FIRE (facilitating implementation of research evidence) : a study protocol

Research evidence underpins best practice, but is not always used in healthcare. The Promoting Action on Research Implementation in Health Services (PARIHS) framework suggests that the nature of evidence, the context in which it is used, and whether those trying to use evidence are helped (or facilitated) affect the use of evidence. Urinary incontinence has a major effect on quality of life of older people, has a high prevalence, and is a key priority within European health and social care policy. Improving continence care has the potential to improve the quality of life for older people and reduce the costs associated with providing incontinence aids

Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB

Passage and survival of Acaciella angustissima (Mill.) Britton & Rose and Aeschynomene paniculata Willd. ex Vogel seed through the sheep gut

Acaciella angustissima (syn. Acacia angustissima) (white ball acacia) and Aeschynomene paniculata Willd. ex Vogel (pannicle joint vetch), were rejected for release after their identification as potential weeds in pasture evaluation trials. These plants are now targeted for control and, where possible, eradication from old experimental sites across Queensland. It is suspected that domestic livestock, feral and native animals contribute to the movement of these seeds through the ingestion and defecation of viable seeds across the landscape. This aspect was explored by feeding the intact seeds of these two species to sheep in metabolism cages. Sheep faeces were collected each day for 5 days after which time the faeces were sieved and the surviving intact seeds were then collected, counted and germination tests undertaken. The results show that seeds of both species pass through sheep with most seeds being passed after 48 h with a percentage of these seeds being viable. Of the number of seeds fed, 4.25% were recovered for A. angustissima and 1.4% for A. paniculata. Seed recovered from the faeces had 0% and 13% germination for A. angustissima and A. paniculata respectively, but with additional post-digestion hot water scarification germination increased to 75% and 33% for A. angustissima and A. paniculata respectively. This paper discusses these results and the implications for the possible spread of these species across the northern Australian landscape

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients

International audienceGenetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46x10-12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16x10-11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors

Erwartungsbildung über den Wahlausgang und ihr Einfluss auf die Wahlentscheidung

Erwartungen über den Wahlausgang haben einen festen Platz sowohl in Rational-Choice-Theorien des Wählerverhaltens als auch in stärker sozialpsychologisch orientierten Ansätzen. Die Bildung von Erwartungen und ihr Einfluss auf die Wahlentscheidung ist dabei jedoch ein noch relativ unerforschtes Gebiet. In diesem Beitrag werden anhand von Wahlstudien für Belgien, Österreich und Deutschland verschiedene Fragen der Erwartungsbildung und ihrer Auswirkungen untersucht. Zunächst wird die Qualität der Gesamterwartungen analysiert und verschiedene Faktoren identifiziert, die einen systematischen Einfluss auf die Erwartungsbildung haben. Im zweiten Schritt wenden wir uns den Einzelerwartungen über verschiedene Parteien und Koalitionen zu und finden eine moderate Verzerrung zugunsten der präferierten Parteien und Koalitionen. Dabei kann gezeigt werden, dass der Effekt des Wunschdenkens mit dem politischen Wissen und dem Bildungsgrad abnimmt. Schließlich werden in einem letzten Schritt zwei unterschiedliche Logiken für die Auswirkungen von Erwartungen getestet, das rationale Kalkül des koalitionsstrategischen Wählens zur Vermeidung der Stimmenvergeudung sowie der sozialpsychologisch begründete Bandwagon-Effekt. Das Ausmaß an politischem Wissen scheint dabei eine zentrale vermittelnde Variable zwischen den beiden Logiken zu sein

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

TRE-FX:Delivering a federated network of trusted research environments to enable safe data analytics

Trusted Research Environments (TREs) are secure locations in which data are placed for researchers to analyse. TREs host administrative data, hospital data or any other data that needs to remain securely isolated, but it is hard for a researcher to perform an analysis across multiple TREs, requesting and gathering the outputs from each one. This is a common problem in the UK's devolved healthcare system of geographical and governance boundaries. There are different ways of implementing TREs and the analysis tools that use them. A solution must be straightforward for existing, independent systems to adopt, must cope with the variety of system implementations, and must work within the "Five Safes" framework that enables data services to provide safe research access to data. TRE-FX assembled leading infrastructure researchers, analysis tool makers, TRE providers and public engagement specialists to streamline the exchange of data requests and results. The "Five Safes RO-Crate" standard packages up (Crates) the Objects needed for Research requests and results with the information needed for the tools and TRE providers to ensure that the crates are reviewed and processed according to Five Safes principles. TRE-FX showed how this works using software components and an end-to-end demonstrator implemented by a TRE in Wales. Two other TREs, in Scotland and England, are preparing to follow suit. Two analysis tool providers (Bitfount and DataSHIELD) modified their systems to use the RO-Crates. The next step is practical implementation as part of the HDR UK programme. Two large European projects will develop the approach further. TRE-FX shows that it is possible to streamline how analysis tools access multiple TREs while enabling the TREs to ensure that the access is safe. The approach scales as more TREs are added and can be adopted by established systems. Researchers will then be able to perform an analysis across multiple TREs much more easily, widening the scope of their research and making more effective use of the UK's data. If we had had this for COVID-19 data analysis, it would have super-charged researchers to be able to quickly answer pressing questions across the UK. This work was funded by UK Research &amp; Innovation [Grant Number MC_PC_23007] as part of Phase 1 of the DARE UK (Data and Analytics Research Environments UK) programme, delivered in partnership with Health Data Research UK (HDR UK) and Administrative Data Research UK (ADR UK)