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Why We Should Avoid Transfusions

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1 Why We Should Avoid Transfusions
Economics and Quality Care: The Case for Patient Blood Management Irwin Gross, M.D., Medical Director Transfusion Services, Eastern Maine Medical Center Why We Should Avoid Transfusions

2 Disclosures Medical Advisory Board – Strategic Healthcare Group

3 A little about Eastern Maine Medical Center
370 bed community and tertiary care hospital in rural Maine Large hospitalist service High risk obstetrics Trauma center, Level 2 Dialysis center Family Practice residency Cardiac surgery program Approx. 450 cases/yr. Active heme/onc service 10 oncologists No transplant surgery

4 Patient Blood Management (PBM)
The timely application of evidence-based medical and surgical concepts designed to maintain hemoglobin concentration, optimize hemostasis and minimize blood loss in an effort to improve patient outcome.

5 Optimize erythro-poieis Harness & optimize physiologic
What is Patient Blood Management: The Three Pillars 1st Pillar 2nd Pillar 3rd Pillar Optimize erythro-poieis Minimize bleeding & blood loss Harness & optimize physiologic tolerance of anemia © Axel Hofmann/Shannon Farmer – SHEF Meeting Perth August 2010

6 Can Patient Blood Management Reduce the Need for Transfusions?

7 Red Cell Units Transfused FY 1994 – FY 2010
9470

8 Patients Transfused: FY 1994 - 2011

9 Transfusion Rates All Cases: CABG, Valve, CABG/Valve
April 2008 – March 2011 Transfusion rate in 2006: 48% 23% 14%

10 Cardiac Surgery and Transfusions
With reduction in transfusion rate from 48% to approximately 20% , there was a reduction in: Perioperative AMI New onset renal failure Perioperative infection Stroke Length of stay No change in mortality

11 Transfusion Rate: Orthopedics

12 Blood Transfusion: A Growth Industry
Copyrights 2006 – 2011 Strategic Healthcare Group LLC. All Rights Reserved

13 Our Demographic Challenge
Rapidly increasing percentage of population over the age of 65 and decreasing percentage of population between 17 and 65 Decrease in eligible donors Increase in population that are transfusion recipients Demand may exceed supply in the near future

14 Transfusion is expensive!

15 per unit in the EMHS System
Between $832 and $1284 per unit in the EMHS System

16 Blood and Blood Components: Cost Savings – All Components (EMMC)
Total blood acquisition costs in FY ‘06 were $3,200,000 Cost savings compared to base year, FY ’06* FY ’07 $ ,000 FY ’08 $ 1,400,000 FY ’09 $ 1,600,000 FY ’10 $ 1,550,000 Total (Acquisition) $ 5,400,000 Total (ABC) $ 17,280,000 ** * No change in per unit cost from blood supplier from 2007 – 2010 * Using ABC 3.2 times acquisition cost

17 The Macroeconomic Burden of Transfusion
Retrospective cohort study by American College of Medical Quality Evaluated all 38.7 million hospitalizations in U.S. in 2004 Adjusted for age, gender, comorbidities, admission type and DRG Charges per transfused patient were $17,194 more than charges for non-transfused, matched patient Total excess financial burden: $40 billion Am J Med Qual 2010;25:

18 Is Blood Utilization in the U.S. Optimal?
Copyright 2006 – 2011 Strategic Healthcare Group LLC. All Rights Reserved

19 Observed Variation in Hospital-Specific Transfusion Rates for Primary Isolated CABG Surgery With Cardiopulmonary Bypass During 2008 (N = 798 Sites)‏ Bennett-Guerrero, E. et al. JAMA 2010;304:

20 Are Transfusions Safe: Risk vs. Benefit
The risks of transfusion are increasingly well defined and extend far beyond concerns about disease transmission (e.g. HIV, hepatitis) The benefits of red cell transfusion, except in severe hemorrhage, have never been proven While anemia is associated with poorer outcomes, red cell transfusion to treat anemia does not appear to improve outcomes

21 Impact of Transfusion on Patient Outcomes
Author (year) Population n Impact of Blood Transfusion Leal-Novel et al (2001) Cardiac surgery 738 - Higher mortality rate - Longer ICU stay Wu et al (2001) Elderly with MI 78,974 - Lower 30-day mortality (if admission Hct<33*) - Higher 30-day mortality (if admission Hct>36) Engoren et al (2002) 1,915 - Higher 5-year mortality rate Vincent et al (2002) Critically ill 3,534 - Higher 14- and 28-day mortality rate Malone et al (2003) Trauma 15,534 Higher mortality rate - More ICU admission - Longer ICU/hospital stay Corwin et al (2004) 4,892 - Longer length of stay - More number of complications Dunne et al (2004) 9,539 - More SIRS Innerhofer et al (2005) Orthopedic surgery 308 - More infections Weber et al (2005) 695 - Longer time to ambulation Koch et al (2006) 5,841 - More AF

22 Impact of Transfusion on Patient Outcomes
Author (year) Population n Impact of Blood Transfusion Koch et al (2005) Cardiac surgery 11,963 - Higher postop mortality rate - Higher postop morbidity rate (RF, prolonged ventilatory support, serious infection, cardiac complications, & neurologic events) Murphy et al (2007) 8,598 - Higher mortality rate - More ischemic complications - More infectious complications Surgenor et al (2009) 3,254 - Decreased survival after cardiac surgery Pedersen et al (2009) Total hip replacement 4,508 - More pneumonia Nikolsky et al (2009) PCI after MI 2,060 - Higher 30-day and 1-year mortality rate van Straten et al (2010) 10,435 - Worse early survival D’Ayala et al (2010) Lower extremity amputation 300 - More postop adverse events - Longer ICU/hospital stay O’Keeffe et al (2010) Lower extremity revascularization 8,799 - More pulmonary complications Veenith et al (2010) Elderly undergoing cardiac surgery 874

23 Transfusion and Outcomes
Following transfusion: In all of the studies, Hb increased Is this a useful metric of clinical efficacy? In 79% of the studies, DO2 increased In 16% of the studies, VO2 increased In none of the studies, did ischemia (as measured by lactate) improve In all of the studies, transfused patients had poorer outcomes

24 Efficacy of RBC Transfusion in the Critically Ill
Meta-analysis - 45 observational studies of 272,596 patients Included surgical (trauma, general, ortho, neuro, and cardiac) and general ICU patients 42 of 45 studies: risks outweighed benefits of transfusion; risk neutral in 2 studies Transfusion an independent risk factor for increased: Mortality Infection Multi-organ dysfunction ARDS Marik, et al CCM 2008;36:

25 Adverse Effects of Allogeneic Blood
Storage Lesion TRIM TRALI: 1 in 2,000 transfusions; primarily plasma rich products; up to 20% mortality Hemolytic transfusion rxns: (1:4,000) Bacterial contamination (Plts.-1:75,000) HIV, HCV, HBV Febrile and allergic reactions: 1-2% Other: ARDS, TA-GVH, SIRS, TACO, TAHA, unknown viruses

26 Storage lesion, TRIM, SIRS, etc?
Adverse effects of RBC transfusion contrasted with other risks.Risk is depicted on a logarithmic scale. Relative risk of: Storage lesion, TRIM, SIRS, etc? Adverse effects of RBC transfusion contrasted with other risks.Risk is depicted on a logarithmic scale. Shaded bars represent the risk per RBC unit transfused, and unshaded bars represent the risk for fatality per person per year for various life events. During 2007 through 2008, HIV incidence in blood donors was 3.1 per 100 000 person-years. Residual risk was estimated as 1:1 467 000 transfused blood components or 6.8 per 10 million transfused components (10). During 2007 through 2008, HCV incidence in blood donors was 5.1 per 100 000 person-years with residual risk estimate of 0.87 per million transfused blood components (1:1 149 000) or 8.7 per 10 million transfused components (10). For 2006 to 2008, HBV incidence in blood donors was 3.41 to 3.43 per 100 000 person-years. The estimated residual risk for HBV was 1 in 282 000 to 1 in 357 000 transfused blood components (11) or 2.8 per million to 3.6 per million transfused blood components. In a recently published, large, prospective study with active recipient surveillance, the rate of TRALI occurrence in 2009 was 0.81 (95% CI, 0.44 to 1.49) per 10 000 transfused blood components or 8.1 per 100 000 transfused blood components (12). Although the literature has a wide range of TRALI risk estimates (1, 13–16), we have selected the rate reported in this recent prospective study. Three studies of TACO have produced similar results. In a study of 901 intensive care unit patients, 6% of patients who received transfusions developed TACO. Median units transfused were 2 RBCs and 3 overall (including plasma and platelets) (17). The rate per transfused RBC unit was 2 to 3 per 100. In 382 patients undergoing hip and knee replacement, 1% developed TACO after surgery (18). In a study of patients having total hip and knee arthroplasty, 8% developed fluid overload necessitating diuretic use and 4% of patients who did not receive transfusions developed fluid overload, leading to a TACO estimate of 4% (19). In published studies from the late 1990s, the risk for fatal hemolysis was estimated to range from 1.3 to 1.7 per million (5.9 to 7.7 per 10 million) transfused RBC units in 1 report (20) and 1 per 1 800 000 or 8.5 per 10 million in a second report (21). More recently, transfusion-related fatalities due to hemolysis reported to the U.S. Food and Drug Administration averaged 12.5 deaths per year from 2005 to 2010 (22). With 15 million RBC units transfused per year, the estimated risk for death due to hemolysis is 1:1 250 000 or 8 per 10 million RBC units. Fever (febrile nonhemolytic transfusion reactions) was estimated to be 1.1% with prestorage leukoreduction and 2.15% with poststorage leukoreduction (23). Death from medical error as reported by the Institute of Medicine was 1.3 to 2.9 per 1000 hospital admissions (24). Life-threatening transfusion reaction, defined as reactions requiring major medical intervention (for example, vasopressors, intubation, or transfer to an intensive care unit), occurred in 1:139 908 transfusions or 7.1 per million transfusions (1). Fatal motor vehicle accidents were estimated at 13.1 per 100 000 persons in 2008 or 1.3 per 10 000 persons (25). The rate of firearm homicide (which excludes suicide) was 4 per 100 000 persons in 2008 (25). Fatal falls were estimated at 8.2 deaths per 100 000 persons in 2008 (25). Lightning fatalities ranged from 0.02 per million (2 per 100 million) persons in California and Massachusetts to 2.0 per million persons in Wyoming (0 risk in Hawaii, Rhode Island, and Alaska) (26). The odds of being killed on a single airline flight on the 30 airlines with the best accident rates were 1 per 29.4 million. Among the 25 airlines with the worst accident records, rates were 1.7 per million per flight (27). Modified from Dzik and colleagues (2002) (28). HBV = hepatitis B virus; HCV = hepatitis C virus; RBC = red blood cell; TACO = transfusion-associated circulatory overload; TRALI = transfusion-related acute lung injury. Carson J L et al. Ann Intern Med doi: / ©2012 by American College of Physicians

27 Storage Lesion: Tissue Oxygenation and Red Cell Transfusions
Copyright 2006 – 2011 Strategic Healthcare Group LLC. All Rights Reserved

28 Phase Contrast Video – Single file RBCs Click to play

29 Cytoscan – Pre & Post Transfusion Click to play

30

31 RCTs to Evaluate Red Cell Storage
Age of Blood Evaluation (ABLE): comparing 8 day old blood vs. standard issue (2-42 days) in ICU patients Outcome: 90 day all-cause mortality Age of Red Blood Cells in Premature Infants (ARIPI): 8 day old blood vs. standard issue Outcome: 90 day all-cause mortality and organ dysfunction Red Cell Storage and Duration and Outcomes in Cardiac Surgery: < 14 day vs. > 20 day old blood Outcome: Post-op mortality Red Cell Storage Duration Study (RECESS): Cardiac surgery patients randomized to < 10 days vs. > 21 day old blood Outcome: Change in Composite Multi-organ Dysfunction Score (MODS)

32 Adverse Effects of Allogeneic Blood
“Stored RBCs resulted in significantly malperfused and underoxygenated microvasculature “ Decreased functional capillary density May contribute to multi-organ failure Applies to stored autologous blood Tsai, A.G. et al. Transfusion 2004;44:

33 Transfusion Related Immunomodulation (TRIM)

34 Transfusion and Cadaver Renal Allograft Survival

35 Transfusion Related Immunomodulation (TRIM)
Improved renal allograft survival Increase in nosocomial infection rates leading to increased LOS, resource consumption, total hospital costs Increased cancer recurrence rates in transfused patients Increased long-term mortality in CABG A linear dose-response curve of adverse clinical effects is well documented in large studies using multivariate analysis

36 Nosocomial Infections And Transfusion

37 Nosocomial Infection Rates in Critically Ill Patients
Prospective cohort study Patients stratified by probability of survival into quartiles Lowest quartile for survival: transfusion had no impact on infections Highest quartile for survival: transfusion resulted in significant increase on infections P < .0001 Percent of Patients Patients stratified by probability of survival into quartiles. In lowest quartile for survival, transfusion had no impact on infections or mortality. Largest impact in quartile with highest probability of survival. 157/2,085 61/428 96/1,657 Taylor RW, et al. Crit Care Med. 2006;34:

38 Small Amounts of Intraoperative Blood Loss Heralds Worse Postoperative Outcome
Database study of NSQIP data with propensity–score matching 8728 nonvascular thoracic operations 6.6 % received one or two units during surgery After propensity adjustment Increased pulmonary complications and LOS Increased systemic sepsis and wound infections Composite morbidity 43% vs.32% Ferraris, et al. Ann Thorac Surg 2011 Excluded patients who received 4 or more unit pre-op or post op

39 S. aureus and Iron Surface Determinant (IsdB) .
Host Specificity of Staphylococcus aureus.  S. aureus uses the iron-regulated surface determinant (Isd) group of proteins to acquire iron from hemoglobin. It secretes a hemolytic toxin that releases hemoglobin from red cells. The released hemoglobin then binds to the staphylococcal receptor, iron surface determinant B (IsdB) on the bacterial cell surface. Heme is extracted from hemoglobin and is transported across the cell wall and cytoplasmic membrane by other Isd proteins. After its release from heme, iron becomes available as a nutrient within the bacterial cell. The increased affinity of the S. aureus IsdB for human hemoglobin (Panel A) versus mouse hemoglobin (Panel B) accounts for the enhanced availability of iron and, in part, for the host specificity of S. aureus. Lowy FD. N Engl J Med 2011;364:

40 Transfusion and Mortality

41 Association Between Blood Transfusion and Risk of Death
Marik, et al CCM 2008;36:

42 Transfusion and Mortality in CABG
Retrospective study of long-term outcome in 1,915 patients after primary CABG Excluded patients who died within 30 days of surgery Transfused patients (546) were matched by propensity score (age, gender, size, LOS, perfusion time and STS risk) with pts. not transfused and 5-year mortality compared Adjusted 5-year mortality 70% higher in transfused group (p<0.001) STS = society of Thoracic surgeons Engoren et al, Ann Thorac Surg 2002;74:1180-6

43 Mortality and Transfusion-Cardiac Surgery
Fig 3. Kaplan-Meier estimates of survival based on equal propensity scores of any transfusion (XFN) versus no transfusion (No XFN). (CABG = coronary artery bypass grafting Engoren et al, Ann Thorac Surg 74:1180-6, 2002

44 Transfusion and ARDS

45 Association Between ARDS and Transfusion
Marik, et al CCM 2008;36:

46 Transfusions in Acute Coronary Syndrome

47 Blood Transfusion and Clinical Outcomes in Patients with ACS
Retrospective analysis of 24,112 patients from GUSTO IIb, PURSUIT, and PARAGON B trials Main outcome: 30 day mortality Data adjusted for baseline characteristics: bleeding, transfusion propensity, nadir hematocrit Transfusion was associated with a hazard ratio for death of 3.94 (3.26 – 4.25) Inflection point is Hct < 24% Rao, et al. JAMA, Oct. 6, 2004, Vol 292, No pp

48 Transfusion and Cancer Survival

49 Influence of Transfusion on Outcome in Pancreatic Cancer
67 patients underwent pancreaticoduodenectomy for cure 25 patients received > 3 units No difference in tumor size, stage, histology compared to group receiving < 2 units Median and cumulative 3 year and 5 year survival worse with > 3 units 5 year survival 68.9% vs. 30.2% World J Surg, 2008

50 Influence of Transfusion on Colorectal Cancer Recurrence
Cochrane meta-analysis involving 12,127 patients Evaluated role of transfusion in colorectal cancer recurrence Overall OR for recurrence was 1.41 (95% CI ) in transfused patients Amato, A, et al. Cochrane Database System Rev 2006;(1): CD005033

51 Lymphoma and Transfusion
Meta-analysis of 14 studies Case control and cohort studies Outcome reported as relative risk (RR) Previous RBC transfusion associated with later development of non-Hodgkin lymphoma, RR 1.2 (95%CI , P< .01) In subset analysis, risk greatest for development of chronic lymphocytic leukemia/small lymphocytic lymphoma Castillo, JJ, et al. Blood. 2010;116(16): )

52 Radiation Therapy, Transfusion and Outcomes: DAHANCA 7 Study
Evaluated effect of transfusion on disease-specific and overall survival in head/neck SCCa Low hemoglobin group had poorer survival than high hemoglobin group Low hgb group with transfusion showed trend toward poorer survival than low hgb group without transfusion Acta Oncologica, 2011; 50:

53 Risk vs. Benefit “The issue (no longer) is whether or not blood transfusion is harmful, but the inflection point at which it is associated with more harm than benefit.” -Rao et al, JAMA 2005;292(13)

54 Blood Product Transfusions
The Traditional Concept Blood products are an effective therapeutic intervention The New Concept Transfusion of blood products is an undesirable outcome to be avoided Goodnough L.T.

55 “Primum non nocere” (First, Do No Harm)
The accumulating evidence suggests that, when we fail to prevent an avoidable transfusion, we are harming patients.

56 When to Transfused Red Cells: The Transfusion Threshold

57 Copyright 2006 – 2011 Strategic Healthcare Group LLC
Copyright 2006 – 2011 Strategic Healthcare Group LLC. All Rights Reserved

58 Survival in Patients with Profound Anemia in the Absence of Transfusion Ford, et al, Blood : Abstract 949 Hb Level (gm/dL) Survival 6/7 (85.7%) 9/11 (81.8%) 29/32 (90.6%) 30/30 (100%) 48/48 (100%) Overall 122/128 (95.3%)

59 Transfusion in Critical Care: TRICC Trial
A prospective, randomized trial comparing a restrictive red cell transfusion strategy vs. a liberal transfusion strategy Copyright 2006 – 2011 Strategic Healthcare Group LLC. All Rights Reserved

60 Transfusion in Critical Care
838 critically ill patients randomized to a restrictive (7-9 g/dl) or liberal (10-12 g/dl) transfusion strategy Overall 30 day mortality similar (no transfusion benefit in liberal transfusion group) Mortality rates significantly lower in restrictive transfusion group for those with APACHE score < 20 and those < age 55 No difference in patients with clinically significant heart disease Hebert. NEJM 1999;340:409-17

61 Carson , JL et al. NEJM. December, 2011
Liberal or Restrictive Transfusion in High-Risk Patients after Hip Surgery Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS) RCT of patients with hip fracture requiring surgery > age 50 (mean age 81.6 years) with cardiovascular disease (62.9%) or risk factors for CVD (37.1%) Randomized to liberal (single unit if Hgb < 10 g/dL) vs. restrictive (single unit for Hgb < 8 g/dl or symptomatic from anemia Carson , JL et al. NEJM. December, 2011

62 Carson , JL et al. NEJM. December, 2011
Liberal or Restrictive Transfusion in High-Risk Patients after Hip Surgery Results Primary outcome: death or inability to walk 10 feet without assistance at 60 days No difference between liberal and restrictive transfusion group Low rate of cardiovascular adverse events in both groups 65% fewer units transfused in restrictive group and half received no transfusion Carson , JL et al. NEJM. December, 2011

63 The “10/30 Rule” Should be Banished (also the 9/27 rule and 8/24 rule)
No single hemoglobin threshold should be used to make a transfusion decision No rigid “transfusion trigger” based on hemoglobin alone But… for most patients, consideration of red cell transfusion should begin at hemoglobin of 7 gm/dl (hematocrit of 21%)

64 Distribution of Pretransfusion Hematocrits
2006 Mean % SD 2010 Mean % SD % Transfusions Restrictive transfusion trigger before we started blood management

65 Red Cells Should Not be Ordered in “Pairs”
For Red Cells: In the absence of acute hemorrhage RBC’s should be given as single units Each unit should be an independent clinical decision Each unit represents an incremental increase in adverse consequences Remember: transfusion of red cells may NOT increase oxygen delivery at a tissue level Napolitano - Crit Care Med 2009 Vol. 37, No. 12

66 Reduce Phlebotomy and Procedure-related Blood Losses
Meticulous surgical hemostasis Meticulous hemostasis with “bedside” procedures Minimize phlebotomy blood loss Only necessary labs Smallest sample practical

67 Role of Intravenous Iron in Inpatients
Most inpatients have inflammation and functional iron deficiency (FID) Chronic inflammatory diseases Malignancy Perioperative Trauma Oral iron is poorly tolerated, poorly absorbed, and not bioavailable Intravenous iron may play a role in improving erythropoiesis There may also be a limited role for ESAs in inpatients

68 Conclusions Red cell transfusions in patients who are not bleeding and have hemoglobin levels greater than 6-7 g/dL are generally associated with worse outcomes The best way to optimize oxygen delivery to the tissues is not by transfusing stored RBCs; instead: Optimize oxygenation Optimize hemodynamics

69 Conclusions Even mild anemia contributes to all cause morbidity and mortality and should be evaluated and treated, when possible Anemia management before elective surgery helps decrease transfusion rates Intravenous iron replacement may be effective at increasing hemoglobin in patients with anemia of chronic inflammation and in patients with an acute inflammatory process Limited role for ESAs in inpatients

70 © Axel Hofmann/Shannon Farmer – SHEF Meeting Perth August 2010
Triad of Independent Risk Factors for Adverse Outcomes Anemia independently associated with increased: morbidity hospital length of stay likelihood of transfusion mortality Spahn DR. Anesthesiology 2010; 113(2) 1-14 Beattie WS, et al Anesthesiology 2009; 110(3) Dunne JR, et al J Surg Res 2002; 102: Shander A. Am J Med 2004; 116(7A) 58S-69S Anemia Bleeding associated with increased Morbidity ICU and hospital length of stay Mortality Elective : ~0.1% Subgroups: Vascular 5–8% Up to 20% with severe bleeding Major organ damage 30–40% Causes On average 75 – 90% local surgical interruption or vessel interruption 10–25% acquired or congenital coagulopathy Shander A. Surgery 2007 Blood loss & bleeding RBC transfusion independently associated in a dose-dependent relationship with increased: Morbidity ICU and hospital length of stay Mortality Beattie WA, et al Anesthesiology 2009 Murphy GJ, et al Circulation 2007 Salim A, et al J Am Coll Surg 2008 Bernard AC, et al J Am Coll Surg 2008 Transfusion © Axel Hofmann/Shannon Farmer – SHEF Meeting Perth August 2010 Hearnshaw SA, et al Aliment Pharmacol Ther 2010 Blair SD, et al Br J Surg 1986

71 So Why Practice Patient Blood Management?
“Stewardship” of the blood supply Optimal use of blood Efficient use of resources Higher quality and safety: better patient care Lower costs

72 Optimize erythro-poieis Harness & optimize physiologic
Patient Blood Management: The Three Pillars 1st Pillar 2nd Pillar 3rd Pillar Optimize erythro-poieis Minimize bleeding & blood loss Harness & optimize physiologic tolerance of anemia Pre-op anemia screening Refer for further evaluation if necessary ESAs Intravenous Iron Note: anemia is a contraindication for elective surgery Identify and manage bleeding risk and anticoagulants ANH Cell Salvage DDAVP TXA, Amicar Topical hemostatics Meticulous surgical hemostasis Avoid secondary hemorrhage Minimize phlebotomy Optimize hemodynamics Optimize ventilation and oxygenation Low hemoglobin threshold for transfusion Minimize oxygen consumption Avoid/treat infections promptly © Axel Hofmann/Shannon Farmer – SHEF Meeting Perth August 2010

73 Before I go, a topic for another time
There is a substantial LACK of evidence that an increased PT/INR (at least < 2.0) can or should be used to make clinical decisions re: benefit of pre-procedure frozen plasma Avoid prophylactic plasma transfusions No proven clinical benefit Substantial risk of acute pulmonary reactions

74


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