المؤلفون: Inês Farinha, Liam G Heaney

المصدر: Respiratory Research, Vol 25, Iss 1, Pp 1-8 (2024)

مصطلحات موضوعية: Asthma, Clinical remission, Biologics, Diseases of the respiratory system, RC705-779

الوصف: Abstract Severe asthma is associated with an increased risk for exacerbations, reduced lung function, fixed airflow obstruction, and substantial morbidity and mortality. The concept of remission in severe asthma as a new treatment goal has recently gained attention due to the growing use of monoclonal antibody therapies, which target specific pathologic pathways of inflammation. This review evaluates the current definitions of asthma remission and unveils some of the barriers for achieving this state in the severe asthma population. Although there is no unified definition, the concept of clinical remission in asthma should be based on a sustained period of symptom control, elimination of oral corticosteroid exposure and exacerbations, and stabilization of pulmonary function. The conjugation of these criteria seems a realistic treatment target in a minority of asthmatic patients. Some unmet needs in severe asthma may affect the achievement of clinical remission. Late intervention with targeted therapies in the severe asthma population may increase the risk of corticosteroid exposure and the development of irreversible structural airway changes. Moreover, airway infection is an important component in persistent exacerbations in patients on biologic therapies. Phenotyping exacerbations may be useful to guide therapy decisions and to avoid the liberal use of oral corticosteroids. Another challenge associated with the aim of clinical remission in severe asthma is the multifaceted interaction between the disease and its associated comorbidities. Behavioural factors should be evaluated in case of persistent symptoms despite optimised treatment, and assessing biomarkers and targeting treatable traits may allow for a more objective way of reaching remission. The concept of clinical remission will benefit from an international consensus to establish unifying criteria for its assessment, and it should be addressed in the future management guidelines.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1465-993XTest

الوصول الحر: https://doaj.org/article/09f6f8dbcc124cbe973622b66a521cc7Test

المؤلفون: Azeem Majeed, Liam G Heaney, Zhiyi Lan, Tamsin Morris, Olivia Fulton, Adrian P J Rabe, Wei J Loke, Danuta Kielar, Vivian H Shih, Lynda Olinger, Mihaela G Musat, Sharada Harricharan

المصدر: BMJ Open Respiratory Research, Vol 11, Iss 1 (2024)

مصطلحات موضوعية: Medicine, Diseases of the respiratory system, RC705-779

الوصف: Introduction Effective treatment of severe asthma requires patient adherence to inhaled and biological medications. Previous work has shown that patient support programmes (PSP) can improve adherence in patients with chronic diseases, but the impact of PSPs in patients with severe asthma treated with biologics has not been thoroughly investigated.Methods We conducted a systematic literature review to understand the impact of PSPs on treatment adherence, asthma control and health-related quality of life (HRQoL) in patients with severe asthma. Embase, MEDLINE and EconLit databases were searched for studies published from 2003 (the year of the first biological approval for severe asthma) to June 2023 that described PSP participation among patients with severe asthma on biological treatment. Direct pooling of outcomes was not possible due to the heterogeneity across studies, so an indirect treatment comparison (ITC) was performed to determine the effect of PSP participation on treatment discontinuation. The ITC used patient-level data from patients treated with benralizumab either enrolled in a PSP (VOICE study, Connect 360 PSP) or not enrolled in a PSP (Benralizumab Patient Access Programme study) in the UK.Findings 25 records of 21 studies were selected. Six studies investigated the impact of PSPs on treatment adherence, asthma control or HRQoL. All six studies reported positive outcomes for patients enrolled in PSPs; the benefits of each PSP were closely linked to the services provided. The ITC showed that patients in the Connect 360 PSP group were less likely to discontinue treatment compared with the non-PSP group (OR 0.26, 95% CI 0.11 to 0.57, p

وصف الملف: electronic resource

العلاقة: https://bmjopenrespres.bmj.com/content/11/1/e001799.fullTest; https://doaj.org/toc/2052-4439Test

الوصول الحر: https://doaj.org/article/51f2b637096243fca634b9a2028a55b5Test

المؤلفون: Ling-Pei Ho, Liam G Heaney, Ran Wang, Chris Brightling, Joanna Porter, Stefan J Marciniak, Tom Wilkinson, Jane C Davies, Laurence Pearmain, Alex R Horsley, Lorcan P McGarvey, Ratko Djukanović, Nick Schindler, Sean Knight, Miriam Bennett, Rebecca C Robey, Tracy Hussell

المصدر: BMJ Open Respiratory Research, Vol 9, Iss 1 (2022)

مصطلحات موضوعية: Medicine, Diseases of the respiratory system, RC705-779

الوصف: Background The COVID-19 pandemic has presented substantial new challenges to clinical and research teams. Our objective was to analyse the experience of investigators and research delivery staff regarding the research response to COVID-19 in order to identify these challenges as well as solutions for future pandemic planning.Methods We conducted a survey of diverse research staff involved in delivery of COVID-19 clinical trials across the UK. This was delivered online across centres linked to the NIHR Respiratory Translational Research Collaboration. Responses were analysed using a formal thematic analysis approach to identify common themes and recommendations.Results 83 survey participants from ten teaching hospitals provided 922 individual question responses. Respondents were involved in a range of research delivery roles but the largest cohort (60%) was study investigators. A wide range of research experiences were captured, including early and late phase trials. Responses were coded into overarching themes. Among common observations, complex protocols without adaptation to a pandemic were noted to have hampered recruitment. Recommendations included the need to develop and test pandemic-specific protocols, and make use of innovations in information technology. Research competition needs to be avoided and drug selection processes should be explicitly transparent.Conclusions Delivery of clinical trials, particularly earlier phase trials, in a pandemic clinical environment is highly challenging, and was reactive rather than anticipatory. Future pandemic studies should be designed and tested in advance, making use of pragmatic study designs as far as possible and planning for integration between early and later phase trials and regulatory frameworks.

وصف الملف: electronic resource

العلاقة: https://bmjopenrespres.bmj.com/content/9/1/e001226.fullTest; https://doaj.org/toc/2052-4439Test

الوصول الحر: https://doaj.org/article/752596b5ea4e496192277c545c4c7e49Test

المؤلفون: Tracy Jackson, Michael D Shields, Liam G Heaney, Marilyn Kendall, Christina J Pearce, Chi Yan Hui, Hilary Pinnock

المصدر: PLoS ONE, Vol 12, Iss 11, p e0187478 (2017)

مصطلحات موضوعية: Medicine, Science

الوصف: Financial incentives are utilised in healthcare systems in a number of countries to improve quality of care delivered to patients by rewarding practices or practitioners for achieving set targets.To systematically review the evidence investigating the impact of financial incentives for implementation of supported self-management on quality of care including: organisational process outcomes, individual behavioural outcomes, and health outcomes for individuals with asthma or diabetes; both conditions with an extensive evidence base for self-management.We followed Cochrane methodology, using a PICOS search strategy to search eight databases in November 2015 (updated May 2017) including a broad range of implementation methodologies. Studies were weighted by robustness of methodology, number of participants and the quality score. We used narrative synthesis due to heterogeneity of studies.We identified 2,541 articles; 12 met our inclusion criteria. The articles were from the US (n = 7), UK (n = 4) and Canada (n = 1). Measured outcomes were HbA1c tests undertaken and/or the level achieved (n = 10), written action plans for asthma (n = 1) and hospital/emergency department visits (n = 1). Three of the studies were part of a larger incentive scheme including many conditions; one focused on asthma; eight focussed on diabetes. In asthma, the proportion receiving 'perfect care' (including providing a written action plan) increased from 4% to 88% in one study, and there were fewer hospitalisations/emergency department visits in another study. Across the diabetes studies, quality-of-care/GP performance scores improved in three, were unchanged in six and deteriorated in one.Results for the impact of financial incentives for the implementation of self-management were mixed. The evidence in diabetes suggests no consistent impact on diabetic control. There was evidence from a single study of improved process and health outcomes in asthma. Further research is needed to confirm these findings and understand the process by which financial incentives may impact (or not) on care.Protocol registration number: CRD42016027411.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC5673190?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/7a73a90f7133441e8e7ed80cbe111507Test

المؤلفون: Jeremy C Parker, Isobel Douglas, Jennifer Bell, David Comer, Keith Bailie, Grzegorz Skibinski, Liam G Heaney, Michael D Shields

المصدر: PLoS ONE, Vol 10, Iss 6, p e0129546 (2015)

مصطلحات موضوعية: Medicine, Science

الوصف: Epithelial remodelling in asthma is characterised by goblet cell hyperplasia and mucus hypersecretion for which no therapies exist. Differentiated bronchial air-liquid interface cultures from asthmatic children display high goblet cell numbers. Epidermal growth factor and its receptor have been implicated in goblet cell hyperplasia.We hypothesised that EGF removal or tyrphostin AG1478 treatment of differentiating air-liquid interface cultures from asthmatic children would result in a reduction of epithelial goblet cells and mucus secretion.In Aim 1 primary bronchial epithelial cells from non-asthmatic (n = 5) and asthmatic (n = 5) children were differentiated under EGF-positive (10 ng/ml EGF) and EGF-negative culture conditions for 28 days. In Aim 2, cultures from a further group of asthmatic children (n = 5) were grown under tyrphostin AG1478, a tyrosine kinase inhibitor, conditions. All cultures were analysed for epithelial resistance, markers of differentiation using immunocytochemistry, ELISA for MUC5AC mucin secretion and qPCR for MUC5AC mRNA.In cultures from asthmatic children the goblet cell number was reduced in the EGF negative group (p = 0.01). Tyrphostin AG1478 treatment of cultures from asthmatic children had significant reductions in goblet cells at 0.2 μg/ml (p = 0.03) and 2 μg/ml (p = 0.003) as well as mucus secretion at 2 μg/ml (p = 0.04).We have shown in this preliminary study that through EGF removal and tyrphostin AG1478 treatment the goblet cell number and mucus hypersecretion in differentiating air-liquid interface cultures from asthmatic children is significantly reduced. This further highlights the epidermal growth factor receptor as a potential therapeutic target to inhibit goblet cell hyperplasia and mucus hypersecretion in asthma.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC4461195?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/fe4e892ac2054e788c6d572b009fadadTest

المؤلفون: Surendran Thavagnanam, Jeremy C Parker, Michael E McBrien, Grzegorz Skibinski, Michael D Shields, Liam G Heaney

المصدر: PLoS ONE, Vol 9, Iss 1, p e85802 (2014)

مصطلحات موضوعية: Medicine, Science

الوصف: INTRODUCTION: Differentiated paediatric epithelial cells can be used to study the role of epithelial cells in asthma. Nasal epithelial cells are easier to obtain and may act as a surrogate for bronchial epithelium in asthma studies. We assessed the suitability of nasal epithelium from asthmatic children to be a surrogate for bronchial epithelium using air-liquid interface cultures. METHODS: Paired nasal and bronchial epithelial cells from asthmatic children (n = 9) were differentiated for 28 days under unstimulated and IL-13-stimulated conditions. Morphological and physiological markers were analysed using immunocytochemistry, transepithelial-electrical-resistance, Quantitative Real-time-PCR, ELISA and multiplex cytokine/chemokine analysis. RESULTS: Physiologically, nasal epithelial cells from asthmatic children exhibit similar cytokine responses to stimulation with IL-13 compared with paired bronchial epithelial cells. Morphologically however, nasal epithelial cells differed significantly from bronchial epithelial cells from asthmatic patients under unstimulated and IL-13-stimulated conditions. Nasal epithelial cells exhibited lower proliferation/differentiation rates and lower percentages of goblet and ciliated cells when unstimulated, while exhibiting a diminished and varied response to IL-13. CONCLUSIONS: We conclude that morphologically, nasal epithelial cells would not be a suitable surrogate due to a significantly lower rate of proliferation and differentiation of goblet and ciliated cells. Physiologically, nasal epithelial cells respond similarly to exogenous stimulation with IL-13 in cytokine production and could be used as a physiological surrogate in the event that bronchial epithelial cells are not available.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC3903489?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/30cfb9520c024ddc9b8dd4615c104011Test

المؤلفون: Chris Newby, Liam G Heaney, Andrew Menzies-Gow, Rob M Niven, Adel Mansur, Christine Bucknall, Rekha Chaudhuri, John Thompson, Paul Burton, Chris Brightling, British Thoracic Society Severe Refractory Asthma Network

المصدر: PLoS ONE, Vol 9, Iss 7, p e102987 (2014)

مصطلحات موضوعية: Medicine, Science

الوصف: Severe refractory asthma is a heterogeneous disease. We sought to determine statistical clusters from the British Thoracic Society Severe refractory Asthma Registry and to examine cluster-specific outcomes and stability.Factor analysis and statistical cluster modelling was undertaken to determine the number of clusters and their membership (N = 349). Cluster-specific outcomes were assessed after a median follow-up of 3 years. A classifier was programmed to determine cluster stability and was validated in an independent cohort of new patients recruited to the registry (n = 245).Five clusters were identified. Cluster 1 (34%) were atopic with early onset disease, cluster 2 (21%) were obese with late onset disease, cluster 3 (15%) had the least severe disease, cluster 4 (15%) were the eosinophilic with late onset disease and cluster 5 (15%) had significant fixed airflow obstruction. At follow-up, the proportion of subjects treated with oral corticosteroids increased in all groups with an increase in body mass index. Exacerbation frequency decreased significantly in clusters 1, 2 and 4 and was associated with a significant fall in the peripheral blood eosinophil count in clusters 2 and 4. Stability of cluster membership at follow-up was 52% for the whole group with stability being best in cluster 2 (71%) and worst in cluster 4 (25%). In an independent validation cohort, the classifier identified the same 5 clusters with similar patient distribution and characteristics.Statistical cluster analysis can identify distinct phenotypes with specific outcomes. Cluster membership can be determined using a classifier, but when treatment is optimised, cluster stability is poor.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC4109965?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/70c674ec43c8481fa98f40da71e7d52fTest

المؤلفون: Jeremy C Parker, Surendran Thavagnanam, Grzegorz Skibinski, Jeremy Lyons, Jennifer Bell, Liam G Heaney, Michael D Shields

المصدر: PLoS ONE, Vol 8, Iss 5, p e61023 (2013)

مصطلحات موضوعية: Medicine, Science

الوصف: Asthma is a chronic inflammatory disease characterised by airways remodelling. In mouse models IL-9 and IL-13 have been implicated in airways remodelling including mucus hypersecretion and goblet cell hyperplasia. Their role, especially that of IL-9, has been much less studied in authentic human ex vivo models of the bronchial epithelium from normal and asthmatic children. We assessed the effects of IL-9, IL-13 and an IL-9/IL-13 combination, during differentiation of bronchial epithelial cells from normal (n = 6) and asthmatic (n = 8) children. Cultures were analysed for morphological markers and factors associated with altered differentiation (MUC5AC, SPDEF and MMP-7). IL-9, IL-9/IL-13 combination and IL-13 stimulated bronchial epithelial cells from normal children had fewer ciliated cells [14.8% (SD 8.9), p = 0.048, 12.4 (SD 6.1), p = 0.016 and 7.3% (SD 6.6), p = 0.031] respectively compared with unstimulated [(21.4% (SD 9.6)]. IL-9 stimulation had no effect on goblet cell number in either group whereas IL-9/IL-13 combination and IL-13 significantly increased goblet cell number [24.8% (SD 8.8), p = 0.02), 32.9% (SD 8.6), p = 0.007] compared with unstimulated normal bronchial cells [(18.6% (SD 6.2)]. All stimulations increased MUC5AC mRNA in bronchial epithelial cells from normal children and increased MUC5AC mucin secretion. MMP-7 localisation was dysregulated in normal bronchial epithelium stimulated with Th2 cytokines which resembled the unstimulated bronchial epithelium of asthmatic children. All stimulations resulted in a significant reduction in transepithelial electrical resistance values over time suggesting a role in altered tight junction formation. We conclude that IL-9 does not increase goblet cell numbers in bronchial epithelial cell cultures from normal or asthmatic children. IL-9 and IL-13 alone and in combination, reduce ciliated cell numbers and transepithelial electrical resistance during differentiation of normal epithelium, which clinically could inhibit mucociliary clearance and drive an altered repair mechanism. This suggests an alternative role for IL-9 in airways remodelling and reaffirms IL-9 as a potential therapeutic target.

وصف الملف: electronic resource

العلاقة: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23671562/?tool=EBITest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/5bb2d40dc8944e4ba251ac5f51bc8b24Test

المؤلفون: Omer Elneima, Hamish J. C. McAuley, Olivia C Leavy, James D. Chalmers, Ling-Pei Ho, Michael Marks, Krisnah Poinasamy, Betty Raman, Aarti Shikotra, Amisha Singapuri, Marco Sereno, Victoria C. Harris, Linzy Houchen-Wolloff, Ruth M. Saunders, Neil J Greening, Matthew Richardson, Jennifer K. Quint, Andrew Briggs, Annemarie B Docherty, Steven Kerr, Ewen M Harrison, Nazir I Lone, Mathew Thorpe, Liam G. Heaney, Keir E. Lewis, Raminder Aul, Paul Beirne, Charlotte E Bolton, Jeremy S. Brown, Gourab Choudhury, Nawar Diar Bakerly, Nicholas Easom, Carlos Echevarria, Jonathan Fuld, Nick Hart, John R. Hurst, Mark G. Jones, Dhruv Parekh, Paul Pfeffer, Najib M Rahman, Sarah L Rowland-Jones, AA Roger Thompson, Caroline J. Jolley, Ajay M Shah, Dan G. Wootton, Trudie Chalder, Melanie J Davies, Anthony De Soyza, John R. Geddes, William Greenhalf, Simon Heller, Luke S Howard, Joseph Jacob, R Gisli Jenkins, Janet M Lord, William D-C Man, Gerry P. McCann, Stefanie Neubauer, Peter JM Openshaw, Joanna C. Porter, Matthew J. Rowland, Janet T Scott, Malcolm G Semple, Sally J. Singh, David C. Thomas, Mark Toshner, Nikki Smith, Aziz Sheikh, Christopher E Brightling, Louise V. Wain, Rachael A. Evans, PHOSP-COVID collaborative group

مصطلحات موضوعية: Uncategorized, Uncategorised value

الوصف: Key Features The Post-Hospitalisation COVID-19 (PHOSP-COVID) study is a national UK multicentre cohort study of patients who were hospitalized for COVID-19 and subsequently discharged. PHOSP-COVID was established to investigate the medium- and long-term sequelae of severe COVID-19 requiring hospitalization, understand the underlying mechanisms of these sequelae, evaluate the medium- and long-term effects of COVID-19 treatments and to serve as a platform to enable future studies, including clinical trials. Data collected covered a wide range of physical measures, biological samples and patient-reported outcome measures (PROMs). Participants could join the cohort either in Tier 1 only with remote data collection using hospital records, a PROMs app and postal saliva sample for DNA; or in Tier 2 in which they were invited to attend two specific research visits for further data collection and biological research sampling. These research visits occurred at 5 (range 2–7) months and 12 (range 10–14) months post-discharge. Participants could also participate in specific nested studies (Tier 3) at selected sites. All participants were asked to consent to further follow-up for 25 years via linkage to their electronic healthcare records and to be re-contacted for further research. In total, 7935 participants were recruited from 83 UK sites: 5238 to Tier 1 and 2697 to Tier 2, between August 2020 and March 2022. Cohort data are held in a Trusted Research Environment and samples stored in a central biobank. Data and samples can be accessed upon request and subject to approvals from https://www.phosp.org/data-sample-requestTest/.

العلاقة: 2381/24449206.v1; https://figshare.com/articles/journal_contribution/Cohort_Profile_Post-hospitalisation_COVID-19_study_PHOSP-COVID_/24449206Test

الإتاحة: https://figshare.com/articles/journal_contribution/Cohort_Profile_Post-hospitalisation_COVID-19_study_PHOSP-COVID_/24449206Test

المؤلفون: Xue Zeng, Jing Qing, Chi-Ming Li, Jiamiao Lu, Tracy Yamawaki, Yi-Hsiang Hsu, Bryan Vander Lugt, Hailing Hsu, John Busby, PJ McDowell, David J Jackson, Ratko Djukanovic, John G Matthews, Joseph R Arron, Peter Bradding, Christopher E Brightling, Rekha Chaudhuri, David F Choy, D Cowan, SJ Fowler, Timothy C Hardman, Tim Harrison, Peter Howarth, James Lordan, AH Mansur, Andrew Menzies-Gow, Ian D Pavord, Samantha Walker, Ashley Woodcock, Liam G Heaney, investigators for the UK MRC Refractory Asthma Stratification Program

مصطلحات موضوعية: Uncategorized, investigators for the UK MRC Refractory Asthma Stratification Program (RASP-UK)

الوصف: Background Patients with Type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2-inflammation with corticosteroids (CS). Objectives To analyze whole blood transcriptome from 738 samples in T2-biomarker high/low severe asthma patients to relate transcriptomic signatures to T2-biomarkers and asthma symptom scores. Methods Bulk RNAseq data were generated for blood samples (baseline, Week24, Week48) from 301 participants recruited to a randomized clinical trial of CS optimization in severe asthma. Unsupervised clustering, differential gene expression analysis, and pathway analysis were performed. Patients were grouped by T2-biomarker status and symptoms. Associations between clinical characteristics and differentially expressed genes (DEGs) associated with biomarker and symptom levels were investigated. Results Unsupervised clustering identified two clusters; Cluster 2 patients were blood eosinophil low/symptom high and more likely to be receiving oral CS (OCS). Differential gene expression analysis of these clusters, with and without stratification for OCS, identified 2,960 and 4,162 DEGs respectively. 627/2,960 genes remained after adjusting for OCS by subtracting OCS signature genes. Pathway analysis identified dolichyl-diphosphooligosaccharide biosynthesis and assembly of RNA polymerase I complex as significantly enriched pathways. No stable DEGs were associated with high symptoms in T2-biomarker low patients, but numerous associated with elevated T2-biomarkers, including 15 that were up-regulated at all time-points irrespective of symptom level. Conclusions OCS have a considerable effect on whole blood transcriptome. DEG analysis demonstrates a clear T2-biomarker transcriptomic signature, but no signature was found in association with T2-biomarker low patients, including those with a high symptom burden.

العلاقة: 2381/23600112.v1; https://figshare.com/articles/journal_contribution/Blood_transcriptomic_signature_in_type-2_biomarker_low_severe_asthma_and_asthma_control_/23600112Test

الإتاحة: https://figshare.com/articles/journal_contribution/Blood_transcriptomic_signature_in_type-2_biomarker_low_severe_asthma_and_asthma_control_/23600112Test