Key words:
Heart Transplantation, pediatrics
Introduction
Over the last fi ve decades, pediatric cardiac
transplantation has been performed as treatment
for palliated Congenital Heart Disease (CHD) and
Cardiomyopathy refractory to surgical and medical
therapy. Recent advancements and availability of life
support technologies, improved pre and peri-operative
management of these critically ill patients, refi nement
of surgical techniques and enhanced understanding
of immunology and robust immunosuppression,
has lead to a remarkable improvement in event free
survival after heart transplantation.
Historical perspective
The fi rst human heart transplant was performed on
December 3rd, 1967 at Cape Town, South Africa by
Dr. Christian Barnard1, 2,3. Three days later, the fi rst
pediatric human heart transplant was accomplished
in Brooklyn, New York on a 19-day-old infant with
severe Ebstein’s anomalyafter a failed central shunt4.
“We stand on the shoulders of those that have gone
before us”.
These words are certainly true as we refl ect on the
advances made in pediatric heart transplantation.
Early pediatric heart transplantation was successfully
accomplished at Stanford University in the late
1970’s, when only azathioprine and corticosteroids
were available for immune suppression. Nonetheless,
morbidity and mortality associated with pediatric heart transplantation remained high due to a lack
of adequate immune suppression. The introduction
of Cyclosporine by a pioneer of solid organ
transplantation, Dr. Thomas Starzel, made heart
transplantation a reality as it greatly simplifi ed the
immune suppression management, decreased the
morbidity due to corticosteroids and made heart
transplantation economically feasible.
In the decade of the 1980’s, Stanford, Columbia
University and the University of Pittsburgh were the
referral centers for pediatric heart transplantation.
Nonetheless, their early success resulted in the
exponential growth in the number of centers
performing pediatric heart transplantation. A major
advance in pediatric heart transplantation occurred
at Loma Linda University when their program, led
by Dr. Leonard Bailey, focused nearly entirely on
heart transplantation of the infant with Hyopoplastic
Left Heart disease (HLHS). The result of Norwood
palliation was dismal, thus infant transplantation was
a welcomed option.
In 1993, the Pediatric Heart Transplant Study
(PHTS) group was founded by six pediatric heart
transplant centers to advance the clinical science and
treatment of children after listing for heart transplant.
The purpose was to establish and maintain an event
driven database for heart transplantation, which could
be used to stimulate basic and clinical research in the
fi eld of pediatric heart transplantation. As of March
2014, there are 46 participating centers contributing
data on over 6000 listing and nearly 5000 pediatric
heart transplants. The PHTS has created a body of
literature that has had a major impact on the care of
infants and children after heart transplantation. Based
on data reported by the ISHLT, the trend of pediatric
heart transplantation has shown a steady increase in
the last 20 years (Figure 1).
Indications for heart transplantation
Primary indications for heart transplantation are:
end stage palliated congenital heart disease, primary
transplantation in lethal congenital heart malformations,
i.e. HLHS, pulmonary atresia with intact ventricular
septum and sinusoids, and Cardiomyopathy. The
indication for pediatric heart transplantation varies
across different age groups, with CHD being the
primary indication of heart transplant for infants, while
cardiomyopathy is the primary indication of heart
transplantation for older children (Figure 2)10, 11.
The past consensus guidelines for heart transplantation
have included12-15:
Ongoing need for intravenous inotropic or mechanical
circulatory support
Complex CHD not amenable to surgical palliation
or repair or if it carries a higher risk/mortality than
transplantation
Progressive decline of ventricular function or functional
status despite optimal medical management with
diuretics, digitalis, angiotensin-converting enzyme inhibitors and beta-blockers.
Malignant arrhythmia or survival after cardiac arrest,
which is unresponsive to medical therapy, ablation or
implantable defi brillator.
Progressive pulmonary hypertension due to systemic
ventricular failure precluding transplantation at a
later date.
Growth failure secondary to severe congestive heart
failure (CHF) despite optimal medical management.
Very poor quality of life secondary to severe CHF.
Progressive decline in functional status and/or highrisk
conditions with fontan palliation.
The American Heart Association (AHA) formulated
a working group to better outline the indications
for heart transplantation16. Level A evidence for
indications of heart transplantation is lacking, however
there is Level B evidence available as depicted in
Table116. Due to improved surgical repair of CHD, the
prevalence of adult CHD will continue to increase.
As such, there will be a continuous evolution of the
indications for transplantation specifi c for this group of patients. The AHA has suggested that presence of
severe hypoplasia of the pulmonary arteries or veins
and non-reactive severe elevations of pulmonary
vascular resistance (PVR) would preclude orthotopic
heart transplantation (OHT).
Organ allocation and matching
United Network for Organ Sharing (UNOS)
maintains a network (UNet) accessible to all
transplant professionals, linking all transplant
centers and organ procurement organizations
(OPO). Upon identifi cation of an organ donor,
transplant coordinator from an OPO enters the donor
information in UNet. These data are used to create
a ranked list of potential recipients, called a “match
run”. Factors infl uencing the list include tissue match,
ABO type, waiting list duration, immune status,
degree of medical urgency and distance between
the potential recipient & donor17-18. Other factors
infl uencing the acceptance of a donor heart offer include: the need for a non-lung donor for a patient
that requires extensive reconstruction of pulmonary
arteries or re-routing of systemic venous return and
HLA incompatibility based on virtual crossmatch.
ABO compatibility has been the standard of care
in solid organ transplantation for all age groups.
Recently, ABO incompatible heart transplants
have been performed in infants have an immature
immune system with lower levels of anti-A & anti-B
antibodies. Hence, infants have lower probability of
antibody formation against donor ABO antigens, as
demonstrated by current medical evidence showing
no difference in mortality, morbidity and graft failure
in ABO incompatible (ABOi) vs ABO compatible
(ABOc) heart transplantation19-22. According to the
PHTS database, there is equivalent one-year survival
and survival from rejection in ABOi and ABOc
transplantation21.
Pediatric heart transplant candidates who have not
received a heart transplant before their 18th birthday
shall continue to qualify for medical urgency status
based on Organ Procurement and Transplantation
Network (OPTN) guidelines. A heart from an organ
donor < 18 years of age is allocated to a pediatric
heart recipient candidate before being allocated to an
adult candidate. A heart transplant candidate who is
under 18 years of age at the time of listing is assigned
the status code as shown in Table 2.
Donor management
Management of the donor heart is a critical part in
the process of transplantation. Organ donation can be
after declaration of brain death or cardio-circulatory
death (DCD donor)23. Brain death is followed by
an intense catecholamine surge, causing peripheral
vasoconstriction, tachycardia and hypertension and,
in turn, increased myocardial oxygen demand. This
results in myocytolysis, contraction band necrosis,
subendocardial hemorrhage, edema & interstitial
mononuclear infi ltration24. Subsequently, hypotension
and circulatory collapse occurs secondary to decreased
systemic vascular resistance (SVR) requiring fl uid
resuscitation and high doses of inotropes. Also, brain
death leads to alterations in hormone levels secondary
to loss of central regulation and primarily includes
low antidiuretic hormone, depletion of cortisol, free
T3 and insulin. Usual protocol used for optimizing the
management of a potential donor includes25-27:
Maintain CVP 6-10 mm Hg, correct acidosis (pH
7.40-7.45), correct hypoxemia (pO2> 80 mm Hg & O2 saturations > 95%), correct anemia (Hematocrit ≥
30%), inotropes to maintain MAP ≥ 60 mmHg (target
dopamine or dobutamine< 10 μg/kg/min).
Echocardiogram to rule out structural anomalies
Hormonal resuscitation if LVEF < 45%
T3: Bolus 4 μg + infusion @ 3 μg/hour
Vasopressin: 1 unit bolus + infusion @ 0.5-4 units/
hour (titrate to SVR of 800-1200)
Methylprednisolone: 15 mg/kg bolus
Insulin: 1 unit/hour (titrate blood glucose to 120-180
mg/dL)
Use of high dose dopamine or dobutamine (> 20
μg/kg/min) and/or epinephrine > 0.1 μg/kg/min is
predictive of donor heart failure.
Transplantation after cardio-circulatory death is
ethically controversial and debatable23,27, hence DCD
heart donors has not achieved widespread application.
Evaluation and management of the patient
awaiting heart transplantation
Evaluation of the patient awaiting a heart transplant
includes15:
Cardiac catheterization:
Hemodynamic assessment
and measurement of left and right heart pressures,
pulmonary vascular resistance (PVR). In presence of elevated PVR, reactivity is elicited with 100% oxygen,
nitric oxide, prostacyclin prior to listing28. PVR > 6
Wood units/m2 and a trans-pulmonary gradient (TPG)
>15 mmHg with non-reactive PVR is suggestive of a
high-risk candidate for transplantation.
Exercise test:
Exercise treadmill test (Bruce protocol)
is used to evaluate maximal oxygen consumptions
(MVO2) in ambulatory heart failure patients. Patients
with MVO2 < 12 ml/kg/minhave very poor 1 year
survival rate, 12-14 ml/kg/min have severe clinical
limitations and MVO2> 14 ml/kg/min are considered
to have preserved exercise capacity and exhibit
similar or higher survival rates as expected after
transplantation15,29,30.
Assessment of end-organ function:
Pre-existing
renal and hepatic dysfunction must be assessed
due to toxicity of immunosuppression therapy
post-transplant. The interactions between various
medications must be evaluated closely with special
attention to systemic side effects15.
Infectious disease evaluation:
IgG and IgM serologies
for CMV, EBV, Toxoplasma Gondii, hepatitis viruses,
HIV and HSV must be obtained. Patient must receive
PPD and vaccines including varicella, measles,
mumps, rubella, H. infl uenza, pneumococcus, hepatitis
A and B prior to transplantation.
HLA sensitization:
HLA antibodies to Class I and
II are determined and reported as panel reactive
antibodies (PRA). PRA > 10% is considered positive
and is associated with lower survival compared to
non-sensitized patients. Previous blood transfusions,
childbirth, cryopreserved tissue valves, allograft
conduits and organ transplants increase the risk of
sensitization31,32.
Psychosocial assessment:
Assessment for reliable
& strong support system due to mandatory clinical
follow up & medication compliance is also critical.
Illicit drug use and previous behaviors of noncompliance
can prevent allocation of this limited and
valuable resource to a particular patient.
Patient management is individualized except for the
basic principles of care of any critically ill patient in
the intensive care unit.
Hemodynamic assessment and data obtained by
catheterization guides patient management with the
goal of optimizing preload and afterload. Milrinone
is the inotrope of choice in patients awaiting
transplantation33, 34. Milrinone has a long half-life, is
excreted by kidneys and should be used cautiously
in patients with hypotension, renal disease and
arrhythmias. In our experience, low dose dobutamine
(5-10 μg/kg/min) or epinephrine (0.01-0.05 μg/kg/
min) is benefi cial in patients who are not stabilized on
monotherapy with milrinone38. Diuresis is necessary
to prevent pulmonary edema and fl uid overload;
however, patients may need to be on continuous
infusion for gentle diuresis.
Patients with poor cardiac function are prone to
pulmonary and systemic thrombosis, and embolization,
making anticoagulation necessary. Heparin is the
preferred drug as it can be easily reversed if a donor
heart becomes available. Warfarin is an acceptable
option for anticoagulation. We have used direct
thrombin inhibitors like bivalrudin and argatroban in
patients on ventricular assist devices with inability
to achieve therapeutic levels despite maximal
doses of heparin or with history of heparin induced
thrombocytopenia (HIT). Bivalrudin is unique in
undergoing non-organ elimination by proteolysis with
a short half-life (t ½) of about 25 minutes35.
Mechanical support: ECMO (Extracorporeal
membrane oxygenation) or Ventricular Assist Device
(VAD). Progressive end organ dysfunction despite
maximal medical management is an indication for
mechanical support. This can essentially be used
as a bridge to recovery or bridge to transplantation.
Mechanical support can be used in patients
with cardiogenic shock due to myocarditis with
anticipation of recovery of function or as a bridge to
transplantation19, 36. Current options for pediatric VAD
use are limited due to the pump sizes required for
pediatric patients. Currently, Thoratec, Berlin Heart
EXCOR VAD, and DeBakey centrifugal pump are
the only VADs available for pediatric use. Survival
at 12 months post transplant in patients supported
with EXCOR was similar to overall pediatric heart
transplants and higher than patients supported with
ECMO36,37. In our experience at the Congenital Heart
Center at University of Florida, EXCOR VAD has
been used extensively in children of all age groups,
including newborns to older children, as a bridge
to transplant. We have implanted the Syncardia
“Total Artifi cial Heart” in an adolescent patient who presented with cardiogenic shock secondary to
coronary allograft vasculopathy (CAV). The support
devices have enabled us to aggressively rehabilitate
our patients prior to transplantation.
The techniques for performing an orthotopic heart
transplant were pioneered at Stanford University by
Dr. Norman Shumway and his colleagues15,39: The
following two techniques are used:
Orthotopic heart transplantation (OHT, Figure 3, a and
b): OHT using bi-atrial technique is the most commonly
used approach39,40. Bi-cavalanastomosis has been
described and shown to preserve sinus node function41-43.
Heterotopic heart transplantation (HHT, Figure 3,
c): In this technique the donor heart is implanted
adjacent to the recipient. The indications for HHT
currently are donor/recipient size mismatch (weight
ratio < 75%) and elevated PVR as an untrained donor
right ventricle may be unable to pump against high
pulmonary pressures. HHT has been shown to be
associated with lower overall survival and higher rates
of complications, especially atelectasis, thrombosis
in native heart, mitral & tricuspid regurgitation and
malignant ventricular arrhythmias in the native
heart15, 44-47. This procedure is rarely performed today.
Post-operative management
Immediate post-operative care includes supportive
respiratory management with early extubation,
unless there is a contraindication. Usually, a fi xed
cardiac output is observed with heart rates ranging
from 90-110 bpm, which may be inadequate for
newborns. In our experience, isoprotenol can be
titrated to achieve an acceptable heart rate and
augment cardiac output38,48. Catechoamines should
always be continued for a minimum of 72 hours after
transplantation. Hypertension can be seen if the donor
heart is oversized for the recipient or in the presence
of increased SVR due to long-standing heart failure
with normal stroke volume of the new heart allograft.
Systemic hypertension should be aggressively treated
with after-load reduction because of the potential
for abdominal and cerebral re-perfusion injury. All
transplanted hearts have diastolic dysfunction due to
ischemic injury, but improve rapidly in the initial hours
and days after transplant. Diastolic dysfunction needs
to be considered when giving bolus fl uid resuscitation
or blood transfusion49. PVR Index (transpulmonary gradient/ cardiac index) > 9 can be predictive of lower
30-day survival post transplant50.
Postoperative temporary pacing can be initiated in
case of junctional rhythm or sinus node dysfunction.
Permanent pacing is recommended if sinus or atrial
rhythm does not return spontaneously within 2 weeks.
Rejection
Recipient’s immune response to the foreign antigens
manifests as rejection. Rejection can be hyperacute,
acute cellular rejection (ACR), antibody-mediated
rejection (AMR) or chronic rejection. Hyperacute
rejection is rare, manifests within minutes to hours
after transplantation and is associated with presence
of preformed antibodies to donor antigens (especially
blood group or anti-HLA antibodies)15. ACR is a
host T-cell mediated response to allograft and is characterized by varying degrees of lymphocytic
infi ltrate and myocyte necrosis on biopsy specimens.
AMR or B-cell mediated rejection is characterized by
micro vascular injury and can be seen in the absence
histologic evidence of ACR51. ACR classifi cation is
based on revised ISHLT criteria into no rejection
(0R), mild (1R), moderate (2R), and severe (3R)
rejection. AMR is classifi ed based on the presence
of histopathologic or immunopathologic (CD68+ or
C4d+) features alone or in combination52.
Immunosuppression
Following solid organ transplantation, antigenpresenting
cells (APC, leukocytes/dendritic cells) are
presented to recipient with the allograft and sensitize
the recipient. T-cells are signaled by the APC to
proliferate, causing migration of the CD3+ cells to the
graft and, in the presence of complement, cause myocyte
injury (Cellular rejection). Calcineurin (Tacrolimus/
Cyclosporine) inhibitors block recognition between
APC and T cells, preventing lymphocyte proliferation.
Administration of IL-2 receptor blocker or small
doses of Tacrolimus before implantation blocks this
signaling process. The potential for AMR has different
implications and management.
Allosensitization53 can lead to two-fold higher
mortality in the fi rst year after transplantation. UNOS
recommends routine screening for alloreactive
antibodies (PRA) in patients’ serum. The management
of the sensitized donor in the perioperative and postoperative
period presents a signifi cant challenge.
Pre-operative and intra-operative plasmapheresis
is critical to preventing hyperacute allograft injury.
Modifi cation of maintenance immune suppression is
also indicated. In many situations, the introduction
of B cell and plasma cell therapy is necessary to
maintain good allograft function.
The protocols for immune suppression have an
induction and maintenance phase. The protocols
are center specifi c and usually consist of a
combination of steroids, antiproliferative agents
(mycophenolatemofetil or azathioprine) and
Calcineurin inhibitor (tacrolimus or cyclosporine).
Steroids benefi t by immunosuppression, membranestabilization
and antioxidant properties38.
The immune suppression strategy used at our
center is outlined in Tables 3 and 4. The induction protocol used consists of high dose corticosteroids,
IL-2 receptor antagonist (simulant), anti-thymocyte
globulin (ATG) followed by calcineurin inhibitors
(CNI) cyclosporine or tacrolimus. Simulect is
administered at a dose of 12 mg/m2 followed by
methylprednisolone (10mg/kg, maximum 500mg),
one dose prior to cardiopulmonary bypass and another
dose just after release of aortic cross clamp. Rabbit
ATG (1.5 mg/kg) is started in the fi rst 24 hours after
transplantation for 3-7 days. Methylprednisolone is
used at high doses (10 mg/kg) in the initial 24 hours
and tapered to 1 mg/kg/day 7-10 days after transplant.
Tacrolimus is usually initiated on the second day after
transplantation with target levels between 10-15 ng/
dL. Cyclosporine is generally used in patients with
tacrolimus intolerance or in infant transplants. In the
maintenance phase, we attempt to wean the steroids
within the fi rst 6 months after transplant. Based
on the clinical course, other immune suppression
medication, such as CNI, mycophenolatemofetil
(MMF), are added and dose titrated for target levels
(Table 4). Sirolimus (rapamycin (mTOR) inhibitor)
is an alternative medication for patients with high
risk of CAV and rejection to standard therapy (after
one month as it can impair wound healing).
In a recent report from ISHLT, 71% of pediatric
hearts transplant recipients received induction
therapy of which 47% received ATG and 25% IL-2-R
antagonists. Polyclonal therapy was shown to have
better survival than IL-2R receptor alone. Induction
therapy did not infl uence frequency of rejection up to
one year after transplantation, freedom from CAV or
lymphoma10. Highest risk of acute cellular rejection
(ACR) is in the fi rst month after transplantation. There
has been a gradual increase in use of tacrolimus from
52% (2001-2006) to 78% (2007 onwards). Use of
MPA also increased to 86% from 64% with a decline
in azathioprine. Steroids are still prescribed to 71%
of patients on discharge. ISHLT 16th Pediatric Heart
Transplant Report shows that 95% of patients 5 years
post transplant were on CNI, of which 71% were on
tacrolimus10.
Follow up
Surveillance endomyocardial biopsies (EMB) &
hemodynamic measurements (right atrial pressure, mean pulmonary artery pressure, pulmonary capillary
wedge pressure, thermodilution cardiac output) are
performed in the cardiac catheterization laboratory
starting about 2 weeks after transplantation. The risk
of rejection is highest in the fi rst year after transplant
and can be subclinical (signifi cant lymphocytic
infi ltrate without clinical or echocardiographic
changes). EMB’s are considered gold standard for
diagnosis. Acute cellular rejection is classifi ed as
mild; moderate or severe54; any rejection episode
moderate to severe is treated with a course of steroids
followed by repeat EMB.
Survival
Heart transplant during infancy shows a higher
median survival rate as compared to older children
(Figure 4). From early 1980s to current era, there has
been a signifi cant improvement in survival primarily
in the early post-operative period (Figure 5). Pretransplant
diagnosis of cardiomyopathy in infants had
a favorable prognosis as compared to CHD. Survival
rates for CHD have fared similar to re-transplant10.
ECMO support as bridge to transplant has a poor
survival compared to VAD or TAH (Figure 6).
In most centers, graft survival in the fi rst year
approaches 100%. Primary graft failure followed by rejection was the leading cause of early death. Early
discontinuation of prednisone has been clearly shown
to have a long-term survival benefi t (Figure 7). CAV
is the major cause of late graft loss and mortality.
Freedom from CAV (%) post-transplant is shown in
Figure 8. In our experience, patients who have had
any episode of hemodynamically signifi cant rejection
are more prone to develop CAV.
Long-term complications Infections
Various pre-operative and intra-operative factors
predispose to infections, like failure to thrive,
immune suppression, associated illnesses, prolonged
indwelling lines and donor factors. Prophylactic
pre-operative antibiotics are used, not recommend
beyond 24 hours. Strict isolation is maintained and
a high index of suspicion is observed. Bacterial
infections are most commonly seen; CMV infection
is the most commonly seen viral infection.
Renal dysfunction
About 5% of patients required renal replacement
therapy (dialysis or renal transplant) at 11 years
post-transplant. The most common etiology is
nephrotoxicity secondary to CNI use.,. Renal
dysfunction was more common in adolescents (14%)
compared to infants and young children (5-7%)10.
Hypertension due to CNI use, steroid effects and
cardiac denervation is seen in 60-90% of children57.
Malignancy
According to the latest ISHLT report, 18% of patients
develop malignancy by 15 years post-transplant.
Lymphoma is the most common malignancy in this
population; higher incidence has been observed with
the use of tacrolimus10,58.
Coronary allograft vasculopathy (CAV)
CAV is a major cause of morbidity and mortality due to
chronic graft dysfunction. It is seen in 8% of the patients
by year 1, 30% after 5 years and 50% patient’s 10 years post transplant60. Coronary angiography is routinely
performed in patients’ post-transplant for detection of
CAV with the exception of infants. Noninvasive tests
like stress testing and multislice coronary computed
tomography angiography61 have been evaluated;
however, coronary angiography still remains the gold
standard. Accelerated fi bro- proliferative changes,
which affect the coronary arteries, cause CAV63.
HLA-DR mismatches, older donor, hypertension in
donor, younger recipient, diabetes, hyperlipidemia
and obesity in recipient are common risk factors for
CAV59,62. HMG -CoAreductase inhibitors (statins)
like pravastatin or atorvastatin have been shown to
improve lipid profi le, decrease rejection, improved
survival and decreased incidence of CAV64-68. CAV
can present as multiple sequential lesions; diffuse
narrowing, pruning of distal vessels or focal lesions of
proximal vessels (Figure 9). After detection of CAV,
patients need to be closely monitored, with longterm
cardiac retransplantation being the therapeutic
option with 1 and 5-year survival of 56% and 38%63,
respectively. Sirolimus (rapamycinmTOR inhibitor) can prevent development or delay progression of CAV
by inhibiting arterial smooth muscle and endothelial
cell proliferation69,70. Atrialtachyarrhythmias have
been associated with increased incidence of rejection
or undiagnosed CAV (8%)71. In a recent retrospective
study from St. Louis Children’s hospital, intraatrial
reentry and ectopic atrial tachycardia were the
most common rhythm disturbances identifi ed after
heart transplantation without increased incidence of
rejection72.
Neurodevelopmental outcomes & Functional status
Developmental outcomes can be in the low-normal
range after transplantation and are similar after surgery
for CHD73. School performance has been shown to
be sub-optimal with a 10-15 point lower score on
IQ testing73. Depression is seen in 50% of patients
one year after heart transplantation74. Commonly
encountered problems after transplantation are school
or cognitive problems related to memory in 15.3%
children, attention in 12.6%, missed school days in CHDs are repaired, the prevalence of patients with
adult congenital heart disease is increasing. Many of
these patients may need transplantation in the future. post-surgery for CHD75.It is of paramount importance
to identify and intervene in a timely manner for any
cognitive disability to optimize the outcomes.
Conclusion
With improved immune suppression, organ support
technologies, ventricular assist devices, improved
surgical and cardiopulmonary bypass techniques the
morbidity associated with transplantation is reduced
and the survival rates improve. However, limited
availability of organs makes it important to allocate
them to the sickest and the patients who will benefit the
most. Future research will need to focus on decreasing
chronic rejection, CAV and malignancy. As the
surgical techniques are improving and more complex
CHDs are repaired, the prevalence of patients with
adult congenital heart disease is increasing. Many of
these patients may need transplantation in the future.
Mechanical circulatory support is also an evolving
field, providing the patients with additional time to
allow for bridge to transplantation or recovery.
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