Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3

This project was supported by Queen Mary Innovation Ltd Proof of Concept Fund (2012/13) and The William Harvey Research Foundation

A web-based simulation of a longitudinal clinic used in a 4-week ambulatory rotation: a cohort study

<p>Abstract</p> <p>Background</p> <p>Residency training takes place primarily on inpatient wards. In the absence of a resident continuity clinic, internal medicine residents rely on block rotations to learn about continuity of care. Alternate methods to introduce continuity of care are needed.</p> <p>Methods</p> <p>A web-based tool, Continuity of Care Online Simulations (COCOS), was designed for use in a one-month, postgraduate clinical rotation in endocrinology. It is an interactive tool that simulates the continuing care of any patient with a chronic endocrine disease. Twenty-three residents in internal medicine participated in a study to investigate the effects of using COCOS during a clinical rotation in endocrinology on pre-post knowledge test scores and self-assessment of confidence.</p> <p>Results</p> <p>Compared to residents who did the rotation alone, residents who used COCOS during the rotation had significantly higher improvements in test scores (% increase in pre-post test scores +21.6 [standard deviation, SD, 8.0] vs. +5.9 [SD 6.8]; p < .001). Test score improvements were most pronounced for less commonly seen conditions. There were no significant differences in changes in confidence. Residents rated COCOS very highly, recommending its use as a standard part of the rotation and throughout residency.</p> <p>Conclusion</p> <p>A stand-alone web-based tool can be incorporated into an existing clinical rotation to help residents learn about continuity of care. It has the most potential to teach residents about topics that are less commonly seen during a clinical rotation. The adaptable, web-based format allows the creation of cases for most chronic medical conditions.</p

The need for children's advocacy centres : hearing the voices of children

Children and young people (CYP) can be empowered to take on roles as agents of change in their own communities. CYP want to be heard and should be actively involved in the coproduction, design and development of services aimed at them to ensure that the resulting services are acceptable and accessible. Little analysis of the framing and discourse of coproduction in different contexts has been undertaken. Building on Children’s Advocacy Centre models from the United States of America (which are held in high esteem by local communities), there is perceived value of such a centre in the UK. A service development initiative was designed to work with children from Greater Manchester (UK) to determine the potential for the establishment of a children’s advocacy centre in the North of England. This report presents the design and outcome of the initiative and contributes to the literature on the co-production of such service development projects with CYP, notably the means of achieving that outcome. Recommendations are made for the piloting of an Advocacy House model in the UK with collaborative efforts between CYP as well as health, education, law enforcement, social care providers, charities and voluntary groups. A community-inclusive partnership, underpinned by the principles of co-production and co-design, is integral to the further development of this pilot

On Tackling the Limits of Resolution in SAT Solving

The practical success of Boolean Satisfiability (SAT) solvers stems from the CDCL (Conflict-Driven Clause Learning) approach to SAT solving. However, from a propositional proof complexity perspective, CDCL is no more powerful than the resolution proof system, for which many hard examples exist. This paper proposes a new problem transformation, which enables reducing the decision problem for formulas in conjunctive normal form (CNF) to the problem of solving maximum satisfiability over Horn formulas. Given the new transformation, the paper proves a polynomial bound on the number of MaxSAT resolution steps for pigeonhole formulas. This result is in clear contrast with earlier results on the length of proofs of MaxSAT resolution for pigeonhole formulas. The paper also establishes the same polynomial bound in the case of modern core-guided MaxSAT solvers. Experimental results, obtained on CNF formulas known to be hard for CDCL SAT solvers, show that these can be efficiently solved with modern MaxSAT solvers

Innovator resilience potential: A process perspective of individual resilience as influenced by innovation project termination

Innovation projects fail at an astonishing rate. Yet, the negative effects of innovation project failures on the team members of these projects have been largely neglected in research streams that deal with innovation project failures. After such setbacks, it is vital to maintain or even strengthen project members’ innovative capabilities for subsequent innovation projects. For this, the concept of resilience, i.e. project members’ potential to positively adjust (or even grow) after a setback such as an innovation project failure, is fundamental. We develop the second-order construct of innovator resilience potential, which consists of six components – self-efficacy, outcome expectancy, optimism, hope, self-esteem, and risk propensity – that are important for project members’ potential of innovative functioning in innovation projects subsequent to a failure. We illustrate our theoretical findings by means of a qualitative study of a terminated large-scale innovation project, and derive implications for research and management

Neuroimaging correlates of brain injury in Wilson's disease: a multimodal, whole-brain MRI study

Wilson's disease is an autosomal-recessive disorder of copper metabolism with neurological and hepatic presentations. Chelation therapy is used to 'de-copper' patients but neurological outcomes remain unpredictable. A range of neuroimaging abnormalities have been described and may provide insights into disease mechanisms, in addition to prognostic and monitoring biomarkers. Previous quantitative MRI analyses have focussed on specific sequences or regions of interest, often stratifying chronically-treated patients according to persisting symptoms as opposed to initial presentation. In this cross-sectional study, we performed a combination of unbiased, whole-brain analyses on T1-weighted, fluid-attenuated inversion recovery, diffusion-weighted and susceptibility-weighted imaging data from 40 prospectively-recruited patients with Wilson's disease (age range 16-68). We compared patients with neurological (n = 23) and hepatic (n = 17) presentations to determine the neuroradiological sequelae of the initial brain injury. We also subcategorized patients according to recent neurological status, classifying those with neurological presentations or deterioration in the preceding six months as having 'active' disease. This allowed us to compare patients with active (n = 5) and stable (n = 35) disease and identify imaging correlates for persistent neurological deficits and copper indices in chronically-treated, stable patients. Using a combination of voxel-based morphometry and region-of-interest volumetric analyses, we demonstrate that grey matter volumes are lower in the basal ganglia, thalamus, brainstem, cerebellum, anterior insula and orbitofrontal cortex when comparing patients with neurological and hepatic presentations. In chronically-treated, stable patients, the severity of neurological deficits correlated with grey matter volumes in similar, predominantly subcortical regions. In contrast, the severity of neurological deficits did not correlate with the volume of white matter hyperintensities, calculated using an automated lesion segmentation algorithm. Using tract-based spatial statistics, increasing neurological severity in chronically-treated patients was associated with decreasing axial diffusivity in white matter tracts whereas increasing serum non-caeruloplasmin-bound ('free') copper and active disease were associated with distinct patterns of increasing mean, axial and radial diffusivity. Whole-brain quantitative susceptibility mapping identified increased iron deposition in the putamen, cingulate and medial frontal cortices of patients with neurological presentations relative to those with hepatic presentations and neurological severity was associated with iron deposition in widespread cortical regions in chronically-treated patients. Our data indicate that composite measures of subcortical atrophy provide useful prognostic biomarkers, whereas abnormal mean, axial and radial diffusivity are promising monitoring biomarkers. Finally, deposition of brain iron in response to copper accumulation may directly contribute to neurodegeneration in Wilson's disease

A review of RCTs in four medical journals to assess the use of imputation to overcome missing data in quality of life outcomes

Background: Randomised controlled trials (RCTs) are perceived as the gold-standard method for evaluating healthcare interventions, and increasingly include quality of life (QoL) measures. The observed results are susceptible to bias if a substantial proportion of outcome data are missing. The review aimed to determine whether imputation was used to deal with missing QoL outcomes. Methods: A random selection of 285 RCTs published during 2005/6 in the British Medical Journal, Lancet, New England Journal of Medicine and Journal of American Medical Association were identified. Results: QoL outcomes were reported in 61 (21%) trials. Six (10%) reported having no missing data, 20 (33%) reported ≤ 10% missing, eleven (18%) 11%–20% missing, and eleven (18%) reported >20% missing. Missingness was unclear in 13 (21%). Missing data were imputed in 19 (31%) of the 61 trials. Imputation was part of the primary analysis in 13 trials, but a sensitivity analysis in six. Last value carried forward was used in 12 trials and multiple imputation in two. Following imputation, the most common analysis method was analysis of covariance (10 trials). Conclusion: The majority of studies did not impute missing data and carried out a complete-case analysis. For those studies that did impute missing data, researchers tended to prefer simpler methods of imputation, despite more sophisticated methods being available.The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Government Health Directorate. Shona Fielding is also currently funded by the Chief Scientist Office on a Research Training Fellowship (CZF/1/31)