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Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients

Primary Purpose

Hyperglycemia Stress

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Dulaglutide
Placebo
Continuous glucose monitor (CGM), blinded
Sponsored by
Emory University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Hyperglycemia Stress focused on measuring Perioperative, Surgery, Stress Hyperglycemia

Eligibility Criteria

45 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria

Inclusion criteria (Aim 1):

  • Men and women between the ages of 45 and 80 years undergoing non-cardiac general or vascular surgery
  • BMI ≥30 kg/m2 without a previously known history of DM

Inclusion criteria (Aim 2):

  • Men and women without known history of diabetes with ages between 45 and 80 years undergoing non-cardiac general or vascular surgery participating in Aim 1.
  • BMI ≥30 kg/m2 and pre-DM or DM by OGTT or HbA1c.

Exclusion Criteria:

Exclusion criteria (Aim 1):

  • Patients prescribed or taking antihyperglycemic medications
  • Patients undergoing cardiac surgery or patients anticipated to require ICU care
  • Patients expected to be admitted less than 48-72 hours after surgery
  • Severely impaired renal function (eGFR < 30 mL/min) or clinically significant hepatic failure
  • Treatment with oral (equivalent to prednisone > 5 mg/day) or injectable corticosteroids
  • Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study; unable to consent
  • Pregnant or breast feeding at time of enrollment
  • Prisoners

Exclusion criteria (Aim 2):

  • Same as in Aim 1, with the following additional exclusion criteria:
  • Patients undergoing gastrointestinal surgery or at high risk for gastrointestinal obstruction/ileus or expected to require gastrointestinal suction
  • Patients with delayed gastric emptying, pancreatic or gallbladder disease
  • Patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN2)

Sites / Locations

  • Emory University HospitalRecruiting
  • Grady HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Continuous Glucose Monitoring

Dulaglutide

Placebo

Arm Description

Aim 1 participants will have a continuous glucose monitor (CGM) placed preoperatively and will wear the CGM throughout hospitalization.

Aim 2 participants randomized to receive dulaglutide within 72 hours prior to a planned surgery.

Aim 2 participants randomized to receive a placebo to match dulaglutide within 72 hours prior to a planned surgery.

Outcomes

Primary Outcome Measures

Incidence of stress hyperglycemia (SH)
Incidence of stress hyperglycemia will be determine in a population at high-risk for perioperative dysglycemia among participants in Aim 1.
Percentage of time in target glucose range (70-140 mg/dL) by CGM
Proportion of time in target glucose range (70-140 mg/dL) by CGM data will be calculated for participants of Aim 2.

Secondary Outcome Measures

Baseline Insulin Secretion
Baseline insulin secretion between patients with and without stress hyperglycemia will be examined among participants in Aim 1.
Baseline Insulin Sensitivity
Baseline insulin sensitivity between patients with and without stress hyperglycemia will be examined among participants in Aim 1.
Mean Onset of Stress Hyperglycemia (Glucose >140 mg/dL)
Mean onset time of stress hyperglycemia by CGM (glucose >140 mg/dL) during the postoperative period will be examined for participants of Aim 1.
Mean Duration of Stress Hyperglycemia (Glucose >140 mg/dL)
The mean duration of stress hyperglycemia by CGM (glucose >140 mg/dL) during the postoperative period will be examined for participants of Aim 1.
Mean Daily Glucose Values
The mean daily glucose values values, as measured by both point-of-care (POC) glucose testing and CGM data, will be examined among participants in Aim 1.
Maximum Daily Glucose Values
The maximum daily glucose values values, as measured by both POC glucose testing and CGM data, will be examined among participants in Aim 1.
Total Daily Insulin Dose
The total daily insulin dose in patients with and without stress hyperglycemia will be examined among participants in Aim 1.
Length of Hospital Stay
The length of hospital stay (in days) in patients with and without stress hyperglycemia will be examined among participants in Aim 1.
Number of ICU Transfers
The number of ICU transfers in patients with and without stress hyperglycemia will be examined among participants in Aim 1.
Number of Hospital Readmissions After Discharge
Number of hospital readmissions after discharge patients with and without stress hyperglycemia (SH) will be examined among participants in Aim 1.
Number of Emergency Room Visits After Discharge
The number of emergency room visits after discharge patients with and without stress hyperglycemia (SH) will be examined among participants in Aim 1.
Number of Participants Experiencing Complications
A composite of complications including wound infection, respiratory failure, pneumonia, acute kidney injury (increase in creatinine by 0.5 mg/dL), and major adverse cardiac events (MACE) will be examined among participants in Aim 1.
Percentage of Time in Hyperglycemia (Glucose>140 mg/dL)
The percentage of time in hyperglycemia with glucose>140 mg/dL will be examined for participants of Aim 2.
Percentage of Time in Hyperglycemia (Glucose>180 mg/dL)
The percentage of time in hyperglycemia with glucose>180 mg/dL will be examined for participants of Aim 2.
Percentage of Time in Hypoglycemia (Glucose <70 mg/dL)
The percentage of time in hypoglycemia with glucose <70 mg/dL will be examined for participants of Aim 2.
Percentage of Time in Hypoglycemia (Glucose <54 mg/dL)
The percentage of time in hypoglycemia with glucose <54 mg/dL will be examined for participants of Aim 2.
Percentage of Time in Hypoglycemia (Glucose <40 mg/dL)
The percentage of time in hypoglycemia with glucose <40 mg/dL will be examined for participants of Aim 2.
Mean Onset of Stress Hyperglycemia During the Postoperative Period
The mean onset time of stress hyperglycemia during the postoperative period by CGM data will be examined for participants of Aim 2.
Mean Duration of Stress Hyperglycemia During the Postoperative Period
The mean duration of stress hyperglycemia during the postoperative period by CGM data will be examined for participants of Aim 2.
Mean Daily Glucose Values (Aim 2)
The mean daily glucose values values, as measured by both POC glucose testing and CGM data, will be examined among participants in Aim 2.
Maximum Daily Glucose Values (Aim 2)
The maximum daily glucose values values, as measured by both POC glucose testing and CGM data, will be examined among participants in Aim 2.
Perioperative Insulin Requirements
Perioperative insulin requirements will be assessed as the total daily insulin dose, among participants from Aim 2.
Change in Plasma Cortisol Level
Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.
Change in Level of Free Fatty Acids (FFA)
Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.
Change in High Sensitivity C-reactive Protein (hsCRP) Level
Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.
Change in Tumor Necrosis Factor-alpha (TNF-α) Level
Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.
Change in Adiponectin Level
Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.
Change in Level of Thiobarbituric Acid Reactive Substances (TBARS)
Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.

Full Information

First Posted
April 23, 2021
Last Updated
April 28, 2023
Sponsor
Emory University
Collaborators
National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT04862234
Brief Title
Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients
Official Title
Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 29, 2021 (Actual)
Primary Completion Date
May 30, 2025 (Anticipated)
Study Completion Date
May 30, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Emory University
Collaborators
National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Hyperglycemia is seen in approximately 30% of patients who do not have a history of diabetes and undergo general surgery. Hyperglycemia in this setting is associated with increased risk of postoperative complications. The purpose of this study is to investigate risk factors for developing high sugars during the time of surgery, and if these high sugars can be prevented by the use of an injectable diabetes medication (dulaglutide) prior to surgery.
Detailed Description
Stress hyperglycemia (SH), defined as a blood glucose >140 mg/dl in hospitalized patients without a prior history of diabetes mellitus (DM) is associated with increased risk of complications and mortality compared to patients with normoglycemia and with known history of DM. Increased counterregulatory hormones (cortisol, glucagon, epinephrine, growth hormone), free fatty acids, inflammation and oxidative stress are likely involved in the pathogenesis of impaired insulin secretion and action leading to stress hyperglycemia. However, no prospective studies have comprehensively examined preoperative glycemic control profiles and their association with the incidence, clinical predictors and underlying mechanisms of SH in general surgical patients. Accordingly, the researchers propose a prospective study investigating clinical, metabolic and inflammatory/oxidative stress biomarker profiles leading to SH. This study will use continuous glucose monitoring (CGM) technology to fully characterize the onset, duration and severity of SH during the perioperative period. Given the association between stress hyperglycemia and poor hospital outcomes, this study aims to determine if the prevention of stress hyperglycemia is feasible with the single administration of a weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA), a common medication used to treat patients with established diabetes. In addition, the researchers will explore the role of beta-cell function, insulin resistance, and inflammation on the pathogenesis of stress hyperglycemia. The goals of this study are to: 1) conduct an extensive analysis of preoperative glycemic control and its relationship to clinical, metabolic and biomarker profiles of SH in a high-risk population, and 2) conduct a pilot randomized controlled trial to prospectively determine if single dose use of dulaglutide can improve perioperative glycemic control compared to insulin administration (standard-of-care). Patients qualifying for the study will be approached at their preoperative clinic visit and invited to participate in the prospective observational study arm (Aim 1), and in the interventional trial for prevention of SH with dulaglutide (Aim 2) if they meet inclusion criteria based on oral glucose tolerance testing (OGTT) or lab testing performed for Aim 1. Within 72 hours prior to planned surgery, consented patients will present to the clinical research center (CRC) to undergo evaluation with OGTT and lab testing with CGM placement. Those patients with OGTT or lab results consistent with a diagnosis of prediabetes or newly diagnosed diabetes will be asked if they would like to participate in Aim 2. Patients consenting to participate in Aim 2 will be randomized to receive a subcutaneous injection of dulaglutide 0.75 mg or placebo during the CRC visit, and glycemic control parameters will be followed postoperatively during surgical admission (up to 14 days). In addition to the above, baseline and postoperative levels of serum inflammatory and oxidative stress markers will be obtained to provide further information regarding beta-cell function and insulin resistance in relation to the development of stress hyperglycemia.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hyperglycemia Stress
Keywords
Perioperative, Surgery, Stress Hyperglycemia

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Participants with normoglycemia will be in Aim 1. Participants with lab results indicative of pre-DM or DM will be randomized to Aim 1 or Aim 2, and those in Aim 2 will be further randomized to receive dulaglutide or placebo.
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
245 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Continuous Glucose Monitoring
Arm Type
Experimental
Arm Description
Aim 1 participants will have a continuous glucose monitor (CGM) placed preoperatively and will wear the CGM throughout hospitalization.
Arm Title
Dulaglutide
Arm Type
Experimental
Arm Description
Aim 2 participants randomized to receive dulaglutide within 72 hours prior to a planned surgery.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Aim 2 participants randomized to receive a placebo to match dulaglutide within 72 hours prior to a planned surgery.
Intervention Type
Drug
Intervention Name(s)
Dulaglutide
Other Intervention Name(s)
Trulicity
Intervention Description
A subcutaneous injection of dulaglutide 0.75 mg will be administered within 72 hours prior to a planned surgical intervention.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
A subcutaneous injection of a saline placebo will be administered within 72 hours prior to a planned surgical intervention.
Intervention Type
Device
Intervention Name(s)
Continuous glucose monitor (CGM), blinded
Other Intervention Name(s)
FreeStyle Libre Pro
Intervention Description
Continuous glucose monitor (CGM) sensor will be placed preoperatively and continued during surgical hospitalization to monitor glucose levels. CGM provides an estimated capillary blood glucose (BG) level through direct measurement of interstitial glucose levels every 5-15 minutes.
Primary Outcome Measure Information:
Title
Incidence of stress hyperglycemia (SH)
Description
Incidence of stress hyperglycemia will be determine in a population at high-risk for perioperative dysglycemia among participants in Aim 1.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Percentage of time in target glucose range (70-140 mg/dL) by CGM
Description
Proportion of time in target glucose range (70-140 mg/dL) by CGM data will be calculated for participants of Aim 2.
Time Frame
Up to 14 days (depending on length of hospitalization)
Secondary Outcome Measure Information:
Title
Baseline Insulin Secretion
Description
Baseline insulin secretion between patients with and without stress hyperglycemia will be examined among participants in Aim 1.
Time Frame
Baseline
Title
Baseline Insulin Sensitivity
Description
Baseline insulin sensitivity between patients with and without stress hyperglycemia will be examined among participants in Aim 1.
Time Frame
Baseline
Title
Mean Onset of Stress Hyperglycemia (Glucose >140 mg/dL)
Description
Mean onset time of stress hyperglycemia by CGM (glucose >140 mg/dL) during the postoperative period will be examined for participants of Aim 1.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Mean Duration of Stress Hyperglycemia (Glucose >140 mg/dL)
Description
The mean duration of stress hyperglycemia by CGM (glucose >140 mg/dL) during the postoperative period will be examined for participants of Aim 1.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Mean Daily Glucose Values
Description
The mean daily glucose values values, as measured by both point-of-care (POC) glucose testing and CGM data, will be examined among participants in Aim 1.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Maximum Daily Glucose Values
Description
The maximum daily glucose values values, as measured by both POC glucose testing and CGM data, will be examined among participants in Aim 1.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Total Daily Insulin Dose
Description
The total daily insulin dose in patients with and without stress hyperglycemia will be examined among participants in Aim 1.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Length of Hospital Stay
Description
The length of hospital stay (in days) in patients with and without stress hyperglycemia will be examined among participants in Aim 1.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Number of ICU Transfers
Description
The number of ICU transfers in patients with and without stress hyperglycemia will be examined among participants in Aim 1.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Number of Hospital Readmissions After Discharge
Description
Number of hospital readmissions after discharge patients with and without stress hyperglycemia (SH) will be examined among participants in Aim 1.
Time Frame
Up to 3 months after discharge
Title
Number of Emergency Room Visits After Discharge
Description
The number of emergency room visits after discharge patients with and without stress hyperglycemia (SH) will be examined among participants in Aim 1.
Time Frame
Up to 3 months after discharge
Title
Number of Participants Experiencing Complications
Description
A composite of complications including wound infection, respiratory failure, pneumonia, acute kidney injury (increase in creatinine by 0.5 mg/dL), and major adverse cardiac events (MACE) will be examined among participants in Aim 1.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Percentage of Time in Hyperglycemia (Glucose>140 mg/dL)
Description
The percentage of time in hyperglycemia with glucose>140 mg/dL will be examined for participants of Aim 2.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Percentage of Time in Hyperglycemia (Glucose>180 mg/dL)
Description
The percentage of time in hyperglycemia with glucose>180 mg/dL will be examined for participants of Aim 2.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Percentage of Time in Hypoglycemia (Glucose <70 mg/dL)
Description
The percentage of time in hypoglycemia with glucose <70 mg/dL will be examined for participants of Aim 2.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Percentage of Time in Hypoglycemia (Glucose <54 mg/dL)
Description
The percentage of time in hypoglycemia with glucose <54 mg/dL will be examined for participants of Aim 2.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Percentage of Time in Hypoglycemia (Glucose <40 mg/dL)
Description
The percentage of time in hypoglycemia with glucose <40 mg/dL will be examined for participants of Aim 2.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Mean Onset of Stress Hyperglycemia During the Postoperative Period
Description
The mean onset time of stress hyperglycemia during the postoperative period by CGM data will be examined for participants of Aim 2.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Mean Duration of Stress Hyperglycemia During the Postoperative Period
Description
The mean duration of stress hyperglycemia during the postoperative period by CGM data will be examined for participants of Aim 2.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Mean Daily Glucose Values (Aim 2)
Description
The mean daily glucose values values, as measured by both POC glucose testing and CGM data, will be examined among participants in Aim 2.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Maximum Daily Glucose Values (Aim 2)
Description
The maximum daily glucose values values, as measured by both POC glucose testing and CGM data, will be examined among participants in Aim 2.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Perioperative Insulin Requirements
Description
Perioperative insulin requirements will be assessed as the total daily insulin dose, among participants from Aim 2.
Time Frame
Up to 14 days (depending on length of hospitalization)
Title
Change in Plasma Cortisol Level
Description
Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.
Time Frame
Baseline, 48 to 72 hours postoperatively
Title
Change in Level of Free Fatty Acids (FFA)
Description
Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.
Time Frame
Baseline, 48 to 72 hours postoperatively
Title
Change in High Sensitivity C-reactive Protein (hsCRP) Level
Description
Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.
Time Frame
Baseline, 48 to 72 hours postoperatively
Title
Change in Tumor Necrosis Factor-alpha (TNF-α) Level
Description
Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.
Time Frame
Baseline, 48 to 72 hours postoperatively
Title
Change in Adiponectin Level
Description
Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.
Time Frame
Baseline, 48 to 72 hours postoperatively
Title
Change in Level of Thiobarbituric Acid Reactive Substances (TBARS)
Description
Samples will be collected prior to surgery and 48 to 72 hours after surgery to assess inflammatory and oxidative stress biomarkers.
Time Frame
Baseline, 48 to 72 hours postoperatively

10. Eligibility

Sex
All
Minimum Age & Unit of Time
45 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria (Aim 1): Men and women between the ages of 45 and 80 years undergoing non-cardiac general or vascular surgery BMI ≥30 kg/m^2 without a previously known history of DM Inclusion criteria (Aim 2): Men and women without known history of diabetes with ages between 45 and 80 years undergoing non-cardiac general or vascular surgery participating in Aim 1. BMI ≥30 kg/m2 and pre-DM or DM by OGTT or HbA1c. Exclusion criteria (Aim 1): Patients prescribed or taking antihyperglycemic medications Patients undergoing cardiac surgery or patients anticipated to require ICU care Patients expected to be admitted less than 48-72 hours after surgery Severely impaired renal function (eGFR < 30 mL/min) or clinically significant hepatic failure Treatment with oral (equivalent to prednisone > 5 mg/day) or injectable corticosteroids Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study; unable to consent Pregnant or breast feeding at time of enrollment Prisoners Exclusion criteria (Aim 2): Same as in Aim 1, with the following additional exclusion criteria: Patients undergoing gastrointestinal surgery or at high risk for gastrointestinal obstruction/ileus or expected to require gastrointestinal suction Patients with delayed gastric emptying, pancreatic or gallbladder disease Patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN2)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Georgia Davis, MD
Phone
404-251-8957
Email
georgia.marie.davis@emory.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Georgia Davis, MD
Organizational Affiliation
Emory University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Emory University Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Georgia Davis, MD
Phone
404-251-8957
Email
georgia.marie.davis@emory.edu
Facility Name
Grady Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Georgia Davis, MD
Phone
404-251-8957
Email
georgia.marie.davis@emory.edu

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant data that underlie the results reported in the publication for this study (including text, tables, figures, and appendices) will be available to other researchers, after deidentification.
IPD Sharing Time Frame
Data will be made available for sharing beginning 3 months and ending 5 years following article publication.
IPD Sharing Access Criteria
Data will be made available for sharing with researchers who provide a methodologically sound proposal, in order to achieve aims in the approved proposal. Proposals should be directed to gmdavis@emory.edu. To gain access, data requestors will need to sign a data access/use agreement.

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Perioperative Stress Hyperglycemia in General and Vascular Surgery Patients

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