Renal transplantation in children managed with lymphocyte depleting agents and low-dose maintenance tacrolimus monotherapy

OBJECTIVE. Describe the safety and efficacy of antithymocyte globulin or alemtuzumab preconditioning, steroid avoidance and reduced calcineurin inhibitor (CNI) immunosuppression in 34 children undergoing renal transplantation. METHODS. ATG (n=8) or alemtuzumab (n=26) were infused at the time of transplantation. This was followed by low-dose twice a day tacrolimus monotherapy with consolidation to once daily dosing by 6 months and once every other day dosing by 12 months. Follow-up ranged from 0.5-2.9 years (mean 1.33 years), with a minimum of 6 months. RESULTS. Both ATG and alemtuzumab were well tolerated. Lymphopenia occurred routinely and resolved after 3-6 months. Acute cellular rejection occurred in 9%; it was related to medical nonadherence in two patients and resulted in one graft loss at 1.5 years. Important adverse events included transient neutropenia in 10 children (none with serious infection), and autoimmune hemolytic anemia in two (resolved with a steroid course in both and conversion to sirolimus in one). Estimated glomerular filtration rate (e-GFR) was stable and averaged 88 mL/min/1.73 m at latest follow-up. Fifteen preadolescents had a greater increase in height Z-score at 1 year (1.3 vs. 0.5, P=0.001), and a higher e-GFR (94.8±21 vs. 76.6±20 ml/min/1.73 m, P<0.05), when compared to case-matched historical controls who were weaned off steroids by 6 months after transplantation and received twice daily tacrolimus monotherapy. CONCLUSION. This simple regimen appears safe, has a low risk for acute cellular rejection or other adverse effects, and is associated with excellent growth and renal function. Such a regimen may also improve compliance and limit CNI nephrotoxicity. © 2007 Lippincott Williams & Wilkins, Inc

Free breakfasts in schools: design and conduct of a cluster randomised controlled trial of the Primary School Free Breakfast Initiative in Wales [ISRCTN18336527]

Background: School-based breakfast provision is increasingly being seen as a means of improving educational performance and dietary behaviour amongst children. Furthermore, recognition is growing that breakfast provision offers potential as a means of addressing social inequalities in these outcomes. At present however, the evidence base on the effectiveness of breakfast provision in bringing about these improvements is limited. Methods/Design: This paper describes the research design of a large scale evaluation of the effectiveness of the Welsh Assembly Government's Primary School Free Breakfast Initiative. A cluster randomised trial, with school as the unit of randomisation was used for the outcome evaluation, with a nested qualitative process evaluation. Quantitative outcome measures included dietary habits, attitudes, cognitive function, classroom behaviour, and school attendance. The study recruited 111 primary schools in Wales, of which 56 were randomly assigned to control condition and 55 to intervention. Participants were Year 5 and 6 students (aged 9–11 years) in these schools. Data were collected for all 111 schools at each of three time points: baseline, 4 month and 12 month follow-up. This was achieved through a repeated cross-sectional survey of approximately 4350 students on each of these occasions. Of those students in Year 5 at baseline, 1975 provided data at one or both of the follow-ups, forming a nested cohort. The evaluation also included a nested process evaluation, using questionnaires, semi-structured interviews and case studies with students, school staff, and local authority scheme coordinators as key informants. Discussion: An overview of the methods used for the evaluation is presented, providing an example of the feasibility of conducting robust evaluations of policy initiatives using a randomised trial design with nested process evaluation. Details are provided of response rates and the flow of participants. Reflection is offered on methodological issues encountered at various stages through the course of the study, focusing upon issues associated with conducting a randomised trial of a government policy initiative, and with conducting research in school settings. Trial registration: Current Controlled Trials ISRCTN1833652

The cost effectiveness of NHS physiotherapy support for occupational health (OH) services

Background: Musculoskeletal pain is detrimental to quality of life (QOL) and disruptive to activities of daily living. It also places a major economic burden on healthcare systems and wider society. In 2006, the Welsh Assembly Government (WAG) established a three tiered self-referral Occupational Health Physiotherapy Pilot Project (OHPPP) comprising: 1.) telephone advice and triage, 2.) face-to-face physiotherapy assessment and treatment if required, and 3.) workplace assessment and a return-to-work facilitation package as appropriate. This study aimed to evaluate the feasibility and cost-effectiveness of the pilot service. Methods: A pragmatic cohort study was undertaken, with all OHPPP service users between September 2008 and February 2009 being invited to participate. Participants were assessed on clinical status, yellow flags, sickness absence and work performance at baseline, after treatment and at 3 month follow up. Cost-effectiveness was evaluated from both top-down and bottom-up perspectives and cost per Quality Adjusted Life Year (cost/QALY) was calculated. The cost-effectiveness analysis assessed the increase in service cost that would be necessary before the cost-effectiveness of the service was compromised. Results A total of 515 patients completed questionnaires at baseline. Of these, 486 were referred for face to face assessment with a physiotherapist and were included in the analysis for the current study. 264 (54.3%) and 199 (40.9%) were retained at end of treatment and 3 month follow up respectively. An improvement was observed at follow up in all the clinical outcomes assessed, as well as a reduction in healthcare resource usage and sickness absence, and improvement in self-reported work performance. Multivariate regression indicated that baseline and current physical health were associated with work-related outcomes at follow up. The costs of the service were £194-£360 per service user depending on the method used, and the health gains contributed to a cost/QALY of £1386-£7760, which would represent value for money according to current UK thresholds. Sensitivity analyses demonstrated that the service would remain cost effective until the service costs were increased to 160% per user. Conclusions: This pragmatic evaluation of the OHPPP indicated that it was likely to be feasible in terms of service usage and could potentially be cost effective in terms of QALYs. Further, the study confirmed that improving physical health status for musculoskeletal pain patients is important in reducing problems with work capacity and related costs. This study suggests that this type of service could be potentially be useful in reducing the burden of pain and should be further investigated, ideally via randomised controlled trials assessing effectiveness and cost-effectiveness

A pragmatic randomised controlled trial of the Welsh National Exercise Referral Scheme: protocol for trial and integrated economic and process evaluation

Background: The benefits to health of a physically active lifestyle are well established and there is evidence that a sedentary lifestyle plays a significant role in the onset and progression of chronic disease. Despite a recognised need for effective public health interventions encouraging sedentary people with a medical condition to become more active, there are few rigorous evaluations of their effectiveness. Following NICE guidance, the Welsh national exercise referral scheme was implemented within the context of a pragmatic randomised controlled trial. Methods/Design: The randomised controlled trial, with nested economic and process evaluations, recruited 2,104 inactive men and women aged 16+ with coronary heart disease (CHD) risk factors and/or mild to moderate depression, anxiety or stress. Participants were recruited from 12 local health boards in Wales and referred directly by health professionals working in a range of health care settings. Consenting participants were randomised to either a 16 week tailored exercise programme run by qualified exercise professionals at community sports centres (intervention), or received an information booklet on physical activity (control). A range of validated measures assessing physical activity, mental health, psycho-social processes and health economics were administered at 6 and 12 months, with the primary 12 month outcome measure being 7 day Physical Activity Recall. The process evaluation explored factors determining the effectiveness or otherwise of the scheme, whilst the economic evaluation determined the relative cost-effectiveness of the scheme in terms of public spending. Discussion: Evaluation of such a large scale national public health intervention presents methodological challenges in terms of trial design and implementation. This study was facilitated by early collaboration with social research and policy colleagues to develop a rigorous design which included an innovative approach to patient referral and trial recruitment, a comprehensive process evaluation examining intervention delivery and an integrated economic evaluation. This will allow a unique insight into the feasibility, effectiveness and cost effectiveness of a national exercise referral scheme for participants with CHD risk factors or mild to moderate anxiety, depression, or stress and provides a potential model for future policy evaluations. Trial registration: Current Controlled Trials ISRCTN4768044

Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

SummaryWe describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Psychometric Properties and Correlates of Precarious Manhood Beliefs in 62 Nations

Precarious manhood beliefs portray manhood, relative to womanhood, as a social status that is hard to earn, easy to lose, and proven via public action. Here, we present cross-cultural data on a brief measure of precarious manhood beliefs (the Precarious Manhood Beliefs scale [PMB]) that covaries meaningfully with other cross-culturally validated gender ideologies and with country-level indices of gender equality and human development. Using data from university samples in 62 countries across 13 world regions (N = 33,417), we demonstrate: (1) the psychometric isomorphism of the PMB (i.e., its comparability in meaning and statistical properties across the individual and country levels); (2) the PMB’s distinctness from, and associations with, ambivalent sexism and ambivalence toward men; and (3) associations of the PMB with nation-level gender equality and human development. Findings are discussed in terms of their statistical and theoretical implications for understanding widely-held beliefs about the precariousness of the male gender role