Exploring the interdependencies of research funders in the UK

Investment in medical research is vital to the continuing improvement of the UK's health and wealth. It is through research that we expand our understanding of disease and develop new treatments for patients. Medical research charities currently contribute over £1 billion annually to medical research in the UK, of which over £350 million is provided by Cancer Research UK. Many charities, including Cancer Research UK, receive no government funding for their research activity. Cancer Research UK is engaged in a programme of work in order to better understand the medical research funding environment and demonstrate the importance of sustained investment. A key part of that is the Office of Health Economics‟ (OHE) 2011 report “Exploring the interdependency between public and charitable medical research”. This study found that there are substantial benefits, both financial and qualitative, from the existence of a variety of funders and that reductions in the level of government financial support for medical research are likely to have broader negative effects. This contributed to other evidence which found that the activities and funding of the charity, public and private sectors respectively are complementary, i.e. mutually reinforcing, rather than duplicative or merely substituting for one another. “Exploring the interdependencies of research funders in the UK” by the Office of Health Economics (OHE) and SPRU: Science and Technology Policy Research at the University of Sussex, represents a continued effort to build the evidence base around the funding of medical research. This report uncovers the extent to which funders of cancer research are interdependent, nationally and internationally. Key figures show that two thirds of publications acknowledging external support have relied on multiple funders, while just under half benefited from overseas funding, and almost a fifth are also supported by industry. In addition the analysis shows that the general public would not want tax funding of cancer research to be reduced, but would not donate enough to charities to compensate for any such reduction

Moving beyond physical education subject knowledge to develop knowledgeable teachers of the subject

All knowledge is socially constructed, including physical education teachers’ knowledge of their subject. It is acquired from other people either formally and deliberately (e.g. by being taught) or informally and casually (e.g. by interacting with physical education teachers or playing in a sports team). The social aspects of learning appear to be particularly strong in physical education. This has implications for the development of knowledge for teaching, with trainee teachers focusing on the development of subject, and particularly content, knowledge. Focusing on subject knowledge reinforces a traditional view of physical education as it is, not as it might be to meet the needs of young people today. It is argued that attention needs to be given not only to the knowledge, skills and competencies that trainee teachers ought to develop but also to the social aspects of their learning and development and the context in which they learn. Attention also needs to be given to how the ability to think critically can be developed so that trainee teachers can become reflective practitioners able to challenge and, where appropriate, change the teaching of the subject. Only by doing this can the particularly strong socialisation which shapes the values and beliefs of physical education teachers begin to be challenged. However, as the process of developing knowledgeable teachers is ongoing it is also necessary to look beyond teacher training to continuing professional development

Moving beyond physical education subject knowledge to develop knowledgeable teachers of the subject

All knowledge is socially constructed, including physical education teachers’ knowledge of their subject. It is acquired from other people either formally and deliberately (e.g. by being taught) or informally and casually (e.g. by interacting with physical education teachers or playing in a sports team). The social aspects of learning appear to be particularly strong in physical education. This has implications for the development of knowledge for teaching, with trainee teachers focusing on the development of subject, and particularly content, knowledge. Focusing on subject knowledge reinforces a traditional view of physical education as it is, not as it might be to meet the needs of young people today. It is argued that attention needs to be given not only to the knowledge, skills and competencies that trainee teachers ought to develop but also to the social aspects of their learning and development and the context in which they learn. Attention also needs to be given to how the ability to think critically can be developed so that trainee teachers can become reflective practitioners able to challenge and, where appropriate, change the teaching of the subject. Only by doing this can the particularly strong socialisation which shapes the values and beliefs of physical education teachers begin to be challenged. However, as the process of developing knowledgeable teachers is ongoing it is also necessary to look beyond teacher training to continuing professional development

Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia

Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4+/CD44+/CD62L+ and CD4+/CD44+/CD62L-/CD27+ T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injur

Validation of the modified Fresno Test: assessing physical therapists' evidence based practice knowledge and skills

<p>Abstract</p> <p>Background</p> <p>Health care educators need valid and reliable tools to assess evidence based practice (EBP) knowledge and skills. Such instruments have yet to be developed for use among physical therapists. The Fresno Test (FT) has been validated only among general practitioners and occupational therapists and does not assess integration of research evidence with patient perspectives and clinical expertise. The purpose of this study was to develop and validate a modified FT to assess EBP knowledge and skills relevant to physical therapist (PT) practice.</p> <p>Methods</p> <p>The FT was modified to include PT-specific content and two new questions to assess integration of patient perspectives and clinical expertise with research evidence. An expert panel reviewed the test for content validity. A cross-sectional cohort representing three training levels (EBP-novice students, EBP-trained students, EBP-expert faculty) completed the test. Two blinded raters, not involved in test development, independently scored each test. Construct validity was assessed through analysis of variance for linear trends among known groups. Inter and intra-rater reliability, internal consistency, item discrimination index, item total correlation, and difficulty were analyzed.</p> <p>Results</p> <p>Among 108 participants (31 EBP-novice students, 50 EBP-trained students, and 27 EBP-expert faculty), there was a statistically significant (p < 0.0001) difference in total score corresponding to training level. Total score reliability and psychometric properties of items modified for discipline-specific content were excellent [inter-rater (ICC (2,1)] = 0.91); intra-rater (ICC (2,1)] = 0.95, 0.96)]. Cronbach's α was 0.78. Of the two new items, only one had strong psychometric properties.</p> <p>Conclusions</p> <p>The 13-item modified FT presented here is a valid, reliable assessment of physical therapists' EBP knowledge and skills. One new item assesses integration of patient perspective as part of the EBP model. Educators and researchers may use the 13-item modified FT to evaluate PT EBP curricula and physical therapists' EBP knowledge and skills.</p

Personalized Drug Dosage – Closing the Loop

A brief account is given of various approaches to the individualization of drug dosage, including the use of pharmacodynamic markers, therapeutic monitoring of plasma drug concentrations, genotyping, computer-guided dosage using ‘dashboards’, and automatic closed-loop control of pharmacological action. The potential for linking the real patient to his or her ‘virtual twin’ through the application of physiologically-based pharmacokinetic modeling is also discussed

RecBCD coordinates repair of two ends at a DNA double-strand break, preventing aberrant chromosome amplification

DNA double-strand break (DSB) repair is critical for cell survival. A diverse range of organisms from bacteria to humans rely on homologous recombination for accurate DSB repair. This requires both coordinate action of the two ends of a DSB and stringent control of the resultant DNA replication to prevent unwarranted DNA amplification and aneuploidy. In Escherichia coli, RecBCD enzyme is responsible for the initial steps of homologous recombination. Previous work has revealed recD mutants to be nuclease defective but recombination proficient. Despite this proficiency, we show here that a recD null mutant is defective for the repair of a two-ended DSB and that this defect is associated with unregulated chromosome amplification and defective chromosome segregation. Our results demonstrate that RecBCD plays an important role in avoiding this amplification by coordinating the two recombining ends in a manner that prevents divergent replication forks progressing away from the DSB site

Predictors of 25(OH)D half-life and plasma 25(OH)D concentration in The Gambia and the UK

Summary: Predictors of 25(OH)D3 half-life were factors associated with vitamin D metabolism, but were different between people in The Gambia and the UK. Country was the strongest predictor of plasma 25(OH)D concentration, probably as a marker of UVB exposure. 25(OH)D3 half-life may be applied as a tool to investigate vitamin D expenditure.  Introduction: The aim of this study was to investigate predictors of 25(OH)D3 half-life and plasma 25(OH)D concentration.  Methods: Plasma half-life of an oral tracer dose of deuterated-25(OH)D3 was measured in healthy men aged 24–39 years, resident in The Gambia, West Africa (n = 18) and in the UK during the winter (n = 18), countries that differ in calcium intake and vitamin D status. Plasma and urinary markers of vitamin D, calcium, phosphate and bone metabolism, nutrient intakes and anthropometry were measured.  Results: Normally distributed data are presented as mean (SD) and non-normal data as geometric mean (95 % CI). Gambian compared to UK men had higher plasma concentrations of 25(OH)D (69 (13) vs. 29 (11) nmol/L; P < 0.0001); 1,25(OH)2D (181 (165, 197) vs. 120 (109, 132) pmol/L; P < 0.01); and parathyroid hormone (PTH) (50 (42, 60) vs. 33 (27, 39); P < 0.0001). There was no difference in 25(OH)D3 half-life (14.7 (3.5) days vs. 15.6 (2.5) days) between countries (P = 0.2). In multivariate analyses, 25(OH)D, 1,25(OH)2D, vitamin D binding protein and albumin-adjusted calcium (Caalb) explained 79 % of variance in 25(OH)D3 half-life in Gambians, but no significant predictors were found in UK participants. For the countries combined, Caalb, PTH and plasma phosphate explained 39 % of half-life variability. 1,25(OH)2D, weight, PTH and country explained 81 % of variability in 25(OH)D concentration; however, country alone explained 74 %.  Conclusion: Factors known to affect 25(OH)D metabolism predict 25(OH)D3 half-life, but these differed between countries. Country predicted 25(OH)D, probably as a proxy measure for UVB exposure and vitamin D supply. This study supports the use of 25(OH)D half-life to investigate vitamin D metabolism

Sensitivity of the UK clinical practice research datalink to detect neurodevelopmental effects of medicine exposure in utero:comparative analysis of an antiepileptic drug-exposed cohort

Introduction: Electronic healthcare data have several advantages over prospective observational studies, but the sensitivity of data on neurodevelopmental outcomes and its comparability with data generated through other methodologies is unknown. Objectives: The objectives of this study were to determine whether data from the UK Clinical Practice Research Datalink (CPRD) produces similar risk estimates to a prospective cohort study in relation to the risk of neurodevelopmental disorders (NDDs) following prenatal antiepileptic drug (AED) exposure. Methods: A cohort of mother–child pairs of women with epilepsy (WWE) was identified in the CPRD and matched to a cohort without epilepsy. The study period ran from 1 January 2000 to 31 March 2007 and children were required to be in the CPRD at age 6 years. AED exposure during pregnancy was determined from prescription data and children with an NDD diagnosis by 6 years were identified from Read clinical codes. The prevalence and risk of NDDs was calculated for mother–child pairs in WWE stratified by AED regimen and for those without epilepsy. Comparisons were made with the results of the prospective Liverpool and Manchester Neurodevelopment Group study which completed assessment on 201 WWE and 214 without epilepsy at age 6 years. Results: In the CPRD, 1018 mother–child pairs to WWE and 6048 to women without epilepsy were identified. The CPRD identified a lower prevalence of NDDs than the prospective study. In both studies, NDDs were more frequently reported in children of WWE than women without epilepsy, although the CPRD risk estimate was lower (2.16 vs. 0.96%, p < 0.001 and 7.46 vs. 1.87%, p = 0.0128). NDD prevalence differed across AED regimens but the CPRD data did not replicate the significantly higher risk of NDDs following in utero monotherapy valproate exposure (adjusted odds ratio [ORadj] 2.02, 95% confidence interval [CI] 0.52–7.86) observed in the prospective study (ORadj 6.05, 95% CI 1.65–24.53). Conclusion: It was possible to identify NDDs in the CPRD; however, the CPRD appears to under-record these outcomes. Larger studies are required to investigate further

Integrating Algorithmic Parameters into Benchmarking and Design Space Exploration in 3D Scene Understanding

System designers typically use well-studied benchmarks to evaluate and improve new architectures and compilers. We design tomorrow's systems based on yesterday's applications. In this paper we investigate an emerging application, 3D scene understanding, likely to be signi cant in the mobile space in the near future. Until now, this application could only run in real-time on desktop GPUs. In this work, we examine how it can be mapped to power constrained embedded systems. Key to our approach is the idea of incremental co-design exploration, where optimization choices that concern the domain layer are incrementally explored together with low-level compiler and architecture choices. The goal of this exploration is to reduce execution time while minimizing power and meeting our quality of result objective. As the design space is too large to exhaustively evaluate, we use active learning based on a random forest predictor to nd good designs. We show that our approach can, for the rst time, achieve dense 3D mapping and tracking in the real-time range within a 1W power budget on a popular embedded device. This is a 4.8x execution time improvement and a 2.8x power reduction compared to the state-of-the-art