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Around 150 staff and students from across the department gathered at Lady Margaret Hall in Oxford on Thursday 6 February for our sixth annual NDS Research Away Day.
To keep the transplantation community informed about recently published level 1 evidence in organ transplantation ESOT and the Centre for Evidence in Transplantation have developed the Transplant Trial Watch. The Transplant Trial Watch is a monthly overview of 10 new randomised controlled trials (RCTs) and systematic reviews. This page of Transplant International offers commentaries on methodological issues and clinical implications on two articles of particular interest from the CET Transplant Trial Watch monthly selection. For all high quality evidence in solid organ transplantation, visit the Transplant Library: www.transplantlibrary.com.
Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.
BACKGROUND: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. MATERIALS AND METHODS: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. RESULTS: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. CONCLUSION: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.
Recovery from chronic fatigue syndrome: a systematic review—heterogeneity of definition limits study comparison
BackgroundPaediatric chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a common illness with a major impact on quality of life. Recovery is poorly understood. Our aim was to describe definitions of recovery in paediatric CFS/ME, the rate of recovery and the time to recovery.MethodsThis systematic review included a detailed search of MEDLINE, EMBASE, PsycInfo and Cochrane Library between 1994 and July 2018. Inclusion criteria were (1) clinical trials and observational studies, (2) participants aged <19 years with CFS/ME, (3) conducted in Western Healthcare systems and (4) studies including a measure of recovery and time taken to recover.ResultsTwelve papers (10 studies) were identified, involving 826 patients (range 23–135). Recovery rates were highly varied, ranging between 4.5% and 83%.Eleven distinct definitions of recovery were used; six were composite outcomes while five used unidimensional outcomes. Outcome measures used to define recovery were highly heterogeneous. School attendance (n=8), fatigue (n=6) and physical functioning (n=4) were the most common outcomes included in definition of recovery. Only five definitions included a personal measure of recovery.ImplicationsDefinitions of recovery are highly variable, likely secondary to differences in study design, outcomes used, follow-up and study populations. Heterogeneous definitions of recovery limit meaningful comparison between studies, highlighting the need for a consensus definition going forward. Recovery is probably best defined from the child’s own perspective with a single self-reported measure. If composite measures are used for research, there should be agreement on the core outcome set used.
A LAT-Based Signaling Complex in the Immunological Synapse as Determined with Live Cell Imaging Is Less Stable in T Cells with Regulatory Capability
Peripheral immune regulation is critical for the maintenance of self-tolerance. Here we have investigated signaling processes that distinguish T cells with regulatory capability from effector T cells. The murine Tg4 T cell receptor recognizes a peptide derived from the self-antigen myelin basic protein. T cells from Tg4 T cell receptor transgenic mice can be used to generate effector T cells and three types of T cells with regulatory capability, inducible regulatory T cells, T cells tolerized by repeated in vivo antigenic peptide exposure or T cells treated with the tolerogenic drug UCB9608 (a phosphatidylinositol 4 kinase IIIβ inhibitor). We comparatively studied signaling in all of these T cells by activating them with the same antigen presenting cells presenting the same myelin basic protein peptide. Supramolecular signaling structures, as efficiently detected by large-scale live cell imaging, are critical mediators of T cell activation. The formation of a supramolecular signaling complex anchored by the adaptor protein linker for activation of T cells (LAT) was consistently terminated more rapidly in Tg4 T cells with regulatory capability. Such termination could be partially reversed by blocking the inhibitory receptors CTLA-4 and PD-1. Our work suggests that attenuation of proximal signaling may favor regulatory over effector function in T cells.
International validation of the European Organisation for Research and Treatment of Cancer QLQ-BRECON23 quality-of-life questionnaire for women undergoing breast reconstruction.
BACKGROUND: The aim was to carry out phase 4 international field-testing of the European Organisation for Research and Treatment of Cancer (EORTC) breast reconstruction (BRECON) module. The primary objective was finalization of its scale structure. Secondary objectives were evaluation of its reliability, validity, responsiveness, acceptability and interpretability in patients with breast cancer undergoing mastectomy and reconstruction. METHODS: The EORTC module development guidelines were followed. Patients were recruited from 28 centres in seven countries. A prospective cohort completed the QLQ-BRECON15 before mastectomy and the QLQ-BRECON24 at 4-8 months after reconstruction. The cross-sectional cohort completed the QLQ-BRECON24 at 1-5 years after reconstruction, and repeated this 2-8 weeks later (test-retest reliability). All participants completed debriefing questionnaires. RESULTS: A total of 438 patients were recruited, 234 in the prospective cohort and 204 in the cross-sectional cohort. A total of 414 reconstructions were immediate, with a comparable number of implants (176) and donor-site flaps (166). Control groups comprised patients who underwent two-stage implant procedures (72, 75 per cent) or delayed reconstruction (24, 25 per cent). Psychometric scale validity was supported by moderate to high item-own scale and item-total correlations (over 0·5). Questionnaire validity was confirmed by good scale-to-sample targeting, and computable scale scores exceeding 50 per cent, except nipple cosmesis (over 40 per cent). In known-group comparisons, QLQ-BRECON24 scales and items differentiated between patient groups defined by clinical criteria, such as type and timing of reconstruction, postmastectomy radiotherapy and surgical complications, with moderate effect sizes. Prospectively, sexuality and surgical side-effects scales showed significant responsiveness over time (P
Improving outcomes for primary school children at risk of cerebral visual impairment (the CVI project): protocol of a feasibility study for a cluster-randomised controlled trial and health economic evaluation
IntroductionCerebral visual impairment (CVI) refers to a spectrum of brain-related vision problems. CVI is associated with poor educational and mental health outcomes. An intervention has been developed to help children with CVI, involving input from clinicians, teachers and parents. The effectiveness of this intervention needs to be evaluated. This study aims to guide any refinements to the intervention or the design of a future cluster-randomised trial that may be needed.Methods and analysisThis study will include all methods anticipated for a future cluster-randomised controlled trial. Eight primary schools will be recruited and randomised to receive the intervention or carry on with usual practice. The intervention will comprise an information pack for schools and access to a local paediatric ophthalmology clinic (who are prepared to assess them for CVI), for up to 5% of participating children. Outcome assessments will be carried out at baseline (before randomisation) and after 4–5 months of intervention period. Assessments will include children’s self-reported quality of life, their learning ability and behaviour as reported by teachers, and family functioning reported by parents. Cost data will include service use, family expenditure on additional support (eg, private appointments and administration) and school spending and resource used in helping children with special educational needs or disability. A process evaluation (PE) will collect additional data relating to the implementation of the intervention and the trial processes, in the school and clinic settings. The protocol for the PE will be reported separately.Ethics and disseminationEthical permission was obtained from the University of Bristol Faculty of Health Sciences Ethical Committee. The results will inform the design of a future trial to assess the effectiveness and cost-effectiveness of the intervention and will be shared with participants, CVI-support groups and peer-viewed journals.Trial registration numberISRCTN13762177; Pre-results.
The impact of assistive technology on burden and psychological well-being in informal caregivers of people with dementia (ATTILA Study).
Introduction: Assistive technology and telecare (ATT) may alleviate psychological burden in informal caregivers of people with dementia. This study assessed the impact of ATT on informal caregivers' burden and psychological well-being. Methods: Individuals with dementia and their informal caregivers were recruited to a randomized-controlled trial assessing effectiveness of ATT. Caregivers were allocated to two groups according to their cared-for person's randomization to a full or basic package of ATT and were assessed on caregiver burden, state anxiety, and depression. Caregivers' data from three assessments over 6 months of the trial were analyzed. Results: No significant between- or within-group differences at any time point on caregivers' burden, anxiety, and depression levels were found. Discussion: Full ATT for people with dementia did not impact caregivers' psychological outcomes compared to basic ATT. The length of follow up was restricted to 6 months.