In transthyretin amyloid cardiomyopathy, mitral regurgitation (MR) severity may be underestimated by conventional (semi-)quantitative echocardiographic criteria due to restrictive low-flow hemodynamics. We sought to define and validate disease-specific MR risk thresholds and compare their prognostic performance with guideline definitions.

In a multicenter cohort study (8 centers, 4 countries), 1101 patients with newly diagnosed transthyretin amyloid cardiomyopathy (derivation, n=722; validation, n=379) underwent standardized echocardiography with blinded core laboratory analysis, including MR measures (vena contracta width, effective regurgitant orifice area, regurgitant volume, and regurgitant fraction). All-cause mortality and time to first heart failure hospitalization (HFH) served as end points. Prognostic thresholds were derived from spline analysis, validated externally, and compared with American Heart Association/American College of Cardiology, European Society of Cardiology/European Association for Cardiothoracic Surgery, and American Society of Echocardiography definitions.

During a median follow-up of 24.9 months (interquartile range, 12.0-42.0), 314 patients (28.5%) died and 244 (22.2%) experienced HFH. All MR metrics independently predicted mortality and HFH (all P<0.05). Spline-derived thresholds identified intermediate risk at vena contracta width ≥3.0 mm, effective regurgitant orifice area ≥0.10 cm², regurgitant volume ≥15 mL, and regurgitant fraction ≥20% and high risk at effective regurgitant orifice area >0.25 cm², regurgitant volume >38 mL, and regurgitant fraction >35%. Compared with guideline grading (≈12%-13%), the composite MR grading scheme classified a significantly higher proportion (21%) as severe MR and provided superior discrimination for clinical outcomes at 12 and 24 months in both the derivation and validation cohort. After multivariable adjustment, only the composite MR grading scheme remained strongly predictive for both mortality (hazard ratio, 1.20 [1.07-1.36]) and HFH (hazard ratio, 1.21 [1.05-1.38]).

Quantitative MR thresholds in transthyretin amyloid cardiomyopathy are substantially lower than current guideline cutoffs. A validated, risk-based composite MR grading scheme improves prediction of both mortality and HFH, better reflecting the restrictive low-flow pathophysiology of transthyretin amyloid cardiomyopathy and supporting disease-specific MR grading.

URL: https://www.clinicaltrials.gov; Unique identifier: NCT06836011.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, and effective targeted therapies remain limited. Fedratinib, a clinically approved JAK2 inhibitor, has shown antitumor activity in hematologic malignancies, however, its role in HCC remains unclear. This study aimed to investigate the antitumor effects of fedratinib in HCC.

The effects of fedratinib were examined in Huh7 and Hepa1-6 HCC cells using proliferation, migration, invasion, apoptosis, and cell cycle assays. Cell-based surface plasmon resonance (SPR) was used to assess concentration-dependent whole-cell association signals between fedratinib and intact HCC cell monolayers. In vivo, Hepa1-6-Luc subcutaneous allografts were treated with intraperitoneal fedratinib. Western blotting and enzymatic assays were performed to detect STAT3, AKT, calpain-1 and Bcl-2.

Fedratinib markedly inhibited proliferation, migration and invasion of HCC cells while inducing apoptosis and cell cycle arrest in a dose-dependent manner. SPR demonstrated concentration-dependent whole-cell association signals between fedratinib and intact HCC cell monolayers. In the allograft model, fedratinib significantly reduced tumor growth and bioluminescence signal intensity without causing obvious short-term systemic toxicity. In terms of molecular changes, fedratinib decreased the phosphorylation levels of STAT3 and AKT without affecting total protein expression, reduced calpain-1 expression and enzymatic activity, as well as downregulation of the anti-apoptotic protein Bcl-2.

These results demonstrate that fedratinib treatment is associated with reduced STAT3 and AKT phosphorylation, diminished calpain-1 expression and enzymatic activity, and impaired malignant phenotypes in HCC, providing preliminary evidence supporting further evaluation of fedratinib as a candidate therapeutic agent for HCC.

Kidney transplantation remains the most effective treatment for end-stage kidney disease; however, long-term graft survival is constrained by rejection and chronic graft injury, and donor shortages continue to drive interest in xenotransplantation. The complement system is increasingly recognized both as a terminal effector of antibody-mediated injury and as a regulatory network linking antibody responses, endothelial activation, ischemia-reperfusion injury, coagulation, and innate immune cell responses. In this review, we compare the role of complement in allogeneic and xenogeneic kidney transplantation and provide an overview of emerging therapeutic strategies. In allogeneic transplantation, donor-specific anti-HLA and anti-ABO blood group antibodies activate complement, particularly via the classical pathway, and contribute to antibody-mediated rejection. Although C4d deposition is a key marker of complement activation, its clinical significance depends on the presence of microvascular inflammation, endothelial injury, and other immune mechanisms. Complement-binding donor-specific antibodies may improve risk stratification, whereas the clinical benefits of inhibiting C5, C3, and upstream complement in chronic active antibody-mediated rejection remain uncertain. In xenotransplantation, α-Gal and non-Gal antigens, their corresponding natural antibodies, complement activation via the classical, lectin, and alternative pathways, and interspecies incompatibilities in complement regulation collectively promote vascular endothelial injury and thromboinflammation. Multiplex genetic modification of donor pigs, including deletion of major carbohydrate antigens and expression of human complement and coagulation regulatory proteins, has substantially mitigated hyperacute rejection. However, achieving durable xenograft survival requires effective control of macrophages, natural killer cells, neutrophils, and their interactions with the graft endothelium. Therefore, integrated strategies combining genetic complement regulation, pharmacological complement inhibition, coagulation regulation, and innate immune modulation may be essential for preventing chronic allograft injury and improving long-term kidney xenograft survival.

Chronic obstructive pulmonary disease (COPD) is among the leading causes of mortality worldwide, and patients experience a high prevalence of concomitant cardiovascular diseases (CVDs). In this study, we aimed to determine whether never smokers with COPD exhibit an increased risk of CVD compared with those without COPD and whether this risk parallels that observed in smokers with COPD.

We conducted a prospective cohort study using data from the China Kadoorie Biobank (CKB). Spirometry was performed on all the participants, and COPD was defined as the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) <0.7. Eligible participants in our study were free of diagnosed CVDs, including ischemic heart disease, heart failure, hypertension, or atrial fibrillation at baseline. The clinical outcomes were the incidences of these 4 CVDs and their overall incidence during follow-up. Cox proportional hazard models were used to estimate the associations of COPD and smoking status with incident CVD outcomes.

Among all eligible participants (n = 366,161, 20,887 with COPD), 40,861 incident cases of CVD events were observed during a median follow-up time of 10 years. Compared with never smokers without COPD, those with COPD exhibited a significantly higher risk of overall CVD, with hazard ratios (HRs) of 1.23 (95% CI: 1.09-1.39) for men and 1.24 (95% CI: 1.17-1.31) for women. Among male COPD participants, the incidence rates of overall CVD, ischemic heart disease, and hypertension, but not that of heart failure, were similar between never smokers and smokers. In contrast, female COPD participants who never smoked exhibited lower risks across all cardiovascular endpoints compared with their smoking counterparts. These results remained unchanged after propensity score matching.

In never smokers, COPD per se serves as an independent risk factor for CVD. Among men with COPD, smoking exposure confers no added hazard, whereas women with COPD who smoke remain at higher risk for CVD than their never-smoking counterparts.

Lupeol has drawn a significant attention due to its broad-spectrum pharmacological activity as a natural pentacyclic triterpenoid isolated from abundant plant sources. It exhibits antiinflammatory, antioxidant, antimicrobial, anticancer, and cardioprotective activities through the interaction of key signaling pathways, including NF-κB, MAPK, and PI3K/Akt. This review presents an overview of recent advances in the use of lupeol for chronic diseases, including cancer, cardiovascular disorders, metabolic syndromes, inflammatory conditions, and neurological diseases. Specific focus is on new formulation solutions designed to surmount the key limitations affecting lupeol, including its very low aqueous solubility and poor bioavailability. Such strategies include lipid nanoparticles, polymeric carriers, nano-formulations, and chemical moieties that enhance drug stability and targeted delivery. Moreover, the review highlights the combinatorial usage of lupeol with other plant components and conventional drugs and their synergistic effects. Recent cosmeceutical applications of lupeol, especially in skin care, wound healing, and UV protection, are also discussed. In summary, this review aims to compile recent advances in lupeol pharmacology and formulation research, whilst identifying knowledge gaps that need to be addressed before subsequent clinical/ industrial progression.

Infective endocarditis (IE) in patients with malignancy represents a high-risk clinical cohort, yet nationwide data on outcomes and predictors of mortality remain limited. Using the United States National Inpatient Sample (2016-2022), we identified hospitalizations involving IE and a malignancy diagnosis. Inpatient mortality, complications, and temporal trends were analyzed overall and across malignancy subtypes, causative organisms, and prosthetic valve status. Survey-weighted multivariable logistic regression was performed across the full IE cohort. Of 635 715 IE hospitalizations, 44 060 (6.9%) involved a malignancy diagnosis. Inpatient mortality was higher in this group than among IE hospitalizations without malignancy (13.5% vs 9.8%; P < .001), and malignancy remained associated with mortality after adjustment (adjusted odds ratio 1.29; 95% CI 1.19-1.39; P < .001). The proportion of IE hospitalizations involving malignancy increased from 6.7% in 2016 to 7.7% in 2022. Fungal infection, shock, acute kidney injury, and stroke were associated with mortality. Prosthetic-valve IE had lower mortality than non-prosthetic-valve IE (7.7% vs 13.9%; P < .001). These findings identify a high-risk, heterogeneous phenotype and support earlier diagnostic evaluation and coordinated oncology, cardiology, and infectious diseases management.

Apolipoprotein A (ApoA) family members-ApoA-I, ApoA-II, ApoA-IV, and ApoA-V-play important roles in the vasculature that extend beyond lipid transport to regulate lipid-immune crosstalk, vascular homeostasis, and triglyceride metabolism. ApoA-I mediates reverse cholesterol transport, yet its cardioprotective capacity depends on functional integrity rather than HDL-cholesterol levels alone. ApoA-II, ApoA-IV, and ApoA-V exhibit context-dependent roles ranging from enhancing cholesterol efflux and triglyceride clearance to modulating inflammation, oxidative stress, endothelial activation, and thrombosis. Post-translational modifications such as oxidation, glycation, and citrullination within inflammatory milieus can convert protective ApoA proteins into dysfunctional or proinflammatory mediators. Genetic variations within APOA gene clusters have clarified the causal contribution of triglyceride-rich lipoproteins to atherosclerotic risk, shifting emphasis from HDL quantity toward lipoprotein quality and remnant cholesterol burden. In this comprehensive review, we synthesize structural, genetic, mechanistic, and clinical evidence to evaluate the position of the 4 ApoA proteins as context-dependent modulators of cardiovascular disease. We highlight the dualistic nature of their actions and examine failed clinical trials of ApoA-I infusions and mimetic peptides. We conclude by discussing how shifting focus from HDL quantity toward lipoprotein quality and preservation of ApoA functional integrity may inform more precise approaches to residual cardiovascular risk and triglyceride-driven atherogenesis.

To characterize the clinical presentation and management of anaphylaxis in infants and toddlers.

We conducted a retrospective cohort study of patients aged 0 to 24 months presenting to a pediatric emergency department between June 2019 and June 2022 with concern for anaphylaxis. Patients were identified using International Classification of Diseases, Ninth and 10th Revision codes associated with anaphylaxis and confirmed to meet 2006 National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network clinical criteria by chart review. Demographic and clinical information-including presenting symptoms, administered treatment, and patient disposition-were abstracted from the electronic medical record. Treatments of interest included epinephrine, antihistamines, corticosteroids, albuterol, and intravenous fluids. Data were analyzed descriptively.

Among 225 potentially eligible encounters, we identified 155 patients who met inclusion criteria. Median age was 10.8 months (interquartile range: 8.4 to 15.6). Food triggered 96.1% of episodes. Skin and mucosal symptoms occurred in 99.4% of patients, gastrointestinal symptoms in 74.2%, respiratory symptoms in 57.4%, and cardiovascular symptoms in 5.8%. Intramuscular epinephrine was administered to 87.1% of patients, 90.4% of whom received a single dose. Most patients (88.4%) were discharged home, and none of those admitted required additional epinephrine.

In this cohort, reactions were most often food-triggered and characterized by mucocutaneous symptoms with gastrointestinal and/or mild-to-moderate respiratory symptoms. Severe respiratory or cardiovascular involvement was uncommon. Symptoms tended to resolve after a single dose of epinephrine, and most patients were discharged home.

The emergence of the Omicron variant (B.1.1.529) of SARS-CoV-2 represents a new challenge due to its high transmissibility and potential resistance to existing treatments. While Remdesivir, an FDA-approved antiviral, has been widely used in managing COVID-19 cases, its efficacy against the Omicron variant remains uncertain and warrants further investigation. This systematic review and meta-analysis evaluates the effectiveness of remdesivir in individuals infected with the Omicron variant.

A systematic search of MEDLINE (PubMed), Embase, Cochrane Library, Google Scholar, and ClinicalTrials.gov identified relevant cohort studies. Data extraction and risk of bias assessment followed PRISMA guidelines, with statistical analysis conducted by random-effects model using the RevMan. In addition, subgroup analysis and sensitivity analysis were applied as necessary.

Fourteen cohort studies with 964,156 participants were included. Remdesivir significantly reduced all-cause death among hospitalized individuals (OR: 0.70, 95% CI [0.60-0.81]), all-cause hospitalization (OR: 0.27, 95% CI [0.14-0.54]), and COVID-19-related death (OR: 0.13, 95% CI [0.03-0.58]). However, its effect on oxygen supplementation was not significant (OR: 0.52, 95% CI [0.08-3.52]).

These findings reinforce the role of Remdesivir in preventing severe COVID-19 outcomes among patients infected with the Omicron variant.