Thromboembolic Events in the Hemodialysis Setting: Understanding Risk Profiles and Cumulative Incidences to Inform Clinical Trial Design.

Background: People with kidney failure have a high risk of cardiovascular morbidity/death, including thromboembolic events. Factor XIa inhibitors are a new class of anticoagulants in development that may offer antithrombotic benefits with a lower risk of incremental bleeding events than traditional therapies. We investigated major adverse vascular events (MAVEs), a relevant composite outcome for testing novel antithrombotic agents, in a large cohort of patients on hemodialysis, to better understand the key requirements to adequately design a phase 3 trial.

EGR2 is an epigenomic regulator of phagocytosis and antifungal immunity in alveolar macrophages.

Alveolar macrophages (AMs) act as gatekeepers of the lung's immune responses, serving essential roles in recognizing and eliminating pathogens. The transcription factor (TF) early growth response 2 (EGR2) has been recently described as required for mature AMs in mice; however, its mechanisms of action have not been explored. Here, we identified EGR2 as an epigenomic regulator and likely direct proximal transcriptional activator in AMs using epigenomic approaches (RNA sequencing, ATAC sequencing, and CUT&RUN).

Results of the COMPASS Trial Analyzed Using Win Ratio Compared With Conventional Analytic Approaches.

Background: Win ratio (WR) is a newer analytic approach for trials with composite end points that accounts for the relative importance of individual components. Our objective was to compare the results of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial analyzed using WR with those obtained using conventional statistical approaches.

Methods: We used an unmatched WR analysis for first and total (first plus recurrent) events to examine effects of rivaroxaban with aspirin and rivaroxaban alone vs aspirin alone on primary efficacy (cardiovascular death, stroke, myocardial infarction), safety (modified International Society on Thrombosis and Haemostasis major bleeding), and net clinical benefit (primary efficacy plus fatal or critical organ bleeding) end points.

Risk of recurrent venous thromboembolism and major bleeding according to risk factor profiles in Asian patients: a subgroup analysis EINSTEIN-Extension and EINSTEIN-CHOICE.

Background: Risks of recurrence and major bleeding with extended anticoagulation in Asian patients with venous thromboembolism (VTE) are similar to those in non-Asian patients but risks according to baseline risk factor profiles is not well documented.

Methods: Subgroup analysis of two randomized trials, which compared once-daily rivaroxaban (20 mg or 10 mg) with placebo or aspirin (100 mg) for extended treatment in Asian patients with VTE who had completed 6-12 months of anticoagulation. Index events were classified as unprovoked, provoked by major persistent risk factors, minor persistent risk factors, minor transient risk factors, or major transient risk factors.

A Phase II randomized controlled trial evaluated antithrombotic treatment with fesomersen in patients with kidney failure on hemodialysis.

Patients with kidney failure on hemodialysis (KF-HD) are at high risk for both atherothrombotic events and bleeding. This Phase IIb study evaluated the dose-response of fesomersen, an inhibitor of hepatic Factor XI expression, versus placebo, for bleeding and atherothrombosis in patients with KF-HD. Patients were randomized to receive fesomersen 40, 80, or 120 mg once-monthly, or matching placebo, for up to 12 months.

Transglutaminase 2 associated with PI3K and PTEN in a membrane-bound signalosome platform blunts cell death.

Atypically expressed transglutaminase 2 (TG2) has been identified as a poor prognostic factor in a variety of cancers. In this study, we evaluated the contribution of TG2 to the prolonged cell survival of differentiated acute promyelocytic leukaemia (APL) cells in response to the standard treatment with combined retinoic acid (ATRA) and arsenic trioxide (ATO). We report that one advantage of ATRA + ATO treatment compared to ATRA alone diminishes the amount of activated and non-activated CD11b/CD18 and CD11c/CD18 cell surface integrin receptors.

Anticoagulation in pediatric cancer-associated venous thromboembolism: a subgroup analysis of EINSTEIN-Jr.

Anticoagulant treatment of pediatric cancer-associated venous thromboembolism (VTE) has not been prospectively evaluated. Management of anticoagulation for cancer-associated VTE is often challenged by drug interactions and treatment interruptions. A total of 56 of the 500 children (11.

Sex-specific differences in clot resolution 3 weeks after acute pulmonary embolism managed with anticoagulants-A substudy of the EINSTEIN-PE study.

Background: It is unknown whether differences in clot structure and resolution contribute to the reported risk differences of recurrent venous thromboembolism (VTE) between men and women.

Patients/methods: We used data from the EINSTEIN-PE study, a randomized, multicenter, non-inferiority study in which patients 18 years and older with acute symptomatic pulmonary embolism (PE) were randomized to rivaroxaban or enoxaparin followed by a vitamin K antagonist. PE was diagnosed by computed tomography pulmonary angiography scan or high-probability ventilation/perfusion scintigraphy.

Heavy menstrual bleeding in women on anticoagulant treatment for venous thromboembolism: Comparison of high- and low-dose rivaroxaban with aspirin.

Background: Rivaroxaban may induce heavy menstrual bleeding. It is unknown if this effect is dose related or if rivaroxaban is associated with more menstrual bleeding than aspirin.

Objectives: To demonstrate and compare menstrual patterns and actions taken among women receiving aspirin and two doses of rivaroxaban.

Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT).

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist).

Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety.

Background: The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described.

Safety and efficacy of anticoagulant therapy in pediatric catheter-related venous thrombosis (EINSTEIN-Jr CVC-VTE).

Anticoagulant treatment of pediatric central venous catheter-related venous thromboembolism (CVC-VTE) has not been specifically evaluated. In EINSTEIN-Jr, 500 children with any VTE received rivaroxaban or standard anticoagulants. A predefined analysis of the CVC-VTE cohort was performed.

Transglutaminase 2 Has Metabolic and Vascular Regulatory Functions Revealed by In Vivo Activation of Alpha1-Adrenergic Receptor.

The multifunctional tissue transglutaminase has been demonstrated to act as α1-adrenergic receptor-coupled G protein with GTPase activity in several cell types. To explore further the pathophysiological significance of this function we investigated the in vivo effects of the α1-adrenergic receptor agonist phenylephrine comparing responses in wild type and TG2 mice. Injection of phenylephrine, but not a beta3-adrenergic agonist (CL-316,243), resulted in the long-term decline of the respiratory exchange ratio and lower lactate concentration in TG2 mice indicating they preferred to utilize fatty acids instead of glucose as fuels.

Rivaroxaban in Peripheral Artery Disease after Revascularization.

Background: Patients with peripheral artery disease who have undergone lower-extremity revascularization are at high risk for major adverse limb and cardiovascular events. The efficacy and safety of rivaroxaban in this context are uncertain.

Methods: In a double-blind trial, patients with peripheral artery disease who had undergone revascularization were randomly assigned to receive rivaroxaban (2.

The effectiveness of filtering glycopeptide peak list files for Y ions.

Intact glycopeptide analysis is becoming more common with developments in mass spectrometry instrumentation and fragmentation approaches. In particular, collision-based fragmentation approaches such as higher energy collisional dissociation (HCD) and radical-driven fragmentation approaches such as electron transfer dissociation (ETD) provide complementary information, but bioinformatic strategies to utilize this combined information are currently lacking. In this work we adapted a software tool, MS-Filter, to search HCD peak list files for predicted Y ions based on matched EThcD results to propose additional glycopeptide assignments.

Novel O-linked sialoglycan structures in human urinary glycoproteins.

Glycopeptides represent cross-linked structures between chemically and physically different biomolecules. Mass spectrometric analysis of O-glycopeptides may reveal the identity of the peptide, the composition of the glycan and even the connection between certain sugar units, but usually only the combination of different MS/MS techniques provides sufficient information for reliable assignment. Currently, HCD analysis followed by diagnostic sugar fragment-triggered ETD or EThcD experiments is the most promising data acquisition protocol.

Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.

Background: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism.

Methods: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist).

Safety and efficacy of the partial adenosine A1 receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced ejection fraction: a phase IIb, randomized, double-blind, placebo-controlled trial.

Aims: Neladenoson bialanate is a partial adenosine A1 receptor agonist with demonstrated beneficial effects on cardiac function in animal models. We aimed to assess the dose-response effect of neladenoson bialanate on cardiac structure and function, clinical outcome, and safety in patients with heart failure (HF) with reduced ejection fraction (HFrEF).

Methods And Results: PANTHEON was a dose-finding, phase IIb, randomized, double-blind, placebo-controlled trial conducted in 92 centres in 11 countries including 462 patients with chronic HFrEF, randomized to once daily oral dose of neladenoson bialanate (5, 10, 20, 30, and 40 mg) or placebo.

Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies.

Background: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents.

Methods: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years.

The BACH1-HMOX1 Regulatory Axis Is Indispensable for Proper Macrophage Subtype Specification and Skeletal Muscle Regeneration.

The infiltration and subsequent in situ subtype specification of monocytes to effector/inflammatory and repair macrophages is indispensable for tissue repair upon acute sterile injury. However, the chromatin-level mediators and regulatory events controlling this highly dynamic macrophage phenotype switch are not known. In this study, we used a murine acute muscle injury model to assess global chromatin accessibility and gene expression dynamics in infiltrating macrophages during sterile physiological inflammation and tissue regeneration.

Analysis of microRNA expression in brush cytology specimens improves the diagnosis of pancreatobiliary cancer.

Background/objectives: Malignant pancreatobiliary strictures are in many cases clinically indistinguishable and present a major problem to endoscopy specialists. Intraductal sampling procedures such as brush cytology are commonly used for diagnosis with a sensitivity that is low for a diagnostic test used in daily clinical practice. MicroRNA (miR) alterations detected in many cancers are disease-specific, which can be utilized in clinical applications.