{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T21:49:59Z","timestamp":1793915399628,"version":"4.8.0"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001729","name":"Stiftelsen f\u00f6r\u00a0Strategisk Forskning","doi-asserted-by":"publisher","award":["RB13-0192"],"award-info":[{"award-number":["RB13-0192"]}],"id":[{"id":"10.13039\/501100001729","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2017-06086"],"award-info":[{"award-number":["2017-06086"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2017-02965"],"award-info":[{"award-number":["2017-02965"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2020-01990"],"award-info":[{"award-number":["2020-01990"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2020-01990"],"award-info":[{"award-number":["2020-01990"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003792","name":"Hj\u00e4rnfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003792","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004047","name":"Karolinska Institutet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Stockholm Region-Karolinska Institutet regional agreement on medical training and clinical research (ALF grant) Swedish Alzheimer\u2019s Foundation Center for Innovative Medicine (CIMED) Stockholm Region"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Psychiatry"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    For early detection of Alzheimer\u2019s disease, it is important to find biomarkers with predictive value for disease progression and clinical manifestations, such as cognitive decline. Individuals can now be profiled based on their biomarker status for A\u03b242 (A) or tau (T) deposition and neurodegeneration (N). The aim of this study was to compare the cerebrospinal fluid (CSF) and imaging (PET\/MR) biomarkers in each ATN category and to assess their ability to predict longitudinal cognitive decline. A subset of 282 patients, who had had at the same time PET investigations with amyloid-\u03b2 and tau tracers, CSF sampling, and structural MRI (18% within 13 months), was selected from the ADNI dataset. The participants were grouped by clinical diagnosis at that time: cognitively normal, subjective memory concern, early or late mild cognitive impairment, or AD. Agreement between CSF (amyloid-\u03b2-1-42(A), phosphorylated-Tau181(T), total-Tau(N)), and imaging (amyloid-\u03b2 PET (florbetaben and florbetapir)(A), tau PET (flortaucipir)(T), hippocampal volume (MRI)(N)) positivity in ATN was assessed with Cohen\u2019s Kappa. Linear mixed-effects models were used to predict decline in the episodic memory. There was moderate agreement between PET and CSF for A biomarkers (Kappa\u2009=\u20090.39\u20130.71), while only fair agreement for T biomarkers (Kappa\u2009\u2264\u20090.40, except AD) and discordance for N biomarkers across all groups (Kappa\u2009\u2264\u20090.14) was found. Baseline PET tau predicted longitudinal decline in episodic memory irrespective of CSF p-Tau181 positivity (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009\u2264\u20090.02). Baseline PET tau and amyloid-\u03b2 predicted decline in episodic memory (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009\u2264\u20090.0001), but isolated PET amyloid-\u03b2 did not. Isolated PET Tau positivity was only observed in 2 participants (0.71% of the sample). While results for amyloid-\u03b2 were similar using CSF or imaging, CSF and imaging results for tau and neurodegeneration were not interchangeable. PET tau positivity was superior to CSF p-Tau181 and PET amyloid-\u03b2 in predicting cognitive decline in the AD continuum within 3 years of follow-up.\n                  <\/jats:p>","DOI":"10.1038\/s41380-021-01263-2","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T23:41:01Z","timestamp":1633045261000},"page":"5888-5898","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":140,"title":["Alzheimer\u2019s disease profiled by fluid and imaging markers: tau PET best predicts cognitive decline"],"prefix":"10.1038","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5206-8651","authenticated-orcid":false,"given":"Marco","family":"Bucci","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5679-0297","authenticated-orcid":false,"given":"Konstantinos","family":"Chiotis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7345-5151","authenticated-orcid":false,"given":"Agneta","family":"Nordberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,1]]},"reference":[{"issue":"4","key":"1263_CR1","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","volume":"14","author":"CR Jack Jr.","year":"2018","unstructured":"Jack CR Jr., Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: toward a biological definition of Alzheimer\u2019s disease. Alzheimer\u2019s Dement: J Alzheimer\u2019s Assoc. 2018;14(4):535\u201362.","journal-title":"Alzheimer\u2019s Dement: J Alzheimer\u2019s Assoc"},{"issue":"21","key":"1263_CR2","doi-asserted-by":"publisher","first-page":"e2233","DOI":"10.1212\/WNL.0000000000009485","volume":"94","author":"N Mattsson-Carlgren","year":"2020","unstructured":"Mattsson-Carlgren N, Leuzy A, Janelidze S, Palmqvist S, Stomrud E, Strandberg O, et al. The implications of different approaches to define AT (N) in Alzheimer disease. Neurology. 2020;94(21):e2233\u2013e2244.","journal-title":"Neurology"},{"key":"1263_CR3","doi-asserted-by":"crossref","unstructured":"Provost K, Iaccarino L, Soleimani-Meigooni DN, Baker S, Edwards L, Eichenlaub U, et al. Comparing ATN-T designation by tau PET visual reads, tau PET quantification, and CSF PTau181 across three cohorts. Eur J Nucl Med Mol Imaging. 2021.","DOI":"10.1007\/s00259-020-05152-8"},{"issue":"6","key":"1263_CR4","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/S1474-4422(21)00066-1","volume":"20","author":"B Dubois","year":"2021","unstructured":"Dubois B, Villain N, Frisoni GB, Rabinovici GD, Sabbagh M, Cappa S, et al. Clinical diagnosis of Alzheimer\u2019s disease: recommendations of the International Working Group. Lancet Neurol. 2021;20(6):484\u201396.","journal-title":"Lancet Neurol"},{"issue":"6","key":"1263_CR5","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1016\/S1474-4422(21)00077-6","volume":"20","author":"WJ Jagust","year":"2021","unstructured":"Jagust WJ. The changing definition of Alzheimer\u2019s disease. Lancet Neurol. 2021;20(6):414\u20135.","journal-title":"Lancet Neurol"},{"issue":"1","key":"1263_CR6","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1186\/s13195-021-00817-4","volume":"13","author":"K Delmotte","year":"2021","unstructured":"Delmotte K, Schaeverbeke J, Poesen K, Vandenberghe R. Prognostic value of amyloid\/tau\/neurodegeneration (ATN) classification based on diagnostic cerebrospinal fluid samples for Alzheimer\u2019s disease. Alzheimers Res Ther. 2021;13(1):84.","journal-title":"Alzheimers Res Ther"},{"issue":"11","key":"1263_CR7","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1001\/jama.2018.12917","volume":"320","author":"R Ossenkoppele","year":"2018","unstructured":"Ossenkoppele R, Rabinovici GD, Smith R, Cho H, Sch\u00f6ll M, Strandberg O, et al. Discriminative accuracy of [18F] flortaucipir positron emission tomography for Alzheimer disease vs other neurodegenerative disorders. JAMA. 2018;320(11):1151\u201362.","journal-title":"JAMA"},{"issue":"4","key":"1263_CR8","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1001\/jamaneurol.2019.4749","volume":"77","author":"P-F Meyer","year":"2020","unstructured":"Meyer P-F, Binette AP, Gonneaud J, Breitner JC, Villeneuve S. Characterization of Alzheimer disease biomarker discrepancies using cerebrospinal fluid phosphorylated tau and AV1451 positron emission tomography. JAMA Neurol. 2020;77(4):508\u201316.","journal-title":"JAMA Neurol"},{"issue":"4","key":"1263_CR9","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1007\/s11682-012-9186-z","volume":"6","author":"PK Crane","year":"2012","unstructured":"Crane PK, Carle A, Gibbons LE, Insel P, Mackin RS, Gross A, et al. Development and assessment of a composite score for memory in the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI). Brain imaging Behav. 2012;6(4):502\u201316.","journal-title":"Brain imaging Behav"},{"issue":"7","key":"1263_CR10","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1016\/j.jalz.2015.05.005","volume":"11","author":"PS Aisen","year":"2015","unstructured":"Aisen PS, Petersen RC, Donohue M, Weiner MW. Initiative AsDN. Alzheimer\u2019s Disease Neuroimaging Initiative 2 Clinical Core: progress and plans. Alzheimers Dement. 2015;11(7):734\u20139.","journal-title":"Alzheimers Dement"},{"issue":"3","key":"1263_CR11","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.jalz.2010.03.006","volume":"6","author":"PS Aisen","year":"2010","unstructured":"Aisen PS, Petersen RC, Donohue MC, Gamst A, Raman R, Thomas RG, et al. Clinical core of the Alzheimer\u2019s Disease Neuroimaging Initiative: progress and plans. Alzheimers Dement. 2010;6(3):239\u201346.","journal-title":"Alzheimers Dement"},{"key":"1263_CR12","doi-asserted-by":"publisher","first-page":"378","DOI":"10.2967\/jnumed.111.090340","volume":"53","author":"AD Joshi","year":"2012","unstructured":"Joshi AD, Pontecorvo MJ, Clark CM, Carpenter AP, Jennings DL, Sadowsky CH, et al. Study Investigators: performance characteristics of amyloid PET with florbetapir F 18 in patients with Alzheimer\u2019s disease and cognitively normal subjects. J Nucl Med. 2012;53:378\u201384.","journal-title":"J Nucl Med"},{"issue":"16","key":"1263_CR13","doi-asserted-by":"publisher","first-page":"eaaz2387","DOI":"10.1126\/sciadv.aaz2387","volume":"6","author":"N Mattsson-Carlgren","year":"2020","unstructured":"Mattsson-Carlgren N, Andersson E, Janelidze S, Ossenkoppele R, Insel P, Strandberg O, et al. A\u03b2 deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer\u2019s disease. Sci Adv. 2020;6(16):eaaz2387.","journal-title":"Sci Adv"},{"issue":"5","key":"1263_CR14","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.jalz.2015.09.009","volume":"12","author":"T Bittner","year":"2016","unstructured":"Bittner T, Zetterberg H, Teunissen CE, Ostlund RE Jr, Militello M, Andreasson U, et al. Technical performance of a novel, fully automated electrochemiluminescence immunoassay for the quantitation of \u03b2-amyloid (1\u201342) in human cerebrospinal fluid. Alzheimer\u2019s Dement. 2016;12(5):517\u201326.","journal-title":"Alzheimer\u2019s Dement"},{"issue":"11","key":"1263_CR15","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1016\/j.jalz.2018.01.013","volume":"14","author":"SE Schindler","year":"2018","unstructured":"Schindler SE, Gray JD, Gordon BA, Xiong C, Batrla-Utermann R, Quan M, et al. Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging. Alzheimers Dement. 2018;14(11):1460\u20139.","journal-title":"Alzheimers Dement"},{"issue":"1","key":"1263_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-54204-z","volume":"9","author":"K Blennow","year":"2019","unstructured":"Blennow K, Shaw LM, Stomrud E, Mattsson N, Toledo JB, Buck K, et al. Predicting clinical decline and conversion to Alzheimer\u2019s disease or dementia using novel Elecsys A\u03b2(1\u201342), pTau and tTau CSF immunoassays. Sci Rep. 2019;9(1):19024.","journal-title":"Sci Rep"},{"issue":"Pt 12","key":"1263_CR17","doi-asserted-by":"publisher","first-page":"3747","DOI":"10.1093\/brain\/awv283","volume":"138","author":"CR Jack Jr","year":"2015","unstructured":"Jack CR Jr, Wiste HJ, Weigand SD, Knopman DS, Mielke MM, Vemuri P, et al. Different definitions of neurodegeneration produce similar amyloid\/neurodegeneration biomarker group findings. Brain. 2015;138(Pt 12):3747\u201359.","journal-title":"Brain"},{"issue":"9","key":"1263_CR18","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1016\/j.jalz.2019.05.006","volume":"15","author":"J-T Yu","year":"2019","unstructured":"Yu J-T, Li J-Q, Suckling J, Feng L, Pan A, Wang Y-J, et al. Frequency and longitudinal clinical outcomes of Alzheimer\u2019s AT (N) biomarker profiles: a longitudinal study. Alzheimer\u2019s Dement. 2019;15(9):1208\u201317.","journal-title":"Alzheimer\u2019s Dement"},{"issue":"6","key":"1263_CR19","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/S1474-4422(17)30077-7","volume":"16","author":"CR Jack Jr","year":"2017","unstructured":"Jack CR Jr, Wiste HJ, Weigand SD, Therneau TM, Knopman DS, Lowe V, et al. Age-specific and sex-specific prevalence of cerebral \u03b2-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50\u201395 years: a cross-sectional study. Lancet Neurol. 2017;16(6):435\u201344.","journal-title":"Lancet Neurol"},{"issue":"3","key":"1263_CR20","doi-asserted-by":"publisher","first-page":"276","DOI":"10.11613\/BM.2012.031","volume":"22","author":"ML McHugh","year":"2012","unstructured":"McHugh ML. Interrater reliability: the kappa statistic. Biochem Med. 2012;22(3):276\u201382.","journal-title":"Biochem Med"},{"key":"1263_CR21","first-page":"2","volume-title":"R: A language and environment for statistical computing","author":"Core Team R.","year":"2013","unstructured":"Core Team R. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2013. P. 2."},{"issue":"1","key":"1263_CR22","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1186\/s13195-020-00665-8","volume":"12","author":"T Guo","year":"2020","unstructured":"Guo T, Korman D, La Joie R, Shaw LM, Trojanowski JQ, Jagust WJ, et al. Normalization of CSF pTau measurement by A\u03b240 improves its performance as a biomarker of Alzheimer\u2019s disease. Alzheimer\u2019s Res Ther. 2020;12(1):97.","journal-title":"Alzheimer\u2019s Res Ther"},{"issue":"Pt 4","key":"1263_CR23","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1093\/brain\/aww015","volume":"139","author":"S Palmqvist","year":"2016","unstructured":"Palmqvist S, Mattsson N, Hansson O. Initiative AsDN. Cerebrospinal fluid analysis detects cerebral amyloid-\u03b2 accumulation earlier than positron emission tomography. Brain. 2016;139(Pt 4):1226\u201336.","journal-title":"Brain"},{"issue":"1","key":"1263_CR24","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.exger.2009.10.010","volume":"45","author":"H Hampel","year":"2010","unstructured":"Hampel H, Blennow K, Shaw LM, Hoessler YC, Zetterberg H, Trojanowski JQ. Total and phosphorylated tau protein as biological markers of Alzheimer\u2019s disease. Exp Gerontol. 2010;45(1):30\u201340.","journal-title":"Exp Gerontol"},{"issue":"1","key":"1263_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12031-011-9665-5","volume":"47","author":"H Rosenmann","year":"2012","unstructured":"Rosenmann H. CSF biomarkers for amyloid and tau pathology in Alzheimer\u2019s disease. J Mol Neurosci. 2012;47(1):1\u201314.","journal-title":"J Mol Neurosci"},{"issue":"Pt 9","key":"1263_CR26","doi-asserted-by":"publisher","first-page":"2320","DOI":"10.1093\/brain\/awm136","volume":"130","author":"S Engelborghs","year":"2007","unstructured":"Engelborghs S, Sleegers K, Cras P, Brouwers N, Serneels S, De Leenheir E, et al. No association of CSF biomarkers with APOEepsilon4, plaque and tangle burden in definite Alzheimer\u2019s disease. Brain. 2007;130(Pt 9):2320\u20136.","journal-title":"Brain"},{"issue":"Pt 10","key":"1263_CR27","doi-asserted-by":"publisher","first-page":"e82","DOI":"10.1093\/brain\/awm140","volume":"130","author":"K Buerger","year":"2007","unstructured":"Buerger K, Alafuzoff I, Ewers M, Pirttil\u00e4 T, Zinkowski R, Hampel H. No correlation between CSF tau protein phosphorylated at threonine 181 with neocortical neurofibrillary pathology in Alzheimer\u2019s disease. Brain. 2007;130(Pt 10):e82\u2013e82.","journal-title":"Brain"},{"issue":"1","key":"1263_CR28","first-page":"e12099","volume":"12","author":"LL Raket","year":"2020","unstructured":"Raket LL, K\u00fchnel L, Schmidt E, Blennow K, Zetterberg H, Mattsson-Carlgren N. Utility of plasma neurofilament light and total tau for clinical trials in Alzheimer\u2019s disease. Alzheimers Dement. 2020;12(1):e12099.","journal-title":"Alzheimers Dement"},{"key":"1263_CR29","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.arr.2016.01.002","volume":"30","author":"L Pini","year":"2016","unstructured":"Pini L, Pievani M, Bocchetta M, Altomare D, Bosco P, Cavedo E, et al. Brain atrophy in Alzheimer\u2019s Disease and aging. Ageing Res Rev. 2016;30:25\u201348.","journal-title":"Ageing Res Rev"},{"issue":"8","key":"1263_CR30","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1001\/archneurol.2011.167","volume":"68","author":"MR Sabuncu","year":"2011","unstructured":"Sabuncu MR, Desikan RS, Sepulcre J, Yeo BT, Liu H, Schmansky NJ, et al. The dynamics of cortical and hippocampal atrophy in Alzheimer disease. Arch Neurol. 2011;68(8):1040\u20138.","journal-title":"Arch Neurol"},{"issue":"1","key":"1263_CR31","doi-asserted-by":"publisher","first-page":"e-1","DOI":"10.1016\/j.jalz.2013.01.002","volume":"9","author":"KA Johnson","year":"2013","unstructured":"Johnson KA, Minoshima S, Bohnen NI, Donohoe KJ, Foster NL, Herscovitch P, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer\u2019s Association. Alzheimers Dement. 2013;9(1):e-1\u201316.","journal-title":"Alzheimers Dement"},{"issue":"1","key":"1263_CR32","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1007\/s00259-012-2237-2","volume":"40","author":"A Nordberg","year":"2013","unstructured":"Nordberg A, Carter SF, Rinne J, Drzezga A, Brooks DJ, Vandenberghe R, et al. A European multicentre PET study of fibrillar amyloid in Alzheimer\u2019s disease. Eur J Nucl Med Mol Imaging. 2013;40(1):104\u201314.","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"1263_CR33","doi-asserted-by":"crossref","unstructured":"Villemagne VL, Lopresti BJ, Dore V, Tudorascu D, Ikonomovic MD, Burnham S, et al. What is T+? A Gordian knot of tracers, thresholds & topographies. J Nucl Med. 2021:62;614\u2013619.","DOI":"10.2967\/jnumed.120.245423"}],"container-title":["Molecular Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41380-021-01263-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-021-01263-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41380-021-01263-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T14:39:11Z","timestamp":1642084751000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41380-021-01263-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10]]},"references-count":33,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2021,10]]}},"alternative-id":["1263"],"URL":"https:\/\/doi.org\/10.1038\/s41380-021-01263-2","relation":{},"ISSN":["1359-4184","1476-5578"],"issn-type":[{"value":"1359-4184","type":"print"},{"value":"1476-5578","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10]]},"assertion":[{"value":"31 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 July 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 August 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 October 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}