Publications by authors named "Shubha Srinivasan"

21 Publications

  • Page 1 of 1

Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: an Australian perspective.

Am J Prev Cardiol 2021 Jun 4;6:100151. Epub 2021 Feb 4.

School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia.

Introduction: Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease, with significant potential for positive impact on public health and healthcare savings. New clinical practice recommendations are presented in an abridged guidance to assist practitioners in enhancing the care of all patients with FH.

Main Recommendations: Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. There is a key role for general practitioners (GPs) working in collaboration with specialists with expertise in lipidology. Advice is given on genetic and cholesterol testing and risk notification of biological relatives undergoing cascade testing for FH; all healthcare professionals should develop skills in genomic medicine. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors, and appropriate use of low-density lipoprotein (LDL)-cholesterol lowering therapies, including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recommendations on service design are provided in the full guidance.

Potential Impact On Care Of Fh: These recommendations need to be utilised using judicious clinical judgement and shared decision making with patients and families. Models of care need to be adapted to both local and regional needs and resources. In Australia new government funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of these recommendations. A broad implementation science strategy is, however, required to ensure that the guidance translates into benefit for all families with FH.
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http://dx.doi.org/10.1016/j.ajpc.2021.100151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315409PMC
June 2021

Essentials of a new clinical practice guidance on familial hypercholesterolaemia for physicians.

Intern Med J 2021 May;51(5):769-779

School of Medicine, University of Western Australia, Perth, Western Australia, Australia.

Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease. New clinical practice recommendations are presented to assist practitioners in enhancing the care of all patients with FH. Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors and appropriate use of low-density lipoprotein (LDL)-cholesterol-lowering therapies including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The recommendations need to be utilised using judicious clinical judgement and shared decision-making with patients and families. New government-funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of the recommendations. However, a comprehensive implementation science and practice strategy is required to ensure that the guidance translates into benefit for all families with FH.
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http://dx.doi.org/10.1111/imj.15327DOI Listing
May 2021

Role of cross-campus multidisciplinary team meetings in decision-making for children and adolescents with differences of sex development/intersex.

J Paediatr Child Health 2021 Sep 30;57(9):1402-1407. Epub 2021 Apr 30.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, NSW, Australia.

Aim: Management of children with differences/disorders of sex development (DSD) is complex with limited evidence to guide clinical decisions. Regular multidisciplinary team meetings were set up in Sydney and Melbourne paediatric hospitals to enable systematic peer review of complex decision-making. We aim to describe the workload and role of these meetings.

Methods: The multidisciplinary team forum includes invited representatives from endocrinology, urology, gynaecology, genetics, psychology, social work, clinical ethics, laboratory and hospital executive and meetings occur 1-3 times monthly. Descriptive data were collected from de-identified meeting referrals and minutes between August 2012 to August 2018 (Sydney) and January 2014 to August 2018 (Melbourne).

Results: A total of 192 referrals (142 new and 50 follow-ups) aged 1 week to 17 years were discussed across the two sites. 46, XY DSD (n = 81) was the most common sub-classification. Consideration of surgical options and optimal management of gonads with malignant potential were amongst the common reasons for referral to the multidisciplinary team meetings. Surgical interventions were considered but not recommended after review for 38 of 154 (24.7%) procedures. Gonad retention to allow potential functional benefit was recommended in 15/46 (32.6%) referrals. Evidence of premalignant or malignant changes was found in 20/57 (35%) gonads removed, with dysgenetic features and atrophy/streak features in 6 (10.5%) and 27 (47.4%) gonads respectively.

Conclusion: Formal DSD multidisciplinary team meetings provide a framework and opportunity for multi and interdisciplinary discussions amongst representatives from several specialities to help make complex decision-making.
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http://dx.doi.org/10.1111/jpc.15474DOI Listing
September 2021

Familial hypercholesterolaemia: Experience of a tertiary paediatric lipid clinic.

J Paediatr Child Health 2021 08 8;57(8):1201-1207. Epub 2021 Apr 8.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

Aim: To review the experience of a dedicated paediatric multidisciplinary lipid clinic in the management of familial hypercholesterolaemia (FH) by studying the demographics, clinical presentations as well as statin therapy and outcomes.

Methods: Retrospective database review of all patients under 18 years old seen in the lipid clinic at an Australian tertiary paediatric hospital between April 1999 and August 2017. Outcome measures collected included patient demographics, family history, lipid profile, age at treatment commencement, treatment outcomes and complications.

Results: One hundred and eight patients (53 males) were seen in the lipid clinic. Eighty-five had low-density lipoprotein cholesterol (LDL-C) levels at or above the 75th percentile for sex prior to treatment. Of these, 75 had a first-degree relative with hypercholesterolaemia and/or early cardiac death. Four patients had clinical manifestations. Thirty-two patients (14 males) were started on statin therapy for likely FH. LDL-C levels reduced by 2.4 mmol/L (1.4 to 2.7) in boys and 1.9 mmol/L (0.8 to 2.8) in girls at 12 month follow-up. Five patients reported side effects requiring adjustment in therapy. Main reasons for not starting statin therapy in eligible patients were parental refusal and/or lost to follow up (77%).

Conclusion: A dedicated multidisciplinary lipid clinic is helpful for streamlining and monitoring management of paediatric FH. Clinical manifestations of FH are rare in children and may represent more severe form of FH or other lipid disorder. Statin therapy is efficacious and well tolerated but current recommended targets of treatment are difficult to attain. Greater awareness and coordinated services are required to overcome poor family engagement.
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http://dx.doi.org/10.1111/jpc.15426DOI Listing
August 2021

Investigating paediatric hypoglycaemia: Dynamic studies at a tertiary paediatric hospital.

J Paediatr Child Health 2021 06 11;57(6):888-893. Epub 2021 Jan 11.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

Aim: Paediatric hypoglycaemia often requires specific investigations to determine aetiology. Samples from the time of hypoglycaemia may not be available and a diagnostic fasting test may be required. Additionally, fasting studies can determine safe fasting intervals and prolonged oral glucose challenges can assess hypoglycaemia due to abnormal post-prandial glucose handling. This audit reviewed the current utility and yield of fasting studies, prolonged oral glucose challenges and starch loads.

Methods: Retrospective audit of clinical record to determine purpose and outcome of tests performed at a Tertiary Paediatric Endocrine/Metabolic Testing Unit in Sydney, Australia, from 2013 to 2018 inclusive.

Results: One hundred and thirty-eight children (aged 3 weeks-17 years) underwent 170 tests: 122 fasting studies, 20 five-hour OGTTs, 22 uncooked corn starch loads and six modified waxy maize starch (Glycosade) loads. The majority were for diagnostic purposes (n = 113, 66%), with 57 (34%) to guide management in patients with known diagnoses. Following diagnostic studies, 35 (31%) patients received a pathological diagnosis, the most common of which (n = 19, 17%) was accelerated starvation. Hypoglycaemia developed in n = 15/113 (13%) during the diagnostic studies. Management studies helped determine length of safe fast, adjustment of medication or diet and document resolution of pathology.

Conclusion: Fasting studies remain a safe and effective method to assist with diagnoses, confirm or exclude pathological causes of childhood hypoglycaemia and to guide management of known diagnoses in the paediatric population.
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http://dx.doi.org/10.1111/jpc.15349DOI Listing
June 2021

Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia.

Heart Lung Circ 2021 Mar 9;30(3):324-349. Epub 2020 Dec 9.

School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia.

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.
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http://dx.doi.org/10.1016/j.hlc.2020.09.943DOI Listing
March 2021

Evaluation of a Two-Tier Screening Pathway for Congenital Adrenal Hyperplasia in the New South Wales Newborn Screening Programme.

Int J Neonatal Screen 2020 Sep 12;6(3):63. Epub 2020 Aug 12.

Department of NSW Newborn Screening Programme, The Sydney Children Hospital Network, Westmead, NSW 2145, Australia;

In Australia, all newborns born in New South Wales (NSW) and the Australia Capital Territory (ACT) have been offered screening for rare congenital conditions through the NSW Newborn Screening Programme since 1964. Following the development of the Australian Newborn Bloodspot Screening National Policy Framework, screening for congenital adrenal hyperplasia (CAH) was included in May 2018. As part of the assessment for addition of CAH, the national working group recommended a two-tier screening protocol determining 17α-hydroxyprogesterone (17OHP) concentration by immunoassay followed by steroid profile. A total of 202,960 newborns were screened from the 1 May 2018 to the 30 April 2020. A threshold level of 17OHP from first tier immunoassay over 22 nmol/L and/or top 2% of the daily assay was further tested using liquid chromatography tandem mass spectrometry (LC-MS/MS) steroid profiling for 17OHP (MS17OHP), androstenedione (A4) and cortisol. Samples with a ratio of (MS17OHP + A4)/cortisol > 2 and MS17OHP > 200 nmol/L were considered as presumptive positive. These newborns were referred for clinical review with a request for diagnostic testing and a confirmatory repeat dried blood spot (DBS). There were 10 newborns diagnosed with CAH, (9 newborns with salt wasting CAH). So far, no known false negatives have been notified, and the protocol has a sensitivity of 100%, specificity of 99.9% and a positive predictive value of 71.4%. All confirmed cases commenced treatment by day 11, with none reported as having an adrenal crisis by the start of treatment.
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http://dx.doi.org/10.3390/ijns6030063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569785PMC
September 2020

A guide to differences/disorders of sex development/intersex in children and adolescents.

Aust J Gen Pract 2020 07;49(7):417-422

BSc (Med), MBBS, PhD, MRCP (UK), FRACP, Senior Staff Specialist, Institute of Endocrinology and Diabetes, The [email protected] Hospital at Westmead, NSW; Clinical Senior Lecturer, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, NSW.

Background: Differences/disorders of sex development (DSD) or 'intersex' encompass a broad range of congenital variations in the complex pathways involved in the development of sex characteristics. Components of these pathways include sex chromosomes, genes involved in gonadal development, hormone production and action, and the development of internal and external genital structures. Many variations are rare, and some (eg congenital adrenal hyperplasia) are associated with urgent medical needs. People born with variations in sex characteristics may present in the neonatal period with atypical genitalia, during childhood and adolescence with atypical pubertal development or in adulthood with hormone imbalance, fertility issues and/or sexual health concerns.

Objective: An overview of DSD is presented in relation to presenting features and management challenges in the paediatric population.

Discussion: An experienced multidisciplinary team that uses a shared decision-making approach with a medical, surgical, ethical, psychological and human rights framework is required to maximise long-term positive outcomes for people born with variations in sex characteristics.
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http://dx.doi.org/10.31128/AJGP-03-20-5266DOI Listing
July 2020

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

Genome Biol 2016 11 29;17(1):243. Epub 2016 Nov 29.

Department of Medical Genetics, Sydney Children's Hospital, Randwick, NSW, Australia.

Background: Disorders 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.

Results: We 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.

Conclusions: Our 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.
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http://dx.doi.org/10.1186/s13059-016-1105-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126855PMC
November 2016

Metabolic syndrome in children and adolescents: Old concepts in a young population.

J Paediatr Child Health 2016 Oct 14;52(10):928-934. Epub 2016 Jun 14.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

Many years after first being described, there is still no clear consensus on diagnostic criteria for metabolic syndrome, particularly in children. However, identification of this cluster of cardiovascular risk factors especially in children with co-morbidities, is important in order to reduce their future risk of chronic disease and morbidity. Sustained multidisciplinary and family-based early intervention is required, aiming primarily at life-style change.
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http://dx.doi.org/10.1111/jpc.13190DOI Listing
October 2016

Improved insulin sensitivity and body composition, irrespective of macronutrient intake, after a 12 month intervention in adolescents with pre-diabetes; RESIST a randomised control trial.

BMC Pediatr 2014 Nov 25;14:289. Epub 2014 Nov 25.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW, 2145, Australia.

Background: A higher protein to carbohydrate ratio in the diet may potentiate weight loss, improve body composition and cardiometabolic risk, including glucose homeostasis in adults. The aim of this randomised control trial was to determine the efficacy of two structured lifestyle interventions, differing in dietary macronutrient content, on insulin sensitivity and body composition in adolescents. We hypothesised that a moderate-carbohydrate (40-45% of energy), increased-protein (25-30%) diet would be more effective than a high-carbohydrate diet (55-60%), moderate-protein (15%) diet in improving outcomes in obese, insulin resistant adolescents.

Methods: Obese 10-17 year olds with either pre-diabetes and/or clinical features of insulin resistance were recruited at two hospitals in Sydney, Australia. At baseline adolescents were prescribed metformin and randomised to one of two energy restricted diets. The intervention included regular contact with the dietician and a supervised physical activity program. Outcomes included insulin sensitivity index measured by an oral glucose tolerance test and body composition measured by dual-energy x-ray absorptiometry at 12 months.

Results: Of the 111 adolescents recruited, 85 (77%) completed the intervention. BMI expressed as a percentage of the 95th percentile decreased by 6.8% [95% CI: -8.8 to -4.9], ISI increased by 0.2 [95% CI: 0.06 to 0.39] and percent body fat decreased by 2.4% [95% CI: -3.4 to -1.3]. There were no significant differences in outcomes between diet groups at any time.

Conclusion: When treated with metformin and an exercise program, a structured, reduced energy diet, which is either high-carbohydrate or moderate-carbohydrate with increased-protein, can achieve clinically significant improvements in obese adolescents at risk of type 2 diabetes.

Trial Registration: Australian New Zealand Clinical Trail Registry ACTRN12608000416392 . Registered 25 August 2008.
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http://dx.doi.org/10.1186/s12887-014-0289-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252020PMC
November 2014

Environmental determinants of type 1 diabetes: a role for overweight and insulin resistance.

J Paediatr Child Health 2014 Nov 3;50(11):874-9. Epub 2014 Jun 3.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.

Rates of type 1 diabetes are rising globally, with a decreasing proportion of high-risk genotypes and twin concordance rates below 50%. Therefore, environmental factors such as viruses, nutrition and overweight have been examined as putative aetiological agents. The accelerator hypothesis proposes that overweight and insulin resistance are central to both type 1 and type 2 diabetes and may explain, in part, the rise in type 1 diabetes incidence. The temporal rise in body mass index at type 1 diabetes onset and the observation that pre-diabetic children are heavier and more insulin resistant than their peers suggests convergence of type 1 and type 2 diabetes phenotypes. The influence of insulin resistance may begin in utero, although the aetiological role of birthweight in type 1 diabetes remains unclear. Further research to elucidate the role of these modifiable risk factors in today's obesogenic environment may provide future potential for diabetes prevention.
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http://dx.doi.org/10.1111/jpc.12616DOI Listing
November 2014

Heart rate variability in pubertal girls with type 1 diabetes: its relationship with glycaemic control, insulin resistance and hyperandrogenism.

Clin Endocrinol (Oxf) 2014 Jun 6;80(6):818-24. Epub 2013 Jun 6.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Paediatrics and Child Health & Department of Ophthalmology, University of Sydney, Sydney, NSW, Australia.

Objective: To examine the association between glycaemic control, insulin resistance and hyperandrogenism on cardiac autonomic function in peripubertal girls with type 1 diabetes.

Design: Prospective, clinic-based study of 125 girls with diabetes and 46 age-matched nondiabetic girls.

Measurements: Heart rate variability (HRV) parameters derived from a 10-min ECG recording using LabChart Pro were as follows: standard deviation of mean NN intervals (SDNN), where NN = adjacent QRS complexes; root mean squared difference of successive NN intervals (RMSSD) - estimates of overall HRV; and low-/high-frequency (LF:HF) ratio - an estimate of the sympathovagal balance. Androgens and sex hormone binding globulin (SHBG) were measured in girls with diabetes, and free androgen index (FAI) calculated. HRV and anthropometry were measured in nondiabetic controls.

Results: Adolescents with diabetes (median age 15·1 years [13·3-16·0], diabetes duration 7·0 years [4·6-10·0] and median HbA1c 8·4% [7·5-9·3]) had higher HR and lower HRV compared with controls. Using multivariate models in the diabetes group, higher HR was associated with higher HbA1c, total daily dose insulin/kg body weight and systolic BP standard deviation scores (SDS), whilst reduced HRV was associated with higher HbA1c (SDNN, RMSSD and LF:HF ratio), lower SHBG (SDNN and RMSSD) and higher weight SDS (LF:HF ratio). Higher FAI was associated with higher HR and reduced HRV measures in the univariate analyses only.

Conclusions: In adolescent girls with diabetes, reduced HRV parameters are associated with worse glycaemic control, lower SHBG and higher weight SDS. SHBG should be considered in the cardiac risk models for this population.
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http://dx.doi.org/10.1111/cen.12238DOI Listing
June 2014

Optimal macronutrient content of the diet for adolescents with prediabetes; RESIST a randomised control trial.

J Clin Endocrinol Metab 2013 May 26;98(5):2116-25. Epub 2013 Mar 26.

The Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, New South Wales 2145, Australia.

Context: Prediabetes and clinical insulin resistance in adolescents are rapidly emerging clinical problems with serious health outcomes.

Objective: The objective of this study was to determine the efficacy of 2 structured lifestyle interventions, both differing in diet macronutrient composition, on insulin sensitivity.

Design: This study was a randomized controlled trial, known as Researching Effective Strategies to Improve Insulin Sensitivity in Children and Teenagers, in 2 hospitals in Sydney, Australia.

Participants: Participants included overweight or obese 10- to 17-year-olds with either prediabetes and/or clinical features of insulin resistance.

Intervention: At baseline adolescents were prescribed metformin and randomized to a structured diet, which was either high carbohydrate or moderate carbohydrate with increased protein. The program commenced with a 3-month dietary intervention, with the addition of an exercise intervention in the next 3 months.

Outcomes: The outcomes included an insulin sensitivity, anthropometry, and cardiometabolic profile at 6 months.

Results: One hundred eleven subjects (66 girls) were recruited and 98 subjects (58 girls) completed the 6-month intervention. After 3 months the mean insulin sensitivity index increased by 0.3 [95% confidence interval (CI) 0.2-0.4]. After 6 months the mean insulin (picomoles per liter) to glucose ratio (millimoles per liter) decreased by 7.2 [95%CI -12.0 to -2.3], body mass index, expressed as a percentage of the 95th centile, decreased by 9% (95% CI -3 to -15), but there was no significant change in the lipids. There were no significant differences in outcomes between the diet groups at any time point.

Conclusions: These results are in contrast with our hypothesis that adolescents randomized to the increased protein diet would have better outcomes. Further strategies are required to better address prediabetes and clinical features of insulin resistance in adolescents.
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http://dx.doi.org/10.1210/jc.2012-4251DOI Listing
May 2013

Evaluation of glycaemic status in young people with clinical insulin resistance; fasting glucose, fasting insulin or an oral glucose tolerance test?

Clin Endocrinol (Oxf) 2010 Apr 28;72(4):475-80. Epub 2009 Jul 28.

Division of Research, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia.

Objective: It is important to identify young people with prediabetes for early intervention. However, it is unclear how to best screen overweight and obese young people for prediabetes. The objective of this study was to compare fasting indices with an oral glucose tolerance test (OGTT) in diagnosing prediabetes.

Design: Retrospective review.

Patients: A total of 224 young people, aged 12.0 years (range: 3.2-17.3 years), with clinical features of insulin resistance, who had an OGTT between 2000 and 2007 at a tertiary children's hospital, Sydney, Australia.

Measurements: Oral glucose tolerance test.

Results: A total of 168 (75%) participants had normal glucose tolerance, 45 (20%) had prediabetes and 11 (5%) had type 2 diabetes; 29 of those with prediabetes and 10 with type 2 diabetes were identified by fasting glucose criteria alone. Young people with normal fasting glucose and fasting insulin < or =180 pmol/l had lower insulin resistance (homeostasis model assessment median 1.9 vs. 4.2, P < 0.001), higher insulin sensitivity index (2.4 vs. 1.0, P < 0.001) and a lower early insulin response (insulinogenic index 2.5 vs. 4.1, P < 0.001) compared to those with normal fasting glucose and higher fasting insulin levels. If a fasting insulin cut point (< or =180 pmol/l) was used in addition to fasting glucose to determine the need for an OGTT, 114 (68%) young people with normal glucose tolerance would have avoided the test. By contrast, the diagnosis of impaired glucose tolerance, identified by an OGTT, would have been missed in three children.

Conclusion: Fasting glucose and insulin levels should be measured in young people with insulin resistance before undertaking a time- and resource-intensive OGTT.
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http://dx.doi.org/10.1111/j.1365-2265.2009.03677.xDOI Listing
April 2010

Paediatric bilateral adrenal phaeochromocytomas in association with a novel mutation in the von Hippel Lindau gene.

J Paediatr Child Health 2008 Sep;44(9):514-6

Department of Academic Surgery, The Children's Hospital at Westmead and The University of Sydney, Sydney, Australia.

Functional phaeochromocytoma and paraganglioma are rare in children and adolescents. We report a 12-year-old male with bilateral phaeochromocytoma in whom germ line testing identified a novel mutation in the von Hippel Lindau gene. Early age of onset, bilateral phaeochromocytoma and other clinical features should prompt germ line DNA testing for mutations in genes associated with familial phaeochromocytoma and paraganglioma syndromes.
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http://dx.doi.org/10.1111/j.1440-1754.2008.01360.xDOI Listing
September 2008

Body mass index and waist circumference in midchildhood and adverse cardiovascular disease risk clustering in adolescence.

Am J Clin Nutr 2007 Sep;86(3):549-55

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Westmead, Australia.

Background: Body mass index (BMI) may not indicate the level of central adiposity associated with the clustering of cardiovascular disease (CVD) risk factors. Hence, it has been recommended that waist circumference be used as an alternative measure.

Objective: The objective was to investigate whether waist circumference in midchildhood is more effective at predicting cardiovascular disease risk clustering in adolescence than is BMI.

Design: Anthropometric measurements were made in 342 children aged 8 y. Seven years later, anthropometric measurements were made in 290 participants, and metabolic profiles were determined in 172 participants.

Results: At 15 y, between 9.4% and 11.0% of adolescents were defined as having CVD risk clustering. Children who were overweight or obese at 8 y of age were 7 times (odds ratio: 6.9; 95% CI: 2.5, 19.0; P < 0.001) as likely to have CVD risk clustering in adolescence than were their peers who were not overweight or obese. Those with an increased waist circumference at 8 y were 4 times (3.6; 1.0, 12.9; P = 0.061) as likely to have CVD risk clustering in adolescence than were children with a smaller waist circumference. Neither BMI nor waist circumference were predictive of CVD risk clustering if adiposity was not included as a risk factor.

Conclusions: The association between measures of adiposity in midchildhood and later adverse CVD risk is a result of the tracking of adiposity status. Our results do not support the need to measure waist circumference in children, in addition to BMI, to identify those at increased risk of CVD risk factor clustering in adolescence.
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http://dx.doi.org/10.1093/ajcn/86.3.549DOI Listing
September 2007

Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin.

J Clin Endocrinol Metab 2006 Jun 4;91(6):2074-80. Epub 2006 Apr 4.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Locked Bag 4001 Westmead, New South Wales 2145, Australia.

Context: Metformin therapy for adults and children with type 2 diabetes is well established. However, its role in the treatment of insulin resistance and obesity in children and adolescents is less clearly defined.

Objective: We assessed the effect of metformin on body composition and insulin sensitivity in pediatric subjects with exogenous obesity.

Design And Setting: Patients referred to a pediatric endocrine clinic were enrolled in a randomized, double-blind, crossover trial.

Patients: Twenty-eight patients (13 males) aged 9-18 yr participated in the study.

Intervention: Patients received metformin (1 g twice daily) and placebo for 6 months, each with a 2-wk washout period.

Main Outcome Measures: Body composition (anthropometry, dual-energy x-ray absorptiometry, and abdominal magnetic resonance imaging), and insulin sensitivity (Si; minimal model, fasting insulin and glucose) were measured at baseline and 6 and 12 months.

Results: Mean age of subjects at baseline was 12.5 +/- 2.2 yr, median body mass index z-score 2.54 (range, 1.93-2.85). Metformin had a greater treatment effect over placebo for weight (-4.35 kg, P = 0.02), body mass index (-1.26 kg/m(2), P = 0.002), waist circumference (-2.8 cm, P = 0.003), sc abdominal adipose tissue (-52.5 cm(2), P = 0.002), and fasting insulin (-2.2 mU/liter, P = 0.011). Si improved in 45% of subjects while on metformin and 27% of subjects while on placebo (P = 0.21).

Conclusions: Metformin therapy for obese insulin-resistant pediatric patients results in significant improvement in body composition and fasting insulin. Although improvement in Si was noted in many individuals, Si was a less useful parameter for analysis of group data, possibly because of effects of variable compliance and changing Si during puberty.
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http://dx.doi.org/10.1210/jc.2006-0241DOI Listing
June 2006

Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

N Engl J Med 2004 Apr;350(18):1838-49

Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, United Kingdom.

Background: Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes.

Methods: We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene.

Results: Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced.

Conclusions: Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas.
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http://dx.doi.org/10.1056/NEJMoa032922DOI Listing
April 2004

An ambulatory stabilisation program for children with newly diagnosed type 1 diabetes.

Med J Aust 2004 Mar;180(6):277-80

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia.

Objectives: (i) To evaluate the benefits and adverse effects of a Diabetes Day Care Program (DDCP); and (ii) to compare outcomes in two cohorts diagnosed before and after implementing the DDCP ("pre-DDCP" and "post-DDCP").

Design: Outcomes from the pre-DDCP cohort were compared with those of the post-DDCP cohort.

Setting: The study was conducted from March 2001 to October 2002 at the Children's Hospital at Westmead.

Participants: The pre-DDCP cohort comprised all children newly diagnosed with type 1 diabetes from March 2000 to November 2000 (n = 49). The post-DDCP cohort were those diagnosed from November 2000 to August 2001 (n = 61).

Main Outcome Measures: Length of stay, adverse events, insulin requirement and glycohaemoglobin (HbA(1c)) level over the first year after diagnosis were ascertained from medical records. Questionnaires to measure parents' knowledge of diabetes, emotional adjustment to diabetes, and responsibility for and conflict over specific diabetes management tasks were completed by parents at 6-monthly intervals.

Results: Median length of hospital stay decreased from 5.14 days (range, 2-10) to 1.70 days (range, 0-10) (P < 0.001). There were no differences between the two cohorts in insulin requirement at 12 months (pre-DDCP: 0.9 U/kg [95% CI, 0.8-1.0]; post-DDCP: 0.8 U/kg [95% CI, 0.7-0.9]; P = 0.22), HbA(1c) level at 12 months (pre-DDCP: 8.4% [95% CI, 8.0%-8.9%]; post-DDCP: 8.2% [95% CI, 7.9%-8.5%]; P = 0.37) and adverse events over the first year after diagnosis. Both groups reported similar scores for the parental questionnaires.

Conclusions: Ambulatory stabilisation of children with type 1 diabetes provides similar metabolic outcomes for the child, and comparable levels of diabetes knowledge and similar psychosocial outcomes for the family, to inpatient stabilisation programs.
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March 2004
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