CoChat
Sign Up
Cited by 39Sepsis Diagnosis and TreatmentInflammation biomarkers and pathwaysCOVID-19 Clinical Research Studies

Multi-Omics Endotypes in ICU Sepsis-Induced Immunosuppression

Open access
Garduno, Alexis, Cusack, Rachael, Leone, Marc, Einav, Sharon, Martin-Loeches, Ignacio·2023·Microorganisms
DOI 10.3390/microorganisms11051119PMC PMC10221354
Open this paper in CoChat — free accountOpen PDF

Abstract

It is evident that the admission of some patients with sepsis and septic shock to hospitals is occurring late in their illness, which has contributed to the increase in poor outcomes and high fatalities worldwide across age groups. The current diagnostic and monitoring procedure relies on an inaccurate and often delayed identification by the clinician, who then decides the treatment upon interaction with the patient. Initiation of sepsis is accompanied by immune system paralysis following “cytokine storm”. The unique immunological response of each patient is important to define in terms of subtyping for therapy. The immune system becomes activated in sepsis to produce interleukins, and endothelial cells express higher levels of adhesion molecules. The proportions of circulating immune cells change, reducing regulatory cells and increasing memory cells and killer cells, having long-term effects on the phenotype of CD8 T cells, HLA-DR, and dysregulation of microRNA. The current narrative review seeks to highlight the potential application of multi-omics data integration and immunological profiling at the single-cell level to define endotypes in sepsis and septic shock. The review will consider the parallels and immunoregulatory axis between cancer and immunosuppression, sepsis-induced cardiomyopathy, and endothelial damage. Second, the added value of transcriptomic-driven endotypes will be assessed through inferring regulatory interactions in recent clinical trials and studies reporting gene modular features that inform continuous metrics measuring clinical response in ICU, which can support the use of immunomodulating agents.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/microorganisms11051119

Cites

7 of 7 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Omics data were absent from the multimodal studies included in this review.

    “although omics data have been used in unimodal AI models for the ICU [74–76], they were absent from the multimodal studies included in this review.”

    From Multimodal Artificial Intelligence for Precision Critical Care: A Scoping Review (2026) · cites this paper as [74]

    The Introduction describes using gene-expression data with machine-learning algorithms for sepsis and cites an ICU artificial-neural-network study. It does not establish that those AI models were unimodal. The statement that omics data were absent from the citing review’s multimodal studies is the citing authors’ own finding, not a claim attributed to this source. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 135

  1. [1]Fleischmann-Struzek C. Mellhammar L. Rose N. Cassini A. Rudd K.E. Schlattmann P. Allegranzi B. Reinhart K. Incidence and mortality of hospital-and ICU-treated sepsis: Results from an updated and expanded systematic review and meta-analysis Intensive Care Med. 2020 46 1552 1562 10.1007/s00134-020-06151-x 32572531 PMC7381468 · DOI · Paper page
  2. [2]Sweeney T.E. Liesenfeld O. Wacker J. He Y.D. Rawling D. Remmel M. Coyle S. Midic U. Kotsaki A. Kanavou A. Validation of Inflammopathic, Adaptive, and Coagulopathic Sepsis Endotypes in Coronavirus Disease 2019 Crit. Care Med. 2021 49 e170 e178 10.1097/CCM.0000000000004786 33201004 · DOI
  3. [3]DeMerle K.M. Angus D.C.M. Baillie J.K.M. Brant E. Calfee C.S.M. Carcillo J. Chang C.-C.H. Dickson R. Evans I.M. Gordon A.C. Sepsis Subclasses: A Framework for Development and Interpretation Crit. Care Med. 2021 49 748 759 10.1097/CCM.0000000000004842 33591001 PMC8627188 · DOI
  4. [4]Grondman I. Koeken V. Karageorgos A. Li W. Antonakos N. Zhang B. Damoraki G. Xu C.J. Giamarellos-Bourboulis E. Li Y. Single-cell transcriptomics identifies different immune signatures between macrophage activation-like syndrome and immune paralysis in sepsis Medrxiv 2023 10.1101/2023.03.17.23287390 · DOI
  5. [5]Pelaia T.M. Shojaei M. McLean A.S. The Role of Transcriptomics in Redefining Critical Illness Crit. Care 2023 27 89 10.1186/s13054-023-04364-2 36941625 PMC10027592 · DOI
  6. [6]Zimmerman J.J. Fccm The Classic Critical Care Conundrum Encounters Precision Medicine* Pediatr. Crit. Care Med. 2023 24 251 253 10.1097/PCC.0000000000003141 36862441 PMC9991068 · DOI
  7. [7]Muriello M. Basel D. Rapid Exome and Genome Sequencing in the Intensive Care Unit Crit. Care Clin. 2022 38 173 184 10.1016/j.ccc.2021.11.001 35369941 · DOI
  8. [8]Chien J.-Y. Yu C.-J. Hsueh P.-R. Utility of Metagenomic Next-Generation Sequencing for Etiological Diagnosis of Patients with Sepsis in Intensive Care Units Microbiol. Spectr. 2022 10 e0074622 10.1128/spectrum.00746-22 35861525 PMC9430677 · DOI
  9. [9]Wang C. Li Y. Li S. Chen M. Hu Y. Proteomics Combined with RNA Sequencing to Screen Biomarkers of Sepsis Infect. Drug Resist. 2022 15 5575 5587 10.2147/IDR.S380137 36172619 PMC9512028 · DOI
  10. [10]Martinez G.S. Ostadgavahi A.T. Al-Rafat A.M. Garduno A. Cusack R. Bermejo-Martin J.F. Martin-Loeches I. Kelvin D. Model-interpreted outcomes of artificial neural networks classifying immune biomarkers associated with severe infections in ICU Front. Immunol. 2023 14 1137850 10.3389/fimmu.2023.1137850 36969221 PMC10034398 · DOI
  11. [11]Bai Y. Xia J. Huang X. Chen S. Zhan Q. Using machine learning for the early prediction of sepsis-associated ARDS in the ICU and identification of clinical phenotypes with differential responses to treatment Front. Physiol. 2022 13 2591 10.3389/fphys.2022.1050849 36579020 PMC9791185 · DOI
  12. [12]Tyler S.R. Chun Y. Ribeiro V.M. Grishina G. Grishin A. Hoffman G.E. Do A.N. Bunyavanich S. Merged Affinity Network Association Clustering: Joint multi-omic/clinical clustering to identify disease endotypes Cell Rep. 2021 35 108975 10.1016/j.celrep.2021.108975 33852839 PMC8195153 · DOI
  13. [13]Kyriazopoulou E. on behalf of the Hellenic Sepsis Study Group Leventogiannis K. Norrby-Teglund A. Dimopoulos G. Pantazi A. Orfanos S.E. Rovina N. Tsangaris I. Gkavogianni T. Macrophage activation-like syndrome: An immunological entity associated with rapid progression to death in sepsis BMC Med. 2017 15 172 10.1186/s12916-017-0930-5 28918754 PMC5603161 · DOI
  14. [14]Gómez H. Anderko R.R. Carcillo J.A. Identifying inflammatory phenotypes to target mechanism-specific treatments in sepsis Cell Rep. Med. 2022 3 100823 10.1016/j.xcrm.2022.100823 36384087 PMC9729868 · DOI
  15. [15]Bodinier M. Peronnet E. Brengel-Pesce K. Conti F. Rimmelé T. Textoris J. Vedrine C. Quemeneur L. Griffiths A.D. Tan L.K. Monocyte Trajectories Endotypes Are Associated With Worsening in Septic Patients Front. Immunol. 2021 12 795052 10.3389/fimmu.2021.795052 34912347 PMC8667763 · DOI
  16. [16]Sadaka F. EthmaneAbouElMaali C. Cytron M.A. Fowler K. Javaux V.M. O’brien J. Predicting Mortality of Patients With Sepsis: A Comparison of APACHE II and APACHE III Scoring Systems J. Clin. Med. Res. 2017 9 907 910 10.14740/jocmr3083w 29038667 PMC5633090 · DOI
  17. [17]Seymour C.W. Liu V.X. Iwashyna T.J. Brunkhorst F.M. Rea T.D. Scherag A. Assessment of clinical criteria for sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA 2016 315 762 774 10.1001/jama.2016.0288 26903335 PMC5433435 · DOI · Paper page
  18. [18]Sinapidis D. Kosmas V. Vittoros V. Koutelidakis I.M. Pantazi A. Stefos A. Katsaros K.E. Akinosoglou K. Bristianou M. Toutouzas K. Progression into sepsis: An individualized process varying by the interaction of comorbidities with the underlying infection BMC Infect. Dis. 2018 18 242 10.1186/s12879-018-3156-z 29843641 PMC5975439 · DOI
  19. [19]Leijte G.P. Rimmelé T. Kox M. Bruse N. Monard C. Gossez M. Monneret G. Pickkers P. Venet F. Monocytic HLA-DR expression kinetics in septic shock patients with different pathogens, sites of infection and adverse outcomes Crit. Care 2020 24 110 10.1186/s13054-020-2830-x 32192532 PMC7082984 · DOI
  20. [20]Davenport E.E. Burnham K.L. Radhakrishnan J. Humburg P. Hutton P. Mills T.C. Rautanen A. Gordon A.C. Garrard C. Hill A.V. Genomic landscape of the individual host response and outcomes in sepsis: A prospective cohort study Lancet Respir. Med. 2016 4 259 271 10.1016/S2213-2600(16)00046-1 26917434 PMC4820667 · DOI
  21. [21]Kwok A.J. Allcock A. Ferreira R.C. Smee M. Cano-Gamez E. Burnham K.L. Zurke Y.-X. McKechnie S. Monaco C. Udalova I. Identification of deleterious neutrophil states and altered granulopoiesis in sepsis Medrxiv 2022 10.1101/2022.03.22.22272723 · DOI
  22. [23]Steinhagen F. Schmidt S.V. Schewe J.-C. Peukert K. Klinman D.M. Bode C. Immunotherapy in sepsis—Brake or accelerate? Pharmacol. Ther. 2020 208 107476 10.1016/j.pharmthera.2020.107476 31931100 · DOI
  23. [24]Nathan N. Sculier J.P. Ameye L. Paesmans M. Bogdan-Dragos G. Meert A.P. Sepsis and septic shock definitions in patients with cancer admitted in ICU J. Intensive Care Med. 2021 36 255 261 10.1177/0885066619894933 31868072 · DOI
  24. [25]Camou F. Didier M. Leguay T. Milpied N. Daste A. Ravaud A. Mourissoux G. Guisset O. Issa N. Long-term prognosis of septic shock in cancer patients Support. Care Cancer 2019 28 1325 1333 10.1007/s00520-019-04937-4 31243586 · DOI
  25. [26]Gudiol C. Albasanz-Puig A. Cuervo G. Carratalà J. Understanding and Managing Sepsis in Patients With Cancer in the Era of Antimicrobial Resistance Front. Med. 2021 8 636547 10.3389/fmed.2021.636547 33869250 PMC8044357 · DOI
  26. [27]Alkhateeb T. Development, Expansion and Role of Myeloid-Derived Suppressor Cells in Post-Sepsis Immune Suppression Doctoral Dissertation East Tennessee State University Johnson City, TN, USA 2020
  27. [28]Washburn M.L. Wang Z. Walton A.H. Goedegebuure S.P. Figueroa D.J. Van Horn S. Grossman J. Remlinger K. Madsen H. Brown J. T Cell– and Monocyte-Specific RNA-Sequencing Analysis in Septic and Nonseptic Critically Ill Patients and in Patients with Cancer J. Immunol. 2019 203 1897 1908 10.4049/jimmunol.1900560 31484735 PMC6761013 · DOI
  28. [29]Chen C.-W. Bennion K.B. Swift D.A. Morrow K.N. Zhang W. Oami T. Coopersmith C.M. Ford M.L. Tumor-Specific T Cells Exacerbate Mortality and Immune Dysregulation during Sepsis J. Immunol. 2021 206 2412 2419 10.4049/jimmunol.2000865 33911005 PMC8121248 · DOI
  29. [30]Vigneron C. Mirouse A. Merdji H. Rousseau C. Cousin C. Alby-Laurent F. Mira J.-P. Chiche J.-D. Llitjos J.-F. Pène F. Sepsis inhibits tumor growth in mice with cancer through Toll-like receptor 4-associated enhanced Natural Killer cell activity Oncoimmunology 2019 8 e1641391 10.1080/2162402X.2019.1641391 31646090 PMC6791422 · DOI
  30. [31]Riché F. Chousterman B.G. Valleur P. Mebazaa A. Launay J.-M. Gayat E. Protracted immune disorders at one year after ICU discharge in patients with septic shock Crit. Care 2018 22 42 10.1186/s13054-017-1934-4 29467023 PMC5822646 · DOI
  31. [32]Shankar-Hari M. Saha R. Wilson J. Prescott H.C. Harrison D. Rowan K. Rubenfeld G.D. Adhikari N.K.J. Rate and risk factors for rehospitalisation in sepsis survivors: Systematic review and meta-analysis Intensive Care Med. 2020 46 619 636 10.1007/s00134-019-05908-3 31974919 PMC7222906 · DOI
  32. [33]Calsavara A.J. Nobre V. Barichello T. Teixeira A.L. Post-sepsis cognitive impairment and associated risk factors: A systematic review Aust. Crit. Care 2018 31 242 253 10.1016/j.aucc.2017.06.001 28645546 · DOI
  33. [34]Fenner B.P. Darden D.B. Kelly L.S. Rincon J. Brakenridge S.C. Larson S.D. Moore F.A. Efron P.A. Moldawer L.L. Immunological Endotyping of Chronic Critical Illness After Severe Sepsis Front. Med. 2021 7 616694 10.3389/fmed.2020.616694 33659259 PMC7917137 · DOI
  34. [35]Darden D.B. Ghita G.L. Wang Z. Stortz J.A. Lopez M.-C. Cox M.C. Hawkins R.B. Rincon J.C. Kelly L.S. Fenner B.P. Chronic Critical Illness Elicits a Unique Circulating Leukocyte Transcriptome in Sepsis Survivors J. Clin. Med. 2021 10 3211 10.3390/jcm10153211 34361995 PMC8348105 · DOI
  35. [36]Darden D.B. Dong X. Brusko M.A. Kelly L. Fenner B. Rincon J.C. Dirain M.L. Ungaro R. Nacionales D.C. Gauthier M. A Novel Single Cell RNA-seq Analysis of Non-Myeloid Circulating Cells in Late Sepsis Front. Immunol. 2021 12 696536 10.3389/fimmu.2021.696536 34484194 PMC8415415 · DOI
  36. [37]Darden D.B. Bacher R. Brusko M.A. Knight P. Hawkins R.B. Cox M.C. Dirain M.L. Ungaro R. Single cell RNA-SEQ of human myeloid derived suppressor cells in late sepsis reveals multiple subsets with unique transcriptional responses: A pilot study Shock 2021 55 587 10.1097/SHK.0000000000001671 33021571 PMC8019679 · DOI
  37. [38]Joffre J. Hellman J. Ince C. Ait-Oufella H. Endothelial responses in sepsis Am. J. Respir. Crit. Care Med. 2020 202 361 370 10.1164/rccm.201910-1911TR 32101446 · DOI
  38. [40]Ricaño-Ponce I. Riza A.-L. de Nooijer A.H. Pirvu A. Dorobantu S. Dragos A. Streata I. Roskanovic M. Grondman I. Dumitrescu F. Characterization of sepsis inflammatory endotypes using circulatory proteins in patients with severe infection: A prospective cohort study BMC Infect. Dis. 2022 22 778 10.1186/s12879-022-07761-0 36209073 PMC9547371 · DOI
  39. [41]Mazer M.B. Caldwell C. Hanson J. Mannion D. Turnbull I.R. Drewry A. Osborne D. Walton A. Blood T. Moldawer L.L. A whole blood enzyme-linked immunospot assay for functional immune endotyping of septic patients J. Immunol. 2021 206 23 36 10.4049/jimmunol.2001088 33239423 PMC8026772 · DOI
  40. [42]Astapenko D. Benes J. Cerny V. Clinical Relevance of the Endothelial Glycocalyx in Critically Ill Patients Annu. Update Intensive Care Emerg. Med. 2020 2020 213 222 10.1007/978-3-030-37323-8_17 · DOI
  41. [43]Alphonsus C.S. Rodseth R. The endothelial glycocalyx: A review of the vascular barrier Anaesthesia 2014 69 777 784 10.1111/anae.12661 24773303 · DOI · Paper page
  42. [44]An G. Nieman G. Vodovotz Y. Computational and systems biology in trauma and sepsis: Current state and future perspectives Int. J. Burn. Trauma 2012 2 1 PMC3415970 22928162
  43. [45]Olivier M. Asmis R. Hawkins G.A. Howard T.D. Cox L.A. The Need for Multi-Omics Biomarker Signatures in Precision Medicine Int. J. Mol. Sci. 2019 20 4781 10.3390/ijms20194781 31561483 PMC6801754 · DOI
  44. [46]Langston J.C. Rossi M.T. Yang Q. Ohley W. Perez E. E Kilpatrick L. Prabhakarpandian B. Kiani M.F. Omics of endothelial cell dysfunction in sepsis Vasc. Biol. 2022 4 R15 R34 10.1530/VB-22-0003 35515704 PMC9066943 · DOI
  45. [47]Itenov T.S. Murray D.D. Jensen J.U.S. Sepsis: Personalized Medicine Utilizing ‘Omic’ Technologies—A Paradigm Shift? Healthcare 2018 6 111 10.3390/healthcare6030111 30205441 PMC6163606 · DOI
  46. [48]Alsaffar H. Martino N. Garrett J.P. Adam A.P. Interleukin-6 promotes a sustained loss of endothelial barrier function via Janus kinase-mediated STAT3 phosphorylation and de novo protein synthesis Am. J. Physiol. Physiol. 2018 314 C589 C602 10.1152/ajpcell.00235.2017 29351406 · DOI
  47. [50]Amalakuhan B. Habib S.A. Mangat M. Reyes L.F. Rodriguez A.H. Hinojosa C.A. Soni N.J. Gilley R.P. Bustamante C.A. Anzueto A. Endothelial adhesion molecules and multiple organ failure in patients with severe sepsis Cytokine 2016 88 267 273 10.1016/j.cyto.2016.08.028 27701021 PMC5121929 · DOI
  48. [51]Leone M. Boutière B. Camoin-Jau L. Albanèse J. Horschowsky N. Mège J.-L. Martin C. Dignat-George F. Systemic endothelial activation is greater in septic than in traumatic-hemorrhagic shock but does not correlate with endothelial activation in skin biopsies Crit. Care Med. 2002 30 808 814 10.1097/00003246-200204000-00015 11940750 · DOI
  49. [52]Murakami J. Ohtani A. Murata S. Protective effect of T-686, an inhibitor of plasminogen activator inhibitor-1 production, against the lethal effect of lipopolysaccharide in mice Jpn. J. Pharmacol. 1997 75 291 294 10.1254/jjp.75.291 9434261 · DOI
  50. [53]Renckens R. Roelofs J.J.T.H. Bonta P.I. Florquin S. de Vries C.J.M. Levi M. Carmeliet P. Veer C.V. van der Poll T. Plasminogen activator inhibitor type 1 is protective during severe Gram-negative pneumonia Blood 2007 109 1593 1601 10.1182/blood-2006-05-025197 17032919 · DOI
  51. [54]Jambusaria A. Hong Z. Zhang L. Srivastava S. Jana A. Toth P.T. Dai Y. Malik A.B. Rehman J. Author response: Endothelial heterogeneity across distinct vascular beds during homeostasis and inflammation Elife 2019 9 e51413 10.7554/eLife.51413 31944177 PMC7002042 · DOI
  52. [55]Lipowsky H.H. Microvascular Rheology and Hemodynamics Microcirculation 2005 12 5 15 10.1080/10739680590894966 15804970 · DOI
  53. [56]Burghoff S. Schrader J. Secretome of Human Endothelial Cells under Shear Stress J. Proteome Res. 2011 10 1160 1169 10.1021/pr100937a 21184611 · DOI
  54. [57]Wei J.-X. Jiang H.-L. Chen X.-H. Endothelial cell metabolism in sepsis World J. Emerg. Med. 2023 14 10 10.5847/wjem.j.1920-8642.2023.019 36713343 PMC9842459 · DOI
  55. [58]Yang K. Fan M. Wang X. Xu J. Wang Y. Gill P.S. Ha T. Liu L. Hall J.V. Williams D.L. Lactate induces vascular permeability via disruption of VE-cadherin in endothelial cells during sepsis Sci. Adv. 2022 8 eabm8965 10.1126/sciadv.abm8965 35476437 PMC9045716 · DOI
  56. [59]Mao L. Sun M. Chen Z. Zeng Z. Wu J. Chen Z. Zhang W. Huang Q. The Pyruvate Dehydrogenase Complex Mitigates LPS-Induced Endothelial Barrier Dysfunction by Metabolic Regulation Shock. Inj. Inflamm. Sepsis: Lab. Clin. Approaches 2022 57 308 317 10.1097/SHK.0000000000001931 35759309 · DOI
  57. [60]Wang L. Cao Y. Gorshkov B. Zhou Y. Yang Q. Xu J. Ma Q. Zhang X. Wang J. Mao X. Ablation of endothelial Pfkfb3 protects mice from acute lung injury in LPS-induced endotoxemia Pharmacol. Res. 2019 146 104292 10.1016/j.phrs.2019.104292 31167111 PMC7310404 · DOI
  58. [61]Gill S.E. Rohan M. Mehta S. Role of pulmonary microvascular endothelial cell apoptosis in murine sepsis-induced lung injury in vivo Respir. Res. 2015 16 109 10.1186/s12931-015-0266-7 26376777 PMC4574190 · DOI
  59. [62]Wang Z. Rui T. Yang M. Valiyeva F. Kvietys P.R. Alveolar Macrophages from Septic Mice Promote Polymorphonuclear Leukocyte Transendothelial Migration via an Endothelial Cell Src Kinase/NADPH Oxidase Pathway J. Immunol. 2008 181 8735 8744 10.4049/jimmunol.181.12.8735 19050294 · DOI
  60. [63]Fatmi A. Saadi W. Beltrán-García J. García-Giménez J.L. Pallardó F.V. The Endothelial Glycocalyx and Neonatal Sepsis Int. J. Mol. Sci. 2023 24 364 10.3390/ijms24010364 PMC9820255 36613805 · DOI
  61. [64]Goligorsky M.S. Sun D. Glycocalyx in Endotoxemia and Sepsis Am. J. Pathol. 2020 190 791 798 10.1016/j.ajpath.2019.06.017 32035882 PMC7180514 · DOI
  62. [65]Yeh C.-L. Pai M.-H. Shih Y.-M. Shih J.-M. Yeh S.-L. Intravenous Arginine Administration Promotes Proangiogenic Cells Mobilization and Attenuates Lung Injury in Mice with Polymicrobial Sepsis Nutrients 2017 9 507 10.3390/nu9050507 28513569 PMC5452237 · DOI
  63. [66]Wijnands K.A.P. Hoeksema M.A. Meesters D.M. van den Akker N.M.S. Molin D.G.M. Briedé J.J. Ghosh M. Köhler S.E. Van Zandvoort M.A.M.J. De Winther M.P.J. Arginase-1 Deficiency Regulates Arginine Concentrations and NOS2-Mediated NO Production during Endotoxemia PLoS ONE 2014 9 e86135 10.1371/journal.pone.0086135 24465919 PMC3897658 · DOI
  64. [67]Lin J.-J. Chan O.-W. Hsiao H.-J. Wang Y. Hsia S.-H. Chiu C.-H. Decreased ADAMTS 13 Activity is Associated with Disease Severity and Outcome in Pediatric Severe Sepsis Medicine 2016 95 e3374 10.1097/MD.0000000000003374 27100422 PMC4845826 · DOI
  65. [68]Anand D. Ray S. Srivastava L.M. Bhargava S. Evolution of serum hyaluronan and syndecan levels in prognosis of sepsis patients Clin. Biochem. 2016 49 768 776 10.1016/j.clinbiochem.2016.02.014 26953518 · DOI
  66. [69]Huang X. Hu H. Sun T. Zhu W. Tian H. Hao D. Wang T. Wang X. Plasma Endothelial Glycocalyx Components as a Potential Biomarker for Predicting the Development of Disseminated Intravascular Coagulation in Patients with Sepsis J. Intensive Care Med. 2021 36 1286 1295 10.1177/0885066620949131 32799720 · DOI
  67. [70]Zonda G.I. Zonda R. Cernomaz T.A. Paduraru L. Avasiloaiei A.L. Grigoriu B.D. Endocan—A potential diagnostic marker for early onset sepsis in neonates J. Infect. Dev. Ctries. 2019 13 311 317 10.3855/jidc.11202 32045375 · DOI
  68. [71]Saldir M. Tunc T. Cekmez F. Cetinkaya M. Kalayci T. Fidanci K. Babacan O. Erdem G. Kocak N. Sari E. Endocan and Soluble Triggering Receptor Expressed on Myeloid Cells-1 as Novel Markers for Neonatal Sepsis Pediatr. Neonatol. 2015 56 415 421 10.1016/j.pedneo.2015.03.006 26341458 · DOI
  69. [72]Ince C. The microcirculation is the motor of sepsis Crit. Care 2005 9 S13 S19 10.1186/cc3753 16168069 PMC3226164 · DOI
  70. [73]De Backer D. Creteur J. Preiser J.C. Dubois M.J. Vincent J.L. Microvascular blood flow is altered in patients with sepsis Am. J. Respir. Crit. Care Med. 2002 166 98 104 10.1164/rccm.200109-016OC 12091178 · DOI
  71. [74]De Backer D. Donadello K. Sakr Y. Ospina-Tascon G. Salgado D. Scolletta S. Vincent J.L. Microcirculatory alterations in patients with severe sepsis: Impact of time of assessment and relationship with outcome Crit. Care Med. 2013 41 791 799 10.1097/CCM.0b013e3182742e8b 23318492 · DOI
  72. [75]Dilken O. Ergin B. Ince C. Assessment of sublingual microcirculation in critically ill patients: Consensus and debate Ann. Transl. Med. 2020 8 793 10.21037/atm.2020.03.222 32647718 PMC7333125 · DOI
  73. [76]Cusack R. Leone M. Rodriguez A.H. Martin-Loeches I. Endothelial Damage and the Microcirculation in Critical Illness Biomedicines 2022 10 3150 10.3390/biomedicines10123150 36551905 PMC9776078 · DOI
  74. [77]Leone M. Blidi S. Antonini F. Meyssignac B. Bordon S. Garcin F. Charvet A. Blasco V. Albanese J. Martin C. Oxygen tissue saturation is lower in nonsurvivors than in survivors after early resuscitation of septic shock J. Am. Soc. Anesthesiol. 2009 111 366 371 10.1097/ALN.0b013e3181aae72d 19602965 · DOI
  75. [78]Pries A.R. Secomb T.W. Gaehtgens P. The endothelial surface layer Pflugers Arch. 2000 440 653 666 10.1007/s004240000307 11007304 · DOI
  76. [79]Chelazzi C. Villa G. Mancinelli P. De Gaudio A.R. Adembri C. Glycocalyx and sepsis-induced alterations in vascular permeability Crit. Care 2015 19 26 10.1186/s13054-015-0741-z 25887223 PMC4308932 · DOI
  77. [80]Mehta D. Malik A.B. Signaling mechanisms regulating endothelial permeability Physiol. Rev. 2006 86 279 367 10.1152/physrev.00012.2005 16371600 · DOI
  78. [81]Martin-Fernandez M. Vaquero-Roncero L.M. Almansa R. Gómez-Sánchez E. Martín S. Tamayo E. Esteban-Velasco M.C. Ruiz-Granado P. Aragón M. Calvo D. Endothelial dysfunction is an early indicator of sepsis and neutrophil degranulation of septic shock in surgical patients BJS Open 2020 4 524 534 10.1002/bjs5.50265 32073224 PMC7260414 · DOI
  79. [82]Fang Y. Li C. Shao R. Yu H. Zhang Q. The role of biomarkers of endothelial activation in predicting morbidity and mortality in patients with severe sepsis and septic shock in intensive care: A prospective observational study Thromb. Res. 2018 171 149 154 10.1016/j.thromres.2018.09.059 30312800 · DOI
  80. [83]Ince C. Personalized physiological medicine Crit. Care 2017 21 308 10.1186/s13054-017-1907-7 29297391 PMC5751773 · DOI
  81. [84]Edul V.S.K. Ince C. Navarro N. Previgliano L. Risso-Vazquez A. Rubatto P.N. Dubin A. Dissociation between sublingual and gut microcirculation in the response to a fluid challenge in postoperative patients with abdominal sepsis Ann. Intensive Care 2014 4 39 10.1186/s13613-014-0039-3 25625013 PMC4298674 · DOI
  82. [85]Mehta C. Gao P. Bhatt D.L. Harrington R.A. Skerjanec S. Ware J.H. Optimizing trial design: Sequential, adaptive, and enrichment strategies Circulation 2009 119 597 605 10.1161/CIRCULATIONAHA.108.809707 19188520 · DOI
  83. [86]Stanski N.L. Wong H.R. Prognostic and predictive enrichment in sepsis Nat. Rev. Nephrol. 2019 16 20 31 10.1038/s41581-019-0199-3 31511662 PMC7097452 · DOI
  84. [87]Temmesfeld-Wollbrück B. Hocke A.C. Suttorp N. Hippenstiel S. Adrenomedullin and endothelial barrier function Thromb. Haemost. 2007 98 944 951 10.1160/TH07-02-0128 18000597 · DOI
  85. [88]Tsakadze N. Zakaria R. Matheson P. Garrison R. Mechanism of adrenomedullin (AM)-mediated vasodilation in rat ileum Circulation 2006 16 775 10.1016/j.jss.2005.11.498 · DOI
  86. [89]Samson W.K. Adrenomedullin and the control of fluid and electrolyte homeostasis Annu. Rev. Physiol. 1999 61 363 389 10.1146/annurev.physiol.61.1.363 10099693 · DOI
  87. [90]Czyzyk T.A. Ning Y. Hsu M.-S. Peng B. Mains R.E. Eipper B.A. Pintar J.E. Deletion of peptide amidation enzymatic activity leads to edema and embryonic lethality in the mouse Dev. Biol. 2005 287 301 313 10.1016/j.ydbio.2005.09.001 16225857 · DOI
  88. [91]Isumi Y. Shoji H. Sugo S. Tochimoto T. Yoshioka M. Kangawa K. Matsuo H. Minamino N. Regulation of Adrenomedullin Production in Rat Endothelial Cells Endocrinology 1998 139 838 846 10.1210/endo.139.3.5789 9492011 · DOI
  89. [92]Tomoda Y. Isumi Y. Katafuchi T. Minamino N. Regulation of adrenomedullin secretion from cultured cells Peptides 2001 22 1783 1794 10.1016/S0196-9781(01)00519-8 11754964 · DOI
  90. [93]Agorreta J. Zulueta J.J. Montuenga L.M. Garayoa M. Adrenomedullin expression in a rat model of acute lung injury induced by hypoxia and LPS Am. J. Physiol. Cell. Mol. Physiol. 2005 288 L536 L545 10.1152/ajplung.00314.2004 15579624 · DOI
  91. [94]Zhou M. Chaudry I.H. Wang P. The small intestine is an important source of adrenomedullin release during polymicrobial sepsis Am. J. Physiol. Integr. Comp. Physiol. 2001 281 R654 R660 10.1152/ajpregu.2001.281.2.R654 11448871 · DOI
  92. [95]Hocke A.C. Temmesfeld-Wollbrueck B. Schmeck B. Berger K. Frisch E.M. Witzenrath M. Brell B. Suttorp N. Hippenstiel S. Perturbation of endothelial junction proteins by Staphylococcus aureus α-toxin: Inhibition of endothelial gap formation by adrenomedullin Histochem. Cell Biol. 2006 126 305 316 10.1007/s00418-006-0174-5 16596365 · DOI
  93. [96]Struck J. Tao C. Morgenthaler N.G. Bergmann A. Identification of an Adrenomedullin precursor fragment in plasma of sepsis patients Peptides 2004 25 1369 1372 10.1016/j.peptides.2004.06.019 15350706 · DOI
  94. [97]Buendgens L. Yagmur E. Ginsberg A. Weiskirchen R. Wirtz T. Abu Jhaisha S. Eisert A. Luedde T. Trautwein C. Tacke F. Midregional Proadrenomedullin (MRproADM) Serum Levels in Critically Ill Patients Are Associated with Short-Term and Overall Mortality during a Two-Year Follow-Up Mediat. Inflamm. 2020 2020 7184803 10.1155/2020/7184803 PMC7428945 32831638 · DOI
  95. [98]Valenzuela-Sánchez F. Valenzuela-Méndez B. De Austria R.B. Rodríguez-Gutiérrez J.F. García E. Fernández-Ruiz L. González-García M. Rello J. Plasma levels of mid-regional pro-adrenomedullin in sepsis are associated with risk of death Minerva Anestesiol. 2018 85 366 375 10.23736/S0375-9393.18.12687-3 30207133 · DOI
  96. [99]Elke G. the SepNet Critical Care Trials Group Bloos F. Wilson D.C. Brunkhorst F.M. Briegel J. Reinhart K. Loeffler M. Kluge S. Nierhaus A. The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis—A secondary analysis of a large randomised controlled trial Crit. Care 2018 22 79 10.1186/s13054-018-2001-5 29562917 PMC5863464 · DOI
  97. [100]Andrés C. Andaluz-Ojeda D. Cicuendez R. Nogales L. Martín S. Martin-Fernandez M. Almansa R. Bermejo-Martin J.F. MR-proADM to detect specific types of organ failure in infection Eur. J. Clin. Investig. 2020 50 e13246 10.1111/eci.13246 32307701 · DOI
  98. [101]Geven C. Kox M. Pickkers P. Adrenomedullin and Adrenomedullin-Targeted Therapy as Treatment Strategies Relevant for Sepsis Front. Immunol. 2018 9 292 10.3389/fimmu.2018.00292 29520277 PMC5827550 · DOI
  99. [102]Wagner K. Wachter U. A Vogt J. Scheuerle A. McCook O. Weber S. Gröger M. Stahl B. Georgieff M. Möller P. Adrenomedullin binding improves catecholamine responsiveness and kidney function in resuscitated murine septic shock Intensive Care Med. Exp. 2013 1 2 10.1186/2197-425X-1-2 26266790 PMC4796991 · DOI
  100. [103]Geven C. Peters E. Schroedter M. Struck J. Bergmann A. McCook O. Radermacher P. Kox M. Pickkers P. Effects of the Humanized Anti-Adrenomedullin Antibody Adrecizumab (HAM8101) on Vascular Barrier Function and Survival in Rodent Models of Systemic Inflammation and Sepsis Shock 2018 50 648 654 10.1097/SHK.0000000000001102 29324627 · DOI
  101. [104]Voors A.A. Kremer D. Geven C. Ter Maaten J.M. Struck J. Bergmann A. Pickkers P. Metra M. Mebazaa A. Düngen H.-D. Adrenomedullin in heart failure: Pathophysiology and therapeutic application Eur. J. Heart Fail. 2019 21 163 171 10.1002/ejhf.1366 30592365 PMC6607488 · DOI
  102. [105]Bertrand J. Bollmann M. Soluble syndecans: Biomarkers for diseases and therapeutic options Br. J. Pharmacol. 2018 176 67 81 10.1111/bph.14397 29931674 PMC6284332 · DOI
  103. [106]Alexopoulou A.N. Multhaupt H.A. Couchman J.R. Syndecans in wound healing, inflammation and vascular biology Int. J. Biochem. Cell Biol. 2007 39 505 528 10.1016/j.biocel.2006.10.014 17097330 · DOI
  104. [107]Subramanian S.V. Fitzgerald M.L. Bernfield M. Regulated Shedding of Syndecan-1 and -4 Ectodomains by Thrombin and Growth Factor Receptor Activation J. Biol. Chem. 1997 272 14713 14720 10.1074/jbc.272.23.14713 9169435 · DOI
  105. [108]Fernández-Sarmiento J. Molina C.F. Salazar-Pelaez L.M. Flórez S. Alarcón-Forero L.C. Sarta M. Hernández-Sarmiento R. Villar J.C. Biomarkers of glycocalyx injury and endothelial activation are associated with clinical outcomes in patients with sepsis: A systematic review and meta-analysis J. Intensive Care Med. 2023 38 95 105 10.1177/08850666221109186 35722738 · DOI
  106. [109]Nelson A. Berkestedt I. Bodelsson M. Circulating glycosaminoglycan species in septic shock Acta Anaesthesiol. Scand. 2014 58 36 43 10.1111/aas.12223 24341693 · DOI
  107. [110]Jannaway M. Yang X. Meegan J.E. Coleman D.C. Yuan S.Y. Thrombin-cleaved syndecan-3/-4 ectodomain fragments mediate endothelial barrier dysfunction PLoS ONE 2019 14 e0214737 10.1371/journal.pone.0214737 31091226 PMC6519803 · DOI
  108. [111]Sack K.D. Kellum J.A. Parikh S.M. The Angiopoietin-Tie2 Pathway in Critical Illness Crit. Care Clin. 2020 36 201 216 10.1016/j.ccc.2019.12.003 32172809 PMC8843037 · DOI
  109. [112]Lukasz A. Hillgruber C. Oberleithner H. Kusche-Vihrog K. Pavenstädt H. Rovas A. Hesse B. Goerge T. Kümpers P. Endothelial glycocalyx breakdown is mediated by angiopoietin-2 Cardiovasc. Res. 2017 113 671 680 10.1093/cvr/cvx023 28453727 · DOI
  110. [113]Drost C.C. Rovas A. Kusche-Vihrog K. Van Slyke P. Kim H. Hoang V.C. Maynes J.T. Wennmann D.O. Pavenstädt H. Linke W. Tie2 activation promotes protection and reconstitution of the endothelial glycocalyx in human sepsis Thromb. Haemost. 2019 119 1827 1838 31493777
  111. [114]Rovas A. Osiaevi I. Buscher K. Sackarnd J. Tepasse P.R. Fobker M. Kühn J. Braune S. Göbel U. Thölking G. Microvascular dysfunction in COVID-19: The MYSTIC study Angiogenesis 2021 24 145 157 10.1007/s10456-020-09753-7 33058027 PMC7556767 · DOI
  112. [115]Siner J.M. Bhandari V. Engle K.M. Elias J.A. Siegel M.D. Elevated serum angiopoietin 2 levels are associated with increased mortality in sepsis Shock 2009 31 348 353 10.1097/SHK.0b013e318188bd06 18791490 · DOI
  113. [116]Yang K.-Y. Liu K.-T. Chen Y.-C. Chen C.-S. Lee Y.-C. Perng R.-P. Feng J.-Y. Plasma soluble vascular endothelial growth factor receptor-1 levels predict outcomes of pneumonia-related septic shock patients: A prospective observational study Crit. Care 2011 15 R11 10.1186/cc9412 21219633 PMC3222041 · DOI
  114. [119]Beyer D. Hoff J. Sommerfeld O. Zipprich A. Gaßler N. Press A.T. The liver in sepsis: Molecular mechanism of liver failure and their potential for clinical translation Mol. Med. 2022 28 84 10.1186/s10020-022-00510-8 35907792 PMC9338540 · DOI
  115. [120]Shi R. Wang J. Zhang Z. Leng Y. Chen A.F. ASGR1 promotes liver injury in sepsis by modulating monocyte-to-macrophage differentiation via NF-κB/ATF5 pathway Life Sci. 2023 315 121339 10.1016/j.lfs.2022.121339 36621538 · DOI
  116. [121]Li M. Cai S.-Y. Boyer J.L. Mechanisms of bile acid mediated inflammation in the liver Mol. Asp. Med. 2017 56 45 53 10.1016/j.mam.2017.06.001 PMC5662014 28606651 · DOI
  117. [122]Xerri A. Gallardo F. Kober F. Mathieu C. Fourny N. Tran T.T. Mege J.-L. Singer M. Lalevée N. Bernard M. Female hormones prevent sepsis-induced cardiac dysfunction: An experimental randomized study Sci. Rep. 2022 12 4939 10.1038/s41598-022-08889-4 35322092 PMC8943058 · DOI
  118. [123]Zhou T. Qian H. Zheng N. Lu Q. Han Y. GYY4137 ameliorates sepsis-induced cardiomyopathy via NLRP3 pathway Biochim. et Biophys. Acta (BBA)-Mol. Basis Dis. 2022 1868 166497 10.1016/j.bbadis.2022.166497 35868482 · DOI
  119. [124]Pu J. Gao F. He Y. Integrated Bioinformatics Analysis Reveals APEX1 as a Potential Biomarker for Septic Cardiomyopathy BioRxiv 2023 10.1101/2023.01.03.522553 · DOI
  120. [125]Liu V.X. Fielding-Singh V. Greene J.D. Baker J.M. Iwashyna T.J. Bhattacharya J. Escobar G.J. The timing of early antibiotics and hospital mortality in sepsis Am. J. Respir. Crit. Care Med. 2017 196 856 863 10.1164/rccm.201609-1848OC 28345952 PMC5649973 · DOI · Paper page
  121. [126]Scicluna B.P. A van Vught L. Zwinderman A.H. A Wiewel M. E Davenport E. Burnham K.L. Nürnberg P. Schultz M.J. Horn J. Cremer O.L. Classification of patients with sepsis according to blood genomic endotype: A prospective cohort study Lancet Respir. Med. 2017 5 816 826 10.1016/S2213-2600(17)30294-1 28864056 · DOI
  122. [127]Wong H.R. Cvijanovich N. Lin R. Allen G.L. Thomas N.J. Willson D.F. Freishtat R.J. Anas N. Meyer K. A Checchia P. Identification of pediatric septic shock subclasses based on genome-wide expression profiling BMC Med. 2009 7 34 10.1186/1741-7015-7-34 19624809 PMC2720987 · DOI
  123. [128]Seymour C.W. Kennedy J.N. Wang S. Chang C.-C.H. Elliott C. Xu Z. Berry S. Clermont G. Cooper G. Gomez H. Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis JAMA 2019 321 2003 2017 10.1001/jama.2019.5791 31104070 PMC6537818 · DOI · Paper page
  124. [129]Sweeney T.E. Azad T. Donato M. Haynes W.A. Perumal T.M. Henao R. Bermejo-Martin J.F. Almansa R. Tamayo E. Howrylak J.A. Unsupervised Analysis of Transcriptomics in Bacterial Sepsis Across Multiple Datasets Reveals Three Robust Clusters Crit. Care Med. 2018 46 915 925 10.1097/CCM.0000000000003084 29537985 PMC5953807 · DOI
  125. [130]Nusshag C. Morath C. Uhle F. Sweeney T. Liesenfeld O. Merle U. Zeier M. Brenner T. Weigand M.A. 1189: Transcriptomic endotypes implicate a unique risk profile for kidney-related outcomes in sepsis Crit. Care Med. 2022 51 593 10.1097/01.ccm.0000910492.10894.86 · DOI
  126. [131]Leventogiannis K. Kyriazopoulou E. Antonakos N. Kotsaki A. Tsangaris I. Markopoulou D. Grondman I. Rovina N. Theodorou V. Antoniadou E. Toward personalized immunotherapy in sepsis: The PROVIDE randomized clinical trial Cell Rep. Med. 2022 3 100817 10.1016/j.xcrm.2022.100817 36384100 PMC9729870 · DOI
  127. [132]Vandewalle J. Luypaert A. De Bosscher K. Libert C. Therapeutic Mechanisms of Glucocorticoids Trends Endocrinol. Metab. 2018 29 42 54 10.1016/j.tem.2017.10.010 29162310 · DOI
  128. [133]Vandewalle J. Libert C. Glucocorticoids in Sepsis: To Be or Not to Be Front. Immunol. 2020 11 1318 10.3389/fimmu.2020.01318 32849493 PMC7396579 · DOI
  129. [134]Martin-Loeches I. Torres A. Corticosteroids for CAP, influenza and COVID-19: When, how and benefits or harm? Eur. Respir. Rev. 2021 30 200346 10.1183/16000617.0346-2020 33568526 PMC7877325 · DOI
  130. [135]Antcliffe D.B. Burnham K.L. Al-Beidh F. Santhakumaran S. Brett S.J. Hinds C.J. Ashby D. Knight J.C. Gordon A.C. Transcriptomic Signatures in Sepsis and a Differential Response to Steroids. From the VANISH Randomized Trial Am. J. Respir. Crit. Care Med. 2019 199 980 986 10.1164/rccm.201807-1419OC 30365341 PMC6467319 · DOI
  131. [138]Bentzer P. Fjell C. Walley K.R. Boyd J. Russell J.A. Plasma cytokine levels predict response to corticosteroids in septic shock Intensive Care Med. 2016 42 1970 1979 10.1007/s00134-016-4338-z 27071387 · DOI
  132. [139]Martin-Loeches I. the GRECIA group Muriel-Bombín A. Ferrer R. Artigas A. Sole-Violan J. Lorente L. Andaluz-Ojeda D. Prina-Mello A. Herrán-Monge R. The protective association of endogenous immunoglobulins against sepsis mortality is restricted to patients with moderate organ failure Ann. Intensive Care 2017 7 44 10.1186/s13613-017-0268-3 28429310 PMC5399013 · DOI
  133. [140]Jarczak D. Kluge S. Nierhaus A. Use of Intravenous Immunoglobulins in Sepsis Therapy—A Clinical View Int. J. Mol. Sci. 2020 21 5543 10.3390/ijms21155543 32756325 PMC7432410 · DOI
  134. [141]Nakamori Y. Park E.J. Shimaoka M. Immune deregulation in sepsis and septic shock: Reversing immune paralysis by targeting PD-1/PD-L1 pathway Front. Immunol. 2021 11 624279 10.3389/fimmu.2020.624279 33679715 PMC7925640 · DOI
  135. [142]Hotchkiss R.S. Colston E. Yende S. Angus D.C. Moldawer L.L. Crouser E.D. Martin G.S. Coopersmith C.M. Brakenridge S. Mayr F.B. Immune checkpoint inhibition in sepsis: A Phase 1b randomized, placebo-controlled, single ascending dose study of anti-PD-L1 (BMS-936559) Crit. Care Med. 2019 47 632 10.1097/CCM.0000000000003685 30747773 PMC7254685 · DOI

Cited by

Sorted by citations

Authors
Garduno, A., Cusack, R., Leone, M., Einav, S., & Martin-Loeches, I.
Affiliations
  • Trinity College Dublin (IE)
  • St. James's Hospital (IE)
  • Department of Anesthesia, Intensive Care and Trauma Center, Nord University Hospital, Aix Marseille University, APHM, 13015 Marseille, France
  • Hebrew University of Jerusalem (IL)
  • Department of Clinical Medicine, Trinity College, University of Dublin, D02 PN40 Dublin, Ireland
ORCID
Venue
Microorganisms
Publisher
MDPI AG
Published
2023-04-25
Volume
11
Issue
5
Pages
1119
ISSN
2076-2607 (ISSN-L)
DOI
10.3390/microorganisms11051119
PMC
PMC10221354
OpenAlex
W4366987332
Cited by
39
References
7
Citations by year
2026: 20 · 2025: 11 · 2024: 5 · 2023: 3
FWCI
1.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Microorganisms (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
SFI (Science Foundation Ireland) (20/COV/0038)
Topics
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
  • Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Keywords
sepsis, septic shock, sepsis-induced immunosuppression, endotypes, multi-omics integration, cytokine storm, HLA-DR, microRNA dysregulation, septic cardiomyopathy, endothelial injury, tumor immunosuppression, gene regulatory interactions, immunomodulating agents

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review