Socioeconomic representativeness of Australian, Canadian and British cohorts from the paediatric diabetes AdDIT study: comparisons to regional and national data.

BACKGROUND: Given limited data regarding the involvement of disadvantaged groups in paediatric diabetes clinical trials, this study aimed to evaluate the socioeconomic representativeness of participants recruited into a multinational clinical trial in relation to regional and national type 1 diabetes reference populations. METHODS: Retrospective, cross-sectional evaluation of a subset of adolescent type 1 diabetes cardiorenal intervention trial (AdDIT) participants from Australia (n = 144), Canada (n = 312) and the UK (n = 173). Validated national measures of deprivation were used: the Index of Relative Socioeconomic Disadvantage (IRSD) 2016 (Australia), the Material Resources (MR) dimension of the Canadian Marginalisation index 2016 (Canada) and the Index of Multiple Deprivation (IMD) 2015 (UK). Representativeness was assessed by comparing the AdDIT cohort's distribution of deprivation quintiles with that of the local paediatric type 1 diabetes population (regional), and the broader type 1 diabetes population for which the trial's intervention was targeted (national). RESULTS: Recruited study cohorts from each country had higher proportions of participants with higher SES, and significant underrepresentation of lower SES, in relation to their national references. The socioeconomic make-up in Australia mirrored that of the regional population (p = 0.99). For Canada, the 2nd least deprived (p = 0.001) and the most deprived quintiles (p < 0.001) were over- and under-represented relative to the regional reference, while the UK featured higher regional and national SES bias with over-representation and under-representation from the least-deprived and most-deprived quintiles (p < 0.0001). CONCLUSIONS: Significant national differences in trial participation of low SES participants were observed, highlighting limitations in access to clinical research and the importance of reporting sociodemographic representation in diabetes clinical trials. TRIAL REGISTRATION: NCT01581476. Registered on 20 April 2012.

A Detailed Histologic and Molecular Assessment of the Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma.

Diffuse sclerosing variant papillary thyroid carcinoma (DS-PTC) is characterized clinically by a predilection for children and young adults, bulky neck nodes, and pulmonary metastases. Previous studies have suggested infrequent BRAFV600E mutation but common RET gene rearrangements. Using strict criteria, we studied 43 DS-PTCs (1.9% of unselected PTCs in our unit). Seventy-nine percent harbored pathogenic gene rearrangements involving RET, NTRK3, NTRK1, ALK, or BRAF; with the remainder driven by BRAFV600E mutations. All 10 pediatric cases were all gene rearranged (P = .02). Compared with BRAFV600E-mutated tumors, gene rearrangement was characterized by psammoma bodies involving the entire lobe (P = .038), follicular predominant or mixed follicular architecture (P = .003), pulmonary metastases (24% vs none, P = .04), and absent classical, so-called "BRAF-like" atypia (P = .014). There was no correlation between the presence of gene rearrangement and recurrence-free survival. Features associated with persistent/recurrent disease included pediatric population (P = .030), gene-rearranged tumors (P = .020), microscopic extrathyroidal extension (P = .009), metastases at presentation (P = .007), and stage II disease (P = .015). We conclude that DS-PTC represents 1.9% of papillary thyroid carcinomas and that actionable gene rearrangements are extremely common in DS-PTC. DS-PTC can be divided into 2 distinct molecular subtypes and all BRAFV600E-negative tumors (1.5% of papillary thyroid carcinomas) are driven by potentially actionable oncogenic fusions.

Thyroid nodules in children and adolescents: Investigation and management.

Clinically detectable thyroid nodules are less common in children than adults. However, they are associated with an increased risk of malignancy. Therefore, thorough evaluation of paediatric thyroid nodules is necessary, and an understanding of the features associated with a higher risk of malignancy is important to guide management and referral. Thyroid cancer in children differs significantly from that seen in adults in terms of genetics, presentation, response to treatment and prognosis. Children often present with more advanced disease, but the vast majority have excellent long-term prognosis. Evaluation and management of thyroid nodules and thyroid cancer require a multidisciplinary team approach and involvement of specialists with experience in this field. This review summarises investigative pathways for thyroid nodules in children and outlines current management strategies for paediatric thyroid nodules and cancer.

Optimal Frequency of Retinopathy Screening in Adolescents With Type 1 Diabetes: Markov Modeling Approach Based on 30 Years of Data.

OBJECTIVE: Current guidelines recommend biennial diabetic retinopathy (DR) screening commencing at the age of 11 years and after 2-5 years' duration of type 1 diabetes. Growing evidence suggests less frequent screening may be feasible. RESEARCH DESIGN AND METHODS: Prospective data were collected from 2,063 youth with type 1 diabetes who were screened two or more times between 1990 and 2019. Baseline (mean ± SD) age was 13.3 ± 1.8 years, HbA1c was 8.6 ± 1.3% (70.1 ± 14.7 mmol/mol), diabetes duration was 5.6 ± 2.8 years, and follow-up time was 4.8 ± 2.8 years. DR was manually graded from 7-field retinal photographs using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Markov chain was used to calculate probabilities of DR change over time and hazard ratio (HR) of DR stage transition. RESULTS: The incidence of moderate nonproliferative DR (MNPDR) or worse was 8.6 per 1,000 patient-years. Probabilities of transition to this state after a 3-year interval were from no DR, 1.3%; from minimal DR, 5.1%; and from mild DR, 22.2%, respectively. HRs (95% CIs) for transition per 1% current HbA1c increase were 1.23 (1.16-1.31) from no DR to minimal NPDR, 1.12 (1.03-1.23) from minimal to mild NPDR, and 1.28 (1.13-1.46) from mild to MNPDR or worse. HbA1c alone explained 27% of the transitions between no retinopathy and MNPDR or worse. The addition of diabetes duration into the model increased this value to 31% (P = 0.03). Risk was also increased by female sex and higher attained age. CONCLUSIONS: These results support less frequent DR screening in youth with type 1 diabetes without DR and short duration. Although DR progression to advanced stages is generally slow, higher HbA1c greatly accelerates it.

Cardiac Autonomic Nerve Dysfunction Predicts Incident Retinopathy and Early Kidney Dysfunction in Adolescents With Type 1 Diabetes.

OBJECTIVE: Cardiac autonomic neuropathy (CAN) may contribute to vascular complications in diabetes. We hypothesized that adolescents with CAN are at greater risk of diabetic retinopathy and early kidney dysfunction. RESEARCH DESIGN AND METHODS: In this prospective longitudinal study of 725 adolescents with type 1 diabetes without retinopathy and albuminuria at baseline, early CAN was defined as one or more abnormalities in seven heart rate tests derived from a 10-min electrocardiogram. Retinopathy was defined as the presence of one or more microaneurysms, early kidney dysfunction as an albumin excretion rate (AER) >7.5 µg/min, and albuminuria as an AER >20 µg/min. Multivariable generalized estimating equations were used to examine the association between CAN and retinopathy or early kidney dysfunction. Cox proportional hazards regression analysis was used to assess cumulative risks of incident retinopathy and albuminuria. RESULTS: At baseline, the mean age of the sample was 13.6 ± 2.6 years, 52% were male, and mean diabetes duration was 6.1 ± 3.3 years. Over a median follow-up of 3.8 (interquartile range 2.2-7.5) years, the complication rate 27% for retinopathy, 16% for early kidney dysfunction, and 3% for albuminuria. The mean study HbA1c was 72.3 ± 16 mmol/mmol (8.6 ± 1.4%). CAN predicted incident retinopathy (odds ratio 2.0 [95% CI 1.4, 2.9]) and early kidney dysfunction (1.4 [1.0, 2.0]) after adjusting for HbA1c and diabetes duration. CAN also predicted retinopathy (hazard ratio 1.57 [95% CI 1.09, 2.26]) and albuminuria (2.30 [1.05, 5.04]) independently of HbA1c. CONCLUSIONS: CAN predicted incident retinopathy and kidney dysfunction in adolescents with type 1 diabetes, likely reflecting autonomic microvascular dysregulation contributing to complications. Therefore, screening and interventions to reduce CAN may influence the risk of complications.

Higher frequency of cardiovascular autonomic neuropathy in youth with type 2 compared to type 1 diabetes: Role of cardiometabolic risk factors.

OBJECTIVE: Cardiovascular autonomic neuropathy (CAN) is an overlooked but common and serious diabetes complication. We examined CAN in youth with diabetes and associations with cardiovascular risk factors. RESEARCH DESIGN AND METHODS: This was a prospective cohort of youth aged <20 years with type 2 or type 1 diabetes (n = 66/1153, median age 15.4/16.5 years, duration 1.7/8.0 years), assessed between 2009 and 2020. CAN was defined as ≥2 abnormal heart rate variability measures across time, geometric, and frequency domains. Obesity was defined as BMI ≥ 95th percentile and severe obesity as ≥120% of 95th percentile. Multivariable generalized estimating equations (GEE) were used to examine putative risk factors for CAN, including diabetes type, obesity, and HbA1c . RESULTS: At most recent assessment, youth with type 2 versus type 1 diabetes had median: HbA1 c 7.1% (54 mmol/mol) versus 8.7% (72 mmol/mol) and BMI SDS (2.0 vs. 0.7); frequency of CAN (47% vs. 27%), peripheral nerve abnormality (47% vs. 25%), hypertension (29% vs. 12%), albuminuria (21% vs. 3%), and severe obesity (35% vs. 2%). In multivariable GEE, CAN was associated with type 2 diabetes: Odds Ratio 2.53, 95% CI 1.46, 4.38, p = 0.001, higher BMI SDS: 1.49, 95% CI 1.29, 1.73, p < 0.0001, and obesity: 2.09, 95% CI 1.57, 2.78, p < 0.0001. CONCLUSIONS: Youth with type 2 diabetes have a higher frequency of CAN, peripheral nerve abnormality, hypertension, albuminuria and severe obesity despite shorter diabetes duration and younger age. Our findings highlight the importance of targeting modifiable risk factors to prevent cardiovascular disease in youth with diabetes.

Childhood type 1 diabetes is associated with abnormal bone development.

OBJECTIVE: To describe bone mineral density (BMD), bone structure, and fracture prevalence in adolescents with type 1 diabetes (T1D) and explore their associations with glycemic control and microvascular complications. RESEARCH DESIGN AND METHODS: Cross sectional study of 64 adolescents (38 males) with T1D duration >10 years who underwent dual-energy X-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), fracture survey, plantar fascia thickness, and microvascular complications assessment. RESULTS: Mean age was 16.6 ± 2.1 years, diabetes duration 12.8 ± 2.2 years and HbA1c 8.9 ± 1.7% (74 mmol/mol). Fracture prevalence was 50%. DXA areal BMD (Z-score) was reduced for femoral neck (-0.5 ± 1.3, p = 0.008) and arm (-0.4 ± 1.0, p < 0.001), while total areal BMD and lumbar spine BMD were normal. In pQCT (Z-score), trabecular volumetric BMD (vBMD) was reduced for tibia (-0.4 ± 0.8, p < 0.001) and radius (-0.8 ± 1.4, p < 0.001) whereas cortical vBMD was increased at both sites (tibia: 0.5 ± 0.6, p < 0.001, radius: 0.7 ± 1.5, p < 0.001). Muscle cross-sectional area (CSA) was reduced for upper (-0.6 ± 1.2, p < 0.001) and lower (-0.4 ± 0.7, p < 0.001) limbs. DXA total areal BMD was positively correlated with BMI (p < 0.01) and age at T1D diagnosis (p = 0.04). Lower radial bone CSA, total and lumbar spine BMD were associated with autonomic nerve dysfunction. HbA1c, diabetes duration, fracture history and other microvascular complications were not significantly associated with bone parameters. CONCLUSIONS: Adolescents with childhood-onset T1D have site-specific bone deficits in upper and lower limbs but normal total and lumbar spine BMD. T1D appears to have differential effects on trabecular and cortical bone compartments. Future longitudinal analysis is warranted to examine whether these changes translate in to increased fracture risk.

Urinary albumin/creatinine ratio tertiles predict risk of diabetic retinopathy progression: a natural history study from the Adolescent Cardio-Renal Intervention Trial (AdDIT) observational cohort.

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.

Hemoglobin A1c Patterns of Youth With Type 1 Diabetes 10 Years Post Diagnosis From 3 Continents.

OBJECTIVES: Distinct hemoglobin A1c (HbA1c) trajectories during puberty are identified in youth with established type 1 diabetes (T1D). We used data from 3 international registries to evaluate whether distinct HbA1c trajectories occur from T1D onset. METHODS: Participants were <18 years old at diagnosis with at least 1 HbA1c measured within 12 months post diagnosis, along with ≥3 duration-year-aggregated HbA1c values over 10 years of follow-up. Participants from the Australasian Diabetes Data Network (n = 7292), the German-Austrian-Luxembourgian-Swiss diabetes prospective follow-up initiative (Diabetes Patienten Verlaufsdokumentation) (n = 39 226) and the US-based Type 1 Diabetes Exchange Clinic Registry (n = 3704) were included. With group-based trajectory modeling, we identified unique HbA1c patterns from the onset of T1D. RESULTS: Five distinct trajectories occurred in all 3 registries, with similar patterns of proportions by group. More than 50% had stable HbA1c categorized as being either low stable or intermediate stable. Conversely, ∼15% in each registry were characterized by stable HbA1c >8.0% (high stable), and ∼11% had values that began at or near the target but then increased (target increase). Only ∼5% of youth were above the target from diagnosis, with an increasing HbA1c trajectory over time (high increase). This group differed from others, with higher rates of minority status and an older age at diagnosis across all 3 registries (P ≤ .001). CONCLUSIONS: Similar postdiagnostic HbA1c patterns were observed across 3 international registries. Identifying the youth at the greatest risk for deterioration in HbA1c over time may allow clinicians to intervene early, and more aggressively, to avert increasing HbA1c.

Baseline extended zone retinal vascular calibres associate with sensory nerve abnormalities in adolescents with type 1 diabetes: A prospective longitudinal study.

OBJECTIVE: The relationship between retinal vascular calibres (RVCs) and diabetic neuropathy is unclear. We investigated associations between RVCs and sensory nerve abnormality in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: In a prospective longitudinal study of 889 adolescents with type 1 diabetes with baseline mean (±SD) age 14.1 ± 1.5 years and HbA1c IFCC 69.4 ± 14.1 mmol/mol (8.6 ± 1.3%), RVCs were assessed from baseline retinal photographs: 'central zone' calibres, summarized as central retinal arteriolar (CRAE) and venular equivalents (CRVE) and 'extended zone' calibres: mean width of arterioles (MWa) and venules (MWv). Sensory nerve abnormality was defined as at least one abnormal sensory quantitative testing from two thermal and two vibration threshold tests measured at foot every 1-2 years. Associations between baseline RVC and sensory nerve function were examined using generalized estimating equations and cumulative risk by Cox regression analyses. RESULTS: During a median study follow-up of 6.2 [IQR 3.7-10.4] years, sensory nerve abnormality was found in 27% of adolescents. Narrower extended zone calibre quartiles but not CRAE or CRVE quartiles were independently associated with sensory nerve abnormality: MWa (Q1 vs. Q2-4: OR 1.35 (95% CI 1.02, 1.61) and MWv (Q1 vs. Q2-4: 1.31 (1.03, 1.7)), after adjusting for HbA1c , duration and blood pressure. Similarly, in Cox regression, the narrowest quartiles were associated with sensory nerve abnormality: MWa hazard ratio (HR) 1.5 (1.3, 1.8) and MWv 1.6 (1.4, 1.9). CONCLUSIONS: Narrower extended zone retinal calibres were associated with sensory nerve abnormality in adolescents with type 1 diabetes and may present useful biomarkers to understand the pathophysiology of neuropathy.

Insulin micro-secretion in Type 1 diabetes and related microRNA profiles.

The aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical factors. In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels. Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood (< 18 y.o.), and diabetes duration was stratified as ≤ 10 years, 10-20 years and > 20 years. Plasma C-peptide was measured by ultrasensitive ELISA. Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform. C-peptide was detectable in 55.3% of (n = 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes, p < 0.0001 and in all (n = 253) participants without diabetes (CON). C-peptide levels, when detectable, were lower in the individuals with diabetes than in the CON group [median lower quartile (LQ)-upper quartile (UQ)] 5.0 (2.6-28.7) versus 650.9 (401.2-732.4) pmol/L respectively, p < 0.0001 and lower in childhood versus adult-onset diabetes [median (LQ-UQ) 4.2 (2.6-12.2) pmol/L vs. 8.0 (2.3-80.5) pmol/L, p = 0.02, respectively]. In the childhood-onset group more people with longer diabetes duration (> 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%, p for trend < 0.05). Nine miRs significantly correlated with detectable C-peptide levels in people with diabetes and 16 miRs correlated with C-peptide levels in CON. Our cross-sectional study results are supportive of (a) greater beta-cell function loss in younger onset Type 1 diabetes; (b) persistent insulin secretion in adult-onset diabetes and possibly regenerative secretion in childhood-onset long diabetes duration; and (c) relationships of C-peptide levels with circulating miRs. Confirmatory clinical studies and related basic science studies are merited.

Australian experience with total pancreatectomy with islet autotransplantation to treat chronic pancreatitis.

BACKGROUND: This study aimed to describe the clinical outcomes of total pancreatectomy with islet autotransplantation (TP-IAT) in Australia. METHODS: Individuals selected for TP-IAT surgery according to the Minnesota Criteria (Appendix) without evidence of diabetes were evaluated including time to transplantation from pancreatectomy, islet numbers infused and post-transplantation HbA1c, C-peptide, total daily insulin and analgesic requirement. RESULTS: Sixteen individuals underwent TP-IAT from Australia and New Zealand between 2010 and 2020. Two recipients are deceased. The median islet equivalents/kg infused was 4244 (interquartile range (IQR) 2290-7300). The median C-peptide 1 month post-TP-IAT was 384 (IQR 210-579) pmol/L and at median 29.5 (IQR 14.5-46.5) months from transplant was 395 (IQR 139-862) pmol/L. Insulin independence was achieved in eight of 15 (53.3%) surviving recipients. A higher islet equivalents transplanted was most strongly associated with the likelihood of insulin independence (P < 0.05). Of the 15 surviving recipients, 14 demonstrated substantial reduction in analgesic requirement. CONCLUSION: The TP-IAT programme in Australia has been a successful new therapy for the management of individuals with chronic pancreatitis including hereditary forms refractory to medical treatment to improve pain management with 50% insulin independence rates.

Barth syndrome with severe dilated cardiomyopathy and growth hormone resistance: a case report.

OBJECTIVES: To describe the metabolic and endocrine features of a patient with Barth syndrome who showed evidence of growth hormone resistance. CASE PRESENTATION: A male proband deteriorated rapidly with lactic acidosis after a circumcision at age three weeks and was found to have severe dilated cardiomyopathy. A cardiomyopathy gene panel led to the diagnosis of TAZ-deficiency Barth syndrome. He subsequently experienced hypotonia and gross motor delay, feeding difficulties for the first four years, constitutional growth delay and one episode of ketotic hypoglycaemia. Cardiomyopathy resolved on oral anti-failure therapy by age three years. He had a hormonal pattern of growth hormone resistance, and growth hormone treatment was considered, however height velocity improved spontaneously after age 3½ years. He also had biochemical primary hypothyroidism. CONCLUSIONS: With careful metabolic management with l-arginine supplementation, overnight corn starch, and a prescribed exercise program, our patient's strength, endurance, level of physical activity and body composition improved significantly by age six years.

Type 2 diabetes in children and adolescents across Australia and New Zealand: A 6-year audit from The Australasian Diabetes Data Network (ADDN).

OBJECTIVES: To assess the clinical and demographic characteristics of children and adolescents across Australia and New Zealand (NZ) with type 2 diabetes. METHODS: We performed a descriptive audit of data prospectively reported to the Australasian Diabetes Data Network (ADDN) registry. Data were collected from six tertiary pediatric diabetes centers across Australia (New South Wales, Queensland, South Australia, Western Australia, and Victoria) and NZ (Auckland). Children and adolescents diagnosed with type 2 diabetes aged ≤ 18 years with data reported to ADDN between 2012 and 2017 were included. Age, sex, ethnicity, HbA1c, blood pressure, BMI, waist circumference and lipid profile at first visit were assessed. RESULTS: There were 269 cases of type 2 diabetes in youth reported to ADDN between 2012 and 2017. The most common ethnicities were Indigenous Australian in 56/243 (23%) and NZ Maori or Pacifica in 47 (19%). Median age at diagnosis was 13.7 years and 94% of participants were overweight or obese. Indigenous Australian and Maori/Pacifica children were younger at diagnosis compared with nonindigenous children: median 13.3 years (indigenous Australian); 13.1 years (Maori/Pacifica); 14.1 years (nonindigenous), p = 0.005. HbA1c was higher in indigenous Australian (9.4%) and Maori/Pacifica youth (7.8%) compared with nonindigenous (6.7%) p < 0.001. BMI-SDS was higher in Maori/Pacifica youth (2.3) compared with indigenous Australian (2.1) and nonindigenous (2.2) p = 0.011. CONCLUSIONS: Indigenous Australian and Maori/Pacifica youth in ADDN were younger and had worse glycaemic control at diagnosis of type 2 diabetes. Our findings underscore the need to consider targeted and earlier screening in these "high-risk" populations.

Vascular Effects of ACE (Angiotensin-Converting Enzyme) Inhibitors and Statins in Adolescents With Type 1 Diabetes.

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<0.001 for reactive hyperemia index and pulse wave velocity, respectively). ACE inhibitors improve endothelial function in high-risk adolescents as they transition through puberty. The longer-term protective effects of this intervention at this early age remain to be determined. Registration- URL: https://www.clinicaltrials.gov; Unique identifier NCT01581476.

Biomarkers associated with early stages of kidney disease in adolescents with type 1 diabetes.

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 and > 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.

Extended-Zone Retinal Vascular Caliber and Risk of Diabetic Retinopathy in Adolescents with Type 1 Diabetes.

PURPOSE: Retinal vascular caliber has been linked to diabetic retinopathy (DR). Newer imaging technologies allow analysis of retinal vascular caliber beyond the standard areas surrounding the optic disc. We investigated the vascular caliber in extended zones in prediction of DR in adolescents with type 1 diabetes. DESIGN: Prospective, longitudinal study. PARTICIPANTS: Adolescents (n = 904) who attended the diabetes complications assessment service at the Children's Hospital at Westmead. METHODS: Retinal caliber was assessed from baseline retinal photographs with a semiautomated computer software Singapore I Vessel Assessment: standard zone retinal vessel calibers were summarized as central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE), and extended-zone vessels (>2 disc diameters from the optic disc margin) were summarized as mean width of arterioles (MWa) and mean width of venules (MWv). MAIN OUTCOME MEASURES: Retinal vessel calibers at baseline (upper 3 quartiles vs. lowest quartiles [Q2-4 vs. Q1]) and moderate DR (stage 3 or more) were analyzed using multivariate generalized estimating equations, with results expressed as odds ratios (OR) and 95% confidence intervals (CIs). RESULTS: Among the 904 participants, baseline mean age ± standard deviation was 14.0 ± 1.5 years, hemoglobin A1C (HbA1C) level was 8.5 ± 1.3%, and median diabetes duration 4.6 years. After a median 3-year follow-up, 15% of adolescents demonstrated moderate DR. Wider extended-zone retinal arteriolar caliber (MWa; OR, 3.6 [95% CI, 2.06-6.1], comparing Q2-4 vs. Q1) and venular caliber (MWv; OR, 4.2 [95% CI, 2.2-7.5]) predicted moderate DR after adjusting for HbA1C and blood pressure. Standard zone CRAE and CRVE were not associated with moderate DR. CONCLUSIONS: Extended-zone retinal vessel caliber predicts moderate DR in adolescents with type 1 diabetes.

Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity.

Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A;I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.