Tolvaptan and urea in paediatric hyponatraemia.

BACKGROUND: The syndrome of inappropriate antidiuretic hormone (SIADH) is usually treated with fluid restriction. This can be challenging in patients with obligate fluid intake for nutrition or medication. Pharmaceutical treatment with tolvaptan and urea is available but minimal paediatric data are available. We review the efficacy and safety of tolvaptan and urea in paediatric patients with SIADH. METHODS: Retrospective review of paediatric inpatients with clinical diagnosis of SIADH. Patients were identified from pharmacy records based on tolvaptan and urea prescriptions. Relevant information was extracted from patient electronic records. The main outcome measures included the number of days to sodium normalisation, the daily change in plasma sodium concentration, and the maximum increase of plasma sodium concentration in 24 h. Reported side effects were captured. RESULTS: Thirteen patients received tolvaptan and six urea. Five patients had both agents (tolvaptan converted to urea). Tolvaptan led to plasma sodium normalisation in 10/13 (77%) within 6 days (median 2.5 days, range [1, 6]), with a median change of sodium concentration of 7 mmol/L (- 1, 14) within the first 24 h of treatment. Three patients experienced a change in plasma sodium > 10 mmol/l/day but had no apparent side effects. Urea led to sodium normalisation in 5/6 (83%) patients. The median number of days to normalisation with urea was 2 (1, 10) with a median change of plasma sodium concentration of 2 mmol/L (- 1, 6) within the first 24 h. All patients tolerated tolvaptan and/or urea without unexpected side effects. CONCLUSIONS: Tolvaptan and urea appear to be safe and effective when fluid restriction is challenging in paediatric SIADH. A higher resolution version of the Graphical abstract is available as Supplementary information.

Outcome of Non-hematological Autoimmunity After Hematopoietic Cell Transplantation in Children with Primary Immunodeficiency.

PURPOSE: Knowledge of post-hematopoietic cell transplantation (HCT) non-hematological autoimmune disease (AD) is far from satisfactory. METHOD: This multicenter retrospective study focuses on incidence, risk factors, and outcomes of post-HCT AD in 596 children with primary immunodeficiency (PID) who were transplanted from 2009 to 2018. RESULTS: The indications of HCT were severe combined immunodeficiency (SCID, n = 158, 27%) and non-SCID PID (n = 438, 73%). The median age at HCT was 2.3 years (range, 0.04 to 18.3 years). The 5-year overall survival for the entire cohort was 79% (95% cumulative incidence (CIN), 74-83%). The median follow-up of surviving patients was 4.3 years (0.08 to 14.7 years). The CIN of post-HCT AD was 3% (2-5%) at 1 year post-HCT, 7% (5-11%) at 5 years post-HCT, and 11% (7-17%) at 8 years post-HCT. The median onset of post-HCT AD was 2.2 years (0.12 to 9.6 years). Autoimmune thyroid disorder (n = 19, 62%) was the most common post-HCT AD, followed by neuromuscular disorders (n = 7, 22%) and rheumatological manifestations (n = 5, 16%). All patients but one required treatment for post-HCT AD. After multivariate analysis, age at transplant (p = 0.01) and T cell-depleted graft (p < 0.001) were significant predictors of post-HCT AD. None of the T cell-depleted graft recipients developed post-HCT AD. Patients with a lower CD3+ count at 6 months post-HCT had a significant higher incidence of post-HCT AD compared to disease controls. Graft-versus-host disease, viral infection, and donor chimerism had no association with post-HCT AD. CONCLUSION: Post-HCT AD occurred in 11% at 8 years post-HCT and its occurrence was associated with older age at HCT and unmanipulated graft.

The SARS-CoV-2 pandemic is associated with increased severity of presentation of childhood onset type 1 diabetes mellitus: A multi-centre study of the first COVID-19 wave.

OBJECTIVE: Children are usually mildly affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19). However, the pandemic has caused collateral damage to those with non-COVID-19 diseases. We aimed to determine the impact of the COVID-19 pandemic on the presentation of newly diagnosed childhood onset type 1 diabetes. METHODS: This was a cross-sectional study conducted over a 1-year period. We compared the severity of presentation of new-onset type 1 diabetes in children under the age of 18 presenting to the multi-centre North Central London diabetes network before (1 July 2019 to 22 March 2020) and during (23 March 2020 to 30 June 2020) the first wave of the COVID-19 pandemic in the United Kingdom. RESULTS: Over the 1-year study period, a total of 30 children presented with new-onset type 1 diabetes during the pre-pandemic period and 17 presented during the first COVID-19 wave. Children presented more frequently in diabetic ketoacidosis (DKA) during the first COVID-19 wave compared with pre-pandemic (pre-pandemic: mild 13%, moderate 6.7%, severe 10%; first COVID-19 wave: mild 5.9%, moderate 24%, severe 47%; p = 0.002). During the first COVID-19 wave, DKA presentations in children with a family history of type 1 diabetes were fewer compared to those without a family history (33.3% vs. 100.0%; p = 0.006). Children presenting in severe DKA pre-pandemic were younger than those not in severe DKA (3.9 years vs. 12.2 years, p < 0.001) but this difference was not significant during the first COVID-19 wave (10.1 years vs. 11.2 years, p = 0.568). Presenting HbA1c measurement was higher in those presenting during the first COVID-19 wave (13.0 ± 1.7 vs. 10.4 ± 3.2%; 119 ± 19 vs. 90 ± 35 mmol/mol; p = 0.008). CONCLUSION: The COVID-19 pandemic is associated with increased severity of presentation of childhood onset type 1 diabetes. Whatever the context, young people with suspected new-onset type 1 diabetes should be referred for urgent clinical review.

International benchmarking in type 1 diabetes: Large difference in childhood HbA1c between eight high-income countries but similar rise during adolescence-A quality registry study.

OBJECTIVES: To identify differences and similarities in HbA1c levels and patterns regarding age and gender in eight high-income countries. SUBJECTS: 66 071 children and adolescents below18 years of age with type 1 diabetes for at least 3 months and at least one HbA1c measurement during the study period. METHODS: Pediatric Diabetes Quality Registry data from Austria, Denmark, England, Germany, Norway, Sweden, the United States, and Wales were collected between 2013 and 2014. HbA1c, gender, age, and duration were used in the analysis. RESULTS: Distribution of gender and age groups was similar in the eight participating countries. The mean HbA1c varied from 60 to 73 mmol/mol (7.6%-8.8%) between the countries. The increase in HbA1c between the youngest (0-9 years) to the oldest (15-17 years) age group was close to 8 mmol/mol (0.7%) in all countries (P < .001). Females had a 1 mmol/mol (0.1%) higher mean HbA1c than boys (P < .001) in seven out of eight countries. CONCLUSIONS: In spite of large differences in the mean HbA1c between countries, a remarkable similarity in the increase of HbA1c from childhood to adolescence was found.

Inequalities in glycemic control in childhood onset type 2 diabetes in England and Wales-A national population-based longitudinal study.

BACKGROUND: Not much is known about glycaemic-control trajectories in childhood-onset type 2 diabetes (T2D). We investigated characteristics of children and young people (CYP) with T2D and inequalities in glycemic control. METHODS: We studied 747 CYP with T2D, <19 years of age in 2009-2016 (from the total population-based National Pediatric Diabetes Audit [>95% diabetes cases in England/Wales]). Linear mixed-effects modeling was used to assess socioeconomic and ethnic differences in longitudinal glycated hemoglobin (HbA1c ) trajectories during 4 years post-diagnosis (3326 HbA1c data points, mean 4.5 data points/subject). Self-identified ethnicity was grouped into six categories. Index of Multiple Deprivation (a small geographical area-level deprivation measure) was grouped into SES quintiles for analysis. RESULTS: Fifty-eight percent were non-White, 66% were female, and 41% were in the most disadvantaged SES quintile. Mean age and HbA1c at diagnosis were 13.4 years and 68 mmol/mol, respectively. Following an initial decrease between diagnosis and end of year 1 (-15.2 mmol/mol 95%CI, -19.2, -11.2), HbA1c trajectories increased between years 1 and 3 (10 mmol/mol, 7.6, 12.4), followed by slight gradual decrease subsequently (-1.6 mmol/mol, -2, -1.1). Compared to White CYP, Pakistani children had higher HbA1c at diagnosis (13.2 mmol/mol, 5.6-20.9). During follow-up, mixed-ethnicity and Pakistani CYP had poorer glycemic control. Compared to children in the most disadvantaged quintile, those in the most advantaged had lower HbA1c at diagnosis (-6.3 mmol, -12.6, -0.1). Differences by SES remained during follow-up. Mutual adjustment for SES and ethnicity did not substantially alter the above estimates. CONCLUSIONS: About two-thirds of children with childhood-onset T2D were non-White, female adolescents, just under half of whom live in the most disadvantaged areas of England and Wales. Additionally, there are substantial socioeconomic and ethnic inequalities in diabetes control.

Predictors of glycemic control in the first year of diagnosis of childhood onset type 1 diabetes: A systematic review of quantitative evidence.

Early glycemic control is associated with reduced future vascular complications risk in type 1 diabetes (T1D). The aim of this study was to systematically review evidence on the predictors of glycemic control within 12 months of diagnosis of childhood onset T1D. Inclusion criteria for the electronic search were: interventional and observational studies that assessed and quantified an association between the predictor and glycemic control within 12 months of diagnosis of childhood onset T1D. A total of 17 915 articles were identified from 6 databases and 20 studies were finally included in the analysis. Harvest plots and narrative synthesis were used to summarize data from intervention (n = 0), prospective/retrospective cohort (n = 15), and cross-sectional (n = 5) studies. Significant predictors of poorer glycemic control 0 to 3 months after diagnosis were older age and female gender. Non-white ethnicity, diabetes autoantibody positivity, measures of deprivation, and non-private health insurance were potential predictors. Predictors of poorer glycemic control 4 to 12 months after diagnosis were: older age, non-white ethnicity, a single parent family, high hemoglobin A1c (HbA1c) levels at diagnosis, longer T1D duration, and non-intensive insulin therapy. Potential predictors included: family with health issues, clinical factors, and comorbidities at diagnosis. Most significant predictors of poor glycemic control within 12 months of diagnosis of childhood onset T1D are non-modifiable. These factors need to be recognized and addressed through individualized and multidisciplinary diabetes care. Further research is required to confirm the association of potential predictors with early glycemic control.

Fifteen-minute consultation: Monogenic forms of diabetes with onset after age 6 months.

Monogenic forms of diabetes (historically known as Maturity Onset Diabetes of the Young (MODY)) are caused by single gene mutations inherited in an autosomal dominant fashion that result in reduced pancreatic beta cell function. Children with these forms of diabetes may be misdiagnosed as having type 1 or 2 diabetes, which has important implications for treatment, genetic counselling, screening of family members and prognosis. Useful tools now exist to aid in their diagnosis and management. Here, we attempt to outline the clinical features that will help the physician make the differentiation from other diabetes subtypes.

Impact of deprivation, ethnicity, and insulin pump therapy on developmental trajectories of diabetes control in COB type 1 diabetes.

BACKGROUND: There is marked variation in diabetes outcomes for children and adolescents across the UK. We used modelling techniques to examine the independent contributions of deprivation, ethnicity, insulin pump use, and health service use on HbA1c trajectories across adolescence. METHODS: Prospective data from a large UK Paediatric & Adolescent Diabetes Service on subjects with type 1 diabetes (T1D) aged 9-17 years from January 2008 to December 2013: 2560 HbA1c datapoints were available on 384 patients [193 (50.4%) female]. Sequential multilevel growth models assessed the effects of sex, duration of diabetes, deprivation, ethnicity, insulin pump use, and health service use on HbA1c . Growth mixture models were used to identify discrete HbA1c trajectories across adolescence. RESULTS: Mean clinic HbA1c decreased from 2008 to 2013 by 0.122% (95% confidence interval: 0.034, 0.210; P = .007) per year. The optimal multilevel growth model showed mean HbA1c increased with age (B = 0.414, P < .0001), and that mean HbA1c was predicted by white/British ethnicity (B = -0.748, P = .004), clinic visits (B = 0.041, P = .04), and pump use (B = -0.568, P < .0001) but not deprivation. The optimal mixture model was a four trajectory group solution, with 45.1% in Good Control, 39.6% with Deteriorating Control, 6.5% with Rapidly Deteriorating Control, and 8.8% in Poor Control across adolescence. Only pump use predicted trajectory group membership, being protective against membership of all other trajectories compared with Good Control. CONCLUSIONS: Increasing uptake of insulin pumps and ensuring access to health services are likely to be the most effective means of reducing inequalities in outcomes of T1D in children and young people.

The effect of socioeconomic deprivation on efficacy of continuous subcutaneous insulin infusion: a retrospective paediatric case-controlled survey.

UNLABELLED: We aimed to retrospectively evaluate the efficacy of continuous subcutaneous insulin infusion (CSII) therapy in relation to social deprivation in an urban paediatric type 1 diabetic population. Data were compared between 51 children on CSII therapy (mean age 11.2 years and duration of follow-up 1.9 years) and matched controls on multiple daily injection (MDI) therapy. Social deprivation was measured using the UK Office of National Statistics 2007 Index of Multiple Deprivation. Using linear mixed modelling analysis, lower HbA1c levels at 24 months were associated with CSII not MDI therapy (P = 0.02), after adjustment for known variables. Children with the least educated parents showed a rise in HbA1c levels from baseline on MDI therapy (least versus most educated tertile; HbA1c change +0.5% [95% confidence interval -0.1 to 1.1] versus 0% [-0.8 to 0.8]), whereas this was not observed in CSII therapy (least versus most educated tertile; HbA1c change -0.3% [-0.7 to +0.1] versus -0.2% [-0.7 to +0.3], P value for ANCOVA = 0.02, after adjusting for income and employment). CONCLUSION: Parental educational deprivation was associated with a failure of MDI but not CSII therapy. These outcomes need confirmation by larger studies.

A Single-Center, Observational Study of 607 Children and Young People Presenting With Differences of Sex Development (DSD).

Context: Differences of sex development (DSD) represent a wide range of conditions presenting at different ages to various health professionals. Establishing a diagnosis, supporting the family, and developing a management plan are important. Objective: We aimed to better understand the presentation and prevalence of pediatric DSD. Methods: A retrospective, observational cohort study was undertaken in a single tertiary pediatric center of all children and young people (CYP) referred to a DSD multidisciplinary team over 25 years (1995-2019). In total, 607 CYP (520 regional referrals) were included. Data were analyzed for diagnosis, sex-assignment, age and mode of presentation, additional phenotypic features, mortality, and approximate point prevalence. Results: Among the 3 major DSD categories, sex chromosome DSD was diagnosed in 11.2% (68/607) (most commonly 45,X/46,XY mosaicism), 46,XY DSD in 61.1% (371/607) (multiple diagnoses often with associated features), while 46,XX DSD occurred in 27.7% (168/607) (often 21-hydroxylase deficiency). Most children (80.1%) presented as neonates, usually with atypical genitalia, adrenal insufficiency, undescended testes or hernias. Those presenting later had diverse features. Rarely, the diagnosis was made antenatally (3.8%, n = 23) or following incidental karyotyping/family history (n = 14). Mortality was surprisingly high in 46,XY children, usually due to complex associated features (46,XY girls, 8.3%; 46,XY boys, 2.7%). The approximate point prevalence of neonatal referrals for investigation of DSD was 1 in 6347 births, and 1 in 5101 overall throughout childhood. Conclusion: DSD represent a diverse range of conditions that can present at different ages. Pathways for expert diagnosis and management are important to optimize care.

Cardiovascular risk factors from diagnosis in children with type 1 diabetes mellitus: a longitudinal cohort study.

Background: For childhood onset type 1 diabetes (T1D), the pathogenesis of atherosclerosis is greatly accelerated and results in early cardiovascular disease (CVD) and increased mortality. However, cardioprotective interventions in this age group are not routinely undertaken. Aims: To document prevalence of cardiovascular risk factors from diagnosis of childhood T1D and their relationship with disease duration and ethnicity. Methods: Routinely collected clinical records for 565 children with T1D were retrospectively analyzed. Data were collected from diagnosis and at routine check-ups at pediatric diabetes clinics across Barts Health National Health Service Trust. Age at diagnosis was 8.5 years (0.9-19.4). Mean follow-up 4.3 years (0-10.8). 48% were boys and 60% were non-white. Linear longitudinal mixed effects models were used to evaluate relationships between risk factors and diabetes duration. Results: CVD risk factors were present at first screening; 33.8% of children were overweight or obese, 20.5% were hypertensive (elevated diastolic blood pressure (BP)) and total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol were abnormal in 63.5%, 34.2% and 22.0%, respectively. Significant associations between diabetes duration and annual increases of body mass index (0.6 kg/m2), BP (0.1 SD score) and lipids (0.02-0.06 mmol/L) were noted. Annual increases were significantly higher in black children for BP and Bangladeshi children for lipids. Bangladeshi children also had greatest baseline levels. Conclusions: CVD risk factors are present in up to 60% of children at diagnosis of T1D and increase in prevalence during the early years of the disease. Commencing screening in younger children and prioritizing appropriate advice and attention to ethnic variation when calculating risk should be considered.

Evaluation of the pituitary function with insulin tolerance (hypoglycaemia) testing: are there any differences using insulin lispro compared to regular insulin?

BACKGROUND/AIM: The insulin tolerance test (ITT) remains the gold standard for evaluating the pituitary function, but has potential risks when hypoglycaemia is induced. There are scarce data using short-acting insulin analogs for ITTs. This pilot study compares the effects of insulin lispro (LPI) with regular insulin (RGI) during an ITT. METHODS: Patients with suspected hypopituitarism (n = 103) randomly received either LPI (n = 51) or RGI (n = 52). RESULTS: All patients reported signs and symptoms when hypoglycaemia was induced. In the LPI group, hypoglycaemia occurred sooner (23.6 +/- 1.6 vs. 28.3 +/- 1.4 min, p < 0.05), and duration of hypoglycaemia (25.0 +/- 1.7 vs. 31.9 +/- 1.9 min, p < 0.05) and time for blood glucose levels to return to a 'safe' level (>3.3 mmol/l; 56.5 +/- 2.3 vs. 76.0 +/- 2.1 min, p < 0.001) were shorter as compared with the RGI group. No differences in peak growth hormone and cortisol levels were observed between the two groups. CONCLUSIONS: Our data suggest that despite inducing similar symptomatology, LPI exerted a quicker onset and a shorter duration of hypoglycaemia as compared with RGI. Thus, using LPI might reduce the potential risks associated with an ITT by shortening the hypoglycaemic phase of the test.

Exploring Variation in Glycemic Control Across and Within Eight High-Income Countries: A Cross-sectional Analysis of 64,666 Children and Adolescents With Type 1 Diabetes.

OBJECTIVE: International studies on childhood type 1 diabetes (T1D) have focused on whole-country mean HbA1c levels, thereby concealing potential variations within countries. We aimed to explore the variations in HbA1c across and within eight high-income countries to best inform international benchmarking and policy recommendations. RESEARCH DESIGN AND METHODS: Data were collected between 2013 and 2014 from 64,666 children with T1D who were <18 years of age across 528 centers in Germany, Austria, England, Wales, U.S., Sweden, Denmark, and Norway. We used fixed- and random-effects models adjusted for age, sex, diabetes duration, and minority status to describe differences between center means and to calculate the proportion of total variation in HbA1c levels that is attributable to between-center differences (intraclass correlation [ICC]). We also explored the association between within-center variation and children's glycemic control. RESULTS: Sweden had the lowest mean HbA1c (59 mmol/mol [7.6%]) and together with Norway and Denmark showed the lowest between-center variations (ICC ≤4%). Germany and Austria had the next lowest mean HbA1c (61-62 mmol/mol [7.7-7.8%]) but showed the largest center variations (ICC ∼15%). Centers in England, Wales, and the U.S. showed low-to-moderate variation around high mean values. In pooled analysis, differences between counties remained significant after adjustment for children characteristics and center effects (P value <0.001). Across all countries, children attending centers with more variable glycemic results had higher HbA1c levels (5.6 mmol/mol [0.5%] per 5 mmol/mol [0.5%] increase in center SD of HbA1c values of all children attending a specific center). CONCLUSIONS: At similar average levels of HbA1c, countries display different levels of center variation. The distribution of glycemic achievement within countries should be considered in developing informed policies that drive quality improvement.

Effects of recombinant human IGF-I/IGF-binding protein-3 complex on glucose and glycerol metabolism in type 1 diabetes.

Recombinant human IGF-I (rhIGF-I) complexed with its natural binding protein IGF-binding protein (IGFBP)-3 (rhIGF-I/IGFBP-3) is a novel formulation that has been shown to improve insulin sensitivity in type 1 diabetes, yet the mechanisms are not clear. We used stable isotopes to investigate the effects of rhIGF-I/IGFBP-3 on glucose and glycerol metabolism in type 1 diabetes. Fifteen subjects (age 13-24 years; 10 males) were studied on three occasions in random order. Each study period lasted for two days, and an injection of either placebo or rhIGF-I/IGFBP-3 (0.1-0.8 mg x kg(-1) x day (-1)) was given subcutaneously at 6:00 p.m. on days 1 and 2. Following the second injection, the subjects were kept euglycemic overnight by a variable rate insulin infusion, followed by a 4-h, two-step (insulin 0.6 and 1.5 mU x kg(-1) x min (-1)) hyperinsulinemic-euglycemic clamp. During the overnight basal steady state, rhIGF-I/IGFBP-3 dose-dependently reduced endogenous glucose production rate (R(a)) (P = 0.004), while peripheral glucose uptake (R(d)) was not different from placebo. The increase in glucose R(d) during hyperinsulinemic clamp was greater following rhIGF-I/IGFBP-3 than placebo, both during the first (P = 0.008) and second step (P = 0.008) of the clamp. No significant differences were found in glycerol R(a), a measure of lipolysis, between rhIGF-I/IGFBP-3 and placebo. In conclusion, rhIGF-I/IGFBP-3 enhances glucose metabolism by controlling both endogenous glucose output and peripheral glucose uptake.

Ethnic differences in early glycemic control in childhood-onset type 1 diabetes.

Some ethnic minorities with type 1 diabetes (T1D) have worse glycemic control (higher glycated hemoglobin (HbA1c)) and increased risk for vascular complications. There is limited evidence on the impact of ethnicity on early glycemic control when most patients experience transient remission postdiagnosis. We examined associations between ethnicity and longitudinal HbA1c trajectories during the first 6 months postdiagnosis in a multiethnic cohort in East London. RESEARCH DESIGN AND METHODS: Data on 443 (50% female) children <19 years of age, with T1D and attending one of three clinics in East London between January 2005 and December 2015 were included. Linear mixed-effects modeling was used to assess ethnic differences in longitudinal HbA1c trajectories during the first 6 months postdiagnosis (1,028 HbA1c data points), adjusting for sex, age at diagnosis, socioeconomic status and pH at diagnosis. Growth curve modeling was used to plot discrete HbA1c trajectories by ethnicity. RESULTS: Longitudinal modeling revealed that all ethnic minorities had higher mean HbA1c at diagnosis compared with White children and highest in Bangladeshi (9.7 mmol/mol, 95% CI 5.1 to 14.3), Asian-Other (5.8 mmol/mol, 95% CI 2.2 to 9.3) and Somali (5.2 mmol/mol, 95% CI 0.1 to 10.2) children, and these differences persisted over the 6-month period after diagnosis. During the first month, HbA1c decreased on average by 19.6 mmol/mol (95% CI -21 to -18) for all children. Population averaged HbA1c decreased between diagnosis and 4 months, followed by a gradual increase in HbA1c levels (mean difference of -30 mmol/mol between diagnosis and 6 months). CONCLUSIONS: Ethnic minorities present with higher HbA1c at diagnosis, with the largest mean differences observed in Bangladeshi, Asian-Other and Somali children. These higher levels (indicating poorer glycemic control) track into the first 6 months postdiagnosis.

Diabetic Ketoacidosis Severity at Diagnosis and Glycaemic Control in the First Year of Childhood Onset Type 1 Diabetes-A Longitudinal Cohort Study.

It is unclear whether diabetic ketoacidosis (DKA) severity at diagnosis affects the natural history of type 1 diabetes (T1D). We analysed associations between DKA severity at diagnosis and glycaemic control during the first year post-diagnosis. We followed 341 children with T1D, <19 years (64% non-white) attending paediatric diabetes clinics in East London. Data were extracted from routine medical registers. Subjects were categorized with normal, mild, moderate, or severe DKA. Linear mixed-effects modelling was used to assess differences in longitudinal HbA1c trajectories (glycaemic control) during 12 months post-diagnosis (1288 HbA1c data-points) based on DKA, adjusting for sex, age, ethnicity, SES (Socioeconomic Status) and treatment type. Females (OR 1.6, 95% CI 1.1-2.4) and younger age, 0-6 vs. 13-18 years (OR 2.9, 95% CI 1.5-5.6) had increased risk for DKA at diagnosis. Moderate or severe DKA was associated with higher HbA1c at diagnosis (adjusted estimates 8 mmol/mol, 2-14, and 10 mmol/mol, 4-15, respectively, compared to normal DKA). Differences in HbA1c trajectories by DKA were no longer apparent at six months post-diagnosis. All subjects experienced a steep decrease in HbA1c during the first three months followed by a gradual increase. While, DKA severity was not associated with glycaemic control at 12 months post-diagnosis, age at diagnosis, ethnicity, gender, and treatment type were significantly associated. For example, Black and mixed ethnicity children had increased risk for poor glycaemic control compared to White children (adjusted RRR 5.4, 95% CI 1.7-17.3 and RRR 2.5, 95% CI 1.2-6.0, respectively). DKA severity at diagnosis is associated with higher initial HbA1c but not glycaemic control from six months post-diagnosis. Age at diagnosis, ethnicity, gender, and insulin pump are associated with glycaemic control at one year post-diagnosis.

Psycho-educational interventions for children and young people with Type 1 Diabetes in the UK: How effective are they? A systematic review and meta-analysis.

AIMS: To synthesise evidence from UK-based randomised trials of psycho-educational interventions in children and young people (CYP) with Type 1 Diabetes (T1D) to inform the evidence-base for adoption of such interventions into the NHS. METHODS: We searched Medline, Embase, Cochrane, PsycINFO, CINAHL, and Web of Science up to March 2016. Two reviewers independently selected UK-based randomised trials comparing psycho-educational interventions for improving management of T1D for CYP with a control group of usual care or attention control. The main outcome was glycaemic control measured by percentage of glycated haemoglobin (HbA1c); secondary outcomes included psychosocial functioning, diabetes knowledge, adverse and other clinical outcomes. A narrative synthesis and meta-analysis were conducted. Pooled effect sizes of standardised mean difference (SMD) were calculated. RESULTS: Ten eligible trials of three educational and seven psycho-educational interventions were identified. Most interventions were delivered by non-psychologists and targeted adolescents with more than one year duration of diabetes. Meta-analysis of nine of these trials (N = 1,838 participants) showed a non-significant reduction in HbA1c attributable to the intervention (pooled SMD = -0.06, 95% CI: -0.21 to 0.09). Psycho-educational interventions aiming to increase children's self-efficacy had a moderate, beneficial effect (SMD = 0.50, 95% CI: 0.13 to 0.87). No benefits on diabetes knowledge and other indicators of psychosocial functioning were identified. CONCLUSIONS: There is insufficient evidence to recommend the use of particular psycho-educational programme for CYP with T1D in the UK. Further trials with sufficient power and reporting standards are needed. Future trials could consider active involvement of psychological specialists in the delivery of psychologically informed interventions and implementation of psycho-educational interventions earlier in the course of the disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015010701.

Ethnic Minorities Are at Greater Risk for Childhood-Onset Type 2 Diabetes and Poorer Glycemic Control in England and Wales.

PURPOSE: Ethnic minority children are at a greater risk for type 2 diabetes (T2D). However, current prevalence of T2D among children and young people is unknown in England and Wales. In addition, little is known on glycemic control in pediatric T2D globally. METHODS: Using data from the National Paediatric Diabetes Audit for 2012-2013 with >98% coverage of diabetes cases, we estimated (1) the overall, gender- and ethnic-specific prevalence of T2D in children and young people <16 years and (2) whether ethnicity predicts glycemic control (measured by mean HbA1c) in children and young people <19 years. Ethnicity was self-identified and categorized into white, Asian, black, mixed, other, and "not stated." Multivariable linear regression was used to estimate differences in glycemic control by ethnicity adjusting for socioeconomic status, age, diabetes duration, and gender. RESULTS: A total of 307 children and young people aged <16 years were identified with T2D in the National Paediatric Diabetes Audit for 2012-2013. Overall prevalence of T2D was 2.9/100,000. Females had a higher prevalence of T2D than males (4.3 vs. 1.5/100,000). The highest prevalence was found in Asian (12.2/100,000) followed by mixed ethnicity (4.4/100,000) females. Children of mixed ethnicity had significantly higher mean HbA1c compared with white children (9.7% [83 mmol/mol] vs. 7.8% [62 mmol/mol], p < .001, and adjusted mean difference of 4.2% [22.3 mmol/mol], 95% confidence interval = 3.1%-5.2% [10.9-33.7 mmol/mol]), but there were no significant differences between the other ethnic minority groups. CONCLUSIONS: Children of all ethnic minorities particularly females have an increased prevalence of T2D. Those belonging to mixed ethnic backgrounds are at increased risk for poorer glycemic control.

Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty.

CONTEXT: Steroid sulfatase (STS) cleaves the sulfate moiety off steroid sulfates, including dehydroepiandrosterone (DHEA) sulfate (DHEAS), the inactive sulfate ester of the adrenal androgen precursor DHEA. Deficient DHEA sulfation, the opposite enzymatic reaction to that catalyzed by STS, results in androgen excess by increased conversion of DHEA to active androgens. STS deficiency (STSD) due to deletions or inactivating mutations in the X-linked STS gene manifests with ichthyosis, but androgen synthesis and metabolism in STSD have not been studied in detail yet. PATIENTS AND METHODS: We carried out a cross-sectional study in 30 males with STSD (age 6-27 y; 13 prepubertal, 5 peripubertal, and 12 postpubertal) and 38 age-, sex-, and Tanner stage-matched healthy controls. Serum and 24-hour urine steroid metabolome analysis was performed by mass spectrometry and genetic analysis of the STS gene by multiplex ligation-dependent probe amplification and Sanger sequencing. RESULTS: Genetic analysis showed STS mutations in all patients, comprising 27 complete gene deletions, 1 intragenic deletion and 2 missense mutations. STSD patients had apparently normal pubertal development. Serum and 24-hour urinary DHEAS were increased in STSD, whereas serum DHEA and testosterone were decreased. However, total 24-hour urinary androgen excretion was similar to controls, with evidence of increased 5α-reductase activity in STSD. Prepubertal healthy controls showed a marked increase in the serum DHEA to DHEAS ratio that was absent in postpubertal controls and in STSD patients of any pubertal stage. CONCLUSIONS: In STSD patients, an increased 5α-reductase activity appears to compensate for a reduced rate of androgen generation by enhancing peripheral androgen activation in affected patients. In healthy controls, we discovered a prepubertal surge in the serum DHEA to DHEAS ratio that was absent in STSD, indicative of physiologically up-regulated STS activity before puberty. This may represent a fine tuning mechanism for tissue-specific androgen activation preparing for the major changes in androgen production during puberty.