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

AIMS/HYPOTHESIS: We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control. METHODS: This was a prospective observational study in 710 normoalbuminuric adolescents with type 1 diabetes from the non-intervention cohorts of the Adolescent Cardio-Renal Intervention Trial (AdDIT). Participants were classified as 'high ACR' or 'low ACR' (lowest and middle ACR tertiles) using baseline standardised log10 ACR. The primary outcome, 3DR, was determined from centrally graded, standardised two-field retinal photographs. 3DR risk was determined using multivariable Cox regression for the effect of high ACR, with HbA1c, BP, LDL-cholesterol and BMI as covariates; diabetes duration was the time-dependent variable. RESULTS: At baseline mean ± SD age was 14.3 ± 1.6 years and mean ± SD diabetes duration was 7.2 ± 3.3 years. After a median of 3.2 years, 83/710 (12%) had developed 3DR. In multivariable analysis, high ACR (HR 2.1 [1.3, 3.3], p=0.001), higher mean IFCC HbA1c (HR 1.03 [1.01, 1.04], p=0.001) and higher baseline diastolic BP SD score (HR 1.43 [1.08, 1.89], p=0.01) were independently associated with 3DR risk. CONCLUSIONS/INTERPRETATION: High ACR is associated with greater risk of 3DR in adolescents, providing a target for future intervention studies. TRIAL REGISTRATION: isrctn.org ISRCTN91419926.

Microbiome in health and disease.

There has been an exponential rise in research into the microbiota of the human gastrointestinal tract, particularly of the genomic content (the microbiome). The vast number of micro-organisms residing in our gut has an integral role in essential processes, including growth and development. Probiotics, live micro-organisms with putative benefits on health have become ubiquitous as treatments for many conditions, despite often limited robust clinical trial data. However, the resurgence of faecal microbial transplantation as an effective treatment modality provides further promise that manipulation of our microbiome can have clinical benefits. This review will present the recent evidence for the role of the microbiome in development and growth, and focus on the evidence for its manipulation in paediatric diseases. We will show that while there is promising data in specific diseases, there remain many unanswered questions. Only through a deeper understanding of our complex internal ecosystem will we be able to move to the next stage of targeted microbial therapy.

Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination.

Investigations of humans with disorders of sex development (DSDs) resulted in the discovery of many of the now-known mammalian sex-determining genes, including SRY, RSPO1, SOX9, NR5A1, WT1, NR0B1, and WNT4. Here, the locus for an autosomal sex-determining gene was mapped via linkage analysis in two families with 46,XY DSD to the long arm of chromosome 5 with a combined, multipoint parametric LOD score of 6.21. A splice-acceptor mutation (c.634-8T>A) in MAP3K1 segregated with the phenotype in the first family and disrupted RNA splicing. Mutations were demonstrated in the second family (p.Gly616Arg) and in two of 11 sporadic cases (p.Leu189Pro, p.Leu189Arg)-18% prevalence in this cohort of sporadic cases. In cultured primary lymphoblastoid cells from family 1 and the two sporadic cases, these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex. Map3k1 within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination. Thus, mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination.

International perspective on research priorities and outcome measures of importance in the care of children with acute exacerbations of asthma: a qualitative interview study.

BACKGROUND: Acute exacerbations of asthma are common in children, however, treatment decisions for severe exacerbations are challenging due to a lack of robust evidence. In order to create more robust research, a core set of outcome measures needs to be developed. In developing these outcomes, it is important to understand the views of clinicians who care for these children in particular, views that relate to outcome measures and research priorities. METHODS: To determine the views of clinicians, a total of 26 semistructured interviews based on the theoretical domains framework were conducted. These included experienced clinicians from emergency, intensive care and inpatient paediatrics across 17 countries. The interviews were recorded, and later transcribed. All data analyses were conducted in Nvivo by using thematic analysis. RESULTS: The length of stay in hospital and patient-focused parameters, such as timing to return to school and normal activity, were the most frequently highlighted outcome measures, with clinicians identifying the need to achieve a consensus on key core outcome measure sets. Most research questions focused on understanding the best treatment options, including the role of novel therapies and respiratory support. CONCLUSION: Our study provides an insight into what research questions and outcome measures clinicians view as important. In addition, information on how clinicians define asthma severity and measure treatment success will assist with methodological design in future trials. The current findings will be used in parallel with a further Paediatric Emergency Research Network study focusing on the child and family perspectives and will contribute to develop a core outcome set for future research.

Diabetic Ketoacidosis at Onset of Type 1 Diabetes and Long-term HbA1c in 7,961 Children and Young Adults in the Australasian Diabetes Data Network.

OBJECTIVE: The relationship between diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes and long-term glycemic control varies between studies. We aimed, firstly, to characterize the association of DKA and its severity with long-term HbA1c in a large contemporary cohort, and secondly, to identify other independent determinants of long-term HbA1c. RESEARCH DESIGN AND METHODS: Participants were 7,961 children and young adults diagnosed with type 1 diabetes by age 30 years from 2000 to 2019 and followed prospectively in the Australasian Diabetes Data Network (ADDN) until 31 December 2020. Linear mixed-effect models related variables to HbA1c. RESULTS: DKA at diagnosis was present in 2,647 participants (33.2%). Over a median 5.6 (interquartile range 3.2, 9.4) years of follow-up, participants with severe, but not moderate or mild, DKA at diagnosis had a higher mean HbA1c (+0.23%, 95% CI 0.11,0.28; [+2.5 mmol/mol, 95% CI 1.4,3.6]; P < 0.001) compared with those without DKA. Use of continuous subcutaneous insulin infusion (CSII) was independently associated with a lower HbA1c (-0.28%, 95% CI -0.31, -0.25; [-3.1 mmol/mol, 95% CI -3.4, -2.8]; P < 0.001) than multiple daily injections, and CSII use interacted with severe DKA to lower predicted HbA1c. Indigenous status was associated with higher HbA1c (+1.37%, 95% CI 1.15, 1.59; [+15.0 mmol/mol, 95% CI 12.6, 17.4]; P < 0.001), as was residing in postcodes of lower socioeconomic status (most vs. least disadvantaged quintile +0.43%, 95% CI 0.34, 0.52; [+4.7 mmol/mol, 95% CI 3.4, 5.6]; P < 0.001). CONCLUSIONS: Severe, but not mild or moderate, DKA at diagnosis was associated with a marginally higher HbA1c over time, an effect that was modified by use of CSII. Indigenous status and lower socioeconomic status were independently associated with higher long-term HbA1c.

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

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.

Delayed brachial artery dilation response and increased resting blood flow velocity in young children with mild sleep-disordered breathing.

AIM: This study aimed to evaluate whether the vascular dysfunction perceived in adults with sleep-disordered breathing (SDB) was also evident in children with snoring referred for evaluation of clinically suspected SDB. OBJECTIVES: This study compared flow-mediated dilatation (FMD), measured at the brachial artery, at rest and during hyperaemic stress between children who snore [n = 23; mean standard deviation (SD) age = 7.51 (1.3) years] and healthy, non-snoring children [n = 11; age = 8.0 (1.3) years]. METHODS: Children with suspected obstructive sleep apnoea (OSA) and healthy non-snoring controls underwent overnight polysomnography (PSG). Using standard techniques, non-invasive FMD and brachial arterial blood flow velocity during rest and hyperaemia were subsequently measured by ultrasound imaging MEASUREMENTS: Resting and hyperaemic velocity time integral (area under the curve of mean systolic velocity × ejection time), maximal dilation response (highest percentage difference from baseline diameter) and the time taken to reach maximal dilation were calculated. RESULTS: Children awaiting adenotonsillectomy compared to healthy non-snoring control children had higher velocity time integrals at rest (14 ± 3 m vs. 20 ± 8 m, p < 0.01) and during hyperaemic stress (56 ± 6m vs. 63 ± 13m, p < 0.01) despite having only mild SDB on polysomnographic assessment. Lower nadir oxygen saturation values during non-rapid eye movement sleep were negatively associated with higher resting (r = -0.58, p <0.001) and hyperaemic (r = -0.36, p < 0.05) velocity time integrals. Maximal FMD dilatation response was not significantly different between snoring and non-snoring groups, but the estimated time to reach maximal dilation was significantly delayed in children who snored (60.7 ± 28.4 vs. 39.2 ± 13.2 s, p < 0.05). CONCLUSIONS: Children with mild SDB showed increased blood flow velocity at rest and during hyperaemic stress suggesting altered cardiovascular and haemodynamic function. The delay in time to maximal vessel dilatation in children who snored also suggests possible reduced vascular compliance in response to hyperaemic sheer stress. Mild SDB appears to alter the peripheral vascular response in young children. The long-term vascular implications of these changes in the growing child are unknown and warrant further investigation.

Gastric Emptying Is More Rapid in Adolescents With Type 1 Diabetes and Impacts on Postprandial Glycemia.

CONTEXT: Gastric emptying is a critical determinant of postprandial glycemic control in health and type 1 diabetes. There are few studies that assess the relationship between gastric emptying and postprandial glycaemia in adolescents with type 1 diabetes. OBJECTIVE: The objectives of the study were to quantify gastric emptying in adolescents with type 1 diabetes and examine its relationship to postprandial glycaemia and autonomic function. DESIGN: This was a case-control study. Gastric half-emptying time of a solid meal was measured by a (13)C-octanoate breath test. Cardio-autonomic function was measured by heart rate variability. Chronic and postprandial gastrointestinal symptoms were evaluated by questionnaire and visual analog scales. Blood glucose concentrations were monitored frequently during the study. SETTING: The study was conducted at a tertiary pediatric hospital in South Australia. PARTICIPANTS: Thirty adolescents (aged 15 ± 2.5 y) with type 1 diabetes and age- and sex-matched controls (gastric emptying, n = 20; heart rate variability, n = 135) participated in the study. MAIN OUTCOME: Gastric half-emptying time was the main outcome in the study. RESULTS: Gastric emptying was more rapid in subjects with type 1 diabetes than controls [median half emptying time 78 (interquartile range 61-99) vs 109 (interquartile range 71-124) min, P = .02]. The postprandial rise in blood glucose at 60 minutes was strongly related to gastric half-emptying time (R = -0.65, P = .0001). Gastric emptying was slower in subjects with fasting hyperglycemia but was not related to heart rate variability. Nausea, bloating, and anxiety were related to fasting glycemia (P = .03). CONCLUSION: Rapid gastric emptying is a major determinant of postprandial glycemia in adolescents with type 1 diabetes. This observation has significant implications for therapy.

Early atherosclerosis relates to urinary albumin excretion and cardiovascular risk factors in adolescents with type 1 diabetes: Adolescent type 1 Diabetes cardio-renal Intervention Trial (AdDIT).

OBJECTIVE: The origins of cardiovascular and renal disease in type 1 diabetes begin during childhood. We aimed to evaluate carotid (cIMT) and aortic intima-media thickness (aIMT) and their relationship with cardiovascular risk factors and urinary albumin excretion in adolescents with type 1 diabetes in the Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT). RESEARCH DESIGN AND METHODS: A total of 406 adolescents with type 1 diabetes, who were 14.1 ± 1.9 years old with type 1 diabetes duration of 6.7 ± 3.7 years, and 57 age-matched control subjects provided clinical and biochemical data and ultrasound measurements of vascular structure (cIMT and aIMT). Vascular endothelial and smooth muscle function was also measured in 123 of 406 with type 1 diabetes and all control subjects. RESULTS: In type 1 diabetic subjects, mean/maximal aIMT (P < 0.006; <0.008), but not mean/maximal cIMT, was greater than in control subjects. Mean/maximal aIMT related to urinary albumin-to-creatinine ratio (multiple regression coefficient [SE], 0.013 [0.006], P = 0.03; 0.023 [0.007], P = 0.002), LDL cholesterol (0.019 [0.008], P = 0.02; 0.025 [0.011], P = 0.02), and age (0.010 [0.004], P = 0.004; 0.012 [0.005], P = 0.01), independent of other variables. Mean/maximal cIMT was greater in males (0.023 [0.006], P = 0.02; 0.029 [0.007], P < 0.0001), and mean cIMT related independently to systolic blood pressure (0.001 [0.001], P = 0.04). Vascular smooth muscle function related to aIMT and cIMT but not to urinary albumin excretion. CONCLUSIONS: aIMT may be a more sensitive marker of atherosclerosis than cIMT in type 1 diabetes during mid-adolescence. Higher urinary albumin excretion, even within the normal range, is associated with early atherosclerosis and should direct clinical attention to modifiable cardiovascular risk factors.