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Background and Objectives Valuing children’s health states for use in economic evaluations is globally relevant and is of particular relevance in jurisdictions where a cost-utility analysis is the preferred form of analysis for decision making. Despite this, the challenges with valuing child health mean that there are many remaining questions for debate about the approach to elicitation of values. The aim of this paper was to identify and describe the methods used to value children’s health states and the specific issues that arise in the use of these methods. Methods We conducted a systematic search of electronic databases to identify studies published in English since 1990 that used preference elicitation methods to value child and adolescent (under 18 years of age) health states. Eligibility criteria comprised valuation studies concerning both child-specific patient-reported outcome measures and child health states defined in other ways, and methodological studies of valuation approaches that may or may not have yielded a value set algorithm. Results A total of 77 eligible studies were identified from which data on country setting, aims, condition (general population or clinically specific), sample size, age of respondents, the perspective that participants were asked to adopt, source of values (respondents who completed the preference elicitation tasks) and methods questions asked were extracted. Extracted data were classified and evaluated using narrative synthesis methods. The studies were classified into three groups: (1) studies comparing elicitation methods (n = 30); (2) studies comparing perspectives (n = 23); and (3) studies where no comparisons were presented (n = 26); selected studies could fall into more than one group. Overall, the studies varied considerably both in methods used and in reporting. The preference elicitation tasks included time trade-off, standard gamble, visual analogue scaling, rating/ranking, discrete choice experiments, best-worst scaling and willingness to pay elicited through a contingent valuation. Perspectives included adults’ considering the health states from their own perspective, adults taking the perspective of a child (own, other, hypothetical) and a child/adolescent taking their own or the perspective of another child. There was some evidence that children gave lower values for comparable health states than did adults that adopted their own perspective or adult/parents that adopted the perspective of children. Conclusions Differences in reporting limited the conclusions that can be formed about which methods are most suitable for eliciting preferences for children’s health and the influence of differing perspectives and values. Difficulties encountered in drawing conclusions from the data (such as lack of consensus and poor reporting making it difficult for users to choose and interpret available values) suggest that reporting guidelines are required to improve the consistency and quality of reporting of studies that value children’s health using preference-based techniques.

Objectives The EuroQol Group has developed an extended version of the EQ-5D-Y-3L with five response levels for each of its five dimensions (EQ-5D-Y-5L). The psychometric performance has been reported in several studies for the EQ-5D-Y-3L but not for the EQ-5D-Y-5L. This study aimed to psychometrically evaluate the EQ-5D-Y-3L and EQ-5D-Y-5L Chichewa (Malawi) versions. Methods The EQ-5D-Y-3L, EQ-5D-Y-5L and PedsQL™ 4.0 Chichewa versions were administered to children and adolescents aged 8–17 years in Blantyre, Malawi. Both of the EQ-5D-Y versions were evaluated for missing data, floor/ceiling effects, and validity (convergent, discriminant, known-group and empirical). Results A total of 289 participants (95 healthy, and 194 chronic and acute) self-completed the questionnaires. There was little problem with missing data (p > 0.05) with respect to gender and age, but not for school grade (p Conclusions Both versions of the EQ-5D-Y-3L and EQ-5D-Y-5L had issues with missing data in younger children. Convergent validity, discriminant validity with respect to gender and age, and known-group validity of either measures were also met for use among children and adolescents in this population, although with some limitations (discriminant validity by grade and empirical validity). The EQ-5D-Y-3L seems particularly suited for use in younger children (8–12 years) and the EQ-5D-Y-5L in adolescents (13–17 years). However, further psychometric testing is required for test re-test reliability and responsiveness that could not be carried out in this study due to COVID-19 restrictions.

IntroductionLarge-for-gestational age (LGA) fetuses have an increased risk of shoulder dystocia. This can lead to adverse neonatal outcomes and death. Early induction of labour in women with a fetus suspected to be macrosomic may mitigate the risk of shoulder dystocia. The Big Baby Trial aims to find if induction of labour at 38+0–38+4weeks’ gestation, in pregnancies with suspected LGA fetuses, reduces the incidence of shoulder dystocia.Methods and analysisThe Big Baby Trial is a multicentre, prospective, individually randomised controlled trial of induction of labour at 38+0to 38+4weeks’ gestation vs standard care as per each hospital trust (median gestation of delivery 39+4) among women whose fetuses have an estimated fetal weight >90th customised centile according to ultrasound scan at 35+0to 38+0weeks’ gestation. There is a parallel cohort study for women who decline randomisation because they opt for induction, expectant management or caesarean section. Up to 4000 women will be recruited and randomised to induction of labour or to standard care. The primary outcome is the incidence of shoulder dystocia; assessed by an independent expert group, blind to treatment allocation, from delivery records. Secondary outcomes include birth trauma, fractures, haemorrhage, caesarean section rate and length of inpatient stay. The main trial is ongoing, following an internal pilot study. A qualitative reporting, health economic evaluation and parallel process evaluation are included.Ethics and disseminationThe study received a favourable opinion from the South West—Cornwall and Plymouth Health Research Authority on 23/03/2018 (IRAS project ID 229163). Study results will be reported in the National Institute for Health Research journal library and published in an open access peer-reviewed journal. We will plan dissemination events for key stakeholders.Trial registration numberISRCTN18229892.

Background The Mental Well-being Adjusted Life Year (MWALY) is an alternative outcome measure to the quality-adjusted life year (QALY) in economic evaluations of interventions aimed at improving mental well-being. However, there is a lack of preference-based mental well-being instruments for capturing population mental well-being preferences. Objectives To derive a UK preference-based value set for the Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS). Methods 225 participants that were interviewed between December 2020 and August 2021 completed 10 composite time trade-off (C-TTO) and 10 discrete choice experiment (DCE) interviewer-administered exercises. Heteroskedastic Tobit and conditional logit models were used to model C-TTO and DCE responses respectively. The DCE utility values were rescaled to a C-TTO comparable scale through anchoring and mapping. An inverse variance weighting hybrid model (IVWHM) was used to derive weighted-average coefficients from the modelled C-TTO and DCE coefficients. Model performance was assessed using statistical diagnostics. Results The valuation responses confirmed the feasibility and face validity of the C-TTO and DCE techniques. Apart from the main effects models, statistically significant associations were estimated between the predicted C-TTO value and participants’ SWEMWBS scores, gender, ethnicities, education levels, and the interaction terms between age and useful feeling. The IVWHM was the most optimal model with the fewest logically inconsistent coefficients and the lowest pooled standard errors. The utility values generated by the rescaled DCE models and the IVWHM were generally higher than those of the C-TTO model. The predictive ability of the two DCE rescaling methods was similar according to the mean absolute deviation and root mean square deviation statistics. Conclusions This study has produced the first preference-based value set for a measure of mental well-being. The IVWHM provided a desirable blend of both C-TTO and DCE models. The value set derived by this hybrid approach can be used for cost-utility analyses of mental well-being interventions.

Additional file 1. Trial information leaflets (for schools, parents/carers and young people) and trial poster.

Additional file 4. Parent consent form and young person assent form.

Additional file 2. Process evaluation focus group question frameworks.

Additional file 3. Process evaluation family interview question framework.

Background Child and family social workers in the UK work closely with other agencies including schools and the police, and typically they are based in local authority offices. This study will evaluate the effectiveness of placing social workers in schools (SWIS) on the need for social care interventions. SWIS was piloted in three local authorities in 2018–2020, and findings from a feasibility study of the pilots suggests SWIS may operate through three key pathways: (1) by enhancing schools’ response to safeguarding issues, (2) through increased collaboration between social workers, school staff, and parents, and (3) by improving relationships between social workers and young people. Methods The study is a two-arm pragmatic cluster randomised controlled trial building on three feasibility studies which found SWIS to be promising. Social workers will work within secondary schools across local authorities in England. 280 mainstream secondary schools will be randomly allocated with a 1:1 ratio to SWIS or a comparison arm, which will be schools that continue as normal, without a social worker. The primary outcome will be the rate of Child Protection (Section 47) enquiries. Secondary outcomes will comprise rate of referrals to children’s social care, rate of Child in Need (Section 17) assessments, days spent in care, and educational attendance and attainment. The study also includes an economic evaluation, and an implementation and process evaluation. Social care outcomes will be measured in July 2022, and educational outcomes will be measured in July 2023. Days in care will be measured at both time points. Discussion Findings will explore the effectiveness and cost-effectiveness of SWIS on the need for social care interventions. A final report will be published in January 2024. Trial registration The study was registered retrospectively with the International Standard Randomised Controlled Trial Number registry on 13.11.2020 (ISRCTN90922032).

Additional file 1. The SPIRIT checklist with page numbers.

BACKGROUND: Hyperglycaemia and hypoglycaemia are common in preterm infants and have been associated with increased risk of mortality and morbidity. Interventions to reduce risk associated with these exposures are particularly challenging due to the infrequent measurement of blood glucose concentrations, with the potential of causing more harm instead of improving outcomes for these infants. Continuous glucose monitoring (CGM) is widely used in adults and children with diabetes to improve glucose control, but has not been approved for use in neonates. The REACT trial aimed to evaluate the efficacy and safety of CGM in preterm infants requiring intensive care. METHODS: This international, open-label, randomised controlled trial was done in 13 neonatal intensive care units in the UK, Spain, and the Netherlands. Infants were included if they were within 24 h of birth, had a birthweight of 1200 g or less, had a gestational age up to 33 weeks plus 6 days, and had parental written informed consent. Infants were randomly assigned (1:1) to real-time CGM or standard care (with masked CGM for comparison) using a central web randomisation system, stratified by recruiting centre and gestational age (

Additional file 2. The WAX SWAT study protocol.

Objective: To investigate the variation in severe neonatal morbidity among very preterm (VPT) infants across European regions and whether morbidity rates are higher in regions with low compared with high mortality rates.Design: Area-based cohort study of all births before 32 weeks of gestational age.Setting: 16 regions in 11 European countries in 2011/2012.Patients: Survivors to discharge from neonatal care (n=6422).Main outcome measures: Severe neonatal morbidity was defined as intraventricular haemorrhage grades III and IV, cystic periventricular leukomalacia, surgical necrotizing enterocolitis and retinopathy of prematurity grades >= 3. A secondary outcome included severe bronchopulmonary dysplasia (BPD), data available in 14 regions. Common definitions for neonatal morbidities were established before data abstraction from medical records. Regional severe neonatal morbidity rates were correlated with regional in-hospital mortality rates for live births after adjustment on maternal and neonatal characteristics.Results: 10.6% of survivors had a severe neonatal morbidity without severe BPD (regional range 6.4%23.5%) and 13.8% including severe BPD (regional range 10.0%-23.5%). Adjusted inhospital mortality was 13.7% (regional range 8.4%-18.8%). Differences between regions remained significant after consideration of maternal and neonatal characteristics (P< 0.001) and severe neonatal morbidity rates were not correlated with mortality rates (P= 0.50).Conclusion: Severe neonatal morbidity rates for VPT survivors varied widely across European regions and were independent of mortality rates.

Background Progesterone prophylaxis is widely used to prevent preterm birth but is not licensed and there is little information on long-term outcome. Objective To determine the effect of progesterone prophylaxis in women at high risk of preterm birth on obstetric, neonatal and childhood outcomes. Design Double-blind, randomised placebo-controlled trial. Setting Obstetric units in the UK and Europe between February 2009 and April 2013. Participants Women with a singleton pregnancy who are at high risk of preterm birth because of either a positive fibronectin test or a negative fibronectin test, and either previous spontaneous birth at ≤ 34 weeks+0 of gestation or a cervical length of ≤ 25 mm. Interventions Fibronectin test at 18+0 to 23+0 weeks of pregnancy to determine risk of preterm birth. Eligible women were allocated (using a web-based randomisation portal) to 200 mg of progesterone or placebo, taken vaginally daily from 22+0 to 24+0 until 34+0 weeks’ gestation. Participants, caregivers and those assessing the outcomes were blinded to group assignment until data collection was complete. Main outcome measures There were three primary outcomes, as follows: (1) obstetric – fetal death or delivery before 34+0 weeks’ gestation; (2) neonatal – a composite of death, brain injury on ultrasound scan (according to specific criteria in the protocol) and bronchopulmonary dysplasia; and (3) childhood – the Bayley-III cognitive composite score at 22–26 months of age. Results In total, 96 out of 600 (16%) women in the progesterone group and 108 out of 597 (18%) women in the placebo group had the primary obstetric outcome [odds ratio (OR) 0.86, 95% confidence interval (CI) 0.61 to 1.22]. Forty-six out of 589 (8%) babies of women in the progesterone group and 62 out of 587 (11%) babies of women in the placebo group experienced the primary neonatal outcome [OR 0.72, 95% CI 0.44 to 1.17]. The mean Bayley-III cognitive composite score of the children at 2 years of age was 97.3 points [standard deviation (SD) 17.9 points; n = 430] in the progesterone group and 97.7 points (SD 17.5 points; n = 439) in the placebo group (difference in means –0.48, 95% CI –2.77 to 1.81). Limitations Overall compliance with the intervention was 69%. Harms There were no major harms, although there was a trend of more deaths from trial entry to 2 years in the progesterone group (20/600) than in the placebo group (16/598) (OR 1.26, 95% CI 0.65 to 2.42). Conclusions In this study, progesterone had no significant beneficial or harmful effects on the primary obstetric, neonatal or childhood outcomes.The OPPTIMUM trial is now complete. We intend to participate in a comprehensive individual patient-level data meta-analysis examining women with a singleton pregnancy with a variety of risk factors for preterm birth. Trial registration Current Controlled Trials ISRCTN14568373. Funding This trial was funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC–NIHR partnership.

The relationship between health care expenditure and health outcomes has been the subject of recent academic inquiry in order to inform cost-effectiveness thresholds for health technology assessment agencies. Previous studies in public health systems have relied upon data aggregated at the national or regional level; however, there remains debate about whether the supply side effect of changes to expenditure are identifiable using data at this level of aggregation. We use detailed patient data derived from electronic neonatal records across England along with routinely available cost data to estimate the effect of changes to patient expenditure on clinical health outcomes in a well-defined patient population. A panel of 32 neonatal intensive care units for the period 2009-2013 was constructed. Accounting for the potential endogeneity of expenditure a 100 pound increase in the cost per intensive care cot day (sample average cost: 1,127) pound is estimated to reduce the risk of mortality of 0.38 percentage points (sample average mortality: 11.0%) in neonatal intensive care. This translates into a cost per life saved in neonatal intensive care of approximately 420,000 pound.

Background Process evaluation is increasingly common alongside complex randomised controlled trials (RCTs). This evaluation helps in understanding the mechanisms of impact and how the study processes were executed, and it includes any contextual factors which may have implications for the trial results and any future implementation. This process evaluation is for the Chronic Headache Education and Self-management Study (CHESS) RCT, which is evaluating an education and self-management group behavioural intervention for people with chronic headache. Chronic headache is defined as headaches which are present for 15 or more days per month. The most common types are chronic migraine and chronic tension type and medication overuse headaches. Methods We will use a mixed methods approach. Quantitative data will be taken from routine trial data which will help us to assess the reach of the study; i.e. did we reach those whom we expected and from where? Intervention attendance (dose received) and attrition and qualitative data will augment our understanding about reasons why people may not wish to take part in or failed to attend sessions. Interviews with intervention facilitators and trial participants will gain different perspectives on taking part in the trial. Fidelity will be assessed through listening to audio recordings for adherence to course content and competence of the facilitation of a sample of sessions. Discussion Our process evaluation will allow us to gain insight into how the trial was delivered, the obstacles and enablers encountered and the possible reasons why the interventions may or may not be effective. Trial registration ISRCTN79708100. Registered on 16 December 2015. Electronic supplementary material The online version of this article (10.1186/s13063-019-3372-x) contains supplementary material, which is available to authorized users.

Background: Clinical data offer potential to advance patient care. Neonatal specialised care is a high cost NHS service received by approximately 80,000 newborn infants each year. Objectives: To 1) develop the use of routinely recorded operational clinical data from Electronic Patient Records (EPR), secure national coverage, evaluate and improve the quality of clinical data, and develop their use as a national resource to improve neonatal healthcare and outcomes; test the hypotheses that 2) clinical and research data are of comparable quality; 3) routine NHS clinical assessment at age two-years reliably identifies children with neurodevelopmental impairment; and 4) trial-based economic evaluations of neonatal interventions can be reliably conducted using clinical data; 5) test methods to link NHS datasets; 6) evaluate parent views of personal data in research Design: Six interrelated work-streams; quarterly extractions of predefined data from neonatal EPR; approvals from the National Research Ethics Service, Health Research Authority Confidentiality Advisory Group, Caldicott Guardians and lead neonatal clinicians of participating NHS Trusts Setting: NHS neonatal units Participants: Neonatal clinical teams; parents of babies admitted to NHS neonatal units Interventions: In work-stream 3 we employed the Bayley-III scales to evaluate neurodevelopmental status and the Quantitative Checklist of Autism in Toddlers (Q-CHAT) to evaluate social-communication skills. In work-stream 6 we recruited parents with previous experience of a child in neonatal care to assist in the design of a questionnaire directed at the parents of infants admitted to neonatal units. Data sources: Data extracted from the EPR of admissions to NHS neonatal units Main outcomes and results: We created a National Neonatal Research Database (NNRD) containing a defined extract from real-time, point-of-care, clinician-entered EPR from all NHS neonatal units in England, Wales and Scotland (n=200), established a UK Neonatal Collaborative of all NHS Trusts providing neonatal specialised care, and created a new NHS Information standard, the Neonatal Data-Set (ISB 1595, See: http://webarchive.nationalarchives.gov.uk/+/http://www.isb.nhs.uk/documents/isb-1595/amd-32-2012/index_html, accessed 25/06/2018). We found low discordancy between clinical (NNRD) and research data for most important infant and maternal characteristics, and higher prevalence clinical outcomes. Compared with research assessments, NHS clinical assessment at age two-years has lower sensitivity but high specificity for identifying children with neurodevelopmental impairment. Completeness and quality are higher for clinical than administrative NHS data; linkage is feasible and substantially enhances data quality and scope. The majority of hospital resource inputs for economic evaluations of neonatal interventions can be extracted reliably from the NNRD. In general there is strong parent support for sharing routine clinical data for research purposes. Limitations: We were only able to include data from all English neonatal units from 2012 onwards and conduct only limited cross validation of NNRD data directly against data in paper case notes. We were unable to conduct qualitative analyses of parent perspectives. We were also only able to assess the utility of trial-based economic evaluations of neonatal interventions using a single trial. We suggest results should be validated against other trials. Conclusions: We show it is possible to obtain research-standard data from neonatal EPR, and achieve complete population coverage but highlight the importance of implementing systematic examination of NHS data quality and completeness and testing methods to improve these measures. Currently available EPR data do not enable ascertainment of neurodevelopmental outcomes reliably in very preterm infants. Measures to maintain high quality and completeness of clinical and administrative data are important health service goals. As parent support for sharing clinical data for research is underpinned by strong altruistic motivation, improving wider public understanding of benefits may enhance informed decision making. Future work: We aim to implement a new paradigm for newborn healthcare in which continuous incremental improvement is achieved efficiently and cost-effectively by close integration of evidence generation with clinical care through the use of high quality EPR data. In future work we aim to automate completeness and quality checks and make recording processes more “user-friendly” and constructed in ways to minimise the likelihood of missing or erroneous entries. The development of criteria that provide assurance that data conform to pre-specified completeness and quality criteria would be an important development. The benefits of EPR data might be extended by testing their use in large pragmatic clinical trials. It would also be of value to develop methods to quality assure EPR data including involving parents, and link the NNRD to other health, social care and educational datasets to facilitate the acquisition of life-long outcomes across multiple domains.

Background and aims: Little is known about the long-term economic consequences of smoking during pregnancy. We estimated the association between smoking in pregnancy and the costs of delivering health-care to infants and children in England, and investigated which aspects of care are the key drivers of these costs.Methods: We used Hospital Episode Statistics (HES) linked with Clinical Practice Research Datalink (CPRD) data in England from January 2003 to January 2015 in children with longitudinal data for at least 1, 5 and 10 years after birth. Poisson regression provided rate ratios (RR) and 95% confidence intervals (CIs) comparing health-care episode rates between those exposed and not exposed to smoking during pregnancy. Linear regression was used to compare estimated costs between groups (pound sterling, 2015 prices) and generalized linear multivariable (GLM) models adjusted for potentially moderating factors.Results: A total of 93152 singleton pregnancies with the required data were identified. Maternal smoking in pregnancy was associated with higher primary care, prescription and hospital in-patient episode rates, but lower out-patient visit and diagnostic test rates. Adjusting for year of birth, socio-economic deprivation, parity, sex of child and delivery method showed that maternal smoking in pregnancy was associated with increased child health-care costs at 1 year [average cost difference for children of smokers, beta = pound 91.18, 95% confidence interval (CI) = pound 47.52-134.83 and 5 years of age (beta = pound 221.80, 95% CI = pound 17.78-425.83], but not at 10 years of age (beta = pound 365.94, 95% CI = - pound 192.72 to pound 924.60).Conclusion: In England, maternal smoking in pregnancy is associated with increased child health-care costs over the first 5 years of life; these costs are driven primarily by greater hospital in-patient care.

Aim The aim of this study was to compare the cost-effectiveness of intramedullary nail fixation and ‘locking’ plate fixation in the treatment of extra-articular fractures of the distal tibia. Patients and Methods An economic evaluation was conducted from the perspective of the United Kingdom National Health Service (NHS) and personal social services (PSS), based on evidence from the Fixation of Distal Tibia Fractures (UK FixDT) multicentre parallel trial. Data from 321 patients were available for analysis. Costs were collected prospectively over the 12-month follow-up period using trial case report forms and participant-completed questionnaires. Cost-effectiveness was reported in terms of incremental cost per quality adjusted life year (QALY) gained, and net monetary benefit. Sensitivity analyses were conducted to test the robustness of cost-effectiveness estimates. Results Mean NHS and PSS costs were significantly lower for patients treated with an intramedullary nail than for those treated with a locking plate (-£970, 95% confidence interval (CI) -1685 to -256; p = 0.05). There was a small increase in QALYs gained in the nail fixation group (0.01, 95% CI -0.03 to 0.06; p = 0.52). The probability of cost-effectiveness for nail fixation exceeded 90% at cost-effectiveness thresholds as low as £15 000 per additional QALY. The cost-effectiveness results remained robust to several sensitivity analyses. Conclusion This trial-based economic evaluation suggests that nail fixation is a cost-effective alternative to locking plate fixation.

Rigorous estimates of preference-based utilities are important inputs into economic evaluations of childhood obesity interventions, yet no published review currently exists examining utility by weight status in paediatric populations. A comprehensive systematic literature review and meta-analysis was therefore undertaken, pooling data on preference-based health state utilities by weight status in children using a random-effects model. Tests for heterogeneity were performed, and publication bias was assessed. Of 3,434 potentially relevant studies identified, 11 met our eligibility criteria. Estimates of Cohen's d statistic suggested a small effect of weight status on preference-based utilities. Mean utility values were estimated as 0.85 (95% uncertainty interval [UI] 0.84–0.87), 0.83 (95% UI 0.81–0.85), 0.82 (95% UI 0.79–0.84) and 0.83 (95% UI 0.80–0.86) for healthy weight, overweight, obese and overweight/obese states, respectively. Meta-analysis of studies reporting utility values for both healthy weight and overweight/obese participants found a statistically significant weighted mean difference (0.015, 95% UI 0.003–0.026). A small but statistically significant difference was also estimated between healthy weight and overweight participants (0.011, 95% UI 0.004–0.018). Study findings suggest that paediatric-specific benefits of obesity interventions may not be well reflected by available utility measures, potentially underestimating cost-effectiveness if weight loss in childhood/adolescence improves health or well-being.\ud

INTRODUCTION: Hyperglycaemia is common in the very preterm infant and has been associated with adverse outcomes. Preventing hyperglycaemia without increasing the risk of hypoglycaemia has proved challenging. The development of real-time continuous glucose monitors (CGM) to inform treatment decisions provides an opportunity to reduce this risk. This study aims to assess the feasibility of CGM combined with a specifically designed paper guideline to target glucose control in the preterm infant. METHODS AND ANALYSES: The Real Time Continuous Glucose Monitoring in Neonatal Intensive Care (REACT) trial is an international multicentre randomised controlled trial. 200 preterm infants =1200 g and =24 hours of age will be randomly allocated to either real-time CGM or standard care (with blinded CGM data collection). The primary outcome is time in target 2.6-10 mmol/L during the study intervention assessed using CGM. Secondary outcomes include efficacy relating to glucose control, utility including staff acceptability, safety outcomes relating to incidence and prevalence of hypoglycaemia and health economic analyses. ETHICS AND DISSEMINATION: The REACT trial has been approved by the National Health Service Health Research Authority National Research Ethics Service Committee East of England (Cambridge Central); Medical Ethics Review Committee, VU University Medical Centre, Amsterdam, The Netherlands and the Research Ethics Committee, Sant Joan de Déu Research Foundation, Barcelona, Spain. Recruitment began in July 2016 and will continue until mid-2018. The trial has been adopted by the National Institute of Health Research Clinical Research Network portfolio (ID: 18826) and is registered with anInternational Standard Randomised Control Number (ISRCTN registry ID: 12793535). Dissemination plans include presentations at scientific conferences, scientific publications and efforts at stakeholder engagement. TRIAL REGISTRATION NUMBER: ISRCTN12793535; Pre-results.

Objective Given the continuing debate about the benefits of caesarean section for very preterm infants, we sought to describe caesarean section rates for infants between 28 and 31 weeks of gestation in European regions and their association with regional mortality and short-term morbidity. Study design Singletons and twins without lethal congenital anomalies alive at onset of labour from 28 to 31 weeks of gestation from the 2003 MOSAIC cohort of very preterm births in 10 European regions were analysed (N = 3310). Determinants included maternal and fetal characteristics as well as regional caesarean section rates for all births. We explored correlations between caesarean section rates and mortality and morbidity on the regional level. Results 95% of infants from pregnancies complicated by hypertension or severe growth restriction detected antenatally were delivered by caesarean section (regional range: 90–100%) versus 55.4% (range: 29–84%) for other pregnancies. Regional caesarean section rates for births at all gestations ranged from 14% to 38% and were correlated with very preterm caesarean rates (p = 0.011). Determinants of caesarean section differed between regions with high versus low rates: multiples were more likely to be born by caesarean section in regions with high rates. There were no regional level correlations between caesarean section rates and mortality and morbidity. Conclusions With the exception of pregnancies with hypertension and growth restriction, there was broad variation in very preterm caesarean section rates between regions after adjustment for clinical factors. Given maternal risks associated with caesarean section, more research on its optimal use for very preterm deliveries is necessary.

Background: Human immunodeficiency virus self-testing (HIVST) is effective, with scale-up underway in sub-Saharan Africa. We assessed cost-effectiveness of adding HIVST to existing facility-based HIV testing and counseling (HTC) services. Both 2010 (initiate at CD4

Health economists working on clinical trial based economic evaluations are often asked at a preliminary stages of studies, and sometimes before data are available, to propose a plan for the collection and analysis of information on resource use, costs and quality of life. Questions that frequently arise when designing a Health Economics Analysis Plan (HEAP) for a clinical trial include what information should be included as standard within the HEAP, whether and how a proposed plan can be changed, how health economists and statisticians should split responsibility for data preparation and analyses, how missing data should be dealt with, and whether there are circumstances when a HEAP is not needed (for example in a feasibility study).

Introduction Pregnancy and the first few years of a child’s life are important windows of opportunity in which to equalize life chances. A Better Start (ABS) is an area-based intervention being delivered in five areas of socioeconomic disadvantage across England. This protocol describes an evaluation of the impact and cost-effectiveness of ABS. Methods and analysis The evaluation of ABS comprises a mixed-methods design including impact, cost effectiveness and process components. It involves a cohort study in the five ABS areas and 15 matched comparison sites (n=2885), beginning in pregnancy in 2017 and ending in 2024 when the child is age 7, with a separate cross-sectional baseline survey in 2016/17. Process data will include a profiling of the structure and services being provided in the five ABS sites at baseline and yearly thereafter, and data regarding the participating families and the services that they receive. Eligible participants will include pregnant women living within the designated sites, with recruitment beginning at 16 weeks of pregnancy. Data collection will involve interviewer-administered and self-completion surveys at eight time-points. Primary outcomes include nutrition, socio-emotional development, speech, language and learning. Data analysis will include the use of propensity score techniques to construct matched programme and comparison groups, and a range of statistical techniques to calculate the difference in differences between the intervention and comparison groups. The economic evaluation will involve a within-cohort study economic evaluation to compare individual-level costs and outcomes, and a decision analytic cost-effectiveness model to estimate the expected incremental cost per unit change in primary outcomes for ABS in comparison to usual care. Ethics and dissemination Ethical approval to conduct the study has been obtained. The learning and dissemination workstream involves working within and across the sites to generate learning via communities of practice and a range of learning and dissemination events. STRENGTHS AND LIMITATIONS OF STUDY • The study involves a large longitudinal design with matched comparison sites • The designation of ABS areas was not random, and statistical matching will be used to select comparison areas and propensity score techniques will be used to match individual in ABS areas to individuals in comparison areas • Concurrent implementation data will provide important information about systems level change • Recruitment in pregnancy of disadvantaged women will present many difficulties and uptake may be low • Loss to follow-up by 7 years may be high

Summary Background Systemic sepsis is a major cause of death in preterm neonates. There are compelling theoretical reasons why treatment with haemopoietic colony-stimulating factors might reduce sepsis and improve outcomes, and as a consequence these agents have entered into use in neonatal medicine without adequate evidence. We assessed whether granulocyte-macrophage colony stimulating factor (GM-CSF) administered as prophylaxis to preterm neonates at high risk of neutropenia would reduce sepsis, mortality, and morbidity. Methods We undertook a single-blind, multicentre, randomised controlled trial in 26 centres between June, 2000, and June, 2006. 280 neonates of below or equal to 31 weeks' gestation and below the 10th centile for birthweight were randomised within 72 h of birth to receive GM-CSF 10 μg/kg per day subcutaneously for 5 days or standard management. From recruitment to day 28 a detailed daily clinical record form was completed by the treating clinicians. Primary outcome was sepsis-free survival to 14 days from trial entry. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN42553489. Findings Neutrophil counts after trial entry rose significantly more rapidly in infants treated with GM-CSF than in control infants during the first 11 days (difference between neutrophil count slopes 0·34×10 9 /L/day; 95% CI 0·12–0·56). There was no significant difference in sepsis-free survival for all infants (93 of 139 treated infants, 105 of 141 control infants; difference −8%, 95% CI −18 to 3). A meta-analysis of this trial and previous published prophylactic trials showed no survival benefit. Interpretation Early postnatal prophylactic GM-CSF corrects neutropenia but does not reduce sepsis or improve survival and short-term outcomes in extremely preterm neonates. Funding Action Medical Research.

Background The relationship between monogenic and polygenic forms of epilepsy is poorly understood, and the extent to which the genetic and acquired epilepsies share common pathways is unclear. Here, we use an integrated systems-level analysis of brain gene expression data to identify molecular networks disrupted in epilepsy. Results We identify a co-expression network of 320 genes (M30), which is significantly enriched for non-synonymous de novo mutations ascertained from patients with monogenic epilepsy, and for common variants associated with polygenic epilepsy. The genes in M30 network are expressed widely in the human brain under tight developmental control, and encode physically interacting proteins involved in synaptic processes. The most highly connected proteins within M30 network are preferentially disrupted by deleterious de novo mutations for monogenic epilepsy, in line with the centrality-lethality hypothesis. Analysis of M30 expression revealed consistent down-regulation in the epileptic brain in heterogeneous forms of epilepsy including human temporal lobe epilepsy, a mouse model of acquired temporal lobe epilepsy, and a mouse model of monogenic Dravet (SCN1A) disease. These results suggest functional disruption of M30 via gene mutation or altered expression as a convergent mechanism regulating susceptibility to epilepsy broadly. Using the large collection of drug-induced gene expression data from Connectivity Map, several drugs were predicted to preferentially restore the down-regulation of M30 in epilepsy toward health, most notably valproic acid, whose effect on M30 expression was replicated in neurons. Conclusions Taken together, our results suggest targeting the expression of M30 as a potential new therapeutic strategy in epilepsy.

Introduction Femoroacetabular impingement (FAI) syndrome is a recognised cause of young adult hip pain. There has been a large increase in the number of patients undergoing arthroscopic surgery for FAI; however, a recent Cochrane review highlighted that there are no randomised controlled trials (RCTs) evaluating treatment effectiveness. We aim to compare the clinical and cost-effectiveness of arthroscopic surgery versus best conservative care for patients with FAI syndrome.\ud \ud Methods We will conduct a multicentre, pragmatic, assessor-blinded, two parallel arm, RCT comparing arthroscopic surgery to physiotherapy-led best conservative care. 24 hospitals treating NHS patients will recruit 344 patients over a 26-month recruitment period. Symptomatic adults with radiographic signs of FAI morphology who are considered suitable for arthroscopic surgery by their surgeon will be eligible. Patients will be excluded if they have radiographic evidence of osteoarthritis, previous significant hip pathology or previous shape changing surgery. Participants will be allocated in a ratio of 1:1 to receive arthroscopic surgery or conservative care. Recruitment will be monitored and supported by qualitative intervention to optimise informed consent and recruitment. The primary outcome will be pain and function assessed by the international hip outcome tool 33 (iHOT-33) measured 1-year following randomisation. Secondary outcomes include general health (short form 12), quality of life (EQ5D-5L) and patient satisfaction. The primary analysis will compare change in pain and function (iHOT-33) at 12 months between the treatment groups, on an intention-to-treat basis, presented as the mean difference between the trial groups with 95% CIs. The study is funded by the Health Technology Assessment Programme (13/103/02).\ud \ud Ethics and dissemination Ethical approval is granted by the Edgbaston Research Ethics committee (14/WM/0124). The results will be disseminated through open access peer-reviewed publications, including Health Technology Assessment, and presented at relevant conferences.\ud \ud Trial registration number ISRCTN64081839; Pre-results.

Although high income countries have made substantial progress towards reducing child mortality over recent decades, rates vary markedly between and within countries, and modifiable factors continue to be identified in many deaths. A series of three articles in The Lancet has described the epidemiology of child mortality and a standardised approach to child death reviews in high income countries. Patterns of child mortality at different ages are delineated into five broad categories: perinatal, congenital, acquired natural, external, and unexplained; while contributory factors are described across four broad domains: factors intrinsic to the child, the physical environment, the social environment, and service delivery. This commentary attempts to draw on the conclusions of these three articles and make practical recommendations on strategies in three key areas with perhaps the greatest potential to further reduce child mortality in high income countries: perinatal conditions, particularly preterm birth; acquired natural conditions, such as sepsis or acute respiratory problems; and external causes, including road traffic fatalities.

Musculoskeletal shoulder problems are common after breast cancer treatment. Early postoperative exercises targeting the upper limb may improve shoulder function. This protocol describes a National Institute for Health Research-funded randomised controlled trial (RCT) to evaluate the clinical and cost-effectiveness of an early supervised structured exercise programme compared with usual care, for women at high risk of developing shoulder problems after breast cancer surgery.MethodsThis pragmatic two-armed, multicentre RCT is underway within secondary care in the UK. PRevention Of Shoulder ProblEms tRial (PROSPER) aims to recruit 350 women from approximately 15 UK centres with follow-up at 6 weeks, 6 and 12 months after randomisation. Recruitment processes and intervention development were optimised through qualitative research during a 6-month internal pilot phase. Participants are randomised to the PROSPER intervention or best practice usual care only. The PROSPER intervention is delivered by physiotherapists and incorporates three main components: shoulder-specific exercises targeting range of movement and strength; general physical activity and behavioural strategies to encourage adherence and support exercise behaviour. The primary outcome is upper arm function assessed using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire at 12 months postrandomisation. Secondary outcomes include DASH subscales, acute and chronic pain, complications, health-related quality of life and healthcare resource use. We will interview a subsample of 20 participants to explore their experiences of the trial interventions.DiscussionThe PROSPER study is the first multicentre UK clinical trial to investigate the clinical and cost-effectiveness of supported exercise in the prevention of shoulder problems in high-risk women undergoing breast cancer surgery. The findings will inform future clinical practice and provide valuable insight into the role of physiotherapy-supported exercise in breast cancer rehabilitation.Protocol versionVersion 2.1; dated 11 January 2017Trial registration numberISRCTN35358984; Pre-results.

Contains fulltext : 88875.pdf (Publisher’s version ) (Closed access) BACKGROUND: About 10% of twins are born before 32 weeks of gestation and very preterm birth rates are increasing. Preterm twins tend to have more favourable outcomes than singletons of the same gestational age, but fewer data are available for very preterm infants. This study aims to determine whether outcomes differ between very preterm twins and singletons. METHOD: This study was of a population-based cohort of very preterm babies in 10 European regions in 2003. Mortality and morbidity to discharge from hospital were compared for twins and singletons between 24 and 31 weeks of gestation, who were alive at the onset of labour and without lethal congenital anomalies. Clinical characteristics, pregnancy complications and healthcare factors were taken into consideration. RESULTS: Between 28 and 31 weeks of gestation, mortality and oxygen dependency at 36 corrected weeks of gestation were lower for twins than singletons (3.9 versus 6.5% and 7.1 versus 10.4%, respectively), but this advantage disappeared after controlling for medical and healthcare factors. Hypertension, growth restriction and haemorrhaging were less frequent complications of twin birth and more twins received antenatal corticosteroids and were born in level III units. In contrast, between 24 and 27 weeks of gestation, twins had higher adjusted risks of mortality and Grade III/IV intraventricular haemorrhaging [adjusted ORs 1.5 (95% CI 1.1-2.2) and 1.5 (1.0-2.1)]. These adverse outcomes were concentrated among twins from same sex pairs with discordant birthweights. CONCLUSIONS: Between 24 and 27 weeks of gestation, risks of mortality and severe cranial haemorrhaging were higher for twins than singletons if they were from same sex pairs with discordant birthweights. 01 april 2010

OBJECTIVES. We sought to compare guidelines for level III units in 10 European regions and analyze the characteristics of neonatal units that care for very preterm infants. METHODS. The MOSAIC (Models of Organising Access to Intensive Care for Very Preterm Births) project combined a prospective cohort study on all births between 22 and 31 completed weeks of gestation in 10 European regions and a survey of neonatal unit characteristics. Units that admitted ≥5 infants at RESULTS. Six of 9 guidelines for level III units included minimum size criteria, based on number of intensive care beds (6 guidelines), neonatal admissions (2), ventilated patients (1), obstetric intensive care beds (1), and deliveries (2). The characteristics of level III units varied, and many were small or unspecialized by recommended criteria: 36% had fewer than 50 very preterm annual admissions, 22% ventilated fewer than 50 infants annually, and 28% had fewer than 6 intensive care beds. Level II units were less specialized, but some provided mechanical ventilation (57%) or high-frequency ventilation (20%) or had neonatal surgery facilities (17%). Sixty-nine percent of level III and 36% of level I or II units had continuous medical coverage by a qualified pediatrician. Twenty-two percent of infants who were CONCLUSIONS. No consensus exists in Europe about size or other criteria for NICUs. A better understanding of the characteristics associated with high-quality neonatal care is needed, given the high proportion of very preterm infants who are cared for in units that are considered small or less specialized by many recommendations.

Objectives To characterize early childhood social-communication skills and autistic traits in children born very preterm using the Quantitative Checklist for Autism in Toddlers (Q-CHAT) and explore neonatal and sociodemographic factors associated with Q-CHAT scores. Study design Parents of children born before 30 weeks gestation and enrolled in a study evaluating routinely collected neurodevelopmental data between the post-menstrual ages of 20 and 28 months were invited to complete the Q-CHAT questionnaire. Children with severe neurosensory disabilities and cerebral palsy were excluded. Participants received neurodevelopmental assessments using the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III). Q-CHAT scores of this preterm cohort were compared with published general population scores. The association between Bayley-III cognitive and language scores and neonatal and sociodemographic factors with Q-CHAT scores were examined. Results Q-CHAT questionnaires were completed from 141 participants. At a mean post-menstrual age of 24 months, the Q-CHAT scores of the preterm cohort (mean 33.7, SD 8.3) were significantly higher than published general population scores (mean 26.7; SD 7.8), indicating greater social-communication difficulty and autistic behavior. Preterm children received higher scores, particularly in the categories of restricted, repetitive, stereotyped behavior, communication, and sensory abnormalities. Lower Bayley-III language scores and non-white ethnicity were associated with higher Q-CHAT scores. Conclusions Preterm children display greater social-communication difficulty and autistic behavior than the general population in early childhood as assessed by the Q-CHAT. The implications for longer-term outcome will be important to assess.

Background Linkage between routinely collected hospital birth and other records offers the potential for epidemiological and public health research by developing population-level birth cohorts with cradle-to-grave follow-up. Data from births in English National Health Service hospitals are collected in the Hospital Episode Statistics (HES) database but are of uncertain quality. Methods We examined the range and completeness of birth information recorded in HES and tested an approach for minimizing the effect of hospital-level variations by selecting hospitals with high completeness of recording (≥90%) for key fields. We discuss important methodological considerations when using routine healthcare data to develop a birth cohort. Results The proportion of missing data in key birth record fields has been decreasing annually, such as gestational age and birth weight (from 46.2 and 43.9% in 2005/06 to 18.1 and 16.9% in 2009/10, respectively). We compared the important characteristics such as size and access to specialist neonatal care between 71 high-coding and 85 low-coding hospitals and found no significant differences, suggesting hospitals with high birth record completeness may be generalizable and representative of all hospitals. Conclusions The completeness of recording of hospital birth information varies greatly between hospitals in England but is improving. It may be preferable and valid to construct cohorts from only hospitals with high completeness of recording.

This study presents the results of a pilot learning intervention for improving children’s ideas about plant protection. The research was executed in two phases. The first phase aimed at exploring children’s ideas about plant protection. These ideas were taken into account for the design and development of a digital learning environment. The second phase concerned the development, implementation and evaluation of the learning environment. In the first phase, 262 participants (10–12 years old) were asked to write a short text about ‘Environmental protection’. During the second phase, twenty-six participants (10–12 years old) were asked to write a text on ‘How we can protect the endemic plants’, before and after the implementation of the learning activities. Responses were content analysed and their meaning was classified according to the coding scheme of Blanchet-Cohen, Ragan, and Amsden (Children, Youth and Environments 2003; 13: 1–7). The results of the first phase showed that participants mentioned individual lifestyle actions of environmental protection and, therefore, the learning environment should emphasise the importance of other types of environmental protection (eg political actions, legislation, social actions). The proposed learning activities enriched participants’ awareness about the importance of social and legal actions for plant protection. 47 3 150 156

Phagocytosis of apoptotic cells is essential during development and tissue remodeling. Our previous study has shown that the P2X7 receptor regulates phagocytosis of nonopsonized particles and bacteria. In this study, we demonstrate that P2X7 also mediates phagocytosis of apoptotic lymphocytes and neuronal cells by human monocyte-derived macrophages under serum-free conditions. ATP inhibited this process to a similar extent as observed with cytochalasin D. P2X7-transfected HEK-293 cells acquired the ability to phagocytose apoptotic lymphocytes. Injection of apoptotic thymocytes into the peritoneal cavity of wild-type mice resulted in their phagocytosis by macrophages, but injection of ATP prior to thymocytes markedly decreased this uptake. In contrast, ATP failed to inhibit phagocytosis of apoptotic thymocytes in vivo by P2X7-deficient peritoneal macrophages. The surface expression of P2X7 on phagocytes increased significantly during phagocytosis of either beads or apoptotic cells. A peptide screen library containing 24 biotin-conjugated peptides mimicking the extracellular domain of P2X7 was used to evaluate the binding profile to beads, bacteria, and apoptotic cells. One peptide showed binding to all particles and cell membrane lipids. Three other cysteine-containing peptides uniquely bound the surface of apoptotic cells but not viable cells, whereas substitution of alanine for cysteine abolished peptide binding. Several thiol-reactive compounds including N-acetyl-L-cysteine abolished phagocytosis of apoptotic SH-SY5Y cells by macrophages. These data suggest that the P2X 7 receptor in its unactivated state acts like a scavenger receptor, and its extracellular disulphide bonds play an important role in direct recognition and engulfment of apoptotic cells. Copyright © 2011 by The American Association of Immunologists, Inc.

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