Paediatrics (RCH) - Research Publications
Now showing items 1-12 of 2390
Tuberculosis in migrants to Australia: Outcomes of a national screening program
(Elsevier BV, 2021-05-01)
Background: Few low-incidence countries are on track to achieve the ambitious target of reaching TB pre- elimination by 2035. Australia is a high-income country with a low burden of TB, which is particularly concentrated in migrant populations. As part of Australia’s migration program, permanent, provisional and humanitarian visa applicants are screened for TB, along with some applicants for temporary visas. Methods: We calculated the prevalence of all forms of active TB and bacteriologically-confirmed TB among onshore and offshore applicants for visas to Australia from July 2014 to June 2017, and investigated associated risk factors using logistic regression. Findings: Visa applicants were predominantly young adults from various Asian countries. Among 2,381,217 applicants, 1263 cases of active TB were diagnosed, including 852 cases of bacteriologically- confirmed TB. Overall TB prevalence was 53.0 per 10 0,0 0 0, corresponding to one TB diagnosis for every 1887 applicants screened. TB rates increased with age and were higher among humanitarian applicants and those previously treated for TB, although most cases occurred in applicants without these risk factors. TB prevalence by country of origin was similar to WHO estimates for some countries, but considerably lower for others. For several highly represented countries of origin, rates appear to have fallen relative to earlier comparable studies. Interpretation: Prevalence of TB among visa applicants to Australia and the consequent risk to the Australian community appear to be declining and remain low. In this context, support for TB control pro- grams overseas and preventive interventions are likely to have the greatest impact on domestic TB burden.
The incidence of acute respiratory infection in Indonesian infants and association with vitamin D deficiency.
(Public Library of Science (PLoS), 2021)
BACKGROUND: Vitamin D deficiency has been associated with acute respiratory infection (ARI) in early life, but this has not been evaluated in Indonesia. We aimed to determine the incidence of ARI in Indonesian infants, and to evaluate the association with vitamin D deficiency. METHODS: From 23 December 2015 to 31 December 2017, we conducted a community-based prospective cohort study in Yogyakarta province. We enrolled 422 pregnant women and followed their infants from birth until 12 months of age for ARI episodes. Vitamin D status was measured at birth and at age six months. We performed Cox proportional hazard regression analysis to evaluate the association between vitamin D deficiency and pneumonia incidence. RESULTS: At study completion, 95% (400/422) of infants retained with a total of 412 child years of observation (CYO). The incidence of all ARI and of WHO-defined pneumonia was 3.89 (95% CI 3.70-4.08) and 0.25 (95% CI 0.21-0.30) episodes per CYO respectively. Vitamin D deficiency at birth was common (90%, 308/344) and associated with more frequent episodes of ARI non-pneumonia (adjusted odds ratio 4.48, 95% CI:1.04-19.34). Vitamin D status at birth or six months was not associated with subsequent pneumonia incidence, but greater maternal sun exposure during pregnancy was associated with a trend to less frequent ARI and pneumonia in infants. CONCLUSION: ARI, pneumonia, and vitamin D deficiency at birth were common in Indonesian infants. Minimising vitamin D deficiency at birth such as by supplementation of mothers or safe sun exposure during pregnancy has the potential to reduce ARI incidence in infants in this setting.
Paediatric tuberculosi: new advances to close persistent gaps
(Elsevier BV, 2021-03)
Young children are most vulnerable to develop severe forms of tuberculosis (TB) and are over- represented among TB deaths. Almost all children estimated to have died from TB were never diagnosed or offered TB treatment. Improved access to TB preventive treatment (TPT) requires major upscaling of household contact investigation with allocation of adequate resources. Symptom-based screening is often discouraged in adults for fear of generating drug resistance, if TB cases are missed. However, the situation in vulnerable young children is different, as they present minimal risk of drug resistance generation. Further, the perceived need for additional diagnostic evaluation presents a major barrier to TPT access and underlies general reluctance to consider pragmatic decentralised models of care. Widespread roll-out of Xpert MTB/RIF Ultra1 represents an opportunity for improved case detection in young children, but attaining full impact will require the use of non-sputum specimens. The new Fujifilm SILVAMP TB LAM1 urine assay demonstrated good diagnostic accuracy in HIV-positive and malnourished children, but further validation is required. Given the limited accuracy of all available tests and the excellent tolerance of TB drugs in children, the global community may have to accept some over- treatment if we want to close the persistent case detection gap in young children.
Effects of a professional development program on emergent literacy-promoting practices and environments in early childhood education and care
(Taylor & Francis, 2021-01-01)
The years from birth to five are critical for building the emergent literacy skills that precede learning to read and write. Early childhood education and care services are in a unique position to support emergent literacy development, particularly for children in socio-economically disadvantaged communities. This article reports the findings of a small cluster randomised controlled trial of the Let’s Read professional development program involving 12 centres and 223 educators in Australia. Through eLearning and on-site coaching, the program of relatively short duration and intensity supported educators of children from birth to school age. While the small sample size means the results must be interpreted with caution, the findings were promising. Despite variation in the fidelity of implementation, educators and centres in the intervention group showed more positive scores after participating in Let’s Read than those who did not across all areas of educator practice and classroom quality. Changes were most encouraging for educators of infants and toddlers. These results suggest there is measurable value in professional development involving coaching for improving emergent literacy-promoting practices of early childhood educators, including those working within disadvantaged communities. Concurrent fidelity and impact research should be undertaken with any wider implementation.
Sleep and cardiometabolic risk: a cluster analysis of actigraphy-derived sleep profiles in adults and children.
(Oxford University Press (OUP), 2021-01-30)
STUDY OBJECTIVES: Sleep plays an important role in cardiometabolic health. While the importance of considering sleep as a multidimensional construct is widely appreciated, studies have largely focused on individual sleep characteristics. The association between actigraphy-derived sleep profiles and cardiometabolic health in healthy adults and children has not been examined. METHODS: This study used actigraphy-measured sleep data collected between February 2015 and March 2016 in the Child Health CheckPoint study. Participants wore actigraphy monitors (GENEActiv Original, Cambs, UK) on their non-dominant wrist for seven days and sleep characteristics (period, efficiency, timing and variability) were derived from raw actigraphy data. Actigraphy-derived sleep profiles of 1,043 Australian children aged 11-12 years and 1337 adults were determined using K-means cluster analysis. The association between cluster membership and biomarkers of cardiometabolic health (blood pressure, body mass index, apolipoproteins, glycoprotein acetyls, composite metabolic syndrome severity score) were assessed using Generalised Estimating Equations, adjusting for geographic clustering, with sex, socioeconomic status, maturity stage (age for adults, pubertal status for children) and season of data collection as covariates. RESULTS: Four actigraphy-derived sleep profiles were identified in both children and adults: Short sleepers, Late to bed, Long sleepers, and Overall good sleepers. The Overall good sleeper pattern (characterised by adequate sleep period time, high efficiency, early bedtime and low day-to-day variability) was associated with better cardiometabolic health in the majority of comparisons (80%). CONCLUSION: Actigraphy-derived sleep profiles are associated with cardiometabolic health in adults and children. The Overall good sleeper pattern is associated with more favourable cardiometabolic health.
Nontyphoid Salmonella Disease
Nontyphoidal Salmonella (NTS) typically causes self-limiting enterocolitis in high-income settings. In sub-Saharan Africa (SSA), however, NTS is a major cause of bloodstream infections, termed invasive nontyphoidal Salmonella (iNTS) disease, causing an estimated 1.9 million cases and 388,000 deaths annually. In SSA, specific clades of Salmonella Typhimurium and Salmonella Enteritidis associated with genomic degradation and multi-drug resistance have emerged. iNTS disease disproportionately affects adults with advanced HIV infection and young children with immature immunity, HIV, and malaria. Children in SSA bear two-thirds of the burden of disease. The non-specific nature of iNTS disease makes it difficult to differentiate from other causes of non-focal febrile illness, and the widespread emergence of multi-drug resistance and emerging cephalosporin resistance presents increasing treatment challenges. iNTS disease causes a large burden of morbidity and mortality in SSA, and there is much that is still unknown about environmental and host reservoirs and transmission of the pathogen and about optimal therapy for this condition. iNTS is also a problem in other resource-limited areas among individuals with HIV, malaria, and compromised or immature immune systems, although SSA accounts for the largest global burden. Vaccine acceleration is a high priority.
Community intervention for child tuberculosis active contact investigation and management: study protocol for a parallel cluster randomized controlled trial.
(Springer Science and Business Media LLC, 2021-03-02)
BACKGROUND: There are major gaps in the management of pediatric tuberculosis (TB) contact investigation for rapid identification of active tuberculosis and initiation of preventive therapy. This study aims to evaluate the impact of a community-based intervention as compared to facility-based model for the management of children in contact with bacteriologically confirmed pulmonary TB adults in low-resource high-burden settings. METHODS/DESIGN: This multicenter parallel open-label cluster randomized controlled trial is composed of three phases: I, baseline phase in which retrospective data are collected, quality of data recording in facility registers is checked, and expected acceptability and feasibility of the intervention is assessed; II, intervention phase with enrolment of index cases and contact cases in either facility- or community-based models; and III, explanatory phase including endpoint data analysis, cost-effectiveness analysis, and post-intervention acceptability assessment by healthcare providers and beneficiaries. The study uses both quantitative and qualitative analysis methods. The community-based intervention includes identification and screening of all household contacts, referral of contacts with TB-suggestive symptoms to the facility for investigation, and household initiation of preventive therapy with follow-up of eligible child contacts by community healthcare workers, i.e., all young (< 5 years) child contacts or older (5-14 years) child contacts living with HIV, and with no evidence of TB disease. Twenty clusters representing TB diagnostic and treatment facilities with their catchment areas are randomized in a 1:1 ratio to either the community-based intervention arm or the facility-based standard of care arm in Cameroon and Uganda. Randomization was stratified by country and constrained on the number of index cases per cluster. The primary endpoint is the proportion of eligible child contacts who initiate and complete the preventive therapy. The sample size is of 1500 child contacts to identify a 10% difference between the arms with the assumption that 60% of children will complete the preventive therapy in the standard of care arm. DISCUSSION: This study will provide evidence of the impact of a community-based intervention on household child contact screening and management of TB preventive therapy in order to improve care and prevention of childhood TB in low-resource high-burden settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03832023 . Registered on 6 February 2019.
Executive function mediates the prospective association between neurostructural differences within the central executive network and anti-social behavior after childhood traumatic brain injury
BACKGROUND: Despite increasing evidence of a link between early life brain injury and anti-social behavior, very few studies have assessed factors that explain this association in children with traumatic brain injury (TBI). One hypothesis suggests that childhood TBI elevates risk for anti-social behavior via disruption to anatomically distributed neural networks implicated in executive functioning (EF). In this longitudinal prospective study, we employed high-resolution structural neuroimaging to (a) evaluate the impact of childhood TBI on regional morphometry of the central executive network (CEN) and (b) evaluate the prediction that lower EF mediates the prospective relationship between structural differences within the CEN and postinjury anti-social behaviors. METHODS: This study involved 155 children, including 112 consecutively recruited, hospital-confirmed cases of mild-severe TBI and 43 typically developing control (TDC) children. T1-weighted brain magnetic resonance imaging (MRI) sequences were acquired sub-acutely in a subset of 137 children [TBI: n = 103; TDC: n = 34]. All participants were evaluated using direct assessment of EF 6 months postinjury, and parents provided ratings of anti-social behavior 12 months postinjury. RESULTS: Severe TBI was associated with postinjury volumetric differences within the CEN and its putative hub regions. When compared with TD controls, the TBI group had significantly worse EF, which was associated with more frequent anti-social behaviors and abnormal CEN morphometry. Mediation analysis indicated that reduced EF mediated the prospective association between postinjury volumetric differences within the CEN and more frequent anti-social behavior. CONCLUSIONS: Our longitudinal prospective findings suggest that detection of neurostructural abnormalities within the CEN may aid in the early identification of children at elevated risk for postinjury executive dysfunction, which may in turn contribute to chronic anti-social behaviors after early life brain injury. Findings underscore the potential value of early surveillance and preventive measures for children presenting with neurostructural and/or neurocognitive risk factors.
Evidence Based Selection of Commonly Used RT-qPCR Reference Genes for the Analysis of Mouse Skeletal Muscle
(PUBLIC LIBRARY SCIENCE, 2014-02-11)
The ability to obtain accurate and reproducible data using quantitative real-time Polymerase Chain Reaction (RT-qPCR) is limited by the process of data normalization. The use of 'housekeeping' or 'reference' genes is the most common technique used to normalize RT-qPCR data. However, commonly used reference genes are often poorly validated and may change as a result of genetic background, environment and experimental intervention. Here we present an analysis of 10 reference genes in mouse skeletal muscle (Actb, Aldoa, Gapdh, Hprt1, Ppia, Rer1, Rn18s, Rpl27, Rpl41 and Rpl7L1), which were identified as stable either by microarray or in the literature. Using the MIQE guidelines we compared wild-type (WT) mice across three genetic backgrounds (R129, C57BL/6j and C57BL/10) as well as analyzing the α-actinin-3 knockout (Actn3 KO) mouse, which is a model of the common null polymorphism (R577X) in human ACTN3. Comparing WT mice across three genetic backgrounds, we found that different genes were more tightly regulated in each strain. We have developed a ranked profile of the top performing reference genes in skeletal muscle across these common mouse strains. Interestingly the commonly used reference genes; Gapdh, Rn18s, Hprt1 and Actb were not the most stable. Analysis of our experimental variant (Actn3 KO) also resulted in an altered ranking of reference gene suitability. Furthermore we demonstrate that a poor reference gene results in increased variability in the normalized expression of a gene of interest, and can result in loss of significance. Our data demonstrate that reference genes need to be validated prior to use. For the most accurate normalization, it is important to test several genes and use the geometric mean of at least three of the most stably expressed genes. In the analysis of mouse skeletal muscle, strain and intervention played an important role in selecting the most stable reference genes.
Direct repression of MYB by ZEB1 suppresses proliferation and epithelial gene expression during epithelial-to-mesenchymal transition of breast cancer cells
INTRODUCTION: Epithelial-to-mesenchymal transition (EMT) promotes cell migration and is important in metastasis. Cellular proliferation is often downregulated during EMT, and the reverse transition (MET) in metastases appears to be required for restoration of proliferation in secondary tumors. We studied the interplay between EMT and proliferation control by MYB in breast cancer cells. METHODS: MYB, ZEB1, and CDH1 expression levels were manipulated by lentiviral small-hairpin RNA (shRNA)-mediated knockdown/overexpression, and verified with Western blotting, immunocytochemistry, and qRT-PCR. Proliferation was assessed with bromodeoxyuridine pulse labeling and flow cytometry, and sulforhodamine B assays. EMT was induced with epidermal growth factor for 9 days or by exposure to hypoxia (1% oxygen) for up to 5 days, and assessed with qRT-PCR, cell morphology, and colony morphology. Protein expression in human breast cancers was assessed with immunohistochemistry. ZEB1-MYB promoter binding and repression were determined with Chromatin Immunoprecipitation Assay and a luciferase reporter assay, respectively. Student paired t tests, Mann-Whitney, and repeated measures two-way ANOVA tests determined statistical significance (P < 0.05). RESULTS: Parental PMC42-ET cells displayed higher expression of ZEB1 and lower expression of MYB than did the PMC42-LA epithelial variant. Knockdown of ZEB1 in PMC42-ET and MDA-MB-231 cells caused increased expression of MYB and a transition to a more epithelial phenotype, which in PMC42-ET cells was coupled with increased proliferation. Indeed, we observed an inverse relation between MYB and ZEB1 expression in two in vitro EMT cell models, in matched human breast tumors and lymph node metastases, and in human breast cancer cell lines. Knockdown of MYB in PMC42-LA cells (MYBsh-LA) led to morphologic changes and protein expression consistent with an EMT. ZEB1 expression was raised in MYBsh-LA cells and significantly repressed in MYB-overexpressing MDA-MB-231 cells, which also showed reduced random migration and a shift from mesenchymal to epithelial colony morphology in two dimensional monolayer cultures. Finally, we detected binding of ZEB1 to MYB promoter in PMC42-ET cells, and ZEB1 overexpression repressed MYB promoter activity. CONCLUSIONS: This work identifies ZEB1 as a transcriptional repressor of MYB and suggests a reciprocal MYB-ZEB1 repressive relation, providing a mechanism through which proliferation and the epithelial phenotype may be coordinately modulated in breast cancer cells.
Placental pseudo-malignancy from a DNA methylation perspective: unanswered questions and future directions.
(Frontiers Media SA, 2013)
The growing fetus is dependent on adequate placental function for delivery of essential nutrients and oxygen, and for waste removal. The placenta also plays an important protective role; shielding the developing baby from the maternal immune system and adverse environmental exposures. Fundamental to these processes is correct invasion of the decidua and remodeling of maternal vasculature, each of which show remarkable parallels to tumorogenesis, with the obvious exception that the former is usually a tightly controlled process. It is not surprising that these physiological similarities are mirrored in gene expression and epigenetic parallels, many not found in any other aspect of human development. In this perspective, we summarize known DNA methylation similarities between placenta and human tumors, and discuss the implications and knowledge gaps associated with these findings. We also speculate on the potential origin of common DNA methylation features in these two disparate aspects of human physiology.
Contribution of Brain Size to IQ and Educational Underperformance in Extremely Preterm Adolescents
(PUBLIC LIBRARY SCIENCE, 2013-10-09)
OBJECTIVES: Extremely preterm (EP) survivors have smaller brains, lower IQ, and worse educational achievement than their term-born peers. The contribution of smaller brain size to the IQ and educational disadvantages of EP is unknown. This study aimed (i) to compare brain volumes from multiple brain tissues and structures between EP-born (< 28 weeks) and term-born (≥ 37 weeks) control adolescents, (ii) to explore the relationships of brain tissue volumes with IQ and basic educational skills and whether this differed by group, and (iii) to explore how much total brain tissue volume explains the underperformance of EP adolescents compared with controls. METHODS: Longitudinal cohort study of 148 EP and 132 term controls born in Victoria, Australia in 1991-92. At age 18, magnetic resonance imaging-determined brain volumes of multiple tissues and structures were calculated. IQ and educational skills were measured using the Wechsler Abbreviated Scale of Intelligence (WASI) and the Wide Range Achievement Test(WRAT-4), respectively. RESULTS: Brain volumes were smaller in EP adolescents compared with controls (mean difference [95% confidence interval] of -5.9% [-8.0, -3.7%] for total brain tissue volume). The largest relative differences were noted in the thalamus and hippocampus. The EP group had lower IQs(-11.9 [-15.4, -8.5]), spelling(-8.0 [-11.5, -4.6]), math computation(-10.3 [-13.7, -6.9]) and word reading(-5.6 [-8.8, -2.4]) scores than controls; all p-values<0.001. Volumes of total brain tissue and other brain tissues and structures correlated positively with IQ and educational skills, a relationship that was similar for both the EP and controls. Total brain tissue volume explained between 20-40% of the IQ and educational outcome differences between EP and controls. CONCLUSIONS: EP adolescents had smaller brain volumes, lower IQs and poorer educational performance than controls. Brain volumes of multiple tissues and structures are related to IQ and educational outcomes. Smaller total brain tissue volume is an important contributor to the cognitive and educational underperformance of adolescents born EP.