IMPORTANCEMutations of the glucocerebrosidase gene, GBA1 (OMIM 606463), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported that ambroxol increases β-glucocerebrosidase (GCase) enzyme activity and reduces α-synuclein levels. These observations support a potential role for ambroxol therapy in modifying a relevant pathogenetic pathway in PD.OBJECTIVE To assess safety, tolerability, cerebrospinal fluid (CSF) penetration, and target engagement of ambroxol therapy with GCase in patients with PD with and without GBA1 mutations.INTERVENTIONS An escalating dose of oral ambroxol to 1.26 g per day.

OBJECTIVEInsulin resistance (IR) is associated with diabetes. IR is higher during puberty in both sexes, with some studies showing the increase to be independent of changes in adiposity. Few longitudinal studies have reported on children, and it remains unclear when the rise in IR that is often attributed to puberty really begins. We sought to establish from longitudinal data its relationship to pubertal onset, and interactions with age, sex, adiposity, and IGF-1.RESEARCH DESIGN AND METHODSThe EarlyBird Diabetes study is a longitudinal prospective cohort study of healthy children aged 5–14 years. Homeostasis model assessment (HOMA-IR), skinfolds (SSF), adiposity (percent fat, measured by dual-energy X-ray absorptiometry), serum leptin, and IGF-1 were measured annually in 235 children (134 boys). Pubertal onset was adduced from Tanner stage (TS) and from the age at which luteinizing hormone (LH) first became serially detectable (≥0.2 international units/L).RESULTSIR rose progressively from age 7 years, 3–4 years before TS2 was reached or LH became detectable. Rising adiposity and IGF-1 together explained 34% of the variance in IR in boys and 35% in girls (both P < 0.001) over the 3 years preceding pubertal onset. The contribution of IGF-1 to IR was greater in boys, despite their comparatively lower IGF-1 levels.CONCLUSIONSIR starts to rise in mid-childhood, some years before puberty. Its emergence relates more to the age of the child than to pubertal onset. More than 60% of the variation in IR prior to puberty was unexplained. The demography of childhood diabetes is changing, and prepubertal IR may be important.

SummaryBackgroundAlthough childhood overweight and obesity prevalence has increased substantially worldwide in the past three decades, scarce evidence exists for effective preventive strategies. We aimed to establish whether a school-based intervention for children aged 9–10 years would prevent excessive weight gain after 24 months.MethodsThis pragmatic cluster randomised controlled trial of the Healthy Lifestyles Programme (HeLP), a school-based obesity prevention intervention, was done in 32 schools in southwest England. All state-run primary and junior schools in Devon and Plymouth (UK) with enough pupils for at least one year-5 class were eligible. Schools were assigned (1:1) using a computer-generated sequence to either intervention or control, stratified by the number of year-5 classes (one vs more than one) and the proportion of children eligible for free school meals (<19% [the national average] vs ≥19%). HeLP was delivered to year-5 children (ages 9–10 years) over 1 year, and included dynamic and interactive activities such as physical activity workshops, education sessions delivered by teachers with short homework tasks, drama sessions, and setting goals to modify behaviour (with parental support and one-to-one discussions with HeLP coordinators). The primary outcome was change in body-mass index (BMI) standard deviation score (SDS) between baseline and 24 months, analysed in children with BMI data available for both timepoints. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN15811706, and the trial status is complete.FindingsBetween March 21, 2012, and Sept 30, 2013, 32 eligible schools with 1324 children were recruited, of which 16 schools (676 children) were randomly assigned to the HeLP intervention and 16 schools (648 children) to control. All schools that began the trial completed the intervention, and 1244 children (628 in intervention group and 616 in control group) had BMI data at both baseline and 24 months for the primary outcome analysis. Mean BMI SDS was 0·32 (SD 1·16) at baseline and 0·35 (1·25) at 24 months in the intervention group, and 0·18 (1·14) at baseline and 0·22 (1·22) at 24 months in the control group. With adjustment for school-level clustering, baseline BMI scores, sex, cohort, and number of year-5 classes and socioeconomic status of each school, the mean difference in BMI SDS score (intervention–control) at 24 months was −0·02 (95% CI −0·09 to 0·05), p=0·57. One parent reported an adverse event related to their child's eating and activity behaviours, but agreed for the child to continue trial participation after discussion with the chief investigator.InterpretationDespite a theoretically informed and extensively piloted intervention that achieved high levels of engagement, follow-up, and fidelity of delivery, we found no effect of the intervention on preventing overweight or obesity. Although schools are an ideal setting in which to deliver population-based interventions, school-based interventions might not be suffic...

ObjectivesMotivated by recent calls to use electronic health records for research, we reviewed the application and development of methods for addressing the bias from unmeasured confounding in longitudinal data.Study Design and SettingMethodological review of existing literature. We searched MEDLINE and EMBASE for articles addressing the threat to causal inference from unmeasured confounding in nonrandomized longitudinal health data through quasi-experimental analysis.ResultsAmong the 121 studies included for review, 84 used instrumental variable analysis (IVA), of which 36 used lagged or historical instruments. Difference-in-differences (DiD) and fixed effects (FE) models were found in 29 studies. Five of these combined IVA with DiD or FE to try to mitigate for time-dependent confounding. Other less frequently used methods included prior event rate ratio adjustment, regression discontinuity nested within pre-post studies, propensity score calibration, perturbation analysis, and negative control outcomes.ConclusionWell-established econometric methods such as DiD and IVA are commonly used to address unmeasured confounding in nonrandomized longitudinal studies, but researchers often fail to take full advantage of available longitudinal information. A range of promising new methods have been developed, but further studies are needed to understand their relative performance in different contexts before they can be recommended for widespread use.

Adiposity-related endocrine mechanisms and chronic inflammation were associated with the prepubertal decline of SHBG, and lower SHBG levels anticipated earlier puberty. These findings may be relevant to the occurrence of earlier puberty in recent decades.

Dean SG, Hillsdon M, et al. Cluster randomised controlled trial and economic and process evaluation to determine the effectiveness and cost-effectiveness of a novel intervention [Healthy Lifestyles Programme (HeLP)] to prevent obesity in school children. Public Health Res 2018;6(1). This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (www.publicationethics.org/). Public Health ResearchEditorial contact: journals.library@nihr.ac.ukThe full PHR archive is freely available to view online at www.journalslibrary.nihr.ac.uk/phr. Print-on-demand copies can be purchased from the report pages of the NIHR Journals Library website: www.journalslibrary.nihr.ac.uk Criteria for inclusion in the Public Health Research journalReports are published in Public Health Research (PHR) if (1) they have resulted from work for the PHR programme, and (2) they are of a sufficiently high scientific quality as assessed by the reviewers and editors.Reviews in Public Health Research are termed 'systematic' when the account of the search appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others. PHR programmeThe Public Health Research (PHR) programme, part of the National Institute for Health Research (NIHR), evaluates public health interventions, providing new knowledge on the benefits, costs, acceptability and wider impacts of non-NHS interventions intended to improve the health of the public and reduce inequalities in health. The scope of the programme is multi-disciplinary and broad, covering a range of interventions that improve public health. The Public Health Research programme also complements the NIHR Health Technology Assessment programme which has a growing portfolio evaluating NHS public health interventions.For more information about the PHR programme please visit the website: http://www.nets.nihr.ac.uk/programmes/phr This reportThe research reported in this issue of the journal was funded by the PHR programme as project number 10/3010/01. The contractual start date was in March 2012. The final report began editorial review in November 2016 and was accepted for publication in February 2017. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The PHR editors and production house have tried to ensure the accuracy of the authors' report and would like to thank the reviewers for their constructive comments on the final report document. However, they do not accept liability for damages or losses arising from material published in this report.This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the PHR programme or the Department of Health. If there are verbatim quotations included in this publication the views and opinions express...

Background There is modest evidence that exercise referral schemes increase physical activity in inactive individuals with chronic health conditions. There is a need to identify additional ways to improve the effects of exercise referral schemes on long-term physical activity. Objectives To determine if adding the e-coachER intervention to exercise referral schemes is more clinically effective and cost-effective in increasing physical activity after 1 year than usual exercise referral schemes. Design A pragmatic, multicentre, two-arm randomised controlled trial, with a mixed-methods process evaluation and health economic analysis. Participants were allocated in a 1 : 1 ratio to either exercise referral schemes plus e-coachER (intervention) or exercise referral schemes alone (control). Setting Patients were referred to exercise referral schemes in Plymouth, Birmingham and Glasgow. Participants There were 450 participants aged 16–74 years, with a body mass index of 30–40 kg/m2, with hypertension, prediabetes, type 2 diabetes, lower limb osteoarthritis or a current/recent history of treatment for depression, who were also inactive, contactable via e-mail and internet users. Intervention e-coachER was designed to augment exercise referral schemes. Participants received a pedometer and fridge magnet with physical activity recording sheets, and a user guide to access the web-based support in the form of seven ‘steps to health’. e-coachER aimed to build the use of behavioural skills (e.g. self-monitoring) while strengthening favourable beliefs in the importance of physical activity, competence, autonomy in physical activity choices and relatedness. All participants were referred to a standard exercise referral scheme. Primary outcome measure Minutes of moderate and vigorous physical activity in ≥ 10-minute bouts measured by an accelerometer over 1 week at 12 months, worn ≥ 16 hours per day for ≥ 4 days including ≥ 1 weekend day. Secondary outcomes Other accelerometer-derived physical activity measures, self-reported physical activity, exercise referral scheme attendance and EuroQol-5 Dimensions, five-level version, and Hospital Anxiety and Depression Scale scores were collected at 4 and 12 months post randomisation. Results Participants had a mean body mass index of 32.6 (standard deviation) 4.4 kg/m2, were referred primarily for weight loss and were mostly confident self-rated information technology users. Primary outcome analysis involving those with usable data showed a weak indicative effect in favour of the intervention group (n = 108) compared with the control group (n = 124); 11.8 weekly minutes of moderate and vigorous physical activity (95% confidence interval –2.1 to 26.0 minutes; p = 0.10). Sixty-four per cent of intervention participants logged on at least once; they gave generally positive feedback on the web-based support. The intervention had no effect on other physical activity outcomes, exercise referral scheme attendance (78% in the control group vs. 75% in the intervention group) or EuroQol-5 Dimensions, five-level version, or Hospital Anxiety and Depression Scale scores, but did enhance a number of process outcomes (i.e. confidence, importance and competence) compared with the control group at 4 months, but not at 12 months. At 12 months, the intervention group incurred an additional mean cost of £439 (95% confidence interval –£182 to £1060) compared with the control group, but generated more quality-adjusted life-years (mean 0.026, 95% confidence interval 0.013 to 0.040), with an incremental cost-effectiveness ratio of an additional £16,885 per quality-adjusted life-year. Limitations A significant proportion (46%) of participants were not included in the primary analysis because of study withdrawal and insufficient device wear-time, so the results must be interpreted with caution. The regression model fit for the primary outcome was poor because of the considerable proportion of participants [142/243 (58%)] who recorded no instances of ≥ 10-minute bouts of moderate and vigorous physical activity at 12 months post randomisation. Future work The design and rigorous evaluation of cost-effective and scalable ways to increase exercise referral scheme uptake and maintenance of moderate and vigorous physical activity are needed among patients with chronic conditions. Conclusions Adding e-coachER to usual exercise referral schemes had only a weak indicative effect on long-term rigorously defined, objectively assessed moderate and vigorous physical activity. The provision of the e-coachER support package led to an additional cost and has a 63% probability of being cost-effective based on the UK threshold of £30,000 per quality-adjusted life-year. The intervention did improve some process outcomes as specified in our logic model. Trial registration Current Controlled Trials ISRCTN15644451. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 63. See the NIHR Journals Library website for further project information.

Greater BF is associated with larger bones, but also denser bones in girls. The effects of fat and puberty are complex and gender specific, but BF of contemporary UK children does not appear to be deleterious to bone quality.