Paediatrics (RCH) - Research Publications
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ItemTobacco product use and smoking frequency among US adults with intellectual and developmental disabilities(WILEY, 2018-08)BACKGROUND: People with intellectual and developmental disabilities (IDD) have been overlooked in tobacco use research although they are likely to experience tobacco-related health disparities. This study examined tobacco product use and smoking frequency and amount among a sample of US Special Olympics athletes with IDD. METHODS: Multiple regression analysis was used to test whether age, gender, body mass index, blood pressure, bone density, eating fruits and vegetables and family member tobacco use were correlated with the number of cigarettes smoked per day. RESULTS: The sample of people with IDD who used tobacco (n = 501) were aged 18-75 (M = 33.37) and 76.4% were male. About 73.6% reported cigarette use only, 10.6% reported dual or poly use of cigarettes and other tobacco products (cigars, pipe, and chewing tobacco) and 15.8% reported using only tobacco products other than cigarettes. Men were more likely than women to use tobacco products other than cigarettes. Of the cigarette smokers, 79.6% were daily smokers, and their mean cigarettes per day was 10.08 (SD = 9.50). Special Olympics athletes who did not have low bone density and those who consumed fruits and vegetables less than daily reported higher numbers of cigarettes per day. CONCLUSIONS: Although people with IDD are less likely to use tobacco than the general population, study results suggest that people with IDD who smoke cigarettes are just as likely as smokers in the general US population to smoke daily. Improving overall health behaviours may be important in helping smokers with IDD to reduce their tobacco use. Research is needed to understand longitudinal patterns of tobacco use and how to prevent tobacco use among people with IDD.
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ItemPenetrating head injuries in children presenting to the emergency department in Australia and New Zealand: A PREDICT prospective study(WILEY, 2018-08)AIM: Penetrating head injuries (pHIs) are associated with high morbidity and mortality. Data on pHIs in children outside North America are limited. We describe the mechanism of injuries, neuroimaging findings, neurosurgery and mortality for pHIs in Australia and New Zealand. METHODS: This was a planned secondary analysis of a prospective observational study of children <18 years who presented with a head injury of any severity at any of 10 predominantly paediatric Australian/New Zealand emergency departments (EDs) between 2011 and 2014. We reviewed all cases where clinicians had clinically suspected pHI as well as all cases of clinically important traumatic brain injuries (death, neurosurgery, intubation >24 h, admission >2 days and abnormal computed tomography). RESULTS: Of 20 137 evaluable patients with a head injury, 21 (0.1%) were identified to have sustained a pHI. All injuries were of non-intentional nature, and there were no gunshot wounds. The mechanisms of injuries varied from falls, animal attack, motor vehicle crashes and impact with objects. Mean Glasgow Coma Scale on ED arrival was 10; 10 (48%) had a history of loss of consciousness, and 7 (33%) children were intubated pre-hospital or in the ED. Fourteen (67%) children underwent neurosurgery, two (10%) craniofacial surgery, and five (24%) were treated conservatively; four (19%) patients died. CONCLUSIONS: Paediatric pHIs are very rare in EDs in Australia and New Zealand but are associated with high morbidity and mortality. The absence of firearm-related injuries compared to North America is striking and may reflect Australian and New Zealand firearm regulations.
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ItemIntragenic DNA methylation in buccal epithelial cells and intellectual functioning in a paediatric cohort of males with fragile X(NATURE PORTFOLIO, 2018-02-26)Increased intragenic DNA methylation of the Fragile X Related Epigenetic Element 2 (FREE2) in blood has been correlated with lower intellectual functioning in females with fragile X syndrome (FXS). This study explored these relationships in a paediatric cohort of males with FXS using Buccal Epithelial Cells (BEC). BEC were collected from 25 males with FXS, aged 3 to 17 years and 19 age-matched male controls without FXS. Methylation of 9 CpG sites within the FREE2 region was examined using the EpiTYPER approach. Full Scale IQ (FSIQ) scores of males with FXS were corrected for floor effect using the Whitaker and Gordon (WG) extrapolation method. Compared to controls, children with FXS had significant higher methylation levels for all CpG sites examined (p < 3.3 × 10-7), and within the FXS group, lower FSIQ (WG corrected) was associated with higher levels of DNA methylation, with the strongest relationship found for CpG sites within FMR1 intron 1 (p < 5.6 × 10-5). Applying the WG method to the FXS cohort unmasked significant epi-genotype-phenotype relationships. These results extend previous evidence in blood to BEC and demonstrate FREE2 DNA methylation to be a sensitive epigenetic biomarker significantly associated with the variability in intellectual functioning in FXS.
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ItemIncomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features(BMC, 2019-05-03)BACKGROUND: Fragile X syndrome (FXS) is a common monogenic cause of intellectual disability with autism features. While it is caused by loss of the FMR1 product (FMRP), mosaicism for active and inactive FMR1 alleles, including alleles termed premutation (PM: 55-199 CGGs), is not uncommon. Importantly, both PM and active full mutation (FM: ≥ 200 CGGs) alleles often express elevated levels of mRNA that are thought to be toxic. This study determined if complete FMR1 mRNA silencing from FM alleles and/or levels of FMR1 mRNA (if present) in blood are associated with intellectual functioning and autism features in FXS. METHODS: The study cohort included 98 participants (70.4% male) with FXS (FM-only and PM/FM mosaic) aged 1-43 years. A control group of 14 females were used to establish control FMR1 mRNA reference range. Intellectual functioning and autism features were assessed using the Mullen Scales of Early Learning or an age-appropriate Wechsler Scale and the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2), respectively. FMR1 mRNA was analysed in venous blood collected at the time of assessments, using the real-time PCR relative standard curve method. RESULTS: Females with FXS had significantly higher levels of FMR1 mRNA (p < 0.001) than males. FMR1 mRNA levels were positively associated with age (p < 0.001), but not with intellectual functioning and autistic features in females. FM-only males (aged < 19 years) expressing FM FMR1 mRNA had significantly higher ADOS calibrated severity scores compared to FM-only males with completely silenced FMR1 (p = 0.011). However, there were no significant differences between these subgroups on intellectual functioning. In contrast, decreased levels of FMR1 mRNA were associated with decreased intellectual functioning in FXS males (p = 0.029), but not autism features, when combined with the PM/FM mosaic group. CONCLUSION: Incomplete silencing of toxic FM RNA may be associated with autistic features, but not intellectual functioning in FXS males. While decreased levels of mRNA may be more predictive of intellectual functioning than autism features. If confirmed in future studies, these findings may have implications for patient stratification, outcome measure development, and design of clinical and pre-clinical trials in FXS.
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ItemSignificantly Elevated FMR1 mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing(MDPI, 2019-08-02)Although fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥200 cytosine-guanine-guanine (CGG) repeats, and a decrease in FMR1 mRNA and its protein (FMRP), incomplete silencing has been associated with more severe autism features in FXS males. This study reports on brothers (B1 and B2), aged 5 and 2 years, with autistic features and language delay, but a higher non-verbal IQ in comparison to typical FXS. CGG sizing using AmplideX PCR only identified premutation (PM: 55-199 CGGs) alleles in blood. Similarly, follow-up in B1 only revealed PM alleles in saliva and skin fibroblasts; whereas, an FM expansion was detected in both saliva and buccal DNA of B2. While Southern blot analysis of blood detected an unmethylated FM, methylation analysis with a more sensitive methodology showed that B1 had partially methylated PM alleles in blood and fibroblasts, which were completely unmethylated in buccal and saliva cells. In contrast, B2 was partially methylated in all tested tissues. Moreover, both brothers had FMR1 mRNA ~5 fold higher values than those of controls, FXS and PM cohorts. In conclusion, the presence of unmethylated FM and/or PM in both brothers may lead to an overexpression of toxic expanded mRNA in some cells, which may contribute to neurodevelopmental problems, including elevated autism features.