{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T15:49:11Z","timestamp":1794498551241,"version":"4.9.1"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,11,29]],"date-time":"2018-11-29T00:00:00Z","timestamp":1543449600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,11,29]],"date-time":"2018-11-29T00:00:00Z","timestamp":1543449600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","award":["150735"],"award-info":[{"award-number":["150735"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr&amp;#x00E5;det","doi-asserted-by":"publisher","award":["2015-00550"],"award-info":[{"award-number":["2015-00550"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"EC | European Research Council","doi-asserted-by":"publisher","award":["AdG294556"],"award-info":[{"award-number":["AdG294556"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["14CVD02"],"award-info":[{"award-number":["14CVD02"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004063","name":"Knut och Alice Wallenbergs Stiftelse","doi-asserted-by":"publisher","award":["2015.0030"],"award-info":[{"award-number":["2015.0030"]}],"id":[{"id":"10.13039\/501100004063","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Diabetes mellitus is associated with cognitive impairment and various central nervous system pathologies such as stroke, vascular dementia, or Alzheimer\u2019s disease. The exact pathophysiology of these conditions is poorly understood. Recent reports suggest that hyperglycemia causes cerebral microcirculation pathology and blood-brain barrier (BBB) dysfunction and leakage. The majority of these reports, however, are based on methods including <jats:italic>in vitro<\/jats:italic> BBB modeling or streptozotocin-induced diabetes in rodents, opening questions regarding the translation of the <jats:italic>in vitro<\/jats:italic> findings to the <jats:italic>in vivo<\/jats:italic> situation, and possible direct effects of streptozotocin on the brain vasculature. Here we used a genetic mouse model of hyperglycemia (<jats:italic>Ins2<\/jats:italic><jats:sup><jats:italic>AKITA<\/jats:italic><\/jats:sup>) to address whether prolonged systemic hyperglycemia induces BBB dysfunction and leakage. We applied a variety of methodologies to carefully evaluate BBB function and cellular integrity <jats:italic>in vivo<\/jats:italic>, including the quantification and visualization of specific tracers and evaluation of transcriptional and morphological changes in the BBB and its supporting cellular components. These experiments did neither reveal altered BBB permeability nor morphological changes of the brain vasculature in hyperglycemic mice. We conclude that prolonged hyperglycemia does not lead to BBB dysfunction, and thus the cognitive impairment observed in diabetes may have other causes.<\/jats:p>","DOI":"10.1038\/s41598-018-35576-0","type":"journal-article","created":{"date-parts":[[2018,11,23]],"date-time":"2018-11-23T15:43:25Z","timestamp":1542987805000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Prolonged systemic hyperglycemia does not cause pericyte loss and permeability at the mouse blood-brain barrier"],"prefix":"10.1038","volume":"8","author":[{"given":"Maarja Andaloussi","family":"M\u00e4e","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8104-4464","authenticated-orcid":false,"given":"Giacomo","family":"Bertuzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Raschperger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0709-7808","authenticated-orcid":false,"given":"Michael","family":"Vanlandewijck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqun","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khayrun","family":"Nahar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Dalheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J.","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e0rbara","family":"Lavi\u00f1a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1466-3633","authenticated-orcid":false,"given":"Annika","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christer","family":"Betsholtz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8558-3107","authenticated-orcid":false,"given":"Guillem","family":"Genov\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,11,29]]},"reference":[{"key":"35576_CR1","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1056\/NEJMra1005073","volume":"366","author":"DA Antonetti","year":"2012","unstructured":"Antonetti, D. A., Klein, R. & Gardner, T. W. Diabetic retinopathy. N. Engl. J. Med. 366, 1227\u20131239 (2012).","journal-title":"N. Engl. J. Med."},{"key":"35576_CR2","doi-asserted-by":"publisher","first-page":"15018","DOI":"10.1038\/nrdp.2015.18","volume":"1","author":"MC Thomas","year":"2015","unstructured":"Thomas, M. C. et al. Diabetic kidney disease. Nat Rev Dis Primers 1, 15018 (2015).","journal-title":"Nat Rev Dis Primers"},{"key":"35576_CR3","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1210\/er.2007-0034","volume":"29","author":"CT Kodl","year":"2008","unstructured":"Kodl, C. T. & Seaquist, E. R. Cognitive dysfunction and diabetes mellitus. Endocr. Rev. 29, 494\u2013511 (2008).","journal-title":"Endocr. Rev."},{"key":"35576_CR4","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1007\/s11481-017-9752-7","volume":"12","author":"M Bogush","year":"2017","unstructured":"Bogush, M., Heldt, N. A. & Persidsky, Y. Blood Brain Barrier Injury in Diabetes: Unrecognized Effects on Brain and Cognition. J Neuroimmune Pharmacol 12, 593\u2013601 (2017).","journal-title":"J Neuroimmune Pharmacol"},{"key":"35576_CR5","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nrneurol.2017.188","volume":"14","author":"MD Sweeney","year":"2018","unstructured":"Sweeney, M. D., Sagare, A. P. & Zlokovic, B. V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14, 133\u2013150 (2018).","journal-title":"Nat Rev Neurol"},{"key":"35576_CR6","first-page":"125","volume":"2","author":"S Prasad","year":"2014","unstructured":"Prasad, S., Sajja, R. K., Naik, P. & Cucullo, L. Diabetes Mellitus and Blood-Brain Barrier Dysfunction: An Overview. J Pharmacovigil 2, 125 (2014).","journal-title":"J Pharmacovigil"},{"key":"35576_CR7","doi-asserted-by":"publisher","first-page":"H2660","DOI":"10.1152\/ajpheart.00489.2006","volume":"291","author":"JD Huber","year":"2006","unstructured":"Huber, J. D., VanGilder, R. L. & Houser, K. A. Streptozotocin-induced diabetes progressively increases blood-brain barrier permeability in specific brain regions in rats. Am. J. Physiol. Heart Circ. Physiol. 291, H2660\u20138 (2006).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"35576_CR8","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1124\/jpet.116.237057","volume":"359","author":"TS Salameh","year":"2016","unstructured":"Salameh, T. S., Shah, G. N., Price, T. O., Hayden, M. R. & Banks, W. A. Blood-Brain Barrier Disruption and Neurovascular Unit Dysfunction in Diabetic Mice: Protection with the Mitochondrial Carbonic Anhydrase Inhibitor Topiramate. J. Pharmacol. Exp. Ther. 359, 452\u2013459 (2016).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"35576_CR9","doi-asserted-by":"publisher","first-page":"2331","DOI":"10.2337\/db11-0159","volume":"60","author":"YD Muller","year":"2011","unstructured":"Muller, Y. D. et al. Immunosuppressive effects of streptozotocin-induced diabetes result in absolute lymphopenia and a relative increase of T regulatory cells. Diabetes 60, 2331\u20132340 (2011).","journal-title":"Diabetes"},{"key":"35576_CR10","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1258\/la.2010.010090","volume":"45","author":"MC Deeds","year":"2011","unstructured":"Deeds, M. C. et al. Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models. Lab. Anim. 45, 131\u2013140 (2011).","journal-title":"Lab. Anim."},{"key":"35576_CR11","doi-asserted-by":"publisher","first-page":"887","DOI":"10.2337\/diab.46.5.887","volume":"46","author":"M Yoshioka","year":"1997","unstructured":"Yoshioka, M., Kayo, T., Ikeda, T. & Koizumi, A. A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL\/6 (Akita) mutant mice. Diabetes 46, 887\u2013894 (1997).","journal-title":"Diabetes"},{"key":"35576_CR12","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/nature09522","volume":"468","author":"A Armulik","year":"2010","unstructured":"Armulik, A. et al. Pericytes regulate the blood-brain barrier. Nature 468, 557\u2013561 (2010).","journal-title":"Nature"},{"key":"35576_CR13","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1038\/nature25739","volume":"554","author":"M Vanlandewijck","year":"2018","unstructured":"Vanlandewijck, M. et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature 554, 475\u2013480 (2018).","journal-title":"Nature"},{"key":"35576_CR14","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.neurobiolaging.2016.11.017","volume":"51","author":"S Janelidze","year":"2017","unstructured":"Janelidze, S. et al. Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype. Neurobiol. Aging 51, 104\u2013112 (2017).","journal-title":"Neurobiol. Aging"},{"key":"35576_CR15","doi-asserted-by":"publisher","first-page":"e0143407","DOI":"10.1371\/journal.pone.0143407","volume":"10","author":"M Vanlandewijck","year":"2015","unstructured":"Vanlandewijck, M. et al. Functional Characterization of Germline Mutations in PDGFB and PDGFRB in Primary Familial Brain Calcification. PLoS ONE 10, e0143407 (2015).","journal-title":"PLoS ONE"},{"key":"35576_CR16","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/nm1787","volume":"14","author":"EJ Su","year":"2008","unstructured":"Su, E. J. et al. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat Med 14, 731\u2013737 (2008).","journal-title":"Nat Med"},{"key":"35576_CR17","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1096\/fj.05-4944fje","volume":"20","author":"C Bondjers","year":"2006","unstructured":"Bondjers, C. et al. Microarray analysis of blood microvessels from PDGF-B and PDGF-Rbeta mutant mice identifies novel markers for brain pericytes. FASEB J. 20, 1703\u20131705 (2006).","journal-title":"FASEB J."},{"key":"35576_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/srep35108","volume":"6","author":"L He","year":"2016","unstructured":"He, L. et al. Analysis of the brain mural cell transcriptome. Sci Rep 6, 35108 (2016).","journal-title":"Sci Rep"},{"key":"35576_CR19","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2013-14-4-r36","volume":"14","author":"D Kim","year":"2013","unstructured":"Kim, D. et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14, R36 (2013).","journal-title":"Genome Biol"},{"key":"35576_CR20","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1038\/nbt.1621","volume":"28","author":"C Trapnell","year":"2010","unstructured":"Trapnell, C. et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28, 511\u2013515 (2010).","journal-title":"Nat. Biotechnol."},{"key":"35576_CR21","doi-asserted-by":"publisher","first-page":"2210","DOI":"10.1167\/iovs.04-1340","volume":"46","author":"AJ Barber","year":"2005","unstructured":"Barber, A. J. et al. The Ins2Akita mouse as a model of early retinal complications in diabetes. Invest Ophthalmol Vis Sci 46, 2210\u20132218 (2005).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"35576_CR22","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.bbr.2004.06.005","volume":"157","author":"C Choeiri","year":"2005","unstructured":"Choeiri, C. et al. Longitudinal evaluation of memory performance and peripheral neuropathy in the Ins2C96Y Akita mice. Behav. Brain Res. 157, 31\u201338 (2005).","journal-title":"Behav. Brain Res."},{"key":"35576_CR23","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1111\/ceo.12084","volume":"41","author":"S McLenachan","year":"2013","unstructured":"McLenachan, S., Chen, X., McMenamin, P. G. & Rakoczy, E. P. Absence of clinical correlates of diabetic retinopathy in the Ins2Akita retina. Clin. Experiment. Ophthalmol. 41, 582\u2013592 (2013).","journal-title":"Clin. Experiment. Ophthalmol."},{"key":"35576_CR24","doi-asserted-by":"publisher","first-page":"3218","DOI":"10.2174\/09298673113209990022","volume":"20","author":"E Beltramo","year":"2013","unstructured":"Beltramo, E. & Porta, M. Pericyte loss in diabetic retinopathy: mechanisms and consequences. Curr. Med. Chem. 20, 3218\u20133225 (2013).","journal-title":"Curr. Med. Chem."},{"key":"35576_CR25","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.pharmthera.2016.11.008","volume":"171","author":"D Ferland-McCollough","year":"2017","unstructured":"Ferland-McCollough, D., Slater, S., Richard, J., Reni, C. & Mangialardi, G. Pericytes, an overlooked player in vascular pathobiology. Pharmacol. Ther. 171, 30\u201342 (2017).","journal-title":"Pharmacol. Ther."},{"key":"35576_CR26","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.lfs.2016.08.001","volume":"162","author":"FS Sorrentino","year":"2016","unstructured":"Sorrentino, F. S., Allkabes, M., Salsini, G., Bonifazzi, C. & Perri, P. The importance of glial cells in the homeostasis of the retinal microenvironment and their pivotal role in the course of diabetic retinopathy. Life Sci. 162, 54\u201359 (2016).","journal-title":"Life Sci."},{"key":"35576_CR27","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.neuroscience.2017.05.018","volume":"356","author":"J Biswas","year":"2017","unstructured":"Biswas, J., Gupta, S., Verma, D. K. & Singh, S. Streptozotocin alters glucose transport, connexin expression and endoplasmic reticulum functions in neurons and astrocytes. Neuroscience 356, 151\u2013166 (2017).","journal-title":"Neuroscience"},{"key":"35576_CR28","doi-asserted-by":"publisher","first-page":"2794","DOI":"10.1007\/s12035-015-9144-z","volume":"53","author":"J Biswas","year":"2016","unstructured":"Biswas, J. et al. Streptozotocin Induced Neurotoxicity Involves Alzheimer\u2019s Related Pathological Markers: a Study on N2A Cells. Mol. Neurobiol. 53, 2794\u20132806 (2016).","journal-title":"Mol. Neurobiol."},{"key":"35576_CR29","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.jneuroim.2017.03.008","volume":"306","author":"AS Hidmark","year":"2017","unstructured":"Hidmark, A. S., Nawroth, P. P. & Fleming, T. STZ causes depletion of immune cells in sciatic nerve and dorsal root ganglion in experimental diabetes. J. Neuroimmunol. 306, 76\u201382 (2017).","journal-title":"J. Neuroimmunol."},{"key":"35576_CR30","doi-asserted-by":"publisher","first-page":"4154","DOI":"10.1167\/iovs.08-1824","volume":"49","author":"SB Smith","year":"2008","unstructured":"Smith, S. B. et al. In vivo protection against retinal neurodegeneration by sigma receptor 1 ligand (+)\u2212pentazocine. Invest Ophthalmol Vis Sci 49, 4154\u20134161 (2008).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"35576_CR31","doi-asserted-by":"publisher","first-page":"2921","DOI":"10.1167\/iovs.12-9662","volume":"53","author":"MJ Mattapallil","year":"2012","unstructured":"Mattapallil, M. J. et al. The Rd8 mutation of the Crb1 gene is present in vendor lines of C57BL\/6N mice and embryonic stem cells, and confounds ocular induced mutant phenotypes. Invest Ophthalmol Vis Sci 53, 2921\u20132927 (2012).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"35576_CR32","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1111\/pedi.12127","volume":"15","author":"M Garg","year":"2014","unstructured":"Garg, M., Thamotharan, M., Becker, D. J. & Devaskar, S. U. Adolescents with clinical type 1 diabetes display reduced red blood cell glucose transporter isoform 1 (GLUT1). Pediatr Diabetes 15, 511\u2013518 (2014).","journal-title":"Pediatr Diabetes"},{"key":"35576_CR33","first-page":"1986","volume":"86","author":"SG Hasselbalch","year":"2001","unstructured":"Hasselbalch, S. G., Knudsen, G. M., Capaldo, B., Postiglione, A. & Paulson, O. B. Blood-brain barrier transport and brain metabolism of glucose during acute hyperglycemia in humans. J. Clin. Endocrinol. Metab. 86, 1986\u20131990 (2001).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"35576_CR34","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1016\/S0006-8993(00)01942-9","volume":"858","author":"R Duelli","year":"2000","unstructured":"Duelli, R. et al. Increased cerebral glucose utilization and decreased glucose transporter Glut1 during chronic hyperglycemia in rat brain. Brain Res. 858, 338\u2013347 (2000).","journal-title":"Brain Res."},{"key":"35576_CR35","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1016\/j.seizure.2013.07.003","volume":"22","author":"V De Giorgis","year":"2013","unstructured":"De Giorgis, V. & Veggiotti, P. GLUT1 deficiency syndrome 2013: current state of the art. Seizure 22, 803\u2013811 (2013).","journal-title":"Seizure"},{"key":"35576_CR36","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1093\/eurheartj\/ehu179","volume":"36","author":"F Paneni","year":"2015","unstructured":"Paneni, F. et al. Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes. Eur. Heart J. 36, 817\u2013828 (2015).","journal-title":"Eur. Heart J."},{"key":"35576_CR37","doi-asserted-by":"publisher","first-page":"110","DOI":"10.3390\/ijms19010110","volume":"19","author":"C Altmann","year":"2018","unstructured":"Altmann, C. & Schmidt, M. H. H. The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration. Int J Mol Sci 19, 110 (2018).","journal-title":"Int J Mol Sci"},{"key":"35576_CR38","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/nrneph.2015.37","volume":"11","author":"E Ahlqvist","year":"2015","unstructured":"Ahlqvist, E., van Zuydam, N. R., Groop, L. C. & McCarthy, M. I. The genetics of diabetic complications. Nat Rev Nephrol 11, 277\u2013287 (2015).","journal-title":"Nat Rev Nephrol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-35576-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-35576-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-35576-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T12:09:52Z","timestamp":1671624592000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-35576-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,29]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["35576"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-35576-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,29]]},"assertion":[{"value":"6 September 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 November 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 2018","order":3,"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"}}],"article-number":"17462"}}