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  • Journal article
    Garcia-Marcos L, Edwards J, Kennington E, Aurora P, Baraldi E, Carraro S, Gappa M, Louis R, Moreno-Galdo A, Peroni DG, Pijnenburg M, Priftis KN, Sanchez-Solis M, Schuster A, Walker S, Blakey J, Compton C, Fleming L, Fowler S, Gaillard E, Gibson F, Glenn Crater G, Niven R, Roberts A, Ryan D, Seppala U, Usmani O, van der Schee M, van Sont Jet al., 2018,

    Priorities for future research into asthma diagnostic tools: A PAN-EU consensus exercise from the European asthma research innovation partnership (EARIP)

    , Clinical and Experimental Allergy, Vol: 48, Pages: 104-120, ISSN: 0954-7894

    The diagnosis of asthma is currently based on clinical history, physical examination and lung function, and to date, there are no accurate objective tests either to confirm the diagnosis or to discriminate between different types of asthma. This consensus exercise reviews the state of the art in asthma diagnosis to identify opportunities for future investment based on the likelihood of their successful development, potential for widespread adoption and their perceived impact on asthma patients. Using a two-stage e-Delphi process and a summarizing workshop, a group of European asthma experts including health professionals, researchers, people with asthma and industry representatives ranked the potential impact of research investment in each technique or tool for asthma diagnosis and monitoring. After a systematic review of the literature, 21 statements were extracted and were subject of the two-stage Delphi process. Eleven statements were scored 3 or more and were further discussed and ranked in a face-to-face workshop. The three most important diagnostic/predictive tools ranked were as follows: “New biological markers of asthma (eg genomics, proteomics and metabolomics) as a tool for diagnosis and/or monitoring,” “Prediction of future asthma in preschool children with reasonable accuracy” and “Tools to measure volatile organic compounds (VOCs) in exhaled breath.”.

  • Journal article
    Farne H, Groves H, Gill S, stokes I, Mccolloch S, karoly E, Trujillo-Torralbo M, Johnston S, Mallia P, Tregoning Jet al., 2018,

    Comparative metabolomic sampling of upper and lower airways by four different methods to identify biochemicals that may support bacterial growth

    , Frontiers in Cellular and Infection Microbiology, Vol: 8, ISSN: 2235-2988

    Bacteria need nutrients from the host environment to survive, yet we know little about which biochemicals are present in the airways (the metabolome), which of these biochemicals are essential for bacterial growth and how they change with airway disease. The aims of this pilot study were to develop and compare methodologies for sampling the upper and lower airway metabolomes and to identify biochemicals present in the airways that could potentially support bacterial growth. Eight healthy human volunteers were sampled by four methods: two standard approaches - nasal lavage and induced sputum, and two using a novel platform, synthetic adsorptive matrix (SAM) strips—nasosorption and bronchosorption. Collected samples were analyzed by Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS). Five hundred and eighty-one biochemicals were recovered from the airways belonging to a range of metabolomic super-pathways. We observed significant differences between the sampling approaches. Significantly more biochemicals were recovered when SAM strips were used, compared to standard sampling techniques. A range of biochemicals that could support bacterial growth were detected in the different samples. This work demonstrates for the first time that SAM strips are a highly effective method for sampling the airway metabolome. This work will assist further studies to understand how changes in the airway metabolome affect bacterial infection in patients with underlying airway disease.

  • Journal article
    Grigg J, Nibber A, Paton JY, Chisholm A, Guilbert TW, Kaplan A, Turner S, Roche N, Hillyer E, Price DB, van Aalderen WMC, Murray CS, Phipatanakul W, Sonnappa S, Hoe TO, Martin RJ, Papi A, Szefler SJ, Skinner D, McQueen RB, Usmani OSet al., 2018,

    Matched cohort study of therapeutic strategies to prevent preschool wheezing/asthma attacks

    , JOURNAL OF ASTHMA AND ALLERGY, Vol: 11, ISSN: 1178-6965
  • Journal article
    Owen J, Kamila S, Shrivastava S, Carugo D, Bernardino de la Serna J, Mannaris C, Pereno V, Browning R, Beguin E, McHale AP, Callan JF, Stride Eet al., 2018,

    The Role of PEG-40-stearate in the Production, Morphology, and Stability of Microbubbles.

    , Langmuir

    Phospholipid coated microbubbles are currently in widespread clinical use as ultrasound contrast agents and under investigation for therapeutic applications. Previous studies have demonstrated the importance of the coating nanostructure in determining microbubble stability and its dependence upon both composition and processing method. While the influence of different phospholipids has been widely investigated, the role of other constituents such as emulsifiers has received comparatively little attention. Herein, we present an examination of the impact of polyethylene glycol (PEG) derivatives upon microbubble structure and properties. We present data using both pegylated phospholipids and a fluorescent PEG-40-stearate analogue synthesized in-house to directly observe its distribution in the microbubble coating. We examined microbubbles of clinically relevant sizes, investigating both their surface properties and population size distribution and stability. Domain formation was observed only on the surface of larger microbubbles, which were found to contain a higher concentration of PEG-40-stearate. Lipid analogue dyes were also found to influence domain formation compared with PEG-40-stearate alone. "Squeezing out" of PEG-40-stearate was not observed from any of the microbubble sizes investigated. At ambient temperature, microbubbles formulated with DSPE-PEG(2000) were found to be more stable than those containing PEG-40-stearate. At 37 °C, however, the stability in serum was found to be the same for both formulations, and no difference in acoustic backscatter was detected. This could potentially reduce the cost of PEGylated microbubbles and facilitate simpler attachment of targeting or therapeutic species. However, whether PEG-40-stearate sufficiently shields microbubbles to inhibit physiological clearance mechanisms still requires investigation.

  • Conference paper
    Moore AJS, Dean LSN, Fraceto LF, Lima R, Tetley TDet al., 2018,

    THE EFFECTS OF A NOVEL POLY(EPSILON-CAPROLACTONE) NANOCAPSULE CONTAINING THE PESTICIDE ATRAZINE ON HUMAN ALVEOLAR EPITHELIUM

    , Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A20-A21, ISSN: 0040-6376
  • Conference paper
    Fei L, Fraser J, Padmanaban V, Boniface A, Wyman E, Maguire M, Stone M, Elkin S, Mallia Pet al., 2018,

    FRAILTY IN HOSPITALISED COPD PATIENTS

    , Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A170-A170, ISSN: 0040-6376
  • Conference paper
    Finney LJ, Belchamber KBR, Kemp SV, Fenwick P, Mallia P, Donaldson G, Johnston SL, Donnelly L, Wedzicha JAet al., 2018,

    HUMAN RHINOVIRUS IMPAIRS THE INNATE IMMUNE RESPONSE TO BACTERIA IN MACROPHAGES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

    , Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A9-A9, ISSN: 0040-6376
  • Journal article
    Loeckx M, Rabinovich RA, Demeyer H, Louvaris Z, Tanner R, Rubio N, Frei A, De Jong C, Gimeno-Santos E, Rodrigues FM, Buttery SC, Hopkinson NS, Busching G, Strassmann A, Serra I, Vogiatzis I, Garcia-Aymerich J, Polkey MI, Troosters Tet al., 2018,

    Smartphone-based physical activity telecoaching in chronic obstructive pulmonary disease: Mixed-methods study on patient experiences and lessons for implementation

    , JMIR mHealth and uHealth, Vol: 6, ISSN: 2291-5222

    Background: Telecoaching approaches can enhance physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD). However, their effectiveness is likely to be influenced by intervention-specific characteristics.Objective: This study aimed to assess the acceptability, actual usage, and feasibility of a complex PA telecoaching intervention from both patient and coach perspectives and link these to the effectiveness of the intervention.Methods: We conducted a mixed-methods study based on the completers of the intervention group (N=159) included in an (effective) 12-week PA telecoaching intervention. This semiautomated telecoaching intervention consisted of a step counter and a smartphone app. Data from a project-tailored questionnaire (quantitative data) were combined with data from patient interviews and a coach focus group (qualitative data) to investigate patient and coach acceptability, actual usage, and feasibility of the intervention. The degree of actual usage of the smartphone and step counter was also derived from app data. Both actual usage and perception of feasibility were linked to objectively measured change in PA.Results: The intervention was well accepted and perceived as feasible by all coaches present in the focus group as well by patients, with 89.3% (142/159) of patients indicating that they enjoyed taking part. Only a minority of patients (8.2%; 13/159) reported that they found it difficult to use the smartphone. Actual usage of the step counter was excellent, with patients wearing it for a median (25th-75th percentiles) of 6.3 (5.8-6.8) days per week, which did not change over time (P=.98). The smartphone interface was used less frequently and actual usage of all daily tasks decreased significantly over time (P<.001). Patients needing more contact time had a smaller increase in PA, with mean (SD) of +193 (SD 2375) steps per day, +907 (SD 2306) steps per day, and +1489 (SD 2310) steps per day in high, medium, and low contact

  • Journal article
    Cowie MR, Gallagher AM, Simonds AK, 2018,

    Treating central sleep apnoea in heart failure: is pull better than push?

    , European Journal of Heart Failure, Vol: 20, Pages: 1755-1759, ISSN: 1388-9842
  • Journal article
    Li F, Xu M, Wang M, Wang L, Wang H, Zhang H, Chen Y, Gong J, Zhang JJ, Adcock IM, Chung KF, Zhou Xet al., 2018,

    Roles of mitochondrial ROS and NLRP3 inflammasome in multiple ozone-induced lung inflammation and emphysema

    , Respiratory Research, Vol: 19, ISSN: 1465-9921

    BackgroundMitochondrial damage leading to oxidant stress may play an important role in the pathogenesis of airflow obstruction and emphysema. NLPR3 inflammasome can be activated by mitochondrial ROS (mtROS) and other stimuli. We examined the importance of mtROS and NLRP3 inflammasome and their interactions in multiple ozone-induced lung inflammation and emphysema.MethodsC57/BL6 mice were exposed to ozone (2.5 ppm, 3 h) or filtered air twice a week over 6 weeks. MitoTEMPO (20 mg/kg), an inhibitor of mtROS, and VX765 (100 mg/kg), an inhibitor of caspase-1 activity, were administered by intraperitoneal or intragastric injection respectively 1 h prior to each ozone exposure for 6 weeks.ResultsOzone-exposed mice had increased bronchoalveolar lavage (BAL) total cells and levels of IL-1β, KC and IL-6, augmented lung tissue inflammation scores, enhanced oxidative stress with higher serum 8-OHdG concentrations, emphysema with greater mean linear intercept (Lm), airway remodeling with increased airway smooth muscle mass and airflow limitation as indicated by a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV25/FVC, FEV50/FVC). Both MitoTEMPO and VX765 reduced lung inflammation scores, cytokine levels, oxidative stress and increased mitochondrial fission proteins. VX765 also attenuated emphysema, airway remodeling and airflow limitation. MitoTEMPO inhibited the increased expression of mitochondrial complex II and IV and of NLPR3 while VX765 inhibited the expression and activity of NLRP3 and caspase-1 pathway in the lung.ConclusionsBoth mtROS and NLRP3 inflammasome play a role in ozone-induced lung inflammation while only NLRP3 is involved in ozone-induced emphysema.

  • Journal article
    Compte M, Lykke Harwood S, Munoz IG, Navarro R, Zonca M, Perez-Chacon G, Erce-Llamazares A, Merino N, Tapia-Galisteo A, Cuesta AM, Mikkelsen K, Caleiras E, Nunez-Prado N, Aznar MA, Lykkemark S, Martinez-Torrecuadrada J, Melero I, Blanco FJ, Bernardino de la Serna J, Zapata JM, Sanz L, Alvarez-Vallina Let al., 2018,

    A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity

    , Nature Communications, Vol: 9, ISSN: 2041-1723

    The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with FcγR interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8N/CEGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8N/CEGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8N/CEGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate FcγR interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy.

  • Journal article
    Simonds AK, 2018,

    Happy ever after? A new assessment tool for long-term noninvasive ventilation: the S-3-NIV questionnaire

    , EUROPEAN RESPIRATORY JOURNAL, Vol: 52, ISSN: 0903-1936
  • Journal article
    Buttery S, Kemp S, Shah P, Waller D, Jordan S, Lee JL, Banya W, Steiner M, Hopkinson Net al., 2018,

    The CELEB trial: Comparative effectiveness of lung volume reduction surgery for emphysema and bronchoscopic lung volume reduction with valve placement. A protocol for a randomised controlled trial

    , BMJ Open, Vol: 8, ISSN: 2044-6055

    Introduction: Although lung volume reduction surgery and bronchoscopic lung volume reduction with endobronchial valves have both been shown to improve lung function, exercise capacity and quality of life in appropriately selected patients with emphysema, there are no direct comparison data between the two procedures to inform clinical decision making. Methods and Analysis: We describe the protocol of the CELEB study (ISRCTN19684749), a randomised controlled trial which will compare outcomes at 1 year between the two procedures, using a composite disease severity measure, the iBODE score, which includes body mass index, lung function, breathlessness and exercise capacity.Ethics and Dissemination: Ethical approval to conduct the study has been obtained from the Fulham Research Ethics Committee, London (16/LO/0286). The outcome of this trial will provide information to guide treatment choices in this population and will be presented at national and international meetings and published in peer-reviewed journals. We will also disseminate the main results to all participants in a letter.

  • Journal article
    Wang Y, Xu J, Meng Y, Adcock IM, Yao Xet al., 2018,

    Role of inflammatory cells in airway remodeling in COPD

    , International Journal of Chronic Obstructive Pulmonary Disease, Vol: 13, Pages: 3341-3348, ISSN: 1176-9106

    COPD is characterized by chronic bronchitis, chronic airway obstruction, and emphysema, leading to a progressive and irreversible decline in lung function. Inflammation is central for the development of COPD. Chronic inflammation in COPD mainly involves the infiltration of neutrophils, macrophages, lymphocytes, and other inflammatory cells into the small airways. The contribution of resident airway structural cells to the inflammatory process is also important in COPD. Airway remodeling consists of detrimental changes in structural tissues and cells including airway wall thickening, epithelial metaplasia, goblet cell hypertrophy, and smooth muscle hyperplasia. Persistent airway inflammation might contribute to airway remodeling and small airway obstruction. However, the underlying mechanisms remain unclear. In this review, we will provide an overview of recent insights into the role of major immunoinflammatory cells in COPD airway remodeling.

  • Conference paper
    Meldrum K, Robertson SB, Gant TW, Tetley TD, Smith R, Leonard MOet al., 2018,

    Transcriptional changes underlying cerium dioxide nanoparticle modulation of allergen induced type II airway inflammation

    , 54th Congress of the European-Societies-of-Toxicology (EUROTOX) - Toxicology Out of the Box, Publisher: ELSEVIER IRELAND LTD, Pages: S213-S213, ISSN: 0378-4274
  • Journal article
    Jia M, Yan X, Jiang X, Wu Y, Xu J, Meng Y, Yang Y, Shan X, Zhang X, Mao S, Gu W, Pavlidis S, Barnes PJ, Adcock IM, Huang M, Yao Xet al., 2018,

    Ezrin, a Membrane Cytoskeleton Cross Linker Protein, as a Marker of Epithelial Damage in Asthma.

    , Am J Respir Crit Care Med

    RATIONALE: Bronchial epithelial cell damage occurs in patients with bronchial asthma. Ezrin, a membrane-cytoskeleton protein, maintains cellular morphology and intercellular adhesion and protects the barrier function of epithelial cells. OBJECTIVES: To study the role of ezrin in bronchial epithelial cells injury and correlate its expression with asthma severity. METHODS: Levels of ezrin were measured in exhaled breath condensate (EBC) and serum in asthma patients and bronchoalveolar lavage fluid (BALF) from a mouse model of asthma by ELISA. The regulation of IL-13 on ezrin protein levels was studied in primary bronchial epithelial cells (PBECs). Ezrin knockdown using shRNA was studied in human bronchial epithelial 16HBE cells. RESULTS: Ezrin levels were decreased in asthmatic EBC (392.7±34.99 vs 150.5±10.22 pg/ml, p<0.0001) and serum (700.7±55.59 vs 279.2±25.83pg/ml, p<0.0001) compared to normal subjects. Levels were much lower in uncontrolled (p<0.001) and partly-controlled patients (p<0.01) compared to well-controlled subjects. EBC and serum ezrin levels correlated with lung function in asthma patients and serum ezrin levels were negatively correlated with serum IL-13 and periostin. IL-13-induced down-regulation of ezrin expression in PBECs was significantly attenuated by the JAK2 (Janus tyrosine kinase 2) inhibitor TG101348. Ezrin knockdown changed 16HBE cell morphology, enlarged intercellular spaces and increased their permeability. Ezrin expression was decreased in the lung tissue and BALF of 'asthmatic' mice and negatively correlated with BALF IL-13 level. CONCLUSIONS: Ezrin down-regulation is associated with IL-13-induced epithelial damage and might be a potential biomarker of asthma control.

  • Journal article
    Visca D, Mori L, Tsipouri V, Fleming S, Firouzi A, Bonini M, Pavitt MJ, Alfieri V, Canu S, Bonifazi M, Boccabella C, De Lauretis A, Stock CJW, Saunders P, Montgomery A, Hogben C, Stockford A, Pittet M, Brown J, Chua F, George PM, Molyneaux PL, Margaritopoulos GA, Kokosi M, Kouranos V, Russell AM, Birring SS, Chetta A, Maher TM, Cullinan P, Hopkinson NS, Banya W, Whitty JA, Adamali H, Spencer LG, Farquhar M, Sestini P, Wells AU, Renzoni EAet al., 2018,

    Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial

    , Lancet Respiratory Medicine, Vol: 6, Pages: 759-770, ISSN: 2213-2600

    BACKGROUND: In fibrotic interstitial lung diseases, exertional breathlessness is strongly linked to health-related quality of life (HRQOL). Breathlessness is often associated with oxygen desaturation, but few data about the use of ambulatory oxygen in patients with fibrotic interstitial lung disease are available. We aimed to assess the effects of ambulatory oxygen on HRQOL in patients with interstitial lung disease with isolated exertional hypoxia. METHODS: AmbOx was a prospective, open-label, mixed-method, crossover randomised controlled clinical trial done at three centres for interstitial lung disease in the UK. Eligible patients were aged 18 years or older, had fibrotic interstitial lung disease, were not hypoxic at rest but had a fall in transcutaneous arterial oxygen saturation to 88% or less on a screening visit 6-min walk test (6MWT), and had self-reported stable respiratory symptoms in the previous 2 weeks. Participants were randomly assigned (1:1) to either oxygen treatment or no oxygen treatment for 2 weeks, followed by crossover for another 2 weeks. Randomisation was by a computer-generated sequence of treatments randomly permuted in blocks of constant size (fixed size of ten). The primary outcome, which was assessed by intention to treat, was the change in total score on the King's Brief Interstitial Lung Disease questionnaire (K-BILD) after 2 weeks on oxygen compared with 2 weeks of no treatment. General linear models with treatment sequence as a fixed effect were used for analysis. Patient views were explored through semi-structured topic-guided interviews in a subgroup of participants. This study was registered with ClinicalTrials.gov, number NCT02286063, and is closed to new participants with all follow-up completed. FINDINGS: Between Sept 10, 2014, and Oct 5, 2016, 84 patients were randomly assigned, 41 randomised to ambulatory oxygen first and 43 to no oxygen. 76 participants completed the trial. Compared with no oxygen, ambulatory oxygen was ass

  • Journal article
    Allinson JP, Hardy R, Donaldson GC, Wedzicha JAet al., 2018,

    Childhood exposures, asthma, smoking, interactions and the catch-up hypothesis

    , Annals of the American Thoracic Society, Vol: 15, Pages: 1241-1242, ISSN: 2329-6933
  • Journal article
    Hoffmann C, Hanisch M, Heinsohn JAB, Dostal V, Jehn M, Liebers U, Pankow W, Donaldson GC, Witt Cet al., 2018,

    Increased vulnerability of COPD patient groups to urban climate in view of global warming

    , International Journal of Chronic Obstructive Pulmonary Disease, Vol: 13, Pages: 3493-3501, ISSN: 1176-9106

    Purpose: Patients with COPD show an increase in acute exacerbations (AECOPD) during the cold season as well as during heat waves in the summer months. Due to global climate changes, extreme weather conditions are likely to occur more frequently in the future. The goal of this study was to identify patient groups most at risk of exacerbations during the four seasons of the year and to determine at which temperature threshold the daily hospital admissions due to AECOPD increase during the summer.Patients and methods: We analyzed retrospective demographic and medical data of 990 patients, who were hospitalized for AECOPD in Berlin, Germany. The cases were grouped into the following cohorts: “spring” (admission between March and May), “summer” (June – August), “autumn” (September – November), and “winter” (December – February). AECOPD hospital admissions from 2006 and 2010 were grouped into a “hot summer” cohort and cases from 2011 and 2012 into a “cold summer” data-set. Climate data were obtained from the German Meteorological Office.Results: Patients hospitalized for a COPD exacerbation during winter were significantly older than summertime patients (P=0.040) and also thinner than patients exacerbating in spring (P=0.042). COPD exacerbations during hot summer periods happened more often to patients with a history of myocardial infarction (P=0.014) or active smokers (P=0.011). An AECOPD during colder summers occurred in patients with a higher Charlson index, who suffered in increased numbers from peripheral vascular diseases (P=0.016) or tumors (P=0.004). Summertime hospital admissions increased above a daily minimum temperature of 18.3°C (P=0.006).Conclusion: The identification of COPD patient groups most at risk for climate related exacerbations enables climate-adapted prevention through patient guidance and treatment. In view of global climate changes, discovering vulnerabi

  • Journal article
    Moroni-Zentgraf P, Usmani OS, Halpin DMG, 2018,

    Inhalation devices

    , Canadian Respiratory Journal, Vol: 2018, ISSN: 1198-2241

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