Methodology for the development of a Canadian national EMS research agenda

<p>Abstract</p> <p>Background</p> <p>Many health care disciplines use evidence-based decision making to improve patient care and system performance. While the amount and quality of emergency medical services (EMS) research in Canada has increased over the past two decades, there has not been a unified national plan to enable research, ensure efficient use of research resources, guide funding decisions and build capacity in EMS research. Other countries have used research agendas to identify barriers and opportunities in EMS research and define national research priorities. The objective of this project is to develop a national EMS research agenda for Canada that will: 1) explore what barriers to EMS research currently exist, 2) identify current strengths and opportunities that may be of benefit to advancing EMS research, 3) make recommendations to overcome barriers and capitalize on opportunities, and 4) identify national EMS research priorities.</p> <p>Methods/Design</p> <p>Paramedics, educators, EMS managers, medical directors, researchers and other key stakeholders from across Canada will be purposefully recruited to participate in this mixed methods study, which consists of three phases: 1) qualitative interviews with a selection of the study participants, who will be asked about their experience and opinions about the four study objectives, 2) a facilitated roundtable discussion, in which all participants will explore and discuss the study objectives, and 3) an online Delphi consensus survey, in which all participants will be asked to score the importance of each topic discovered during the interviews and roundtable as they relate to the study objectives. Results will be analyzed to determine the level of consensus achieved for each topic.</p> <p>Discussion</p> <p>A mixed methods approach will be used to address the four study objectives. We anticipate that the keys to success will be: 1) ensuring a representative sample of EMS stakeholders, 2) fostering an open and collaborative roundtable discussion, and 3) adhering to a predefined approach to measure consensus on each topic. Steps have been taken in the methodology to address each of these <it>a priori </it>concerns.</p

A comprehensive candidate gene approach identifies genetic variation associated with osteosarcoma

<p>Abstract</p> <p>Background</p> <p>Osteosarcoma (OS) is a bone malignancy which occurs primarily in adolescents. Since it occurs during a period of rapid growth, genes important in bone formation and growth are plausible modifiers of risk. Genes involved in DNA repair and ribosomal function may contribute to OS pathogenesis, because they maintain the integrity of critical cellular processes. We evaluated these hypotheses in an OS association study of genes from growth/hormone, bone formation, DNA repair, and ribosomal pathways.</p> <p>Methods</p> <p>We evaluated 4836 tag-SNPs across 255 candidate genes in 96 OS cases and 1426 controls. Logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI).</p> <p>Results</p> <p>Twelve SNPs in growth or DNA repair genes were significantly associated with OS after Bonferroni correction. Four SNPs in the DNA repair gene <it>FANCM </it>(ORs 1.9-2.0, <it>P </it>= 0.003-0.004) and 2 SNPs downstream of the growth hormone gene <it>GH1 </it>(OR 1.6, <it>P </it>= 0.002; OR 0.5, <it>P </it>= 0.0009) were significantly associated with OS. One SNP in the region of each of the following genes was significant: <it>MDM2</it>, <it>MPG</it>, <it>FGF2</it>, <it>FGFR3</it>, <it>GNRH2</it>, and <it>IGF1</it>.</p> <p>Conclusions</p> <p>Our results suggest that several SNPs in biologically plausible pathways are associated with OS. Larger studies are required to confirm our findings.</p

The Arabidopsis Resistance-Like Gene SNC1 Is Activated by Mutations in SRFR1 and Contributes to Resistance to the Bacterial Effector AvrRps4

The SUPPRESSOR OF rps4-RLD1 (SRFR1) gene was identified based on enhanced AvrRps4-triggered resistance in the naturally susceptible Arabidopsis accession RLD. No other phenotypic effects were recorded, and the extent of SRFR1 involvement in regulating effector-triggered immunity was unknown. Here we show that mutations in SRFR1 in the accession Columbia-0 (Col-0) lead to severe stunting and constitutive expression of the defense gene PR1. These phenotypes were temperature-dependent. A cross between srfr1-1 (RLD background) and srfr1-4 (Col-0) showed that stunting was caused by a recessive locus in Col-0. Mapping and targeted crosses identified the Col-0-specific resistance gene SNC1 as the locus that causes stunting. SRFR1 was proposed to function as a transcriptional repressor, and SNC1 is indeed overexpressed in srfr1-4. Interestingly, co-regulated genes in the SNC1 cluster are also upregulated in the srfr1-4 snc1-11 double mutant, indicating that the overexpression of SNC1 is not a secondary effect of constitutive defense activation. In addition, a Col-0 RPS4 mutant showed full susceptibility to bacteria expressing avrRps4 at 24°C but not at 22°C, while RLD susceptibility was not temperature-dependent. The rps4-2 snc1-11 double mutant showed increased, but not full, susceptibility at 22°C, indicating that additional cross-talk between resistance pathways may exist. Intriguingly, when transiently expressed in Nicotiana benthamiana, SRFR1, RPS4 and SNC1 are in a common protein complex in a cytoplasmic microsomal compartment. Our results highlight SRFR1 as a convergence point in at least a subset of TIR-NBS-LRR protein-mediated immunity in Arabidopsis. Based on the cross-talk evident from our results, they also suggest that reports of constitutive resistance phenotypes in Col-0 need to consider the possible involvement of SNC1

An Analysis of the Systemic Risks Posed by Fannie Mae and Freddie Mac and an Evaluation of the Policy Options for Reducing those Risks

Fannie Mae and Freddie Mac are government-sponsored enterprises that are central players in U.S. secondary mortgage markets. Over the past decade, these institutions have amassed enormous mortgage- and non-mortgage-oriented investment portfolios that pose significant interest-rate risks to the companies and a systemic risk to the financial system. This paper describes the nature of these risks and systemic concerns and then evaluates several policy options for reducing the institutions’ investment portfolios. We conclude that limits on portfolio size (assets or liabilities) would be the most desirable approach to mitigating the systemic risk posed by Fannie Mae and Freddie Mac

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology

Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 x 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 x 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 x 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 x 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 x 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 x 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies

Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1,2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments

Recent progress in the upgrade of the TCV EC-system with two 1MW/2s dual-frequency (84/126GHz) gyrotrons

The upgrade of the EC-system of the TCV tokamak has entered in its realization phase and is part of a broader upgrade of TCV. The MW-class dual-frequency gyrotrons (84 or 126GHz/2s/1MW) are presently being manufactured by Thales Electron Devices with the first gyrotron foreseen to be delivered at SPC by the end of 2017. In parallel to the gyrotron development, for extending the level of operational flexibility of the TCV EC-system the integration of the dual-frequency gyrotrons adds a significant complexity in the evacuated 63.5mm-diameter HE11 transmission line system connected to the various TCV low-field side and top launchers. As discussed in [1], an important part of the present TCV-upgrade consists in inserting a modular closed divertor chamber. This will have an impact on the X3 top-launcher which will have to be reduced in size. For using the new compact launcher we are considering employing a Fast Directional Switch (FADIS), combining the two 1MW/126GHz/2s rf-beams into a single 2MW rf-beam