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INTRODUCTION: The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is an ongoing Australian prospective cohort study investigating how modifiable prenatal and early-life exposures drive the development of islet autoimmunity and type 1 diabetes (T1D) in children. In this profile, we describe the cohort's parental demographics, maternal and neonatal outcomes and human leukocyte antigen (HLA) genotypes. RESEARCH DESIGN AND METHODS: Inclusion criteria were an unborn child, or infant aged less than 6 months, with a first-degree relative (FDR) with T1D. The primary outcome was persistent islet autoimmunity, with children followed until a T1D diagnosis or 10 years of age. Demographic data were collected at enrollment. Lifestyle, clinical and anthropometric data were collected at each visit during pregnancy and clinical pregnancy and birth data were verified against medical case notes. Data were compared between mothers with and without T1D. HLA genotyping was performed on the ENDIA child and all available FDRs. RESULTS: The final cohort comprised 1473 infants born to 1214 gestational mothers across 1453 pregnancies, with 80% enrolled during pregnancy. The distribution of familial T1D probands was 62% maternal, 28% paternal and 11% sibling. The frequency of high-risk HLA genotypes was highest in T1D probands, followed by ENDIA infants, and lowest among unaffected family members. Mothers with T1D had higher rates of pregnancy complications and perinatal intervention, and larger babies of shorter gestation. Parent demographics were comparable to the Australian population for age, parity and obesity. A greater percentage of ENDIA parents were Australian born, lived in a major city and had higher socioeconomic advantage and education. CONCLUSIONS: This comprehensive profile provides the context for understanding ENDIA's scope, methodology, unique strengths and limitations. Now fully recruited, ENDIA will provide unique insights into the roles of early-life factors

Background: Little is known about the effect of dysglycemia during cystic fibrosis pulmonary exacerbation (PEx) on recovery of FEV1 percentage predicted (ppFEV1) Methods: Continuous glucose monitoring (CGM) was commenced at the time of admission to hospital for PEx and continued for 6 weeks. The CGM indices, percentage of time glucose greater than 7.8 mmol/L (%T>7.8) and mean glucose were evaluated as predictors of absolute ppFEV1 change following treatment of PEx. Result(s): Of the 20 participants who completed the study 13 (65%) had cystic fibrosis related diabetes (CFRD). The mean of both CGM indices were highest during the first week of pulmonary exacerbation and continued to decline over the first 4 weeks at which point they plateaued. Using multivariate regression models, factors which were predictive of maximum attained ppFEV1 change over 6 weeks were %T>7.8, mean glucose, HbA1c and preadmission ppFEV1 change from baseline. These relationships were independent of a diagnosis of CFRD, which was not associated with ppFEV1 recovery. In a longitudinal model of ppFEV1 change at weeks 1, 2 and 6, the CGM index %T>7.8 approached significance as a predictive variable. Conclusion(s): Hyperglycemia during PEx in adult CF patients is associated with poorer ppFEV1 recovery. Conversely, there was no association observed between CFRD diagnosis and ppFEV1 improvement, suggesting that optimization of glycemic control in CFRD patients may positively influence recovery of lung function. Further clinical trials are required to evaluate the merits of intensive glycemic control in CFRD during PEx.Copyright © 2021

Introduction: We aimed to compare the mental health of mothers, with and without type 1 diabetes (T1D), during pregnancy and postpartum, and to examine the relationship between glycaemic control and mental health in T1D. Objective(s): We hypothesised that mental health in trimester 3 (T3) and post-partum is less favourable in mothers with T1D, and that poorer mental health scores relate directly to glycaemic control. Method(s): Participants were 800/946 women enrolled in the Environmental Determinants of Islet Autoimmunity (ENDIA) study, an Australiawide pregnancy-birth prospective cohort following children with a first-degree relative with T1D, from 2016-2020.Women with and without T1D (n=518, 282) completed the Edinburgh Postnatal Depression Scale (EPDS) and Perceived Stress Scale (PSS) during T3, (median [IQR], 34 [32, 36] weeks) and early post-partum (median 14 [13, 16] weeks). Linear mixed regression models were adjusted for parity. Result(s): Women without T1D were aged mean (SD) 33.1 (4.4) years; 31.9 (4.4) years with T1D. Pre-existing mental health issues requiring psychotropic medications were of similar number in non-T1D n=17 [6%] and T1D n=41 [8%]. EPDS and PSS scores did not differ between non-T1D and T1D mothers at T3 or post-partum (all p>=0.5; Table 1). EPDS scores were less favourable at T3 compared with postpartum (p=0.01), independent of T1D status, and by post-partum 12/47 women had improved to below the threshold (=12) recommended for intervention. HbA1c during pregnancy in 398/518 women (76.8%) with T1D did not relate to EPDS (r2=0.01, p=0.2) or PSS (r2=0.02, p=0.4) scores. Median [IQR] HbA1c was 6.3% [5.8-6.9]. Conclusion(s): Overall, mental health in late pregnancy and postpartum was not adversely impacted by T1D. Glycaemic control did not relate to mental health scores in mothers with T1D. A generalised improvement in mental health between T3 and post-partum was independent of T1D status.

Background: The gut microbiome changes in response to a range of environmental conditions, life events and disease states. Pregnancy is a natural life event that involves major physiological adaptation yet studies of the microbiome in pregnancy are limited and their findings inconsistent. Pregnancy with type 1 diabetes (T1D) is associated with increased maternal and fetal risks but the gut microbiome in this context has not been characterized. By whole metagenome sequencing (WMS), we defined the taxonomic composition and function of the gut bacterial microbiome across 70 pregnancies, 36 in women with T1D. Result(s): Women with and without T1D exhibited compositional and functional changes in the gut microbiome across pregnancy. Profiles in women with T1D were distinct, with an increase in bacteria that produce lipopolysaccharides and a decrease in those that produce short-chain fatty acids, especially in the third trimester. In addition, women with T1D had elevated concentrations of fecal calprotectin, a marker of intestinal inflammation, and serum intestinal fatty acid-binding protein (I-FABP), a marker of intestinal epithelial damage. Conclusion(s): Women with T1D exhibit a shift towards a more pro-inflammatory gut microbiome during pregnancy, associated with evidence of intestinal inflammation. These changes could contribute to the increased risk of pregnancy complications in women with T1D and are potentially modifiable by dietary means. [MediaObject not available: see fulltext.]Copyright © 2021, The Author(s).

Gestational diabetes mellitus (GDM) is common and is associated with an increased risk of adverse pregnancy outcomes. However, the prevailing one-size-fits-all approach that treats all women with GDM as having equivalent risk needs revision, given the clinical heterogeneity of GDM, the limitations of a population-based approach to risk, and the need to move beyond a glucocentric focus to address other intersecting risk factors. To address these challenges, we propose using a clinical prediction model for adverse pregnancy outcomes to guide risk-stratified approaches to treatment tailored to the individual needs of women with GDM. This will allow preventative and therapeutic interventions to be delivered to those who will maximally benefit, sparing expense, and harm for those at a lower risk.Copyright © 2021 Cambridge University Press. All rights reserved.

Background: Hybrid closed-loop systems may offer improved HbA1c levels, more time-in-range, and less hypoglycemia than alternative treatment strategies. However, it is unclear if glycemic improvements offset this technology's higher acquisition costs. Among adults with type 1 diabetes in Australia, we sought to evaluate the cost-effectiveness of a hybrid closed-loop system in comparison with the current standard of care, comprising insulin injections and capillary glucose testing. Method(s): Cost-effectiveness analysis was performed using decision analysis in combination with a Markov model to simulate disease progression in a cohort of adults with type 1 diabetes and compare the downstream health and economic consequences of hybrid closed-loop therapy versus current standard of care. Transition probabilities and utilities were sourced from published studies. Costs were considered from the perspective of the Australian health care system. A lifetime horizon was considered, with annual discount rates of 5% applied to future costs and outcomes. Uncertainty was assessed with probabilistic and deterministic sensitivity analyses. Result(s): Use of a hybrid closed-loop system resulted in an incremental cost-effectiveness ratio of Australian dollars (AUD) 37,767 per quality-adjusted life year (QALY) gained. This is below the traditionally cited willingness to pay a threshold of $50,000 per QALY gained in the Australian setting. Sensitivity analyses that varied baseline glycemic control, treatment effects, technology costs, age, discount rates, and time horizon indicated the results to be robust. Conclusion(s): For adults with type 1 diabetes, hybrid closed-loop therapy is likely to be cost-effective compared with multiple daily injections and capillary glucose testing in Australia.Copyright © 2020, Mary Ann Liebert, Inc., publishers.

Gestational diabetes (GDM) increases the risk of pregnancy complications. However, these risks are not the same for all affected women and may be mediated by inter-related factors including ethnicity, body mass index and gestational weight gain. This study was conducted to identify, compare, and critically appraise prognostic prediction models for pregnancy complications in women with gestational diabetes (GDM). A systematic review of prognostic prediction models for pregnancy complications in women with GDM was conducted. Critical appraisal was conducted using the prediction model risk of bias assessment tool (PROBAST). Five prediction modelling studies were identified, from which ten prognostic models primarily intended to predict pregnancy complications related to GDM were developed. While the composition of the pregnancy complications predicted varied, the delivery of a large-for-gestational age neonate was the subject of prediction in four studies, either alone or as a component of a composite outcome. Glycaemic measures and body mass index were selected as predictors in four studies. Model evaluation was limited to internal validation in four studies and not reported in the fifth. Performance was inadequately reported with no useful measures of calibration nor formal evaluation of clinical usefulness. Critical appraisal using PROBAST revealed that all studies were subject to a high risk of bias overall driven by methodologic limitations in statistical analysis. This review demonstrates the potential for prediction models to provide an individualised absolute risk of pregnancy complications for women affected by GDM. However, at present, a lack of external validation and high risk of bias limit clinical application. Future model development and validation should utilise the latest methodological advances in prediction modelling to achieve the evolution required to create a useful clinical tool. Such a tool may enhance clinical decision-making and support a risk

We aimed to compare the impact of different family probands on the quality of the ENDIA infants' diet. ENDIA is an early life cohort following children at-risk of type 1 diabetes (T1D) with a mother, father or sibling with T1D. Parents' nutrition knowledge influences children's preferences and intake. We hypothesised that having a T1D sibling would improve the infant's diet quality, compared to having a T1D parent, due to more recent nutrition education. We also measured other influences on infant diet. Infant diet was recorded using three telephone assisted 24 hour recalls on weekend and weekdays with photograph-guided reports of portion sizes. Data were analysed in Foodworks Professional Version 8, Australia. Linear regression models, with generalised estimating equations, compared diet intake between infants. Diet intake of 433 infants, mean age 12.6 months (SD 0.7), did not show a statistically significant difference depending on whether their mother (58%), father (31%) or sibling (11%) had T1D. Mean infant weight z -score was 0.46 (SD 1.09). Mother probands were 32.9 (4.6) years, fathers 35.4 (5.1), siblings 7.6 (3.3). T1D duration [median (IQR)] was 17.8 (11.6-24.8) years for mothers, 17.4 (9.9-25.2) fathers, 3.2 (1.7-4.6) siblings. Energy intake in all groups exceeded daily requirements by 440-743 kilojoules (excess 13-23% of recommended intake) and protein intake of 38.2 (14) g was triple the estimated daily requirement. Increase in maternal age by one year was associated with a decrease in infant daily sodium intake of 7 mg (95% CI 2.11 -12.54, p=0.006). Infants with any sibling had a daily increase of 0.3 teaspoon of added sugar (95% CI 0.02 - 0.062, p=0.03) and 74 mg of sodium (95% CI 24-125, p=0.004). Infant diet quality was not improved by having a sibling with T1D and more recent nutrition education. Infants with any sibling had increased intake of salt and sugar. Most infants consumed excess energy but their weight remained in the healthy range.

Background: Tobacco smoking and diabetes mellitus contribute significantly to the overall health burden and mortality of Australians. We aimed to assess the relationship of smoking with glycemic control, metabolic profile and complications in Australian patients living with diabetes. Method(s): We analysed the 2011-2017 biennial Australian National Diabetes Audit cross-sectional data. Patients were classified as current, past or never smokers. Linear (or quantile) and logistic regression models were used to assess for associations. Result(s): Data from 15,352 patients were analysed, including 72.2% with type 2 diabetes. Current smokers comprised 13.5% of the study population. Current and past smokers had a median HbA1c that was 0.49% and 0.14% higher than never smokers, respectively, as well as higher triglyceride and lower HDL levels (all p values <.0001). Compared to never smokers, current smokers had higher odds of severe hypoglycemia and current and past smokers had higher odds of myocardial infarction, stroke, peripheral vascular disease, lower limb amputation, erectile dysfunction and peripheral neuropathy (all p values <=.001), with no significant change over time. Conclusion(s): When compared to never smokers, current and past smokers had poorer glycemic and lipid control and higher odds of macrovascular and microvascular complications. Despite this, current smoking remains prevalent among Australians with diabetes.Copyright © 2020 Elsevier Inc.

Introduction Gestational diabetes (GDM) is a common yet highly heterogeneous condition. The ability to calculate the absolute risk of adverse pregnancy outcomes for an individual woman with GDM would allow preventative and therapeutic interventions to be delivered to women at high-risk, sparing women at low-risk from unnecessary care. The Prediction for Risk-Stratified care for women with GDM (PeRSonal GDM) study will develop, validate and evaluate the clinical utility of a prediction model for adverse pregnancy outcomes in women with GDM. Methods and analysis We undertook formative research to conceptualise and design the prediction model. Informed by these findings, we will conduct a model development and validation study using a retrospective cohort design with participant data collected as part of routine clinical care across three hospitals. The study will include all pregnancies resulting in births from 1 July 2017 to 31 December 2018 coded for a diagnosis of GDM (estimated sample size 2430 pregnancies). We will use a temporal split-sample development and validation strategy. A multivariable logistic regression model will be fitted. The performance of this model will be assessed, and the validated model will also be evaluated using decision curve analysis. Finally, we will explore modes of model presentation suited to clinical use, including electronic risk calculators. Ethics and dissemination This study was approved by the Human Research Ethics Committee of Monash Health (RES-19-0000713 L). We will disseminate results via presentations at scientific meetings and publication in peer-reviewed journals. Trial registration details Systematic review proceeding this work was registered on PROSPERO (CRD42019115223) and the study was registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12620000915954); Pre-results.Copyright © 2020 Royal Society of Chemistry. All rights reserved.

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. Method(s): 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. Result(s): 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. Conclusion(s): Pancreatic exocrine function decreases in the majority of young at-risk children who progress to IA and T1D.Copyright © 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Purpose: Kidney disease caused by type 1 diabetes can progress to end stage renal disease and can increase mortality risk. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) plays a major role in producing oxidative stress in the kidney in diabetes, and its activity is attenuated by GKT137831, an oral Nox inhibitor with predominant inhibitory action on Nox-1 and Nox - 4. Previous studies have demonstrated renoprotective effects with GKT137831 in various experimental models of type 1 diabetes-related kidney disease. This study will evaluate the effect of GKT137831 in treating clinical diabetic kidney disease. Design(s): This is a multi-center, randomized, placebo-controlled trial, parallel arm study evaluating the effect on albuminuria of treatment with GKT137831 400 mg BID for 48 weeks. The study will randomize 142 participants who have persistent albuminuria and estimated glomerular filtration rate (eGFR) at baseline of at least 40 ml/min/1.73m2. Primary outcome measures: Difference between arms in urine albumin to creatinine ratio. Secondary outcome measures include eGFR. Conclusion(s): This study is important because it may identify a new way of slowing renal disease progression in people with type 1 diabetes and albuminuria already receiving standard of care treatment.Copyright © 2019

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.

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.

not available.Copyright © 2018

Background: Gestational diabetes (GDM) is increasingly common and has significant implications during pregnancy and for the long-term health of the mother and offspring. However, it is a heterogeneous condition with inter-related factors including ethnicity, body mass index and gestational weight gain significantly modifying the absolute risk of complications at an individual level. Predicting the risk of pregnancy complications for an individual woman with GDM presents a useful adjunct to therapeutic decision-making and patient education. Diagnostic prediction models for GDM are prevalent. In contrast, prediction models for risk of complications in those with GDM are relatively novel. This study will systematically review published prognostic prediction models for pregnancy complications in women with GDM, describe their characteristics, compare performance and assess methodological quality and applicability. Method(s): Studies will be identified by searching MEDLINE and Embase electronic databases. Title and abstract screening, full-text review and data extraction will be completed independently by two reviewers. The included studies will be systematically assessed for risk of bias and applicability using appropriate tools designed for prediction modelling studies. Extracted data will be tabulated to facilitate qualitative comparison of published prediction models. Quantitative data on predictive performance of these models will be synthesised with meta-analyses if appropriate. Discussion(s): This review will identify and summarise all published prognostic prediction models for pregnancy complications in women with GDM. We will compare model performance across different settings and populations with meta-analysis if appropriate. This work will guide subsequent phases in the prognosis research framework: further model development, external validation and model updating, and impact assessment. The ultimate model will estimate the absolute risk of pregnancy complicat

Aim: With no current randomized trials, we explored the impact of tight compared with standard treatment targets on pregnancy outcomes in gestational diabetes mellitus (GDM). Method(s): This cohort study of singleton births >= 28 weeks' gestation was conducted at two major Australian maternity services (2009-2013). Standardized maternal, neonatal and birth outcomes were examined using routine healthcare data and compared for women with GDM at Service One (n = 2885) and Service Two (n = 1887). Services applied different treatment targets: Service One (standard targets, reference group) fasting < 5.5 mmol/l, 2-h postprandial < 7.0 mmol/l; Service Two (tight targets) fasting < 5.0 mmol/l, 2-h postprandial < 6.7 mmol/l. Multivariable regression with propensity score adjustment was used to examine associations between targets and outcomes. Result(s): GDM prevalence and insulin use were 7.9% and 31% at Service One, and 5.7% and 46% at Service Two. There were no differences in primary outcomes: birthweight > 90th centile [adjusted odds ratio (OR) 1.06, 95% confidence interval (CI) 0.87-1.30] and < 10th centile (OR 0.84, 95% CI 0.70-1.01), or secondary outcomes gestational hypertension, pre-eclampsia, shoulder dystocia or a perinatal composite. Service Two with tight targets had increased induction of labour (OR 3.63, 95% CI 3.17-4.16), elective Caesarean section (OR 1.75, 95% CI 1.37-2.23) and Apgar scores < 7 at 5 min (OR 1.54, 95% CI 1.05-2.25), decreased hypoglycaemia (OR 0.76, 95% CI 0.61-0.94]), jaundice (OR 0.47, 95% CI 0.35-0.63) and respiratory distress (OR 0.68, 95% CI 0.47-0.98). Conclusion(s): Tight GDM treatment targets were associated with greater insulin use and no difference in primary birthweight outcomes. The service with tight targets had higher obstetric intervention, lower rates of reported hypoglycaemia, jaundice, respiratory distress and lower Apgar scores. High-quality interventional data are required before tight treatment targets can be implemented

Aims/hypothesis: The aim of this work was to investigate clinical outcomes following severe hypoglycaemia requiring prehospital emergency medical services (EMS) management. Method(s): We carried out a prospective, observational study of adults with diabetes attended by prehospital EMS for management of severe hypoglycaemia between April 2016 and July 2017. Information on precipitants, hospitalisation, length of hospital stay and recurrence was collected at 1 and 3 months following the episode of severe hypoglycaemia. Median and logistic regression models examined predictive factors. Result(s): Five hundred and five adults (61% male, median age 67 years) participated in the study. Fifty-two per cent had type 1 diabetes, 43% type 2 diabetes and 5% were unsure of their diabetes type. Following EMS management of the index episode of severe hypoglycaemia, 50.3% were transported to hospital. Of those transported, 41.3% were admitted to hospital for ongoing management (20.8% of all participants). The following factors predicted hospital admission: older age (OR 1.28 [95% CI 1.02, 1.60] per 10 years), greater number of comorbidities (OR 1.27 [95% CI 1.08, 1.48] per morbidity), moderate-severe injury accompanying the hypoglycaemia (OR 5.24 [95% CI 1.07, 25.8] compared with nil-mild injury) and unknown cause of hypoglycaemia (OR 2.21 [95% CI 1.24, 3.94] compared with known cause). The median (interquartile range) length of hospital stay was 4 (2-7) days. During follow-up, recurrent severe hypoglycaemia attended by prehospital EMS was experienced by 10.7% of participants. Predictive factors of recurrent severe hypoglycaemia in 3 months were decreased HbA1c (OR 1.97 [95% CI 1.27, 3.06] per 10 mmol/mol decrease) and a greater number of antecedent severe hypoglycaemia episodes (OR 1.12 [95% CI 1.03, 1.23] per episode). Conclusions/interpretation: Following an episode of severe hypoglycaemia managed by EMS, one-fifth of participants required hospital admission, more likely in thos

Glomerular hyperfiltration has been associated with obesity, insulin resistance, and systolic blood pressure (SBP). However, previous studies are limited by confounders such as pre-existing diabetes or hypertension, or have used indirect measures of adiposity and insulin sensitivity (IS). Therefore, we examined the relationship between estimated glomerular filtration rate (eGFR) and IS measured by the hyperinsulinaemic euglycaemic clamp in a healthy population on no medications. We performed oral glucose tolerance test (OGTT) and measured % body fat (DEXA), BMI, blood pressure and M-value (hyperinsulinaemic euglycaemic clamp) in 104 individuals (44 females and 60 males). The majority of the study population (n=89, 85.6%) were classified on their BMI as overweight/obese. eGFR was related to age, BMI, M-value (IS), 2-hour glucose levels post OGTT and white blood cell count (WBC) (all p<0.05); but not to SBP (p=0.1) or fasting glucose levels (p=0.2). After adjustment for gender, BMI, SBP and WBC, the inverse association between eGFR and M-value (p=0.001), and 2-hour glucose post OGTT (p=0.02) persisted. In conclusion, although eGFR has been associated with BMI and blood pressure in previous studies, in our healthy population, eGFR was more closely related to markers of glucose metabolism (IS and 2-hour glucose post OGTT) than to BMI and blood pressure.

AIM: With no current randomized trials, we explored the impact of tight compared with standard treatment targets on pregnancy outcomes in gestational diabetes mellitus (GDM). METHODS: This cohort study of singleton births ≥ 28 weeks' gestation was conducted at two major Australian maternity services (2009-2013). Standardized maternal, neonatal and birth outcomes were examined using routine healthcare data and compared for women with GDM at Service One (n = 2885) and Service Two (n = 1887). Services applied different treatment targets: Service One (standard targets, reference group) fasting < 5.5 mmol/l, 2-h postprandial < 7.0 mmol/l; Service Two (tight targets) fasting < 5.0 mmol/l, 2-h postprandial < 6.7 mmol/l. Multivariable regression with propensity score adjustment was used to examine associations between targets and outcomes. RESULTS: GDM prevalence and insulin use were 7.9% and 31% at Service One, and 5.7% and 46% at Service Two. There were no differences in primary outcomes: birthweight > 90th centile [adjusted odds ratio (OR) 1.06, 95% confidence interval (CI) 0.87-1.30] and < 10th centile (OR 0.84, 95% CI 0.70-1.01), or secondary outcomes gestational hypertension, pre-eclampsia, shoulder dystocia or a perinatal composite. Service Two with tight targets had increased induction of labour (OR 3.63, 95% CI 3.17-4.16), elective Caesarean section (OR 1.75, 95% CI 1.37-2.23) and Apgar scores < 7 at 5 min (OR 1.54, 95% CI 1.05-2.25), decreased hypoglycaemia (OR 0.76, 95% CI 0.61-0.94]), jaundice (OR 0.47, 95% CI 0.35-0.63) and respiratory distress (OR 0.68, 95% CI 0.47-0.98). CONCLUSIONS: Tight GDM treatment targets were associated with greater insulin use and no difference in primary birthweight outcomes. The service with tight targets had higher obstetric intervention, lower rates of reported hypoglycaemia, jaundice, respiratory distress and lower Apgar scores. High-quality interventional data are required before tight treatment targets can be implemented.

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

To optimise fecal sampling for reproducible analysis of the gut microbiome, we compared different methods of sample collection and sequencing of 16S rRNA genes at two centers. Samples collected from six individuals on three consecutive days were placed in commercial collection tubes (OMNIgeneGut OMR-200) or in sterile screw-top tubes in a home fridge or home freezer for 6-24 h, before transfer and storage at-80 °C. Replicate samples were shipped to centers in Australia and the USA for DNA extraction and sequencing by their respective PCR protocols, and analysed with the same bioinformatic pipeline. Variation in gut microbiome was dominated by differences between individuals. Minor differences in the abundance of taxa were found between collection-processing methods and day of collection, and between the two centers. We conclude that collection with storage and transport at 4 °C within 24 h is adequate for 16S rRNA analysis of the gut microbiome. Other factors including differences in PCR and sequencing methods account for relatively minor variation compared to differences between individuals.

To optimise fecal sampling for reproducible analysis of the gut microbiome, we compared different methods of sample collection and sequencing of 16S rRNA genes at two centers. Samples collected from six individuals on three consecutive days were placed in commercial collection tubes (OMNIgeneGut OMR-200) or in sterile screw-top tubes in a home fridge or home freezer for 6-24 h, before transfer and storage at-80 °C. Replicate samples were shipped to centers in Australia and the USA for DNA extraction and sequencing by their respective PCR protocols, and analysed with the same bioinformatic pipeline. Variation in gut microbiome was dominated by differences between individuals. Minor differences in the abundance of taxa were found between collection-processing methods and day of collection, and between the two centers. We conclude that collection with storage and transport at 4 °C within 24 h is adequate for 16S rRNA analysis of the gut microbiome. Other factors including differences in PCR and sequencing methods account for relatively minor variation compared to differences between individuals.

Background: There are no contemporary cohorts examining pregnancy outcomes in women with type 2 diabetes (T2D) in Australia. Aim(s): To compare pregnancy outcomes in women with and without T2D, and assess effects of body mass index (BMI) and glycaemic control on outcomes. Material(s) and Method(s): An historical cohort study was conducted of all singleton births > 20 weeks gestation at a specialist maternity network in Australia from 2010 to 2013. Data were extracted from the Birthing Outcomes System database. Multivariable logistic regression analysis was used to examine associations between presence of T2D and pregnancy outcomes. Result(s): Outcomes for 138 pregnancies with T2D and 27 075 pregnancies in women without diabetes were compared (type 1 diabetes and gestational diabetes excluded). Women with T2D were older and more overweight compared to women without diabetes (P < 0.01). Their babies were born earlier (P < 0.01) with increased risk of large for gestational age (adjusted odds ratio 2.13 (95% CI 1.37-3.32)), hypoglycaemia (4.90 (2.79-8.61)), jaundice (2.58 (1.61-4.13)) and shoulder dystocia (2.72 (1.09-6.78)), but not congenital malformations or perinatal death. Women with T2D had a higher risk of induction (4.03 (2.71-5.99)), caesarean section (2.10 (1.44-3.04)), preterm birth (2.74 (1.78-4.24)) and pre-eclampsia (2.75 (1.49-5.10)). An HbA1c >= 6.0% (42 mmol/mol) was associated with increased preterm birth, special care nursery admission, hypoglycaemia and jaundice. Conclusion(s): Despite availability of preconception care, good glycaemic control and specialist management, T2D remains associated with increased adverse obstetric and neonatal outcomes. Further research to examine predictors of adverse outcomes may assist in targeted antenatal surveillance and management.Copyright © 2016 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists

Aims: This study examines prehospital Emergency Medical Service (EMS) utilisation and patterns of demand for hyperglycaemia management, including characteristics of individuals and factors related to hospital transport. Material(s) and Method(s): A state-wide, community-based observational study of all patients requiring prehospital EMS for hyperglycaemia during a 7 year study period (Jan 2009-Dec 2015) using electronic data from the Ambulance Victoria data warehouse was conducted. Pre-specified variables related to patient demographics, comorbidities, examination findings, paramedic treatment and transport outcomes were obtained. Logistic regression was used to assess factors associated with transport to hospital. Result(s): There were 11,417 cases of hyperglycaemia attended by paramedics during the study period, accounting for 0.3-0.4% of the total annual EMS caseload, and equating to 0.54 attendances per 100 people with diabetes in the state of Victoria, Australia, per year. There was a significant increase in annual utilisation, with a rate ratio of 1.62 between 2009 (2.42 cases per 10,000 population) and 2015 (3.91 cases per 10,000 population). Fifty-one percent of cases had type 2 diabetes, 37% had type 1 diabetes, 4% had diabetes with the type unspecified and 8% had no recorded history of diabetes. Ninety percent of cases were transported to hospital. Factors associated with increased odds of transport to hospital included no known history of diabetes, regional/rural locations, case time between 0600 and <1800 hours, increasing number of comorbidities and increasingly unstable vital sign observations. Conclusion(s): There is substantial utilisation of prehospital EMS for hyperglycaemia. With increased population prevalence of diabetes predicted, further research on opportunities for prevention, as well as optimal management in the prehospital environment is warranted.Copyright © 2017 Villani et al. This is an open access article distributed under the terms of

Background: We aimed to compare glycemic control, insulin requirements, and outcomes in women with type 1 diabetes in pregnancy treated with continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI). Method(s): A retrospective cohort study was conducted of singleton pregnancies (>20 weeks gestation) in women with type 1 diabetes (2010-2015) at a specialist multidisciplinary maternity network in Australia. Antenatal characteristics, diabetes history and treatment details, and maternal and neonatal outcomes were compared for women with type 1 diabetes using CSII and MDI. Bolus calculator settings were reviewed for CSII. Data were obtained from individual medical records, linkage to pathology, and the Birthing Outcomes System database. Result(s): There were no differences in maternal characteristics or diabetes history between women managed with CSII (n = 40) and MDI (n = 127). Women treated with CSII required less insulin and less increase in total daily insulin dose/kg than MDI (40% vs. 52%). Both groups achieved similar glycemic control and no differences in pregnancy outcome. In the CSII group, carbohydrate:insulin ratios were intensified across gestation (30% breakfast, 27% lunch, 22% dinner), and insulin sensitivity factors (ISFs) changed little (7% breakfast, 0% lunch, -10% dinner). Conclusion(s): There was no difference in glycemic control or pregnancy outcomes in women using CSII or MDI managed in a multidisciplinary setting. Greater adjustments are needed to ISFs with CSII therapy. Overall, these data do not support recommending CSII in pregnancy with potentially higher patient and staff demands and costs and lack of improvement in HbA1c and pregnancy outcomes.© Copyright 2017, Mary Ann Liebert, Inc.

Glomerular hyperfiltration has been associated with obesity, insulin resistance, and systolic blood pressure (SBP). However, previous studies are limited by confounders such as pre-existing diabetes or hypertension, or have used indirect measures of adiposity and insulin sensitivity (IS). Therefore, we examined the relationship between estimated glomerular filtration rate (eGFR) and IS measured by the hyperinsulinaemic euglycaemic clamp in a healthy population on no medications. We performed oral glucose tolerance test (OGTT) and measured % body fat (DEXA), BMI, blood pressure and M-value (hyperinsulinaemic euglycaemic clamp) in 104 individuals (44 females and 60 males). The majority of the study population (n = 89, 85.6%) were classified on their BMI as overweight/obese. eGFR was related to age, BMI, M-value (IS), 2-hour glucose levels post OGTT and white blood cell count (WBC) (all p < 0.05); but not to SBP (p = 0.1) or fasting glucose levels (p = 0.2). After adjustment for gender, BMI, SBP and WBC, the inverse association between eGFR and M-value (p = 0.001), and 2-hour glucose post OGTT (p = 0.02) persisted. In conclusion, although eGFR has been associated with BMI and blood pressure in previous studies, in our healthy population, eGFR was more closely related to markers of glucose metabolism (IS and 2-hour glucose post OGTT) than to BMI and blood pressure.

Objective: To compare contemporary pregnancy outcomes in women with and without type 1 diabetes, and to examine the effects of obesity and glycaemic control on these outcomes. Design and setting: Historical cohort study in a specialist diabetes and maternity network in Victoria. Participant(s): All singleton births (at least 20 weeks' gestation), 2010e2013, were analysed: 107 pregnancies to women with type 1 diabetes and 27 075 pregnancies to women without diabetes. Women with type 2 diabetes or gestational diabetes were excluded. Method(s): Data were extracted from the Birthing Outcomes System database; associations between type 1 diabetes and pregnancy outcomes were analysed by multivariable regression. Main Outcome Measure(s): Mode of birth; maternal and neonatal outcomes. Result(s): The mean body mass index was higher for women with type 1 diabetes than for women without diabetes (mean, 27.3 kg/m2 [SD, 5.0] v 25.7 kg/m2 [SD, 5.9]; P = 0.01); the median gestation period for their babies was shorter (median, 37.3 weeks [IQR, 34.6e38.1] v 39.4 weeks [IQR, 38.4e40.4]; P<0.001)and they were more likely to be large for gestational age (LGA) (adjusted odds ratio [aOR], 7.9; 95% CI, 5.3e11.8). Women with type 1 diabetes were more likely to have had labour induced (aOR, 3.0; 95% CI, 2.0e4.5), a caesarean delivery (aOR, 4.6; 95% CI, 3.1e7.0), or a pre-term birth (aOR, 6.7; 95% CI, 4.5e10.0); their babies were more likely to have shoulder dystocia (aOR, 8.2; 95% CI, 3.6e18.7), hypoglycaemia (aOR, 10.3; 95% CI, 6.8e15.6), jaundice (aOR, 5.1; 95% CI, 3.3e7.7), respiratory distress (aOR, 2.5; 95% CI, 1.4e4.4) or to suffer perinatal death (aOR, 4.3; 95% CI, 1.9e9.9). In women with type 1 diabetes, greater obesity was associated with increased odds for an LGA baby or congenital malformation, and increased HbA1c levels were associated with pre-term birth and perinatal death. Conclusion(s): Women with type 1 diabetes, even when managed in a specialist setting, still experience ad

Aims Diabetes is associated with several acute, life-threatening complications yet there are limited data on the utilisation of prehospital services for their management. This study aimed to examine the utilisation of emergency medical services (EMS) for prehospital hypoglycaemia, including patient characteristics and factors related to hospital transportation. Methods An observational study of patients requiring EMS for hypoglycaemia across Victoria, Australia over three years was conducted. Pre-specified data including patient demographics, comorbidities, examination findings and transport outcomes were obtained. Logistic regression was used to assess factors associated with transportation. Results During the study period, 12,411 hypoglycaemia events were attended by paramedics for people with diabetes. The majority were individuals with type 1 diabetes (58.8%), followed by type 2 diabetes (35.2%) and unspecified diabetes type (5.9%). Thirty-eight percent of patients were transported to hospital by EMS following hypoglycaemia. Factors associated with transport by EMS included extremes of age (< 15 and > 75 years), female gender, type 2 diabetes, event at a nursing home or hospital/community clinic, presence of comorbidities and time of day. Conclusions Examination of the utilisation of EMS for hypoglycaemia has identified a previously unquantified need for emergency care for people with diabetes as well as factors related to hospital transportation.Copyright © 2016 Elsevier Inc.

Background Few contemporary studies have compared pregnancy outcomes in women with type 1 diabetes (T1D) and women without diabetes. The independent effects of obesity and glycaemic control on adverse outcomes remain unclear. We sought to address these gaps. Methods A large observational study was conducted of singleton births >20 weeks gestation from 2010-2013 at Monash Health, one of the largest health services in Australia. Data were extracted from the Birthing Outcomes System database. Multivariable regression analysis was used to examine associations between T1D and pregnancy outcome, adjusting for confounders including age, body mass index (BMI), parity, smoking, country of birth and gestational age. Results Outcomes for 107 pregnancies with T1D and 27 074 pregnancies with normal glucose tolerance were analyzed. Women with T1D were more overweight than women without diabetes (mean+/-SD: 27.3+/-5.0 vs 25.7+/-5.9 kg/m2,p=0.01), but there were no differences in age, parity or smoking. Women with T1D had earlier birth (median+IQR: 37.3+3.5 vs 39.4+2.0 weeks, p<0.001), increased risk of induction of labour (adjusted OR 3.05 [95% CI 2.06-4.50]), caesarean section (4.66 [3.10-7.00]) and preterm birth (7.42 [4.99-11.04]) compared to women without diabetes. Babies of women with T1D had increased macrosomia (7.93 [5.33-11.81]), shoulder dystocia (8.16 [3.57-18.65]), hypoglycaemia (10.33 [6.84-15.58]), jaundice (5.05 [3.30-7.73]), respiratory distress (2.47 [1.40-4.36]), intensive care admission (3.37 [1.55- 7.34]) and perinatal death (4.32 [1.88-9.92]) compared to babies of women without diabetes. In women with T1D, mean HbA1c was 7.0+/-1.2% during pregnancy. A 1kg/m2 increase in maternal BMI was associated with increased risk of macrosomia (1.12 [1.01-1.24]) and congenital malformations (1.26 [1.02-1.55]). A 1% increase in mean HbA1c was associated with increased risk of preterm birth (1.85 [1.13-3.02]) and perinatal death (5.09 [1.48-17.48]), but was not associated wi

Objective: There is insufficient evidence for treatment targets in Gestational Diabetes Mellitus (GDM). We aimed to explore the impact of different treatment targets on pregnancy outcomes. Method(s): An observational study was conducted of singleton births >20 weeks at Monash Health (MH) and Royal Women's Hospital (RWH) from 2009-2013. Data (pregnancy details, maternal and neonatal outcomes) were obtained from each hospital's pregnancy database. Outcomes for women with GDM at MH (n = 2891) and RWH (n = 1930) were compared [diagnosis: 2 h 75 g OGTT at 24-28 weeks with fasting glucose >=5.5 mmol/L and/or 2 h >= 8.0 mmol/L]. Each hospital follows a similar GDM management protocol but applies different treatment targets: MH fasting <5.5 mmol/L, 2 h post-prandial <7.0 mmol/L; RWH fasting <5.0 mmol/L, 2 h < 6.7 mmol/L. Descriptive statistics are presented. Multivariable regression analysis will be used to examine associations between GDM treatment and adverse outcomes. Result(s): The prevalence of GDM and requirement for insulin at MH were 7.9% and 31%, and at RWH with stricter treatment targets were 6.3% and 47% respectively. Over half of women with GDM were overweight or obese. The rate of special care nursery admission (29.6% vs 17.0%) was higher at MH compared to RWH, but rates of induction of labour (30.6% vs 56.6%) and caesarean section (33.8% vs 39.5%) were lower (all p < 0.001), partly reflecting hospital protocols. Babies of women with GDM were born later (mean gestation 39 +/- 2 vs 38 +/- 2 wk, p < 0.001) at MH compared to RWH, and had higher rates of respiratory distress (3.6% vs 1.2%, p < 0.001), hypoglycaemia (9.9% vs 2.2%, p < 0.001) and macrosomia (11.3% vs 9.5%, p = 0.035), but lower rates of pre-term birth (8.5% vs 11.3%, p = 0.001) and stillbirth (0.3% vs 0.7%, p = 0.024). Rates of shoulder dystocia and jaundice were comparable. Conclusion(s): Stricter treatment targets for GDM appear to reduce macrosomia, without increasing neonatal hypoglycaemia or spe

Objective: To determine the prevalence of diabetes in inpatients in Melbourne hospitals. Design(s): Point prevalence survey of all inpatients in each hospital on a single day between 30 November 2010 and 22 November 2012. Setting(s): 11 hospitals in metropolitan Melbourne including community, secondary and tertiary hospitals and one aged care and rehabilitation centre. Participant(s): 2308 adult inpatients in all wards apart from intensive care, emergency, obstetrics and psychiatry. Main Outcome Measure(s): Point prevalence of self-reported diabetes, details of current medication, self-reported frequency of complications. Result(s): Diabetes status was obtained in 2273 of 2308 inpatients (98.5%). Of these, 562 (24.7%) had diabetes (95% CI, 22.9%-26.5%). Diabetes prevalence ranged from 15.7% to 35.1% in diff erent hospitals (P < 0.001). Patients with diabetes were older, heavier and more likely to be taking lipidlowering, antihypertensive and blood-thinning medications. Of 388 patients with complete medication information, 270 (69.6%) were taking oral hypoglycaemic agents alone or in combination with insulin, 158 (40.7%) were treated with insulin (67 [17.3%] with insulin alone) and 51 (13.1%) were not taking medication for diabetes. The frequency of diabetes complications was very high: 207/290 (71.4%) for any microvascular complication, 275/527 (52.2%) for any macrovascular complication and 227/276 (82.2%) for any complication. Conclusion(s): The high burden of diabetes in Melbourne hospital inpatients has major implications for patient health and health care expenditure. Optimising care of these high-risk patients has the potential to decrease inpatient morbidity and length of stay as well as preventing or delaying future complications. A formal Australian national audit of inpatient diabetes would determine its true prevalence and consequences, allowing rational planning to deal with shortcomings in its management.Copyright © MJA 2014, All rights reserved.

Immune checkpoint inhibitors offer patients with advanced melanoma substantial improvements in survival. Unlike chemotherapy, immune checkpoint inhibitors such as ipilimumab and pembrolizumab cause unique immune-related adverse events (irAEs), including the development of endocrinopathies. We report a case of a man aged 60 years who developed diabetic ketoacidosis (DKA) following the use of pembrolizumab for the treatment of metastatic melanoma. He received four cycles of ipilimumab, before proceeding to pembrolizumab. Five weeks after initiating pembrolizumab, he presented in DKA with a pH of 7.0, bicarbonate of 7 mmol/L, blood glucose of 27 mmol/L and serum ketones of 5.9 mmol/L. Antibodies to glutamic acid decarboxylase (anti-GAD) and Islet antigen 2 (IA-2) were negative and C-peptide was low at 57 pmol/L (300-2350 pmol/L). There was no personal or family history of autoimmune conditions. Standard immunosuppression for irAEs was started using prednisolone in an attempt to salvage beta cell function but was unsuccessful. To the best of our knowledge, this is the first reported attempt at reversing pembrolizumab-induced type 1 diabetes using glucocorticoids.Copyright © 2016 BMJ Publishing Group Ltd.

Background There is limited data on pregnancy outcomes with continuous subcutaneous insulin infusion (CSII) compared to multiple daily injections (MDI) in women with type 1 diabetes (T1D). Recent reviews of observational studies have found a possible increase in birthweight, but no difference in pregnancy outcomes, although included studies were small and potentially biased. We explored a broad range of pregnancy outcomes in a large cohort of women treated with CSII or MDI managed in a specialist multidisciplinary diabetes and maternity clinic. Methods An observational study was conducted of singleton pregnancies >20 weeks gestation in women with T1D (n=107) from 2010-2013 at Monash Health, one of the largest health services in Australia. Demographic and outcome data were extracted from the Birthing Outcomes System database, and details of diabetes treatment were obtained from the medical record. Univariable and multivariable logistic regression analysis was used to examine associations between mode of insulin delivery and pregnancy outcome, adjusting for potential confounders including age, body mass index (BMI), parity, smoking, country of birth and gestational age. Results Twenty pregnancies were managed with CSII and 87 were managed with MDI in women with T1D. Total daily dose of insulin was lower in the CSII compared to MDI group (median+IQR: 56+28 units versus 84+60 units, p<0.01). There were no significant differences in age, BMI or parity between groups. Women treated with CSII had similar glycaemic control to women treated with MDI in each trimester and throughout the pregnancy (mean+/-SD: HbA1c 7 3 +/- 0 9% vs 72+/-12%, p=0.75). Babies were born at a median gestation of 37 weeks in both groups, and there was no difference in birthweight in women managed with CSII compared to MDI (3211+/-1106g vs 3237+/-972g, p=0.92). There was no significant difference between groups in regards to maternal outcomes (gestational hypertension and pre-eclampsia), mode of birt