Supporting Treatment decision making to Optimise the Prevention of STROKE in Atrial Fibrillation: The STOP STROKE in AF study. Protocol for a cluster randomised controlled trial

Background: Suboptimal uptake of anticoagulation for stroke prevention in atrial fibrillation has persisted for over 20 years, despite high-level evidence demonstrating its effectiveness in reducing the risk of fatal and disabling stroke.Methods: The STOP STROKE in AF study is a national, cluster randomised controlled trial designed to improve the uptake of anticoagulation in primary care. General practitioners from around Australia enrolling in this \u27distance education\u27 program are mailed written educational materials, followed by an academic detailing session delivered via telephone by a medical peer, during which participants discuss patient de-identified cases. General practitioners are then randomised to receive written specialist feedback about the patient de-identified cases either before or after completing a three-month posttest audit. Specialist feedback is designed to provide participants with support and confidence to prescribe anticoagulation. The primary outcome is the proportion of patients with atrial fibrillation receiving oral anticoagulation at the time of the posttest audit.Discussion: The STOP STROKE in AF study aims to evaluate a feasible intervention via distance education to prevent avoidable stroke due to atrial fibrillation. It provides a systematic test of augmenting academic detailing with expert feedback about patient management.Trial registration: Australian Clinical Trials Registry Registration Number: ACTRN12611000076976. 2012 Gattellari et al.; licensee BioMed Central Ltd

Study protocol: The DESPATCH study: Delivering stroke prevention for patients with atrial fibrillation - a cluster randomised controlled trial in primary healthcare

Background: Compelling evidence shows that appropriate use of anticoagulation in patients with nonvalvular atrial fibrillation reduces the risk of ischaemic stroke by 67% and all-cause mortality by 26%. Despite this evidence, anticoagulation is substantially underused, resulting in avoidable fatal and disabling strokes.Methods: DESPATCH is a cluster randomised controlled trial with concealed allocation and blinded outcome assessment designed to evaluate a multifaceted and tailored implementation strategy for improving the uptake of anticoagulation in primary care. We have recruited general practices in South Western Sydney, Australia, and randomly allocated practices to receive the DESPATCH intervention or evidence-based guidelines (control). The intervention comprises specialist decisional support via written feedback about patient-specific cases, three academic detailing sessions (delivered via telephone), practice resources, and evidence-based information. Data for outcome assessment will be obtained from a blinded, independent medical record audit. Our primary endpoint is the proportion of nonvalvular atrial fibrillation patients, over 65 years of age, receiving oral anticoagulation at any time during the 12-month posttest period.Discussion: Successful translation of evidence into clinical practice can reduce avoidable stroke, death, and disability due to nonvalvular atrial fibrillation. If successful, DESPATCH will inform public policy, providing quality evidence for an effective implementation strategy to improve management of nonvalvular atrial fibrillation, to close an important evidence-practice gap.Trial registration: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12608000074392. 2011 Gattellari et al; licensee BioMed Central Ltd

Mesenchymal stromal cells:inhibiting PDGF receptors or depleting fibronectin induces mesodermal progenitors with endothelial potential

Realizing the full therapeutic potential of mesenchymal stromal/stem cells (MSCs) awaits improved understanding of mechanisms controlling their fate. Using MSCs cultured as spheroids to recapitulate a three-dimensional cellular environment, we show that perturbing the mesenchymal regulators, platelet-derived growth factor (PDGF) receptors or fibronectin, reverts MSCs toward mesodermal progenitors with endothelial potential that can potently induce neovascularization in vivo. MSCs within untreated spheroids retain their mesenchymal spindle shape with abundant smooth muscle α-actin filaments and fibronectin-rich matrix. Inhibiting PDGF receptors or depleting fibronectin induces rounding and depletes smooth muscle α-actin expression; these cells have characteristics of mesenchymoangioblasts, with enhanced expression of mesendoderm and endoderm transcription factors, prominent upregulation of E-cadherin, and Janus kinase signaling-dependent expression of Oct4A and Nanog. PDGF receptor-inhibited spheroids also upregulate endothelial markers platelet endothelial cell adhesion molecule 1 and vascular endothelial-cadherin and secrete many angiogenic factors, and in vivo they potently stimulate neovascularization, and their MSCs integrate within functional blood vessels that are perfused by the circulation. Thus, MSC potency and vascular induction are regulated by perturbing mesenchymal fate

Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity

The intestinal epithelium must balance efficient absorption of nutrients with partitioning commensals and pathogens from the bodies’ largest immune system. If this crucial barrier fails, inappropriate immune responses can result in inflammatory bowel disease or chronic infection. Enteroendocrine cells represent 1% of this epithelium and have classically been studied for their detection of nutrients and release of peptide hormones to mediate digestion. Intriguingly, enteroendocrine cells are the key sensors of microbial metabolites, can release cytokines in response to pathogen associated molecules and peptide hormone receptors are expressed on numerous intestinal immune cells; thus enteroendocrine cells are uniquely equipped to be crucial and novel orchestrators of intestinal inflammation. In this review, we introduce enteroendocrine chemosensory roles, summarize studies correlating enteroendocrine perturbations with intestinal inflammation and describe the mechanistic interactions by which enteroendocrine and mucosal immune cells interact during disease; highlighting this immunoendocrine axis as a key aspect of innate immunity

Brachiaria Hybrids with Larger Root Length Densities Show Greater Shoot Vigor under Drought

Brachiaria grasses are the most widely planted forages in Tropical America, and their demand is increasing across Africa and South-East Asia. One of the most limiting factors affecting productivity of Brachiaria forage grasses is seasonal drought. Genotypic variation for drought resistance has been found among Brachiaria forage grasses, making possible to genetically improve the productivity of Brachiaria forage grasses under water-limiting conditions (Rao, 2014). The ongoing Brachiaria breeding program at the International Center for Tropical Agriculture (CIAT) has been developing and testing Brachiaria hybrids that combine resistance to biotic constraints with adaptation to abiotic stresses such as drought. Adaptation to drought conditions greatly relies on an efficient root system that facilitates water capture in drying soil. Among root traits, greater root length density (the length of roots per unit volume of soil, RLD cm/cm3) generally indicates greater ability for water uptake in drying soil (Wasson et al., 2012). Screening of forage germplasm for resistance to drought conditions has often overlooked root traits. This is because of the difficulty to separate roots out of soil, which inevitably ends up in a very low-through-put system. However, new imaging techniques allow rapid estimation and quantification of RLD within the soil (i.e., without the need to separate roots from soil). The following work was therefore performed to evaluate the variation in dry mass, water uptake and RLD of 103 hybrids of Brachiaria after three weeks of growth under drought conditions. We hypothesized that hybrids with greater RLD could extract (particularly with increasing depth) more water in drying soil, which in turn is reflected in greater shoot dry mass production after three weeks of drought treatment

Numerical study of the strongly screened vortex glass model in an external field

The vortex glass model for a disordered high-T_c superconductor in an external magnetic field is studied in the strong screening limit. With exact ground state (i.e. T=0) calculations we show that 1) the ground state of the vortex configuration varies drastically with infinitesimal variations of the strength of the external field, 2) the minimum energy of global excitation loops of length scale L do not depend on the strength of the external field, however 3) the excitation loops themself depend sensibly on the field. From 2) we infer the absence of a true superconducting state at any finite temperature independent of the external field.Comment: 6 pages RevTeX, 5 eps-figures include

Regulation of Nitrification in Soil: Advances in Integration of \u3cem\u3eBrachiaria\u3c/em\u3e Hybrids to Intensify Agriculture and to Mitigate Climate Change

Higher rates of nitrification in soil facilitate nitrogen (N) losses from agricultural systems through nitrate-leaching and denitrification. Plants’ ability to produce and release nitrification inhibitors from roots and suppress soil-nitrifier activity is termed ‘biological nitrification inhibition’ (BNI) (Subbarao et al., 2015). Up to 70% of applied N-fertilizer is lost (via NO3−leaching and gaseous-N emissions) from agricultural systems and the annual economic loss from lost N-fertilizer is estimated at 90 US$ billion. Previous research has indicated that Brachiaria humidicola (Bh), a tropical forage grass that is well adapted to infertile and waterlogged soils, has high capacity to inhibit nitrification in soil and reduce emissions of a highly potent greenhouse gas, nitrous oxide (N2O) (Subbarao et al., 2009). CIAT has an on-going Brachiaria breeding program that generates interspecific (B. decumbens, B. brizantha, B. ruziziensis) and intraspecific (Bh) hybrids that combine several desirable attributes. An interinstitutional and multidisciplinary project was initiated in 2012 to integrate Brachiaria hybrids into crop-livestock systems of smallholders to improve livestock productivity and mitigate climate change by reducing nitrification in soil (Rao et al., 2014). Here we report the major advances from the last three years of work from this project

Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti-Cyclic Citrullinated Peptide-Negative Rheumatoid Arthritis

OBJECTIVE: Genetic polymorphisms within the HLA region explain only a modest proportion of anti-cyclic citrullinated peptide (anti-CCP)-negative rheumatoid arthritis (RA) heritability. However, few non-HLA markers have been identified so far. This study was undertaken to replicate the associations of anti-CCP-negative RA with non-HLA genetic polymorphisms demonstrated in a previous study. METHODS: The Rheumatoid Arthritis Consortium International densely genotyped 186 autoimmune-related regions in 3,339 anti-CCP-negative RA patients and 15,870 controls across 6 different populations using the Illumina ImmunoChip array. We performed a case-control replication study of the anti-CCP-negative markers with the strongest associations in that discovery study, in an independent cohort of anti-CCP-negative UK RA patients. Individuals from the arcOGEN Consortium and Wellcome Trust Case Control Consortium were used as controls. Genotyping in cases was performed using Sequenom MassArray technology. Genome-wide data from controls were imputed using the 1000 Genomes Phase I integrated variant call set release version 3 as a reference panel. RESULTS: After genotyping and imputation quality control procedures, data were available for 15 non-HLA single-nucleotide polymorphisms in 1,024 cases and 6,348 controls. We confirmed the known markers ANKRD55 (meta-analysis odds ratio [OR] 0.80; P = 2.8 × 10(-13) ) and BLK (OR 1.13; P = 7.0 × 10(-6) ) and identified new and specific markers of anti-CCP-negative RA (prolactin [PRL] [OR 1.13; P = 2.1 × 10(-6) ] and NFIA [OR 0.85; P = 2.5 × 10(-6) ]). Neither of these loci is associated with other common, complex autoimmune diseases. CONCLUSION: Anti-CCP-negative RA and anti-CCP-positive RA are genetically different disease subsets that only partially share susceptibility factors. Genetic polymorphisms located near the PRL and NFIA genes represent examples of genetic susceptibility factors specific for anti-CCP-negative RA

PADI4 genotype is not associated with rheumatoid arthritis in a large UK Caucasian population

BACKGROUND: Polymorphisms of the peptidylarginine deiminase type 4 (PADI4) gene confer susceptibility to rheumatoid arthritis (RA) in East Asian people. However, studies in European populations have produced conflicting results. This study explored the association of the PADI4 genotype with RA in a large UK Caucasian population. METHODS: The PADI4_94 (rs2240340) single nucleotide polymorphism (SNP) was directly genotyped in a cohort of unrelated UK Caucasian patients with RA (n=3732) and population controls (n=3039). Imputed data from the Wellcome Trust Case Control Consortium (WTCCC) was used to investigate the association of PADI4_94 with RA in an independent group of RA cases (n=1859) and controls (n=10 599). A further 56 SNPs spanning the PADI4 gene were investigated for association with RA using data from the WTCCC study. RESULTS: The PADI4_94 genotype was not associated with RA in either the present cohort or the WTCCC cohort. Combined analysis of all the cases of RA (n=5591) and controls (n=13 638) gave an overall OR of 1.01 (95% CI 0.96 to 1.05, p=0.72). No association with anti-CCP antibodies and no interaction with either shared epitope or PTPN22 was detected. No evidence for association with RA was identified for any of the PADI4 SNPs investigated. Meta-analysis of previously published studies and our data confirmed no significant association between the PADI4_94 genotype and RA in people of European descent (OR 1.06, 95% CI 0.99 to 1.13, p=0.12). CONCLUSION: In the largest study performed to date, the PADI4 genotype was not a significant risk factor for RA in people of European ancestry, in contrast to Asian populations