A 3-Level Prognostic Classification in Septic Shock Based on Cortisol Levels and Cortisol Response to Corticotropin
Abstract
CONTEXT: The hypothalamic-pituitary-adrenal axis is a major determinant of the host response to stress. The relationship between its activation and patient outcome is not known. OBJECTIVE: To evaluate the prognostic value of cortisol levels and a short corticotropin stimulation test in patients with septic shock. DESIGN AND SETTING: Prospective inception cohort study conducted between October 1991 and September 1995 in 2 teaching hospital adult intensive care units in France. PARTICIPANTS: A total of 189 consecutive patients who met clinical criteria for septic shock. INTERVENTION: A short corticotropin stimulation test was performed in all patients by intravenously injecting 0.25 mg of tetracosactrin; blood samples were taken immediately before the test (T0) and 30 (T30) and 60 (T60) minutes afterward. MAIN OUTCOME MEASURES: Twenty-eight-day mortality as a function of variables collected at the onset of septic shock, including cortisol levels before the corticotropin test and the cortisol response to corticotropin (delta max, defined as the difference between T0 and the highest value between T30 and T60). RESULTS: The 28-day mortality was 58% (95% confidence interval [CI], 51%-65%) and median time to death was 17 days (95% CI, 14-27 days). In multivariate analysis, independent predictors of death (P < or = .001 for all) were McCabe score greater than 0, organ system failure score greater than 2, arterial lactate level greater than 2.8 mmol/L, ratio of PaO2 to fraction of inspired oxygen no more than 160 mm Hg, cortisol level at T0 greater than 34 microg/dL and delta max no more than 9 microg/dL. Three groups of patient prognoses were identified: good (cortisol level at T0 < or = 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 26%), intermediate (cortisol level at T0 34 microg/dL and delta max < or = 9 microg/dL or cortisol level at T0 > 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 67%), and poor (cortisol level at T0 > 34 microg/dL and delta max < or = 9 microg/dL; 28-day mortality rate, 82%). CONCLUSION: Our data suggest that a short corticotropin test has a good prognostic value and could be helpful in identifying patients with septic shock at high risk for death.
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“It has been suggested, for example, that glucocorticoids might primarily benefit patients with hyporesponsiveness to adrenocorticotropic hormone stimulation (40).”
BackgroundAdrenal function in sepsis: The retrospective Corticus cohort study
Lipiner, D., Sprung, C. L., Laterre, P., Weiss, Y., Goodman, S. V., Vogeser, M., Briegel, J., Keh, D., Singer, M., Moreno, R. P., et al. (2007) · Critical Care Medicine · doi:10.1097/01.ccm.0000259465.92018.6e · Cited by 237 · see citing works
“The current study confirmed that the proportion of patients with adrenal dysfunction varied from 10% to 71% according to various definitions proposed in the literature (2,8–10,16) and that nonsurvivors had higher baseline cortisol levels and a lower cortisol response to corticotropin (2, 9).”
BackgroundInfluentialSelf-citationCorticosteroid Supplementation for Adrenal Insufficiency
Coursin, D. B. (2002) · JAMA · doi:10.1001/jama.287.2.236 · Cited by 230 · see citing works
“Currently, the concept of acute administration of smaller doses of glucocorticoids equivalent to physiologic or slightly supraphysiologic stress levels in selected patients with sepsis or patients dependent upon vasopressors is under evaluation.(19,22,24,31-37) Recent data suggest an imbalance between systemic inflamm…”
BackgroundThe clinical importance of adrenal insufficiency in acute hepatic dysfunction
Harry, R., Auzinger, G. M., & Wendon, J. A. (2002) · Hepatology · doi:10.1053/jhep.2002.34514 · Cited by 226 · see citing works
The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock
Cuthbertson, B. H., Sprung, C. L., Annane, D., Chevret, S., Garfield, M. J., Goodman, S. V., Laterre, P., Vincent, J., Freivogel, K., Reinhart, K., et al. (2009) · Intensive Care Medicine · doi:10.1007/s00134-009-1603-4 · Cited by 210 · see citing works
“Critically ill patients treated with etomidate have been found to have a greater incidence of an IRC [14, 15, 22], and the prognostic importance of adrenal insufficiency in septic shock has been well described [ 16 ].”
BackgroundSelf-citationEndotoxin tolerance: is there a clinical relevance?
Cavaillon, J., Adrie, C., Fitting, C., & Adib‐Conquy, M. (2003) · Journal of Endotoxin Research · doi:10.1179/096805103125001487 · Cited by 213 · see citing works
The hepatoadrenal syndrome: A common yet unrecognized clinical condition*
Marik, P. E., Gayowski, T., & Starzl, T. E. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000164541.12106.57 · Cited by 212 · see citing works
“Furthermore, as noted previously by Annane and colleagues (18), a very high serum cortisol was associated with a high mortality rate.”
BackgroundCorticosteroids for treating sepsis
Annane, D., Bellissant, É., Bollaert, P. E., Briegel, J., Keh, D., & Kupfer, Y. Y. (2015) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd002243.pub3 · Cited by 214 · see citing works
Self-citationMartín‐Loeches, I., Lisboa, T. C., Rhodes, A., Moreno, R. P., Silva, E., Sprung, C. L., Chiche, J., Barahona, D., Villabon, M., Balasini, C., et al. (2010) · Intensive Care Medicine · doi:10.1007/s00134-010-2078-z · Cited by 211 · see citing works
“Endogenous glucocorticoids as end-effectors play a role in inhibiting inflammation [29] but are not always effective in suppressing the ''cytokine storm'' driven by COPD chronic obstructive pulmonary disease systemic inflammation, even though cortisol levels have been correlated with grades of illness severity and mor…”
BackgroundDuration of adrenal inhibition following a single dose of etomidate in critically ill patients
Vinclair, M., Broux, C., Faure, P., Brun, J., Genty, C., Jacquot, C., Chabre, O., & Payen, J. (2007) · Intensive Care Medicine · doi:10.1007/s00134-007-0970-y · Cited by 200 · see citing works
“Specifically, an increase in serum cortisol concentration of less than 250 nmol/l (9 μg/dl) irrespective of basal cortisol level was used as the diagnostic criterion for CST nonresponders (delta cortisol) [10, 21].”
BackgroundMethodJackson, W. L. (2005) · CHEST Journal · doi:10.1378/chest.127.3.1031 · Cited by 195 · see citing works
Cortisol Response in Relation to the Severity of Stress and Illness
Widmer, I. E., Puder, J. J., König, C., Pargger, H., Zerkowski, H. R., Girard, J., & Müller, B. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0354 · Cited by 225 · see citing works
“In sepsis, patients with basal cortisol levels greater than 935 nmol/liter ( 34 g/dl) and a rise of cortisol upon ACTH stimulation of less than 250 nmol/liter ( 9 g/dl) have a mortality of 80% (19), arguably pointing to the presence of relative adrenal insufficiency.”
BackgroundResultAbsolute and relative adrenal insufficiency in children with septic shock*
Pizarro, C. F., Troster, E. J., Damiani, D., & Carcillo, J. A. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000159854.23324.84 · Cited by 192 · see citing works
“Recently, investigators have reported hemodynamic and survival benefits associated with the use of more physiologic steroid replacement therapy in adult patients with relative adrenal insufficiency and vasopressor-dependent septic shock (2, 3).”
BackgroundMethodInfluentialReducing mortality in sepsis: new directions.
Vincent, J., Abraham, E. H., Annane, D., Bernard, G. R., Rivers, E. P., & den Berghe, G. V. (2002) · Critical Care · doi:10.1186/cc1860 · Cited by 190 · see citing works
“Relative adrenal insufficiency is common in patients with refractory septic shock (50–75% of patients) [39].”
BackgroundSelf-citationThe evaluation and management of shock
Holmes, C. L., & Walley, K. R. (2003) · Clinics in Chest Medicine · doi:10.1016/s0272-5231(03)00107-2 · Cited by 187 · see citing works
“Acute adrenal insufficiency can present as shock in many settings including trauma, hemorrhage [15], childbirth (Sheehan’s syndrome) [16], and adrenal insufficiency of sepsis [17].”
BackgroundMalerba, G., Romano-Girard, F., Cravoisy, A., Dousset, B., Nace, L., L�vy, B., & Bollaert, P.-E. (2005) · Intensive Care Medicine · doi:10.1007/s00134-004-2550-8 · Cited by 179 · see citing works
“In studies with sufficient population sampling this so-called “relative” or “occult” adrenocortical deficiency has been consistently demonstrated to be independently associated with increased ICU mortality, irrespective of baseline cortisol levels [3, 4, 5, 6].”
BackgroundResultInfluentialMetabolomic Derangements Are Associated with Mortality in Critically Ill Adult Patients
Rogers, A. J., McGeachie, M. J., Baron, R. M., Gazourian, L., Haspel, J. A., Nakahira, K., Fredenburgh, L. E., Hunninghake, G. M., Raby, B. A., Matthay, M. A., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087538 · Cited by 175 · see citing works
“Similarly, cortisol has long been recognized to be elevated in critically ill patients because of hypothalamus-pituitary-adrenal axis stimulation, [25,26] though exact mechanisms for cortisol elevation are”
BackgroundO’Brien, J. M., Ali, N. A., Aberegg, S. K., & Abraham, E. H. (2007) · The American Journal of Medicine · doi:10.1016/j.amjmed.2007.01.035 · Cited by 179 · see citing works
Should Vascular Catheters Be Removed from All Patients with Candidemia? An Evidence-Based Review
Nucci, M., & Anaissie, E. (2002) · Clinical Infectious Diseases · doi:10.1086/338714 · Cited by 175 · see citing works
The effect of etomidate on adrenal function in critical illness: a systematic review
Albert, S. G., Ariyan, S., & Rather, A. (2011) · Intensive Care Medicine · doi:10.1007/s00134-011-2160-1 · Cited by 174 · see citing works
“The first [18] documented that mortality increased with ‘‘non-response’’ to CST [Dcortisol B 250 nmol/L (B9 lg/dL)].”
BackgroundProceedings of the 55th Annual Convention of the American Association of Equine Practitioners
Frisbie, D. D., & Ross, C. M. (2009) · Cited by 175 · see citing works
Jean-Baptiste, E. (2007) · Journal of Intensive Care Medicine · doi:10.1177/0885066606297123 · Cited by 172 · see citing works
“However, septic patients with adrenal insufficiency have a higher mortality [57].”
BackgroundHypothalamic-Pituitary-Adrenal Insufficiency
Zaloga, G. P., & Marik, P. E. (2001) · Critical Care Clinics · doi:10.1016/s0749-0704(05)70150-0 · Cited by 172 · see citing works
Glucocorticoids and acute lung injury
Thompson, B. (2003) · Critical Care Medicine · doi:10.1097/01.ccm.0000057900.19201.55 · Cited by 168 · see citing works
“The authors postulated that diminished adrenal reserve was present in patients with a blunted response to ACTH and that limited reserve contributed to excess mortality (25).”
BackgroundMeduri, G. U., Muthiah, M. P., Carratù, P., Eltorky, M., & Chrousos, G. P. (2005) · Neuroimmunomodulation · doi:10.1159/000091126 · Cited by 167 · see citing works
Monocyte Human Leukocyte Antigen–DR Transcriptional Downregulation by Cortisol during Septic Shock
Le Tulzo, Y., Pangault, C., Amiot, L., Guilloux, V., Tribut, O., Arvieux, C., Camus, C., Fauchet, R., Thomas, R., & Drénou, B. (2004) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200309-1329oc · Cited by 166 · see citing works
Relative adrenal insufficiency in the preterm and term infant
Fernandez, E. F., & Watterberg, K. L. (2009) · Journal of Perinatology · doi:10.1038/jp.2009.24 · Cited by 166 · see citing works
Corticosteroids for treating sepsis in children and adults
Annane, D., Bellissant, É., Bollaert, P. E., Briegel, J., Keh, D., Kupfer, Y. Y., Pirracchio, R., & Rochwerg, B. N. (2019) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd002243.pub4 · Cited by 173 · see citing works
Self-citationPhysiological-dose steroid therapy in sepsis [ISRCTN36253388]
Yıldız, O., Doğanay, M., Aygen, B., Güven, M., Keleştimur, F., & Tutuş, A. (2002) · Critical Care · doi:10.1186/cc1498 · Cited by 163 · see citing works
“[17] reported that SOFA score, high plasma cortisol levels and weak response of cortisol to ACTH were also associated with mortality.”
BackgroundInfluentialCortisol levels and mortality in severe sepsis
Sam, S., Corbridge, T. C., Mokhlesi, B., Comellas, A. P., & Molitch, M. E. (2003) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2004.01923.x · Cited by 161 · see citing works
“This factor, in addition to lack of uniform criteria for diagnosis of AI in severe sepsis has led to the reported incidence of AI varying from 1·5% to 54% (Sibbald et al., 1977; Finlay & McKee, 1982; Rothwell et al., 1991; Soni et al., 1995; Annane et al., 2000; Rivers et al., 2001; Marik and Zaloga, 2003).”
BackgroundRegulation of cortisol bioavailability—effects on hormone measurement and action
Perogamvros, I., Ray, D., & Trainer, P. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.134 · Cited by 155 · see citing works
Systemic Steroids in Severe Sepsis and Septic Shock
Patel, G. P., & BALK, R. A. (2011) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201011-1897ci · Cited by 154 · see citing works
“They also found an 82% mortality rate associated with a basal plasma cortisol level greater than 34 mg/dl and a change of less than or equal to 9 mg/dl after ACTH (Δmax< 9 mg/dl) (44).”
BackgroundNew strategies for clinical trials in patients with sepsis and septic shock
Cohen, J. B., Guyatt, G. H., Bernard, G. R., Calandra, T., Cook, D., Elbourne, D. R., Marshall, J. C., Nunn, A., & Opal, S. M. (2001) · Critical Care Medicine · doi:10.1097/00003246-200104000-00039 · Cited by 158 · see citing works
“Another example would be documentation of an impaired hypothalamic-pituitaryadrenal axis before randomization in trials of corticosteroid therapy (23).”
BackgroundTherapeutic Intervention and Targets for Sepsis
Rice, T. W., & Bernard, G. R. (2004) · Annual Review of Medicine · doi:10.1146/annurev.med.56.082103.104356 · Cited by 158 · see citing works
Kleiman, A., Hübner, S., Parkitna, J. M. R., Neumann, A., Hofer, S., Weigand, M. A., Bauer, M., Schmid, W., Schütz, G., Libert, C., et al. (2012) · The FASEB Journal · doi:10.1096/fj.11-192112 · Cited by 152 · see citing works
Prigent, H., Maxime, V., & Annane, D. (2004) · Critical Care · doi:10.1186/cc2878 · Cited by 151 · see citing works
“This phenomenon may explain the blunted response to exogenous ACTH that is observed in about 50% of patients with severe sepsis [38].”
BackgroundSelf-citationde Jong, M. F. C., Molenaar, N., Beishuizen, A., & Groeneveld, A. B. J. (2015) · Critical Care · doi:10.1186/s13054-014-0721-8 · Cited by 150 · see citing works
“Together with the exclusion of etomidate-treated patients, this selection may also explain the relatively low frequency of adrenal dysfunction of about 30% in our patients, whereas adrenal insufficiency may occur in up to 60% of those with septic shock [6-8,10-12,14,15,18,27].”
BackgroundResultInfluentialAdrenal function and dysfunction in critically ill patients
Téblick, A., Peeters, B., Langouche, L., & den Berghe, G. V. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0185-7 · Cited by 156 · see citing works
Adrenal Insufficiency in High-Risk Surgical ICU Patients
Rivers, E. P., Gaspari, M., Mlynarek, M. E., Horst, H., Fath, J. J., Wortsman, J., & Saad, G. A. (2001) · CHEST Journal · doi:10.1378/chest.119.3.889 · Cited by 147 · see citing works
le Roux, C. W., Chapman, G. A., Kong, W. M., Dhillo, W. S., Jones, J., & Alaghband-Zadeh, J. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-021532 · Cited by 146 · see citing works
Bellissant, É. (2000) · Clinical Pharmacology & Therapeutics · doi:10.1067/mcp.2000.109354 · Cited by 144 · see citing works
Adrenal insufficiency: etiology, diagnosis and treatment
Neary, N., & Nieman, L. (2010) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e328338f608 · Cited by 140 · see citing works
Klose, M., Juul, A., Struck, J., Morgenthaler, N. G., Kosteljanetz, M., & Feldt‐Rasmussen, U. (2007) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2007.02931.x · Cited by 142 · see citing works
Endocrine aspects of acute and prolonged critical illness
Vanhorebeek, I., Langouche, L., & Van den Berghe, G. (2006) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0071 · Cited by 141 · see citing works
Acevedo, J., Fernández, J., Prado, V., Silva, A., Castro, M., Pavesi, M., Roca, D., Jiménez, W., Ginès, P., & Arroyo, V. (2013) · Hepatology · doi:10.1002/hep.26535 · Cited by 140 · see citing works
“It was first described and has been mainly studied in critically ill patients (severe sepsis, septic shock, head injury, pancreatitis, burns, and major surgery) who require high circulating cortisol levels to modulate systemic inflammatory response, maintain the vascular tone and permeability, and adapt metabolism to…”
BackgroundSepsis and septic shock: Pathogenesis and treatment perspectives
Minasyan, H. A. (2017) · Journal of Critical Care · doi:10.1016/j.jcrc.2017.04.015 · Cited by 140 · see citing works
“Primary and secondary adrenal insufficiency occurs in patients with sepsis and is associated with a poor outcome [68-71].”
BackgroundCorticosteroids in septic shock: a systematic review and network meta-analysis
Gibbison, B., López-López, J. A., Higgins, J. P. T., Miller, T., Angelini, G. D., Lightman, S. L., & Annane, D. (2017) · Critical Care · doi:10.1186/s13054-017-1659-4 · Cited by 137 · see citing works
“…have been attempts to identify and treat a group of patients are thought to be relatively deficient in glucocorticoids during their critical illness (critical illness-related corticosteroid insufficiency [1]), although sensitive and specific diagnostic tests for this remain to be found [28 – 31].”
BackgroundSelf-citationGlucocorticoids and Inflammation Revisited: The State of the Art
Franchimont, D. P., Kino, T., Galon, J., Meduri, G. U., & Chrousos, G. P. (2002) · NeuroImmunoModulation · doi:10.1159/000069969 · Cited by 131 · see citing works
CORTISOL LEVELS AND ADRENAL RESERVE AFTER SUCCESSFUL CARDIAC ARREST RESUSCITATION
kimian, G. H., Baugnon, T., Thuong, M., Monchi, M., Dabbane, H., Jaby, D., Rhaoui, A., Laurent, I., Moret, G., Fraisse, F. O., et al. (2004) · Shock · doi:10.1097/01.shk.0000132489.79498.c7 · Cited by 130 · see citing works
Glucocorticoid regulation of the inflammatory response to injury
Yeager, M. P., Guyre, P. M., & Munck, A. U. (2004) · Acta Anaesthesiologica Scandinavica · doi:10.1111/j.1399-6576.2004.00434.x · Cited by 124 · see citing works
The Glucocorticoid Receptor: Isoforms, Functions, and Contribution to Glucocorticoid Sensitivity
Lockett, J., Inder, W. J., & Clifton, V. L. (2024) · Endocrine Reviews · doi:10.1210/endrev/bnae008 · Cited by 135 · see citing works
Impact of neutropenia duration on short-term mortality in neutropenic critically ill cancer patients
Darmon, M., Azoulay, É., Alberti, C., Fieux, F., Moreau, D., Gall, J. L., & Schlemmer, B. (2002) · Intensive Care Medicine · doi:10.1007/s00134-002-1528-7 · Cited by 126 · see citing works
“Even when prolonged neutropenia is expected, early management with noninvasive MV, human recombinant activated C protein, and steroids for adult respiratory distress syndrome or septic shock [10, 28, 29, 30, 31] may ensure a favorable outcome.”
BackgroundIntensive Insulin in Intensive Care
Malhotra, A. (2006) · New England Journal of Medicine · doi:10.1056/nejme058304 · Cited by 125 · see citing works
Cui, X., Moayeri, M., Li, Y., Li, X., Haley, M., Fitz, Y., Correa-Araujo, R., Banks, S. M., Leppla, S. H., & Eichacker, P. Q. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00593.2003 · Cited by 123 · see citing works
“These two actions could both interfere with normal vascular tone and provide an alternate mechanism for hypotension with LeTx (1, 34, 36, 40).”
Novel Therapies for Sepsis: A Review
Deans, K. J., Haley, M., Natanson, C., Eichacker, P. Q., & Minneci, P. C. (2005) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/01.ta.0000158244.69179.94 · Cited by 122 · see citing works
Siraux, V., Backer, D. D., Yalavatti, G., Mélot, C., Gervy, C., Mockel, J., & Vincent, J. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000185641.87051.7c · Cited by 122 · see citing works
“(7) showed, in a study of 189 patients with septic shock, that the combination of baseline plasma cortisol levels and cortisol response to 250 g of corticotropin could predict mortality in septic shock.”
BackgroundMethodInfluential
- Authors
- Annane, D.
- Affiliations
- Hôpital Raymond-Poincaré (FR)
- Corresponding author
- Annane, Djillali
- ORCID
- Annane, Djillali
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2000-02-23
- Volume
- 283
- Issue
- 8
- Pages
- 1038
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2156618518
- Cited by
- 1,000
- References
- 40
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 15 · 2023: 19 · 2022: 15 · 2021: 13 · 2020: 19 · 2019: 22 · 2018: 27 · 2017: 27 · 2016: 27 · 2015: 26 · 2014: 44 · 2013: 35 · 2012: 38
- FWCI
- 38.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Keywords
- septic shock, cortisol, ACTH stimulation test, tetracosactrin, hypothalamic-pituitary-adrenal axis, prognostic stratification, 28-day mortality, stress response, organ failure, lactate, PaO2/FiO2 ratio, intensive care unit patients, corticosteroid therapy, sepsis
- MeSH terms
- Adult, Cosyntropin, Female, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Male, Middle Aged, Pituitary-Adrenal System, Prognosis, Prospective Studies, Severity of Illness Index, Shock, Septic, Biomarkers, Multivariate Analysis, Proportional Hazards Models, Survival Analysis
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