The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

<it>Lactobacillus acidophilus </it>induces a slow but more sustained chemokine and cytokine response in naïve foetal enterocytes compared to commensal <it>Escherichia coli</it>

<p>Abstract</p> <p>Background</p> <p>The first exposure to microorganisms at mucosal surfaces is critical for immune maturation and gut health. Facultative anaerobic bacteria are the first to colonise the infant gut, and the impact of these bacteria on intestinal epithelial cells (IEC) may be determinant for how the immune system subsequently tolerates gut bacteria.</p> <p>Results</p> <p>To mirror the influence of the very first bacterial stimuli on infant IEC, we isolated IEC from mouse foetuses at gestational day 19 and from germfree neonates. IEC were stimulated with gut-derived bacteria, Gram-negative <it>Escherichia coli </it>Nissle and Gram-positive <it>Lactobacillus acidophilus </it>NCFM, and expression of genes important for immune regulation was measured together with cytokine production. <it>E. coli </it>Nissle and <it>L. acidophilus </it>NCFM strongly induced chemokines and cytokines, but with different kinetics, and only <it>E. coli </it>Nissle induced down-regulation of Toll-like receptor 4 and up-regulation of Toll-like receptor 2. The sensitivity to stimulation was similar before and after birth in germ-free IEC, although Toll-like receptor 2 expression was higher before birth than immediately after.</p> <p>Conclusions</p> <p>In conclusion, IEC isolated before gut colonisation occurs at birth, are highly responsive to stimulation with gut commensals, with <it>L. acidophilus </it>NCFM inducing a slower, but more sustained response than <it>E. coli </it>Nissle. <it>E. coli </it>may induce intestinal tolerance through very rapid up-regulation of chemokine and cytokine genes and down-regulation of Toll-like receptor 4, while regulating also responsiveness to Gram-positive bacteria.</p

Collagen induces maturation of human monocyte-derived dendritic cells by signaling through osteoclast-associated receptor

Osteoclast-associated receptor (OSCAR) is widely expressed on human myeloid cells. Collagen types (Col)I, II, and III have been described as OSCAR ligands, and ColII peptides can induce costimulatory signaling in receptor activator for NF-κB–dependent osteoclastogenesis. In this study, we isolated collagen as an OSCAR-interacting protein from the membranes of murine osteoblasts. We have investigated a functional outcome of the OSCAR–collagen interaction in human monocyte-derived dendritic cells (DCs). OSCAR engagement by ColI/II-induced activation/maturation of DCs is characterized by upregulation of cell surface markers and secretion of cytokines. These collagen-matured DCs (Col-DCs) were efficient drivers of allogeneic and autologous naive T cell proliferation. The T cells expanded by Col-DCs secreted cytokines with no clear T cell polarization pattern. Global RNA profiling revealed that multiple proinflammatory mediators, including cytokines and cytokine receptors, components of the stable immune synapse (namely CD40, CD86, CD80, and ICAM-1), as well as components of TNF and TLR signaling, are transcriptional targets of OSCAR in DCs. Our findings indicate the existence of a novel pathway by which extracellular matrix proteins locally drive maturation of DCs during inflammatory conditions, for example, within synovial tissue of rheumatoid arthritis patients, where collagens become exposed during tissue remodeling and are thus accessible for interaction with infiltrating precursors of DCs