Publications by authors named "Fergus Cameron"

140 Publications

School Support for Children with Type 1 Diabetes Mellitus: The Parental Perspective.

J Paediatr Child Health 2021 Oct 13. Epub 2021 Oct 13.

Department of Endocrinology and Diabetes, The Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/jpc.15788DOI Listing
October 2021

Effect of a Hybrid Closed-Loop System on Glycemic and Psychosocial Outcomes in Children and Adolescents With Type 1 Diabetes: A Randomized Clinical Trial.

JAMA Pediatr 2021 Oct 11. Epub 2021 Oct 11.

Children's Diabetes Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.

Importance: Hybrid closed-loop (HCL) therapy has improved glycemic control in children and adolescents with type 1 diabetes; however, the efficacy of HCL on glycemic and psychosocial outcomes has not yet been established in a long-term randomized clinical trial.

Objective: To determine the percentage of time spent in the target glucose range using HCL vs current conventional therapies of continuous subcutaneous insulin infusion or multiple daily insulin injections with or without continuous glucose monitoring (CGM).

Design, Setting, And Participants: This 6-month, multicenter, randomized clinical trial included 172 children and adolescents with type 1 diabetes; patients were recruited between April 18, 2017, and October 4, 2019, in Australia. Data were analyzed from July 25, 2020, to February 26, 2021.

Interventions: Eligible participants were randomly assigned to either the control group for conventional therapy (continuous subcutaneous insulin infusion or multiple daily insulin injections with or without CGM) or the intervention group for HCL therapy.

Main Outcomes And Measures: The primary outcome was the percentage of time in range (TIR) within a glucose range of 70 to 180 mg/dL, measured by 3-week masked CGM collected at the end of the study in both groups. Secondary outcomes included CGM metrics for hypoglycemia, hyperglycemia, and glycemic variability and psychosocial measures collected by validated questionnaires.

Results: A total of 135 patients (mean [SD] age, 15.3 [3.1] years; 76 girls [56%]) were included, with 68 randomized to the control group and 67 to the HCL group. Patients had a mean (SD) diabetes duration of 7.7 (4.3) years and mean hemoglobin A1c of 64 (11) mmol/mol, with 110 participants (81%) receiving continuous subcutaneous insulin infusion and 72 (53%) receiving CGM. In the intention-to-treat analyses, TIR increased from a mean (SD) of 53.1% (13.0%) at baseline to 62.5% (12.0%) at the end of the study in the HCL group and from 54.6% (12.5%) to 56.1% (12.2%) in the control group, with a mean adjusted difference between the 2 groups of 6.7% (95% CI, 2.7%-10.8%; P = .002). Hybrid closed-loop therapy also reduced the time that patients spent in a hypoglycemic (<70 mg/dL) range (difference, -1.9%; 95% CI, -2.5% to -1.3%) and improved glycemic variability (coefficient of variation difference, -5.7%; 95% CI, -10.2% to -0.9%). Hybrid closed-loop therapy was associated with improved diabetes-specific quality of life (difference, 4.4 points; 95% CI, 0.4-8.4 points), with no change in diabetes distress. There were no episodes of severe hypoglycemia or diabetic ketoacidosis in either group.

Conclusions And Relevance: In this randomized clinical trial, 6 months of HCL therapy significantly improved glycemic control and quality of life compared with conventional therapy in children and adolescents with type 1 diabetes.

Trial Registration: ANZCTR identifier: ACTRN12616000753459.
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http://dx.doi.org/10.1001/jamapediatrics.2021.3965DOI Listing
October 2021

T cell receptor recognition of hybrid insulin peptides bound to HLA-DQ8.

Nat Commun 2021 08 25;12(1):5110. Epub 2021 Aug 25.

Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

HLA-DQ8, a genetic risk factor in type I diabetes (T1D), presents hybrid insulin peptides (HIPs) to autoreactive CD4+ T cells. The abundance of spliced peptides binding to HLA-DQ8 and how they are subsequently recognised by the autoreactive T cell repertoire is unknown. Here we report, the HIP (GQVELGGGNAVEVLK), derived from splicing of insulin and islet amyloid polypeptides, generates a preferred peptide-binding motif for HLA-DQ8. HLA-DQ8-HIP tetramer T cells from the peripheral blood of a T1D patient are characterised by repeated TRBV5 usage, which matches the TCR bias of CD4+ T cells reactive to the HIP peptide isolated from the pancreatic islets of a patient with T1D. The crystal structure of three TRBV5+ TCR-HLA-DQ8-HIP complexes shows that the TRBV5-encoded TCR β-chain forms a common landing pad on the HLA-DQ8 molecule. The N- and C-termini of the HIP is recognised predominantly by the TCR α-chain and TCR β-chain, respectively, in all three TCR ternary complexes. Accordingly, TRBV5 + TCR recognition of HIP peptides might occur via a 'polarised' mechanism, whereby each chain within the αβTCR heterodimer recognises distinct origins of the spliced peptide presented by HLA-DQ8.
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http://dx.doi.org/10.1038/s41467-021-25404-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387461PMC
August 2021

Increasing evidence of the benefits of a transition coordinator in type 1 diabetes.

Diabetologia 2021 Oct 14;64(10):2348-2351. Epub 2021 Aug 14.

Department of Endocrinology & Diabetes, The Royal Children's Hospital, Melbourne, Australia.

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http://dx.doi.org/10.1007/s00125-021-05536-xDOI Listing
October 2021

Neural differentiation medium for human pluripotent stem cells to model physiological glucose levels in human brain.

Brain Res Bull 2021 Aug 19;173:141-149. Epub 2021 May 19.

Department of Anatomy & Physiology, University of Melbourne, Australia; Illawarra Health and Medical Research Institute, Molecular Horizons, University of Wollongong, Australia; Department of Biomedical Engineering, University of Melbourne, Australia. Electronic address:

Cortical neurospheres (NSPs) derived from human pluripotent stem cells (hPSC), have proven to be a successful platform to investigate human brain development and neuro-related diseases. Currently, many of the standard hPSC neural differentiation media, use concentrations of glucose (approximately 17.5-25 mM) and insulin (approximately 3.2 μM) that are much greater than the physiological concentrations found in the human brain. These culture conditions make it difficult to analyse perturbations of glucose or insulin on neuronal development and differentiation. We established a new hPSC neural differentiation medium that incorporated physiological brain concentrations of glucose (2.5 mM) and significantly reduced insulin levels (0.86 μM). This medium supported hPSC neural induction and formation of cortical NSPs. The revised hPSC neural differentiation medium, may provide an improved platform to model brain development and to investigate neural differentiation signalling pathways impacted by abnormal glucose and insulin levels.
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http://dx.doi.org/10.1016/j.brainresbull.2021.05.016DOI Listing
August 2021

Modeling Type 1 Diabetes Using Pluripotent Stem Cell Technology.

Front Endocrinol (Lausanne) 2021 1;12:635662. Epub 2021 Apr 1.

Department of Cell Biology, Murdoch Children's Research Institute, Parkville, Vic, Australia.

Induced pluripotent stem cell (iPSC) technology is increasingly being used to create models of monogenic human disorders. This is possible because, by and large, the phenotypic consequences of such genetic variants are often confined to a specific and known cell type, and the genetic variants themselves can be clearly identified and controlled for using a standardized genetic background. In contrast, complex conditions such as autoimmune Type 1 diabetes (T1D) have a polygenic inheritance and are subject to diverse environmental influences. Moreover, the potential cell types thought to contribute to disease progression are many and varied. Furthermore, as HLA matching is critical for cell-cell interactions in disease pathogenesis, any model that seeks to test the involvement of particular cell types must take this restriction into account. As such, creation of an model of T1D will require a system that is cognizant of genetic background and enables the interaction of cells representing multiple lineages to be examined in the context of the relevant environmental disease triggers. In addition, as many of the lineages critical to the development of T1D cannot be easily generated from iPSCs, such models will likely require combinations of cell types derived from and sources. In this review we imagine what an ideal model of T1D might look like and discuss how the required elements could be feasibly assembled using existing technologies. We also examine recent advances towards this goal and discuss potential uses of this technology in contributing to our understanding of the mechanisms underlying this autoimmune condition.
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http://dx.doi.org/10.3389/fendo.2021.635662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047192PMC
April 2021

Investigating potential protein markers of cardiovascular disease in children with type 1 diabetes mellitus.

Proteomics Clin Appl 2021 05 16;15(2-3):e2000060. Epub 2021 Apr 16.

Haematology Research, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia.

Background: Type 1 diabetes mellitus (T1DM) is a metabolic disease characterized by dysglycaemia. Cardiovascular disease (CVD) is a major complication among T1DM patients and the leading cause of mortality later in life.

Methods: The study subjects consisted of T1DM children with poor glycemic control (HbA1c > 7.5%) and healthy age and gender matched controls. Venous blood samples were collected and tested by utilizing a novel immunoassay panel with 96 protein biomarkers. Data were analyzed using non-linear regression analysis and the expression of biomarkers was compared between T1DM and healthy control groups using an unpaired student's t-test. Dynamic principal component analysis (PCA) was operated based on the differentially expressed proteins.

Results: Ten T1DM children and 10 healthy controls were analyzed. Twelve CVD markers show significant differential expression between T1DM patients and healthy controls (p < 0.05). Dynamic PCA clustering based on differentially expressed proteins demonstrated an obvious clustering between the two populations.

Conclusions: This preliminary study reveals the feasibility of utilizing a novel immunoassay panel to investigate potential biomarkers for predicting incipient CVD in children with T1DM. In future, longitudinal studies are required to track the relationships between measurements of the selected protein markers and the development of CVD in T1DM patients.
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http://dx.doi.org/10.1002/prca.202000060DOI Listing
May 2021

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

J Clin Endocrinol Metab 2021 01;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

Has subsidized continuous glucose monitoring improved outcomes in pediatric diabetes?

Pediatr Diabetes 2020 11 10;21(7):1292-1300. Epub 2020 Sep 10.

Diabetes Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia.

Introduction: In 2017, the Australian Federal Government fully subsidized continuous glucose monitoring (CGM) devices for patients under 21 years of age with T1D with the aim of reducing rates of severe hypoglycaemia (SH) and improving metabolic control. The aim of this study was to reports on metabolic outcomes in youth from a single tertiary centre.

Methods: The study design was observational. Data were obtained on youth who commenced CGM between May 2017 and December 2019.

Results: Three hundred and forty one youth who commenced CGM and had clinical outcome data for a minimum of 4 months. 301, 261, 216, 172, and 125 had outcome data out to 8, 12, 16, 20, and 24 months, respectively. Cessation occurred between 27.9% and 32.8% of patients 12 to 24 months after CGM commencement. HbA1c did not change in patients who continued to use CGM. In the 12 months prior to starting CGM the rate of severe hypoglycaemia events were 5.0 per 100 patient years. The rates of severe hypoglycaemia in those continuing to use CGM at 4, 8, 12, 16, 20, and 24 months, were 5.2, 5.1, 1.6, 6.1, 2.4, and 0 per 100 patient years, respectively.

Discussion: Our experience of patients either ceasing or underusing CGM is less than reported in other cohorts but is nonetheless still high. There may have been a reduction in rates of severe hypoglycaemia over the 24 months follow up period; however, the absolute numbers of events were so low as to preclude meaningful statistical analysis.
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http://dx.doi.org/10.1111/pedi.13106DOI Listing
November 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

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

Successful post-transition engagement can be predicted at the time of transition in type 1 diabetes.

Diabetes Res Clin Pract 2020 05 16;163:108023. Epub 2020 Jan 16.

Department of Endocrinology & Diabetes, Murdoch Children's Research Institute at The Royal Children's Hospital, 50 Flemington Road, Parkville, Melbourne, VIC 3052, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.diabres.2020.108023DOI Listing
May 2020

Effect of frequency of sensor use on glycaemic control in individuals on sensor-augmented pump therapy with and without Predictive Low Glucose Management System.

Diabetes Res Clin Pract 2020 Jan 19;159:107989. Epub 2019 Dec 19.

Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Australia; Department of Endocrinology and Diabetes, Women's and Children's Hospital, Adelaide, Australia; Department of Endocrinology and Diabetes, John Hunter Children's Hospital, Newcastle, Australia; Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, The University of Sydney, Sydney, Australia; Department of Endocrinology and Diabetes, Royal Children's Hospital, Melbourne, Australia.

Improved frequency of sensor use improves glycaemic control. Furthermore, there is no deterioration of glycaemic control with increased sensor use in individuals on Predictive Low Glucose Management (PLGM) system. Younger children are more likely to have better sensor uptake than older children.
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http://dx.doi.org/10.1016/j.diabres.2019.107989DOI Listing
January 2020

Metabolism, cognition, and the brain throughout life.

Neurobiol Dis 2020 02 28;134:104698. Epub 2019 Nov 28.

Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

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http://dx.doi.org/10.1016/j.nbd.2019.104698DOI Listing
February 2020

Induced pluripotent stem cell macrophages present antigen to proinsulin-specific T cell receptors from donor-matched islet-infiltrating T cells in type 1 diabetes.

Diabetologia 2019 12 12;62(12):2245-2251. Epub 2019 Sep 12.

Murdoch Children's Research Institute, Flemington Road, Parkville, VIC, 3052, Australia.

Aims/hypothesis: Type 1 diabetes is an autoimmune disorder characterised by loss of insulin-producing beta cells of the pancreas. Progress in understanding the cellular and molecular mechanisms underlying the human disease has been hampered by a dearth of appropriate human experimental models. We previously reported the characterisation of islet-infiltrating CD4 T cells from a deceased organ donor who had type 1 diabetes.

Methods: Induced pluripotent stem cell (iPSC) lines derived from the above donor were differentiated into CD14 macrophages and tested for their capacity to present antigen to T cell receptors (TCRs) derived from islet-infiltrating CD4 T cells from the same donor.

Results: The iPSC macrophages displayed typical macrophage morphology, surface markers (CD14, CD86, CD16 and CD11b) and were phagocytic. In response to IFNγ treatment, iPSC macrophages upregulated expression of HLA class II, a characteristic that correlated with their capacity to present epitopes derived from proinsulin C-peptide to a T cell line expressing TCRs derived from islet-infiltrating CD4 T cells of the original donor. T cell activation was specifically blocked by anti-HLA-DQ antibodies but not by antibodies directed against HLA-DR.

Conclusions/interpretation: This study provides a proof of principle for the use of iPSC-derived immune cells for modelling key cellular interactions in human type 1 diabetes.
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http://dx.doi.org/10.1007/s00125-019-04988-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861360PMC
December 2019

Carlo Acerini - raging against the dying of the light.

Diabet Med 2019 09;36(9):1187-1188

Murdoch Children's Research Institute, Melbourne, Australia.

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http://dx.doi.org/10.1111/dme.14070DOI Listing
September 2019

The effect of type 1 diabetes on the developing brain.

Lancet Child Adolesc Health 2019 06 12;3(6):427-436. Epub 2019 Apr 12.

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

The effect of type 1 diabetes on the developing brain is a topic of primary research interest. A variety of potential dysglycaemic insults to the brain can cause cellular and structural injury and lead to altered neuropsychological outcomes. These outcomes might be subtle in terms of cognition but appear to persist into adult life. Age and circumstance at diagnosis appear to play a substantial role in potential CNS injury. A history of diabetic ketoacidosis and chronic hyperglycaemia appear to be more injurious than previously suspected, whereas a history of severe hypoglycaemia is perhaps less injurious. Neurocognitive deficits manifest across multiple cognitive domains, including executive function and speed of information processing. Some evidence suggests that subtle brain injury might directly contribute to psychological and mental health outcomes. Impaired executive function and mental health, in turn, could affect patients' adherence and the ability to make adaptive lifestyle choices. Impaired executive functioning creates a potential feedback loop of diabetic dysglycaemia leading to brain injury, further impaired executive function and mental health, which results in suboptimal adherence, and further dysglycaemia. Clinicians dealing with patients with suboptimal glycaemic outcomes should be aware of these potential issues.
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http://dx.doi.org/10.1016/S2352-4642(19)30055-0DOI Listing
June 2019

Characteristics of Automated Insulin Suspension and Glucose Responses with the Predictive Low-Glucose Management System.

Diabetes Technol Ther 2019 01 26;21(1):28-34. Epub 2018 Dec 26.

1 Children's Diabetes Center, Telethon Kids Institute, The University of Western Australia, Perth, Australia.

Background: The Predictive Low-Glucose Management (PLGM) system suspends basal insulin when hypoglycemia is predicted and reduces hypoglycemia. The aim of this analysis was to explore the characteristics of automated insulin suspension and sensor glucose (SG) responses following PLGM-initiated pump suspension.

Research Design And Methods: Children and adolescents with type 1 diabetes used the Medtronic MiniMed™ 640G pump as part of a randomized controlled trial. Data collected on a subgroup of participants on PLGM (suspend before low enabled) from CareLink Therapy Management Software were analyzed to explore the time and duration of PLGM-initiated pump suspension. Day and nighttime were defined as 06:00 am to 10:00 pm and 10:00 pm to 6:00 am, respectively.

Results: There were 20,183 suspend before low events in 8523 days (2.37 events/day). The mean suspend duration was 55.0 ± 32.7 min (day 50.0 ± 30.1, night 71.7 ± 35.1; P < 0.001). Although a 2-h pump suspension was more frequent at night (day 5%, night 18%), a patient-initiated resumption occurred more during day (day 34%, night 12%). SG values did not reach <3.5 and <3 mmol/L in 79% and 91% of the events, respectively. The 2-h SG following pump resumption was higher following autoresumption during the day (day vs. night 9.3 mmol/L vs. 8.4 mmol/L; P < 0.001).

Conclusions: Longer suspends and fewer glycemic excursions occur at night compared with day. The higher glycemic daytime excursions could be due to carbohydrate consumption to increase glucose levels and highlights the need for health care professionals to educate patients about carbohydrate intake around pump suspension.
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http://dx.doi.org/10.1089/dia.2018.0205DOI Listing
January 2019

Type 1 diabetes: new and fellow travellers.

Authors:
Fergus Cameron

Lancet Child Adolesc Health 2019 01 6;3(1):4-6. Epub 2018 Nov 6.

Department of Endocrinology and Diabetes, Royal Children's Hospital, Parkville, VIC 3052, Australia. Electronic address:

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http://dx.doi.org/10.1016/S2352-4642(18)30337-7DOI Listing
January 2019

NR5A1 gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients.

Hum Mutat 2019 02 30;40(2):207-216. Epub 2018 Nov 30.

Murdoch Children's Research Institute, Melbourne, Australia.

Several recent reports have described a missense variant in the gene NR5A1 (c.274C>T; p.Arg92Trp) in a significant number of 46,XX ovotesticular or testicular disorders of sex development (DSDs) cases. The affected residue falls within the DNA-binding domain of the NR5A1 protein, however the exact mechanism by which it causes testicular development in 46,XX individuals remains unclear. We have screened a cohort of 26 patients with 46,XX (ovo)testicular DSD and identified three unrelated individuals with this NR5A1 variant (p.Arg92Trp), as well as one patient with a novel NR5A1 variant (c.779C>T; p.Ala260Val). We examined the functional effect of these changes, finding that while protein levels and localization were unaffected, variant NR5A1 proteins repress the WNT signaling pathway and have less ability to upregulate the anti-testis gene NR0B1. These findings highlight how NR5A1 variants impact ovarian differentiation across multiple pathways, resulting in a switch from ovarian to testis development in genetic females.
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http://dx.doi.org/10.1002/humu.23672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492147PMC
February 2019

Two's company, is three a crowd? Ethical cognition in decision making and the role of industry third parties in pediatric diabetes care.

Pediatr Diabetes 2019 02 5;20(1):15-22. Epub 2018 Nov 5.

Children's Bioethics Centre, Royal Children's Hospital, Melbourne, Australia.

Families of children with diabetes increasingly obtain health information from a variety of sources. Doctor-patient relationships have accordingly become more fluid and dynamic with input from other parties. These outside parties include representatives from the diabetes health care industry-industry third parties (ITPs). This review is an exploration of the ethical principles and cognitive processes involved when doctors and patients negotiate around health care practices and the role of ITPs in that dialogue. Ethical principles of conflicts of interest, beneficence (act in the best interests of the patient), non-maleficence (act so as to do no harm) and justice (act so as to allocate resources fairly or justly) are relevant considerations. Reflexive and analytic thinking and various cognitive biases also play a significant part in clinical decision making. A complex case example is analyzed to highlight a process of ethical cognition in decision making to ensure high-value care and optimal patient outcomes.
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http://dx.doi.org/10.1111/pedi.12786DOI Listing
February 2019

Proinsulin C-peptide is an autoantigen in people with type 1 diabetes.

Proc Natl Acad Sci U S A 2018 10 1;115(42):10732-10737. Epub 2018 Oct 1.

Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia;

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells, found within the islets of Langerhans in the pancreas, are destroyed by islet-infiltrating T cells. Identifying the antigenic targets of beta-cell reactive T cells is critical to gain insight into the pathogenesis of T1D and develop antigen-specific immunotherapies. Several lines of evidence indicate that insulin is an important target of T cells in T1D. Because many human islet-infiltrating CD4 T cells recognize C-peptide-derived epitopes, we hypothesized that full-length C-peptide (PI), the peptide excised from proinsulin as it is converted to insulin, is a target of CD4 T cells in people with T1D. CD4 T cell responses to full-length C-peptide were detected in the blood of: 14 of 23 (>60%) people with recent-onset T1D, 2 of 15 (>13%) people with long-standing T1D, and 1 of 13 (<8%) HLA-matched people without T1D. C-peptide-specific CD4 T cell clones, isolated from six people with T1D, recognized epitopes from the entire 31 amino acids of C-peptide. Eighty-six percent (19 of 22) of the C-peptide-specific clones were restricted by HLA-DQ8, HLA-DQ2, HLA-DQ8, or HLA-DQ2, HLA alleles strongly associated with risk of T1D. We also found that full-length C-peptide was a much more potent agonist of some CD4 T cell clones than an 18mer peptide encompassing the cognate epitope. Collectively, our findings indicate that proinsulin C-peptide is a key target of autoreactive CD4 T cells in T1D. Hence, full-length C-peptide is a promising candidate for antigen-specific immunotherapy in T1D.
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http://dx.doi.org/10.1073/pnas.1809208115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196477PMC
October 2018

Clinic attendance and disengagement of young adults with type 1 diabetes after transition of care from paediatric to adult services (TrACeD): a randomised, open-label, controlled trial.

Lancet Child Adolesc Health 2017 Dec 5;1(4):274-283. Epub 2017 Oct 5.

Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Melbourne, VIC, Australia.

Background: Care transition from paediatric to adult services for young adults with type 1 diabetes is frequently associated with decreased attendance at outpatient hospital clinics and increased disengagement from specialist services. We aimed to assess the effect of an appointment-management intervention on clinic attendance and disengagement after transition.

Methods: We did a randomised, open-label, controlled trial of patients aged 17-19 years with type 1 diabetes. Participants were recruited from a tertiary paediatric diabetes service at the Royal Children's Hospital (Melbourne, VIC, Australia) and had to be scheduled for transition to adult services at one of eight centres in Melbourne. We randomly assigned participants (1:1), using sequential sealed opaque envelopes, to either appointment management (intervention) or current care (control). The appointment manager acted as the point of contact between intervention group participants and the relevant adult clinics, and provided personalised pre-appointment telephone and short message service (SMS) reminders with automatic rebooking of missed appointments. No contact was initiated with the control group after recruitment, and any self-initiated contact with the investigating team was directed to the participant's previous treating paediatric physician. The intervention continued throughout the trial until at least 12 months of follow-up data were obtained for all participants. We assessed the mean frequency of adult clinic attendance and disengagement from services during 0-12 months after transition (primary outcomes) and 12-24 months after transition (secondary outcomes), analysed by intention to treat. We used regression analyses, adjusted for clinic attendance and glycated haemoglobin concentration pre-transition, to analyse the effect of the intervention. This study is registered with the Australian New Zealand Clinical Trials Registry (number ACTRN12611001012965).

Findings: Between Jan 4, 2012, and Dec 31, 2014, we randomly assigned 120 individuals, 60 to the intervention and 60 to control. During 0-12 months after transition, the mean number of clinics attended was 2·3 (SD 1·1) in the intervention group and 2·3 (1·4) in the control group (p=0·84; adjusted β 0·1, SE 0·2, p=0·88); three (6%) of 49 participants in the intervention group and six (11%) of 55 in the control group disengaged from services (p=0·38; adjusted odds ratio [OR] 0·5, 95% CI 0·1-2·3, p=0·36). At 12-24 months post-transition, mean clinic attendance was 2·5 (SD 1·3) in the intervention group and 1·4 (SD 1·8) in the control group (p=0·001; adjusted β 0·9, SE 0·4, p=0·009); two (6%) of 32 in the intervention group and 18 (49%) of 37 in the control group disengaged from services (p=0·001; adjusted OR 0·1, 95% CI 0·1-0·2, p=0·001). Neither the intervention nor pre-transition clinic attendance had an independent effect on glycated haemoglobin after transition.

Interpretation: Appointment management did not increase clinic attendance and did not decrease disengagement with services 0-12 months after transition to adult services, but had a positive effect during 12-24 months after transition.

Funding: Australasian Paediatric Endocrine Group and Lilly.
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http://dx.doi.org/10.1016/S2352-4642(17)30089-5DOI Listing
December 2017

Effect of 6 months hybrid closed-loop insulin delivery in young people with type 1 diabetes: a randomised controlled trial protocol.

BMJ Open 2018 08 13;8(8):e020275. Epub 2018 Aug 13.

Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia.

Introduction: Automated insulin delivery (also known as closed loop, or artificial pancreas) has shown potential to improve glycaemic control and quality of life in people with type 1 diabetes (T1D). Automated insulin delivery devices incorporate an insulin pump with continuous glucose monitoring(CGM) and an algorithm, and adjust insulin in real time. This study aims to establish the safety and efficacy of a hybrid closed-loop (HCL) system in a long-term outpatient trial in people with T1D aged 12 -<25 years of age, and compare outcomes with standard therapy for T1D as used in the contemporary community.

Methods And Analysis: This is an open-label, multicentre, 6-month, randomised controlled home trial to test the MiniMed Medtronic 670G system (HCL) in people with T1D aged 12 -<25 years, and compare it to standard care (multiple daily injections or continuous subcutaneous insulin infusion (CSII), with or without CGM). Following a run-in period including diabetes and carbohydrate counting education, dosage optimisation and baseline glucose control data collection, participants are randomised to either HCL or to continue on their current treatment regimen. The primary aim of the study is to compare the proportion of time spent in target sensor glucose range (3.9-10.0 mmol/L) on HCL versus standard therapy. Secondary aims include a range of glucose control parameters, psychosocial measures, health economic measures, biomarker status, user/technology interactions and healthcare professional expectations. Analysis will be intention to treat. A study in adults with an aligned design is being conducted in parallel to this trial.

Ethics And Dissemination: Ethics committee permissions were gained from respective institutional review boards. The findings of the study will provide high-quality evidence on the role of HCL in clinical practice.
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http://dx.doi.org/10.1136/bmjopen-2017-020275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091910PMC
August 2018

ISPAD Clinical Practice Consensus Guidelines 2018: Diabetes in adolescence.

Pediatr Diabetes 2018 10;19 Suppl 27:250-261

Instituto de Investigaciones Materno Infantil, Facultad de Medicina, University of Chile, Santiago, Chile.

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http://dx.doi.org/10.1111/pedi.12702DOI Listing
October 2018

Effect of 6 months of hybrid closed-loop insulin delivery in adults with type 1 diabetes: a randomised controlled trial protocol.

BMJ Open 2018 06 9;8(6):e020274. Epub 2018 Jun 9.

Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.

Introduction: Manual determination of insulin dosing largely fails to optimise glucose control in type 1 diabetes. Automated insulin delivery via closed-loop systems has improved glucose control in short-term studies. The objective of the present study is to determine the effectiveness of 6 months' closed-loop compared with manually determined insulin dosing on time-in-target glucose range in adults with type 1 diabetes.

Methods And Analysis: This open-label, seven-centre, randomised controlled parallel group clinical trial will compare home-based hybrid closed-loop versus standard diabetes therapy in Australia. Adults aged ≥25 years with type 1 diabetes using intensive insulin therapy (via multiple daily injections or insulin pump, total enrolment target n=120) will undertake a run-in period including diabetes and carbohydrate-counting education, clinical optimisation and baseline data collection. Participants will then be randomised 1:1 either to 26 weeks of MiniMed 670G hybrid closed-loop system therapy (Medtronic, Northridge, CA, USA) or continuation of their current diabetes therapy. The hybrid closed-loop system delivers insulin automatically to address basal requirements and correct to target glucose level, while bolus doses for meals require user initiation and carbohydrate estimation. Analysis will be intention to treat, with the primary outcome time in continuous glucose monitoring (CGM) target range (3.9-10.0 mmol/L) during the final 3 weeks of intervention. Secondary outcomes include: other CGM parameters, HbA, severe hypoglycaemia, psychosocial well-being, sleep, cognition, electrocardiography, costs, quality of life, biomarkers of vascular health and hybrid closed-loop system performance. Semistructured interviews will assess the expectations and experiences of a subgroup of hybrid closed-loop users.

Ethics And Dissemination: The study has Human Research Ethics Committee approval. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results will be disseminated at scientific conferences and via peer-reviewed publications.

Trial Registration Number: ACTRN12617000520336; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2017-020274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009467PMC
June 2018

Polymicrogyria in association with hypoglycemia points to mutation in the mTOR pathway.

Eur J Med Genet 2018 Dec 5;61(12):738-740. Epub 2018 Jun 5.

Department of Neurology, Royal Children's Hospital, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia.

We report a 16-month-old male with congenital megalencephaly, polymicrogyria and persistent hypoglycemia caused by a mosaic PIK3CA pathogenic variant. Hypoinsulinaemic, hypoketotic hypoglycaemia is a rare complication of pathogenic variants in the PI3K-AKT-mTOR pathway genes including AKT2, AKT3, CCND2, PIK3R2 and PIK3CA, and has been identified in a PIK3CA mutant mouse model. Our case highlights the importance of considering PI3K-AKT-mTOR pathway variants as a cause for megalencephaly and cortical malformation when the phenotype includes hypoglycaemia. Recognizing the association of hypoglycemia with PI3K-AKT-mTOR pathway variants can provide a clue to the genetic basis of the cortical malformation. Patients with megalencephaly and a cortical malformation may be considered at risk of hypoglycaemia and monitored accordingly, at least until a PI3K-AKT-mTOR pathway variant has been excluded.
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http://dx.doi.org/10.1016/j.ejmg.2018.06.002DOI Listing
December 2018

Common Issues Seen in Paediatric Diabetes Clinics, Psychological Formulations, and Related Approaches to Management.

J Diabetes Res 2018 27;2018:1684175. Epub 2018 Feb 27.

Department of Endocrinology and Diabetes, Royal Children's Hospital, Melbourne, VIC, Australia.

Diabetes is a chronic disease and its management is associated with multiple challenges. This is particularly the case in children and adolescents. Factors that contribute to difficulties in managing diabetes in youth include psychological characteristics, family dynamics, and social behavior. The purpose of this article is to highlight some psychological issues in children and adolescents with diabetes. We aim to present selected case scenarios encountered by health professionals and to provide tips on strategies for managing psychological aspect of diabetes. We tackle the psychological issues related to diabetes under four main categories: maladaptive disorders, eating disorders, family psychopathology, and family dysfunction. Psychotherapy and psychoanalysis are useful modalities in diabetes management. The psychological intervention is aimed at supporting patients and families to reach a balance between a normal family routine and a good glycemic control. We demonstrate unique requirements in coordinating care for children and adolescents with diabetes and highlight the importance of encouraging a positive behavior. Managing diabetes in children and adolescents needs to be in the form of a collaborative work between health care professionals, children and adolescents, and their families. Caring, supportive family backed up by experienced multidisciplinary team is the best approach to prevent psychological difficulties.
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http://dx.doi.org/10.1155/2018/1684175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848057PMC
September 2018

Higher parental occupational social contact is associated with a reduced risk of incident pediatric type 1 diabetes: Mediation through molecular enteroviral indices.

PLoS One 2018 17;13(4):e0193992. Epub 2018 Apr 17.

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

We aimed to examine the association between parental occupational social contact and hygiene factors on type 1 diabetes (T1D) risk and possible mediation of these effects through child enteroviral infection. We interviewed 333 incident T1D cases and 660 controls from 2008-2011 in Melbourne, Australia. Enteroviral indices (ribonucleic acid by reverse transcription polymerase chain reaction and Coxsackie B virus antibody levels) in peripheral blood were measured in nested case control samples. Parent occupational social contact was assessed by the number of well or sick children, adults or animals contacted daily through work. Higher parental occupational social contact was strongly associated with reduced T1D risk with evidence of dose response (contact with the well or sick score, Adjusted odds ratio (AOR) per category: 0.73 (95% Confidence Interval (CI): 0.66, 0.81); P<0.001 or AOR 0.63 (95% CI: 0.53, 0.75); P<0.001) respectively). Nine of the ten parental social contact indices, were significant mediated through one or more enteroviral indices. The strength of association between enterovirus presence and T1D onset increased with child age (1.2 fold increase per year; P = 0.05). Lower child hand hygiene enhanced the adverse effect of low parental occupational contact with the sick; Synergy Index 5.16 (95% CI: 3.61, 7.36). The interaction between hand washing and parental occupational contact is more consistent with protection against parental enteroviral shedding than the sharing of a protective infectious agent or microbiome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193992PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903611PMC
July 2018
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