developments in clinical risk prediction algorithms and cardiovascular imaging have enabled more accurate risk stratification of patients. Early initiation of cholesterol-lowering therapies can reduce the progression of atherosclerosis and prevent cardiovascular events. Newer treatments offer the possibility of normalising plasma LDL cholesterol concentrations even in homozygous familial hypercholesterolaemia, the most severe form of the condition. Despite these advances, familial hypercholesterolaemia is still inadequately diagnosed and undertreated, with many affected people remaining at high risk of early cardiovascular disease. The application of implementation science to expanding knowledge of familial hypercholesterolaemia has enabled the development and design of potentially more effective models of care. This Review discusses the contemporary knowledge of familial hypercholesterolaemia and its unmet clinical needs.

The SELECT trial found semaglutide reduced major adverse cardiovascular events (MACE) in patients with overweight or obesity with cardiovascular disease but without diabetes. We report a prespecified analysis of the SELECT trial on the relationships between baseline adiposity measures, treatment-induced adiposity changes, and subsequent MACE risk.

Patients aged at least 45 years, with a BMI of at least 27 kg/m² were enrolled in 41 countries (804 sites) and randomised 1:1 to once-weekly semaglutide 2·4 mg or placebo. The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). Adiposity measures included weight and waist circumference. In this analysis, risk of MACE occurring after 20 weeks was assessed between patients by adiposity changes in the first 20 weeks and, in a separate analysis, all in-trial MACE were assessed between patients by adiposity changes over 104 weeks. This trial is registered with ClinicalTrials.gov, NCT03574597.

Semaglutide significantly reduced MACE incidence compared with placebo among 17 604 patients enrolled in SELECT, with consistent benefits across all baseline weight and waist circumference categories. In the semaglutide group, analyses for linear trends showed lower baseline bodyweight and waist circumference were associated with lower incidence of MACE-an average 4% reduction in risk per 5 kg lower bodyweight (hazard ratio [HR] 0·96 [95% CI 0·94-0·99]; p=0·001) and per 5 cm smaller waist circumference (0·96 [0·93-0·99]; p=0·004). In the placebo group, lower baseline waist circumference (0·96 [0·94-0·99]; p=0·007), but not bodyweight (0·99 [0·97-1·01]; p=0·28), was associated with a lower MACE risk and weight loss was paradoxically associated with increased MACE risk. In those receiving semaglutide there was no linear trend linking weight loss at week 20 to subsequent MACE risk, but greater waist circumference reduction at week 20 was associated with lower subsequent MACE risk, and waist circumference reduction by week 104 was associated with lower in-trial risk of MACE. An estimated 33% of the observed benefit on MACE was mediated through waist circumference reduction (HR 0·86 [95% CI 0·77-0·97] after adjustment for time-varying changes in waist circumference).

The cardioprotective effects of semaglutide were independent of baseline adiposity and weight loss and had only a small association with waist circumference, suggesting some mechanisms for benefit beyond adiposity reduction.

Novo Nordisk.

Doxorubicin (DOX) is an effective first-line chemotherapeutic agent used to treat various kinds of cancers. The most serious side effect of DOX is its irreversible cardiotoxicity. Salviae Miltiorrhizae Radix et Rhizoma, which is the dry root of the natural plant Salvia miltiorrhiza and is named "Danshen" in Chinese, is a widely used Chinese Materia Medica for the treatment of cardiovascular and cerebrovascular disorders in traditional Chinese medicine.

This study aims to review the potential protective effect of Danshen against DOX-induced cardiotoxicity (DIC).

A comprehensive systematic search was performed in various electronic databases, including Web of Science, PubMed and Scopus up to July 2025 according to the PRISMA guideline. Two hundred and sixty studies were screened in accordance with a predefined set of inclusion and exclusion criteria. Thirty-five eligible articles were finally included in the current systematic review. All the characteristics and underlying mechanisms of Danshen protecting against DIC were summarized. Additionally, all the Danshen-related clinical trials evaluating their treatment effects for cardiovascular and cerebrovascular diseases were extracted and summarized from the registration databases of clinical trials.

Danshen ameliorated DOX-caused pathological alterations of cardiac cells/tissue, decrease of surviving cardiomyocytes, body weight, heart weight and the ratio of heart to body weight, and increase of mortality. Eleven active ingredients and derivatives of Danshen including tanshinone IIA, sodium tanshinone IIA sulfonate, tanshinone I, salvianolic acid A, salvianolic acid B, salvianolic acid C, cryptotanshinone, ferulic acid, danshensu, dihydrotanshinone I and diethyl blechnic, were identified with potential protective effects against DIC in vitro and in vivo as well as the eight extracts and formulas of S. miltiorrhiza including salvianolic acids, S. miltiorrhiza aqueous extract, Compound DanShen Dripping Pill, Danhong injection, Qiliqiangxin, herbal formula B307, Qishen granule and Ershen Zhenwu Decoction. The underlying mechanisms were associated with the Danshen's multiple pharmacological activities, such as anti-apoptosis, anti-oxidative stress, anti-inflammation, anti-mitochondrial dysfunction, maintenance of intracellular Ca²⁺ homeostasis and regulating autophagy by targeting PI3K/Akt/JNK/GSK-3β/mPTP, MAPKs, Bax/Bcl-xL/Caspases, Keap1-Nrf2/NQO1/GPX4, SIRT3/Ac-SOD2, NF-κB, TGF-β/Smads, RhoA/ROCK, AMPK/PGC-1α/NRF-1/TFAM, miR-30a/Beclin1/LAMP1 signaling pathways. Moreover, Danshen-related clinical trials mainly focused on the treatment of cardiovascular and cerebrovascular diseases without clinical trials specifically for the evaluation of Danshen-related agents for the treatment of DIC.

Danshen significantly alleviates DIC according to the previous experimental studies. But no previous study is implemented under cancer condition. A well-designed clinical study that targets certain cancer is an urgent requirement for the verification of Danshen's clinical efficacy in the future, in particular clarifying without affecting the anti-cancer efficacy of DOX.