Endothelial cells (ECs) line the inner surface of blood vessels and play a substantial role in vascular biology. Endothelial dysfunction (ED) is strongly correlated with the initiation and progression of many vascular diseases. Regulated cell death, such as ferroptosis, is one of the multiple mechanisms that lead to ED. Ferroptosis is an iron-dependent programmed cell death associated with various vascular diseases, such as cardiovascular, cerebrovascular, and pulmonary vascular diseases. This review summarized ferroptosis of ECs in vascular diseases and discussed potential therapeutic strategies for treating ferroptosis of ECs. In addition to lipid peroxidation inhibitors and iron chelators, a growing body of evidence showed that clinical drugs, natural products, and intervention of noncoding RNAs may also inhibit ferroptosis of ECs.

Background This study aimed to provide a comprehensive review of adverse events (AEs) associated with factor Xa (FXa) inhibitors in pediatric patients. Methods We searched PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and the European Union Clinical Trials Register for English-language records from the establishment of the database up to October 17, 2023. Both randomized controlled trials and single-arm trials were included. AEs were analyzed using a Bayesian hierarchical model. For the pharmacovigilance study, data from the US Food and Drug Administration Adverse Event Reporting System from January 1, 2007, to December 31, 2023, were obtained. The proportional imbalance method and the Medicines and Healthcare products Regulatory Agency method were used to detect AE signals. Further characterization of patients presenting with AEs was performed. Results Of 451 records identified, 12 eligible studies were included. A total of 50.6% (95% Bayesian credible interval [CrI] 33.1–67.2, τ = 0.796) of patients experienced at least one AE, and 9.9% (95% CrI 3.9–19.5, τ = 0.552) developed at least one serious AE. Major and clinically relevant non-major bleeding occurred in 2.4% (95% CrI 0.8–4.8, τ = 1.61) of patients. The most common bleeding AEs were epistaxis (8.4% [95% CrI 3.9–14.9, τ = 1.96]), subcutaneous hematoma (6.4% [95% CrI 0.5–26.2, τ = 0.54]), and wound hemorrhage (3.7% [95% CrI 0.4–13.3, τ = 0.55]). Non-hemorrhagic AEs were pyrexia (9.2% [95% CrI 4.6–15.3, τ = 1.18]), vomiting (7.8% [95% CrI 4.0–12.3, τ = 0.08]), and abdominal pain (7.4% [95% CrI 1.5–19.4, τ = 0.84]). A total of 39 AE signals were detected in the pharmacovigilance study. The top three highest overall relative odds ratio (ROR) for AEs were observed for haemorrhoidal hemorrhage at 1211.82 (95% CI, 312.69–4696.29), thrombophlebitis at 134.64 (95% CI, 42.18–429.81), and deep vein thrombosis at 68.3 (95% CI, 42.53–109.68). Patients experiencing bleeding AEs had received a mean dosage of rivaroxaban 0.16 mg/kg and apixaban 0.08 mg/kg. Conclusions Systematically quantified AEs of FXa inhibitors in clinical trials and real-world studies provide an important guide for clinicians. The use of FXa inhibitors in pediatric patients is associated with an acceptable rate of AEs. The most common bleeding AE was epistaxis. Pediatric patients treated with FXa inhibitors were more prone to hemorrhoidal hemorrhage. A safe approach may involve prior use of other anticoagulants followed by careful administration of FXa inhibitors, with a dosing regimen tailored to age and weight. Close monitoring is recommended for peri-procedural anticoagulation and vomiting.

(1) Background: The purpose of this study was to evaluate the effect of gene polymorphisms on prothrombin time (PT) and activated partial thromboplastin time (APTT) in a healthy Chinese population. (2) Methods: A total of 403 healthy volunteers from a series of novel oral anticoagulants (NOACs) bioequivalence trials in China were included. Coagulation tests for PT and APTT were performed in the central lab at Peking University First Hospital. Whole-exome sequencing (WES) and genome-wide association analysis were performed. (3) Results: In the correlation analysis of PT, 105 SNPs from 84 genes reached the genome-wide significance threshold (p < 1 × 10⁻⁵). Zinc Finger Protein 594 (ZNF594) rs184838268 (p = 4.50 × 10⁻¹⁹) was most significantly related to PT, and Actinin Alpha 1 (ACTN1) was found to interact most with other candidate genes. Significant associations with previously reported candidate genes Aurora Kinase B (AURKB), Complement C5(C5), Clock Circadian Regulator (CLOCK), and Histone Deacetylase 9(HDAC9) were detected in our dataset (p < 1 × 10⁻⁵). PiggyBac Transposable Element Derived 2(PGBD2) rs75935520 (p = 4.49 × 10⁻⁶), Bromodomain Adjacent To Zinc Finger Domain 2A(BAZ2A) rs199970765 (p = 5.69 × 10⁻⁶) and Protogenin (PRTG) rs80064850 (p = 8.69 × 10⁻⁶) were significantly correlated with APTT (p < 1 × 10⁻⁵). The heritability values of PT and APTT were 0.83 and 0.64, respectively; (4) Conclusion: The PT and APTT of healthy populations are affected by genetic polymorphisms. ZNF594 and ACTN1 variants could be novel genetic markers of PT, while PRTG polymorphisms might be associated with APTT levels. The findings could be attributed to ethnic differences, and need further investigation.

What is known and objective Dopamine D₂ receptor (DRD2) polymorphisms are inconsistently associated with elevated prolactin levels related to risperidone treatment. The aim of this systematic review and meta‐analysis was to investigate whether DRD2 polymorphisms could modulate prolactin levels in patients treated with risperidone. Methods Three electronic databases (PubMed, EMBASE and the Cochrane Library) were searched for studies investigating the effect of DRD2 polymorphisms on prolactin levels in patients treated with risperidone until May 2018. Summary standard mean differences (SMDs) and 95% confidence intervals (CIs) were calculated with Hedges' g tests for effect estimates using random effects models. The heterogeneity, sensitivity, univariable meta‐regression, subgroup analyses and publication biases were calculated. Results and discussion After initially identifying 886 studies, 772 patients from eight studies were included. Summary SMDs indicated that compared with A1 non‐carriers, Taq1A A1 carriers did not have different risperidone‐related prolactin levels (SMD: 0.13; 95% CI: −0.18 to 0.43; P = 0.423) among patients with schizophrenia (SCZ; SMD: 0.07; 95% CI: −0.14 to 0.29; P = 0.505) or among those without SCZ (SMD: 0.16; 95% CI: −0.39 to 0.71; P = 0.562). There was no significant difference between Del carriers and Del non‐carriers with regard to risperidone‐related prolactin levels (SMD: −0.00; 95% CI: −0.59 to 0.58; P = 0.996). In an Asian subgroup analysis, we also noted that compared with Taq1A A1A2 carriers, Taq1A A1A1 carriers had lower prolactin levels (SMD: −0.34; 95% CI: −0.66 to −0.02; P = 0.040). However, there was no significant difference in prolactin levels between A1A1 carriers and A2A2 carriers (SMD: −0.27; 95% CI: −0.60 to 0.05; P = 0.098), or between A2 carriers and A2 non‐carriers (SMD: 0.29; 95% CI: −0.01 to 0.59; P = 0.059). Based on univariable meta‐regression analyses, the effects of publication year, study design, ethnicity, comparison groups and study quality could bias the identified association of DRD2 Taq1A with risperidone‐related prolactin levels. What is new and conclusion The findings of this study suggest that there is no significant difference between Taq1A A1 carriers and non‐A1 carriers with regard to risperidone‐related prolactin levels. As there were few A1 homozygotes, large prospective studies with robust designs are still needed to investigate whether A1A1 could affect risperidone‐related prolactin levels in the Asian population.

Human leukocyte antigen (HLA) alleles are implicated in drug-induced hypersensitivity, including by nevirapine and abacavir. The purpose of this meta-analysis was to evaluate the relationship between HLA polymorphisms and hypersensitivity to antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients. We conducted a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library for studies that evaluated the associations of HLA polymorphisms with antiretroviral therapy-induced hypersensitivity published in April 2019. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were considered as estimates of the effect. The meta-analysis included 17 studies that assessed a total of 4273 patients. First, carriers of HLA-A *24 were associated with an increased risk of hypersensitivity among patients with HIV who received antiretroviral therapy (OR: 12.12; P = 0.018). Second, five SNPs of HLA-B genotypes, including *18 (OR: 1.63; P = 0.028), *35 (OR: 2.31; P = 0.002), *39 (OR: 11.85; P = 0.040), *51 (OR: 1.66; P = 0.028), and *81 (OR: 8.11; P = 0.021), were associated with an increased risk of hypersensitivity. Conversely, carriers of HLA-B *15 were associated with a reduced risk of hypersensitivity (OR: 0.43; P < 0.001). Third, HLA-C *04 was associated with an increased risk of hypersensitivity (OR: 3.09; P < 0.001), whereas a lower risk for hypersensitivity was observed in patients who were carriers of HLA-C *02 (OR: 0.22; P = 0.030), *03 (OR: 0.53; P = 0.049), and *07 (OR: 0.61; P = 0.044). Finally, carriers of HLA-DRB1 *05 (OR: 0.18; P = 0.006) and *15 (OR: 0.23; P = 0.013) were associated with a reduced risk of hypersensitivity among patients receiving antiretroviral therapy. The findings of this meta-analysis indicated patients carrying HLA-A *24, HLA-B *18, *35, *39, *51, *81, HLA-C *04 were associated with a higher risk of hypersensitivity. Conversely, subjects carrying HLA-B *15, HLA-C *02, *03, *07, HLA-DRB1 *05, *15 were associated with a reduced risk of hypersensitivity.

Introduction: Levosimendan is a calcium-sensitizing inotropic agent recommended for Heart Failure (HF) treatment but contraindicated in patients with Creatinine Clearance (Ccr) below 30 mL/min. This study aims to systematically evaluate its efficacy and safety in patients with severe renal insufficiency. Methods: A systematic literature search was conducted in PubMed, Embase, and the Cochrane Library. Randomized Controlled Trials (RCTs) and cohort studies comparing the efficacy and safety of levosimendan in patients with severe renal insufficiency were included. Studies reporting outcomes only in patients with normal renal function or those with Ccr greater than 30 mL/min were excluded. The primary outcome was all-cause mortality. Discussion: The absence of mortality benefit may reflect levosimendan's altered pharmacokinetics and competing uremic risks in severe renal insufficiency. However, renoprotective mechanisms have been primarily characterized in populations without renal impairment, and the prolonged half-life of OR-1896 in this setting may potentiate both hemodynamic effects and adverse events. Conclusion: This study found that available evidence from small, heterogeneous observational studies is insufficient to determine whether levosimendan affects mortality in severe renal insufficiency. These findings do not support any clinical recommendation, provide no basis to modify the existing contraindication for Ccr below 30 mL/min, and highlight the need for further RCTs with comprehensive endpoints.