Search

C-peptide declines in type 1 diabetes, although many long-duration patients retain low, but detectable levels. Histological analyses confirm that β-cells can remain following type 1 diabetes onset. We explored the trends observed in C-peptide decline in the UK Genetic Resource Investigating Diabetes (UK GRID) cohort (N = 4,079), with β-cell loss in pancreas donors from the network for Pancreatic Organ donors with Diabetes (nPOD) biobank and the Exeter Archival Diabetes Biobank (EADB) (combined N = 235), stratified by recently reported age at diagnosis endotypes (

Aims/hypothesis We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control. Methods This was a prospective observational study in 710 normoalbuminuric adolescents with type 1 diabetes from the non-intervention cohorts of the Adolescent Cardio-Renal Intervention Trial (AdDIT). Participants were classified as ‘high ACR’ or ‘low ACR’ (lowest and middle ACR tertiles) using baseline standardised log10 ACR. The primary outcome, 3DR, was determined from centrally graded, standardised two-field retinal photographs. 3DR risk was determined using multivariable Cox regression for the effect of high ACR, with HbA1c, BP, LDL-cholesterol and BMI as covariates; diabetes duration was the time-dependent variable. Results At baseline mean ± SD age was 14.3 ± 1.6 years and mean ± SD diabetes duration was 7.2 ± 3.3 years. After a median of 3.2 years, 83/710 (12%) had developed 3DR. In multivariable analysis, high ACR (HR 2.1 [1.3, 3.3], p=0.001), higher mean IFCC HbA1c (HR 1.03 [1.01, 1.04], p=0.001) and higher baseline diastolic BP SD score (HR 1.43 [1.08, 1.89], p=0.01) were independently associated with 3DR risk. Conclusions/interpretation High ACR is associated with greater risk of 3DR in adolescents, providing a target for future intervention studies. Trial registration isrctn.org ISRCTN91419926. Graphical abstract

ObjectiveWhile several studies have shown that milk formula feeding is associated with faster infant weight gain compared with exclusively breast feeding (EBF), we explored the possible reverse association that infant weight gain influences the duration of EBF.DesignProspective birth cohort study (Cambridge Baby Growth Breastfeeding Study) born 2015–2018.SettingCambridge, UK.ParticipantsFull-term, singleton, normal birthweight infants who received EBF for 2–5 completed weeks (n=54), 6–11 weeks (n=14) or 12 or more weeks (n=80).InterventionWeight gain from birth to 2 and 6 weeks.Main outcome and measureDuration of EBF.ResultsFaster infant weight gain during EBF predicted longer duration of EBF. Among all 148 infants, each +1 unit gain in weight SD score (SDS) between birth and 2 weeks (while all infants received EBF) reduced the likelihood of stopping EBF between 2 and 5 weeks by ~70% (OR 0.32; 95% CI 0.12 to 0.77; adjusted for sex, gestational age at birth, birth weight and mother’s age, prepregnancy BMI and education). Similarly, among infants EBF for 6 or more weeks (n=94), each +1 unit gain in weight SDS between birth and 6 weeks reduced the likelihood of stopping EBF between 6 and 11 weeks by ~80% (OR 0.18; 95% CI 0.05 to 0.63).ConclusionsSlower early infant weight gain was consistently associated with subsequent earlier discontinuation of EBF. We conjecture that broader recognition of the wide range of normal infant growth might encourage parents to not stop EBF earlier than they intended.

Human milk oligosaccharides (HMOs) are indigestible carbohydrates with prebiotic, pathogen decoy and immunomodulatory activities that are theorized to substantially impact infant health. The objective of this study was to monitor HMO concentrations over 1 year to develop a long-term longitudinal dataset. HMO concentrations in the breast milk of healthy lactating mothers of the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) were measured at birth, 2 weeks, 6 weeks, 3 months, 6 months and 12 months postpartum. HMO quantification was conducted by high-performance anion-exchange chromatography with pulsed amperometric detection using a newly validated “dilute-and-shoot” method. This technique minimizes sample losses and expedites throughput, making it particularly suitable for the analysis of large sample sets. Varying patterns of individual HMO concentrations were observed with changes in lactation timepoint and maternal secretor status, with the most prominent temporal changes occurring during the first 3 months. These data provide valuable information for the development of human milk banks in view of targeted distribution of donor milk based on infant age. Maternal FUT2 genotype was determined based on identification at single-nucleotide polymorphism rs516246 and compared with the genotype expected based on phenotypic markers in the HMO profile. Surprisingly, two mothers genotyped as secretors produced milk that displayed very low levels of 2′-fucosylated moieties. This unexpected discrepancy between genotype and phenotype suggests that differential enzyme expression may cause substantial variation in HMO profiles between genotypically similar mothers, and current genotypic methods of secretor status determination may require validation with HMO markers from milk analysis.

Low birthweight and reduced height gain during infancy (stunting) may arise at least in part from adverse early life environments that trigger epigenetic reprogramming that may favor survival. We examined differential DNA methylation patterns using targeted methyl sequencing of regions regulating gene activity in groups of rural Gambian infants: (a) low and high birthweight (DNA from cord blood (n = 16 and n = 20, respectively), from placental trophoblast tissue (n = 21 and n = 20, respectively), and DNA from peripheral blood collected from infants at 12 months of age (n = 23 and n = 17, respectively)), and, (b) the top 10% showing rapid postnatal length gain (high, n = 20) and the bottom 10% showing slow postnatal length gain (low, n = 20) based on z score change between birth and 12 months of age (LAZ) (DNA from peripheral blood collected from infants at 12 months of age). Using BiSeq analysis to identify significant methylation marks, for birthweight, four differentially methylated regions (DMRs) were identified in trophoblast DNA, compared to 68 DMRs in cord blood DNA, and 54 DMRs in 12‐month peripheral blood DNA. Twenty‐five DMRs were observed to be associated with high and low length for age (LAZ) at 12 months. With the exception of five loci (associated with two different genes), there was no overlap between these groups of methylation marks. Of the 194 CpG methylation marks contained within DMRs, 106 were located to defined gene regulatory elements (promoters, CTCF‐binding sites, transcription factor‐binding sites, and enhancers), 58 to gene bodies (introns or exons), and 30 to intergenic DNA. Distinct methylation patterns associated with birthweight between comparison groups were observed in DNA collected at birth (at the end of intrauterine growth window) compared to those established by 12 months (near the infancy/childhood growth transition). The longitudinal differences in methylation patterns may arise from methylation adjustments, changes in cellular composition of blood or both that continue during the critical postnatal growth period, and in response to early nutritional and infectious environmental exposures with impacts on growth and longer‐term health outcomes.

C-peptide declines in type 1 diabetes although many long-duration patients retain low, but detectable levels. Histological analyses confirm that beta cells can remain following type 1 diabetes onset. We explored the trends observed in C-peptide decline in UK Genetic Resource Investigating Diabetes (UK GRID) cohort (N=4,079), with beta cell loss in pancreas donors from the network for Pancreatic Organ donors with Diabetes (nPOD) biobank and the Exeter Archival Diabetes Biobank (EADB) (combined N=235), stratified by recently reported age at diagnosis endotypes (< 7, 7-12, ≥ 13 years) across increasing diabetes durations. The proportion of individuals with detectable C-peptide declined beyond the first year after diagnosis, but this was most marked in the youngest age group (< 1 year duration: age < 7 years: 18/20 (90%), 7-12 years: 107/110 (97%), ≥ 13 years: 58/61 (95%) versus. 1-5 years post diagnosis: < 7 years: 172/522 (33%), 7-12 years: 604/995 (61%), ≥ 13 years: 225/289 (78%)). A similar profile was observed in beta cell loss, with those diagnosed at younger ages experiencing more rapid loss of islets containing insulin-positive (insulin+) beta cells < 1 year post diagnosis: age < 7 years: 23/26 (88%), 7-12 years: 32/33 (97%), ≥ 13 years: 22/25 (88%) versus. 1-5 years post diagnosis: < 7 years: 1/12 (8.3%) ,7-12 years: 7/13 (54%), ≥ 13 years: 7/8 (88%)). These data should be considered in the planning and interpretation of intervention trials designed to promote beta cell retention and function.

Objective We describe a new method for identifying and quantifying the magnitude and rate of short‐term weight faltering episodes, and assess how (a) these episodes relate to broader growth outcomes, and (b) different data collection intervals influence the quantification of weight faltering. Materials and methods We apply this method to longitudinal growth data collected every other day across the first year of life in Gambian infants (n = 124, males = 65, females = 59). Weight faltering episodes are identified from velocity peaks and troughs. Rate of weight loss and regain, maximum weight loss, and duration of each episode were calculated. We systematically reduced our dataset to mimic various potential measurement intervals, to assess how these intervals affect the ability to derive information about short‐term weight faltering episodes. We fit linear models to test whether metrics associated with growth faltering were associated with growth outcomes at 1 year, and generalized additive mixed models to determine whether different collection intervals influence episode identification and metrics. Results Three hundred weight faltering episodes from 119 individuals were identified. The number and magnitude of episodes negatively impacted growth outcomes at 1 year. As data collection interval increases, weight faltering episodes are missed and the duration of episodes is overestimated, resulting in the rate of weight loss and regain being underestimated. Conclusions This method identifies and quantifies short‐term weight faltering episodes, that are in turn negatively associated with growth outcomes. This approach offers a tool for investigators interested in understanding how short‐term weight faltering relates to longer‐term outcomes.

An increased albumin-creatinine ratio within the normal range can identify adolescents at higher risk of developing adverse cardio-renal outcomes as they progress into adulthood. Utilizing a parallel randomized controlled trial and observational cohort study, we characterized the progression of vascular phenotypes throughout this important period and investigated the effect of ACE (angiotensin-converting enzyme) inhibitors and statins in high-risk adolescents. Endothelial function (flow-mediated dilation and reactive hyperemia index) and arterial stiffness (carotid-femoral pulse wave velocity) were assessed in 158 high-risk participants recruited to a randomized, double-blind placebo-controlled 2×2 factorial trial (randomized, placebo-controlled trial) of ACE inhibitors and/or statins in adolescents with type 1 diabetes (AdDIT [Adolescent Type 1 Diabetes cardio-renal Intervention Trial]). Identical measures were also assessed in 215 lower-risk individuals recruited to a parallel observational study. In the randomized, placebo-controlled trial, high-risk patients randomized to ACE inhibitors had improved flow-mediated dilation after 2 to 4 years of follow-up (mean [95% CI]: 6.6% [6.0–7.2] versus 5.3% [4.7–5.9]; P =0.005), whereas no effect was observed following statin use (6.2% [5.5–6.8] versus 5.8% [5.1–6.4]; P =0.358). In the observational study, patients classed as high-risk based on albumin-creatinine ratio showed evidence of endothelial dysfunction at the end of follow-up (flow-mediated dilation=4.8% [3.8–5.9] versus 6.3% [5.8–6.7] for high-risk versus low-risk groups; P =0.015). Neither reactive hyperemia index nor pulse wave velocity were affected by either treatment ( P >0.05 for both), but both were found to increase over the duration of follow-up (0.07 [0.03–0.12]; P =0.001 and 0.5 m/s [0.4–0.6]; P Registration— URL: https://www.clinicaltrials.gov ; Unique identifier NCT01581476.

OBJECTIVES: To identify biomarkers of renal disease in adolescents with type 1 diabetes (T1D) and to compare findings in adults with T1D.METHODS: Twenty-five serum biomarkers were measured, using a Luminex platform, in 553 adolescents (median [interquartile range] age: 13.9 [12.6, 15.2] years), recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Associations with baseline and final estimated glomerular filtration rate (eGFR), rapid decliner and rapid increaser phenotypes (eGFR slopes 3 mL/min/1.73m2 /year, respectively), and albumin-creatinine ratio (ACR) were assessed. Results were also compared with those obtained in 859 adults (age: 55.5 [46.1, 64.4) years) from the Scottish Diabetes Research Network Type 1 Bioresource.RESULTS: In the adolescent cohort, baseline eGFR was negatively associated with trefoil factor-3, cystatin C, and beta-2 microglobulin (B2M) (B coefficient[95%CI]: -0.19 [-0.27, -0.12], P = 7.0 × 10-7 ; -0.18 [-0.26, -0.11], P = 5.1 × 10-6 ; -0.12 [-0.20, -0.05], P = 1.6 × 10-3 ), in addition to clinical covariates. Final eGFR was negatively associated with osteopontin (-0.21 [-0.28, -0.14], P = 2.3 × 10-8 ) and cystatin C (-0.16 [-0.22, -0.09], P = 1.6 × 10-6 ). Rapid decliner phenotype was associated with osteopontin (OR: 1.83 [1.42, 2.41], P = 7.3 × 10-6 ), whereas rapid increaser phenotype was associated with fibroblast growth factor-23 (FGF-23) (1.59 [1.23, 2.04], P = 2.6 × 10-4 ). ACR was not associated with any of the biomarkers. In the adult cohort similar associations with eGFR were found; however, several additional biomarkers were associated with eGFR and ACR.CONCLUSIONS: In this young population with T1D and high rates of hyperfiltration, osteopontin was the most consistent biomarker associated with prospective changes in eGFR. FGF-23 was associated with eGFR increases, whereas trefoil factor-3, cystatin C, and B2M were associated with baseline eGFR.

Objective Patients with thyrotoxicosis are treated with anti-thyroid drug (ATD) using block and replace (BR) or a smaller, titrated dose of ATD (dose titration, DT). Design A multi-centre, phase III, open-label trial of newly diagnosed paediatric thyrotoxicosis patients randomised to BR/DT. We compared the biochemical response to BR/DT in the first 6 months of therapy. Methods Patients commenced 0.75 mg/kg carbimazole (CBZ) daily with randomisation to BR/DT. We examined baseline patient characteristics, CBZ dose, time to serum thyroid-stimulating hormone (TSH)/free thyroxine (FT4) normalisation and BMI Z-score change. Results There were 80 patients (baseline) and 78 patients (61 female) at 6 months. Mean CBZ dose was 0.9 mg/kg/day (BR) and 0.5 mg/kg/day (DT). There was no difference in time to non-suppressed TSH concentration; 16 of 39 patients (BR) and 11 of 39 (DT) had suppressed TSH at 6 months. Patients with suppressed TSH had higher mean baseline FT4 levels (72.7 vs 51.7 pmol/L; 95% CI for difference 1.73, 31.7; P = 0.029). Time to normalise FT4 levels was reduced in DT (log-rank test, P = 0.049) with 50% attaining normal FT4 at 28 days (95% CI 25, 32) vs 35 days in BR (95% CI 28, 58). Mean BMI Z-score increased from 0.10 to 0.81 at 6 months (95% CI for difference 0.57, 0.86; P < 0.001) and was greatest in patients with higher baseline FT4 concentrations. Conclusions DT-treated patients normalised FT4 concentrations more quickly than BR. Overall, 94% of patients have normal FT4 levels after 6 months, but 33% still have TSH suppression. Excessive weight gain occurs with both BR and DT therapy.

Growth patterns of breastfed infants show substantial inter-individual differences, partly influenced by breast milk (BM) nutritional composition. However, BM nutritional composition does not accurately indicate BM nutrient intakes. This study aimed to examine the associations between both BM intake volumes and macronutrient intakes with infant growth. Mother–infant dyads (n 94) were recruited into the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) from a single maternity hospital at birth; all infants received exclusive breast-feeding (EBF) for at least 6 weeks. Infant weight, length and skinfolds thicknesses (adiposity) were repeatedly measured from birth to 12 months. Post-feed BM samples were collected at 6 weeks to measure TAG (fat), lactose (carbohydrate) (both by 1H-NMR) and protein concentrations (Dumas method). BM intake volume was estimated from seventy infants between 4 and 6 weeks using dose-to-the-mother deuterium oxide (2H2O) turnover. In the full cohort and among sixty infants who received EBF for 3+ months, higher BM intake at 6 weeks was associated with initial faster growth between 0 and 6 weeks (β + se 3·58 + 0·47 for weight and 4·53 + 0·6 for adiposity gains, both P < 0·0001) but subsequent slower growth between 3 and 12 months (β + se − 2·27 + 0·7 for weight and −2·65 + 0·69 for adiposity gains, both P < 0·005). BM carbohydrate and protein intakes at 4–6 weeks were positively associated with early (0–6 weeks) but tended to be negatively related with later (3–12 months) adiposity gains, while BM fat intake showed no association, suggesting that carbohydrate and protein intakes may have more functional relevance to later infant growth and adiposity.

Funder: Danone Nutricia Research, Funder: EU Commission for JPI HDHL program ‘Call III Biomarkers’ for project: BioFN ‐ Biomarkers for Infant Fat Mass Development and Nutrition; Grant(s): 696295, Summary: Background: Anthropometry‐based equations are commonly used to estimate infant body composition. However, existing equations were designed for newborns or adolescents. We aimed to (a) derive new prediction equations in infancy against air‐displacement plethysmography (ADP‐PEA Pod) as the criterion, (b) validate the newly developed equations in an independent infant cohort and (c) compare them with published equations (Slaughter‐1988, Aris‐2013, Catalano‐1995). Methods: Cambridge Baby Growth Study (CBGS), UK, had anthropometry data at 6 weeks (N = 55) and 3 months (N = 64), including skinfold thicknesses (SFT) at four sites (triceps, subscapular, quadriceps and flank) and ADP‐derived total body fat mass (FM) and fat‐free mass (FFM). Prediction equations for FM and FFM were developed in CBGS using linear regression models and were validated in Sophia Pluto cohort, the Netherlands, (N = 571 and N = 447 aged 3 and 6 months, respectively) using Bland–Altman analyses to assess bias and 95% limits of agreement (LOA). Results: CBGS equations consisted of sex, age, weight, length and SFT from three sites and explained 65% of the variance in FM and 79% in FFM. In Sophia Pluto, these equations showed smaller mean bias than the three published equations in estimating FM: mean bias (LOA) 0.008 (−0.489, 0.505) kg at 3 months and 0.084 (−0.545, 0.713) kg at 6 months. Mean bias in estimating FFM was 0.099 (−0.394, 0.592) kg at 3 months and −0.021 (−0.663, 0.621) kg at 6 months. Conclusions: CBGS prediction equations for infant FM and FFM showed better validity in an independent cohort at ages 3 and 6 months than existing equations.

Funder: Danone Nutricia Research; Id: http://dx.doi.org/10.13039/100015766, Summary: Background and Objectives: Early life is a critical window for adiposity programming. Metabolic‐profile in early life may reflect this programming and correlate with later life adiposity. We investigated if metabolic‐profile at 3 months of age is predictive for body composition at 2 years and if there are differences between boys and girls and between infant feeding types. Methods: In 318 healthy term‐born infants, we determined body composition with skinfold measurements and abdominal ultrasound at 3 months and 2 years of age. High‐throughput‐metabolic‐profiling was performed on 3‐month‐blood‐samples. Using random‐forest‐machine‐learning‐models, we studied if the metabolic‐profile at 3 months can predict body composition outcomes at 2 years of age. Results: Plasma metabolite‐profile at 3 months was found to predict body composition at 2 years, based on truncal: peripheral‐fat‐skinfold‐ratio (T:P‐ratio), with a predictive value of 75.8%, sensitivity of 100% and specificity of 50%. Predictive value was higher in boys (Q2 = 0.322) than girls (Q2 = 0.117). Of the 15 metabolite variables most strongly associated with T:P‐ratio, 11 were also associated with visceral fat at 2 years of age. Conclusion: Several plasma metabolites (LysoPC(22:2), dimethylarginine and others) at 3 months associate with body composition outcome at 2 years. These results highlight the importance of the first months of life for adiposity programming.

Funder: Department of Health, BACKGROUND: Levels of obesity are rising in South Africa, notably among adolescent females. Excessive energy-dense diets and physical inactivity are among the factors contributing to this increase. Given that these factors are largely behavioural, understanding young people's views of obesity can contribute to more targeted behavioural interventions. Yet little is known of how rural South African adolescents view obesity. OBJECTIVES: The aim of this study was to explore rural South African adolescents' views of obesity, including their understanding of its causes, consequences, and solutions. METHODS: This qualitative study took place within the MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt) study area, in rural northeast South Africa. Three focus group discussions were held with male (n = 16) and female adolescents (n = 15), aged 14-19 years in 2018. Data were analysed using thematic analysis and the Social Cognitive Theory used to frame the findings. RESULTS: Participants presented conflicting views of obesity, with both positive and negative opinions expressed. Causes of obesity were seen to be multifactorial, including genetics, diet, lack of physical activity, and HIV treatment. Adolescents proposed medication and hospitalisation as ways to address obesity. When discussing interventions to address obesity, adolescents expressed the need for more information, suggesting that providing information to both themselves and their family members as part of interventions would be important. CONCLUSIONS: Rural South African adolescents have a complex perspective of obesity, likely driven in part by the current nutrition transition underway and do not inherently see individual behaviour as a driver or mitigator of obesity. Complex interventions including the involvement of other household members are needed to change adolescents' views on the role of the individual, and ultimately, change both individual and household behaviour to prevent obesity.

BackgroundHyperglycaemia and hypoglycaemia are common in preterm infants and are associated with increased mortality and morbidity. Continuous glucose monitoring is widely used to target glucose control in adults and children, but not in neonates.ObjectiveTo evaluate the role of continuous glucose monitoring in the preterm infant.DesignThe REAl-time Continuous glucose moniToring in neonatal intensive care project combined (1) a feasibility study, (2) a multicentre randomised controlled trial and (3) a pilot of ‘closed-loop’ continuous glucose monitoring. The feasibility study comprised a single-centre study (n = 20). Eligibility criteria included a birthweight ≤ 1200 g and aged ≤ 48 hours. Continuous glucose monitoring was initiated to support glucose control. The efficacy and safety outcomes guided the design of the randomised controlled trial. The randomised controlled trial comprised a European multicentre trial (n = 182). Eligibility criteria included birthweight ≤ 1200 g and aged ≤ 24 hours. Exclusion criteria included any lethal congenital abnormality. Continuous glucose monitoring was initiated to support glucose control within 24 hours of birth. In the intervention group, the continuous glucose monitoring sensor provided real-time data on glucose levels, which guided clinical management. In control infants, the continuous glucose monitoring data were masked, and glucose level was managed in accordance with standard clinical practice and based on the blood glucose levels. The primary outcome measure was the percentage of time during which the sensor glucose level was within the target range of 2.6–10 mmol/l. Secondary outcome measures included mean sensor glucose level, the percentage of time during which the sensor glucose level was within the target range of 4–8 mmol/l, the percentage of time during which the sensor glucose level was in the hyperglycaemic range (i.e. > 15 mmol/l) and sensor glucose level variability. Safety outcomes included hypoglycaemia exposure. Acceptability assessment and health economic analyses were carried out and further exploratory health outcomes were explored. The mean percentage of time in glucose target range of 2.6–10 mmol/l was 9% higher in infants in the continuous glucose monitoring group (95% confidence interval 3% to 14%;p = 0.002), and the mean time in the target range of 4–8 mmol/l was 12% higher in this group (95% confidence interval 4% to 19%;p = 0.004). There was no difference in the number of episodes of hypoglycaemia. Exploratory outcomes showed a reduced risk of necrotising enterocolitis in the intervention arm (odds ratio 0.33, 95% confidence interval 0.13 to 0.78;p = 0.01). Health economic analyses demonstrated that continuous glucose monitoring was cost-effective on the basis of the cost per additional case of adequate glucose control between 2.6 and 10 mmol/l. The ‘closed-loop’ study was a single-center pilot study, with eligibility criteria including a birthweight of ≤ 1200 g and aged ≤ 48 hours. Infants underwent continuous glucose monitoring for the first week of life (n = 21), with those in the intervention group receiving closed-loop insulin delivery between 48 and 72 hours of age. The primary outcome of percentage of time in the target range (i.e. sensor glucose 4–8 mmol/l) increased from a median of 26% (interquartile range 6–64%) to 91% (interquartile range 78–99%) during closed-loop insulin delivery (p LimitationsThese studies have not defined the optimal targets for glucose control or the best strategies to achieve them in these infants.Future workStudies are needed to evaluate the longer-term impact of targeting glucose control on clinical outcomes.ConclusionsContinuous glucose monitoring in extremely preterm infants can improve glucose control, with closed-loop insulin delivery having further potential to target glucose levels. Staff and parents felt that the use of continuous glucose monitoring improved care and the results of the health economic evaluation favours the use of continuous glucose monitoring.Trial registrationCurrent Controlled Trials ISRCTN12793535.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full inEfficacy and Mechanism Evaluation; Vol. 8, No. 16. See the NIHR Journals Library website for further project information. Medtronic plc provided some MiniMed™ 640G systems and Nova Biomedical (Waltham, MA, USA) provided point-of-care devices.

Funder: Medical Research Council; Grant(s): Unit programmes: MC_UU_12015/2 and MC_UU_00006/2, Funder: Wellcome Trust, Growth and nutrition during early life have been strongly linked to future health and metabolic risks. The Cambridge Baby Growth Study (CBGS), a longitudinal birth cohort of 2229 mother-infant pairs, was set up in 2001 to investigate early life determinant factors of infant growth and body composition in the UK setting. To carry out extensive profiling of breastmilk intakes and composition in relation to infancy growth, the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) was established upon the original CBGS. The strict inclusion criteria were applied, focusing on a normal birth weight vaginally delivered infant cohort born of healthy and non-obese mothers. Crucially, only infants who were exclusively breastfed for the first 6 weeks of life were retained in the analysed study sample. At each visit from birth, 2 weeks, 6 weeks, and then at 3, 6, 12, 24, and 36 months, longitudinal anthropometric measurements and blood spot collections were conducted. Infant body composition was assessed using air displacement plethysmography (ADP) at 6 weeks and 3 months of age. Breast milk was collected for macronutrients and human milk oligosaccharides (HMO) measurements. Breast milk intake volume was also estimated, as well as sterile breastmilk and infant stool collection for microbiome study.

Objectives: To determine differences in body composition and glucose metabolism according to childhood growth outcomes in a population-based sample of children born small for gestational age (SGA). Methods: A single-centre study of 259 children born SGA identified through hospital records and contacted when aged 4–7 years. Questionnaire data on pre/perinatal history and growth parameters during childhood was collected from the parents, and in a subgroup of 150 children face-to-face assessments were performed, including anthropometric parameters, lean and fat mass, blood pressure, fasting glucose, and C-peptide. Results: Based on the questionnaires, few children had formal clinic follow-up of growth, but 7% of the cohort showed a height and weight of 2, p = 0.04), trunk-to-limb fat mass ratio (0.63 ± 0.14 vs. 0.56 ± 0.08, p = 0.002), systolic blood pressure SDS (0.09 ± 0.71 vs. –0.32 ± 0.63, p = 0.008), fasting glucose (4.5 ± 0.5 vs. 4.3 ± 0.5 mmol/L, p = 0.03), and C-peptide (306 ± 116 vs. 256 ± 112 pmol/L, p = 0.08). Among children with weight catch-up growth, those with less height gain had a lower limb lean mass index (4.25 ± 0.48 vs. 4.48 ± 0.56 kg/m2, p = 0.02) and fat mass index (1.57 ± 0.59 vs. 1.83 ± 0.77 kg/m2, p = 0.04). Conclusions: Within this population-based sample of SGA children, catch-up growth in weight was associated with higher abdominal fat mass, blood pressure and glycemia; furthermore, in these children, less height gain was associated with reduced limb lean and fat mass.

Background An increasing body of evidence supports the view that both an adverse intrauterine milieu and rapid postnatal weight gain in children born small for gestational age (SGA) contribute towards the risk for the development of chronic diseases in adult life. Content The aim of this review was to identify and summarize the published evidence on metabolic and cardiovascular risk, as well as risk of impaired cardiac function, intellectual capacity, quality of life, pubertal development and bone strength among children born SGA. The review will then address whether growth hormone (GH) therapy, commonly prescribed to reduce the height deficit in children born SGA who do not catch up in height, increases or decreases these risks over time. Summary Overall, there are limited data in support of a modest beneficial effect of GH therapy on the adverse metabolic and cardiovascular risk observed in short children born SGA. Evidence to support a positive effect of GH on bone strength and psychosocial outcomes is less convincing. Outlook Further evaluation into the clinical relevance of any potential long-term benefits of GH therapy on metabolic and cardiovascular endpoints is warranted.

Objective: Closed-loop systems have been used to optimise insulin delivery in children with diabetes, but they have not been tested in neonatal intensive care. Extremely preterm infants are prone to hyperglycaemia and hypoglycaemia; both of which have been associated with adverse outcomes. Insulin sensitivity is notoriously variable in these babies and glucose control is time-consuming, with management requiring frequent changes of dextrose-containing fluids and careful monitoring of insulin treatment. We aimed to evaluate the feasibility of closed-loop management of glucose control in these infants. Design and Setting: Single centre feasibility study with a randomized parallel design in a neonatal intensive care unit. Eligibility criteria included birth weight, Funding was provided by the Evelyn Trust, the National Institute of Health Research EME Program and the National Institute of Health Research Cambridge Biomedical Research Centre. Medtronic provided the continuous glucose monitoring system and sensors. Medtronic had no role in design of the study, the gathering of data, access to data, preparation of the manuscript or decision to publish the results.

OBJECTIVE: To quantify age-related variability of insulin needs during day and night closed-loop insulin delivery. RESEARCH DESIGN AND METHODS: We retrospectively analyzed data from hybrid closed-loop studies involving young children (1-6 years old, n = 20), children (7-12 years, n = 21), adolescents (13-17 years, n = 15), and adults (>18 years, n = 58) with type 1 diabetes. The coefficient of variation quantified variability of insulin needs during 3 weeks of unrestricted-living hybrid closed-loop use. RESULTS: Data from 2,365 nights and 2,367 days in 114 participants were analyzed. The coefficient of variation of insulin delivery was higher in young children compared with adults (mean difference at nighttime 10.7 percentage points [95% CI 2.9-18.4], P = 0.003; daytime 6.4 percentage points [95% CI 2.0-10.9], P = 0.002) and compared with adolescents (mean difference at nighttime 10.2 percentage points [95% CI 0.0-20.4], P = 0.049; daytime 7.0 percentage points [95% CI 1.1-12.8], P = 0.014). CONCLUSIONS: Diabetes management in young children is complicated by higher variability in insulin requirements, supporting fast-track clinical practice adoption of closed-loop in this vulnerable population. With increasing application of insulin pump therapy and continuous glucose monitors, hybrid closed-loop has become a feasible treatment modality for people with type 1 diabetes (1,2). Apart from manual meal-time boluses, insulin delivery is autonomously modulated by a control algorithm based on real-time sensor glucose values. Insulin delivery may vary considerably from day to day and night to night due to varying activity levels, insulin set-changes, meal timings and composition, and other factors(3,4).Todate,theassociationbetweenageandinsulinvariabilityhasnotbeen assessed.Inthepresentanalysis,weinvestigatewhetherinsulinrequirementsmaybe more variable in younger age.

BACKGROUND: Presumed benefits of human milk (HM) in avoiding rapid infancy weight gain and later obesity could relate to its nutrient composition. However, data on breast milk composition and its relation with growth are sparse. OBJECTIVE: We investigated whether short-chain fatty acids (SCFAs), known to be present in HM and linked to energy metabolism, are associated with infancy anthropometrics. METHODS: In a prospective birth cohort, HM hindmilk samples were collected from 619 lactating mothers at 4-8 wk postnatally [median (IQR) age: 33.9 (31.3-36.5) y, body mass index (BMI) (kg/m2): 22.8 (20.9-25.2)]. Their offspring, born at 40.1 (39.1-41.0) wk gestation with weight 3.56 (3.22-3.87) kg and 51% male, were assessed with measurement of weight, length, and skinfold thickness at ages 3, 12, and 24 mo, and transformed to age- and sex-adjusted z scores. HM SCFAs were measured by 1H-nuclear magnetic resonance spectroscopy (NMR) and GC-MS. Multivariable linear regression models were conducted to analyze the relations between NMR HM SCFAs and infancy growth parameters with adjustment for potential confounders. RESULTS: NMR peaks for HM butyrate, acetate, and formic acid, but not propionate, were detected. Butyrate peaks were 17.8% higher in HM from exclusively breastfeeding mothers than mixed-feeding mothers (P = 0.003). HM butyrate peak values were negatively associated with changes in infant weight (standardized B = -0.10, P = 0.019) and BMI (B = -0.10, P = 0.018) between 3 and 12 mo, and negatively associated with BMI (B = -0.10, P = 0.018) and mean skinfold thickness (B = -0.10, P = 0.049) at age 12 mo. HM formic acid peak values showed a consistent negative association with infant BMI at all time points (B < = -0.10, P < = 0.014), whereas HM acetate was negatively associated with skinfold thickness at 3 mo (B = -0.10, P = 0.028) and 24 mo (B = -0.10, P = 0.036). CONCLUSIONS: These results suggest that HM SCFAs play a beneficial role in weight gain and adiposity during infancy. Further knowledge of HM SCFA function may inform future strategies to support healthy growth.

Diabetes vascular complications, including cardiovascular disease, diabetic nephropathy and retinopathy, have a negative effect on the long-term prognosis of young people with type 1 diabetes mellitus (T1DM). Poor glycaemic control and consequent increased HbA1c levels are major risk factors for the development of vascular complications. HbA1c levels are the main focus of current management strategies; however, the recommended target is rarely achieved in adolescents. Thus, a clear need exists for improved biomarkers to identify high-risk young people early and to develop new intervention strategies. Evidence is accumulating that early increases in urinary albumin excretion could be predictive of adolescents with T1DM who are at an increased risk of developing vascular complications, independent of HbA1c levels. These findings present an opportunity to move towards the personalized care of adolescents with T1DM, which takes into consideration changes in albumin excretion and other risk factors in addition to HbA1c levels.

OBJECTIVE This study explored the link between HLA polymorphisms that predispose to type 1 diabetes and birth size, infancy growth and/or circulating IGF-1 in a general population-based birth cohort. RESEARCH DESIGN AND METHODS The Cambridge Baby Growth Study is a prospective observational birth cohort study that recruited 2,229 newborns for follow-up in infancy. Of these, 612 children had DNA available for genotyping single nucleotide polymorphisms in the HLA region that capture the highest risk of type 1 diabetes: rs17426593 for DR4, rs2187668 for DR3 and rs7454108 for DQ8. Multivariate linear regression models at critical ages (cross-sectional) and mixed-effects models (longitudinal) were performed under additive genetic effects to test for associations between HLA polymorphisms and infancy weight, length, skinfold thickness (indicator of adiposity), and concentrations of IGF-1 and IGF-binding protein-3 (IGFBP-3). RESULTS In longitudinal models, the minor allele of rs2187668 tagging DR3 was associated with faster linear growth (P=0.007), more pronounced in boys (P=3x10-7) than girls (P=0.07), and with increasing IGF-1 (P=0.002) and IGFBP-3 (P=0.003) concentrations in infancy. Cross-sectionally, the minor alleles of rs7454108 tagging DQ8 and rs17426593 tagging DR4 were respectively associated with lower IGF-1 concentrations at age 12 months (P=0.003) and greater skinfold thickness at age 24 months (P=0.003). CONCLUSIONS The variable associations of DR4, DR3 and DQ8 alleles with growth measures and IGF-1 levels in infants from the general population could explain the heterogeneous growth trajectories observed in genetically at-risk cohorts. These findings could suggest distinct mechanisms involving endocrine pathways related to the HLA-conferred type 1 diabetes risk.

Objective Previously we observed that maternal multiple micronutrient supplementation in pregnancy was associated with increased offspring size at birth and adiposity, as well as with maternal gestational diabetes risk, in the Cambridge Baby Growth Study. In this study we therefore investigated whether folic acid supplementation specifically is associated with similar changes, to test the hypothesis that folic acid supplementation mediates such changes. Results The majority of mothers who reported supplementing with folic acid in pregnancy (n = 776 in total, 526 of which took multiple micronutrient preparations) did so either from pre- (n = 139) or post-conception (n = 637) largely for all or just the first half of pregnancy. A minority of mothers (n = 198) reported not supplementing with folic acid. Folic acid supplementation in pregnancy was not associated with birth weight [β’ = − 0.003, p = 0.9], height [β’ = − 0.013, p = 0.6], head circumference [β’ = 0.003, p = 0.09] or adiposity (ponderal index [β’ = 0.020, p = 0.5], skinfolds thicknesses [β’ = − 0.029 to + 0.008, p = 0.4–0.9]). Neither was it associated with the development of maternal gestational diabetes (risk ratio 1.2 [0.6‒2.2], p = 0.6). These results suggest that folic acid supplementation in pregnancy did not mediate the previously observed increases in offspring size at birth and adiposity, or the raised gestational diabetes risk, in response to supplementation with multiple micronutrients.

Context Delta like noncanonical notch ligand 1 (DLK1) is a paternally expressed imprinted gene that encodes an epidermal growth factor repeat-containing transmembrane protein. A bioactive, truncated DLK1 protein is present in the circulation and has roles in development and metabolism. Objective We sought to investigate links between maternal pregnancy circulating DLK1 concentrations and: (1) maternal and fetal DLK1 genotypes, (2) maternal insulin resistance and secretion, and (3) offspring size at birth. Patients, design, and setting We measured third-trimester maternal serum DLK1 concentrations and examined their associations with parentally transmitted fetal and maternal DLK1 genotypes, indices of maternal insulin resistance and secretion derived from 75-g oral glucose tolerance tests performed around week 28 of pregnancy, and offspring size at birth in 613 pregnancies from the Cambridge Baby Growth Study. Results Maternal DLK1 concentrations were associated with the paternally transmitted fetal DLK1 rs12147008 allele (P = 7.8 × 10-3) but not with maternal rs12147008 genotype (P = 0.4). Maternal DLK1 concentrations were positively associated with maternal prepregnancy body mass index (P = 3.5 × 10-6), and (after adjustment for maternal body mass index) with both maternal fasting insulin resistance (Homeostatic Model Assessment of Insulin Resistance: P = 0.01) and measures of maternal insulin secretion in response to oral glucose (insulinogenic index: P = 1.2 × 10-3; insulin disposition index: P = 0.049). Further positive associations were found with offspring weight (P = 0.02) and head circumference at birth (P = 0.04). Conclusion These results are consistent with a partial paternal or placental origin for the maternal circulating DLK1 which may lead to increased maternal circulating DLK1 concentrations, stimulation of maternal insulin resistance and compensatory hyperinsulinemia during pregnancy, and the promotion of fetal growth.

Background: Altered lipid metabolism in early life has been associated with subsequent weight gain and predicting this could aid in obesity prevention and risk management. Here, a lipidomic approach was used to identify circulating markers for future obesity risk in translational murine models and validate in a human infant cohort.Methods: Lipidomics was performed on the plasma of APOE*3 Leiden, Ldlr-/-.Leiden, and the wild-type C57BL/6J mice to capture candidate biomarkers predicting subsequent obesity parameters after exposure to high-fat diet. The identified candidate biomarkers were mapped onto corresponding lipid metabolism pathways and were investigated in the Cambridge Baby Growth Study. Infants' growth and adiposity were measured at 0-24 months. Capillary dried blood spots were sampled at 3 months for lipid profiling analysis.Findings: From the mouse models, cholesteryl esters were correlated with subsequent weight gain and other obesity parameters after HFD period (Spearman's r >= 0.5, FDR p values

We report the largest and most ancestrally diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 152 regions associated to false discovery rate < 0.01, including 36 regions associated to genome-wide significance for the first time. Credible sets of disease-associated variants are specifically enriched in immune cell accessible chromatin, particularly in CD4+ effector T cells. Colocalization with chromatin accessibility quantitative trait loci (QTL) in CD4+ T cells identified five regions where differences in T1D risk and chromatin accessibility are potentially driven by the same causal variant. Allele-specific chromatin accessibility further refined the set of putative causal variants with functional relevance in CD4+ T cells and integration of whole blood expression QTLs identified candidate T1D genes, providing high-yield targets for mechanistic follow-up. We highlight rs72938038 in BACH2 as a candidate causal T1D variant, where the T1D risk allele leads to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritise potential drug targets by integrating genetic evidence, functional genomic maps, and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D, including proposed genetic regulatory mechanisms of T1D-associated variants and genetic support for therapeutic targets for immune intervention.

Multiple micronutrient supplementation (MMS) in pregnancy has previously been associated with positive effects on fetal growth, but its value in high-income countries remains controversial. In this study, we investigated effects of pregnancy MMS on offspring size at birth and adiposity, along with risks of various maternal outcomes of pregnancy, using the prospective Cambridge Baby Growth Study. Maternal MMS was reported in 528 out of 970 women who completed pregnancy questionnaires. Gestational diabetes (GDM) was assessed using results from 75 g oral glucose tolerance tests at week 28 of pregnancy. Offspring size at birth was assessed using standard anthropometric measurements and adiposity using skinfold calipers. MMS was associated with increased risk of developing GDM (risk ratio = 1.86 (1.13&ndash, 3.08), p = 0.02), as well as increased offspring size at birth in terms of weight (p = 0.03), head circumference (p = 0.04), and flank, and subscapular and triceps skinfold thicknesses (p = 0.04, 0.03, and 0.003, respectively). There was no association with quadriceps skinfold thickness (p = 0.2), suggesting that the increased adiposity was partially regionalized. In women who underwent oral glucose tolerance testing, nearly all of these associations were attenuated by adjusting for GDM. These results suggest that the increased offspring size at birth, including (regionalized) adiposity associated with pregnancy, and MMS may be partially related to the development of GDM.

ObjectiveHyperglycaemia is common in very preterm infants and is associated with adverse outcomes. Preventing hyperglycaemia without increasing the risk of hypoglycaemia is difficult. Real time tracking with continuous glucose monitors (CGM) may improve glucose control. We assessed the feasibility and safety of CGM to target glucose control in preterm infants, to inform a randomised controlled trial (RCT).DesignWe performed a single centre study in very preterm infants during the first week of life. Accuracy was assessed by comparison of CGM with blood glucose levels (n=20 infants). In a separate pilot study of efficacy (n=20), real-time CGM combined with a paper guideline to target glucose control (2.6–10 mmol/L) was compared with standard neonatal care (masked CGM). Questionnaires were used to assess staff acceptability.ResultsNo concerns were raised about infection or skin integrity at sensor site. The sensor performed well compared with point-of-care blood glucose measurements, mean bias of −0.27 (95% CI −0.35 to −0.19). Per cent time in target range (sensor glucose 2.6–10 mmol/L) was greater with CGM than POC (77% vs 59%, respectively) and per cent time sensor glucose >10 mmol/L was less with CGM than POC (24% vs 40%, respectively). The CGM also detected clinically unsuspected episodes of hypoglycaemia. Staff reported that the use of the CGM positively improved clinical care.ConclusionsThis study suggests that CGM has sufficient accuracy and utility in preterm infants to warrant formal testing in a RCT.

Funder: National Institute for Health Research Cambridge Biomedical Research Centre, Background: Autism is more prevalent in males than in females. Hypotheses related to the extreme male brain theory of autism suggest that heightened androgen exposure during early development contributes to autistic traits. Whilst prior research focused mostly on the prenatal period, the current study tests the influences of androgen exposure during both the prenatal and the early postnatal periods on autistic traits during childhood. Methods: Anthropometric measures that are putative biomarkers of early androgen exposure were employed. Anogenital distance (AGD) was measured at birth and 3 months of age in boys and girls. Penile length at birth and 3 months of age was also measured in boys. When the children were 9–13 years old, a parent‐reported questionnaire (the 10‐item children’s version of the Autism Spectrum Quotient; AQ‐10 Child) was used to assess autistic traits in 97 boys and 110 girls. Results: There were no significant associations between any of the AGD or penile length measures and scores on the AQ‐10 Child in boys, girls or the entire sample. Conclusions: The current study provides the first test of whether early measurements of AGD and/or penile length predict subsequent autistic traits. The current findings do not support a relationship between prenatal or early postnatal androgen exposure and autistic traits. The current study augments prior research showing no consistent relationship between early androgen exposure and autistic traits.

Background: hyperglycaemia and hypoglycaemia are common in preterm infants and have been associated with increased risk of mortality and morbidity. Interventions to reduce risk associated with these exposures are particularly challenging due to the infrequent measurement of blood glucose concentrations, with the potential of causing more harm instead of improving outcomes for these infants. Continuous glucose monitoring (CGM) is widely used in adults and children with diabetes to improve glucose control, but has not been approved for use in neonates. The REACT trial aimed to evaluate the efficacy and safety of CGM in preterm infants requiring intensive care. Methods: this international, open-label, randomised controlled trial was done in 13 neonatal intensive care units in the UK, Spain, and the Netherlands. Infants were included if they were within 24 h of birth, had a birthweight of 1200 g or less, had a gestational age up to 33 weeks plus 6 days, and had parental written informed consent. Infants were randomly assigned (1:1) to real-time CGM or standard care (with masked CGM for comparison) using a central web randomisation system, stratified by recruiting centre and gestational age (Findings: between July 4, 2016, and Jan 27, 2019, 182 infants were enrolled, 180 of whom were randomly assigned (85 to real-time CGM, 95 to standard care). 70 infants in the real-time CGM intervention group and 85 in the standard care group had CGM data and were included in the primary analysis. Compared with infants in the standard care group, infants managed using CGM had more time in the 2·6–10 mmol/L glucose concentration target range (mean proportion of time 84% [SD 22] vs 94% [11]; adjusted mean difference 8·9% [95% CI 3·4–14·4]), equivalent to 13 h (95% CI 5–21). More infants in the standard care group were exposed to at least one episode of sensor glucose concentration of less than 2·6 mmol/L for more than 1 h than those in the intervention group (13 [15%] of 85 vs four [6%] of 70). There were no serious adverse events related to the use of the device or episodes of infection. Interpretation: real-time CGM can reduce exposure to prolonged or severe hyperglycaemia and hypoglycaemia. Further studies using CGM are required to determine optimal glucose targets, strategies to obtain them, and the potential effect on long-term health outcomes. Funding: National Institute for Health Research Efficacy and Mechanisms Evaluation Programme.

Objective First-line treatment of thyrotoxicosis in young people is thionamide anti-thyroid drug (ATD) in a blocking dose with levothyroxine replacement (block and replace, BR) or in a smaller dose tailored to render the patient euthyroid (dose titration, DT). Our objective was to determine which regimen provides more stable biochemical control. Design A multi-centre phase III, open-label randomised trial comparing BR with DT in patients aged 2–17 years with newly diagnosed thyrotoxicosis at 15 UK centres. Methods Patients were randomised shortly after diagnosis and treated for 3 years. The primary outcome was the percentage of serum thyroid-stimulating hormone (TSH) levels in the reference range between 6 months and 3 years. Secondary outcomes included the proportion of Free thyroxine (FT4) levels in the reference range, adverse event frequency and 4 years outcome (remission/relapse). Results Eighty-two patients were randomised, with details on clinical course in 81 (62 Female); 40 were allocated to BR (41 DT). Three withdrew with one ineligible. The mean percentage of serum TSH within reference range was 60.2% in BR and 63.8% in DT patients; adjusted difference 4.3%, 95% CI (−7.8 to 16.4); P = 0.48. Proportions for FT4 were 79.2% in BR and 85.7% in DT patients; adjusted difference 6.8%, (−0.2 to 15.6); P = 0.13. Three patients developed neutropenia – all on BR. 6 BR and 10 DT patients were in remission at 4y. Conclusion This randomised trial has shown no evidence to suggest that BR, when managing the young patient with thyrotoxicosis, is associated with improved biochemical stability when compared to DT.