BACKGROUND: Sepsis-induced crosstalk between macrophages and cardiomyocytes is a critical pathogenic mechanism underlying cardiac dysfunction. However, clinically effective pharmacological interventions to mitigate the associated cytokine storm remain limited. PURPOSE: In this study, we aimed to investigate the role of thymol, a natural small-molecule bioactive compound, in regulating macrophage function in septic cardiomyopathy (SCM). METHODS: The following methodologies were employed to investigate the cardioprotective effects of thymol in sepsis and its underlying mechanisms. For in vivo studies, a septic mouse model was established via cecal ligation and puncture (CLP), followed by thymol administration. Cardiac function and macrophage responses were assessed using survival analysis, echocardiography, hematoxylin and eosin (HE) staining, TUNEL assay, flow cytometry, and immunofluorescence staining. In vitro, a co-culture system of RAW264.7 macrophages and HL-1 cardiomyocytes stimulated with lipopolysaccharide (LPS) was used to examine macrophage‑cardiomyocyte interactions. Mechanistic exploration involved proteomic sequencing, western blotting, quantitative polymerase chain reaction (qPCR), and biochemical analyses. Key signaling pathways were further validated by chromatin immunoprecipitation (ChIP) and co‑immunoprecipitation (Co‑IP). Additionally, Krüppel-like factor 4 (Klf4) knockout mice, RNA sequencing (RNA-Seq), liquid chromatography‑tandem mass spectrometry (LC‑MS/MS)‑based proteomics, molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) assay, and surface plasmon resonance (SPR) were utilized to identify the direct molecular target of thymol and elucidate its regulatory role in downstream signaling pathways. RESULTS: Thymol treatment ameliorated cardiac dysfunction and promoted macrophage polarization toward the M2 phenotype. Furthermore, thymol reduced the secretion of tumor necrosis factor-α (TNF-α) by macrophages, thereby inhibiting cardiomyocyte pyroptosis. Mechanistically, RNA-Seq analysis revealed that thymol upregulated KLF4 expression, and macrophage-specific deletion of Klf4 abolished the beneficial effects of thymol on heart failure. We also identified phosphorylase kinase alpha 2 (PHKA2) as a direct binding target of thymol at GLU 546. This interaction enhanced PHKA2 kinase activity, leading to phosphorylation of the downstream transcription factor forkhead box A1 (FOXA1). Importantly, phosphorylated PHKA2 translocated into the nucleus and bound to the promoter region of Klf4, facilitating its transcriptional activation. CONCLUSIONS: Our findings demonstrate that thymol alleviates the cytokine storm in SCM, highlighting its potential as a therapeutic candidate for this condition.

A man in his 60s with advanced infra-Hisian conduction disease underwent dual-chamber pacemaker implantation with left bundle branch area pacing. Postimplant telemetry demonstrated intermittent pacing spikes apparently not followed by QRS complexes, raising concern for failure to capture or lead dislodgment. However, the patient remained asymptomatic and device interrogation showed preserved sensing, stable lead impedance, and normal capture thresholds. Careful inspection of the telemetry tracing revealed preserved T waves and subtle low-amplitude ventricular depolarizations despite the apparent absence of visible QRS complexes. The findings were attributed to telemetry processing artifact with preserved ventricular activation during unipolar left bundle branch area pacing.

Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system characterized by inflammation, reactive gliosis, and progressive neuroaxonal damage resulting in heterogeneous clinical and histopathological manifestations. As MS often leads to disability at a young age, it represents a substantial socio-economic burden in developed countries. The etiopathogenesis of MS is multifactorial and incompletely understood, involving genetic, immunologic, and environmental factors. Recent research highlights immune responses to Epstein-Barr virus, blood-brain barrier disruption, microbiome-gut-brain axis alterations, oxidative damage, and mitochondrial dysfunction. Studying patients with newly diagnosed MS without significant comorbidities provides insight into early disease mechanisms before disability development or long-term treatment effects. This mini-review focuses on early vascular and metabolic alterations that may contribute to MS, including lipoprotein subfractions as markers of incipient atherosclerosis, endothelial dysfunction as an initiating vascular event, and autonomic nervous system imbalance during disease progression. It also addresses insulin sensitivity as a key metabolic factor alongside chronic inflammation and oxidative damage as interconnected mechanisms driving tissue injury. Metabolic changes reflecting neuronal impairment, mitochondrial dysfunction, and astroglial activation are detectable in both lesional and normal-appearing white matter in early stages. Reduced antioxidant capacity supports a role of oxidative damage in MS pathogenesis. Accelerated vascular aging, independent of traditional cardiovascular risk factors, may progress from endothelial dysfunction to structural atherosclerotic changes. Subtle alterations in lipoprotein profiles further suggest an increased risk of atherosclerosis, potentially influenced by inflammatory activity and oxidative damage, with possible sex-specific differences. Autonomic dysfunction appears to develop secondary to disease progression rather than as a primary driver of pathogenesis.

Vascular endothelial dysfunction plays a critical role in the development of atherosclerosis; however, the mechanisms by which endothelial cells contribute to plaque instability remain incompletely understood. In this study, we performed an integrated analysis of single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data to characterize endothelial cell heterogeneity associated with carotid plaque instability. Clustering analysis, gene set variation analysis (GSVA), differential gene expression analysis, and KEGG pathway enrichment were conducted to identify key endothelial cell subsets and their functional characteristics. We identified three endothelial cell subsets (subsets 9, 10, and 11) that were significantly enriched in unstable plaques and exhibited upregulation of multiple pro-inflammatory cytokines. Pathway analysis revealed that these subsets were associated with activation of the PI3K - Akt signaling pathway and other inflammation-related pathways. Furthermore, findings were validated in an apolipoprotein E-deficient (ApoE-/-) mouse model, where increased expression of placental growth factor (PGF) and a higher proportion of PGF-positive endothelial cells were observed in atherosclerotic lesions. In conclusion, this study reveals the heterogeneity of endothelial cells in atherosclerotic plaques and identifies pro-inflammatory endothelial subsets potentially associated with plaque instability, providing new insights into the pathogenesis of atherosclerosis.: This study was approved by the Experimental Animal Ethics Committee of Guizhou University of Chinese Medicine (approval number: 2,024,010).

BACKGROUND: Only one-fifth of patients meeting the criteria for intravenous (IV) iron therapy received IV iron in the real-world practice. Pharmacists-providers collaborative iron deficiency (ID) clinic was developed to implement guideline-directed IV iron therapy. OBJECTIVE: To evaluate the 4-year performance of the pharmacists-providers collaborative ID treatment clinic in the heart failure (HF) service. METHODS: A single-center retrospective cohort study was conducted to evaluate the performance of the iron deficiency pharmacists-providers collaborative care clinic during the induction and maintenance phases of IV iron therapy. The study included patients who were seen by HF providers and received the IV iron consultation with HF pharmacists. The study included patients aged 18 years or older who were diagnosed with HF or pulmonary hypertension and received at least 1 dose of IV iron in outpatient settings. It was managed by the pharmacists-providers collaborative IV iron clinic. The primary outcome was adherence to all of the following criteria: the IV iron appropriate use criteria, laboratory requirements, and dosing during the induction course. The use of oral iron therapy was evaluated. RESULTS: A total of 187 patients were included in the final cohort. The median follow-up period of the IV iron consulting team was 372 (176, 623) days. One hundred fifty-two patients (81.3%) were adherent to the appropriate criteria. The most common reasons for nonadherence were the absence of maintenance laboratory requirements (15.5%), failure to administer all induction doses (1.6%), inappropriate use (1.1%), and incorrect dose (0.5%). Among 15 patients on oral iron therapy, the consulting team discontinued it in 3 patients (20.0%) during follow-up. CONCLUSION AND RELEVANCE: The pharmacists-providers collaborative IV iron clinic was effective to implement IV iron therapy in heart failure care settings. These results highlight the importance of multidisciplinary care management for ID in real-world HF practice.

Cerebral small vessel disease (CSVD) is a leading cause of vascular cognitive impairment, yet its earliest stages remain clinically silent and poorly detected. Although white matter hyperintensities (WMHs) are widely used neuroimaging markers, conventional cardiovascular risk scores and cognitive testing lack sensitivity to subclinical cerebrovascular injury. This study investigated whether circulating microparticles (MPs) and fractal analysis of the Circle of Willis (CoW), reflecting cerebrovascular network-hemodynamic complexity, could provide an early, mechanistically informative marker of silent CSVD. Sixty asymptomatic adults with low-to-moderate cardio-cerebrovascular risk (QRISK3) underwent 3 T MRI, cognitive testing, and circulating MPs profiling. Cerebrovascular fractal dimension of the CoW (Df [W]) was computed from 3D time-of-flight magnetic resonance angiography. Multivariable regression, mediation analysis (10,000 bootstraps), and ROC analyses were performed. Reduced D (W) was strongly associated with greater WMHs burden (p < 0.001) and significantly outperformed QRISK3 and MPs in discriminating WMHs (AUC = 0.928 vs. ~0.75). Leukocyte-derived (CD62L) and platelet-derived (CD62P) MPs were elevated in participants with WMHs and correlated with both WMHs burden and D (W), but lost independent significance after adjustment for WMHs, indicating upstream systemic vascular injury. Mediation analysis confirmed that MPs influenced WMHs' burden primarily through their effect on cerebrovascular D (W). A combined biological-imaging model integrating MPs and D (W) achieved near-perfect diagnostic accuracy (AUC = 0.952). Despite marked vascular and microstructural abnormalities, neurocognitive performance was preserved, with only a weak association between processing speed and D (W), consistent with network reserve in early CSVD. Thus, cerebrovascular fractal complexity may capture the structural imprint of cumulative vascular injury and enable biologically grounded detection of preclinical CSVD.

BACKGROUND: To investigate immune-related adverse events (irAEs) in patients with non-small cell lung cancer receiving immune checkpoint inhibitor (ICI) therapy, and to identify clinical factors associated with irAE onset, thus supporting safer immunotherapy through effective monitoring. METHODS: This retrospective cohort study was conducted at Tohoku Medical and Pharmaceutical University Hospital over approximately 5 years. Hospitalized patients with non-small cell lung cancer who received immune checkpoint inhibitors for the first time were included. Physicians and pharmacists evaluated the occurrence, severity, and timing of irAEs. Cox proportional hazards regression and Fine-Gray competing risk analyses were performed to identify factors associated with irAE development. RESULTS: Among the 203 enrolled patients, 92 (45.3%) experienced irAEs, totaling 110 events. The most common irAE was interstitial lung disease (23 cases, 20.9%), followed by thyroid dysfunction (20 cases, 18.2%). In multivariable Cox regression analysis, comorbid heart failure was significantly associated with a reduced risk of irAE development (hazard ratio, 0.299; 95% confidence interval [CI], 0.135-0.663; p = 0.003), and this association remained significant in the Fine-Gray competing risk model (subdistribution hazard ratio, 0.335; 95% CI, 0.147-0.766; p = 0.009). To address potential multicollinearity, an alternative model incorporating regular use of renin-angiotensin-aldosterone system inhibitors in place of comorbid heart failure also demonstrated a significant association with irAE incidence. CONCLUSIONS: In this Japanese non-small cell lung cancer cohort, comorbid heart failure emerged as a potential modifier of irAE incidence, suggesting that baseline cardiac conditions may influence susceptibility to immune‑related toxicity. These findings underscore the importance of incorporating comorbidity profiles into individualized irAE monitoring strategies during cancer immunotherapy.

BACKGROUND: Metabolic syndrome (MetS) is a major global public health problem associated with cardiovascular disease, type 2 diabetes mellitus (T2D), and increased mortality. Chronic psychological stress has been proposed as a contributor to metabolic dysfunction; however, evidence linking perceived stress to MetS and its individual components remains inconsistent. The Perceived Stress Scale (PSS) is a widely validated instrument for assessing subjective stress, yet its association with metabolic outcomes has not been systematically synthesised. AIMS: The objective of this study was to systematically review the evidence and evaluate the association between perceived stress, measured using the PSS, and metabolic parameters related to MetS. METHODS: A systematic search of peer-reviewed literature identified studies assessing perceived stress using the PSS-10 or PSS-14 and reporting metabolic outcomes in adults. Associations between perceived stress and metabolic parameters were examined using random-effects meta-regression models, with stress scores standardised to allow comparability across PSS versions. Outcomes included anthropometric measures, blood pressure, glycaemic markers, lipid profile, and insulin resistance. RESULTS: Thirty studies comprising 12,491 participants were included. Most metabolic parameters, including body mass index, waist circumference, blood pressure, fasting glucose, and triglycerides, showed no significant association with perceived stress. In contrast, insulin resistance assessed by HOMA-IR was positively associated with perceived stress (β = 0.463, 95% CI: 0.159-0.767). Borderline associations were observed for high-density lipoprotein cholesterol and total cholesterol. Although substantial heterogeneity was present across analyses, the HOMA-IR association was exploratory and sensitive to the inclusion of individual studies. CONCLUSIONS: Higher perceived stress may be associated with insulin resistance (HOMA-IR) but not with traditional anthropometric, glycaemic, or blood pressure measures; this finding is exploratory and causal inferences cannot be established. These results highlight the potential relevance of psychosocial stress as a contributor to metabolic vulnerability; stress assessment may be considered in preventive and clinical strategies pending higher-certainty evidence.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with significant attention focused on the development of therapeutic drugs and research into pathogenic mechanisms. In the real world, cardiotoxicity induced by multiple factors commonly exists and is closely associated with cardiovascular diseases. Traditional toxicity testing models (such as animal experiments and two-dimensional cell cultures) have limited clinical translation value due to species differences, inability to simulate the complex microenvironment of the human body, and cellular interactions. Cardiac organoids, as an emerging three-dimensional (3D) culture platform, possess 3D structure, multicellular composition, organ-specific functions, and self-organizing capabilities, which can highly mimic the physiological and pathological characteristics of the heart, providing a more precise humanized model for the study of cardiovascular disease mechanisms, drug development, and toxicity assessment. This paper systematically reviews the construction strategies of cardiac organoids and their application progress in toxicology: Firstly, it explores the construction standards and technical optimization of cardiac organoids, focusing on human-engineered heart tissue (hEHT) models and various cardiac organoid models that mimic the human heart, with particular attention to their unique characteristics, utility, and limitations. Secondly, through bibliometric analysis using CiteSpace, it reveals research hotspots and trends in cardiac organoid applications for toxicology, specifically by extracting collaboration networks, conducting co-citation analysis, and co-occurrence analysis. Finally, it summarizes specific applications of cardiac organoids in toxicology, including drug toxicity assessment, environmental pollutant toxicity evaluation, cardiac developmental toxicity studies, disease model construction, and multi-organ cascade studies for systemic toxicity assessment.

BACKGROUND: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality among individuals with type 2 diabetes mellitus (T2DM), imposing a substantial burden on healthcare systems. This systematic review and network meta-analysis evaluated the comparative efficacy of antidiabetic medications and combination therapies in reducing cardiovascular outcomes in patients with T2DM. METHODS: PubMed (Medline), Embase, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to December 30, 2024, for randomized controlled trials (RCTs) assessing cardiovascular outcomes in adults with T2DM treated with metformin, sulfonylureas, thiazolidinediones (TZDs), dipeptidyl peptidase‑4 (DPP‑4) inhibitors, glucagon‑like peptide‑1 (GLP‑1) receptor agonists, sodium-glucose cotransporter‑2 (SGLT2) inhibitors, or insulin. Outcomes included cardiovascular mortality, myocardial infarction (MI), stroke, heart failure, hospitalization for cardiovascular events, and unstable angina. Risk of bias was assessed using the Cochrane RoB 2.0 tool, and analyses were conducted with a random-effects model in Stata (version 18). RESULTS: From 10,514 records, 133 RCTs involving 289,558 participants (mean age: 64.7 years) were included. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) significantly reduced cardiovascular mortality (RR = 0.85, 95% CI: 0.75-0.98; high-certainty evidence) and stroke (RR = 0.83, 95% CI: 0.74-0.93; high-certainty evidence). SGLT2 inhibitors significantly reduced heart failure (RR = 0.64, 95% CI: 0.53-0.77; high-certainty evidence) and hospitalization for cardiovascular events (RR = 0.72, 95% CI: 0.68-0.77; high-certainty evidence). An indirect comparison suggested lower cardiovascular mortality with DPP-4 inhibitors versus GLP-1 receptor agonists, although this finding should be interpreted cautiously due to network imbalance. CONCLUSIONS: GLP-1 RAs and SGLT2 inhibitors are associated with significant reductions in specific cardiovascular outcomes in patients with T2DM, particularly in reducing cardiovascular mortality, stroke, heart failure, and hospitalization. Treatment decisions should integrate patient-specific risk profiles and cost-effectiveness to optimize outcomes.

BACKGROUND: Pregnancy in women with rare vascular diseases is highly challenging, as it can be associated with significant maternal and foetal risks, requiring complex and multidisciplinary management. Care across countries remains insufficiently characterized, and both patients and healthcare providers across Europe highlight the need for better structures and organization to support this critical and potentially life-threatening phase. OBJECTIVE: To describe current practices, perspectives, and challenges faced by patients and healthcare professionals in the management of pregnancy in women with rare vascular diseases. METHODS: A survey developed by the European Reference Networks (ERN) pregnancy working group was extended with VASCERN-specific questions, resulting in a 13-item questionnaire. The survey was distributed to healthcare providers and patient representatives (ePAGs). Qualitative data from open-ended responses were analysed using an inductive thematic approach. RESULTS: 36 responses were collected from 145 invited VASCERN members, resulting in a 25% response rate and representing 10 European countries. Most respondents were healthcare providers (83%). 17% were patient representatives. Thematic analysis identified five recurring themes, including the need for coordinated and collaborative multidisciplinary approaches, variability in the practices regarding preconception and genetic counselling, limited access to specialised centres for pregnancy monitoring, and the importance of structured delivery planning and postnatal follow-up. CONCLUSIONS: This survey clearly shows that there are common concerns about pregnancy in women with rare vascular diseases. Improvement actions mainly involve better education and drawing up multidisciplinary care pathways and guidelines that will lead to better access and organisation of care. Initiatives in this direction have already been taken within VASCERN.

BACKGROUND: Non-syndromic familial thoracic aortic aneurysm and dissection (ns-FTAAD) is an inherited disease that follows an autosomal dominant pattern; however, pinpointing the responsible genes is often complex. The MYLK gene has been identified as one implicated in TAAD, which necessitates careful and specialized clinical oversight. Systematically gathering evidence on the disease-causing potential of rare genetic variants through detailed family studies is crucial for developing more effective treatment protocols for individuals with this life-threatening hereditary condition. This study reports the identification of a novel pathogenic variant causing ns-FTAAD and provides a comprehensive review of all associated TAAD variants. METHODS: We report an Iranian family with ns-FTAAD associated with a novel MYLK germline variant. We evaluated all relevant clinical and genetic information. Whole-exome sequencing (WES) was used for variant detection, and Sanger sequencing was performed for validation. A literature search for all TAAD types was conducted on PubMed. The extracted data included the total number of patients studied, the subset with MYLK variants, specific nucleotide and protein changes, patient demographics, pathological features, and clinical symptoms. RESULTS: Exome sequencing led to the identification of a novel variant, NM_053025.4:c.2208_2230dup (p.Ile744Argfs*9), that led to a premature stop codon and nonsense-mediated decay. Five people were variant carriers and three people were non-carriers. A total of 1,440 patients clinically diagnosed with TAAD were recruited in these studies, among whom 59 were carriers of an MYLK variant. Among the 34 variants collected, the distribution was as follows: missense (58.82%), frameshift (14.71%), splicing (5.88%), CNVs (5.88%), and other (14.71%). CONCLUSION: Our study expands the mutational landscape of MYLK-related ns-FTAAD with a novel pathogenic variant. The aggregation of all reported cases highlights that while missense variants predominate, loss-of-function mechanisms like frameshift variants are a significant cause of disease. These findings are crucial for risk assessment, familial screening, and the clinical management of affected families.

BACKGROUND: Prolonged postoperative intensive care unit (ICU) length of stay (LOS) after coronary artery bypass grafting (CABG) drives resource use yet remains difficult to anticipate at the 24-hour ICU evaluation moment when extended monitoring beyond 72 h is first considered. We developed and externally validated an interpretable machine-learning decision-support calculator for this deployment moment. METHODS: Adult CABG patients were identified from MIMIC-IV 3.1 (n = 6,919; 7:3 stratified split for development) and eICU-CRD 2.0 (n = 5,972; external validation). The outcome was prolonged ICU LOS (> 3 days). Elastic Net plus Boruta selected eight bedside features collected within the first 24 h of ICU admission: 24-hour fluid intake, Charlson Comorbidity Index (CCI), Sequential Organ Failure Assessment (SOFA) score, Simplified Acute Physiology Score II (SAPS-II), Glasgow Coma Scale (GCS), vasopressor use, congestive heart failure, and atrial fibrillation. Nine machine-learning algorithms were compared by 10-fold cross-validation paired t-tests with Bonferroni and Benjamini-Hochberg correction. Calibration metrics included Hosmer-Lemeshow test, Integrated Calibration Index (ICI), expected-to-observed ratio, intercept, and slope (full Methods). SHapley Additive exPlanations (SHAP) provided per-patient feature attribution. RESULTS: CatBoost was selected as the deployed model. On the MIMIC-IV internal test set (n = 2,076), the area under the receiver-operating-characteristic curve (AUC) was 0.7739 (95% confidence interval 0.7379-0.8099), Hosmer-Lemeshow p = 0.224, calibration slope 0.973. On the eICU-CRD external cohort, AUC was 0.6452 (95% CI 0.6311-0.6602), calibration slope 0.998, ICI 0.023. At the prevalence-anchored threshold of 0.30, sensitivity was 0.55, specificity 0.65, positive predictive value 0.40, and negative predictive value 0.77. Decision Curve Analysis showed positive net benefit over treat-all and treat-none across t = 0.20-0.40. SHAP top-3 features were 24-hour fluid intake, CCI, and atrial fibrillation. CONCLUSIONS: The model provides decision support at the post-CABG 24-hour ICU evaluation moment with modest discrimination and well-calibrated probabilities at deployment. The deployed online calculator renders per-patient feature contributions transparent at the bedside via SHAP; prospective validation is required before clinical deployment.

BACKGROUND: Advanced diagnostics like reverse transcription polymerase chain reaction (RT-PCR) improve accuracy, limit infectious disease transmission and decrease mortality. This study evaluated the utility of RT-PCR for detecting infectious agents, including Nontuberculous mycobacteria (NTM), to guide clinical decision-making. METHODS: This retrospective study analyzed infectious disease data from Apollo Imperial Hospitals Ltd., Chattogram, Bangladesh from June 2019 to July 2024. Of 810 anonymized records extracted from the molecular biology laboratory, 786 samples with complete diagnostic information undergoing RT-PCR testing were included. Associations between positivity and socio-demographic/clinical factors (e.g., gender, sample type, pathogen tested) were analyzed using chi-square tests and binary logistic regression. RESULTS: Among 786 patients, the mean age and SD was 38.8 ± 19.3 years with 87.1% adults or elderly (> 60 years old), and 53.7% were female. Samples comprised blood (31.6%), tissue (27.2%), body fluids (19.3%), swabs (8.1%), sputum (6.1%), pus (4.8%), and urine (2.8%). Overall, 100 (12.7%) specimens were positive by RT-PCR. Mycobacteria were detected in 6.4%, including Mycobacterium tuberculosis (MTB; 2.9%) and nontuberculous mycobacteria (NTM; 3.5%). The gender and clinical samples had significant difference with unadjusted OR, while pathogens were significantly associated with tests results (adjusted OR: 0.16, 95% CI: 0.03-0.87; P < 0.05) respectively. Male patients and specimens tested for respiratory pathogen panel (RPP) had higher odds of positivity, while body fluid, tissue, HPV/HSV, and Mycobacterial samples had lower odds of positivity. CONCLUSIONS: RT-PCR is a reliable diagnostic tool with higher sensitivity (up to 95%) and specificity (up to 100%) for infectious diseases, with potential for greater optimization in Bangladesh, especially for NTM detection. Improved specimen selection and clinical practices can enhance positivity rates and reduce costs. The NTP should prioritize better NTM detection to prevent misdiagnosis and improper treatment. WHO global report on tuberculosis should highlight NTM to guide policy and management strategies. CLINICAL TRIAL NUMBER: Not applicable.

BACKGROUND: Population ageing has become an immediate global imperative, with older adults disproportionately afflicted by multimorbidity, a complex interplay of co-existing chronic diseases that erodes health-related quality of life (HRQoL). Multimorbidity is associated with impairments in physical and mental functioning, which undermine older adults' autonomy and contributes to declines in HRQoL. However, vital data that explore these relationships remain absent for older populations residing in long-term care facilities (LTCFs) across sub-Saharan Africa. This study examines multimorbidity prevalence in LTCF residing older adults and its associations with depression, HRQoL outcomes and physical activity. METHODS: A cross-sectional study among 396 older adults from 17 randomly selected South African LTCFs employed the Geriatric Depression Scale, EQ-5D-3 L, and Weighted Functional Comorbidity Index. Descriptive statistics, correlation analyses and TwoStep cluster analysis elucidated multimorbidity patterns. RESULTS: Multimorbidity affected 76.77% of participants, with variation across four distinct clusters. The Cardiovascular-Respiratory cluster comprised 33.8% predominance. Multimorbidity was significantly predicted by poorer HRQoL and increasing age, χ²(140, n = 396) = 228.19, p < .001. Depression prevalence reached 35.10%, with higher scores associated with greater multimorbidity burden (ρ = 0.28, p < .01) and reduced HRQoL. An inverse correlation between the Weighted Functional Comorbidity Index and EQ-5D-3 L scores (ρ = -0.33, p < .001) reflected multimorbidity's negative impact on HRQoL. Multimorbidity was inversely associated with Short Physical Performance Battery scores, lower physical activity, and directly to waist-to-hip ratios. CONCLUSION: Advancing age is strongly associated with an increased burden of multimorbidity, which is intricately linked to depressive symptoms, diminished HRQoL, reduced muscular strength, central adiposity, and physical inactivity. These findings highlight the urgent need for integrated interventions in institutionalised older adults in sub-Saharan Africa and should inform policy reform aimed at strengthening long-term care and healthy ageing strategies.

BACKGROUND: Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality among aging populations. Single-time-point risk assessments may not reflect dynamic cardiometabolic changes. The cardiometabolic index (CMI), integrating triglyceride-to-HDL cholesterol ratio and waist-to-height ratio, reflects both atherogenic dyslipidemia and central adiposity, but its longitudinal prognostic value remains unclear. Thus, this study aims to evaluate the associations of baseline CMI, longitudinal change patterns, cumulative exposure, and absolute change (ΔCMI) with incident CVD among Chinese adults aged ≥ 45 years. METHODS: Data from the China Health and Retirement Longitudinal Study (CHARLS). Baseline analyses included 9120 participants. Longitudinal analyses included 6164 participants. CVD (including heart diseases and stroke) was ascertained during follow-up. Multivariable Cox proportional hazard models were fitted with adjustment for confounding factors. RESULTS: Higher baseline CMI was independently associated with increased CVD risk with a non-linear association and an inflection point at 0.42. Compared with stable low CMI, participants with persistently high CMI showed the highest CVD risk (HR = 1.31; 95%CI: 1.14, 1.50), followed by progression from low-to-high CMI (HR = 1.23; 95%CI: 1.04, 1.46), whereas improvement from high-to-low was not associated with excess risk. Among participants with low baseline CMI, higher cumulative CMI and less favorable ΔCMI were associated with increased CVD risk. Incorporating longitudinal CMI changes modestly but significantly improved risk discrimination and reclassification beyond baseline assessment. CONCLUSIONS: CMI is a dynamic, threshold-dependent predictor of CVD, independent of LDL-C and hsCRP. Longitudinal monitoring enhances risk stratification beyond single measurements.

OBJECTIVE: We present a natural language processing pipeline to extract and re-compute a pre-existing score, the IMPACT-score, in a children's hospital belonging to the APHP hospitals. MATERIALS AND METHODS: Predictive variables and adverse events occurrences were extracted from the EHR of each patient. Data extraction involved rule-based and machine learning approaches depending on the format of the data. The machine learning text-classifiers were trained on active learning annotated dataset. Once the registry was automatically populated, we computed the IMPACT-score model in our patients and we performed a logistic regression analysis to find the specific odd ratio fitting our cohort and obtain the IMPACT-score-Necker. RESULTS: We extracted clinical data from 2,980 patients. When applied to our hospital cohort, the IMPACT-score-Necker achieved an AUC of 0.719 whereas the original IMPACT-score achieved an AUC of 0.642. As a reminder, the IMPACT-score achieved an AUC of 0.752 in the NCDR-IMPACT validation cohort. DISCUSSION: Local calibration of the IMPACT-score on our cohort enhanced predictive accuracy, improving the AUC from 0.642 to 0.719, and addressing differences between our population and the original NCDR-IMPACT cohort. This reinforces the need for model adaptation to local data, as patient demographic and clinical variations can significantly impact performance. Local EHR data warehouses could be leveraged for recalibration and continuous monitoring, ensuring that AI tools remain accurate, ethical, and practical for clinicians in their clinical practice. CONCLUSION: Our results underscore the need for real-world model validation, and EHRs offer a reliable source for training and validating AI models.

BACKGROUND AND AIM: This study aimed to assess the prospective association between zinc (Zn) deficiency and the risk of cardiovascular diseases (CVD), CVD mortality and all-cause mortality in adults with type 2 diabetes (T2DM). METHOD: This prospective cohort study, embedded in the Tehran Lipid and Glucose Study (TLGS), including 632 adults with T2DM (mean age = 59.6 ± 12.4 years, 38% men) enrolled at 2009-2011 and followed until 2020. Serum zinc (SZn) concentrations were measured using flame atomic absorption spectrometry (FAAS), and Zn deficiency was defined as SZn < 85 µg/dL. Multivariable Cox proportional hazard models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of outcomes in the Zn-deficient compared to Zn-sufficient group. RESULTS: Mean baseline SZn concentration was 116 ± 44.5 µg/dL, and 22% were Zn-deficient. Over a median follow-up of 9.3 years, 34.7% of participants experienced incident CVD events, while 6.3% and 18.5% died from CVD and all causes, respectively. Zn deficiency was associated with a significantly increased risk of CVD events (HR = 1.86, 95%CI = 1.06-3.28, P = 0.031) in the fully adjusted model. Each 10 µg/dL increase in SZn was associated with a borderline-significant reduced risk of CVD (HR = 0.97, 95%CI = 0.93-1.00, P = 0.050). Zn status was not associated with CVD mortality or all-cause mortality. CONCLUSION: Zn deficiency is associated with a significantly increased risk of CVD events in patients with T2DM. Increased SZn concentration was associated with reduced risk of CVD events in patients with T2DM.

Pulmonary hypertension complicating heart failure with preserved ejection fraction (HFpEF), particularly the combined post- and pre-capillary form (CpcPH), has lacked any mechanism-specific therapy, as repeated trials of pulmonary vasodilators have failed or caused harm. This mini-review highlights findings from the Phase 2 CADENCE study evaluating sotatercept, an activin signaling inhibitor that targets vascular remodeling rather than vascular tone. Sotatercept met its primary endpoint by reducing pulmonary vascular resistance at 24 weeks and produced concordant improvements in mean pulmonary artery pressure, wedge pressure, 6-minute walk distance, NYHA class, and NT-proBNP, without the compensatory rise in left-sided filling pressure that characterizes vasodilator therapy. Notably, the lower 0.3 mg/kg dose appeared to outperform the 0.7 mg/kg dose across several hemodynamic and functional endpoints while offering a more favorable safety profile. These findings position sotatercept as the first non-vasodilatory, potentially disease-modifying option for advanced HFpEF-associated pulmonary hypertension, and a confirmatory Phase 3 trial is warranted to determine whether this hemodynamic benefit translates into durable clinical outcomes.

Bleeding complications remain a major concern in patients supported by long-term left ventricular assist devices (LVADs). Although gastrointestinal bleeding is common, hemobilia due to rupture of a hepatic artery aneurysm is extremely rare. A 47-year-old man with end-stage heart failure underwent implantation of a continuous-flow LVAD as a bridge to transplantation and was maintained on long-term anticoagulation therapy. He developed anemia with abdominal pain and melena. Imaging at the first hospitalization revealed a hepatic artery aneurysm with suspected hemobilia. After temporary stabilization, he was readmitted with recurrent melena and abdominal pain. Subsequent imaging demonstrated rapid aneurysmal enlargement with rupture into the biliary tract. Emergency angiography followed by transcatheter arterial embolization using detachable coils and n-butyl cyanoacrylate achieved complete hemostasis while preserving hepatic arterial flow. Anticoagulation was resumed without thrombotic complications, and the patient subsequently underwent successful transplantation without recurrence. Hepatic artery aneurysm rupture into the biliary tract is a rare but life-threatening complication in patients receiving long-term LVAD support. Prompt multidisciplinary management and endovascular intervention are essential for favorable outcomes.

Although intermittent theta-burst stimulation (iTBS) has emerged as a promising time-efficient and non-invasive neuromodulatory strategy in post-stroke motor rehabilitation, its clinical efficacy remains variable across patients and studies. In this review, we propose a multiscale framework for understanding how iTBS may support post-stroke motor recovery while emphasizing the current limits of translational evidence. At the microscopic and mesoscopic levels, preclinical studies suggest that iTBS contributes to early post-stroke repair by modulating ferroptosis, endoplasmic reticulum stress-related apoptosis, pyroptosis, neuroimmune responses involving astrocytes, white matter integrity, neurovascular remodeling, and neurotrophic signaling. These mechanisms are acknowledged to provide a biological substrate for post-stroke plasticity. At the clinical neurophysiological and neuroimaging levels, the available human studies indicate that iTBS modulates corticospinal excitability, cortical oscillatory dynamics, interhemispheric interactions, and large-scale motor-network organization. We herein further discuss the determinants of treatment variability, including stroke stage, lesion location, corticospinal tract integrity, baseline impairment severity, stimulation target, dosage parameters, co-interventions, genetic polymorphisms, and endogenous brain state. Current evidence remains limited due to small-sample size, heterogeneous protocols, incomplete safety and dose reporting, and temporal and geographic concentrations of the available studies. We posit that investigators in their future studies prioritize standardized reporting, multicenter and internationally diverse trials, biomarker-guided stratification, individualized electric-field modeling, and closed-loop stimulation strategies. Overall, iTBS remains a promising but protocol-sensitive and patient-dependent intervention, and this review provides a hypothesis-generating framework for future mechanistic and clinical studies in post-stroke motor rehabilitation.

Coronary artery bypass grafting (CABG) with temporary micro-axial ventricular assist device (Impella, Johnson and Johnson, Danvers, MA, USA) for peri-operative recovery has been utilized among patients with reduced left ventricular ejection fraction (LVEF). We hypothesized that Impella recovery CABG would be associated with increased two-year survival, compared to traditional intra-aortic balloon pump (IABP) recovery CABG. 151 patients with low LVEF (≤ 25%) underwent on-pump CABG at our hospital system between July 2017 and March 2025. Patients who underwent CABG without mechanical assistance, had a cardiac arrest within 24 hours of CABG, prior organ transplantation, or chronic dialysis were excluded. Propensity score analysis matched patients with Impella recovery (n = 19) and IABP recovery CABG (n = 19), and Kaplan-Meier analysis compared two-year survival between these groups. Patients who received Impella recovery CABG had significantly greater two-year survival at 100% compared to the IABP group at 60.5% (95% CI 39.9-91.7%) (log-rank p = 0.01). Impella recovery was associated with greater aortic cross clamp (p = 0.02) and cardiopulmonary bypass (p < 0.001) times and longer ICU stays (p = 0.008). There were no significant differences in major postoperative complications, including re-exploration for bleeding, stroke, and renal failure. Our exploratory study found that Impella recovery CABG was associated with decreased mortality compared to IABP recovery among patients with reduced LVEF. Larger cohorts with longer follow-up are necessary to assess whether this advanced mechanical support method confers a meaningful survival benefit in this high-risk patient population.

BACKGROUND: Cardiac complications are among the most common causes of death in patients after pediatric kidney transplantation (KTx), but defined diagnostic procedures identifying young patients at risk are not established. Cardiovascular magnetic resonance (CMR) imaging with native T1 mapping allows detection of diffuse myocardial alterations but is not routinely available for cardiovascular screening. Whether abnormalities detected by echocardiography reflect underlying myocardial structural changes remains unclear. METHODS: Pediatric KTx recipients underwent comprehensive transthoracic echocardiography and CMR imaging with native T1 mapping. Associations between echocardiographic measures and T1 values were analyzed using multivariable linear regressions. Receiver operating characteristics analyses assessed the ability of septal E/e' to identify elevated T1 values, with area under the curve (AUC) and optimal cut-offs determined using positive likelihood ratios (LR +). RESULTS: Forty-six pediatric KTx recipients (16 ± 3.5 years old; time since KTx 7.9 ± 5.3 years) were included. Diastolic echocardiographic abnormalities were common, with 87% exhibiting at least one abnormal diastolic parameter. Septal T1 was associated with septal E/e', A-wave, and pulmonary venous atrial reversal, while lateral T1 was associated only with septal E/e'. Optimal septal E/e' cut-offs were 10.550 for detecting an elevated septal T1 (LR +  = 7.143) and 10.630 for detecting an elevated lateral T1 (LR +  = 9). CONCLUSIONS: Pediatric KTx recipients with structural myocardial alterations on CMR imaging exhibit detectable abnormalities in routine echocardiographic diastolic parameters. Especially a markedly elevated septal E/e' could identify patients at increased risk for underlying myocardial involvement and justify the use of CMR imaging in post-transplant follow-up.