Publications by authors named "Maria E Craig"

164 Publications

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

Diabet Med 2021 Jul 29:e14662. Epub 2021 Jul 29.

The Children's Hospital at Westmead, Sydney, Australia.

Objective: The relationship between retinal vascular calibers (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" calibers, summarized as Central Retinal Arteriolar (CRAE) and venular equivalents (CRVE) and "extended zone" calibers: 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%. Narrower extended zone caliber 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 associated with sensory nerve abnormality: MWa hazard ratio (HR) 1.5 (1.3, 1.8), MWv 1.6 (1.4, 1.9).

Conclusions: Narrower extended zone retinal calibers were associated with sensory nerve abnormality in adolescents with type 1 diabetes and may present useful biomarkers to understand the pathophysiology of neuropathy.
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http://dx.doi.org/10.1111/dme.14662DOI Listing
July 2021

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

Pediatrics 2021 Jul 27. Epub 2021 Jul 27.

Division of Child and Adolescent Health, The University of Sydney, Sydney, Australia.

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 ( = 7292), the German-Austrian-Luxembourgian-Swiss diabetes prospective follow-up initiative (Diabetes Patienten Verlaufsdokumentation) ( = 39 226) and the US-based Type 1 Diabetes Exchange Clinic Registry ( = 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 ( ≤ .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.
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http://dx.doi.org/10.1542/peds.2020-048942DOI Listing
July 2021

Bone Mineral Density and Type 1 Diabetes in Children and Adolescents: A Meta-analysis.

Diabetes Care 2021 Jul 20. Epub 2021 Jul 20.

School of Women's and Child's Health, University of New South Wales, Sydney, New South Wales, Australia

Background: There is substantial evidence that adults with type 1 diabetes have reduced bone mineral density (BMD); however, findings in youth are inconsistent.

Purpose: To perform a systematic review and meta-analysis of BMD in youth with type 1 diabetes using multiple modalities: DXA, peripheral quantitative computed tomography (pQCT), and/or quantitative ultrasound (QUS).

Data Sources: PubMed, Embase, Scopus, and Web of Science from 1 January 1990 to 31 December 2020, limited to humans, without language restriction.

Study Selection: Inclusion criteria were as follows: cross-sectional or cohort studies that included BMD measured by DXA, pQCT, or QUS in youth (aged <20 years) with type 1 diabetes and matched control subjects.

Data Extraction: We collected data for total body, lumbar spine, and femoral BMD (DXA); tibia, radius, and lumbar spine (pQCT); and phalanx and calcaneum (QUS). Weighted mean difference (WMD) or standardized mean difference was estimated and meta-regression was performed with age, diabetes duration, and HbA as covariates.

Data Synthesis: We identified 1,300 nonduplicate studies; 46 met the inclusion criteria, including 2,617 case and 3,851 control subjects. Mean ± SD age was 12.6 ± 2.3 years. Youth with type 1 diabetes had lower BMD: total body (WMD -0.04 g/cm, 95% CI -0.06 to -0.02; = 0.0006), lumbar spine (-0.02 g/cm, -0.03 to -0.0; = 0.01), femur (-0.04 g/cm, -0.05 to -0.03; < 0.00001), tibial trabecular (-11.32 g/cm, -17.33 to -5.30; = 0.0002), radial trabecular (-0.91 g/cm, -1.55 to -0.27; = 0.005); phalangeal (-0.32 g/cm, -0.38 to -0.25; < 0.00001), and calcaneal (standardized mean difference -0.69 g/cm, -1.11 to -0.26; = 0.001). With use of meta-regression, total body BMD was associated with older age (coefficient -0.0063, -0.0095 to -0.0031; = 0.002) but not with longer diabetes duration or HbA.

Limitations: Meta-analysis was limited by the small number of studies with use of QUS and pQCT and by lack of use of BMD scores in all studies.

Conclusions: Bone development is abnormal in youth with type 1 diabetes, assessed by multiple modalities. Routine assessment of BMD should be considered in all youth with type 1 diabetes.
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http://dx.doi.org/10.2337/dc20-3128DOI Listing
July 2021

Utilisation, access and recommendations regarding technologies for people living with type 1 diabetes: consensus statement of the ADS/ADEA/APEG/ADIPS Working Group.

Med J Aust 2021 Jun 20. Epub 2021 Jun 20.

University of Sydney, Sydney, NSW.

Introduction: Type 1 diabetes presents significant challenges for optimal management. Despite intensive glycaemic control being the standard of care for several decades, glycaemic targets are infrequently achieved and the burden of complications remains high. Therefore, the advancement of diabetes management technologies has a major role in reducing the clinical and economic impact of the disease on people living with type 1 diabetes and on health care systems. However, a national framework is needed to ensure equitable and sustainable implementation of these technologies as part of holistic care.

Main Recommendations: This consensus statement considers technologies for insulin delivery, glucose sensing and insulin dose advice that are commercially available in Australia. While international position statements have provided recommendations for technology implementation, the ADS/ADEA/APEG/ADIPS Working Group believes that focus needs to shift from strict trial-based glycaemic criteria towards engagement and individualised management goals that consider the broad spectrum of benefits offered by technologies.

Changes In Management As Result Of This Statement: This Australian consensus statement from peak national bodies for the management of diabetes across the lifespan outlines a national framework for the optimal implementation of technologies for people with type 1 diabetes. The Working Group highlights issues regarding equity of access to technologies and services, scope of clinical practice, credentialling and accreditation requirements, regulatory issues with "do-it-yourself" technology, national benchmarking, safety reporting, and ongoing patient advocacy.
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http://dx.doi.org/10.5694/mja2.51118DOI Listing
June 2021

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

Sci Rep 2021 Jun 3;11(1):11727. Epub 2021 Jun 3.

NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.

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.
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http://dx.doi.org/10.1038/s41598-021-90856-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175359PMC
June 2021

Growth from birth to 6 months of infants with and without intrauterine preeclampsia exposure.

J Dev Orig Health Dis 2021 May 12:1-5. Epub 2021 May 12.

Women's and Children's Health, St George Hospital, Sydney, Australia.

Intrauterine preeclampsia exposure affects the lifelong cardiometabolic health of the child. Our study aimed to compare the growth (from birth to 6 months) of infants exposed to either a normotensive pregnancy or preeclampsia and explore the influence of being born small for gestational age (SGA). Participants were children of women participating in the Post-partum, Physiology, Psychology and Paediatric follow-up cohort study. Birth and 6-month weight and length z-scores were calculated for term and preterm (<37 weeks) babies, and change in weight z-score, rapid weight gain (≥0.67 increase in weight z-score) and conditional weight gain z-score were calculated. Compared with normotensive exposed infants (n = 298), preeclampsia exposed infants (n = 84) were more likely to be born SGA (7% versus 23%; P < 0.001), but weight gain from birth to 6 months, by any measure, did not differ between groups. Infants born SGA, irrespective of pregnancy exposure, were more likely to have rapid weight gain and had greater increases in weight z-score compared with those not born SGA. Preeclampsia exposed infants born SGA may benefit from interventions designed to prevent future cardiometabolic disease.
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http://dx.doi.org/10.1017/S2040174421000167DOI Listing
May 2021

Respiratory viral co-infections among SARS-CoV-2 cases confirmed by virome capture sequencing.

Sci Rep 2021 02 16;11(1):3934. Epub 2021 Feb 16.

School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.

Accumulating evidence supports the high prevalence of co-infections among Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients, and their potential to worsen the clinical outcome of COVID-19. However, there are few data on Southern Hemisphere populations, and most studies to date have investigated a narrow spectrum of viruses using targeted qRT-PCR. Here we assessed respiratory viral co-infections among SARS-CoV-2 patients in Australia, through respiratory virome characterization. Nasopharyngeal swabs of 92 SARS-CoV-2-positive cases were sequenced using pan-viral hybrid-capture and the Twist Respiratory Virus Panel. In total, 8% of cases were co-infected, with rhinovirus (6%) or influenzavirus (2%). Twist capture also achieved near-complete sequencing (> 90% coverage, > tenfold depth) of the SARS-CoV-2 genome in 95% of specimens with Ct < 30. Our results highlight the importance of assessing all pathogens in symptomatic patients, and the dual-functionality of Twist hybrid-capture, for SARS-CoV-2 whole-genome sequencing without amplicon generation and the simultaneous identification of viral co-infections with ease.
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http://dx.doi.org/10.1038/s41598-021-83642-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887263PMC
February 2021

Current Perspectives on the Role of Very-Low-Energy Diets in the Treatment of Obesity and Type 2 Diabetes in Youth.

Diabetes Metab Syndr Obes 2021 18;14:215-225. Epub 2021 Jan 18.

School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia.

In both developed and developing countries, pediatric obesity and type 2 diabetes are an increasing public health concern: globally 5.6% of girls and 7.8% of boys aged ≥5 years have obesity. The incidence of type 2 diabetes has increased in youth in recent decades and disproportionately affects those from ethnic/racial minority groups and disadvantaged backgrounds. For the treatment of both conditions, conventional lifestyle intervention is frequently ineffective, access to bariatric surgery is very limited and many young people are unsuitable or unwilling to undergo surgery. A very-low-energy diet (VLED) provides a viable alternative and may be effective for weight reduction and improved glycemic control in youth, based on one systematic review. In particular, in the treatment of type 2 diabetes, a chart review and a pilot study both demonstrated that a VLED can reduce the requirement for medications, including insulin, and lead to the remission of diabetes. However, long-term follow-up and safety data remain limited and therefore a VLED is inconsistently recommended by clinical practice guidelines for the treatment of pediatric obesity and type 2 diabetes. In clinical practice, VLED use in children and adolescents is uniquely challenging due to intolerance of expected side effects, difficulty adhering to the highly restrictive diet and difficulty with behaviour change within the current social context and environment. Ultimately, more research, including larger, longer-term trials with comprehensive safety monitoring are required to strengthen the evidence base. This would inform clinical practice guidelines, which may facilitate more widespread utilization of VLED programs in the management of obesity and type 2 diabetes in youth.
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http://dx.doi.org/10.2147/DMSO.S238419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822089PMC
January 2021

Associations between diet, the gut microbiome and short chain fatty acids in youth with islet autoimmunity and type 1 diabetes.

Pediatr Diabetes 2021 May 1;22(3):425-433. Epub 2021 Feb 1.

Women's and Children's Hospital, Adelaide, South Australia, Australia.

Aim: We aimed to characterize associations between diet and the gut microbiome and short chain fatty acid (SCFA) products in youth with islet autoimmunity or type 1 diabetes (IA/T1D) in comparison with controls.

Research Design And Methods: Eighty participants (25 diagnosed with T1D, 17 with confirmed IA, 38 sibling or unrelated controls) from the Australian T1D Gut Study cohort were studied (median [IQR] age 11.7 [8.9, 14.0] years, 43% female). A Food Frequency Questionnaire characterized daily macronutrient intake over the preceding 6 months. Plasma and fecal SCFA were measured by gas chromatography; gut microbiome composition and diversity by 16S rRNA gene sequencing.

Results: A 10 g increase in daily carbohydrate intake associated with higher plasma acetate in IA/T1D (adjusted estimate +5.2 (95% CI 1.1, 9.2) μmol/L p = 0.01) and controls (adjusted estimate +4.1 [95% CI 1.7, 8.5] μmol/L p = 0.04). A 5 g increase in total fat intake associated with lower plasma acetate in IA/T1D and controls. A 5% increase in noncore (junk) food intake associated with reduced richness (adjusted estimate -4.09 [95%CI -7.83, -0.35] p = .03) and evenness (-1.25 [95% CI -2.00, -0.49] p < 0.01) of the gut microbiome in IA/T1D. Fiber intake associated with community structure of the microbiome in IA/T1D.

Conclusions: Modest increments in carbohydrate and fat intake associated with plasma acetate in all youth. Increased junk food intake associated with reduced diversity of the gut microbiome in IA/T1D alone. These associations with the gut microbiome in IA/T1D support future efforts to promote SCFA by using dietary interventions.
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http://dx.doi.org/10.1111/pedi.13178DOI Listing
May 2021

The virome in early life and childhood and development of islet autoimmunity and type 1 diabetes: A systematic review and meta-analysis of observational studies.

Rev Med Virol 2020 Dec 30:e2209. Epub 2020 Dec 30.

School of Women's and Children's Health, University of New South Wales Faculty of Medicine, Sydney, New South Wales, Australia.

Viruses are postulated as primary candidate triggers of islet autoimmunity (IA) and type 1 diabetes (T1D), based on considerable epidemiological and experimental evidence. Recent studies have investigated the association between all viruses (the 'virome') and IA/T1D using metagenomic next-generation sequencing (mNGS). Current associations between the early life virome and the development of IA/T1D were analysed in a systematic review and meta-analysis of human observational studies from Medline and EMBASE (published 2000-June 2020), without language restriction. Inclusion criteria were as follows: cohort and case-control studies examining the virome using mNGS in clinical specimens of children ≤18 years who developed IA/T1D. The National Health and Medical Research Council level of evidence scale and Newcastle-Ottawa scale were used for study appraisal. Meta-analysis for exposure to specific viruses was performed using random-effects models, and the strength of association was measured using odds ratios (ORs) and 95% confidence intervals (CIs). Eligible studies (one case-control, nine nested case-control) included 1,425 participants (695 cases, 730 controls) and examined IA (n = 1,023) or T1D (n = 402). Meta-analysis identified small but significant associations between IA and number of stool samples positive for all enteroviruses (OR 1.14, 95% CI 1.00-1.29, p = 0.05; heterogeneity χ  = 1.51, p = 0.68, I  = 0%), consecutive positivity for enteroviruses (1.55, 1.09-2.20, p = 0.01; χ  = 0.19, p = 0.91, I  = 0%) and number of stool samples positive specifically for enterovirus B (1.20, 1.01-1.42, p = 0.04; χ  = 0.03, p = 0.86, I  = 0%). Virome analyses to date have demonstrated associations between enteroviruses and IA that may be clinically significant. However, larger prospective mNGS studies with more frequent sampling and follow-up from pregnancy are required to further elucidate associations between early virus exposure and IA/T1D.
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http://dx.doi.org/10.1002/rmv.2209DOI Listing
December 2020

We All Have a Role to Play: Redressing Inequities for Children Living with CAH and Other Chronic Health Conditions of Childhood in Resource-Poor Settings.

Int J Neonatal Screen 2020 Sep 25;6(4). Epub 2020 Sep 25.

College of Medicine & Public Health, Flinders University, Adelaide 5042, Australia.

CLAN (Caring and Living as Neighbours) is an Australian-based non-governmental organisation (NGO) committed to equity for children living with chronic health conditions in resource-poor settings. Since 2004, CLAN has collaborated with a broad range of partners across the Asia Pacific region to improve quality of life for children living with congenital adrenal hyperplasia (CAH). This exploratory case study uses the Knowledge to Action (KTA) framework to analyse CLAN's activities for children living with CAH in the Asia Pacific. The seven stages of the KTA action cycle inform a systematic examination of comprehensive, collaborative, sustained actions to address a complex health challenge. The KTA framework demonstrates the "how" of CLAN's approach to knowledge creation and exchange, and the centrality of community development to multisectoral collaborative action across a range of conditions, cultures and countries to redressing child health inequities. This includes a commitment to: affordable access to essential medicines and equipment; education, research and advocacy; optimisation of medical management; encouragement of family support groups; efforts to reduce financial burdens; and ethical, transparent program management as critical components of success. Improvements in quality of life and health outcomes are achievable for children living with CAH and other chronic health conditions in resource-poor settings. CLAN's strategic framework for action offers a model for those committed to #LeaveNoChildBehind.
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http://dx.doi.org/10.3390/ijns6040076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711668PMC
September 2020

Determinants of Cardiovascular Risk in 7000 Youth With Type 1 Diabetes in the Australasian Diabetes Data Network.

J Clin Endocrinol Metab 2021 Jan;106(1):133-142

School of Public Health and Preventive Medicine, Monash University, Clayton, VIC, Australia.

Context: Cardiovascular disease occurs prematurely in type 1 diabetes. The additional risk of overweight is not well characterized.

Objective: The primary aim was to measure the impact of body mass index (BMI) in youth with type 1 diabetes on cardiovascular risk factors. The secondary aim was to identify other determinants of cardiovascular risk.

Design: Observational longitudinal study of 7061 youth with type 1 diabetes followed for median 7.3 (interquartile range [IQR] 4-11) years over 41 (IQR 29-56) visits until March 2019.

Setting: 15 tertiary care diabetes centers in the Australasian Diabetes Data Network.Participants were aged 2 to 25 years at baseline, with at least 2 measurements of BMI and blood pressure.

Main Outcome Measure: Standardized systolic and diastolic blood pressure scores and non-high-density lipoprotein (HDL) cholesterol were co-primary outcomes. Urinary albumin/creatinine ratio was the secondary outcome.

Results: BMI z-score related independently to standardized blood pressure z- scores and non-HDL cholesterol. An increase in 1 BMI z-score related to an average increase in systolic/diastolic blood pressure of 3.8/1.4 mmHg and an increase in non-HDL cholesterol (coefficient + 0.16 mmol/L, 95% confidence interval [CI], 0.13-0.18; P < 0.001) and in low-density lipoprotein (LDL) cholesterol. Females had higher blood pressure z-scores, higher non-HDL and LDL cholesterol, and higher urinary albumin/creatinine than males. Indigenous youth had markedly higher urinary albumin/creatinine (coefficient + 2.15 mg/mmol, 95% CI, 1.27-3.03; P < 0.001) and higher non-HDL cholesterol than non-Indigenous youth. Continuous subcutaneous insulin infusion was associated independently with lower non-HDL cholesterol and lower urinary albumin/creatinine.

Conclusions: BMI had a modest independent effect on cardiovascular risk. Females and Indigenous Australians in particular had a more adverse risk profile.
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http://dx.doi.org/10.1210/clinem/dgaa727DOI Listing
January 2021

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

Hypertension 2020 12 26;76(6):1734-1743. Epub 2020 Oct 26.

From the Institute of Cardiovascular Science, University College London, United Kingdom (S.T.C., J.E.D.).

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]; =0.005), whereas no effect was observed following statin use (6.2% [5.5-6.8] versus 5.8% [5.1-6.4]; =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; =0.015). Neither reactive hyperemia index nor pulse wave velocity were affected by either treatment (>0.05 for both), but both were found to increase over the duration of follow-up (0.07 [0.03-0.12]; =0.001 and 0.5 m/s [0.4-0.6]; <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.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15721DOI Listing
December 2020

ISPAD Clinical Practice Consensus Guideline: Diabetic ketoacidosis in the time of COVID-19 and resource-limited settings-role of subcutaneous insulin.

Pediatr Diabetes 2020 12 12;21(8):1394-1402. Epub 2020 Oct 12.

Sydney Children's Hospital Network, Sydney, New South Wales, Australia.

The International Society for Pediatric and Adolescent Diabetes Clinical Practice Consensus Guideline 2018 for management of diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar state provide comprehensive guidance for management of DKA in young people. Intravenous (IV) infusion of insulin remains the treatment of choice for treating DKA; however, the policy of many hospitals around the world requires admission to an intensive care unit (ICU) for IV insulin infusion. During the coronavirus 2019 (COVID-19) pandemic or other settings where intensive care resources are limited, ICU services may need to be prioritized or may not be appropriate due to risk of transmission of infection to young people with type 1 or type 2 diabetes. The aim of this guideline, which should be used in conjunction with the ISPAD 2018 guidelines, is to ensure that young individuals with DKA receive management according to best evidence in the context of limited ICU resources. Specifically, this guideline summarizes evidence for the role of subcutaneous insulin in treatment of uncomplicated mild to moderate DKA in young people and may be implemented if administration of IV insulin is not an option.
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http://dx.doi.org/10.1111/pedi.13118DOI Listing
December 2020

Microbiome Understanding in Maternity Study (MUMS), an Australian prospective longitudinal cohort study of maternal and infant microbiota: study protocol.

BMJ Open 2020 09 15;10(9):e040189. Epub 2020 Sep 15.

School of Women's and Children's Health, University of New South Wales Faculty of Medicine, Sydney, New South Wales, Australia.

Introduction: Pregnancy induces significant physiological and cardiometabolic changes, and is associated with alterations in the maternal microbiota. Increasing rates of prepregnancy obesity, metabolic abnormalities and reduced physical activity, all impact negatively on the microbiota causing an imbalance between the commensal microorganisms (termed dysbiosis), which may drive complications, such as gestational diabetes or hypertensive disorders. Considerable work is needed to define the inter-relationships between the microbiome, nutrition, physical activity and pregnancy outcomes. The role of the microbiota during pregnancy remains unclear. The aim of the study is to define microbiota signatures longitudinally throughout pregnancy and the first year post birth, and to identify key clinical and environmental variables that shape the female microbiota profile during and following pregnancy.

Methods And Analysis: The Microbiome Understanding in Maternity Study (MUMS) is an Australian prospective longitudinal cohort study involving 100 mother-infant pairs. Women are enrolled in their first trimester and followed longitudinally. Assessment occurs at <13+0, 20+0-24+6 and 32+0-36+6 weeks gestation, birth and 6 weeks, 6 months and 12 months postpartum. At each assessment, self-collected oral, vaginal and faecal samples are collected with an additional postpartum skin swab and breastmilk sample. Each infant will have oral, faecal and skin swab samples collected. Measurements include anthropometrics, body composition, blood pressure, serum hormonal and metabolic parameters and vaginal pH. Dietary intake, physical activity and psychological state will be assessed using validated self-report questionnaires, and pregnancy and infant outcomes recorded. Parametric and non-parametric hypothesis tests will be used to test the association between high-risk and low-risk pregnancies and their outcomes.

Ethics And Dissemination: The study received the following approval: South Eastern Sydney Local Health District Research Ethics Committee (17/293 (HREC/17/POWH/605). Results will be made available to the participants of MUMS, their families and the funding bodies; in the form of a summary document. Results for the greater maternity care community and other researchers will be disseminated through conferences, local, national and international presentations and peer-reviewed publications.

Trial Registration Number: ACTRN12618000471280 (prospectively registered).
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http://dx.doi.org/10.1136/bmjopen-2020-040189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493111PMC
September 2020

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

Pediatr Diabetes 2020 11 17;21(7):1322-1332. Epub 2020 Aug 17.

Department of Paediatrics, University of Cambridge, Cambridge, UK.

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/1.73m /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 ; -0.18 [-0.26, -0.11], P = 5.1 × 10 ; -0.12 [-0.20, -0.05], P = 1.6 × 10 ), in addition to clinical covariates. Final eGFR was negatively associated with osteopontin (-0.21 [-0.28, -0.14], P = 2.3 × 10 ) and cystatin C (-0.16 [-0.22, -0.09], P = 1.6 × 10 ). Rapid decliner phenotype was associated with osteopontin (OR: 1.83 [1.42, 2.41], P = 7.3 × 10 ), whereas rapid increaser phenotype was associated with fibroblast growth factor-23 (FGF-23) (1.59 [1.23, 2.04], P = 2.6 × 10 ). 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.
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http://dx.doi.org/10.1111/pedi.13095DOI Listing
November 2020

Blood pressure postpartum (BP) RCT protocol: Follow-up and lifestyle behaviour change strategies in the first 12 months after hypertensive pregnancy.

Pregnancy Hypertens 2020 Oct 9;22:1-6. Epub 2020 Jul 9.

Department of Renal Medicine, St George Hospital, Kogarah, New South Wales, Australia; St George and Sutherland Clinical School, UNSW Medicine, University of New South Wales, Sydney, Australia.

Objectives: Women who had hypertensive disorders of pregnancy (HDP) are twice as likely to experience maternal cardiovascular disease later in life. The primary aim of this study (BP) is to compare outcomes of 3 different management strategies, including lifestyle behaviour change (LBC), in the first 12 months postpartum in women who had HDP in their preceding pregnancy. Secondary aims include assessing the effects on other cardiometabolic parameters.

Study Design: Three-arm multicentre randomised trial in metropolitan Australian hospitals, (registration: ACTRN12618002004246) target sample size 480. Participants are randomised to one of three groups: 1) Optimised usual care: information package and family doctor follow-up 6 months postpartum 2) Brief intervention: information package as per group 1, plus assessment and brief LBC counselling at a specialised clinic with an obstetric physician and dietitian 6 months postpartum 3) Extended intervention: as per group 2 plus enrolment into a 6 month telephone-based LBC program from 6 to 12 months postpartum. All women have an outcome assessment at 12 months.

Main Outcome Measures: Primary outcomes: (a) BP change or (b) weight change and/or waist circumference change.

Secondary Outcomes: maternal health-related quality of life, engagement and retention in LBC program, biochemical markers, vascular function testing, infant weight trajectory, incremental cost-effectiveness ratios. The study is powered to detect a 4 mmHg difference in systolic BP between groups, or a 4 kg weight loss difference/2cm waist circumference change.

Conclusions: BP will provide evidence regarding the feasibility and effectiveness of postpartum LBC interventions and structured clinical follow-up in improving cardiovascular health markers after HDP.
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http://dx.doi.org/10.1016/j.preghy.2020.07.001DOI Listing
October 2020

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

Ophthalmol Retina 2020 12 21;4(12):1151-1157. Epub 2020 May 21.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, Australia; Discipline of Child and Adolescent Health, University of Sydney, Sydney, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.oret.2020.05.009DOI Listing
December 2020

Changes in pancreatic exocrine function in young at-risk children followed to islet autoimmunity and type 1 diabetes in the ENDIA study.

Pediatr Diabetes 2020 09 9;21(6):945-949. Epub 2020 Jun 9.

Robinson Research Institute, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.

Backgrounds: We aimed to monitor pancreatic exocrine function longitudinally in relation to the development of islet autoimmunity (IA) and type 1 diabetes (T1D) in at-risk children with a first-degree relative with T1D, who were followed prospectively in the Environmental Determinants of Islet Autoimmunity (ENDIA) study.

Methods: Fecal elastase-1 (FE-1) concentration was measured longitudinally in 85 ENDIA children from median age 1.0 (IQR 0.7,1.3) year. Twenty-eight of 85 children (progressors) developed persistent islet autoantibodies at median age of 1.5 (IQR 1.1,2.5) years, of whom 11 went on to develop clinical diabetes. The other 57 islet autoantibody-negative children (non-progressors) followed similarly were age and gender-matched with the progressors. An adjusted linear mixed model compared FE-1 concentrations in progressors and non-progressors.

Results: Baseline FE-1 did not differ between progressors and non-progressors, or by HLA DR type or proband status. FE-1 decreased over time in progressors in comparison to non-progressors (Wald statistic 5.46, P = .02); in some progressors the fall in FE-1 preceded the onset of IA.

Conclusions: Pancreatic exocrine function decreases in the majority of young at-risk children who progress to IA and T1D.
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http://dx.doi.org/10.1111/pedi.13056DOI Listing
September 2020

Incidence of type 1 diabetes in 0 to 14 year olds in Australia from 2002 to 2017.

Pediatr Diabetes 2020 08 31;21(5):707-712. Epub 2020 May 31.

Telethon Kids Institute, Perth, Western Australia, Australia.

Objective: To determine the incidence of childhood onset type 1 diabetes in Australia from 2002 to 2017, and analyze incidence rate trends by calendar year, sex, and age at diagnosis.

Research Design And Methods: Children newly diagnosed with type 1 diabetes aged <15  years between 2002 and 2017 were identified from the National Diabetes Register, estimated to be ~99% complete. Data were obtained for diagnosis year, sex, age, and residential State/Territory at time of diagnosis. Population estimates by year, sex, single year of age, and State/Territory were obtained from the Australian Bureau of Statistics and Poisson regression used to examine incidence and trends by calendar year, sex, and age group at diagnosis.

Results: Between 2002 and 2017, there were 16 783 newly diagnosed cases of type 1 diabetes in children aged < 15 years (8684 boys: 8099 girls), giving a mean incidence of 25.0/1 00 000 person years (95%CI: 24.6, 25.4). A sinusoidal pattern in the incidence rate trend was observed with 5-yearly cycles providing the best model fit. No significant difference was observed in boys compared to girls (IRR 0.98 [95%CI: 0.95, 1.01]). Compared to 0 to 4  year olds, the mean incidence was 75% higher in 5 to 9  year olds, and 224% higher in 10 to 14 year olds. A decreasing incidence rate trend was observed in 0 to 4  year old boys and girls.

Conclusions: This study reports updated incidence and incidence rate trends in children and adolescents diagnosed with type 1 diabetes in Australia. A cyclical pattern in incidence trend persists, with an overall decreasing trend observed only in the youngest age group.
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http://dx.doi.org/10.1111/pedi.13025DOI Listing
August 2020

Higher frequency of vertebrate-infecting viruses in the gut of infants born to mothers with type 1 diabetes.

Pediatr Diabetes 2020 03 7;21(2):271-279. Epub 2020 Jan 7.

School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.

Background: Microbial exposures in utero and early life shape the infant microbiome, which can profoundly impact on health. Compared to the bacterial microbiome, very little is known about the virome. We set out to characterize longitudinal changes in the gut virome of healthy infants born to mothers with or without type 1 diabetes using comprehensive virome capture sequencing.

Methods: Healthy infants were selected from Environmental Determinants of Islet Autoimmunity (ENDIA), a prospective cohort of Australian children with a first-degree relative with type 1 diabetes, followed from pregnancy. Fecal specimens were collected three-monthly in the first year of life.

Results: Among 25 infants (44% born to mothers with type 1 diabetes) at least one virus was detected in 65% (65/100) of samples and 96% (24/25) of infants during the first year of life. In total, 26 genera of viruses were identified and >150 viruses were differentially abundant between the gut of infants with a mother with type 1 diabetes vs without. Positivity for any virus was associated with maternal type 1 diabetes and older infant age. Enterovirus was associated with older infant age and maternal smoking.

Conclusions: We demonstrate a distinct gut virome profile in infants of mothers with type 1 diabetes, which may influence health outcomes later in life. Higher prevalence and greater number of viruses observed compared to previous studies suggests significant underrepresentation in existing virome datasets, arising most likely from less sensitive techniques used in data acquisition.
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http://dx.doi.org/10.1111/pedi.12952DOI Listing
March 2020

Next generation sequencing of human enterovirus strains from an outbreak of enterovirus A71 shows applicability to outbreak investigations.

J Clin Virol 2020 01 17;122:104216. Epub 2019 Nov 17.

Virology Research Laboratory, Serology and Virology Division (SAViD), NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia; Serology and Virology Division (SAViD), NSW Health Pathology East, Department of Microbiology, Prince of Wales Hospital, Sydney, NSW 2031, Australia; School of Women's and Children's Health, University of New South Wales Medicine, Sydney, NSW 2052, Australia.

Background: The most recent documented Australian outbreak of enterovirus A71 (EV-A71) occurred in Sydney from 2012 to 2013. Over a four-month period more than 100 children presented to four paediatric hospitals with encephalitic presentations including fever and myoclonic jerks. The heterogeneous presentations included typical encephalomyelitis, and cardiopulmonary complications.

Objectives: To characterise the genomes of enterovirus strains circulating during the 2013 Sydney EV-A71 outbreak and determine their phylogeny, phylogeography and association between genome and clinical phenotype.

Study Design: We performed an analysis of enterovirus (EV) positive specimens from children presenting to hospitals in the greater Sydney region of Australia during the 2013 outbreak. We amplified near full-length genomes of EV, and used next generation sequencing technology to sequence the virus. We used phylogenetic/phylogeographic analysis to characterize the outbreak viruses.

Results: We amplified and sequenced 23/63 (37 %) genomes, and identified the majority (61 %) as EV-A71. The EV-A71 sequences showed high level sequence homology to C4a genogroups of EV-A71 circulating in China and Vietnam during 2012-13. Phylogenetic analysis showed EV-A71 strains associated with more severe symptoms, including encephalitis or cardiopulmonary failure, grouped together more closely than those from patients with hand, foot and mouth disease. Amongst the non-EV-A71 sequences were five other EV subtypes (representing enterovirus subtypes A and B), reflecting the diversity of EV co-circulation within the community.

Conclusions: This is the first Australian study investigating the near full-length genome of EV strains identified during a known outbreak of EV-A71. EV-A71 sequences were very similar to strains circulating in Asia during the same time period. Whole genome sequencing offers additional information over routine diagnostic testing such as characterisation of emerging recombinant strains and inform vaccine design.
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http://dx.doi.org/10.1016/j.jcv.2019.104216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384352PMC
January 2020

Longitudinal trajectories of BMI z-score: an international comparison of 11,513 Australian, American and German/Austrian/Luxembourgian youth with type 1 diabetes.

Pediatr Obes 2020 02 5;15(2):e12582. Epub 2019 Nov 5.

Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Ulm, Germany.

Background: BMI fluctuations during puberty are common. Data on individual change in BMI from childhood to young adulthood are limited in youth with type 1 diabetes.

Objectives: To compare longitudinal trajectories of body mass index z score (BMIz) from childhood to adolescence across three registries spanning five countries.

Methods: Data sources: T1DX (USA), DPV (Germany/Austria/Luxembourg) and ADDN (Australia). The analysis included 11,513 youth with type 1 diabetes, duration >1 year, at least one BMI measure at baseline (age 8-10 years) and >5 aggregated BMI measures by year of age during follow-up until age 17 years. BMIz was calculated based on WHO charts. Latent class growth modelling was used to identify subgroups following a similar trajectory of BMIz over time.

Results: Five distinct trajectories of BMIz were present in the T1DX and ADDN cohorts, while six trajectories were identified in the DPV cohort. Boys followed more often a low/near-normal pattern while elevated BMIz curves were more likely in girls (ADDN; DPV). For T1DX cohort, no sex differences were observed. Comparing the reference group (BMIz ~0) with the other groups during puberty, higher BMIz was significantly associated with older age at T1D onset, racial/ethnic minority and elevated HbA1c (all p<0.05).

Conclusion: This multinational study presents unique BMIz trajectories in youth with T1D across three continents. The prevalence of overweight and the longitudinal persistence of overweight support the need for close monitoring of weight and nutrition in this population. The international and individual differences likely result from diverse genetic, environmental and therapeutic factors.
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http://dx.doi.org/10.1111/ijpo.12582DOI Listing
February 2020

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

Nat Immunol 2019 10 18;20(10):1299-1310. Epub 2019 Sep 18.

Research School of Chemistry, The Australian National University, Canberra, Australian Capital Territory, Australia.

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.
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http://dx.doi.org/10.1038/s41590-019-0492-0DOI Listing
October 2019

Associations between circulating inflammatory markers, diabetes type and complications in youth.

Pediatr Diabetes 2019 12 2;20(8):1118-1127. Epub 2019 Oct 2.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

Background: Inflammation is implicated in the pathogenesis of diabetes and its complications in adults. Little is known about the relative contribution of inflammation in common types of diabetes in youth: type 1 diabetes (T1D), type 2 diabetes (T2D), and cystic fibrosis-related diabetes (CFRD). This study investigates inflammatory markers by diabetes type and complication status, and assesses indicators of inflammation and complications.

Methods: A cross-sectional study of 134 T1D, 32 T2D, 32 CFRD and 48 subjects without diabetes (including 11 with CF and normal glucose tolerance) was undertaken. Inflammation was assessed by sE-selectin by ELISA, hsCRP by turbidimetry, WCC and ESR. Nephropathy was defined by albuminuria, autonomic neuropathy by heart rate variability, and peripheral neuropathy by vibration and thermal threshold testing and retinopathy by seven-field stereoscopic fundus photography. Descriptive statistics, parametric and non-parametric ANOVA and regression analyses were performed, with significance at P < .05.

Results: Of 198 diabetic participants; 49% female, mean (SD) age, median diabetes duration and median HbA1c were 16 (2.5) and 6 (3-9) years, and 8.1 (6.9-9.3)%, respectively. All inflammatory markers were lower in T1D than in other diabetes groups (P < .05) but higher than in non-diabetic controls. T2D (n = 32) and CFRD (n = 32) subjects had comparable elevated levels of inflammation. Body mass index (BMI) was a strong independent explanatory variable of inflammation. In multivariate analysis, hsCRP and ESR were associated with complications in addition to HbA1c, BMI, and diastolic BP.

Conclusions: Circulating inflammatory markers are elevated in adolescents with diabetes, being higher and comparable in T2D and CFRD than in T1D. Inflammation is independently associated with diabetes complications, consistent with inflammation driving vascular pathology in diabetes.
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http://dx.doi.org/10.1111/pedi.12913DOI Listing
December 2019

Early-life factors contributing to type 1 diabetes.

Diabetologia 2019 10 27;62(10):1823-1834. Epub 2019 Aug 27.

School of Women's and Children's Health, University of New South Wales Faculty of Medicine, Sydney, NSW, Australia.

The incidence of type 1 diabetes has increased since the mid-twentieth century at a rate that is too rapid to be attributed to genetic predisposition alone. While the disease can occur at any age, mounting evidence from longitudinal cohort studies of at-risk children indicate that type 1 diabetes associated autoantibodies can be present from the first year of life, and that those who develop type 1 diabetes at a young age have a more aggressive form of the disease. This corroborates the hypothesis that environmental exposures in early life contribute to type 1 diabetes risk, whether related to maternal influences on the fetus during pregnancy, neonatal factors or later effects during infancy and early childhood. Studies to date show a range of environmental triggers acting at different time points, suggesting a multifactorial model of genetic and environmental factors in the pathogenesis of type 1 diabetes, which integrally involves a dialogue between the immune system and pancreatic beta cells. For example, breastfeeding may have a weak protective effect on type 1 diabetes risk, while use of an extensively hydrolysed formula does not. Additionally, exposure to being overweight pre-conception, both in utero and postnatally, is associated with increased risk of type 1 diabetes. Epidemiological, clinical and pathological studies in humans support a role for viral infections, particularly enteroviruses, in type 1 diabetes, but definitive proof is lacking. The role of the early microbiome and its perturbations in islet autoimmunity and type 1 diabetes is the subject of investigation in ongoing cohort studies. Understanding the interactions between environmental exposures and the human genome and metagenome, particularly across ethnically diverse populations, will be critical for the development of future strategies for primary prevention of type 1 diabetes.
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http://dx.doi.org/10.1007/s00125-019-4942-xDOI Listing
October 2019

Five heterogeneous HbA1c trajectories from childhood to adulthood in youth with type 1 diabetes from three different continents: A group-based modeling approach.

Pediatr Diabetes 2019 11 28;20(7):920-931. Epub 2019 Aug 28.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, Australia.

Objectives: Only a fraction of youth meet established targets for glycemic control; many experience deteriorating control over time. We compared trajectories of hemoglobin A1c (HbA1c) among youth from three trans-continental type 1 diabetes (T1D) registries and identified clinical variables associated with the odds of following increasing vs stable trajectories.

Research Design And Methods: Analyses included longitudinal data from 15 897 individuals age 8 to 18 with T1D for at least 2 years and HbA1c measurements in at least 5 years during the observation period. Cohorts were selected from Australasian Diabetes Data Network (ADDN; Australia), German/Austrian/Luxembourgian Diabetes-Patienten-Verlaufsdokumentation initiative (DPV; Germany/Austria/Luxembourga), and the T1D Exchange Clinic Network (T1DX; US) clinic registries. Group-based trajectory modeling and multivariable logistic regression identified unique HbA1c trajectories and their predictors.

Results: Five heterogeneous trajectories of glycemic control in each registry were identified: low, intermediate, high stable; intermediate and high increasing. The overall HbA1c level for each trajectory group tended to be lowest in the DPV, higher in the ADDN, and highest in the T1DX. The absolute level of HbA1c and the proportion of individuals within each trajectory varied across registries: 17% to 22% of individuals followed an increasing trajectory. Compared with maintaining a stable trajectory, following an increasing trajectory was significantly associated with ethnic minority status, lower height z-score, higher BMI z-score, insulin injection therapy, and the occurrence of severe hypoglycemia; however, these factors were not consistent across the three registries.

Conclusions: We report the first multinational registry-based comparison of glycemic control trajectories among youth with T1D from three continents and identify possible targets for intervention in those at risk of an increasing HbA1c trajectory.
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http://dx.doi.org/10.1111/pedi.12907DOI Listing
November 2019

Preponderance of Variation Associated With Autosomal Dominant Immune Dysregulation in the MYPPPY Motif.

Front Immunol 2019 23;10:1544. Epub 2019 Jul 23.

Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.

One of the primary targets of immune checkpoint inhibition is the negative immune regulatory molecule CTLA-4. Immune-related adverse events are commonly observed following CTLA-4 inhibition in melanoma treatment, and a spectrum of these conditions are also observed in individuals with germline haploinsufficiency of . Here we describe a heterozygous missense variant of in a young girl with childhood-onset autoimmune hepatitis and polyarthritis, the latter responding to treatment with CTLA-4-Ig fusion protein. This variant lay within the highly conserved MYPPPY motif of CTLA-4: a critical structural determinant of ligand binding, which is also bound by the anti-CTLA-4 monoclonal antibody ipilimumab. Within the spectrum of variants reported, missense variants in the MYPPPY motif were overrepresented when compared to variants within a control population, highlighting the physiological importance of this motif in both the genetic and pharmacological regulation of autoimmunity and anti-tumor immunity.
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http://dx.doi.org/10.3389/fimmu.2019.01544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664875PMC
November 2020

Using population data to understand the epidemiology and risk factors for diabetic ketoacidosis in Australian children with type 1 diabetes.

Pediatr Diabetes 2019 11 16;20(7):901-908. Epub 2019 Jul 16.

Child Population and Translational Health Research, Children's Hospital at Westmead Clinical School, The University of Sydney, Camperdown, New South Wales, Australia.

Background: Children with type 1 diabetes (T1D) are at risk of diabetic ketoacidosis (DKA) at T1D diagnosis and/or subsequently.

Objective: The objective is to determine the incidence and prevalence of T1D by the presence of DKA and identify the characteristics of subsequent DKA episodes.

Subjects: The study population included all children aged <15 years with T1D during a hospital/day-stay admission in New South Wales, Australia, from 1 January 2001 to 31 December 2013. T1D and DKA were identified using International Classification of Diseases Australian Modification codes.

Methods: Data sources included routinely collected longitudinally linked population hospitalization and birth records. Chi-squared analyses, logistic, and multinomial regression were used to determine the association between child characteristics and admissions with and without DKA.

Results: The point prevalence of T1D among 0-14-year olds on 31 December 2013 was 144.2 per 100 000. For children aged 0-12 years, the incidence of T1D was 16.3 per 100 000 child-years. One-third had DKA at T1D diagnosis and were more likely to be readmitted with DKA than those without DKA at T1D diagnosis. Children with more than one readmission for DKA were more likely to be female, reside in an inner regional area or an area of socioeconomic disadvantage, and be Australian-born. Among all hospitalizations of children with T1D, those with DKA were more likely to be aged 10-14 years, require intensive care, have longer length of stay, and admitted outside school days.

Conclusion: Routinely collected administrative health data are a reliable source to monitor incidence and health service use of childhood T1D. Children at risk of repeated DKA, particularly females, adolescents, and those from inner regional or socioeconomically disadvantaged areas, should be targeted during education and follow-up.
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http://dx.doi.org/10.1111/pedi.12891DOI Listing
November 2019
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