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

 

G44Emmanuel Kaye BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
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399 results found

Mall MA, Brugha R, Gartner S, Legg J, Moeller A, Mondejar-Lopez P, Prais D, Pressler T, Ratjen F, Reix P, Robinson PD, Selvadurai H, Stehling F, Ahluwalia N, Arteaga-Solis E, Bruinsma BG, Jennings M, Moskowitz SM, Noel S, Tian S, Weinstock TG, Wu P, Wainwright CE, Davies JCet al., 2022, Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study., Am J Respir Crit Care Med, Vol: 206, Pages: 1361-1369

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA we

Journal article

Stanford GE, Jones M, Charman SC, Bilton D, Usmani OS, Davies JC, Simmonds NJet al., 2022, Clinimetric analysis of outcome measures for airway clearance in people with cystic fibrosis: a systematic review, Therapeutic Advances in Respiratory Disease, Vol: 16, Pages: 1-12, ISSN: 1753-4666

Background:Airway clearance techniques (ACTs) are integral to cystic fibrosis (CF) management. However, there is no consensus as to which outcome measures (OMs) are best for assessing ACT efficacy.Objectives:To summarise OMs that have been assessed for their clinimetric properties (including validity, feasibility, reliability, and reproducibility) within the context of ACT research in CF.Design and Methods:A systematic review was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) standards. Any parallel or cross-over randomised controlled trial (RCT) investigating outcome measures for ACT in the CF population were eligible for inclusion. The search was performed in five medical databases, clinicaltrials.gov, and abstracts from international CF conferences. The authors planned to independently assess study quality and risk of bias using the COnsensus-based Standards for the selection of health status Measurement InstrumeNts (COSMIN) risk of bias checklist with external validity assessment based upon study details (participants and study intervention). Two review authors (GS and MJ) independently screened search results against inclusion criteria, and further data extraction were planned but not required.Results:No completed RCTs from the 187 studies identified met inclusion criteria for the primary or post hoc secondary objective. Two ongoing trials were identified.Discussion and conclusion:This empty systematic review highlights that high-quality RCTs are urgently needed to investigate and validate the clinimetric properties of OMs used to assess ACT efficacy. With the changing demographics of CF combined with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, an accurate assessment of the current benefit of ACT or the effect of ACT withdrawal is a high priority for clinical practice and future research; OMs which have been validated for this purpose are essenti

Journal article

Hine C, Desai M, Davies J, Sapey E, Nagakumar Pet al., 2022, A systematic review of lung clearance index in non-cystic fibrosis, non-primary ciliary dyskinesia bronchiectasis, Respiratory Medicine, Vol: 201, Pages: 1-8, ISSN: 0954-6111

BackgroundNon cystic fibrosis, non primary ciliary dyskinesia bronchiectasis (nCFnPCD-BE) results in significant morbidity with few evidence-based treatments.Objectiveassessments are required to assess severity and evaluate treatment. Lung clearance index (LCI) measures ventilation inhomogeneity and is a sensitive test of disease in CF; its use in nCFnPCD-BE is unclear.MethodsA systematic review of LCI in nCFnPCD-BE was performed using standard methodology (protocol registered on PROSPERO, University of York).ResultsOf 276 records identified, 12 articles, describing 519 adult and paediatric patients in cross-sectional studies were included, addressing several domains.1: What is the utility of LCI in detecting disease and severity?LCI detected disease in adults, differentiating bronchiectasis from controls (AUC 0.90 to 0.96) and mild from moderate/severe bronchiectasis on CT (AUC 0.73).2: Does LCI correlate with spirometry and imaging?LCI correlated with spirometry in adult (r = −0.37 to −0.61) and paediatric (r = −0.6) groups, signs of bronchiectasis on CT, and CT scoring systems (modified Reiff).3: Does LCI relate to subjective scores of severity?In adults, LCI correlated with St. George's Respiratory Questionnaire (r = 0.18) and Bronchiectasis Severity Index (r = 0.45).4: Does LCI identify response to intervention?LCI did not change in studies examining LCI pre-post intervention (adults treated for exacerbation and undergoing physiotherapy).Overall study quality was variable.ConclusionContrary to data in CF, the review did not identify good quality studies defining the role of LCI in children with bronchiectasis. In adults, LCI was a sensitive measure of disease severity and correlated with clinical assessment tools.

Journal article

McLachlan G, Alton EWFW, Boyd AC, Clarke NKK, Davies JCC, Gill DRR, Griesenbach U, Hickmott JWW, Hyde S, Miah KMM, Molina CJet al., 2022, Progress in Respiratory Gene Therapy, HUMAN GENE THERAPY, Vol: 33, Pages: 893-912, ISSN: 1043-0342

Journal article

Davies J, Hughes D, Rosenthal M, Cuthbertson L, ramadan N, Felton I, Simmonds N, Loebinger M, price H, Armstrong-James D, elborn S, Cookson W, Moffatt Met al., 2022, An invisible threat? Aspergillus positive cultures and co-infecting bacteria in airway sample, Journal of Cystic Fibrosis, ISSN: 1569-1993

BackgroundAspergillus fumigatus (Af) infection is associated with poor lung health in chronic suppurative lung diseases but often goes undetected. We hypothesised that inhibition of Af growth by Pseudomonas aeruginosa (Pa) increases the frequency of false-negative Af culture in co-infected people. Using a substantial group of cystic fibrosis (CF) airway samples, we assessed the relationship between Af and bacterial pathogens, additionally comparing fungal culture with next-generation sequencing.MethodsFrequency of co-culture was assessed for 44,554 sputum/BAL cultures, from 1,367 CF patients between the years 2010–2020. In a subgroup, Internal Transcribed Spacer-2 (ITS2) fungal sequencing was used to determine sequencing-positive, culture-negative (S+/C-) rates.ResultsPa+ samples were nearly 40% less likely (P<0.0001) than Pa- samples to culture Af, an effect that was also seen with some other Gram-negative isolates. This impact varied with Pa density and appeared to be moderated by Staphylococcus aureus co-infection. Sequencing identified Af-S+/C- for 40.1% of tested sputa. Samples with Pa had higher rates of Af-S+/C- (49.3%) than those without (35.7%; RR 1.38 [1.02–1.93], P<0.05). Af-S+/C- rate was not changed by other common bacterial infections. Pa did not affect the S+/C- rates of Candida, Exophiala or Scedosporium.ConclusionsPa/ Af co-positive cultures are less common than expected in CF. Our findings suggest an Af-positive culture is less likely in the presence of Pa. Interpretation of negative cultures should be cautious, particularly in Pa-positive samples, and a companion molecular diagnostic could be useful. Further work investigating mechanisms, alternative detection techniques and other chronic suppurative lung diseases is needed.

Journal article

Dobra R, Bentley S, Edmondson C, Ovens M, Saunders C, Short C, Wilson G, Davies JC, Bush Aet al., 2022, Going the Extra Mile: Why Clinical Research in Cystic Fibrosis Must Include Children, CHILDREN-BASEL, Vol: 9

Journal article

Murphy R, Coates M, Thrane S, Sabnis A, Harrison J, Schelenz S, Edwards A, Vorup-Jensen T, Davies Jet al., 2022, Synergistic activity of repurposed peptide drug glatiramer acetate with tobramycin against cystic fibrosis Pseudomonas aeruginosa, Microbiology Spectrum, Vol: 10, ISSN: 2165-0497

Pseudomonas aeruginosa is the most common pathogen infecting the lungs of people with cystic fibrosis (CF), causing both acute and chronic infections. Intrinsic and acquired antibiotic resistance, coupled with the physical barriers resulting from desiccated CF sputum, allow P. aeruginosa to colonize and persist in spite of antibiotic treatment. As well as the specific difficulties in eradicating P. aeruginosa from CF lungs, P. aeruginosa is also subject to the wider, global issue of antimicrobial resistance. Glatiramer acetate (GA) is a peptide drug, used in the treatment of multiple sclerosis (MS), which has been shown to have moderate antipseudomonal activity. Other antimicrobial peptides (AMPs) have been shown to be antibiotic resistance breakers, potentiating the activities of antibiotics when given in combination, restoring and/or enhancing antibiotic efficacy. Growth, viability, MIC determinations, and synergy analysis showed that GA improved the efficacy of tobramycin (TOB) against reference strains of P. aeruginosa, reducing TOB MICs and synergizing with the aminoglycoside. This was also the case for clinical strains from people with CF. GA significantly reduced the MIC50 of TOB for viable cells from 1.69 mg/L (95% confidence interval [CI], 0.26 to 8.97) to 0.62 mg/L (95% CI, 0.15 to 3.94; P = 0.002) and the MIC90 for viable cells from 7.00 mg/L (95% CI, 1.18 to 26.50) to 2.20 mg/L (95% CI, 0.99 to 15.03; P = 0.001), compared to results with TOB only. Investigation of mechanisms of GA activity showed that GA resulted in significant disruption of outer membranes, depolarization of cytoplasmic membranes, and permeabilization of P. aeruginosa and was the only agent tested (including cationic AMPs) to significantly affect all three mechanisms.

Journal article

Sawicki GS, Chilvers M, McNamara J, Naehrlich L, Saunders C, Sermet-Gaudelus I, Wainwright CE, Ahluwalia N, Campbell D, Harris RS, Paz-Diaz H, Shih JL, Davies JCet al., 2022, A Phase 3, open-label, 96-week trial to study the safety, tolerability, and efficacy of tezacaftor/ivacaftor in children >= 6 years of age homozygous for F508del or heterozygous for F508del and a residual function CFTR variant, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: 675-683, ISSN: 1569-1993

Journal article

Davies J, Horsley A, Brightling C, Djukanovic R, Heaney LG, Hussell T, Marciniak SJ, McGarvey L, Porter JC, Wilkinson T, Ho L-Pet al., 2022, Early-phase clinical trials in a pandemic: learning from the response to COVID-19, The Lancet Respiratory Medicine, Vol: 10, Pages: 625-627, ISSN: 2213-2600

Journal article

King JA, Nichols A-L, Bentley S, Carr SB, Davies JCet al., 2022, An Update on CFTR Modulators as New Therapies for Cystic Fibrosis., Paediatr Drugs, Vol: 24, Pages: 321-333

Over the past decade there have been significant developments in the field of Cystic Fibrosis Transmembrane Regulator modulator drugs. Following treatment in patients with cystic fibrosis with common gating mutations using the potentiator drug ivacaftor, successive development of corrector drugs used in combination has led to highly effective modulator therapy being available to more than 85% of the cystic fibrosis population over 12 years of age in the form of elexacaftor/tezacaftor/ivacaftor. In this article, we review the evidence from clinical trials and mounting real-world observational and registry data that demonstrates the impact highly effective modulators have on both pulmonary and extra-pulmonary manifestations of cystic fibrosis. As clinical trials progress to younger patient groups, we discuss the challenges to demonstrating drug efficacy in early life, and also consider practicalities of drug development in an ever-shrinking modulator-naïve population. Drug-drug interactions are an important consideration in people with cystic fibrosis, where polypharmacy is commonplace, but also as the modulated population look to remain healthier for longer, we identify trials that aim to address treatment burden too. Inequity of care, through drug cost or ineligibility for modulators by genotype, is widening without apparent strategies to address this; however, we present evidence of hopeful early-stage drug development for non-modulatable genes and summarise the current state of gene-therapy development.

Journal article

Balfour-Lynn IM, Puckey M, Simmonds NJ, Davies JCet al., 2022, Revisiting a diagnosis of cystic fibrosis - Uncertainties and considerations, PAEDIATRIC RESPIRATORY REVIEWS, Vol: 42, Pages: 29-34, ISSN: 1526-0542

Journal article

Dixon E, Dick K, Ollosson S, Jones D, Mattock H, Bentley S, Saunders C, Matthews J, Dobra B, King J, Edmondson C, Davies JCet al., 2022, Telemedicine and cystic fibrosis: Do we still need face-to-face clinics?, PAEDIATRIC RESPIRATORY REVIEWS, Vol: 42, Pages: 23-28, ISSN: 1526-0542

Journal article

King J, Nichols A, Bentley S, Carr S, Davies Jet al., 2022, An update on CFTR modulators as new therapies for Cystic Fibrosis, Paediatric Drugs, Vol: 24, Pages: 321-333, ISSN: 1174-5878

Over the past decade there have been significant developments in the field of Cystic Fibrosis Transmembrane Regulator modulator drugs. Following treatment in patients with cystic fibrosis with common gating mutations using the potentiator drug ivacaftor, successive development of corrector drugs used in combination has led to highly effective modulator therapy being available to more than 85% of the cystic fibrosis population over 12 years of age in the form of elexacaftor/tezacaftor/ivacaftor. In this article, we review the evidence from clinical trials and mounting real-world observational and registry data that demonstrates the impact highly effective modulators have on both pulmonary and extra-pulmonary manifestations of cystic fibrosis. As clinical trials progress to younger patient groups, we discuss the challenges to demonstrating drug efficacy in early life, and also consider practicalities of drug development in an ever-shrinking modulator-naïve population. Drug–drug interactions are an important consideration in people with cystic fibrosis, where polypharmacy is commonplace, but also as the modulated population look to remain healthier for longer, we identify trials that aim to address treatment burden too. Inequity of care, through drug cost or ineligibility for modulators by genotype, is widening without apparent strategies to address this; however, we present evidence of hopeful early-stage drug development for non-modulatable genes and summarise the current state of gene-therapy development.

Journal article

Robinson PD, Jensen R, Seeto RA, Stanojevic S, Saunders C, Short C, Davies JC, Ratjen Fet al., 2022, Impact of cross-sensitivity error correction on representative nitrogen-based multiple breath washout data from clinical trials., J Cyst Fibros, Vol: 21, Pages: e204-e207

Journal article

Irving S, Bayfield K, Davies JC, Bush Aet al., 2022, Curvilinearity provides additional information to lung clearance index only in a minority of children with early cystic fibrosis lung disease, ERJ Open Research, Vol: 8, ISSN: 2312-0541

Curvilinearity, as calculated from multiple-breath washout, is abnormal in a small number of children with cystic fibrosis when other tests are still normal https://bit.ly/3p9QAV4.

Journal article

Davies J, Goss C, Fajac I, Jain R, Seibold W, Gupta A, Hsu M-C, Sutharsan S, Mall Met al., 2022, Efficacy and safety of inhaled ENaC inhibitor BI 1265162 in patients with cystic fibrosis: BALANCE–CF™ 1 – a randomised, Phase II study, European Respiratory Journal, Vol: 59, ISSN: 0903-1936

Background: Inhibition of the epithelial sodium channel (ENaC) in cystic fibrosis (CF) airways provides a mutation-agnostic approach that could improve mucociliary clearance in all CF patients. BI 1265162 is an ENaC inhibitor with demonstrated preclinical efficacy and safety already demonstrated in humans.Objective: We present results from BALANCE-CF™ 1, a Phase II, placebo-controlled, randomised, double-blind study of four dose levels of BI 1265162 versus placebo for 4 weeks on top of standard of care in adults and adolescents with CF.Results: Initially, 28 randomised subjects (n=14 each BI 1265162 200 µg BID, placebo BID) were assessed at an interim futility analysis. Compared with placebo, numerical changes of –0.8% (95%CI –6.6, 4.9) in ppFEV1 and +2.1 units (95%CI –2.4, 6.5) in LCI were observed in the active group, meeting a predefined stopping rule; accordingly, the study was terminated. Recruitment had continued during the interim analysis and pending results; 24 patients were added across three dose levels and placebo. The final results including these patients (+1.5% ppFEV1, 200 µg BID dose versus placebo) were not supportive of relevant clinical effect. LCI change was also not supportive, although interpretation was limited due to insufficient traces meeting quality criteria. A 9.4-point improvement in CFQ-R Respiratory Domain was observed in the 200 µg BID dose group versus placebo. BI 1265162 up to 200 µg BID was safe and well-tolerated. Pharmacokinetics were similar to those in healthy volunteers.Conclusion: BI 1265162 was safe, but did not demonstrate a potential for clinical benefit. Development has been terminated.

Journal article

Short C, Semple T, Saunders C, Hughes D, Irving S, Gardener L, Rosenthal M, Robinson PD, Davies JCet al., 2022, A Short extension to multiple breath washout provides additional signal of distal airway disease in people with CF: A pilot study, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: 146-154, ISSN: 1569-1993

Journal article

Southern KW, Castellani C, Lammertyn E, Smyth A, VanDevanter D, van Koningsbruggen-Rietschel S, Barben J, Bevan A, Brokaar E, Collins S, Connett GJ, Daniels TWV, Davies J, Declercq D, Gartner S, Gramegna A, Hamilton N, Hauser J, Kashirskaya N, Kessler L, Lowdon J, Makukh H, Martin C, Morrison L, Nazareth D, Noordhoek J, O'Neill C, Owen E, Oxley H, Raraigh KS, Raynal C, Robinson K, Roehmel J, Schwarz C, Sermet I, Shteinberg M, Sinha I, Takawira C, van Mourik P, Verkleij M, Waller MD, Duff Aet al., 2022, Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis, Journal of Cystic Fibrosis, ISSN: 1569-1993

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF. The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy. We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF. Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy.

Journal article

Hughes DA, Archangelidi O, Coates M, Armstrong-James D, Elborn SJ, Carr SB, Davies JCet al., 2022, Clinical characteristics of Pseudomonas and Aspergillus co-infected cystic fibrosis patients: A UK registry study, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: 129-135, ISSN: 1569-1993

Journal article

Davies J, Kos R, Brinkman P, Neerincx A, Paff T, Gerritsen M, Lammers A, Kraneveld A, Heijerman H, Janssens H, Majoor C, Weersink E, Sterk P, Haarman E, Bos L, Maitland-van der Zee A, on behalf of the Amsterdam Mucociliary Clearance Disease AMCD Research Group and the Amsterdam UMC Breath Research Groupet al., 2022, Targeted exhaled breath analysis for detection of Pseudomonas aeruginosa in cystic fibrosis patients, Journal of Cystic Fibrosis, Vol: 21, Pages: e28-e34, ISSN: 1569-1993

BackgroundPseudomonas aeruginosa (PA) is an important respiratory pathogen for cystic fibrosis (CF) patients. Routine microbiology surveillance is time-consuming, and is best performed on expectorated sputum. As alternative, volatile organic compounds (VOCs) may be indicative of PA colonisation. In this study, we aimed to identify VOCs associated with PA in literature and perform targeted exhaled breath analysis to recognize PA positive CF patients non-invasively.MethodsThis study consisted of 1) a literature review to select VOCs of interest, and 2) a cross-sectional CF study. Definitions used: A) PA positive, PA culture at visit/chronically; B) PA free, no PA culture in ≥12 months. Exhaled VOCs were identified via quadrupole MS. The primary endpoint was the area under the receiver operating characteristics curve (AUROCC) of individual VOCs as well as combined VOCs against PA culture.Results241 VOCs were identified in literature, of which 56 were further evaluated, and 13 could be detected in exhaled breath in our cohort. Exhaled breath of 25 pediatric and 28 adult CF patients, PA positive (n=16) and free (n=28) was available. 3/13 VOCs were significantly (p<0.05) different between PA groups in children; none were in adults. Notably, a composite model based on 5 or 1 VOC(s) showed an AUROCC of 0.86 (CI 0.71–1.0) and 0.87 (CI 0.72–1.0) for adults and children, respectively.ConclusionsTargeted VOC analysis appears to discriminate children and adults with and without PA positive cultures with clinically acceptable sensitivity values.

Journal article

Edmondson C, Westrupp N, Seddon P, Olden C, Wallis C, Dawson C, Brodlie M, Baxter F, McCormick J, MacFarlane S, Rice D, Macleod A, Brooker R, Connon M, Ghayyda S, Blaikie L, Thursfield R, Brown L, Price A, Fleischer E, Itterman J, Hughes D, Barrett P, Surette M, Donnelly C, Mateos-Corral D, Padley G, Wallenburg J, Brownlee K, Alton EWFW, Bush A, Davies JCet al., 2022, The feasibility of home monitoring of young people with cystic fibrosis: results from CLIMB-CF, Journal of Cystic Fibrosis, Vol: 21, Pages: 70-77, ISSN: 1569-1993

BACKGROUND: CF is traditionally assessed in clinic. It is unclear if home monitoring of young people with CF is feasible or acceptable. The COVID-19 pandemic has made home monitoring more of a necessity. We report the results of CLIMB-CF, exploring home monitoring's feasibility and potential obstacles. METHODS: We designed a mobile app and enrolled participants with CF aged 2-17 years and their parents for six months. They were asked to complete a variety of measures either daily or twice a week. During the study, participants and their parents completed questionnaires exploring depression, anxiety and quality of life. At the end of the study parents and participants completed acceptability questionnaires. RESULTS: 148 participants were recruited, 4 withdrew prior to starting the study. 82 participants were female with median (IQR) age 7.9 (5.2-12 years). Median data completeness was 40.1% (13.6-69.9%) for the whole cohort; when assessed by age participants aged ≥ 12 years contributed significantly less (15.6% [9.8-30%]). Data completeness decreased over time. There was no significant difference between parental depression and anxiety scores at the start and the end of the study nor in CFQ-R respiratory domain scores for participants ≥ 14 years. The majority of participants did not feel the introduction of home monitoring impacted their daily lives. CONCLUSIONS: Most participants felt home monitoring did not negatively impact their lives and it did not increase depression, anxiety or decrease quality of life. However, uptake was variable, and not well sustained. The teenage years pose a particular challenge and further work is required.

Journal article

King J, Murphy R, Davies JC, 2022, Pseudomonas aeruginosa in the Cystic Fibrosis Lung., Adv Exp Med Biol, Vol: 1386, Pages: 347-369, ISSN: 0065-2598

Cystic fibrosis is a common genetically inherited, multisystem disorder caused by loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an apically situated anion channel. In the lung, lack of CFTR leads to airway surface dehydration, mucociliary clearance failure and an acidic pH in which innate defence molecules are rendered ineffective. Infection occurs early in life, with P. aeruginosa dominating by adolescence. The characteristic features of the CF airway highlighted above encourage persistence of infection, but P. aeruginosa also possess an array of mechanisms with which they attack host defences and render themselves protected from antimicrobials. Early eradication is usually successful, but this is usually transient. Chronic infection is manifest by biofilm formation which is resistant to treatment. Outcomes for people with CF have improved greatly in the last few decades, but particularly so with the recent advent of small molecule CFTR modulators. However, despite impressive efficacy on lung function and exacerbation frequency, most people with chronic infection remain with their pathogens. There is an active pipeline of new treatments including anti-biofilm and anti-quorum sensing molecules and non-drug approaches such as bacteriophage. Studies are reviewed and challenges for future drug development considered.

Journal article

Ahmed B, Cox MJ, Cuthbertson L, James P, Gardner L, Cookson W, Davies J, Moffatt M, Bush Aet al., 2021, Comparison of the airway microbiota in children with chronic suppurative lung disease, BMJ Open Respiratory Research, Vol: 8, Pages: 1-10, ISSN: 2052-4439

Rationale:The airway microbiota is important in chronic suppurative lung diseases (CSLD), such as primary ciliary dyskinesia (PCD) and cystic fibrosis (CF). This comparison has not previously been described but is important because difference between the two diseases may relate to the differing prognoses and lead to pathological insights and potentially, new treatments. Objectives:To compare the longitudinal development of the airway microbiota in children with PCD to that of CF and relate this to age and clinical status. Methods:Sixty-two age-matched children (age range 0.5–17 years) with PCD or CF (n=31 in each group) were recruited prospectively and followed for 1.1 years. Throat swabs or sputum as well as clinical information were collected at routine clinical appointments. 16S rRNA gene sequencing was performed. Measurements and Main Results:The microbiota was highly individual and more diverse in PCD and differed in community composition when compared with CF. Whilst Streptococcus was the most abundant genus in both conditions, Pseudomonas was more abundant in CF with Haemophilus more abundant in PCD (Padj=0.0005). In PCD only, an inverse relationship was seen in the relative abundance of Streptococcus and Haemophilus with age. Conclusions:Bacterial community composition differs between children with PCD and those with CF. Pseudomonas is more prevalent in CF and Haemophilus in PCD, at least until infection with Pseudomonas supervenes. Interactions between organisms, particularly members of Haemophilus, Streptococcus, and Pseudomonas genera appear important. Study of the interactions between these organisms may lead to new therapies or risk stratification.

Journal article

Davies JC, 2021, The life rafts sailed; Now let's take stock and set the course ahead (Commentary), JOURNAL OF CYSTIC FIBROSIS, Vol: 20, Pages: S29-S30, ISSN: 1569-1993

Journal article

Bayfield KJ, Douglas TA, Rosenow T, Davies JC, Elborn SJ, Mall M, Paproki A, Ratjen F, Sly PD, Smyth AR, Stick S, Wainwright CE, Robinson PDet al., 2021, Time to get serious about the detection and monitoring of early lung disease in cystic fibrosis, THORAX, Vol: 76, Pages: 1255-1265, ISSN: 0040-6376

Journal article

Dobra R, Elborn JS, Madge S, Allen L, Boeri M, Kee F, Goundry S, Purcell T, Saunders C, Davies JCet al., 2021, Guiding the rational design of patient-centred drug trials in Cystic Fibrosis: A Delphi study, JOURNAL OF CYSTIC FIBROSIS, Vol: 20, Pages: 986-993, ISSN: 1569-1993

Journal article

Derichs N, Taylor-Cousar JL, Davies JC, Fajac I, Tullis E, Nazareth D, Downey DG, Rosenbluth D, Malfroot A, Saunders C, Jensen R, Solomon GM, Vermeulen F, Kaiser A, Willmann S, Saleh S, Droebner K, Sandner P, Bear CE, Hoffmann A, Ratjen F, Rowe SMet al., 2021, Riociguat for the treatment of Phe508del homozygous adults with cystic fibrosis, JOURNAL OF CYSTIC FIBROSIS, Vol: 20, Pages: 1018-1025, ISSN: 1569-1993

Journal article

Bentley S, Davies J, Gastine S, Donovan J, Standing JFet al., 2021, Clinical pharmacokinetics and dose recommendations for posaconazole gastro-resistant tablets in children with Cystic Fibrosis, Journal of Antimicrobial Chemotherapy, Vol: 76, Pages: 3247-3254, ISSN: 0305-7453

ObjectivesTo investigate the population pharmacokinetics of posaconazole gastro-resistant tablets in children with Cystic Fibrosis (CF), and perform simulations to recommend optimal doses.Patients and methodsChildren from a paediatric CF centre who had received posaconazole tablets and underwent therapeutic drug monitoring were identified from Pharmacy records. Relevant clinical data was collated from case notes and electronic patient records and used to develop an allometrically scaled population pharmacokinetic model. A step-wise covariate model building exercise evaluated the influence of interacting medicines and liver function.Results One hundred posaconazole serum concentrations were collected from 37 children with a median age of 14 years (range 7-17). Posaconazole pharmacokinetics were adequately described by a one-compartment model with inter-individual variability on clearance. Dose simulations demonstrated a 77-83% probability of attaining a trough target of 1 mg/L with a dose of 300 mg every 12 hours for 2 doses then 300 mg once daily (OD) in children aged 6-11 years; and 86-88% with a dose of 400 mg every 12 hours for 2 doses then 400 mg OD in adolescents aged 12-17 years. This dose scheme also yields a 90% probability of achieving an AUC of 30 mg.h/L. AUC and trough concentration were highly correlated (r2=0.98). Simulations showed that trough concentrations of >0.75 mg/L would exceed an AUC of 30mg.h/L in 90% of patients.ConclusionsA starting dose of 300mg OD in 6-11 years and 400mg OD in 12-17 years (following loading doses) yields a 90% probability of attaining an AUC of 30 mg.h/L.

Journal article

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