Publications
256 results found
Gorlitz F, Lightley J, Kumar S, et al., 2019, Automated multiwell plate STORM: towards open source super-resolved high content analysis, Conference on Advances in Microscopic Imaging II, Publisher: SPIE-INT SOC OPTICAL ENGINEERING, ISSN: 0277-786X
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- Citations: 1
Anders KL, Belchamber KBR, Gaboriau DCA, et al., 2019, Dynein Has Defective Activity in COPD Macrophage Phagocytosis, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wrench CL, Baker JR, Fenwick PS, et al., 2019, Senescence and Fibrotic Markers Are Induced by Oxidative Stress in Small Airway Fibroblasts from COPD Patients, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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- Citations: 2
Fenwick P, Taylor A, Ujetz J, et al., 2019, Antagonism of Sphingosine-1-Phosphate Receptors Improves Macrophage Phagocytosis of Bacteria in COPD Patients, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Finney LJ, Belchamber KBR, Kemp SV, et 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
Belchamber KBR, Thomas C, Dunne A, et al., 2018, Comparison of fluticasone propionate and budesonide on COPD macrophage and neutrophil function, International Journal of COPD, Vol: 2018, Pages: 2883-2897, ISSN: 1176-9106
Background: Inhaled corticosteroid (ICS) use is associated with increased rates of pneumonia in COPD patients. The underlying mechanism is unknown although recent data suggest that pneumonia is more frequent in patients treated with fluticasone propionate (FP) than budesonide. Macrophages and neutrophils from COPD patients are deficient in clearing bacteria and this might explain increased bacterial colonisation in COPD. ICS may further suppress this response; therefore, we examined the effect of FP and budesonide on phagocytosis of common respiratory pathogens by monocyte-derived macrophages (MDM) and neutrophils.Methods: MDM from COPD patients (n=20-24) were pre-incubated with FP or budesonide for 1 or 18 h after which phagocytosis of fluorescently labelled inert beads or heat-killed Haemophilus influenzae or Streptococcus pneumoniae were measured fluorimetrically after 1 or 4 h. Additionally, the following was measured: CXCL-8, IL-6 and TNFα concentrations in supernatants by ELISA, MDM scavenger receptor expression by flow cytometry, and the MDM ability to kill bacteria. Neutrophils from COPD patients (n=8) were pre-incubated with corticosteroids for 1 h, and phagocytosis of bacteria was measured by flow cytometry. Results: After 1 h pre-incubation, neither corticosteroid altered MDM phagocytosis of beads or H. influenzae; however, budesonide (10-7M) increased phagocytosis of S. pneumoniae by 23% (P<0.05). After 18 h pre-incubation, neither corticosteroid altered MDM phagocytosis of any prey, although phagocytosis of H. influenzae by budesonide was significantly greater compared to FP at 10-6 and 10-5M (P<0.05). The 1 h pre-incubation with either corticosteroid inhibited bacteria-induced CXCL-8 release (at 10-7 and 10-5M, P<0.05); however, this effect was lost at 18 h pre-incubation. There was no change in receptor expression, bacterial killing or neutrophil phagocytosis by either corticosteroid. Conclusions: These data suggest that dissolved FP an
Wrench C, Baker J, Fenwick P, et al., 2018, Small airway fibroblasts from COPD patients are senescent and pro-fibrotic, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 4
Bewley M, Budd R, Ryan E, et al., 2018, Opsonic phagocytosis in chronic obstructive pulmonary disease is enhanced by Nrf2 agonists, American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 739-750, ISSN: 1073-449X
Rationale: Previous studies have identified defects in bacterial phagocytosis by alveolar macrophages (AM) in patients with chronic obstructive pulmonary disease (COPD) but the mechanisms and clinical consequences remain incompletely defined.Objectives: To examine the effect of COPD on AM phagocytic responses and identify the mechanisms, clinical consequences and potential for therapeutic manipulation of these defects.Methods: We isolated alveolar macrophages (AM) and monocyte-derived macrophages (MDM) from a cohort of COPD patients and controls within the MRC COPD-MAP consortium and measured phagocytosis of bacteria in relation to opsonic conditions and clinical features.Measurements and Main Results: COPD AM and MDM have impaired phagocytosis of S. pneumoniae. COPD AM have a selective defect in uptake of opsonized bacteria, despite the presence of anti-pneumococcal antibodies in bronchoalveolar lavage, not observed in MDM or healthy donor’s AM. AM defects in phagocytosis in COPD are significantly associated with exacerbation frequency, isolation of pathogenic bacteria and health related quality of life scores. Bacterial binding and initial intracellular killing of opsonized bacteria in COPD AM was not reduced. COPD AM have reduced transcriptional responses to opsonized bacteria, including cellular stress responses that include transcriptional modules involving antioxidant defenses and Nrf2-regualted genes. Agonists of the cytoprotective transcription factor Nrf2 (sulforaphane and Compound 7) reverse defects in phagocytosis of S. pneumoniae and non-type able Haemophilus influenzae by COPD AM. Conclusions: Patients with COPD have clinically relevant defects in opsonic phagocytosis by AM, associated with impaired transcriptional responses to cellular stress, which are reversed by therapeutic targeting with Nrf2 agonists.
Bhandari A, Baker J, Donnelly L, et al., 2018, Metformin regulates sirtuin expression in airway epithelial cells, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Finney L, Belchamber K, Fenwick P, et al., 2018, Human rhinovirus impairs macrophage innate immune responses to bacteria via the interferon pathway in COPD, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Baker J, Vuppusetty C, Colley T, et al., 2018, MicroRNA-570 is a novel regulator of cellular senescence and inflammaging, FASEB Journal, ISSN: 0892-6638
Diseases of accelerated aging often occur together (multimorbidity), and their prevalence is increasing, with high societal and health care costs. Chronic obstructive pulmonary disease (COPD) is one such condition, in which one half of patients exhibit ≥4 age-related diseases. Diseases of accelerated aging share common molecular pathways, which lead to the detrimental accumulation of senescent cells. These senescent cells no longer divide but release multiple inflammatory proteins, known as the senescence-associated secretory phenotype, which may perpetuate and speed disease. Here, we show that inhibiting miR-570-3p, which is increased in COPD cells, reverses cellular senescence by restoring the antiaging molecule sirtuin-1. MiR-570-3p is induced by oxidative stress in airway epithelial cells through p38 MAP kinase-c-Jun signaling and drives senescence by inhibiting sirtuin-1. Inhibition of elevated miR-570-3p in COPD small airway epithelial cells, using an antagomir, restores sirtuin-1 and suppresses markers of cellular senescence (p16INK4a, p21Waf1, and p27Kip1), thereby restoring cellular growth by allowing progression through the cell cycle. MiR-570-3p inhibition also suppresses the senescence-associated secretory phenotype (matrix metalloproteinases-2/9, C-X-C motif chemokine ligand 8, IL-1β, and IL-6). Collectively, these data suggest that inhibiting miR-570-3p rejuvenates cells via restoration of sirtuin-1, reducing many of the abnormalities associated with cellular senescence.—Baker, J. R., Vuppusetty, C., Colley, T., Hassibi, S., Fenwick, P. S., Donnelly, L. E., Ito, K., Barnes, P. J. MicroRNA-570 is a novel regulator of cellular senescence and inflammaging.
Dai Y, Yeo SCM, Barnes P, et al., 2018, Pre-clinical pharmacokinetic and metabolomic analyses of isorhapontigenin, a dietary resveratrol derivative, Frontiers in Pharmacology, Vol: 9, ISSN: 1663-9812
Background: Isorhapontigenin (trans–3,5,4′-trihydroxy–3′–methoxystilbene, ISO), a dietary resveratrol (trans–3,5,4′–trihydroxystilbene) derivative, possesses various health-promoting activities. To further evaluate its medicinal potentials, the pharmacokinetic and metabolomic profiles of ISO were examined in Sprague-Dawley rats.Methods: The plasma pharmacokinetics and metabolomics were monitored by liquid chromatography–tandem mass spectrometry (LC–MS/MS) and gas chromatography–tandem mass spectrometry (GC–MS/MS), respectively.Results: Upon intravenous injection (90 μmol/kg), ISO exhibited a fairly rapid clearance (CL) and short mean residence time (MRT). After a single oral administration (100 μmol/kg), ISO was rapidly absorbed and showed a long residence in the systemic circulation. Dose escalation to 200 μmol/kg resulted in higher dose-normalized maximal plasma concentrations (Cmax/Dose), dose-normalized plasma exposures (AUC/Dose), and oral bioavailability (F). One-week repeated daily dosing of ISO did not alter its major oral pharmacokinetic parameters. Pharmacokinetic comparisons clearly indicated that ISO displayed pharmacokinetic profiles superior to resveratrol as its Cmax/Dose, AUC/Dose, and F were approximately two to three folds greater than resveratrol. Metabolomic investigation revealed that 1-week ISO administration significantly reduced plasma concentrations of arachidonic acid, cholesterol, fructose, allantoin, and cadaverine but increased tryptamine levels, indicating its impact on metabolic pathways related to health-promoting effects.Conclusion: ISO displayed favorable pharmacokinetic profiles and may be a promising nutraceutical in view of its health-promoting properties.
Yanagisawa S, Baker JR, Vuppusetty C, et al., 2018, The dynamic shuttling of SIRT1 between cytoplasm and nuclei in bronchial epithelial cells by single and repeated cigarette smoke exposure, PLoS ONE, Vol: 13, ISSN: 1932-6203
SIRT1 (silent information regulator 2 homolog 1) is a crucial cellular survival protein especially in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types. Here, we show for the first time the dynamics of SIRT1 in the presence of single or concurrent cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). In BEAS-2B HBEC or primary HBEC, SIRT1 was localized predominantly in cytoplasm, and the CSE (3%) induced nuclear translocation of SIRT1 from cytoplasm in the presence of L-buthionine sulfoximine (an irreversible inhibitor of γ-glutamylcystein synthetase), mainly through the activation of phosphatidylinositol 3-kinase (PI3K) α subunit. This SIRT1 nuclear shuttling was associated with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase (SOD) 2 and 3; therefore seemed to be an adaptive response. When BEAS-2B cells were pretreated with repeated exposure to a lower concentration of CSE (0.3%), the CSE-induced SIRT1 shuttling and resultant SOD2/3 mRNA induction were significantly impaired. Thus, this result offers a useful cell model to mimic the impaired anti-oxidant capacity in cigarette smoking-associated lung disease such as chronic obstructive pulmonary disease.
Wrench C, Belchamber K, Bercusson A, et al., 2018, Reduced Clearance of Fungal Spores by Chronic Obstructive Pulmonary Disease GM-CSF- and M-CSF-derived Macrophages, Publisher: American Thoracic Society, Pages: 271-273, ISSN: 1044-1549
Pabreja K, Erriah M, Baines KJ, et al., 2018, Effect of Galectin-3 on Macrophage Efferocytosis in Asthma, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Belchamber K, Barnes PJ, Donnelly L, 2018, Aberrant Scavenger Receptor Response to Bacterial Phagocytosis in COPD Macrophages, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Wang Z, Singh R, Miller BE, et al., 2017, Sputum microbiome temporal variability and dysbiosis in chronic obstructive pulmonary disease exacerbations: an analysis of the COPDMAP study, Thorax, Vol: 73, Pages: 331-338, ISSN: 1468-3296
BACKGROUND: Recent studies suggest that lung microbiome dysbiosis, the disease associated disruption of the lung microbial community, might play a key role in chronic obstructive pulmonary disease (COPD) exacerbations. However, characterising temporal variability of the microbiome from large longitudinal COPD cohorts is needed to better understand this phenomenon. METHODS: We performed a 16S ribosomal RNA survey of microbiome on 716 sputum samples collected longitudinally at baseline and exacerbations from 281 subjects with COPD at three UK clinical centres as part of the COPDMAP consortium. RESULTS: The microbiome composition was similar among centres and between stable and exacerbations except for a small significant decrease of Veillonella at exacerbations. The abundance of Moraxella was negatively associated with bacterial alpha diversity. Microbiomes were distinct between exacerbations associated with bacteria versus eosinophilic airway inflammation. Dysbiosis at exacerbations, measured as significant within subject deviation of microbial composition relative to baseline, was present in 41% of exacerbations. Dysbiosis was associated with increased exacerbation severity indicated by a greater fall in forced expiratory volume in one second, forced vital capacity and a greater increase in CAT score, particularly in exacerbations with concurrent eosinophilic inflammation. There was a significant difference of temporal variability of microbial alpha and beta diversity among centres. The variation of beta diversity significantly decreased in those subjects with frequent historical exacerbations. CONCLUSIONS: Microbial dysbiosis is a feature of some exacerbations and its presence, especially in concert with eosinophilic inflammation, is associated with more severe exacerbations indicated by a greater fall in lung function. TRIAL REGISTRATION NUMBER: Results, NCT01620645.
Duffett EC, Fenwick PS, Barnes PJ, et al., 2017, PHOSPHOINOSITIDE-3 KINASE AND MEK INHIBITION PREVENTS UPTAKE OF BACTERIA BY AIRWAY EPITHELIAL CELLS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A111-A111, ISSN: 0040-6376
Belchamber KBR, Donnelly LE, 2017, Correcting the "Wandering" Neutrophil with Statins A Novel Antiaging Strategy?, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 196, Pages: 1243-1244, ISSN: 1073-449X
Erriah M, Pabreja K, Baines KJ, et al., 2017, EFFEROCYTOSIS OF APOPTOTIC GRANULOCYTES BY MONOCYTE-DERIVED MACROPHAGES IN ADULTS WITH ASTHMA, Publisher: WILEY, Pages: 83-83, ISSN: 1323-7799
Bewley MA, Preston JA, Mohasin M, et al., 2017, Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 196, Pages: 845-855, ISSN: 1073-449X
Roux BT, Heward JA, Donnelly LE, et al., 2017, Catalog of Differentially Expressed Long Non-Coding RNA following Activation of Human and Mouse Innate Immune Response, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
Despite increasing evidence to indicate that long non-coding RNAs (lncRNAs) are novel regulators of immunity, there has been no systematic attempt to identify and characterize the lncRNAs whose expression is changed following the induction of the innate immune response. To address this issue, we have employed next-generation sequencing data to determine the changes in the lncRNA profile in four human (monocytes, macrophages, epithelium, and chondrocytes) and four mouse cell types (RAW 264.7 macrophages, bone marrow-derived macrophages, peritoneal macrophages, and splenic dendritic cells) following exposure to the pro-inflammatory mediators, lipopolysaccharides (LPS), or interleukin-1β. We show differential expression of 204 human and 210 mouse lncRNAs, with positional analysis demonstrating correlation with immune-related genes. These lncRNAs are predominantly cell-type specific, composed of large regions of repeat sequences, and show poor evolutionary conservation. Comparison within the human and mouse sequences showed less than 1% sequence conservation, although we identified multiple conserved motifs. Of the 204 human lncRNAs, 21 overlapped with syntenic mouse lncRNAs, of which five were differentially expressed in both species. Among these syntenic lncRNA was IL7-AS (antisense), which was induced in multiple cell types and shown to regulate the production of the pro-inflammatory mediator interleukin-6 in both human and mouse cells. In summary, we have identified and characterized those lncRNAs that are differentially expressed following activation of the human and mouse innate immune responses and believe that these catalogs will provide the foundation for the future analysis of the role of lncRNAs in immune and inflammatory responses.
Paschalaki KE, Zampetaki A, Baker JR, et al., 2017, Downregulation of MicroRNA-126 Augments DNA Damage Response in Cigarette Smokers and COPD Patients., Am J Respir Crit Care Med
Yanagisawa S, Baker JR, Vuppusetty C, et al., 2017, Decreased phosphatase PTEN amplifies PI3K signaling and enhances pro-inflammatory cytokine release in COPD, American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol: 313, Pages: L230-L239, ISSN: 1522-1504
The phosphatidylinositol 3-kinase (PI3K) pathway is activated in chronic obstructive pulmonary disease (COPD), but the regulatory mechanisms for this pathway are yet to be elucidated. Our aim was to determine the expression and role of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the PI3K pathway, in COPD. PTEN expression and activity were measured in the peripheral lung of COPD patients compared to smoking and non-smoking controls. The direct influence of cigarette smoke extract (CSE) on PTEN expression was assessed using primary lung epithelial cells and a cell line (BEAS-2B) in the presence or absence of L-buthionine-sulfoximine (BSO) to deplete intracellular glutathione. The impact of PTEN knock-down by RNA interference on cytokine production was also examined. In peripheral lung, PTEN protein was significantly decreased in patients with COPD compared to the subjects without COPD (p < 0.001), and positively correlated with the severity of air-flow obstruction (FEV1 % predicted; r = 0.50; p = 0.0012), although no difference was observed in PTEN activity. Conversely, phosphorylated Akt, as a marker of PI3K activation, showed a negative correlation with PTEN protein levels (r = -0.41; p = 0.0042). Both in primary bronchial epithelial cells and BEAS-2B cell line, CSE decreased PTEN protein, which was reversed by N-acetylcysteine treatment. PTEN knock-down potentiated Akt phosphorylation and enhanced production of pro-inflammatory cytokines, such as IL-6, CXCL8, CCL2 and CCL5. In conclusion, oxidative stress reduces PTEN protein levels, which may result in increased PI3K signaling and amplification of inflammation in COPD.
Yeo SCM, Fenwick PS, Barnes PJ, et al., 2017, Isorhapontigenin, a bioavailable dietary polyphenol, suppresses airway epithelial cell inflammation through a corticosteroid-independent mechanism, British Journal of Pharmacology, Vol: 174, Pages: 2043-2059, ISSN: 1476-5381
Background and PurposeChronic obstructive pulmonary disease (COPD) is a corticosteroid-resistant airway inflammatory condition. Resveratrol has exhibited anti-inflammatory activities in COPD but has weak potency and poor pharmacokinetics. This study aims to evaluate the potential of isorhapontigenin, another dietary polyphenol, as a novel anti-inflammatory agent for COPD by examining its effects in vitro and its pharmacokinetics in vivo.Experimental ApproachPrimary human airway epithelial cells derived from healthy and COPD subjects and A549 epithelial cells were incubated with isorhapontigenin or resveratrol and stimulated with IL-1β in the presence or absence of cigarette smoke extract. Their effects on the release of IL-6 and chemokine (C-X-C motif) ligand 8 (CXCL8) were determined and the activation of NF-κB, AP-1, MAPKs and PI3K/Akt/FoxO3A pathways compared to dexamethasone were evaluated. The pharmacokinetic profiles of isorhapontigenin were assessed in Sprague-Dawley rats after respective intravenous and oral administration.Key ResultsIsorhapontigenin exhibited concentration-dependent inhibition of IL-6 and CXCL8 release, with IC50 values at least two-fold lower than resveratrol. These were associated with suppressed NF-κB and AP-1 activation and notably, the PI3K/Akt/FoxO3A pathway that was relatively insensitive to dexamethasone. In vivo, isorhapontigenin was rapidly absorbed with abundant plasma exposure after oral dosing. Its oral bioavailability was approximately 50% higher than resveratrol.Conclusions and ImplicationsIsorhapontigenin, an orally bioavailable dietary polyphenol, displayed superior anti-inflammatory effects compared to resveratrol. Furthermore, it suppressed the PI3K/Akt pathway that is insensitive to corticosteroids. These favourable efficacy and pharmacokinetic properties support its further development as a novel anti-inflammatory agent for COPD.
Belchamber KBR, Donnelly LE, 2017, Macrophage Dysfunction in Respiratory Disease., Pages: 299-313
In the healthy lung, macrophages maintain homeostasis by clearing inhaled particles, bacteria, and removing apoptotic cells from the local pulmonary environment. However, in respiratory diseases including chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis, macrophages appear to be dysfunctional and may contribute to disease pathogenesis. In COPD, phagocytosis of bacterial species and apoptotic cells by both alveolar macrophages and monocyte-derived macrophages is significantly reduced, leading to colonization of the lung with pathogenic bacteria. COPD macrophages also release high levels of pro-inflammatory cytokines and chemokines, including CXCL8, TGFβ, and CCL2, driving recruitment of other inflammatory cells including neutrophils and monocytes to the lungs and promoting disease progression.In asthma, defective phagocytosis and efferocytosis have also been reported, and macrophages appear to have altered cell surface receptor expression; however, it is as yet unclear how this contributes to disease progression but may be important in driving Th2-mediated inflammation. In cystic fibrosis, macrophages also display defective phagocytosis, and reduced bacterial killing, which may be driven by the pro-inflammatory environment present in the lungs of these patients.The mechanisms behind defective macrophage function in lung diseases are not currently understood, but potential mechanisms include alterations in phagocytic receptor expression levels, oxidative stress, but also the possibility that specific diseases are associated with a specific, altered, macrophage phenotype that displays reduced function. Identification of the mechanisms responsible may present novel therapeutic opportunities for treatment.
Walton GM, Belchamber KBR, Hughes SM, et al., 2017, Non-Typeable Haemophilus Influenzae Is Associated With Rapid Lung Function Decline And Poor Macrophage And Neutrophil Phagocytosis In Patients With Alpha-1 Anti-Trypsin Deficiency, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Tilman J, Barnes PJ, Donnelly L, 2017, COPD Monocyte-Derived And Tissue Macrophages Are Driven By Gm-Csf Towards A Pro-Inflammatory Phenotype, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Belchamber KBR, Barnes PJ, Donnelly L, 2017, Altered Scavenger Receptor Expression In COPD Macrophages After Bacterial Phagocytosis, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Dacie RL, Belchamber KB, Donnelly LE, 2016, THE EFFECTS OF ELECTRONIC CIGARETTE FLAVOURINGS ON MACROPHAGE CYTOKINE RELEASE AND PHAGOCYTOSIS, British Thoracic Society Winter Meeting 2016, Publisher: BMJ PUBLISHING GROUP, Pages: A72-A73, ISSN: 0040-6376
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