Researchers' experiences of the design and conduct challenges associated with parallel-group cluster-randomised trials and views on a novel open-cohort design

BACKGROUND: Two accepted designs exist for parallel-group cluster-randomised trials (CRTs). Closed-cohort designs follow the same individuals over time with a single recruitment period before randomisation, but face challenges in settings with high attrition. (Repeated) cross-sectional designs recruit at one or more timepoints before and/or after randomisation, collecting data from different individuals present in the cluster at these timepoints, but are unsuitable for assessment of individual change over time. An 'open-cohort' design allows individual follow-up with recruitment before and after cluster-randomisation, but little literature exists on acceptability to inform their use in CRTs. AIM: To document the views and experiences of expert trialists to identify: a) Design and conduct challenges with established parallel-group CRT designs,b) Perceptions of potential benefits and barriers to implementation of open-cohort CRTs,c) Methods for minimising, and investigating the impact of, bias in open-cohort CRTs. METHODS: Qualitative consultation via two expert workshops including triallists (n = 24) who had worked on CRTs over a range of settings. Workshop transcripts were analysed using Descriptive Thematic Analysis utilising inductive and deductive coding. RESULTS: Two central organising concepts were developed. Design and conduct challenges with established CRT designs confirmed that current CRT designs are unable to deal with many of the complex research and intervention circumstances found in some trial settings (e.g. care homes). Perceptions of potential benefits and barriers of open cohort designs included themes on: approaches to recruitment; data collection; analysis; minimising/investigating the impact of bias; and how open-cohort designs might address or present CRT design challenges. Open-cohort designs were felt to provide a solution for some of the challenges current CRT designs present in some settings. CONCLUSIONS: Open-cohort CRT designs hold promise for addressing the challenges associated with standard CRT designs. Research is needed to provide clarity around definition and guidance on application.</p

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

Researchers’ experiences of the design and conduct challenges associated with parallel-group cluster-randomised trials and views on a novel open-cohort design

Background Two accepted designs exist for parallel-group cluster-randomised trials (CRTs). Closed-cohort designs follow the same individuals over time with a single recruitment period before randomisation, but face challenges in settings with high attrition. (Repeated) cross-sectional designs recruit at one or more timepoints before and/or after randomisation, collecting data from different individuals present in the cluster at these timepoints, but are unsuitable for assessment of individual change over time. An ‘open-cohort’ design allows individual follow-up with recruitment before and after cluster-randomisation, but little literature exists on acceptability to inform their use in CRTs. Aim To document the views and experiences of expert trialists to identify: a) Design and conduct challenges with established parallel-group CRT designs, b) Perceptions of potential benefits and barriers to implementation of open-cohort CRTs, c) Methods for minimising, and investigating the impact of, bias in open-cohort CRTs. Methods Qualitative consultation via two expert workshops including triallists (n = 24) who had worked on CRTs over a range of settings. Workshop transcripts were analysed using Descriptive Thematic Analysis utilising inductive and deductive coding. Results Two central organising concepts were developed. Design and conduct challenges with established CRT designs confirmed that current CRT designs are unable to deal with many of the complex research and intervention circumstances found in some trial settings (e.g. care homes). Perceptions of potential benefits and barriers of open cohort designs included themes on: approaches to recruitment; data collection; analysis; minimising/investigating the impact of bias; and how open-cohort designs might address or present CRT design challenges. Open-cohort designs were felt to provide a solution for some of the challenges current CRT designs present in some settings. Conclusions Open-cohort CRT designs hold promise for addressing the challenges associated with standard CRT designs. Research is needed to provide clarity around definition and guidance on application

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

Tumour grade on core biopsy and evidence of axillary involvement on ultrasound predicts response in elderly co-morbid patients treated with primary hormone therapy for oestrogen receptor positive breast carcinoma

A high proportion of elderly and comorbid patients die with breast cancer rather than from breast cancer. Elderly comorbid patients who initially respond to primary hormone therapy have a less than 30% incidence of delayed treatment failure during their life time; however patients with grade III disease or an abnormal axillary ultrasound are twice as likely to fail first choice PHT

Researchers' experiences of the design and conduct challenges associated with parallel-group cluster-randomised trials and views on a novel open-cohort design.

BackgroundTwo accepted designs exist for parallel-group cluster-randomised trials (CRTs). Closed-cohort designs follow the same individuals over time with a single recruitment period before randomisation, but face challenges in settings with high attrition. (Repeated) cross-sectional designs recruit at one or more timepoints before and/or after randomisation, collecting data from different individuals present in the cluster at these timepoints, but are unsuitable for assessment of individual change over time. An 'open-cohort' design allows individual follow-up with recruitment before and after cluster-randomisation, but little literature exists on acceptability to inform their use in CRTs.AimTo document the views and experiences of expert trialists to identify: a) Design and conduct challenges with established parallel-group CRT designs,b) Perceptions of potential benefits and barriers to implementation of open-cohort CRTs,c) Methods for minimising, and investigating the impact of, bias in open-cohort CRTs.MethodsQualitative consultation via two expert workshops including triallists (n = 24) who had worked on CRTs over a range of settings. Workshop transcripts were analysed using Descriptive Thematic Analysis utilising inductive and deductive coding.ResultsTwo central organising concepts were developed. Design and conduct challenges with established CRT designs confirmed that current CRT designs are unable to deal with many of the complex research and intervention circumstances found in some trial settings (e.g. care homes). Perceptions of potential benefits and barriers of open cohort designs included themes on: approaches to recruitment; data collection; analysis; minimising/investigating the impact of bias; and how open-cohort designs might address or present CRT design challenges. Open-cohort designs were felt to provide a solution for some of the challenges current CRT designs present in some settings.ConclusionsOpen-cohort CRT designs hold promise for addressing the challenges associated with standard CRT designs. Research is needed to provide clarity around definition and guidance on application

CD20-induced lymphoma cell death is independent of both caspases and its redistribution into Triton X-100 insoluble membrane rafts

Rituximab is routinely used for the treatment of neoplasia, although the mechanism of action remains uncertain. In the current study, CD20-induced apoptosis was investigated with a panel of anti-CD20 monoclonal antibodies (mAb) in a wide range of cell lines. A hierarchy of mAb activity was apparent, with the B1 mAb generally the most potent. Apoptosis through CD20 was dependent on the nature of mAb binding and correlated with the extent of homotypic cell adhesion induced. However, using anti-CD20 mAb, which vary in the extent to which they redistribute wild-type and mutant CD20 molecules to membrane rafts, we showed that CD20-induced apoptosis was independent of translocation to TX-100 insoluble rafts. Using crmA-transfected cells and caspase inhibitors, we showed that phosphatidylserine translocation and mitochondrial permeability transition evoked during CD20-induced apoptosis appeared caspase independent. Furthermore, in cytoplasts which lack mitochondria and in Bcl2-transfected cells, phosphatidylserine was still translocated to the cell surface after CD20 stimulation. Together, these data imply that CD20 can evoke apoptosis without the involvement of mitochondria and caspases and irrespective of redistribution into TX-100 insoluble membrane rafts.<br/

Modulated Self-Assembly of an Interpenetrated MIL-53 Sc Metal-Organic Framework with Excellent Volumetric H2 Storage and Working Capacity

Experimental data to accompany the manuscrip

Modulated self-assembly of an interpenetrated MIL-53 Sc metal-organic framework with excellent volumetric H2 storage and working capacity

No abstract available