Based on the in vitro pharmacodynamics against Pseudomonas aeruginosa previously published by our group and these pharmacokinetic findings, dose escalating trials may be warranted to maximize efficacy.

Background-Health related quality of life (HRQoL) measurement is important in determining the impact of disease on daily functioning and subsequently informing interventions. In cystic fibrosis (CF) generic HRQoL measures have been employed but these may not be suYciently specific. The aim of the current work was to develop and validate a disease specific HRQoL measure for adults and adolescents with cystic fibrosis. Methods-Areas of concern to adults and adolescents with CF were identified by unstructured interviews, selfadministered questionnaires, consultation with multidisciplinary specialist staV, a review of the relevant literature, and examination of other HRQoL measures. Advances in the care and treatment of cystic fibrosis (CF) have resulted in most patients surviving into adulthood.1 Despite these improvements, CF remains a progressive and ultimately fatal multisystem disease that has a heavy treatment regimen.2 Given this, a new goal for intervention in CF should be to measure and improve health related quality of life (HRQoL) in relation to medical and psychosocial interventions. The measurement of HRQoL complements clinical measures of disease status such as respiratory function tests. Once developed a questionnaire would be useful as (a) an outcome measure in clinical trials, (b) for the assessment of disease progression, and (c) for the monitoring of individual patients.To date, HRQoL in adults with CF has been measured using either generic scales 3-5 or disease specific respiratory measures.6-9 These measures were not developed for the CF population and are limited since they do not reflect areas of functioning that are particularly salient to the adult with CF. Because of this the data are likely to lack sensitivity and be problematic in their interpretation. This work aims to develop, test, and validate a disease specific measure of HRQoL for adults and adolescents with CF. The measure should include areas of functioning that are meaningful to adults with CF, be brief enough to be applied in a clinical setting (that is, completion time of about 10 minutes), be simple to administer and score (for use in clinical settings and postal surveys), and be sensitive enough to detect both changes in health within the individual and diVerences between levels of disease severity.The development, testing, and validation of the Cystic Fibrosis Quality of Life (CFQoL) questionnaire took place over four phases: (1) initial item generation and testing of a preliminary questionnaire; (2) testing and validation of a second version of the questionnaire including concurrent and discriminative validity; (3) test-retest reliability of a third and final version of the questionnaire; and (4) sensitivity testing of the final version of the questionnaire. The step by step development and validation of the CFQoL is reflected in the structure of this paper with the various methods and results sections reported in sequential order for each stage of development and testing. Thorax 2000;55:946-954 946

Abstractresolved during or shortly after treatment. Significant changes were seen in mean Background -Patients with cystic fibrosis serum urea levels in both groups, but in have received more intravenous antibiotic only four patients to a level above the norcourses as median survival has steadily mal range, and in creatinine clearance in increased. A number of centres have adthe dual therapy group. At 24 month follow opted a policy of regular (three monthly) up no long term adverse consequences rather than on demand intravenous antifrom intravenous colistin were found in pseudomonal antibiotics. More widepatients who completed the study. spread bacterial antibiotic resistance has Conclusions -Intravenous colistin is an resulted from this increased antibiotic use.effective treatment for Pseudomonas Most Pseudomonas aeruginosa strains reaeruginosa associated pulmonary exmain fully sensitive to colistin but its use acerbations in patients with cystic fibrosis. has been resisted owing to concerns about Assessment of the individual effect of each neurotoxicity and nephrotoxicity. A study treatment regimen suggests a greater was carried out to assess the safety and efficacy when colistin is combined with a efficacy of intravenous colistin in the treatsecond antibiotic to which the pseudoment of acute respiratory exacerbations in monas shows in vitro sensitivity. Changes adult patients with cystic fibrosis.in renal function should be monitored. Methods -Patients with chronic Pseudo- (Thorax 1997;52:987-993) monas aeruginosa colonisation who presented with protocol defined respiratory Keywords: colistin, cystic fibrosis, Pseudomonas aerutract exacerbations were randomised to ginosa, nephrotoxicity, neurotoxicity. receive treatment for 12 days with either colistin (2 MU tds intravenously) alone or with a second anti-pseudomonal anti-Cohort survival curves from 1968 for children biotic. Comparisons of the absolute values born with cystic fibrosis show an increasing life of respiratory function tests on days 1, 5, expectancy with a median survival presently and 12 and of overnight oxygen saturation of about 29 years 1 2 and an expected median on days 1 and 12 were the primary outcome survival for today's children of 40 years.3 This measures. Patient's weight, clinical and success directly reflects better patient nutrition, chest radiographic scores, and peripheral better and individualised physiotherapy, and blood markers of inflammation were also the advent of effective anti-pseudomonal antidocumented. The effect of each treatment biotics. 4 More frequent antibiotic usage inregimen individually was assessed by the evitably has resulted in a greater prevalence change in clinical measurements from of bacterial antibiotic resistance and patient baseline values. Adverse renal effects were hypersensitivity reactions. 5-9Resistance of monitored by measurement of serum Pseudomonas aeruginosa to colistin is still unlevels of urea and electrolytes, creatinine usual 7 but cystic fibrosis specialist physicians clearance, and war...

While important associations were identified, much of the variance in HRQoL remains unexplained. Other clinical and psychosocial variables merit investigation. A longitudinal study is required to investigate how the disease trajectory and associated treatments affect an individual's quality of life.

Disease severity has an impact on HRQoL in adolescents and adults with CF. Some differences emerged between males and females, with females generally reporting poorer HRQoL. Evidence indicated that males and females perceived their health status differently, with females having a more accurate perception of objective clinical health status.

Advances in the treatment and life expectancy of cystic fibrosis (CF) patients mean that motherhood is now a realistic option for many women with CF. This qualitative study explored the psychosocial impact and adjustments made when women with CF become mothers. Women with CF (n = 11) were recruited via an online forum and participated in semistructured telephone interviews about their experiences of becoming a mother. Transcriptions were analysed using Grounded Theory. Analysis revealed three core categories: (i) “Living with CF”: how becoming a mother impacted on health and treatment adherence, requiring a change in support from the CF team, (ii) “Becoming a Mother”: balancing issues common to new mothers with their CF, and (iii) “Pooling Personal Resources”: coping strategies in managing the dual demands of child and CF care. Participants experienced a variety of complex psychosocial processes. Most participants acknowledged an initial negative impact on CF care; however over time they reported successful adaptation to managing dual commitments and that adherence and motivation to stay well had improved. This study highlights the need for preconceptual psychosocial counselling and postpartum adjustment to CF care.

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Previously, we showed that serum and monocytes from patients with CF exhibit an enhanced NLRP3-inflammasome signature with increased IL-18, IL-1β, caspase-1 activity and ASC speck release (Scambler et al. eLife 2019). Here we show that CFTR modulators down regulate this exaggerated proinflammatory response following LPS/ATP stimulation. In vitro application of ivacaftor/lumacaftor or ivacaftor/tezacaftor to CF monocytes showed a significant reduction in IL-18, whereas IL-1β was only reduced with ivacaftor/tezacaftor. Thirteen adults starting ivacaftor/lumacaftor and eight starting ivacaftor/tezacaftor were assessed over three months. Serum IL-18 and TNF decreased significantly with treatments, but IL-1β only declined following ivacaftor/tezacaftor. In (LPS/ATP-stimulated) PBMCs, IL-18/TNF/caspase-1 were all significantly decreased and IL-10 was increased with both combinations. Ivacaftor/tezacaftor alone showed a significant reduction in IL-1β and pro-IL-1β mRNA. This study demonstrates that these CFTR modulator combinations have potent anti-inflammatory properties, in addition to their ability to stimulate CFTR function, which could contribute to improved clinical outcomes.