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Aims: To obtain preliminary data on the impact of motivational interviewing, a counselling approach to behaviour change, on glycaemic control, wellbeing, and self-care of adolescents with diabetes. Methods: Twenty two […]

The appearance of this radiograph caused considerable concern in the casualty department. It shows the left wrist of an 11 year old girl and was taken following suspicion of a [...]

BACKGROUND: Body fat mass (FM) and fat free mass (FFM) in childhood are often estimated by conversion of a measured variable into compartmental body composition using constants or regression equations that have been previously derived in healthy individuals. Application of such constants or equations to children with disease states may lead to inappropriate conclusions since the 'normal' relationships may become altered. AIMS AND Methods: To test this hypothesis by taking measurements of body composition using dual energy x ray absorptiometry (DEXA) as a 'gold standard' method and calculating hydration and body potassium constants using isotopic water dilution and whole body potassium counting. Measurements of bioelectrical impedance (BIA) by two different analysers (RJL and Holtain) were also performed to allow comparison with body water measurements. RESULTS: Measurements were performed in 35 children treated for acute lymphoblastic leukaemia (ALL) and compared to those in 21 children treated for a variety of other malignancies and 32 healthy sibling controls. The mean hydration and potassium content of FFM was significantly reduced in the ALL group compared to both other malignancies and controls. Application of equations derived from controls for the measurement of FFM derived from bioelectrical impedance led to an underestimation of 1.15 kg when compared to that derived from DEXA in children treated for ALL but not in other malignancies. For all groups combined, BIA was significantly different in the two analysers. CONCLUSION: Care needs to be taken in the application of equations derived from the normal population to body composition measurement in children treated for ALL. [ABSTRACT FROM AUTHOR]

Aims: To define outcome measures for auditing the clinical care of children and adolescents with insulin dependent diabetes mellitus (IDDM) and to assess the benefit of appointing a dedicated paediatric trained diabetes specialist nurse (PDSN).Methods: Retrospective analysis of medical notes and hospital records. Glycaemic control, growth, weight gain, microvascular complications, school absence, and the proportion of children undergoing an annual clinical review and diabetes education session were assessed. The effect of the appointment of a PDSN on the frequency of hospital admission, length of inpatient stay, and outpatient attendance was evaluated.Results: Children with IDDM were of normal height and grew well for three years after diagnosis, but grew suboptimally thereafter. Weight gain was above average every year after diagnosis. Glycaemic control was poor at all ages with only 16% of children having an acceptable glycated haemoglobin. Eighty five per cent of patients underwent a formal annual clinical review, of whom 16% had background retinopathy and 20% microalbuminuria in one or more samples. After appointing the PDSN the median length of hospital stay for newly diagnosed patients decreased from five days to one day, with 10 of 24 children not admitted. None of the latter was admitted during the next year. There was no evidence of the PDSN affecting the frequency of readmission or length of stay of children with established IDDM. Non-attendance at the outpatient clinic was reduced from a median of 19 to 10%.Conclusions: Outcome measures for evaluating the care of children with IDDM can be defined and evaluated. Specialist nursing support markedly reduces the length of hospital stay of newly diagnosed patients without sacrificing the quality of care. [ABSTRACT FROM AUTHOR]

The prevalence of osteopenia in children with inflammatory bowel disease (IBD) is unknown. The effect of nutritional state, disease activity, and steroid therapy on bone mineral content (BMC) of whole body, lumbar spine, and left femoral neck measured by dual energy x ray absorptiometry in 32 children with IBD was assessed by comparison with 58 healthy local school children. Using the control data, a predicted BMC was calculated taking into account bone area, age, height, weight, and pubertal stage. The measured BMC in children with IBD was expressed as a percentage of this predicted value (% BMC). Mean (SD) % BMC was significantly reduced for the whole body and left femoral neck in the children with IBD (97.0 (4.5)% and 93.1 (12.0)% respectively, p < 0.05). Of the children with IBD, 41% had a % BMC less than 1 SD below the mean for the whole body and 47% at the femoral neck. Reduction in % BMC was associated with steroid usage but not with the magnitude of steroid dose, disease activity, or biochemical markers of bone metabolism. In conclusion, osteopenia is relatively common in childhood IBD and may be partly related to the previous use of steroids. [ABSTRACT FROM AUTHOR]

Many long term sequelae result from previous treatment for malignancy in childhood. However, little information exists on cardiopulmonary response and energy expenditure during exercise and their possible associations with excess body fat. Measurements of body composition and exercise capacity both at low intensity and maximal aerobic capacity were made on 56 long term survivors of childhood malignancy (35 survivors of acute lymphoblastic leukaemia (ALL) and 21 survivors of other malignancies) and 32 siblings acting as controls. Female survivors of ALL had significantly greater mean (SD) body fat than survivors of other malignancies and siblings (32.5 (6.4)% v 24.3 (4.4)% and 26.3 (8.5)% respectively, p < 0.005). Energy expenditure at low intensity exercise was reduced in survivors of ALL, and negatively correlated with body fat after controlling for weight (partial r range -0.21 to -0.47, p < 0.05). Stroke volume, measured indirectly, was reduced and heart rate raised in ALL survivors at sub-maximal exercise levels. Peak oxygen consumption was significantly reduced in girls and boys treated for ALL compared with siblings (30.5 v 41.3 ml/kg/min for girls, p < 0.05 and 39.9 v 47.6 ml/kg/min for boys, p < 0.05 respectively). Reduced exercise capacity may account in part for the excess adiposity observed in long term survivors of ALL. [ABSTRACT FROM AUTHOR]

Background: There is a lack of high quality, child-centred and effective health information to support development of self-care practices and expertise in children with acute and long-term conditions. In type 1 diabetes, clinical guidelines indicate that high-quality, child-centred information underpins achievement of optimal glycaemic control with the aim of minimising acute readmissions and reducing the risk of complications in later life. This paper describes the development of a range of child-centred diabetes information resources and outlines the study design and protocol for a randomized controlled trial to evaluate the information resources in routine practice. The aim of the diabetes information intervention is to improve children and young people's quality of life by increasing self-efficacy in managing their type 1 diabetes.Methods/design: We used published evidence, undertook qualitative research and consulted with children, young people and key stakeholders to design and produce a range of child-centred, age-appropriate children's diabetes diaries, carbohydrate recording sheets, and assembled child-centred, age-appropriate diabetes information packs containing published information in a folder that can be personalized by children and young people with pens and stickers. Resources have been designed for children/young people 6-10; 11-15; and 16-18 years.To evaluate the information resources, we designed a pragmatic randomized controlled trial to assess the effectiveness, cost effectiveness, and implementation in routine practice of individually tailored, age-appropriate diabetes diaries and information packs for children and young people age 6-18 years, compared with currently available standard practice.Children and young people will be stratified by gender, length of time since diagnosis (< 2 years and > 2 years) and age (6-10; 11-15; and 16-18 years). The following data will be collected at baseline, 3 and 6 months: PedsQL (generic, diabetes and parent versions), and EQ-5 D (parent and child); NHS resource use and process data (questionnaire and interview). Baseline and subsequent HbA1c measurements, blood glucose meter use, readings and insulin dose will be taken from routine test results and hand-held records when attending routine 3-4 monthly clinic visits.The primary outcome measure is diabetes self-efficacy and quality-of-life (Diabetes PedsQL). Secondary outcomes include: HbA1c, generic quality of life, routinely collected NHS/child-held data, costs, service use, acceptability and utility.Trial Registration: ISRCTN17551624. [ABSTRACT FROM AUTHOR]

Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (T H 1 and T H 17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12-18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (T H 17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of T H 17.1 cells co-expressing IL-2 and granulocyte-macrophage colony-stimulating factor (IL-2 + GM-CSF + T H 17.1 cells, P = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of T H 17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380)., (© 2024. The Author(s).)

Background: Children presenting to primary care with suspected type 1 diabetes should be referred immediately to secondary care to avoid life-threatening diabetic ketoacidosis. However, early recognition of children with type 1 diabetes is challenging. Children might not present with classic symptoms, or symptoms might be attributed to more common conditions. A quarter of children present with diabetic ketoacidosis, a proportion unchanged over 25 years. Our aim was to investigate whether a machine-learning algorithm could lead to earlier detection of type 1 diabetes in primary care., Methods: We developed the predictive algorithm using Welsh primary care electronic health records (EHRs) linked to the Brecon Dataset, a register of children newly diagnosed with type 1 diabetes. Children were included from their first primary care record within the study period of Jan 1, 2000, to Dec 31, 2016, until either type 1 diabetes diagnosis, they turned 15 years of age, or study end. We developed an ensemble learner (SuperLearner) using 26 potential predictors. Validation of the algorithm was done in English EHRs from the Clinical Practice Research Datalink (primary care) and Hospital Episode Statistics, focusing on the ability of the algorithm to identify children who went on to develop type 1 diabetes and the time by which diagnosis could be anticipated., Findings: The development dataset comprised 34 754 400 primary care contacts, relating to 952 402 children, and the validation dataset comprised 43 089 103 primary care contacts, relating to 1 493 328 children. Of these, 1829 (0·19%) children younger than 15 years in the development dataset, and 1516 (0·10%) in the validation dataset had a reliable date of type 1 diabetes diagnosis. If set to give an alert in 10% of contacts, an estimated 71·6% (95% CI 68·8-74·4) of the children with type 1 diabetes would receive an alert by the algorithm in the 90 days before diagnosis, with diagnosis anticipated, on average, by an estimated 9·34 days (95% CI 7·77-10·9)., Interpretation: If implemented into primary care settings, this predictive algorithm could substantially reduce the proportion of patients with new-onset type 1 diabetes presenting in diabetic ketoacidosis. Acceptability of alert thresholds should be explored in primary care., Funding: Diabetes UK., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: To quantify associations of educational outcomes with type 1 diabetes status and glycemic management (HbA1c)., Research Design and Methods: This was a record linkage study of schools and higher (college) education data sets linked to national diabetes audits. The population includes all Welsh children attending school between 2009 and 2016, yielding eight academic cohorts with attainment data, including 263,426 children without diabetes and 1,212 children diagnosed with type 1 diabetes. Outcomes include standardized educational attainment for those aged 16 years, higher education participation for those aged ≥18 years, and school absences among those aged 6-16 years., Results: Comparison between children with type 1 diabetes and children without diabetes showed no strong evidence of associations for student attainment (0.001 SD, 95% CI -0.047 to 0.049, P < 0.96, n = 1,212 vs. 263,426) or higher education entry rates (odds ratio 1.067, 95% CI 0.919-1.239, P < 0.39, n = 965 vs. 217,191), despite nine more sessions of absence from school annually (P < 0.0001). However, attainment in children in the most optimal HbA1c quintile was substantially better than for children without diabetes (0.267 SD, 95% CI 0.160-0.374, P < 0.001) while being worse than for children without diabetes in the least optimal quintile (-0.395 SD, 95% CI -0.504 to -0.287, P < 0.001). Attainment did not differ by duration of "exposure" to diabetes based on age at diagnosis., Conclusions: Despite more school absences, diabetes diagnosis is not associated with educational attainment or entry into higher education, although attainment does vary by HbA1c level, which may be explained in part (or wholly) by unobserved shared personal, family, or socioeconomic characteristics associated with both success in education and effective glycemic self-management., (© 2022 by the American Diabetes Association.)

Introduction: Most individuals newly diagnosed with type 1 diabetes (T1D) have 10%-20% of beta-cell function remaining at the time of diagnosis. Preservation of residual beta-cell function at diagnosis may improve glycaemic control and reduce longer-term complications.Immunotherapy has the potential to preserve endogenous beta-cell function and thereby improve metabolic control even in poorly compliant individuals. We propose to test ustekinumab (STELARA), a targeted and well-tolerated therapy that may halt T-cell and cytokine-mediated destruction of beta-cells in the pancreas at the time of diagnosis., Methods and Analysis: This is a double-blind phase II study to assess the safety and efficacy of ustekinumab in 72 children and adolescents aged 12-18 with new-onset T1D.Participants should have evidence of residual functioning beta-cells (serum C-peptide level >0.2nmol/L in the mixed-meal tolerance test (MMTT) and be positive for at least one islet autoantibody (GAD, IA-2, ZnT8) to be eligible.Participants will be given ustekinumab/placebo subcutaneously at weeks 0, 4 and 12, 20, 28, 36 and 44 in a dose depending on the body weight and will be followed for 12 months after dose 1.MMTTs will be used to measure the efficacy of ustekinumab for preserving C-peptide area under the curve at week 52 compared with placebo. Secondary objectives include further investigations into the efficacy and safety of ustekinumab, patient and parent questionnaires, alternative methods for measuring insulin production and exploratory mechanistic work., Ethics and Dissemination: This trial received research ethics approval from the Wales Research Ethics Committee 3 in September 2018 and began recruiting in December 2018.The results will be disseminated using highly accessed, peer-reviewed medical journals and presented at conferences., Trial Registration Number: ISRCTN14274380., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objective: The aim of this economic evaluation was to assess whether home management could represent a cost-effective strategy in the patient pathway of type 1 diabetes (T1D). This is based on the Delivering Early Care In Diabetes Evaluation trial (ISRCTN78114042), which compared home versus hospital management from diagnosis in childhood diabetes and found no statistically significant difference in glycaemic control at 24 months., Design: Cost-effectiveness analysis alongside a randomised controlled trial., Setting: Eight paediatric diabetes centres in England, Wales and Northern Ireland., Participants: 203 clinically well children aged under 17 years, with newly diagnosed T1D and their carers., Outcome Measures: The base-case analysis adopted n National Health Service (NHS) perspective. A scenario analysis assessed costs from a broader societal perspective. The incremental cost-effectiveness ratio (ICER), expressed as cost per mmol/mol reduction in glycated haemoglobin (HbA1c), was based on the mean difference in costs between the home and hospital groups, divided by mean differences in effectiveness (HbA1c). Uncertainty was considered in terms of the probability of cost-effectiveness., Results: At 24 months postintervention, the base-case analysis showed a difference in costs between home and hospital, in favour of home management (mean difference -£2,217; 95% CI -£2825 to -£1,609; p<0.001). Home care dominated, with an ICER of £7434 (saved) per mmol/mol reduction of HbA1c. The results of the scenario analysis also favoured home management. The greatest driver of cost differences was hospitalisation during the initiation period., Conclusions: Home management from diagnosis of children with T1D who are medically stable represents a less costly approach for the NHS in the UK, without impacting clinical effectiveness., Trial Registration Number: ISRCTN78114042., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Although primary adrenal insufficiency (PAI) in children and young people is often due to congenital adrenal hyperplasia (CAH) or autoimmunity, other genetic causes occur. The relative prevalence of these conditions is poorly understood., Objective: We investigated genetic causes of PAI in children and young people over a 25 year period., Design Setting and Participants: Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research centers between 1993 and 2018. We pre-excluded those with CAH, autoimmune, or metabolic causes. We obtained additional data from NR0B1 (DAX-1) clinical testing centers., Intervention and Outcome Measurements: Genetic analysis involved a candidate gene approach (1993 onward) or next generation sequencing (NGS; targeted panels, exomes) (2013-2018)., Results: A genetic diagnosis was reached in 103/155 (66.5%) individuals. In 5 children the adrenal insufficiency resolved and no genetic cause was found. Pathogenic variants occurred in 11 genes: MC2R (adrenocorticotropin receptor; 30/155, 19.4%), NR0B1 (DAX-1; 7.7%), CYP11A1 (7.7%), AAAS (7.1%), NNT (6.5%), MRAP (4.5%), TXNRD2 (4.5%), STAR (3.9%), SAMD9 (3.2%), CDKN1C (1.3%), and NR5A1 /steroidogenic factor-1 (SF-1; 0.6%). Additionally, 51 boys had NR0B1 variants identified through clinical testing. Although age at presentation, treatment, ancestral background, and birthweight can provide diagnostic clues, genetic testing was often needed to define the cause., Conclusions: PAI in children and young people often has a genetic basis. Establishing the specific etiology can influence management of this lifelong condition. NGS approaches improve the diagnostic yield when many potential candidate genes are involved., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Studies of prevalence and the demographic profile of type 1 diabetes are challenging because of the relative rarity of the condition, however, these outcomes can be determined using routine healthcare data repositories. Understanding the epidemiology of type 1 diabetes allows for targeted interventions and care of this life-affecting condition., Objectives: To describe the prevalence, incidence and demographics of persons with type 1 diabetes diagnosed in Wales, UK, using the Secure Anonymised Information Linkage (SAIL) Databank., Methods: Data derived from primary and secondary care throughout Wales available in the SAIL Databank were used to identify people with type 1 diabetes to determine the prevalence and incidence of type 1 diabetes over a 10 year period (2008-18) and describe the demographic and clinical characteristics of this population by age, socioeconomic deprivation and settlement type. The seasonal variation in incidence rates was also examined., Results: The prevalence of type 1 diabetes in 2018 was 0.32% in the whole population, being greater in men compared to women (0.35% vs 0.28% respectively); highest in those aged 15-29 years (0.52%) and living in the most socioeconomically deprived areas (0.38%). The incidence of type 1 diabetes over 10 years was 14.0 cases/100,000 people/year for the whole population of Wales. It was highest in children aged 0-14 years (33.6 cases/100,000 people/year) and areas of high socioeconomic deprivation (16.8 cases/100,000 people/year) and least in those aged 45-60 years (6.5 cases/100,000 people/year) and in areas of low socioeconomic deprivation (11.63 cases/100,000 people/year). A seasonal trend in the diagnoses of type 1 diabetes was observed with higher incidence in winter months., Conclusion: This nation-wide retrospective epidemiological study using routine data revealed that the incidence of type 1 diabetes in Wales was greatest in those aged 0-14 years with a higher incidence and prevalence in the most deprived areas. These findings illustrate the need for health-related policies targeted at high deprivation areas to include type 1 diabetes in their remit., Competing Interests: Statement on conflicts of interest: None of the authors expressed any conflict of interest.

Aims/hypothesis: The aim of this work was to evaluate geographical variability and trends in the prevalence of diabetic ketoacidosis (DKA), between 2006 and 2016, at the diagnosis of childhood-onset type 1 diabetes in 13 countries over three continents., Methods: An international retrospective study on DKA at diagnosis of diabetes was conducted. Data on age, sex, date of diabetes diagnosis, ethnic minority status and presence of DKA at diabetes onset were obtained from Australia, Austria, Czechia, Denmark, Germany, Italy, Luxembourg, New Zealand, Norway, Slovenia, Sweden, USA and the UK (Wales). Mean prevalence was estimated for the entire period, both overall and by country, adjusted for sex and age group. Temporal trends in annual prevalence of DKA were estimated using logistic regression analysis for each country, before and after adjustment for sex, age group and ethnic minority status., Results: During the study period, new-onset type 1 diabetes was diagnosed in 59,000 children (median age [interquartile range], 9.0 years [5.5-11.7]; male sex, 52.9%). The overall adjusted DKA prevalence was 29.9%, with the lowest prevalence in Sweden and Denmark and the highest in Luxembourg and Italy. The adjusted DKA prevalence significantly increased over time in Australia, Germany and the USA while it decreased in Italy. Preschool children, adolescents and children from ethnic minority groups were at highest risk of DKA at diabetes diagnosis in most countries. A significantly higher risk was also found for females in Denmark, Germany and Slovenia., Conclusions/interpretation: DKA prevalence at type 1 diabetes diagnosis varied considerably across countries, albeit it was generally high and showed a slight increase between 2006 and 2016. Increased awareness of symptoms to prevent delay in diagnosis is warranted, especially in preschool children, adolescents and children from ethnic minority groups.

Context and Objectives: The Controlled Antenatal Thyroid Screening Study I (CATS-I) was a randomized controlled trial investigating the effects of levothyroxine therapy for suboptimal gestational thyroid function (SGTF), comparing outcomes in children of treated (SGTF-T) with untreated (SGTF-U) women during pregnancy. This follow-up study, CATS-II, reports the long-term effects on anthropometric, bone, and cardiometabolic outcomes in mothers and offspring and includes a group with normal gestational thyroid function (NGTF)., Design & Participants: 332 mothers (197 NGTF, 56 SGTF-U, 79 SGTF-T) aged 41.2±5.3 years (mean±SD) and 326 paired children assessed 9.3±1.0 years after birth for (i) body mass index (BMI); (ii) lean, fat, and bone mass by dual-energy X-ray absorptiometry; (iii) blood pressure, augmentation index, and aortic pulse-wave-velocity; and (iv) thyroid function, lipids, insulin, and adiponectin. The difference between group means was compared using linear regression., Results: Offspring's measurements were similar between groups. Although maternal BMI was similar between groups at CATS-I, after 9 years (at CATS-II) SGTF-U mothers showed higher BMI (median [interquartile ratio] 28.3 [24.6-32.6] kg/m2) compared with NGTF (25.8 [22.9-30.0] kg/m2; P = 0.029), driven by fat mass increase. At CATS-II SGTF-U mothers also had higher thyroid-stimulating hormone (TSH) values (2.45 [1.43-3.50] mU/L) than NGTF (1.54 [1.12-2.07] mU/L; P = 0.015), since 64% had never received levothyroxine. At CATS-II, SGTF-T mothers had BMI (25.8 [23.1-29.8] kg/m2, P = 0.672) and TSH (1.68 [0.89-2.96] mU/L; P = 0.474) values similar to NGTF mothers., Conclusions: Levothyroxine supplementation of women with SGTF did not affect long-term offspring anthropometric, bone, and cardiometabolic measurements. However, absence of treatment was associated with sustained long-term increase in BMI and fat mass in women with SGTF., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims/hypothesis: The aim of this study was to describe the characteristics and outcomes of pregnancies in a national cohort of teenage (<20 years) and young adult women (≥20 years) with and without childhood-onset (<15 years) type 1 diabetes. We hypothesised that, owing to poor glycaemic control during the teenage years, pregnancy outcomes would be poorer in teenage mothers with type 1 diabetes than young adult mothers with type 1 diabetes and mothers without diabetes., Methods: The Brecon Register of childhood-onset type 1 diabetes diagnosed in Wales since 1995 was linked to population-based datasets in the Secure Anonymised Information Linkage (SAIL) Databank, creating an electronic cohort (e-cohort) of legal births (live or stillbirths beyond 24 weeks' gestation) to women aged less than 35 years between 1995 and 2013 in Wales. Teenage pregnancy rates were calculated based on the number of females in the same birth cohort in Wales. Pregnancy outcomes, including pre-eclampsia, preterm birth, low birthweight, macrosomia, congenital malformations, stillbirths and hospital admissions during the first year of life, were obtained from electronic records for the whole Welsh population. We used logistic and negative binomial regression to compare outcomes among teenage and young adult mothers with and without type 1 diabetes., Results: A total of 197,796 births were eligible for inclusion, including 330 to girls and women with childhood-onset type 1 diabetes, of whom 68 were teenagers (age 14-19 years, mean 17.9 years) and 262 were young adults (age 20-32 years, mean 24.0 years). The mean duration of diabetes was 14.3 years (9.7 years for teenagers; 15.5 years for young adults). Pregnancy rates were lower in teenagers with type 1 diabetes than in teenagers without diabetes (mean annual teenage pregnancy rate between 1999 and 2013: 8.6 vs 18.0 per 1000 teenage girls, respectively; p < 0.001). In the background population, teenage pregnancy was associated with deprivation (p < 0.001), but this was not the case for individuals with type 1 diabetes (p = 0.85). Glycaemic control was poor in teenage and young adult mothers with type 1 diabetes (mean HbA 1c based on closest value to conception: 81.3 and 80.2 mmol/mol [9.6% and 9.5%], respectively, p = 0.78). Glycaemic control improved during pregnancy in both groups but to a greater degree in young adults, who had significantly better glycaemic control than teenagers by the third trimester (mean HbA 1c : 54.0 vs 67.4 mmol/mol [7.1% vs 8.3%], p = 0.01). All adverse outcomes were more common among mothers with type 1 diabetes than mothers without diabetes. Among those with type 1 diabetes, hospital admissions during the first year of life were more common among babies of teenage vs young adult mothers (adjusted OR 5.91 [95% CI 2.63, 13.25]). Other outcomes were no worse among teenage mothers with type 1 diabetes than among young adult mothers with diabetes., Conclusions/interpretation: Teenage girls with childhood-onset type 1 diabetes in Wales are less likely to have children than teenage girls without diabetes. Teenage pregnancy in girls with type 1 diabetes, unlike in the background population, is not associated with social deprivation. In our cohort, glycaemic control was poor in both teenage and young adult mothers with type 1 diabetes. Pregnancy outcomes were comparable between teenage and young adult mothers with type 1 diabetes, but hospital admissions during the first year of life were five times more common among babies of teenage mothers with type 1 diabetes than those of young adult mothers with diabetes.

Objective: To estimate the effectiveness of standardised self-management kits for children with type 1 diabetes., Design: Pragmatic trial with randomisation ratio of two intervention: one control. Qualitative process evaluation., Setting: 11 diabetes clinics in England and Wales., Participants: Between February 2010 and August 2011, we validly randomised 308 children aged 6-18 years; 201 received the intervention., Intervention: We designed kits to empower children to achieve glycaemic control, notably by recording blood glucose and titrating insulin. The comparator was usual treatment. OUTCOME MEASURES AT 3 AND 6 MONTHS: Primary: Diabetes Pediatric Quality of Life Inventory (PedsQL). Secondary: HbA1c; General PedsQL; EQ-5D; healthcare resource use., Results: Of the five Diabetes PedsQL dimensions, Worry showed adjusted scores significantly favouring self-management kits at 3 months (mean child-reported difference =+5.87; Standard error[SE]=2.19; 95% confidence interval [CI]) from +1.57 to +10.18; p=0.008); but Treatment Adherence significantly favoured controls at 6 months (mean child-reported difference=-4.68; SE=1.74; 95%CI from -8.10 to -1.25; p=0.008). Intervention children reported significantly worse changes between 3 and 6 months on four of the five Diabetes PedsQL dimensions and on the total score (mean difference=-3.20; SE=1.33; 95% CI from -5.73 to -0.67; p=0.020). There was no evidence of change in HbA1c; only 18% of participants in each group achieved recommended levels at 6 months. No serious adverse reactions attributable to the intervention or its absence were reported.Use of kits was poor. Few children or parents associated blood glucose readings with better glycaemic control. The kits, costing £185, alienated many children and parents., Conclusions: Standardised kits showed no evidence of benefit, inhibited diabetes self-management and increased worry. Future research should study relationships between children and professionals, and seek new methods of helping children and parents to manage diabetes., Trial Registration Number: ISRCTN17551624., Competing Interests: Competing interests: Professor JWG has received payments from Pfizer, Bayer and Ipsen for lectures, development of educational presentations and travel/accommodation to attend scientific meetings and advisory board meetings. His employer (Cardiff University) has also received funding from Novo Nordisk to support the development of patient-support materials used in the Development and Evaluation of a Psychosocial Intervention for Children and Teenagers Experiencing Diabetes (DEPICTED) research study., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Context & Objectives: The Controlled Antenatal Thyroid Screening (CATS) study was the first randomized controlled trial to investigate effects of treating suboptimal gestational thyroid function (SGTF) on child cognition. Since observational studies indicated that SGTF may also increase symptoms of autism and attention-deficit/hyperactivity disorder (ADHD), the CATS cohort was used to investigate whether treatment of mothers affected their children's behavior., Design & Participants: Mothers (N = 475) completed 3 questionnaires: the Strengths and Difficulties Questionnaire (SDQ), the Child ADHD Questionnaire, and the Social Communication Questionnaire (SCQ, used as a screen for autism spectrum disorder [ASD]), about their children (mean age 9.5 years). Group comparisons of total scores, numbers of children above clinical thresholds, and association between high maternal free thyroxine (FT4) (> 97.5th percentile of the UK cohort, "overtreated") and child neurodevelopment were reported., Results: There were no differences in total scores between normal gestational thyroid function (GTF) (n = 246), treated (n = 125), and untreated (n = 104) SGTF groups. More children of treated mothers scored above clinical thresholds, particularly the overtreated. Scores were above thresholds in SDQ conduct (22% vs 7%), SCQ total scores (7% vs 1%), and ADHD hyperactivity (17% vs 5%) when comparing overtreated (n = 40) and untreated (N = 100), respectively. We identified significantly higher mean scores for SDQ conduct (adjusted mean difference [AMD] 0.74; 95% confidence interval [CI], 0.021-1.431; P = 0.040, effect size 0.018) and ADHD hyperactivity (AMD 1.60, 95% CI, 0.361-2.633; P = 0.003, effect size 0.028) comparing overtreated with normal-GTF children., Conclusions: There was no overall association between SGTF and offspring ADHD, ASD, or behavior questionnaire scores. However, children of "overtreated" mothers displayed significantly more ADHD symptoms and behavioral difficulties than those of normal-GTF mothers. Thyroxine supplementation during pregnancy requires monitoring to avoid overtreatment., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The primary objective of this systematic review was to evaluate available literature on whether type 1 diabetes mellitus (T1DM) has an impact on educational attainment in individuals undertaking high stakes standardised testing at the end of compulsory schooling., Design: A systematic review was undertaken comparing educational attainment for individuals with and without T1DM who have undertaken high stakes testing at the end of compulsory schooling., Data Sources: A comprehensive search of MEDLINE, MEDLINE (epub ahead of print, in-process and other non-indexed citations), EMBASE, Web of Science, British Education Index, Education Resources Information Center and Cumulative Index to Nursing and Allied Health Literature was undertaken on 15 January 2018 and updated on 17 January 2019., Eligibility Criteria: Included studies fulfilled the following criteria: observational study or randomised controlled trial; included individuals who have undertaken high stakes testing at the end of compulsory schooling; compared the grades obtained by individuals with T1DM with a representative population control., Data Extraction and Synthesis: Two reviewers performed study selection and data extraction independently. Quality and risk of bias in the observational studies included were assessed using the Newcastle-Ottawa Scale. A detailed narrative synthesis of the included studies was completed., Results: 3103 articles were identified from the database search, with two Swedish cohort studies (using the same linked administrative data) meeting final inclusion criteria. A small but statistically significant difference was reported in mean final grades, with children with T1DM found to have lower mean grades than their non-diabetic counterparts (adjusted mean difference 0.07-0.08)., Conclusions: More contemporary research is required to evaluate the impact of T1DM in childhood on educational attainment in individuals undertaking high stakes standardised testing at the end of compulsory schooling, taking into consideration the substantial advances in management of T1DM in the last decade., Prospero Registration Number: CRD42017084078., Competing Interests: Competing interests: RF has received a grant from the Medical Research Council MR/N015428/1 for his work as principal investigator of the project ‘Investigating the inter-relationship between diabetes and children’s educational achievement’., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objective: To determine whether, in children with newly diagnosed type 1 diabetes who were not acutely unwell, management at home for initiation of insulin treatment and education of the child and family, would result in improved clinical and psychological outcomes at 2 years postdiagnosis., Design: A multicentre randomised controlled trial (January 2008/October 2013)., Setting: Eight paediatric diabetes centres in England, Wales and Northern Ireland., Participants: 203 clinically well children aged under 17 years, with newly diagnosed type 1 diabetes and their carers., Intervention: Management of the initiation period from diagnosis at home, for a minimum of 3 days, to include at least six supervised injections and delivery of pragmatic educational care., Main Outcome Measures: Primary outcome was glycosylated haemoglobin (HbA1c) concentration at 24 months postdiagnosis. Secondary outcomes included coping, anxiety, quality of life and use of NHS resources., Results: 203 children, newly diagnosed, were randomised to commence management at home (n=101) or in hospital (n=102). At the 24 month primary end point, there was one withdrawal and a follow-up rate of 194/202 (96%). Mean HbA1c in the home treatment arm was 72.1 mmol/mol and in the hospital treated arm 72.6 mmol/mol. There was a negligible difference between the mean HbA1c levels in the two arms adjusted for baseline (1.01, 95% CI 0.93 to 1.09). There were mostly no differences in secondary outcomes at 24 months, apart from better child self-esteem in the home-arm. No home-arm children were admitted to hospital during initiation and there were no adverse events at that time. The number of investigations was higher in hospital patients during the follow-up period. There were no differences in insulin regimens between the two arms., Conclusions: There is no evidence of a difference between home-based and hospital-based initiation of care in children newly diagnosed with type 1 diabetes across relevant outcomes., Trial Registration Number: ISRCTN78114042., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In recent decades, the prevalence of overweight and obesity has become increasingly common such that it is now the major nutritional problem worldwide. Obesity occurs when dietary energy intake exceeds energy expenditure and has arisen in many societies due to an increasingly "obesogenic" environment in which physical activity has declined and yet children continue to be exposed to unhealthy, energy-dense diets. Additional risks for the development of obesity also include psychological issues and genetic factors. Obesity has many adverse health consequences including development of insulin resistance, Type 2 diabetes, and the metabolic syndrome. There are also important genetic influences on the likelihood of developing insulin resistance. Given the limited success of therapeutic interventions to treat obesity and the metabolic syndrome, there has been an increased interest in preventative strategies. These are likely to be most successful when targeting the young and will require a combination of approaches which will need inter-disciplinary collaborations across health and local government to target families, schools, and local environments to facilitate behavior changes which influence young people's eating behaviors and habitual levels of physical activity., (Copyright © 2019 Gregory.)

Context: The α subunit of the stimulatory G protein (Gαs) links numerous receptors to adenylyl cyclase. Gαs, encoded by GNAS, is expressed predominantly from the maternal allele in certain tissues. Thus, maternal heterozygous loss-of-function mutations cause hormonal resistance, as in pseudohypoparathyroidism type Ia, whereas somatic gain-of-function mutations cause hormone-independent endocrine stimulation, as in McCune-Albright syndrome., Objective: We report two unrelated boys presenting with a new combination of clinical findings that suggest both gain and loss of Gαs function., Design and Setting: Clinical features were studied and sequencing of GNAS was performed. Signaling capacities of wild-type and mutant Gαs were determined in the presence of different G protein-coupled receptors (GPCRs) under basal and agonist-stimulated conditions., Results: Both unrelated patients presented with unexplained hyponatremia in infancy, followed by severe early onset gonadotrophin-independent precocious puberty and skeletal abnormalities. An identical heterozygous de novo variant (c.1136T>G; p.F376V) was found on the maternal GNAS allele in both patients; this resulted in a clinical phenotype that differed from known Gαs-related diseases and suggested gain of function at the vasopressin 2 receptor (V2R) and lutropin/choriogonadotropin receptor (LHCGR), yet increased serum PTH concentrations indicative of impaired proximal tubular PTH1 receptor (PTH1R) function. In vitro studies demonstrated that Gαs-F376V enhanced ligand-independent signaling at the PTH1R, LHCGR, and V2R and, at the same time, blunted ligand-dependent responses. Structural homology modeling suggested mutation-induced modifications at the C-terminal α5 helix of Gαs that are relevant for interaction with GPCRs and signal transduction., Conclusions: The Gαs p.F376V mutation causes a previously unrecognized multisystem disorder., (Copyright © 2019 Endocrine Society.)

Imaging of pressure-sensitive paint (PSP) for pressure measurement on moving surfaces is problematic due to the movement of the object within the finite exposure time of the imager, resulting in the blurring of the blade edges. The blurring problem is particularly challenging when high-sensitivity PSP with a long lifetime is used, where the long luminescence time constant of exponential light decay following a burst of excitation light energy results in blurred images. One method to ameliorate this effect is image deconvolution using a point spread function (PSF) based on an estimation of the luminescent time constant. Prior implementations of image deconvolution for PSP deblurring have relied upon a spatially invariant time constant in order to reduce computational time. However, the use of an assumed value of time constant leads to errors in the point spread function, particularly when strong pressure gradients (which cause strong spatial gradients in the decay time constant) are involved. This work introduces an iterative method of image deconvolution, where a spatially variant PSF is used. The point-by-point PSF values are found in an iterative manner, since the time constant depends on the local pressure value, which can only be found from the reduced PSP data. The scheme estimates a super-resolved spatially varying blur kernel with sub-pixel resolution without filtering the blurred image, and then restores the image using classical iterative regularization tools. A kernel-free forward model has been used to generate test images with known pressure surface maps and a varying amount of noise to evaluate the applicability of this scheme in different experimental conditions. A spinning disk setup with a grazing nitrogen jet for producing strong pressure gradients has also been used to evaluate the scheme on a real-world problem. Results including the convergence history and the effect of a regularization-iteration count are shown, along with a comparison with the previous PSP deblurring method.

Introduction: Type 1 diabetes has the potential to significantly impact children's educational attainment. With the increase in incidence, quantifying this effect would be useful to assess how much additional support should be focused on children with type 1 diabetes in school., Methods and Analysis: We will conduct a systematic review of all observational studies and randomised controlled trials, including individuals both with and without a diagnosis of type 1 diabetes who have undertaken high stakes testing at the end of compulsory schooling when under 18 years of age. The search will cover both peer-reviewed and grey literature available from January 2004 to January 2018. The following seven databases will be searched: Ovid MEDLINE (1946 to present), Ovid MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid EMBASE (1947 to present), Thomson Reuters Web of Science, EBSCO Education Resources Information Center, EBSCO British Education Index and EBSCO Cumulative Index to Nursing and Allied Health Literature. Study selection and data extraction will be performed independently by two reviewers with any disagreements resolved via a third reviewer. The quality and risk of bias in the observational studies included in this review will be assessed using the Newcastle-Ottawa Scale. We aim to conduct a meta-analysis and will assess heterogeneity between the included studies and potential for publication bias if sufficient (>10) studies are included., Results and Dissemination: Formal ethical approval is not required as individual patient data will not be collected. Results will be disseminated through peer-reviewed publication and conference presentations., Prospero Registration Number: CRD42017084078., Competing Interests: Competing interests: RF has received a grant from the Medical Research Council MR/N015428/1 for his work as principal investigator of the project ‘Investigating the inter-relationship between diabetes and children’s educational achievement’., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

Background: The risk of developing long-term complications of type 1 diabetes (T1D) is related to glycaemic control and is reduced by the use of intensive insulin treatment regimens: multiple daily injections (MDI) (≥ 4) and continuous subcutaneous insulin infusion (CSII). Despite a lack of evidence that the more expensive treatment with CSII is superior to MDI, both treatments are used widely within the NHS., Objectives: (1) To compare glycaemic control during treatment with CSII and MDI and (2) to determine safety and cost-effectiveness of the treatment, and quality of life (QoL) of the patients., Design: A pragmatic, open-label randomised controlled trial with an internal pilot and 12-month follow-up with 1 : 1 web-based block randomisation stratified by age and centre., Setting: Fifteen diabetes clinics in hospitals in England and Wales., Participants: Patients aged 7 months to 15 years., Interventions: Continuous subsutaneous insulin infusion or MDI initiated within 14 days of diagnosis of T1D., Data Sources: Data were collected at baseline and at 3, 6, 9 and 12 months using paper forms and were entered centrally. Data from glucometers and CSII were downloaded. The Health Utilities Index Mark 2 was completed at each visit and the Pediatric Quality of Life Inventory (PedsQL, diabetes module) was completed at 6 and 12 months. Costs were estimated from hospital patient administration system data., Outcomes: The primary outcome was glycosylated haemoglobin (HbA 1c ) concentration at 12 months. The secondary outcomes were (1) HbA 1c concentrations of < 48 mmol/mol, (2) severe hypoglycaemia, (3) diabetic ketoacidosis (DKA), (4) T1D- or treatment-related adverse events (AEs), (5) change in body mass index and height standard deviation score, (6) insulin requirements, (7) QoL and (8) partial remission rate. The economic outcome was the incremental cost per quality-adjusted life-year (QALY) gained., Results: A total of 293 participants, with a median age of 9.8 years (minimum 0.7 years, maximum 16 years), were randomised (CSII, n  = 149; MDI, n  = 144) between May 2011 and January 2015. Primary outcome data were available for 97% of participants (CSII, n  = 143; MDI, n  = 142). At 12 months, age-adjusted least mean squares HbA 1c concentrations were comparable between groups: CSII, 60.9 mmol/mol [95% confidence interval (CI) 58.5 to 63.3 mmol/mol]; MDI, 58.5 mmol/mol (95% CI 56.1 to 60.9 mmol/mol); and the difference of CSII - MDI, 2.4 mmol/mol (95% CI -0.4 to 5.3 mmol/mol). For HbA 1c concentrations of < 48 mmol/mol (CSII, 22/143 participants; MDI, 29/142 participants), the relative risk was 0.75 (95% CI 0.46 to 1.25), and for partial remission rates (CSII, 21/86 participants; MDI, 21/64), the relative risk was 0.74 (95% CI 0.45 to 1.24). The incidences of severe hypoglycaemia (CSII, 6/144; MDI, 2/149 participants) and DKA (CSII, 2/144 participants; MDI, 0/149 participants) were low. In total, 68 AEs (14 serious) were reported during CSII treatment and 25 AEs (eight serious) were reported during MDI treatment. Growth outcomes did not differ. The reported insulin use was higher with CSII (mean difference 0.1 unit/kg/day, 95% CI 0.0 to 0.2 unit/kg/day; p  = 0.01). QoL was slightly higher for those randomised to CSII. From a NHS perspective, CSII was more expensive than MDI mean total cost (£1863, 95% CI £1620 to £2137) with no additional QALY gains (-0.006 QALYs, 95% CI -0.031 to 0.018 QALYs)., Limitations: Generalisability beyond 12 months is uncertain., Conclusions: No clinical benefit of CSII over MDI was identified. CSII is not a cost-effective treatment in patients representative of the study population., Future Work: Longer-term follow-up is required to determine if clinical outcomes diverge after 1 year. A qualitative exploration of patient and professional experiences of MDI and CSII should be considered., Trial Registration: Current Controlled Trials ISRCTN29255275 and EudraCT 2010-023792-25., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 22, No. 42. See the NIHR Journals Library website for further project information. The cost of insulin pumps and consumables supplied by F. Hoffman-La Roche AG (Basel, Switzerland) for the purpose of the study were subject to a 25% discount on standard NHS costs., Competing Interests: Joanne Blair undertakes paid advisory work for, and has received funding for research, to attend academic meetings and to support a nursing salary from, Novo Nordisk Ltd (Gatwick, UK), a pharmaceutical company that manufactures some of the insulins used in the SubCutaneous Insulin: Pumps or Injections? (SCIPI) study. The work undertaken by Joanne Blair for Novo Nordisk Ltd relates to growth hormone therapy and not diabetes. Mohammed Didi has received payment for advisory work and funding to attend academic meetings and to support a nursing salary from Novo Nordisk Ltd. The work undertaken by Mohammed Didi for Novo Nordisk Ltd relates to growth hormone therapy and not diabetes. Mohammed Didi has received expenses from Merck Serono Ltd (Feltham, UK) to attend educational meetings. Carrol Gamble is a member of the Efficacy and Mechanism Evaluation Programme Board of the National Institute for Health Research. Dyfrig Hughes is a member of the Health Technology Assessment (HTA) Clinical Trials Board (2010–16), the HTA Funding Teleconference (2015–16) and the Pharmaceuticals Panel (2008–12). John W Gregory reports grants from Cardiff University during the conduct of the study, and membership of the HTA Commissioning Board (2010–14). John W Gregory received speaker fees from Pfizer Inc. and Eli Lilly and Company (Basingstoke, UK), fees for attending an advisory board for Eli Lilly and Company and financial assistance to attend annual meetings of the European Society for Paediatric Endocrinology from Sanofi Genzyme (Guildford, UK), Merck Serono Ltd, Ipsen and Novo Nordisk Ltd.

Context and Objective: The Controlled Antenatal Thyroid Screening (CATS) study investigated treatment of suboptimal gestational thyroid function (SGTF) on childhood cognition and found no difference in intelligence quotient (IQ) at 3 years between children of treated and untreated SGTF mothers. We have measured IQ in the same children at age 9.5 years and included children from normal gestational thyroid function (normal-GTF) mothers., Design, Setting, and Participants: One examiner, blinded to participant group, assessed children's IQ (Wechsler Intelligence Scale for Children, Fourth Edition UK), long-term memory, and motor function (Developmental Neuropsychological Assessment II) from children of 119 treated and 98 untreated SGTF mothers plus children of 232 mothers with normal-GTF. Logistic regression explored the odds and percentages of an IQ < 85 in the groups., Results: There was no difference in IQ < 85 between children of mothers with normal-GTF and combined SGTF, i.e., treated and untreated (fully adjusted odds ratio [OR] = 1.15 [95% confidence interval (CI) 0.52, 2.51]; P = 0.731). Furthermore, there was no significant effect of treatment [untreated OR = 1.33 (95% CI 0.53, 3.34); treated OR = 0.75 (95% CI 0.27, 2.06) P = 0.576]. IQ < 85 was 6.03% in normal-GTF, 7.56% in treated, and 11.22% in untreated groups. Analyses accounting for treated-SGTF women with free thyroxine > 97.5th percentile of the entire CATS-I cohort revealed no significant effect on a child's IQ < 85 in CATS-II. IQ at age 3 predicted IQ at age 9.5 (P < 0.0001) and accounted for 45% of the variation., Conclusions: Maternal thyroxine during pregnancy did not improve child cognition at age 9.5 years. Our findings confirmed CATS-I and suggest that the lack of treatment effect may be a result of the similar proportion of IQ < 85 in children of women with normal-GTF and SGTF.

Aims: The aim of this study was to explore from the perspectives of key stakeholders involved in the pathway to diagnosis, the barriers and facilitators to a timely diagnosis of type 1 diabetes in childhood., Methods: Qualitative interviews and free-text analyses were undertaken in 21 parents with a child diagnosed with type 1 diabetes, 60 parents without a child diagnosed with type 1 diabetes, 9 primary healthcare professionals, 9 teachers and 3 community diabetes liaison nurses . Data were analysed thematically and 30% double coded., Results: Two key themes were identified, namely the importance of widespread awareness and knowledge and seeking healthcare professional help . Parents with a child diagnosed with type 1 diabetes described seeking opinions from a number of individuals prior to seeking health professional help. Healthcare professionals recognized the rarity of the condition and the need for it to be kept on their "radar", to ensure they considered it when examining an unwell child. The process of obtaining a primary healthcare appointment was identified as potentially playing a crucial role in the diagnostic process. However, most parents with a child diagnosed with type 1 diabetes described receiving an appointment on the day they sought it., Conclusions: Knowledge and awareness of type 1 diabetes in childhood remain limited in the general population and misconceptions persist relating to how children present with this serious condition. An effective community-based intervention to raise awareness amongst key stakeholders is required to ensure children receive a timely diagnosis once symptomatic.

Context: Serum thyroid hormone levels differ between children and adults, but have not been studied longitudinally through childhood., Objective: To assess changes in thyroid-stimulating hormone (TSH) and thyroid hormone levels over childhood and their interrelationships., Design: Cohort study., Setting: The Avon Longitudinal Study of Parents and Children, a population-based birth cohort., Participants: A total of 4442 children who had thyroid function measured at age 7, and 1263 children who had thyroid function measured at age 15. Eight hundred eighty-four children had measurements at both ages., Main Outcome Measures: Reference ranges for TSH, free tri-iodothyronine (FT3), free thyroxine (FT4), their longitudinal stability, and interrelationships., Results: Children at age 7 years had a higher FT3 [6.17 pmol/L, standard deviation (SD) 0.62] than children at age 15 (5.83 pmol/L, SD 0.74); P < 0.0001 with 23.2% of children at age 7 having FT3 above the adult reference range. Higher FT3 levels at age 7 in boys (P = 0.0001) and girls (P = 0.04) were associated with attainment of a more advanced pubertal stage at age 13. TSH was positively associated with FT3 at age 7 and age 15 even after adjusting for confounders. In contrast, TSH was negatively associated with FT4., Conclusions: There are substantial changes in TSH and thyroid hormone levels over childhood, in particular for FT3, which appear to relate to pubertal readiness. Our data provide increased insight into the evolution of the pituitary-thyroid axis over childhood and may have implications for determining optimal ranges for thyroid hormone replacement in children., (Copyright © 2017 Endocrine Society)

Context: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken., Objective: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico., Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico., Results: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases., Conclusions: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.

Objective: Seamless transition of endocrine patients from the paediatric to adult setting is still suboptimal, especially in patients with complex disorders, i.e., small for gestational age, Turner or Prader-Willi syndromes; Childhood Cancer Survivors, and those with childhood-onset growth hormone deficiency., Methods: An expert panel meeting comprised of European paediatric and adult endocrinologists was convened to explore the current gaps in managing the healthcare of patients with endocrine diseases during transition from paediatric to adult care settings., Results: While a consensus was reached that a team approach is best, discussions revealed that a 'one size fits all' model for transition is largely unsuccessful in these patients. They need more tailored care during adolescence to prevent complications like failure to achieve target adult height, reduced bone mineral density, morbid obesity, metabolic perturbations (obesity and body composition), inappropriate/inadequate puberty, compromised fertility, diminished quality of life and failure to adapt to the demands of adult life. Sometimes it is difficult for young people to detach emotionally from their paediatric endocrinologist and/or the abrupt change from an environment of parental responsibility to one of autonomy. Discussions about impending transition and healthcare autonomy should begin in early adolescence and continue throughout young adulthood to ensure seamless continuum of care and optimal treatment outcomes., Conclusions: Even amongst a group of healthcare professionals with a great interest in improving transition services for patients with endocrine diseases, there is still much work to be done to improve the quality of healthcare for transition patients., (© 2016 The authors.)

Background: Glycated haemoglobin (HbA1c) is an important outcome measure in diabetes clinical trials. For multicentre designs, HbA1c can be measured locally at participating centres or by sending blood samples to a central laboratory. This study analyses the agreement between local and central measurements, using 1-year follow-up data collected in a multicentre randomised controlled trial (RCT) of newly diagnosed children with type I diabetes., Methods: HbA1c measurements were routinely analysed both locally and centrally at baseline and then at 3, 6, 9 and 12 months and the data reported in mmol/mol. Agreement was assessed by calculating the bias and 95 % limits of agreement, using the Bland-Altman analysis method. A predetermined benchmark for clinically acceptable margin of error between measurements was subjectively set as ±10 % for HbA1c. The percentage of pairs of measurements that were classified as clinically acceptable was calculated. Descriptive statistics were used to examine the agreement within centres. Treatment group was not considered., Results: Five hundred and ninety pairs of measurement, representing 255 children and 15 trial centres across four follow-up time points, were compared. There was no significant bias: local measurements were an average of 0.16 mmol/mol (SD = 4.5, 95 % CI -0.2 to 0.5) higher than central. The 95 % limits of agreement were -8.6 to 9.0 mmol/mol (local minus central). Eighty percent of local measurements were within ±10 % of corresponding central measurements. Some trial centres were more varied in the differences observed between local and central measurements: IQRs ranging from 3 to 9 mmol/mol; none indicated systematic bias., Conclusions: Variation in agreement between HbA1c measurements was greater than had been expected although no overall bias was detected and standard deviations were similar. Discrepancies were present across all participating centres. These findings have implications for the comparison of standards of clinical care between centres, the design of future multicentre RCTs and existing quality assurance processes for HbA1c measurements. We recommend that centralised HbA1c measurement is preferable in the multicentre clinical trial setting., Trial Registration: Eudract No. 2010-023792-25 , registered on 4 November 2010.

Fast-response pressure sensitive paint (PSP) is used in this work to measure and analyze the acoustic pressure field in a rectangular cavity. The high spatial resolution and fast frequency response of PSP effectively captures the spatial and temporal detail of surface pressure resulting in the acoustic pressure field. In this work, a high-speed camera is used to generate a continuous time record of the acoustic pressure fluctuations with PSP. Since the level of the acoustic pressure is near the resolution limit of the sensor system, advanced analysis techniques are used to extract the spatial modes of the pressure field. Both dynamic mode decomposition (DMD) and proper orthogonal decomposition (POD) are compared with phase averaging for data analysis. While all three techniques effectively extract the pressure field and reduce the impact of sensor noise, DMD and POD are more robust techniques that can be applied to aperiodic or multi-frequency signals. Furthermore, DMD is better than POD at suppressing noise in particular regions of the spectrum and at effectively separating spectral energy when multiple acoustic excitation frequencies are present.

Context: Free T3 (FT3) has been positively associated with body mass index (BMI) in cross-sectional studies in healthy individuals. This is difficult to reconcile with clinical findings in pathological thyroid dysfunction., Objective: We aimed to investigate whether childhood adiposity influences FT3 levels., Design: Mendelian randomization using genetic variants robustly associated with BMI., Setting: Avon Longitudinal Study of Parents and Children, a population-based birth cohort., Participants: A total of 3014 children who had thyroid function measured at age 7, who also underwent dual x-ray absorptiometry scans at ages 9.9 and 15.5 years and have genetic data available., Main Outcome Measures: FT3., Results: Observationally at age 7 years, BMI was positively associated with FT3: β-standardized (β-[std]) = 0.12 (95% confidence interval [CI]: 0.08, 0.16), P = 4.02 × 10(-10); whereas FT4 was negatively associated with BMI: β-(std) = -0.08 (95% CI: -0.12, -0.04), P = 3.00 × 10(-5). These differences persisted after adjustment for age, sex, and early life environment. Genetic analysis indicated 1 allele change in BMI allelic score was associated with a 0.04 (95% CI: 0.03, 0.04) SD increase in BMI (P = 6.41 × 10(-17)). At age 7, a genetically determined increase in BMI of 1.89 kg/m(2) was associated with a 0.22 pmol/L (95% CI: 0.07, 0.36) increase in FT3 (P = .004) but no substantial change in FT4 0.01 mmol/L, (95% CI: -0.37, 0.40), P = .96., Conclusion: Our analysis shows that children with a genetically higher BMI had higher FT3 but not FT4 levels, indicating that higher BMI/fat mass has a causal role in increasing FT3 levels. This may explain the paradoxical associations observed in observational analyses. Given rising childhood obesity levels, this relationship merits closer scrutiny.

Experiments and numerical simulations have been used in this work to understand the step response characteristics of Polymer/Ceramic Pressure-Sensitive Paint (PC-PSP). A recently developed analytical model describing the essential physics in PC-PSP quenching kinetics is used, which includes the effect of both diffusion time scale and luminescent lifetime on the net response of PC-PSP. Step response simulations using this model enables an understanding of the effects of parameters, such as the diffusion coefficient of O₂ in the polymer/ceramic coating, attenuation of excitation light, ambient luminescent lifetime, sensitivity, and the magnitude and direction of pressure change on the observed response time scales of PC-PSP. It was found that higher diffusion coefficient and greater light attenuation lead to faster response, whereas longer ambient lifetime and larger sensitivity lead to slower response characteristics. Due to the inherent non-linearity of the Stern-Volmer equation, response functions also change with magnitude and direction of the pressure change. Experimental results from a shock tube are presented where the effects of varying the roughness, pressure jump magnitude and luminophore probe have been studied. Model parameters have been varied to obtain a good fit to experimental results and this optimized model is then used to obtain the response time for a step decrease in pressure, an estimate of which is currently not obtainable from experiments.

Background: Intensive insulin therapy with continuous subcutaneous insulin infusion (CSII) devices or multiple daily injections (MDI) reduces the risk of long-term vascular complications of type I diabetes (TID). Both treatments are used routinely, but there is little evidence to demonstrate superiority of either treatment. If CSII treatment reduces the risk of long-term complications or is associated with an improved quality of life (QoL), the additional cost of this therapy may be compensated for by a reduction in long-term health expenditure. If there is no demonstrable difference between treatments, health-care resources may be better invested elsewhere. This study aims to address this gap in knowledge., Methods/design: This is a pragmatic, randomised controlled trial (RCT). Fifteen centres, selected to represent a population with a broad demographic, will recruit 316 patients, newly diagnosed with TID, aged between 7 months and 15 years. Exclusion criteria include additional pathologies or treatments likely to affect glycaemic control and a first-degree relative with TID. Randomisation to CSII or MDI is stratified for age, gender and recruiting centre. The randomised treatment starts within 15 days of diagnosis. Patients will be trained to adjust their insulin dose according to carbohydrate intake and blood glucose level. Study visits coincide with routine clinic appointments at 3, 6, 9 and 12 months when data relating to routine clinical assessments, adverse events and concomitant medications are collected. Health utilities questionnaires are completed at each visit and a diabetes-specific QoL questionnaire (PedsQL) at diagnosis, 6 and 12 months. The primary outcome is glycaemic control (HbA1c) at 12 months. Secondary outcome measures include QoL, insulin use, growth and weight gain, adverse events and a health economics appraisal., Discussion: This is the first adequately powered RCT comparing CSII and MDI in a non-selected population, treated according to standard practice guidelines. It will produce data that are meaningful to individual patients and local and national policymakers., Trial Registration: The study was registered with the European Clinical Trials Database on 4 November 2010, reference 2010-023792-25.

Objectives: To estimate the excess in admissions associated with type1 diabetes in childhood., Design: Matched-cohort study using anonymously linked hospital admission data., Setting: Brecon Group Register of new cases of childhood diabetes in Wales linked to hospital admissions data within the Secure Anonymised Information Linkage Databank., Population: 1577 Welsh children (aged between 0 and 15 years) from the Brecon Group Register with newly-diagnosed type-1 diabetes between 1999-2009 and 7800 population controls matched on age, sex, county, and deprivation, randomly selected from the local population., Main Outcome Measures: Difference in all-cause hospital admission rates, 30-days post-diagnosis until 31 May 2012, between participants and controls., Results: Children with type-1 diabetes were followed up for a total of 12,102 person years and were at 480% (incidence rate ratios, IRR 5.789, (95% CI 5.34 to 6.723), p<0.0001) increased risk of hospital admission in comparison to matched controls. The highest absolute excess of admission was in the age group of 0-5 years, with a 15.4% (IRR 0.846, (95% CI 0.744 to 0.965), p=0.0061) reduction in hospital admissions for every 5-year increase in age at diagnosis. A trend of increasing admission rates in lower socioeconomic status groups was also observed, but there was no evidence of a differential rate of admissions between men and women when adjusted for background risk. Those receiving outpatient care at large centres had a 16.1% (IRR 0.839, (95% CI 0.709 to 0.990), p=0.0189) reduction in hospital admissions compared with those treated at small centres., Conclusions: There is a large excess of hospital admissions in paediatric patients with type-1 diabetes. Rates are highest in the youngest children with low socioeconomic status. Factors influencing higher admission rates in smaller centres (eg, "out of hours resources") need to be explored with the aim of targeting modifiable influences on admission rates., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Children whose mothers had low thyroid hormone levels during pregnancy have been reported to have decreased cognitive function. The reported research is part of the follow-on study of the Controlled Antenatal Thyroid Screening Study (CATS I), a randomised controlled trial which investigated the impact of treated vs. untreated low thyroid hormone level in women during pregnancy with the primary outcome being the child's IQ at age 3. No significant differences in IQ were found between the treated and untreated groups. These children are now aged between 7 and 10 years and aspects of their cognitive functioning including their IQ are being reassessed as part of CATS II., Methods/design: Cognitive assessments generate an IQ score and further tests administered will investigate long term memory function and motor coordination. The aim is to complete the assessments with 40% of the children born to mothers either in the treated or untreated low thyroid hormone groups (n = 120 per group). Also children born to mothers who had normal thyroid functioning during CATS I are being assessed for the first time (n = 240) to provide a comparison. Assessments are conducted either in the research facility or the participant's home., Discussion: The study is designed to assess the cognitive functioning of children born to mothers with low thyroid hormone levels and normal thyroid functioning during pregnancy. This is the largest study of its type and also is distinguishable in its longitudinal design. The research has the potential to have a significant impact on public health policy in the UK; universal screening of thyroid hormone levels in pregnancy may be the recommendation.

Background: Type 1 diabetes occurs more frequently in younger children who are often pre-school age and enter the education system with diabetes-related support needs that evolve over time. It is important that children are supported to optimally manage their diet, exercise, blood glucose monitoring and insulin regime at school. Young people self-manage at college/university., Method: Theory-informed mixed-method systematic review to determine intervention effectiveness and synthesise child/parent/professional views of barriers and facilitators to achieving optimal diabetes self-care and management for children and young people age 3-25 years in educational settings., Results: Eleven intervention and 55 views studies were included. Meta-analysis was not possible. Study foci broadly matched school diabetes guidance. Intervention studies were limited to specific contexts with mostly high risk of bias. Views studies were mostly moderate quality with common transferrable findings.Health plans, and school nurse support (various types) were effective. Telemedicine in school was effective for individual case management. Most educational interventions to increase knowledge and confidence of children or school staff had significant short-term effects but longer follow-up is required. Children, parents and staff said they struggled with many common structural, organisational, educational and attitudinal school barriers. Aspects of school guidance had not been generally implemented (e.g. individual health plans). Children recognized and appreciated school staff who were trained and confident in supporting diabetes management.Research with college/university students was lacking. Campus-based college/university student support significantly improved knowledge, attitudes and diabetes self-care. Self-management was easier for students who juggled diabetes-management with student lifestyle, such as adopting strategies to manage alcohol consumption., Conclusion: This novel mixed-method systematic review is the first to integrate intervention effectiveness with views of children/parents/professionals mapped against school diabetes guidelines. Diabetes management could be generally improved by fully implementing and auditing guideline impact. Evidence is limited by quality and there are gaps in knowledge of what works. Telemedicine between healthcare providers and schools, and school nurse support for children is effective in specific contexts, but not all education systems employ onsite nurses. More innovative and sustainable solutions and robust evaluations are required. Comprehensive lifestyle approaches for college/university students warrant further development and evaluation.

Background: The Nurse Family Partnership programme was developed in the USA where it is made available to pregnant young mothers in some socially deprived geographic areas. The related Family Nurse Partnership programme was introduced in England by the Department of Health in 2006 with the aim of improving outcomes for the health, wellbeing and social circumstances of young first-time mothers and their children., Methods / Design: This multi-centre individually randomised controlled trial will recruit 1600 participants from 18 Primary Care Trusts in England, United Kingdom. The trial will evaluate the effectiveness of Family Nurse Partnership programme and usual care versus usual care for nulliparous pregnant women aged 19 or under, recruited by 24 weeks gestation and followed until the child's second birthday. Data will be collected from participants at baseline, 34-36 weeks gestation, 6, 12, 18 and 24 months following birth. Routine clinical data will be collected from maternity, primary care and hospital episodes statistics. Four primary outcomes are to be reported from the trial: birth weight; prenatal tobacco use; child emergency attendances and/or admissions within two years of birth; second pregnancy within two years of first birth., Discussion: This trial will evaluate the effectiveness and cost effectiveness of the Family Nurse Partnership in England. The findings will provide evidence on pregnancy and early childhood programme outcomes for policy makers, health professionals and potential recipients in three domains (pregnancy and birth, child health and development, and parental life course and self-sufficiency) up to the child's second birthday., Trial Registration: Trial registration number: ISRCTN23019866.

Objective: To evaluate the effectiveness on glycaemic control of a training programme in consultation skills for paediatric diabetes teams., Design: Pragmatic cluster randomised controlled trial., Setting: 26 UK secondary and tertiary care paediatric diabetes services., Participants: 79 healthcare practitioners (13 teams) trained in the intervention (359 young people with type 1 diabetes aged 4-15 years and their main carers) and 13 teams allocated to the control group (334 children and their main carers)., Intervention: Talking Diabetes programme, which promotes shared agenda setting and guiding communication style, through flexible menu of consultation strategies to support patient led behaviour change., Main Outcome Measures: The primary outcome was glycated haemoglobin (HbA(1c)) level one year after training. Secondary outcomes were clinical measures (hypoglycaemic episodes, body mass index, insulin regimen), general and diabetes specific quality of life, self reported and proxy reported self care and enablement, perceptions of the diabetes team, self reported and carer reported importance of, and confidence in, undertaking diabetes self management measured over one year. Analysis was by intention to treat. An integrated process evaluation included audio recording a sample of 86 routine consultations to assess skills shortly after training (intervention group) and at one year follow-up (intervention and control group). Two key domains of skill assessment were use of the guiding communication style and shared agenda setting., Results: 660/693 patients (95.2%) provided blood samples at follow-up. Training diabetes care teams had no effect on HbA(1c) levels (intervention effect 0.01, 95% confidence interval -0.02 to 0.04, P=0.5), even after adjusting for age and sex of the participants. At follow-up, trained staff (n=29) were more capable than controls (n=29) in guiding (difference in means 1.14, P<0.001) and agenda setting (difference in proportions 0.45, 95% confidence interval 0.22 to 0.62). Although skills waned over time for the trained practitioners, the reduction was not significant for either guiding (difference in means -0.33, P=0.128) or use of agenda setting (difference in proportions -0.20, -0.42 to 0.05). 390 patients (56%) and 441 carers (64%) completed follow-up questionnaires. Some aspects of diabetes specific quality of life improved in controls: reduced problems with treatment barriers (mean difference -4.6, 95% confidence interval -8.5 to -0.6, P=0.03) and with treatment adherence (-3.1, -6.3 to -0.01, P=0.05). Short term ability to cope with diabetes increased in patients in intervention clinics (10.4, 0.5 to 20.4, P=0.04). Carers in the intervention arm reported greater excitement about clinic visits (1.9, 1.05 to 3.43, P=0.03) and improved continuity of care (0.2, 0.1 to 0.3, P=0.01)., Conclusions: Improving glycaemic control in children attending specialist diabetes clinics may not be possible through brief, team-wide training in consultation skills., Trial Registration: Current Controlled Trials ISRCTN61568050.

Context: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available., Objective: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort., Design: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries., Results: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles., Conclusions: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.