{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T06:04:20Z","timestamp":1789365860920,"version":"build-2803163510"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Spontaneous intracerebral hemorrhage (ICH) carries high early mortality and long-term disability; however, circulating biomarkers that capture both bleeding severity and prognosis are lacking. Neutrophil extracellular trap formation (NETosis), quantifiable in plasma as citrullinated histone H3 (H3Cit), cell-free DNA (cfDNA), and nucleosomes, is implicated in secondary brain injury after ICH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Three hundred fifteen adults with first-ever spontaneous ICH within 24\u202fh of onset and 160 community controls were enrolled. Plasma H3Cit, cfDNA and nucleosomes, admission hematoma volume, NIHSS, and GCS were recorded; the modified Rankin Scale (mRS) was assessed at 12\u202fmonths. NETosis biomarkers entered linear, logistic, and Cox regressions as log2-transformed continuous variables and were adjusted progressively for time-to-sampling, demographics, vascular risk factors, surgical treatment, NIHSS, and hematoma volume. Incremental predictive value over a clinical baseline model was assessed using area under the receiver operating characteristic curve (AUC)\/concordance index (C-index), continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All three biomarkers were higher in ICH than controls (all\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001) and were several-fold higher in 12-month decedents than survivors, despite no difference in absolute neutrophil count. After adjustment, H3Cit was independently associated with hematoma volume, NIHSS and GCS; cfDNA and nucleosomes were independently associated with hematoma volume. After full adjustment for demographics, vascular risk factors, surgical treatment, NIHSS, and hematoma volume, each doubling of H3Cit (OR: 1.577, 95% CI: 1.368\u20131.838), cfDNA (OR: 1.687, 95% CI: 1.259\u20132.291), and nucleosomes (OR: 1.622, 95% CI: 1.297\u20132.057) independently predicted 12-month mRS\u202f\u2265\u202f3 (all\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001); per doubling, H3Cit (HR: 1.358, 95% CI: 1.207\u20131.528), cfDNA (HR: 1.619, 95% CI: 1.287\u20132.038), and nucleosomes (HR: 1.568, 95% CI: 1.310\u20131.877) independently predicted 12-month death. Adding H3Cit raised the AUC for mRS\u202f\u2265\u202f3 from 0.814 to 0.869 (\u0394AUC: 0.055,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001) and the C-index for death from 0.765 to 0.818 (\u0394C: 0.052,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001); for cfDNA and nucleosomes, the gains in discrimination were not significant, although NRI and IDI improved.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Plasma H3Cit, cfDNA, and nucleosomes within 24\u202fh of ICH track hemorrhage severity and predict 12-month mRS\u202f\u2265\u202f3 and death beyond established clinical scores, with H3Cit showing the most consistent incremental value.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1901302","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T05:40:36Z","timestamp":1789364436000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Circulating NETosis biomarkers predict severity, 12-month functional outcome, and survival after spontaneous intracerebral hemorrhage"],"prefix":"10.3389","volume":"17","author":[{"given":"Chaoshuai","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital of Henan Medical University","place":["Weihui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital of Henan Medical University","place":["Weihui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital of Henan Medical University","place":["Weihui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Henan Medical University","place":["Weihui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shifang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital of Henan Medical University","place":["Weihui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Hui","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital of Henan Medical University","place":["Weihui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1038\/s41572-023-00424-7","article-title":"Intracerebral haemorrhage","volume":"9","author":"Puy","year":"2023","journal-title":"Nat Rev Dis Primers"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1038\/s41582-024-01035-w","article-title":"Intracerebral haemorrhage - mechanisms, diagnosis and prospects for treatment and prevention","volume":"20","author":"Seiffge","year":"2024","journal-title":"Nat Rev Neurol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1177\/17474930241307876","article-title":"World stroke organization (Wso): global intracerebral hemorrhage factsheet 2025","volume":"20","author":"Parry-Jones","year":"2025","journal-title":"Int J 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