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The aim of this dissertation is to explore experiences and describe outcomes of healthcare transition in cystic fibrosis (CF). Chapter one introduces the central concepts of this dissertation, describes current gaps in the literature on healthcare transition in cystic fibrosis and introduces the Expanded Socioecological Model for Adolescent and Young Adult Readiness for Transition (Expanded SMART), which guides the three studies of this dissertation. Chapter two is a qualitative meta-synthesis of 63 studies describing adolescent, young adult, and parent experiences of healthcare transition across a variety of chronic conditions. Chapter three is a qualitative study exploring perceptions of CF management responsibility among a sample of 15 adolescent with CF and parent dyads. Chapter four uses national Cystic Fibrosis Foundation Patient Registry data to examine healthcare transition outcomes associated with participation in the transition preparation program CF R.I.S.E. Chapter five synthesizes the three studies of this dissertation and provides recommendations for practice, policy, and research.

Introduction: Gene therapy is currently being developed for people with cystic fibrosis (CF), a life-threatening condition for which there is no cure. The UK CF Gene Therapy Consortium are preparing for a multi-dose gene therapy trial of sufficient duration that clinical benefit may be seen. Aims: The current study aimed to explore the expectations and beliefs of cystic fibrosis (CF) patients involved in the preparatory phase of the gene therapy trial (the Run-in study), from which participants will be selected for the multi-dose actual gene therapy trial. Method: Twelve participants (six with mild and six with moderate CF) were interviewed using a semi-structured interview. Interviews were recorded, transcribed verbatim and then analysed using a Constructivist Grounded Theory approach. Results: Since entering the Run-in study, half of the patients had increased their expectations of gene therapy being an effective future treatment. Most of the participants hoped to derive clinical benefit from the trial itself though half were unsure of what to expect. Whilst half of the participants expressed the hope of a future cure for CF, the remainder saw gene therapy only in terms of an improved treatment. Participants used several strategies to manage their expectations including not thinking too far ahead and trusting the research team. Discussion: The findings indicate that participants in the Run-in trial are generally eager to be involved in the gene therapy trial and have developed a strong sense of trust in the research team conducting the trials. The levels of optimism expressed for personal benefit from trial were higher than those from earlier studies. Some of the positive expectations were unlikely to be met by the gene therapy trial and participants risk disappointment. However other patients participated with apparently realistic expectations and it seems likely that some patients would have participated even without prospect for personal benefit. Possible areas of psychological support are discussed e.g. a standard clinical interview for all those not accepted for the gene therapy trial; screening for anxiety pre-, during and post-participation.

The grief experienced by mothers and fathers when their child is diagnosed with a life threatening chronic-illness was investigated in order to validate the presence of grief in these parents and look at the factors that influence it. More specifically, I was interested in whether the grief experience differed for mothers and fathers and the impact that perceptions and coping have on both these gender differences in grief and on grief in general. The particular population investigated in this study were parents of children with Cystic Fibrosis. Participants were recruited through questionnaires randomly sent out by the National Cystic Fibrosis Association. In all, 37 mothers and 15 fathers took part. Results not only confirmed presence of grief in these parents but also indicated that this grief differs for mothers and fathers, with mothers reporting significantly higher levels of physical distress. In line with the literature no gender differences were found in regards to perception of impact parents felt their child's chronic-illness had had on their lives. Contrary to what was expected, however, no differences were found amongst the coping strategies used by mothers and fathers. In regards to the question of which factors have the greatest impact on the grief experienced by mothers and fathers combined, the coping strategy of self-blame was found to be the most important, followed closely by negative perceptions. The significance of these findings and their implications for parents and the people who work with them was discussed.

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Background: Lung clearance index (LCI), obtained by multiple breath washout testing (MBW), is a sensitive measure of lung disease in infants. It has been identified as a particularly suitable endpoint for clinical trials in cystic fibrosis (CF), but has potential applications in many other conditions. However, MBW in infants presents a number of technical challenges. Conventional MBW is based on simultaneous measurement of flow and gas. These two signals are then aligned and combined to derive expired gas volumes and measures of ventilation inhomogeneity: this process becomes increasingly vulnerable to errors in gas signal alignment at rapid respiratory rates. At present, no existing system for infant MBW meets all the criteria set out in international guidelines, and there is no simple method of assessing lung function outside research laboratories in this population. This thesis describes an alternative method of performing MBW in infants. In this method, expired gas is collected and analysed to derive functional residual capacity (FRC) and LCI. There is no need to simultaneously measure flow, and therefore no need for the complicated step of integrating flow and gas signals. Dead space is also significantly reduced by removing the flowmeter. Methods: In the first phase of testing, an existing lung model was modified to generate realistic infant breathing parameters with high accuracy. The prototype system was modified to improve accuracy and subsequently tested at FRC of 100-250mls with respiratory rates of 20-60min-1. In the second phase, testing proceeded to an in vivo pilot study of the novel method in children with cystic fibrosis and healthy controls. Practical applicability of the system was determined by the number of successful duplicate tests, and within-subject repeatability. Comparison was made with LCI measurements obtained using a respiratory mass spectrometer, currently considered the gold standard for infant LCI. Results: In a total of 103 tests performed in the lung model, overall mean error (standard deviation) of FRC measurement was -1.0(3.3)%, with 90% of tests falling within +/-5%. 13 patients were excluded from the clinical study due to being unsedated or inadequately sedated and therefore failing to tolerate the test. A total of 25 patients (7 children with CF, 18 healthy control children) were deemed to be adequately sedated at the start of the test, of these 20 patients (7 with CF) successfully underwent duplicate testing (80% success rate). Mean FRC for healthy controls was 19.5ml/kg, and mean LCI 6.45. For children with CF, mean FRC was 21.8ml/kg and mean LCI 6.98. Mean within-subject coefficient of variation for FRC was 7.18% and for LCI 5.94%. Of 4 infants assessed with both the novel method and the respiratory mass spectrometer, there was good correlation in FRC measurement (mean difference -8.1%). Comparison of LCI with the mass spectrometer was affected by technical difficulties with the test; in those patients who underwent technically adequate tests with both methods, mean difference in LCI between the two methods was 1.65%. Discussion: FRC measurement using the novel method has superior accuracy in vitro than previously described systems. Data from the pilot study suggest that this is a feasible and reproducible method of performing LCI in infants and young children, as long as they are adequately sedated. Results in both children with CF and controls fall within the expected range, and well within accuracy limits set by international guidelines. However, the system and testing protocol could be further improved to reduce the number of technically inadequate tests having to be excluded. This could provide a more accessible alternative to previously described systems for infant MBW.

abstract: Introduction: Cystic fibrosis (CF) is the most common life-shortening autosomal recessive genetic disease affecting Caucasians. The disease is characterized by a dysfunctional cystic fibrosis transmembrane regulator (CFTR) protein and aberrant mucus accumulation that subsequently alters the physicochemical environment in numerous organ systems. These mucosal perturbations have been associated with inflammation and microbial dysbiosis, most notably in the lungs and gastrointestinal (GI) tract. Genistein, a soy isoflavone and dietary polyphenol, has been shown to modulate CFTR function in cell cultures and murine models, as well exert sex-dependent improvement of survival rates in a CF mouse model. However, it is unknown whether dietary genistein affects gut microbiome diversity and community structure in cystic fibrosis. This study sought to examine associations between dietary genistein treatment and gut microbiome diversity and community structure in a murine model of CF. Methods: Twenty-four male and female mice homozygous for the DF508 CFTR gene mutation were maintained on one of three diet regimens for a 45-day period (n=11, standard chow; n=7, Colyte-treated water and standard chow; n=6, 600 mg dietary genistein per kg body weight). One fecal pellet was collected per mouse post-treatment, and microbial genomic DNA was extracted from the fecal samples, quantified, amplified, and sequenced on the Illumina MiSeq platform. QIIME 2 was used to conduct alpha- and beta-diversity analyses on all samples. Results: Measures of alpha-diversity were significantly decreased in the dietary genistein group as compared to either standard chow or Colyte groups. Measures of beta-diversity showed that community structure differed significantly between dietary treatment groups; these differences were further illustrated by distinct clustering of taxa as shown by principal coordinates analysis plots. Conclusion: This 3-arm parallel experimental study showed that dietary genistein treatment was associated with decreased microbial diversity and differences in microbial community structure in DF508 mice. / Dissertation/Thesis / Masters Thesis Nutrition 2019

Doctor of Philosophy / Cystic fibrosis (CF) is the most common inherited lethal disorder among Caucasian populations. Chronic pulmonary infections, particularly from Pseudomonas aeruginosa, are the major determinant of the morbidity and mortality of people with CF. It is generally accepted that people with CF acquire this pathogen independently from their surrounding environment, and that individual CF patients carry unique strains different from others. The spread of this pathogen from patient to patient is thought to be rare and occurs particularly among closely contacted cases such as CF siblings. However, over the past decade, there have been several reports of an emergence of clonal P. aeruginosa strains commonly found infecting a number of CF patients. One such report is from the CF paediatric clinic at the Royal Children’s Hospital in Melbourne in which more than half of the patients were infected with a single strain or clone, subsequently called Australian epidemic strain 1 or AES-1. A preliminary survey showed that AES-1 had spread extensively along the Australian eastern seaboard among CF patients attending other CF centres in Melbourne, Sydney and Brisbane, including adult patients at the Royal Prince Alfred Hospital (RPAH), Sydney. Another clonal strain, subsequently called AES-2, was identified in both CF adults and children at the Prince Charles Hospital and the Royal Children’s Hospital, in Brisbane. The total extent of prevalence of the AES-1 and AES-2 strains at the RPAH as well as the clinical status of patients who carried these strains was unknown. Moreover, the pathogenicity of these two clonal strains had not been investigated. The studies presented in this thesis investigated the prevalence of these clonal strains among CF patients attending the adult CF clinic at RPAH, Sydney by using pulsed-field gel electrophoresis. Overall, 50% of 112 patients with P. aeruginosa were found to be infected with clonal strains. The AES-1 and AES-2 strains were identified in 38% and 5% of the patients respectively. Two new clonal strains, called Sydney-1 and Sydney-2, were also identified. Patients with clonal strains had a significant increase in their number of exacerbations and hospitalisation days, and tended to have lower pulmonary functions when compared to patients infected with non-clonal strains. By using a variety of bioassays to examine the pathogenicity of the clonal and non-clonal strains, it was found that both AES-1 and AES-2 produced more virulence factors and were more resistant to antibiotics when compared to the non-clonal strains. AES-1 and AES-2 were associated with increased production of proteases, including elastase, alkaline protease and protease IV. Overall the results presented in this thesis suggest that there may be a link between virulence and transmissibility of this pathogen. The studies presented in this thesis also compared the biofilm forming capacities of the AES-1 and non-clonal isolates. AES-1 was shown to have greater biofilm-forming capacity than the non-clonal strains, when they were grown on a glass surface, suggesting a possible association between clonality and biofilm formation. A model for the study of bacteria grown in conditions similar to CF sputum was also developed. P. aeruginosa grown in this model was found to develop into clumps which may be comparable to the biofilm structure in the CF lung. This model was shown to be beneficial for transcriptomic and proteomic studies which are underway within the research group. AES-1 was also found to have phenotypic variations between isolates. By applying the amplified fragment length polymorphism technique, more subtypes of this clone were revealed. However, these detected subtypes did not correlate with the different phenotypes, suggesting minor mutations such as single point polymorphisms may be responsible for the phenotypic diversity within the clone. The final part of this thesis was devoted to examining the safety of a novel CF treatment: hypertonic saline (HS) inhalation. HS was shown to increase airway mucociliary clearance, while increased osmolarity associated with the use of HS was also shown to have an inhibitory effect on the formation of biofilms. Findings in this study proved that there was no evidence of strain selection in patients who received the long-term treatment with HS. The study also demonstrated that AES-1 was significantly more persistent in the CF lung than the non-clonal strains. The present thesis not only defines the clonal strains of P. aeruginosa and their implications for infected patients, but also provides a general understanding into the pathogenesis of both clonal and non-clonal strains infecting CF lungs.