Publications
452 results found
O'Neill K, Ferguson K, Cosgrove D, et al., 2020, Multiple Breath Washout (MBW) in bronchiectasis clinical trials – Is it feasible?, European Respiratory Journal, Vol: 6, Pages: 1-10, ISSN: 0903-1936
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 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. 18/22 (82%) were MBW naïve. Participant knowledge and confidence increased significantly (p<0.001). By the end of the study recruitment, 15/22 sites (68%) had completed certification with a mean (range) time since training of 6.2 (3-14) months. In the BronchUK clinimetrics study, 468/589 (79%) tests met45 the quality criteria following central over-reading, compared with 137/236 (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 naive sites and patients with worse lung function may have contributed to the lower success rate in the i-BEST-1 study.
Stanford G, Davies JC, Usmani O, et al., 2020, Investigating outcome measures for assessing airway clearance techniques in adults with cystic fibrosis: protocol of a single-centre randomised controlled crossover trial, BMJ Open Respiratory Research, Vol: 7, ISSN: 2052-4439
INTRODUCTION: Airway clearance techniques (ACTs) are a gold standard of cystic fibrosis management; however, the majority of research evidence for their efficacy is of low standard; often attributed to the lack of sensitivity from outcome measures (OMs) used historically. This randomised controlled trial (RCT) investigates these standard OMs (sputum weight, forced expiratory volume in 1 s) and new OMs (electrical impedance tomography (EIT), multiple breath washout (MBW) and impulse oscillometry (IOS)) to determine the most useful measures of ACT. METHODS AND ANALYSIS: This is a single-centre RCT with crossover design. Participants perform MBW, IOS and spirometry, and then are randomised to either rest or supervised ACT lasting 30-60 min. MBW, IOS and spirometry are repeated immediately afterwards. EIT and sputum are collected during rest/ACT. On a separate day, the OMs are performed with the other intervention. Primary endpoint is difference in change in OMs before and after ACT/rest. Sample size was calculated with 80% power and significance of 5% for each OM (target n=64). ETHICS AND DISSEMINATION: Ethics approval was gained from the London-Chelsea Research Ethics Committee (reference 16/LO/0995, project ID 154635). Dissemination will involve scientific conference presentation and publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: ISRCTN11220163 and NCT02721498.
van Koningsbruggen-Rietschel S, Davies J, Pressler T, et al., 2020, Inhaled dry powder alginate oligosaccharide (OligoG) in cystic fibrosis: A randomized, double-blind, placebo-controlled cross-over Phase 2b study, European Respiratory Journal, Vol: 6, ISSN: 0903-1936
Background: OligoG is a low molecular-weight alginate oligosaccharide that improves the viscoelastic properties of CF mucus and disrupts biofilms, thereby potentiating the activity of antimicrobial agents. The efficacy of inhaled OligoG was evaluated in adult patients with cystic fibrosis (CF). Methods: A randomized, double-blind, placebo-controlled multi-centre cross-over study was used to demonstrate safety and efficacy of inhaled dry powder OligoG. Subjects were randomly allocated to receive OligoG 1050mg per day (10 capsules TID) or matching placebo for 28-days, with 28-day washout periods following each treatment period. The primary endpoint was absolute change in percent predicted FEV1 at the end of 28-day treatment. The ITT population (N=65) was defined as randomised to treatment with at least one administration of study medication and post-dosing evaluation.Results:Ninety adult subjects were screened and 65 randomized. Statistically significant improvement in FEV1 was not observed in the ITT population. Adverse events (AEs) included nasopharyngitis, cough and pulmonary exacerbation. The number and proportions of patients with AEs and SAEs were similar between OligoG and placebo group.Conclusions: Inhalation of OligoG-DPI over 28-days was safe in adult CF subjects. Statistically significant improvement of FEV1 was not reached. The planned analyses did not indicate a significant treatment benefit with OligoG compared to placebo. Post-hoc exploratory analyses showed subgroup results which indicate that further studies of OligoG in this patient population are justified.
Rosenfeld M, Wainwright C, Sawicki GS, et al., 2020, IVACAFTOR IN 4-TO <6-MONTH-OLD INFANTS WITH CYSTIC FIBROSIS AND A GATING MUTATION: RESULTS OF A 2-PART, SINGLE-ARM, PHASE 3 STUDY, Publisher: WILEY, Pages: S200-S200, ISSN: 8755-6863
Edmondson C, Westrupp N, Wallenburg J, et al., 2020, WHAT IS FEASIBLE WHEN IT COMES TO MONITORING YOUNG PEOPLE WITH CYSTIC FIBROSIS AT HOME? THE RESULTS OF THE CLIMB-CF STUDY, Publisher: WILEY, Pages: S297-S297, ISSN: 8755-6863
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- Citations: 2
Murphy RA, Thrane S, Schelenz S, et al., 2020, SYNERGY WITH GLATIRAMER ACETATE REDUCES TOBRAMYCIN MINIMUM INHIBITORY CONCENTRATIONS AGAINST <i>PSEUDOMONAS AERUGINOSA</i> FROM CYSTIC FIBROSIS AIRWAYS, Publisher: WILEY, Pages: S154-S155, ISSN: 8755-6863
Gardner L, Pinto LA, Davies JC, et al., 2020, THE USE OF THORACIC CT TO DETERMINE BONE MINERAL DENSITY IN ADULTS AND CHILDREN WITH CYSTIC FIBROSIS, Publisher: WILEY, Pages: S87-S87, ISSN: 8755-6863
Kos R, Brinkman P, Neerincx AH, et al., 2020, Targeted exhaled breath analysis for detection of Pseudomonas aeruginosa in cystic fibrosis patients, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Alton EWFW, Boyd AC, Davies JC, et al., 2020, Gene Therapy for Respiratory Diseases: Progress and a Changing Context, HUMAN GENE THERAPY, Vol: 31, Pages: 911-916, ISSN: 1043-0342
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- Citations: 4
Nichols AL, Davies JC, Jones D, et al., 2020, Restoration of exocrine pancreatic function in older children with cystic fibrosis on ivacaftor, Paediatric Respiratory Reviews, Vol: 35, Pages: 99-102, ISSN: 1526-0542
Prior to the use of cystic fibrosis (CF) modulator therapy, exocrine pancreatic insufficiency in CF was thought to be irreversible. Improvement in pancreatic function on ivacaftor has been reported in open label studies in 1-5 year olds. The mechanism by which ivacaftor might improve exocrine pancreatic function is unclear. Although the effect of ivacaftor on pancreatic function may be more significant in younger children, evidence is mounting that there may still be potential for improvement in older children on long term therapy.
De Boeck K, Lee T, Amaral M, et al., 2020, Cystic fibrosis drug trial design in the era of CFTR modulators associated with substantial clinical benefit: stakeholders' consensus view, JOURNAL OF CYSTIC FIBROSIS, Vol: 19, Pages: 688-695, ISSN: 1569-1993
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- Citations: 10
Mayer-Hamblett N, Van Koningsbruggen-Rietschel S, Nichols DP, et al., 2020, Building global development strategies for cf therapeutics during a transitional cftr modulator era, JOURNAL OF CYSTIC FIBROSIS, Vol: 19, Pages: 677-687, ISSN: 1569-1993
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- Citations: 18
Isaac SM, Jensen R, Anagnostopoulou P, et al., 2020, Evaluation of a multiple breath nitrogen washout system in children, PEDIATRIC PULMONOLOGY, Vol: 55, Pages: 2108-2114, ISSN: 8755-6863
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- Citations: 2
Trucco F, Carruthers E, Davies JC, et al., 2020, Inflammation in children with neuromuscular disorders and sleep disordered breathing, SLEEP MEDICINE, Vol: 72, Pages: 118-121, ISSN: 1389-9457
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- Citations: 4
Short C, Saunders C, Davies JC, 2020, Horses for courses: Learning from functional tests of pulmonary health?, PEDIATRIC PULMONOLOGY, Vol: 55, Pages: 1855-1858, ISSN: 8755-6863
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- Citations: 4
Bentley S, Davies JC, Carr SB, et al., 2020, Combination antifungal therapy for <i>Scedosporium</i> species in cystic fibrosis, PEDIATRIC PULMONOLOGY, Vol: 55, Pages: 1993-1995, ISSN: 8755-6863
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- Citations: 7
Kyrilli S, Henry T, Wilschanski M, et al., 2020, Insights into the variability of nasal potential difference, a biomarker of CFTR activity, Journal of Cystic Fibrosis, Vol: 19, Pages: 620-626, ISSN: 1569-1993
BACKGROUND: Nasal potential difference (NPD) is used to evaluate CFTR function in vivo. We aimed to evaluate the intrasubject and intersubject variability of NPD measurements. METHODS: We reviewed NPD tracings of 116 patients with CF enrolled in the placebo arm of a multicenter study. Patients carried at least one nonsense mutation and underwent repeated NPD tests every 16 weeks. NPD parameters included basal potential difference (basal PD), inhibition of sodium absorption by amiloride (Δ Amiloride), chloride (Cl-) transport in response to a Cl--free solution (Δ Low Cl-), isoproterenol (Δ Isoproterenol), the sum of Δ Low Cl- and Δ Isoproterenol (Δ Low Cl--Isoproterenol) and ATP (Δ ATP). RESULTS: Basal PD and Δ Amiloride displayed the highest variabilities, mainly stemming from intercenter and intrasubject effect. Δ Low Cl-, Δ Isoproterenol and Δ Low Cl--Isoproterenol demonstrated a large intrasubject variability but a smaller intersubject variability. The intrasubject measurement variability for Δ Low Cl--Isoproterenol, was within ± 7.2 mV with 95% probability. It was greater in patients reporting ongoing pulmonary exacerbations. CONCLUSIONS: The large intercenter variability of basal PD and Δ Amiloride highlights the operator-dependent aspect of these measurements. A difference greater than 7.2 mV in Δ Low Cl--Isoproterenol in a given patient on CFTR modulator can be attributed, with 95% probability, to a treatment effect rather than to the variability inherent in the measurement.
Saunders C, jensen R, Robinson PD, et al., 2020, Integrating the multiple breath washout test into international multicentre trials, Journal of Cystic Fibrosis, Vol: 19, Pages: 602-607, ISSN: 1569-1993
BackgroundThe 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.MethodsHere 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.ResultsThree 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%).ConclusionWith 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.
Morris-Rosendahl DJ, Edwards M, McDonnell MJ, et al., 2020, Whole-gene sequencing of CFTR reveals a high prevalence of the intronic variant c.3874-4522A>G in cystic fibrosis., American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 1438-1441, ISSN: 1073-449X
Kos R, Brinkman P, Neerincx AH, et al., 2020, ePS6.01 Targeted analysis of volatile organic compounds for detection of Pseudomonas aeruginosa in cystic fibrosis patients by exhaled breath analysis, Journal of Cystic Fibrosis, Vol: 19, Pages: S52-S52, ISSN: 1569-1993
Bayfield KJ, Alton E, Irving S, et al., 2020, “Nitrogen offset in N2 multiple washout method”. Katie J. Bayfield, Eric Alton, Samantha Irving, Andrew Bush, Jane C. Davies. ERJ Open Res 2019; 6: 00043-2020, ERJ Open Research, Vol: 6, Pages: 1-1, ISSN: 2312-0541
This article was originally published with the sentence “Thank you for the opportunity to respond to the correspondence by J.G. Nielsen from Innovision about our recent paper”. The authors have since been made aware that J.G. Nielsen sold Innovision ApS (Glamsbjerg, Denmark) prior to the submission of his correspondence and, at the time of writing, has no financial interests in any business relating to lung clearance index technologies. This sentence has now been changed to “Thank you for the opportunity to respond to the correspondence by J.G. Nielsen about our recent paper” in the article itself.
Bayfield KJ, Alton E, Irving S, et al., 2020, Nitrogen offset in N-2 multiple washout method, ERJ Open Research, Vol: 6, Pages: 1-2, ISSN: 2312-0541
Turnbull A, Hughes D, Davies J, 2020, Selective sampling of the lower airway in children with CF: what are we missing?, American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 747-748, ISSN: 1073-449X
Langawi MA, Byrnes C, Davies JC, et al., 2020, ‘Go for it, dream big, work hard and persist’: A message to the next generation of CF leaders in recognition of International Women's Day 2020, Journal of Cystic Fibrosis, Vol: 19, Pages: 184-193, ISSN: 1569-1993
The focus for International Women's Day 2020 is gender equity:'We can actively choose to challenge stereotypes, fight bias, broaden perceptions, improve situations and celebrate women's achievements. Collectively, each one of us can help create a gender equal world.' We have come together as an international group of women holding senior positions within CF to raise awareness. There is growing recognition of gender imbalance within our sector in senior leadership, grant and publication success. Several institutions, such as National Institutes of Health, have missions to tackle this. The issues raised by our panellists were wide-ranging: decisions around starting a family, impact on career progression; experiences of bias in appointments or promotions; selfbelief. We hope that raising these issues will encourage future leaders in CF to step up, to build teams based on fairness, equity and diversity, and to catalyse steps towards this goal in their institutions and society more widely.
Davies J, Bayfield K, Alton E, et al., 2020, Letter to the ERJ OPEN reply 24th January 2020
Bell SC, Mall MA, Gutierrez H, et al., 2020, The future of cystic fibrosis care: a global perspective, The Lancet Respiratory Medicine, Vol: 8, Pages: 65-124, ISSN: 2213-2600
Soren O, Rineh A, Silva DG, et al., 2020, Cephalosporin nitric oxide-donor prodrug DEA-C3D disperses biofilms formed by clinical cystic fibrosis isolates of Pseudomonas aeruginosa, Journal of Antimicrobial Chemotherapy, Vol: 75, Pages: 117-125, ISSN: 0305-7453
ObjectivesThe cephalosporin nitric oxide (NO)-donor prodrug DEA-C3D (‘DiEthylAmin-Cephalosporin-3′-Diazeniumdiolate’) has been shown to initiate the dispersal of biofilms formed by the Pseudomonas aeruginosa laboratory strain PAO1. In this study, we investigated whether DEA-C3D disperses biofilms formed by clinical cystic fibrosis (CF) isolates of P. aeruginosa and its effect in combination with two antipseudomonal antibiotics, tobramycin and colistin, in vitro.Methodsβ-Lactamase-triggered release of NO from DEA-C3D was confirmed using a gas-phase chemiluminescence detector. MICs for P. aeruginosa clinical isolates were determined using the broth microdilution method. A crystal violet staining technique and confocal laser scanning microscopy were used to evaluate the effects of DEA-C3D on P. aeruginosa biofilms alone and in combination with tobramycin and colistin.ResultsDEA-C3D was confirmed to selectively release NO in response to contact with bacterial β-lactamase. Despite lacking direct, cephalosporin/β-lactam-based antibacterial activity, DEA-C3D was able to disperse biofilms formed by three P. aeruginosa clinical isolates. Confocal microscopy revealed that DEA-C3D in combination with tobramycin produces similar reductions in biofilm to DEA-C3D alone, whereas the combination with colistin causes near complete eradication of P. aeruginosa biofilms in vitro.ConclusionsDEA-C3D is effective in dispersing biofilms formed by multiple clinical isolates of P. aeruginosa and could hold promise as a new adjunctive therapy to patients with CF.
Turnbull A, Pyle C, Patel D, et al., 2020, Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis, Journal of Cystic Fibrosis, Vol: 19, Pages: 40-48, ISSN: 1569-1993
BackgroundProline–glycine–proline (PGP) is a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP-9) and prolylendopeptidase (PE), and capable of eliciting neutrophil chemotaxis and epithelial remodelling. PGP is normally then degraded by leukotriene A4 hydrolase (LTA4H) to limit inflammation and remodelling. This study hypothesized that early and persistent airway neutrophilia in Cystic Fibrosis (CF) may relate to abnormalities in the PGP pathway and sought to understand underlying mechanisms.MethodsBroncho-alveolar lavage (BAL) fluid was obtained from 38 CF (9 newborns and 29 older children) and 24 non-CF children. BAL cell differentials and levels of PGP, MMP-9, PE and LTA4H were assessed.ResultsWhilst PGP was present in all but one of the older CF children tested, it was absent in non-CF controls and the vast majority of CF newborns. BAL levels of MMP-9 and PE were elevated in older children with CF relative to CF newborns and non-CF controls, correlating with airway neutrophilia and supportive of PGP generation. Furthermore, despite extracellular LTA4H commonly being greatly elevated concomitantly with inflammation to promote PGP degradation, this was not the case in CF children, potentially owing to degradation by neutrophil elastase.ConclusionsA striking imbalance between PGP-generating and -degrading enzymes enables PGP accumulation in CF children from early life and potentially supports airway neutrophilia.
Davies JC, Wang LT, Panorchan P, et al., 2019, IVACAFTOR TREATMENT IN PATIENTS 6 TO <12 MONTHS OLD WITH CYSTIC FIBROSIS WITH A CFTR GATING MUTATION: RESULTS OF A 2-PART, SINGLE-ARM, PHASE 3 STUDY, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A12-A12, ISSN: 0040-6376
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Davies J, Alton E, Simbo A, et al., 2019, Training dogs to differentiate Pseudomonas aeruginosa from other cystic fibrosis bacterial pathogens: not to be sniffed at?, European Respiratory Journal, Vol: 54, ISSN: 0903-1936
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