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Abstract Background A third of children born in England have at least one parent born outside the United Kingdom (UK), yet family migration history is infrequently studied as a social determinant of child health. We describe rates of hospital admissions in children aged up to 5 years by parental migration and socioeconomic group. Methods Birth registrations linked to Hospital Episode Statistics were used to derive a cohort of 4,174,596 children born in state-funded hospitals in England between 2008 and 2014, with follow-up until age 5 years. We looked at eight maternal regions of birth, maternal country of birth for the 6 most populous groups and parental migration status for the mother and second parent (UK-born/non-UK-born). We used Index of Multiple Deprivation (IMD) quintiles to indicate socioeconomic deprivation. We fitted negative binomial/Poisson regression models to model associations between parental migration groups and the risk of hospital admissions, including interactions with IMD group. Results Overall, children whose parents were both born abroad had lower emergency admission rates than children with parents both born in the UK. Children of UK-born (73.6% of the cohort) mothers had the highest rates of emergency admissions (171.6 per 1000 child-years, 95% confidence interval (CI) 171.4–171.9), followed by South Asia-born mothers (155.9 per 1000, 95% CI 155.1–156.7). The high rates estimated in the South Asia group were driven by children of women born in Pakistan (186.8 per 1000, 95% CI 185.4–188.2). A socioeconomic gradient in emergency admissions was present across all maternal regions of birth groups, but most pronounced among children of UK-born mothers (incidence rate ratio 1.43, 95% CI 1.42–1.44, high vs. low IMD group). Patterns of planned admissions followed a similar socioeconomic gradient and were highest among children with mothers born in Middle East and North Africa, and South Asia. Conclusions Overall, we found the highest emergency admission rates among children of UK-born parents from the most deprived backgrounds. However, patterns differed when decomposing maternal place of birth and admission reason, highlighting the importance of a nuanced approach to research on migration and health.

Abstract Background Findings from studies assessing Long Covid in children and young people (CYP) need to be assessed in light of their methodological limitations. For example, if non-response and/or attrition over time systematically differ by sub-groups of CYP, findings could be biased and any generalisation limited. The present study aimed to (i) construct survey weights for the Children and young people with Long Covid (CLoCk) study, and (ii) apply them to published CLoCk findings showing the prevalence of shortness of breath and tiredness increased over time from baseline to 12-months post-baseline in both SARS-CoV-2 Positive and Negative CYP. Methods Logistic regression models were fitted to compute the probability of (i) Responding given envisioned to take part, (ii) Responding timely given responded, and (iii) (Re)infection given timely response. Response, timely response and (re)infection weights were generated as the reciprocal of the corresponding probability, with an overall ‘envisioned population’ survey weight derived as the product of these weights. Survey weights were trimmed, and an interactive tool developed to re-calibrate target population survey weights to the general population using data from the 2021 UK Census. Results Flexible survey weights for the CLoCk study were successfully developed. In the illustrative example, re-weighted results (when accounting for selection in response, attrition, and (re)infection) were consistent with published findings. Conclusions Flexible survey weights to address potential bias and selection issues were created for and used in the CLoCk study. Previously reported prospective findings from CLoCk are generalisable to the wider population of CYP in England. This study highlights the importance of considering selection into a sample and attrition over time when considering generalisability of findings.

Background Women’s underage marriage (

Abstract BackgroundTwo-thirds of the 2.4 million newborn deaths that occurred in 2020 within the first 28 days of life might have been avoided by implementing existing low-cost evidence-based interventions for all sick and small newborns. An open-source digital quality improvement tool (Neotree) combining data capture with education and clinical decision support is a promising solution for this implementation gap. ObjectiveWe present results from a cost analysis of a pilot implementation of Neotree in 3 hospitals in Malawi and Zimbabwe. MethodsWe combined activity-based costing and expenditure approaches to estimate the development and implementation cost of a Neotree pilot in 1 hospital in Malawi, Kamuzu Central Hospital (KCH), and 2 hospitals in Zimbabwe, Sally Mugabe Central Hospital (SMCH) and Chinhoyi Provincial Hospital (CPH). We estimated the costs from a provider perspective over 12 months. Data were collected through expenditure reports, monthly staff time-use surveys, and project staff interviews. Sensitivity and scenario analyses were conducted to assess the impact of uncertainties on the results or estimate potential costs at scale. A pilot time-motion survey was conducted at KCH and a comparable hospital where Neotree was not implemented. ResultsTotal cost of pilot implementation of Neotree at KCH, SMCH, and CPH was US $37,748, US $52,331, and US $41,764, respectively. Average monthly cost per admitted child was US $15, US $15, and US $58, respectively. Staff costs were the main cost component (average 73% of total costs, ranging from 63% to 79%). The results from the sensitivity analysis showed that uncertainty around the number of admissions had a significant impact on the costs in all hospitals. In Malawi, replacing monthly web hosting with a server also had a significant impact on the costs. Under routine (nonresearch) conditions and at scale, total costs are estimated to fall substantially, up to 76%, reducing cost per admitted child to as low as US $5 in KCH, US $4 in SMCH, and US $14 in CPH. Median time to admit a baby was 27 (IQR 20-40) minutes using Neotree (n=250) compared to 26 (IQR 21-30) minutes using paper-based systems (n=34), and the median time to discharge a baby was 9 (IQR 7-13) minutes for Neotree (n=246) compared to 3 (IQR 2-4) minutes for paper-based systems (n=50). ConclusionNeotree is a time- and cost-efficient tool, comparable with the results from limited similar mHealth decision-support tools in low- and middle-income countries. Implementation costs of Neotree varied substantially between the hospitals, mainly due to hospital size. The implementation costs could be substantially reduced at scale due to economies of scale because of integration to the health systems and reductions in cost items such as staff and overhead. More studies assessing the impact and cost-effectiveness of large-scale mHealth decision-support tools are needed.

Robin sequence (RS), a congenital disorder of jaw maldevelopment and glossoptosis, poses a substantial healthcare burden and has long-term health implications if airway obstruction is suboptimally treated. This study describes the global birth prevalence of RS and investigates whether prevalence estimates differ by geographical location, ethnicity or study data source (registry versus non-registry data). The protocol was prospectively registered with PROSPERO. Databases were searched using keywords and subject terms for “Robin sequence”, “epidemiology”, “incidence” and “birth prevalence”. Meta-analysis was performed fitting random effects models with arcsine transformation. From 34 eligible studies (n=2722 RS cases), pooled birth prevalence was 9.5 per 100 000 live births (95% CI 7.1–12.1) with statistical heterogeneity. One third of studies provided a case definition for RS and numerous definitions were used. A total of 22 countries were represented, predominantly from European populations (53% of studies). There was a trend towards higher birth prevalence in European populations and lower prevalence from registry-based studies. Only two studies reported ethnicity. This study indicates that RS occurs globally. To investigate geographical differences in prevalence, additional studies from non-European populations and reporting of ethnicity are needed. Heterogeneity of estimates may be due to variable diagnostic criteria and ascertainment methods. Recently published consensus diagnostic criteria may reduce heterogeneity among future studies.

Abstract Background There is limited understanding of the drivers of increasing infant accident and emergency (A&E) attendances and emergency hospital admissions across England. We examine variations in use of emergency hospital services among infants by local areas in England and investigate the extent to which infant and socio-economic factors explain these variations. Methods Birth cohort study using linked administrative Hospital Episode Statistics data in England. Singleton live births between 1-April-2012 and 31-March-2019 were followed up for 1 year; from 1-April-2013 (from the discharge date of their birth admission) until their first birthday, death or 31-March-2019. Mixed effects negative binomial models were used to calculate incidence rate ratios for A&E attendances and emergency admissions and mixed effects logistic regression models estimated odds ratio of conversion (the proportion of infants subsequently admitted after attending A&E). Models were adjusted for individual-level factors and included a random effect for local authority (LA). Results The cohort comprised 3,665,414 births in 150 English LAs. Rates of A&E attendances and emergency admissions were highest amongst: infants born

Objectives To compare neonatal mortality in English hospitals by time of day and day of the week according to care pathway.Design Retrospective cohort linking birth registration, birth notification and hospital episode data.Setting National Health Service (NHS) hospitals in England.Participants 6 054 536 liveborn singleton births from 2005 to 2014 in NHS maternity units in England.Main outcome measures Neonatal mortality.Results After adjustment for confounders, there was no significant difference in the odds of neonatal mortality attributed to asphyxia, anoxia or trauma outside of working hours compared with working hours for spontaneous births or instrumental births. Stratification of emergency caesareans by onset of labour showed no difference in mortality by birth timing for emergency caesareans with spontaneous or induced onset of labour. Higher odds of neonatal mortality attributed to asphyxia, anoxia or trauma out of hours for emergency caesareans without labour translated to a small absolute difference in mortality risk.Conclusions The apparent ‘weekend effect’ may result from deaths among the relatively small numbers of babies who were coded as born by emergency caesarean section without labour outside normal working hours. Further research should investigate the potential contribution of care-seeking and community-based factors as well as the adequacy of staffing for managing these relatively unusual emergencies.

Abstract Introduction The prevalence of gestational diabetes (GD) is increasing globally. While universal risk factors for GD are reasonably well understood, questions remain regarding risks for women living with HIV (WLWH). We aimed to describe GD prevalence, evaluate associated maternal risk factors and assess specific birth outcomes in WLWH in the UK and Ireland. Methods We analysed all pregnancies (≥24 weeks’ gestation) in women diagnosed with HIV before delivery, reported to the UK‐based Integrated Screening Outcomes Surveillance Service between 2010 and 2020. Every report of GD was considered as a case. A multivariable logistic regression model, adjusted for women with more than one pregnancy fitted with generalized estimating equations (GEE) assessed the effect of independent risk factors. Results There were 10,553 pregnancies in 7916 women, of which 460 (4.72%) pregnancies had reported GD. Overall, the median maternal age was 33 years (Q1:29–Q3:37), and 73% of pregnancies were in Black African women. WLWH with GD (WLWH‐GD) were older (61% vs. 41% aged ≥35 years, p < 0.001) and more likely to be on treatment at conception (74% vs. 64%, p < 0.001) than women without GD. WLWH‐GD were more likely to have a stillbirth (odds ratio [OR]: 5.38, 95% CI: 2.14–13.5), preterm delivery (OR: 2.54, 95% CI: 1.95–3.32) and fetal macrosomia (OR: 1.14, 95% CI: 1.04–1.24). Independent risk factors for GD included estimated year of delivery (GEE‐adjusted odds ratio [GEE‐aOR]: 1.14, 95% CI: 1.10–1.18), advanced maternal age (≥35 years) (GEE‐aOR: 2.87, 95% CI: 1.54–5.34), Asian (GEE‐aOR: 2.63, 95% CI: 1.40–4.63) and Black African (GEE‐aOR: 1.55, 95% CI: 1.13–2.12) ethnicity. Timing and type of antiretroviral therapy showed no evidence of a relationship with GD in multivariable analyses; however, women with a CD4 count ≤350 cells/μl were 27% less likely to have GD than women with CD4 counts >350 cells/μl (GEE‐aOR: 0.73, 95% CI: 0.50–0.96). Conclusions GD prevalence increased over time among WLWH but was not significantly different from the general population. Maternal age, ethnicity and CD4 count were risk factors based on available data. Stillbirth and preterm delivery were more common in WLWH‐GD than other WLWH over the study period. Further studies are required to build upon these results.

Abstract Background Childhood hearing loss (HL) predicts poor mental health and is associated with a higher risk of communication difficulties. The relationship of childhood HL with specific types of poor mental health (such as depressive symptoms or self-harm) and peer victimisation remains unclear. Methods We analysed data from the Millennium Cohort Study (MCS), a prospective observational cohort study of children living in the UK at age 9 months and born between 2000 to 2002. Data were available on the children and their families at ages 9 months, then at 3, 5, 7, 11, and 14 years. Participants were 10,858 singleton children with self-reported data on peer victimisation, depressive symptoms, and self-harm at age 14 years. Multivariable logistic regression models were fitted to estimate odds ratios (OR) for HL with peer victimisation, depressive symptoms, and self-harm. HL presence was examined in terms of any HL between ages 9 months and 14 years, as well as by HL trajectory type (defined by onset and persistence). Analyses were adjusted for potential sources of confounding, survey design, and attrition at age 14 years. Interactions between sex and HL were examined in each model and multiple imputation procedures used to address missing data. Results Children with any HL had increased odds of depressive symptoms (OR: 1.32, 95% CI: 1.09–1.60), self-harm (1.41, 1.12–1.78) and, in girls only, peer victimisation (girls: 1.81, 1.29–2.55; boys: 1.05, 0.73–1.51), compared to those without HL. HL with later age at onset and persistence to age 14 years was the only trajectory associated with all outcomes. Conclusions Childhood HL may predict peer victimisation (in girls), depressive symptoms, and self-harm. Further research is needed to identify HL trajectories and methods to facilitate good mental health in children with HL.

Abstract Arginase deficiency is a rare autosomal recessive urea cycle disorder (UCD) caused by mutations in the ARG1 gene encoding arginase that catalyses the hydrolysis of arginine to ornithine and urea. Patients have hyperargininaemia and progressive neurological impairment but generally suffer fewer metabolic decompensations compared to other UCDs. The objective is to describe the clinical features, biochemical profile, neuroradiological findings and experience of managing children with arginase deficiency. Twenty‐year retrospective review of patient medical records at a single metabolic centre was performed. Six patients from three unrelated families were identified. Mean age at first symptom was 3.3 (1.5–9.0) years, while mean age at diagnosis was 8.8 (0.16–15.92) years. Four patients developed spastic diplegia and two of six with spastic quadriplegia with classical features including hyperreflexia, clonus and toe walking. This resulted in gait abnormalities that have been monitored using the GAITRite system and required Achilles tendon release in five children. Generalised tonic‐clonic seizures and/or absences were present in three of six children and were controlled with anticonvulsants. All patients had moderate learning difficulties. Neuroimaging showed cerebral/cerebellar atrophy in four patients and basal ganglia abnormalities in two. Arginine levels were universally elevated throughout follow‐up despite protein restriction, essential amino acid supplementation and ammonia scavengers, and neurological outcome was generally poor. Two patients died following severe metabolic decompensation in adolescence. Children with arginase deficiency continue to present a management challenge of what appears to be an inexorable course of neurocognitive impairment. Further insight into disease mechanisms may provide insight into novel treatment strategies.

Childhood visual impairment can have a significant impact on an individual's development. To improve clinical care and develop appropriate psychosocial interventions of these patients, it is necessary to understand the contributing and modifiable factors that both identify individuals in greater need and could be targeted in interventions. Here we investigate the broader individual, family, and environmental factors associated with vision-related quality of life (VQoL) of children and young people with visual impairment (CYP-VI). Data for this cross-sectional study were collected from September 2014 to May 2017 to develop and validate two vision-specific patient-reported outcome measures (PROMs) for CYP-VI. Patients were recruited from 22 hospitals in the United Kingdom and were aged 7-18 years with visual impairment as per WHO criteria. Participants self-completed the two PROMs, VQoL and Functional Vision Questionnaires. Clinical characteristics were extracted from medical records. Their carers provided information on family sociodemographic backgrounds. Associations between the VQoL scores and other factors were examined using Spearman's correlation, Kruskal-Wallis, Wilcoxon rank-sum tests, and quantile regression models. The sample consisted of 152 CYP-VI (67 females). Better VQoL was significantly associated with better functional vision overall (rSpearman = -0.52), parent-reported absence of additional chronic conditions (dCohen = 0.46), attending mainstream (versus other) school (dCohen = 0.44), higher socio-economic status (rSpearman = 0.17) and higher parental education level (rSpearman = 0.20). No other investigated factors were significantly associated with VQoL. The final quantile regression model included functional vision scores and the presence of additional health condition. Variation in self-reported VQoL in CYP-VI can be partly accounted for by factors relating to the clinical status of the affected child and, more importantly, by non-health-related factors. This needs to be considered in clinical practice when assessing vision-specific outcomes and providing support to CYP-VI, as well as in the development of future interventions.

BackgroundAmblyopia is a neurodevelopmental condition resulting in reduced vision for which whole population child vision screening is undertaken. Cross-sectional studies have established an association between amblyopia and lower academic self-concept, slower reading speed. No difference has been found in educational performance in adolescence whilst there are mixed associations with educational attainment in adults. Educational trajectories and intentions have not been studied previously. We analyse if those treated for amblyopia have different educational performance and trajectories for core subjects during statutory schooling, or subsequent higher education (university) intentions than their peers without eye conditions.Methods and findingsData from the Millennium Cohort Study of children born in the United Kingdom in 2000-01 and followed-up to age 17 years (n = 9989). Using a validated approach drawing on parental self-report on eye conditions and treatment coded by clinical reviewers, participants were grouped into mutually exclusive categories: no eye conditions, strabismus alone, refractive amblyopia, strabismic/mixed (refractive plus strabismic) amblyopia. The outcomes were levels and trajectories of passing English, Maths, Science at ages 7-16 years, passing national exams at age 16, and intentions at ages 14-17 to pursue higher (university) education. Adjusted analyses showed that amblyopia status was not associated with performance in English, Maths, and Science at any key stage, attainment in national exams, or intending to go to university. Similarly, the age-related trajectories of performance in core subjects and higher education intentions did not differ between the groups. There were no significant differences in main reason for having or not having university intentions.ConclusionsWe found no associations between a history of amblyopia and either adverse performance or age-related attainment trajectories in core subjects during key stages of statutory schooling as well as the absence of an association with intentions for higher education. These results should be reassuring to affected children and young people, and their families, teachers and physicians.

Abstract Introduction Improving peri‐ and postnatal facility‐based care in low‐resource settings (LRS) could save over 6000 babies' lives per day. Most of the annual 2.4 million neonatal deaths and 2 million stillbirths occur in healthcare facilities in LRS and are preventable through the implementation of cost‐effective, simple, evidence‐based interventions. However, their implementation is challenging in healthcare systems where one in four babies admitted to neonatal units die. In high‐resource settings healthcare systems strengthening is increasingly delivered via learning healthcare systems to optimise care quality, but this approach is rare in LRS. Methods Since 2014 we have worked in Bangladesh, Malawi, Zimbabwe, and the UK to co‐develop and pilot the Neotree system: an android application with accompanying data visualisation, linkage, and export. Its low‐cost hardware and state‐of‐the‐art software are used to support healthcare professionals to improve postnatal care at the bedside and to provide insights into population health trends. Here we summarise the formative conceptualisation, development, and preliminary implementation experience of the Neotree. Results Data thus far from ~18 000 babies, 400 healthcare professionals in four hospitals (two in Zimbabwe, two in Malawi) show high acceptability, feasibility, usability, and improvements in healthcare professionals' ability to deliver newborn care. The data also highlight gaps in knowledge in newborn care and quality improvement. Implementation has been resilient and informative during external crises, for example, coronavirus disease 2019 (COVID‐19) pandemic. We have demonstrated evidence of improvements in clinical care and use of data for Quality Improvement (QI) projects. Conclusion Human‐centred digital development of a QI system for newborn care has demonstrated the potential of a sustainable learning healthcare system to improve newborn care and outcomes in LRS. Pilot implementation evaluation is ongoing in three of the four aforementioned hospitals (two in Zimbabwe and one in Malawi) and a larger scale clinical cost effectiveness trial is planned.

BackgroundEnvironmental exposures in early life explain variability in many physiological and behavioural traits in adulthood. Recently, we showed that exposure to a composite marker of low maternal capital explained the clustering of adverse behavioural and physical traits in adult daughters in a Brazilian birth cohort. These associations were strongly mediated by whether or not the daughter had reproduced by the age of 18 years. Using evolutionary life history theory, we attributed these associations to trade-offs between competing outcomes, whereby daughters exposed to low maternal capital prioritised investment in reproduction and defence over maintenance and growth. However, little is known about such trade-offs in sons.MethodsWe investigated 2,024 mother–son dyads from the same birth cohort. We combined data on maternal height, body mass index, income, and education into a composite “maternal capital” index. Son outcomes included reproductive status at the age of 18 years, growth trajectory, adult anthropometry, body composition, cardio-metabolic risk, educational attainment, work status, and risky behaviour (smoking, violent crime). We tested whether sons' early reproduction and exposure to low maternal capital were associated with adverse outcomes and whether this accounted for the clustering of adverse outcomes within individuals.ResultsSons reproducing early were shorter, less educated, and more likely to be earning a salary and showing risky behaviour compared to those not reproducing, but did not differ in foetal growth. Low maternal capital was associated with a greater likelihood of sons' reproducing early, leaving school, and smoking. High maternal capital was positively associated with sons' birth weight, adult size, and staying in school. However, the greater adiposity of high-capital sons was associated with an unhealthier cardio-metabolic profile.ConclusionExposure to low maternal investment is associated with trade-offs between life history functions, helping to explain the clustering of adverse outcomes in sons. The patterns indicated future discounting, with reduced maternal investment associated with early reproduction but less investment in growth, education, or healthy behaviour. However, we also found differences compared to our analyses of daughters, with fewer physical costs associated with early reproduction. Exposure to intergenerational “cycles of disadvantage” has different effects on sons vs. daughters, hence interventions may have sex-specific consequences.

Objectives Potential ‘weekend effects’ in healthcare prompt concerns that care could be of lower quality during non-working hours, but may reflect differences in case mix or other factors This research aimed to compare neonatal mortality in English hospitals from 2005 to 2014 by time of day and day of the week. Approach We analysed data from a retrospective cohort of 6,054,536 singleton births in England 2005—2014, created by linking ONS birth and death registration and birth notification data with Hospital Episode Statistics. Working hours were defined as 07:00—19:00 on weekdays, and non-working hours were all other times on weekdays and all weekends and public holidays. The primary outcome was all-cause neonatal mortality unattributed to congenital anomaly. We also modelled cause-specific neonatal mortality attributed to asphyxia, anoxia or trauma (AAT). On advice through our public involvement and strategy, analysis was stratified by mode of onset of labour and method of delivery. Results After adjustment for confounders, the odds of all-cause neonatal mortality outside of working hours were similar to those during working hours for spontaneous births, instrumental births and emergency caesareans. Planned caesareans occurring in non-working hours had a high crude risk compared to planned caesareans in working hours, but were considered to be unreliably recorded and likely to reflect emergency caesarean delivery of babies originally scheduled for planned caesarean birth. Further stratification of emergency caesareans by onset of labour showed higher odds of cause-specific neonatal mortality (AAT) during non-working compared with working hours for emergency caesareans without labour recorded but not for emergency caesareans after spontaneous or induced onset of labour. Conclusion It may be that the apparent ‘weekend effect’ is caused by deaths among the relatively small number of babies who were born by caesarean section apparently without labour outside normal working hours. Obstetric staffing should be planned to allow for these relatively unusual emergencies.

Abstract Background Osteonecrosis of the femoral head is a common complication in the treatment of developmental dysplasia of the hip (DDH). While functional outcomes of affected patients are good in childhood, it is not clear how they change during the transition to young adulthood. This study determined the relationship between osteonecrosis and hip function, physical function and health status in adolescents and young adults. Methods We performed a cross-sectional study of 169 patients with a mean age of 19.7 ± 3.8 years with and without osteonecrosis following an open or closed reduction (1995–2005). We also performed a separate longitudinal evaluation of an historical cohort of 54 patients with osteonecrosis, embedded in this sample. All completed patient-reported outcome measures in 2015/2016 to quantify hip function (maximum score 100); physical function (maximum score 100); and general health status (maximum score 1). We graded all radiographs for subtype of osteonecrosis (Bucholz-Ogden); acetabular dysplasia (centre-edge angle); subluxation (Shenton’s line); and osteoarthritis (Kellgren-Lawrence). Analyses were adjusted for the number of previous surgical procedures on the hip and for the severity of residual hip dysplasia. Results In 149 patients (186 hips) with and without osteonecrosis, the mean differences (95% confidence interval) in hip function, physical function and quality of life were − 4.7 (− 10.26, 0.81), − 1.03 (− 9.29, 7.23) and 0.10 (− 1.15, 1.18), respectively. Adjusted analyses stratified across types of osteonecrosis showed that only patients with Bucholz-Odgen grade III had reduced hip function (p

Purpose Retinal signatures of systemic disease (‘oculomics’) are increasingly being revealed through a combination of high-resolution ophthalmic imaging and sophisticated modelling strategies. Progress is currently limited not mainly by technical issues, but by the lack of large labelled datasets, a sine qua non for deep learning. Such data are derived from prospective epidemiological studies, in which retinal imaging is typically unimodal, cross-sectional, of modest number and relates to cohorts, which are not enriched with subpopulations of interest, such as those with systemic disease. We thus linked longitudinal multimodal retinal imaging from routinely collected National Health Service (NHS) data with systemic disease data from hospital admissions using a privacy-by-design third-party linkage approach.Participants Between 1 January 2008 and 1 April 2018, 353 157 participants aged 40 years or older, who attended Moorfields Eye Hospital NHS Foundation Trust, a tertiary ophthalmic institution incorporating a principal central site, four district hubs and five satellite clinics in and around London, UK serving a catchment population of approximately six million people.Findings to date Among the 353 157 individuals, 186 651 had a total of 1 337 711 Hospital Episode Statistics admitted patient care episodes. Systemic diagnoses recorded at these episodes include 12 022 patients with myocardial infarction, 11 735 with all-cause stroke and 13 363 with all-cause dementia. A total of 6 261 931 retinal images of seven different modalities and across three manufacturers were acquired from 1 54 830 patients. The majority of retinal images were retinal photographs (n=1 874 175) followed by optical coherence tomography (n=1 567 358).Future plans AlzEye combines the world’s largest single institution retinal imaging database with nationally collected systemic data to create an exceptional large-scale, enriched cohort that reflects the diversity of the population served. First analyses will address cardiovascular diseases and dementia, with a view to identifying hidden retinal signatures that may lead to earlier detection and risk management of these life-threatening conditions.

Neonatal encephalopathy (NE) accounts for ~23% of the 2.4 million annual global neonatal deaths. Approximately 99% of global neonatal deaths occur in low-resource settings, however, accurate data from these low-resource settings are scarce. We reviewed risk factors of neonatal mortality in neonates admitted with neonatal encephalopathy from a tertiary neonatal unit in Zimbabwe. A retrospective review of risk factors of short-term neonatal encephalopathy mortality was conducted at Sally Mugabe Central Hospital (SMCH) (November 2018 -October 2019). Data were gathered using a tablet-based data capture and quality improvement newborn care application (Neotree). Analyses were performed on data from all admitted neonates with a diagnosis of neonatal encephalopathy, incorporating maternal, intrapartum, and neonatal risk predictors of the primary outcome: mortality. 494/2894 neonates had neonatal encephalopathy on admission and were included. Of these, 94 died giving a neonatal encephalopathy-case fatality rate (CFR) of 190 per 1000 admitted neonates. Caesarean section (odds ratio (OR) 2.95(95% confidence interval (CI) 1.39-6.25), convulsions (OR 7.13 (1.41-36.1)), lethargy (OR 3.13 (1.24-7.91)), Thompson score "11-14" (OR 2.98 (1.08-8.22)) or "15-22" (OR 17.61 (1.74-178.0)) were significantly associated with neonatal death. No maternal risk factors were associated with mortality. Nearly 1 in 5 neonates diagnosed with neonatal encephalopathy died before discharge, similar to other low-resource settings but more than in typical high-resource centres. The Thompson score, a validated, sensitive and specific tool for diagnosing neonates with neonatal encephalopathy was an appropriate predictive clinical scoring system to identify at risk neonates in this setting. On univariable analysis time-period, specifically a period of staff shortages due to industrial action, had a significant impact on neonatal encephalopathy mortality. Emergency caesarean section was associated with increased mortality, suggesting perinatal care is likely to be a key moment for future interventions.

BackgroundThe UK National Screening Committee currently recommends against antenatal screening for Hepatitis C virus (HCV) infection in England due to lack of HCV prevalence data and treatment licensed for use in pregnancy. We aimed to produce regional and national estimates of the number and proportion of livebirths to HCV seropositive women in England in 2013 and 2018.MethodsA logistic regression model fitted in the Bayesian framework estimated probabilities of HCV seropositivity among 24,599 mothers delivering in the North Thames area of England in 2012 adjusted by maternal age and region of birth. These probabilities were applied to the underlying population structures of women delivering livebirths in England in 2013 and 2018 to estimate the number of livebirths to HCV seropositive women in these years nationally and by region. The Bayesian approach allowed the uncertainty associated with all estimates to be properly quantified.ResultsNationally, the estimated number of livebirths to women seropositive for HCV for England was 464 (95% credible interval [CI] 300-692) in 2013 and 481 (95%CI 310-716) in 2018, or 70.0 (95%CI 45.0-104.1) per 100,000 and 76.9 (95%CI 49.5-114.4) per 100,000 in these years respectively. Regions with the highest estimated number of livebirths to HCV seropositive women in 2013 and 2018 included London with 118.5 and 124.4 and the South East with 67.0 and 74.0 per 100,000 livebirths.ConclusionFew previous studies have investigated HCV among pregnant women in England. These findings complement and supplement existing research by providing national and regional estimates for the number of livebirths to HCV seropositive women in England. Bayesian modelling allows future national and regional estimates to be produced and the associated uncertainty to be properly quantified.

Background Women’s early marriage (

In this retrospective observational study, we evaluated the impact of the COVID-19 pandemic in London on paediatric radiology activity, as a surrogate of overall hospital activity. We showed a large reduction in overall outpatient imaging activity: 49 250 records occurred in the 371 days post COVID-19 period compared with an expected 67 806 records pre COVID-19 period, representing 18 556 ‘missed’ records. Governmental restrictions were associated with reductions in activity, with the largest reduction in activity during tiers 3 and 4 restrictions. Rescheduling such missed outpatients’ appointments represents considerable resource planning and the associated clinical impact on paediatric healthcare remains to be determined.

Parenting programmes can improve parenting quality and, in turn, children's mental health. If scaled-up, they have the potential to reduce population inequalities and prevalence in child mental health problems (MHP). However, this cannot be investigated with trials. Using data from the UK Millennium Cohort Study (18,000 children born 2000–2002), we simulated population impact of scale-up of seven parenting programmes. Predicted probabilities of child MHP (Strengths and Difficulties Questionnaire) by household income quintile (Risk ratios [RRs] and differences [RDs], 95% confidence intervals [CI]) were estimated from logistic marginal structural models, adjusting for parenting quality scores (Child-Parent Relationship Scale at 3 years) and confounders. The impact of scaling-up parenting programmes was simulated by re-estimating predicted probabilities of child MHP after increasing parenting scores according to intervention intensity, targeting mechanisms and programme uptake levels. Analyses included data from 14,399 children, with survey weights and multiple imputation addressing sampling design, attrition and item missingness. Prevalence of child MHP at 5 years was 11.3% (11.4% unadjusted), with relative and absolute income inequalities (RR = 4.8[95%CI:3.6–5.9]; RD = 15.8%[13.4–18.2]). In simulations, universal, non-intensive parenting programmes reduced prevalence (9.4%) and absolute inequalities (RR = 5.0[95%CI:3.8–6.2]; RD = 13.6%[11.5–15.7]). Intensive programmes, targeting a range of potential risk criteria (e.g. receipt of means-tested benefits), reduced inequalities (RR = 4.0[95%CI:3.0–4.9]; RD = 12.4%[10.3–14.6] and, to a lesser extent, prevalence (10.3%). By simulating implementation of parenting programmes, we show that universal non-intensive and targeted intensive approaches have the potential to reduce child MHP at population level, and to reduce but not eliminate inequalities, with important implications for future policy and practice.

Background: Tuberous Sclerosis Complex (TSC) is a genetic disorder characterised by the development of benign tumours secondary to loss of inhibitory regulation of the mTOR (mechanistic Target of Rapamycin) intracellular growth pathway. Metformin inhibits the mTOR pathway. We investigated whether metformin would reduce growth of hamartomas associated with tuberous sclerosis complex. Methods: In this multicentre randomized, double-blind, placebo-controlled trial, patients with a clinical diagnosis of tuberous sclerosis, aged over 10 years and with at least one renal angiomyolipoma of greater than 1 cm in diameter were enrolled. Participants were randomly allocated (1:1) by a secure website to receive metformin or placebo for 12 months. The primary outcome was percentage volume change of renal angiomyolipomas (AML) at 12 months compared to baseline. Secondary outcomes were percentage change at 12 months from baseline in volume of cerebral Subependymal Giant Cell Astrocytomas (SEGA); appearance of facial and ungual hamartomas; frequency of epileptic seizures; and adaptive behaviour. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 92545532, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2011-001319-30. Findings: Between 1 November 2012 and 30 September 2015 72 patients were screened and 55 were randomly assigned to metformin (28) or placebo (27). Four participants withdrew between randomisation and starting treatment. All 51 patients who started therapy completed the trial and were assessed for outcome at 12 months. The median percentage change in angiomyolipoma (AML) volume was +7.6% (IQR -1.8% to +42.6%) for the placebo group and +8.9% (IQR 1.3% to 19.5%) for the metformin group (p = 0.28). Twenty-seven patients had SEGAs: 13 received placebo and 14 metformin. The median percentage change in SEGA volume was +3.0% (IQR -22.8% to +27.7%) for the placebo group and – 20.8% (IQR – 47.1% to - 5.0%) for the metformin group (p = 0.03). Twenty-one patients were assessed for seizure frequency: 9 received placebo and 12 received metformin. In the metformin group, a mean reduction of 43.7% from baseline in seizures was observed and in the placebo group a 3.1% mean reduction was observed, with a difference in response of 40.6% (95% CI -3.1% to +84.2%, p = 0.03). There were no significant differences between metformin and placebo groups for the other secondary outcomes. There were no deaths. Three serious adverse events (SAEs) occurred during the trial (all patients on metformin). Interpretation: Metformin did not reduce AML volume. Metformin did reduce SEGA volume and seizure frequency compared with placebo. There may be a role for metformin in slowing or reversing growth of some life-threatening hamartomas in TSC and for reducing seizure frequency. Further study is justified. Funding: This study was funded by the National Institute for Health and Research (NIHR) through the The Research for Patient Benefit Programme (RfPB).

ObjectivesWe investigated whether perceived social support among adolescent students moderated the association between violence exposure and internalising symptoms in São Paulo city, Brazil.MethodsWe tested the stress-buffering model using data from the cross-sectional school-based, survey São Paulo Project on the Social Development of Children and Adolescents. Internalising symptoms were measured using an adapted version of the Social Behaviour Questionnaire; serious victimisation, being bullied once/week, school violence and community violence, friend and teacher support were scales adapted by the research team; the Alabama Parenting Questionnaire measured parenting style. Linear mixed-effects models were used to quantify moderation effects of (i) social support between violence exposure and internalising symptoms and (ii) gender between violence exposure and internalising symptoms across schools.ResultsAcross schools, being bullied once/week, school violence, and community violence were associated with a significant (pConclusionsAdolescent students in São Paulo exposed to violence have a higher likelihood of internalising symptoms, compared to those who are not. Support from parents, friends, and teachers, independent of violence, appear to be protective against internalising symptoms, pointing to potential programmes that could improve adolescent mental health.

BackgroundAmblyopia is a neurodevelopmental condition causing reduced vision, for which programmes of whole population child vision screening exist throughout the world. There is an ongoing debate about the value of screening due to the lack of evidence about meaningful functional impacts of amblyopia. Our objective was to determine whether amblyopia is associated with school readiness and early cognitive performance.Methods and findingsData from the prospective Millennium Cohort Study of children born in the United Kingdom in 2000-01 and followed-up to age 7 years (n = 13,967). Using parental self-report on eye conditions and treatment coded by clinical reviewers, participants were grouped into no eye conditions, strabismus alone, refractive amblyopia, or strabismic/mixed (refractive plus strabismic) amblyopia. The outcomes were poor school readiness using Bracken School Readiness Assessment 10 points) irrespective of whether treatment had already started. The age-related cognitive trajectories of children with amblyopia did not differ from those without any eye conditions for either NV (p = 0.62) or PC (p = 0.51). These associations are at population rather than individual level, so it might be that some individuals with amblyopia did experience significant adverse outcomes that are not captured by summary statistics.ConclusionsAmblyopia is not significantly associated with adverse cognitive performance and trajectories in early schooling and there is no evidence that this is due to a mediating effect of treatment. Although amblyopia combined with strabismus is associated with poor school readiness, this is not translated into poor cognitive performance. These novel findings may explain the lack of association reported between amblyopia and educational outcomes in adult life and suggest that the impact of amblyopia on education is not of itself a justification for whole population child vision screening aimed at detecting this disorder.

Background: Early childbirth is associated with adverse maternal and child health outcomes. In South Asia, where women generally marry before having children, public health efforts need to focus on delaying marriage. Female education is widely considered the primary means to achieve this. However, it remains unclear how much education is required to delay marriage to the universal minimum age of 18 years, or what predicts marriage age in women lacking any education. This is crucial to address in the Terai region of Nepal which has the highest proportion of children out of school and where girls marry and have their first pregnancy early.Methods: We analyzed data from 6,406 women aged 23–30 years from a cluster-randomized trial in lowland Terai Nepal. Using Kaplan-Meier survival analysis, multivariable logistic and Cox proportional hazards regression models, we investigated associations between women's education level and age at marriage and first pregnancy, and the interval between these events. Among the uneducated women, we investigated associations of husband's education level with the same outcomes.Results: Compared to uneducated women, educated women had a greater probability of delaying marriage until the age of 18 years and of pregnancy until 20 years. Women needed to complete grade 9, and ideally 11, to substantially increase their odds of marrying after 18 years. Delaying first pregnancy to 20 years was largely due to marrying later; education had little extra effect. The association of marriage with first pregnancy age worked independently of education. However, later-marrying women, who generally had completed more education, had their first pregnancy sooner after marriage than earlier marrying women. Most uneducated women, regardless of their husbands' level of education, still married under the legal age of marriage.Conclusion: Delaying marriage to majority age requires greater efforts to ensure girls get to school in the first place, and complete secondary education. Since currently only 36% of girls in the Terai attend secondary school, parallel efforts to delay marriage are crucial to prevent early childbearing. Sexual and reproductive health programmes in school and in women's groups for married and uneducated adolescents may help prepare for marriage and pregnancy.

Abstract Background Niemann-Pick disease type C (NPC) is a lysosomal storage disease with a heterogeneous neurodegenerative clinical course. Multiple therapies are in clinical trials and inclusion criteria are currently mainly based on age and neurological signs, not taking into consideration differential individual rates of disease progression. Results In this study, we have evaluated a simple metric, denoted annual severity increment score (ASIS), that measures rate of disease progression and could easily be used in clinical practice. We show that ASIS is stable over several years and can be used to stratify patients for clinical trials. It achieves greater homogeneity of the study cohort relative to age-based inclusion and provides an evidence-based approach for establishing inclusion/exclusion criteria. In addition, we show that ASIS has prognostic value and demonstrate that treatment with an experimental therapy - acetyl-DL-leucine - is associated with a reduction in ASIS scores. Conclusion ASIS has the potential to be a useful metric for clinical monitoring, trial recruitment, for prognosis and measuring response to therapy.

The local dependence function (LDF) describes changes in the correlation structure of continuous bivariate random variables along their range. Bivariate density functions with Beta marginals can be used to model jointly a wide variety of data with bounded outcomes in the (0,1) range, e.g. proportions. In this paper we obtain expressions for the LDF of bivariate densities constructed using three different copula models (Frank, Gumbel and Joe) with Beta marginal distributions, present examples for each, and discuss an application of these models to analyse data collected in a study of marks obtained on a statistics exam by postgraduate students.

Background: Some individuals appear prone to multiple adverse outcomes, including poor health, school dropout, risky behavior and early reproduction. This clustering remains poorly understood. Drawing on evolutionary life history theory, we hypothesized that maternal investment in early life would predict the developmental trajectory and adult phenotype of female offspring. Specifically, we predicted that daughters receiving low investment would prioritize the life history functions of “reproduction” and “defense” over “growth” and “maintenance,” increasing the risk of several adverse outcomes.Methods: We investigated 2,091 mother-daughter dyads from a birth cohort in Pelotas, Brazil. We combined data on maternal height, body mass index, income, and education into a composite index of “maternal capital.” Daughter outcomes included reproductive status at 18 years, growth, adult anthropometry, body composition, cardio-metabolic risk, educational attainment, work status, and risky behavior. We tested whether daughters' early reproduction (

Background: Studies of daily variations in the numbers of births in England and Wales since the 1970s have found a pronounced weekly cycle, with numbers of daily births being highest from Tuesdays to Fridays and lowest at weekends and on public holidays. Mortality appeared to be higher at weekends. As time of birth was not included in national data systems until 2005, there have been no previous analyses by time of day. Objectives: To link data from birth registration and birth notification to data about care during birth and any subsequent hospital admissions and to quality assure the linkage. To use the linked data to analyse births and their outcomes by time of day, day of the week and year of birth. Design: A retrospective birth cohort analysis of linked routine data. Setting: England and Wales. Outcome measures: Mortality of babies and mothers, and morbidity recorded at birth and any subsequent hospital admission. Population and data sources: Birth registration and notification records of 7,013,804 births in 2005–14, already linked to subsequent death registration records for babies, children and women who died within 1 year of giving birth, were provided by the Office for National Statistics. Stillbirths and neonatal deaths data from confidential enquiries for 2005–9 were linked to the registration records. Data for England were linked to Hospital Episode Statistics (HES) and data for Wales were linked to the Patient Episode Database for Wales and the National Community Child Health Database. Results: Cross-sectional analysis of all births in England and Wales showed a regular weekly cycle. Numbers of births each day increased from Mondays to Fridays. Numbers were lowest at weekends and on public holidays. Overall, numbers of births peaked between 09.00 and 12.00, followed by a much smaller peak in the early afternoon and a decrease after 17.00. Numbers then increased from 20.00, peaking at around 03.00–05.00, before falling again after 06.00. Singleton births after spontaneous onset and birth, including births in freestanding midwifery units and at home, were most likely to occur between midnight and 06.00, peaking at 04.00–06.00. Elective caesarean births were concentrated in weekday mornings. Births after induced labours were more likely to occur at hours around midnight on Tuesdays to Saturdays, irrespective of the mode of birth. Limitations: The project was delayed by data access and information technology infrastructure problems. Data from confidential enquiries were available only for 2005–9 and some HES variables were incomplete. There was insufficient time to analyse the mortality and morbidity outcomes. Conclusions: The timing of birth varies by place of birth, onset of labour and mode of birth. These patterns have implications for midwifery and medical staffing. Future work: An application has now been submitted for funding to analyse the mortality outcomes and further funding will be sought to undertake the other outstanding analyses. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 7, No. 18. See the NIHR Journals Library website for further project information.

Background In longitudinal health research, combining the richness of cohort data to the extensiveness of routine data opens up new possibilities, providing information not available from one data source alone. In this study, we set out to extend information from a longitudinal birth cohort study by linking to the cohort child’s routine primary and secondary health care data. The resulting linked datasets will be used to examine health outcomes and patterns of health service utilisation for a set of common childhood health problems. We describe the experiences and challenges of acquiring and linking electronic health records for participants in a national longitudinal study, the UK Millennium Cohort Study (MCS). Method Written parental consent to link routine health data to survey responses of the MCS cohort member, mother and her partner was obtained for 90.7% of respondents when interviews took place at age seven years in the MCS. Probabilistic and deterministic linkage was used to link MCS cohort members to multiple routinely-collected health data sources in Wales and Scotland. Results Overall linkage rates for the consented population using country-specific health service data sources were 97.6% for Scotland and 99.9% for Wales. Linkage rates between different health data sources ranged from 65.3% to 99.6%. Issues relating to acquisition and linkage of data sources are discussed. Conclusions Linking longitudinal cohort participants with routine data sources is becoming increasingly popular in population data research. Our results suggest that this is a valid method to enhance information held in both sources of data.

ContextPermanent childhood hearing loss (PCHL) can affect speech, language, and wider outcomes. Adverse effects are mitigated through universal newborn hearing screening (UNHS) and early intervention.ObjectiveWe undertook a systematic review and meta-analysis to estimate prevalence of UNHS-detected PCHL (bilateral loss ≥26 dB HL) and its variation by admission to neonatal intensive care unit (NICU). A secondary objective was to report UNHS programme performance (PROSPERO: CRD42016051267).Data sourcesMultiple electronic databases were interrogated in January 2017, with further reports identified from article citations and unpublished literature (November 2017).Study selectionUNHS reports from very highly-developed (VHD) countries with relevant prevalence and performance data; no language or date restrictions.Data extractionThree reviewers independently extracted data and assessed quality.ResultsWe identified 41 eligible reports from 32 study populations (1799863 screened infants) in 6195 non-duplicate references. Pooled UNHS-detected PCHL prevalence was 1.1 per 1000 screened children (95% confidence interval [CI]: 0.9, 1.3; I2 = 89.2%). This was 6.9 times (95% CI: 3.8, 12.5) higher among those admitted to NICU. Smaller studies were significantly associated with higher prevalences (Egger's test: p = 0.02). Sensitivity and specificity ranged from 89-100% and 92-100% respectively, positive predictive values from 2-84%, with all negative predictive values 100%.LimitationsResults are generalisable to VHD countries only. Estimates and inferences were limited by available data.ConclusionsIn VHD countries, 1 per 1000 screened newborns require referral to clinical services for PCHL. Prevalence is higher in those admitted to NICU. Improved reporting would support further examination of screen performance and child demographics.

BackgroundUkraine has the second largest European HIV epidemic. This study aimed to describe stigma, demographic and social factors and their association with anxiety among perinatally and behaviourally-HIV-infected (PHIV; BHIV) young people in Kiev and Odessa.Methods104 PHIV and 100 BHIV young people aged 13-25 years completed a confidential tablet-based survey. Survey tools included the Hospital Anxiety and Depression Scale (HADS) (anxiety sub-scale scores of 8-10 indicating mild and ≥11 moderate/severe symptoms in last 7 days), Rosenberg Self-Esteem Scale (RSES) and HIV Stigma Scale (HSS) (short version, composite of disclosure, negative self-image and public attitudes sub-scales). Unadjusted Poisson regression models were fitted to explore factors associated with moderate/severe anxiety symptoms.ResultsPHIV and BHIV young people were of median age 15.5 [IQR 13.9-17.1] and 23.0 [21.0-24.3] years, having registered for HIV care a median 12.3 [10.3-14.4] and 0.9 [0.2-2.4] years previously; 97% (97/100) and 66% (65/99) respectively were on ART. Overall 43% (95%CI 36-50%) reported any and 13% (95%CI 9-19%) moderate/severe anxiety symptoms, with no difference by HIV acquisition mode (p = 0.405) or gender (p = 0.700). 42% (75/180) reported history of an emotional health problem for which they had not been referred/attended for care. Moderate/severe anxiety symptoms were associated with HIV-related stigma (prevalence ratio (PR) 1.24 95%CI 1.14-1.34 per HSS unit increase), lower self-esteem (PR 0.83 95%CI 0.78-0.90 per RSES point increase), CD4 ≤350 cells/mm3 (PR 2.29 95%CI 1.06-4.97), having no-one at home who knew the respondent's HIV status (PR 9.15 95%CI 3.40-24.66 vs all know) and, among BHIV, less stable living situation (PR 6.83 95%CI 1.99-23.48 for ≥2 vs no home moves in last 3 years) and history of drug use (PR 4.65 95%CI 1.83-11.85).ConclusionsResults indicated unmet need for psychosocial support. Further work is needed to explore strategies for mental health support, particularly around disclosure, self-esteem and stigma.

IntroductionChildren and young people (CYP) are encouraged to increase time spent being physically active, especially in moderate and vigorous intensity pursuits. However, there is limited evidence on the prospective association of activity levels with injuries resulting in use of hospital services. We examined the relationship between objectively-measured physical activity (PA) and subsequent injuries resulting in hospital admissions or accident and emergency department (A&E) attendances, using linked electronic hospital records (EHR) from a nationally representative prospective cohort of CYP in Wales and Scotland.MethodsWe analysed accelerometer-based estimates of moderate to vigorous (MVPA) and vigorous PA (VPA) from 1,585 (777 [46%] boys) seven-year-old Millennium Cohort Study members, living in Wales or Scotland, whose parents consented to linkage of cohort records to EHRs up until their 14th birthday. Negative binomial regression models adjusted by potential individual, household and area-level confounders, were fitted to estimate associations between average daily minutes of MVPA, and VPA (in 10-minute increments), and number of injury-related hospital admissions and/or A&E attendances from age nine to 14 years.ResultsCYP spent a median of 59.5 and 18.1 minutes in MVPA and VPA/day respectively, with boys significantly more active than girls; 47.3% of children experienced at least one injury-related admission or A&E attendance during the study period. Rates of injury-related hospital admission and/or A&E attendance were positively associated with MVPA and VPA in boys but not in girls: respective adjusted incidence rate ratios (95% CI) for boys: 1.09 (1.01, 1.17) and 1.16 (1.00, 1.34), and for girls: 0.94 (0.86, 1.03) and 0.85 (0.69, 1.04).ConclusionBoys but not girls who engage in more intense PA at age seven years are at higher risk of injury-related hospital admission or A&E attendance when aged nine to 14 years than their less active peers. This may reflect gender differences in the type and associated risks of activities undertaken. EHRs can make a useful contribution to injury surveillance and prevention if routinely augmented with information on context and setting of the injuries sustained. Injury prevention initiatives should not discourage engagement in PA and outdoor play given their over-riding health and social benefits.

Background Harmonisation of different data sources from various electronic health records (EHRs) across systems enhances the potential scope and granularity of data available to health data research. Objective To describe data harmonisation of routine electronic healthcare records in Wales and Scotland linked to a UK longitudinal birth cohort, the Millennium Cohort Study (MCS). Methods Comparable secondary care data was linked, with parental consent, to MCS information for 1838 and 1431 children participating in MCS and residing in Wales and Scotland, by assigning, respectively, unique Anonymised Linkage Fields to personbased records in the privacy protecting Secure Anonymised Information Linkage (SAIL) databank at Swansea University, and by the National Health Service (NHS) Information Standards Division. Survey and non-response weights were created to account for the clustered sample, sample attrition and consent to linkage. Heterogeneous variables from the Patient Episode Dataset for Wales, Emergency Department Data Set for Wales, Scottish Medical Record 01 and Accident and Emergency dataset for Scotland were harmonised enabling data to be pooled and standardised for research. Findings Overall linkage to harmonised health care data was achieved for 98.9% (99.9% for Wales and 97.6% for Scotland) of consented MCS participants. 66% of children experienced at least one hospital admission (total 5747 hospital admissions) up to their 14th birthday, while 60% attended A&E departments at least once (total 5221 attendances) between their 9th and 14th birthday. We managed date granularity by generating random dates of birth, standardising periods of data collection, identifying inconsistencies and then mapping and bridging differences in definitions of periods of care across countries and datasets. Conclusions Combining and harmonising data from multiple sources and linking them to information from a longitudinal cohort create useful resources for population health research. These methods are reproducible and can be utilised by other researchers and projects.

Background Databanks of primary care electronic health records (pcEHRs) are a valuable resource for life course research, however loss to follow up due to changing general practice has received little attention. Objective We investigated factors associated with changing general practice (GP) in early life and continuity of participation in the Secure Anonymised Information Linkage (SAIL) databank, to which approximately 80% of Welsh practices contribute. Methods We analysed linked pcEHRs for 1834 (882 girls) Millennium Cohort Study participants, resident in Wales, with consent to health record linkage. We studied time from first to next practice registration using Cox proportional hazards models, and estimated mutually-adjusted hazard ratios (aHRs) for child, household and practice factors. Findings There were 3065 Welsh GP registrations for 1834 children. By age 5 years, 25% changed practice at least once, with 1070 (58.3%), 477 (26.0%), 287 (15.7%) registered with 1, 2, or 3+ GPs respectively by age 14 years. Changing practice was related to maternal age (aHRs; 95% CI: 0.96; 0.95,0.98), living in rural areas (0.75;0.56,0.99), initial registration with a non-SAIL-practice (2.16;1.60,2.93), recent address change (1.62;1.21,2.16), and no maternal educational qualifications (1.40;1.15,1.71). Overall, 305 (16.6%) children had never registered with a SAIL practice. Of 403 children initially registered with a SAIL practice who then changed practice, 66.7% re-registered with a SAIL practice. Conclusions In a nationally representative sample of Welsh children, the majority remained registered with the same practice up to age 14 years, with change in practice varying by maternal and household factors. Continuity of participation in the Welsh SAIL databank over early life is high, reflecting the high proportion of practices contributing, and the high proportion of children registered with them. Geographically contiguous primary care databanks, such as SAIL, enable a high proportion of children to be followed over time despite changing general practice.

BACKGROUND:Maternity care has to be available 24 hours a day, seven days a week. It is known that obstetric intervention can influence the time of birth, but no previous analysis at a national level in England has yet investigated in detail the ways in which the day and time of birth varies by onset of labour and mode of giving birth. METHOD:We linked data from birth registration, birth notification, and Maternity Hospital Episode Statistics and analysed 5,093,615 singleton births in NHS maternity units in England from 2005 to 2014. We used descriptive statistics and negative binomial regression models with harmonic terms to establish how patterns of timing of birth vary by onset of labour, mode of giving birth and gestational age. RESULTS:The timing of birth by time of day and day of the week varies considerably by onset of labour and mode of birth. Spontaneous births after spontaneous onset are more likely to occur between midnight and 6am than at other times of day, and are also slightly more likely on weekdays than at weekends and on public holidays. Elective caesarean births are concentrated onto weekday mornings. Births after induced labours are more likely to occur at hours around midnight on Tuesdays to Saturdays and on days before a public holiday period, than on Sundays, Mondays and during or just after a public holiday. CONCLUSION:The timing of births varies by onset of labour and mode of birth and these patterns have implications for midwifery and medical staffing. Further research is needed to understand the processes behind these findings.

Temporal characterisation of physical activity in children is required for effective strategies to increase physical activity (PA). Evidence regarding determinants of physical activity in childhood and their time-dependent patterns remain inconclusive. We used functional data analysis (FDA) to model temporal profiles of daily activity, measured objectively using accelerometers, to identify diurnal and seasonal PA patterns in a nationally representative sample of primary school-aged UK children. We hypothesised that PA levels would be lower in girls than boys at play times and after school, higher in children participating in social forms of exercise (such as sport or play), and lower among those not walking to school.Children participating in the UK-wide Millennium Cohort Study wore an Actigraph GT1M accelerometer for seven consecutive days during waking hours. We modelled 6,497 daily PA profiles from singleton children (3,176 boys; mean age: 7.5 years) by means of splines, and used functional analysis of variance to examine the cross-sectional relation of time and place of measurement, demographic and behavioural characteristics to smoothed PA profiles.Diurnal and time-specific patterns of activity showed significant variation by sex, ethnicity, UK country and season of measurement; girls were markedly less active than boys during school break times than boys, and children of Indian ethnicity were significantly less active during school hours (9:30-12:00). Social activities such as sport clubs, playing with friends were associated with higher level of PA in afternoon (15:00-17:30) and early evenings (17:30-19:30). Lower PA levels between 8:30-9:30 and 17:30-19:30 were associated with mode of travel to and from school, and number of cars in regular use in the household.Diminished PA in primary school aged children is temporally patterned and related to modifiable behavioural factors. FDA can be used to inform and evaluate public health policies to promote childhood PA.

OBJECTIVE: To investigate the scale-up of antenatal combination antiretroviral therapy (cART) in Ukraine since this became part of the national policy for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV). METHODS: Data on 3535 HIV-positive pregnant women who were enrolled into the Ukraine European Collaborative Study in 2008-2010 were analysed. Factors associated with receipt of zidovudine monotherapy (AZTm) - rather than cART - and rates of mother-to-child transmission (MTCT) of HIV were investigated. FINDINGS: cART coverage increased significantly, from 22% of deliveries in 2008 to 61% of those in 2010. After adjusting for possible confounders, initiation of antenatal AZTm - rather than cART - was associated with cohabiting (versus being married; adjusted prevalence ratio, aPR: 1.09; 95% confidence interval, CI: 1.02-1.16), at least two previous live births (versus none; aPR: 1.22; 95% CI: 1.11-1.35) and a diagnosis of HIV infection during the first or second trimester (versus before pregnancy; aPR: 1.11; 95% CI: 1.03-1.20). The overall MTCT rate was 4.1% (95% CI: 3.4-4.9); 42% (49/116) of the transmissions were from the 8% (n = 238) of women without antenatal ART. Compared with AZTm, cART was associated with a 70% greater reduction in the risk of MTCT (adjusted odds ratio: 0.30; 95% CI: 0.16-0.56). CONCLUSION: Between 2008 and 2010, access to antenatal cART improved substantially in Ukraine, but implementation of the World Health Organization's Option-B policy was slow. For MTCT to be eliminated in Ukraine, improvements in the retention of women in HIV care and further roll-out of Option B are urgently needed.

Objective To examine whether physical activity (PA) and sedentary time (ST) in primary school-aged children are associated with adiposity at the start of secondary school, and whether these associations differ by sex or ethnic group.Design Nationally representative prospective cohort study.Setting Children born across the UK, between 2000 and 2002.Participants 6497 singleton children.Outcome measures Measures of adiposity (body mass index (BMI), fat mass index (FMI) and fat free mass index (FFMI))—obtained at 7 and 11 years.Explanatory measures Total daily PA (mean counts per minute (cpm)); minutes of moderate-to-vigorous PA (MVPA); and ST. All assessed at 7 years using accelerometers.Results In cross-sectional analyses, total PA was inversely associated with FMI (3.7% (95% CI 2.7% to 4.7%) reduction per 150 cpm increase), as was MVPA (4.2% (CI 3.2% to 5.2%) reduction per 20 min/day increase). Associations were stronger in black and South Asian ethnic groups. Total PA and MVPA were not associated with FFMI. ST was positively associated with FMI (1.3% (CI 0.2% to 2.3%) increase per 50 min/day increase) and inversely associated with FFMI (0.5% (CI 0.2% to 0.7%) reduction per 50 min/day increase). Longitudinally, MVPA at age 7 years remained inversely associated with FMI at age 11 years (1.5% (CI 0.4% to 2.6%) reduction per 20 min/day increase). No association was found between total PA and ST and any of the later adiposity measures.Conclusions 7-year-old children who are more physically active are less likely to be obese at that age and at age 11 years. These associations were particularly evident in children from black or South Asian ethnicity at age 7 years and in boys at age 11 years. Measurements of fat mass provide valuable insights into ethnic differences in associations between adiposity and activity.

Globally, puerperal sepsis accounts for an estimated 8-12% of maternal deaths, but evidence is lacking on the extent to which clean delivery practices could improve maternal survival. We used data from the control arms of four cluster-randomised controlled trials conducted in rural India, Bangladesh and Nepal, to examine associations between clean delivery kit use and hand washing by the birth attendant with maternal mortality among home deliveries.We tested associations between clean delivery practices and maternal deaths, using a pooled dataset for 40,602 home births across sites in the three countries. Cross-sectional data were analysed by fitting logistic regression models with and without multiple imputation, and confounders were selected a priori using causal directed acyclic graphs. The robustness of estimates was investigated through sensitivity analyses.Hand washing was associated with a 49% reduction in the odds of maternal mortality after adjusting for confounding factors (adjusted odds ratio (AOR) 0.51, 95% CI 0.28-0.93). The sensitivity analysis testing the missing at random assumption for the multiple imputation, as well as the sensitivity analysis accounting for possible misclassification bias in the use of clean delivery practices, indicated that the association between hand washing and maternal death had been over estimated. Clean delivery kit use was not associated with a maternal death (AOR 1.26, 95% CI 0.62-2.56).Our evidence suggests that hand washing in delivery is critical for maternal survival among home deliveries in rural South Asia, although the exact magnitude of this effect is uncertain due to inherent biases associated with observational data from low resource settings. Our findings indicating kit use does not improve maternal survival, suggests that the soap is not being used in all instances that kit use is being reported.

Mouse models of the GM2 gangliosidoses, Tay–Sachs and Sandhoff disease, are null for the hexosaminidase α and β subunits respectively. The Sandhoff (Hexb−/−) mouse has severe neurological disease and mimics the human infantile onset variant. However, the Tay–Sachs (Hexa−/−) mouse model lacks an overt phenotype as mice can partially bypass the blocked catabolic pathway and escape disease. We have investigated whether a subset of Tay–Sachs mice develop late onset disease. We have found that ∼65% of the mice develop one or more clinical signs of the disease within their natural life span (n = 52, P < 0.0001). However, 100% of female mice with repeat breeding histories developed late onset disease at an earlier age (n = 21, P < 0.0001) and displayed all clinical features. Repeat breeding of a large cohort of female Tay–Sachs mice confirmed that pregnancy induces late onset Tay–Sachs disease. Onset of symptoms correlated with reduced up-regulation of hexosaminidase B, a component of the bypass pathway.

Accelerometers are designed to measure plausible human activity, however extremely high count values (EHCV) have been recorded in large-scale studies. Using population data, we develop methodological principles for establishing an EHCV threshold, propose a threshold to define EHCV in the ActiGraph GT1M, determine occurrences of EHCV in a large-scale study, identify device-specific error values, and investigate the influence of varying EHCV thresholds on daily vigorous PA (VPA).We estimated quantiles to analyse the distribution of all accelerometer positive count values obtained from 9005 seven-year old children participating in the UK Millennium Cohort Study. A threshold to identify EHCV was derived by differentiating the quantile function. Data were screened for device-specific error count values and EHCV, and a sensitivity analysis conducted to compare daily VPA estimates using three approaches to accounting for EHCV.Using our proposed threshold of ≥ 11,715 counts/minute to identify EHCV, we found that only 0.7% of all non-zero counts measured in MCS children were EHCV; in 99.7% of these children, EHCV comprised < 1% of total non-zero counts. Only 11 MCS children (0.12% of sample) returned accelerometers that contained negative counts; out of 237 such values, 211 counts were equal to -32,768 in one child. The medians of daily minutes spent in VPA obtained without excluding EHCV, and when using a higher threshold (≥19,442 counts/minute) were, respectively, 6.2% and 4.6% higher than when using our threshold (6.5 minutes; p

BackgroundWhen using accelerometers to measure physical activity, researchers need to determine whether subjects have worn their device for a sufficient period to be included in analyses. We propose a minimum wear criterion using population-based accelerometer data, and explore the influence of gender and the purposeful inclusion of children with weekend data on reliability.MethodsAccelerometer data obtained during the age seven sweep of the UK Millennium Cohort Study were analysed. Children were asked to wear an ActiGraph GT1M accelerometer for seven days. Reliability coefficients(r) of mean daily counts/minute were calculated using the Spearman-Brown formula based on the intraclass correlation coefficient. An r of 1.0 indicates that all the variation is between- rather than within-children and that measurement is 100% reliable. An r of 0.8 is often regarded as acceptable reliability. Analyses were repeated on data from children who met different minimum daily wear times (one to 10 hours) and wear days (one to seven days). Analyses were conducted for all children, separately for boys and girls, and separately for children with and without weekend data.ResultsAt least one hour of wear time data was obtained from 7,704 singletons. Reliability increased as the minimum number of days and the daily wear time increased. A high reliability (r = 0.86) and sample size (n = 6,528) was achieved when children with ≥ two days lasting ≥10 hours/day were included in analyses. Reliability coefficients were similar for both genders. Purposeful sampling of children with weekend data resulted in comparable reliabilities to those calculated independent of weekend wear.ConclusionQuality control procedures should be undertaken before analysing accelerometer data in large-scale studies. Using data from children with ≥ two days lasting ≥10 hours/day should provide reliable estimates of physical activity. It's unnecessary to include only children with accelerometer data collected during weekends in analyses.

Many children can be exposed to multiple adversities in low and middle-income countries (LMICs) placing them at potential risk of psychological problems. However, there is a paucity of research using large representative cohorts examining the psychological adjustment of children in school settings in these countries. Children's psychological adjustment has been shown to affect educational progress which is critical for their future. This study, based in a rural, socio-economically disadvantaged area of South Africa, aimed to examine the prevalence of children's psychological problems as well as possible risk and protective factors.Rates of psychological problems in 10-12 year olds were examined using teacher- and child-report questionnaires. Data on children from 10 rural primary schools, selected by stratified random sampling, were linked to individual and household data from the Agincourt health and socio-demographic surveillance system collected from households over 15 years.A total of 1,025 children were assessed. Teachers identified high levels of behavioural and emotional problems (41%). Children reported lower, but substantial rates of anxiety/depression (14%), and significant post-traumatic stress symptoms (24%); almost a quarter felt unsafe in school. Risk factors included being a second-generation former refugee and being from a large household. Protective factors highlight the importance of maternal factors, such as being more educated and in a stable partnership.The high levels of psychological problems identified by teachers are a serious public health concern, as they are likely to impact negatively on children's education, particularly given the large class sizes and limited resources in rural LMIC settings. Despite the high levels of risk, a proportion of children were managing well and research to understand resilience could inform interventions.

HIV-positive women have an increased risk of invasive cervical cancer but cytologic screening is effective in reducing incidence. Little is known about cervical screening coverage or the prevalence of abnormal cytology among HIV-positive women in Ukraine, which has the most severe HIV epidemic in Europe.Poisson regression models were fitted to data from 1120 women enrolled at three sites of the Ukraine Cohort Study of HIV-infected Childbearing Women to investigate factors associated with receiving cervical screening as part of HIV care. All women had been diagnosed as HIV-positive before or during their most recent pregnancy. Prevalence of cervical abnormalities (high/low grade squamous intraepithelial lesions) among women who had been screened was estimated, and associated factors explored.Overall, 30% (337/1120) of women had received a cervical screening test as part of HIV care at study enrolment (median 10 months postpartum), a third (115/334) of whom had been tested >12 months previously. In adjusted analyses, women diagnosed as HIV-positive during (vs before) their most recent pregnancy were significantly less likely to have a screening test reported, on adjusting for other potential risk factors (adjusted prevalence ratio (APR) 0.62, 95% CI 0.51-0.75 p

BACKGROUND:Households from vulnerable groups experiencing epidemiological transitions are known to be affected concomitantly by under-nutrition and obesity. Yet, it is unknown to what extent this double burden affects refugee populations dependent on food assistance. We assessed the double burden of malnutrition among Western Sahara refugees living in a protracted emergency. METHODS AND FINDINGS:We implemented a stratified nutrition survey in October-November 2010 in the four Western Sahara refugee camps in Algeria. We sampled 2,005 households, collecting anthropometric measurements (weight, height, and waist circumference) in 1,608 children (6-59 mo) and 1,781 women (15-49 y). We estimated the prevalence of global acute malnutrition (GAM), stunting, underweight, and overweight in children; and stunting, underweight, overweight, and central obesity in women. To assess the burden of malnutrition within households, households were first classified according to the presence of each type of malnutrition. Households were then classified as undernourished, overweight, or affected by the double burden if they presented members with under-nutrition, overweight, or both, respectively. The prevalence of GAM in children was 9.1%, 29.1% were stunted, 18.6% were underweight, and 2.4% were overweight; among the women, 14.8% were stunted, 53.7% were overweight or obese, and 71.4% had central obesity. Central obesity (47.2%) and overweight (38.8%) in women affected a higher proportion of households than did GAM (7.0%), stunting (19.5%), or underweight (13.3%) in children. Overall, households classified as overweight (31.5%) were most common, followed by undernourished (25.8%), and then double burden-affected (24.7%). CONCLUSIONS:The double burden of obesity and under-nutrition is highly prevalent in households among Western Sahara refugees. The results highlight the need to focus more attention on non-communicable diseases in this population and balance obesity prevention and management with interventions to tackle under-nutrition. Please see later in the article for the Editors' Summary.

BACKGROUND:Accurate objective assessment of sedentary and physical activity behaviours during childhood is integral to the understanding of their relation to later health outcomes, as well as to documenting the frequency and distribution of physical activity within a population. PURPOSE:To calibrate the Actigraph GT1M accelerometer, using energy expenditure (EE) as the criterion measure, to define thresholds for sedentary behaviour and physical activity categories suitable for use in a large scale epidemiological study in young children. METHODS:Accelerometer-based assessments of physical activity (counts per minute) were calibrated against EE measures (kcal x kg(-1) x hr(-1)) obtained over a range of exercise intensities using a COSMED K4b(2) portable metabolic unit in 53 seven-year-old children. Children performed seven activities: lying down viewing television, sitting upright playing a computer game, slow walking, brisk walking, jogging, hopscotch and basketball. Threshold count values were established to identify sedentary behaviour and light, moderate and vigorous physical activity using linear discriminant analysis (LDA) and evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS:EE was significantly associated with counts for all non-sedentary activities with the exception of jogging. Threshold values for accelerometer counts (counts x minute(-1)) were