Athol U Wells

Royal Brompton and Harefield NHS Foundation Trust, Harefield, England, United Kingdom

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Publications (481)2458.31 Total impact

  • No preview · Article · Feb 2016 · Pneumologie
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    ABSTRACT: Background: Irrreversible interstitial lung disease (ILD) is associated with high morbidity and mortality. Palliative care needs of patients and caregivers are not routinely assessed; there is no tool to identify needs and triage support in clinical practice. Objective: The study objective was to adapt and face/content validate a palliative needs assessment tool for people with ILD. Methods: The Needs Assessment Tool: Progressive Disease-Cancer (NAT:PD-C) was adapted to reflect the palliative care needs identified from the ILD literature and patient/caregiver interviews. Face and content validity of the NAT:PD-ILD was tested using patient/caregiver focus groups and an expert consensus group. Participants in the study were two English tertiary health care trusts' outpatients clinics. There were four focus groups: two patient (n = 7; n = 4); one caregiver (n = 3); and one clinician (n = 8). There was a single caregiver interview, and an expert consensus group-academics (n = 3), clinicians (n = 9), patients (n = 4), and caregivers (n = 2). Each item in the tool was revised as agreed by the groups. Expert consensus was reached. Results: Overall, the tool reflected participants' experience of ILD. Each domain was considered relevant. Adaptations were needed to represent the burden of ILD: respiratory symptoms (especially cough) and concerns about sexual activity were highlighted. All emphasized assessment of caregiver need as critical, and the role of caregivers in clinical consultations. Conclusions: The NAT:PD-ILD appears to have face and content validity. The inclusion of the family caregiver in the consultation as someone with their own needs as well as a source of information was welcomed. Reliability testing and construct validation of the tool are ongoing.
    Full-text · Article · Feb 2016 · Journal of palliative medicine

  • No preview · Article · Jan 2016

  • No preview · Article · Jan 2016
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    ABSTRACT: Objective: Early diffuse cutaneous systemic sclerosis (dcSSc) is characterized by rapid changes in the skin and internal organs. The objective of this study was to develop a composite response index in dcSSc (CRISS) for use in randomized controlled trials (RCTs). Methods: We developed 150 paper patient profiles with standardized clinical outcome elements (core set items) using patients with dcSSc. Forty scleroderma experts rated 20 patient profiles each and assessed whether each patient had improved or not improved over a period of 1 year. Using the profiles for which raters had reached a consensus on whether the patients were improved versus not improved (79% of the profiles examined), we fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to followup were entered as covariates. We tested the final index in a previously completed RCT. Results: Sixteen of 31 core items were included in the patient profiles after a consensus meeting and review of test characteristics of patient-level data. In the logistic regression model in which the included core set items were change over 1 year in the modified Rodnan skin thickness score, the forced vital capacity, the patient and physician global assessments, and the Health Assessment Questionnaire disability index, sensitivity was 0.982 (95% confidence interval 0.982-0.983) and specificity was 0.931 (95% confidence interval 0.930-0.932), and the model with these 5 items had the highest face validity. Subjects with a significant worsening of renal or cardiopulmonary involvement were classified as not improved, regardless of improvements in other core items. With use of the index, the effect of methotrexate could be differentiated from the effect of placebo in a 1-year RCT (P = 0.02). Conclusion: We have developed a CRISS that is appropriate for use as an outcome assessment in RCTs of early dcSSc.
    Full-text · Article · Jan 2016 · Arthritis and Rheumatology
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    ABSTRACT: Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosis produce low levels of prostaglandin E2, due to a limited capacity to up-regulate cyclooxygenase-2. This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood.In the present study we examined whether the reduced level of cyclooxygenase-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5 Aza-2'-deoxycytidine restored cyclooxygenase-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of prostaglandin E2 production, collagen mRNA expression and sensitivity to apoptosis. Cyclooxygenase-2 methylation assessed by bisulphite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, c8orf4, which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knock-down of c8orf4 in control fibroblasts down-regulated cyclooxygenase-2 and prostaglandin E2 production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates cyclooxygenase-2 expression in lung fibroblasts through binding of the proximal promoter.We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate cyclooxygenase-2 expression and cyclooxygenase-2 derived prostaglandin E2 synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4.
    No preview · Article · Jan 2016 · Clinical Science
  • Koralia E Paschalaki · Joseph Jacob · Athol U Wells
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    ABSTRACT: The monitoring of lung involvement in patients with connective tissue diseases is central to optimal long-term management and is directed towards: (a) the detection of supervening lung involvement not present at presentation and (b) the identification of disease progression in established lung disease. For both goals, accurate surveillance requires multi-disciplinary evaluation with the integration of symptomatic change, serial pulmonary function trends and imaging data. Evaluated in isolation, each of these monitoring domains has significant limitations. Symptomatic change may be confounded by a wide variety of systemic factors. Pulmonary function tests provide the most reliable data, but are limited by measurement variability, the heterogeneity of functional patterns and the confounding effects of non-pulmonary factors. Chest radiography is insensitive to change but may provide rapid confirmation of major disease progression or alert the clinician to respiratory co-morbidities. Although high-resolution computed tomography has a central role in assessing disease severity, it should be used very selectively as a monitoring tool due to the associated radiation burden. Ancillary tests include echocardiography and exercise testing to proactively identify cases of pulmonary hypertension and worsening of oxygenation. In summary, a multi-disciplinary approach is essential for the identification of disease progression and prompt treatment of comorbidities that severely impact on the morbidity and mortality of disease.
    No preview · Article · Jan 2016 · Respiration
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    Full-text · Article · Jan 2016 · European Respiratory Journal
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    ABSTRACT: Objective: In systemic sclerosis (SSc), pulmonary function tests (PFTs) have been included in screening algorithms for pulmonary hypertension (PH). However, in combined pulmonary fibrosis and emphysema (CPFE), the interpretation of PFT is confounded. We examined the prevalence of CPFE in SSc patients with interstitial lung disease (SSc-ILD) and the effect of CPFE on PFTs used to evaluate the severity of SSc-ILD and the likelihood of PH. Methods: HRCT scans of 333 SSc-ILD patients were evaluated for the presence of emphysema, extent of interstitial lung disease. The effects of emphysema were quantified on relationships between pulmonary function variables and a) the extent of SSc-ILD on HRCT; and b) echocardiographic evidence of PH. Results: Emphysema was present in 41/333 cases overall (12.3%), in 26/132 smokers (19.7%) and in 15/201 life-long non smokers (7.5%). With the extent of fibrosis taken into account, emphysema was associated with signficant additional changes from expected values in DLco (- 24.1%, p<0.0005), pO2, (p=0.04), and FVC/DLco (+ 34.8%, p<0.0005) but not in FVC. These effects were identical in smokers and non-smokers. On multivariate analysis, the presence of emphysema had a greater effect than echocardiographic PH on FVC/DLco, whether analysed as a continuous variable or using thresholds of 1.6 or 2.0. Conclusion: In SSc-ILD, emphysema is sporadically present in non-smokers and is associated with a low pack-year smoking history in smokers. The confounding effect of CPFE on measures of gas exchange has major implications for the construction of screening algorithms for PH in SSc-ILD. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · Arthritis and Rheumatology
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    ABSTRACT: In the 2013 reclassification of the idiopathic interstitial pneumonias (IIPs), two rare IIPs (idiopathic lymphoid interstitial pneumonia (LIP), idiopathic pleuroparenchymal fibroelastosis (IPPFE)) and two rare histologic patterns (acute fibrinous and organizing pneumonia (AFOP), bronchiolocentric pattern of interstitial pneumonia (BPIP)) are described. All these entities are rare with small series published to date, mostly containing primary and secondary forms of disease. LIP is histologically characterized by diffuse polyclonal lymphoid cell infiltrate surrounding the airways and expanding the interstitium. Thin-walled cysts and diffuse ground glass are considered the typical radiologic features. The clinical course is highly variable with corticosteroid responsiveness evident in approximately half of cases. IPPFE is defined histologically by coexisting upper lobe pleural and intra-alveolar fibrosis with elastosis. Dense subpleural irregular fibrosis and consolidation are the cardinal radiologic features. A history of recurrent lower respiratory tract infection is frequent. Responses to immunomodulation have not been reported and the rate of progression appears to be highly variable. AFOP is a rare histologic pattern lying within the spectrum of acute/subacute lung injury, characterized by organizing pneumonia and intra-alveolar fibrin deposition without hyaline membranes. BPIP is characterized histologically by fibrosis and/or inflammation confined to the alveolar interstitium around bronchovascular bundles, overlapping with peribronchial metaplasia and fibrosis in some series. Currently, AFOP and BPIP are both best viewed as histological entities rather than true clinical disorders, in the absence of characteristic associated imaging patterns and clinical features.
    No preview · Article · Dec 2015 · Respirology
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    ABSTRACT: Background: The extent of lung involvement visualized by high-resolution computed tomography (HRCT) is a predictor of decline in forced vital capacity (FVC) in scleroderma-interstitial lung disease. Our objective was to evaluate the performance of three different HRCT-defined staging systems in the Scleroderma Lung Study I (SLS I) over a 1-year period. Methods: We assessed two visual semiquantitative scores: the maximum fibrosis score (MaxFib, the fibrosis score in the zone of maximal lung involvement) and visual assessment of total lung involvement (TLI) as proposed by Goh and Wells. In addition, we evaluated the computer-aided diagnosis and calculated the quantitative percentage with fibrosis (QLF) and TLI. Results: The mean duration of the disease was 3.2 years, and the mean FVC was 67.7 %. Regardless of the staging system used, a greater degree of fibrosis/TLI on HRCT scans was associated with a greater decline in FVC in the placebo group. Using the MaxFib and QLF, the mean absolute changes in FVC from baseline were 0.1 % and -1.4 %, respectively, in <25 % lung involvement vs. a change of -6.2 % and -6.9 %, respectively, with >25 % involvement (negative score denotes worsening in FVC). Conversely, cyclophosphamide was able to stabilize decline in FVC in subjects with greater degree of involvement detected by HRCT. Using the visual MaxFib and QLF, the mean absolute improvements in FVC were 1.2 and 1.1, respectively, with >25 % involvement. Conclusions: HRCT-defined lung involvement was a predictor of decline in FVC in SLS I. The choice of staging system for cohort enrichment in a clinical trial depends on feasibility. Trial registration: identifier: NCT00004563 (Scleroderma Lung Study I) ISRCTN15982171. Registered 19 Aug 2015.
    Full-text · Article · Dec 2015 · Arthritis research & therapy
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    ABSTRACT: Objectives: To establish the level of observer variation for the current ATS/ERS/JRS/ALAT criteria for a diagnosis of usual interstitial pneumonia (UIP) on CT among a large group of thoracic radiologists of varying levels of experience. Materials and methods: 112 observers (96 of whom were thoracic radiologists) categorised CTs of 150 consecutive patients with fibrotic lung disease using the ATS/ERS/JRS/ALAT CT criteria for a UIP pattern (3 categories-UIP, possibly UIP and inconsistent with UIP). The presence of honeycombing, traction bronchiectasis and emphysema was also scored using a 3-point scale (definitely present, possibly present, absent). Observer agreement for the UIP categorisation and for the 3 CT patterns in the entire observer group and in subgroups stratified by observer experience, were evaluated. Results: Interobserver agreement across the diagnosis category scores among the 112 observers was moderate, ranging from 0.48 (IQR 0.18) for general radiologists to 0.52 (IQR 0.20) for thoracic radiologists of 10-20 years' experience. A binary score for UIP versus possible or inconsistent with UIP was examined. Observer agreement for this binary score was only moderate. No significant differences in agreement levels were identified when the CTs were stratified according to multidisciplinary team (MDT) diagnosis or patient age or when observers were categorised according to experience. Observer agreement for each of honeycombing, traction bronchiectasis and emphysema were 0.59±0.12, 0.42±0.15 and 0.43±0.18, respectively. Conclusions: Interobserver agreement for the current ATS/ERS/JRS/ALAT CT criteria for UIP is only moderate among thoracic radiologists, irrespective of their experience, and did not vary with patient age or the MDT diagnosis.
    No preview · Article · Nov 2015 · Thorax
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    ABSTRACT: Objective To address the impact of bronchoscopic lung cryobiopsy (BLC) on diagnostic confidence in the multidisciplinary diagnosis of IPF. Methods In this cross-sectional study we selected 117 patients with fibrotic ILDs without a typical usual interstitial pneumonia pattern on HRCT. All cases underwent lung biopsies: 58 were BLC and 59 were SLB. Two clinicians, two radiologists and two pathologists sequentially reviewed clinical-radiological findings and biopsy results, recording at each step in the process their diagnostic impressions and confidence levels. Measurements and Main Results We observed a major increase in diagnostic confidence after the addition of BLC, similar to SLB (from 29 to 63%, p= 0.0003 and from 30 to 65%, P= 0.0016 of high confidence IPF diagnosis, in the BLC group and SLB group respectively). The overall inter-observer agreement in IPF diagnosis was similar for both approaches (BLC overall kappa 0.96; SLB overall kappa 0.93). IPF was the most frequent diagnosis (50% and 39% in the BLC and SLB group respectively; p=0.23). After the addition of histopathologic information 17% of cases in the BLC group and 19% of cases in the SLB group, mostly iNSIP and HP, were reclassified as IPF. Conclusions BLC is a new biopsy method that has a meaningful impact on diagnostic confidence in the multidisciplinary diagnosis of ILDs, and may prove useful in the diagnosis of IPF. This study provides a robust rationale for future studies investigating the diagnostic accuracy of BLC compared to SLB.
    No preview · Article · Nov 2015 · American Journal of Respiratory and Critical Care Medicine
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    ABSTRACT: The objective of this study was to determine the safety and efficacy of carlumab in the treatment of idiopathic pulmonary fibrosis (IPF).A phase 2, randomised, double-blind placebo-controlled dose-ranging study was conducted in patients with IPF (n=126). Patients were randomised to carlumab (1 mg·kg(-1), 5 mg·kg(-1), or 15 mg·kg(-1)) or placebo every 4 weeks. The primary endpoint was the rate of percentage change in forced vital capacity (FVC). Secondary endpoints were time to disease progression, absolute change in FVC, relative change in diffusing capacity of the lung for carbon monoxide (DLCO), and St George's Respiratory Questionnaire (SGRQ) total score.Due to a pre-planned, unfavourable interim benefit-risk analysis, dosing was suspended. The rate of percentage change in FVC showed no treatment effect (placebo -0.582%, 1 mg·kg(-1) -0.533%, 5 mg·kg(-1) -0.799% and 15 mg·kg(-1) -0.470%; p=0.261). All active treatment groups showed a greater decline in FVC (1 mg·kg(-1) -290 mL, 5 mg·kg(-1) -370 mL and 15 mg·kg(-1) -320 mL) compared with placebo (-130 mL). No effect on disease progression, DLCO, infection rates or mortality was observed. SGRQ scores showed a nonsignificant trend toward worsening with active treatment. Unexpectedly, free CC-chemokine ligand 2 levels were elevated above baseline at both 24 and 52 weeks. A higher proportion of patients with one or more serious adverse events was observed in the 5 mg·kg(-1) group (53.1%) compared with 1 mg·kg(-1) (15.2%), 15 mg·kg(-1) (21.9%) and placebo (46.4%), although no unexpected serious adverse events were noted.Although dosing was stopped prematurely, it is unlikely that carlumab provides benefit to IPF patients.
    No preview · Article · Oct 2015 · European Respiratory Journal

  • No preview · Article · Oct 2015 · Chest
  • Vasileios Kouranos · Joe Jacob · Athol U. Wells
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    ABSTRACT: In sarcoidosis, reduction in mortality and the prevention of disability due to major organ involvement are treatment goals. Thus, it is important to recognize severe disease and identify patients at higher risk of progression to severe disease. In this article, fibrotic lung disease and cardiac sarcoidosis are reviewed as the major contributors to sarcoidosis mortality and morbidity. In the absence of a standardized definition of severe pulmonary disease, a multidisciplinary approach to clinical staging is suggested, based on symptoms, pulmonary function tests, and imaging findings at presentation, integrated with the duration of disease and longitudinal disease behavior during early follow-up.
    No preview · Article · Oct 2015
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    ABSTRACT: Background: Idiopathic pulmonary fibrosis is a progressive lung disease with variable course in individuals. The Gender-Age-Physiology (GAP) Index stage uses clinical variables to stage mortality risk. It is unknown whether clinical staging predicts future pulmonary function decline. We assess whether the GAP stage predicts future pulmonary function decline, and whether interval pulmonary function change predicts mortality after accounting for stage. Methods: Patients with Idiopathic Pulmonary Fibrosis (n=657) were identified retrospectively at three tertiary referral centers and baseline GAP stage assessed. Mixed models describe average trajectories of forced vital capacity (FVC) and diffusion capacity (DLCO). Multivariable Cox proportional hazards models assess whether pulmonary function declines of 10% or more in 6 months predict mortality after accounting for stage. Results: Over 2 years, GAP stage was not associated with differences in yearly lung function decline. After accounting for stage, a 10% decrease in FVC or DLCO over 6 months independently predicted death or transplant (FVC HR=1.37, DLCO HR 1.30, both p≤0.03). GAP stage 2 patients with declining pulmonary function experienced a survival profile similar to GAP 3 patients with 1-year event-free survival of 59.3% (CI95% 49.4-67.8) versus 56.9% (CI95% 42.2-69.1). Conclusions: Baseline GAP stage predicts death or lung transplantation, but not the rate of future pulmonary function decline. After accounting for GAP stage, a decline of 10% or more over 6 months independently predicts death or lung transplant.
    No preview · Article · Oct 2015 · Chest
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    ABSTRACT: Background Fibroblastic foci profusion on histopathology and severity of traction bronchiectasis on highresolution computed tomography (HRCT) have been shown to be predictors of mortality in patients with idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the relationship between fibroblastic foci (FF) profusion and HRCT patterns in patients with a histopathologic diagnosis of usual interstitial pneumonia (UIP), fibrotic non-specific interstitial pneumonia (NSIP) and chronic hypersensitivity pneumonitis (CHP). Methods The HRCT scans of 162 patients with a histopathologic diagnosis of UIP or fibrotic NSIP (n = 162) were scored on extent of groundglass opacification, reticulation, honeycombing, emphysema and severity of traction bronchiectasis. For each patient, a fibroblastic foci profusion score based on histopathologic appearances was assigned. Relationships between extent of fibroblastic foci and individual HRCT patterns were investigated using univariate correlation analysis and multivariate linear regression. Results Increasing extent of reticulation (P < 0.0001) and increasing severity of traction bronchiectasis (P < 0.0001) were independently associated with increasing FF score within the entire cohort. Within individual multidisciplinary team diagnosis subgroups, the only significant independent association with FF score was severity of traction bronchiectasis in patients with idiopathic pulmonary fibrosis (IPF)/UIP (n = 66, r2 = 0.19, P < 0.0001) and patients with chronic hypersensitivity pneumonitis (CHP) (n = 49, r2 = 0.45, P < 0.0001). Furthermore, FF score had the strongest association with severity of traction bronchiectasis in patients with IPF (r2 = 0.34, P < 0.0001) and CHP (r2 = 0.35, P < 0.0001). There was no correlation between FF score and severity of traction bronchiectasis in patients with fibrotic NSIP. Global disease extent had the strongest association with severity of traction bronchiectasis in patients with fibrotic NSIP (r2 = 0.58, P < 0.0001). Conclusion In patients with fibrotic lung disease, profusion of fibroblastic foci is strikingly related to the severity of traction bronchiectasis, particularly in IPF and CHP. This may explain the growing evidence that traction bronchiectasis is a predictor of mortality in several fibrotic lung diseases.
    Preview · Article · Sep 2015 · BMC Medicine
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    ABSTRACT: For many years has been well known that smoking could cause lung damage. Chronic obstructive pulmonary disease and lung cancer have been the two most common smoking-related lung diseases. In the recent years, attention has also focused on the role of smoking in the development of interstitial lung diseases (ILDs). Indeed, there are three diseases, namely respiratory bronchiolitis-associated ILD, desquamative interstitial pneumonia and pulmonary Langerhans cell histiocytosis, that are currently considered aetiologically linked to smoking and a few others which are more likely to develop in smokers. Here, we aim to focus on the most recent findings regarding the role of smoking in the pathogenesis and clinical behaviour of ILDs. Copyright ©ERS 2015.
    Preview · Article · Sep 2015 · European Respiratory Review

  • No preview · Article · Sep 2015 · European Respiratory Journal

Publication Stats

17k Citations
2,458.31 Total Impact Points


  • 1995-2016
    • Royal Brompton and Harefield NHS Foundation Trust
      • • Respiratory Medicine
      • • Department of Paediatrics
      Harefield, England, United Kingdom
  • 2002-2015
    • Imperial College London
      • • Section of Immunology
      • • Department of Computing
      Londinium, England, United Kingdom
    • Utrecht University
      Utrecht, Utrecht, Netherlands
  • 2013
    • University of Crete
      • School of Medicine
      Retimo, Crete, Greece
  • 2012
    • Imperial College Healthcare NHS Trust
      • Division of Respiratory Medicine
      Londinium, England, United Kingdom
  • 2002-2012
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
  • 2011
    • Royal United Hospital Bath NHS Trust
      Bath, England, United Kingdom
  • 2010
    • Heart Research Institute (UK)
      Norwich, England, United Kingdom
    • University Hospital of Parma
      Parma, Emilia-Romagna, Italy
  • 1995-2010
    • The Heart Lung Center
      Londinium, England, United Kingdom
  • 2008
    • Vancouver General Hospital
      • Department of Radiology
      Vancouver, British Columbia, Canada
  • 2007
    • Hôpital Avicenne – Hôpitaux Universitaires Paris-Seine-Saint-Denis
      Bobigny, Île-de-France, France
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, CA, United States
    • National Heart Institute
      New Dilli, NCT, India
  • 2004-2007
    • King's College London
      • Division of Asthma, Allergy and Lung Biology
      Londinium, England, United Kingdom
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 2005
    • Canterbury District Health Board
      Christchurch, Canterbury, New Zealand
  • 2000-2005
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 2003
    • St. Antonius Ziekenhuis
      Nieuwegen, Utrecht, Netherlands
    • ICL
      Londinium, England, United Kingdom
  • 1997-2003
    • University of Auckland
      • Department of Medicine
      Окленд, Auckland, New Zealand
  • 2001
    • Masaryk University
      • Faculty of Medicine
      Brünn, South Moravian, Czech Republic
  • 1999
    • Auckland City Hospital
      Окленд, Auckland, New Zealand

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