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Trajectory of Mortality and Health-Related Quality of Life Morbidity Following Community-Acquired Pediatric Septic Shock*

Zimmerman, Jerry J. MD, PhD1; Banks, Russell MS2; Berg, Robert A. MD3; Zuppa, Athena MD3; Newth, Christopher J. MD4; Wessel, David MD5; Pollack, Murray M. MD5; Meert, Kathleen L. MD6; Hall, Mark W. MD7; Quasney, Michael MD, PhD8; Sapru, Anil MD9; Carcillo, Joseph A. MD10; McQuillen, Patrick S. MD11; Mourani, Peter M. MD12; Wong, Hector MD13; Chima, Ranjit S. MD13; Holubkov, Richard PhD2; Coleman, Whitney MRA, BSN2; Sorenson, Samuel BS2; Varni, James W. PhD14; McGalliard, Julie BA1; Haaland, Wren MPH1; Whitlock, Kathryn MPH1; Dean, J. Michael MD2; Reeder, Ron W. PhD2; for the Life After Pediatric Sepsis Evaluation (LAPSE) Investigators

Author Information
doi: 10.1097/CCM.0000000000004123

Abstract

Sepsis remains a major cause of childhood mortality worldwide (1,2). In developed nations, the mortality risk associated with pediatric septic shock has decreased from 50% to 60% in the 1950–1960s to 5–10% currently (3–5). Although this statistic represents a paramount achievement for pediatric critical care medicine, it ignores the increasing morbidity burden of children surviving sepsis (6). With recognition that critical illness begins and ends outside of the ICU and hospital (7), clinicians and researchers alike are increasingly interested in long-term, patient-centered, clinically meaningful outcomes for critically ill patients. Previous investigations have reported increased risk for chronic disability, hospital readmission, and late mortality for children surviving sepsis, but these studies were frequently limited by small sample size, lack of baseline status quantification, and/or variable time intervals for follow-up evaluation(s) (8–13).

Accordingly, Specific Aim 1 of the Life After Pediatric Sepsis Evaluation (LAPSE) (R01HD073362) prospective, cohort-outcome investigation was conducted to characterize critically ill children with contemporary, community-acquired septic shock and to describe the trajectory of mortality and health-related quality of life (HRQL) morbidity among those who survived. LAPSE investigators hypothesized that critically ill children with septic shock would demonstrate long-term mortality and significant HRQL morbidity during the year following admission for the sepsis event. A companion article examines critical illness variables associated with long-term death or persistent, serious HRQL disability among children initially surviving septic shock (14).

MATERIALS AND METHODS

Performance Sites, Study Conduct, Study Participants, Definitions

Twelve U.S. academic PICU research teams (eFig. 1, Supplemental Digital Content 1, http://links.lww.com/CCM/F145) enrolled critically ill children with septic shock into the investigation. Details of performance sites, principal investigators, co-principal investigators, research coordinators, and allied research personnel are summarized in the acknowledgment section. Research coordinators continuously screened PICU admissions for potential study participants. Complete inclusion and exclusion criteria are provided in eText 1 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145). Responsible attending physicians directed hemodynamic resuscitation, antimicrobial administration, mechanical ventilation, renal replacement therapy, extracorporeal life support, blood product transfusion, and nutritional management that were not mandated by the study protocol. Institutional review boards approved the study for each performance site, and parents provided written permission prior to patient participation. Developmentally appropriate patients were requested to provide assent for their own continued study participation following PICU discharge.

All patient participants exhibited septic shock that was operationally defined as documented or suspected infection with onset within 48 hours of hospital admission; and presence of greater than or equal to 2 systemic inflammatory response syndrome criteria (15), including abnormal leukocyte count/differential and/or abnormal body temperature; and requirement for fluid resuscitation and vasoactive-inotropic support that was initiated within 72 hours of hospital admission and within 48 hours of PICU admission. At enrollment, research coordinators collected data related to demographics, infectious disease, chronic comorbid conditions (16) (eText 2, Supplemental Digital Content 1, http://links.lww.com/CCM/F145), and immunodeficiency (eText 3, Supplemental Digital Content 1, http://links.lww.com/CCM/F145). Patients were assessed for initial illness severity using Pediatric Risk of Mortality (PRISM)–IV (17) and Pediatric Logistic Organ Dysfunction (PELOD)–2 score around PICU admission (18). Durations of vasoactive-inotropic support, mechanical ventilation, and PICU and hospital stay were recorded.

Patients were serially assessed by research staff for functional status utilizing Pediatric Cerebral Performance Category (PCPC) and Pediatric Overall Performance Category (POPC) (19) and the Functional Status Scale (FSS) (20) at study entry (reflecting baseline pre-sepsis status during the month prior to PICU admission), study day 7, and study day 28 or hospital discharge, whichever occurred first. Similarly, participating families completed serial parent-proxy assessments of their child’s HRQL utilizing the Pediatric Quality of Life Inventory (PedsQL), 4.0 Generic Core Scales (21,22) or PedsQL Infant Scales (23) or the Stein-Jessop Functional Status Scale (short form, 14 item, double element, FSII-R) (24). Parents selected the HRQL instrument that they believed provided the most meaningful assessment for their child. HRQL was assessed at study entry (reflecting baseline pre-sepsis status), study day 7 and 1, 3, 6, and 12 months following PICU admission for the septic shock event. Both surveys employ a 0–100 point scale. For consistency, magnitude of HRQL morbidity is reported in multiples 4.5 points, a minimal clinically important difference (MCID) established for PedsQL (21), but not FSII-R. Detailed methodology for serial assessments of functional status and HRQL is provided in eText 4 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145).

Data Collection, Organization, and Analysis

Clinical data related to PICU admission were entered into an electronic data capture system provided by the data coordinating center at the University of Utah (OpenClinica, LLC, Waltham, MA). Data managers monitored data quality throughout the study. Parent-proxy HRQL assessments were entered into a separate database managed by the Seattle Children’s Research Institute (DatStat, Seattle, WA).

Interval or continuous variables are reported as medians and interquartile ranges, while variables collected categorically are summarized with counts and percentages. Sample size calculations for this investigation are detailed in eText 5 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145). Bar graphs provide longitudinal summaries for PedsQL and FSII-R, as well as PCPC/POPC and FSS at each study time point for which data were collected. Differences in long-term outcomes, focused on change from baseline status, were measured using standard statistical tests such as the Wilcoxon rank-sum test, Fisher exact test, and the Cochran-Armitage test for trend. To account for potential bias due to loss of follow-up, longitudinal HRQL data were also analyzed utilizing multiple imputation techniques as discussed in eText 6 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145).

Analyses were performed using SAS 9.4 (SAS Institute, Cary, NC) and R Version 3.4.4 (The R Foundation for Statistical Computing, Vienna, Austria). p values are based on a two-sided alternative with p values of less than 0.05 considered significant. Results are reported according to STrengthening the Reporting of OBservational studies in Epidemiology Guidelines for cohort studies (25).

RESULTS

The study flow diagram, Figure 1, and eTable 1 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) summarize exclusions and the number of patients with complete change from baseline survey information available for each study time point. From January 1, 2014, to June 30, 2017, 838 patients were screened, 632 were eligible, 570 (90%) were approached, 392 (62% of those eligible) were enrolled, and 389 provided complete baseline clinical data. Cumulative study enrollment and hospital survival are summarized graphically in eFigure 2 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145). Of the enrolled patients with complete baseline data, 35 of 389 died (9%) during hospitalization and an additional 16 of 389 subjects died (4%) during the 1-year follow-up.

Figure 1.
Figure 1.:
Life After Pediatric Sepsis Evaluation (LAPSE) flow diagram. FSII-R = Functional Status II-Revised, HRQL = health-related quality of life, PedsQL = Pediatric Quality of Life Inventory.

Patient Characteristics

Table 1 summarizes demographics, illness severity, and resource utilization for the study cohort. Separate summaries are provided for all patients and for those completing a baseline HRQL survey, as only the latter group (n = 358) was used for subsequent change from baseline analyses. With broad overall age distribution, proportion of male patients exceeded females by 4%. Children with chronic conditions comprised 51% of the cohort; 18% were immunocompromised. Durations of vasoactive-inotropic infusion and mechanical ventilation support (median [Q1–Q3]) were 3.0 days (2.0–6.0 d) and 8.0 days (5.0–14.0 d); and durations of PICU and hospital stay were 9.4 days (5.6–15.4 d) and 15.7 days (9.2–26.0 d). Additional data indicated that patients’ health insurance status (n = 351) was primarily private insurance (44%) or Medicaid (55%). Prior to hospitalization, 95% of patients resided at their home. At month 1 follow-up, 146 of 235 patients (62%) were residing at home, while 88 of 235 (37%) remained hospitalized. Among all enrolled patients, 89 of 389 (23%) were hospitalized for more than 28 days. Cohort infection characteristics are summarized in eTables 2 and 3 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145). Bacterial infection, viral infection, combined bacterial and viral infection, and no infection were documented in 49%, 45%, 20%, and 32% among all enrolled patients, respectively.

TABLE 1.
TABLE 1.:
Study Cohort Demographics, Initial Illness Severity, Resource Utilization

Functional Status Changes

Figure 2 and eTable 4 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) summarize graphically and numerically changes in PCPC and POPC scores over time. At baseline, only 38% of patients exhibited normal POPC. Median Baseline POPC score was 2.0 (1.0–3.0), while median change in POPC was 0.0 (0.0–1.0) comparing baseline and day 28/hospital discharge. Assuming normality, a mean change in POPC of 0.6 was observed with 95% CI (0.5–0.7) indicating a significant deterioration in functional status (p < 0.001). At day 28/hospital discharge, 85 of 384 children (22%) exhibited poor gross functional status (POPC ≥ 3 and an increase of ≥ 1 from baseline).

Figure 2.
Figure 2.:
Distributions of Pediatric Cerebral Performance Category (PCPC) and Pediatric Overall Performance Category (POPC) scores over time. Baseline = status in the month preceding PICU admission for the sepsis event, discharge = assessment at day 28 or hospital discharge, which ever occurred first.

Figure 3 and eTable 5 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) summarize graphically and numerically changes in FSS scores over time. Baseline FSS (n = 389) was 6.0 (6.0–12.0), with normal FSS status recorded (% of patients) for the following dimensions: communication (65.3%), feeding (64.5%), mental status (74.3%), motor function (63.8%), respiratory status (78.7%), and sensory function (79.7%). At day 28/hospital discharge (n = 359), total FSS increased to 9.0 (6.0–15.0) (p < 0.001), again documenting a significant deterioration of functional status. eTable 5 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) summarizes itemized data for all FSS dimensions and substantiates a deterioration in communication, feeding, mental status, motor function, respiratory and sensory function, during hospitalization for pediatric septic shock.

Figure 3.
Figure 3.:
Distribution of Functional Status Scale categories over time. Baseline = status in the month preceding PICU admission for the sepsis event, discharge = assessment at day 28 or hospital discharge, which ever occurred first.

Health-Related Quality of Life Changes

Less than 10% of subjects provided assent for self-report of HRQL. Accordingly, parent proxy-report is described for all HRQL data. Most families, 227 of 364 (62%), selected the PedsQL instruments for HRQL assessments. Baseline and month 1 absolute PedsQL scores were 78.3 (65.9–92.4) (n = 222) and 64.7 (47.8–81.9) (n = 142), respectively. Median change for PedsQL, comparing Baseline and month 1, was –11.0 (–29.2 to 5.55) (p < 0.001), reflecting a significant deterioration in HRQL. Assuming normality, an estimated mean change of –12.2 with 95% CI (–16.3 to –8.08) was observed. This CI reflects at least a MCID deterioration in PedsQL at month 1.

Figure 4A and eTable 6 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) display graphical and numerical percentages of patients failing to return to their baseline PedsQL over the 1-year follow-up, utilizing multiples of 4.5 points, the MCID for this HRQL instrument. Additional plots of PedsQL longitudinal data are presented in eFigure 3 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145). At 1, 3, 6, and 12 month assessments, 56%, 41%, 32%, and 38% of patients assessed with PedsQL remained at least 4.5 points (1 × MCID) below their baseline HRQL, while 40%, 16%, 15%, and 17% remained at least 18.0 points (4 × MCID) below their baseline HRQL.

Figure 4.
Figure 4.:
Longitudinal assessment of failure to return to baseline health-related quality of life (HRQL) utilizing the Pediatric Quality of Life Inventory (A) and Functional Status II-Revised (FSII-R) (B) instruments. Magnitude of HRQL deterioration is depicted in multiples of 4.5 points, namely 4.5, 9.0, 13.5, and 18.0 points.

Some families, 137 of 364 (38%), selected the FSII-R instrument because they considered it more meaningful and relevant to their children, who typically manifested significant developmental delay. Baseline and month 1 absolute FSII-R scores were 71.4 (60.7–83.4) (n = 136) and 73.1 (60.7–82.1) (n = 93), respectively. Median change for FSII-R, comparing baseline and month 1, was 0.0 (–10.7 to 10.7) (p = 0.93). Assuming normality, an estimated mean change of –1.1 with 95% CI (–5.3 to 3.0) was observed. Figure 4B and eTable 7 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) display graphical and numerical percentages of patients failing to return to their baseline FSII-R over the 1-year follow-up, again utilizing multiples of 4.5 points for this HRQL instrument. Additional plots of FSII-R longitudinal data are presented in eFigure 4 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145). At 1, 3, 6, and 12 month assessments, 39%, 32%, 27%, and 31% of patients assessed with FSII-R remained at least 4.5 points below their baseline HRQL, while 14%, 14%, 9%, and 19% remained at least 18.0 points below their baseline HRQL.

In total, at 1, 3, 6, and 12 months following PICU admission for the septic shock event, 8%, 11%, 12%, and 13% of patients had died, and among survivors with adequate change from baseline data, 50%, 37%, 30%, and 35% of surviving patients had not regained their baseline HRQL. Patients assessed with the FSII-R instrument, as a whole, seemed to demonstrate less deterioration from and faster recovery to baseline HRQL. Patients assessed with either HRQL instrument appeared to exhibit a plateau in HRQL recovery, months 3–12 (Fig. 4).

Patients Lost to Follow-Up

Inspection of Figure 1 and eTable 1 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) reveals significant loss to follow-up for the study cohort, despite parental incentives for continued participation. eTable 8 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) documents that patients who were lost to follow-up at the month 3 assessment exhibited similar initial illness severity as per initial PRISM-IV and PELOD-2 scores, as well as duration of vasoactive-inotropic and mechanical ventilation support and PICU and hospital stay, as compared with patients who completed the month 3 survey. However, patients lost to follow-up accrued higher summation of daily PELOD-2 scores and more frequently required renal replacement therapy and extracorporeal life support. Data analysis employing multiple imputation techniques, to account for patients lost to follow-up, suggests an even greater burden of long-term HRQL morbidity among children surviving septic shock (eFigs. 5 and 6, Supplemental Digital Content 1, http://links.lww.com/CCM/F145). Specifically, imputation tended to predict lower values for missing HRQL measures, consistent with the notion that patients without completed surveys had at least some measures of higher illness severity, and higher illness severity was associated with higher risk for adverse HRQL outcomes.

DISCUSSION

This investigation reports several significant, novel findings: First, in-hospital and 1-year mortality from community-acquired septic shock were 9% and 13%, but among the survivors, 35% had not yet regained their baseline HRQL 1 year later. Second, for the cohort as a whole, HRQL improved between 1 and 3 months, but further improvement was not apparent over the ensuing 9 months. Accordingly, a 3-month follow-up may represent a pivotal checkpoint relative to monitoring and intervening for post-intensive care syndrome among children surviving septic shock (26,27). Third, 51% of the patients enrolled demonstrated significant chronic comorbid conditions as assessed by the Pediatric Medical Complexity Algorithm, with impaired baseline functional status per POPC and FSS, even though such children comprise only 3% of the overall pediatric population (28). This preponderance of critically ill children with chronic conditions is consistent with national PICU data (29). Although the median baseline score for patients assessed with PedsQL was similar to published norms (30) for generally healthy children, the median baseline score for patients assessed with FSII-R was significantly lower than normative data for chronically ill children (24). These observations confirm that children with chronic conditions bear a disproportionate burden of critical illness, including sepsis. Fourth, patients assessed with FSII-R unexpectedly exhibited less decline from and seemingly faster resolution toward baseline HRQL compared with patients assessed with PedsQL. This finding may relate to differential views of what constitutes HRQL and HRQL recovery among parents of children with severe developmental disability (30). Alternatively, this finding may reflect greater sensitivity to change for the PedsQL instrument. Fifth, fortunately, the majority of children recovered to or exceeded their baseline HRQL 1 year following septic shock. Improved HRQL following acute illness has been previously reported (13) and may relate to actual improvement in HRQL status (e.g., successful chemotherapy, organ transplantation, curative surgery), potential parental recall bias of lower HRQL at baseline, or the acute illness as a life-transforming event (13).

Collectively, this study demonstrates substantial HRQL morbidity among many critically ill children surviving septic shock. Previous investigations have reported increased risk for chronic disability, hospital readmission, and late mortality for children surviving sepsis, but these studies, largely retrospective in design, were variably limited by small sample size, lack of baseline HRQL ascertainment, and/or variable time intervals for follow-up evaluation(s) (8–13). The LAPSE investigation enrolled a moderate-sized, prospectively derived cohort, from 12 tertiary PICUs across the United States. Accordingly, the results are likely to be generalizable among pediatric academic centers, but perhaps not for community hospital PICUs. Children enrolled into LAPSE were assessed for chronic, comorbid conditions (16), and underwent baseline functional status and HRQL evaluations. Establishing a baseline for subsequent HRQL comparisons is feasible and provides the best approach for differentiating the effects of chronic conditions versus acute illness on long-term HRQL morbidity.

This study has several limitations. First, subjects lost to follow-up was problematic, especially because these events were likely not random. Although HRQL and functional status are clearly important outcome measures (31), results from this study highlight the logistical challenges when such outcomes are used for long-term endpoints. A variety of strategies (http://www.improveLTO.com/cohort-retention-tools/) have been suggested and evaluated (32) to maximize subject research participation retention including financial incentives for participants that were employed in the current investigation. Second, this investigation focused on community-acquired pediatric sepsis. It is likely that patients with hospital-acquired sepsis demonstrate a greater burden of acute and chronic comorbidities that may impact short- and long-term outcomes. Third, some would argue that HRQL or functional status should be based on patient-reported data (33,34) (https://www.fda.gov/downloads/drugs/guidances/ucm193282.pdf) utilizing a single instrument. However, the practicality of patient-reported data for critically ill children is limited, as they are frequently very young, routinely sedated, and often developmentally delayed. Furthermore, as the consumers of pediatric healthcare, families are uniquely positioned to provide their perspectives of pediatric HRQL (35). In addition to PedsQL, LAPSE investigators used FSII-R as a measure of HRQL. Although the name FSII-R suggests this instrument is primarily a functional status measure, in fact, it is generally regarded as a validated measure of general health status for children of all ages (36,37), and some parents preferred this tool to describe their child’s situation. Accordingly, in order to maintain involvement of families with children with severe developmental disability and record meaningful parent-proxy information, we offered use of either tool. Ultimately, this decision was likely a strength of the investigation in terms of inclusion and diversity in enrollment and continued study engagement. Trajectories of failure to recover HRQL following pediatric septic shock, presented separately for the two instruments in Figure 4A and B, and eFigures 5 and 6 (Supplemental Digital Content 1,http://links.lww.com/CCM/F145) appear remarkably similar. Fourth, recall bias, as was used to establish baseline HRQL for this investigation, is a limitation inherent in any retrospective evaluation. However, parents were informed of the importance of accuracy for this baseline assessment, at a time when they were not overtly stressed, typically following resuscitation and stabilization of their child.

CONCLUSIONS

This investigation provides the first longitudinal description of long-term mortality and clinically relevant, enduring HRQL morbidity among children encountering community-acquired septic shock. Pediatric septic shock is not only life threatening in terms of ongoing risk for mortality, but also life-altering among children surviving their septic shock. All-cause 28-day mortality alone no longer articulates the entire story of pediatric septic shock outcomes. In addition to ensuring survival from septic shock, optimizing a child’s long-term HRQL is an equally important goal for pediatric septic shock critical care.

ACKNOWLEDGMENTS

The Life After Pediatric Sepsis Evaluation (LAPSE) Investigators thank all subjects and families for participating in the LAPSE investigation. The following is a summary of LAPSE Performance Sites, Principal Investigators (PI), Co-investigators (CI), Research Coordinators (RC), and Allied Research Personnel: Children’s Hospital of Michigan, Detroit, MI: Kathleen L. Meert, PI; Sabrina Heidemann, CI; Ann Pawluszka, RC; Melanie Lulic, RC. Children’s Hospital of Philadelphia, Philadelphia, PA: Robert A Berg, PI; Athena Zuppa, CI; Carolann Twelves, RC; Mary Ann DiLiberto, RC. Children’s National Medical Center, Washington, DC: Murray Pollack, PI; David Wessel, PI; John Berger, CI; Elyse Tomanio, RC; Diane Hession, RC; Ashley Wolfe, RC. Children’s Hospital of Colorado, Denver, CO: Peter Mourani, PI; Todd Carpenter, CI; Diane Ladell, RC; Yamila Sierra, RC; Alle Rutebemberwa, RC. Nationwide Children’s Hospital, Columbus, OH: Mark Hall, PI; Andy Yates, CI; Lisa Steele, RC; Maggie Flowers, RC; Josey Hensley, RC. Mattel Children’s Hospital, University of California Los Angeles, Los Angeles, CA: Anil Sapru, PI; Rick Harrison, CI, Neda Ashtari, RC; Anna Ratiu, RC. Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA: Joe Carcillo, PI; Michael Bell, CI; Leighann Koch, RC; Alan Abraham, RC. Benioff Children’s Hospital, University of California, San Francisco, San Francisco, CA: Patrick McQuillen, PI; Anne McKenzie, RC; Yensy Zetino, RC. Children’s Hospital of Los Angeles, Los Angeles, CA: Christopher Newth, PI; Jeni Kwok, RC; Amy Yamakawa, RC. CS Mott Children’s Hospital, University of Michigan, Ann Arbor, MI: Michael Quasney, PI; Thomas Shanley, CI; CJ Jayachandran, RC. Cincinnati Children’s Hospital, Cincinnati, OH: Ranjit Chima, PI; Hector Wong, CI; Kelli Krallman, RC; Erin Stoneman, RC; Laura Benken, RC; Toni Yunger, RC. St Louis Children’s Hospital, Washington University, St Louis, MO: Alan Doctor, PI; Micki Eaton, RC. Seattle Children’s Hospital, Seattle Children’s Research Institute (LAPSE Follow-up Center), University of Washington, Seattle, WA: Jerry J. Zimmerman, PI; Catherine Chen, RC; Erin Sullivan, RC; Courtney Merritt, RC; Deana Rich, RC; Julie McGalliard; Wren Haaland; Kathryn Whitlock; Derek Salud. University of Utah (LAPSE Data Coordinating Center), Salt Lake City, UT: J. Michael Dean, PI; Richard Holubkov, CI; Whit Coleman, RC; Samuel Sorenson, RC; Ron Reeder; Russell Banks; Angie Webster; Jeri Burr; Stephanie Bisping; Teresa Liu; Emily Stock; Kristi Flick. Texas A&M University, College Station, TX: James Varni.

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Keywords:

children; functional status; health-related quality of life; long-term outcomes; mortality; septic shock

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