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Background: The incidence of type 1 diabetes has increased worldwide, particularly in younger children and those with lower genetic susceptibility. These observations suggest factors in the modern environment promote pancreatic islet autoimmunity and destruction of insulin-producing beta cells. The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is investigating candidate environmental exposures and gene-environment interactions that may contribute to the development of islet autoimmunity and type 1 diabetes. Methods/design: ENDIA is the only prospective pregnancy/birth cohort study in the Southern Hemisphere investigating the determinants of type 1 diabetes in at-risk children. The study will recruit 1,400 unborn infants or infants less than six months of age with a first-degree relative (i.e. mother, father or sibling) with type 1 diabetes, across five Australian states. Pregnant mothers/infants will be followed prospectively from early pregnancy through childhood to investigate relationships between genotype, the development of islet autoimmunity (and subsequently type 1 diabetes), and prenatal and postnatal environmental factors. ENDIA will evaluate the microbiome, nutrition, bodyweight/composition, metabolome-lipidome, insulin resistance, innate and adaptive immune function and viral infections. A systems biology approach will be used to integrate these data. Investigation will be by 3-monthly assessments of the mother during pregnancy, then 3-monthly assessments of the child until 24 months of age and 6-monthly thereafter. The primary outcome measure is persistent islet autoimmunity, defined as the presence of autoantibodies to one or more islet autoantigens on consecutive tests. Discussion: Defining gene-environment interactions that initiate and/or promote destruction of the insulin-producing beta cells in early life will inform approaches to primary prevention of type 1 diabetes. The strength of ENDIA is the prospective, comprehensive and frequent systems-wide profiling from early pregnancy through to early childhood, to capture dynamic environmental exposures that may shape the development of islet autoimmunity. [ABSTRACT FROM AUTHOR]

Aim To describe the presence and type of disturbed eating behaviours and thoughts in a combined male/female Australian sample of adolescents with type 1 diabetes, and examine the association of eating behaviours and thoughts with glycaemic control as evidenced by high glycosylated haemoglobin levels ( HbA1c). Methods In this cross-sectional descriptive study, 124 adolescents aged 13-18 years were invited to complete three self-administered questionnaires. The Youth Eating Disorder Examination Questionnaire ( YEDE-Q) and the Eating Disorder Inventory −3 Risk Composite ( EDI-3 RC) assessed risk for an eating disorder. The third questionnaire, the Strengths and Difficulties Questionnaire ( SDQ) assessed emotional and behavioural concerns. Clinical data were collected from the medical records, routine clinic appointments and the adolescent. Results Any disturbed eating behaviour was reported by approximately one-third of participants (32.3%) and was common in females and males (37.9% vs. 25.9%). Binge eating (17.7%), driven exercise (13.0%) and dietary restraint (8.9%) were the most common disturbed eating behaviours, although restraint was not evident in males. Insulin manipulation/omission (5.6%), vomiting (3.3%), laxative (0.8%) or diuretic use (0.8%) were less common. Regression analysis showed a significant association between HbA1c and more disturbed eating behaviours and thoughts which remained significant when adjusted for confounders. Conclusions High rates of disturbed eating behaviours and thoughts were seen in this Australian sample of adolescents with type 1 diabetes. High scores on both eating disorder measures were associated with poorer glycaemic control. These results highlight the need to screen for disordered eating in adolescents with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background NR5 A1 loss-of-function mutations are increasingly found to be the cause of 46, XY disorders of sex development ( DSD). Objective To determine the presence of NR5A1 mutations in an Australasian cohort of 17 46, XY DSD patients with presumed androgen insensitivity syndrome ( AIS) who were negative for androgen receptor gene ( AR) mutation. Design Exons 2-7 of NR5A1 were PCR amplified and sequenced. Gene expression and cellular localization studies were performed on a novel NR5A1 variant c.74 A> G (p. Y25 C) identified in this study. Results We identified one novel mutation, c.74 A> G (p. Y25 C) in a patient characterized by penoscrotal hypospadias with bifid scrotum. He had elevated testosterone and gonadotropins in early infancy. Functional analysis of p. Y25 C in vitro demonstrated reduced transcriptional activation by SF-1 and partially impaired nuclear localization in a proportion of transfected human adrenal NCI- H295 R cells. Conclusion This is the first reported case of a DSD patient with a NR5 A1 mutation and elevated testosterone levels. Our finding supports evaluation of NR5 A1 mutations in 46, XY DSD patients with a range of testosterone levels. [ABSTRACT FROM AUTHOR]

Aim: Eating disorder screening tools have not been adequately validated for use with adolescents with type 1 diabetes. This study compared the Youth Eating Disorder Examination-Questionnaire (YEDE-Q) and the Eating Disorder Inventory-3 Risk Composite (EDI-3RC) against the child Eating Disorder Examination (chEDE). These screening tools were chosen because they broadly assess eating disorder psychopathology and have subscales helpful for clinical management. Methods: In this cross-sectional study, 124 adolescents with type 1 diabetes aged 13-18 years completed two self-administered questionnaires, the YEDE-Q and the EDI-3RC. Cronbach's alpha was used to assess internal consistency of the tools. Fifty-one adolescents, randomly selected, participated in the chEDE. Intraclass correlations and Spearman's correlations were used to measure concordance of the chEDE with the YEDE-Q and EDI-3RC. Results: The YEDE-Q and EDI-3RC demonstrated good subscale internal consistency; Cronbach's alpha for YEDE-Q (0.78-0.95) and EDI-3RC (0.79-0.94). High levels of concurrent validity with the chEDE were seen with both tools. Conclusion: Preliminary evidence is provided for the validation of the YEDE-Q and EDI-3RC for use in adolescents with type 1 diabetes. The YEDE-Q also defines individual disturbed eating behaviours with frequency ratings which can be helpful for tailoring early intervention. [ABSTRACT FROM AUTHOR]

Background: There is considerable evidence supporting the role of vitamin D deficiency in the pathogenesis of type 1 diabetes mellitus (T1DM). Vitamin D deficiency is also associated with impairment of insulin synthesis and secretion. There have been no formal studies looking at the relationship between 25(OH)-vitamin D3 and the severity of diabetic ketoacidosis (DKA) in children at presentation with T1DM. Objective: To determine the relationship between measured 25(OH)-vitamin D3 levels and the degree of acidosis in children at diagnosis with T1DM. Subjects: Children presenting with new-onset T1DM at a tertiary children’s hospital. Methods: 25(OH)-vitamin D3 and bicarbonate levels were measured in children at presentation with newly diagnosed T1DM. Those with suboptimal 25(OH)-vitamin D3 levels (<50 nmol/L) had repeat measurements performed without interim vitamin D supplementation. Results: Fourteen of the 64 children had low 25(OH)-vitamin D3 levels at presentation, and 12 of these had low bicarbonate levels (<18 mmol/L) (p = 0.001). Bicarbonate explained 20% of the variation in vitamin D level at presentation (partial r2 = 0.20, p < 0.001) and ethnic background a further 10% (partial r2 = 0.10, p = 0.002). The levels of 25(OH)-vitamin D3 increased in 10 of the 11 children with resolution of the acidosis. Conclusions: Acid–base status should be considered when interpreting 25(OH)-vitamin D3 levels in patients with recently diagnosed T1DM. Acidosis may alter vitamin D metabolism, or alternatively, low vitamin D may contribute to a child’s risk of presenting with DKA. [ABSTRACT FROM AUTHOR]

21-Hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia, with an incidence of 1:14000 live births and equal prevalence among males and females. Newborns with the most severe "salt-wasting" form of 21-OHD are susceptible to salt-wasting crises in the first few weeks of life. This is associated with morbidity and mortality. 21-OHD newborn screening (NBS) is currently performed in many countries. Despite several prominent medical societies recommending 21-OHD NBS, no state in Australia currently screens for this condition. We report a case that illustrates the need to reconsider including 21-OHD in NBS. 21-OHD NBS can be reliable, sensitive and effective in reducing morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background The importance of gut bacteria in human physiology, immune regulation, and disease pathogenesis is well established. In contrast, the composition and dynamics of the gut virome are largely unknown; particularly lacking are studies in pregnancy. We used comprehensive virome capture sequencing to characterize the gut virome of pregnant women with and without type 1 diabetes (T1D), longitudinally followed in the Environmental Determinants of Islet Autoimmunity study. Methods In total, 61 pregnant women (35 with T1D and 26 without) from Australia were examined. Nucleic acid was extracted from serial fecal specimens obtained at prenatal visits, and viral genomes were sequenced by virome capture enrichment. The frequency, richness, and abundance of viruses were compared between women with and without T1D. Results Two viruses were more prevalent in pregnant women with T1D: picobirnaviruses (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.0–17.1; P =.046) and tobamoviruses (OR, 3.2; 95% CI, 1.1–9.3; P =.037). The abundance of 77 viruses significantly differed between the 2 maternal groups (≥2-fold difference; P <.02), including 8 Enterovirus B types present at a higher abundance in women with T1D. Conclusions These findings provide novel insight into the composition of the gut virome during pregnancy and demonstrate a distinct profile of viruses in women with T1D. [ABSTRACT FROM AUTHOR]

Aim: To compare HbA1c and clinical outcomes in adolescents and young adults with type 1 diabetes (T1D), with or without celiac disease (CD). Methods: Longitudinal data were extracted from ADDN, a prospective clinical diabetes registry. Inclusion criteria were T1D (with or without CD), ≥ 1 HbA1c measurement, age 16–25 years and diabetes duration ≥ 1 year at last measurement. Multivariable Generalised Estimated Equation models were used for longitudinal analysis of variables associated with HbA1c. Results: Across all measurements, those with coexisting T1D and CD had lower HbA1c when compared to those with T1D alone (8.5 ± 1.5% (69.4 ± 16.8 mmol/mol) vs. 8.7 ± 1.8% (71.4 ± 19.8 mmol/mol); p < 0.001); lower HbA1c was associated with shorter diabetes duration (B = − 0.06; 95% CI − 0.07 to − 0.05; p < 0.001), male sex (B = − 0.24; − 0.36 to − 0.11; p < 0.001), insulin pump therapy use (B = − 0.46; − 0.58 to − 0.34; p < 0.001), coexistence of T1D and CD (B = − 0.28; − 0.48 to − 0.07; p = 0.01), blood pressure (B = − 0.16; − 0.23 to − 0.09; p < 0.001) and body mass index (B = -− 0.03; − 0.02 to − 0.04; p = 0.01) in the normal range. At last measurement, 11.7% of the total population had a HbA1c < 7.0% (53.0 mmol/mol). Conclusions: Across all measurements, coexisting T1D and CD is associated with lower HbA1c when compared to T1D alone. However, HbA1c is above target in both groups. [ABSTRACT FROM AUTHOR]

Aim: To determine low‐density lipoprotein cholesterol (LDL‐C) screening frequency and levels, and factors associated with elevated LDL‐C, in Australasian youth with type 1 diabetes (T1D). Methods: Data were extracted from the Australasian Diabetes Data Network (ADDN), a prospective clinical quality registry, on all T1D healthcare visits attended by young people aged 16–25 years (with T1D duration of >1 year) between January 2011 and December 2020. The primary outcomes were elevated LDL‐C > 2.6 mmol/L (100 mg/dL) and threshold for treatment: >3.4 mmol/L (130 mg/dL), according to consensus guidelines. Multivariable Generalised Estimated Equations (GEE) were used to examine factors associated with elevated LDL‐C across all visits. Results: A cohort of 6338 young people (52.6% men) were identified, of whom 1603 (25.3%) had ≥1 LDL‐C measurement documented. At last measurement, mean age, age at T1D diagnosis and T1D duration were 18.3 ± 2.4, 8.8 ± 4.5 and 8.9 ± 4.8 years, respectively. LDL‐C was elevated in 737 (46.0%) and at the treatment threshold in 250 (15.6%). In multivariable GEE elevated LDL‐C continuously was associated with older age (OR = 0.07; 0.01–0.13, p = 0.02), female sex (OR = 0.31; 0.18–0.43; p < 0.001), higher HbA1c (OR = 0.04; 0.01–0.08; p = 0.01) and having an elevated BMI (OR = 0.17, 0.06–0.39, p < 0.001). Conclusions: LDL‐C screening and levels are suboptimal in this cohort, increasing future cardiovascular complication risk. There is an urgent need to understand how healthcare services can support improved screening and management of dyslipidaemia in this population. [ABSTRACT FROM AUTHOR]

Aim: Hypertension increases complication risk in type 1 diabetes (T1D). We examined blood pressure (BP) in adolescents and young adults with T1D from the Australasian Diabetes Data Network, a prospective clinical diabetes registry in Australia and New Zealand. Methods: This was a longitudinal study of prospectively collected registry data. Inclusion criteria: T1D (duration ≥ 1 year) and age 16–25 years at last visit (2011–2020). Hypertension was defined as (on ≥ 3 occasions) systolic BP and/or diastolic BP > 95th percentile for age < 18 years, and systolic BP > 130 and/or diastolic BP > 80 mmHg for age ≥ 18 years. Multivariable Generalised Estimating Equations were used to examine demographic and clinical factors associated with BP in the hypertensive range across all visits. Results: Data from 6338 young people (male 52.6%) attending 24 participating centres across 36,655 T1D healthcare visits were included; 2812 (44.4%) had BP recorded at last visit. Across all visits, 19.4% of youth aged < 18 years and 21.7% of those aged ≥ 18 years met criteria for hypertension. In both age groups, BP in the hypertensive range was associated with male sex, injection (vs. pump) therapy, higher HbA1c, and higher body mass index. Conclusions: There is a high proportion of adolescents and young adults reported with BP persistently in hypertensive ranges. Findings flag the additive contribution of hypertension to the well-established body of evidence indicating a need to review healthcare models for adolescents and young adults with T1D. [ABSTRACT FROM AUTHOR]

The incidence of type 1 diabetes globally has increased dramatically over the last 50 years. Proposed environmental reasons for this increase mirror the modern lifestyle. Type 1 diabetes can be viewed as part of the non- communicable disease epidemic in our modern society. Meanwhile rapidly evolving new technologies are advancing our understanding of how human microbial communities interface with the immune system and metabolism, and how the modern pro-inflammatory environment is changing these communities and contributing to the rapid rise of non-communicable disease. The majority of children who present with clinical type 1 diabetes are of school age; however 80% of children who develop type 1 diabetes by 18 years of age will have detectable islet autoantibodies by 3 years of age. The evolving concept that type 1 diabetes in many children has developmental origins has directed research questions in search of prevention back to pregnancy and early life. To this end the world's first pregnancy to early childhood cohort study in at-risk children has commenced. [ABSTRACT FROM AUTHOR]

OBJECTIVE This study examined the association between cardiac autonomic dysfunction and high albumin-to-creatinine ratio (ACR) in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS Adolescents recruited as part of a multicenter screening study (n = 445, 49% female, aged 10-17 years, mean duration 6.9 years; mean HbA1c 8.4%, 68 mmol/mol) underwent a 10-min continuous electrocardiogram recording for heart rate variability analysis. Time-domain heart rate variability measures included baseline heart rate, SD of the R-R interval (SDNN), and root mean squared difference of successive R-R intervals (RMSSD). Spectral analysis included sympathetic (low-frequency) and parasympathetic (high-frequency) components. Standardized ACR were calculated from six early morning urine collections using an established algorithm, reflecting age, sex, and duration, and stratified into ACR tertiles, where the upper tertile reflects higher nephropathy risk. RESULTS The upper-tertile ACR group had a faster heart rate (76 vs. 73 bpm; P < 0.01) and less heart rate variability (SDNN 68 vs. 76 ms, P = 0.02; RMSSD 63 vs. 71 ms, P = 0.04). HbA1c was 8.5% (69mmol/mmol) in the upper tertile vs. 8.3% (67mmol/mol) in the lower tertiles (P = 0.07). In multivariable analysis, upper-tertile ACR was associated with faster heart rate (β = 2.5, 95% CI 0.2-4.8, P = 0.03) and lower RMSSD (β = -9.5, 95% CI -218.2 to -20.8, P = 0.03), independent of age and HbA1c. CONCLUSIONS Adolescents at potentially higher risk for nephropathy show an adverse cardiac autonomic pro le, indicating sympathetic overdrive, compared with the lower- risk group. Longitudinal follow-up of this cohort will further characterize the relationship between autonomic and renal dysfunction and the effect of inter- ventions in this population. [ABSTRACT FROM AUTHOR]

Using a Cre/loxP system, we have determined the phenotypic consequences attributable to in vivo deletion of both Rb1 and Trp53 in the mouse adrenal medulla. The coablation of these two tumor suppressor genes during embryogenesis did not disrupt adrenal gland development but resulted in the neoplastic transformation of the neural crest--derived adrenal medulla, yielding pheochromocytomas (PCCs) that developed with complete penetrance and were inevitably bilateral. Despite their typically benign status, these PCCs had profound ramifications on mouse vitality, with effected mice having a median survival of only 121 days. Evaluation of these PCCs by both immunohistochemistry and electron microscopy revealed that most Rb1-/-:Trp53-/- chromaffin cells possessed atypical chromagenic vesicles that did not seem capable of appropriately storing synthesized catecholamines. The structural remodeling of the heart in mice harboring Rb1-/-:Trp53-/- PCCs suggests that the mortality of these mice may be attributable to the inappropriate release of catecholamines from the mutated adrenal chromaffin cells. On the basis of the collective data from Rb1 and Trp53 knockout mouse models, it seems that the conversion of Rb1 loss--driven adrenal medulla hyperplasia to PCC can be greatly enhanced by the compound loss of Trp53, whereas the loss of Trp53 alone is generally ineffectual on adrenal chromaffin cell homeostasis. Consequently, the Trp53 tumor suppressor gene is an efficient genetic modifier of Rb1 loss in the development of PCC, and their compound loss in the adrenal medulla has a profound impact on both cellular homeostasis and animal vitality. [ABSTRACT FROM AUTHOR]

Abstract: The calcium-dependent lectins DC-SIGN and DC-SIGNR (collectively termed DC-SIGN/R) bind to high-mannose carbohydrates on a variety of viruses. In contrast, the related lectin LSECtin does not recognize mannose-rich glycans and interacts with a more restricted spectrum of viruses. Here, we analyzed whether these lectins differ in their mode of ligand engagement. LSECtin and DC-SIGNR, which we found to be co-expressed by liver, lymph node and bone marrow sinusoidal endothelial cells, bound to soluble Ebola virus glycoprotein (EBOV-GP) with comparable affinities. Similarly, LSECtin, DC-SIGN and the Langerhans cell-specific lectin Langerin readily bound to soluble human immunodeficiency virus type-1 (HIV-1) GP. However, only DC-SIGN captured HIV-1 particles, indicating that binding to soluble GP is not necessarily predictive of binding to virion-associated GP. Capture of EBOV-GP by LSECtin triggered ligand internalization, suggesting that LSECtin like DC-SIGN might function as an antigen uptake receptor. However, the intracellular fate of lectin–ligand complexes might differ. Thus, exposure to low-pH medium, which mimics the acidic luminal environment in endosomes/lysosomes, released ligand bound to DC-SIGN/R but had no effect on LSECtin interactions with ligand. Our results reveal important differences between pathogen capture by DC-SIGN/R and LSECtin and hint towards different biological functions of these lectins. [Copyright &y& Elsevier]

Objectives: To examine the relationship between kidney hyperfiltration during adolescence and subsequent changes in estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR) in a young cohort of participants with type 1 diabetes. Additionally, to explore urinary mitochondrial DNA:nuclear DNA ratio (mtDNA:nDNA) as a marker of metabolic stress and its association with early changes in kidney function., Methods: Eighty adolescents were studied at baseline [mean (SD) age 14.2 (1.5) years; mean diabetes duration 6.7 (3.0) years] and followed up 9.2 (1.3) years later. Blood pressure, HbA1c, lipids, eGFR, UACR and heart rate variability were assessed at each visit. Urinary mtDNA:nDNA was measured by quantitative PCR (qPCR)., Results: Overall, 4.2% of participants had diabetic kidney disease (DKD) at follow-up. Hyperfiltration at baseline (>135 mL/min/1.73m2) was seen in 31% of adolescents and was associated with a decline in eGFR at follow-up when adjusted for sex, diabetes duration and HbA1c [hyperfiltration -1.46 (3.07) mL/min/1.73 m2/year vs non-hyperfiltration -0.51 (2.48) mL/min/1.73m2/year, P=0.02]. Participants with hyperfiltration also had higher odds of undergoing rapid eGFR decline (>3 mL/min/1.73m2/year) compared to those without hyperfiltration [OR 14.11, 95% CI (2.30-86.60), P=0.004]. Baseline urinary mtDNA:nDNA was significantly associated with both greater annual rate of eGFR decline and rapid eGFR decline in univariable but not multivariable modelling., Conclusion: Hyperfiltration during adolescence is significantly associated with greater reduction in eGFR and higher risk of rapid eGFR decline after ∼9 years, following transition into young adulthood in type 1 diabetes. Urinary mtDNA:nDNA measured during adolescence may be a novel predictor of early changes in kidney function., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Objectives: We hypothesised that growth hormone (GH) deficiency (GHD) in children with attention deficit hyperactivity disorder (ADHD) is rare. This study aimed to determine any distinct clinical or biochemical parameters, including GH provocation testing, in children with ADHD on psychostimulants or idiopathic short stature (ISS)., Methods: Retrospective cross-sectional study of children who had GH provocative testing between 1998 and 2013 at one tertiary paediatric endocrine centre. Clinical data included age, sex, anthropometry, pubertal staging, bone age, diagnostic code as per the European Society Paediatric Endocrinology (ESPE), GH provocation test results, thyroid function tests, serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) levels., Results: Four hundred ninety-three subjects underwent GH provocation testing for investigation of short stature to exclude GHD during the study period. Fifty-one children had a diagnosis of ADHD. In the remaining children, the diagnosis was Idiopathic short stature (n=240), GHD +/- hypopituitarism (n=60), and 142 subjects had other causes of short stature. Children with ADHD were older, had higher height and weight SDS and were GH-sufficient. All 51 children with ADHD had a normal serum IGFBP-3, while 20 out of these 51 subjects had a low serum IGF-1., Conclusions: GHD in children with ADHD on psychostimulant medication is rare. GH testing in children with ADHD may not be necessary, particularly if serum IGFBP-3 is in the normal range. We suggest IGFBP-3 could be used as a surrogate marker of GH sufficiency in children with ADHD. However, this needs to be confirmed with a larger study group., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Type 1 diabetes (T1D) is well-recognised as a continuum heralded by the development of islet autoantibodies, progression to islet autoimmunity causing beta cell destruction, culminating in insulin deficiency and clinical disease. Abnormalities of glucose homeostasis are known to exist well before the onset of typical symptoms. Laboratory-based tests such as the oral glucose tolerance test (OGTT) and glycated haemoglobin (HbA 1c ) have been used to stage T1D and assess the risk of progression to clinical T1D. Continuous glucose monitoring (CGM) can detect early glycaemic abnormalities and can therefore be used to monitor for metabolic deterioration in pre-symptomatic, islet autoantibody positive, at-risk individuals. Early identification of these children can not only reduce the risk of presentation with diabetic ketoacidosis (DKA), but also determine eligibility for prevention trials, which aim to prevent or delay progression to clinical T1D. Here, we describe the current state with regard to the use of the OGTT, HbA 1c , fructosamine and glycated albumin in pre-symptomatic T1D. Using illustrative cases, we present our clinical experience with the use of CGM, and advocate for an increased role of this diabetes technology, for monitoring metabolic deterioration and disease progression in children with pre-symptomatic T1D., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

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 log 10 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 HbA 1c , 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 HbA 1c (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., (© 2022. The Author(s).)

Background: The importance of gut bacteria in human physiology, immune regulation, and disease pathogenesis is well established. In contrast, the composition and dynamics of the gut virome are largely unknown; particularly lacking are studies in pregnancy. We used comprehensive virome capture sequencing to characterize the gut virome of pregnant women with and without type 1 diabetes (T1D), longitudinally followed in the Environmental Determinants of Islet Autoimmunity study., Methods: In total, 61 pregnant women (35 with T1D and 26 without) from Australia were examined. Nucleic acid was extracted from serial fecal specimens obtained at prenatal visits, and viral genomes were sequenced by virome capture enrichment. The frequency, richness, and abundance of viruses were compared between women with and without T1D., Results: Two viruses were more prevalent in pregnant women with T1D: picobirnaviruses (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.0-17.1; P = .046) and tobamoviruses (OR, 3.2; 95% CI, 1.1-9.3; P = .037). The abundance of 77 viruses significantly differed between the 2 maternal groups (≥2-fold difference; P < .02), including 8 Enterovirus B types present at a higher abundance in women with T1D., Conclusions: These findings provide novel insight into the composition of the gut virome during pregnancy and demonstrate a distinct profile of viruses in women with T1D.

We describe a 4-year-old boy with developmental delay who was found to carry by clinical grade (CG) molecular cytogenetics (MCs) a chromosome Xq26 microduplication. The report prompted a referral of the patient for possible X-linked acrogigantism (X-LAG), a well-defined condition (MIM300942) due to chromosomal microduplication of a nearby region. The patient was evaluated clinically and investigated for endocrine abnormalities related to X-LAG and not only did he not have acrogigantism, but his growth parameters and other hormones were all normal. We then performed high definition MCs and the duplication copy number variant (CNV) was confirmed to precisely map outside the X-LAG critical region and definitely did not harbor the X-LAG candidate gene, GPR101 . The patient's phenotype resembled that of other patients with Xq26 CNVs. The case is instructive for the need for high definition MCs when CG MCs' results are inconsistent with the patient's phenotype. It is also useful for further supporting the contention that GPR101 is the gene responsible for X-LAG.

Aims/hypothesis: We examined the hypothesis that elevation in urinary albumin creatinine ratio (ACR) in adolescents with type 1 diabetes is associated with abnormal retinal vascular geometry (RVG) phenotypes., Methods: A cross-sectional study at baseline of the relationship between ACR within the normoalbuminuric range and RVG in 963 adolescents aged 14.4 ± 1.6 years with type 1 diabetes (median duration 6.5 years) screened for participation in AdDIT. A validated algorithm was used to categorise log 10 ACR into tertiles: upper tertile ACR was defined as 'high-risk' for future albuminuria and the lower two tertiles were deemed 'low-risk'. RVG analysis, using a semi-automated computer program, determined retinal vascular calibres (standard and extended zones) and tortuosity. RVG measures were analysed continuously and categorically (in quintiles: Q1-Q5) for associations with log 10 ACR and ACR risk groups., Results: Greater log 10 ACR was associated with narrower vessel calibres and greater tortuosity. The high-risk group was more likely to have extended zone vessel calibres in the lowest quintile (arteriolar Q1 vs Q2-Q5: OR 1.67 [95% CI 1.17, 2.38] and venular OR 1.39 [0.98, 1.99]) and tortuosity in the highest quintile (Q5 vs Q1-Q4: arteriolar OR 2.05 [1.44, 2.92] and venular OR 2.38 [1.67, 3.40]). The effects of retinal vascular calibres and tortuosity were additive such that the participants with the narrowest and most tortuous vessels were more likely to be in the high-risk group (OR 3.32 [1.84, 5.96]). These effects were independent of duration, blood pressure, BMI and blood glucose control., Conclusions/interpretation: Higher ACR in adolescents is associated with narrower and more tortuous retinal vessels. Therefore, RVG phenotypes may serve to identify populations at high risk of diabetes complications during adolescence and well before onset of clinical diabetes complications.

Objective: To investigate growth hormone (GH) treatment and treatment cessation with respect to efficacy and efficiency. To identify factors that best classify or predict cessation type: completed treatment (CT), early cessation (EC), or non-response (NR)., Design: Observational study (1990-2013) of the Australian GH Program comparing CT, EC, and NR groups with respect to demographic, clinical, and response criteria. All patients treated for GH deficiency (GHD; 909), short stature and slow growth (SSSG; 2144), and Turner Syndrome (TS; 626) were included. Information was retrieved from the OZGROW database., Results: 51.9% of patients were EC, 40.7% CT and 7.4% NR.Median treatment durations for NR patients were often longer than patients who completed treatment. EC and NR groups were both associated with poor growth response with males overrepresented.Socioeconomic status differentiated NR (higher) and EC (lower) groups., Conclusions: EC was observed at very high rates and appears, generally, to be a little-recognised but frequent problem in GH therapy.EC and delayed recognition of NR may be interrelated being differentiated by the decision to cease or continue treatment following poor response.Poor treatment compliance is likely a major causal factor in EC.Strategies to address poor response and compliance have been developed, however, given the scale of these problems, it may be that long acting GH formulations or individualized treatment need consideration., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Dysfunction in effector memory has been proposed to contribute to autoimmunity in type 1 diabetes (T1D). Using a unique cohort of age- and sex-matched T1D patients, nonaffected siblings, and unrelated control children, we undertook a detailed analysis of proliferation, activation, effector responses, and apoptosis in reactivated CD4(+)Tm cells during T-cell receptor stimulation. Across cohorts, there was no difference in the proliferation of reactivated CD4(+)Tm cells. In T1D patients and siblings, CD4(+)Tm cells easily acquired the activated CD25(+) phenotype and effectively transitioned from a central (CD62L(+)Tcm) to an effector memory (CD62L(-)Tem) phenotype with an elevated cytokine "signature" comprising interferon (IFN)-γ and interleukin-10 in T1D patients and IFN-γ in siblings. This amplified Tem phenotype also exhibited an exaggerated immune shutdown with heightened sensitivity to activation-induced cell death and Fas-independent apoptosis. Apoptosis resulted in the elimination of one-half of the effector memory in T1D patients and siblings compared with one-third of the effector memory in control subjects. These data suggest genetic/environment-driven immune alteration in T1D patients and siblings that manifests in an exaggerated CD4(+)Tem response and shutdown by apoptosis. Further immunological studies are required to understand how this exaggerated CD4(+)Tem response fits within the pathomechanisms of T1D and how the effector memory can be modulated for disease treatment and/or prevention., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Treatment of cells with cytokines and growth factors leads to the synthesis of Suppressor of Cytokine Signalling (SOCS) proteins that act as potent negative regulators of signalling via the Jak/STAT pathway. We used immunohistochemistry to identify cells and pathologies where SOCS3 expression might influence acute and chronic inflammatory responses in human tissues. Epitope and GFP tagged SOCS3 fusion proteins were localised predominantly in the nucleus of transfected cells and a validated anti SOCS3 antiserum revealed the expression of SOCS3 in the nucleus and cytoplasm of macrophages, endothelial and epithelial cells in a wide range of normal tissues in tissue microarrays (n = 31 different tissues). Nuclear SOCS3 was only seen in cells expressing a high level of the protein. Comparative immunostaining of acute, chronically and granulomatously inflamed human tissues revealed higher levels of nuclear and cytoplasmic SOCS3 expression in inflamed than in corresponding normal tissues, particularly in recruited leukocyte populations, but also in epithelia. The staining appeared more intense, suggesting higher expression levels, in areas where inflammation was more acute, consistent with the time course of SOCS3 induction described in vitro. Expression of SOCS3 protein by leucocytes and other cell types in tissue sections could be a useful marker of cells undergoing acute or chronic stimulation by cytokines in vivo.

Introduction: It has been postulated that central adrenal insufficiency (CAI), resulting from hypothalamic dysfunction, may contribute to the increased unexplained death rates in Prader Willi syndrome (PWS). A study using the overnight metyrapone test reported a 60% prevalence of CAI in children with PWS. We used a low-dose Synacthen test to screen for CAI in children with PWS., Methods: We studied 41 children with genetic diagnosis of PWS [20 males; mean age, 7.68 (±5.23) yr] in five pediatric endocrinology centers in Australasia. All participants were randomly selected, and none had a history of Addisonian crisis. Ten of the cohort were receiving sex hormone therapy, 19 were receiving GH, and four were receiving T4. Their mean body mass index z-score was +1.48 (±1.68). Baseline morning ACTH and cortisol levels were measured, followed by iv administration of 1 μg Synacthen. Post-Synacthen cortisol levels were measured at 30 min, and a cortisol level above 500 nmol/liter was considered normal., Results: The mean baseline ACTH and cortisol were 15 (±14) ng/liter and 223 (±116) nmol/liter, respectively. The mean 30-min plasma cortisol was 690 (±114) nmol/liter, and the average increase from baseline was 201%., Conclusions: Our result suggests that CAI is rare in children with PWS.

Maturity Onset Diabetes of Young (MODY) is a monogenic and autosomal dominant form of diabetes mellitus with onset of the disease often before 25 years of age. It is due to dysfunction of pancreatic beta cells characterised by non-ketotic diabetes and absence of pancreatic auto-antibodies. It is frequently mistaken for type 1 or type 2 diabetes mellitus. Diagnosis of MODY is important as the GCK subtype has better prognosis and may not require any treatment. Subtypes HNF1A and HNF4A are sensitive to sulfonylureas, however diabetes complications are common if not treated early. Moreover, there is genetic implication for the patient and family. Rare MODY subtypes can be associated with pancreatic and renal anomalies as well as exocrine dysfunction of the pancreas. So far there are six widely accepted subtypes of MODY described but the list has grown to nine. Although the majority of diabetes mellitus in youth remains type 1 and the incidence of type 2 is rising, MODY should be considered in patients with non-ketotic diabetes at presentation, and in patients with a strong family history of diabetes mellitus without pancreatic auto-antibodies. Furthermore the diagnosis must be confirmed by molecular studies. With advancement in genomic technology, rapid screening for MODY mutations will become readily available in the future.

21-Hydroxylase Deficiency (21-OH Deficiency) represents the most common form of Congenital Adrenal Hyperplasia (CAH), a complex and heterogenous group of conditions, characterised by defects in one of the five enzymes involved in adrenal steroidogenesis. Defects in this steroidogenic enzyme, the product of the CYP21A2 gene, cause disruption in the pathway involved in cortisol and aldosterone production and consequently, the accumulation of their steroid precursors as well as a resulting adrenocorticotrophic hormone (ACTH)-driven overproduction of adrenal androgens. Treatment with glucocorticoid, with or without mineralocorticoid and salt replacement, is directed at preventing adrenal crises and ensuring normal childhood growth by alleviating hyperandrogenism. Conventionally, two clinical forms of 21-OH Deficiency are described - the classical form, separated into salt-wasting and simple-virilising phenotypes, and the non-classical form. They are differentiated by their hormonal profile, predominant clinical features and age of presentation. A greater understanding of the genotype-phenotype correlation supports the view that 21-OH Deficiency is a continuum of phenotypes as opposed to a number of distinct phenotypical entities. Significant advancements in technologies such as Tandem Mass Spectrometry (TMS) and improvements in gene analysis, such as complete PCR-based sequencing of the involved gene, have resulted in remarkable developments in the areas of diagnosis, treatment and treatment monitoring, neonatal screening, prenatal diagnosis and prenatal therapy.