Jennifer Couper

Health-related quality of life of children and adolescents with chronic illness--a two year prospective study

The aim of this study was to compare the self-reported health-related quality of life (HRQL) of children and adolescents with diabetes, asthma or cystic fibrosis (CF) with the HRQL of a large community sample, to assess the extent to which the HRQL of the children and adolescents with chronic illness changes over time, and to examine the consistency of changes in different HRQL domains. One hundred and twenty three young people aged 10–16 years with asthma, diabetes, or CF were recruited from specialist paediatric clinics. Children rated their HRQL using the Child Health Questionnaire (CHQ) and three disease-specific measures at baseline, 6, 12, 18 and 24 months post-baseline. In several areas, the HRQL of children with chronic illness was significantly worse than that of children in the community sample. Over the 2 years of the study, although children with asthma and diabetes did not report significant changes in CHQ scores rating their physical health, they reported significant improvements in scores rating the extent to which health problems interfered with physical and family activities. CHQ scores describing their physical health reported by children with CF declined significantly but there was no significant change in scores rating interference with physical and family activities.

Aortic intima media thickness is an early marker of atherosclerosis in children with type 1 diabetes mellitus.

OBJECTIVE To compare aortic intima media thickness (aIMT) to carotid intima media thickness (cIMT) as a marker of early atherosclerosis in children with type 1 diabetes mellitus and to examine the associations of aIMT to known cardiovascular risk factors. STUDY DESIGN 66 children with type 1 diabetes mellitus (age, 14.1 +/- 2.5 years; 37 male) and 32 healthy control subjects (age, 14.2 +/- 3 years; 15 male) underwent assessment of vascular structure (cIMT and aIMT) and vascular function (flow mediated dilatation [FMD] and glyceryl trinitrate induced dilatation [GTN]). Fasting blood tests were taken to measure levels of hemoglobin A1c, high sensitive C reactive protein, total homocyst(e)ine, serum folate, red cell folate, and lipids. RESULTS aIMT, but not cIMT, was significantly greater in the children with type 1 diabetes mellitus than in control subjects (P < .001). In children with type 1 diabetes mellitus, aIMT correlated with glycosylated hemoglobin (r = 0.31, P = .01) and was independently associated with age (beta = 0.38, P = .001) and low-density lipoprotein cholesterol level (beta = 0.38, P = .001). Vascular function (GTN) was worse in children with type 1 diabetes mellitus who had an aIMT >95th percentile, as defined with the control subjects. CONCLUSIONS aIMT is an earlier marker than cIMT of preclinical atherosclerosis in children with type 1 diabetes mellitus and relates to known cardiovascular risk factors and metabolic control.

Treatment burden and health-related quality of life of children with diabetes, cystic fibrosis and asthma

Aim:  To identify the time required by children with cystic fibrosis (CF), diabetes or asthma to complete daily treatment tasks and the hassle they experienced when completing these tasks. To compare parent and child reports of daily treatment time and hassle. To investigate the relationship between treatment time and hassle, and (i) children’s health‐related quality of life (HRQL); and (ii) disease severity.

Relationship of Smoking and Albuminuria in Children with Insulin-dependent Diabetes

Recent evidence suggests the rise in urinary albumin excretion preceding diabetic nephropathy may represent a continuum. We therefore studied factors relating to albumin excretion rate in children with insulin‐dependent diabetes. Normal overnight albumin excretion rate was determined in 690 healthy schoolchildren. The 95th centile was 7.2 μg min−1. Patients included 169 children with IDDM aged 12.4 ± 3.1 years who performed 4.8 ± 0.4 overnight collections during 15 ± 0.5 months and were analysed cross sectionally. They were stratified accordingly to mean albumin excretion rate: normal < 7.2 μg min−1, borderline 7.2–20 μg min−1, microalbuminuria 20–200 μg min−1; 96/169 patients performed 6.4 ± 0.2 overnight collections during 24 months follow‐up and were analysed longitudinally. Cigarette smoking was determined by history and urine cotinine levels. Smoking correlated with albumin excretion rate, independent of age and other variables, in cross‐sectional and longitudinal analysis (p < 0.003). Smoking was more prevalent in the borderline albuminuria and microalbuminuria groups (p < 0.004, p < 0.001). Mean HbA1c during follow‐up and mean HbA1c since diagnosis were significantly higher in the microalbuminuric group, compared with the normal patient group. HbA1c since diagnosis, mean blood pressure, lipoprotein(a), and apolipoprotein B did not correlate with albumin excretion rate, after controlling for other variables. Our findings highlight the continuing need for strategies to prevent smoking in this age group.

Weight gain in early life predicts risk of islet autoimmunity in children with a first degree relative with type 1 diabetes

OBJECTIVE—In a prospective birth cohort study, we followed infants who had a first-degree relative with type 1 diabetes to investigate the relationship between early growth and infant feeding and the risk of islet autoimmunity. RESEARCH DESIGN AND METHODS—Infants with a first-degree relative with type 1 diabetes were identified during their mothers pregnancy. Dietary intake was recorded prospectively to determine duration of breast-feeding and age at introduction of cows milk protein, cereals, meat, fruit, and vegetables. At 6-month reviews, length (or height) and weight, antibodies to insulin, GAD65, the tyrosine phosphatase-like insulinoma antigen, and tissue transglutaminase were measured. Islet autoimmunity was defined as persistent elevation of one or more islet antibodies at consecutive 6-month intervals, including the most recent measure, and was the primary outcome measure. RESULTS—Follow-up of 548 subjects for 5.7 ± 3.2 years identified 46 children with islet autoimmunity. Weight z score and BMI z score were continuous predictors of risk of islet autoimmunity (adjusted hazard ratios 1.43 [95% CI 1.10–1.84], P = 0.007, and 1.29 [1.01–1.67], P = 0.04, respectively). The risk of islet autoimmunity was greater in subjects with weight z score >0 than in those with weight z score ≤0 over time (2.61 [1.26–5.44], P = 0.01). Weight z score and BMI z score at 2 years and change in weight z score between birth and 2 years, but not dietary intake, also predicted risk of islet autoimmunity. CONCLUSIONS—Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes.

Power Spectral Analysis of Heart Rate Variability in Children and Adolescents With IDDM

OBJECTIVE To investigate power spectral analysis (PSA) of heart rate variability (HRV) in children and adolescents with IDDM, its relationship with other measures of HRV and standard cardiovascular responses, and factors associated with reduced HVR. RESEARCH DESIGN AND METHODS A total of 130 subjects with IDDM aged 12.8 ± 3.2 years and 108 healthy control subjects were studied. Power spectra were analyzed from supine electrocardiograph (ECG) recordings by processing into consecutive R-R intervals and analysis using fast Fourier transformation. Standard cardiovascular responses to deep breathing and standing were performed. RESULTS IDDM subjects had a reduction in total power including both low-frequency (0.05–0.14 Hz; P = 0.0001) and high-frequency (0.14–0.40 Hz; P = 0.0002) components. These changes were seen from diagnosis. Other measures of HRV, coefficient of variation (CV) and standard deviation (SD) of mean resting heart rate, were also significantly lower in IDDM. All 20 (15%) of the 130 IDDM subjects with total power < the 5th percentile in control subjects also had reduced HRV when measured by CV of heart rate. There was an independent relationship between age and the high-frequency component in IDDM subjects and control subjects. Total power correlated with mean heart rate (r = −0.56; P < 0.0001), CV of heart rate (r = 0.90; P < 0.00001), SD of heart rate (r = 0.91; P < 0.00001), heart rate response to deep breathing (r = 0.45; P < 0.0001), and duration in IDDM subjects. There was no correlation with short-term or long-term metabolic control. Retesting of 27 subjects showed a variability in total power and its components comparable to other measures of HRV and standard heart rate responses. CONCLUSIONS Changes in HRV are a sensitive and reproducible measure of early autonomic dysfunction in childhood. In this age-group, PSA appears no more sensitive a measure of reduced HRV than other closely correlated measures of HRV.

Folate and vitamin B6 rapidly normalize endothelial dysfunction in children with type 1 diabetes mellitus.

BACKGROUND. Endothelial dysfunction, a precursor of vascular disease, begins early in type 1 diabetes mellitus and is associated with folate status. METHODS. A randomized, double-blind, placebo-controlled study of folate (5 mg daily) and vitamin B6 (100 mg daily) in 124 children with type 1 diabetes determined the immediate and 8-week effects of these vitamins, alone and in combination, on endothelial function. Endothelial function, assessed as flow-mediated dilation and glyceryltrinitrate-induced dilation with high-resolution ultrasound of the brachial artery, was measured at baseline, at 2 and 4 hours after the first dose (n = 35), and at 4 and 8 weeks of treatment (n = 122). RESULTS. Flow-mediated dilation normalized in all treatment groups. From baseline to 8 weeks, flow-mediated dilation improved with folate from 2.6% ± 4.3% (mean ± SD) to 9.7% ± 6.0%, with vitamin B6 from 3.5% ± 4.0% to 8.3% ± 4.2%, and with folate/vitamin B6 from 2.8% ± 3.5% to 10.5% ± 4.4%. This improvement in flow-mediated dilation occurred within 2 hours and was maintained at 8 weeks for each treatment. Flow-mediated dilation in the placebo group, and glyceryltrinitrate-induced dilation in all groups, did not change. Increases in serum folate, red cell folate, and serum vitamin B6 levels related to increases in flow-mediated dilation. Improvement in flow-mediated dilation was independent of changes in total plasma homocyst(e)ine, glucose, hemoglobin A1c, and high-sensitivity C-reactive protein levels. Baseline red cell folate levels and baseline diastolic blood pressure were related inversely to improvement in flow-mediated dilation. Serum triglyceride and low-density lipoprotein cholesterol inversely related to baseline flow-mediated dilation. CONCLUSIONS. High-dose folate and vitamin B6 normalized endothelial dysfunction in children with type 1 diabetes. This effect was maintained over 8 weeks, with no additional benefit from combination treatment.

Progression of borderline increases in albuminuria in adolescents with insulin-dependent diabetes mellitus

We aimed to determine the natural history of borderline increases in albuminuria in adolescents with insulin‐dependent (Type 1) diabetes mellitus (IDDM) and factors which are associated with progression to persistent microalbuminura. Fifty‐five normotensive adolescents with IDDM and intermittent microalbuminura (overnight albumin excretion ratte of 20–200 μg min−1 on one of three consecutive timed collections, n  = 29) or borderline albuminura (mean overnight albumin excretion rate of 7.2–20 μg min−1 on one of three consecutive timed collections, n  = 30) were followed prospectively at 3 monthly intervals. The endpoint was persistent microalbuminuria defined as a minimum of three of four consecutive overnight albumin excretion rates of greater than 20 μg min−1 . One hundred and forty‐two adolescents with IDDM and normoalbuminura were also followed prospectively. Fifteen of the 59 patients (25.4 %) with intermittent (9/29) or borderline (6/30) albuminura progressed to persistent microalbuminura (progressors) over 28 (15–50) months [median (range)] in comparison with two of the 142 patients with normoalbuminuria at entry (relative risk =12.6; p  =0.001). Progressors to persistent microalbuminura were pubertal and had higher systolic (p  = 0.02) and diastolic (p  = 0.02) blood pressure, and HbAlc (p  = 0.004) than non‐progressors. All patients remained normotensive. Glomerular filtration rate, apolipoproteins, dietary phosphorus, protein and sodium intakes, and prevalence of smoking did not differ between progressors and non‐progressors. Total renin was higher in the diabetic patients without a difference between progressors and non‐progressors. In conclusion there is a relatively high rate of progression to persistent microalbuminuria in pubertal adolescents with borderline increases in albuminura and duration greater than 3 years. These patients require attention to minimize associated factors of poor metabolic control and higher blood pressure in the development of incipient nephropathy. © 1997 John Wiley & Sons, Ltd.

A two-year prospective study of the health-related quality of life of children with chronic illness – the parents’ perspective

The aim of this study was to assess prospectively changes in the health-related quality of life (HRQL) of children and adolescents with diabetes, asthma or cystic fibrosis (CF). One hundred and twenty-two parents of children aged 10–16 years with asthma, diabetes, or CF were recruited from specialist paediatric clinics. Parents described their children’s HRQL using the Child Health Questionnaire (PF98) at baseline, 6, 12, 18 and 24 months post-baseline. They reported that the general health of children with CF was significantly worse than that of children with asthma and diabetes at baseline. In other domains there were few differences between the HRQL of children in the three groups. In several domains, the HRQL of children with asthma or diabetes improved over the 2years of the study. This improvement was less evident for children with CF.

Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort

BackgroundDisorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously.ResultsWe analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management.ConclusionsOur massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.