Paediatrics (RCH) - Research Publications
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ItemNo long-term evidence of hyporesponsiveness after use of pneumococcal conjugate vaccine in children previously immunized with pneumococcal polysaccharide vaccine(Elsevier, 2016-06)Background: A randomized controlled trial in Fiji examined the immunogenicity and effect on nasopharyngeal carriage after 0, 1, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) in infancy followed by 23-valent pneumococcal polysaccharide vaccine (23vPPV; Pneumovax) at 12 months of age. At 18 months of age, children given 23vPPV exhibited immune hyporesponsiveness to a micro-23vPPV (20%) challenge dose in terms of serotype-specific IgG and opsonophagocytosis, while 23vPPV had no effect on vaccine-type carriage. Objective: This follow-up study examined the long-term effect of the 12-month 23vPPV dose by evaluating the immune response to 13-valent pneumococcal conjugate vaccine (PCV13) administration 4 to 5 years later. Methods: Blood samples from 194 children (now 5-7 years old) were taken before and 28 days after PCV13 booster immunization. Nasopharyngeal swabs were taken before PCV13 immunization. We measured levels of serotype-specific IgG to all 13 vaccine serotypes, opsonophagocytosis for 8 vaccine serotypes, and memory B-cell responses for 18 serotypes before and after PCV13 immunization. Results: Paired samples were obtained from 185 children. There were no significant differences in the serotype-specific IgG, opsonophagocytosis, or memory B-cell response at either time point between children who did or did not receive 23vPPV at 12 months of age. Nasopharyngeal carriage of PCV7 and 23vPPV serotypes was similar among the groups. Priming with 1, 2, or 3 PCV7 doses during infancy did not affect serotype-specific immunity or carriage. Conclusion: Immune hyporesponsiveness induced by 23vPPV in toddlers does not appear to be sustained among preschool children in this context and does not affect the pneumococcal carriage rate in this age group.
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ItemThe Effect of Intermittent Antenatal Iron Supplementation on Infant Outcomes in Rural Vietnam: A Cluster Randomized Trial(SCIENCEDOMAIN International, 2015)Objectives: Intermittent antenatal iron supplementation is an attractive alternative to daily dosing during pregnancy, however the impact of this strategy on infant outcomes remains unclear. We compared the effect of intermittent antenatal iron supplementation with daily iron supplementation on maternal and infant outcomes in rural Vietnam. Methods: This cluster randomised trial was conducted in Ha Nam province, Vietnam. 1,258 pregnant women in 104 communes were assigned to daily iron-folic acid (IFA), twice weekly IFA, or twice weekly multiple micronutrient (MMN) supplementation. Primary outcome was birth weight. Results: There was no difference in birth weights of infants of women receiving twice weekly IFA compared to daily IFA (mean difference [MD] 28 g; 95% CI -22 to 78), or twice weekly MMN compared to daily IFA (MD -36.8 g; 95% CI -82 to 8.2). At 32 wk gestation, maternal ferritin was lower in women receiving twice weekly compared to daily IFA (geometric mean ratio (GMR) 0.73; 95% CI 0.67 to 0.80), and in women receiving twice weekly MMN compared to daily IFA (GMR 0.62; 95% CI 0.57 to 0.68), with no difference in hemoglobin levels. Infants of mothers who received twice weekly IFA had higher cognitive scores at 6 mo of age compared to those who received daily IFA (MD 1.89; 95% CI 0.23 to 3.56). Conclusions: Twice-weekly antenatal IFA supplementation achieved similar mean birthweight, and improved cognitive scores in infants at 6 months of age, compared to daily IFA supplementation, and should be considered for use in settings with low anemia prevalence.
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ItemExcessive alcohol use and its association with risky sexual behaviour: a cross-sectional analysis of data from Victorian secondary school students(WILEY, 2013-02)OBJECTIVE: Estimate the prevalence of sexual behaviour and alcohol use and examine the association between excessive alcohol use and risky sexual behaviour in late secondary students in Victoria, Australia. METHOD: The sample of Year 11 students from government and independent schools participating in the 2008 International Youth Development Study (n=450) was representative of the Victorian school population. Logistic regression analyses examined the associations between sexual behaviour, binge and compulsive drinking, adjusting for socio-demographic, school and family factors. RESULTS: Under half (44%) the students had experienced sex in the past year, half (50%) had engaged in binge drinking in the past two weeks and 26% reported compulsive drinking in the past year. Of those who reported sex in the past year (n=197), 34% had sex without a condom at the last sexual encounter and 28% later regretted sex due to alcohol. The likelihood of experiencing sex was increased by binge (OR=2.44, 95%CI 1.44-4.12) and compulsive drinking (OR=2.15, 95%CI 1.29-3.60). For those sexually active, binge drinking increased the risk of having three or more sexual partners (OR=3.37, 95%CI 1.11-10.26) and compulsive drinking increased the likelihood of regretted sex due to alcohol (OR=4.43, 95%CI 2.10-9.31). Excessive drinking was not associated with condom non-use. CONCLUSION AND IMPLICATIONS: Risky sex - multiple sexual partners and regretted sex due to alcohol - and excessive drinking are highly prevalent and co-associated among Victorian late secondary students.
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ItemThe clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: findings from an international multicentre registry(OXFORD UNIV PRESS, 2018-03)AIMS: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. METHODS AND RESULTS: This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities. CONCLUSION: This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events.
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ItemAtrioventricular block after ASD closure(BMJ PUBLISHING GROUP, 2016)OBJECTIVE: Secundum atrial septal defect (ASD) is a common congenital heart defect. There is limited data on both early and late atrioventricular (AV) block post ASD closure. The aim of this study was to determine the incidence and risk factors of AV block associated with ASD closure. METHODS: A retrospective analysis of all patients who underwent ASD closure either with a device or surgical method at the Royal Children's Hospital Melbourne between 1996 and 2010 was performed. Baseline demographics, procedural details and follow-up data were collected from medical records. RESULTS: A total of 378 patients were identified; 242 in the device group and 136 in the surgical group. Fourteen patients (3.7%) had AV block (1 with second degree and 13 with first degree) at a median follow-up of 28 months; 11/242 (4.5%) in the device group and 3/135 (2.2%) in the surgical group (p=0.39). Six patients had new-onset AV block after ASD closure. In the device subgroup, patients with AV block at follow-up had a larger indexed device size compared with those without (22 (15-31) vs 18(7-38), p=0.02). Multivariate analysis revealed the presence of AV block either pre procedure or post procedure to be the only variables associated with late AV block. CONCLUSIONS: Late AV block in patients with repaired ASD is rare and most likely independent of the technique used. In the device subgroup, the only risk factor identified to be associated with late AV block was the presence of either preprocedural or postprocedural AV block, so long-term follow-up for these patients should be provided.
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ItemKidney organoids: accurate models or fortunate accidents(COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2019-10-01)There are now many reports of human kidney organoids generated via the directed differentiation of human pluripotent stem cells (PSCs) based on an existing understanding of mammalian kidney organogenesis. Such kidney organoids potentially represent tractable tools for the study of normal human development and disease with improvements in scale, structure, and functional maturation potentially providing future options for renal regeneration. The utility of such organotypic models, however, will ultimately be determined by their developmental accuracy. While initially inferred from mouse models, recent transcriptional analyses of human fetal kidney have provided greater insight into nephrogenesis. In this review, we discuss how well human kidney organoids model the human fetal kidney and how the remaining differences challenge their utility.
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ItemYY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction.(Elsevier BV, 2017-06-01)Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.
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ItemNeonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence(COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2012-08)Comparison between groups of monozygotic (MZ) and dizygotic (DZ) twins enables an estimation of the relative contribution of genetic and shared and nonshared environmental factors to phenotypic variability. Using DNA methylation profiling of ∼20,000 CpG sites as a phenotype, we have examined discordance levels in three neonatal tissues from 22 MZ and 12 DZ twin pairs. MZ twins exhibit a wide range of within-pair differences at birth, but show discordance levels generally lower than DZ pairs. Within-pair methylation discordance was lowest in CpG islands in all twins and increased as a function of distance from islands. Variance component decomposition analysis of DNA methylation in MZ and DZ pairs revealed a low mean heritability across all tissues, although a wide range of heritabilities was detected for specific genomic CpG sites. The largest component of variation was attributed to the combined effects of nonshared intrauterine environment and stochastic factors. Regression analysis of methylation on birth weight revealed a general association between methylation of genes involved in metabolism and biosynthesis, providing further support for epigenetic change in the previously described link between low birth weight and increasing risk for cardiovascular, metabolic, and other complex diseases. Finally, comparison of our data with that of several older twins revealed little evidence for genome-wide epigenetic drift with increasing age. This is the first study to analyze DNA methylation on a genome scale in twins at birth, further highlighting the importance of the intrauterine environment on shaping the neonatal epigenome.
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ItemHigh-level mobility skills in children and adolescents with traumatic brain injury(TAYLOR & FRANCIS INC, 2015-12-06)AIM: To evaluate the reliability, validity and responsiveness of the High-level Mobility Assessment Tool (HiMAT) in children and adolescents with traumatic brain injury (TBI) and to compare the mobility skills of children with TBI to those of healthy peers. METHOD: The mobility skills of 52 children with moderate and severe TBI (36 males; mean age = 12 years, range = 6-17) were assessed using the HiMAT and the Pediatric Evaluation of Disability Inventory (PEDI). Inter-rater reliability, re-test reliability and responsiveness of the HiMAT were evaluated in sub-groups by comparing results scored at several time-points. The HiMAT scores of children with TBI were compared with those of a healthy comparative cohort. RESULTS: The HiMAT demonstrated excellent inter-rater reliability (ICC = 0.93), re-test reliability (ICC = 0.98) and responsiveness to change (p = 0.002). The PEDI demonstrated a ceiling effect in mobility assessment of ambulant children with TBI. The HiMAT scores of children with TBI were lower than those of their healthy peers (p < 0.001). INTERPRETATION: The HiMAT is a reliable, valid and sensitive measure of high-level mobility skills following childhood TBI. The high-level mobility skills of children with TBI are less proficient than their peers.
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ItemNew Australovenator hind limb elements pertaining to the holotype reveal the most complete Neovenatorid leg.(Public Library of Science (PLoS), 2013)We report new skeletal elements pertaining to the same individual which represents the holotype of Australovenator wintonensis, from the 'Matilda Site' in the Winton Formation (Upper Cretaceous) of western Queensland. The discovery of these new elements means that the hind limb of Australovenator is now the most completely understood hind limb among Neovenatoridae. The new hind limb elements include: the left fibula; left metatarsal IV; left pedal phalanges I-2, II-1, III-4, IV-2, IV-3; and right pedal phalanges, II-2 and III-1. The detailed descriptions are supported with three dimensional figures. These coupled with the completeness of the hind limb will increase the utility of Australovenator in comparisons with less complete neovenatorid genera. These specimens and the previously described hind limb elements of Australovenator are compared with other theropods classified as neovenatorids (including Neovenator, Chilantaisaurus, Fukuiraptor, Orkoraptor and Megaraptor). Hind limb length proportion comparisons indicate that the smaller neovenatorids Australovenator and Fukuiraptor possess more elongate and gracile hind limb elements than the larger Neovenator and Chilantaisaurus. Greater stride lengths to body size exist in both Fukuiraptor and Australovenator with the femur discovered to be proportionally shorter the rest of the hind limb length. Additionally Australovenator is identified as possessing the most elongate metatarsus. The metatarsus morphology varies with body size. The larger neoventorids possess a metatarsus with greater width but shorter length compared to smaller forms.