Protocol for a process-oriented qualitative evaluation of the Waltham Forest and East London Collaborative (WELC) integrated care pioneer programme using the Researcher-in-Residence model

INTRODUCTION: The integration of health and social care in England is widely accepted as the answer to fragmentation, financial concerns and system inefficiencies, in the context of growing and ageing populations with increasingly complex needs. Despite an expanding body of literature, there is little evidence yet to suggest that integrated care can achieve the benefits that its advocates claim for it. Researchers have often adopted rationalist and technocratic approaches to evaluation, treating integration as an intervention rather than a process. Results have usually been of limited use to practitioners responsible for health and social care integration. There is, therefore, a need to broaden the evidence base, exploring not only what works but also how integrated care can most successfully be implemented and delivered. For this reason, we are carrying out a formative evaluation of the Waltham Forest and East London Collaborative (WELC) integrated care pioneer programme. Our expectation is that this will add value to the literature by focusing on the processes by which the vision and objectives of integrated care are translated through phases of development, implementation and delivery from a central to a local perspective, and from a strategic to an operational perspective. METHODS AND ANALYSIS: The qualitative and process-oriented evaluation uses an innovative participative approach-the Researcher-in-Residence model. The evaluation is underpinned by a critical ontology, an interpretive epistemology and a critical discourse analysis methodology. Data will be generated using interviews, observations and documentary gathering. ETHICS AND DISSEMINATION: Emerging findings will be interpreted and disseminated collaboratively with stakeholders, to enable the research to influence and optimise the effective implementation of integrated care across WELC. Presentations and publications will ensure that learning is shared as widely as possible. The study has received ethical approval from University College London's Research Ethics Committee and has all appropriate NHS governance clearances

Evidence for variation in the effective population size of animal mitochondrial DNA

Background: It has recently been shown that levels of diversity in mitochondrial DNA are remarkably constant across animals of diverse census population sizes and ecologies, which has led to the suggestion that the effective population of mitochondrial DNA may be relatively constant. Results: Here we present several lines of evidence that suggest, to the contrary, that the effective population size of mtDNA does vary, and that the variation can be substantial. First, we show that levels of mitochondrial and nuclear diversity are correlated within all groups of animals we surveyed. Second, we show that the effectiveness of selection on non-synonymous mutations, as measured by the ratio of the numbers of non-synonymous and synonymous polymorphisms, is negatively correlated to levels of mitochondrial diversity. Finally, we estimate the effective population size of mitochondrial DNA in selected mammalian groups and show that it varies by at least an order of magnitude. Conclusions: We conclude that there is variation in the effective population size of mitochondria. Furthermore we suggest that the relative constancy of DNA diversity may be due to a negative correlation between the effective population size and the mutation rate per generation

The role of mutation rate variation and genetic diversity in the architecture of human disease

Background We have investigated the role that the mutation rate and the structure of genetic variation at a locus play in determining whether a gene is involved in disease. We predict that the mutation rate and its genetic diversity should be higher in genes associated with disease, unless all genes that could cause disease have already been identified. Results Consistent with our predictions we find that genes associated with Mendelian and complex disease are substantially longer than non-disease genes. However, we find that both Mendelian and complex disease genes are found in regions of the genome with relatively low mutation rates, as inferred from intron divergence between humans and chimpanzees, and they are predicted to have similar rates of non-synonymous mutation as other genes. Finally, we find that disease genes are in regions of significantly elevated genetic diversity, even when variation in the rate of mutation is controlled for. The effect is small nevertheless. Conclusions Our results suggest that gene length contributes to whether a gene is associated with disease. However, the mutation rate and the genetic architecture of the locus appear to play only a minor role in determining whether a gene is associated with disease

Evidence for Pervasive Adaptive Protein Evolution in Wild Mice

The relative contributions of neutral and adaptive substitutions to molecular evolution has been one of the most controversial issues in evolutionary biology for more than 40 years. The analysis of within-species nucleotide polymorphism and between-species divergence data supports a widespread role for adaptive protein evolution in certain taxa. For example, estimates of the proportion of adaptive amino acid substitutions (alpha) are 50% or more in enteric bacteria and Drosophila. In contrast, recent estimates of alpha for hominids have been at most 13%. Here, we estimate alpha for protein sequences of murid rodents based on nucleotide polymorphism data from multiple genes in a population of the house mouse subspecies Mus musculus castaneus, which inhabits the ancestral range of the Mus species complex and nucleotide divergence between M. m. castaneus and M. famulus or the rat. We estimate that 57% of amino acid substitutions in murids have been driven by positive selection. Hominids, therefore, are exceptional in having low apparent levels of adaptive protein evolution. The high frequency of adaptive amino acid substitutions in wild mice is consistent with their large effective population size, leading to effective natural selection at the molecular level. Effective natural selection also manifests itself as a paucity of effectively neutral nonsynonymous mutations in M. m. castaneus compared to humans

Viperin interacts with PEX19 to mediate peroxisomal augmentation of the innate antiviral response.

Peroxisomes are recognized as significant platforms for the activation of antiviral innate immunity where stimulation of the key adapter molecule mitochondrial antiviral signaling protein (MAVS) within the RIG-I like receptor (RLR) pathway culminates in the up-regulation of hundreds of ISGs, some of which drive augmentation of multiple innate sensing pathways. However, whether ISGs can augment peroxisome-driven RLR signaling is currently unknown. Using a proteomics-based screening approach, we identified Pex19 as a binding partner of the ISG viperin. Viperin colocalized with numerous peroxisomal proteins and its interaction with Pex19 was in close association with lipid droplets, another emerging innate signaling platform. Augmentation of the RLR pathway by viperin was lost when Pex19 expression was reduced. Expression of organelle-specific MAVS demonstrated that viperin requires both mitochondria and peroxisome MAVS for optimal induction of IFN-β. These results suggest that viperin is required to enhance the antiviral cellular response with a possible role to position the peroxisome at the mitochondrial/MAM MAVS signaling synapse, furthering our understanding of the importance of multiple organelles driving the innate immune response against viral infection

Nurturing the young shoots of talent: Using action research for exploration and theory building

This is an Author's Accepted Manuscript of an article published in European Early Childhood Education Research Journal, 19(4), 433-450, 2011, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/1350293X.2011.623515.This paper reports the outcomes of a set of action research projects carried out by teacher researchers in 14 local education authorities in England, working collaboratively with university tutors, over a period of three years. The common aim of all the projects was to explore practical ways of nurturing the gifts and talents of children aged four–seven years. The project was funded by the Department of Education and Skills in England as part of the government's gifted and talented programme. The project teachers felt that their understanding of issues relating to nurturing the gifts and talents of younger children was enhanced through their engagement in the project. It was possible to map the findings of the projects to the English government's National Quality Standards for gifted and talented education which include: (1) identification; (2) effective provision in the classroom; (3) enabling curriculum entitlement and choice; (4) assessment for learning; (5) engaging with community, families and beyond. The findings are also analysed within the framework of good practice in educating children in the first years of schooling. Participating practitioners felt that action research offered them a suitable methodology to explore the complexity of the topic of giftedness through cycles of planning, action and reflection and personal theory building

Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity

Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA(-) RA and observed independent associations for serine and leucine at position 11 in HLA-DRbeta1 (p = 1.4 x 10(-13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 x 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1( *)03 (encoding serine at 11) and HLA-B( *)08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DRbeta1 Ser11+Leu11: p = 5.8 x 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 x 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DRbeta1 position 11 were distinct (p \u3c 2.9 x 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 x 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions

The effects of locomotion on sensory-evoked haemodynamic responses in the cortex of awake mice

Investigating neurovascular coupling in awake rodents is becoming ever more popular due, in part, to our increasing knowledge of the profound impacts that anaesthesia can have upon brain physiology. Although awake imaging brings with it many advantages, we still do not fully understand how voluntary locomotion during imaging affects sensory-evoked haemodynamic responses. In this study we investigated how evoked haemodynamic responses can be affected by the amount and timing of locomotion. Using an awake imaging set up, we used 2D-Optical Imaging Spectroscopy (2D-OIS) to measure changes in cerebral haemodynamics within the sensory cortex of the brain during either 2 s whisker stimulation or spontaneous (no whisker stimulation) experiments, whilst animals could walk on a spherical treadmill. We show that locomotion alters haemodynamic responses. The amount and timing of locomotion relative to whisker stimulation is important, and can significantly impact sensory-evoked haemodynamic responses. If locomotion occurred before or during whisker stimulation, the amplitude of the stimulus-evoked haemodynamic response was significantly altered. Therefore, monitoring of locomotion during awake imaging is necessary to ensure that conclusions based on comparisons of evoked haemodynamic responses (e.g., between control and disease groups) are not confounded by the effects of locomotion

Sleep diplomacy alone will widen sleep disparities - Authors' reply.

Timothy Daly argues that preexisting sleep disparities according to socioeconomic status will make behavioural approaches and lifestyle advice widen sleep disparities. Although we fully agree that strong public policy measures must be implemented to reduce socioeconomic status inequalities in brain health,1 and in particular those that might impact sleep problems, there is good evidence reporting the success of behavioural interventions to improve sleep conditions in different populations.2 Specific interventions have been proposed in lowsocioeconomic status populations, which should also be included in our sleep diplomacy3 category.Fil: Golombek, Diego Andres. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de San Andrés; ArgentinaFil: Booi, Laura. Trinity College; Irlanda. Leeds Beckett University; Reino UnidoFil: Campbell, Dominic. Trinity College; IrlandaFil: Dawson, Walter D.. Trinity College; Irlanda. University of California; Estados Unidos. Global Brain Health Institute; Estados Unidos. Oregon Health and Science University; Estados Unidos. Portland State University; Estados UnidosFil: Eyre, Harris. University of California; Estados Unidos. Rice University; Estados UnidosFil: Lawlor, Brian. Trinity College; IrlandaFil: Ibañez, Agustin Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de San Andrés; Argentina. Trinity College; Irlanda. University of California; Estados Unidos. Global Brain Health Institute; Estados Unidos. Universidad Adolfo Ibañez; Chil