Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Background The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. Methods In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. Results A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. Conclusions In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048 .)

Exploring the motivations and practices of parents home educating their children with ASD

This thesis focuses on the experiences of eight families who chose to home educate their children with autism spectrum disorder (ASD). Each child had previously attended pre-school or primary school and their parents withdrew them due to a concern that their full range of needs were not being met. The thesis adds to the existing research on home education which is underresearched globally and in the UK, especially in connection with children who have a special educational need and disabilities (SEN/D), specifically autism. The fieldwork for this two-phase qualitative design took place during 2013-2015. The findings are based upon parental questionnaires and semi-structured interviews with 15 parents and eight of the children, and four informal observations in four different family homes. This thesis examined four research questions. Firstly, the characteristics of the parents and their children with ASD; secondly, parents' motivations for home educating and the processes that were involved; thirdly, how parents organised their home education, the approaches and practices applied and what resources they used; and finally, their views on the perceived advantages and disadvantages of home education are discussed. The thesis draws upon theories of child-centred education and Vygotsky’s Zone of Proximal Development (ZPD). Findings demonstrate that multiple factors influenced parents' decision to home educate such as their child's dislike of school, and educational professionals' lack of knowledge and understanding regarding their children's needs. The eight mothers, who were the main educators, used different pedagogic approaches that were informed by their children's holistic needs. These generally involved the use of first hand experiences and kinaesthetic learning; similar features are found in the theories and practices of child-centred approaches. The thesis concludes by discussing its contribution to knowledge about home education and autism, especially in relation to highlighting inflexible and inconsistent practices at school, and a lack of understanding about the individual needs of children with ASD by educational professionals

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission

Normal levels of p27Xic1 are necessary for somite segmentation and determining pronephric organ size

The Xenopus laevis cyclin dependent kinase inhibitor p27Xic1 has been shown to be involved in exit from the cell cycle and differentiation of cells into a quiescent state in the nervous system, muscle tissue, heart and retina. We show that p27Xic1 is expressed in the developing kidney in the nephrostomal regions. Using over-expression and morpholino oligonucleotide (MO) knock-down approaches we show normal levels of p27Xic1 regulate pronephros organ size by regulating cell cycle exit. Knock-down of p27Xic1 expression using a MO prevented myogenesis, as previously reported; an effect that subsequently inhibits pronephrogenesis. Furthermore, we show that normal levels of p27Xic1 are required for somite segmentation also through its cell cycle control function. Finally, we provide evidence to suggest correct paraxial mesoderm segmentation is not necessary for pronephric induction in the intermediate mesoderm. These results indicate novel developmental roles for p27Xic1, and reveal its differentiation function is not universally utilised in all developing tissues

Redesign of Industrial Apparatus using Multi-Objective Bayesian Optimisation

This is the author accepted manuscriptIntroduction. Design optimisation using Computational Fluid Dynamics (CFD) often requires extremising multiple (and often conflicting) objectives simultaneously. For instance, a heat exchanger design will require maximising the heat transfer across the media, while minimising the pressure drop across the apparatus. In such cases, usually there is no unique solution, but a range of solutions trading off between the objectives. The set of solutions optimally trading off the objectives are known as the Pareto set, and in practice only an approximation of the set may be achieved. Multi-Objective Evolutionary Algorithms (MOEAs) are known to perform well in estimating the optimal Pareto set. However, they require thousands of function evaluations, which is impractical with computationally expensive simulations. An alternative is to use Multi-Objective Bayesian Optimisation (MOBO) method that has been proved to be an effective approach with limited budget on function evaluations [1]. In this work, we illustrate a newly developed MOBO framework in [1] with OpenFOAM 2.3.1 to locate a good estimation of the optimal Pareto set for a range of industrial cases.This work was supported by the UK Engineering and Physical Sciences Research Council (EPSRC) grant (reference number: EP/M017915/1) for the CEMPS, University of Exeter, UK

Application of multi-objective Bayesian shape optimisation to a sharp-heeled Kaplan draft tube

The draft tube of a hydraulic turbine plays an important role for the efficiency and power characteristics of the overall system. The shape of the draft tube affects its performance, resulting in an increasing need for data-driven optimisation for its design. In this paper, shape optimisation of an elbow-type draft tube is undertaken, combining Computational Fluid Dynamics and a multi-objective Bayesian methodology. The chosen design objectives were to maximise pressure recovery, and minimise wall-frictional losses along the geometry. The design variables were chosen to explore potential new designs, using a series of subdivision-curves and splines on the inflow cone, outer-heel, and diffuser. The optimisation run was performed under part-load for the Kaplan turbine. The design with the lowest energy-loss identified on the Pareto-front was found to have a straight tapered diffuser, chamfered heel, and a convex inflow cone. Analysis of the performance quantities showed the typically used energy-loss factor and pressure recovery were highly correlated in cases of constant outflow cross-sections, and therefore unsuitable for use of multi-objective optimisation. Finally, a number of designs were tested over a range of discharges. From this it was found that reducing the heel size increased the efficiency over a wider operating range

A qualitative study into the perceived barriers of accessing healthcare among a vulnerable population involved with a community centre in Romania

(1) Interview guide for family members, and (2) Interview guide for staff members. (DOCX 103 kb

Standardizing and Scaling up Quality Adolescent Friendly Health Services in Tanzania.

Adolescents in Tanzania require health services that respond to their sexual and reproductive health - and other - needs and are delivered in a friendly and nonjudgemental manner. Systematizing and expanding the reach of quality adolescent friendly health service provision is part of the Tanzanian Ministry of Health and Social Welfare's (MOHSW) multi-component strategy to promote and safeguard the health of adolescents. We set out to identify the progress made by the MOHSW in achieving the objective it had set in its National Adolescent Health and Development Strategy: 2002-2006, to systematize and extend the reach of Adolescent Friendly Health Services (AFHS) in the country. We reviewed plans and reports from the MOHSW and journal articles on AFHS. This was supplemented with several of the authors' experiences of working to make health services in Tanzania adolescent friendly. The MOHSW identified four key problems with what was being done to make health services adolescent friendly in the country - firstly, it was not fully aware of the various efforts under way; secondly, there was no standardized definition of AFHS; thirdly, it had received reports that the quality of the AFHS being provided by some organizations was poor; and fourthly, only small numbers of adolescents were being reached by the efforts that were under way. The MOHSW responded to these problems by mapping existing services, developing a standardized definition of AFHS, charting out what needed to be done to improve their quality and expand their coverage, and integrating AFHS within wider policy and strategy documents and programmatic measurement instruments. It has also taken important preparatory steps to stimulate and support implementation. The MOHSW is aware that the focus of the effort must now shift from the national to the regional, council and local levels. The onus is on regional and council health management teams as well as health facility managers to take the steps needed to ensure that all adolescents in the country obtain the sexual and reproductive health (SRH) services they need, delivered in a friendly and non-judgemental manner. But they cannot do this without substantial and ongoing support