{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T13:24:18Z","timestamp":1793021058709,"version":"4.5.0"},"reference-count":57,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2017,11,12]],"date-time":"2017-11-12T00:00:00Z","timestamp":1510444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008272","name":"Novartis Pharmaceuticals Corporation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000073","name":"Autism Speaks","doi-asserted-by":"publisher","award":["5735"],"award-info":[{"award-number":["5735"]}],"id":[{"id":"10.13039\/100000073","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001771","name":"Tuberous Sclerosis Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001771","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To evaluate if short\u2010term treatment with everolimus was safe and could improve neurocognition and behavior in children with\n                      <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This was a prospective, double\u2010blind randomized, placebo\u2010controlled two\u2010center phase\n                      <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>\n                      study. Participants diagnosed with\n                      <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\n                      and age 6\u201321\u00a0years were treated with 4.5\u00a0mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      per day of oral everolimus (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a032) or matching placebo (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a015) taken once daily for 6\u00a0months. For efficacy, a comprehensive neurocognitive and behavioral evaluation battery was performed at baseline, 3\u00a0months, and 6\u00a0months. For safety, adverse events recorded continuously via patient diary were categorized and graded per\n                      <jats:styled-content style=\"fixed-case\">NCI<\/jats:styled-content>\n                      Common Toxicity Criteria for Adverse Events, version 3.0 (\n                      <jats:styled-content style=\"fixed-case\">CTCAE<\/jats:styled-content>\n                      3.0). Analyses were performed on the intention\u2010to\u2010treat population (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a047).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Nearly all assessment measures failed to demonstrate significant differences between the two groups at the end of 6\u00a0months. Only one measure each of executive function (Cambridge Neuropsychological Test Automated Battery Stockings of Cambridge) favoring placebo (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.025) and social cognition (Social Responsiveness Scale Social Cognition Subscale) favoring everolimus (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.011) was observed. A total of 473 adverse events (\n                      <jats:styled-content style=\"fixed-case\">AE<\/jats:styled-content>\n                      ) were reported. The average number of total\n                      <jats:styled-content style=\"fixed-case\">AE<\/jats:styled-content>\n                      per subject was similar for both placebo and everolimus. Most were mild or moderate in severity and serious\n                      <jats:styled-content style=\"fixed-case\">AE<\/jats:styled-content>\n                      were rare.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      While safe, oral everolimus administered once daily for 6\u00a0months did not significantly improve neurocognitive functioning or behavior in children with\n                      <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.494","type":"journal-article","created":{"date-parts":[[2017,11,12]],"date-time":"2017-11-12T19:06:36Z","timestamp":1510513596000},"page":"877-887","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":126,"title":["Everolimus for treatment of tuberous sclerosis complex\u2010associated neuropsychiatric disorders"],"prefix":"10.1002","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7250-7391","authenticated-orcid":false,"given":"Darcy A.","family":"Krueger","sequence":"first","affiliation":[{"name":"Division of Neurology Department of Pediatrics Cincinnati Children's Hospital Medical Center University of Cincinnati Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjali","family":"Sadhwani","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Boston Children's Hospital and Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna W.","family":"Byars","sequence":"additional","affiliation":[{"name":"Division of Neurology Department of Pediatrics Cincinnati Children's Hospital Medical Center University of Cincinnati Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petrus J.","family":"de Vries","sequence":"additional","affiliation":[{"name":"Division of Child &amp; Adolescent Psychiatry University of Cape Town Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N.","family":"Franz","sequence":"additional","affiliation":[{"name":"Division of Neurology Department of Pediatrics Cincinnati Children's Hospital Medical Center University of Cincinnati Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicky H.","family":"Whittemore","sequence":"additional","affiliation":[{"name":"National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajna","family":"Filip\u2010Dhima","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Murray","sequence":"additional","affiliation":[{"name":"Autism Speaks Boston Massachusetts"},{"name":"Division of Developmental &amp; Behavioral Pediatrics Department of Pediatrics Cincinnati Children's Hospital Medical Center University of Cincinnati Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kush","family":"Kapur","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7044-2953","authenticated-orcid":false,"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital Harvard Medical School Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,11,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.017"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.09.034"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61279-9"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2014.10.004"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)00069-1"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.1983.tb13771.x"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23960"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31419-2"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0955-08.2008"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1566"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2012.03.048"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21317"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2005.03538.x"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21331"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11310"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2012.10.014"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.03.030"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.08.024"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1788"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M512524200"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1101\/lm.1067808"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1014715108"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2012.01.017"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-0445"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2013.08.001"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1001671"},{"key":"e_1_2_9_28_1","volume-title":"Abbreviated scale of intelligence","author":"Wechsler DW","year":"1999"},{"key":"e_1_2_9_29_1","volume-title":"Expressive vocabulary test \u2010 2 (EVT\u20102)","author":"Williams K","year":"2007"},{"key":"e_1_2_9_30_1","volume-title":"Pebody picture vocabulary test \u2010 4 (PPVT\u20104)","author":"Dunn L","year":"2007"},{"key":"e_1_2_9_31_1","unstructured":"Cambridge Cognition Ltd. CANTAB [Cognitive assessment software]. Cambridge UK. 2017. Available at:http:\/\/www.cambridgecognition.com\/cantab\/(Last accessed 10 14 2017)"},{"key":"e_1_2_9_32_1","volume-title":"WRAML2: wide range assessment of memory and learning","author":"Adams W","year":"2003"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-79948-3_187"},{"key":"e_1_2_9_34_1","volume-title":"Vineland adaptive behavior scales: second edition (Vineland II), survey interview form\/caregiver rating form","author":"Sparrow SS","year":"2005"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1076\/chin.8.2.121.8727"},{"key":"e_1_2_9_36_1","volume-title":"Behavior assessment system for children, Second Edition (BASC\u20102)","author":"Reynolds C","year":"2008"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/1469-7610.00494"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1025014929212"},{"key":"e_1_2_9_39_1","volume-title":"Wide range achievement test 4","author":"Wilkinson G","year":"2006"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61134-9"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182815428"},{"key":"e_1_2_9_42_1","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini Y","year":"1995","journal-title":"J R Statis Soc B."},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1198\/jasa.2009.0116"},{"key":"e_1_2_9_44_1","volume-title":"Longitudinal data analysis","author":"Hedeker D","year":"2006"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781119013563"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2017.02.007"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2009.02474.x"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61767-X"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073812449904"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073807309788"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003002"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2011.03.010"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2015.11.011"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2011.211995"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12484"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291715000264"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073812465122"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2015.09.013"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Facn3.494","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.494","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T11:48:38Z","timestamp":1719575318000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.494"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,12]]},"references-count":57,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2017,12]]}},"alternative-id":["10.1002\/acn3.494"],"URL":"https:\/\/doi.org\/10.1002\/acn3.494","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,12]]},"assertion":[{"value":"2017-08-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-09-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-11-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}