INTRODUCTION: Artificial intelligence (AI) is playing a transformative role in cardiovascular care by enabling more precise prediction of adverse clinical events across prevention, imaging, electrophysiology, and interventional practice. AI models integrate high-dimensional clinical data and imaging-derived phenotypes to improve risk stratification beyond traditional scoring systems, identifying patients who may benefit from earlier, targeted interventions. AREAS COVERED: This review examines recent advances in AI-based cardiovascular event prediction, focusing on coronary artery disease, heart failure, cardiac arrhythmias, and valvular heart disease. In these domains, AI transcends conventional markers - such as ejection fraction and stenosis severity - to extract prognostically relevant insights from complex data streams. Despite this potential, clinical translation remains limited. Many models are retrospective, rely heavily on discrimination metrics, and lack consistent validation across diverse health systems and patient subgroups. Furthermore, risk estimates are rarely linked to explicit management pathways. TO FACILITATE ADOPTION, WE PRIORITIZE: rigorous external and prospective validation with a focus on calibration and fairness; coupling predictions with actionable care algorithms; and developing interpretable, workflow-integrated tools. Overcoming these barriers is essential to establishing AI-based risk prediction as a reliable clinical standard.

BACKGROUND Patients with left ventricular assist devices (LVADs) who require emergency non-cardiac surgery are at high risk due to long-term anticoagulation and the consequences of underlying heart failure. Approximately 3.3% of LVAD patients require emergency abdominal surgery, which is associated with a higher in-patient mortality rate. This report describes the case of a 43-year-old man with an implantable cardioverter defibrillator (ICD) and a left ventricular assist device (LVAD) who required emergency surgery for a strangulated umbilical hernia. CASE REPORT A 43-year-old man with an ICD and an LVAD who had been taking warfarin and clopidogrel presented with a 2-day history of abdominal pain and vomiting. Physical examination revealed a strangulated umbilical hernia and a non-strangulated right-sided inguinal hernia. The strangulated portion of the small intestine was resected, then an end-to-end intestinal anastomosis and closure of the umbilical and inguinal hernias were performed. In the next 2 days he developed symptoms of intraperitoneal bleeding; therefore, a decision was made to totally withhold anticoagulant and antiplatelet medication and administer 2 units of packed red blood cells concentrate and 1 unit of platelet concentrate. Despite prolonged anticoagulation interruption, the patient survived without LVAD thrombosis or ischemic complications and was transferred to the LVAD implantation center. CONCLUSIONS This report aims to accentuate the high-stakes decisions made to maintain a balance between thrombotic and hemorrhagic risk in our patient. It is advisable to consult the specialized implantation center overseeing the patient's ongoing care before performing emergency surgery.

INTRODUCTION: The management of newborns with persistent pulmonary hypertension has critical importance. These infants require immediate on-site intensive care, which must be continued during transport until arrival at a tertiary regional center. Inhaled nitric oxide is an effective pulmonary vasodilator, and its use during transport may support the treatment of pulmonary hypertension and ensure adequate gas exchange until handover in the intensive care unit. Since March 2018, the Neonatal Transport Service of the Peter Cerny Foundation has been the only provider in Hungary to administer inhaled nitric oxide during neonatal transport. OBJECTIVE: To evaluate the use of inhaled nitric oxide during definitive on-site management and neonatal transport. METHOD: In this retrospective cohort study, we analyzed data from newborn infants born between March 2018 and March 2025 who were transported by the Neonatal Transport Service of the Peter Cerny Foundation and received inhaled nitric oxide therapy. 5 patients were excluded due to postnatal age over one week or postmenstrual age exceeding 46 weeks, and 3 additional patients were excluded because of incomplete ventilation data. RESULTS: A total of 41 cases were included in the analysis. The mean gestational age was 38 weeks (range: 28-41). The most common primary diagnosis was meconium aspiration syndrome (n = 19), followed by congenital diaphragmatic hernia (n = 7). Prior to transport, 21 infants (51%) received surfactant therapy. 8 transports originated from outside the service's primary catchment area. In 9 cases, inhaled nitric oxide therapy was initiated by the local care team; in the remaining cases, treatment was started by the neonatal transport team, in more than one-third of patients before 6 hours of life. In 24 cases (58%), infants were transported using high-frequency oscillatory ventilation. 14 newborns (43.7%) showed a response to inhaled nitric oxide, defined as at least a 20% reduction in oxygen requirement by the end of transport. Extracorporeal membrane oxygenation therapy was initiated after transport in 3 cases. DISCUSSION AND CONCLUSION: The administration of inhaled nitric oxide during neonatal transport is feasible and safe, and provides effective support for the initiation and maintenance of definitive intensive care in critically ill newborns until transfer to a regional tertiary center. Orv Hetil. 2026; 167(21): 824-832.

BACKGROUND: Older adults with type 2 diabetes mellitus (T2DM) are at high risk of both cardiovascular complications and cognitive decline, with major implications for independence and self-management. Endothelial dysfunction and impaired angiogenic capacity may play a key role. This study investigated the association between circulating angiogenic T cells (Tang cells) and cognitive function in older adults with T2DM and explored the potential impact of glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy. METHODS: A cross-sectional study was conducted on 154 T2DM patients aged 60-80 years, treated either with GLP-1 receptor agonist (GLP-1RA) plus metformin or metformin alone. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Circulating CD3+CD31+CXCR4+ Tang cells were quantified by flow cytometry. Propensity score matching was applied to control for age, body weight and HbA1c. RESULTS: In the overall cohort, higher Tang cell levels were significantly associated with better cognitive performance (MoCA, r = 0.423; MMSE, r = 0.428; both P < 0.001). After matching, 35 patients in each treatment group were included in the comparative analysis. The GLP-1RA + MET group showed significantly higher circulating Tang cell levels than the MET group, both in absolute counts and as percentage of CD3+ T cells (P < 0.001). CONCLUSIONS: Circulating Tang cell levels are positively associated with cognitive function in older adults with T2DM. GLP-1RA therapy is associated with higher Tang cell levels compared with metformin alone, suggesting a potential association with mechanisms related to endothelial repair in diabetes-related cognitive impairment in older age.

Non-valvular atrial fibrillation (NVAF) serves as a primary cause of cardioembolic stroke, with left atrial thrombus (LAT) functioning as its major thrombotic substrate. The systemic immune-inflammation index (SII) has gained recognition as a dependable biomarker in cardiovascular disease. Nevertheless, its relationship with LAT in NVAF patients has not been thoroughly characterized in large-scale investigations. This retrospective study enrolled 847 NVAF patients who underwent transesophageal echocardiography (TEE). The primary outcome was TEE-detected left atrial thrombus (LAT). Patients were stratified into LAT-positive and LAT-negative groups. Univariable and multivariable logistic regression analyses identified independent predictors of LAT. Receiver operating characteristic (ROC) curve analysis evaluated the diagnostic performance of SII compared to the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and CHA₂DS₂-VASc score. Restricted cubic spline (RCS) analysis assessed the dose-response relationship between SII and LAT risk, and prespecified subgroup analyses examined whether this association remained consistent according to oral anticoagulant (OAC) use and other clinical strata. Of 847 patients, 142 (16.8%) were LAT-positive. Elevated SII was an independent predictor of LAT (OR = 1.13, 95% CI: 1.08-1.18 per 100-unit increase; P < 0.001) after adjusting for conventional risk factors. The optimal SII cutoff was 712.5 (AUC 0.786), showing slightly better discrimination than NLR, PLR, and CHA₂DS₂-VASc score. RCS analysis revealed a significant nonlinear dose-response relationship between SII and LAT risk, and the association remained consistent in both adequate-OAC and non-OAC subgroups. Elevated SII is independently associated with LAT in NVAF patients and offers useful discriminatory performance as an adjunct, rather than a standalone substitute, for established clinical assessment. As a readily accessible hematological parameter, SII may help identify patients with a low probability of LAT while supporting individualized decisions regarding TEE referral and anticoagulation management.

Pulmonary embolism (PE) is a preventable yet often deadly cardiovascular event. We aimed to investigate PE mortality trends from 1968-2023 and forecast rates through 2040 in the U.S. We analyzed CDC WONDER death certificates for adults ≥ 25 years. Age-adjusted mortality rates (AAMRs), annual percent changes (APCs) were used to analyse trends and Auto-ARIMA/Prophet forecasting models were used for future projections, all stratified by sex, age, race, and contributing cause of death. From 1968-2023, 516,187 PE deaths occurred, with a mean AAMR of 6.06 per 100,000 (AAPC -1.85). Mean AAMRs were 6.76 in men and 5.57 in women. By age, rates averaged 0.98 for adults 25-44 years, 3.96 for 45-64 years, and 21.73 for ≥ 65 years. Black adults had a mean AAMR of 10.87 versus 5.76 in White adults. From 1999-2023, PE death linked to Coronary Artery Disease, COPD, infection, and diabetes declined, while PE death linked to hypertension rose and heart failure related PE plateaued. Forecasts project an overall AAMR of 3.63 by 2040 (2.32 in men, 3.25 in women), with the highest predicted rate of 9.24 among adults ≥ 65 years. Projected racial AAMRs are 3.70 in White and 7.71 in Black individuals. Hypertension and heart failure linked rates are expected to rise further. Despite a sustained decline in PE death since 1968, persistent racial gaps, aging populations, and rising hypertension and heart-failure related PE threaten progress, highlighting the need for targeted prevention and equitable cardiovascular risk management.

Atrial fibrillation (AF) is the most common arrhythmia in end-stage renal disease (ESRD) patients on dialysis. These patients face high risks of both thromboembolism and bleeding. Pivotal randomized controlled trials (RCTs) of direct oral anticoagulants (DOACs) excluded these patients, leaving the optimal anticoagulant choice uncertain. We conducted a systematic review and meta-analysis investigating the efficacy and safety of DOACs versus VKAs in AF patients undergoing dialysis. We searched PubMed, Scopus, Web of Science, and Cochrane Library for RCTs and observational studies. Primary outcomes were ischemic stroke, major bleeding, and all-cause mortality. Secondary outcomes included ischemic stroke or systemic embolism, other bleeding events, hemorrhagic stroke, myocardial infarction, and cardiovascular mortality. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. Four RCTs and nine observational studies were included in this study, encompassing 31,238 patients. DOACs were associated with significantly lower risk of major bleeding (RR: 0.68, 95% CI [0.49-0.95], I = 89.0%), gastrointestinal bleeding (RR: 0.74, 95% CI [0.61-0.90], I = 37.1%), and hemorrhagic stroke (RR: 0.23, 95% CI [0.07-0.78], I = 1.5%) compared to VKAs. Both groups showed similar risk of ischemic stroke (RR: 0.59, 95% CI [0.32-1.09], I = 40.8%), all-cause mortality (RR: 0.85, 95% CI [0.68-1.07], I = 73.2%). Other secondary outcomes also showed no significant differences. In AF patients with ESRD receiving dialysis, DOACs provide similar efficacy and lower bleeding risk compared to VKAs. Among DOACs, apixaban appears to offer the greatest net clinical benefit in this population.

Pulmonary vascular disease (PVD) and ischemic heart disease (IHD) are major contributors to cardiovascular mortality in U.S. adults. This retrospective study aims to examine mortality trends and demographic disparities between 1999 and 2020. However, both diseases have been studied individually, but their combined temporal trends remain unexplored. The CDC WONDER database was used to obtain data for adults aged ≥ 45 years. AAMRs per 100,000 population and APC were calculated using Joinpoint regression, stratified by demographic, geographic, and urbanization categories. PVD and IHD together reported a total of 184,780 deaths. The overall AAMR increased from 6.9 to 8.9 per 100,000 between 1999 and 2020. Mortality rates were higher in men (8.8) compared to females (6.0) throughout the study period. Black or African American individuals had the highest AAMR (8.9), demonstrating a current surge in 2018. Similarly, non-metropolitan areas consistently experienced greater AAMR (8.5) than metropolitan areas (6.9), with a steep rise after 2018 (APC = 14.72%). Furthermore, mortality was greatest in the South; however, the Midwest region reported the highest AAMRs (8). Additionally, individuals aged 85 + had the highest CMR (44.6). Lastly, Vermont had the highest AMMRs (13.6) among other states. PVD- and IHD-related mortality depicted a recent steep increase despite an initial decline, with considerable differences across demographic and regional groups. This highlights the importance of a direct call to action by expanding preventive care, spreading awareness, and early diagnosis with management to address these inequities and decrease the growing burden.

BACKGROUND AND OBJECTIVES: Neuroendocrine tumors are a rare and heterogeneous group of neoplasms that frequently cause carcinoid syndrome, characterized by diarrhea, flushing, and carcinoid heart disease. A recent therapy for carcinoid syndrome involves inhibition of tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, using telotristat ethyl. Telotristat has demonstrated clinical control of carcinoid syndrome; however, its potential antitumoral effects remain unclear. This study aimed to evaluate the antitumor activity of telotristat ethyl alone and in combination with everolimus in neuroendocrine tumor models. METHODS: Cell viability was assessed in three neuroendocrine tumor cell lines of pancreatic (BON-1, QGP-1) and intestinal (HROC57) origin following treatment with telotristat ethyl. Combination treatments with telotristat ethyl and everolimus or other antitumoral agents were evaluated for effects on cell viability, apoptosis, and cell cycle distribution. In vivo efficacy was examined in nude mice bearing BON-1-derived xenografts treated with telotristat ethyl, everolimus, or the combination. Tumor growth, toxicity, proliferation (Ki67), and apoptosis (active caspase-3) were analyzed. RESULTS: Telotristat ethyl reduced cell viability in all three neuroendocrine tumor cell lines. Combination with everolimus, but not with other antitumoral treatments, synergistically decreased cell viability, induced apoptosis, and reduced the proportion of cells in the G2/M phase. In nude mice bearing BON-1 xenografts, combined treatment with telotristat ethyl and everolimus arrested tumor growth without signs of toxicity compared with single treatments. At the end of treatment, tumors from combination-treated mice showed a reduction in proliferation (Ki67) comparable to single-treated groups and an increase in apoptosis as indicated by active caspase-3. CONCLUSIONS: Telotristat ethyl exhibits antitumoral activity in neuroendocrine tumor models in vivo. Moreover, the combination of telotristat ethyl and everolimus, two therapies already used in clinical practice, may represent a safe and effective therapeutic strategy for neuroendocrine tumors.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cerebral small-vessel disease caused by NOTCH3 mutations, yet its pathogenic mechanisms remain incompletely understood due to limited disease models. The NOTCH3 R544C mutation is a prevalent hotspot in East Asian populations, but patient-derived iPSC models are lacking. Here, we generated an iPSC line from peripheral blood mononuclear cells of a middle-aged CADASIL patient carrying a heterozygous NOTCH3 c.1630C > T (p.Arg544Cys, R544C) mutation using a Sendai virus (SeV)-based reprogramming approach. The iPSCs exhibited typical morphology, normal 46, XY karyotype, expressed pluripotency markers (OCT4, NANOG, TRA-1-60, SSEA-4), and cleared SeV vectors after passaging. They differentiated into derivatives of all three germ layers, and STR analysis confirmed donor identity. Functionally, CADASIL iPSCs showed abnormal accumulation of the NOTCH3 extracellular domain (NOTCH3ECD) with unchanged NOTCH3 full-length and intracellular domain levels, and upregulation of canonical downstream genes HEY1, NRARP, and HES1, indicating activation of the NOTCH3 signaling pathway. This study establishes and characterizes a NOTCH3 R544C patient-derived iPSC line, providing a valuable model for investigating CADASIL pathogenesis and potential therapeutic strategies, with novel insights into early NOTCH3ECD accumulation and pathway activation.

BACKGROUND: Economic models support healthcare decision makers to efficiently assess value and allocate resources; formal validation is critical to ensure confidence in model outputs. The Obesity Lifecycle Model is a patient-level simulation model capturing natural history, clinical complications, quality-of-life and economic outcomes associated with obesity; however, it has yet to undergo formal external and cross-validation. OBJECTIVE: The aim of this study was to validate the Obesity Lifecyle Model as per best practice guidelines from the Professional Society for Health Economics and Outcomes Research (ISPOR) and the Society for Medical Decision Making (SMDM) Task Force. METHODS: Relevant data sources and outcomes were identified for all validations. Selected validation studies informed the model to simulate study outcomes. The model was populated with study characteristics to reproduce studies used in model development (dependent validation), studies not used in model development (independent validation), or other published models (cross-validation). Accuracy between predicted and observed outcomes was assessed using standard statistical methods and mean error calculations. RESULTS: The model demonstrated overall concordance with observed outcomes, supported by coefficient of determination (R) and ordinary least squares linear regression line (OLS LRL) estimates generally close to 1.0. Independent validation showed an underprediction for cardiovascular disease (CVD) and mortality with an OLS LRL of 0.9309 and an R of 0.8984 across all populations (normoglycaemic/prediabetic populations: OLS LRL = 0.9485, R = 0.8854; T2DM populations: OLS LRL = 0.9208, R = 0.9068). CONCLUSIONS: The Obesity Lifecycle Model demonstrates favourable concordance with observed clinical and quality-of-life outcomes, supporting its use for evaluating obesity-related complications and informing healthcare decision making.

Coronary artery disease (CAD) remains the leading cause of death worldwide. Integrating coronary physiology into treatment decision-making is essential to optimize outcomes. Fractional flow reserve (FFR) is the gold standard for assessing the severity of CAD (ischemia) and guiding percutaneous coronary intervention (PCI). However, a single value of FFR cannot capture the spatial distribution of CAD along the vessel. The pullback pressure gradient (PPG) obtained from manual FFR pullbacks is a novel metric for characterizing pressure loss patterns on a continuous scale: values approaching 1.0 represent a focal CAD pattern, whereas values close to 0 represent diffuse disease. PPG predicts flow improvement and angina relief after PCI. This review summarizes the current evidence on PPG and discusses the integration of this novel approach in CAD management.

Renal denervation (RDN) has emerged as a potential therapeutic strategy to modulate autonomic imbalance and attenuate inflammation in cardiovascular disease. However, the mechanisms underlying its cardioprotective effects remain incompletely understood. In this study, we evaluated the functional and molecular effects of RDN in a rabbit model of experimental autoimmune myocarditis (EAM). A total of twenty-four male New Zealand white rabbits were randomly assigned to four groups: control, EAM, EAM with RDN for 4 weeks (EAM-RDN4W), and EAM with RDN for 6 weeks (EAM-RDN6W). Echocardiographic assessment demonstrated that EAM induced marked systolic dysfunction, as reflected by a reduction in left ventricular ejection fraction (LVEF) (approximately 65% in CTRL vs. 36% in EAM), whereas RDN was associated with partial preservation of cardiac performance, with recovery of LVEF to ~ 52% at 6 weeks after RDN. Histological analysis and TUNEL staining showed that RDN was associated with attenuation of myocardial inflammatory infiltration and cardiomyocyte apoptosis. RDN also reduced sympathetic activation, as evidenced by reduced ChAT-positive area in cardiac tissue and decreased circulating catecholamine levels. At the molecular level, RDN was associated with a shift toward improved calcium-handling balance, characterized by downregulation of Cav1.2, NCX, and RyR and upregulation of SERCA2a and phosphorylated phospholamban (p-PLB). Furthermore, RDN was associated with reduced activation of the MAPK/ERK pathway, as evidenced by decreased phosphorylation of Raf, MEK, ERK, and CREB. Collectively, these findings indicate that RDN is associated with improved cardiac function in EAM and with mitigation of inflammation-related myocardial injury, in parallel with coordinated changes in neurohumoral activity, calcium signaling, and MAPK/ERK pathway activation.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising inflammatory biomarker for coronary heart disease (CHD). This study aimed to evaluate the diagnostic value of Lp-PLA2, both alone and in combination with fasting blood glucose (FBG) and granulocyte count (GC), while exploring age- and sex-specific diagnostic thresholds. METHODS: This retrospective case-control study enrolled 206 CHD patients and 89 non-CHD controls. Serum biomarkers were measured, multivariable logistic regression identified independent risk factors, and diagnostic performance was assessed using receiver operating characteristic (ROC) curves. RESULTS: Sex, hypertension, diabetes, Lp-PLA2, FBG, and GC were identified as independent risk factors for CHD. ROC analysis revealed optimal cutoff values of 137 μg/L for Lp-PLA2 (AUC = 0.913), 6.8 mmol/L for FBG (AUC = 0.611), and 4.5 × 10 /L for GC (AUC = 0.687). The combined model achieved an AUC of 0.917, with sensitivity of 0.956 and specificity of 0.708 at a predicted probability threshold of 0.4. CONCLUSION: Elevated serum Lp-PLA2 and GC were independently associated with CHD, whereas FBG showed an inverse adjusted association that should be interpreted cautiously. Lp-PLA2 showed the highest diagnostic efficacy, while combined assessment improved sensitivity. The proposed age- and sex-specific cutoffs may provide preliminary subgroup-specific reference values that require external validation.

BACKGROUND AND AIMS: Current guidance recommends better low-density lipoprotein cholesterol (LDL-C) control in patients with elevated lipoprotein(a) [Lp(a)] as Lp(a) lowering therapies are unavailable. Whether risks attributable to Lp(a) are mitigated in patients with coronary artery disease (CAD) who achieve LDL-C <55 mg/dL remains unknown. METHODS: Multicentre retrospective observational study analysing 1581 Japanese patients with CAD [Lp(a)-JAPAN: jRCT1050260016]. Risk of major adverse cardiovascular events (MACE) (cardiac death + non-fatal myocardial infarction + coronary revascularization in non-culprit segments) was compared according to Lp(a) levels (<30, ≥30 and <50, and ≥50 mg/dL) and among LDL-C strata (<55 mg/dL vs ≥55 mg/dL) 8 weeks after percutaneous coronary intervention. RESULTS: During the 5.1-year observation among patients with LDL-C ≥55 mg/dL (n=1069), MACE occurred in 21.3% with risk of MACE increasing with Lp(a) levels (3.9, 7.9 and 11.0 events per 100 person-years for <30 mg/dL, ≥30 and <50 mg/dL, and ≥50 mg/dL, respectively; log-rank p<0.001). Among those with LDL-C <55 mg/dL (n=512), the proportion with MACE was lower overall (4.3%, p<0.001). However, elevated Lp(a) levels still identified those at higher risk of MACE (1.4, 4.7 and 7.5 events per 100 person-years in Lp(a) <30 mg/dL, ≥30 and <50 mg/dL, and ≥50mg/dL, respectively; p<0.001). Standardized 5-year MACE rate was over twice and five times higher in patients with Lp(a) ≥30 and <50 mg/dL (17.0%; adjusted hazard ratio [HR] 3.80, 95% confidence interval [CI] 1.78-8.11, p<0.001) and ≥50 mg/dL (33.4%; adjusted HR 6.90, 95% CI 3.53-13.46, p<0.001) compared to Lp(a) <30 mg/dL (5.0%). The receiver-operating characteristic analyses identified Lp(a) ≥28.2 mg/dL as the threshold for MACE (area under the curve 0.68, p<0.001). CONCLUSIONS: Whilst lower achieved LDL-C attenuates in part the risk from Lp(a), elevated Lp(a) levels still associate with worse cardiovascular outcomes. The Lp(a) threshold among Japanese patients with CAD at risk of recurrent events appears lower than in Caucasian populations, which merits further evaluation.

BACKGROUND: Metabolic syndrome (MetS) is a key predictor of non-communicable diseases (NCDs) and mortality, causing public health challenge worldwide. This study aimed to estimate the incidence rates and to assess the risk factors of MetS among adults in a prospective cohort study. METHODS: This population-based cohort study was conducted on 10,009 adult individuals in southwest Iran. After applying the exclusion criteria to the baseline cohort, 1,781 at-risk individuals were eligible and included for follow-up. Incidence rates (IRs) of metabolic syndrome were calculated by dividing the number of new events during the follow-up period by the person-years at risk. The effects of various explanatory variables on these incidence rates were assessed using Poisson regression models. RESULTS: The overall incidence rate of metabolic syndrome (MetS) was 102.23 per 1,000 person-years, higher in females than males, and incidence was significantly associated with older age, female sex, marital status (married / divorced), higher BMI, history of cardiovascular disease, as well as abnormal FBS and elevated triglyceride levels (all p < 0.05). CONCLUSION: Targeted public health strategies and lifestyle interventions are crucial for reducing the incidence of metabolic syndrome, particularly among high-risk groups such as women, older adults, and individuals with a history of cardiovascular disease.

BACKGROUND: Advanced therapy medicinal products (ATMPs) comprise gene therapies, somatic cell therapies, tissue engineered products (TEPs), and combined ATMPs. These modalities have the potential to deliver durable or curative benefit in oncological, genetic, chronic, and rare diseases with high unmet medical need. Yet in Europe, access remains limited, uneven, and often commercially unsustainable: clinically promising therapies frequently fail to progress beyond early development or are withdrawn after regulatory approval for reasons related to scalability and reimbursement rather than lack of clinical benefit. METHODS: This study was designed as a qualitative, interview-based analysis to identify the major barriers faced by ATMP stakeholders to the clinical translation and patient access of cell therapies in Europe. We collected structured oral and written questionnaire/interview input from six stakeholders operating in the European ATMP landscape and synthesized the material into cross-cutting themes related to health technology assessment, manufacturing, regulatory implementation, and market dynamics. RESULTS: Stakeholders consistently report that HTA approaches optimized for conventional pharmacological therapies often overemphasize short-term budget impact and insufficiently account for long-term clinical benefit, downstream healthcare and societal costs, and the durability of therapeutic effects. In parallel, substantial variability across donors, batches, manufacturing and delivery settings, together with fragmented GMP infrastructure, uneven national execution of clinical trial and access pathways, and chronic underinvestment, undermines reproducibility and scalability. Although the European Medicines Agency (EMA) offers facilitation instruments including early scientific dialogue and accelerated or supportive regulatory pathways, their potential to improve predictability is frequently attenuated by Member State heterogeneity and discontinuities across regional innovation ecosystems. CONCLUSION: From a stakeholder's perspective, key recommendations including revising HTA frameworks to better reflect long-term lifetime value, investing to improve the accessibility to GMP facilities, strengthening ATMP regulatory expertise and access to early scientific advice, enabling cross-border ecosystems, and addressing structural market failure through public risk-sharing mechanisms.

BACKGROUND: Classic lissencephaly is a malformation of cortical development that includes agyria and pachygyria. The major clinical symptoms are developmental impairment, muscular hypotonia, and drug-resistant epilepsy. The severity of the clinical phenotype depends on the associated gene and mutation. This study aimed to systematically investigate the genotype-specific course of the disease including neurodevelopmental outcome, medical complications, use of non-pharmacological supportive therapies, and its impact on the quality of life of the affected families. METHODS: 47 patients with genetically and radiologically confirmed lissencephaly were included with mutation in LIS1/PAFAH1B1 (n = 38), DCX (n = 5 males), DYNC1H1 (n = 2), TUBA1A (n = 1) and TUBG1 (n = 1) genes. Standardized questionnaires were completed by families and treating pediatricians. Quality of life was assessed with the PedsQL™ Family Impact Module. RESULTS: Prenatal abnormalities, most commonly microcephaly, were observed in 14/37 (38%) of LIS1/PAFAH1B1 patients and 2/5 (40%) of DCX patients. Early symptoms included microcephaly, developmental delay, muscular hypotonia, and epileptic seizures. The median age at suspected diagnosis was 5 months for LIS1/PAFAH1B1 patients and 9 months for DCX patients. Compared to LIS1/PAFAH1B1, DCX-related lissencephaly patients showed significantly better neurodevelopmental outcome in reaching more advanced milestones such as walking unassisted (z=-2.23, p = 0.026) and speaking sentences (z=-2.53, p = 0.011). Frequent medical complications included recurrent respiratory infections (14/38 (37%) of LIS1/PAFAH1B1 patients; 1/4 (25%) of DCX patients) and dysphagia/ vomiting (23/37 (62%); 2/4 (50%)), which may require tube feeding (15/38 (40%); 1/5 (20%)). A median of eight different supportive therapies was used per patient (range 1-17), with physiotherapy and respiratory therapy considered the most effective. The scores obtained for health-related quality of life (HRQL) were low (parental HRQL mean 61.23; SD 16.79). CONCLUSIONS: Our study confirms the severely impaired developmental potential and frequent neurological and medical complications in lissencephaly patients from an early age. The psychomotor prognosis in LIS1/PAFAH1B1-related lissencephaly is significantly worse compared to DCX-related lissencephaly. Supportive therapies are used intensively and are considered to be very effective. The disease puts a high burden on caregivers and the entire family. This emphasizes the need for appropriate epilepsy treatment, personalized care for patients and professional support for their families.

BACKGROUND: Cardiovascular diseases are common in aging populations and are closely associated with multiple factors. However, the cumulative effects of green-space exposure and air pollutants on cardiovascular disease have not been adequately investigated. METHODS: This study used CHARLS 2015 data and CLHLS 2014 data. Green-space exposure was quantified using the normalized difference vegetation index (NDVI), while exposures to PM2.5, NO and SO were assessed using the China High-resolution Air Pollutant dataset (CHAP). A composite cardiometabolic risk score was derived from five metabolic syndrome (MetS) diagnostic components: abdominal obesity, hypertension, hyperglycemia, hypertriglyceridemia, and low high-density lipoprotein. Generalized linear models (GLMs) were applied to evaluate the effects of green-space exposure and air pollutants on cardiovascular disease risk; single-, two-, and three-pollutant models were fitted, and interaction and sensitivity analyses were conducted to assess the robustness of the findings. RESULTS: Green-space exposure was associated with a lower risk of cardiovascular disease (OR = 0.867, 95% CI: 0.796-0.944, P = 0.001), while exposures to PM2.5, NO, and SO were all linked to an increased risk. Among these pollutants, NO showed the strongest association, with each interquartile range (IQR) increase corresponding to a 25.9% higher risk of cardiovascular disease (OR = 1.259, 95% CI: 1.152-1.377, P < 0.001). Interaction analysis revealed that higher green-space exposure had a more pronounced protective effect under low levels of air pollution. However, under high pollution levels, greater green-space exposure appeared to amplify the adverse effects of pollutants on cardiovascular disease risk. In the multi-pollutant model, after further adjusting for three pollutants, the association between PM2.5 (OR = 1.179, 95% CI: 1.017-1.366, P = 0.028) and NO (OR = 1.165, 95% CI: 1.012-1.341, P = 0.034) and cardiovascular disease risk remained significant. CONCLUSIONS: Evidence indicates that green-space exposure confers protection for cardiovascular health, but this effect is significantly modulated by ambient air pollution.

BACKGROUND: High-intensity interval training (HIIT) is an effective exercise modality in cardiac rehabilitation; however, participation in conventional centre-based programs remains suboptimal due to barriers such as limited accessibility and adherence. Mobile health (mHealth) technologies may improve accessibility and supervision of exercise training. While previous studies have primarily focused on training modality, evidence comparing different delivery models of HIIT-based cardiac rehabilitation remains limited. This study aimed to compare the effectiveness and safety of mHealth-supported versus centre-based delivery of a standardized HIIT cardiac rehabilitation program in patients with stable coronary heart disease (CHD). METHODS: Between December 2024 and April 2025, 98 adults with stable CHD eligible for Phase II cardiac rehabilitation were enrolled and randomly assigned to either the control group (n = 49) or the intervention group (n = 49). Both groups performed the same standardized HIIT protocol; the control group received supervised centre-based rehabilitation, whereas the intervention group performed mHealth-supported home-based training with real-time monitoring and individualized feedback via the Xin'ankang mHealth platform. Primary outcomes included the six-minute walk distance (6MWD), cardiopulmonary exercise testing (CPET) parameters, and SF-36 quality of life scores. Secondary outcomes included anxiety, depression, and sleep quality. RESULTS: Baseline characteristics were generally comparable between groups, although minor differences were observed in certain SF-36 domains. After adjustment for baseline values, the intervention group demonstrated significant improvements compared to the control group in sleep quality scores (3.17 ± 2.09 vs. 4.83 ± 2.09), peak METs (5.83 ± 0.09 vs. 4.94 ± 0.09), anaerobic threshold METs (4.29 ± 0.07 vs. 3.53 ± 0.07), peak VO₂ (20.12 ± 0.30 vs. 16.70 ± 0.30 ml/kg/min), and 6MWD (563.83 ± 3.21 vs. 531.49 ± 3.21 m) (all P < 0.05). Improvements in SF-36 scores were observed in several domains, although no significant difference was found in vitality or mental health. Subgroup analyses revealed consistent improvements across age groups, while a sex-specific difference was observed for changes in VO₂ peak. CONCLUSION: Compared with centre-based delivery of the same HIIT program, mHealth-supported HIIT was associated with greater improvements in cardiopulmonary function, exercise capacity, and quality of life in patients with CHD. These findings suggest that delivery modality may influence the effectiveness of HIIT-based cardiac rehabilitation. TRIAL REGISTRATION: Clinical Trial Registration Number: ChiCTR2500104462, June 17, 2025.

BACKGROUND: Primary cardiac tumors are rare, and cardiac involvement by Burkitt lymphoma is exceptionally uncommon, particularly when presenting with extensive intracavitary growth. Such tumors may rapidly lead to hemodynamic compromise due to obstruction of venous inflow and impairment of cardiac filling, often requiring urgent surgical intervention. Establishing cardiopulmonary bypass in these settings may be technically challenging, especially when conventional inferior vena cava cannulation is precluded by tumor extension. CASE PRESENTATION: We report a unique case of a 30-year-old male who presented with acute heart failure and severe hemodynamic instability caused by massive biatrial involvement of Burkitt lymphoma. Imaging revealed large intracavitary tumors extending into the inferior vena cava and pulmonary veins, resulting in near-complete obstruction of venous return. During emergency surgery, standard inferior vena cava cannulation and snaring were not feasible due to tumor invasion. To achieve adequate venous drainage and enable cardiopulmonary bypass, an unconventional technique using a cuffed endotracheal tube as a temporary inferior vena cava cannula was successfully employed. This approach allowed effective tumor debulking, restoration of intracardiac blood flow, and subsequent initiation of definitive systemic chemotherapy. Histopathological and molecular analysis confirmed Burkitt lymphoma with a high proliferative index and c-MYC gene translocation. At one-year follow-up, the patient demonstrated complete metabolic remission on ¹⁸F-FDG PET/CT (Deauville score 1). CONCLUSIONS: This case illustrates the critical role of emergency surgical intervention as a bridge to definitive chemotherapy in life-threatening cardiac lymphoma. Our experience extends the applicability of endotracheal tube-assisted venous cannulation beyond its original description and suggests that this technique may serve as a valuable bailout option in emergency cardiac oncology surgery when conventional inferior vena cava cannulation is technically impossible.

BACKGROUND: Cardiovascular diseases (CVDs) caused by diabetes pose a significant health burden. CVD risk communication refers to the process of conveying CVD risk information to the public or patients at the individual and community levels and encouraging them to adopt effective preventive measures. However, Chinese general practitioners (GPs) do not adequately communicate CVD risks to their patients. Training may enhance the risk communication skills of GPs. Therefore, this pilot study aims to develop, implement, and preliminarily evaluate a tailored training program to enhance the skills of GPs in communicating cardiovascular risks to people with diabetes. METHODS: This is a pilot study employing a mixed-methods approach for evaluation of an educational intervention.The curriculum was designed via a literature review and discussions with experts from general practice, endocrinology, and cardiology. Following Kern's six-step teaching model, the training was delivered through a 4-session (160-min) training program. GPs from local community health service centers were invited to participate in the training program. Participants' learning outcomes were assessed using quantitative methods, while qualitative assessments focused on their experiences and perceptions of the learning process. RESULTS: One male GP and nine female GPs from 10 different community health service centers participated in the training. Post-training knowledge test scores (71.50 ± 10.55) were significantly higher than pre-training scores (47.50 ± 9.20), with a mean difference of 24.00 (95% CI: 16.31, 31.69; P < 0.001). Post-training qualitative interviews revealed enhanced participant attitudes, knowledge, and skills, with a positive impact on clinical practice. Participants suggested further refining communication elements, incorporating video demonstrations, and revising assessment materials to optimize the training program. CONCLUSION: The training program developed in this study preliminarily demonstrates feasibility, effectiveness, and wide acceptance and offers an innovative educational framework for type 2 diabetes management. Despite the inherent limitations of the pilot study, such as its limited sample size and single-center design, this work establishes a crucial foundation for subsequent curriculum refinement, expansion of the training scale, and evaluation of long-term outcomes.

BACKGROUND: Drug exposure is one of the potential mechanisms implicated in the onset or exacerbation of psoriasis. To date, several cardiovascular agents have been implicated. Sacubitril/valsartan (SV) has been widely used in the treatment of hypertension and heart failure (HF). Its common adverse reactions include angioedema, hypotension, renal impairment, and hyperkalemia. However, SV may cause psoriasis, which needs clinical attention. CASE PRESENTATION: This report describes a case of a middle-aged male patient who developed psoriasis following SV therapy. The rashes presented as well-demarcated red or violaceous plaques with noticeable scaling. After being diagnosed with psoriasis, he was started on topical clobetasol propionate ointment, and SV was discontinued and replaced with ramipril for blood pressure control. During follow-up, the skin lesions showed marked improvement. However, the patient developed similar cutaneous manifestations again when SV was re-administered. He had previously developed psoriasis while using nifedipine, but transitioned to olmesartan and subsequently improved significantly with topical medication. Sacubitril enhances the effect of natriuretic peptides, which may be accompanied by a compensatory increase in angiotensin Ⅱ (Ang Ⅱ) levels, possibly contributing to the psoriasis. CONCLUSION: To the best of our knowledge, this is the first reported case worldwide of psoriasis potentially associated with SV, and the underlying mechanism appears likely to be related to sacubitril. It serves as a caution for clinicians prescribing SV, particularly in patients with a history of psoriasis or positivity for the HLA-Cw*0602 allele. Further studies are warranted to confirm the mechanism by which sacubitril induces psoriasis.

BACKGROUND: Minimally invasive cardiac surgery via minithoracotomy is associated with postoperative pain. Continuous BRILMA (block of the lateral branches of the intercostal nerves in the mid-axillary line) and intercostal cryoanalgesia are opioid-sparing techniques, but comparative evidence in this setting is limited. METHODS: In this prospective comparative observational study, consecutive adults undergoing minimally invasive cardiac surgery received either continuous BRILMA or intercostal cryoanalgesia according to routine institutional practice. Treatment allocation was not determined by the study protocol and no randomization was performed. Pain at rest and during deep inspiration was assessed using the Numerical Rating Scale (NRS) after extubation and at 24, 48, and 72 h, discharge, and 30 days. The primary endpoint was pain at rest over the first 72 h. Secondary outcomes included inspiratory pain, opioid consumption during the first 72 postoperative hours, neuropathic pain, pulmonary complications, and hospital stay. Longitudinal analyses were performed using linear mixed models adjusted for age, sex, and surgical time. RESULTS: Sixty-three patients were analyzed (BRILMA n = 33; cryoanalgesia n = 30). Pain decreased significantly over time in both groups (p < 0.001), with significant group-by-time interactions at rest (p = 0.002) and during deep inspiration (p < 0.001). BRILMA was associated with lower early pain scores, particularly at 72 h, whereas cryoanalgesia showed comparable or lower pain levels at 30 days. Although a greater proportion of patients in the cryoanalgesia group required rescue opioids, cumulative opioid exposure in the first 72 h was low in both groups. Neuropathic pain incidence was low and similar between techniques. CONCLUSION: BRILMA was associated with lower early postoperative pain scores, while cryoanalgesia showed a trend toward lower pain levels at 30 days. Overall opioid requirements and neuropathic pain rates were low, suggesting that both regional techniques may represent suitable regional analgesic strategies in this setting. TRIAL REGISTRATION: The study was prospectively registered at ClinicalTrials.gov (NCT06086535; October 17, 2023). Ethical approval was obtained from the Clinical Research Ethics Committee of Vall d'Hebron University Hospital (Barcelona, Spain) (protocol number: PR(AG)324/2022; approved on November 25, 2022).

BACKGROUND: Mucosally-applied aminoglycosides have demonstrated host-directed antiviral activity in preclinical models through induction of interferon-stimulated genes (ISGs). However, it remains unknown if systemically administered aminoglycosides elicit comparable effects in humans. METHODS: We conducted a single-centre randomized, double-blind, placebo-controlled trial in Singapore in 32 healthy adults who were randomized 1:1 using sequentially sealed envelopes, to receive single-dose intravenous gentamicin 5 mg/kg or placebo. Participants were subsequently challenged with live-attenuated yellow fever 17D (YF17D) virus and followed for 30 days. The primary outcome was the proportion of participants with detectable YF17D RNAemia. Secondary outcomes included RNAemia levels, symptom rates, neutralizing antibody titers, and innate immune transcriptomic changes. RESULTS: We found no significant differences between the gentamicin and placebo groups in detectable RNAemia (62.5% [n = 10/16] vs. 68.8% [n = 11/16], p > 0.99), mean RNAemia levels (3.93 log area under the curve [AUC] vs. 3.51 log AUC, p = 0.81), symptom rates (56% [n = 9/16] vs. 25% [n = 4/16], p = 0.15) or antibody titers (mean log PRNT titer: 3.89 vs. 3.71, p = 0.37). However, transcriptomic profiling demonstrated upregulation of ISGs RSAD2 and OASL and the transcription factor IRF3 in gentamicin-treated individuals, with concomitantly higher protein expression of chemokines CCL2, CXCL12 and IL-27. CONCLUSIONS: This study represents, to our knowledge, the first in humans to evaluate the host-directed antiviral effects of systemic aminoglycosides. Our findings suggest that, whilst modest and insufficient to control systemic viral infection, the immunomodulatory effects of aminoglycosides warrant continued exploration as a potential preventive strategy against mucosal viral infections.