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Sex-specific outcomes and management in critically ill septic patients

Published:October 12, 2020DOI:https://doi.org/10.1016/j.ejim.2020.10.009

      Highlights

      • This large retrospective analysis includes 17,146 patients.
      • Females receive more often mechanical ventilation and vasopressors.
      • After adjustment for all relevant confounders, there is no sex-specific impact on ICU mortality.

      Abstract

      Background

      : Female and male critically ill septic patients might differ with regards to risk distribution, management, and outcomes. We aimed to compare male versus female septic patients in a large collective with regards to baseline risk distribution and outcomes.

      Methods

      : In total, 17,146 patients were included in this analysis, 8781 (51%) male and 8365 (49%) female patients. The primary endpoint was ICU-mortality. Baseline characteristics and data on organ support were documented. Multilevel logistic regression analyses were used to assess sex-specific differences.

      Results

      : Female patients had lower SOFA scores (5 ± 5 vs. 6 ± 6; p<0.001) and creatinine (1.20±1.35 vs. 1.40±1.54; p<0.001). In the total cohort, the ICU mortality was 10% and similar between female and male (10% vs. 10%; p = 0.34) patients. The ICU remained similar between sexes after adjustment in model-1 (aOR 1.05 95% CI 0.95–1.16; p = 0.34); model-2 (aOR 0.91 95% CI 0.79–1.05; p = 0.18) and model-3 (aOR 0.93 95% CI 0.80–1.07; p = 0.29). In sensitivity analyses, no major sex-specific differences in mortality could be detected.

      Conclusion

      : In this study no clinically relevant sex-specific mortality differences could be detected in critically ill septic patients. Possible subtle gender differences could play a minor role in the acute situation due to the severity of the disease in septic patients.

      Keywords

      1. Introduction

      Sepsis is a life-threatening condition triggered by an “out-of-proportion” immune response to an infection [
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      ]. Also, in an American epidemiologic study, sepsis incidence was higher in men compared to women [
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      The epidemiology of sepsis in the United States from 1979 through 2000.
      ].
      The literature regarding gender-specific mortality in patients with sepsis is contradictory. Nachtigall et al. reported higher mortality in female septic patients [
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      • Wernecke K.D.
      • et al.
      Gender-related outcome difference is related to course of sepsis on mixed ICUs: a prospective, observational clinical study.
      ]. However, in another study, Nasir et al. reported higher survival and lower interleukin-6 plasma levels in females [
      • Nasir N.
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      ]. A recent study reported data from Medical Information Mart for Intensive Care-III supported the link between female sex and lower mortality [
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      • et al.
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      ]. Other studies reported similar outcomes in both male and female septic patients [
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      • Franitza M.
      • Toliat M.R.
      • et al.
      Association of Gender with outcome and host response in critically ill sepsis patients.
      ].
      Sex-specific differences in outcomes were also observed for other acute diseases [
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      • Ecarnot F.
      • Bassand J.P.
      Propensity score-matched analysis of effects of clinical characteristics and treatment on gender difference in outcomes after acute myocardial infarction.
      ,
      • Keil U.
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      Sex differences in mortality after myocardial infarction: is there evidence for an increased risk for women?.
      ,
      • Vaccarino V.
      • Krumholz H.M.
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      • Horwitz R.I.
      Sex differences in mortality after myocardial infarction. Is there evidence for an increased risk for women?.
      ,
      • Malacrida R.
      • Genoni M.
      • Maggioni A.P.
      • Spataro V.
      • Parish S.
      • Palmer A.
      • Collins R.
      • Moccetti T.
      A comparison of the early outcome of acute myocardial infarction in women and men. The Third International Study of Infarct Survival Collaborative Group.
      ]. Some studies reported sex-specific differences in ICU patients [
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      • Parish S.
      • Palmer A.
      • Collins R.
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      ,
      • Pietropaoli A.P.
      • Glance L.G.
      • Oakes D.
      • Fisher S.G.
      Gender differences in mortality in patients with severe sepsis or septic shock.
      ,
      • Schoeneberg C.
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      • Hussmann B.
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      Gender-specific differences in severely injured patients between 2002 and 2011: data analysis with matched-pair analysis.
      ,
      • Park J.
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      • Cho J.
      • Park C.M.
      • Park H.
      • Cho J.
      • Guallar E.
      • et al.
      A nationwide analysis of intensive care unit admissions, 2009-2014 - The Korean ICU National Data (KIND) study.
      ]. Female and male critically ill patients were reported to differ regarding baseline risk distribution, and these disparities could lead to distinct outcomes [
      • Tibullo L.
      • Esquinas A.
      Outcomes difference in non-invasive ventilation in 'very old' patients with acute respiratory failure: occult gender effect?.
      ,
      • Cilloniz C.
      • Dominedo C.
      • Ielpo A.
      • Ferrer M.
      • Gabarrus A.
      • Battaglini D.
      • Bermejo-Martin J.
      • Meli A.
      • Garcia-Vidal C.
      • Liapikou A.
      • et al.
      Risk and prognostic factors in very old patients with sepsis secondary to community-acquired pneumonia.
      ]. In elderly critically ill patients with sepsis, male sex was linked to decreased survival [
      • Martin G.S.
      • Mannino D.M.
      • Eaton S.
      • Moss M.
      The epidemiology of sepsis in the United States from 1979 through 2000.
      ,
      • Cilloniz C.
      • Dominedo C.
      • Ielpo A.
      • Ferrer M.
      • Gabarrus A.
      • Battaglini D.
      • Bermejo-Martin J.
      • Meli A.
      • Garcia-Vidal C.
      • Liapikou A.
      • et al.
      Risk and prognostic factors in very old patients with sepsis secondary to community-acquired pneumonia.
      ]. A trend towards lower mortality in women compared to male patients was observed in a sub-study of the FROG-ICU study, which evaluated elderly critically ill patients [
      • Hollinger A.
      • Gayat E.
      • Feliot E.
      • Paugam-Burtz C.
      • Fournier M.C.
      • Duranteau J.
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      • Leone M.
      • Jaber S.
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      • et al.
      Gender and survival of critically ill patients: results from the FROG-ICU study.
      ].
      However, most of these studies were single-centered and analyzed relatively few patients. The eICU Collaborative Research Database is a multi-center ICU database, including over 200 000 admissions [
      • Pollard T.J.
      • Johnson A.E.W.
      • Raffa J.D.
      • Celi L.A.
      • Mark R.G.
      • Badawi O.
      The eICU Collaborative Research Database, a freely available multi-center database for critical care research.
      ]. We aimed to compare male versus female septic patients in this large collective regarding baseline risk distribution, management, and outcomes.

      2. Methods

      2.1 Study subjects

      The eICU Collaborative Research Database is a multi-center intensive care unit (ICU) database, including over 200,000 admissions of 335 ICUs from 208 hospitals across the USA in 2014 and 2015 [
      • Pollard T.J.
      • Johnson A.E.W.
      • Raffa J.D.
      • Celi L.A.
      • Mark R.G.
      • Badawi O.
      The eICU Collaborative Research Database, a freely available multi-center database for critical care research.
      ]. We extracted baseline characteristics and organ support on day one. The database is released under the Health Insurance Portability and Accountability Act (HIPAA) safe harbor provision. This study included patients of the eICU database diagnosed with sepsis based on the method established by Angus et al., which identifies patients via billing codes [
      • Angus D.C.
      • Linde-Zwirble W.T.
      • Lidicker J.
      • Clermont G.
      • Carcillo J.
      • Pinsky M.R.
      Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.
      ]. Management strategies were defined as the use of vasopressors and mechanical ventilation. The type of primary infection site and the ethical background were extracted.

      2.2 Statistical analysis

      Continuous data points are expressed as median ± interquartile range. Differences between independent groups were calculated using Mann Whitney U test accordingly. Categorical data are expressed as numbers (percentage). The Chi-square test was applied to calculate univariate differences between groups.
      The primary exposure was sex (male or female), and the primary outcome was ICU-mortality. The secondary outcomes were the management strategies, mechanical ventilation, and vasopressor use. Three sequential random effects, multilevel logistic regression models were used to evaluate the impact of sex on ICU-mortality. First, a baseline model with sex as a fixed effect and ICU as random effect (model-1) was fitted. Second, to model-1, patient characteristics (age, SOFA score, BMI, infection source, ethnics) (model-2) were added to the model. Third, to model-2, management strategies (model-3) were added to the model. Model-1 and model-2 were used to evaluate the primary and secondary outcomes, whereas model-3 was only used to assess the primary outcomes. Adjusted odds ratios (aOR) with respective 95% confidence intervals (95%CI) were calculated. Multiple sensitivity analyses, analyzing only patients with creatinine above and below 2.0 mg/dL (arbitrary cut-off), lactate above and below 2.0 mmol/L (arbitrary cut-off), age above and below 65 years (arbitrary cut-off), and SOFA above and below 10 (arbitrary cut-off), with and without mechanical ventilation, with and without the vasopressor use and with pulmonary focus were performed.
      All tests were two-sided, and a p-value of <0.05 was considered statistically significant. Stata/IC 16.1 (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC) was used for all statistical analyses.

      3. Results

      In total, 8365 (49%) female and 8781 (51%) male septic patients were included in this study. Baseline characteristics and risk distribution of the unadjusted cohort are shown in Table 1. There were no clinically relevant differences between male and female patients except for lower SOFA scores (5 ± 5 vs. 6 ± 6 points; p<0.001) and creatinine (1.20±1.35 vs. 1.40±1.54 mg/dL; p<0.001) in female patients. There were other differences, including age (66±22 vs. 66±21; p = 0.04), and lactate (1.80±1.92 vs. 1.80±1.80 mmol/L; p = 0.006). The most recent primary infection focus was the lung and the urinary tract. Male suffered significantly less from urinary tract infections (19% vs. 27%; p<0.001), while males were predominantly affected from pulmonary (40% vs. 35%; p<0.001) and cutaneous illnesses (10% vs. 8%; p<0.001; Table 1).
      Table 1Baseline characteristics in the total cohort, male versus female patients.
      FemaleMalep-value
      n = 8365n = 8781
      BMI28 (12)27 (9)<0.001
      Age (years)66 (22)66 (21)0.04
      Age >65 years4326 (52)4617 (53)0.26
      SOFA score5 (5)6 (6)<0.001
      SOFA >10976 (12)1249 (14)<0.001
      Heart rate >110bpm2106 (27)2183 (27)0.67
      O2 saturation <90%379 (5)416 (5)0.54
      Body temperature >38 °C886 (11)1051 (13)0.003
      Creatinine (mg/dL)1.20 (1.35)1.40 (1.54)<0.001
      Creatinine >2.0 mg/dL2084 (27)2707 (33)<0.001
      Lactate (mmol/L)1.80 (1.92)1.80 (1.80)0.006
      Lactate >2.0 mmol/L2128 (43)2285 (44)0.33
      Focus
      UTI2280 (27)1679 (19)<0.001
      Pulmonary2919 (35)3512 (40)<0.001
      GI1051 (13)1058 (12)0.31
      Cutaneous646 (8)836 (10)<0.001
      Unknown904 (11)1083 (12)0.002
      Other514 (6)609 (7)0.04
      Gynecologic51 (1)4 (<1)<0.001
      Ethnic
      Caucasian6566 (79)6770 (77)0.03
      AfricanAmerican833 (10)974 (11)0.02
      Hispanic333 (4)330 (4)0.45
      Asian140 (2)128 (2)0.27
      Native American82 (1)62 (1)0.54
      Other411 (5)517 (6)0.005
      Length of stay (h)53 (71)54 (76)0.55
      SOFA - Sepsis-related organ failure assessment; BMI – body mass index; UTI – urinary tract infection; GI - gastrointestinal.
      After the adjustment for the ICU cluster as random effect (model-1), there was no difference between both genders regarding the use of mechanical ventilation (aOR 1.03 95%CI 0.95–1.11; 0.52) and vasopressors (aOR 0.94 95%CI 0.88–1.01; 0.07) Table 2). After adding patient-specific confounders (model-2), males evidenced a lower odds for both the use of mechanical ventilation (aOR 0.78 95%CI 0.70–0.87; <0.001) and vasopressors (aOR 0.87 95%CI 0.79–0.97; 0.01; Table 2). This finding of lower odds for the use of mechanical ventilation in model-2 (aOR 0.67 95%CI 0.51–0.88; p = 0.004) persisted in the subgroup of patients with pulmonary focus.
      Table 2Associations of primary exposure (sex) with mortality and management strategies in three multilevel logistic regression models.
      Crude events
      Female (n = 8365)Male (n = 8781)Model 1Model 2Model 3
      n (%)n (%)aOR (95%CI, p-value)aOR (95%CI, p-value)aOR (95%CI, p-value)
      ICU mortality836 (10)906 (10)1.05 (0.95–1.16; 0.34)0.91 (0.79–1.05; 0.18)0.93 (0.80–1.07; 0.29)
      Management
      Mechanical ventilation1110 (28)1010 (25)1.03 (0.95–1.11; 0.52)0.78 (0.70–0.87; <0.001)
      Vasopressor use1547 (38)1427 (35)0.94 (0.88–1.01; 0.07)0.87 (0.79–0.97; 0.01)
      Model 1 - ICU cluster as random effect.
      Model 2 - Model 1 plus patient level (SOFA, BMI, age, ethnics, infection focus, heart rate, lactate concentration).
      SOFA - Sepsis-related organ failure assessment; BMI – body mass index.
      In the total cohort, the ICU mortality was 10% and similar between female and male (10% vs. 10%; p = 0.34) patients. The ICU remained similar between sexes after adjustment in model-1 (aOR 1.05 95% CI 0.95–1.16; p = 0.34); model-2 (aOR 0.91 95% CI 0.79–1.05; p = 0.18) and model-3 (aOR 0.93 95% CI 0.80–1.07; p = 0.29). In sensitivity analyses, no major sex-specific differences in mortality could be detected (Fig. 1).
      Fig. 1
      Fig. 1Forest plot of OR of female versus male for different subgroups according to model-1 (aOR 95%CI). Neither in younger (>65 years; aOR 0.95 0.83–1.09) patients, patients with lactate ≤2.0 (aOR 1.09 95%CI 0.71–1.36) and lactate >2.0 (aOR 0.95 95%CI 0.82–1.10), patients with (aOR 1.09 95%CI 0.95–1.24) and without (aOR 1.06 95%CI 0.90–1.25) vasopressor use; with (aOR 1.04 95%CI 0.89–1.21) and without (aOR 1.05 95%CI 0.91–1.21); with creatinine ≤2.0 (aOR 0.85 95%CI 0.74–0.99) and with creatinine >2.0 (aOR 1.10 95%CI 0.94–1.29); with SOFA≤10 (aOR 1.02 95%CI 0.89–1.16) and SOFA>10 (aOR 0.87 95%CI 0.73–1.04); with a heart rate ≤110 (aOR 1.01 95%CI 0.89–1.15) and heart rate >110 (aOR 1.11 95%CI 0.93–1.32) sex-specific differences could be detected.
      Only in older (≤65 years; aOR 1.20 95%CI 1.02–1.41) patients and in patients with creatinine ≤2.0 mg/dL (aOR 0.74 95%CI 0.74–0.99), a trend towards sex specific mortality could be detected.
      SOFA - Sepsis-related organ failure assessment.

      4. Discussion

      In this study we could not detect any significant gender-specific differences in ICU mortality based on multicenter data from critically ill septic patients on ICU. This result could be confirmed in several sensitivity analyses as well as after correction for several possible confounders.
      In theory, both biological and non-biological factors could impact sex-specific outcomes after critical care. Biological factors include genetics, but also endocrine, neurohumoral and immunological factors [
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      ]. There was a numerical trend towards a higher age in men, but the proportion of patients over 65 years of age was similarly high in both sexes. Furthermore, in addition to clinical disease severity expressed as SOFA, creatinine concentration was higher in men. This finding is consistent with recent evidence showing that the male gender is per se associated with a higher baseline creatinine level. This higher concentration does not necessarily reflect lower kidney function [
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      ]. However, in male kidney epithelial cells are also more susceptible to injury compared to female, which could also contribute to this laboratory finding [
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      ]. However, even in the sensitivity analyses in patients with or without elevated creatinine levels, we could not detect any differences in mortality between the sexes. Thus, we interpret the observed difference in creatinine concentrations primarily as not clinically relevant. Furthermore, both model-2 and model-3 were corrected for creatinine levels.
      The results of the present analysis confirm the FROG-ICU study, which observed no sex-related differences in outcomes in more than 2000 critically ill patients [
      • Hollinger A.
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      • et al.
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      ]. Also, no sex-specific difference was observed in a large Austrian cohort study on 25,998 patients without age-restriction after adjustment for illness [
      • Valentin A.
      • Jordan B.
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      • Metnitz P.G.
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      ]. However, Cillóniz et al. found in 1238 older patients (≥80 years) an increased risk for the development of a community-acquired pneumonic sepsis [
      • Cilloniz C.
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      • Ielpo A.
      • Ferrer M.
      • Gabarrus A.
      • Battaglini D.
      • Bermejo-Martin J.
      • Meli A.
      • Garcia-Vidal C.
      • Liapikou A.
      • et al.
      Risk and prognostic factors in very old patients with sepsis secondary to community-acquired pneumonia.
      ]. In this study, sensitivity analysis in the older patients (arbitrary cut-off at 65 years), revealed no differences in outcomes. Therefore, sex-specific differences in mortality reported in smaller cohorts could be due to lower patient numbers and consecutive selection bias [
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      ].
      Interestingly, after inclusion of the ICU level as random effect and several patient-specific factors (model 2), female patients evidenced higher rates of mechanical ventilation and vasopressor use. However, this difference in the management strategies did not lead to a change in the ICU-mortality (model 3). On the other hand, we could confirm the finding that the odds of using mechanical ventilation were lower in men, even in patients with pulmonary focus. This finding could, therefore, be a statistical random result on the one hand, or it could represent a real sex-specific difference in the management of critically ill patients [
      • Block L.
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      • Syrous A.N.
      • Lindqvist B.
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      • Naredi S.
      Age, SAPS 3 and female sex are associated with decisions to withdraw or withhold intensive care.
      ]. Based on our data, this finding must remain descriptive, and the explanation of the causes remains speculative.

      4.1 Limitations

      This retrospective analysis has several limitations. The present study is limited to ICU-mortality as primary endpoint and some management strategies as secondary endpoints. Outcome differences in the long-term, or differences in functional outcomes could evidence sex-specific differences [
      • Reniers R.L.
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      Risk Perception and Risk-Taking Behaviour during Adolescence: the Influence of Personality and Gender.
      ,
      • Cheng M.H.
      • Chang S.F.
      Frailty as a risk factor for falls among community dwelling people: evidence from a meta-analysis.
      ]. However, these points are beyond the scope of the present study. Sepsis per se is a complex syndrome; its definition and diagnostic criteria underlie continuous changes and debates. This problem affects this retrospective diagnosis. The present study uses the established algorithm by Angus et al. [
      • Angus D.C.
      • Linde-Zwirble W.T.
      • Lidicker J.
      • Clermont G.
      • Carcillo J.
      • Pinsky M.R.
      Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.
      ]. Recently Johnson et al. compared five retrospective algorithms for a similar database in terms of diagnostic accuracy and mortality. In brief, the method established by Angus et al. shows both average capacities in identifying sepsis and predicting intra-hospital mortality. The agreement between all five criteria was acceptable [
      • Johnson A.E.W.
      • Aboab J.
      • Raffa J.D.
      • Pollard T.J.
      • Deliberato R.O.
      • Celi L.A.
      • Stone D.J.
      A comparative analysis of sepsis identification methods in an electronic database.
      ]. Other algorithms for identifying septic patients could therefore identify slightly different patients. However, even in the subgroup with high lactate we could not detect any gender-specific differences. Therefore, we do not assume that the use of other algorithms to identify sepsis would have detected significantly different results. Further, it was not possible to extract microbiological data from the database. In order to at least partially correct our analysis for this limitation, the infection focus was taken into account in the model (model-2 and model-3). [
      • Leligdowicz A.
      • Dodek P.M.
      • Norena M.
      • Wong H.
      • Kumar A.
      • Kumar A.
      Co-operative antimicrobial therapy of septic shock database research G: association between source of infection and hospital mortality in patients who have septic shock.
      ]. It was, however, not possible to check whether a primary eradication of the infection focus was performed. This study reports only on the acute disease state in terms of SOFA scores, but no information on chronic comorbidities.
      Thus, while there are several relevant limitations to this data set and our results, we believe that the finding that there are no large sex-specific differences in ICU mortality in patients with sepsis is robust due to the large patient population.

      4.2 Conclusion

      In this study no clinically relevant sex-specific mortality differences could be detected in critically ill septic patients. Possible subtle gender differences could play a minor role in the acute situation due to the severity of the disease in septic patients.

      5. Declarations

      5.1 Competing interests

      The authors declare that they have no competing interests.

      5.2 Funding

      No (industry) sponsorship has been received for this investigator-initiated study.

      5.3 Availability of data and materials

      All data relevant for this study will be given by the authors upon specific request. Patients or the public WERE NOT involved in the design, or conduct, or reporting, or dissemination plans of our research

      5.4 Conflicts of interest

      The authors whose names are listed immediately above certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

      6. Financial disclosure statement

      No (industry) sponsorship has been received for this investigator-initiated study.

      Declaration of Competing Interest

      The authors declare that they have no competing interests.

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