The incredible years therapeutic dinosaur programme to build social and emotional competence in welsh primary schools: study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>School interventions such as the Incredible Years <it>Classroom </it>Dinosaur Programme targets pupil behaviour across whole classrooms, yet for some children a more intense approach is needed. The Incredible Years <it>Therapeutic </it>Dinosaur Programme is effective for clinically referred children by enhancing social, problem-solving skills, and peer relationship-building skills when delivered in a clinical setting in small groups.</p> <p>The aim of this trial is to evaluate the effectiveness of the Therapeutic Programme, delivered with small groups of children at high-risk of developing conduct disorder, delivered in schools already implementing the Classroom Programme.</p> <p>Methods/Design</p> <p>This is a pragmatic, parallel, randomised controlled trial.</p> <p>Two hundred and forty children (aged 4-8 years) rated by their teacher as above the 'borderline cut-off' for concern on the Strengths and Difficulties Questionnaire, and their parents, will be recruited.</p> <p>Randomisation is by individual within blocks (schools); 1:1 ratio, intervention to waiting list control.</p> <p>Twenty schools will participate in two phases. Two teachers per school will deliver the programme to six intervention children for 2-hours/week for 18 weeks between baseline and first follow-up. The control children will receive the intervention after first follow up.</p> <p>Phase 1 comprises three data collection points - baseline and two follow-ups eight months apart. Phase 2 includes baseline and first follow-up.</p> <p>The Therapeutic Programme includes elements on; Learning school rules; understanding, identifying, and articulating feelings; problem solving; anger management; how to be friendly; how to do your best in school.</p> <p>Primary outcomes are; change in child social, emotional and behavioural difficulties. Secondary outcomes are; teacher and parent mental wellbeing, child academic attainment, child and teacher school attendance. Intervention delivery will be assessed for fidelity.</p> <p>Intention to treat analyses will be conducted. ANCOVA, effect sizes, mediator and moderator analyses will be applied to establish differences between conditions, and for whom the intervention works best for and why.</p> <p>Discussion</p> <p>This trial will provide information on the delivery and effectiveness of a child centred, school-based intervention delivered in small groups of children, at risk of developing more severe conduct problems. The effects on child behaviour in school and home environments, academic attainment, peer interactions, parent and teacher mental health will be assessed.</p> <p>Trial Registration</p> <p>UK Clinical Research Network UKCRNID8615</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN96803379">ISRCTN96803379</a></p

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases

Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation

Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors.The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes.The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response

Preventing Violence in Seven Countries: Global Convergence in Policies

Do governments take the measures that are supported by the best scientific evidence available? We present a brief review of the situation in: Australia, Canada, Germany, the Netherlands, Spain, the United Kingdom, and the United States. Our findings show surprisingly similar developments across countries. While all seven countries are moving towards evidence-based decision making regarding policies and programs to prevent violence, there remain a number of difficulties before this end can be achieved. For example, there continue to be few randomized controlled trials or rigorous quasi-experimental studies on aggression and violence. Results from experimental research are essential to both policy makers and researchers to determine the effectiveness of programs as well as increase our knowledge of the problem. Additionally, all noted that media attention for violence is high in their country, often leading to management by crisis with the result that policies are not based on evidence, but instead seek to appease public outrage. And perhaps because of attendant organizational problems (i.e., in many countries violence prevention was not under the guise of one particular agency or ministry), most have not developed a coordinated policy focusing on the prevention of violence and physical aggression. It is hypothesized that leaders in democratic countries, who must run for election every 4 to 6 years, may feel a need to focus on short-term planning rather than long-term preventive policies since the costs, but not the benefits for the latter would be incurred while they still served in office. We also noted a general absence of expertise beyond those within scientific circles. The need for these ideas to be more widely accepted will be an essential ingredient to real and sustaining change. This means that there must be better communication and increased understanding between researchers and policy makers. Toward those ends, the recent establishment of the Campbell Collaboration, formed to provide international systematic reviews of program effectiveness, will make these results more available and accessible to politicians, administrators and those charged with making key policy decision

Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes.Systematic review and meta-analysis.We included double-blinded, randomised controlled trials (RCTs) evaluating SGLT2-i administered in the highest approved therapeutic doses (canagliflozin 300 mg/day, dapagliflozin 10 mg/day, and empagliflozin 25 mg/day) for ≥12 weeks. Comparison groups could receive placebo or oral antidiabetic drugs (OAD) including metformin, sulphonylureas (SU), or dipeptidyl peptidase 4 inhibitors (DPP-4-i). Trials were identified through electronic databases and extensive manual searches. Primary outcomes were glycated haemoglobin A1c (HbA1c) levels, serious adverse events, death, severe hypoglycaemia, ketoacidosis and CVD. Secondary outcomes were fasting plasma glucose, body weight, blood pressure, heart rate, lipids, liver function tests, creatinine and adverse events including infections. The quality of the evidence was assessed using GRADE.Meta-analysis of 34 RCTs with 9,154 patients showed that SGLT2-i reduced HbA1c compared with placebo (mean difference -0.69%, 95% confidence interval -0.75 to -0.62%). We downgraded the evidence to 'low quality' due to variability and evidence of publication bias (P = 0.015). Canagliflozin was associated with the largest reduction in HbA1c (-0.85%, -0.99% to -0.71%). There were no differences between SGLT2-i and placebo for serious adverse events. SGLT2-i increased the risk of urinary and genital tract infections and increased serum creatinine, and exerted beneficial effects on bodyweight, blood pressure, lipids and alanine aminotransferase (moderate to low quality evidence). Analysis of 12 RCTs found a beneficial effect of SGLT2-i on HbA1c compared with OAD (-0.20%, -0.28 to -0.13%; moderate quality evidence).This review includes a large number of patients with type 2 diabetes and found that SGLT2-i reduces HbA1c with a notable increased risk in non-serious adverse events. The analyses may overestimate the intervention benefit due bias

Living with diabetes: rationale, study design and baseline characteristics for an Australian prospective cohort study

Background: Diabetes mellitus is a major global public health threat. In Australia, as elsewhere, it is responsible for a sizeable portion of the overall burden of disease, and significant costs. The psychological and social impact of diabetes on individuals with the disease can be severe, and if not adequately addressed, can lead to the worsening of the overall disease picture. The Living With Diabetes Study aims to contribute to a holistic understanding of the psychological and social aspects of diabetes mellitus

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group