ORCID Profile
0000-0002-3982-271X
Current Organisations
Royal Australasian College of Physicians
,
Perth Childrens Hospital
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Nanomaterials | Electrochemistry | Catalytic Process Engineering | Nanotechnology | Statistics | Applied Statistics | Statistical Theory
Measurement standards and calibration services not elsewhere classified | Solid Oxide Fuel Cells | Manufacturing not elsewhere classified | Mathematical sciences |
Publisher: American Association for Cancer Research (AACR)
Date: 26-07-2023
DOI: 10.1158/1055-9965.23779466.V1
Abstract: Multivariable adjusted hazard ratios for all-cause and cause-specific hospitalisations, major cancer diagnostic group.
Publisher: Wiley
Date: 2005
DOI: 10.1002/PROS.20154
Abstract: Although up to 30% of men who undergo radical prostatectomy for clinically organ-confined prostate cancer will relapse with disseminated disease, currently it is not possible to predict these patients. Androgen receptor (AR) immunoreactivity in stromal and epithelial compartments of tumor foci was evaluated by video image analysis in 53 radical prostatectomy specimens. Kaplan-Meier and Cox Regression analyses were used to determine whether AR immunostaining was related to rate and risk of relapse, respectively. Ninety-eight percent (52/53) of the tumors contained AR positive malignant epithelial cells. Kaplan-Meier analysis indicated that patients with high AR levels (>64% AR positive nuclear area) in the malignant epithelial cells or low AR levels (<or=45% AR positive nuclear area) in the peritumoral stroma cells, were more likely to relapse earlier following radical prostatectomy. The shortest time to relapse and the highest relapse rate was for patients with both high AR in the malignant epithelial cells and low AR in the peritumoral stromal cells. These findings suggest that AR is an important determinant of disease relapse in early stage prostate cancer, and that altered AR levels in the malignant epithelial cells or in the peritumoral stroma is indicative of non-organ confined prostate cancer.
Publisher: Wiley
Date: 23-11-2014
DOI: 10.1111/JPC.12778
Abstract: Silver-Russell syndrome (SRS) and Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome are described in isolation. However, their co-occurrence has only been rarely reported. Here, we present a case report of an adolescent with SRS who was diagnosed with MRKH during the evaluation of primary amenorrhoea. Multiplex ligation-dependent probe lification analysis showed a normal methylation pattern and normal dosage at 11p15.5. A PubMed search for all peer-reviewed publications (original articles and reviews) using the key words Silver-Russell syndrome, Mayer-Rokitansky-Küster-Hauser syndrome, genetics, hypomethylation and reproductive anomalies identified three cases of SRS with MRKH, two of which were associated with significant hypomethylation of the H19 imprinting control region of the 11p15.5 locus. This report highlights the association between SRS and MRKH. The absence of hypomethylation and normal dosage at 11p15.5 suggests these two rare entities share alternative aetiopathogenic mechanisms.
Publisher: Public Library of Science (PLoS)
Date: 09-08-2018
Publisher: Bioscientifica
Date: 12-1998
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 06-07-2023
DOI: 10.1158/1055-9965.EPI-22-1313
Abstract: The long-term effects of childhood cancer are unclear in the Australian context. We examined hospitalization trends for physical diseases and estimated the associated inpatient care costs in all 5-year childhood cancer survivors (CCS) diagnosed in Western Australia (WA) from 1982 to 2014. Hospitalization records for 2,938 CCS and 24,792 comparisons were extracted from 1987 to 2019 (median follow-up = 12 years, min = 1, max = 32). The adjusted hazard ratio (aHR) of hospitalization with 95% confidence intervals (CI) was estimated using the Andersen–Gill model for recurrent events. The cumulative burden of hospitalizations over time was assessed using the mean cumulative count method. The adjusted mean cost of hospitalization was estimated using the generalized linear models. We identified a higher risk of hospitalization for all-cause (aHR, 2.0 95% CI, 1.8–2.2) physical disease in CCS than comparisons, with the highest risk for subsequent malignant neoplasms (aHR, 15.0 95% CI, 11.3–19.8) and blood diseases (aHR, 6.9 95% CI, 2.6–18.2). Characteristics associated with higher hospitalization rates included female gender, diagnosis with bone tumors, cancer diagnosis age between 5 and 9 years, multiple childhood cancer diagnoses, multiple comorbidities, higher deprivation, increased remoteness, and Indigenous status. The difference in the mean total hospitalization costs for any disease was significantly higher in survivors than comparisons (publicly funded $11,483 United States Dollar, P & 0.05). The CCS population faces a significantly higher risk of physical morbidity and higher cost of hospital-based care than the comparisons. Our study highlights the need for long-term follow-up healthcare services to prevent disease progression and mitigate the burden of physical morbidity on CCS and hospital services.
Publisher: Springer Science and Business Media LLC
Date: 12-2013
DOI: 10.1038/BJC.2013.782
Publisher: Wiley
Date: 29-12-2017
DOI: 10.1111/JPC.13827
Publisher: American Association for Cancer Research (AACR)
Date: 26-07-2023
DOI: 10.1158/1055-9965.23779472.V1
Abstract: The mean cumulative count of hospitalisations for any physical-health disease by attained age, in childhood cancer survivors and their matched comparisons.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: The Endocrine Society
Date: 03-2010
DOI: 10.1210/JC.2009-1563
Abstract: About twice as many boys than girls are treated with GH. Ascertainment bias is a possible explanation. For ascertainment bias, the gender least frequently treated should be relatively shorter, and in an unbiased population s le, equal numbers of boys and girls should be eligible for GH treatment. In 2007 a total of 1485 Australian children received GH (OZGROW database). Heights were also obtained from two recent unbiased surveys consisting of 3596 and 4794 Australian children. Numbers of boys and girls treated with GH were determined for each treatment indication. Height sd scores (SDS) at first presentation for GH-treated boys and girls were assessed. Frequency of boys and girls from two unbiased populations with height SDS less than -2.326 were recorded. OUTCOMES included gender frequencies and height SDSs. HYPOTHESES were formed before interrogation of preexisting databases. More boys than girls received GH (P = 3.68 x 10(-20)). By indication: biochemical GH deficiency (P = 0.001), cranial irradiation (P = 0.002), slow growing (P = 2.09 x 10(-16)), and chronic renal failure (P = 0.061). Approximately equal numbers of girls and boys were treated for hypoglycemia (P = 0.543). Slow-growing girls were relatively shorter than boys for ages spanning 4.50-8.49 yr (P = 3.80 x 10(-4)), but boys were relatively shorter in the 6.00- to 17.99-month age group (P = 0.011). Biochemical boys were relatively shorter than girls (P = 0.023). In the two unbiased surveys, boys outnumbered girls 11 to six and 16 to eight for height SDS less than -2.326. There is a gender bias in this GH-treated population. Ascertainment bias does not appear to be the major cause.
Publisher: Wiley
Date: 03-1997
DOI: 10.1046/J.1365-2265.1997.1250941.X
Abstract: Androgen insensitivity syndrome (AIS) is an X-linked disorder of XY males characterized by varying degrees of impaired masculinization. In many AIS cases, mutations have been identified in the coding sequence of the human androgen receptor (AR) gene which impair receptor function. Cases have also been reported in which reduced AR mRNA expression may contribute to AIS in association with AR gene mutations. The purpose of this study was to define the molecular basis of AIS in members of a family with clinical and laboratory features of partial androgen insensitivity (PAIS). Genital skin fibroblast (GSF) cultures were established from foreskin tissue for androgen receptor binding analysis. Genomic DNA was obtained from blood leucocytes for AR gene nucleotide sequence analysis. AR mRNA levels were determined in total RNA extracted from GSF cultures. Three related subjects with perineo-scrotal hypospadias, bifid scrotum and microphallus were studied. The family pedigree of these subjects suggested an X-linked pattern of inheritance. Hormone assay results were consistent with AIS. AR binding capacity and affinity were determined in three subjects and compared with unaffected male controls. The coding sequence and 1.4 kb of promoter region of the AR gene were lified in overlapping fragments by polymerase chain reaction from genomic DNA and sequenced. GSF AR mRNA was measured by a competitive PCR technique. In the PAIS subjects, AR affinity in cultured GSF was normal (Kd = 0.24, 0.30, 0.48 vs 0.27 +/- 0.07 (SD) nmol/l) but binding capacity was reduced (Bmax = 0.31, 0.36, 0.27 vs 1.26 +/- 0.37 (SD) fmol/microgram DNA). Sequence analysis of the CAG repeat polymorphism within exon 1 of the AR gene showed that both mothers were heterozygous at this locus, and that the three subjects had inherited the same allele. GSF AR mRNA levels were reduced in all three patients compared with controls (0.25, 0.74 and 0.74 vs 3.8 +/- 0.9 (SEM), range 1.8-7.3 amol/microgram total RNA). The nucleotide sequences of the entire AR coding region and of a 1.4 kb segment containing the promoter region were normal. Members of this family with clinical and biochemical evidence of X-linked partial androgen insensitivity syndrome demonstrated normal androgen receptor binding affinity and androgen receptor gene nucleotide sequence but reduced androgen receptor binding capacity and reduced androgen receptor mRNA. These results suggest that partial androgen insensitivity syndrome in this family may be caused by reduced expression of a normal androgen receptor gene.
Publisher: Wiley
Date: 04-2000
DOI: 10.1046/J.1440-1754.2000.00461.X
Abstract: A case of congenital varicella syndrome characterized by intrauterine growth retardation, ocular and neurologic abnormalities, but no cutaneous lesions is reported. This case highlights the risk of embryopathy from varicella infection during pregnancy in non-immune women.
Publisher: Springer Science and Business Media LLC
Date: 09-1998
DOI: 10.1007/PL00006391
Abstract: Androgen effects mediated by the androgen receptor (AR) are essential for male reproductive development and virilization. Comparison of AR DNA coding sequence from five primate species, Homo sapiens (human), Pan troglodytes (chimpanzee), Papio hamadryas (baboon), Macaca fascicularis (macaque), and Eulemur fulvus collaris (collared brown lemur), supports their phylogeny with complete conservation of the DNA and steroid binding domain protein sequence. A linear increase in trinucleotide repeat expansion of homologous CAG and GGC sequences occurs in the NH2-terminal transcriptional activation region and is proportional to the time of species ergence. A serine phosphate/glutamine repeat interaction is observed where increasing CAG repeat length is associated with an increased rate of serine 94 phosphorylation. Disparity in the calculated and apparent molecular weight with CAG repeat expansion of an AR NH2-terminal fragment suggests self-aggregation with increasing glutamine repeat length into the pathological range. These results suggest that a CAG/glutamine repeat expanded during ergence of the higher primate species, which may have a direct effect on AR structure and support a common pathway in CAG trigenic diseases in the pathophysiology of neurodegeneration observed in X-linked spinal bulbar and muscular atrophy.
Publisher: Wiley
Date: 06-2003
DOI: 10.1046/J.1365-2265.2003.01781.X
Abstract: Mutations in the gene for the POU domain transcription factor POU1F1 (human Pit-1) have been reported in patients with GH, TSH and PRL deficiencies. PROP1 (Prophet of Pit-1) gene mutations also cause gonadotrophin deficiencies and in some cases partial ACTH deficiency. This study analyses the POU1F1 and PROP1 genes in a cohort of Australian children with combined pituitary hormone deficiency (CPHD) and correlates results with patient phenotype. Genomic analysis was carried out on 33 patients with CPHD referred from centres around Australia. Clinical data were collected from medical records and referring physicans. POU1F1 mutations were identified in two of four patients with a suggestive phenotype. In a female patient, novel compound heterozygous POU1F1 mutations were identified: Arg143Leu in exon 3 and Leu194Gln in exon 4. This patient presented with failure to thrive at 6 weeks of age and has deficiencies of TSH and GH. A previously described heterozygous Arg271Trp mutation in exon 6 of the POU1F1 gene was identified in a female infant who presented with growth failure and was diagnosed with TSH then GH deficiencies. No PROP1 mutations were identified however, we describe a number of previously unreported PROP1 polymorphisms. No patients presenting with deficiencies of all anterior pituitary hormones early in life had POU1F1 or PROP1 gene mutations. In 33 Australian children with CPHD we have identified POU1F1 mutations in two patients and no PROP1 mutations. We speculate that in the majority of children other genes must be responsible for the CPHD phenotype.
Publisher: Walter de Gruyter GmbH
Date: 20-09-2017
Abstract: Survivors of paediatric brain cancer and/or cranial radiotherapy (CRT) are at an increased risk of developing serious comorbidities. Established risk factors for chronic disease include central obesity, endothelial abnormalities and diminished fitness. Here we characterised anthropometry, body composition, bone mineral density (BMD), heart rate (HR), blood pressure (BP), endothelial function, muscular strength and endurance and aerobic fitness in adolescent and young adult (AYA) survivors. Twenty survivors (10 male, 10 female 20 ± 2 years) were compared with 19 matched controls. Muscular strength was assessed using three repetition maximum tests, while muscular endurance was determined as number of repetitions performed per minute. Peak oxygen uptake (VO 2 peak) was assessed on a treadmill using a modified chronotropic protocol. Anthropometric measurements, HR and BP were taken using standard clinical protocols, while body composition and BMD were determined using dual X-ray absorptiometry (DXA). Endothelial function was measured using the flow mediated dilation technique. Survivors demonstrated deficits in muscular strength (latissimus dorsi pull-down, p = 0.020 bicep curl, p = 0.009), muscular endurance (squats, p = 0.012 sit-ups, p = 0.030 push-ups, p = 0.013), minute ventilation at peak exericse (p = 0.002) and VO 2peak (L/min, p = 0.002 mL/kg/min, p = 0.008 mL/kg LBM/min, p = 0.010). Additionally, survivors had greater waist-to-hip ratios (p = 0.032), resting HR (p = 0.048) and higher percentage of total body (p = 0.017), central (p = 0.009) and peripheral (p = 0.032) fat. Lean body mass (p = 0.004) and BMD (p = 0.005) were lower in the survivor group. AYA survivors of paediatric brain cancer and/or CRT exhibit altered body composition, increased resting HR and reduced BMD, muscular strength, muscular endurance and cardiorespiratory fitness compared to controls.
Publisher: The Endocrine Society
Date: 1996
DOI: 10.1210/JCEM.81.1.8550758
Abstract: Androgen insensitivity is an X-linked disorder of sexual differentiation resulting from mutations in the androgen receptor (AR) gene. In this paper, we report the clinical phenotype and molecular analysis of two siblings with severe partial androgen insensitivity due to a novel mutation in the ligand-binding domain of the AR gene. Binding studies using cultured genital skin fibroblasts demonstrated reduced AR affinity and binding capacity. Nucleotide sequence analysis of the AR gene of both siblings revealed a point mutation causing a glycine to arginine amino acid substitution at position 907 within a conserved region of the ligand-binding domain. A silent guanine to adenine substitution was also identified in the protein-coding region of exon 1. Using an expression vector in which the identified mutation was recreated by site-directed mutagenesis, the mutant receptor was found to have a reduced binding affinity (Kd = 3.06 nmol/L) for mibolerone compared with that of normal AR (Kd = 1.71 nmol/L) when expressed in COS-7 cells. In cotransfection experiments using CV-1 cells and a mouse mammary tumor virus-chlor henicol acetyltransferase reporter system, the concentration of dihydrotestosterone required to induce half-maximal chlor henicol acetyltransferase gene expression was 50-fold higher in cells transfected with the mutant AR complementary DNA than in cells transfected with normal AR complementary DNA. AR messenger ribonucleic acid levels in genital skin fibroblasts determined by both competitive PCR lification and ribonuclease protection assay were decreased compared with normal values. Our studies demonstrate the importance of this region of the AR gene in normal AR function and AR gene expression.
Publisher: The Endocrine Society
Date: 2002
Abstract: We report a 12-month-old infant who presented with a 4-month history of isosexual precocious puberty secondary to an estrogenizing Sertoli-Leydig cell tumor of the ovary. Total serum immunoreactive inhibin and subunits A and B were markedly elevated before surgical resection and subsequently decreased 7 wk later into the normal prepubertal range. Twenty weeks following surgical removal, the patient presented again with central precocious puberty inhibin B levels were raised on this occasion, a luteinizing releasing hormone stimulation test confirmed central precocious puberty. This is the youngest reported occurrence of this rare sex cord stromal neoplasm. The prognosis of this extremely rare tumor presenting at this early juvenile stage is uncertain. This report illustrates the usefulness of serum inhibin as a tumor marker during therapeutic suppression with leuprorelin acetate for central precocious puberty. Analysis of genomic and tumor DNA revealed a normal nucleotide sequence for the LH receptor and the Gαs gene. To understand the molecular pathogenesis of this tumor we analyzed mRNA levels for the inhibin A and B subunits, FSH receptor, LH receptor aromatase, steroidogenic factor-1 and the ER β genes. Molecular characterization reveals the presence of genes specific for granulosa and Leydig cells the relative expression of these genes, in addition to its histologic characteristics, suggests that this tumor may result from a dysdifferentiation of a primordial follicle.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Springer Science and Business Media LLC
Date: 02-03-2018
Publisher: Walter de Gruyter GmbH
Date: 2015
Abstract: Hyperinsulinaemic hypoglycaemia (HH) is characterised by inappropriate insulin secretion and is the most common cause for persistent neonatal hypoglycaemia. The only treatment available for medically unresponsive hypoglycaemia is a near-total pancreatectomy. A neonate with severe HH, due to a homozygous
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2015
Publisher: Bioscientifica
Date: 17-07-2015
DOI: 10.1530/ERC-15-0320
Abstract: Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males 78.4%) with growth hormone excess and a current revious abnormal growth velocity for age or final height s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height ( r =0.23, P =0.02). AIP mutations occurred in 29% microduplication at Xq26.3 – X-linked acrogigantism (X-LAG) – occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP- mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in % of cases.
Publisher: American Association for Cancer Research (AACR)
Date: 26-07-2023
DOI: 10.1158/1055-9965.23779463.V1
Abstract: Adjusted annual mean costs of privately funded hospitalisations per in idual, by all-cause and cause-specific physical diseases.
Publisher: Oxford University Press (OUP)
Date: 06-2016
DOI: 10.1530/EJE-16-0111
Abstract: The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH). A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry. Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues. Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees reconvened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors. LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations.
Publisher: Wiley
Date: 06-06-2012
DOI: 10.1111/J.1365-2265.2011.04230.X
Abstract: To investigate response to growth hormone (GH) in the first, second and third years of treatment for all idiopathic GH-deficient (GHD) and idiopathic short stature (ISS) patients in Australia. Eligibility for subsidized GH treatment in Australia is determined on auxological criteria for the indication of Short Stature and Slow Growth (SSSG), which includes ISS (SSSG-ISS). The biochemical GHD (BGHD, peak GH < 10 mU/l) and SSSG indications are treated similarly: starting dose of 4·5 mg/m(2)/week with provision for incremental dosing. Some ISS patients were specifically diagnosed with familial short stature (SSSG-FSS). Responses for each year of treatment for BGHD, SSSG-ISS and SSSG-FSS cohorts were compared in relation to influencing variables and with international benchmarks. The effect of incremental dosing was assessed. Australian BGHD, SSSG-ISS and SSSG-FSS patients who had completed 1, 2, or 3 years of treatment and were currently receiving GH. Growth hormone dose, change in height-standard deviation score (ΔSDS) and growth velocity (GV). First-year response was 2-3 times greater than that in subsequent years: ΔSDS(1st year) = 0·92, 0·50 and 0·46 for BGHD, SSSG-ISS and SSSG-FSS, respectively. Responses were similar to international reports and inversely related to age at commencement of GH. First-year GV-for-age for BGHD patients was similar to international standards for idiopathic GHD. However, girls had an inferior response to boys when treatment commenced at <6 years of age. First-year GV-for-age for SSSG-ISS/FSS patients was less than ISS standards. Dose increments attenuated the first- to second-year decline in response to BGHD but marginally improved the responses for SSSG-ISS/FSS. The Australian auxology-based GH programme produces comparable responses to international programmes. A lower starting dose is offset by the initiation of treatment at younger ages. Incremental dosing does not appear optimal. A first-year dose of 6·4-6·9 mg/m(2)/week for GHD and 8·9 mg/m(2)/week for ISS with early commencement of GH treatment may be most efficacious.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Hindawi Limited
Date: 11-10-2011
DOI: 10.1002/HUMU.21600
Abstract: DICER1 is crucial for embryogenesis and early development. Forty different heterozygous germline DICER1 mutations have been reported worldwide in 42 probands that developed as children or young adults, pleuropulmonary blastoma (PPB), cystic nephroma (CN), ovarian sex cord-stromal tumors (especially Sertoli-Leydig cell tumor [SLCT]), and/or multinodular goiter (MNG). We report DICER1 mutations in seven additional families that manifested uterine cervix embryonal rhabdomyosarcoma (cERMS, four cases) and primitive neuroectodermal tumor (cPNET, one case), Wilms tumor (WT, three cases), pulmonary sequestration (PS, one case), and juvenile intestinal polyp (one case). One carrier developed (age 25 years) a pleomorphic sarcoma of the thigh another carrier had transposition of great arteries (TGA). These observations show that cERMS, cPNET, WT, PS, and juvenile polyps fall within the spectrum of DICER1-related diseases. DICER1 appears to be the first gene implicated in the etiology of cERMS, cPNET, and PS. Young adulthood sarcomas and perhaps congenital malformations such as TGA may also be associated.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2017
DOI: 10.1038/BJC.2017.147
Publisher: Wiley
Date: 07-03-2011
DOI: 10.1111/J.1365-2265.2011.03937.X
Abstract: To investigate response to growth hormone (GH) in the first, second and third years of treatment in the total clinical cohort of Turner syndrome (TS) patients in Australia. Short stature is the most common clinical manifestation of TS. GH treatment improves growth. Response was measured for each year of treatment. Stepwise multiple regression analyses were used to identify factors that significantly influenced response. Prepubertal TS patients who completed 1 year (n=176), 2 years (n=148), or 3 years (n=117) of treatment and were currently receiving GH. Change in TS specific Height Standard Deviation Score (ΔTSZ) was the main response variable used. Major influencing variables considered included dose, starting age and height, BMI, bone age delay, karyotype, parental height, and interactions between dose and starting age or height. Response was greatest in first year and declined thereafter (median ΔTSZ: 1st year= +0·705, 2nd year= +0·439, 3rd year= +0·377) despite the median dose increasing [1st year= 5·5 mg/m(2) /week (0·23 mg/kg/week), 2nd year= 6·4(0·24), 3rd year= 7·2(0·26)]. An Age*Dose interaction was identified influencing first, second year, and total ΔTSZ. The ΔTSZ over 3 years was significantly influenced by first-year dose. Dose increments only attenuated the general decline in response. An acceptable first-year response (ΔTSZ>1·01) was achieved by only 17·6% of patients. Growth response is greatest and most influenced by dose in the first year. Dose in first year is a major factor contributing to total response. A starting Age*Dose interaction effect was observed such that young girls on a high dose respond disproportionately better. Optimal GH treatment of short stature in TS thus requires early initiation with the highest safe dose in the first year.
Publisher: American Association for Cancer Research (AACR)
Date: 26-07-2023
DOI: 10.1158/1055-9965.23779469
Abstract: Major diagnostic groups of physical-health diseases based on the International Classification of Diseases (ICD), 9th (Clinical modification) and 10th (Australian Modification) revisions.
Publisher: American Association for Cancer Research (AACR)
Date: 26-07-2023
DOI: 10.1158/1055-9965.23779466
Abstract: Multivariable adjusted hazard ratios for all-cause and cause-specific hospitalisations, major cancer diagnostic group.
Publisher: Wiley
Date: 16-11-2010
DOI: 10.1111/J.1365-2265.2010.03874.X
Abstract: Assessment of short stature in many instances is based on a comparison with the Centers for Disease Control's (CDC) growth curves. The secular trend for height may limit the utility of CDC data for contemporary populations. We investigate the effect of the secular trend on Australian and US populations. Describe CDC-defined height SDS distributions of contemporary populations for different ages and genders. Compare observed means and standard deviations (SDs) to expected values of 0 and 1. Compare frequency of in iduals shorter than the CDC-1st centile to those shorter than 1st centile defined empirically from the contemporary population. Healthy Kids Queensland Survey 2006: 1686 boys, 1822 girls. Australian National Children's Nutrition and Physical Activity Survey 2007: 2415 boys, 2379 girls. US National Health and Nutrition Examination Survey 2005-2006: 2160 boys, 2118 girls. Means, SDs and normality of CDC-defined height SDS distributions. Frequency of in iduals shorter than the CDC-1st centile and shorter than an empirically defined 1st centile. In Australia, means of CDC-defined height SDS distributions are always greater than 0 and the CDC-1st centile identifies only the shortest 0·5% of children. Means may vary with age and occasionally between genders in contemporary populations. Normality and SDs of 1 are retained. The secular trend has resulted in an underestimate of the number of Australian children eligible for GH treatment using the CDC-1st centile cut-off. Contemporary, local data should be used to construct standards. Using the 2nd CDC centile would approximate the 1st local centile until new standards are constructed. The secular trend does not account for the gender bias in GH therapy.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Wiley
Date: 30-08-2019
DOI: 10.1111/JPC.14189
Abstract: Studies of published clinical trials involving children have shown frequent omissions in key aspects of design and conduct, but these problems may be artefactual and due to editorial processes and space limitations. To determine actual design and conduct, we analysed the completeness of key domains in trial protocols involving children submitted to Human Research Ethics Committees. The ethics committees of all eight children's hospitals in Australia were invited to participate. De-identified trial protocols submitted for review in 2012 were evaluated using a checklist derived from Consolidated Standards of Reporting Trials, the Cochrane Risk of Bias Tool and Good Clinical Practice guidelines. Four ethics committees agreed to participate, and 69 protocols were analysed. The domains almost always reported were clustered around the background and trial plan (planned interventions for each group (99%), specific objectives (97%) and scientific background (96%)). Risk-of-bias domains such as random sequence generation and blinding of participants were often reported (75-90%). Domains least reported were clustered around the statistical analysis plan (66%), specified intention-to-treat analysis (54%), the justification for the proposed trial based upon a systematic review (48%) and age-specific outcomes (48%). Protocols of trials involving children assessed by ethics committees generally include details on background and basic design, but many key domains in trial design and conduct are not covered. Despite widespread recognition of how problems in the design and conduct of trials may lead to unreliable results, investigators still appear to be omitting key elements in trial protocols.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 26-07-2023
DOI: 10.1158/1055-9965.23779463
Abstract: Adjusted annual mean costs of privately funded hospitalisations per in idual, by all-cause and cause-specific physical diseases.
Publisher: Mary Ann Liebert Inc
Date: 06-2018
Abstract: To assess metabolic function among adolescent and young adult (AYA) survivors of childhood cancer-related brain surgery or cranial irradiation (CRT) and to determine feasibility, safety, and metabolic as well as psychological impact of a 6-month exercise program in this cohort. Twenty AYAs aged 15-23 years were recruited. All had completed cancer treatment by age 15.5 and were more than 1 year after end of treatment. Metabolic function was assessed at baseline (T1), after a 6-month non-intervention period (T2), and after the 6-month intervention (T3). Psychological assessments were performed at T1 and T3. Eight to 12 months after the program (T4), its lasting impact was assessed by questionnaire. The 6-month intervention consisted of small group-based, tailored, supervised exercise sessions combining resistance and aerobic exercise. Sessions were offered up to thrice per week and adherence defined as participation in ≥24 sessions. Flexibility was built into the design with an alternative home-based program offered to those who could not attend the gymnasium. Thirteen of the 20 recruited participants were adherent to the program. There was one fall during exercise, but no injury was sustained. Higher rates of metabolic impairment than would be expected in a healthy cohort were found at baseline both among brain tumor survivors and survivors of total body irradiation. Central adiposity reduced post-intervention (p = 0.014) and improvements in adaptive function were seen. Participants enjoyed the program, but work and study commitments limited attendance. AYA survivors of childhood brain tumors and CRT should be screened for metabolic and psychological well-being. Small group-based exercise is safe, feasible, and enjoyable for this cohort and may benefit them both metabolically and psychologically. ACTRN12614000796684. Retrospectively registered July 28, 2014.
Publisher: Bioscientifica
Date: 21-11-2018
DOI: 10.1159/000481620
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.GHIR.2018.12.004
Abstract: Short stature remains the most common reason for referral to a pediatric Endocrinologist and its management remains a challenge. One of the main controversies is the diagnosis of idiopathic short stature and the role of new technologies for genetic investigation of children with inadequate growth. Complexities in management of children with short stature includes selection of who should receive interventions such as recombinant human growth hormone, and how should this agent dose be adjusted during treatment. Should anthropometrical data be the primary determinant or should biochemical and genetic data be used to improve growth response and safety? Furthermore, what is considered a suboptimal response to growth hormone therapy and how should this be managed? Treatment of children with short stature remains a "hot" topic and more data is needed in several areas. These issues are reviewed in this paper.
Publisher: American Society for Clinical Investigation
Date: 15-09-1996
DOI: 10.1172/JCI118930
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.GHIR.2017.03.001
Abstract: Evaluate benefit and risk of low dose growth hormone treatment (GHT, 4.5mg/m Prospective longitudinal clinical intervention. We evaluated 31 infants (aged 2-12months) and 42 toddlers (13-24months) from the PWS-OZGROW database for height, weight and BMI using the World Health Organization standard deviation scores (SDS At commencement of GHT infants had a lower BMI SDS Initiation of GHT in infants with 4.5mg/m
Publisher: The Endocrine Society
Date: 12-1996
DOI: 10.1210/MEND.10.12.8961263
Abstract: The molecular basis for partial androgen insensitivity associated with adult onset spinal/bulbar muscular atrophy was investigated by transient transfection of human androgen receptor (AR) expression vectors containing increasing CAG repeat lengths in the first exon. An inverse relationship was observed between CAG repeat length and AR mRNA and protein levels. Trinucleotide repeat lengths of 43 and 65 associated with spinal/bulbar muscular atrophy decreased AR mRNA and protein levels but did not alter equilibrium binding affinity for [3H]R1881 or inherent transcriptional activity of AR, expressed as androgen-dependent fold induction of a mouse mammary tumor virus promoter-luciferase reporter vector. The findings indicate that glutamine expansion up to 66 residues in the NH2-terminal domain of AR does not alter AR functional activity. Rather, CAG repeat expansion in the region of the first exon reduces AR mRNA and protein expression. The study reveals a previously unrecognized effect of CAG repeat length on AR mRNA expression and a novel molecular mechanism for androgen resistance.
Publisher: American Association for Cancer Research (AACR)
Date: 26-07-2023
DOI: 10.1158/1055-9965.23779475.V1
Abstract: The mean cumulative count of hospitalisations for any physical-health disease by time since index cancer diagnosis, in childhood cancer survivors.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Wiley
Date: 12-03-2013
DOI: 10.1111/CEN.12012
Publisher: SAGE Publications
Date: 2007
DOI: 10.2350/06-04-0083.1
Abstract: In hyperinsulinism of infancy (HI), unregulated insulin secretion causes hypoglycemia. Pancreatectomy may be required in severe cases, most of which result from a defect in the β-cell K ATP channel, encoded by ABCC8 and KCNJ11. Pancreatic histology may be classified as diffuse or focal disease (the latter associated with single paternal ABCC8 mutations), indicated by the presence of islet cell nuclear enlargement in areas of diffuse abnormality. We investigated genotype-phenotype associations in a heterogeneous Australian cohort. ABCC8 and KCNJ11 genes were sequenced and case histology was reviewed in 21 infants who had pancreatectomy. Ninety-eight control DNA s les were tested by single nucleotide polymorphism analysis. Eighteen ABCC8 mutations were identified, 10 novel. Eleven patients (4 compound heterozygote, 4 single mutation, 3 no mutation detected) had diffuse hyperinsulinism. Nine patients had focal hyperinsulinism (6 single paternal mutation, 2 single mutation of undetermined parental origin, 1 none found) with absence of islet cell nuclear enlargement outside the focal area, although centroacinar cell proliferation and/or nesidiodysplasia was present in 7 cases. Regeneration after near-total pancreatectomy was documented in 4 patients, with aggregates of endocrine tissue observed at subsequent operations in 3. Although the absence of enlarged islet cell nuclei is a useful discriminant of focal hyperinsulinism associated with a paternal ABCC8 mutation, further research is needed to understand the pathophysiology of other histological abnormalities in patients with HI, which may have implications for mechanisms of ductal and islet cell proliferation. Previous surgery should be taken into account when interpreting pancreatic histology.
Publisher: American Association for Cancer Research (AACR)
Date: 26-07-2023
DOI: 10.1158/1055-9965.23779475
Abstract: The mean cumulative count of hospitalisations for any physical-health disease by time since index cancer diagnosis, in childhood cancer survivors.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Springer Science and Business Media LLC
Date: 22-03-2022
DOI: 10.1007/S00431-022-04439-2
Abstract: In iduals with Prader-Willi syndrome (PWS) often have excessive daytime sleepiness and emotional/behavioral disturbances. The objective of this study was to examine whether daytime sleepiness was associated with these emotional/behavioral problems, independent of nighttime sleep-disordered breathing, or the duration of sleep. Caregivers of in iduals with PWS (aged 3 to 25 years) completed the Pediatric Sleep Questionnaire (PSQ), Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), and the parent version of the Developmental Behavior Checklist (DBC-P). Sleep adequacy was adjusted for age by computing sleep duration against age-specific recommendations. The associations between ESS-CHAD and the total DBC and its subscale scores were evaluated by linear regression, adjusted for sleep-related breathing difficulties, sleep adequacy, and body mass index (BMI). There were 54 responses for in iduals with PWS (including 22 males) aged 4.4–24.0 (mean 12.5) years. Daytime sleepiness predicted a substantial proportion of the variance in total DBC-P scores in the unadjusted model (28% β = 0.028 p 0.001) and when adjusted for sleep adequacy, BMI, and sleep-related breathing difficulties (29% β = 0.023 p = 0.007). This relationship was not moderated by BMI Z -scores, but the relationship was more prominent for children younger than 12 years than for children older than 12 years. Conclusions : These findings provide preliminary novel evidence that daytime sleepiness may drive the expression of emotional/behavioral disturbances, and should be explored as a potential modifiable risk factor for these disturbances in PWS, particularly pre-adolescent children. What is Known: • In iduals with Prader-Willi syndrome (PWS) commonly experience excessive daytime sleepiness and exhibit emotional/behavioral disturbances. • In the typically developing population, sleepiness is associated with emotional/behavioral disturbances, independently of sleep-disordered breathing. . What is New: • This study found evidence for a direct link between daytime sleepiness and emotional/behavioral disturbances, independent of sleep-related breathing difficulties, sleep adequacy, and body mass index. • Excessive daytime sleepiness may be a modifiable risk factor for emotional/behavioral disturbances in PWS.
Publisher: American Association for Cancer Research (AACR)
Date: 26-07-2023
DOI: 10.1158/1055-9965.C.6760427.V1
Abstract: AbstractBackground: The long-term effects of childhood cancer are unclear in the Australian context. We examined hospitalization trends for physical diseases and estimated the associated inpatient care costs in all 5-year childhood cancer survivors (CCS) diagnosed in Western Australia (WA) from 1982 to 2014. Methods: Hospitalization records for 2,938 CCS and 24,792 comparisons were extracted from 1987 to 2019 (median follow-up = 12 years, min = 1, max = 32). The adjusted hazard ratio (aHR) of hospitalization with 95% confidence intervals (CI) was estimated using the Andersen–Gill model for recurrent events. The cumulative burden of hospitalizations over time was assessed using the mean cumulative count method. The adjusted mean cost of hospitalization was estimated using the generalized linear models. Results: We identified a higher risk of hospitalization for all-cause (aHR, 2.0 95% CI, 1.8–2.2) physical disease in CCS than comparisons, with the highest risk for subsequent malignant neoplasms (aHR, 15.0 95% CI, 11.3–19.8) and blood diseases (aHR, 6.9 95% CI, 2.6–18.2). Characteristics associated with higher hospitalization rates included female gender, diagnosis with bone tumors, cancer diagnosis age between 5 and 9 years, multiple childhood cancer diagnoses, multiple comorbidities, higher deprivation, increased remoteness, and Indigenous status. The difference in the mean total hospitalization costs for any disease was significantly higher in survivors than comparisons (publicly funded $11,483 United States Dollar, i P /i 0.05). Conclusions: The CCS population faces a significantly higher risk of physical morbidity and higher cost of hospital-based care than the comparisons. Impact: Our study highlights the need for long-term follow-up healthcare services to prevent disease progression and mitigate the burden of physical morbidity on CCS and hospital services. /
Publisher: Oxford University Press (OUP)
Date: 06-2012
DOI: 10.1530/EJE-11-1112
Abstract: Ghrelin plays a major role in GH physiology and energy metabolism. Polymorphisms of its receptor (GH secretagogue receptor (GHSR)) may influence childhood growth and weight regulation. To correlate GHSR polymorphisms with auxological parameters throughout childhood in a healthy cohort. Longitudinal retrospective population-based genetic association study. GHSR genotypes were evaluated in 1362 children and compared with height/length, weight, and body mass index (BMI) data across an observation span of 10 years (0, 1, 3, 5, 8, and 10 years). Five different GHSR SNPs (rs2922126, rs2981464, rs482204, rs562416, and rs572169), minor allele frequency .1, were genotyped. Identification of potential genetic associations with height, weight, and BMI, using additive and dominant/recessive models, was optimized by comparing allele or genotype frequencies between the tallest and the shortest 27% of subjects for each auxological variable. Significance of association was evaluated by χ 2 test. The rs482204 TT genotype, vs TC/CC, was associated with greater stature across the entire observation period ( P .05). Similarly, the rs562416 TT genotype, vs TG/GG, correlated positively with tall stature at 3, 8, and 10 years. Other SNPs and genotypes showed no association with height at any age. No association was found between any tested SNPs and weight or BMI. Longitudinal investigation between birth and 10 years in a population-based cohort revealed a significant association of the rs482204 and rs562416 GHSR polymorphisms on height, whereas no association between GHSR polymorphisms and weight or BMI was ascertainable.
Publisher: American Association for Cancer Research (AACR)
Date: 26-07-2023
DOI: 10.1158/1055-9965.23779472
Abstract: The mean cumulative count of hospitalisations for any physical-health disease by attained age, in childhood cancer survivors and their matched comparisons.
Publisher: American Association for Cancer Research (AACR)
Date: 26-07-2023
DOI: 10.1158/1055-9965.23779469.V1
Abstract: Major diagnostic groups of physical-health diseases based on the International Classification of Diseases (ICD), 9th (Clinical modification) and 10th (Australian Modification) revisions.
Publisher: Bioscientifica
Date: 03-2018
DOI: 10.1530/EC-18-0047
Abstract: The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly. GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry. Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs. Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process. The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly.
Publisher: Bioscientifica
Date: 06-11-2015
DOI: 10.1530/ERC-15-0460
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
DOI: 10.1158/1055-9965.C.6760427
Abstract: AbstractBackground: The long-term effects of childhood cancer are unclear in the Australian context. We examined hospitalization trends for physical diseases and estimated the associated inpatient care costs in all 5-year childhood cancer survivors (CCS) diagnosed in Western Australia (WA) from 1982 to 2014. Methods: Hospitalization records for 2,938 CCS and 24,792 comparisons were extracted from 1987 to 2019 (median follow-up = 12 years, min = 1, max = 32). The adjusted hazard ratio (aHR) of hospitalization with 95% confidence intervals (CI) was estimated using the Andersen–Gill model for recurrent events. The cumulative burden of hospitalizations over time was assessed using the mean cumulative count method. The adjusted mean cost of hospitalization was estimated using the generalized linear models. Results: We identified a higher risk of hospitalization for all-cause (aHR, 2.0 95% CI, 1.8–2.2) physical disease in CCS than comparisons, with the highest risk for subsequent malignant neoplasms (aHR, 15.0 95% CI, 11.3–19.8) and blood diseases (aHR, 6.9 95% CI, 2.6–18.2). Characteristics associated with higher hospitalization rates included female gender, diagnosis with bone tumors, cancer diagnosis age between 5 and 9 years, multiple childhood cancer diagnoses, multiple comorbidities, higher deprivation, increased remoteness, and Indigenous status. The difference in the mean total hospitalization costs for any disease was significantly higher in survivors than comparisons (publicly funded $11,483 United States Dollar, i P /i 0.05). Conclusions: The CCS population faces a significantly higher risk of physical morbidity and higher cost of hospital-based care than the comparisons. Impact: Our study highlights the need for long-term follow-up healthcare services to prevent disease progression and mitigate the burden of physical morbidity on CCS and hospital services. /
Start Date: 07-2002
End Date: 01-2007
Amount: $67,635.00
Funder: Australian Research Council
View Funded ActivityStart Date: 07-2019
End Date: 12-2023
Amount: $390,000.00
Funder: Australian Research Council
View Funded Activity