Fast interior point solution of quadratic programming problems arising from PDE-constrained optimization

Interior point methods provide an attractive class of approaches for solving linear, quadratic and nonlinear programming problems, due to their excellent efficiency and wide applicability. In this paper, we consider PDE-constrained optimization problems with bound constraints on the state and control variables, and their representation on the discrete level as quadratic programming problems. To tackle complex problems and achieve high accuracy in the solution, one is required to solve matrix systems of huge scale resulting from Newton iteration, and hence fast and robust methods for these systems are required. We present preconditioned iterative techniques for solving a number of these problems using Krylov subspace methods, considering in what circumstances one may predict rapid convergence of the solvers in theory, as well as the solutions observed from practical computations

Effects of perceived cocaine availability on subjective and objective responses to the drug

<p>Abstract</p> <p>Rationale</p> <p>Several lines of evidence suggest that cocaine expectancy and craving are two related phenomena. The present study assessed this potential link by contrasting reactions to varying degrees of the drug's perceived availability.</p> <p>Method</p> <p>Non-treatment seeking individuals with cocaine dependence were administered an intravenous bolus of cocaine (0.2 mg/kg) under 100% ('unblinded'; N = 33) and 33% ('blinded'; N = 12) probability conditions for the delivery of drug. Subjective ratings of craving, high, rush and low along with heart rate and blood pressure measurements were collected at baseline and every minute for 20 minutes following the infusions.</p> <p>Results</p> <p>Compared to the 'blinded' subjects, their 'unblinded' counterparts had similar craving scores on a multidimensional assessment several hours before the infusion, but reported higher craving levels on a more proximal evaluation, immediately prior to the receipt of cocaine. Furthermore, the 'unblinded' subjects displayed a more rapid onset of high and rush cocaine responses along with significantly higher cocaine-induced heart rate elevations.</p> <p>Conclusion</p> <p>These results support the hypothesis that cocaine expectancy modulates subjective and objective responses to the drug. Provided the important public health policy implications of heavy cocaine use, health policy makers and clinicians alike may favor cocaine craving assessments performed in the settings with access to the drug rather than in more neutral environments as a more meaningful marker of disease staging and assignment to the proper level of care.</p

Use of flucinolone acetonide for patients with diabetic macular oedema:patient selection criteria and early outcomes in real world setting

Introduction: Fluocinolone acetonide slow release implant (Iluvien®) was approved in December 2013 in UK for treatment of eyes which are pseudophakic with DMO that is unresponsive to other available therapies. This approval was based on evidence from FAME trials which were conducted at a time when ranibizumab was not available. There is a paucity of data on implementation of guidance on selecting patients for this treatment modality and also on the real world outcome of fluocinolone therapy especially in those patients that have been unresponsive to ranibizumab therapy. Method: Retrospective study of consecutive patients treated with fluocinolone between January and August 2014 at three sites were included to evaluate selection criteria used, baseline characteristics and clinical outcomes at 3-month time point. Results: Twenty two pseudophakic eyes of 22 consecutive patients were included. Majority of patients had prior therapy with multiple intravitreal anti-VEGF injections. Four eyes had controlled glaucoma. At baseline mean VA and CRT were 50.7 letters and 631 μm respectively. After 3 months, 18 patients had improved CRT of which 15 of them also had improved VA. No adverse effects were noted. One additional patient required IOP lowering medication. Despite being unresponsive to multiple prior therapies including laser and anti-VEGF injections, switching to fluocinolone achieved treatment benefit. Conclusion: The patient level selection criteria proposed by NICE guidance on fluocinolone appeared to be implemented. This data from this study provides new evidence on early outcomes following fluocinolone therapy in eyes with DMO which had not responded to laser and other intravitreal agents

Mature Peripheral RPE Cells Have an Intrinsic Capacity to Proliferate; A Potential Regulatory Mechanism for Age-Related Cell Loss

Mammalian peripheral retinal pigmented epithelium (RPE) cells proliferate throughout life, while central cells are senescent. It is thought that some peripheral cells migrate centrally to correct age-related central RPE loss.We ask whether this proliferative capacity is intrinsic to such cells and whether cells located centrally produce diffusible signals imposing senescence upon the former once migrated. We also ask whether there are regional differences in expression patterns of key genes involved in these features between the centre and the periphery in vivo and in vitro. Low density RPE cultures obtained from adult mice revealed significantly greater levels of proliferation when derived from peripheral compared to central tissue, but this significance declined with increasing culture density. Further, exposure to centrally conditioned media had no influence on proliferation in peripheral RPE cell cultures at the concentrations examined. Central cells expressed significantly higher levels of E-Cadherin revealing a tighter cell adhesion than in the peripheral regions. Fluorescence-labelled staining for E-Cadherin, F-actin and ZO-1 in vivo revealed different patterns with significantly increased expression on central RPE cells than those in the periphery or differences in junctional morphology. A range of other genes were investigated both in vivo and in vitro associated with RPE proliferation in order to identify gene expression differences between the centre and the periphery. Specifically, the cell cycle inhibitor p27(Kip1) was significantly elevated in central senescent regions in vivo and mTOR, associated with RPE cell senescence, was significantly elevated in the centre in comparison to the periphery.These data show that the proliferative capacity of peripheral RPE cells is intrinsic and cell-autonomous in adult mice. These differences between centre and periphery are reflected in distinct patterns in junctional markers. The regional proliferation differences may be inversely dependent to cell-cell contact

STEPWISE - STructured lifestyle Education for People WIth SchizophrEnia : a study protocol for a randomised controlled trial

BACKGROUND: People with schizophrenia are two to three times more likely to be overweight than the general population. The UK National Institute of Health and Care Excellence (NICE) recommends an annual physical health review with signposting to, or provision of, a lifestyle programme to address weight concerns and obesity. The purpose of this randomised controlled trial is to assess whether a group-based structured education programme can help people with schizophrenia to lose weight. METHODS: Design: a randomised controlled trial of a group-based structured education programme. SETTING: 10 UK community mental health trusts. PARTICIPANTS: 396 adults with schizophrenia, schizoaffective, or first-episode psychosis who are prescribed antipsychotic medication will be recruited. Participants will be overweight, obese or be concerned about their weight. INTERVENTION: participants will be randomised to either the intervention or treatment as usual (TAU). The intervention arm will receive TAU plus four 2.5-h weekly sessions of theory-based lifestyle structured group education, with maintenance contact every 2 weeks and 'booster' sessions every 3 months. All participants will receive standardised written information about healthy eating, physical activity, alcohol and smoking. OUTCOMES: the primary outcome is weight (kg) change at 1 year post randomisation. Secondary outcomes, which will be assessed at 3 and 12 months, include: the proportion of participants who maintained or reduced their weight; waist circumference; body mass index; objectively measured physical activity (wrist accelerometer); self-reported diet; blood pressure; fasting plasma glucose, lipid profile and HbA1c (baseline and 1 year only); health-related quality of life (EQ-5D-5L and RAND SF-36); (adapted) brief illness perception questionnaire; the Brief Psychiatric Rating Scale; the Client Service Receipt Inventory; medication use; smoking status; adverse events; depression symptoms (Patient Health Questionnaire-9); use of weight-loss programmes; and session feedback (intervention only). Outcome assessors will be blind to trial group allocation. Qualitative interviews with a subsample of facilitators and invention-arm participants will provide data on intervention feasibility and acceptability. Assessment of intervention fidelity will also be performed. DISCUSSION: The STEPWISE trial will provide evidence for the clinical and cost-effectiveness of a tailored intervention, which, if successful, could be implemented rapidly in the NHS. TRIAL REGISTRATION: ISRCTN19447796 , registered on 20 March 2014

Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism.

Differences in cortical morphology-in particular, cortical volume, thickness and surface area-have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences (ΔCT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of ΔCT in autism. We identify that these genes are enriched for synaptic transmission pathways and explain significant variation in ΔCT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, Pcorrected  10-14), driven entirely by downregulated genes (OR = 1.87, Pcorrected  10-15). We validated the enrichment for downregulated genes in two independent data sets: Validation 1 (OR = 1.44, Pcorrected = 0.004) and Validation 2 (OR = 1.30; Pcorrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism

Focus on Function – a randomized controlled trial comparing two rehabilitation interventions for young children with cerebral palsy

<p>Abstract</p> <p>Background</p> <p>Children with cerebral palsy receive a variety of long-term physical and occupational therapy interventions to facilitate development and to enhance functional independence in movement, self-care, play, school activities and leisure. Considerable human and financial resources are directed at the "intervention" of the problems of cerebral palsy, although the available evidence supporting current interventions is inconclusive. A considerable degree of uncertainty remains about the appropriate therapeutic approaches to manage the habilitation of children with cerebral palsy. The primary objective of this project is to conduct a multi-site randomized clinical trial to evaluate the efficacy of a task/context-focused approach compared to a child-focused remediation approach in improving performance of functional tasks and mobility, increasing participation in everyday activities, and improving quality of life in children 12 months to 5 years of age who have cerebral palsy.</p> <p>Method/Design</p> <p>A multi-centred randomized controlled trial research design will be used. Children will be recruited from a representative sample of children attending publicly-funded regional children's rehabilitation centers serving children with disabilities in Ontario and Alberta in Canada. Target sample size is 220 children with cerebral palsy aged 12 months to 5 years at recruitment date. Therapists are randomly assigned to deliver either a context-focused approach or a child-focused approach. Children follow their therapist into their treatment arm. Outcomes will be evaluated at baseline, after 6 months of treatment and at a 3-month follow-up period. Outcomes represent the components of the International Classification of Functioning, Disability and Health, including body function and structure (range of motion), activities (performance of functional tasks, motor function), participation (involvement in formal and informal activities), and environment (parent perceptions of care, parental empowerment).</p> <p>Discussion</p> <p>This paper presents the background information, design and protocol for a randomized controlled trial comparing a task/context-focused approach to a child-focused remediation approach in improving functional outcomes for young children with cerebral palsy.</p> <p>Trial registration</p> <p>[clinical trial registration #: NCT00469872]</p

Management of retinal vascular diseases: a patient-centric approach

Retinal vascular diseases are a leading cause of blindness in the Western world. Advancement in the clinical management of these diseases has been fast-paced, with new treatments becoming available as well as license extensions of existing treatments. Vascular endothelial growth factor (VEGF) has been implicated in certain retinal vascular diseases, including wet age-related macular degeneration (AMD), diabetic macular oedema (DMO), and retinal vein occlusion (RVO). Treatment of wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO with an anti-VEGF on an as needed basis, rather than a fixed schedule, allows an individualised treatment approach; providing treatment when patients are most likely to benefit from it, while minimising the number of unnecessary intravitreal injections. Thus, an individualised treatment regimen reduces the chances of over-treatment and under-treatment, optimising both the risk/benefit profile of the treatment and the efficient use of NHS resource. Streamlining of treatment for patients with wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO, by using one treatment with similar posology across all three diseases, may help to minimise burden of clinic capacity and complexity and hence optimise patient outcomes. Informed treatment decisions and efficient clinic throughput are important for optimal patient outcomes in the fast-changing field of retinal vascular diseases