1,303 research outputs found
Screening of young competitive athletes for the prevention of sudden cardiac death with a wireless electrocardiographic transmission device: a pilot study
Individual risk factors predictive of venous thromboembolism in patients with temporary lower limb immobilisation due to injury: a systematic review
BACKGROUND: Patients immobilised after lower limb injury are at risk of venous thromboembolism (VTE). There is international variation in the use of thromboprophylaxis for such patients. Risk based strategies have been adopted to aid decision making in many settings. The accuracy of these strategies is unclear. OBJECTIVES: A systematic review was undertaken to identify all individual patient identifiable risk factors linked to any VTE outcome following lower limb immobilisation. METHODS: Several electronic databases were searched from inception to May 2017. Any studies which included a measurement of VTE patient outcome in adults requiring temporary immobilisation (e.g. leg cast or brace in an ambulatory setting) for an isolated lower limb injury and reported risk factor variables were included. Descriptive statistics and thematic analysis were used to synthesise the evidence. RESULTS: Our database search returned 4771 citations, of which 15 studies reporting outcome data on 80,678 patients were eligible for analysis. Risk factor associations were reported through regression analyses, non-parametric tests and descriptive statistics. All studies were assessed as at moderate or serious risk of bias using the ROBINS-I risk of bias tool. Advancing age and injury type were the only individual risk factors demonstrating a reproducible association with increased symptomatic and/or asymptomatic VTE rates. Several risk factors currently used in scoring tools did not appear to be robustly evaluated for subsequent association with VTE, within these studies. CONCLUSIONS: Clinicians should be aware of the limited evidence to support individual risk factors in guiding thromboprophylaxis use for this patient cohort
Crack-Like Processes Governing the Onset of Frictional Slip
We perform real-time measurements of the net contact area between two blocks
of like material at the onset of frictional slip. We show that the process of
interface detachment, which immediately precedes the inception of frictional
sliding, is governed by three different types of detachment fronts. These
crack-like detachment fronts differ by both their propagation velocities and by
the amount of net contact surface reduction caused by their passage. The most
rapid fronts propagate at intersonic velocities but generate a negligible
reduction in contact area across the interface. Sub-Rayleigh fronts are
crack-like modes which propagate at velocities up to the Rayleigh wave speed,
VR, and give rise to an approximate 10% reduction in net contact area. The most
efficient contact area reduction (~20%) is precipitated by the passage of slow
detachment fronts. These fronts propagate at anomalously slow velocities, which
are over an order of magnitude lower than VR yet orders of magnitude higher
than other characteristic velocity scales such as either slip or loading
velocities. Slow fronts are generated, in conjunction with intersonic fronts,
by the sudden arrest of sub-Rayleigh fronts. No overall sliding of the
interface occurs until either of the slower two fronts traverses the entire
interface, and motion at the leading edge of the interface is initiated. Slip
at the trailing edge of the interface accompanies the motion of both the slow
and sub-Rayleigh fronts. We might expect these modes to be important in both
fault nucleation and earthquake dynamics.Comment: 19 page, 5 figures, to appear in International Journal of Fractur
MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation.
Roughly half of all high-risk neuroblastoma patients present with MYCN amplification. The molecular consequences of MYCN overexpression in this aggressive pediatric tumor have been studied for decades, but thus far, our understanding of the early initiating steps of MYCN-driven tumor formation is still enigmatic. We performed a detailed transcriptome landscaping during murine TH-MYCN-driven neuroblastoma tumor formation at different time points. The neuroblastoma dependency factor MEIS2, together with ASCL1, was identified as a candidate tumor-initiating factor and shown to be a novel core regulatory circuit member in adrenergic neuroblastomas. Of further interest, we found a KEOPS complex member (gm6890), implicated in homologous double-strand break repair and telomere maintenance, to be strongly upregulated during tumor formation, as well as the checkpoint adaptor Claspin (CLSPN) and three chromosome 17q loci CBX2, GJC1 and LIMD2. Finally, cross-species master regulator analysis identified FOXM1, together with additional hubs controlling transcriptome profiles of MYCN-driven neuroblastoma. In conclusion, time-resolved transcriptome analysis of early hyperplastic lesions and full-blown MYCN-driven neuroblastomas yielded novel components implicated in both tumor initiation and maintenance, providing putative novel drug targets for MYCN-driven neuroblastoma
Processes Controlling Tropical Tropopause Temperature and Stratospheric Water Vapor in Climate Models
A warm bias in tropical tropopause temperature is found in the Met Office Unified Model (MetUM), in common with most models from phase 5 of CMIP (CMIP5). Key dynamical, microphysical, and radiative processes influencing the tropical tropopause temperature and lower-stratospheric water vapor concentrations in climate models are investigated using the MetUM. A series of sensitivity experiments are run to separate the effects of vertical advection, ice optical and microphysical properties, convection, cirrus clouds, and atmospheric composition on simulated tropopause temperature and lower-stratospheric water vapor concentrations in the tropics. The numerical accuracy of the vertical advection, determined in the MetUM by the choice of interpolation and conservation schemes used, is found to be particularly important. Microphysical and radiative processes are found to influence stratospheric water vapor both through modifying the tropical tropopause temperature and through modifying upper-tropospheric water vapor concentrations, allowing more water vapor to be advected into the stratosphere. The representation of any of the processes discussed can act to significantly reduce biases in tropical tropopause temperature and stratospheric water vapor in a physical way, thereby improving climate simulations
Prospecting environmental mycobacteria: combined molecular approaches reveal unprecedented diversity
Background: Environmental mycobacteria (EM) include species commonly found in various terrestrial and aquatic environments, encompassing animal and human pathogens in addition to saprophytes. Approximately 150 EM species can be separated into fast and slow growers based on sequence and copy number differences of their 16S rRNA genes. Cultivation methods are not appropriate for diversity studies; few studies have investigated EM diversity in soil despite their importance as potential reservoirs of pathogens and their hypothesized role in masking or blocking M. bovis BCG vaccine.
Methods: We report here the development, optimization and validation of molecular assays targeting the 16S rRNA gene to assess diversity and prevalence of fast and slow growing EM in representative soils from semi tropical and temperate areas. New primer sets were designed also to target uniquely slow growing mycobacteria and used with PCR-DGGE, tag-encoded Titanium amplicon pyrosequencing and quantitative PCR.
Results: PCR-DGGE and pyrosequencing provided a consensus of EM diversity; for example, a high abundance of pyrosequencing reads and DGGE bands corresponded to M. moriokaense, M. colombiense and M. riyadhense. As expected pyrosequencing provided more comprehensive information; additional prevalent species included M. chlorophenolicum, M. neglectum, M. gordonae, M. aemonae. Prevalence of the total Mycobacterium genus in the soil samples ranged from 2.3×107 to 2.7×108 gene targets g−1; slow growers prevalence from 2.9×105 to 1.2×107 cells g−1.
Conclusions: This combined molecular approach enabled an unprecedented qualitative and quantitative assessment of EM across soil samples. Good concordance was found between methods and the bioinformatics analysis was validated by random resampling. Sequences from most pathogenic groups associated with slow growth were identified in extenso in all soils tested with a specific assay, allowing to unmask them from the Mycobacterium whole genus, in which, as minority members, they would have remained undetected
Silencing Early Viral Replication in Macrophages and Dendritic Cells Effectively Suppresses Flavivirus Encephalitis
West Nile (WN) and St. Louis encephalitis (SLE) viruses can cause fatal
neurological infection and currently there is neither a specific treatment nor
an approved vaccine for these infections. In our earlier studies, we have
reported that siRNAs can be developed as broad-spectrum antivirals for the
treatment of infection caused by related viruses and that a small peptide called
RVG-9R can deliver siRNA to neuronal cells as well as macrophages. To increase
the repertoire of broad-spectrum antiflaviviral siRNAs, we screened 25 siRNAs
targeting conserved regions in the viral genome. Five siRNAs were found to
inhibit both WNV and SLE replication in vitro reflecting broad-spectrum
antiviral activity and one of these was also validated in vivo. In addition, we
also show that RVG-9R delivers siRNA to macrophages and dendritic cells,
resulting in effective suppression of virus replication. Mice were challenged
intraperitoneally (i.p.) with West Nile virus (WNV) and treated i.v. with
siRNA/peptide complex. The peritoneal macrophages isolated on day 3 post
infection were isolated and transferred to new hosts. Mice receiving macrophages
from the anti-viral siRNA treated mice failed to develop any disease while the
control mice transferred with irrelevant siRNA treated mice all died of
encephalitis. These studies suggest that early suppression of viral replication
in macrophages and dendritic cells by RVG-9R-mediated siRNA delivery is key to
preventing the development of a fatal neurological disease
Phenotypic Variation and Bistable Switching in Bacteria
Microbial research generally focuses on clonal populations. However, bacterial cells with identical genotypes frequently display different phenotypes under identical conditions. This microbial cell individuality is receiving increasing attention in the literature because of its impact on cellular differentiation, survival under selective conditions, and the interaction of pathogens with their hosts. It is becoming clear that stochasticity in gene expression in conjunction with the architecture of the gene network that underlies the cellular processes can generate phenotypic variation. An important regulatory mechanism is the so-called positive feedback, in which a system reinforces its own response, for instance by stimulating the production of an activator. Bistability is an interesting and relevant phenomenon, in which two distinct subpopulations of cells showing discrete levels of gene expression coexist in a single culture. In this chapter, we address techniques and approaches used to establish phenotypic variation, and relate three well-characterized examples of bistability to the molecular mechanisms that govern these processes, with a focus on positive feedback.
Estimates of array and pool-construction variance for planning efficient DNA-pooling genome wide association studies
<p>Abstract</p> <p>Background</p> <p>Until recently, genome-wide association studies (GWAS) have been restricted to research groups with the budget necessary to genotype hundreds, if not thousands, of samples. Replacing individual genotyping with genotyping of DNA pools in Phase I of a GWAS has proven successful, and dramatically altered the financial feasibility of this approach. When conducting a pool-based GWAS, how well SNP allele frequency is estimated from a DNA pool will influence a study's power to detect associations. Here we address how to control the variance in allele frequency estimation when DNAs are pooled, and how to plan and conduct the most efficient well-powered pool-based GWAS.</p> <p>Methods</p> <p>By examining the variation in allele frequency estimation on SNP arrays between and within DNA pools we determine how array variance [var(e<sub>array</sub>)] and pool-construction variance [var(e<sub>construction</sub>)] contribute to the total variance of allele frequency estimation. This information is useful in deciding whether replicate arrays or replicate pools are most useful in reducing variance. Our analysis is based on 27 DNA pools ranging in size from 74 to 446 individual samples, genotyped on a collective total of 128 Illumina beadarrays: 24 1M-Single, 32 1M-Duo, and 72 660-Quad.</p> <p>Results</p> <p>For all three Illumina SNP array types our estimates of var(e<sub>array</sub>) were similar, between 3-4 × 10<sup>-4 </sup>for normalized data. Var(e<sub>construction</sub>) accounted for between 20-40% of pooling variance across 27 pools in normalized data.</p> <p>Conclusions</p> <p>We conclude that relative to var(e<sub>array</sub>), var(e<sub>construction</sub>) is of less importance in reducing the variance in allele frequency estimation from DNA pools; however, our data suggests that on average it may be more important than previously thought. We have prepared a simple online tool, PoolingPlanner (available at <url>http://www.kchew.ca/PoolingPlanner/</url>), which calculates the effective sample size (ESS) of a DNA pool given a range of replicate array values. ESS can be used in a power calculator to perform pool-adjusted calculations. This allows one to quickly calculate the loss of power associated with a pooling experiment to make an informed decision on whether a pool-based GWAS is worth pursuing.</p
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