{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T12:13:08Z","timestamp":1772626388943,"version":"3.50.1"},"reference-count":35,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2018,5,17]],"date-time":"2018-05-17T00:00:00Z","timestamp":1526515200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["108818"],"award-info":[{"award-number":["108818"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"HSC Research and Development"}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background.<\/ns4:bold>\n                    \u00a0 Childhood asthma is a common complex condition whose aetiology is thought to involve gene-environment interactions in early life occurring at the airway epithelium, associated with immune dysmaturation. \u00a0It is not clear if abnormal airway epithelium cell (AEC) and cellular immune system functions associated with asthma are primary or secondary.\u00a0 To explore this, we will (i) recruit a birth cohort and observe the evolution of respiratory symptoms; (ii) recruit children with and without asthma symptoms; and (iii) use existing data from children in established STELAR birth cohorts.\u00a0\u00a0\u00a0 Novel pathways identified in the birth cohort will be sought in the children with established disease.\u00a0 Our over-arching hypothesis is that epithelium function is abnormal at birth in babies who subsequently develop asthma and progression is driven by abnormal interactions between the epithelium, genetic factors, the developing immune system, and the microbiome in the first years of life.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods.<\/ns4:bold>\n                    \u00a0 One thousand babies will be recruited and nasal AEC collected at 5-10 days after birth for culture.\u00a0 Transcriptomes in AEC and blood leukocytes and the upper airway microbiome will be determined in babies and again at one and three years of age. In a subset of 100 individuals, AEC transcriptomes and microbiomes will also be assessed at three and six months.\u00a0 Individuals will be assigned a wheeze category at age three years.\u00a0 In a cross sectional study, 300 asthmatic and healthy children aged 1 to 16 years will have nasal and bronchial AEC collected for culture and transcriptome analysis, leukocyte transcriptome analysis, and upper and lower airway microbiomes ascertained.\u00a0 Genetic variants associated with asthma symptoms will be confirmed in the STELAR cohorts.\u00a0\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusions.<\/ns4:bold>\n                    \u00a0 This study is the first to comprehensively study the temporal relationship between aberrant AEC and immune cell function and asthma symptoms in the context of early gene-microbiome interactions.\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.14489.1","type":"journal-article","created":{"date-parts":[[2018,5,17]],"date-time":"2018-05-17T10:30:04Z","timestamp":1526553004000},"page":"60","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Pulmonary epithelial barrier and immunological functions at birth and in early life - key determinants of the development of asthma?\u00a0 A description of the protocol for the Breathing Together study"],"prefix":"10.12688","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8393-5060","authenticated-orcid":false,"given":"Steve","family":"Turner","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5218-7071","authenticated-orcid":false,"given":"Adnan","family":"Custovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Ghazal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Grigg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1458-1438","authenticated-orcid":false,"given":"Mindy","family":"Gore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Henderson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8977-6726","authenticated-orcid":false,"given":"Clare M.","family":"Lloyd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ben","family":"Marsland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3246-3774","authenticated-orcid":false,"given":"Ultan F.","family":"Power","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graham","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5192-6418","authenticated-orcid":false,"given":"Sejal","family":"Saglani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jurgen","family":"Schwarze","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3793-3571","authenticated-orcid":false,"given":"Michael","family":"Shields","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Bush","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2018,5,17]]},"reference":[{"key":"ref-1","article-title":"Asthma facts and FAQs","author":"U Asthma","year":"2017"},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"805-10","DOI":"10.1136\/thoraxjnl-2013-204815","article-title":"The association between childhood asthma and adult chronic obstructive pulmonary disease.","volume":"69","author":"A Tai","year":"2014","journal-title":"Thorax."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"23-30","DOI":"10.1164\/rccm.201505-0870OC","article-title":"Outcomes of Childhood Asthma and Wheezy Bronchitis. 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We will amend the introduction as suggested. The 100 microbiome subgroup are chosen without selection for any characteristic, e.g. asthma,&nbsp;atopy or smoking, and we anticipate that this sample size is adequate (acknowledging that the novel nature of our study means that no definitive power calculation is possible).&nbsp; We can clarify that&nbsp;criteria for inclusion for lower airway sampling are individuals who undergo general anaesthesia for a clinically-indicated operation and among these, those with a history of wheezing and those without respiratory symptoms. Participants for groups 3 and 4 will be recruited from the two London centres and Southampton.&nbsp; We can confirm that&nbsp;children found to have a congenital airway narrowing at bronchoscopy&nbsp;will not be categorised as wheezers or asthmatics.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-60\/v1#referee-comment-3640","order":1,"name":"referee-comment-3640","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.15774.r33375, Darryl A Knight, Faculty of Health and Medicine and Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia, 03 Jul 2018, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-60\/v1#referee-response-33375","order":2,"name":"referee-response-33375","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The study is supported by the Wellcome Trust [108818]; and the PHA HSC R&D Division, Northern Ireland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}