Imperial College London

ProfessorJaneDavies

Faculty of MedicineNational Heart & Lung Institute

Professor of Paediatric Respirology & Experimental Medicine
 
 
 
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Contact

 

+44 (0)20 7594 7973j.c.davies

 
 
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Assistant

 

Mrs Gina Rivellini +44 (0)20 7594 7986

 
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Location

 

171Emmanuel Kaye BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
to

312 results found

Davies J, Bayfield K, Alton E, Bush A, Irving Set al., 2020, Letter to the ERJ OPEN reply 24th January 2020

Journal article

Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, Burgel P-R, Tullis E, Castaos C, Castellani C, Byrnes CA, Cathcart F, Chotirmall SH, Cosgriff R, Eichler I, Fajac I, Goss CH, Drevinek P, Farrell PM, Gravelle AM, Havermans T, Mayer-Hamblett N, Kashirskaya N, Kerem E, Mathew JL, McKone EF, Naehrlich L, Nasr SZ, Oates GR, O'Neill C, Pypops U, Raraigh KS, Rowe SM, Southern KW, Sivam S, Stephenson AL, Zampoli M, Ratjen Fet al., 2020, The future of cystic fibrosis care: a global perspective, The Lancet Respiratory Medicine, Vol: 8, Pages: 65-124, ISSN: 2213-2600

Journal article

Soren O, Rineh A, Silva DG, Cai Y, Howlin RP, Allan RN, Feelisch M, Davies JC, Connett GJ, Faust SN, Kelso MJ, Webb JSet al., 2020, Cephalosporin nitric oxide-donor prodrug DEA-C3D disperses biofilms formed by clinical cystic fibrosis isolates of Pseudomonas aeruginosa., J Antimicrob Chemother, Vol: 75, Pages: 117-125

OBJECTIVES: The 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. METHODS: β-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. RESULTS: DEA-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. CONCLUSIONS: DEA-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.

Journal article

Turnbull A, Hughes D, Davies J, 2019, Selective sampling of the lower airway in children with CF: what are we missing?, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

Journal article

Saunders C, jensen R, Robinson PD, Stanojevic S, Klingel M, Short C, Davies J, Ratjen Fet al., 2019, Integrating the multiple breath washout test into international multicentre trials, Journal of Cystic Fibrosis, 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.

Journal article

Kyrilli S, Henry T, Wilschanski M, Fajac I, Davies JC, Jais J-P, Sermet-Gaudelus Iet al., 2019, Insights into the variability of nasal potential difference, a biomarker of CFTR activity, Journal of Cystic Fibrosis, 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.

Journal article

Davies J, Alton E, Simbo A, Murphy R, Ishani S, Williams K, Somerville M, Jolly L, Morant S, Guest Cet 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

Journal article

Southern KW, Barben J, Gartner S, Munck A, Castellani C, Mayell SJ, Davies JC, Winters V, Murphy J, Salinas D, McColley SA, Ren CL, Farrell PMet al., 2019, Inconclusive diagnosis after a positive newborn bloodspot screening result for cystic fibrosis; clarification of the harmonised international definition, JOURNAL OF CYSTIC FIBROSIS, Vol: 18, Pages: 778-780, ISSN: 1569-1993

Journal article

Rosenfeld M, Cunningham S, Harris WT, Lapey A, Regelmann WE, Sawicki GS, Southern KW, Chilvers M, Higgins M, Tian S, Cooke J, Davies JC, KLIMB study groupet al., 2019, An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB)., Journal of Cystic Fibrosis, Vol: 18, Pages: 838-843, ISSN: 1569-1993

BACKGROUND: KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI. METHODS: Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function. RESULTS: All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters. CONCLUSIONS: Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.

Journal article

Murphy RA, Christiansen S, Sabnis A, Schelenz S, Edwards A, Vorup-Jensen T, Davies JCet al., 2019, GLATIRAMER ACETATE IS AN ANTIBIOTIC RESISTANCE BREAKER AGAINST CYSTIC FIBROSIS STRAINS OF PSEUDOMONAS AERUGINOSA VIA DISRUPTION OF THE BACTERIAL OUTER MEMBRANE, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S297-S298, ISSN: 8755-6863

Conference paper

Bayfield KJ, Horsley A, Alton E, Irving S, Bush A, Davies JCet al., 2019, Simultaneous sulfur hexafluoride and nitrogen multiple-breath washout (MBW) to examine inherent differences in MBW outcomes, ERJ Open Research, Vol: 5, ISSN: 2312-0541

Multiple-breath washout (MBW) can be performed with different gases (sulfur hexafluoride (SF6-) and nitrogen (N2)) and different devices, all of which give discrepant results. This study aimed to confirm previously reported differences and explore factors influencing discrepant results; equipment factors or the physical properties of gases used. Methods: Healthy controls (HCs) and participants with cystic fibrosis (CF) completed MBW trials on two commercially available devices (Exhalyzer D (N2) and Innocor (SF6)). Simultaneous washout of both gases at the same time on the commercial equipment and simultaneous washouts using a respiratory mass spectrometer (RMS) were completed in subsets. Primary outcomes were lung clearance index (LCI), breath number and time required to washout. Results: Breath number was higher with N2 washout than SF6 in both HCs and patients with CF, whether washouts were completed individually or simultaneously. The difference was greater in more advanced disease, largely caused by differences in the final part of the washout. Results from commercial devices were similar to those obtained with the RMS. Conclusions: N2 MBW results were higher than SF6 MBW, with some of the largest differences reported to date being observed. The biggest impact was at the end of the washout and this was even the case when gases were washed out simultaneously. N2 and SF6 MBW results are inherently different and should be considered as independent measurements.

Journal article

Martin AD, Davis P, Davies JC, Fletcher O, Smales CMet al., 2019, DEVELOPMENT OF A RAPID POINT-OF-CARE DIAGNOSTIC IMMUNOASSAY FOR THE DETECTION OF P. AERUGINOSA IN CYSTIC FIBROSIS PATIENTS, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S291-S292, ISSN: 8755-6863

Conference paper

Waller MD, Harman K, Bayfield KJ, Saunders C, Simmonds N, Davies JC, Alton Eet al., 2019, OPPORTUNISTIC ASSESSMENT OF UPPER AND LOWER AIRWAY ELECTROPHYSIOLOGY AND LUNG FUNCTION IN CYSTIC FIBROSIS, North American Cystic Fibrosis Conference, Publisher: WILEY, Pages: S163-S163, ISSN: 8755-6863

Conference paper

Davies JC, Drevinek P, Elborn JS, Kerem E, Lee T, European CF Society ECFS Strategic Planning Task Force on Speeding up access to new 4 drugs for CF, Amaral MD, de Boeck K, Davies JC, Drevinek P, Elborn JS, Kerem E, Lee Tet al., 2019, Speeding up access to new drugs for CF: Considerations for clinical trial design and delivery, Journal of Cystic Fibrosis, Vol: 18, Pages: 677-684, ISSN: 1569-1993

The last decade has witnessed developments in the CF drug pipeline which are both exciting and unprecedented, bringing with them previously unconsidered challenges. The Task Force group was brought together to consider these challenges and possible strategies to address them. Over the last 18 months, we have discussed internally and gathered views from a broad range of individuals representing patient organisations, clinical and research teams, the pharmaceutical industry and regulatory agencies. In this and the accompanying article, we discuss two main areas of focus: i) optimising trial design and delivery for speed and efficiency; ii) drug development for patients with rare CFTR mutations. We propose some strategies to tackle the challenges ahead and highlight areas where further thought is needed. We see this as the start of a process rather than the end and hope herewith to engage the wider community in seeking solutions to improved treatments for all patients with CF.

Journal article

Amaral MD, de Boeck K, on behalf of the ECFS Strategic Planning Task Force on Speeding up access to new drugs for CF, Amaral M, Davies JC, de Boeck K, Drevinek P, Elborn S, Kerem E, Lee Tet al., 2019, Theranostics by testing CFTR modulators in patient-derived materials: The current status and a proposal for subjects with rare CFTR mutations, Journal of Cystic Fibrosis, Vol: 18, Pages: 685-692, ISSN: 1569-1993

The last decade has witnessed developments in the CF drug pipeline which are both exciting and unprecedented, bringing with them previously unconsidered challenges. The Task Force group came together to consider these challenges and possible strategies to address them. Over the last 18 months, we have discussed internally and gathered views from a broad range of individuals representing patient organizations, clinical and research teams, the pharmaceutical industry and regulatory agencies. In this and the accompanying article, we discuss two main areas of focus: i) optimising trial design and delivery for speed/efficiency; ii) drug development for patients with rare CFTR mutations. We propose some strategies to tackle the challenges ahead and highlight areas where further thought is needed. We see this as the start of a process rather than the end and hope herewith to engage the wider community in seeking solutions to improved treatments for all patients with CF.

Journal article

Davies JC, Scott S, Dobra R, Brendell R, Brownlee K, Carr SB, Cosgriff R, Simmonds NJ, London Network of Clinical Trials Accelerator Platform sites, Jahan R, Jones A, Matthews J, Brown S, Galono K, Miles K, Pao C, Shafi N, Watson D, Orchard C, Davies G, Pike K, Shah S, Bossley CJ, Fong T, Macedo P, Ruiz G, Waller M, Baker Let al., 2019, Fair selection of participants in clinical trials: The challenge to push the envelope further, Journal of Cystic Fibrosis, Vol: 18, Pages: e48-e50, ISSN: 1569-1993

Journal article

Davies JC, Van de Steen O, van Koningsbruggen-Rietschel S, Drevinek P, Derichs N, McKone EF, Kanters D, Allamassey L, Namour F, de Kock H, Conrath Ket al., 2019, GLPG1837, a CFTR potentiator, in p.Gly551Asp (G551D)-CF patients: An open-label, single-arm, phase 2a study (SAPHIRA1)., Journal of Cystic Fibrosis, Vol: 18, Pages: 693-699, ISSN: 1569-1993

BACKGROUND: Investigation of novel cystic fibrosis transmembrane conductance regulator (CFTR) potentiators, such as GLPG1837, for CF patients with gating mutations is challenging as trials require patients to withhold ivacaftor, the current standard of care. This study explored the feasibility of such a study and the impact of one-week ivacaftor withdrawal. METHODS: This open-label, single-arm study aimed to enrol 32 adults ≥18 years of age with CF and at least one p.Gly551Asp (G551D) mutation. Patients received three increasing GLPG1837 dosages twice-daily for two 7-day and one 14-day period following a one-week ivacaftor washout. The primary outcome was safety; secondary outcomes were changes in sweat chloride concentration, spirometry outcomes, and pharmacokinetics. RESULTS: Twenty-six patients enrolled; 24 completed the study. Adverse events were reported by 53.8-76.9% of patients (dosage-dependent), with respiratory adverse events most common. Mean sweat chloride concentrations decreased from 97.7 mmol/L (baseline) to 68.7 mmol/L (end of GLPG1837 treatment). In ivacaftor-pre-treated patients, mean sweat chloride concentrations rose from 42.5 mmol/L at screening to 98.5 mmol/L after ivacaftor washout. Levels were decreased following GLPG1837 treatment (to 68.8 mmol/L at treatment end). Percent predicted forced expiratory volume in 1 s declined from 73.3% at screening to 68.5% after ivacaftor washout but returned to screening level at treatment end (73.1%). CONCLUSIONS: Patient willingness to participate in the study suggests that the need for a short period of ivacaftor withdrawal may not be a barrier to development of novel potentiators, such as GLPG1837. A one-week ivacaftor washout was generally well tolerated, but resulted in a decline in lung function, which was reversed with GLPG1837 treatment to pre-washout levels. Combined with the concentration-dependent decrease in sweat chloride concentration, results show that GLPG1837 increases CFTR activity in G

Journal article

Davies JC, 2019, Trials and tribulations: The highs and lows of running cystic fibrosis drug studies, PAEDIATRIC RESPIRATORY REVIEWS, Vol: 31, Pages: 25-27, ISSN: 1526-0542

Journal article

Dobra R, Madge S, Martin I, Weldon P, Simmonds N, Davies JCet al., 2019, "Fortunate are those who take the first steps"? The psychosocial impact of novel drug development., Paediatric Respiratory Reviews, Vol: 31, Pages: 9-11, ISSN: 1526-0542

Novel drug development offers people with cystic fibrosis exciting opportunities but is not without challenges. Currently, there is an understandable emphasis on protecting patients' physical health when developing treatments. However, there appears to be little consideration of how novel drug development impacts on psychosocial wellbeing, or the downstream consequences of this. Using an illustrative case and reviewing the literature we explore themes regarding the psychosocial impact of trial participation and novel drug development and identify areas requiring further research. Through this, we hope to prepare healthcare professionals to better understand the needs of their patients in this rapidly evolving landscape.

Journal article

Turnbull A, Pyle C, Patel D, Jackson P, Hilliard T, Regamey N, Tan H-L, Brown S, Thursfield R, Short C, Mc Fie M, Alton E, Gaggar A, Blalock JE, Lloyd C, Bush A, Davies J, Snelgrove Ret al., 2019, Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis, Journal of Cystic Fibrosis, 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.

Journal article

Ahmed B, Cox M, Cuthbertson L, James P, Cookson W, Davies J, Moffatt M, Bush Aet al., 2019, Longitudinal development of the airway microbiota in infants with cystic fibrosis, Scientific Reports, Vol: 9, ISSN: 2045-2322

The pathogenesis of airway infection in cystic fibrosis (CF) is poorly understood. We performed a longitudinal study coupling clinical information with frequent sampling of the microbiota to identify changes in the airway microbiota in infancy that could underpin deterioration and potentially be targeted therapeutically. Thirty infants with CF diagnosed on newborn screening (NBS) were followed for up to two years. Two hundred and forty one throat swabs were collected as a surrogate for lower airway microbiota (median 35 days between study visits) in the largest longitudinal study of the CF oropharyngeal microbiota. Quantitative PCR and Illumina sequencing of the 16S rRNA bacterial gene were performed. Data analyses were conducted in QIIME and Phyloseq in R. Streptococcus spp. and Haemophilus spp. were the most common genera (55% and 12.5% of reads respectively) and were inversely related. Only beta (between sample) diversity changed with age (Bray Curtis r2 = 0.15, P = 0.03). Staphylococcus and Pseudomonas were rarely detected. These results suggest that Streptococcus spp. and Haemophilus spp., may play an important role in early CF. Whether they are protective against infection with more typical CF micro-organisms, or pathogenic and thus meriting treatment needs to be determined.

Journal article

Keating D, Davies J, Moskowitz S, Brown C, Horsley A, Mall M, McKone E, Plant B, Prais D, Taylor-Cousar J, Tullis E, Ramsey B, Uluer A, McKee C, Robertson S, Shilling R, Simard C, Van Goor F, Waltz D, Xuan F, Young T, Rowe Set al., 2019, PHASE 2 SAFETY AND EFFICACY: CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR) MODULATOR REGIMEN VX-659/TEZACAFTOR(TEZ)/IVACAFTOR(IVA), Publisher: WILEY, Pages: 68-68, ISSN: 1323-7799

Conference paper

Filloux A, Davies JC, 2019, Chronic infection by controlling inflammation, NATURE MICROBIOLOGY, Vol: 4, Pages: 378-379, ISSN: 2058-5276

Journal article

Davies G, Griesenbach U, Alton E, Davies JCet al., 2019, 53 - Molecular Therapies for Cystic Fibrosis, Kendig's Disorders of the Respiratory Tract in Children, Pages: 800-811.e3, ISBN: 9780323448871

© 2019 Elsevier Inc. All rights reserved. This chapter describes the therapeutic strategies for cystic fibrosis which are based on targeting cystic fibrosis transmembrane conductance regulator (CFTR), either at the gene or protein level. We provide updates on small molecule CFTR modulators and gene therapy, focusing on clinical development and evaluation. The field has seen significant progress over recent years, particularly with the CFTR potentiator, ivacaftor, in patients with class III mutations. Increased understanding of the abnormalities in the structure and function of CFTR protein will help optimize the approaches required for normalizing function and, in doing so, aid the rational design of clinical trials-both in terms of the development of more efficacious drugs and the selection of appropriate patient populations. While progress with gene therapy remains some way behind, potential benefits (including being mutation agnostic and a nonsystemic route of delivery) remain significant. It may be that future optimal approaches will harness the benefits of more than one of these approaches and lead to considerable synergy. The ultimate goal for molecular and advanced therapies in cystic fibrosis is to find drugs or combinations of drugs capable of restoring CFTR function, applicable to patients with any genetic mutation.

Book chapter

Simmonds NJ, Pabary R, Kohlhaufl J, Waller MD, Alton EA, Davies JDet al., 2018, THE ADDED VALUE OF NASAL POTENTIAL DIFFERENCE MEASUREMENT WHEN FIRST-LINE CYSTIC FIBROSIS (CF) INVESTIGATIONS ARE NON-DIAGNOSTIC, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A84-A85, ISSN: 0040-6376

Conference paper

Dobra R, Edmondson C, Hughes D, Martin I, Davies JCet al., 2018, Potentiators and Correctors in Paediatric Cystic Fibrosis Patients: A Narrative Review, PEDIATRIC DRUGS, Vol: 20, Pages: 555-566, ISSN: 1174-5878

Journal article

Davies JC, Moskowitz SM, Brown C, Horsley A, Mall MA, McKone EF, Plant BJ, Prais D, Ramsey BW, Taylor-Cousar JL, Tullis E, Uluer A, McKee CM, Robertson S, Shilling RA, Simard C, Van Goor F, Waltz D, Xuan F, Young T, Rowe SMet al., 2018, VX-659-Tezacaftor-Ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles, New England Journal of Medicine, Vol: 379, Pages: 1599-1611, ISSN: 0028-4793

BackgroundThe next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659–tezacaftor–ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis.MethodsWe evaluated the effects of VX-659–tezacaftor–ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659–tezacaftor–ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del–MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1).ResultsVX-659–tezacaftor–ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659–tezacaftor–ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659–tezacaftor–ivacaftor resulted in significant mean increases in the percentage of predicted FEV1 through day 29 (P<0.001) of up to 13.3 points in patients with Phe508del–MF genotypes; in patients with the Phe508del–Phe508del genotype already receiving tezacaftor–ivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV1. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire–Revised improved in both patient populations.ConclusionsRobust in vitro activity of VX-659–tezacaftor–ivacaftor t

Journal article

Wertheim D, Olden C, Symes L, Edmondson C, Davies J, Brownlee K, Seddon Pet al., 2018, Home monitoring of respiratory rate from pulse oximetry in children with cystic fibrosis, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

Thursfield RM, Naderi K, Leaver N, Rosenthal M, Alton EWFW, Bush A, Davies JCet al., 2018, Children with cystic fibrosis demonstrate no respiratory immunological, infective or physiological, consequences of vitamin D deficiency, Journal of Cystic Fibrosis, Vol: 17, Pages: 657-665, ISSN: 1569-1993

BACKGROUND: Vitamin D has health benefits in many respiratory diseases but the evidence in CF is unclear. Induction of the antimicrobial peptides cathelicidin (LL37) and human-beta-defensin-2 (HBD-2) may be the mechanism of any benefit. We hypothesised that antimicrobial peptide levels would be decreased, and airway infection and inflammation greater, in CF children with vitamin D deficiency. The objective of the study was to explore relationships between vitamin D, LL37 and HBD-2, and airway infection, inflammation and physiology in children with CF. METHODS: Bronchoalveolar lavage (BALF) and blood were obtained from children undergoing fibreoptic bronchoscopy. Serum vitamin D, BALF HBD-2 and LL37, cultured bacteria and inflammatory markers were measured. Clinical parameters were recorded. RESULTS: 113 patients with CF, 23 with non-CF chronic suppurative lung disease (CSLD) and 6 healthy controls were included. We found no relationship between serum vitamin D and BALF HBD-2 or LL-37. There were no differences in infective or inflammatory markers between vitamin D sufficient and deficient groups. Vitamin D deficient patients (<50 nmol/L) did not have a worse FEV1 (CF: 66 (58-71)% vs. 71.5 (61-76)%, ns; non-CF CSLD: 69 (36-88)% vs. 70 (62-95)%, ns). CONCLUSIONS: In the first bronchoscopic study exploring this question, we demonstrate that vitamin D deficiency is not associated with immunological, infective or clinical markers of disease severity in patients with CF or CSLD.

Journal article

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