Efficacy and safety of AZD1981, a CRTH2 receptor antagonist, in patients with moderate to severe COPD

SummaryObjectiveTo evaluate the efficacy and tolerability of the selective CRTh2 (DP2) receptor antagonist AZD1981 compared with placebo in patients with moderate to severe COPD.MethodsIn this multicentre, randomised, double-blind, parallel-group, phase IIa study (ClinicalTrials.gov identifier: NCT00690482) patients with moderate to severe COPD received either AZD1981 1000 mg twice daily or matching placebo for 4 weeks. Inhaled terbutaline was used as-needed as reliever medication throughout. The co-primary endpoints were change from baseline to end of treatment in pre-bronchodilator forced expiratory volume in 1 s [FEV1] and the Clinical COPD Questionnaire (CCQ). Additional endpoints included other lung function measures, 6-min walk test (6-MWT), COPD symptom score, reliever medication use and tolerability.Results118 patients were randomised to treatment (AZD1981 n = 61; placebo n = 57); 83% of patients were male and the mean age was 63 years (range 43–83). There were no significant differences in the mean difference in change from baseline to end of treatment between AZD1981 and placebo for the co-primary endpoints of pre-bronchodilator FEV1 (AZD1981–placebo: −0.015, 95% CI: −0.10 to 0.070; p = 0.72) and CCQ total score (difference: 0.042, 95% CI: −0.21 to 0.30; p = 0.75). Similarly, no differences were observed between treatments for the other outcomes of lung function, COPD symptom score, 6-MWT, BODE index, and use of reliever medication. AZD1981 was well tolerated.ConclusionThere was no beneficial clinical effect of AZD1981, at a dose of 1000 mg twice daily for 4 weeks, in patients with moderate to severe COPD. AZD1981 was well tolerated and no safety concerns were identified

Airway Wall Expression of OX40/OX40L and Interleukin-4 in Asthma

BackgroundThe costimulatory molecule OX40 and its ligand, OX40L, mediate key aspects of allergic airway inflammation in animal models of asthma, including eosinophilic airway inflammation, airway hyperresponsiveness, and T helper 2 polarization. We sought to examine OX40/OX40L and interleukin (IL)-4 expression in asthma across severities.MethodsBronchial biopsies were obtained from 27 subjects with asthma (mild Global Initiative for Asthma [GINA] 1 [n = 10], moderate GINA 2-3 [n = 7], and severe GINA 4-5 [n = 10]) and 13 healthy controls. The number of OX40+, OX40L+, IL-4+, and IL-4 receptor α (IL-4Rα)+ cells in the lamina propria and airway smooth muscle (ASM) bundle and the intensity of IL-4Rα+ expression by the ASM were assessed.ResultsThe number of OX40+, OX40L+, and IL-4+ cells in the lamina propria and OX40+ and IL-4+ cells in the ASM bundle was significantly increased in subjects with mild asthma, but not in those with moderate or severe asthma, compared with healthy controls. In the subjects with asthma, OX40/OX40L expression was positively correlated with the number of eosinophils and IL-4+ cells in the lamina propria. The number of IL-4Rα+ cells in the lamina propria was significantly increased in moderate-to-severe disease, but not in mild asthma, compared with controls. IL-4Rα expression by the ASM bundle was not different among groups.ConclusionsOX40/OX40L expression is increased in the bronchial submucosa in mild asthma, but not in moderate-to-severe disease, and is related to the degree of tissue eosinophilia and IL-4 expression. Whether these costimulatory molecules have a role as targets for asthma requires further investigation

Characterisation of the proximal airway squamous metaplasia induced by chronic tobacco smoke exposure in spontaneously hypertensive rats

<p>Abstract</p> <p>Background</p> <p>Continuous exposure to tobacco smoke (TS) is a key cause of chronic obstructive pulmonary disease (COPD), a complex multifactorial disease that is difficult to model in rodents. The spontaneously hypertensive (SH) rat exhibits several COPD-associated co-morbidities such as hypertension and increased coagulation. We have investigated whether SH rats are a more appropriate animal paradigm of COPD.</p> <p>Methods</p> <p>SH rats were exposed to TS for 6 hours/day, 3 days/week for 14 weeks, and the lung tissues examined by immunohistochemistry.</p> <p>Results</p> <p>TS induced a CK13-positive squamous metaplasia in proximal airways, which also stained for Ki67 and p63. We hypothesise that this lesion arises by basal cell proliferation, which differentiates to a squamous cell phenotype. Differences in staining profiles for the functional markers CC10 and surfactant D, but not phospho-p38, indicated loss of ability to function appropriately as secretory cells. Within the parenchyma, there were also differences in the staining profiles for CC10 and surfactant D, indicating a possible attempt to compensate for losses in proximal airways. In human COPD sections, areas of CK13-positive squamous metaplasia showed sporadic p63 staining, suggesting that unlike the rat, this is not a basal cell-driven lesion.</p> <p>Conclusion</p> <p>This study demonstrates that although proximal airway metaplasia in rat and human are both CK13+ and therefore squamous, they potentially arise by different mechanisms.</p

IMPaCT Back study protocol. Implementation of subgrouping for targeted treatment systems for low back pain patients in primary care: a prospective population-based sequential comparison.

BACKGROUND: Prognostic assessment tools to identify subgroups of patients at risk of persistent low back pain who may benefit from targeted treatments have been developed and validated in primary care. The IMPaCT Back study is investigating the effects of introducing and supporting a subgrouping for targeted treatment system in primary care. METHODS/DESIGN: A prospective, population-based, quality improvement study in one Primary Care Trust in England with a before and after design. Phases 1 and 3 collect data on current practice, attitudes and behaviour of health care practitioners, patients' outcomes and health care costs. Phase 2 introduces and supports the subgrouping for targeted treatment system, via a multi-component, quality improvement intervention that includes educational courses and outreach visits led by opinion leaders, audit/feedback, mentoring and organisational support to embed the subgrouping tools within IT and clinical management systems.We aim to recruit 1000 low back pain patients aged 18 years and over consulting 7 GP practices within one Primary Care Trust in England, UK. The study includes GPs in participating practices and physiotherapists in associated services. The primary objective is to determine the effect of the subgrouping for targeted treatment system on back pain related disability and catastrophising at 2 and 6 months, comparing data from phase 1 with phase 3. Key secondary objectives are to determine the impact on: a) GPs' and physiotherapists' attitudes and behaviour regarding low back pain; b) The process of care that patients receive; c) The cost-effectiveness and sustainability of the new clinical system. DISCUSSION: This paper details the rationale, design, methods, planned analysis and operational aspects of the IMPaCT Back study. We aim to determine whether the new subgrouping for targeted treatment system is implemented and sustained in primary care, and evaluate its impact on clinical decision-making, patient outcomes and costs. STUDY REGISTRATION: International Standard Randomised Controlled Trial Number Register ISRCTN55174281.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Effect of Narrow Spectrum Versus Selective Kinase Inhibitors on the Intestinal Proinflammatory Immune Response in Ulcerative Colitis

Background: Kinases are key mediators of inflammation, highlighting the potential of kinase inhibitors as treatments for inflammatory disorders. Selective kinase inhibitors, however, have proved disappointing, particularly in the treatment of rheumatoid arthritis and inflammatory bowel disease. Consequently, to improve efficacy, attention has turned to multikinase inhibition. Methods: The activity of a narrow spectrum kinase inhibitor, TOP1210, has been compared with selective kinase inhibitors (BIRB-796, dasatinib and BAY-61-3606) in a range of kinase assays, inflammatory cell assays, and in inflamed biopsies from patients with ulcerative colitis (UC). Effects on recombinant P38α, Src, and Syk kinase activities were assessed using Z-lyte assays (Invitrogen, Paisley, United Kingdom). Anti-inflammatory effects were assessed by measurement of proinflammatory cytokine release from peripheral blood mononuclear cells, primary macrophages, HT29 cells, inflamed colonic UC biopsies, and myofibroblasts isolated from inflamed colonic UC mucosa. Results: TOP1210 potently inhibits P38α, Src, and Syk kinase activities. Similarly, TOP1210 demonstrates potent inhibitory activity against proinflammatory cytokine release in each of the cellular assays and the inflamed colonic UC biopsies and myofibroblasts isolated from inflamed colonic UC mucosa. Generally, the selective kinase inhibitors showed limited and weaker activity in the cellular assays compared with the broad inhibitory profile of TOP1210. However, combination of the selective inhibitors led to improved efficacy and potency in both cellular and UC biopsy assays. Conclusions: Targeted, multikinase inhibition with TOP1210 leads to a broad efficacy profile in both the innate and adaptive immune responses, with significant advantages over existing selective kinase approaches, and potentially offers a much improved therapeutic benefit in inflammatory bowel disease

Economic impact of Tegaderm chlorhexidine gluconate (CHG) dressing in critically ill patients.

PURPOSE: To estimate the economic impact of a Tegaderm(TM) chlorhexidine gluconate (CHG) gel dressing compared with a standard intravenous (i.v.) dressing (defined as non-antimicrobial transparent film dressing), used for insertion site care of short-term central venous and arterial catheters (intravascular catheters) in adult critical care patients using a cost-consequence model populated with data from published sources. MATERIAL AND METHODS: A decision analytical cost-consequence model was developed which assigned each patient with an indwelling intravascular catheter and a standard dressing, a baseline risk of associated dermatitis, local infection at the catheter insertion site and catheter-related bloodstream infections (CRBSI), estimated from published secondary sources. The risks of these events for patients with a Tegaderm CHG were estimated by applying the effectiveness parameters from the clinical review to the baseline risks. Costs were accrued through costs of intervention (i.e. Tegaderm CHG or standard intravenous dressing) and hospital treatment costs depended on whether the patients had local dermatitis, local infection or CRBSI. Total costs were estimated as mean values of 10,000 probabilistic sensitivity analysis (PSA) runs. RESULTS: Tegaderm CHG resulted in an average cost-saving of £77 per patient in an intensive care unit. Tegaderm CHG also has a 98.5% probability of being cost-saving compared to standard i.v. dressings. CONCLUSIONS: The analyses suggest that Tegaderm CHG is a cost-saving strategy to reduce CRBSI and the results were robust to sensitivity analyses

Implementing stratified primary care management for low back pain: cost utility analysis alongside a prospective, population-based, sequential comparison study

STUDY DESIGN: Within-study cost-utility analysis. OBJECTIVE:To explore the cost-utility of implementing stratified care for low back pain (LBP) in general practice, compared with usual care, within risk-defined patient subgroups (that is, patients at low, medium, and high risk of persistent disabling pain). SUMMARY OF BACKGROUND DATA: Individual-level data collected alongside a prospective, sequential comparison of separate patient cohorts with 6-month follow-up. METHODS: Adopting a cost-utility framework, the base case analysis estimated the incremental LBP-related health care cost per additional quality-adjusted life year (QALY) by risk subgroup. QALYs were constructed from responses to the 3-level EQ-5D, a preference-based health-related quality of life instrument. Uncertainty was explored with cost-utility planes and acceptability curves. Sensitivity analyses examined alternative methodological approaches, including a complete case analysis, the incorporation of non-back pain-related health care use and estimation of societal costs relating to work absence. RESULTS: Stratified care was a dominant treatment strategy compared with usual care for patients at high risk, with mean health care cost savings of £124 and an incremental QALY estimate of 0.023. The likelihood that stratified care provides a cost-effective use of resources for patients at low and medium risk is no greater than 60% irrespective of a decision makers' willingness-to-pay for additional QALYs. Patients at medium and high risk of persistent disability in paid employment at 6-month follow-up reported, on average, 6 fewer days of LBP-related work absence in the stratified care cohort compared with usual care (associated societal cost savings per employed patient of £736 and £652, respectively). CONCLUSION: At the observed level of adherence to screening tool recommendations for matched treatments, stratified care for LBP is cost-effective for patients at high risk of persistent disabling LBP only. LEVEL OF EVIDENCE: 2.The IMPaCT Back study was funded by the Health Foundation (grant code: 346/4540) with support from the National Institutes for Health Research (NIHR) Primary Care Research Network-North West, the Keele Academic General Practice Partnership and the Primary Care Musculoskeletal Research Consortium. NEF was supported, in part, by a National Coordinating Centre for Research Capacity Development (NCCRCD) Primary Care Career Scientist Award and is currently supported by an NIHR Research Professorship (NIHR-RP-011-015). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.This is the final published version. It first appeared at http://journals.lww.com/spinejournal/Fulltext/2015/03150/Implementing_Stratified_Primary_Care_Management.14.aspx

Rehabilitation following rotator cuff repair: A multi-centre pilot & feasibility randomised controlled trial (RaCeR)

Objective: To evaluate the feasibility of a multi-centre randomised controlled trial to compare the clinical and cost-effectiveness of early patient-directed rehabilitation versus standard rehabilitation following surgical repair of the rotator cuff of the shoulder. Design: Two-arm, multi-centre pilot and feasibility randomised controlled trial. Setting: Five National Health Service hospitals in England. Participants: Adults (n = 73) with non-traumatic rotator cuff tears scheduled for repair were recruited and randomly allocated remotely prior to surgery. Interventions: Early patient-directed rehabilitation (n = 37); advised to remove their sling as soon as able and move as symptoms allow. Standard rehabilitation (n = 36); sling immobilisation for four weeks. Measures: (1) Randomisation of 20% or more eligible patients. (2) Difference in time out of sling of 40% or more between groups. (3) Follow-up greater than 70%. Results: 73/185 (39%) potentially eligible patients were randomised. Twenty participants were withdrawn, 11 due to not receiving rotator cuff repair. The between-group difference in proportions of participants who exceeded the cut-off of 222.6 hours out of the sling was 50% (80% CI = 29%, 72%), with the early patient-directed rehabilitation group reporting greater time out of sling. 52/73 (71%) and 52/53 (98%) participants were followed-up at 12 weeks when withdrawals were included and excluded respectively. Eighteen full-thickness re-tears were reported (early patient-directed rehabilitation = 7, standard rehabilitation = 11). Five serious adverse events were reported. Conclusion: A main randomised controlled trial is feasible but would require allocation of participants following surgery to counter the issue of withdrawal due to not receiving surgery

Results From England's 2018 Report Card on Physical Activity for Children and Youth

The Active Healthy Kids England 2018 Report Card provides an updated “state of the nation” resource regarding performances on the provision of, and support for, physical activity opportunities for children and young people. Specifically, in this paper we present and discuss key findings from the 2018 Report Card, a release that serves to revise our 2014 and 2016 report cards via the same systematic approach that incorporates best current data. To this end, these data include national surveys, peer-review outputs, and a variety of nonacademic sources including online content and reports from government and nongovernment organizations