{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T16:28:55Z","timestamp":1787329735351,"version":"build-2736575974"},"reference-count":35,"publisher":"American Medical Association (AMA)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Mild hypoxic-ischemic encephalopathy (HIE) spans a broad spectrum of neurological dysfunction, making early identification challenging and leading to undertreatment or overtreatment.<\/jats:p>\n <\/jats:sec>\n \n Objectives<\/jats:title>\n To investigate whether whole-blood gene expression at birth is associated with HIE severity (mild, moderate, or severe), to characterize pathways underlying differential expression, and to evaluate temporal changes over the first 72 hours compared with matched healthy controls.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This case-control study combines data from the COMET (Cooling in Mild Encephalopathy) pilot randomized clinical trial from October 31, 2019, to April 28, 2023, recruiting infants with mild HIE and data from 2 prospective observational studies (January 1, 2017, to June 1, 2019, and September 30, 2019, to September 30, 2025) enrolling infants with moderate or severe HIE and healthy control infants. The settings include 6 tertiary neonatal intensive care units in the United Kingdom and Italy, and the participants were full-term infants (gestational age, \u226536 weeks; birth weight, \u22651.8 kg) with mild, moderate, or severe HIE and healthy control infants. Data were analyzed from October 2025 to February 2026.<\/jats:p>\n <\/jats:sec>\n \n Exposure<\/jats:title>\n Whole-blood RNA next-generation sequencing.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Measures were gene-level counts and pathway enrichment statistics. Primary outcomes were gene expression differences by HIE severity and the temporal evolution of transcriptomic profiles compared with controls.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 112 full-term infants were included: 73 with HIE (40 with mild HIE, 29 with moderate HIE, and 4 with severe HIE; 19 infants with mild HIE [47.5%] and 20 infants with moderate or severe HIE [61.0%] were female) and 39 healthy control infants (23 female infants [59.0%]). The median birth weight was 3.3 kg (IQR, 3.0-3.6 kg) for infants with moderate or severe HIE, 3.3 kg (IQR, 3.1-3.5 kg) for infants with mild HIE, and 3.4 kg (IQR, 3.0-3.6 kg) for controls. The median gestational age was 40.0 weeks (IQR, 39.0-40.6 weeks) for infants with mild HIE, 39.3 weeks (IQR, 39.0-41.0 weeks) for infants with moderate HIE, and 39.4 weeks (IQR, 39.0-40.4 weeks) for infants with severe HIE. Differential expression analysis identified 981 genes in mild HIE and 622 genes in moderate or severe HIE (false discovery rate &amp;lt;0.05), with 37 genes (3.0%) shared. In mild HIE, the processing of capped intron-containing pre-mRNA was downregulated (\n z<\/jats:italic>\n score, \u22120.68;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001), whereas in moderate or severe HIE, autoimmune thyroid disease signaling showed the highest significance (\n z<\/jats:italic>\n score not determined;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001). By 72 hours, transcriptomic disturbances had substantially attenuated, particularly in mild HIE, with gene expression profiles converging toward control levels.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this case-control study of infants with HIE, whole-blood gene expression at birth was associated with HIE severity, distinguishing infants with mild HIE from both controls and those with moderate or severe encephalopathy, supporting its role in risk stratification during the period when neuroprotective interventions remain possible and clinical diagnosis may still be challenging.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2026.29378","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T15:30:31Z","timestamp":1787326231000},"page":"e2629378","source":"Crossref","is-referenced-by-count":0,"title":["Whole-Blood Gene Expression and Hypoxic-Ischemic Encephalopathy at Birth"],"prefix":"10.1001","volume":"9","author":[{"given":"Paolo","family":"Montaldo","sequence":"first","affiliation":[{"name":"Centre for Perinatal Neuroscience, Department of Brain Sciences, Imperial College London, London, United Kingdom"},{"name":"Department of Women\u2019s and Children\u2019s Health and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jethro","family":"Herberg","sequence":"additional","affiliation":[{"name":"Section of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahar","family":"Uppal","sequence":"additional","affiliation":[{"name":"Centre for Perinatal Neuroscience, Department of Brain Sciences, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Puzone","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Cirillo","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Miraglia Del Giudice","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Cirillo","sequence":"additional","affiliation":[{"name":"Department of Advanced Medical and Surgical Sciences, University of Campania \u201cLuigi Vanvitelli,\u201d Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Caredda","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reema","family":"Garegrat","sequence":"additional","affiliation":[{"name":"Centre for Perinatal Neuroscience, Department of Brain Sciences, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuti","family":"Pant","sequence":"additional","affiliation":[{"name":"Centre for Perinatal Neuroscience, Department of Brain Sciences, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anchal","family":"Dhawan","sequence":"additional","affiliation":[{"name":"Centre for Perinatal Neuroscience, Department of Brain Sciences, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thilipan","family":"Thaventhiran","sequence":"additional","affiliation":[{"name":"Centre for Perinatal Neuroscience, Department of Brain Sciences, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mia","family":"Cunliffe","sequence":"additional","affiliation":[{"name":"Centre for Perinatal Neuroscience, Department of Brain Sciences, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narendra","family":"Aladangady","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Homerton Healthcare NHS Foundation Trust, London, United Kingdom"},{"name":"Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Fleming","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Homerton Healthcare NHS Foundation Trust, London, United Kingdom"},{"name":"Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balamurugan","family":"Palanisami","sequence":"additional","affiliation":[{"name":"Neonatal Medicine, Liverpool Women\u2019s NHS Foundation Trust, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aung","family":"Soe","sequence":"additional","affiliation":[{"name":"Oliver Fisher Neonatal Intensive Care Unit, Medway Maritime Hospital, Medway NHS Foundation Trust, Kent, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Palaniappan","family":"Sashikumar","sequence":"additional","affiliation":[{"name":"Oliver Fisher Neonatal Intensive Care Unit, Medway Maritime Hospital, Medway NHS Foundation Trust, Kent, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santosh","family":"Pattnayak","sequence":"additional","affiliation":[{"name":"Oliver Fisher Neonatal Intensive Care Unit, Medway Maritime Hospital, Medway NHS Foundation Trust, Kent, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sundeep","family":"Harigopal","sequence":"additional","affiliation":[{"name":"Neonatal Medicine, Royal Victoria Infirmary, Newcastle Upon Tyne, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seetha","family":"Shankaran","sequence":"additional","affiliation":[{"name":"Department of Neonatal-Perinatal Medicine, Wayne State University, Detroit, Michigan"},{"name":"Department of Pediatrics, The University of Texas at Austin, Dell Children\u2019s Hospital, Austin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudhin","family":"Thayyil","sequence":"additional","affiliation":[{"name":"Centre for Perinatal Neuroscience, Department of Brain Sciences, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"issue":"10513","key":"zoi260806r1","doi-asserted-by":"publisher","first-page":"1811","DOI":"10.1016\/S0140-6736(25)01917-8","article-title":"Global burden of 292 causes of death in 204 countries and territories and 660 subnational locations, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023.","volume":"406","author":"GBD 2023 Causes of Death Collaborators","year":"2025","journal-title":"Lancet"},{"key":"zoi260806r2","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2025.1627448","article-title":"Analysis of global, regional, and national burdens of neonatal encephalopathy from 1990 to 2021: insights from the Global Burden of Disease Study 2021.","volume":"13","author":"Tan","year":"2025","journal-title":"Front Public Health"},{"key":"zoi260806r3","doi-asserted-by":"publisher","DOI":"10.1016\/j.earlhumdev.2022.105541","article-title":"Long-term neuropsychological and behavioral outcome of mild and moderate hypoxic ischemic encephalopathy.","volume":"165","author":"Halpin","year":"2022","journal-title":"Early Hum Dev"},{"issue":"3","key":"zoi260806r4","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1093\/jpepsy\/jsp049","article-title":"Behavioral outcome in children with a history of neonatal encephalopathy following perinatal asphyxia.","volume":"35","author":"van Handel","year":"2010","journal-title":"J Pediatr Psychol"},{"issue":"2","key":"zoi260806r5","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/j.jpeds.2010.02.016","article-title":"Serial MRI and neurodevelopmental outcome in 9- to 10-year-old children with neonatal encephalopathy.","volume":"157","author":"van Kooij","year":"2010","journal-title":"J Pediatr"},{"issue":"1","key":"zoi260806r6","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1001\/jamapediatrics.2019.4011","article-title":"Two-year neurodevelopmental outcomes after mild hypoxic ischemic encephalopathy in the era of therapeutic hypothermia.","volume":"174","author":"Finder","year":"2020","journal-title":"JAMA Pediatr"},{"issue":"6","key":"zoi260806r7","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1038\/s41390-018-0174-x","article-title":"Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months.","volume":"84","author":"Chalak","year":"2018","journal-title":"Pediatr Res"},{"issue":"1","key":"zoi260806r8","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD003311.pub3","article-title":"Cooling for newborns with hypoxic ischaemic encephalopathy.","volume":"2013","author":"Jacobs","year":"2013","journal-title":"Cochrane Database Syst Rev"},{"issue":"3","key":"zoi260806r9","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2021.101244","article-title":"Cooling in mild encephalopathy: costs and perils of therapeutic creep.","volume":"26","author":"Kumar","year":"2021","journal-title":"Semin Fetal Neonatal Med"},{"issue":"8","key":"zoi260806r10","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1001\/jama.2016.11236","article-title":"Diagnostic test accuracy of a 2-transcript host RNA signature for discriminating bacterial vs viral infection in febrile children.","volume":"316","author":"Herberg","year":"2016","journal-title":"JAMA"},{"issue":"15","key":"zoi260806r11","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1001\/jama.2017.1365","article-title":"Diagnosis of bacterial infection using a 2-transcript host RNA signature in febrile infants 60 days or younger.","volume":"317","author":"Kaforou","year":"2017","journal-title":"JAMA"},{"key":"zoi260806r12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2024.105411","article-title":"Predictive gene expression signature diagnoses neonatal sepsis before clinical presentation.","volume":"110","author":"An","year":"2024","journal-title":"EBioMedicine"},{"issue":"4","key":"zoi260806r13","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1001\/jamapediatrics.2020.5227","article-title":"Translation of a host blood RNA signature distinguishing bacterial from viral infection into a platform suitable for development as a point-of-care test.","volume":"175","author":"Pennisi","year":"2021","journal-title":"JAMA Pediatr"},{"issue":"10","key":"zoi260806r14","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2018.2293","article-title":"Diagnosis of Kawasaki disease using a minimal whole-blood gene expression signature.","volume":"172","author":"Wright","year":"2018","journal-title":"JAMA Pediatr"},{"issue":"1","key":"zoi260806r15","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1159\/000492420","article-title":"Whole blood gene expression reveals specific transcriptome changes in neonatal encephalopathy.","volume":"115","author":"Montaldo","year":"2019","journal-title":"Neonatology"},{"issue":"2","key":"zoi260806r16","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.54433","article-title":"Whole-blood gene expression profile after hypoxic-ischemic encephalopathy.","volume":"7","author":"Montaldo","year":"2024","journal-title":"JAMA Netw Open"},{"issue":"1","key":"zoi260806r17","doi-asserted-by":"publisher","first-page":"13100","DOI":"10.1038\/s41598-020-70131-w","article-title":"Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy.","volume":"10","author":"Montaldo","year":"2020","journal-title":"Sci Rep"},{"issue":"5","key":"zoi260806r18","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.9119","article-title":"Whole-body hypothermia vs targeted normothermia for neonates with mild encephalopathy: a multicenter pilot randomized clinical trial.","volume":"7","author":"Montaldo","year":"2024","journal-title":"JAMA Netw Open"},{"issue":"1","key":"zoi260806r19","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1038\/jp.2017.164","article-title":"Prospective research on infants with mild encephalopathy: the PRIME study.","volume":"38","author":"Prempunpong","year":"2018","journal-title":"J Perinatol"},{"issue":"15","key":"zoi260806r20","doi-asserted-by":"publisher","first-page":"1574","DOI":"10.1056\/NEJMcps050929","article-title":"Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.","volume":"353","author":"Shankaran","year":"2005","journal-title":"N Engl J Med"},{"issue":"4","key":"zoi260806r22","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in ingenuity pathway analysis.","volume":"30","author":"Kr\u00e4mer","year":"2014","journal-title":"Bioinformatics"},{"issue":"14","key":"zoi260806r23","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1177\/0961203317711008","article-title":"Angiotensin type 1 receptor A1166C polymorphism and systemic lupus erythematosus: correlation with cellular immunity and oxidative stress markers.","volume":"26","author":"Baniamerian","year":"2017","journal-title":"Lupus"},{"issue":"10","key":"zoi260806r25","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1001\/archneur.1976.00500100030012","article-title":"Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study.","volume":"33","author":"Sarnat","year":"1976","journal-title":"Arch Neurol"},{"issue":"4","key":"zoi260806r26","doi-asserted-by":"publisher","first-page":"3547","DOI":"10.3892\/mmr.2018.9375","article-title":"PI3K\/Akt and HIF-1 signaling pathway in hypoxia-ischemia.","volume":"18","author":"Zhang","year":"2018","journal-title":"Mol Med Rep"},{"issue":"2","key":"zoi260806r27","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1111\/j.1365-2184.2008.00516.x","article-title":"Short-period hypoxia increases mouse embryonic stem cell proliferation through cooperation of arachidonic acid and PI3K\/Akt signalling pathways.","volume":"41","author":"Lee","year":"2008","journal-title":"Cell Prolif"},{"key":"zoi260806r28","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.607444","article-title":"Both hypoxia-inducible factor 1 and MAPK signaling pathway attenuate PI3K\/AKT via suppression of reactive oxygen species in human pluripotent stem cells.","volume":"8","author":"Fojt\u00edk","year":"2021","journal-title":"Front Cell Dev Biol"},{"issue":"2","key":"zoi260806r29","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.yexcr.2017.02.024","article-title":"The regulation of transcriptional repression in hypoxia.","volume":"356","author":"Cavadas","year":"2017","journal-title":"Exp Cell Res"},{"issue":"7","key":"zoi260806r30","doi-asserted-by":"publisher","first-page":"2444","DOI":"10.1038\/s41390-025-03986-2","article-title":"Neonatal encephalopathy and hypoxic-ischemic encephalopathy: the state of the art.","volume":"98","author":"Chakkarapani","year":"2025","journal-title":"Pediatr Res"},{"key":"zoi260806r31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104636","article-title":"Neurosteroid pathway derangement in asphyctic infants treated with hypothermia: an untargeted metabolomic approach.","volume":"92","author":"Valerio","year":"2023","journal-title":"EBioMedicine"},{"issue":"6","key":"zoi260806r32","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.3390\/biomedicines13061431","article-title":"Analysis of energy metabolism and lipid spatial distribution in hypoxic-ischemic encephalopathy revealed by MALDI-MSI.","volume":"13","author":"Zhao","year":"2025","journal-title":"Biomedicines"},{"issue":"1","key":"zoi260806r33","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1186\/s12967-025-06714-w","article-title":"Urinary metabolome at birth in patients with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia and long-term neurodevelopmental outcomes: a 7-year follow up.","volume":"23","author":"Ancona","year":"2025","journal-title":"J Transl Med"},{"key":"zoi260806r34","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.nbd.2014.01.020","article-title":"Fetal hypoxia increases vulnerability of hypoxic-ischemic brain injury in neonatal rats: role of glucocorticoid receptors.","volume":"65","author":"Gonzalez-Rodriguez","year":"2014","journal-title":"Neurobiol Dis"},{"key":"zoi260806r35","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.pneurobio.2014.11.001","article-title":"Epigenetic programming of hypoxic-ischemic encephalopathy in response to fetal hypoxia.","volume":"124","author":"Ma","year":"2015","journal-title":"Prog Neurobiol"},{"key":"zoi260806r21"},{"key":"zoi260806r24","doi-asserted-by":"crossref","unstructured":"Fleming? AM, Dingman? JC, Burrows? CJ. Ribosomal RNA tentacles are targets of free radical damage in mammalian cells during oxidative and inflammatory stress.? bioRxiv. 2025:Preprint posted online September 13, 2025. doi:10.1101\/2025.09.11.675630","DOI":"10.1101\/2025.09.11.675630"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2853161\/montaldo_2026_oi_260806_1786722278.62085.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T15:30:34Z","timestamp":1787326234000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2853161"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,21]]},"references-count":35,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8,3]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2026.29378","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,21]]}}}