Deficiency of adenosine deaminase 2 (DADA2) is caused by mutations in the ADA2 gene and results in an auto-inflammatory state. Hepatosplenomegaly, with or without abnormalities in liver enzymes, has been reported in DADA2. Anti-tumour necrosis factor (anti-TNF) therapy is the standard of care for the prevention of recurrent ischemic strokes and reduction of inflammatory burden. However, little is known about the extent of hepatic involvement and the utility of non-invasive tools for identifying liver disease and monitoring treatment response.

Retrospective analysis was performed on a prospective cohort of 70 patients with DADA2. Patients underwent baseline and annual laboratory testing, abdominal imaging and transient elastography. Hepatomegaly and splenomegaly were assessed on imaging, with splenomegaly defined using the spleen-to-height (SH) ratio. Liver biopsy and esophagogastroduodenoscopy were performed when indicated.

At baseline, elevated ALT was uncommon (29%). Hepatomegaly and splenomegaly were present in 36% and 58%, respectively. Liver biopsies were performed in 12 patients, 8 of whom showed porto-sinusoidal vascular disease (PSVD). Over a median follow-up of 4.5 years, 40% demonstrated persistently elevated ALT levels. Clinically evident portal hypertension was present in 14%, and decompensation events, such as ascites and variceal bleeding, occurred in 5%. Anti-TNF therapy resulted in resolution of splenomegaly in 28% and a reduction in mean SH ratio across the entire cohort. Patients who underwent haematopoietic cell transplantation (HCT) appeared to be at risk for complications such as hepatic graft versus host disease and veno-occlusive disease.

DADA2 vasculopathy appears to affect intrahepatic portal veins and result in PSVD. SH ratio shows significant promise in identifying liver involvement and monitoring treatment response. The improvement in SH suggests that PSVD may be reversible with treatment in this setting. Hepatic evaluation at baseline is encouraged for all patients, and pre-HCT liver biopsy should be considered, as there can be clinically silent liver disease that could potentially cause transplant-related complications.

Prolongation of the QT interval is a known precursor to serious arrhythmias and sudden cardiac death, often triggered by medication use. Current medication risk evaluation platforms rely on literature-based synthesis and may lag behind real-world developments. We aimed to evaluate whether a machine learning (ML) model trained on real-world genomic and medication data can identify associations between drug use and QTc duration, potentially enabling automated risk detection in clinical workflows. We included 10,208 individuals from the FinnGen biobank Expansion Area 3 substudy, integrating prescription records, clinical variables, and genetic information. We applied a nested-cross-validation approach to develop an ML framework to predict QTc duration using clinical characteristics, recent medication purchases, and polygenic score for QTc duration. We performed conventional linear regression analyses to estimate the robustness of the findings. Only a minority of ML-detected drug-QTc associations aligned with known effects listed in expert-curated reference. Several apparent false positives were observed, and effect sizes for true positives, such as amiodarone, were small and likely interpreted as clinically not meaningful (+1 ms in ML vs. +49 ms in linear regression). These findings highlight challenges in using ML to detect meaningful drug effects on ECG. ML models did not reliably identify medications associated with QT-interval prolongation. Consequently, risk quantification using QTc as an intermediate marker of electrophysiological vulnerability was limited in this framework. While new approaches continue to develop in medication safety assessment, a systematic evidence review conducted by clinical pharmacology experts is unlikely to be supplanted in the foreseeable future.

To evaluate rare childhood vasculitides using standardized clinical, laboratory, imaging, and outcome data.

A retrospective cohort of 74 children with 8 rare vasculitides was assessed at a single center. Demographics, imaging, and disease activity (Pediatric Vasculitis Activity Score (PVAS)) and damage (Pediatric Vasculitis Damage Index) scores were recorded at diagnosis, 12 months, and last visit.

Among 74 patients, 39 (52.7%) were girls. Median diagnosis age was 13.5 years. Subtype distribution was vascular Behçet syndrome 22 (29.7%), Takayasu arteritis (TA) 16 (21.6%), deficiency of adenosine deaminase 2 (DADA2) 14 (18.9%), polyarteritis nodosa 11 (14.9%), granulomatosis with polyangiitis (GPA) 6 (8.1%), primary angiitis of the central nervous system (PACNS) 3 (4.1%), eosinophilic GPA 1 (1.4%), and Cogan syndrome 1 (1.4%). The DADA2 had the longest diagnostic delay (median [IQR]: 20 [6-99.75] months), while PACNS had the youngest median age at onset (4.6 [3.07-7.95] years). Overall, 13.5% (n=10) were diagnosed before age 5, showing recurrent fever (60%, n=6) and anemia (50%, n=5), less skin/mucosal (40%, n=4), musculoskeletal (30%, n=3), cardiovascular (20%, n=2), and pulmonary involvement (20%, n=2), and higher PVAS (median 2.0, IQR 1.25-2.75). At 12 months, all had low disease activity. The TA had the longest corticosteroid use, highest damage, and slower remission. Overall remission was 91.9% (n=68/74), while GPA patients had more flares in the first year (median 1.0, IQR 0.25-1.75).

Prognosis was favorable, but TA and monogenic vasculitides showed greater damage. In children <5 years, higher activity but good early response emphasize timely, individualized management.

Given the high costs of treatment with proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) and the limited US Food and Drug Administration label for these treatments in patients with stroke due to atherosclerotic disease, it is unknown whether these agents are cost-effective for reducing recurrent stroke events.

To estimate the theoretical cost-effectiveness of currently available PCSK9i for the prevention of recurrent stroke in patients with high-risk intracranial arterial stenosis.

This economic evaluation was a post hoc trial-based cost-effectiveness analysis of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial from a health care sector perspective. Adult patients with stroke due to intracranial arterial stenosis were included in SAMMPRIS and randomized to aggressive medical management with or without intracranial arterial stenting. Patients from the SAMMPRIS trial with complete covariate data were included in this secondary analysis. Data were analyzed from January to December 2025.

A base-case assumption of 32% relative risk reduction for stroke among PCSK9i based on its low-density lipoprotein-lowering effect.

Based on trial-estimated transition probabilities, annual direct-to-consumer prices for 3 PCSK9i (alirocumab: $6600; evolocumab: $7200; and inclisiran: $7920) and estimated US-based stroke care costs in 2025 US dollars, a decision-analytic Markov cohort model was developed to estimate the cost-effectiveness of PCSK9i for reducing recurrent stroke over a 5-year time horizon, with a 7% annual drug discontinuation rate and a 3% discount rate for future costs and quality-adjusted life-year (QALYs). From 1000 Monte Carlo simulations, the probability of cost-effectiveness of 3 PCSK9i was estimated at a $120 000/QALY threshold. Sensitivity analyses evaluated at an alternative threshold ($50 000/QALY), treatment efficacy (20% to 50%), and stroke care costs (50% to 150% of base estimates). A patient perspective analysis reflecting patients' out-of-pocket costs with insurance coverage was also conducted.

Of the 367 patients from the SAMMPRIS included in this study, 88 were Black (24.0%), 260 were White (70.8%), and 19 Asian, Native Hawaiian or Pacific Islander, more than 1 race, or other (5.2%), and the median (IQR) age at enrollment was 59 (52-69) years. At current direct-to-consumer prices, the probability of cost-effectiveness at a willingness-to-pay threshold of $120 000/QALY over a 5-year horizon was 58.6% (95% CI, 55.5%-61.6%) for alirocumab, 53.8% (95% CI, 50.7%-56.9%) for evolocumab, and 36.7% (95% CI, 33.8%-39.7%) for inclisiran.

This theoretical framework suggests that alirocumab and evolocumab were cost-effective for preventing recurrent stroke in patients with severe intracranial atherosclerosis, with all agents cost-effective under current cost-sharing programs offered by commercial and Medicare plans.

The Naples Prognostic Score (NPS) has demonstrated prognostic value in oncology and certain chronic diseases. Its utility in cardio-renal-metabolic multimorbidity (CRMM) remains unexplored.

This study aims to evaluate the association between NPS and all-cause mortality in individuals with CRMM.

We analyzed data from the National Health and Nutrition Examination Survey (1999-2018) comprising 3,602 adults with CRMM. The NPS was derived from serum albumin, total cholesterol (TC), neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-monocyte ratio (LMR). Weighted Cox proportional hazards models and restricted cubic spline (RCS) analysis were used to evaluate associations between NPS and all-cause mortality.

Over a median follow-up of 79 months, 1,621 (41.4%) deaths occurred. After comprehensive adjustment for potential confounders, each 1-point increase in NPS was associated with a 24.6% higher risk of all-cause mortality (HR 1.246, 95% CI 1.150-1.350, P < 0.0001). The HRs for all-cause mortality was 1.133 (95 % CI: 0.846-1.518, P = 0.401) in the medium NPS group and 1.721 (95 % CI: 1.248-2.375, P = 0.0009) in the high NPS group, as compared with the low NPS group. RCS analysis indicated a nonlinear relationship between NPS and all-cause mortality among participants with CRMM (Pnonlinear=0.014). Weighted quantile sum regression analysis identified NLR as the primary contributor to mortality risk (weight: 0.612 at 2 years, 0.580 at 5 years), followed by TC.

This study identified a positive, nonlinear association between NPS and all-cause mortality in CRMM individuals. The NPS integrates inflammatory, metabolic, and nutritional biomarkers into a practical prognostic tool that may enhance risk stratification and guide personalized management in multimorbidity.

N⁶-methyladenosine (m⁶A) and 5-methylcytosine (m⁵C) are dynamic and reversible RNA modifications that play important roles in cardiovascular diseases (CVDs). By regulating RNA stability, splicing, transport, translation, and degradation, m⁶A and m⁵C shape key pathological processes including endothelial dysfunction, inflammation, apoptosis, fibrosis, impaired contractility, and metabolic remodeling. Core regulators, including METTL3, METTL14, fat mass and obesity-associated protein (FTO), AlkB homolog 5 (ALKBH5), and YTH family proteins for m⁶A, as well as NSUN2, DNMT2, TET2, and ALYREF YBX1 for m⁵C related pathways, display disease stage specific and cell type-specific patterns across atherosclerosis, ischemic cardiomyopathy, heart failure, myocarditis, cardiomyopathy, and rheumatic heart disease, highlighting their potential as diagnostic and prognostic biomarkers. Therapeutically, pharmacological modulation of writers and erasers, adeno-associated virus-based gene delivery, and stem cell-based strategies show encouraging preclinical efficacy, while lifestyle interventions such as exercise may optimize the cardiac RNA methylation landscape. In addition, emerging RNA methylation marks, including N¹-methyladenosine (m¹A),7-methylguanosine (m⁷G), N⁶,2'-O-dimethyladenosine (m⁶Am), and oxidative cytosine derivatives such as 5-hydroxymethylcytosine (hm⁵C) and 5-formylcytosine (f⁵C), further expand the RNA modification landscape of cardiovascular remodeling by linking cap-dependent translation, mitochondrial protein synthesis, and stress adaptation. However, major challenges remain, including resolving RNA methylation dynamics at single-nucleotide and single-cell resolution, integrating RNA methylation with other regulatory layers, and achieving precise cardiac delivery with durable safety. With advances in multi-omics, spatial mapping, nanomedicine, and translational research, targeting RNA methylation offers a promising paradigm for improved diagnosis, risk stratification, and personalized therapy in cardiovascular disease.

This study compares anthropometric, metabolic, cardiovascular, and liver parameters in people living with HIV (PLWH) on antiretroviral therapy (ART), and men on pre-exposure prophylaxis (PrEP) in the same age group.

This was a single-center, cross-sectional study of males aged 18-50 years, receiving ART for HIV or PrEP for at least 6 months, consecutively enrolled at Policlinico Hospital, Milan. Lifestyle factors were assessed using the International Physical Activity Questionnaire and a food diary. Anthropometric measurements included body mass index (BMI), waist circumference, and bioimpedance analysis. Blood samples were analyzed for glycemic parameters, lipid profile, hepatic enzymes, and adipokines, including leptin. Hepatic steatosis and fibrosis were evaluated using FibroScan^®. Group differences were assessed using chi-squared, t tests, and Mann-Whitney tests, while logistic regression determined associations with HIV status.

Eighty-two participants were enrolled: 53 PLWH and 29 PrEP users. PLWH had significantly higher BMI, waist circumference, total fat mass, and triglycerides, as well as total and LDL cholesterol. PrEP users engaged in more vigorous-intensity activity, with no differences in dietary habits. Among PLWH, higher physical activity was associated with lower HOMA index. Leptin levels were significantly higher in PLWH compared to PrEP users. Multivariate analysis identified LDL cholesterol as independently associated with HIV status.

PLWH exhibited greater adiposity and dyslipidemia than PrEP users, with leptin emerging as a potential marker of metabolic dysfunction. Higher physical activity was linked to improved insulin sensitivity, underscoring the role of exercise in mitigating HIV-related metabolic dysregulation.

Magnesium deficiency is prevalent and increasingly recognized as an endocrine-relevant condition due to its involvement in hormone secretion, metabolic homeostasis, and cellular signaling.

To review current evidence on the role of magnesium in key endocrine systems and evaluate its clinical and therapeutic implications.

Magnesium influences glucose metabolism, bone health, thyroid function, reproduction, cardiometabolic regulation, and HPA-axis activity. Clinical evidence shows strong associations between magnesium status and several endocrine diseases.

Magnesium plays a multifaceted endocrine role with clinically significant implications. Improved diagnostic approaches and further interventional studies are warranted.

Substance use represents a relevant yet underrecognized determinant of cardiovascular diseases, acting through substance-specific and often multifactorial mechanisms. This document proposes the concept of substance-related cardiovascular diseases (Sr-CVD) as a possible novel nosological entity, outlining its main clinical implications. Available epidemiological and pathophysiological evidence is reviewed, and the clinical, instrumental, and therapeutic-management features of the main cardiovascular conditions associated with substance use are described. These elements support clinical suspicion, differential diagnosis, and a precision medicine approach. In cases where a definite causal relationship cannot be established, the term "cardiovascular diseases in individuals with substance use" is proposed to identify a population at increased cardiovascular risk with specific clinical needs. Sr-CVD represent a heterogeneous group of conditions requiring a structured and multidisciplinary clinical approach. The introduction of this conceptual framework may improve the recognition, management, and prevention of substance-related cardiovascular damage.

Semaglutide improves cardiovascular disease (CVD) risk in people who are diabetic, overweight or obese through incompletely understood mechanisms. To address this, we explored novel lipidomic and lipo-/glyco-protein profiling with semaglutide therapy.

Secondary analysis of SLIM LIVER (ACTG A5371), an open-label, phase 2b, single-arm trial of 1 mg semaglutide weekly in adult people with HIV (PWH) and metabolic dysfunction-associated steatotic liver disease.

Participants (n = 36) experiencing clinical response (>5 lb weight loss) to semaglutide were included. Lipidomic and lipo-/glyco-protein profiling was performed from stored serum.

Median age was 52 years and BMI 34 kg/m2; 39% were Hispanic, 28% Black, 45% female and 22% had stable statin use. Lipidomics: Semaglutide reduced triglycerides, diglycerides and sphingomyelins and increased some bile acids and phosphatidylcholines. Lipoproteins: CVD-linked species decreased; LDL particle size increased and large HDL particle number decreased. Glycoproteins: Most participants had elevated baseline GlycA and GlycB, CVD-associated markers of systemic inflammation. 56% with elevated Glyc A improved and 32% normalized; 41% with elevated Glyc B improved and 42% normalized. Lipo-/glycol-protein concentrations generally did not correlate with baseline weight, liver fat or insulin resistance or their magnitude of change.

In this first human report of lipidomic and lipo-/glyco-protein profiling during semaglutide therapy in any population, lipidomic changes suggest reductions in toxic lipid species and improved hepatic insulin sensitivity. Significant reductions in CVD-risk associated lipo-/glyco-protein species were observed that did not correlate with magnitude of changes in weight, liver fat or insulin resistance, suggesting an independent mechanism.