Paediatrics (RCH) - Research Publications
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ItemBone mineral density is related to lung function outcomes in young people with cystic fibrosis-A retrospective study(WILEY, 2017-12)INTRODUCTION: Improvements in the medical management of cystic fibrosis (CF) in recent years have resulted in increased prevalence of long-term sequelae of the condition, such as low bone mineral density (BMD) and hence an increased risk of fractures in later life. Aim To explore the interaction between BMD and lung function, nutrition, and genotype. METHODS: This study was a retrospective audit of 202 children with CF from August 2000 to January 2016 to investigate associations between BMD Z-scores with clinical status, nutrition, and genetics using dual-energy absorptiometry X-ray data from the Royal Children's Hospital Melbourne, Australia. RESULTS: Severity of both lung disease (P < 0.0001) and nutritional status (P < 0.05) was found to be strongly associated with BMD Z-scores. CONCLUSIONS: This is the biggest study to date to provide further evidence that the severity of pulmonary disease is related to BMD in CF patients and therefore screening guidelines for bone health in children with CF should target individuals with the poorest clinical status.
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ItemQuantitative assessment of airway dimensions in young children with cystic fibrosis lung disease using chest computed tomography(WILEY, 2017-11)OBJECTIVE: To evaluate lung disease progression using airway and artery (AA) dimensions on chest CT over 2-year interval in young CF patients longitudinally and compare to disease controls cross-sectionally. METHODS: Retrospective analysis of pressure controlled end-inspiratory CTs, 12 routine baseline (CT1 ) and follow up (CT2 ) from AREST CF cohort; 12 disease controls with normal CT. All visible AA-pairs were measured perpendicular to the airway axis. Inner and outer airway diameters and wall (outer-inner radius) thickness were divided by adjacent arteries to compute Ain A-, Aout A-, and AWT A-ratios, respectively. Differences between CF and control data were assessed using mixed effects models predicting AA-ratios per segmental generation (SG). Power calculations were performed with 80% power and ɑ = 0.05. RESULTS: CF, median age CT1 2 years; CT2 3.9 years, 5 males. Controls, median age 2.9 years, 10 males. Total of 4798 AA-pairs measured. Cross-sectionally: Ain A-ratio showed no difference between controls and CF CT1 or CT2 . Aout A-ratio was significantly higher in CF CT1 (SG 2-4) and CT2 (SG 2-5) compared to controls. AWT A-ratio was increased for CF CT1 (SG 1-5) and CT2 (SG 2-6) compared to controls. CF longitudinally: Ain A-ratio was significantly higher at CT2 compared to CT1 . Increase in Aout A-ratio at CT2 compared to CT1 was visible in SG ≥4. Sample sizes of 21 and 58 would be necessary for 50% and 30% Aout A-ratio reductions, respectively, between CF CT2 and controls. CONCLUSION: AA-ratio differences were present in young CF patients relative to disease controls. Aout A-ratio as an objective parameter for bronchiectasis could reduce sample sizes for clinical trials.
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ItemThe airway microbiota in early cystic fibrosis lung disease(WILEY, 2017-11)Infection plays a critical role in the pathogenesis of cystic fibrosis (CF) lung disease. Over the past two decades, the application of molecular and extended culture-based techniques to microbial analysis has changed our understanding of the lungs in both health and disease. CF lung disease is a polymicrobial disorder, with obligate and facultative anaerobes recovered alongside traditional pathogens in varying proportions, with some differences observed to correlate with disease stage. While healthy lungs are not sterile, differences between the lower airway microbiota of individuals with CF and disease-controls are already apparent in childhood. Understanding the evolution of the CF airway microbiota, and its relationship with clinical treatments and outcome at each disease stage, will improve our understanding of the pathogenesis of CF lung disease and potentially inform clinical management. This review summarizes current knowledge of the early development of the respiratory microbiota in healthy children and then discusses what is known about the airway microbiota in individuals with CF, including how it evolves over time and where future research priorities lie.
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ItemAsthma, bones and corticosteroids: Are inhaled corticosteroids associated with fractures in children with asthma?(WILEY, 2017-08)AIM: The prevalence of asthma worldwide among older children varies between 10 and 20%. One of the most effective therapies to treat asthma and prevent exacerbations is inhaled corticosteroids (ICSs). Systemic corticosteroids are known to decrease bone mineral density and increase the risk of fractures among children, but little is known about the effect of ICSs on fracture risk in children with asthma. The aim of this study was to investigate the fracture rates in children with asthma using ICSs. METHODS: A survey on fracture history and risk, bone health and asthma was administered by a researcher to children aged 6-18 years attending a tertiary care children's hospital in Melbourne, Australia over a 6-month period. Fracture risks were compared in children on low or high dose ICS with those not on any ICS and non-asthmatics. RESULTS: A total of 216 healthy control participants were compared with 211 children with asthma - 22% (n = 46) on low dose ICS therapy, 44% (n = 94) on high dose ICS and 34% (n = 71) not on any ICS. There was no difference in the incidence of fractures between children with asthma (24.6% n = 53) and healthy controls (24% n = 51) (χ2 = 0.132; P = 0.717). There were no differences in fracture incidence in the sub-groups of children with asthma (P = 0.695). CONCLUSION: ICS use was not associated with fracture risk in children with asthma.
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ItemLack of small colony variants of Staphylococcus aureus from lower respiratory tract specimens(WILEY, 2017-05)BACKGROUND: Small-colony variants (SCVs) of Staphylococcus aureus are associated with worse lung disease in children with Cystic Fibrosis (CF), exhibit a higher resistance to antibiotics and co-colonize more commonly with Pseudomonas aeruginosa compared to the normal phenotype. The prevalence of SCVs in lower airway specimens from children with CF is largely unknown. METHODS: Each visible morphotype of S. aureus was subcultured onto horse blood agar (HBA) to enable identification of SCVs. RESULTS: Sixty-one samples from 41 children (mean age 11.7 (SD 5.3) years) were identified with a positive S. aureus culture from lower respiratory tract specimens collected in 2014-2015. None of the differing morphotypes isolated were identified as S. aureus SCVs. CONCLUSION: In a center where anti staphylococcal prophylaxis is adopted, S. aureus SCVs were not isolated from the lower airways specimens in young children with CF indicating that acquisition of small colony variant S. aureus may not be a significant clinical problem in young children with CF.
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ItemVitamin D insufficiency in the first 6 months of infancy and challenge-proven IgE-mediated food allergy at 1 year of age: a case-cohort study(WILEY, 2017-08)BACKGROUND: Ecological evidence suggests vitamin D insufficiency (VDI) due to lower ambient ultraviolet radiation (UVR) exposure may be a risk factor for IgE-mediated food allergy. However, there are no studies relating directly measured VDI during early infancy to subsequent challenge-proven food allergy. OBJECTIVE: To prospectively investigate the association between VDI during infancy and challenge-proven food allergy at 1 year. METHODS: In a birth cohort (n = 1074), we used a case-cohort design to compare 25-hydroxyvitamin D3 (25(OH)D3 ) levels among infants with food allergy vs a random subcohort (n = 274). The primary exposures were VDI (25(OH)D3 <50 nM) at birth and 6 months of age. Ambient UVR and time in the sun were combined to estimate UVR exposure dose. IgE-mediated food allergy status at 1 year was determined by formal challenge. Binomial regression was used to examine associations between VDI, UVR exposure dose and food allergy and investigate potential confounding. RESULTS: Within the random subcohort, VDI was present in 45% (105/233) of newborns and 24% (55/227) of infants at 6 months. Food allergy prevalence at 1 year was 7.7% (61/786), and 6.5% (53/808) were egg-allergic. There was no evidence of an association between VDI at either birth (aRR 1.25, 95% CI 0.70-2.22) or 6 months (aRR 0.93, 95% CI 0.41-2.14) and food allergy at 1 year. CONCLUSIONS: There was no evidence that VDI during the first 6 months of infancy is a risk factor for food allergy at 1 year of age. These findings primarily relate to egg allergy, and larger studies are required.
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ItemThe association between higher maternal pre-pregnancy body mass index and increased birth weight, adiposity and inflammation in the newborn(WILEY, 2018-01)BACKGROUND: Excess adiposity and adiposity-related inflammation are known risk factors for cardiovascular disease in adults; however, little is known regarding the determinants of adiposity-related inflammation at birth. OBJECTIVES: The aim of this study was to investigate the association between maternal pre-pregnancy BMI and newborn adiposity and inflammation. METHODS: Paired maternal (28-week gestation) and infant (umbilical cord) blood samples were collected from a population-derived birth cohort (Barwon Infant Study, n = 1074). Data on maternal comorbidities and infant birth anthropomorphic measures were compiled, and infant aortic intima-media thickness was measured by trans-abdominal ultrasound. In a selected subgroup of term infants (n = 161), matched maternal and cord lipids, high-sensitivity C-reactive protein (hsCRP) and maternal soluble CD14 were measured. Analysis was completed by using pairwise correlation and linear regression. Because of their non-normal distribution, pathology blood measures were log transformed prior to analysis. RESULTS: Maternal pre-pregnancy BMI was positively associated with increased birth weight (mean difference 17.8 g per kg m-2 , 95% CI 6.6 to 28.9; p = 0.002), newborn mean skin-fold thickness (mean difference 0.1 mm per kg m-2 , 95% CI 0.0 to 0.1; p < 0.001) and cord blood hsCRP (mean difference of 4.2% increase in hsCRP per kg m-2 increase in pre-pregnancy BMI, 95% CI 0.6 to 7.7%, p = 0.02), but not cord blood soluble CD14. Inclusion of maternal hsCRP as a covariate attenuated the associations between pre-pregnancy BMI and both newborn skin-fold thickness and cord blood hsCRP. CONCLUSION: Higher maternal pre-pregnancy BMI is associated with increased newborn adiposity and inflammation. These associations may be partially mediated by maternal inflammation during pregnancy.
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ItemTelomere length and lung function in a population-based cohort of children and mid-life adults(WILEY, 2019-12)OBJECTIVE: Telomere length is associated with poorer lung health in older adults, possibly from cumulative risk factor exposure, but data are lacking in pediatric and population-based cohorts. We examined associations of telomere length with lung function in children and mid-life adults. METHODS: Data were drawn from a population-based cross-sectional study of 11 to 12 year-olds and mid-life adults. Lung function was assessed by spirometric FEV1 , FVC, FEV 1 /FVC ratio, and MMEF 25-75 . Telomere length was measured by quantitative polymerase chain reaction from blood and expressed as the amount of telomeric genomic DNA to the beta-globin gene (T/S ratio). Associations of telomere length with spirometric parameters were tested by linear and logistic regression models, adjusting for potential confounders of sex, age, body mass index, socioeconomic position, physical activity, inflammation, asthma, pubertal status, and smoking. RESULTS: Mean T/S ratio was 1.09 (n = 1206; SD 0.55) in children and 0.81 (n = 1343; SD 0.38) in adults. In adults, for every additional unit in T/S ratio, FEV 1 /FVC and MMEF 25-75 z-scores were higher (β 0.21 [95% confidence interval, CI; 0.06-0.36] and 0.23 [95% CI; 0.08-0.38], respectively), and the likelihood of being in the lowest quartile for FEV 1 /FVC and MMEF 25-75 z-scores was lower (odds ratios 0.59 [95% CI, 0.39-0.89] and 0.64 [95% CI, 0.41-0.99], respectively). No evidence of association was seen for adult FEV 1 or FVC, or any childhood spirometric index after adjustments. CONCLUSION: Shorter telomere length showed moderate associations with poorer airflow parameters, but not vital capacity (lung volume) in mid-life adults. However, there was no convincing evidence of associations in children.
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ItemNaive regulatory T cells in infancy: Associations with perinatal factors and development of food allergy(WILEY, 2019-09)BACKGROUND: In previous studies, deficits in regulatory T-cell (Treg) number and function at birth have been linked with subsequent allergic disease. However, longitudinal studies that account for relevant perinatal factors are required. The aim of this study was to investigate the relationship between perinatal factors, naïve Treg (nTreg) over the first postnatal year and development of food allergy. METHODS: In a birth cohort (n = 1074), the proportion of nTreg in the CD4+ T-cell compartment was measured by flow cytometry at birth (n = 463), 6 (n = 600) and 12 (n = 675) months. IgE-mediated food allergy was determined by food challenge at 1 year. Associations between perinatal factors (gestation, labour, sex, birth size), nTreg at each time point and food allergy at 1 year were examined by linear regression. RESULTS: A higher proportion of nTreg at birth, larger birth size and male sex was each associated with higher nTreg in infancy. Exposure to labour, as compared to delivery by prelabour Caesarean section, was associated with a transient decrease nTreg. Infants that developed food allergy had decreased nTreg at birth, and the labour-associated decrease in nTreg at birth was more evident among infants with subsequent food allergy. Mode of birth was not associated with risk of food allergy, and there was no evidence that nTreg at either 6 or 12 months were related to food allergy. CONCLUSION: The proportion of nTreg at birth is a major determinant of the proportion present throughout infancy, highlighting the importance of prenatal immune development. Exposure to the inflammatory stimulus of labour appears to reveal differences in immune function among infants at risk of food allergy.
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ItemMulti-centre ethics and research governance review can impede non-interventional clinical research(WILEY, 2019-06)BACKGROUND: The inter-jurisdictional National Mutual Acceptance (NMA) scheme for Human Research Ethics Committee (HREC) approvals of human research is designed to reduce the reported delays and costs of ethical review. Introduction of the NMA set forth an uncoupling of the ethics and governance review processes, permitting a single ethical review for multiple sites, while continuing separate governance review for each centre covering financial and operational aspects of the research project. AIM: To compare the time required to gain ethics and governance approvals in Australia for a non-interventional investigator-led study from December 2015 to approval times for an earlier pre-NMA study utilising a similar study design and study sites and evaluate the effect that the NMA has had on total approval time for non-interventional multi-centre projects. METHODS: We recorded the time taken to obtain ethics and governance approval at 16 sites for our nationwide low-risk non-interventional study looking at the prevalence and aetiology of non-tuberculous mycobacterial infection in people with cystic fibrosis in Australia. RESULTS: Applications were submitted to three hospitals and one university HREC to conduct our study at 16 hospital sites, HREC approval took from 16 to 79 days (median 28). Subsequent site-specific governance approval at 15 hospital sites took 23-225 days (median 83). The entire process of gaining ethical and governance approval to conduct the study at 16 sites took 24 months at an estimated cost of AU$56000 (US$ 42 000). CONCLUSION: Lengthy governance approval processes negate benefits gained from centralised ethics review under the NMA.
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