Publications by authors named "Clare Saunders"

24 Publications

  • Page 1 of 1

Impact of cross-sensitivity error correction on representative nitrogen-based multiple breath washout data from clinical trials.

J Cyst Fibros 2021 Sep 12. Epub 2021 Sep 12.

Translational Medicine, Division of Respiratory Medicine, Sellers Chair of Cystic Fibrosis, Hospital for Sick Children, 555 University Avenue, Toronto Ontario M5G 1 × 8, Canada; University of Toronto, Toronto, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jcf.2021.08.033DOI Listing
September 2021

Riociguat for the treatment of Phe508del homozygous adults with cystic fibrosis.

J Cyst Fibros 2021 Aug 19. Epub 2021 Aug 19.

University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Background: Riociguat is a first-in-class soluble guanylate cyclase stimulator for which preclinical data suggested improvements in cystic fibrosis transmembrane conductance regulator (CFTR) function.

Methods: This international, multicenter, two-part, Phase II study of riociguat enrolled adults with cystic fibrosis (CF) homozygous for Phe508del CFTR. Part 1 was a 28-day, randomized, double-blind, placebo-controlled study in participants not receiving CFTR modulator therapy. Twenty-one participants were randomized 1:2 to placebo or oral riociguat (0.5 mg three times daily [tid] for 14 days, increased to 1.0 mg tid for the subsequent 14 days). The primary and secondary efficacy endpoints were change in sweat chloride concentration and percent predicted forced expiratory volume in 1 second (ppFEV), respectively, from baseline to Day 14 and Day 28 with riociguat compared with placebo.

Results: Riociguat did not alter CFTR activity (change in sweat chloride) or lung function (change in ppFEV) at doses up to 1.0 mg tid after 28 days. The most common drug-related adverse event (AE) was headache occurring in three participants (21%); serious AEs occurred in one participant receiving riociguat (7%) and one participant receiving placebo (14%). This safety profile was consistent with the underlying disease and the known safety of riociguat for its approved indications.

Conclusions: The Rio-CF study was terminated due to lack of efficacy and the changing landscape of CF therapeutic development. The current study⁠, within its limits of a small sample size, did not provide evidence that riociguat could be a valid treatment option for CF.

Clinical Trial Registration Number: NCT02170025.
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http://dx.doi.org/10.1016/j.jcf.2021.07.015DOI Listing
August 2021

A Short extension to multiple breath washout provides additional signal of distal airway disease in people with CF: A pilot study.

J Cyst Fibros 2021 Jul 15. Epub 2021 Jul 15.

Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College London, Manresa Rd, London, United Kingdom; European Cystic Fibrosis Society Lung Clearance Index Core Facility, London, United Kingdom.

Background: Adding a slow vital capacity (SVC) to multiple breath washout (MBW) allows quantification of otherwise overlooked signal from under/un-ventilated lung units (UVLU) and may provide a more comprehensive assessment of airway disease than conventional lung clearance index (LCI).

Methods: We conducted a pilot study on people undergoing MBW tests: 10 healthy controls (HC) and 43 cystic fibrosis (CF) subjects performed an SVC after the standard end of test. We term the new outcome LCI with Short extension (LCI). We assessed (i) CF/ HC differences, (ii) variability (iii) effect of pulmonary exacerbation (PEx)/treatment and (iv) relationship with CF computed tomography (CFCT) scores.

Results: HC/ CF group differences were larger with LCI than LCI (P<0.001). Within the CF group UVLU was highly variable and when abnormal it did not correlate with corresponding LCI. Signal showed little variability during clinical stability (n = 11 CF; 2 visits; median inter-test variability 2.6% LCI 2.5% LCI). PEx signal was significantly greater for LCI both for onset and resolution. Both MBW parameters correlated significantly with total lung CT scores and hyperinflation but only LCI correlated with mucus plugging.

Conclusions: UVLU captured within the LCI varies between individuals; the lack of relationship with LCI demonstrates that new, additional information is being captured. LCI repeatability during clinical stability combined with its larger signal around episodes of PEx may lend it superior sensitivity as an outcome measure. Further studies will build on this pilot data to fully establish its utility in monitoring disease status.
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http://dx.doi.org/10.1016/j.jcf.2021.06.013DOI Listing
July 2021

Entering the era of highly effective modulator therapies.

Pediatr Pulmonol 2021 02;56 Suppl 1:S79-S89

Departments of Cystic Fibrosis and Paediatric Respiratory Medicine, Royal Brompton & Harefield Foundation Trust, London, UK.

Since the discovery of the gene responsible for cystic fibrosis (CF) in 1989, hopes have been pinned on a future with novel therapies tackling the basis of the disease rather than its symptoms. These have become a reality over the last decade with the development through to the clinic of CF transmembrane conductance regulator (CFTR) modulators. These are oral drugs which improve CFTR protein function through either increasing the time the channel pore is open (potentiators) or facilitating its trafficking through the cell to its location on the cell membrane (correctors). The first potentiator, ivacaftor, is now licensed and available clinically in many parts of the world. It is highly effective with impressive clinical impact in the lungs and gastrointestinal tract; longer-term data from patient registries show fewer exacerbations, a slower rate of lung function loss and reduced need for transplantation in patients receiving ivacaftor. However, as a single drug, it is suitable for only a small minority of patients. The commonest CFTR mutation, F508del, requires both correction and potentiation for clinical efficacy. Two dual-agent drugs (lumacaftor/ivacaftor and tezacaftor/ivacaftor) have progressed through to licensing, although their short term impact is more modest than that of ivacaftor; this is likely due to only partial correction of protein misfolding and trafficking. Most recently, triple compounds have been developed: two different corrector molecules (elexacaftor and tezacaftor) which, by addressing different regions in the misfolded F508del protein, more effectively improve trafficking. In addition to large improvements in clinical outcomes in people with two copies of F508del, the combination is sufficiently effective that it works in patients with only one copy of F508del and a second, nonmodulator responsive mutation. For the first time, we thus have a drug suitable for around 85% of people with CF. Even more gains are likely to be possible when these drugs can be used in younger children, although more sensitive outcome measures are needed for this age group. Special consideration is needed for people with very rare mutations; those with nonmodulatable mutation combinations will likely require gene or messenger RNA-based therapeutic approaches, many of which are being explored. Although this progress is hugely to be celebrated, we still have more work to do. The international collaboration between trials networks, pharma, patient organizations, registries, and people with CF is something we are all rightly proud of, but innovative trial design and implementation will be needed if we are to continue to build on this progress and further develop drugs for people with CF.
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http://dx.doi.org/10.1002/ppul.24968DOI Listing
February 2021

Ivacaftor in People with Cystic Fibrosis and a → or Residual Function Mutation.

Ann Am Thorac Soc 2021 03;18(3):433-441

Vertex Pharmaceuticals (Europe) Ltd., London, United Kingdom.

Ivacaftor's clinical effects in the residual function mutations and warrant further characterization. To evaluate ivacaftor's effect in people with cystic fibrosis aged ≥6 years with or residual function mutations and to explore the correlation between ivacaftor-induced organoid-based cystic fibrosis transmembrane conductance regulator function measurements and clinical response to ivacaftor. Participants were randomized (1:1) in this placebo-controlled crossover study; each treatment sequence included two 8-week treatments with an 8-week washout period. The primary endpoint was absolute change in lung clearance index from baseline through Week 8. Additional endpoints included lung function, patient-reported outcomes, and intestinal organoid-based measurements of ivacaftor-induced cystic fibrosis transmembrane conductance regulator function. Of 38 participants, 37 completed the study. The primary endpoint was met; the Bayesian posterior probability of improvement in lung clearance index with ivacaftor versus placebo was >99%. Additional endpoints improved with ivacaftor. Safety findings were consistent with ivacaftor's known safety profile. Dose-dependent swelling was observed in 23 of 25 viable organoid cultures with ivacaftor treatment. Correlations between ivacaftor-induced organoid swelling and clinical endpoints were negligible to low. In people with cystic fibrosis aged ≥6 years with a or mutation, ivacaftor treatment improved clinical endpoints compared with placebo; however, there was no correlation between organoid swelling and change in clinical endpoints. The organoid assay may assist in identification of ivacaftor-responsive mutations but in this study did not predict magnitude of clinical benefit for individual people with cystic fibrosis with these two mutations.Clinical trial registered with ClinicalTrials.gov (NCT03068312).
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http://dx.doi.org/10.1513/AnnalsATS.202006-659OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094270PMC
March 2021

Multiple breath washout in bronchiectasis clinical trials: is it feasible?

ERJ Open Res 2020 Oct 13;6(4). Epub 2020 Oct 13.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University - Belfast, Belfast, UK.

Background: Evaluation of multiple breath washout (MBW) set-up including staff training, certification and central "over-reading" for data quality control is essential to determine the feasibility of MBW in future bronchiectasis studies.

Aims: To assess the outcomes of a MBW training, certification and central over-reading programme.

Methods: MBW training and certification was conducted in European sites collecting lung clearance index (LCI) data in the BronchUK Clinimetrics and/or i-BEST-1 studies. The blended training programme included the use of an eLearning tool and a 1-day face-to-face session. Sites submitted MBW data to trained central over-readers who determined validity and quality.

Results: Thirteen training days were delivered to 56 participants from 22 sites. Of 22 sites, 18 (82%) were MBW naïve. Participant knowledge and confidence increased significantly (p<0.001). By the end of the study recruitment, 15 of 22 sites (68%) had completed certification with a mean (range) time since training of 6.2 (3-14) months. In the BronchUK Clinimetrics study, 468 of 589 (79%) tests met the quality criteria following central over-reading, compared with 137 of 236 (58%) tests in the i-BEST-1 study.

Conclusions: LCI is feasible in a bronchiectasis multicentre clinical trial setting; however, consideration of site experience in terms of training as well as assessment of skill drift and the need for re-training may be important to reduce time to certification and optimise data quality. Longer times to certification, a higher percentage of naïve sites and patients with worse lung function may have contributed to the lower success rate in the i-BEST-1 study.
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http://dx.doi.org/10.1183/23120541.00363-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553113PMC
October 2020

A phase 3, double-blind, parallel-group study to evaluate the efficacy and safety of tezacaftor in combination with ivacaftor in participants 6 through 11 years of age with cystic fibrosis homozygous for F508del or heterozygous for the F508del-CFTR mutation and a residual function mutation.

J Cyst Fibros 2021 01 21;20(1):68-77. Epub 2020 Sep 21.

The University of Queensland, Brisbane, QLD, Australia.

Background: The CFTR modulator tezacaftor/ivacaftor was efficacious and generally safe and well tolerated in Phase 3 studies in participants ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous with a residual function-CFTR mutation (F/F or F/RF respectively). We evaluated tezacaftor/ivacaftor's efficacy and safety over 8 weeks in participants 6 through 11 years of age with these mutations.

Methods: Participants were randomized 4:1 to tezacaftor/ivacaftor or a blinding group (placebo for F/F, ivacaftor for F/RF). The primary endpoint was within-group change from baseline in the lung clearance index 2·5 (LCI) through Week 8. Secondary endpoints were change from baseline in sweat chloride (SwCl), cystic fibrosis questionnaire-revised (CFQ-R) respiratory domain score, and safety.

Results: Sixty-seven participants received at least one study drug dose. Of those, 54 received tezacaftor/ivacaftor (F/F, 42; F/RF, 12), 10 placebo, and 3 ivacaftor; 66 completed the study. The within-group change in LCI was significantly reduced (improved) by -0·51 (95% CI: -0·74, -0·29). SwCl concentration decreased (improved) by -12·3 mmol/L and CFQ-R respiratory domain score increased (improved, nonsignificantly) by 2·3 points. There were no serious adverse events (AEs) or AEs leading to tezacaftor/ivacaftor discontinuation or interruption. The most common AEs (≥10%) in participants receiving tezacaftor/ivacaftor were cough, headache, and productive cough.

Conclusions: Tezacaftor/ivacaftor improved lung function (assessed using LCI) and CFTR function (measured by SwCl concentration) in participants 6 through 11 years of age with F/F or F/RF genotypes. Tezacaftor/ivacaftor was safe and well tolerated; no new safety concerns were identified.
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http://dx.doi.org/10.1016/j.jcf.2020.07.023DOI Listing
January 2021

Evaluation of a multiple breath nitrogen washout system in children.

Pediatr Pulmonol 2020 08 28;55(8):2108-2114. Epub 2020 May 28.

Translational Medicine, Research Institute, Hospital for Sick Children, Toronto, Canada.

Introduction: The multiple breath nitrogen washout (MBW) test offers a sensitive measure of airway function. In this study we aim to (a) assess the validity of the EasyOne Pro LAB (MBW ) in an in vitro lung model, (b) assess the feasibility, repeatability, and reproducibility of MBW and (c) compare outcomes with the Exhalyzer D (MBW ) and body plethysmography.

Methods: In vitro, functional residual capacity (FRC) measurements were assessed using a lung model under quasi-physiological conditions and compared to measured FRC. In vivo plethysmography and MBW were performed in a prospective study of children at two visits (n = 45 healthy; n = 41 cystic fibrosis [CF]). Bland-Altman plots were used to compare agreement between FRC and lung clearance index (LCI) measurements.

Results: In vitro FRC measurements were repeatable but lung volumes were underestimated (mean relative difference -5.4% (limits of agreement [LA] -9.6%; -1.1%), 95% confidence interval (CI) -6.27; -4.45). In vivo, compared to plethysmography, FRC was consistently lower (-19.3% [-40.5; 1.9], 95% CI [-23.9; -14.7]), and showed a volume dependency. LCI values were also higher in children with smaller lung volumes. The within-test coefficient of variation of the FRC and LCI were 4.9% in health, and 5.6% and 6.9% in CF respectively. LCI was reproducible between-visits (mean relative difference [LA] -3.7% [-14.8, -7.5; 95% CI -6.6; -0.73] in health [n = 17] and 0.34% [-13.2, 22.8; 95% CI -5.0; 5.69] in CF [n = 23]). When calculated using the same algorithm, LCI was similar to LCI in health.

Conclusions: MBW measurements are feasible, repeatable, and reproducible, however, MBW-derived outcomes are not interchangeable with MBW .
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http://dx.doi.org/10.1002/ppul.24862DOI Listing
August 2020

Horses for courses: Learning from functional tests of pulmonary health?

Pediatr Pulmonol 2020 08 15;55(8):1855-1858. Epub 2020 May 15.

Royal Brompton and Harefield NHS Foundation Trust, Chelsea, London, UK.

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http://dx.doi.org/10.1002/ppul.24818DOI Listing
August 2020

Integrating the multiple breath washout test into international multicentre trials.

J Cyst Fibros 2020 07 24;19(4):602-607. Epub 2019 Nov 24.

Translational Medicine, Hospital for Sick Children, Toronto, Canada; University of Toronto, Toronto, Canada. Electronic address:

Background: The lung clearance index (LCI), derived from the Multiple Breath Washout (MBW) test, is sensitive to treatment effects and compared with spirometry has higher feasibility in younger children and requires smaller sample sizes. As a result, the LCI has been endorsed by the European CF Society Clinical Trials Network for use as a primary outcome measure in CF clinical trials.

Methods: Here we describe the implementation of standardised protocols for MBW test performance, data collection and quality control to successfully incorporate LCI as a novel outcome measure in a large multicentre phase III clinical trial.

Results: Three regional (North America (NA), Europe (EU), Australia (AUS)) central over-reading centres (CORC) were established to provide a collaborative platform for MBW training, certification and quality control of data. One hundred and thirty-two naïve operators from 53 sites across NA, EU and AUS were successfully trained and certified to perform MBW testing.  Incorporation of a re-screening opportunity in the study protocol resulted a final screening feasibility rate of 93%, success remained high throughout the study resulting in an overall feasibility of MBW study data of 88.1% (1107/1257). MBW test acceptability was similar between geographical regions: NA (88%), EU (89%) and AUS (89%).

Conclusion: With this approach we achieved high MBW test feasibility and sustained collection of good quality data, demonstrating the utility of LCI as an effective primary endpoint in the first international phase III clinical trial to report LCI as the primary outcome.
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http://dx.doi.org/10.1016/j.jcf.2019.11.006DOI Listing
July 2020

Impact of Reducing Pre-Hospital Delay in Response to Heart Attack Symptoms in Australia.

Heart Lung Circ 2019 Aug 31;28(8):1154-1160. Epub 2018 Aug 31.

National Heart Foundation of Australia, Melbourne, Vic, Australia. Electronic address:

Background: This research estimates the broader socioeconomic impacts of reducing pre-hospital delay times across Australia in patients with heart attack symptoms.

Methods: A cost benefit analysis (CBA) was undertaken to demonstrate the costs and benefits of a public awareness/education campaign to reduce pre-hospital delay time from 5.2hours (Base Case) to 4.1hours (Scenario 1) and 2.0hours (Scenario 2). All assumptions underlying the CBA are supported by academic literature. Financial impacts considered include campaign/public education costs, direct inpatient costs and long-term health care costs. Socioeconomic impacts considered include burden of disease, productivity losses, informal care costs and net deadweight loss.

Results: The campaign is expected to generate an additional net benefit of $41.2-139.1 million in comparison to the Base Case, resulting in a benefit cost ratio (BCR) of 3.23-5.06. Disability Adjusted Life Years (DALYs) reduced by 6,046-7,575 years.

Conclusion: This research illustrates that an investment in public awareness/education campaign can generate considerable benefits, more than offsetting the costs associated with the campaign and keeping people living longer such as ongoing health care costs. However, significant effort, supplementary strategies and sustained investment will be required to ensure the impact and benefit is sustained over the long term.
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http://dx.doi.org/10.1016/j.hlc.2018.07.018DOI Listing
August 2019

New directions on lung clearance index variability and feasibility.

J Cyst Fibros 2018 03;17(2):137-139

Royal Brompton Hospital and Imperial College London.

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http://dx.doi.org/10.1016/j.jcf.2018.02.010DOI Listing
March 2018

Developments in multiple breath washout testing in children with cystic fibrosis.

Curr Med Res Opin 2017 04 2;33(4):613-620. Epub 2017 Feb 2.

a NHLI, Imperial College London , UK.

Background: Lung clearance index (LCI) is becoming recognized as an important addition in the monitoring of pediatric cystic fibrosis (CF). The non-invasive technique is easy to perform in all ages, reproducible and increasingly being used in clinical trials. There is interest in utilizing it within the clinic setting but its current use is mostly as a research tool. The procedure is highly dependent on skilled operators and a relaxed testing environment is key to obtaining good quality measurements.

Conclusions: Standardization of LCI is part of an ongoing collaborative, multicenter process. This review describes the background to LCI, discusses technical issues and limitations and provides examples of its utility in clinical and research contexts.
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http://dx.doi.org/10.1080/03007995.2016.1268999DOI Listing
April 2017

A Systematic Approach to Multiple Breath Nitrogen Washout Test Quality.

PLoS One 2016 15;11(6):e0157523. Epub 2016 Jun 15.

Division of Respiratory Medicine, Hospital for Sick Children, Toronto, Canada.

Background: Accurate estimates of multiple breath washout (MBW) outcomes require correct operation of the device, appropriate distraction of the subject to ensure they breathe in a manner representative of their relaxed tidal breathing pattern, and appropriate interpretation of the acquired data. Based on available recommendations for an acceptable MBW test, we aimed to develop a protocol to systematically evaluate MBW measurements based on these criteria.

Methods: 50 MBW test occasions were systematically reviewed for technical elements and whether the breathing pattern was representative of relaxed tidal breathing by an experienced MBW operator. The impact of qualitative and quantitative criteria on inter-observer agreement was assessed across eight MBW operators (n = 20 test occasions, compared using a Kappa statistic).

Results: Using qualitative criteria, 46/168 trials were rejected: 16.6% were technically unacceptable and 10.7% were excluded due to inappropriate breathing pattern. Reviewer agreement was good using qualitative criteria and further improved with quantitative criteria from (κ = 0.53-0.83%) to (κ 0.73-0.97%), but at the cost of exclusion of further test occasions in this retrospective data analysis.

Conclusions: The application of the systematic review improved inter-observer agreement but did not affect reported MBW outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157523PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909265PMC
July 2017

Multiple breath washouts in children can be shortened without compromising quality.

Eur Respir J 2015 Dec 9;46(6):1814-6. Epub 2015 Oct 9.

National Heart and Lung Institute, Imperial College London, London, UK Royal Brompton and Harefield NHS Foundation Trust, London, UK

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http://dx.doi.org/10.1183/13993003.00791-2015DOI Listing
December 2015

Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial.

Lancet Respir Med 2015 Sep 3;3(9):684-691. Epub 2015 Jul 3.

Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

Background: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis.

Methods: We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0.9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867.

Findings: Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3.7%, 95% CI 0.1-7.3; p=0.046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups.

Interpretation: Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials.

Funding: Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Programme.
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http://dx.doi.org/10.1016/S2213-2600(15)00245-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673100PMC
September 2015

Lung clearance index and high-resolution computed tomography scores in primary ciliary dyskinesia.

Am J Respir Crit Care Med 2013 Sep;188(5):545-9

Department of Paediatrics, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom.

Rationale: Lung clearance index (LCI) is a more sensitive measure of lung function than spirometry in cystic fibrosis (CF) and correlates well with abnormalities in high-resolution computed tomography (HRCT) scanning. We hypothesized LCI would be equally sensitive to lung disease in primary ciliary dyskinesia (PCD).

Objectives: To test the relationships between LCI, spirometry, and HRCT in PCD and to compare them to the established relationships in CF.

Methods: Cross-sectional study of 127 patients with CF and 33 patients with PCD, all of whom had spirometry and LCI, of which a subset of 21 of each had HRCT performed. HRCT was scored for individual features and these features compared with physiological parameters.

Measurements And Main Results: Unlike in CF, and contrary to our hypothesis, there was no correlation between spirometry and LCI in PCD and no correlation between HRCT features and LCI or spirometry in PCD.

Conclusions: We show for the first time that HRCT, spirometry, and LCI have different relationships in different airway diseases and that LCI does not appear to be a sensitive test of airway disease in advanced PCD. We hypothesize that this results from dissimilarities between the components of large and small airway disease in CF and PCD. These differences may in part lead to the different prognosis in these two neutrophilic airway diseases.
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http://dx.doi.org/10.1164/rccm.201304-0800OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827705PMC
September 2013

Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation.

Thorax 2013 Jun 9;68(6):532-9. Epub 2013 Feb 9.

UK Cystic Fibrosis Gene Therapy Consortium, London, UK.

Background: Clinical trials in cystic fibrosis (CF) have been hindered by the paucity of well characterised and clinically relevant outcome measures.

Aim: To evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for a clinical trial of CFTR gene therapy.

Methods: A multicentre observational study of adult and paediatric patients with CF (>10 years) treated for a physician-defined exacerbation of CF pulmonary symptoms. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers.

Results: Statistically significant improvements were seen in forced expiratory volume in 1 s (p<0.001, n=32), lung clearance index (p<0.01, n=32), symptoms (p<0.0001, n=37), CT scores for airway wall thickness (p<0.01, n=31), air trapping (p<0.01, n=30) and large mucus plugs (p=0.0001, n=31), serum C-reactive protein (p<0.0001, n=34), serum interleukin-6 (p<0.0001, n=33) and serum calprotectin (p<0.0001, n=31).

Discussion: We identify the key biomarkers of inflammation, imaging and physiology that alter alongside symptomatic improvement following treatment of an acute CF exacerbation. These data, in parallel with our study of biomarkers in patients with stable CF, provide important guidance in choosing optimal biomarkers for novel therapies. Further, they highlight that such acute therapy predominantly improves large airway parameters and systemic inflammation, but has less effect on airway inflammation.
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http://dx.doi.org/10.1136/thoraxjnl-2012-202538DOI Listing
June 2013

Evidence for expectancy as a mediator of avoidance and anxiety in a laboratory model of human avoidance learning.

Q J Exp Psychol (Hove) 2008 Aug;61(8):1199-216

School of Psychology, University of New South Wales, Sydney, NSW 2052, Australia.

A laboratory model was developed to study human avoidance learning. Participants could avoid an electric shock signalled by a 5-s conditioned stimulus (CS) by pressing one of a set of response buttons. Self-reported shock expectancy and skin conductance were recorded during a subsequent 10-s interval before shock. Shock expectancy declined when the correct avoidance response was learned and returned when the response was unavailable. Learning transferred to another shock CS. Parallel effects were observed on skin conductance once performance anxiety was controlled by requiring responding on all trials. Learning was faster when the Pavlovian contingencies were trained before introduction of the instrumental response. The results support a cognitive model of anxiety in which performance of an avoidance response reduces expectancy of an aversive outcome and thereby reduces anxiety.
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http://dx.doi.org/10.1080/17470210701503229DOI Listing
August 2008

Double-edged swords? Collective identity and solidarity in the environment movement.

Authors:
Clare Saunders

Br J Sociol 2008 Jun;59(2):227-53

School of Social Policy, Sociology and Social Research, University of Kent at Canterbury, UK.

Perhaps by virtue of its theoretical slipperiness, collective identity is often hailed as an important feature of social movements for the role it plays in unifying activists and organizations, and so helping them to develop shared concerns and engage in collective action. However, this paper argues that collective identity is the result of group rather than movement level processes, and although it can unite activists within a single movement organization, it is not always beneficial for the broader social movement. Although movements consist of networks of activists and organizations that have a broad shared concern, differing collective identities within the movement can actually be quite divisive. Based on case studies of three organizations in the environmental movement, this paper shows that activists who are most committed to an organization with an encompassing collective identity develop a strong sense of solidarity with other activists similarly committed to that organization. The resultant solidarity leads to the construction of a 'we-them' dichotomy between organizations within the same movement, increasing the chances of hostility between organizations and factions within the movement.
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http://dx.doi.org/10.1111/j.1468-4446.2008.00191.xDOI Listing
June 2008

Lung function from infancy to the preschool years after clinical diagnosis of cystic fibrosis.

Am J Respir Crit Care Med 2008 Jul 10;178(1):42-9. Epub 2008 Apr 10.

Portex Anaesthesia, Intensive Therapy and Respiratory Medicine Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.

Rationale: After recent standardization of forced expiratory maneuvers for both infants and preschool children, longitudinal measurements are now possible from birth.

Objectives: The aim of this study was to investigate the evolution of lung function during the first 6 years of life after a clinical diagnosis of cystic fibrosis (CF) in infancy in children with CF and in healthy control subjects.

Methods: The raised volume technique was used during infancy and incentive spirometry during the preschool years.

Measurements And Main Results: Forty-eight children with CF and 33 healthy control subjects had up to seven (median, 3) measurements. Over these early years, the diagnosis of CF itself accounted for a significant mean reduction of 7.5% (95% confidence interval, 0.9 - 13.6%) in FEV(0.75) and 15.1% (95% confidence interval, 3.6 - 25.3%) in FEF(25-75). Wheeze on auscultation, recent cough, and Pseudomonas aeruginosa (PsA) infection (even if apparently effectively treated) were all independently associated with further reductions in lung function. Premorbid lung function did not predict infection with PsA.

Conclusions: This is the first study to describe physiologic measurements from infancy through the preschool years in subjects with CF and healthy control subjects, the understanding of which is critical for future intervention trials. Airflow obstruction in uncomplicated CF persists through the preschool years despite treatment, with PsA acquisition being associated with further deterioration in lung function, even when apparently eradicated. This suggests that new therapies are needed to treat the airflow obstruction of uncomplicated CF, and rigorous strategies to prevent PsA acquisition.
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http://dx.doi.org/10.1164/rccm.200710-1599OCDOI Listing
July 2008

Reliability and validity of The Awareness of Social Inference Test (TASIT): a clinical test of social perception.

Disabil Rehabil 2006 Dec;28(24):1529-42

School of Psychology, University of New South Wales, Sydney.

Purpose: The Awareness of Social Inference Test (TASIT) is an audiovisual tool designed for the clinical assessment of social perception with alternate forms for re-testing. Part 1 assesses emotion recognition, Parts 2 and 3 assess the ability to interpret conversational remarks meant literally (i.e., sincere remarks and lies) or non-literally (i.e., sarcasm) as well as the ability to make judgments about the thoughts, intentions and feelings of speakers. This paper aims to examine TASIT's reliability and validity.

Method: Some 32 adults with severe, chronic brain injuries were administered Form A twice, one week apart. 38 adults with brain injuries were readministered alternate forms over a period of 5 - 26 weeks. Construct validity was examined in subsets of a sample of 116 adults with brain injuries by relating TASIT performance to standard tests of neuropsychological function and specific social perception measures.

Results: Test-retest reliability ranged from 0.74 - 0.88. Alternate forms reliability ranged from 0.62 - 0.83. TASIT performance was associated with face perception, information processing speed and working memory. Socially relevant new learning and executive tasks were significantly associated with TASIT performance whereas non-social tasks showed little association. Social perception tasks such as Ekman photos and theory of mind stories were also associated.

Conclusions: TASIT has adequate psychometric properties as a clinical test of social perception. It is not overly prone to practice effects and is reliable for repeat administrations. Performance on TASIT is affected by information processing speed, working memory, new learning and executive functioning, but the uniquely social material that comprises the stimuli for TASIT will provide useful insights into the particular difficulties people with clinical conditions experience when interpreting complex social phenomena.
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http://dx.doi.org/10.1080/09638280600646185DOI Listing
December 2006

Quality control for spirometry in preschool children with and without lung disease.

Am J Respir Crit Care Med 2004 May 17;169(10):1152-9. Epub 2004 Mar 17.

Portex Respiratory Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.

The reliability of spirometry is dependent on strict quality control. We examined whether quality control criteria recommended for adults could be applied to children aged 2-5 years. Forty-two children with cystic fibrosis and 37 healthy children attempted spirometry during their first visit to our laboratory. Whereas 59 children (75%) were able to produce a technically satisfactory forced expiration lasting 0.5 second, only 46 (58%) could produce an expiration lasting 1 second, with the youngest children having the most difficulty. Start of test criteria for adults were inappropriate for this age group, with only 16 of 59 children producing a volume of back extrapolation as a proportion of forced vital capacity of less than 5%, whereas all but 4 could produce a volume of back extrapolation of 80 ml or less. More than 90% of children were able to produce a second forced vital capacity and a second forced expired volume in 0.75 second within 10% of their highest. Errors in the spirometry software resulted in inaccurate reporting of expiratory duration and inappropriate timed expired volumes in some children. We describe recommendations for modified start of test and repeatability criteria for this age group, and for improvements in software to facilitate better quality control.
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May 2004
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