BACKGROUND: A higher ratio of IGF-1:IGF binding protein 1 (IGFBP1) was associated with improved prognosis in the CHAARTED trial of docetaxel in participants with metastatic hormone-sensitive prostate cancer (mHSPC). The ENZAMET trial demonstrated the survival benefit of adding enzalutamide to androgen deprivation therapy (ADT) in mHSPC, and included participants who also received docetaxel as standard of care. The aim of this study was to validate the association between levels of circulating IGF-1 and IGFBP1 and survival of ENZAMET participants. METHODS: IGF-1 and IGFBP1 levels were measured in baseline plasma from 845 ENZAMET participants, and associations with clinical progression-free survival (cPFS) and overall survival (OS) were assessed as a post-hoc analysis. RESULTS: A high baseline plasma ratio of IGF-1:IGFBP1 (upper two tertiles) was associated with improved OS (HR 0.75, p 0.008) and improved cPFS (HR 0.82, p 0.034) compared to the lowest tertile. IGF-1:IGFBP1 was not predictive of enzalutamide or docetaxel benefit (no significant interaction with treatment arm or docetaxel use). In participants in the enzalutamide arm, IGF-1:IGFBP1 was an independent predictor for OS and cPFS in bivariable analysis with docetaxel use. The rate of high volume disease was similar in patients with lower IGF-1:IGFBP1 ratio and those with high ratio (~50%). CONCLUSIONS: This analysis demonstrated a consistent association of improved prognosis with high IGF-1:IGFBP1 in mHSPC, but did not identify which participants benefited from docetaxel when treated with enzalutamide.

BACKGROUND: The Polish National Ablation Registry (POL-AR), mandatory for all centers performing catheter ablation and integrated with National Health Fund data, enables prospective analysis of a nationwide cohort with complete inclusion of all consecutive patients. OBJECTIVE: We aimed to assess real-world safety profiles and clinical outcomes of atrial fibrillation (AF) ablation modalities-radiofrequency (RF), cryoballoon (CRYO), and pulsed-field ablation (PFA)-and to report the first-year PFA experience in Poland. METHODS: All AF ablations in 2023 were prospectively analyzed in POL-AR and cross-referenced with National Health Fund data. Only centers with complete reporting were included. Patients were grouped by modality. Major complications, unplanned hospitalizations, cardioversions, repeat ablations, and deaths were assessed at 1 year. Multivariate analysis identified independent predictors of outcomes. RESULTS: Twenty-eight centers reported 3430 patients (CRYO: 2125; RF: 1098; PFA: 207). Procedure time was longest for RF (median 120 min) versus CRYO (75 min) and PFA (65 min); (p < 0.001). No major complications occurred with PFA. Phrenic nerve injury persisted in 1.51% of CRYO, 0.09% of RF, and 0% of PFA patients (p < 0.001). Pericardial effusion was more frequent after RF (0.91% vs. 0.34% for CRYO + PFA; p = 0.032). Overall complication rates were lowest with PFA (0% vs. RF: 2.19%, CRYO: 2.59%). PFA patients required fewer cardioversions during follow-up (p = 0.017). Predictors of poor outcome included age, female sex, left atrium (LA) size, hypertension, and hypertrophic cardiomyopathy (HCM). Favorable outcome was independently associated with higher left ventricular ejection fraction (LVEF), paroxysmal AF, and PFA use (HR 0.70, p = 0.04). CONCLUSION: In the POL-AR registry, PFA was independently associated with favorable outcomes after AF ablation.

Atherosclerosis is a chronic inflammatory disease driven by senescent vascular smooth muscle cells (VSMCs). Salvianolic acid A (SAA) exhibits cardiovascular protective effects; however, its role in atherosclerosis remains unclear. This study aimed to investigate the effects and targets of SAA in atherosclerosis. In vitro studies were performed in senescent VSMCs with heat shock protein 90 alpha (HSP90α) overexpression or knockdown, with or without SAA treatment. In vivo, ApoE mice fed a high-fat diet were treated with SAA and adeno-associated virus-mediated VSMC-specific HSP90α overexpression or knockdown. SAA promoted apoptosis in senescent VSMCs by inhibiting HSP90α. This inhibition promoted ubiquitin-proteasome-dependent degradation of protein kinase B (AKT) and activation of PRKR-Like Endoplasmic Reticulum Kinase (PERK) signaling. SAA increased endoplasmic reticulum-mitochondrial contacts and mitochondrial calcium uptake. These effects were reversed by HSP90α overexpression. In ApoE mice, SAA reduced the burden of senescent VSMCs, decreased the size of plaque, and increased the stability of the fibrous cap. VSMC-specific HSP90α knockdown mimicked the protective effects of SAA, whereas HSP90α overexpression reversed SAA-mediated effects on disease. SAA reduces the burden of senescent VSMCs in atherosclerosis by inhibiting the scaffold function of HSP90α which maintains the AKT-PERK interaction, to reactivate PERK signaling, thereby alleviating disease progression.

BACKGROUND: Atrial fibrillation (AF) often progresses from paroxysmal to persistent forms, culminating in permanent AF, a transition associated with increased risks of stroke, heart failure, and hospitalization. Cryoballoon pulmonary vein isolation (CB-PVI) is an established rhythm-control strategy; however, long-term data on AF progression following ablation remain limited. This study aimed to assess the incidence of progression to permanent AF after CB-PVI and to identify clinical predictors of such progression to guide patient management. METHODS: We analyzed 1330 consecutive patients enrolled in the prospective, multicenter 1STOP registry who underwent CB-PVI between 2012 and 2018 across 13 Italian centers, with ≥ 5 years of follow-up. Baseline clinical, echocardiographic, and procedural characteristics were prospectively collected. RESULTS: During a median follow-up of 81 months, 93 patients (7.0%) progressed to permanent AF. Independent predictors of progression included baseline persistent AF (HR ≈ 2.2, p < 0.001), need for cardioversion during index procedure (HR ≈ 2.2, p = 0.001), and older age (HR 1.05 per year, p < 0.001). Patients progressing to permanent AF had larger left atrium dimensions, higher CHADS-VA scores, and a greater burden of comorbidities. Among patients experiencing AF recurrence, those undergoing repeat ablation had lower rates of progression compared to those without reintervention (11.0% vs. 17.6%). CONCLUSION: In this large multicenter cohort, long-term progression to permanent AF after CB-PVI was relatively uncommon (7%). Baseline AF type, age, and intra-procedural cardioversion independently predicted progression. Early rhythm-control strategies and individualized risk stratification may help delay the transition to permanent AF and improve long-term rhythm outcomes.

Smoking acts as a critical risk factor for atherosclerosis (AS), but the precise molecular mechanisms remain unclear. We performed in vivo experiments with TAR-injected ApoE mice and in vitro co-culture of macrophages with extracellular vesicles (EVs) from TAR-treated endothelial cells (ECs). Single-cell RNA sequencing were used to explore the regulatory effects and molecular pathways of ECs-derived EVs in smoke-related AS. Cigarette TAR significantly stimulated ECs EV secretion and aggravated atherosclerotic plaques, while the EV inhibitor GW4869 alleviated these lesions. RNA-seq indicated TAR facilitated AS by increasing macrophage extracellular traps (METs) formation. Combined in vivo and in vitro proteomics showed TDP43 was highly enriched in circulating EVs from smoking patients, TAR-treated mice, and stimulated ECs. TDP43 knockdown alleviated TAR-induced AS, accompanied by suppressed METs and inflammatory responses. Mechanistically, EV-delivered TDP43 bound macrophage VDAC1 to induce mitochondria-associated membranes (MAMs), triggering Ca overload/METs; 2-APB and BAPTA blocked this process. Retinoic acid (RA) might bind with TDP43 to inhibit MAMs, thereby reducing METs and mitigating smoke-related AS. Cigarette TAR accelerates ASthrough EC EV-packaged TDP43 partly, which binds VDAC1 to induce MAMs, calcium overload, METs, and inflammation. RA may serve as a putative protective molecule for the progression of smoking-related atherosclerotic plaques.

Precise extracellular matrix (ECM) coordination is essential for cardiac septation, yet the molecular etiology of human isolated perimembranous ventricular septal defects (VSD) remains elusive. Here, we constructed a high-resolution single-cell transcriptomic atlas of human VSD, benchmarking the pathological state against a 7-22 week developmental trajectory. Integrating these single-cell profiles with a reference-based spatial transcriptomic map, we deconvolved the distinct molecular signatures of membranous and muscular septal regions. We found that aberrant cardiomyocyte hypertrophy operates alongside a systemic failure in the non-myocyte microenvironment. Crucially, the ECM regulatory network is dysregulated, driven by attenuated endothelial-fibroblast crosstalk and downregulated THBS1-integrin signaling. Supported by in vitro assays, this dysregulation impairs key endothelial-to-mesenchymal transition (EndoMT) programs and transcriptionally suppresses MMP2. Spatial reconstruction confirmed this maturation block compromises both septal regions, indicating a global remodeling arrest that precludes physical closure. Validated by in situ immunofluorescence and a robust correlation between reduced maternal serum MMP2 levels and defect size, our study portrays VSD as a disease driven by microenvironmental insufficiency and arrested remodeling, providing an integrative framework for understanding human cardiac dysmorphogenesis.

Atherosclerotic cardiovascular disease (ASCVD) remains the leading global cause of mortality, with substantial residual inflammatory risk persisting despite statin therapy. We identify a c-Rel-driven CD72 macrophage subset markedly enriched in human and murine atherosclerotic plaques, whose abundance correlates with disease severity. Single-cell transcriptomics and functional assays demonstrate that CD72 macrophages drive endothelial pyroptosis, oxidative stress and dysfunction via pathological crosstalk through the CXCL12-CXCR4 axis. Through transcriptome-based phenotypic screening, we discover Ilexoside K (IK), a natural triterpenoid saponin, as a dual anti-atherosclerotic and anti-pyroptotic lead compound. Molecular docking, dynamics simulations, and surface plasmon resonance (SPR) validate that IK directly binds CXCR4. In vivo, IK significantly alleviates atherosclerotic plaque burden, dyslipidemia, systemic inflammation and endothelial pyroptosis in high-fat diet-fed ApoE mice with favorable safety. Gain-of-function assays confirm that endothelial CXCR4 overexpression abrogates IK's vasculoprotective effects. This study defines CD72 macrophages as a key pro-atherogenic subset and establishes IK as a promising CXCR4-associated agent for ASCVD treatment.

INTRODUCTION: Fetal infections, particularly those caused by TORCH agents (toxoplasmosis, other [syphilis, varicella-zoster, parvovirus B19], rubella, cytomegalovirus, herpes), may significantly affect fetal growth and development, resulting in a substantial risk of morbidity and mortality. Since infections are mostly preventable causes of congenital anomalies, early diagnosis relies on serological and molecular testing and fetal ultrasound. OBJECTIVE: The aim of this study was to assess the prevalence of fetal infections and their detectable ultrasound features. METHOD: This retrospective study was conducted at the Department of Obstetrics and Gynecology, University of Szeged, analyzing fetal TORCH infection cases between 2020 and 2024. We assessed the prevalence of infections and the associated developmental abnormalities proven by ultrasound, and compared the results with national and international data. RESULTS: During the examined period, the prevalence of TORCH infections ranged from 0.00% to 0.14%, compared to international data of 1.2%. In our cohort, fetal T. gondii infections occurred in 0.04-0.08% of cases, parvovirus B19 in 0.053-0.14%, and herpes simplex virus infections in 0.027%. In confirmed cases, central nervous system abnormalities (37.5%) and placental edema (37.5%) were the most common, while other abnormalities - such as fetal anemia, hyperechogenic bowel, nonimmune hydrops fetalis, polyhydramnios, pyelectasis - occurred at a lower rate (12.5%). DISCUSSION: In the literature, the reported prevalence rates of fetal infections are 0.3-2.0% for parvovirus B19, ~1% for herpes simplex virus, and <0.03% for congenital T. gondii infection. Internationally accepted TORCH-related fetal malformations include nonimmune hydrops fetalis, central nervous system malformations, cardiovascular anomalies, polyhydramnios, and hepatosplenomegaly. Based on our results and literature, ultrasound is the most reliable noninvasive modality for detecting infection-related fetal malformations, but to determine infectious causes microbiological investigations are necessary. CONCLUSION: Our prevalence of infections was significantly lower than reported internationally, while ultrasound findings were consistent with the literature. This confirms the international consensus that ultrasound plays a key role in the diagnosis of fetal infections. Orv Hetil. 2026; 167(39): 1552-1564.

STUDY AIMS: Cardiac arrest is a condition with a high mortality rate, with most cases occurring outside hospital. First responders (defined as public responders in our study) play an increasingly important role in management through the early initiation of cardiopulmonary resuscitation and defibrillation. Several studies have shown that the involvement of public responders can result in faster initiation of resuscitation and increased survival. This study evaluated the management of out-of-hospital cardiac arrest by public responders and the effectiveness of the FRED-PA1 automated external defibrillator (AED) available in the canton of Valais, Switzerland. METHODS: This was a retrospective study including consecutive cases of out-of-hospital cardiac arrest occurring between January 2021 and December 2023 in the canton of Valais. Response times of public responders and emergency medical services (EMS) were evaluated, along with initial rhythms, survival, and the performance and safety of the available AEDs. RESULTS: A total of 107 patients were included in the study. In 68% of cases, a public responder arrived at the scene first, with a significantly shorter interval between emergency call and on-site arrival compared with EMSs (p = 0.019). Ventricular fibrillation was more frequent in the EMS group than the public responders group (35 vs 23%) (non-significant [NS]). Survival on arrival at hospital was 19% in the public responder group and 24% in the EMS group (NS). Survival to hospital discharge was 9.6% in the public responder group and 15% in the EMS group (NS). Concerning the AEDs, the rhythm recognition algorithm was deemed to be effective and consistent with current recommendations. CONCLUSION: This retrospective study demonstrates the key role played by public responders, who are frequently the first to arrive at the scene of out-of-hospital cardiac arrests. The FRED-PA1 AED algorithm meets the standards in the literature. However, ongoing prospective studies will highlight and optimise the role of public responders in out-of-hospital cardiac arrests.

Platelets are anucleate yet metabolically active cells that play essential roles in hemostasis, thrombosis, and inflammation by rapidly responding to vascular injury and maintaining vascular integrity. Alteration of platelets can lead to bleeding disorders or thrombotic complications. Therefore, studying their structural and functional properties is essential for understanding their roles in both physiological and pathological processes. Recent advances in experimental techniques have revolutionized platelet research. It has allowed high-resolution structural visualization, precise functional assessment, and detailed mapping of interplatelet interactions. Recently, platelet count and structure have been assessed using specialized techniques. For example, automated hematology analyzers provide accurate platelet counts, while light and electron microscopy reveal platelet morphology and ultrastructure. Flow cytometry evaluates platelet size, granularity, and surface markers. In addition, the platelet function is assessed through different instruments and assays. For example, adhesion is studied using microscopy-based assays, aggregation by light transmission aggregometry. Similarly, activation, and secretion are measured by fluorescence microscopy or flow cytometry. The clot retraction is evaluated using Sonoclot or thromboelastography. Although, several studies have described techniques for assessing the platelet count, structure and function, a single comprehensive narrative review is lacking. Therefore, in this review, we summarize current techniques for assessing platelet structure and function. We also cover both classical and newly developed methods. We highlight recent technical advances and analytical challenges. In addition, we discuss innovations such as artificial intelligence-assisted data analysis. This review aims to help researchers select appropriate methods for studying platelet biology and its role in health and disease.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare clonal non-Langerhans cell histiocytosis characterized by the infiltration of foamy, CD68-positive/CD1a-negative histiocytes into multiple organ systems. Activating MAPK/ERK pathway mutations, most commonly BRAF V600E, represent common targets for ECD therapies. Although vemurafenib has been approved for BRAF V600E-mutant ECD, data regarding dual BRAF and MEK inhibition remain scarce. METHODS: We recently treated three patients with BRAF V600E-mutant ECD using dabrafenib combined with trametinib. The clinical presentations included skeletal, cardiovascular, retroperitoneal, and central nervous system (CNS) involvement. RESULTS: Two patients achieved clinical and radiologic improvement, including resolution of CNS symptoms. Notably, BRAF V600E immunohistochemical staining was faint, equivocal, or negative in all patients, whereas molecular testing confirmed the mutation. One patient developed grade 3 rhabdomyolysis after one year, requiring dose reduction. The third patient maintained stable disease, with positron emission tomography demonstrating decreased fluorodeoxyglucose uptake that indicated early metabolic improvement. CONCLUSION: This case series highlights the effectiveness and tolerability of dabrafenib plus trametinib for BRAF V600E-mutant ECD, including cases with CNS and cardiovascular involvement. Molecular diagnosis and targeted therapy appear to be critical for optimizing outcomes, although further prospective studies are warranted to clarify the long-term effectiveness, resistance mechanisms, and optimal duration of this treatment approach.

Heart failure (HF) is a growing public health crisis that progresses from cardiovascular risk factors to structural/functional heart disease and eventual HF symptoms. Nocturia, long recognized as a HF symptom, has not been characterized along the HF continuum. To characterize nocturia across HF stages, we retrospectively analyzed voiding diaries and clinical data from US male veteran outpatients treated for lower urinary tract symptoms from 2008 to 2022. Patients were categorized into HF stages 0 (no risk factors), A (HF risk factors), B (stage A criteria + structural heart disease), and C (stage B criteria + prototypical HF signs/symptoms). Among 329 men, median actual void number (ANV) differed across HF stages (p = .011) and was maximal at Stage B. Among patients not taking diuretics - nocturnal voiding indices rose progressively through stage C, suggesting diuretic-mediated suppression of nocturia. There were trends toward higher nocturnal urine volume (NUV), nocturnal polyuria index (NPi) and nocturnal maximum voided volume (NMVV) in Stages B and C patient than Stage A. On multivariate analysis, HF stage was predictive of NUV and trended towards predicting ANV, whereas edema was an independent predictor of ANV, NUV, NPi, and NMVV. In a clinical urology population, nocturnal voiding indices were associated with HF stage, with the highest nocturia burden observed in Stage B (pre-HF) and independently with edema. Among men not taking diuretics, nocturia increased progressively through Stage C. These findings support nocturia as an early marker of volume overload that accompanies structural/functional heart disease, potentially preceding overt HF symptoms.

BACKGROUND: Cardiovascular disease is the leading cause of death among patients undergoing peritoneal dialysis (PD). Serum chloride might provide prognostic information independent of serum sodium; however, its association with cardiovascular events in patients undergoing PD remains unclear. The aim of this study was to assess the association between serum chloride concentration and major adverse cardiovascular events (MACE) in patients undergoing PD. METHODS: We conducted a multicenter cohort study using data from the Fukuoka Peritoneal Dialysis Registry. A total of 1,043 PD patients were included after excluding those with a PD duration of <90 days. The primary outcome was MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). Serum chloride was analyzed in tertiles and per 1 mmol/L decrease. Associations were evaluated by multivariable-adjusted Cox proportional hazards models, further adjusting for serum sodium. RESULTS: Over a median follow-up of 681 days, 135 patients experienced MACE. Hypochloremia (< 96 mmol/L) was present in 32.5% of the patients. In multivariable-adjusted models, patients in the lowest serum chloride tertile showed a significantly higher risk of MACE compared with those in the highest tertile (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.28-4.42). Each 1 mmol/L decrease in serum chloride was also associated with increased risk of MACE (HR, 1.08; 95% CI, 1.01-1.16). CONCLUSIONS: Lower serum chloride concentration was independently associated with a higher risk of MACE in PD patients, even after adjusting for serum sodium. Serum chloride might provide information on cardiovascular risk, which was not fully reflected by serum sodium.

BACKGROUND: Nocturia is increasingly recognized as a manifestation of systemic cardiovascular, renal, and metabolic dysfunction, yet its prevalence and prognostic significance within the cardiovascular-kidney-metabolic (CKM) syndrome framework remain unclear. METHODS: We analyzed 11,910 participants from NHANES (2005-2018) and 865 individuals from a hospital-based cohort. Logistic regression assessed associations between CKM stages and nocturia, while Cox proportional hazards models evaluated relationships between nocturia and all-cause and cardiovascular mortality in CKM stages 1-4. Restricted cubic spline analyses explored dose-response relationships. RESULTS: In NHANES, nocturia prevalence increased with CKM stage, from 17.6% in stage 0 to 45.97% in stages 3-4 (P < 0.0001). Compared with stage 0, CKM stages 1-2 and 3-4 were associated with higher odds of nocturia (OR 2.05, 95% CI 1.59-2.64; OR 4.52, 95% CI 3.34-6.10). Nocturia was linked to increased all-cause (HR 1.54, 95% CI 1.34-1.78) and cardiovascular mortality (HR 1.88, 95% CI 1.37-2.57), with significant dose-response relationships. Similar findings were observed in the hospital-based cohort, where CKM stages 1-2 and 3-4 were associated with 2.79-fold and 4.77-fold higher odds of nocturia, respectively. CONCLUSION: Nocturia is common in CKM syndrome and independently associated with increased all-cause and cardiovascular mortality. These findings highlight nocturia as a clinically relevant marker associated with adverse outcomes in CKM populations.

BACKGROUND: Ebstein anomaly is a rare congenital malformation of the tricuspid valve, accounting for less than 1% of all congenital heart diseases. Ebsteinoid anomaly is an uncommon morphological variant characterized by abnormal tricuspid valve leaflet morphology without the classical apical displacement of the septal leaflet seen in Ebstein anomaly. The coexistence of an Ebsteinoid anomaly, giant right atrial aneurysm (RAA), and atrial septal defect (ASD) is exceptionally rare. CASE PRESENTATION: A 15-year-old girl presented with progressive exertional dyspnoea (New York Heart Association [NYHA] class II) and intermittent palpitations. Chest radiography demonstrated marked cardiomegaly. Transthoracic echocardiography revealed a giant right atrium, severe low-pressure tricuspid regurgitation, an ostium secundum ASD, and an Ebsteinoid tricuspid valve with an elongated anterior leaflet and tethered septal leaflet, without apical displacement or right ventricular atrialization. Four-dimensional echocardiography and cardiac computed tomography confirmed the anatomical findings. Cardiac catheterization demonstrated pulmonary artery pressures approximately one-third of systemic pressure, confirming operability. The patient underwent successful tricuspid valve repair, ASD closure, and right atrial reduction atrioplasty. At one-year follow-up, she remained asymptomatic (NYHA class I) with preserved right ventricular function and only trivial residual tricuspid regurgitation. CONCLUSION: This case describes an exceptionally rare combination of Ebsteinoid tricuspid valve anomaly, giant right atrial aneurysm, and an ostium secundum ASD. Multimodality imaging was essential for accurate anatomical delineation and surgical planning. Early surgical correction resulted in excellent clinical and echocardiographic outcomes, underscoring the importance of timely intervention in complex congenital tricuspid valve anomalies.

INTRODUCTION: Health systems are increasingly oriented toward value-based care, emphasizing patient-centered outcomes such as health-related quality of life (HRQoL). During hospitalization, HRQoL reflects the interplay of sociodemographic, geographic, and clinical factors, which may be particularly influential in middle-income settings where structural inequities can affect patient-reported outcomes. OBJECTIVE: To identify factors independently associated with HRQoL measured during hospitalization in adults treated at a high-complexity institution in a middle-income country. METHODS: We conducted a cross-sectional analytical study nested within an institutional prospective cohort (2023-2025). We included hospitalized adults with a complete in-hospital HRQoL assessment using the EQ-5D-3L descriptive system and the EQ visual analogue scale (EQ VAS). The EQ VAS score was analyzed as the primary continuous outcome. Associations were evaluated using bivariate analyses and multivariable linear regression. RESULTS: A total of 46,083 patients were included, with a median EQ-VAS score of 70 (IQR, 60-80). Functional impairment was most commonly reported in usual activities (62.46%). In the multivariable linear regression model, lower EQ-VAS scores were independently associated with increasing age (β = - 0.150 per year) and ICU admission (β = - 1.661), whereas professional education (β = 2.364) and surgical admission (β = 1.672) were associated with higher scores. Across diagnostic groups, mental and behavioural disorders (β = - 2.949) and respiratory diseases (β = - 2.036) showed the strongest negative associations, while pregnancy-related conditions were associated with the highest scores (β = 3.982). CONCLUSION: EQ VAS scores measured during hospitalization were independently associated with sociodemographic and clinical factors, underscoring the multifactorial determinants of self-rated health in acute hospital settings.

BACKGROUND: Chromosome 19p13.3 microdeletion syndrome is a rare and clinically heterogeneous genomic disorder. It is typically characterized by a wide spectrum of manifestations, including global developmental delay, various congenital anomalies, and distinct craniofacial dysmorphisms. Current literature suggests that phenotypic severity and the specific symptoms are highly dependent on the precise size and gene content of the deleted region. METHODS AND RESULTS: Here we report the case of an 8-month-old female infant referred for evaluation of multisystemic complications. Clinical examination revealed a complex phenotype characterized by congenital heart defects, limb anomalies, macrocephaly, and recurrent pulmonary infections. Oligo-Array CGH revealed a 1.8 Mb deletion encompassing 55 genes. Although gastrointestinal symptoms have rarely been reported in this condition, the patient presented with gastrointestinal complications including vomiting and diarrhea. CONCLUSION: This case expands the clinical spectrum of 19p13.3 microdeletion syndrome and underscores the importance of genomic analysis in understanding the underlying disease mechanisms.

Sudden cardiac death (SCD) remains a major global health challenge, characterized by high incidence, low survival rates, and often presenting as the first manifestation of underlying disease. This review provides a comprehensive overview of the genetic and epigenetic landscape of non-familial SCD, emphasizing the multifactorial nature of this complex clinical endpoint. We summarize common single nucleotide polymorphisms and insertion/deletion variants associated with SCD, identified through candidate-gene-based studies and genome-wide association studies, highlighting risk variants clustered in genes involved in cardiovascular function, signal transduction, and cellular metabolism. We also describe the main epigenetic mechanisms - including microRNAs, DNA methylation, and histone modifications - that may contribute to SCD susceptibility and pathogenesis. Tissue-based and circulating microRNAs can act as mechanistic regulators of SCD pathogenesis and have emerged as exploratory biomarker candidates. However, inconsistent directions of association, methodological heterogeneity, and limited independent validation currently preclude their clinical application. DNA methylation studies, though scarce, suggest potential roles for imprinted genes and oxidative stress pathways. Histone modifications and chromatin remodeling represent underexplored but promising areas. We conclude that addressing the missing heritability of SCD and translating these molecular insights into clinical practice will require large-scale, integrative, and multi-ethnic studies combining genomic, epigenomic, and clinical data with functional validation.

Mesenchymal stem/stromal cells (MSCs) have regenerative and immunomodulatory properties and may influence gut microbial responses. This systematic review synthesised preclinical evidence on MSC-associated gut-microbiota modulation and considered its implications for hypertension. PubMed, Scopus, Ovid MEDLINE, EBSCOhost Academic Search Elite and Web of Science were systematically searched. Eligible in vivo studies were synthesised according to PRISMA 2020, and risk of bias was assessed using the SYRCLE tool. Thirty-one studies were included. Among 27 studies reporting α-diversity, 11 described an increase, three a decrease, 11 no significant difference and two a change without a clear direction. Twenty-seven studies reported β-diversity outcomes, with heterogeneous evidence of between-group differences in community composition. Four studies assessed the Firmicutes-to-Bacteroidetes ratio: three reported a lower ratio and one a higher ratio after intervention. Three studies directly quantified short-chain fatty acids, five used direct metabolomics or targeted bile-acid profiling, 18 assessed gut-barrier outcomes and 27 assessed inflammatory or immune outcomes. Of 310 risk-of-bias judgements, 74.5% were unclear and 25.5% were low risk. Only one study used a pulmonary-hypertension model; none directly evaluated systemic hypertension. The findings indicate context-dependent microbial, metabolic, barrier and immune responses rather than a universal restoration pattern. Concurrent microbiota and host changes did not generally demonstrate causal mediation, and enrichment of taxa associated with short-chain fatty-acid production could not substitute for direct metabolite measurement. MSC-associated gut-microbiota modulation is biologically plausible and warrants targeted mechanistic investigation. However, the current preclinical evidence does not establish an antihypertensive effect, particularly in systemic hypertension.

BACKGROUND: Serum uric acid (SUA) has been linked to vascular injury, but its impact on stroke risk in diabetic patients-a population inherently prone to cerebrovascular events-remains uncertain, and whether a threshold effect exists is unclear. METHODS: We included 3718 diabetic patients from two clinical centers. Multivariable-adjusted Cox proportional hazards models with stepwise covariate adjustment were used to assess associations between SUA and overall stroke and its subtypes. Kaplan-Meier curves estimated cumulative incidence across SUA quartiles. Restricted cubic spline regression examined dose-response relationships and potential threshold effects, and sex-stratified analyses were also performed. RESULTS: Elevated SUA was significantly associated with increased risks of stroke and subtypes. The highest SUA quartile showed a significantly higher cumulative risk. RCS revealed threshold effects: risks of stroke, ischemic stroke, and hemorrhagic stroke increased when SUA exceeded 335, 330, and 340 μmol/L, respectively. Sex-stratified analyses yielded consistent findings, with thresholds at 335 μmol/L for males and 350 μmol/L for females. CONCLUSION: In conclusion, this observational study confirms a significant association between SUA and stroke risk in diabetic patients with a threshold effect, suggesting potential clinical value for monitoring and urate-lowering therapy. However, sex-specific threshold findings should be interpreted cautiously as hypothesis-generating, and prospective randomized controlled trials are needed for validation.

OBJECTIVE: This study sought to examine the associations between four inflammatory biomarkers and 1-year adverse cardiovascular outcomes among hospitalized patients with heart failure with reduced ejection fraction (HFrEF) and to compare their prognostic performance. METHODS: A multicenter retrospective cohort study was conducted involving 1814 hospitalized patients with HFrEF (LVEF <40%). Four inflammation-derived biomarkers were derived from standard blood test results. The relationships between these biomarkers and the 1-year incidence of adverse cardiovascular outcomes were analyzed using Cox proportional hazards regression and restricted cubic spline (RCS) modeling. Event-free survival across biomarker tertiles was compared via Kaplan-Meier survival analysis. The discriminative ability of each biomarker was assessed through receiver operating characteristic (ROC) curves, time-dependent ROC analyses, and C-statistics. Additional sensitivity analyses were performed to verify the stability and reliability of the results. RESULTS: Elevated levels of all four biomarkers were significantly associated with an increased risk of adverse cardiovascular outcomes in patients with HFrEF. Each 1-SD increase in systemic inflammation response index (SIRI), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR) was associated with a 32.5%, 46.1%, 54.0%, and 98.3% higher hazard of adverse cardiovascular outcomes, respectively. Tertile analyses showed that the increased risk of adverse cardiovascular outcomes was mainly observed in the highest biomarker tertiles. Among the four markers, SIRI showed better discriminative performance than the other indices in this cohort, with an AUC of 0.705, which was supported by time-dependent ROC and C-statistic analyses. CONCLUSION: Higher SIRI, SII, NLR, and MLR levels were associated with an increased risk of adverse cardiovascular outcomes in patients with HFrEF. SIRI showed numerically better discrimination among hospitalized patients with HFrEF in this cohort, but further external validation is required before clinical application.

INTRODUCTION: Chronological age is often considered when selecting patients for atrial fibrillation (AF) ablation, but age alone may not identify which older patients are most likely to require recurrent rhythm-related care after pulmonary vein isolation (PVI). METHODS: We conducted a single-center observational study of consecutive patients undergoing PVI. The principal registry cohort assessed the same-center recurrence-related rhythm-intervention endpoint, defined as the first post-index repeat PVI or electrical cardioversion. A nested active 2022 cohort assessed broader actively ascertained recurrence. Age was analyzed as < 50, 50-74, and ≥ 75. An exploratory elderly vulnerability score assigned one point each for documented persistent AF, heart failure, chronic kidney disease, and valve disease/surgery. RESULTS: The registry cohort included 2559 patients and 580 same-center rhythm-intervention events. Event rates increased across age groups: 14.2% in patients aged < 50, 20.8% in those aged 50-74, and 29.8% in those aged ≥ 75. Age ≥ 75 was independently associated with higher risk versus age 50-74 in adjusted registry Cox analysis, HR: 1.35, 95% CI: 1.12-1.64,  = 0.002, after 90-day blanking, HR: 1.37, 95% CI: 1.12-1.69,  = 0.002, and in the active cohort, HR: 1.46, 95% CI: 1.01-2.11,  = 0.042. Elderly Score 0 patients were not significantly different from patients aged 50-74 in registry analysis, aHR: 1.13, 95% CI: 0.79-1.63,  = 0.5, or active analysis, aHR: 1.01, 95% CI: 0.49-2.09,  = 0.975, whereas Score ≥ 2 identified higher event burden in both the registry cohort, aHR: 1.85, 95% CI: 1.45-2.35,  < 0.001, and active cohort, aHR: 1.95, 95% CI: 1.23-3.12,  = 0.005. CONCLUSION: Age ≥ 75 was associated with a higher rate of same-center recurrence-related rhythm interventions after PVI, but the risk varied substantially. Clinical vulnerability, not chronological age alone, may better inform counseling and selection of older patients.

BACKGROUND: Apolipoprotein B (ApoB) reflects the number of circulating atherogenic lipoprotein particles and may reveal residual lipid-related risk when LDL cholesterol (LDL-C) appears normal. Whether AHA PREVENT-estimated cardiovascular risk identifies LDL-C-normal adults with discordantly high ApoB remains unclear. METHODS: We analyzed NHANES 2005-2016 adults aged 30-79 years without prevalent cardiovascular disease. Discordantly high ApoB was defined as LDL-C < 100 mg/dL with ApoB ≥ 90 mg/dL. Survey-weighted analyses estimated ApoB-high prevalence across AHA PREVENT-estimated ASCVD, total CVD, and heart failure risk domains. Additional analyses examined alternative PREVENT thresholds, percentile-based ApoB-LDL-C discordance, discrimination using weighted AUC, and attenuation after accounting for shared cardiometabolic determinants. RESULTS: Among 7659 adults in the final analytic sample, 2122 had LDL-C < 100 mg/dL. Within this LDL-C-normal subgroup, elevated PREVENT-estimated ASCVD risk was associated with higher ApoB-high prevalence than low risk (18.1% vs. 8.6%; crude OR 2.36, 95% CI 1.66-3.37). Similar patterns were observed for total CVD risk (16.6% vs. 7.7%; OR 2.39, 95% CI 1.67-3.41) and heart failure risk (15.8% vs. 9.1%; OR 1.87, 95% CI 1.24-2.81). Results were directionally consistent using alternative PREVENT thresholds and percentile-based ApoB-LDL-C discordance definitions. However, discrimination for ApoB ≥ 90 mg/dL was stronger for lipid-specific markers such as non-HDL-C and triglycerides than for PREVENT risk alone, and the PREVENT-ApoB association was substantially attenuated after adjustment for triglycerides and other shared metabolic determinants. CONCLUSIONS: Elevated PREVENT-estimated risk identifies LDL-C-normal adults with higher prevalence of discordantly high ApoB, but this pattern largely reflects shared cardiometabolic determinants rather than independent prediction. PREVENT-based risk stratification may help identify higher-yield groups for ApoB assessment, while prospective outcome studies are needed to determine its clinical utility. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40200-026-02091-3.

To compare the systemic safety profiles of antivascular endothelial growth factor (anti-VEGF) agents using a large real-world dataset. The TriNetX Research Network database was used to identify adults with macular edema secondary to diabetes, retinal vein occlusion, or age-related macular degeneration who received bevacizumab, ranibizumab, or aflibercept (2012-2022) or faricimab (2022-2024). The bevacizumab cohort was matched with the other cohorts using propensity score matching to account for demographic characteristics and comorbidities. Outcomes included stroke, venous thromboembolism, myocardial infarction, hypertension, brain hemorrhage, and renal function. In the propensity score-matched cohorts comparing outcomes between bevacizumab and aflibercept (each n = 9538), bevacizumab was associated with higher mean blood urea nitrogen level (28.07 mg/dL vs 26.89 mg/dL; = .017), higher mean serum creatinine level (1.86 mg/dL vs 1.72 mg/dL; = .004), and lower mean estimated glomerular filtration rate (55.64 mL/min vs 58.01 mL/min; = .003) at 1 to 6 months' follow-up. Compared with the faricimab cohort, the bevacizumab cohort (each n = 3500) showed increased risk of stroke (risk ratio [RR], 1.71, 95% CI, 1.19-2.48), venous thromboembolism (RR, 1.80, 95% CI, 1.11-2.93), myocardial infarction (RR, 1.72, 95% CI, 1.19-2.49), and hypertension (RR, 1.47, 95% CI, 1.19-1.83) within 2 years of follow-up. No significant differences were found between the bevacizumab and ranibizumab cohorts (each n = 2211). Bevacizumab may confer an increased risk of cardiovascular events and differences in renal function parameters compared with aflibercept and faricimab, but not ranibizumab. This underscores the importance of tailoring anti-VEGF therapy to patient-specific profiles, particularly in patients with underlying cardiovascular and renal comorbidities. Further studies in lower-comorbidity populations are needed to clarify these associations.

The soluble urokinase-type plasminogen activator receptor (suPAR) is a promising biomarker associated with various clinical entities. This review considers the association between suPAR and cardiovascular (CV) disease (CVD). We conducted a comprehensive electronic search of the literature on suPAR and CVD. PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library were searched from inception to December 31, 2025. Raised suPAR levels are independently associated with atherosclerosis, coronary artery disease, myocardial infarction, peripheral arterial disease (PAD) and related events and overall CV mortality. suPAR reflects inflammatory pathways distinct from those captured by C-reactive protein and is less affected by anthropometric parameters. suPAR levels correlate with endothelial dysfunction, the severity and extent of PAD and coronary artery calcium score, plaque inflammation and neointima hyperplasia. The variant rs4760 of the Plasminogen Activator, Urokinase Receptor gene that encodes suPAR may promote atherosclerosis. Lifestyle interventions and pharmacologic therapies may reduce suPAR levels. suPAR represents a robust biomarker with the potential to enhance personalized management of CVD. Despite strong evidence supporting its prognostic value, the clinical integration of suPAR remains limited. Future research should investigate its utility in risk stratification, monitoring of therapeutic response, and perioperative CV risk assessment.