{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T17:24:43Z","timestamp":1768584283798,"version":"3.49.0"},"reference-count":49,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T00:00:00Z","timestamp":1641772800000},"content-version":"unspecified","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771230"],"award-info":[{"award-number":["81771230"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771279"],"award-info":[{"award-number":["81771279"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81801130"],"award-info":[{"award-number":["81801130"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82025012"],"award-info":[{"award-number":["82025012"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U1905210"],"award-info":[{"award-number":["U1905210"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U2005201"],"award-info":[{"award-number":["U2005201"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2017Y9094"],"award-info":[{"award-number":["2017Y9094"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2018Y9082"],"award-info":[{"award-number":["2018Y9082"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2019J02010"],"award-info":[{"award-number":["2019J02010"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2019J05076"],"award-info":[{"award-number":["2019J05076"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2021,11,25]]},"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Hereditary spastic paraplegias (HSPs) are uncommon but not rare neurodegenerative diseases. More than 100 pathogenic genes and loci related to spastic paraplegia symptoms have been reported. HSPs have the same core clinical features, including progressive spasticity in the lower limbs, though HSPs are heterogeneous (eg, clinical signs, MRI features, gene mutation). The age of onset varies greatly, from infant to adulthood. In addition, the slow and variable rates of disease progression in patients with HSP represent a substantial challenge for informative assessment of therapeutic efficacy. To address this, we are undertaking a prospective cohort study to investigate genetic\u2013clinical characteristics, find surrogates for monitoring disease progress and identify clinical readouts for treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and analysis<\/jats:title>\n                  <jats:p>In this case-control cohort study, we will enrol 200 patients with HSP and 200 healthy individuals in parallel. Participants will be continuously assessed for 3\u2009years at 12-month intervals. Six aspects, including clinical signs, genetic spectrum, cognitive competence, MRI features, potential biochemical indicators and nerve electrophysiological factors, will be assessed in detail. This study will observe clinical manifestations and disease severity based on different molecular mechanisms, including oxidative stress, cholesterol metabolism and microtubule dynamics, all of which have been proposed as potential treatment targets or modalities. The analysis will also assess disease progression in different types of HSPs and cellular pathways with a longitudinal study using t tests and \u03c7<jats:sup>2<\/jats:sup> tests.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Ethics and dissemination<\/jats:title>\n                  <jats:p>The study was granted ethics committee approval by the first affiliated hospital of Fujian Medical University (MRCTA, ECFAH of FMU (2019)194) in 2019. Findings will be disseminated via presentations and peer-reviewed publications. Dissemination will target different audiences, including national stakeholders, researchers from different disciplines and the general public.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration number<\/jats:title>\n                  <jats:p>\n                     <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04006418\">NCT04006418<\/jats:ext-link>.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/bmjopen-2021-054011","type":"journal-article","created":{"date-parts":[[2022,1,11]],"date-time":"2022-01-11T13:36:55Z","timestamp":1641908215000},"page":"e054011","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Chinese patients with hereditary spastic paraplegias (HSPs): a protocol for a hospital-based cohort study"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct04006418","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Yu-Sen","family":"Qiu","sequence":"first","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Heng","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ru-Ying","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi-Xian","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin","family":"Bi","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Hong","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Jun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng-Wen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiology of The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China"},{"name":"Department of Medical Imaging Technology, College of Medical Technology and Engineering, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shao-Bo","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine of The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Kun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun-Yi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1590-3945","authenticated-orcid":false,"given":"Ying","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9472-8494","authenticated-orcid":false,"given":"Wan-Jin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology of The First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, Fujian, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"2025101812573864000_12.1.e054011.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1247363"},{"key":"2025101812573864000_12.1.e054011.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30235-2"},{"key":"2025101812573864000_12.1.e054011.3","doi-asserted-by":"publisher","DOI":"10.1159\/000358801"},{"key":"2025101812573864000_12.1.e054011.4","doi-asserted-by":"publisher","DOI":"10.1055\/s-0031-1299787"},{"key":"2025101812573864000_12.1.e054011.5","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-018-0269-1"},{"key":"2025101812573864000_12.1.e054011.6","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz291"},{"key":"2025101812573864000_12.1.e054011.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(83)92879-9"},{"key":"2025101812573864000_12.1.e054011.8","doi-asserted-by":"publisher","DOI":"10.1055\/s-2008-1041143"},{"key":"2025101812573864000_12.1.e054011.9","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww111"},{"key":"2025101812573864000_12.1.e054011.10","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24611"},{"key":"2025101812573864000_12.1.e054011.11","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-013-1115-8"},{"key":"2025101812573864000_12.1.e054011.12","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-062111-150400"},{"key":"2025101812573864000_12.1.e054011.13","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.jns.2009.06.027","article-title":"Six cases of SCA3\/MJD patients that mimic hereditary spastic paraplegia in clinic","volume":"285","author":"Wang","year":"2009","journal-title":"J Neurol Sci"},{"key":"2025101812573864000_12.1.e054011.14","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1002\/mds.28523","article-title":"Randomized trial of botulinum toxin type A in hereditary spastic paraplegia - the SPASTOX trial","volume":"36","author":"Diniz de Lima","year":"2021","journal-title":"Mov Disord"},{"key":"2025101812573864000_12.1.e054011.15","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000228242.53336.90"},{"key":"2025101812573864000_12.1.e054011.16","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000122"},{"key":"2025101812573864000_12.1.e054011.17","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.nbd.2017.04.007","article-title":"NF-L in cerebrospinal fluid and serum is a biomarker of neuronal damage in an inducible mouse model of neurodegeneration","volume":"104","author":"Brureau","year":"2017","journal-title":"Neurobiol Dis"},{"key":"2025101812573864000_12.1.e054011.18","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20150710"},{"key":"2025101812573864000_12.1.e054011.19","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00024.2003"},{"key":"2025101812573864000_12.1.e054011.20","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s40291-019-00426-w","article-title":"Genetic and clinical profile of Chinese patients with autosomal dominant spastic paraplegia","volume":"23","author":"Zhao","year":"2019","journal-title":"Mol Diagn Ther"},{"key":"2025101812573864000_12.1.e054011.21","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"2025101812573864000_12.1.e054011.22","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"2025101812573864000_12.1.e054011.23","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"},{"key":"2025101812573864000_12.1.e054011.24","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13190"},{"key":"2025101812573864000_12.1.e054011.25","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10212"},{"key":"2025101812573864000_12.1.e054011.26","unstructured":"Ning Wang YL , Ye Z , Lin Y , et al . Cross sign T2 hyperintensities in atrophic spinal cord of hereditary spastic paraplegia type 5. Available: https:\/\/www.researchsquare.com\/article\/rs-97876\/v1"},{"key":"2025101812573864000_12.1.e054011.27","doi-asserted-by":"crossref","DOI":"10.1016\/j.jneumeth.2019.108565","article-title":"Comparing SPM12 and CAT12 segmentation pipelines: a brain tissue volume-based age and Alzheimer's disease study","volume":"334","author":"Tavares","year":"2019","journal-title":"J Neurosci Methods"},{"key":"2025101812573864000_12.1.e054011.28","doi-asserted-by":"crossref","DOI":"10.1186\/s10194-017-0825-z","article-title":"Cerebral gray matter volume in patients with chronic migraine: correlations with clinical features","volume":"18","author":"Coppola","year":"2017","journal-title":"J Headache Pain"},{"key":"2025101812573864000_12.1.e054011.29","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.pnpbp.2017.12.017","article-title":"Structural and functional brain abnormalities in schizophrenia: a cross-sectional study at different stages of the disease","volume":"83","author":"Zhao","year":"2018","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"2025101812573864000_12.1.e054011.30","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.schres.2018.07.014","article-title":"Altered gyrification in schizophrenia and its relation to other morphometric markers","volume":"202","author":"Spalthoff","year":"2018","journal-title":"Schizophr Res"},{"key":"2025101812573864000_12.1.e054011.31","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1007\/s11682-018-9873-5","article-title":"DTI-derived indexes of brain WM correlate with cognitive performance in vascular MCI and small-vessel disease. A TBSS study","volume":"13","author":"Mascalchi","year":"2019","journal-title":"Brain Imaging Behav"},{"key":"2025101812573864000_12.1.e054011.32","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww068"},{"key":"2025101812573864000_12.1.e054011.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2016.10.009."},{"key":"2025101812573864000_12.1.e054011.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2016.09.026"},{"key":"2025101812573864000_12.1.e054011.35","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/j.neuroimage.2018.09.081","article-title":"Automatic segmentation of the spinal cord and intramedullary multiple sclerosis lesions with convolutional neural networks","volume":"184","author":"Gros","year":"2019","journal-title":"Neuroimage"},{"key":"2025101812573864000_12.1.e054011.36","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1002\/ana.25571","article-title":"Longitudinal spinal cord atrophy in multiple sclerosis using the generalized boundary shift integral","volume":"86","author":"Moccia","year":"2019","journal-title":"Ann Neurol"},{"key":"2025101812573864000_12.1.e054011.37","doi-asserted-by":"publisher","DOI":"10.1177\/1352458517690821"},{"key":"2025101812573864000_12.1.e054011.38","doi-asserted-by":"publisher","DOI":"10.1007\/BF02214761"},{"key":"2025101812573864000_12.1.e054011.39","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1177\/1073191120929093","article-title":"Comparing the psychometric properties of eight embedded performance validity tests in the Rey auditory verbal learning test, Wechsler memory scale logical memory, and brief visuospatial memory test-revised recognition trials for detecting invalid neuropsychological test performance","volume":"28","author":"Pliskin","year":"2021","journal-title":"Assessment"},{"key":"2025101812573864000_12.1.e054011.40","doi-asserted-by":"publisher","DOI":"10.1080\/13854046.2011.564209"},{"key":"2025101812573864000_12.1.e054011.41","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4679(199708)53:5<517::AID-JCLP14>3.0.CO;2-H"},{"key":"2025101812573864000_12.1.e054011.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.acn.2005.07.006"},{"key":"2025101812573864000_12.1.e054011.43","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0176212","article-title":"Use of the MATRICS consensus cognitive battery (MCCB) to evaluate cognitive deficits in bipolar disorder: a systematic review and meta-analysis","volume":"12","author":"Bo","year":"2017","journal-title":"PLoS One"},{"key":"2025101812573864000_12.1.e054011.44","doi-asserted-by":"publisher","DOI":"10.1177\/1352458515576982"},{"key":"2025101812573864000_12.1.e054011.45","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.schres.2019.01.034","article-title":"What is the optimal neuropsychological test battery for schizophrenia in China?","volume":"208","author":"Shi","year":"2019","journal-title":"Schizophr Res"},{"key":"2025101812573864000_12.1.e054011.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2015.09.003"},{"key":"2025101812573864000_12.1.e054011.47","doi-asserted-by":"crossref","DOI":"10.1016\/j.neuroimage.2020.117283","article-title":"Neural mechanisms of AVPR1A RS3-RS1 haplotypes that impact verbal learning and memory","volume":"222","author":"Zhang","year":"2020","journal-title":"Neuroimage"},{"key":"2025101812573864000_12.1.e054011.48","doi-asserted-by":"crossref","DOI":"10.1186\/s12883-019-1435-y","article-title":"Remote ischemic conditioning improves cognition in patients with subcortical ischemic vascular dementia","volume":"19","author":"Liao","year":"2019","journal-title":"BMC Neurol"},{"key":"2025101812573864000_12.1.e054011.49","first-page":"110","article-title":"[Reliability and validity of depression scales of Chinese version: a systematic review]","volume":"38","author":"Sun","year":"2017","journal-title":"Zhonghua Liu Xing Bing Xue Za Zhi"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2021-054011","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T19:57:47Z","timestamp":1760817467000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2021-054011"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1,11]]},"published-print":{"date-parts":[[2022,1]]}},"alternative-id":["10.1136\/bmjopen-2021-054011"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2021-054011","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1]]}}}