Non-Deterministic Kleene Coalgebras

In this paper, we present a systematic way of deriving (1) languages of (generalised) regular expressions, and (2) sound and complete axiomatizations thereof, for a wide variety of systems. This generalizes both the results of Kleene (on regular languages and deterministic finite automata) and Milner (on regular behaviours and finite labelled transition systems), and includes many other systems such as Mealy and Moore machines

Development of an enhanced health-economic model and cost-effectiveness analysis of tiotropium + olodaterol Respimat® fixed-dose combination for chronic obstructive pulmonary disease patients in Italy

Background: The objective of this study was to compare the cost-effectiveness of the fixed-dose combination (FDC) of tiotropium + olodaterol Respimat® FDC with tiotropium alone for patients with chronic obstructive pulmonary disease (COPD) in the Italian health care setting using a newly developed patient-level Markov model that reflects the current understanding of the disease. Methods: While previously published models have largely been based around a cohort approach using a Markov structure and GOLD stage stratification, an individual-level Markov approach was selected for the new model. Using patient-level data from the twin TOnado trials assessing Tiotropium + olodaterol Respimat® FDC versus tiotropium, outcomes were modelled based on the trough forced expiratory volume (tFEV1) of over 1000 patients in each treatment arm, tracked individually at trial visits through the 52-week trial period, and after the trial period it was assumed to decline at a constant rate based on disease stage. Exacerbation risk was estimated based on a random-effects logistic regression analysis of exacerbations in UPLIFT. Mortality by age and disease stage was estimated from an analysis of TIOSPIR trial data. Cost of bronchodilators and other medications, routine management, and costs of treatment for moderate and severe exacerbations for the Italian setting were included. A cost-effectiveness analysis was conducted over a 15-year time horizon from the perspective of the Italian National Health Service. Results: Aggregating total costs and quality-adjusted life years (QALYs) for each treatment cohort over 15 years and comparing tiotropium + olodaterol Respimat® FDC with tiotropium alone, resulted in mean incremental co

The Diabetes Manual trial protocol – a cluster randomized controlled trial of a self-management intervention for type 2 diabetes [ISRCTN06315411]

Background The Diabetes Manual is a type 2 diabetes self-management programme based upon the clinically effective 'Heart Manual'. The 12 week programme is a complex intervention theoretically underpinned by self-efficacy theory. It is a one to one intervention meeting United Kingdom requirements for structured diabetes-education and is delivered within routine primary care. Methods/design In a two-group cluster randomized controlled trial, GP practices are allocated by computer minimisation to an intervention group or a six-month deferred intervention group. We aim to recruit 250 participants from 50 practices across central England. Eligibility criteria are adults able to undertake the programme with type 2 diabetes, not taking insulin, with HbA1c over 8% (first 12 months) and following an agreed protocol change over 7% (months 13 to 18). Following randomisation, intervention nurses receive two-day training and delivered the Diabetes Manual programme to participants. Deferred intervention nurses receive the training following six-month follow-up. Primary outcome is HbA1c with total and HDL cholesterol; blood pressure, body mass index; self-efficacy and quality of life as additional outcomes. Primary analysis is between-group HbA1c differences at 6 months powered to give 80% power to detect a difference in HbA1c of 0.6%. A 12 month cohort analysis will assess maintenance of effect and assess relationship between self-efficacy and outcomes, and a qualitative study is running alongside. Discussion This trial incorporates educational and psychological diabetes interventions into a single programme and assesses both clinical and psychosocial outcomes. The trial will increase our understanding of intervention transferability between conditions, those diabetes related health behaviours that are more or less susceptible to change through efficacy enhancing mechanisms and how this impacts on clinical outcomes

Healing of fracture nonunions treated with low-intensity pulsed ultrasound (LIPUS): A systematic review and meta-analysis

Introduction: Bone fractures fail to heal and form nonunions in roughly 5% of cases, with little expectation of spontaneous healing thereafter. We present a systematic review and meta-analysis of published papers that describe nonunions treated with low-intensity pulsed ultrasound (LIPUS). Methods: Articles in PubMed, Ovid MEDLINE, CINAHL, AMED, EMBASE, Cochrane Library, and Scopus databases were searched, using an approach recommended by the Methodological Index for Non-Randomized Studies (MINORS), with a Level of Evidence rating by two reviewers independently. Studies are included here if they reported fractures older than 3 months, presented new data with a sample N ≥ 12, and reported fracture outcome (Heal/Fail). Results: Thirteen eligible papers reporting LIPUS treatment of 1,441 nonunions were evaluated. The pooled estimate of effect size for heal rate was 82% (95% CI: 77-87%), for any anatomical site and fracture age of at least 3 months, with statistical heterogeneity detected across all primary studies (Q = 41.2 (df = 12), p < 0.001, Tau2 = 0.006, I2 = 71). With a stricter definition of nonunion as fracture age of at least 8 months duration, the pooled estimate of effect size was 84% (95% CI: 77% − 91.6%; heterogeneity present: Q = 21 (df = 8), p < 0.001, Tau2 = 0.007, I2 = 62). Hypertrophic nonunions benefitted more than biologically inactive atrophic nonunions. An interval without surgery of <6 months prior to LIPUS was associated with a more favorable result. Stratification of nonunions by anatomical site revealed no statistically significant differences between upper and lower extremity long bone nonunions. Conclusions: LIPUS treatment can be an alternative to surgery for established nonunions. Given that no spontaneous healing of established nonunions is expected, and that it is challenging to test the efficacy of LIPUS for nonunion by randomized clinical trial, findings are compelling. LIPUS may be most useful in patients for whom surgery is high risk, including elderly patients at risk of delirium, or patients with dementia, extreme hypertension, extensive soft-tissue trauma, mechanical ventilation, metabolic acidosis, multiple organ failure, or coma. With an overall average success rate for LIPUS >80% this is comparable to the success of surgical treatment of non-infected nonunions

Opportunities for improving animal welfare in rodent models of epilepsy and seizures

Animal models of epilepsy and seizures, mostly involving mice and rats, are used to understand the pathophysiology of the different forms of epilepsy and their comorbidities, to identify biomarkers, and to discover new antiepileptic drugs and treatments for comorbidities. Such models represent an important area for application of the 3Rs (replacement, reduction and refinement of animal use). This report provides background information and recommendations aimed at minimising pain, suffering and distress in rodent models of epilepsy and seizures in order to improve animal welfare and optimise the quality of studies in this area. The report includes practical guidance on principles of choosing a model, induction procedures, in vivo recordings, perioperative care, welfare assessment, humane endpoints, social housing, environmental enrichment, reporting of studies and data sharing. In addition, some model-specific welfare considerations are discussed, and data gaps and areas for further research are identified. The guidance is based upon a systematic review of the scientific literature, survey of the international epilepsy research community, consultation with veterinarians and animal care and welfare officers, and the expert opinion and practical experience of the members of a Working Group convened by the United Kingdom's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs)

Perseverative Cognition and Health Behaviors: A Systematic Review and Meta-Analysis

Recent developments in stress theory have emphasized the significance of perseverative cognition (worry and rumination) in furthering our understanding of stress-disease relationships. Substantial evidence has shown that perseverative cognition (PC) is associated with somatic outcomes and numerous physiological concomitants have been identified (i.e., cardiovascular, autonomic, and endocrine nervous system activity parameters). However, there has been no synthesis of the evidence regarding the association between PC and health behaviors. This is important given such behaviors may also directly and/or indirectly influence health and disease outcomes (triggered by PC). Therefore, the aim of the current review was to synthesize available studies that have explored the relationship between worry and rumination and health behaviors (health risk: behaviors which, if performed, would be detrimental to health; health promoting: behaviors which, if performed, would be beneficial for health). A systematic review and meta-analyses of the literature were conducted. Studies were included in the review if they reported the association between PC and health behavior. Studies identified in MEDLINE or PsycINFO (k = 7504) were screened, of which 19 studies met the eligibility criteria. Random-effects meta-analyses suggested increased PC was generally associated with increased health risk behaviors but not health promoting behaviors. Further analyses indicated that increases in rumination (r = 0.122), but not reflection (r = -0.080), or worry (r = 0.048) were associated with health risk behaviors. In conclusion, these results showed that increases in PC are associated with increases in health risk behaviors (substance use, alcohol consumption, unhealthy eating, and smoking) that are driven primarily through rumination. These findings provide partial support for our hypothesis that in Brosschot et al.'s (2006) original perseverative cognition hypothesis, there may be scope for additional routes to pathogenic disease via poorer health behaviors

Psychosis Endophenotypes:A Gene-Set-Specific Polygenic Risk Score Analysis

BACKGROUND AND HYPOTHESIS: Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes. STUDY DESIGN: We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score. STUDY RESULTS: After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: -1.15 µV; 95% CI: -1.70 to -0.59 µV; P = 6 × 10-5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores. CONCLUSIONS: Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models

Knowledge networks and universities : locational and organisational aspects of knowledge transfer interactions

This paper explores the nature of the significant knowledge networks universities form with external organisations through knowledge transfer activities. Focussing on the UK higher education system, the analysis focuses on examining the extent to which organisational and locational characteristics are associated with the nature of these networks, finding that the nature of the networks universities form through knowledge transfer are related to both characteristics. In particular, we find that the institution’s status is important with more established universities are likely to have a more diverse range of organisations with which they interact, as well as a higher number of non-local interactions. In terms of geographic location, we find that universities within lagging regions tend to have more locally focused networks than universities in more leading regions. Overall, the knowledge transfer networking capacity of universities is found to be associated with the regional business environment within which they are situated, with the results going someway to confirming the importance of the role of universities in regional innovation systems, However, it also the case that more established, research focussed, universities are more likely to form part of wider , and possibly even more globalised, knowledge networks. Therefore, both the flow and stock of knowledge within regions is likely to be influenced by the networks formed by its universities, which has implications for both regional innovation capability and regional competitiveness