{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T02:03:35Z","timestamp":1780711415872,"version":"3.54.1"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T00:00:00Z","timestamp":1643846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014461","name":"National Institute for Health Research Biomedical Research Centre","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100014461","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The anterior optic pathway is one of the preferential sites of involvement in CNS inflammatory demyelinating diseases, such as multiple sclerosis and neuromyelitis optica, with optic neuritis being a common presenting symptom. What is more, optic nerve involvement in these diseases is often subclinical, with optical coherence tomography demonstrating progressive neuroretinal thinning in the absence of optic neuritis. The pathological substrate for these findings is poorly understood and requires investigation. We had access to post-mortem tissue samples of optic nerves, chiasms and tracts from 29 multiple sclerosis (mean age 59.5, range 25\u201384 years; 73 samples), six neuromyelitis optica spectrum disorders (mean age 56, range 18\u201384 years; 22 samples), six acute disseminated encephalomyelitis (mean age 25, range 10\u201339 years; 12 samples) cases and five non-neurological controls (mean age 55.2, range 44\u201364 years; 16 samples). Formalin-fixed paraffin-embedded samples were immunolabelled for myelin, inflammation (microglial\/macrophage, T- and B-cells, complement), acute axonal injury and astrocytes. We assessed the extent and distribution of these markers along the anterior optic pathway for each case in all compartments (i.e. parenchymal, perivascular and meningeal), where relevant. Demyelinated plaques were classified as active based on established criteria. In multiple sclerosis, demyelination was present in 82.8% of cases, of which 75% showed activity. Microglia\/macrophage and lymphocyte inflammation were frequently found both in the parenchymal and meningeal compartments in non-demyelinated regions. Acute axonal injury affected 41.4% of cases and correlated with extent of inflammatory activity in each compartment, even in cases that died at advanced age with over 20 years of disease duration. An antero-posterior gradient of anterior optic pathway involvement was observed with optic nerves being most severely affected by inflammation and acute axonal injury compared with the optic tract, where a higher proportion of remyelinated plaques were seen. In neuromyelitis optica spectrum disorder, cases with a history of optic neuritis had extensive demyelination and lost aquaporin-4 reactivity. In contrast, those without prior optic neuritis did not have demyelination but rather diffuse microglial\/macrophage, T- and B-lymphocyte inflammation in both parenchymal and meningeal compartments, and acute axonal injury was present in 75% of cases. Acute demyelinating encephalomyelitis featured intense inflammation, and perivenular demyelination in 33% of cases. Our findings suggest that chronic inflammation is frequent and leads to neurodegeneration in multiple sclerosis and neuromyelitis optica, regardless of disease stage. The chronic inflammation and subsequent neurodegeneration occurring along the optic pathway broadens the plaque-centred view of these diseases and partly explains the progressive neuroretinal changes observed in optic coherence tomography studies.<\/jats:p>","DOI":"10.1093\/brain\/awac030","type":"journal-article","created":{"date-parts":[[2022,2,1]],"date-time":"2022-02-01T12:14:19Z","timestamp":1643717659000},"page":"4308-4319","source":"Crossref","is-referenced-by-count":37,"title":["Anterior optic pathway pathology in CNS demyelinating diseases"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9409-6864","authenticated-orcid":false,"given":"Marco","family":"Pisa","sequence":"first","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Level 6 West Wing, John Radcliffe Hospital, Oxford , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Pansieri","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Level 6 West Wing, John Radcliffe Hospital, Oxford , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Yee","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Level 6 West Wing, John Radcliffe Hospital, Oxford , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Joyce D. and Andrew J. Mandell Center for Comprehensive Multiple Sclerosis Care and Neuroscience Research, Mount Sinai Rehabilitation Hospital, Trinity Health of New England , Hartford, CT , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Isabel","family":"Leite","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Level 6 West Wing, John Radcliffe Hospital, Oxford , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Palace","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Level 6 West Wing, John Radcliffe Hospital, Oxford , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Comi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Vita-Salute San Raffaele University , Milan , Italy"},{"name":"Casa di Cura del Policlinico , Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret M","family":"Esiri","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Level 6 West Wing, John Radcliffe Hospital, Oxford , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letizia","family":"Leocani","sequence":"additional","affiliation":[{"name":"Department of Neurology, Vita-Salute San Raffaele University , Milan , Italy"},{"name":"Experimental Neurophysiology Unit, Institute of Experimental Neurology-INSPE, IRCCS Scientific Institute San Raffaele , Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele C","family":"DeLuca","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, University of Oxford , Level 6 West Wing, John Radcliffe Hospital, Oxford , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,3]]},"reference":[{"key":"2022122116022209400_awac030-B1","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S1474-4422(13)70259-X","article-title":"Optic neuritis","volume":"13","author":"Toosy","year":"2014","journal-title":"Lancet Neurol"},{"key":"2022122116022209400_awac030-B2","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1136\/jnnp.2005.086280","article-title":"Multimodal evoked potentials to assess the evolution of multiple sclerosis: A longitudinal study","volume":"77","author":"Leocani","year":"2006","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2022122116022209400_awac030-B3","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S1474-4422(17)30469-6","article-title":"Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study","volume":"17","author":"Filippi","year":"2018","journal-title":"Lancet Neurol"},{"key":"2022122116022209400_awac030-B4","first-page":"211","article-title":"Clinicopathological study of the visual pathways, eyes, and cerebral hemispheres in 32 cases of disseminated sclerosis","volume":"3","author":"Toussaint","year":"1983","journal-title":"J Clin Neuroophthalmol"},{"key":"2022122116022209400_awac030-B5","doi-asserted-by":"crossref","first-page":"10371","DOI":"10.1038\/s41598-019-46251-3","article-title":"In vivo structural and functional assessment of optic nerve damage in neuromyelitis optica spectrum disorders and multiple sclerosis","volume":"9","author":"Vabanesi","year":"2019","journal-title":"Sci Rep"},{"key":"2022122116022209400_awac030-B6","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1002\/ana.24608","article-title":"Clinicopathological features in anterior visual pathway in neuromyelitis optica","volume":"79","author":"Hokari","year":"2016","journal-title":"Ann Neurol"},{"key":"2022122116022209400_awac030-B7","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1177\/1352458515593406","article-title":"Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis","volume":"22","author":"Ramanathan","year":"2016","journal-title":"Mult Scler"},{"key":"2022122116022209400_awac030-B8","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/S1474-4422(10)70168-X","article-title":"Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis","volume":"9","author":"Petzold","year":"2010","journal-title":"Lancet Neurol"},{"key":"2022122116022209400_awac030-B9","doi-asserted-by":"crossref","first-page":"2469","DOI":"10.1212\/WNL.0000000000004736","article-title":"No evidence of disease activity is associated with reduced rate of axonal retinal atrophy in MS","volume":"89","author":"Pisa","year":"2017","journal-title":"Neurology"},{"key":"2022122116022209400_awac030-B10","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1093\/brain\/awaa458","article-title":"Subclinical anterior optic pathway involvement in early multiple sclerosis and clinically isolated syndromes","volume":"144","author":"Pisa","year":"2021","journal-title":"Brain"},{"key":"2022122116022209400_awac030-B11","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1177\/1352458517694090","article-title":"Cognitive impairment in patients with multiple sclerosis is associated with atrophy of the inner retinal layers","volume":"24","author":"Coric","year":"2018","journal-title":"Mult Scler"},{"key":"2022122116022209400_awac030-B12","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1002\/ana.24487","article-title":"Optical coherence tomography reflects brain atrophy in multiple sclerosis: A four-year study","volume":"78","author":"Saidha","year":"2015","journal-title":"Ann Neurol"},{"key":"2022122116022209400_awac030-B13","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1212\/WNL.0000000000001257","article-title":"Relationships between quantitative spinal cord MRI and retinal layers in multiple sclerosis","volume":"84","author":"Oh","year":"2015","journal-title":"Neurology"},{"key":"2022122116022209400_awac030-B14","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1177\/1352458516637679","article-title":"Retinal degeneration in primary-progressive multiple sclerosis: A role for cortical lesions?","volume":"23","author":"Petracca","year":"2017","journal-title":"Mult Scler"},{"key":"2022122116022209400_awac030-B15","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1177\/1352458519861603","article-title":"Subclinical neurodegeneration in multiple sclerosis and neuromyelitis optica spectrum disorder revealed by optical coherence tomography","volume":"26","author":"Pisa","year":"2020","journal-title":"Mult Scler"},{"key":"2022122116022209400_awac030-B16","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1136\/jnnp-2018-318382","article-title":"Retinal ganglion cell loss in neuromyelitis optica: a longitudinal study","volume":"89","author":"Oertel","year":"2018","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2022122116022209400_awac030-B17","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1177\/1352458517727604","article-title":"Bidirectional degeneration in the visual pathway in neuromyelitis optica spectrum disorder (NMOSD)","volume":"24","author":"Tian","year":"2018","journal-title":"Mult Scler"},{"key":"2022122116022209400_awac030-B18","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1001\/archopht.1953.00920030729007","article-title":"Optic neuropathy in multiple sclerosis; optic neuritis","volume":"50","author":"Gartner","year":"1953","journal-title":"AMA Arch Ophthalmol"},{"key":"2022122116022209400_awac030-B19","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3109\/01658108309009732","article-title":"The optic nerve in multiple sclerosis: A morphological study with retrospective clinico-pathological correlations","volume":"3","author":"Ulrich","year":"1983","journal-title":"Neuro-Ophthalmology"},{"key":"2022122116022209400_awac030-B20","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1111\/j.1755-3768.1990.tb01908.x","article-title":"Histopathology of anterior parts of the optic pathway in patients with multiple sclerose","volume":"68","author":"Mogensen","year":"1990","journal-title":"Acta Ophthalmol"},{"key":"2022122116022209400_awac030-B21","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1111\/nan.12165","article-title":"The influence of HLA-DRB1*15 on motor cortical pathology in multiple sclerosis","volume":"41","author":"Yates","year":"2015","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2022122116022209400_awac030-B22","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s00401-006-0045-0","article-title":"Protein co-expression with axonal injury in multiple sclerosis plaques","volume":"111","author":"Diaz-Sanchez","year":"2006","journal-title":"Acta Neuropathol"},{"key":"2022122116022209400_awac030-B23","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s00401-016-1653-y","article-title":"An updated histological classification system for multiple sclerosis lesions","volume":"133","author":"Kuhlmann","year":"2017","journal-title":"Acta Neuropathol"},{"key":"2022122116022209400_awac030-B24","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1111\/bpa.12209","article-title":"Olfactory pathology in central nervous system demyelinating diseases","volume":"25","author":"DeLuca","year":"2015","journal-title":"Brain Pathol"},{"key":"2022122116022209400_awac030-B25","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci Rep"},{"key":"2022122116022209400_awac030-B26","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1093\/aje\/kwf215","article-title":"Statistical analysis of correlated data using generalized estimating equations: an orientation","volume":"157","author":"Hanley","year":"2003","journal-title":"Am J Epidemiol"},{"key":"2022122116022209400_awac030-B27","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1001\/archneurol.2012.314","article-title":"Epidemiology of neuromyelitis optica in the United States: a multicenter analysis","volume":"69","author":"Mealy","year":"2012","journal-title":"Arch Neurol"},{"issue":"3","key":"2022122116022209400_awac030-B28","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1093\/brain\/awv398","article-title":"The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain","volume":"139","author":"Haider","year":"2016","journal-title":"Brain"},{"key":"2022122116022209400_awac030-B29","doi-asserted-by":"crossref","first-page":"a028936","DOI":"10.1101\/cshperspect.a028936","article-title":"Multiple sclerosis pathology","volume":"8","author":"Lassmann","year":"2018","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"7","key":"2022122116022209400_awac030-B30","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1093\/brain\/awf151","article-title":"A role for humoral mechanisms in the pathogenesis of Devic\u2019s neuromyelitis optica","volume":"125","author":"Lucchinetti","year":"2002","journal-title":"Brain"},{"issue":"2","key":"2022122116022209400_awac030-B31","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1093\/brain\/awp342","article-title":"Acute disseminated encephalomyelitis and multiple sclerosis","volume":"133","author":"Lassmann","year":"2010","journal-title":"Brain"},{"key":"2022122116022209400_awac030-B32","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1002\/ana.24497","article-title":"Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque","volume":"78","author":"Frischer","year":"2015","journal-title":"Ann Neurol"},{"key":"2022122116022209400_awac030-B33","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1212\/01.wnl.0000178984.30534.f9","article-title":"MRI as a marker for disease heterogeneity in multiple sclerosis","volume":"65","author":"Bielekova","year":"2005","journal-title":"Neurology"},{"issue":"Suppl 5","key":"2022122116022209400_awac030-B34","doi-asserted-by":"crossref","first-page":"v16","DOI":"10.1007\/s00415-005-5004-5","article-title":"MRI evidence for multiple sclerosis as a diffuse disease of the central nervous system","volume":"252","author":"Filippi","year":"2005","journal-title":"J Neurol"},{"key":"2022122116022209400_awac030-B35","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/S1474-4422(12)70003-0","article-title":"Association between pathological and MRI findings in multiple sclerosis","volume":"11","author":"Filippi","year":"2012","journal-title":"Lancet Neurol"},{"key":"2022122116022209400_awac030-B36","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S0002-9440(10)64537-3","article-title":"Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions","volume":"157","author":"Kornek","year":"2000","journal-title":"Am J Pathol"},{"key":"2022122116022209400_awac030-B37","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1097\/00005072-199710000-00007","article-title":"Temporal and regional patterns of axonal damage following traumatic brain injury: a beta-amyloid precursor protein immunocytochemical study in rats","volume":"56","author":"Bramlett","year":"1997","journal-title":"J Neuropathol Exp Neurol"},{"key":"2022122116022209400_awac030-B38","doi-asserted-by":"crossref","first-page":"e443","DOI":"10.1212\/NXI.0000000000000443","article-title":"Microglial activation, white matter tract damage, and disability in MS","volume":"5","author":"Rissanen","year":"2018","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"2022122116022209400_awac030-B39","doi-asserted-by":"crossref","first-page":"3318","DOI":"10.1093\/brain\/awaa275","article-title":"Brain TSPO-PET predicts later disease progression independent of relapses in multiple sclerosis","volume":"143","author":"Sucksdorff","year":"2020","journal-title":"Brain"},{"key":"2022122116022209400_awac030-B40","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/ana.23721","article-title":"Cognitive impairment and cortical degeneration in neuromyelitis optica","volume":"73","author":"Saji","year":"2013","journal-title":"Ann Neurol"},{"key":"2022122116022209400_awac030-B41","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1212\/01.wnl.0000254502.87233.9a","article-title":"A secondary progressive clinical course is uncommon in neuromyelitis optica","volume":"68","author":"Wingerchuk","year":"2007","journal-title":"Neurology"},{"key":"2022122116022209400_awac030-B42","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1002\/ana.25463","article-title":"Silent progression in disease activity-free relapsing multiple sclerosis","volume":"85","author":"University of California, San Francisco MS-EPIC Team","year":"2019","journal-title":"Ann Neurol"},{"key":"2022122116022209400_awac030-B43","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1111\/ene.13404","article-title":"Progression of retinal ganglion cell loss in multiple sclerosis is associated with new lesions in the optic radiations","volume":"24","author":"Klistorner","year":"2017","journal-title":"Eur J Neurol"},{"issue":"12","key":"2022122116022209400_awac030-B44","doi-asserted-by":"crossref","first-page":"3165","DOI":"10.1093\/brain\/awl217","article-title":"Remyelination is extensive in a subset of multiple sclerosis patients","volume":"129","author":"Patrikios","year":"2006","journal-title":"Brain"},{"key":"2022122116022209400_awac030-B45","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1111\/j.1365-2990.1978.tb00555.x","article-title":"The cervical cord in multiple sclerosis","volume":"4","author":"Oppenheimer","year":"1978","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2022122116022209400_awac030-B46","doi-asserted-by":"crossref","first-page":"2998","DOI":"10.1093\/brain\/awaa255","article-title":"Vascular disease and multiple sclerosis: a post-mortem study exploring their relationships","volume":"143","author":"Geraldes","year":"2020","journal-title":"Brain"},{"key":"2022122116022209400_awac030-B47","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1136\/practneurol-2017-001787","article-title":"Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease: practical considerations","volume":"19","author":"Jacob","year":"2019","journal-title":"Pract Neurol"},{"key":"2022122116022209400_awac030-B48","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1136\/jnnp-2014-308346","article-title":"Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein","volume":"86","author":"Baumann","year":"2015","journal-title":"J Neurol Neurosurg Psychiatry"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awac030\/46406858\/awac030.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/145\/12\/4308\/48305782\/awac030.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/145\/12\/4308\/48305782\/awac030.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T16:37:48Z","timestamp":1671640668000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/145\/12\/4308\/6521065"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,3]]},"references-count":48,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,2,3]]},"published-print":{"date-parts":[[2022,12,19]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awac030","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12,1]]},"published":{"date-parts":[[2022,2,3]]}}}