Growth reference charts for children with hypochondroplasia.

Hypochondroplasia (HCH) is a rare skeletal dysplasia causing mild short stature. There is a paucity of growth reference charts for this population. Anthropometric data were collected to generate height, weight, and head circumference (HC) growth reference charts for children with a diagnosis of HCH. Mixed longitudinal anthropometric data and genetic analysis results were collected from 14 European specialized skeletal dysplasia centers. Growth charts were generated using Generalized Additive Models for Location, Scale, and Shape. Measurements for height (983), weight (896), and HC (389) were collected from 188 (79 female) children with a diagnosis of HCH aged 0-18 years. Of the 84 children who underwent genetic testing, a pathogenic variant in FGFR3 was identified in 92% (77). The data were used to generate growth references for height, weight, and HC, plotted as charts with seven centiles from 2nd to 98th, for ages 0-4 and 0-16 years. HCH-specific growth charts are important in the clinical care of these children. They help to identify if other comorbidities are present that affect growth and development and serve as an important benchmark for any prospective interventional research studies and trials.

Characteristics and care of young people with type 2 diabetes included in the national diabetes audit datasets for England.

INTRODUCTION: We report contemporary age-related prevalence, characteristics and care of children and young people with type 2 diabetes in England. METHODS: Individuals with a recorded diagnosis of type 2 diabetes between January 2019 and March 2020 were identified from a whole population register. Age, sex, ethnicity, deprivation quintile, weight, HbA1c and receipt of the nine National Institute for Health & Care Excellence (NICE) recommended annual care processes were extracted from electronic clinical records and analysed by pre-specified age bands. RESULTS: In total, 122,780 (4.6%) of 2,642,435 individuals in England with type 2 diabetes were aged under 40 years, comprising; 650 (0.5%) under 16 years, 910 (0.7%) aged 16-18 years, 8245 (6.7%) aged 19-25 and 112,975 (92%) aged 26-39 years. Compared to people with type 2 diabetes aged above 40 years, young people were significantly more likely to be from minority ethnic groups: 51% under 16 years, 41% 16-18 years, 38% 19-25 years, 38% 26-39 years, 27% 40-59 years and 15% 60-79 years were of Black or Asian ethnicity. In addition, those aged under 40 years were more likely to be obese, women, to live in the most-deprived socioeconomic areas and less likely to receive the NICE recommended annual care processes or achieve target HbA1c . INTERPRETATION: The substantial number of people under 40 years of age with type 2 diabetes, are more likely to have characteristics associated with inequalities and are less likely to achieve HbA1c targets and receive recommended care processes. These findings highlight the need to consider novel approaches to service provision for this high-risk group.

International comparison of glycaemic control in people with type 1 diabetes: an update and extension.

AIMS: To update and extend a previous cross-sectional international comparison of glycaemic control in people with type 1 diabetes. METHODS: Data were obtained for 520,392 children and adults with type 1 diabetes from 17 population and five clinic-based data sources in countries or regions between 2016 and 2020. Median HbA1c (IQR) and proportions of individuals with HbA1c < 58 mmol/mol (<7.5%), 58-74 mmol/mol (7.5-8.9%) and ≥75 mmol/mol (≥9.0%) were compared between populations for individuals aged <15, 15-24 and ≥25 years. Logistic regression was used to estimate the odds ratio (OR) of HbA1c < 58 mmol/mol (<7.5%) relative to ≥58 mmol/mol (≥7.5%), stratified and adjusted for sex, age and data source. Where possible, changes in the proportion of individuals in each HbA1c category compared to previous estimates were calculated. RESULTS: Median HbA1c varied from 55 to 79 mmol/mol (7.2 to 9.4%) across data sources and age groups so a pooled estimate was deemed inappropriate. OR (95% CI) for HbA1c < 58 mmol/mol (<7.5%) were 0.91 (0.90-0.92) for women compared to men, 1.68 (1.65-1.71) for people aged <15 years and 0.81 (0.79-0.82) aged15-24 years compared to those aged ≥25 years. Differences between populations persisted after adjusting for sex, age and data source. In general, compared to our previous analysis, the proportion of people with an HbA1c  < 58 mmol/l (<7.5%) increased and proportions of people with HbA1c ≥ 75 mmol/mol (≥9.0%) decreased. CONCLUSIONS: Glycaemic control of type 1 diabetes continues to vary substantially between age groups and data sources. While some improvement over time has been observed, glycaemic control remains sub-optimal for most people with Type 1 diabetes.

A collaborative comparison of international pediatric diabetes registries.

BACKGROUND: An estimated 1.1 million children and adolescents aged under 20 years have type 1 diabetes worldwide. Principal investigators from seven well-established longitudinal pediatric diabetes registries and the SWEET initiative have come together to provide an international collaborative perspective and comparison of the registries. WORK FLOW: Information and data including registry characteristics, pediatric participant clinical characteristics, data availability and data completeness from the Australasian Diabetes Data Network (ADDN), Danish Registry of Childhood and Adolescent Diabetes (DanDiabKids), Diabetes prospective follow-up registry (DPV), Norwegian Childhood Diabetes Registry (NCDR), National Paediatric Diabetes Audit (NPDA), Swedish Childhood Diabetes Registry (Swediabkids), T1D Exchange Quality Improvement Collaborative (T1DX-QI), and the SWEET initiative was extracted up until 31 December 2020. REGISTRY OBJECTIVES AND OUTCOMES: The seven diabetes registries and the SWEET initiative collectively show data of more than 900 centers and around 100,000 pediatric patients, the majority with type 1 diabetes. All share the common objectives of monitoring treatment and longitudinal outcomes, promoting quality improvement and equality in diabetes care and enabling clinical research. All generate regular benchmark reports. Main differences were observed in the definition of the pediatric population, the inclusion of adults, documentation of CGM metrics and collection of raw data files as well as linkage to other data sources. The open benchmarking and access to regularly updated data may prove to be the most important contribution from registries. This study describes aspects of the registries to enable future collaborations and to encourage the development of new registries where they do not exist.

Differences in retinopathy prevalence and associated risk factors across 11 countries in three continents: A cross-sectional study of 156,090 children and adolescents with type 1 diabetes.

OBJECTIVE: To examine the prevalence, time trends, and risk factors of diabetic retinopathy (DR) among youth with type 1 diabetes (T1D) from 11 countries (Australia, Austria, Denmark, England, Germany, Italy, Luxemburg, Netherlands, Slovenia, United States, and Wales). SUBJECTS AND METHODS: Data on individuals aged 10-21 years with T1D for >1 year during the period 2000-2020 were analyzed. We used a cross-sectional design using the most recent year of visit to investigate the time trend. For datasets with longitudinal data, we aggregated the variables per participant and observational year, using data of the most recent year to take the longest observation period into account. DR screening was performed through quality assured national screening programs. Multiple logistic regression models adjusted for the year of the eye examination, age, gender, minority status, and duration of T1D were used to evaluate clinical characteristics and the risk of DR. RESULTS: Data from 156,090 individuals (47.1% female, median age 15.7 years, median duration of diabetes 5.2 years) were included. Overall, the unadjusted prevalence of any DR was 5.8%, varying from 0.0% (0/276) to 16.2% between countries. The probability of DR increased with longer disease duration (aORper-1-year-increase  = 1.04, 95% CI: 1.03-1.04, p < 0.0001), and decreased over time (aORper-1-year-increase  = 0.99, 95% CI: 0.98-1.00, p = 0.0093). Evaluating possible modifiable risk factors in the exploratory analysis, the probability of DR increased with higher HbA1c (aORper-1-mmol/mol-increase-in-HbA1c  = 1.03, 95% CI: 1.03-1.03, p < 0.0001) and was higher among individuals with hypertension (aOR = 1.24, 95% CI: 1.11-1.38, p < 0.0001) and smokers (aOR = 1.30, 95% CI: 1.17-1.44, p < 0.0001). CONCLUSIONS: The prevalence of DR in this large cohort of youth with T1D varied among countries, increased with diabetes duration, decreased over time, and was associated with higher HbA1c, hypertension, and smoking.

Molecular characterization of DICER1-mutated pituitary blastoma.

Pituitary blastoma (PitB) has recently been identified as a rare and potentially lethal pediatric intracranial tumor. All cases that have been studied molecularly possess at least one DICER1 pathogenic variant. Here, we characterized nine pituitary samples, including three fresh frozen PitBs, three normal fetal pituitary glands and three normal postnatal pituitary glands using small-RNA-Seq, RNA-Seq, methylation profiling, whole genome sequencing and Nanostring® miRNA analyses; an extended series of 21 pituitary samples was used for validation purposes. These analyses demonstrated that DICER1 RNase IIIb hotspot mutations in PitBs induced improper processing of miRNA precursors, resulting in aberrant 5p-derived miRNA products and a skewed distribution of miRNAs favoring mature 3p over 5p miRNAs. This led to dysregulation of hundreds of 5p and 3p miRNAs and concomitant dysregulation of numerous mRNA targets. Gene expression analysis revealed PRAME as the most significantly upregulated gene (500-fold increase). PRAME is a member of the Retinoic Acid Receptor (RAR) signaling pathway and in PitBs, the RAR, WNT and NOTCH pathways are dysregulated. Cancer Hallmarks analysis showed that PI3K pathway is activated in the tumors. Whole genome sequencing demonstrated a quiet genome with very few somatic alterations. The comparison of methylation profiles to publicly available data from ~ 3000 other central nervous system tumors revealed that PitBs have a distinct methylation profile compared to all other tumors, including pituitary adenomas. In conclusion, this comprehensive characterization of DICER1-related PitB revealed key molecular underpinnings of PitB and identified pathways that could potentially be exploited in the treatment of this tumor.

Temporal trends in diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes between 2006 and 2016: results from 13 countries in three continents.

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.

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.

Pupillometry measures of autonomic nervous system regulation with advancing age in a healthy pediatric cohort.

PURPOSE: To determine if variables of the pupillary light response mature with age and sex in a healthy pediatric cohort and the utility of pupillometry in assessment among pediatric participants. METHODS: After 1 min in a dark room to establish baseline, pupillometry was performed on 323 healthy, pediatric participants (646 eyes; 2-21 years; 175 females). Variables included initial pupil diameter, pupil diameter after light stimulus, percent pupillary constriction, latency to onset of constriction, average constriction velocity, maximum constriction velocity, average dilation velocity, and time from light stimulus to 75% of the initial pupil diameter. Data analyses employed ANOVAs and non-linear regressions. RESULTS: Analyses of age group differences revealed that participants 12-21 years old had a larger initial pupil diameter and pupil diameter after light stimulus, with males aged 12-18 years demonstrating a larger pupil diameter than all younger participants (ps < 0.05). Participants 12-18 years old had a slower maximum constriction velocity than participants 6-11 years old, with no sex differences (ps < 0.05). Furthermore, males aged 12-18 years old had a smaller percent constriction than males 6-11 years old (ps < 0.05). Regressions revealed that percent constriction and dilation velocity seemed to mature linearly, initial pupil diameter and ending pupil diameter matured quadratically, and the constriction velocity terms matured cubically. CONCLUSIONS: Results revealed maturation of the pupillary light response by age and sex in healthy pediatric participants. Given the value of the pupillary light response as a biomarker, the results provide normative benchmarks for comparison in health and disease, including opiate-exposed and concussion patients.

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.

Use of insulin pump therapy in children and adolescents with type 1 diabetes and its impact on metabolic control: comparison of results from three large, transatlantic paediatric registries.

AIMS/HYPOTHESIS: While the use of insulin pumps in paediatrics has expanded dramatically, there is still considerable variability among countries in the use of pump technology. The present study sought to describe differences in metabolic control and pump use in young people with type 1 diabetes using data collected in three multicentre registries. METHODS: Data for the years 2011 and 2012 from 54,410 children and adolescents were collected from the Prospective Diabetes Follow-up Registry (DPV; n = 26,198), T1D Exchange (T1DX; n = 13,755) and the National Paediatric Diabetes Audit (NPDA; n = 14,457). The modality of insulin delivery, based on age, sex and ethnic minority status, and the impact of pump use on HbA1c levels were compared. RESULTS: The overall mean HbA1c level was higher in the NPDA (8.9 ± 1.6% [74 ± 17.5 mmol/mol]) than in the DPV (8.0 ± 1.6% [64 ± 17.0 mmol/mol], p < 0.001) and T1DX (8.3 ± 1.4% [68 ± 15.4 mmol/mol], p < 0.001). Conversely, pump use was much lower in the NPDA (14%) than in the DPV (41%, p < 0.001) and T1DX (47%, p < 0.001). In a pooled analysis, pump use was associated with a lower mean HbA1c (pump: 8.0 ± 1.2% [64 ± 13.3 mmol/mol] vs injection: 8.5 ± 1.7% [69 ± 18.7 mmol/mol], p < 0.001). In all three registries, those with an ethnic minority status were less likely to be treated with a pump (p < 0.001) and boys were treated with a pump less often compared with girls (p < 0.001). CONCLUSIONS/INTERPRETATION: Despite similar clinical characteristics and proportion of minority participants, substantial differences in metabolic control exist across the three large transatlantic registries of paediatric patients with type 1 diabetes, which appears to be due in part to the frequency of insulin pump therapy.

Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations.

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.

National Trends in Hyperglycemia and Diabetic Ketoacidosis in Children, Adolescents, and Young Adults With Type 1 Diabetes: A Challenge Due to Age or Stage of Development, or Is New Thinking About Service Provision Needed?

OBJECTIVE: Adolescence is associated with high-risk hyperglycemia. This study examines the phenomenon in a life course context. RESEARCH DESIGN AND METHODS: A total of 93,125 people with type 1 diabetes aged 5 to 30 years were identified from the National Diabetes Audit and/or the National Paediatric Diabetes Audit for England and Wales for 2017/2018-2019/2020. For each audit year, the latest HbA1c and hospital admissions for diabetic ketoacidosis (DKA) were identified. Data were analyzed in sequential cohorts by year of age. RESULTS: In childhood, unreported HbA1c measurement is uncommon; however, for 19-year-olds, it increases to 22.3% for men and 17.3% for women, and then reduces to 17.9% and 13.1%, respectively, for 30-year-olds. Median HbA1c for 9-year-olds is 7.6% (60 mmol/mol) (interquartile range 7.1-8.4%, 54-68 mmol/mol) in boys and 7.7% (61 mmol/mol) (8.0-8.4%, 64-68 mmol/mol) in girls, increasing to 8.7% (72 mmol/mol) (7.5-10.3%, 59-89 mmol/mol) and 8.9% (74 mmol/mol) (7.7-10.6%, 61-92 mmol/mol), respectively, for 19-year-olds before falling to 8.4% (68 mmol/mol) (7.4-9.7%, 57-83 mmol/mol) and 8.2% (66 mmol/mol) (7.3-9.7%, 56-82 mmol/mol), respectively, for 30-year-olds. Annual hospitalization for DKA rose steadily in age from 6 years (2.0% for boys, 1.4% for girls) and peaked at 19 years for men (7.9%) and 18 years for women (12.7%), reducing to 4.3% for men and 5.4% for women at age 30 years. For all ages over 9 years, the prevalence of DKA was higher in female individuals. CONCLUSIONS: HbA1c and the prevalence of DKA increase through adolescence and then decline. Measurement of HbA1c, a marker of clinical review, falls abruptly in the late teenage years. Age-appropriate services are needed to overcome these issues.

Central precocious puberty in Sudan: 10 years' experience of paediatric endocrinology centres.

Central precocious puberty (CPP) is frequently seen among cases presenting to our endocrine clinics. The purpose of this study was to have base line data on this condition with an attempt to point out any possible unique features of Sudan and to explore challenges faced in management and how that cultural and traditional practices may hamper care. Here, we are reporting the first data on this aspect from Sudanese subjects. Patients labelled as having CPP in Gafaar Ibnauf Children's Hospital and Soba University Hospital Endocrinology Clinics from January 2006 to 2016 are included in a descriptive hospital-based study which was conducted over 10 years in these two main paediatric endocrinology centres. Records of all patients with CPP were reviewed and challenges in diagnosis and management were identified. Most of the children with CPP presented late. Organic causes were more frequent among girls than what has been reported in the literature; in most boys, it was idiopathic. Almost half of the patients with underlying pathology were older than 6 years of age. Most cases including girls have an organic cause, thus magnetic resonance image should be done in all patients. Management of precocious puberty in a resource-limited country is faced with various challenges (e.g., expensive investigations and medications). We suggest establishing a unified protocol for managing these cases and creating collaboration between governmental, nongovernmental organisations and health services.

Fractures in a tertiary Neonatal Intensive Care Unit in Wales.

AIM: To explore associations with fractures reported in a tertiary neonatal intensive care unit (NICU). METHOD: Babies admitted to NICU from 1998 to 2007 in Cardiff, UK, with fractures during admission were identified. Clinical information was extracted from inpatient records. Results were reported as median (ranges). RESULTS: Seventy-one fractures were recorded in 27 (boys = 16) infants with a gestational age of 28 (23.6-40.4) weeks and birthweight of 920 g (485-4875). Fractures were recognized at 57 (1-128) days of age. Neonates with fractures without clear aetiologies (n = 17) were more preterm (p < 0.001), were born lighter (p < 0.001), required multiple medical interventions, were more commonly osteopenic (p < 0.001), had fractures detected later (p < 0.001) and had more posterior rib fractures (p = 0.009). Rib fractures were detected later than other sites (p = 0.002). Associations with rib fractures included osteopenia (p = 0.04), longer oxygen therapy (p = 0.018), length on total parental nutrition (p = 0.03), later achievement of full enteral feeds (p = 0.038), sepsis (p = 0.038) and surgical procedures (p = 0.004). Posterior rib fractures were more common in babies born more preterm (25.1 vs. 29.4 weeks, p = 0.003) and requiring diuretics (p = 0.027). CONCLUSION: Fractures in premature infants are associated with a variety of predisposing factors. Clinicians evaluating the cause of rib and multiple fractures in preterm neonates shortly after discharge need to take these factors into consideration.

Educational Attainment and Childhood-Onset Type 1 Diabetes.

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.

Temporal Changes in Hemoglobin A1c and Diabetes Technology Use in DPV, NPDA, and T1DX Pediatric Cohorts from 2010 to 2018.

Objective: The German/Austrian Diabetes Patient Follow-up Registry (Diabetes-Patienten-Verlaufsdokumentation or DPV), England/Wales National Pediatric Diabetes Audit (NPDA), and Type 1 Diabetes Exchange (T1DX) in the United States investigated changes in hemoglobin A1c (HbA1c) and diabetes technology use from 2010 to 2018. Methods: Registry/audit data from 2010 to 2018 were analyzed in annual cohorts using linear regression for those <18 years of age with type 1 diabetes diagnosed at age >6 months. Time trends in HbA1c, pump, and continuous glucose monitoring (CGM) use were studied using repeated measurements linear and logistic regression models with an autoregressive covariance structure and with year and data source as independent variables. Results: A total of 1,172,980 visits among 114,264 (54,119 DPV, 43,550 NPDA, 16,595 T1DX) patients were identified. HbA1c remained clinically stable in DPV (7.7% [61 mmol/mol] to 7.6% [60 mmol/mol]), decreased in the NPDA (8.7% [72 mmol/mol] to 7.9% [63 mmol/mol]), and increased in T1DX (8.0% [64 mmol/mol] to 8.5% [69 mmol/mol] from 2010 to 2018). In all registries/audits, insulin pump and CGM use increased over time with greatest pump use in T1DX and lowest uptake reported in NPDA. Conclusions: These data reveal three different longitudinal patterns of change in registry/audit HbA1c from 2010 to 2018. Diabetes technology use increased throughout, at different rates. Quality improvement (QI) programs in DPV have been ongoing for 25 years, began in NPDA in 2009 and T1DX in 2016. We speculate that in England/Wales, development of networks, peer review, and implementation of QI measures contributed to reductions in population HbA1c. Many of these interventions had been implemented in DPV before 2010. Further efforts to understand this improvement, including the role of QI, and continued success within standardized documentation and benchmarking could inform T1DX programs to reduce HbA1c.

Impact of the COVID-19 pandemic on long-term trends in the prevalence of diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes: an international multicentre study based on data from 13 national diabetes registries.

BACKGROUND: An increased prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in children was observed in various diabetes centres worldwide during the COVID-19 pandemic. We aimed to evaluate trends in the prevalence of diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes before and during the COVID-19 pandemic, and to identify potential predictors of changes in diabetic ketoacidosis prevalence during the pandemic. METHODS: For this international multicentre study, we used data from 13 national diabetes registries (Australia, Austria, Czechia, Denmark, Germany, Italy, Luxembourg, New Zealand, Norway, Slovenia, Sweden, USA [Colorado], and Wales). The study population comprised 104 290 children and adolescents aged 6 months to younger than 18 years, who were diagnosed with type 1 diabetes between Jan 1, 2006, and Dec 31, 2021. The observed diabetic ketoacidosis prevalence in 2020 and 2021 was compared to predictions based on trends over the pre-pandemic years 2006-19. Associations between changes in diabetic ketoacidosis prevalence and the severity of the COVID-19 pandemic and containment measures were examined with excess all-cause mortality in the whole population and the Stringency Index from the Oxford COVID-19 Government Response Tracker. FINDINGS: 87 228 children and adolescents were diagnosed with type 1 diabetes between 2006 and 2019, 8209 were diagnosed in 2020, and 8853 were diagnosed in 2021. From 2006 to 2019, diabetic ketoacidosis at diagnosis of type 1 diabetes was present in 23 775 (27·3%) of 87 228 individuals and the mean annual increase in the prevalence of diabetic ketoacidosis in the total cohort from 2006 to 2019 was 1·6% (95% CI 1·3 to 1·9). The adjusted observed prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes was 39·4% (95% CI 34·0 to 45·6) in 2020 and 38·9% (33·6 to 45·0) in 2021, significantly higher than the predicted prevalence of 32·5% (27·8 to 37·9) for 2020 and 33·0% (28·3 to 38·5) for 2021 (p<0·0001 for both years). The prevalence of diabetic ketoacidosis was associated with the pandemic containment measures, with an estimated risk ratio of 1·037 (95% CI 1·024 to 1·051; p<0·0001) per ten-unit increase in the Stringency Index for 2020 and 1·028 (1·009 to 1·047; p=0·0033) for 2021, but was not significantly associated with excess all-cause mortality. INTERPRETATION: During the COVID-19 pandemic, there was a marked exacerbation of the pre-existing increase in diabetic ketoacidosis prevalence at diagnosis of type 1 diabetes in children. This finding highlights the need for early and timely diagnosis of type 1 diabetes in children and adolescents. FUNDING: German Federal Ministry for Education and Research, German Robert Koch Institute, German Diabetes Association, German Diabetes Foundation, Slovenian Research Agency, Welsh Government, Central Denmark Region, and Swedish Association of Local Authorities and Regions.

Neonatal plasma TSH--estimated upper reference intervals for diagnosis and follow up of congenital hypothyroidism.

Age- and method-dependent plasma TSH reference intervals are essential for the diagnosis and management of congenital hypothyroidism. However, accurate reference intervals for plasma TSH have not been adequately defined due to the difficulties in obtaining samples from a healthy paediatric population. To overcome the difficulties in generating such intervals we estimated method-dependent plasma TSH upper-reference intervals by determining the blood spot TSH upper-reference interval from newborn blood spot TSH screening data (N = 10,697) and then derived method-dependent conversion factors for blood spot TSH to plasma TSH concentration from paired-blood spot and plasma TSH measurements. The upper reference interval for blood spot TSH of 3.04 mU/L was obtained from the 97.5th centile of the selected data. Using experimentally-derived conversion factors, estimates of plasma TSH upper reference intervals of 7.6, 6.3, 7.3, 8.3 and 6.5 mU/L were obtained for the Siemens Centaur, Abbott Architect, Roche Elecsys E170, Siemens Immulite 2000 and Beckman access HYPERsensitive TSH assays respectively. These estimated method-dependent plasma TSH upper reference intervals will be of great practical use to clinicians to diagnose and to follow up infants found to have increased blood spot TSH concentrations identified by Newborn Screening programmes.

Delivering early care in diabetes evaluation (DECIDE): a protocol for a randomised controlled trial to assess hospital versus home management at diagnosis in childhood diabetes.

BACKGROUND: There is increased incidence of new cases of type 1 diabetes in children younger than 15 years. The debate concerning where best to manage newly diagnosed children continues. Some units routinely admit children to hospital whilst others routinely manage children at home. A Cochrane review identified the need for a large well-designed randomised controlled trial to investigate any significant differences in comprehensive short and long-term outcomes between the two approaches. The DECIDE study will address these knowledge gaps, providing high quality evidence to inform national and international policy and practice. METHODS/DESIGN: This is a multi-centre randomised controlled trial across eight UK paediatric diabetes centres. The study aims to recruit 240 children newly diagnosed with type 1 diabetes and their parents/carers. Eligible patients (aged 0-17 years) will be remotely randomised to either 'hospital' or 'home' management. Parents/carers of patients will also be recruited. Nursing management of participants and data collection will be co-ordinated by a project nurse at each centre. Data will be collected for 24 months after diagnosis; at follow up appointments at 3, 12 and 24 months and every 3-4 months at routine clinic visits.The primary outcome measure is patients' glycosylated haemoglobin (HbA1c) at 24 months after diagnosis. Additional measurements of HbA1c will be made at diagnosis and 3 and 12 months later. HbA1c concentrations will be analysed at a central laboratory.Secondary outcome measures include length of stay at diagnosis, growth, adverse events, quality of life, anxiety, coping with diabetes, diabetes knowledge, home/clinic visits, self-care activity, satisfaction and time off school/work. Questionnaires will be sent to participants at 1, 12 and 24 months and will include a questionnaire, developed and validated to measure impact of the diagnosis on social activity and independence. Additional qualitative outcome measures include the experience of both approaches by a subgroup of participants (n = 30) and health professionals. Total health service costs will be evaluated. A cost effectiveness analysis will assess direct and indirect health service costs against the primary outcome (HbA1c). DISCUSSION: This will be the first randomised controlled trial to evaluate hospital and home management of children newly diagnosed with type 1 diabetes and the findings should provide important evidence to inform practice and national guidelines. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN78114042.