Papers by Claire Wainwright
The effect of gastrostomy feeding on markers of nutritional status in children with cystic fibrosis
Australian cystic fibrosis BAL study interim analysis
Pediatric Pulmonology, 2005
Viability of pseudomonas aeruginosa (Pa) in cough aerosols from adult cystic fibrosis (CF) patients
Respirology, 2013
Widespread prevalence of related Pseudomonas aeruginosa strains within Australian cystic fibrosis centres
Loss of virulence expression of pseudomonas aeruginosa from cystic fibrosis lung infection over time
The Cochrane library, Sep 17, 2018
Analysis 1.9. Comparison 1 BAL-directed therapy versus standard therapy, Outcome 9 Sensitivity an... more Analysis 1.9. Comparison 1 BAL-directed therapy versus standard therapy, Outcome 9 Sensitivity analysis -Prevalence of P aeruginosa in BAL at 5 years age (40% vs 5%
British Journal of Nutrition, Feb 1, 2006
The importance of nutritional intervention for children with cystic fibrosis (CF) is well recogni... more The importance of nutritional intervention for children with cystic fibrosis (CF) is well recognised. It would be expected that the increase in knowledge over the past decade would be reflected in improvements in nutritional status for the CF paediatric population. The aim of the present paper was to evaluate the nutritional status of children with CF, cross-sectionally and longitudinally. Body cell mass adjusted for gender and size (BCM/Ht p ) was measured in sixty-four children with CF to represent nutritional status and expressed as a Z-score. The cross-sectional results showed a mean BCM/Ht p Z-score of 0•54 (SD 1•21), with males having a slightly higher Z-score than females but with a larger variation. At the initial measurement, only one female and one male were considered sub-optimally nourished. The longitudinal analysis after 2 years showed that the mean population had a significantly decreased BCM/Ht p Z-score; however, when each gender was analysed separately, this decrease was significant only in the males. At the final measurement, only two females and three males were considered sub-optimally nourished. It is evident from our results that children with CF are well nourished, with only a small percentage considered malnourished. It appears that nutritional status decreases with age, with this decline being more evident in males. These results signify that although children with CF are better nourished with current treatment support, intervention needs to continue throughout a CF patient's life to counteract the changes that occur with age.
Viability of pseudomonas aeruginosa (Pa) in cough aerosols from adult cystic fibrosis (CF) patients [Conference Abstract]
Respirology, 2013
Face masks and cough etiquette reduce cough-generated bioaerosols containing pseudomonas aeruginosa in patients with cystic fibrosis
Pediatric Pulmonology, 2016
The 30th Annual North American Cystic Fibrosis Conference, Orange County Convention Center, Orlan... more The 30th Annual North American Cystic Fibrosis Conference, Orange County Convention Center, Orlando, Florida, October 27–29
Pediatric Pulmonology, 2012
Small molecules that correct F508del CFTR folding defects and enhance surface localization compri... more Small molecules that correct F508del CFTR folding defects and enhance surface localization comprise an important therapeutic strategy for cystic fibrosis lung disease. However, compounds that correct the F508del mutation and confer ≥ 20% wild type activity in primary airway epithelial cells have not been readily identified. The inability to obtain robust and therapeutically relevant levels of F508del CFTR correction by a single molecule may in some cases reflect diminished pools of Band B substrate (i.e. from blunted F508del synthesis and/or increased degradation). In the present experiments, we observed markedly diminished steady state levels of F508del (Band B) compared to WT CFTR protein in HeLa and bronchial epithelial cells, even when massive levels of F508del mRNA were overexpressed. In human primary airway cells, the paucity of Band B F508del was even more pronounced (in some cases below levels of detection) although F508del and WT mRNA were comparable. These results suggest an approach to improving F508del CFTR maturation that augments the pool of mutant CFTR suitable for folding repair. In this regard, we show that the proteosome inhibitor epoxomycin induces a large increase in F508del Band B, but (as expected) does not enhance CFTR rescue by C18 (a VX-809 analog), indicating accumulation of an irreversibly misfolded F508del intermediate. In an effort to identify novel compounds that augment "repairable" F508del protein, we developed a rapid throughput compound library screen. Cell-based imaging was used to semi-quantitatively estimate distribution of F508del CFTR by analysis of two-dimensional images. Cells were permeabilized, labeled with antibodies that recognize internal CFTR epitopes, and monitored using Evotec Opera™, an automated confocal microscopy system. We evaluated ~2000 known bioactive compounds from the NIH Roadmap Molecular Libraries Small Molecule Repository. A total of 25 primary hits were identified and one compound, 865022, was found to 1) increase CFTR levels in a dose dependent fashion, 2) augment F508del CFTR Band B compared to control, 3) increase cAMP dependent anion efflux in HeLa cells expressing I539T/F508del CFTR, and 4) stimulate CFTR dependent short circuit current in human bronchial epithelial monolayers. Co-treatment with 865022 and C18 synergistically enhanced F508del CFTR dependent ion transport following activation by forskolin or genistein. These results suggest an approach to increase efficiency of pharmacologic intervention by enlarging the corrector-restorable pool of F508del CFTR.
During the chronic lung infection of patients with cystic fibrosis (CF), Pseudomonas aeruginosa c... more During the chronic lung infection of patients with cystic fibrosis (CF), Pseudomonas aeruginosa can survive for long periods due to adaptive evolution mediated by genetic variation. Hypermutability is considered to play an important role in this adaptive evolution and it has been demonstrated that mutator populations are amplified in the CF lung by hitchhiking with adaptive mutations. Two of the genes that are frequently mutated in isolates from chronic infection are mucA and lasR. Loss-of-function mutations in these genes determine the phenotypic switch to mucoidy and loss of quorum sensing, which are considered hallmarks of chronic virulence. The aims of our study were to investigate (1) the genetic background of the P. aeruginosa subpopulations with non-mutator, weak or strong mutator phenotype and their dynamics during the chronic lung infection, and (2) the time sequence in which the hypermutable, mucoid and quorum-sensing-negative phenotypes emerge during chronic lung infection. For these purposes the sequences of mutS, mutL, uvrD, mutT, mutY and mutM anti-mutator genes as well as of mucA and lasR were analysed in 70 sequential P. aeruginosa isolates obtained from the respiratory secretions of 10 CF patients (one to three isolates per time point). Analysis of the genetic background of the mutator phenotype showed that mutS was the most commonly affected gene followed by mutL in isolates with strong mutator phenotype. The mutT, mutY, mutM genes were affected in isolates with low fold-changes in the mutation frequencies compared to the reference strain PAO1. Isolates with non-mutator, weak or strong mutator phenotype were represented at all time points showing co-existence of these subpopulations, which suggests parallel evolution of the various mutators in the different focal niches of infection in the CF lung. Mutations in mucA and lasR occurred earlier than mutations in the anti-mutator genes, showing that hypermutability is not a prerequisite for the acquisition of mucoidy and loss of quorum sensing, considered hallmarks of chronic virulence. Significantly higher mutation rates and MICs of ceftazidime, meropenem and ciprofloxacin were found for isolates collected late (more than 10 years) during the chronic lung infection compared to isolates collected earlier, which suggests an amplification of the mutator subpopulation by hitchhiking with development of antibiotic resistance. Similar evolutionary pathways concordant with adaptive radiation were observed in different clonal lineages of P. aeruginosa from CF patients.
Survival statistics, estimated using data from national cystic fibrosis (CF) registries, inform t... more Survival statistics, estimated using data from national cystic fibrosis (CF) registries, inform the CF community and monitor disease progression. This study aimed to estimate survival among people with CF in Australia and to identify factors associated with survival. This population-based cohort study used prospectively collected data from 23 Australian CF centres participating in the Australian CF Data Registry (ACFDR) from 2005-2020. Period survival analysis was used to calculate median age of survival estimates for each 5-year window from 2005-2009 until 2016-2020. The overall median survival was estimated using the Kaplan-Meier method. Between 2005-2020 the ACFDR followed 4,601 people with CF, noting 516 (11.2%) deaths including 195 following lung transplantation. Out of the total sample, more than half (52.5%) were male and 395 (8.6%) had undergone lung transplantation. Two thirds of people with CF (66.1%) were diagnosed before six weeks of age or by newborn/prenatal screening....
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Environmental origins of Pseudomanos aeruginosa in children with cystic fibrosis
Airborne bioaerosols are becoming increasingly recognized as a potential route of transmission fo... more Airborne bioaerosols are becoming increasingly recognized as a potential route of transmission for the spread of bacterial and viral respiratory tract infections.
The effect of gastrostomy feeding on markers of nutritional status in children with cystic fibrosis
The Lancet Respiratory Medicine, 2021
VX14-661-110 study group (2021). Long-term safety and efficacy of tezacaftor-ivacaftor in individ... more VX14-661-110 study group (2021). Long-term safety and efficacy of tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an openlabel extension study. The Lancet Respiratory Medicine.
Thorax, 2021
Structural and functional defects within the lungs of children with cystic fibrosis (CF) are dete... more Structural and functional defects within the lungs of children with cystic fibrosis (CF) are detectable soon after birth and progress throughout preschool years often without overt clinical signs or symptoms. By school age, most children have structural changes such as bronchiectasis or gas trapping/hypoperfusion and lung function abnormalities that persist into later life. Despite improved survival, gains in forced expiratory volume in one second (FEV1) achieved across successive birth cohorts during childhood have plateaued, and rates of FEV1decline in adolescence and adulthood have not slowed. This suggests that interventions aimed at preventing lung disease should be targeted to mild disease and commence in early life. Spirometry-based classifications of ‘normal’ (FEV1≥90% predicted) and ‘mild lung disease’ (FEV170%–89% predicted) are inappropriate, given the failure of spirometry to detect significant structural or functional abnormalities shown by more sensitive imaging and lu...
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Papers by Claire Wainwright