BACKGROUNDAlthough many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full-or lower-intensity anticoagulation therapy or aspirin. METHODSIn this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. RESULTSA total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups. CONCLUSIONSAmong patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439.) a bs tr ac t

IMPORTANCEThe efficacy of factor XIa inhibition for thromboprophylaxis is unknown. Osocimab is a long-acting, fully human monoclonal antibody that inhibits factor XIa.OBJECTIVE To compare different doses of osocimab with enoxaparin and apixaban for thromboprophylaxis in patients who have undergone knee arthroplasty. DESIGN, SETTING, AND PARTICIPANTSRandomized, open-label, adjudicator-blinded, phase 2 noninferiority trial with observer blinding for osocimab doses, conducted at 54 hospitals in 13 countries. Adult patients undergoing unilateral knee arthroplasty were randomized from October 2017 through August 2018 and followed up until January 2019.INTERVENTIONS Single intravenous osocimab postoperative doses of 0.3 mg/kg (n = 107), 0.6 mg/kg (n = 65), 1.2 mg/kg (n = 108), or 1.8 mg/kg (n = 106); preoperative doses of 0.3 mg/kg (n = 109) or 1.8 mg/kg (n = 108); or 40 mg of subcutaneous enoxaparin once daily (n = 105) or 2.5 mg of oral apixaban twice daily (n = 105) for at least 10 days or until venography. MAIN OUTCOMES AND MEASURESThe primary outcome was venous thromboembolism incidence between 10 and 13 days postoperatively (assessed by mandatory bilateral venography performed 10 to 13 days after surgery or confirmed symptomatic deep vein thrombosis or pulmonary embolism). A 5% noninferiority margin compared with enoxaparin was chosen. The primary safety outcome of major or clinically relevant nonmajor bleeding was assessed until 10 to 13 days postoperatively. RESULTSOf 813 randomized participants (mean [SD] age, 66.5 years [8.2 years]; body mass index, 32.7 [5.7]; and 74.2% women), 600 were included in the per-protocol population used for the primary analysis. The primary outcome occurred in 18 patients (23.7%) receiving 0.3 mg/kg, 8 (15.7%) receiving 0.6 mg/kg, 13 (16.5%) receiving 1.2 mg/kg, and 14 (17.9%) receiving 1.8 mg/kg of osocimab postoperatively; 23 (29.9%) receiving 0.3 mg/kg and 9 (11.3%) receiving 1.8 mg/kg of osocimab preoperatively; 20 (26.3%) receiving enoxaparin; and 12 (14.5%) receiving apixaban. Osocimab given postoperatively met criteria for noninferiority compared with enoxaparin with risk differences (1-sided 95% CIs) of 10.6% (95% CI, -1.2% to ϱ) at the 0.6-mg/kg dose; 9.9% (95% CI, -0.9% to ϱ) at the 1.2-mg/kg dose, and 8.4% (95% CI, -2.6 to ϱ) at the 1.8-mg/kg dose. The preoperative dose of 1.8 mg/kg of osocimab met criteria for superiority compared with enoxaparin with a risk difference of 15.1%; 2-sided 90% CI, 4.9% to 25.2%). Postoperative and preoperative doses of 0.3 mg/kg of osocimab did not meet the prespecified criteria for noninferiority, with risk differences (1-sided 95% CIs) of 2.6% (95% CI, -8.9% to ϱ) and -3.6% (95% CI, -15.5% to ϱ), respectively. Major or clinically relevant nonmajor bleeding was observed in up to 4.7% of those receiving osocimab, 5.9% receiving enoxaparin, and 2% receiving apixaban.CONCLUSIONS AND RELEVANCE Among patients undergoing knee arthroplasty, postoperative osocimab 0.6 mg/kg, 1.2 mg/kg, and 1.8 mg/kg met criteria for noninferiority compared with ...

We have shown that activation of toll-like receptor 4 (TLR4) and its interferon regulatory factor 3 (IRF3)-dependent downstream signaling pathway are required for the development of liver ischemia/reperfusion injury (IRI). This study focused on the role of TLR4-IRF3 activation pathway products, in particular, chemokine (C-X-C motif) ligand 10 (CXCL10). The induction of CXCL10 by liver IR was rapid (1 hour postreperfusion), restricted (ischemic lobes), and specific (no CXCL9 and CXCL11 induction). I schemia/reperfusion injury (IRI) develops in the absence of exogenous Ag, and innate immunity has been thought to play a dominant pathogenic role. [1][2][3] Liver ischemia activates Kupffer cells, and to a lesser degree endothelial cells as well as hepatocytes, leading to the formation of reactive oxygen species and secretion of proinflammatory cytokines/chemokines. The oxidant stress directly damages endothelial cells/hepatocytes, whereas the soluble factors are largely responsible for leukocyte recruitment and activation, leading to the full development of intrahepatic inflammation causing further organ damage. Although excessive pro-inflammatory response has been recognized as the key element leading to IRI, the mechanisms that initiate and regulate liver inflammation cascade remain to be elucidated.We and others have reported that mammalian sentinel receptor toll-like receptor 4 (TLR4) is involved in the initiation of IRI. [4][5][6][7] We found that livers in TLR4 knockout (KO) mice were protected from IRI and associated inflammation. 4-7 Furthermore, MyD88-independent signaling mediated by IRF3, downstream of TLR4 activation, was critical, because mice deficient in interferon regulatory factor 3 (IRF3) but not MyD88 were protected from IRI. 5 MyD88-dependent signaling in TLR4 activation pathway leads to direct nuclear factor kappa B activation and induction of pro-inflammatory cytokines, whereas the IRF3-mediated signaling induces type 1 IFN

The presence of de novo persistent, complement-binding DQ DSA negatively impacts kidney allograft outcomes. Therefore, early posttransplantation detection, monitoring, and removal of complement-binding DQ might be crucial for improving long-term kidney transplantation outcomes.

The newly discovered T-cell immunoglobulin mucin (TIM) gene family molecules, expressed by T cells, regulate host immunity and tolerance. Although CD4+ T cells mediate innate immunity-dominated liver ischemia-reperfusion injury (IRI), the underlying mechanisms remain obscure. We have recently documented the novel function of TIM-1 pathway in the mechanism of liver IRI and also found that TLR4 activation plays a key triggering role. Using an anti-TIM-3 Ab, we now studied the role of TIM-3 signaling in the model of partial warm liver ischemia followed by reperfusion. Anti-TIM-3 Ab therapy exacerbated the liver damage, as compared with controls. Histological examination has revealed that anti-TIM-3 Ab augmented the hepatocellular damage, increased local neutrophil infiltration, facilitated local accumulation of T cells/macrophages and promoted liver cell apoptosis. Intrahepatic neutrophil activity, induction of pro-inflammatory cytokines/chemokines and expression of cleaved caspase-3/NF-NB/TLR4 were all increased in the treatment group. In parallel, anti-TIM-3 Ab and anti-galectin-9 (Gal-9; TIM-3 ligand) Ab increased IFN-γ production in ConA-stimulated spleen T cells, and TNFα/IL-6 expression in ConA-stimulated macrophage/T cell co-culture system. Interestingly, anti-TIM-3 Ab treatment did not affect liver IRI in TLR4-deficient (KO) mice. In conclusion, TIM-3 blockade exacerbated local inflammation and liver damage, suggesting importance of TIM-3/Gal-9 signaling in the maintenance of hepatic homeostasis. TIM-3-TLR4 cross regulation determined the severity of liver IRI in TLR4-dependent manner, a novel finding of potential importance to modulate tissue innate vs. adaptive responses in liver transplant patients. Thus, harnessing physiological negative T cell co-stimulation signaling on hepatic T cells may minimize innate immunity-mediated liver tissue damage.