M. Tech. Pharmaceutical Sciences / Bacteria are present in natural environments and can develop into biofilms. Mucus-like extracellular matrix produced by biofilms provides protection to biofilm formers by inhibiting antimicrobial penetration and de-activating antimicrobial molecules, while allowing strong attachment onto surfaces. Biofilm development is associated with otitis media and cystic fibrosis. In this study, selected biofilm-formers implicated in otitis media and cystic fibrosis, Pseudomonas aeruginosa and Moraxella catarrhalis, were used to evaluate the effect of combinations of mucoactive substances and antibiotics against their biofilms. Microtiter-plate assay and optical density measurements were used to evaluate antimicrobial and antibiofilm activities. Confocal scanning laser microscopy was used to visualise the effect of selected treatments against biofilms.

Epithelial sodium channels (ENaC) are located throughout the epithelial lining of the respiratory tract and play a crucial role in ion and fluid homeostasis of the lungs. Increasing ENaC activity through stimulation of β₂-adrenergic receptors has been shown to increase sodium and fluid reabsorption from the airspace to the interstitial space. In cystic fibrosis lung disease there is a hyperabsorption of sodium through ENaC which results in dehydration of the airway surface liquid. Previous work has identified a common functional genetic variant of SCNN1A, the gene encoding the ENaC alpha-subunit. This variant manifests as an alanine to threonine substitution at amino acid 663 (T663), with the T663 variant resulting in a more active channel due to a greater number of channels in the membrane. We sought to determine the influence of the T663 variant on exhaled ions, pulmonary function, and the diffusing capacity of the lungs in healthy subjects as well as in patients with cystic fibrosis. We used exercise, which can increase endogenous epinephrine by up to 1000 fold at peak exercise, and albuterol, an exogenous β₂-adrenergic agonist, to stimulate ENaC activity. In healthy individuals we hypothesized that the T663 variant would be beneficial for lung function due to a greater fluid removal, which could improve gas transfer in a healthy lung. In the CF patients we predicted that the T663 variant would be detrimental to lung function due to an exaggerated absorption of sodium and drying/thickening of the mucus layer in the airways. Measurements of exhaled sodium were made in the healthy subjects at baseline, 30, 60, and 90 minutes post-albuterol administration. Subjects with the A663 variant had higher baseline exhaled sodium and a significant decrease in exhaled sodium by 90 minutes after β₂-adrenergic stimulation with albuterol, suggesting a removal of sodium from the airways. No changes in exhaled sodium were seen in the T663 variant in response to albuterol. In response to exercise the A663 variant had a greater increase in the diffusing capacity of the lung than the T663 variant, possibly due to differences in alveolar sodium and therefore fluid handling. Taken together, these results suggest that healthy humans with the A663 variant can increase ENaC activity in response to β₂-adrenergic stimulation, whereas individuals with the T663 variant have a diminished capacity for increasing ENaC activity in response to β₂-adrenergic stimulation. In CF patients, the T663 variant had significantly lower baseline pulmonary function, weight, and body mass index. In response to exercise, patients with the T663 variant had a greater increase in the diffusing capacity of the lungs, possibly due to purinergic inhibition of ENaC. Finally, we recruited additional CF patients to confirm our pulmonary function findings. Individuals with at least one allele resulting in the T663 variant had significantly lower body mass index, and tended to have lower exhaled chloride and pulmonary function. These results suggest greater dehydration of the lung in CF patients with the T663 variant. Overall, these results may suggest that the T663 variant modifies disease severity in CF, although more work is certainly warranted to confirm this result.

Introduction : La fibrose kystique (FK) est une maladie génétique mortelle qui touche principalement les poumons et l’appareil digestif. Elle est causée par des mutations sur le gène codant la protéine du CFTR, un canal chlore exprimé à la surface des organes à sécrétions exocrines. Les fonctions principales du CFTR sont les suivantes: 1) la régulation de l’homéostasie ionique des sécrétions; 2) le maintien de la fluidité des sécrétions et; 3) le transport du glutathion. Le dysfonctionnement de la protéine du CFTR rend les sécrétions visqueuses et épaisses, avec des phénomènes obstructifs qui sont responsables de l’apparition de fibrose au sein des divers organes. Dans le poumon, l’accumulation du mucus épais rend difficile l’élimination des bactéries inhalées, ces dernières établissent alors des cycles d’infection qui endommagent les tissus pulmonaires à travers des processus inflammatoires. Dans le tube digestif, le mucus épais entrave l’absorption d’une quantité suffisante d’éléments nutritifs incluant les principaux antioxydants. L’infection et l’inflammation des poumons favorisent l’apparition d’un stress oxydant qui détruit davantage le tissu pulmonaire. Le déficit en glutathion, probablement lié au dysfonctionnement de la proteine du CFTR, et la malabsorption des antioxydants favorisent l’augmentation du stress oxydant. Une augmentation du stress oxydant a été démontrée au cours du diabète et les produits dérivés du stress oxydant ont été mis en évidence dans la pathogenèse des complications associées au diabète. Une augmentation du stress oxydant a également été montrée durant la FK, mais sans pour autant expliquer la survenue du diabète secondaire à la FK dont la prévalence augmente sans cesse. Objectifs : Notre étude consiste à évaluer l’impact du stress oxydant dans les anomalies du métabolisme du glucose durant la FK, et à étudier son rôle dans les mécanismes de sécrétion d’insuline induite par le glucose. Pour ce faire, nous avons déterminé l’impact de la peroxydation lipidique sur la tolérance au glucose et la défense antioxydante globale, in vivo, chez des patients FK présentant une altération du métabolisme du glucose. De plus, nous avons évalué le rôle du stress oxydatif sur la synthèse et la sécrétion d’insuline, in vitro, dans les cellules pancréatiques βTC-tet. Résultats : Dans l’étude in vivo, nous avons démontré que l’intolérance au glucose et le diabète étaient associés à une augmentation de la peroxydation lipidique, traduite par la hausse des niveaux sanguins de 4-hydroxynonenal lié aux protéines (HNE-P). La défense antioxydante évaluée par la mesure du glutathion sanguin démontre que les niveaux de glutathion oxydé restent également élevés avec l’intolérance au glucose. Dans l’étude in vitro, nos résultats ont mis en évidence que l’exposition de la cellule βTC-tet au stress oxydant: 1) induit un processus de peroxydation lipidique; 2) augmente la sécrétion basale d’insuline; 3) diminue la réponse de la sécrétion d’insuline induite par le glucose; et 4) n’affecte que légèrement la synthèse de novo de l’insuline. Nous avons aussi démontré que les cellules pancréatiques βTC-tet résistaient au stress oxydant en augmentant leur synthèse en glutathion tandis que la présence d’un antioxydant exogène pouvait restaurer la fonction sécrétoire de ces cellules. Conclusion : Le stress oxydant affecte le fonctionnement de la cellule pancréatique β de plusieurs manières : 1) il inhibe le métabolisme du glucose dont les dérivés sont nécessaires à la sécrétion d’insuline; 2) il active la voie de signalisation impliquant les gènes pro-inflammatoires et; 3) il affecte l’intégrité membranaire en induisant le processus de peroxydation lipidique. / Introduction: Cystic fibrosis (CF) is the most prevalent lethal genetic disorder affecting mostly lungs and the gastro-intestinal tract. CF is caused by mutations in the gene encoding the CFTR protein, a chloride channel expressed in organs with exocrine secretions. The main functions of the CFTR channel are the following: 1) regulation of electrolyte composition of secretions; 2) maintenance of fluid secretions and; 3) transport of glutathione. The CFTR protein dysfunction leads to thick and viscous secretions with obstructive phenomena responsible for fibrosis occurence in various organs. In the lungs, accumulation of the thick mucus reduces their capacity to eliminate inhaled bacteria responsible for repeated infections and pulmonary tissue damage through inflammatory processes. In the gastro-intestinal tract, the thicknened micus leads to nutritive elements and the major antioxidants malabsorption. Increased oxidative stress has been associated with the onset of diabetes and oxidative stress by-products have been involved in the pathogenesis of diabetic complications. Increased oxidative stress has also been shown in CF but the relationship between oxidative stress and the occurrence of CF-related diabetes (CFRD) remains unclear. Objectives: Our study aims to investigate the role of oxidative stress in the impaired glucose metabolism in CF patients and its relation with the altered glucose-stimulated insulin secretion process. We first determined the impact of lipid peroxidation on glucose tolerance and the antioxidant status in CF patients with altered glucose tolerance. Secondly, we evaluated the role of oxidative stress on insulin synthesis and secretion in the murine pancreatic β-cell line βTC-tet. Results: In CF patients, we demonstrated that conditions of glucose intolerance and diabetes are associated with increased lipid peroxidation as seen with increased blood levels of 4-hydroxynonenal bound to proteins (HNE-P). The antioxidant status evaluated with blood levels of glutathione showed a strong correlation between levels of oxidized glutathione and glucose intolerance. Acute exposure of βTC-tet to oxidative stress led to: 1) increased lipid peroxidation marker levels; 2) increased insulin release in basal conditions; 3) altered glucose-stimulated insulin secretion process and; 4) no effect on the insulin synthessis pathway. We also demonstrated that pancreatic βTC-tet cells can fight against oxidative stress by upregulating their glutathione synthesis whereas the presence of an exogenous antioxidant can restore their secretory function. Conclusion: Oxidative stress can induce β-cell dysfunction through many pathways: 1) it inhibits the glucose metabolism and its by-products which are required for insulin secretion, 2) it activates the signalling pathway involving the pro-inflammatory genes and; 3) it damages the cell structure by inducting the lipid peroxidation process.

Cystic fibrosis is caused primarily by deletion of Phe508. An exciting discovery was that CFTR’s sister protein, the P-glycoprotein (P-gp) containing the equivalent mutation (ΔY490), could be repaired by a drug-rescue approach. Drug substrates showed specificity, and their mechanism involves direct binding to the transmembrane domains (TMDs) since arginine suppressor mutations were identified in TMDs that mimicked drug-rescue to promote maturation. We tested the possibility of rescuing CFTR processing mutants with a drug-rescue approach. 1) Arginine mutagenesis was performed on TM6, 8, and 12. 2) Correctors were tested for specificity. 3) Truncation mutants were used to map the VX-809 rescue site. Correctors 5a, 5c, and VX-809 were specific for CFTR. VX-809 appeared to specifically rescue CFTR by stabilizing TMD1. Therefore, the TMDs are potential targets to rescue CFTR. Rescue of P-gp and CFTR appeared to occur by different mechanisms since no arginine suppressor mutations were identified in CFTR.

Cystic fibrosis is caused primarily by deletion of Phe508. An exciting discovery was that CFTR’s sister protein, the P-glycoprotein (P-gp) containing the equivalent mutation (ΔY490), could be repaired by a drug-rescue approach. Drug substrates showed specificity, and their mechanism involves direct binding to the transmembrane domains (TMDs) since arginine suppressor mutations were identified in TMDs that mimicked drug-rescue to promote maturation. We tested the possibility of rescuing CFTR processing mutants with a drug-rescue approach. 1) Arginine mutagenesis was performed on TM6, 8, and 12. 2) Correctors were tested for specificity. 3) Truncation mutants were used to map the VX-809 rescue site. Correctors 5a, 5c, and VX-809 were specific for CFTR. VX-809 appeared to specifically rescue CFTR by stabilizing TMD1. Therefore, the TMDs are potential targets to rescue CFTR. Rescue of P-gp and CFTR appeared to occur by different mechanisms since no arginine suppressor mutations were identified in CFTR.

Burkholderia cepacia complex (Bcc) species are opportunistic pathogens in patients with cystic fibrosis (CF), which are able to cause lethal infections. The Bcc are inherently resistant to most classes of antibiotics, which makes successful treatment problematic. Lipid A (also known as endotoxin), the hydrophobic anchor of lipopolysaccaride (LPS), is the bio-active component of LPS. One of several unique characteristics of the lipid A of the Bcc, is the permanent attachment of 4-amino-4-deoxy-L-arabinose (L-Ara4N) to the lipid A molecule. Also, the genes involved in L-Ara4N biosynthesis are necessary for viability in B. cenocepacia. Here we present research on lipid A biosynthesis, modi cation, and transport in the Bcc and highlight promising antimicrobial targets. The synthetic antibiotic CHIR-090 is an inhibitor of LpxC, an enzyme involved in the lipid A biosynthetic pathway. I investigated the activity of CHIR-090 against the Bcc and found that sensitivity to this antibiotic was both species- and strain-specific. CHIR-090 displayed MICs between 0.1 and 12.5 μg/ml against a panel of B. multivorans, the most prevalent Burkholderia species in CF. The species- and strain-specific sensitivity towards CHIR-090 was further explored and a strong correlation was found between the presence of a unique open reading frame, named LpxC2, in resistant species. To address the problem of multiple drug-resistance of the Bcc, we investigated the activity of the pyridoxal 50-phosphate (PLP)-dependent enzyme inhibitor cycloserine (CS) against the Bcc. CS is used as a second line of defense against M. tuberculosis. The activity of the D-enantiomer of CS (DCS) against the Bcc was tested and displayed MICs between 2 and 128 μg/ml and acted bactericidal towards the Bcc. Additionally, DCS inhibition of recombinant ArnB from B. cenocepacia J2315, a PLP-dependent enzyme necessary for viability in the Bcc, was studied. ArnB was inhibited reversibly by DCS. ArnB was further explored as a promising drug-target in the Bcc, but only CS has been identified as an inhibitor so far. In this thesis it was attempted to find the reason why is L-Ara4N modification of lipid A necessary for viability in B. cenocepacia. Therefore, two proteins were characterised, which are involved in lipid A transport: LptA, the periplasmic lipid A binding protein, and LptB, the cytoplasmic ATP-ase. LptA was found to be able to bind both modified and unmodified lipid A in vitro and therefore is not L-Ara4N specific. Furthermore, LptA could bind deep-rough-, rough-, and smooth- LPS, similar to that described for Escherichia coli LptA. The kinetic parameters of LptB were determined in vitro (kcat = 5.71 min-1 and KM = 0.88 mM), and were comparable to E. coli LptB. The ATP-ase activity of LptB was not influenced by the presence of any forms of LPS (modified or non-modified). Therefore, we concluded that both B. cenocepacia J2315 LptA and LptB are not L-Ara4N specific.

Azithromycin improves clinical outcomes in patients with cystic fibrosis (CF), specifically in patients infected with Pseudomonas aeruginosa. Azithromycin shifts macrophage programming away from a pro-inflammatory classical (M1) phenotype, and towards an anti-inflammatory alternative (M2) phenotype; however, little is known about this mechanism, nor of its impact upon immune response to pulmonary infection. We set out to determine the mechanism by which azithromycin is able to alter macrophage phenotype, and assess the effect of azithromycin induced macrophage polarization on inflammation during pulmonary infections. Utilizing macrophage cell culture, we found that azithromycin increased IKKβ, a signaling molecule in the NFκB pathway, which likely is altering macrophage programming. Using a Pseudomonas infection model in mice that lack physiologic alternative macrophage activation, we showed that azithromycin’s ability to alter macrophage function and decrease lung damage was independent of interleukin control of macrophage programming. Azithromycin increased fibrotic protein production both in vivo and in vitro, but blunted immune-driven fibrotic damage. We extended our study to patients with CF, describing gene expression in macrophages isolated from sputum samples. We found markers consistent with a shift toward M2 polarization in these patients. These data suggest potential mechanisms by which azithromycin benefits patients with CF.

In der vorliegenden medizinischen Promotionsschrift werden verschiedene nicht-invasive Untersuchungsverfahren bei erwachsenen Patienten mit Zystischer Fibrose (CF) zur Detektion einer Leberbeteiligung (CFLD) evaluiert. Das diagnostische Standard-verfahren bei vielen Hepatopathien, die Leberbiopsie, ist auf Grund der fokalen Manifestation der CFLD und der häufigen pulmonalen Begleiterkrankung bei CF nicht Bestandteil der Routinediagnostik. CF- Patienten werden daher im Rahmen der vorliegenden Studie mittels konventionellen Ultraschalls, Acoustic Radiation Force Impulse (ARFI) - Imagings, Transienter Elastographie (TE) und verschiedener Fibrosescores untersucht. Ferner wird die Eignung der elastographischen Methoden als Verlaufsparameter bei einem Teil der Studienkohorte evaluiert. Ziel ist die Bewertung des diagnostischen Nutzens der angewandten Untersuchungsmethoden bezüglich der Differenzierung zwischen CF-Patienten ohne Leberbeteiligung, CFLD und CFLD-induzierter Zirrhose. Lebergesunde Probanden und Patienten mit ethyltoxischer Leberzirrhose dienen als Kontrollgruppen. Die Ergebnisse dieser wissenschaftlichen Arbeit zeigen, dass die elastographische Untersuchung der Leber bei erwachsenen CF- Patienten, als nicht-invasives Verfahren im Rahmen der Routinediagnostik zur Detektion einer CFLD-induzierten Zirrhose, ergänzend genutzt werden kann. Für die Beurteilung des klinischen Nutzens als Verlaufsparameter sind weitere Studien notwendig.

This thesis uses the International Classification of Functioning, Disability and Health (ICF) model (World Health Organisation, 2001) to explore the multidimensional presentation of strengths and problems in young people with cystic fibrosis (CF), firstly examining its theoretical “fit” to the health condition, and secondly using it to characterise the performance of those with CF. Few studies in the literature demonstrate such an holistic approach to the physiotherapy assessment and management of this population. It was expected that this description of performance would provide a framework for identifying key areas for physiotherapy exercise intervention. This then formed the basis for further studies to examine the effect of a targeted exercise program (compared to current exercise practice) on inpatient outcomes, as well as on outcomes of outpatient management. The position paper included provides theoretical support for the ICF model as an appropriate tool in the management of young people with CF. Building on this, Study 1 explored the practical utility of the ICF model for describing the presentation of young inpatients and outpatients with CF. Eighty-four participants with CF were recruited as a consecutive series who satisfied selection criteria to provide a cross-sectional view at younger (7-12 years, n=51) and older (13-17 years, n=33) ages. Musculoskeletal, respiratory and physiological measures represented the body structures and functions domain, the six-minute walk test and jump tests were included in the activities domain, and participation was described by the Cystic Fibrosis Questionnaire–Revised Version and Fels Physical Activity Questionnaire. Contextual factors were also considered (age, gender, inpatient/outpatient status). In this exploratory study, performance of this population was compared to normative data where available. Also, correlations between measures within and between ICF domains were examined as suggested by the model itself. Finally, effects of contextual factors on performance were investigated using univariate analysis of variance. This first study and the position paper support the ICF model as an effective tool for describing performance of young people with CF, and for investigating functional relationships within and between domains. Results showed significant differences in this population compared to normative data, and interrelationships were identified within and between ICF domains. Between inpatients and outpatients in the specified age groups, there was a statistically significant difference in means for a number of measures, whereby inpatients displayed consistently poorer mean scores than outpatients, with this effect significantly stronger in the older age group. The application of the ICF model was useful for highlighting areas to target in physiotherapy exercise intervention, and for substantiating selected measures to assess the program’s effectiveness across domains. Study 2 was a randomised controlled trial with blinded assessor, which investigated the effectiveness of a 10-14 day inpatient-based exercise program (the Cystic Fibrosis: Fitness Challenge) (CF:FC) tailored for young people with CF (7-17 years). The CF:FC program (n=15) included exercise strategies based on recommendations from previous work in the field, and from findings from Study 1. This program included a portable exercise package (FitKitTM) designed to be adaptable to limited space environments such as at the hospital bedside, important when inpatients with CF are isolated according to infection control procedures. Participants in the control program (n=16) received the current exercise practice provided for young people with CF at a tertiary hospital, which included mainly aerobic-type activities to affect airway clearance. Performance on study measures (scoped within the framework of the ICF model, presented in Study 1) were compared pre- and post-intervention (admission and completion of the inpatient exercise program) between the groups. This trial showed significant improvements for participants in both groups from admission to discharge for a range of measures, including respiratory function, muscle strength and quality of life measures. Participants in the intervention group showed significantly greater improvements for some measures, for example: ankle dorsiflexor strength, six-minute walk distance and perception of their respiratory status. The continuation of the intervention and control programs into the outpatient setting was the focus of Study 3. The FitKitTM was provided for the intervention group, incorporating strategies to enhance adherence including a physical activity log (PAL) and internet-based follow-up. The control home exercise program consisted of the current practice provided on discharge. Interestingly, the control group improved significantly in hip abductor strength and six-minute walk distance during the outpatient period, whereas the intervention group sustained the improvements gained in the inpatient period but generally showed no further significant improvement. When the change from inpatient admission to outpatient follow-up was considered, it was apparent that greater improvements during the inpatient period provided a ‘buffer’ to accommodate for possible deteriorations in function in the outpatient phase. Issues regarding adherence to exercise programs during the outpatient period are discussed. This thesis confirms the usefulness of the ICF model for describing young people with CF, guiding assessment and review processes to achieve comprehensive management, and strengthening the evidence-base for targeted physiotherapy exercise intervention. A novel, tailored exercise program is introduced which is effective during inpatient periods, and provides a maintenance effect during outpatient periods, but strategies to enhance adherence during outpatient periods require further investigation.

This thesis uses the International Classification of Functioning, Disability and Health (ICF) model (World Health Organisation, 2001) to explore the multidimensional presentation of strengths and problems in young people with cystic fibrosis (CF), firstly examining its theoretical “fit” to the health condition, and secondly using it to characterise the performance of those with CF. Few studies in the literature demonstrate such an holistic approach to the physiotherapy assessment and management of this population. It was expected that this description of performance would provide a framework for identifying key areas for physiotherapy exercise intervention. This then formed the basis for further studies to examine the effect of a targeted exercise program (compared to current exercise practice) on inpatient outcomes, as well as on outcomes of outpatient management. The position paper included provides theoretical support for the ICF model as an appropriate tool in the management of young people with CF. Building on this, Study 1 explored the practical utility of the ICF model for describing the presentation of young inpatients and outpatients with CF. Eighty-four participants with CF were recruited as a consecutive series who satisfied selection criteria to provide a cross-sectional view at younger (7-12 years, n=51) and older (13-17 years, n=33) ages. Musculoskeletal, respiratory and physiological measures represented the body structures and functions domain, the six-minute walk test and jump tests were included in the activities domain, and participation was described by the Cystic Fibrosis Questionnaire–Revised Version and Fels Physical Activity Questionnaire. Contextual factors were also considered (age, gender, inpatient/outpatient status). In this exploratory study, performance of this population was compared to normative data where available. Also, correlations between measures within and between ICF domains were examined as suggested by the model itself. Finally, effects of contextual factors on performance were investigated using univariate analysis of variance. This first study and the position paper support the ICF model as an effective tool for describing performance of young people with CF, and for investigating functional relationships within and between domains. Results showed significant differences in this population compared to normative data, and interrelationships were identified within and between ICF domains. Between inpatients and outpatients in the specified age groups, there was a statistically significant difference in means for a number of measures, whereby inpatients displayed consistently poorer mean scores than outpatients, with this effect significantly stronger in the older age group. The application of the ICF model was useful for highlighting areas to target in physiotherapy exercise intervention, and for substantiating selected measures to assess the program’s effectiveness across domains. Study 2 was a randomised controlled trial with blinded assessor, which investigated the effectiveness of a 10-14 day inpatient-based exercise program (the Cystic Fibrosis: Fitness Challenge) (CF:FC) tailored for young people with CF (7-17 years). The CF:FC program (n=15) included exercise strategies based on recommendations from previous work in the field, and from findings from Study 1. This program included a portable exercise package (FitKitTM) designed to be adaptable to limited space environments such as at the hospital bedside, important when inpatients with CF are isolated according to infection control procedures. Participants in the control program (n=16) received the current exercise practice provided for young people with CF at a tertiary hospital, which included mainly aerobic-type activities to affect airway clearance. Performance on study measures (scoped within the framework of the ICF model, presented in Study 1) were compared pre- and post-intervention (admission and completion of the inpatient exercise program) between the groups. This trial showed significant improvements for participants in both groups from admission to discharge for a range of measures, including respiratory function, muscle strength and quality of life measures. Participants in the intervention group showed significantly greater improvements for some measures, for example: ankle dorsiflexor strength, six-minute walk distance and perception of their respiratory status. The continuation of the intervention and control programs into the outpatient setting was the focus of Study 3. The FitKitTM was provided for the intervention group, incorporating strategies to enhance adherence including a physical activity log (PAL) and internet-based follow-up. The control home exercise program consisted of the current practice provided on discharge. Interestingly, the control group improved significantly in hip abductor strength and six-minute walk distance during the outpatient period, whereas the intervention group sustained the improvements gained in the inpatient period but generally showed no further significant improvement. When the change from inpatient admission to outpatient follow-up was considered, it was apparent that greater improvements during the inpatient period provided a ‘buffer’ to accommodate for possible deteriorations in function in the outpatient phase. Issues regarding adherence to exercise programs during the outpatient period are discussed. This thesis confirms the usefulness of the ICF model for describing young people with CF, guiding assessment and review processes to achieve comprehensive management, and strengthening the evidence-base for targeted physiotherapy exercise intervention. A novel, tailored exercise program is introduced which is effective during inpatient periods, and provides a maintenance effect during outpatient periods, but strategies to enhance adherence during outpatient periods require further investigation.