Intermittent Energy Restriction Is a Feasible, Effective, and Acceptable Intervention to Treat Adolescents with Obesity.

BACKGROUND: Intermittent energy restriction (IER) is an effective obesity management strategy in adults. OBJECTIVE: The aim of this study was to investigate the feasibility, effectiveness, and acceptability of IER in adolescents (aged 12-17 y) with obesity [adult equivalent body mass index (BMI; kg/m2) ≥30]. METHODS: During weeks 1-12 participants followed an IER dietary plan consisting of a very-low-energy diet (VLED) 3 d/wk (500-600 kcal/d) and an eating plan consistent with national dietary guidelines 4 d/wk. For weeks 13-26 participants chose to continue with 1-3 VLED d/wk or follow a prescriptive eating plan. Primary outcomes were feasibility and change in BMI expressed as a percentage of the 95th percentile (BMI %95th percentile) at 12 wk. Secondary outcomes were diet acceptability, body composition, cardiometabolic risk, vascular structure and function, quality of life (Pediatric Quality of Life Inventory), and eating behaviors [Dutch Eating Behavior Questionnaire (DEBQ-C)]. Linear mixed models were used to assess change in outcome measures. RESULTS: Of 45 adolescents invited to participate, 30 adolescents (mean ± SD age: 14.5 ± 1.4 y, female n = 25) with a median BMI of 34.9 (range: 27.7-52.4) were recruited. At 12 wk, 23 participants chose to continue with the VLED 2-3 d/wk, and 21 completed the study, indicating the feasibility of IER. Consistent with intention-to-treat analysis, BMI %95th percentile was reduced at 12 wk (difference in estimated marginal means ± SEMs: -5.6 ± 1.1, P < 0.001) and 26 wk (-5.1 ± 1.9, P = 0.013) compared with baseline. Plasma triglycerides were reduced at 26 wk from baseline (-0.33 ± 0.12 mmol/L, P = 0.03). Body fat percentage reduced between 12 and 26 wk (-1.57% ± 0.76%, P = 0.05). Carotid intima-media thickness (CIMT) (-0.06 ± 0.01 mm, P < 0.001) and flow-mediated dilation (absolute increase 0.44% ± 0.11%, P = 0.001) improved between baseline and 12 wk, with reduced CIMT maintained at 26 wk (P < 0.001). DEBQ-C and Pediatric Quality of Life Inventory scores improved throughout the intervention. Nineteen adolescents completed an acceptability interview, rating IER as easy and pleasant to follow (mean ± SD: +2.1 ± 1.2; +1.9 ± 1.2, respectively) on a Likert scale from -4 to +4. CONCLUSION: IER is a feasible, effective, and acceptable intervention in adolescents with obesity achieving reductions in BMI and cardiovascular disease risk. This trial was registered at www.anzctr.org.au as ACTRN12618000200280.

Cannabidiol for treating drug-resistant epilepsy in children: the New South Wales experience.

OBJECTIVE: To evaluate the tolerability and safety of cannabidiol for treating drug-resistant epilepsy in children, and to describe adverse events associated with such treatment. STUDY DESIGN: Prospective, open label cohort study. SETTING: Three tertiary NSW referral centres with paediatric neurology services. PARTICIPANTS: First 40 children enrolled in the NSW Compassionate Access Scheme for children with drug-resistant epilepsy and uncountable daily seizures. INTERVENTION: Children received cannabidiol as an adjunct anti-epileptic drug, titrated to a maximum of 25 mg/kg/day, for up to 12 weeks. OUTCOME MEASURES: Adverse events, withdrawals, and caregiver and physician Global Impression of Change assessments were recorded at 4, 8 and 12 weeks. Seizure frequency could not be reliably recorded because of disease severity. RESULTS: Thirty-nine patients reported at least one adverse event; many were deemed unrelated to cannabidiol treatment. The most frequent treatment-related adverse event was somnolence (15 participants), which resolved spontaneously in ten patients; it was particularly frequent in patients taking higher clobazam doses. Gastrointestinal effects (nausea, vomiting, diarrhoea) were each reported by seven to nine participants. Four children were withdrawn from treatment, including one with elevated transaminase levels. The caregivers of 12 children felt the overall health of their children had much or very much improved; clinicians assessed seven children as being much or very much improved. CONCLUSION: Cannabidiol as an adjunct treatment had some subjective benefit for overall health, with a manageable adverse event profile. Monitoring changes in liver function and awareness of potential drug interactions is essential. Whether the reported benefit is attributable to cannabidiol cannot be established in an open label study of participants with severe intractable epilepsy.

Hyperglycaemia in early pregnancy: the Treatment of Booking Gestational diabetes Mellitus (TOBOGM) study. A randomised controlled trial.

BACKGROUND: Gestational diabetes mellitus (GDM) causes adverse pregnancy outcomes that can be averted by treatment from 24-28 weeks' gestation. Assessing and treating women for overt diabetes in pregnancy (ODIP) at the first antenatal clinic booking is now recommended in international guidelines. As a consequence, women with milder hyperglycaemia are being diagnosed and treated for early GDM, but randomised controlled trial (RCTs) assessing the benefits and harms of such treatment have not been undertaken. The Treatment Of Booking Gestational diabetes Mellitus (TOBOGM) study is a multi-centre RCT examining whether diagnosing and treating GDM diagnosed at booking improves pregnancy outcomes. Methods and analysis: 4000 adult pregnant women (< 20 weeks' gestation) at risk of ODIP will be recruited from 12 hospital antenatal booking clinics and referred for an oral glucose tolerance test (OGTT). 800 women with hyperglycaemia (ie, booking GDM) according to the 2014 Australasian Diabetes-in-Pregnancy Society criteria for pregnant women at 24-28 weeks' gestation will be randomised to immediate treatment for GDM (intervention) or to no treatment (control), pending the results of a second OGTT at 24-28 weeks' gestation. Antenatal and GDM care will otherwise follow local guidelines. Randomisation will be stratified by site and OGTT glycaemic risk strata. The primary pregnancy outcome is a composite of respiratory distress, phototherapy, birth trauma, birth before 37 weeks' gestation, stillbirth or death, shoulder dystocia, and birthweight ≥ 4.5 kg. The primary neonatal outcome is neonatal lean body mass. The primary maternal outcome is pre-eclampsia. Ethics approval: South Western Sydney Local Health District Research and Ethics Office (reference, 15/LPOOL/551). Dissemination of results: Peer-reviewed publications, scientific meetings, collaboration with research groups undertaking comparable studies, discussions with guideline groups and policy makers. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12616000924459.

Quality of Health Care for Children in Australia, 2012-2013.

Importance: The quality of routine care for children is rarely assessed, and then usually in single settings or for single clinical conditions. Objective: To estimate the quality of health care for children in Australia in inpatient and ambulatory health care settings. Design, Setting, and Participants: Multistage stratified sample with medical record review to assess adherence with quality indicators extracted from clinical practice guidelines for 17 common, high-burden clinical conditions (noncommunicable [n = 5], mental health [n = 4], acute infection [n = 7], and injury [n = 1]), such as asthma, attention-deficit/hyperactivity disorder, tonsillitis, and head injury. For these 17 conditions, 479 quality indicators were identified, with the number varying by condition, ranging from 9 for eczema to 54 for head injury. Four hundred medical records were targeted for sampling for each of 15 conditions while 267 records were targeted for anxiety and 133 for depression. Within each selected medical record, all visits for the 17 targeted conditions were identified, and separate quality assessments made for each. Care was evaluated for 6689 children 15 years of age and younger who had 15 240 visits to emergency departments, for inpatient admissions, or to pediatricians and general practitioners in selected urban and rural locations in 3 Australian states. These visits generated 160 202 quality indicator assessments. Exposures: Quality indicators were identified through a systematic search of local and international guidelines. Individual indicators were extracted from guidelines and assessed using a 2-stage Delphi process. Main Outcomes and Measures: Quality of care for each clinical condition and overall. Results: Of 6689 children with surveyed medical records, 53.6% were aged 0 to 4 years and 55.5% were male. Adherence to quality of care indicators was estimated at 59.8% (95% CI, 57.5%-62.0%; n = 160 202) across the 17 conditions, ranging from a high of 88.8% (95% CI, 83.0%-93.1%; n = 2638) for autism to a low of 43.5% (95% CI, 36.8%-50.4%; n = 2354) for tonsillitis. The mean adherence by condition category was estimated as 60.5% (95% CI, 57.2%-63.8%; n = 41 265) for noncommunicable conditions (range, 52.8%-75.8%); 82.4% (95% CI, 79.0%-85.5%; n = 14 622) for mental health conditions (range, 71.5%-88.8%); 56.3% (95% CI, 53.2%-59.4%; n = 94 037) for acute infections (range, 43.5%-69.8%); and 78.3% (95% CI, 75.1%-81.2%; n = 10 278) for injury. Conclusions and Relevance: Among a sample of children receiving care in Australia in 2012-2013, the overall prevalence of adherence to quality of care indicators for important conditions was not high. For many of these conditions, the quality of care may be inadequate.

The prevalence of Vitamin D deficiency is higher in adult survivors of childhood cancer.

BACKGROUND: It is unclear whether the rate of vitamin D deficiency in paediatric cancer survivors is higher than in the background population, and whether this is of pathological significance. PATIENTS AND METHODS: 25OHD was measured in a previously studied group of 208 survivors (n = 108 paediatric 5-17 years, n = 99 adults 18-39 years) and compared with paediatric (5-17 years; n = 132) and adult controls (25-35 years; n = 1393 from the AusDiab cohort) adjusted for age and gender. Relationships with treatment factors (irradiation, bone marrow transplantation and intensity of treatment) along with overweight/obesity (defined by BMI), abdominal adiposity (waist:height ratio >0·5) and hyperinsulinism or abnormal glucose tolerance (HI/aGT) were sought. RESULTS: 25OHD concentrations were similar in paediatric survivors compared with controls (64·3 ± 21·6 nmol/l vs 66·3 ± 22·8 nmol/l), with no effect of age or gender. Adjusted for gender, rates of 25OHD deficiency (<50 nmol/l) were higher in adult survivors compared with AusDiab controls (42·4% vs 20·8%; P < 0·001). Apart from time since diagnosis (P = 0·03), no relationship with treatment factors was detected. In multivariate regression analysis, abdominal adiposity (P = 0·001), but not overweight/obesity by BMI status nor HI/aGT, was associated with significantly lower 25OHD concentrations. CONCLUSIONS: Adult survivors are at increased risk of abnormalities in vitamin D compared to the background population, probably reflecting longer time since diagnosis. Like others, we have not identified any contributory treatment-related factors. Vitamin D deficiency does not appear to be associated with the development of abnormal glucose tolerance in this population.

Comparison of weight- vs body surface area-based growth hormone dosing for children: implications for response.

OBJECTIVE: To compare weight (per kg)- vs body surface area (BSA, per m(2) )-based growth hormone (GH) dosing formats in children and to derive a useful conversion formula between the two formats. PATIENTS AND DESIGN: Growth hormone doses (>33,000) from 1874 children were obtained from the national Australian database (OZGROW) and used to derive conversion formulae and to confirm the accuracy of a conversion formula based on a weight-only BSA estimate. A further 27,000 doses were used to test the accuracy of all formulae. The best conversion formula was used to compare weight- and surface area-based GH dosing, which included an analysis of first year response (∆SDS height or growth velocity, GV). MEASUREMENTS: Growth hormone doses in mg/m(2) /wk and mg/kg/wk, dose estimates, residuals, first year ∆SDS, first year GV. RESULTS: The formula, [Formula: see text] based on a weight-only BSA estimate, provides accurate dose conversion (mean residual, 0·005 mg/kg/week). A constant mg/m(2) /week dose expressed in terms of mg/kg/week declines quickly with increasing body weight to approximately 15 kg after which the decline continues although less dramatically. For Australian patients, despite an increase in mean per m(2) dose with increased starting weight/age, the per kg dose decreased. This was associated with a greater decline in first year GV than estimated if a per kg dose had been maintained. CONCLUSIONS: Growth hormone doses can be accurately converted between formats. Surface area-based GH dosing is likely to result in a reduced height response as children become heavier when compared with weight-based GH dosing.

Incidence of vitamin D deficiency rickets among Australian children: an Australian Paediatric Surveillance Unit study.

OBJECTIVE: To determine the incidence of and factors associated with vitamin D deficiency rickets in Australian children. DESIGN: 18-month questionnaire-based prospective observational study, using Australian Paediatric Surveillance Unit (APSU) data. SETTING: Australian paediatricians and child health workers, January 2006 - July 2007. PARTICIPANTS: Children aged ≤ 15 years with vitamin D deficiency rickets (25-hydroxyvitamin D [25OHD] ≤ 50 nmol/L, and elevated alkaline phosphatase levels [> 229 IU/L] and/or radiological rickets). MAIN OUTCOME MEASURES: Incidence of vitamin D deficiency rickets. Description of demographics, clinical presentation, identification and further analysis of overrepresented groups, and treatment regimens compared with best-practice guidelines. RESULTS: We identified 398 children with vitamin D deficiency (55% male; median age, 6.3 years [range, 0.2-15 years]). The overall incidence in children ≤ 15 years of age in Australia was 4.9/100 000/year. All had a low 25OHD level (median, 28 nmol/L [range, 5-50 nmol]) and an elevated alkaline phosphatase level (median, 407 IU/L [range, 229-5443 IU/L]), and 48 (12%) were hypocalcaemic. Ninety-five children had wrist x-rays, of whom 67 (71%) had rachitic changes. Most (98%) had dark or intermediate skin colour and 18% of girls were partially or completely veiled. Most children were born in Africa (252; 63%) and 75% of children were refugees. Duration of exclusive breastfeeding was inversely related to serum vitamin D levels in children < 3 years of age. Empirical vitamin D treatment was given to 4% of children before diagnosis. CONCLUSIONS: Vitamin D deficiency rickets is a significant problem in Australia among known high-risk groups. Public health campaigns to prevent, identify and tre@vitamin D deficiency, especially in high-risk groups, are essential.

Validation of longitudinal DXA changes in body composition from pre- to mid-adolescence using MRI as reference.

Dual-energy X-ray absorptiometry (DXA) has been used extensively for bone mineral density and body composition assessments. Surprisingly, the role of DXA in monitoring changes in children's body composition, using direct imaging methods such as magnetic resonance imaging (MRI) as reference, is still yet to be validated. We aimed at validating the use of DXA in monitoring change in the thigh lean soft tissue mass (LSTM) and fat mass (FM) when compared with thigh skeletal muscle mass (SM) and FM, measured using MRI as the reference standard, from childhood to midadolescence. At baseline, 22 healthy children (16 boys and 6 girls) aged 8-11yr were included, and then recalled at pubertal stage Tanner2-Tanner4. LSTM-DXA and FM-DXA of the mid-third femur and SM-MRI and FM-MRI of the same region were measured on the same day. The same protocol was repeated 26-48mo later. At baseline, DXA overestimated LSTM-DXA on average by 222g (95% confidence interval [CI]: 33-410g) with a concordance C-LSTM=0.576. FM-MRI and FM-DXA were not significantly different (95% CI=213 to 199g, the C-FM=0.907). At follow-up, change in LSTM-DXA and FM-DXA were not significantly different to change in SM-MRI and FM-MRI, respectively (95% CI of the difference was -278 to 208g for LSTM, and -148 to 236g for FM). The coefficient of concordance between the 2 techniques was 0.88 for both LSTM and FM. This study validates the use of DXA in monitoring changes in LSTM and FM in children, confirming its significant potential in clinical and research roles in pediatric body composition.

Associations between insulin and glucose concentrations and anthropometric measures of fat mass in Australian adolescents.

BACKGROUND: One of the most serious, yet common co-morbidities of obesity is insulin resistance, which if untreated may progress to type 2 diabetes. This paper describes the insulin and glucose concentration distributions, the prevalence of elevated insulin, the associations between insulin and body mass index (BMI), waist circumference, waist-to-height ratio (WHtR) and fat mass index in a representative sample of Australian adolescents. METHODS: Cross-sectional population-based study of adolescent boys and girls (N = 496, mean age 15.3 years) attending schools in metropolitan Sydney, Australia. Fasting venous blood collected and analysed for insulin and glucose concentrations. Height, weight, waist circumference measured, BMI and waist-to-height ratio calculated. Pubertal status self-reported. RESULTS: Glucose concentrations were normally distributed and were not associated with adiposity. Insulin concentrations were distributed logarithmically, were higher among girls than boys overall and within the same ranges of BMI and waist circumference, but were lower among girls than boys within the same ranges of fat mass adjusted for height. The prevalence of elevated insulin concentration (defined as > 100 pmol/L) was 15.9% and 17.1% among boys and girls, respectively. Correlations between insulin concentration and BMI, waist circumference, WHtR and fat mass adjusted for height were 0.53, 0.49, 0.51 and 0.55, among boys, respectively, and 0.35, 0.40, 0.42 and 0.34, among girls, respectively. CONCLUSIONS: Elevated insulin is highly correlated with adiposity in adolescents. BMI and WHtR are simple measures that can be used to identify young people who should be screened for insulin resistance and other co-morbidities.

Fast track to health - Intermittent energy restriction in adolescents with obesity. A randomised controlled trial study protocol.

BACKGROUND: Intermittent energy restriction (IER) has shown early success in adolescents with obesity, however efficacy trials are needed. This study aims to determine if IER results in lower body mass index (BMI) z-score after 52 weeks in metabolically unhealthy adolescents with obesity compared with continuous energy restriction (CER). METHODS/DESIGN: This is a prospective, randomised, multi-centre trial conducted in tertiary care settings, with three phases: jumpstart (weeks 0-4); intensive intervention (weeks 5-16); continued intervention and/or maintenance (weeks 17-52). During the jumpstart phase, all participants follow a very low energy diet (∼800kcal/3350kJ/day), then transition to their allocated intervention: IER or CER. IER involves three energy-restricted days/week, consuming one-third of daily energy requirements (∼600-700kcal/2500-2950kJ/day), and four days/week of a healthy meal plan. The CER, which is current standard care, has individually tailored energy prescription based on age and sex (13-14years, 1430-1670kcal/6000-7000kJ/day; 15-17years, 1670-1900kcal/7000-8000kJ/day). The study will recruit 186 (93 per arm) treatment-seeking adolescents aged 13-17years with obesity and at least one metabolic co-morbidity. The primary outcome is change in BMI z-score at 52 weeks. Secondary outcomes are changes at 4, 16 and 52 weeks in: body composition; diet quality, food choices and food patterns; cardio-metabolic risk factors; physical activity and sedentary behaviour; sleep and psycho-behavioural measures. DISCUSSION: This study challenges existing clinical paradigms that CER is the only method for weight management in metabolically unhealthy adolescents. If successful, IER may offer an alternate medical nutrition therapy approach for those seeking treatment in tertiary settings. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12617001630303.

Costs of managing conditions associated with obesity among Australian teenagers.

AIM: To determine the health-care charges associated with monitoring and managing, over 1 year, the cases of elevated insulin concentration, elevated alanine aminotransferase concentration and dyslipidaemia due to overweight or obesity among 15-19-year-old Australian males and females. METHODS: Fasting blood samples (n= 500) were collected in 2004 from a representative population sample of adolescents (n= 496; mean age 15.3 years) attending schools in Sydney, Australia. Full service charges and Medicare expenditures for specialist medical and dietary consultations, pathology tests and radiological investigations, over 1 year, under efficient and inefficient health-care delivery models, including and excluding participants in the healthy body mass index (BMI) category. RESULTS: Under an inefficient delivery model and including all participants with elevated risk factors, the Medicare expenditure was $A305.1 million per annum (M pa). Exclusion of participants in the healthy BMI category resulted in an annual Medicare expenditure of $A170.0M pa. Under an efficient delivery model and including all participants with elevated risk factors, the Medicare expenditure was $A295.5M pa. Exclusion of participants in the healthy BMI category reduced annual Medicare expenditure to $A164.8M pa. Medicare expenditure for 15-19-year-olds would increase by 48% if only cases among overweight and obese adolescents were treated and by 85% if all cases were identified and treated. CONCLUSIONS: Short-term management of the health consequences of overweight and obesity among adolescents will increase Medicare expenditure on this group by at least 48%. Failure to treat will delay, but compound, health-care expenditure.

Prediction of appendicular skeletal and fat mass in children: excellent concordance of dual-energy X-ray absorptiometry and magnetic resonance imaging.

BACKGROUND: Body composition studies in children have great potential to help understand the aetiology and evolution of acute and chronic. diseases. AIM: To validate appendicular lean soft tissue mass (LSTM) and fat mass (FM) measured using dual energy X-ray absorptiometry (DXA), with magnetic resonance imaging (MRI) as the reference standard, in healthy peri-pubertal adolescents. DESIGN: Peri-pubertal Caucasian children (n = 74) aged 11-14 years were evaluated. DXA LSTM and FM of the mid third femur were measured and skeletal muscle mass (SM) and FM of the same region were measured on the same day by MRI. RESULTS: There was a strong correlation between MRI SM and DXA LSTM (r2 = 0.98, index of concordance [C] = 0.91). DXA estimation of LSTM exceeded MRI SM by a mean of 189 g, from 6-371 g (p < 0.0001). The discordance between DXA and MRI significantly increased with the absolute value (r = 0.27; p = 0.024). FM was highly correlated (r = 0.98) with a high index of concordance (C = 0.97). CONCLUSION: This study validates the use of DXA in LSTM measurement in children, confirming its potential in clinical and research roles in paediatric diseases affecting and related to body composition.

Clinical indicators for common paediatric conditions: Processes, provenance and products of the CareTrack Kids study.

BACKGROUND: In order to determine the extent to which care delivered to children is appropriate (in line with evidence-based care and/or clinical practice guidelines (CPGs)) in Australia, we developed a set of clinical indicators for 21 common paediatric medical conditions for use across a range of primary, secondary and tertiary healthcare practice facilities. METHODS: Clinical indicators were extracted from recommendations found through systematic searches of national and international guidelines, and formatted with explicit criteria for inclusion, exclusion, time frame and setting. Experts reviewed the indicators using a multi-round modified Delphi process and collaborative online wiki to develop consensus on what constituted appropriate care. RESULTS: From 121 clinical practice guidelines, 1098 recommendations were used to draft 451 proposed appropriateness indicators. In total, 61 experts (n = 24 internal reviewers, n = 37 external reviewers) reviewed these indicators over 40 weeks. A final set of 234 indicators resulted, from which 597 indicator items were derived suitable for medical record audit. Most indicator items were geared towards capturing information about under-use in healthcare (n = 551, 92%) across emergency department (n = 457, 77%), hospital (n = 450, 75%) and general practice (n = 434, 73%) healthcare facilities, and based on consensus level recommendations (n = 451, 76%). The main reason for rejecting indicators was 'feasibility' (likely to be able to be used for determining compliance with 'appropriate care' from medical record audit). CONCLUSION: A set of indicators was developed for the appropriateness of care for 21 paediatric conditions. We describe the processes (methods), provenance (origins and evolution of indicators) and products (indicator characteristics) of creating clinical indicators within the context of Australian healthcare settings. Developing consensus on clinical appropriateness indicators using a Delphi approach and collaborative online wiki has methodological utility. The final indicator set can be used by clinicians and organisations to measure and reflect on their own practice.

Evaluation of adrenal function using the human corticotrophin-releasing hormone test, low dose Synacthen test and 9am cortisol level in children and adolescents with central adrenal insufficiency.

BACKGROUND: The insulin tolerance test (ITT) has become less popular in paediatrics because of the risks associated with hypoglycaemia. Human corticotrophin-releasing hormone (hCRH) test results correlate with the ITT and may be an acceptable method to test for central adrenal insufficiency (CAI). Simpler tests, such as the low dose Synacthen test (LDST) and 9am cortisol, have also been proposed. OBJECTIVE: To compare the ability of the hCRH test, LDST, 9am cortisol level and 24-h cortisol profiles to diagnose CAI in a paediatric population. DESIGN AND SETTING: A cross-sectional study in a tertiary paediatric endocrine clinic. PARTICIPANTS: Thirty-one children and adolescents (aged 2.3-18.3 years) with CAI risk factors had an hCRH test, LDST, 9am cortisol and 24-h cortisol profile performed. RESULTS: Of 23 patients with confirmed CAI (hCRH peak cortisol < 400 nmol/), 19 failed the LDST (peak cortisol < 267 nmol/l, i.e. 10th percentile for controls). Nineteen would have failed based on the 10th percentile cut point for 9am cortisol (< 140 nmol/l). Using receiver operating characteristic (ROC) curve coordinates, a 9am cortisol < 108 nmol/l was sensitive (83%) and specific (99%) for CAI. The 9am cortisol levels measured on two occasions were repeatable (94%) and correlated (r = 0.83, P = 0.01). All eight adrenally sufficient patients (hCRH peak cortisol > or = 400 nmol/l) passed the LDST. Seven had normal 9am cortisol (> or = 140 nmol/l). The 24-h cortisol area under the curve (AUC) for these patients was within the 10th-90th percentiles for control subjects' AUC. The peak cortisol to hCRH and LDST were correlated (r = 0.88, P = 0.01), with no difference between the peaks (mean difference -5.3 nmol/l, P = 0.69). CONCLUSIONS: In children with CAI risk factors, the diagnosis can be made if unstressed 9am cortisol is < 108 nmol/l. As cortisol levels > 381 nmol/l are highly suggestive of normal hypothalamic-pituitary-adrenal (HPA) function, stimulation testing need only be performed if 9am cortisol is 108-381 nmol/l. The LDST should be interpreted cautiously because mild CAI may be missed. When stimulation results are marginal, 24-h cortisol profiles can provide reassurance of normal cortisol status.

Acute phase response and mineral status following low dose intravenous zoledronic acid in children.

INTRODUCTION: Previous reports have shown a high frequency of hypocalcaemia and flu-like symptoms following an initial first zoledronic acid dose of 0.02-0.025 mg/kg in children. METHODS: We systematically evaluated the mineral status and symptomatology of 63 children with a variety of bone disorders treated with an initial zoledronic acid dose of 0.0125 mg/kg. The Mann-Whitney U test, chi-squared test and Fisher's exact test were used as appropriate. RESULTS: 0.0125 mg/kg zoledronic acid reduced the incidence and intensity of hypocalcaemia but not the incidence of the flu-like symptoms compared to higher doses. Within the low dose cohort, flu-like symptoms were associated with an acute inflammatory response. Children who became hypocalcaemic received a higher dose in relation to their body mass index and body surface area. CONCLUSION: Reducing the initial zoledronic acid dose in children decreased the incidence of hypocalcaemia and thus improved safety. Dosing on the basis of body mass index or body surface area instead of body weight may further reduce the incidence of hypocalcaemia.

The clinical utility of alternative, less invasive sampling techniques in the assessment of oral hydrocortisone therapy in children and adolescents with hypopituitarism.

OBJECTIVE: The aim of glucocorticoid replacement therapy in ACTH-deficient patients is to mimic the normal diurnal variation of cortisol. However, current hydrocortisone (HC) replacement results in prolonged episodes of hypocortisolaemia and supraphysiological peaks. Plasma cortisol profiles are an accurate yet labour-intensive method of assessing HC replacement. Salivary and bloodspot cortisol sampling methods are less invasive and may be useful tools for assessing glucocorticoid replacement, particularly in children. Therefore, we aimed to define normal salivary and bloodspot cortisol levels in children and their correlations with the gold standard (plasma cortisol). DESIGN: Cross-sectional study in a paediatric teaching hospital. METHODS: Plasma, saliva and bloodspot cortisol profiles were performed on 30 ACTH-deficient children and 22 healthy siblings. RESULTS: In ACTH-deficient patients taking oral HC, the bloodspot-plasma correlation (p=0.90) was stronger than the salivary-plasma correlation (p=0.49). Using target ranges for salivary and bloodspot cortisol levels based on normal data from control subjects, the less invasive sampling methods had low rates of agreement with plasma cortisol target ranges (saliva 65% and bloodspot 75%). Using the plasma-bloodspot correlation regression equation to convert bloodspot to calculated plasma cortisol, there was a high concordance between calculated and actual measured plasma cortisol (88%). CONCLUSION: Bloodspot cortisol sampling is a feasible and accurate method for monitoring oral HC replacement in paediatric patients without necessitating hospital admission, but salivary sampling is not useful.

Intravenous bisphosphonate therapy for traumatic osteonecrosis of the femoral head in adolescents.

BACKGROUND: Femoral head osteonecrosis as a result of trauma in adolescents has a poor prognosis as a result of femoral head collapse and subsequent degenerative change of the hip. There are currently no satisfactory treatments for adolescents with this condition, although bisphosphonate therapy has improved the outcome in animal models of osteonecrosis. We evaluated bisphosphonate therapy for femoral head osteonecrosis following trauma in adolescents. METHODS: We established a protocol for identifying adolescents with osteonecrosis of the femoral head with use of bone scans immediately after surgical treatment of hips at risk for the development of osteonecrosis following trauma. In a consecutive group of twenty-eight patients with an unstable slipped capital femoral epiphysis (twenty-two patients), femoral neck fracture (four), or traumatic hip dislocation (two), seventeen patients with osteonecrosis were identified. These patients (thirteen boys and four girls with a mean age of 12.7 years) and their families gave consent for the patients to receive treatment with intravenous bisphosphonates. The average duration of the bisphosphonate treatment was 20.3 months (range, seven to thirty-nine months). All patients were followed clinically and radiographically for a minimum of two years. RESULTS: After a mean duration of follow-up of 38.7 months, fourteen patients were pain-free. Clinically, all seventeen patients had a good or excellent outcome. On the average, the Harris hip score was 91.2 points, the Iowa Hip Rating was 92.1 points, and the Global Pediatric Outcomes Data Collection Instrument (PODCI) score was 91.5 points. According to the radiographic classification system of Stulberg et al., nine hips were rated as Class I or II; six, as Class III; and two, as Class IV. CONCLUSIONS: Bisphosphonate therapy may play an adjunctive role in the treatment of adolescents with osteonecrosis of the femoral head following trauma.

Sex differences in aortic augmentation index in adolescents.

BACKGROUND: Augmentation index (AIx) is a noninvasive measure of pulse wave reflection. AIx is associated with cardiovascular disease. Adult women have a higher AIx than men, but the factors determining this sex-related difference remain to be determined. METHODS: To examine factors associated with AIx in adolescents, participants in the Childhood Asthma Prevention Study, followed from birth, were assessed at age 14 years, with AIx standardized to a heart rate of 75/min (AIx_75) and pulse wave velocity. Associations of AIx_75 and pulse wave velocity with height, change in height, and measures of puberty were assessed. RESULTS: AIx_75 was higher in women compared to men [-24.5 (12.1) versus -32.3 (12.4)%; P < 0.001]. Lower AIx_75 was significantly related to greater change in height between 8 and 14 years, but not to achieved height. The sex difference in AIx was not independently related to puberty variables. Differences between sexes included early life weight gain, lipids, height, BMI-Z-score, change in height from 8 to 14 years, and age at peak height velocity. Change in AIx_75 from 8 to 14 years was highly associated with change in height (m) from 8 to 14 years (B = -88.8, 95% confidence interval -137.3 to -40.3, P =  < 0.001). The difference between sexes established at 8 years was not amplified from 8 to 14 years. CONCLUSION: AIx is higher in girls than boys at 14 years and is closely associated with change in height between 8 and 14 years. Measures of puberty do not appear to independently influence the sex difference in AIx in adolescents.

Opposing influences of prenatal and postnatal growth on the timing of menarche.

CONTEXT AND OBJECTIVE: Menarche is a milestone of reproductive development, and its timing may be differentially influenced by the growth conditions before birth and those between birth and puberty. The present study explored the relationships among menarcheal timing and markers of prenatal and midchildhood growth in healthy Australian girls. SETTING, DESIGN, AND PATIENTS: A total of 156 girls aged 8 yr from a birth cohort of full-term babies had height, weight, and waist circumference measured. One hundred three girls had dual x-ray absorptiometry performed and blood analyzed for insulin, leptin, IGF-I, estradiol, and dehydroepiandrosterone sulfate levels. Girls were followed up at age 15 yr and their age of menarche was recorded. MAIN OUTCOME MEASURES: Measures included age of menarche; birth weight and birth length; height, weight, waist circumference, and body composition by dual x-ray absorptiometry; and plasma insulin, leptin, IGF-I, estradiol, and dehydroepiandrosterone sulfate at age 8 yr. RESULTS: Girls with earlier menarche were light and long at birth and had higher total and central adiposity and IGF-I and estradiol levels in midchildhood, compared with those with later menarche. Age of menarche was best predicted by combining size at birth and body mass index z score at age 8 yr (r2 = 0.12; P < 0.001). CONCLUSIONS: The timing of menarche appears to be influenced in opposing directions by pre- and postnatal growth. Menarche was found to occur earlier in girls who were long and light at birth and who had a higher fat mass and circulating IGF-I in childhood. These findings may partly explain ethnic differences and secular trends in the age of menarche.