{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T19:05:50Z","timestamp":1784574350915,"version":"3.55.0"},"reference-count":37,"publisher":"American Diabetes Association","issue":"8","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/100005292","name":"Brigham and Women's Hospital","doi-asserted-by":"publisher","award":["R01 DK102696"],"award-info":[{"award-number":["R01 DK102696"]}],"id":[{"id":"10.13039\/100005292","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005292","name":"Brigham and Women's Hospital","doi-asserted-by":"publisher","award":["R01 HL153969"],"award-info":[{"award-number":["R01 HL153969"]}],"id":[{"id":"10.13039\/100005292","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005292","name":"Brigham and Women's Hospital","doi-asserted-by":"publisher","award":["R01 HL164454"],"award-info":[{"award-number":["R01 HL164454"]}],"id":[{"id":"10.13039\/100005292","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005292","name":"Brigham and Women's Hospital","doi-asserted-by":"publisher","award":["R01 HL167746"],"award-info":[{"award-number":["R01 HL167746"]}],"id":[{"id":"10.13039\/100005292","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ADA","award":["1-17-PDF-103"],"award-info":[{"award-number":["1-17-PDF-103"]}]},{"name":"ADA","award":["K99 HL 148500"],"award-info":[{"award-number":["K99 HL 148500"]}]},{"name":"ADA","award":["R01 DK102696"],"award-info":[{"award-number":["R01 DK102696"]}]},{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["R01 DK102696"],"award-info":[{"award-number":["R01 DK102696"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Independent Research Fund Denmark","award":["8020-00359B"],"award-info":[{"award-number":["8020-00359B"]}]},{"DOI":"10.13039\/100016220","name":"CTSA","doi-asserted-by":"crossref","award":["UL1RR025758"],"award-info":[{"award-number":["UL1RR025758"]}],"id":[{"id":"10.13039\/100016220","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007229","name":"Harvard University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007229","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,8,1]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>Melatonin use quintupled in recent decades. The common melatonin receptor 1B gene (MTNR1B) variant increases risk of type 2 diabetes, raising concerns about melatonin\u2019s adverse metabolic effects and highlighting the need for a genotype-based personalized approach. We aimed\u00a0to comprehensively characterize the actions of melatonin on glucose homeostasis, including first- and second-phase \u03b2-cell responsivity to glucose, \u03b2-cell negative feedback by exogeneous insulin, insulin sensitivity, and whether such effects are stronger in MTNR1B G-allele risk carriers compared with noncarriers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>Twenty-one healthy participants of European ancestry were studied in a randomized, double-blind, placebo-controlled, crossover trial, including 10 MTNR1B risk carriers and 11 noncarriers. Each participant underwent a highly controlled 5-day laboratory protocol, during which they received 5 mg oral melatonin or placebo in randomized order on two nonconsecutive days. Glycemic dynamics were assessed using insulin-modified intravenous glucose tolerance tests with minimal-model analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Melatonin worsened glucose tolerance and reduced early C-peptide responses in risk allele carriers (vs. placebo: 11.7% [95% CI 1.0\u201322.3] and \u221219.2% [\u221233.9 to \u22121.2], respectively; Padj &amp;lt; 0.05) but not in noncarriers. In carriers, impairments stemmed from a 40% (\u221252.4 to \u221224.3; Padj = 0.0003) suppression of glucose-stimulated first-phase \u03b2-cell responsivity, along with a slower insulin-induced decline in second-phase insulin secretion rate (64.3% [23.1\u2013119.2]; Padj = 0.001). In carriers, melatonin also prevented exogenous insulin-induced hypoglycemia compared with placebo (zero vs. seven events, P = 0.001), but not in noncarriers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>These findings identify blunted \u03b2-cell responsivity to glucose and dysregulated insulin negative feedback as key mechanisms linking melatonin signaling to diabetes risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc26-0164","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T13:39:01Z","timestamp":1782394741000},"page":"1498-1506","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["Melatonin Impairs Glucose Tolerance, First-Phase Insulin Secretion, and Insulin Feedback Inhibition; Interaction With\n                    <i>MTNR1B<\/i>\n                    Diabetes Risk Variant"],"prefix":"10.2337","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8793-9330","authenticated-orcid":false,"given":"Jingyi","family":"Qian","sequence":"first","affiliation":[{"name":"Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women\u2019s Hospital 1 , Boston, MA"},{"name":"Division of Sleep Medicine, Harvard Medical School 2 , Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darko","family":"Stefanovski","sequence":"additional","affiliation":[{"name":"Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania 3 , Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip A.K.","family":"Andersen","sequence":"additional","affiliation":[{"name":"Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women\u2019s Hospital 1 , Boston, MA"},{"name":"Department of Biomedical Sciences, University of Copenhagen 4 , Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Vujovic","sequence":"additional","affiliation":[{"name":"Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women\u2019s Hospital 1 , Boston, MA"},{"name":"Division of Sleep Medicine, Harvard Medical School 2 , Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Kelly","sequence":"additional","affiliation":[{"name":"Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women\u2019s Hospital 1 , Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Lepson","sequence":"additional","affiliation":[{"name":"Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women\u2019s Hospital 1 , Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoa","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women\u2019s Hospital 1 , Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Byrne","sequence":"additional","affiliation":[{"name":"Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women\u2019s Hospital 1 , Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women\u2019s Hospital 1 , Boston, MA"},{"name":"Division of Sleep Medicine, Harvard Medical School 2 , Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Mandrup-Poulsen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Copenhagen 4 , Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail","family":"Adler","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Mass General Brigham and Harvard Medical School 5 , Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Garaulet","sequence":"additional","affiliation":[{"name":"Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women\u2019s Hospital 1 , Boston, MA"},{"name":"Department of Physiology, University of Murcia 6 , Murcia, Spain"},{"name":"Instituto Murciano de Investigacion Biosanitaria Virgen de la Arrixaca 7 , Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richa","family":"Saxena","sequence":"additional","affiliation":[{"name":"Division of Sleep Medicine, Harvard Medical School 2 , Boston, MA"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital 8 , Boston, MA"},{"name":"Broad Institute 9 , Cambridge, MA"},{"name":"Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School 10 , Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2014-7582","authenticated-orcid":false,"given":"Frank A.J.L.","family":"Scheer","sequence":"additional","affiliation":[{"name":"Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women\u2019s Hospital 1 , Boston, MA"},{"name":"Division of Sleep Medicine, Harvard Medical School 2 , Boston, MA"},{"name":"Broad Institute 9 , Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"2026072014530375500_B1","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1056\/NEJM200010123431510","article-title":"Melatonin, circadian rhythms, and sleep","volume":"343","author":"Arendt","year":"2000","journal-title":"N Engl J Med"},{"key":"2026072014530375500_B2","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1001\/jama.2021.23652","article-title":"Trends in use of melatonin supplements among US adults, 1999\u20132018","volume":"327","author":"Li","year":"2022","journal-title":"JAMA"},{"key":"2026072014530375500_B3","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/S2213-8587(24)00096-2","article-title":"Use of melatonin supplements and risk of type 2 diabetes and cardiovascular diseases in the USA: insights from three prospective cohort studies","volume":"12","author":"Li","year":"2024","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2026072014530375500_B4","first-page":"1","article-title":"Use of complementary health approaches among children aged 4-17 years in the United States: National Health Interview Survey, 2007\u20132012","author":"Black","year":"2015","journal-title":"Natl Health Stat Report"},{"key":"2026072014530375500_B5","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/0006-8993(95)96872-I","article-title":"Melatonin-induced temperature suppression and its acute phase-shifting effects correlate in a dose-dependent manner in humans","volume":"688","author":"Deacon","year":"1995","journal-title":"Brain Res"},{"key":"2026072014530375500_B6","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/s41574-018-0130-1","article-title":"Melatonin in type 2 diabetes mellitus and obesity","volume":"15","author":"Karamitri","year":"2019","journal-title":"Nat Rev Endocrinol"},{"key":"2026072014530375500_B7","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.tem.2019.11.011","article-title":"Melatonin effects on glucose metabolism: time to unlock the controversy","volume":"31","author":"Garaulet","year":"2020","journal-title":"Trends Endocrinol Metab"},{"key":"2026072014530375500_B8","unstructured":"Phan\n              L\n            , JinY, ZhangH, . ALFA: Allele Frequency Aggregator, 2020. Accessed 22 January 2026. Available from www.ncbi.nlm.nih.gov\/snp\/docs\/gsr\/alfa\/"},{"key":"2026072014530375500_B9","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1046\/j.1365-2265.2001.01232.x","article-title":"Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women","volume":"54","author":"Cagnacci","year":"2001","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2026072014530375500_B10","doi-asserted-by":"crossref","first-page":"e12706","DOI":"10.1111\/jpi.12706","article-title":"Acute metabolic effects of melatonin\u2014a randomized crossover study in healthy young men","volume":"70","author":"Kampmann","year":"2021","journal-title":"J Pineal Res"},{"key":"2026072014530375500_B11","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1016\/j.metabol.2015.08.003","article-title":"Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans","volume":"64","author":"Garaulet","year":"2015","journal-title":"Metabolism"},{"key":"2026072014530375500_B12","doi-asserted-by":"crossref","first-page":"512","DOI":"10.2337\/dc21-1314","article-title":"Interplay of dinner timing and MTNR1B type 2 diabetes risk variant on glucose tolerance and insulin secretion: a randomized crossover trial","volume":"45","author":"Garaulet","year":"2022","journal-title":"Diabetes Care"},{"key":"2026072014530375500_B13","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/j.clnu.2017.04.003","article-title":"Late dinner impairs glucose tolerance in MTNR1B risk allele carriers: a randomized, cross-over study","volume":"37","author":"Lopez-Minguez","year":"2018","journal-title":"Clin Nutr"},{"key":"2026072014530375500_B14","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.5665\/sleep.4088","article-title":"Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening","volume":"37","author":"Rubio-Sastre","year":"2014","journal-title":"Sleep"},{"key":"2026072014530375500_B15","first-page":"E667","article-title":"Quantitative estimation of insulin sensitivity","volume":"236","author":"Bergman","year":"1979","journal-title":"Am J Physiol"},{"key":"2026072014530375500_B16","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1016\/S0026-0495(99)90132-4","article-title":"\u03b2-Cell function during insulin-modified intravenous glucose tolerance test successfully assessed by the C-peptide minimal model","volume":"48","author":"Toffolo","year":"1999","journal-title":"Metabolism"},{"key":"2026072014530375500_B17","first-page":"E172","article-title":"Critical evaluation of the combined model approach for estimation of prehepatic insulin secretion","volume":"274","author":"Watanabe","year":"1998","journal-title":"Am J Physiol"},{"key":"2026072014530375500_B18","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/ng.288","article-title":"Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion","volume":"41","author":"Lyssenko","year":"2009","journal-title":"Nat Genet"},{"key":"2026072014530375500_B19","doi-asserted-by":"crossref","first-page":"S128","DOI":"10.2337\/dc25-S006","article-title":"6. Glycemic goals and hypoglycemia: Standards of Care in Diabetes\u20142025","volume":"48","author":"American Diabetes Association Professional Practice Committee","year":"2025","journal-title":"Diabetes Care"},{"key":"2026072014530375500_B20","doi-asserted-by":"crossref","first-page":"959","DOI":"10.2337\/diab.36.8.959","article-title":"Insulin suppresses its own secretion in vivo","volume":"36","author":"Argoud","year":"1987","journal-title":"Diabetes"},{"key":"2026072014530375500_B21","doi-asserted-by":"crossref","first-page":"101788","DOI":"10.1016\/j.smrv.2023.101788","article-title":"The interrelationship between sleep, diet, and glucose metabolism","volume":"69","author":"St-Onge","year":"2023","journal-title":"Sleep Med Rev"},{"key":"2026072014530375500_B22","doi-asserted-by":"crossref","first-page":"e12965","DOI":"10.1111\/jpi.12965","article-title":"Melatonin decreases human adipose tissue insulin sensitivity","volume":"76","author":"Zambrano","year":"2024","journal-title":"J Pineal Res"},{"key":"2026072014530375500_B23","doi-asserted-by":"crossref","first-page":"2296","DOI":"10.2337\/db16-1452","article-title":"A genome-wide association study of IVGTT-based measures of first-phase insulin secretion refines the underlying physiology of type 2 diabetes variants","volume":"66","author":"Wood","year":"2017","journal-title":"Diabetes"},{"key":"2026072014530375500_B24","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.beem.2010.09.001","article-title":"New evidence for a role of melatonin in glucose regulation","volume":"24","author":"Peschke","year":"2010","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2026072014530375500_B25","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1007\/s00125-009-1359-y","article-title":"Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene","volume":"52","author":"Mulder","year":"2009","journal-title":"Diabetologia"},{"key":"2026072014530375500_B26","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/j.1600-079X.2007.00523.x","article-title":"Function and expression of melatonin receptors on human pancreatic islets","volume":"44","author":"Ramracheya","year":"2008","journal-title":"J Pineal Res"},{"key":"2026072014530375500_B27","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1111\/jpi.12206","article-title":"Melatonin influences somatostatin secretion from human pancreatic \u03b4-cells via MT1 and MT2 receptors","volume":"58","author":"Zibolka","year":"2015","journal-title":"J Pineal Res"},{"key":"2026072014530375500_B28","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/BF00500379","article-title":"Predictive value of intravenous glucose tolerance test insulin secretion less than or greater than the first percentile in islet cell antibody positive relatives of type 1 (insulin-dependent) diabetic patients","volume":"34","author":"Vardi","year":"1991","journal-title":"Diabetologia"},{"key":"2026072014530375500_B29","doi-asserted-by":"crossref","first-page":"S117","DOI":"10.2337\/diabetes.51.2007.S117","article-title":"Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes?","volume":"51","author":"Gerich","year":"2002","journal-title":"Diabetes"},{"key":"2026072014530375500_B30","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.tem.2023.02.001","article-title":"First-phase insulin secretion: can its evaluation direct therapeutic approaches?","volume":"34","author":"Di Giuseppe","year":"2023","journal-title":"Trends Endocrinol Metab"},{"key":"2026072014530375500_B31","doi-asserted-by":"crossref","first-page":"S103","DOI":"10.2337\/diabetes.51.2007.S103","article-title":"Physiological consequences of phasic insulin release in the normal animal","volume":"51","author":"Cherrington","year":"2002","journal-title":"Diabetes"},{"key":"2026072014530375500_B32","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1161\/hc0502.103333","article-title":"Insulin causes endothelial dysfunction in humans: sites and mechanisms","volume":"105","author":"Arcaro","year":"2002","journal-title":"Circulation"},{"key":"2026072014530375500_B33","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1056\/NEJM198205203062002","article-title":"Feedback inhibition of insulin secretion by insulin: relation to the hyperinsulinemia of obesity","volume":"306","author":"Elahi","year":"1982","journal-title":"N Engl J Med"},{"key":"2026072014530375500_B34","first-page":"266","article-title":"Endoplasmic reticulum stress and pancreatic \u03b2-cell death","volume":"22","author":"Fonseca","year":"2011","journal-title":"Trends Endocrinol Metab"},{"key":"2026072014530375500_B35","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s11154-008-9101-5","article-title":"\u03b2-Cell failure as a complication of diabetes","volume":"9","author":"Chang-Chen","year":"2008","journal-title":"Rev Endocr Metab Disord"},{"key":"2026072014530375500_B36","doi-asserted-by":"crossref","first-page":"R321","DOI":"10.1152\/ajpregu.00314.2013","article-title":"Modeling glucose and free fatty acid kinetics during insulin-modified intravenous glucose tolerance test in healthy humans: role of counterregulatory response","volume":"307","author":"Thomaseth","year":"2014","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2026072014530375500_B37","first-page":"503","article-title":"Hypoglycaemia, the most feared complication of insulin therapy","volume":"20","author":"McCrimmon","year":"1994","journal-title":"Diabete Metab"}],"container-title":["Diabetes Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/49\/8\/1498\/887797\/dc260164.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/49\/8\/1498\/887797\/dc260164.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T18:53:13Z","timestamp":1784573593000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/care\/article\/49\/8\/1498\/172119\/Melatonin-Impairs-Glucose-Tolerance-First-Phase"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,6,25]]},"published-print":{"date-parts":[[2026,8,1]]}},"URL":"https:\/\/doi.org\/10.2337\/dc26-0164","relation":{},"ISSN":["0149-5992","1935-5548"],"issn-type":[{"value":"0149-5992","type":"print"},{"value":"1935-5548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]}}}