Search Results (9,233)

Background/Objectives: The widespread adoption of high-fat diets has contributed to a rising incidence of metabolic disorders and associated cardiovascular diseases. This trend exacerbates myocardial ischemia–reperfusion (I/R) injury following interventional or thrombolytic therapy for acute myocardial infarction, leading to higher mortality and heart failure in affected individuals with metabolic dysregulation, for whom effective interventions are limited. Nuciferine, which possesses anti-inflammatory, antioxidant, and metabolic regulatory properties, has shown potential in improving post-I/R cardiac function, yet its mechanism remains unclear. Methods: This study utilized an ex vivo mouse heart model perfused with high-glucose/high-fatty acid solutions to establish a metabolic stress condition mimicking key aspects of the diabetic milieu and to evaluate the underlying mechanisms of nuciferine. Complementarily, a model of lipotoxicity combined with hypoxia/reoxygenation (H/R) injury was established in human cardiomyocyte cells (AC16). Results: Nuciferine significantly improved post-I/R functional recovery and attenuated succinate accumulation, an effect comparable to the succinate dehydrogenase (SDH) inhibitor dimethyl malonate (DMM). Mechanistically, nuciferine bound to an SDH subunit, inhibiting its activity and subsequent reactive oxygen species (ROS) production via mitochondrial reverse electron transport (RET). It also activated Sirt1-dependent pathways, mitigating apoptosis and mitochondrial dysfunction in AC16 cardiomyocytes. The Sirtuin 1 (Sirt1) inhibitor selisistat (EX527) abolished nuciferine’s protection, while DMM mirrored its efficacy, underscoring nuciferine’s dual role in inhibiting SDH-mediated RET and activating Sirt1 in alleviating I/R injury under metabolic stress conditions. Conclusions: These findings suggest that nuciferine confers cardioprotection by simultaneously attenuating RET-related oxidative stress and activating Sirt1. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in dysregulated inflammatory and coagulation pathways that drive immunothrombosis and contribute to adverse clinical outcomes. While individual cytokines and endothelial biomarkers have been associated with disease severity and mortality, the prognostic relevance of combined inflammatory and endothelial signatures remains incompletely characterised. To identify inflammatory cytokines and markers of endothelial activation associated with mortality in patients with severe COVID-19 requiring supplemental oxygen. This retrospective observational study included 73 consecutive adults admitted to a dedicated supplemental oxygen unit with severe COVID-19. Plasma concentrations of IL-1α, IL-1β, IL-6, IL-8, IL-10, TNF-α, von Willebrand factor (VWF) antigen and propeptide, ADAMTS13 antigen and activity, and ADAMTS13 autoantibodies were measured on admission using ELISA-based assays. Associations with mortality were assessed using non-parametric analyses, age-adjusted logistic regression, multivariable logistic regression, and receiver operating characteristic (ROC) curve analysis. Increasing age was independently associated with mortality. After adjustment for age, higher IL-1α concentrations were associated with increased odds of death, whereas a higher IL-6/IL-10 ratio was independently protective. In multivariable models, including non-ratio variables, ADAMTS13 autoantibody levels remained independently associated with mortality. In ratio-based multivariable analysis, both the ADAMTS13 activity/autoantibody ratio and the IL-6/IL-10 ratio were independently protective, while age was no longer significant. IL-10 and ADAMTS13 autoantibodies demonstrated moderate discriminative performance for mortality prediction (AUC ~0.70). A combined biomarker model incorporating IL-1α, IL-8, IL-10, and ADAMTS13 autoantibodies yielded very high predicted mortality probabilities. Our findings highlight IL-1α and ADAMTS13 autoantibodies as independent predictors of mortality in severe COVID-19, reflecting the interplay between inflammatory and endothelial pathways. Biomarker ratios capturing immune and endothelial balance—particularly the ADAMTS13 activity/autoantibody ratio—may enhance risk stratification and support integrated prognostic models. Full article

Background: Improved pediatric cardiac care has markedly increased the adult congenital heart disease (ACHD) population worldwide, creating new clinical and healthcare delivery challenges. However, nationwide evidence on predictors of acute outcomes in ACHD patients, particularly the impact of disrupted specialist care under universal healthcare systems, remains limited. Methods: We conducted a retrospective analysis using Japan’s nationwide administrative database from 2013 to 2022, evaluating hospital admissions of ACHD patients aged ≥15 years. Patients were categorized into surgical, catheter-based, and medical treatment groups. Multilevel logistic regression models identified predictors of in-hospital mortality, including emergency and non-referral admissions as indicators of impaired continuity of specialist care. Results: A total of 27,754 admissions were analyzed (median age 59 years; 49% male). Emergency admissions accounted for 35.2%, non-referral admissions for 9.9%, and overall in-hospital mortality was 5.0%. Older age, admission to non-ACHD centers, higher CHD complexity, emergency admissions, and non-referral admissions were independently associated with increased mortality. In addition, older age, CHD complexity, and admission to non-ACHD centers predicted emergency and non-referral admissions. Conclusions: These findings show persistent gaps in specialist care continuity for ACHD patients despite universal healthcare coverage and support the need for integrated ACHD care networks to improve outcomes in this aging population in Japan. Full article

Background: Direct oral anticoagulants (DOACs) are now the preferred anticoagulant over vitamin K antagonists for patients with atrial fibrillation (AF) and venous thromboembolism (VTE). Variability in drug exposure raises concerns about bleeding and thrombotic events, highlighting the potential value of therapeutic drug monitoring (TDM). Methods: This systematic review and meta-analysis conducted a systematic search of PubMed, Embase, Web of Science, Scopus, Cochrane Library, and ClinicalTrials.gov (from inception to May 2025) and identified studies reporting DOAC levels and clinical outcomes. Two reviewers independently performed screening, data extraction, and risk-of-bias assessment (RoB 2.0, Newcastle–Ottawa Scale). Random-effects meta-analytical models generated pooled estimates, with meta-regression exploring potential sources of variability (DOAC type, drug levels) and exposure–response relationships. Results: Nineteen studies comprising 5770 patients were included in the review. The pooled event rates were 8% for major bleeding (95% CI: 0.05–0.11), 7% for thrombotic events (95% CI: 0.05–0.09), and 3% for mortality (95% CI: 0.03–0.04). Heterogeneity was substantial for bleeding and thrombotic events (I² = 95.6% and 87.3%, respectively) but negligible for mortality (I² = 0%). Meta-regression analyses showed no significant association between mean DOAC concentration and either major bleeding (β = −0.00021, p = 0.35, Adj R² ≈ 0%) or thrombotic events (β = 0.00005, p = 0.78, Adj R² ≈ 0%), indicating that variations in measured plasma levels did not meaningfully explain event rate differences across studies. Conclusions: In this systematic review and meta-analysis, measured DOAC concentrations show limited and inconsistent association with clinical outcomes. While the present synthesis does not demonstrate a statistically robust linear correlation between DOAC plasma concentrations and adverse outcomes, it highlights the multifactorial determinants of bleeding and thrombosis risk underscores the potential value of selective TDM in individualized care. Further prospective, standardized studies are needed to define clinically actionable thresholds and to validate TDM-guided strategies that optimize the delicate balance between safety and efficacy in DOAC therapy. Full article

Background: Obstructive sleep apnea (OSA) affects quality of life and increases cardiovascular risk. Nocturnal oxygen therapy (NOT) offers a potential alternative for patients intolerant to CPAP. The objective of this study was to compare NOT and continuous positive airway pressure (CPAP) by evaluating five-year survival in patients with obstructive sleep apnea. Methods: A retrospective cohort study was conducted using propensity score matching (PSM) methodology. A PSM analysis was conducted to reduce selection bias due to differences in baseline characteristics between patients using CPAP and those receiving oxygen therapy. Balance between treated and untreated groups was assessed using standardized mean differences. A PSM was estimated using a logistic regression model, matching patients adherent to CPAP therapy to those treated with NOT. Results: A total of 497 patients with a confirmed diagnosis of OSA were included in the analysis. The mean age was 62.1 years (SD13.6), and 54.3% (270/497) were male. Overall, 42.1% (209/497) of the patients were over 65 years old. Of the total, 303 patients received CPAP therapy and 194 received NOT. After PSM, a matched cohort of 370 patients (185 per group) was obtained. The CPAP-treated group showed a significantly lower residual Apnea–Hypopnea Index compared to the oxygen therapy group (3.9, IQR: 1.8–6.5 vs. 15, IQR:7.5–29.1; p < 0.001), indicating better physiological control of respiratory events. Treatment with CPAP was associated with a significantly lower risk of mortality compared with NOT across analytical approaches, including weighted logistic regression (OR = 0.11; 95% CI 0.02–0.48; p = 0.004) and PSM with bootstrap estimation (ATT = −0.12; 95% CI −0.22 to −0.01; p = 0.030). Conclusions: In this cohort, higher five-year survival was observed among patients with OSA treated with CPAP compared with those receiving supplemental oxygen. These findings indicate a favorable association between CPAP use and long-term outcomes, supporting its role as the preferred first-line therapy in patients with OSA. Full article

Background: Heart failure (HF) remains a major cause of hospitalizations in the United States (US). Respiratory syncytial virus (RSV) has been associated with HF exacerbations. We compared in-hospital outcomes and healthcare utilization among US HF hospitalizations with and without RSV. Methods: Using the Nationwide Readmissions Database (2016–2022), we propensity-matched HF hospitalizations with a secondary diagnosis of RSV (HF-RSV) 1:1 to those without RSV (HF-noRSV). Multivariable logistic and Poisson regression models were used to assess associations between RSV and outcomes. The primary outcome was in-hospital mortality; secondary outcomes included adverse events, length of stay (LOS), hospitalization costs, and 30-day readmissions. Results: Among 11,158,836 HF hospitalizations, 32,419 (0.29%) had RSV. Compared with matched HF-noRSV hospitalizations, HF-RSV was associated with higher odds of in-hospital mortality (adjusted odds ratio [aOR] 1.12; 95% CI 1.04–1.20), septic shock (aOR 1.40; 95% CI 1.29–1.52), acute respiratory failure (aOR 3.43; 95% CI 3.32–3.55), and noninvasive mechanical ventilation (aOR 2.15; 95% CI 2.04–2.26). HF-RSV had lower odds of cardiogenic shock (aOR 0.82; 95% CI 0.73–0.92), ventricular tachycardia/fibrillation (aOR 0.73; 95% CI 0.68–0.78), ischemic stroke (aOR 0.31; 95% CI 0.27–0.36), transient ischemic attack (aOR 0.33; 95% CI 0.25–0.44), and 30-day readmissions (aOR 0.54; 95% CI 0.46–0.56). HF-RSV hospitalizations had higher costs (adjusted coefficient 0.02; 95% CI 0.01–0.02) and longer LOS (adjusted coefficient 0.14; 95% CI 0.13–0.14). Conclusions: Among US HF hospitalizations, RSV was associated with higher mortality and respiratory-related complications and increased healthcare resource utilization. Full article

Background: Enterococcus faecium bloodstream infections (EF-BSI) cause significant morbidity and mortality in solid organ transplant (SOT) recipients, with the role of vancomycin resistance (VR) remaining controversial as an independent driver. Methods: This was a retrospective cohort study including SOT recipients with EF-BSI at our institution from 2019 to 2023. We used Cox proportional hazards regression to identify predictors of 30-day all-cause mortality. A time-dependent covariate was used to model the effects of receiving targeted, effective antibiotic therapy. Results: A total of 79 patients were included (26.6%, with VR). The overall 30-day mortality was 12.7% (10/79). In univariable analysis, septic shock (Hazard Ratio, HR: 17.1, 95% CI: 3.64–80.8, p < 0.001), the need for Continuous Venovenous Hemofiltration (HR: 6.40, 95% CI: 1.85–22.1, p = 0.003), and a Pitt Bacteremia Score ≥ 2 (HR: 5.17, 95%CI: 1.10–24.3, p = 0.038) were associated with increased mortality, while source control was protective (HR: 0.20, 95% CI: 0.05–0.76, p = 0.018). In the final multivariable model, only septic shock remained an independent predictor of 30-day mortality (HR: 11.4, 95% CI: 1.63–79.5, p = 0.014). VR was not significantly associated with mortality, though the confidence interval was wide and included clinically meaningful effects (HR: 2.07, 95% CI: 0.40–10.6, p = 0.4). Conclusions: In SOT recipients with EF-BSI, 30-day mortality is overwhelmingly driven by the host’s physiological response, manifested as septic shock, rather than the VR profile of the pathogen. The early recognition of severe sepsis/septic shock and the aggressive implementation of supportive care and source control measures in this setting are crucial. Full article

The triad association among type 2 diabetes mellitus (T2DM), metabolic associated fatty liver disease (MAFLD), and incretin secretion dysfunction, including GLP-1 (glucagon-like peptide-1) secretion dysfunction, maintains a critical cardiovascular risk and liver-related mortality. The aim of this study is to establish interactions between the GLP-1 plasma levels and metabolic syndrome clusters and adipokines profile (leptin, adiponectin, resistin) and proinflammatory cytokines (TNFα, IL-6, IL1β, IL-17) in diabetic subjects with or without MAFLD. The data revealed that insulin resistance (HOMA-IR) is present in all groups. MAFLD is more common in men than in women. The average FLI score in group IV was ≥70, confirming the diagnosis of MAFLD. The disorder of GLP-1 secretion is more pronounced in women than in men. HOMA-IR is negatively associated with plasma GLP-1 depletion in the MAFLD, T2DM, and MAFLD + T2DM groups. Adiponectin levels are decreased in all groups, as for GLP-1. In contrast, leptin, resistin, TNFα, IL-6, IL-1β, and IL-17 levels show an inverse correlation with GLP-1. GLP-1 accurately reflects metabolic and inflammatory status in subjects with MAFLD, T2DM, and diabetes—steatosis. The applied multivariate linear regression model confirms a highly significant association between MAFLD and GLP-1. It appears that plasma GLP-1 can be considered as biomarker in MAFLD and T2DM related to sex-gender disparities. Longitudinal studies are required to confirm these data. Full article

Background: Beyond the direct COVID-19 effects, the pandemic’s broader impact on vulnerable groups, such as patients with systemic sclerosis (SSc), is particularly concerning, especially regarding any resulting increase in overall mortality due to healthcare access disruptions. We aimed to determine excess all-cause mortality in SSc patients before and during the pandemic. Methods: We examined mortality data from Thailand’s Ministry of Public Health database for adults with SSc (ICD-10: M34). According to the WHO methodology, a negative binomial distribution model was used to estimate the expected number of deaths using pre-pandemic data (1 January 2015–31 December 2019). We evaluated actual versus expected deaths during the pandemic (1 January 2020 to 31 December 2022), defining excess mortality as the difference between observed and projected deaths under normal conditions. Results: The total number of all-cause deaths in Thailand was 2,325,384 in the pre-pandemic period and 1,634,121 during the pandemic period. The mortality rate among patients with SSc was 3693 before and 3107 during the pandemic. Of those with SSc, 1785 of the deceased were female, and the observed mortality was significantly lower than expected, with an excess death count of −368 (95% CI: −459 to −277), as well as in males with an excess death count of −123 (95% CI: −198 to −48). However, younger SSc patients (aged 18–29 years) experienced significantly higher excess mortality, with an excess death count of 11 (95% CI: 4–18). Conclusions: During the COVID-19 pandemic, neither sex had significantly higher SSc mortality; however, mortality in younger SSc patients increased significantly compared to pre-pandemic levels, underscoring the need for tailored therapies. Full article

This article describes a field- and laboratory-based framework that can be used to monitor the C balance in Mediterranean pine forest ecosystems under different management practices that determine their structure and function. By jointly monitoring stand structure, gas exchange, litter, and decomposition dynamics, this protocol enables the assessment of how management-driven changes regulate carbon uptake, turnover, and losses, thereby affecting carbon sequestration potential. As an example, we suggest the implementation of the protocol at ten (10) permanent monitoring plots across three study areas located in Greece. The first group of plots represents a post-fire chronosequence in pine stands with no management interventions. The second group includes pine stands that exhibit variation in overstory and understory density driven by differences in microclimate and management history. The third group consists of peri-urban pine stands subjected to thinning of varying intensity. The monitoring protocol is implemented across all plots and the collected data can be classified into three analytical domains: (a) demography, encompassing measurements of tree growth and mortality; (b) litter and decomposition dynamics, involving the quantification of litterfall and its seasonality and the estimation of its decomposition rates; and (c) gas exchange, focusing on measurements of leaf photosynthesis and respiration (including relevant leaf functional traits) and monitoring of soil respiration. These three data domains can be used to comparatively consider the effect of forest management on key ecosystem processes and to constrain local-scale vegetation dynamics models. Full article

More than 90% of bladder cancers are classified as urothelial carcinomas (UC), with approximately 75% of these cases presenting as non-muscle-invasive bladder cancer (NMIBC). Bacillus Calmette–Guérin (BCG) is the current standard immunotherapy for NMIBC, yet it suffers from limited efficacy, frequent tumor recurrence, and substantial toxicity. These limitations underscore the need for safer, more effective, and accessible alternatives. We investigated whether uropathogenic Escherichia coli (UPEC), a natural inducer of immune responses in the bladder, could serve as a novel intravesical immunotherapeutic agent. Using orthotopic bladder cancer models in both mice (MB49-luc) and rats (AY-27), we evaluated the efficacy, specificity, immune dependence, and safety of formaldehyde-inactivated UPEC strains, including mutants with altered type 1 fimbriae expression. Intravesical administration of inactivated UPEC significantly reduced tumor burden and prolonged survival, outperforming BCG in murine models and demonstrating equivalent efficacy with markedly reduced toxicity in rats. The antitumor effect was T cell-dependent and partially mediated by type I fimbriae, which facilitated tumor-specific adhesion. Notably, systemic (subcutaneous) administration of UPEC abrogated efficacy and increased mortality, emphasizing the necessity of localized bladder delivery. In conclusion, we identify inactivated UPEC as a potent, tumor-targeting, and T cell-dependent immunotherapeutic agent with a superior safety profile compared to BCG. This approach might represent a promising and practical alternative for bladder cancer treatment. Full article

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide. CVDs are associated with multiple factors, including oxidative stress, mediated endothelial dysfunction, vascular inflammation, and atherothrombosis. Although traditional antioxidant supplementation (such as vitamins C, E, and β-carotene) has shown promising results in rigorous animal model studies, it has consistently failed to demonstrate clinical benefit in most human trials. Consequently, there is a substantial unmet need for novel paradigms involving mechanistically and biologically relevant pharmaceutical-grade antioxidant therapies (“next-generation antioxidants”). Rapid advancements in redox biology, nanotechnology, genetic modulation of redox processes, and metabolic regulation have enabled the development of new antioxidant therapeutics, including mitochondrial-targeted agents, NADPH oxidase (NOX) inhibitors, selenoprotein and Nrf2 activators, engineered nanoparticles, catalytic antioxidants, and RNA-based and gene-editing strategies. These interventions have the potential to modulate specific oxidative pathways that contribute to CVD pathogenesis. This review provides a comprehensive assessment of current oxidative stress–modulating modalities and their potential to inform personalized cardiovascular prevention and treatment strategies. Full article

Acute respiratory distress syndrome (ARDS) is a common condition among intensive care unit patients and is associated with high mortality. Currently, there are no unified therapeutic strategies, including for the use of systemic glucocorticosteroid (GCS) therapy, in the management of ARDS of various etiologies. Using our previously developed non-surgical and reproducible model of unilateral total diffuse alveolar damage (ARDS/DAD) in the left lung of ICR mice, we investigated the effects of GCS with different durations of action and administration regimens on lung function recovery. Our data show that repeated-course administration of dexamethasone promoted complete normalization of respiratory function, as well as restoration of aeration and perfusion of the left lung in mice following ARDS/DAD induction. In contrast, a single administration of the same drug or the use of a prolonged-release formulation, despite exhibiting anti-inflammatory effects, did not provide adequate lung tissue recovery and, in some cases, even exacerbated injury. These results underscore that in ARDS therapy, not just the use but the specific dosing regimen of glucocorticoids is critically important for driving complete functional and structural lung repair. Full article

Recent evidence has highlighted the pivotal roles of reactive oxygen species (ROS) and the SIRT1, AMPK, and mTOR signaling pathways in aging and longevity, making them attractive targets for studies of lifespan-extending interventions. We previously demonstrated that 1,1-diethoxyethane (1,1-DEE) could interact with mitochondrial complex I (NADH–ubiquinone oxidoreductase), leading to transient mitochondrial ROS (mtROS) production and activation of the AMPK pathway. This study further examined the effects of 1,1-DEE on longevity in model organisms. Treatment with 1,1-DEE decreased senescence in endothelial cell EA.hy926. In Caenorhabditis elegans (C. elegans), 1,1-DEE induced a hormetic response and extended the lifespan, whereas its structural isoform, 1,2-diethoxyethane (1,2-DEE), showed no such effect. In rat models, administration of 1,1-DEE markedly improved survival rate, mortality risk, restricted mean survival time (RMST), and median lifespan, associated with an accelerated body weight reduction. Additionally, 1,1-DEE could also enhance learning and memory, as assessed by the Morris water maze test in rats. These findings suggest that 1,1-DEE may serve as a novel small-molecule modulator of mitochondrial function and redox signaling, with potentials for promoting anti-aging and longevity. Full article

Background: Childhood cancer is the leading cause of natural death among children in high-income countries, despite treatment improvements. The Spanish Registry of Childhood Tumours (RETI-SEHOP) systematically records all cases treated within the network of SEHOP units. Using RETI-SEHOP data, we evaluated survival trends to assess progress in patient care, both overall and by tumour. Methods: A total of 20,534 childhood cancer cases (0–14 years) were recorded across the period 1999–2021. The 1-, 3-, and 5-year overall survival (OS) were estimated using the Kaplan–Meier method, applying the cohort approach for 1999–2018 and the period approach for 2019–2022. OS by age and sex was analysed in the recent 2009–2018 incidence cohort. Age-adjusted OS time trends were examined using joinpoint Cox models for 1999–2022. Results: For all tumours combined, 5-year OS increased from 75.4% to 84.6% between 1999–2003 and 2019–2022. While positive trends were identified for all haematological malignancies examined, a more varied scenario was evident for solid tumours, as ependymomas improved fastest (1.51 points annually), and sarcomas, except for rhabdomyosarcoma, remained stagnant. Conclusions: Our results reflect a period characterised by a combination of new therapeutic developments, improved diagnostics, and more refined risk stratification, which has ultimately led to a reduction in disease-related mortality. Full article