The Growth Hormone Deficiency (GHD) Reversal Trial: effect on final height of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated GHD-a non-inferiority Randomised Controlled Trial (RCT).

BACKGROUND: Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I-GHD their condition reverses, with a normal peak GH detected in 64-82% when re-tested at FH. Therefore, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones during puberty. Despite increasing evidence for frequent I-GHD reversal, daily GH injections are traditionally continued until FH is achieved. METHODS/DESIGN: Evidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The GHD Reversal study will include 138 children from routine endocrine clinics in twelve UK and five Austrian centres with I-GHD (original peak GH < 6.7 mcg/L) whose deficiency has reversed on early re-testing. Children will be randomised to either continue or discontinue GH therapy. This phase III, international, multicentre, open-label, randomised controlled, non-inferiority trial (including an internal pilot study) will assess whether children with early I-GHD reversal who stop GH therapy achieve non-inferior near FH SDS (primary outcome; inferiority margin 0.55 SD), target height (TH) minus near FH, HRQoL, bone health index and lipid profiles (secondary outcomes) than those continuing GH. In addition, the study will assess cost-effectiveness of GH discontinuation in the early retesting scenario. DISCUSSION: If this study shows that a significant proportion of children with presumed I-GHD reversal generate enough GH naturally in puberty to achieve a near FH within the target range, then this new care pathway would rapidly improve national/international practice. An assumed 50% reversal rate would provide potential UK health service cost savings of £1.8-4.6 million (€2.05-5.24 million)/year in drug costs alone. This new care pathway would also prevent children from having unnecessary daily GH injections and consequent exposure to potential adverse effects. TRIAL REGISTRATION: EudraCT number: 2020-001006-39.

Understanding parent preferences for NHS paediatric allergy services.

OBJECTIVES: To understand parent preferences for NHS paediatric allergy services. DESIGN: A stated preference study (discrete choice experiment). SETTING: West Midlands, UK. PARTICIPANTS: A sample of parents of children aged 16 years or younger recruited from the general population through a third party company approved by the University of Birmingham. INTERVENTION: An online questionnaire with 18 choice questions describing two hypothetical paediatric allergy specialist clinics described in terms of the clinician, information provision, additional facilities, waiting times and out of pocket expenses. Main outcome measures Preference and willingness to pay estimates for each of the specified attributes. RESULTS: Parents strongly preferred that their children be reviewed by consultants or specialist nurses formally trained in allergy compared with consultants with no formal allergy training [Willingness to pay (WTP) estimates for nurse specialist £150.9 (138.8-163.2), trained allergy consultants £218.7 (205.7-231.9), compared with consultants without formal training]. They were willing to wait longer to see trained practitioners. Parents also expressed a strong preference for improving online information regarding allergies [WTP for written information £18.4 (6.1-30.6) and £72.6 for improved online information (59.9-85.3), compared with verbal information]. Specialist clinics with additional dietician and eczema support were also preferred [WTP £29.9 (19.8-40.1), compared with no additional support]. CONCLUSIONS: Parents showed strong preference for formally trained practitioners in specialist allergy clinics. Access to improved online allergy information and additional facilities within allergy clinics were also preferred. These findings have implications for future commissioning of paediatric allergy services in the UK.

Long term tapering versus standard prednisolone treatment for first episode of childhood nephrotic syndrome: phase III randomised controlled trial and economic evaluation.

OBJECTIVE: To determine whether extending initial prednisolone treatment from eight to 16 weeks in children with idiopathic steroid sensitive nephrotic syndrome improves the pattern of disease relapse. DESIGN: Double blind, parallel group, phase III randomised placebo controlled trial, including a cost effectiveness analysis. SETTING: 125 UK National Health Service district general hospitals and tertiary paediatric nephrology centres. PARTICIPANTS: 237 children aged 1-14 years with a first episode of steroid sensitive nephrotic syndrome. INTERVENTIONS: Children were randomised to receive an extended 16 week course of prednisolone (total dose 3150 mg/m2) or a standard eight week course of prednisolone (total dose 2240 mg/m2). The drug was supplied as 5 mg tablets alongside matching placebo so that participants in both groups received the same number of tablets at any time point in the study. A minimisation algorithm ensured balanced treatment allocation by ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more). MAIN OUTCOME MEASURES: The primary outcome measure was time to first relapse over a minimum follow-up of 24 months. Secondary outcome measures were relapse rate, incidence of frequently relapsing nephrotic syndrome and steroid dependent nephrotic syndrome, use of alternative immunosuppressive treatment, rates of adverse events, behavioural change using the Achenbach child behaviour checklist, quality adjusted life years, and cost effectiveness from a healthcare perspective. Analysis was by intention to treat. RESULTS: No significant difference was found in time to first relapse (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17, log rank P=0.28) or in the incidence of frequently relapsing nephrotic syndrome (extended course 60/114 (53%) v standard course 55/109 (50%), P=0.75), steroid dependent nephrotic syndrome (48/114 (42%) v 48/109 (44%), P=0.77), or requirement for alternative immunosuppressive treatment (62/114 (54%) v 61/109 (56%), P=0.81). Total prednisolone dose after completion of the trial drug was 6674 mg for the extended course versus 5475 mg for the standard course (P=0.07). There were no statistically significant differences in serious adverse event rates (extended course 19/114 (17%) v standard course 27/109 (25%), P=0.13) or adverse event rates, with the exception of behaviour, which was poorer in the standard course group. Scores on the Achenbach child behaviour checklist did not, however, differ. Extended course treatment was associated with a mean increase in generic quality of life (0.0162 additional quality adjusted life years, 95% confidence interval -0.005 to 0.037) and cost savings (difference -£1673 ($2160; €1930), 95% confidence interval -£3455 to £109). CONCLUSIONS: Clinical outcomes did not improve when the initial course of prednisolone treatment was extended from eight to 16 weeks in UK children with steroid sensitive nephrotic syndrome. However, evidence was found of a short term health economic benefit through reduced resource use and increased quality of life. TRIAL REGISTRATION: ISRCTN16645249; EudraCT 2010-022489-29.

Occipital nerve stimulation for chronic migraine--a systematic review and meta-analysis.

BACKGROUND: Chronic migraine is a debilitating headache disorder that has significant impact on quality of life. Stimulation of peripheral nerves is increasingly being used to treat chronic refractory pain including headache disorders. This systematic review examines the effectiveness and adverse effects of occipital nerve stimulation (ONS) for chronic migraine. METHODS: Databases, including the Cochrane Library, MEDLINE, EMBASE, CINAHL and clinical trial registers were searched to September 2014. Randomized controlled trials (RCTs), other controlled and uncontrolled observational studies and case series (n≥ 10) were eligible. RCTs were assessed using the Cochrane risk of bias tool. Meta-analysis was carried out using a random-effects model. Findings are presented in summary tables and forest plots. RESULTS: Five RCTs (total n=402) and seven case series (total n=115) met the inclusion criteria. Pooled results from three multicenter RCTs show that ONS was associated with a mean reduction of 2.59 days (95% CI 0.91 to 4.27, I2=0%) of prolonged, moderate to severe headache per month at 3 months compared with a sham control. Results for other outcomes generally favour ONS over sham controls but quantitative analysis was hampered by incomplete publication and reporting of trial data. Lead migration and infections are common and often require revision surgery. Open-label follow-up of RCTs and case series suggest long-term effectiveness can be maintained in some patients but evidence is limited. CONCLUSIONS: While the effectiveness of ONS compared to sham control has been shown in multiple RCTs, the average effect size is modest and may be exaggerated by bias as achieving effective blinding remains a methodological challenge. Further measures to reduce the risk of adverse events and revision surgery are needed. SYSTEMATIC REVIEW REGISTRATION: this systematic review is an update and expanded work of part of a broader review registered with PROSPERO. Registration No. CRD42012002633.

Medical device procurement in low- and middle-income settings: protocol for a systematic review.

BACKGROUND: Medical device procurement processes for low- and middle-income countries (LMICs) are a poorly understood and researched topic. To support LMIC policy formulation in this area, international public health organizations and research institutions issue a large body of predominantly grey literature including guidelines, manuals and recommendations. We propose to undertake a systematic review to identify and explore the medical device procurement methodologies suggested within this and further literature. Procurement facilitators and barriers will be identified, and methodologies for medical device prioritization under resource constraints will be discussed. METHODS/DESIGN: Searches of both bibliographic and grey literature will be conducted to identify documents relating to the procurement of medical devices in LMICs. Data will be extracted according to protocol on a number of pre-specified issues and variables. First, data relating to the specific settings described within the literature will be noted. Second, information relating to medical device procurement methodologies will be extracted, including prioritization of procurement under resource constraints, the use of evidence (e.g. cost-effectiveness evaluations, burden of disease data) as well as stakeholders participating in procurement processes. Information relating to prioritization methodologies will be extracted in the form of quotes or keywords, and analysis will include qualitative meta-summary. Narrative synthesis will be employed to analyse data otherwise extracted. The PRISMA guidelines for reporting will be followed. DISCUSSION: The current review will identify recommended medical device procurement methodologies for LMICs. Prioritization methods for medical device acquisition will be explored. Relevant stakeholders, facilitators and barriers will be discussed. The review is aimed at both LMIC decision makers and the international research community and hopes to offer a first holistic conceptualization of this topic.

Prevalence and predictors of vitamin D insufficiency in children: a Great Britain population based study.

OBJECTIVES: To evaluate the prevalence and predictors of vitamin D insufficiency (VDI) in children in Great Britain. DESIGN: A nationally representative cross-sectional study survey of children (1102) aged 4-18 years (999 white, 570 male) living in private households (January 1997-1998). Interventions provided information about dietary habits, physical activity, socio-demographics, and blood sample. Outcome measures were vitamin D insufficiency (<50 nmol/L). RESULTS: Vitamin D levels (mean = 62.1 nmol/L, 95%CI 60.4-63.7) were insufficient in 35%, and decreased with age in both sexes (p<0.001). Young People living between 53-59 degrees latitude had lower levels (compared with 50-53 degrees, p = 0.045). Dietary intake and gender had no effect on vitamin D status. A logistic regression model showed increased risk of VDI in the following: adolescents (14-18 years old), odds ratio (OR) = 3.6 (95%CI 1.8-7.2) compared with younger children (4-8 years); non white children (OR = 37 [95%CI 15-90]); blood levels taken December-May (OR = 6.5 [95%CI 4.3-10.1]); on income support (OR = 2.2 [95%CI 1.3-3.9]); not taking vitamin D supplementation (OR = 3.7 [95%CI 1.4-9.8]); being overweight (OR 1.6 [95%CI 1.0-2.5]); <1/2 hour outdoor exercise/day/week (OR = 1.5 [95%CI 1.0-2.3]); watched >2.5 hours of TV/day/week (OR = 1.6[95%CI 1.0-2.4]). CONCLUSION: We confirm a previously under-recognised risk of VDI in adolescents. The marked higher risk for VDI in non-white children suggests they should be targeted in any preventative strategies. The association of higher risk of VDI among children who exercised less outdoors, watched more TV and were overweight highlights potentially modifiable risk factors. Clearer guidelines and an increased awareness especially in adolescents are needed, as there are no recommendations for vitamin D supplementation in older children.