Bivalirudin versus heparin in patients with or without bail-out GPI use: a pre-specified subgroup analysis from the BRIGHT-4 trial.

BACKGROUND: Conflicting results comparing bivalirudin versus heparin anticoagulation in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), in part due to the confounding effect of glycoprotein IIb/IIIa inhibitors (GPI). The aim of the study was to compare the safety and effectiveness of bivalirudin plus a post-PCI high-dose infusion vs heparin with or without bail-out GPI use. METHODS: We conducted a pre-specified subgroup analysis from the BRIGHT-4 trial that randomized 6016 STEMI patients who underwent primary PCI to receive either bivalirudin plus a post-PCI high-dose infusion for 2-4 h or heparin monotherapy. GPI use was only reserved as bail-out therapy for procedural thrombotic complications. The primary outcome was a composite of all-cause death or Bleeding Academic Research Consortium (BARC) types 3-5 bleeding at 30 days. RESULTS: A total of 5250 (87.4%) patients received treatment without GPI while 758 (12.6%) received bail-out GPI. Bail-out GPI use was associated with an increased risk of the primary outcome compared to non-GPI use (5.28% vs. 3.41%; adjusted hazard ratio (aHR), 1.62; 95% confidence interval (CI), 1.13-2.33; P = 0.009) and all-cause death (5.01% vs. 3.12%; aHR, 1.74; 95% CI, 1.20-2.52; P = 0.004) but not in the risk of BARC types 3-5 bleeding (0.53% vs. 0.48%; aHR, 0.90; 95% CI, 0.31-2.66; P = 0.85). Among patients without GPI use, bivalirudin was associated with lower rates of the primary outcome (2.63% vs. 4.21%; aHR, 0.55; 95% CI, 0.39-0.77; P = 0.0005), all-cause death (2.52% vs. 3.74%; aHR, 0.58; 95% CI, 0.41-0.83; P = 0.003), and BARC types 3-5 bleeding (0.15% vs. 0.81%; aHR, 0.19; 95% CI, 0.06-0.57; P = 0.003) compared with heparin. However, among patients requiring bail-out GPI, there were no significant differences observed in the rates of the primary outcome (5.76% vs. 4.87%; aHR, 0.77; 95% CI, 0.36-1.66; P = 0.50; Pinteraction = 0.07) or its individual components between bivalirudin and heparin groups. CONCLUSIONS: Bivalirudin plus a post-PCI high-dose infusion was associated with significantly reduced 30-day composite rate of all-cause death or BARC types 3-5 bleeding compared with heparin monotherapy in STEMI patients undergoing primary PCI without GPI use. However, these benefits might be less pronounced in patients requiring bail-out GPI due to thrombotic complications during primary PCI. TRIAL REGISTRATION: ClinicalTrials.gov NCT03822975.

Gab1 Overexpression Attenuates Susceptibility to Ventricular Arrhythmias in Pressure Overloaded Heart Failure Mouse Hearts.

PURPOSE: Grb2 associated binding protein 1 (Gab1) is an adaptor protein that is important for intracellular signal transduction which involved in several pathological process. However, the role of Gab1 in pressure overload-induced ventricular arrhythmias (VAs) remain poorly understood. In the current study, we aimed to test the role of Gab1 in VA susceptibility induced by pressure overload. METHODS: We overexpressed Gab1 in the hearts using an adeno-associated virus 9 (AAV9) system through tail vein injection. Aortic banding (AB) surgery was performed in C57BL6/J mice to induce heart failure (HF). Four weeks following AB, histology, echocardiography, and biochemical analysis were conducted to investigate cardiac structural remodeling and electrophysiological studies were performed to check the electrical remodeling. Western blot analysis was used to explore the underlying mechanisms. RESULTS: The mRNA and protein expression were downregulated in AB hearts compared to sham hearts. Gab1 overexpression significantly reversed AB-induced cardiac structural remodeling including ameliorated AB-induced cardiac dysfunction, cardiac fibrosis, and inflammatory response. Moreover, Gab1 overexpression also markedly alleviated AB-induced electrical remodeling including ion channel alterations and VA susceptibility. Mechanistically, we found that TLR4/MyD88/NF-κB contributes to the cardio protective effect of Gab1 overexpression on AB-induced VAs. CONCLUSIONS: Our study manifested that Gab1 may serve as a promising anti-arrhythmic target via inhibiting TLR4/MyD88/NF-κB signaling pathway induced by AB.

Fate alteration of bone marrow-derived macrophages ameliorates kidney fibrosis in murine model of unilateral ureteral obstruction.

BACKGROUND: Renal fibrosis is a key pathological feature and final common pathway leading to end-stage kidney failure in many chronic kidney diseases. Myofibroblast is the master player in renal fibrosis. However, myofibroblasts are heterogeneous. Recent studies show that bone marrow-derived macrophages transform into myofibroblasts by transforming growth factor (TGF)-ß-induced macrophage-myofibroblast transition (MMT) in renal fibrosis. METHODS: TGF-ß signaling was redirected by inhibition of ß-catenin/T-cell factor (TCF) to increase ß-catenin/Foxo in bone marrow-derived macrophages. A kidney fibrosis model of unilateral ureteral obstruction was performed in EGFP bone marrow chimera mouse. MMT was examined by flow cytometry analysis of GFP+F4/80+α-SMA+ cells from unilateral ureteral obstruction (UUO) kidney, and by immunofluorescent staining of bone marrow-derived macrophages in vitro. Inflammatory and anti-inflammatory cytokines were analysis by enzyme-linked immunosorbent assay. RESULTS: Inhibition of ß-catenin/TCF by ICG-001 combined with TGF-ß1 treatment increased ß-catenin/Foxo1, reduced the MMT and inflammatory cytokine production by bone marrow-derived macrophages, and thereby, reduced kidney fibrosis in the UUO model. CONCLUSIONS: Our results demonstrate that diversion of ß-catenin from TCF to Foxo1-mediated transcription not only inhibits the ß-catenin/TCF-mediated fibrotic effect of TGF-ß, but also enhances its anti-inflammatory action, allowing therapeutic use of TGF-ß to reduce both inflammation and fibrosis at least partially by changing the fate of bone marrow-derived macrophages.

Bioavailability assessment of difenoconazole to earthworms (Eisenia fetida) in soil by oleic acid-embedded cellulose acetate membrane.

Passive sampling technology is widely used to evaluate the bioavailability of pollutants. However, relatively few studies have used passive sampling membranes (PSMs) to evaluate the environmental risks of pollutants in soil, particularly pesticides. Here, the bioavailability of difenoconazole to earthworms (Eisenia fetida) was evaluated using an oleic acid-embedded cellulose acetate membrane (OECAM) for the first time. Difenoconazole reached 94 % equilibrium (T94%) within 1 d in OECAM. For soil pore water, the freely dissolved concentration (Cfree) of difenoconazole was determined using OECAM (R2 = 0.969). In the soil system, a strong linear correlation between the difenoconazole concentration in OECAM and earthworms was observed (R2 = 0.913). The bioavailability of difenoconazole was affected by the soil type and biochar content. The higher the content of soil organic matter and biochar, the lower the concentration of difenoconazole in earthworms, OECAM, and soil pore water. The concentrations of difenoconazole in pore water, earthworms, and OECAM decreased by 65.3, 42.0, and 41.6 %, respectively, when 0.5 % biochar was added. Difenoconazole mainly enters OECAM and earthworms through passive diffusion with similar uptake pathways. Therefore, the bioavailability of difenoconazole to earthworms in different soils can be evaluated using the OECAM.

Enhanced Catalysis of P-doped SnO2 for the V2+/V3+ Redox Reaction in Vanadium Redox Flow Battery.

In this work, nanosized P-doped SnO2 (SnO2-P) was prepared by a sol-gel method as a catalyst for the V3+/V2+ redox reaction in vanadium redox flow battery. Compared with SnO2, the electrochemical performance of SnO2-P is significantly improved. This is because P doping provides more active sites and shows greatly improved electrical conductivity, thereby increasing the electron transfer rate. As a result, SnO2-P shows better catalytic performance than SnO2. The SnO2-P modified cell is designed, and it exhibits an increase of 47.2 mA h in discharge capacity and 8.7% in energy efficiency compared with the pristine cell at 150 mA cm-2. These increases indicate that the modified cell has a higher electrolyte utilization rate. This study shows that SnO2-P is a new and efficient catalyst for vanadium redox flow battery.

Synergistic Catalysis of SnO2-CNTs Composite for VO 2 + /VO2+ and V2+/V3+ Redox Reactions.

In this study, a SnO2-carbon nanotube (SnO2-CNT) composite as a catalyst for vanadium redox flow battery (VRFB) was prepared using a sol-gel method. The effects of this composite on the electrochemical performance of VO 2 + /VO2+, and on the V2+/V3+ redox reactions and VRFB performance were investigated. The SnO2-CNT composite has better catalytic activity than pure SnO2 and CNT due to the synergistic catalysis of SnO2 and the CNT. SnO2 mainly provides the catalytic active sites and the CNTs mainly provide the three-dimensional structure and high electrical conductivity. Therefore, the SnO2-CNT composite has a larger specific surface area and an excellent synergistic catalytic performance. For cell performance, it was found that the SnO2-CNT cell shows a greater discharge capacity and energy efficiency. In particular, at 150 mA cm-2, the discharge capacity of the SnO2-CNT cell is 28.6 mAh higher than that of the pristine cell. The energy efficiency of the modified cell (7%) is 7.2% higher than that of the pristine cell (62.8%). This study shows that the SnO2-CNT is an efficient and promising catalyst for VRFB.

One-step activation of high-graphitization N-doped porous biomass carbon as advanced catalyst for vanadium redox flow battery.

In this paper, we reported a one-step activation strategy to prepare highly graphitized N-doped porous carbon materials (KDC-FAC) derived from biomass, and adopted ferric ammonium citrate (FAC) as active agent. At high temperature, FAC was decomposed into Fe- and NH3-based materials, further increasing graphitization degree, introducing N-containing functional groups and forming porous structure. KDC-FAC has superior electrocatalytic activity and stability towards V2+/V3+ and VO2+/VO2+ redox reactions. High graphitization degree can enhance the conductivity of carbon material, and porous structure is conducive to increase reaction area of vanadium redox couples. Moreover, N-containing functional groups are beneficial to improve the electrode wettability and serve as active sites. The single cell tests demonstrate that KDC-FAC modified cell exhibits good adaptability under high current density and superb stability in cycling test. Compared with pristine cell, the energy efficiency of KDC-FAC modified cell is increased by 9% at 150 mA cm-2. This biomass-derived carbon-based material proposed in our work is expected to be an excellent catalyst for vanadium redox flow battery.