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(Circulation. 1995;92:3401-3407.)
© 1995 American Heart Association, Inc.
Articles |
Value of Myoglobin, Troponin T, and CK-MBmass in Ruling Out an Acute Myocardial Infarction in the Emergency Room
From the Departments of Cardiology (R.J. de W., R.W.K.) and Clinical Chemistry (G.T.S), Academic Medical Center, University of Amsterdam (the Netherlands), and the Department of Clinical Chemistry (A.S.), University of Leiden (the Netherlands).
Correspondence to Robbert J. de Winter, Department of Cardiology, Room G3-231, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, Netherlands.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion Conclusions References |
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Background Ruling out acute myocardial infarction (AMI) on the basis of rapid assays for cardiac markers will allow early triage of patients and cost-effective use of available coronary care facilities.
Methods and Results We studied the value of myoglobin, creatine kinase (CK)–MBmass, and troponin T in ruling out an AMI in the emergency room in 309 consecutive patients presenting with chest pain. The gold standard for AMI was the combination of history, ECG, and a typical curve of the CK-MB activity (CK-MBact). Myoglobin was the earliest marker, and its negative predictive value (NPV) was significantly higher than for CK-MBmass and troponin T from 3 to 6 hours after the onset of symptoms (myoglobin versus CK-MBmass, P<.03; myoglobin versus troponin T, P<.01). The NPV of myoglobin reached 89% 4 hours after the onset of symptoms. The NPV of CK-MBmass reached 95% 7 hours after the onset of symptoms. Troponin T was not an early marker for ruling out AMI, and NPV changed over time, together with CK-MBact. The early NPV was higher in a subgroup of patients with a low probability of the presence of AMI for the three markers. Cardiac markers rise earlier in patients with large infarcts than in patients with small infarcts as indicated by the cumulative proportion of the marker above the upper reference limit at each time point (myoglobin, P=.04; CK-MBmass, P=.013; troponin T, P=.016).
Conclusions For ruling out AMI in the emergency room, myoglobin is a better marker than CK-MBmass or troponin T from 3 until 6 hours after the onset of symptoms, but the maximal NPV reaches only 89%. At 7 hours, the NPV of CK-MBmass is 95%. The test characteristics are influenced by the probability of the presence of AMI in the patients studied and by the size of their AMI. Infarct size of AMI patients should be reported in studies evaluating cardiac markers.
Key Words: mycardial infarction • diagnosis • myoglobin • troponin T • creatine kinase
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Introduction |
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TopAbstractIntroductionMethods Results Discussion Conclusions References |
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In many patients presenting with chest pain at the emergency room, cardiac markers in serum are measured in the early hours after the onset of symptoms not to detect AMI but rather to exclude MI. Early ruling out of AMI will allow better and more cost-effective triage and management of these patients. According to World Health Organization criteria, the diagnosis of AMI is established when there is typical chest pain suggestive of myocardial ischemia, ST-segment changes or the development of new Q waves on the ECG, and abnormal cardiac enzymes detectable in the peripheral blood. To rule out AMI, one frequently must rely on the measurement of cardiac enzymes or biochemical markers when patients suspected of AMI present with atypical chest pain or a nondiagnostic ECG.
New assays with excellent performance and short turnaround time will allow rapid detection of elevated cardiac markers. The diagnosis of AMI can be established on the basis of these assays as early as 1.5 to 3 hours after the onset of symptoms. Several biochemical markers for the early detection of myocardial damage have been proposed, of which troponin T,1 2 3 4 myoglobin,5 6 7 8 9 10 11 12 13 14 and CK-MBmass6 15 16 17 18 19 are the most promising candidates. However, the emphasis in many studies of the diagnostic properties of these markers has been on the detection rather than the ruling out of AMI. Serum levels of these markers change rapidly in the early hours after the onset of AMI; therefore, sensitivity and specificity of any particular marker change rapidly over time. Moreover, if blood samples are drawn from patients already admitted to a CCU because of suspected AMI, many patients will have large AMI. Infarct size may influence early sensitivity and specificity of the cardiac marker under study, and management decisions in these patients, such as the initiation of thrombolytic therapy, usually are not based on cardiac marker results.
We studied the value of rapid assays for myoglobin, troponin T, and CK-MBmass in ruling out AMI in a large group of consecutive patients in the first 24 hours after the onset of chest pain in the emergency room. The study was designed to focus on patients with a relatively low probability of AMI. We took hourly blood samples during the first 8 hours after the onset of symptoms and every 4 hours thereafter. We asked the attending physician to identify the patients in whom rapid marker results would influence decision making. Also, establishing the exact time of onset of symptoms received special attention.
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Methods |
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TopAbstractIntroductionMethods Results Discussion Conclusions References |
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Study Protocol
All patients with chest pain were seen at the CER, a facility equipped with ECG monitoring where patients can remain under observation for a maximum of 24 hours. Patients with chest pain suggestive of myocardial ischemia within 12 hours after the onset of symptoms were eligible for the study, and all gave informed consent before inclusion. Exclusion criteria were severe skeletal muscle damage or trauma, cardiac resuscitation, and inability or refusal to give informed consent.
Patients with ECG abnormalities on admission that were strongly suggestive of AMI were immediately transferred to the CCU and received standard therapy, including thrombolysis, at the discretion of the physician. Patients with new episodes of chest pain accompanied by ECG changes during their stay in the CER were diagnosed as having severe unstable angina and were referred to the CCU for treatment with intravenous nitrates and heparin. Blood sampling from these patients continued at the CCU for 24 hours. All other patients remained in the CER for observation and blood sampling. The attending physician noted the time of onset of symptoms (t0), frequently after consulting the patients' relatives, and gave an estimate of the accuracy of t0. After the initial histories, physical examinations, and ECGs were taken and before any laboratory results were reported, the physician recorded an estimate of the probability of the presence of myocardial infarction on a four-point scale.
Blood samples were drawn with an indwelling intravenous catheter at 3, 4, 5, 6, 7, 8, 12, 16, 20, and 24 hours after the onset of symptoms.
Routine chemistry and hematology were taken from the first sample. Only the CK-MBact results of samples at 6, 12, 20, and 24 hours after t0 were reported to the physician. Myoglobin, CK-MBmass, and troponin T results were not reported.
The protocol was approved by the Ethics Committee of our institution.
Diagnosis of AMI
The final diagnosis of AMI was established
at hospital discharge
on the basis of the patient's clinical history and symptoms, ECG
abnormalities, and typical rise and fall in the serum
CK-MBact curve, with a peak exceeding 8 U/L using the
results from all time points.
Laboratory Analysis
Blood was collected in 10-mL
heparin-coated tubes and
centrifuged without delay. Cells were discarded, and plasma was
used to perform the myoglobin turbidimetric assay and the
CK-MBact assay. The remaining plasma was stored at
-20°C until further analysis.
CK-MBact
CK-MBact was measured with an ion exchange column
chromatography method as reported
previously.20 In short, CK-MM and CK-MB fractions were
separated on a Sephadex A-50 column. After separation, the activities
were measured with a commercial kit (CPK,
acetylcysteine-activated, product 124184,
Boehringer Mannheim). The reaction was started by the addition
of creatine phosphate, and the activities were measured at 340 nm in a
spectrophotometer. The upper reference limit of CK-MBact in
this assay is 8 U/L.
CK-MBmass
CK-MBmass assay was performed with the
immunochemical method as implemented on the ACS-180 analyzer
(CIBA Corning). The upper reference limit was 8.0 ng/mL; linearity was
from 0 to 500 ng/mL. The turnaround time of the assay (the time from
blood sampling until the availability of the result) was 45
minutes.
Myoglobin
The myoglobin assay (Turbiquant
myoglobin, Behringwerke) for use
with the Behring Turbitimer analyzer was used for rapid
immunoturbidimetric determination of myoglobin concentrations in
plasma. This assay is based on polystyrene particles coated with rabbit
anti-human myoglobin antibodies, which form agglutinates with
myoglobin present in serum or plasma. The agglutination causes an
increase in turbidity measured with a photometer. The measurement range
was 50 to 650 ng/mL. The upper reference limit was 90 ng/mL. The
turnaround time of the assay was 20 minutes.
Troponin T
Troponin T was measured with an ELISA method (Boehringer
Mannheim, product 1289055) on an ES300 analyzer
(Boehringer Mannheim). The upper reference limit was 0.1 ng/mL;
the linearity range of this determination was 0 to 15 ng/mL. The
turnaround time of the assay was 2.5 hours.
Physicians' Estimate of AMI
The attending physicians
were asked to estimate the probability
of the presence of an AMI (>75%, 50% to 75%, 25% to 50%, or
<25%) using the data available on admission without any marker
results. They also estimated the accuracy of t0 on a
three-point scale: accurate within 15 minutes, accurate within 60
minutes, or not accurate within 60 minutes.
Infarct Size
To test the hypothesis that patients with large
infarcts have an
early rise of the three markers, the patients were divided into three
groups according to infarct size as estimated by the
CK-MBact peak. Infarct size categories were defined
prospectively: small, CK-MB peak <60 U/L; medium, CK-MB peak between
61 and 120 U/L; and large, CK-MB peak >120 U/L.
Statistical Analysis
Differences between the NPVs of the
three markers at 3, 4, 5,
and 6 hours after the onset of symptoms were calculated with the
2 test for differences in proportions. For the
cumulative proportion of patients with a marker above the upper
reference limit, the marker was considered to be normal or abnormal for
each patient. The time until the marker rose above the upper reference
limit was calculated. Differences between the cumulative proportion of
patients with a marker above the upper reference limit were then tested
with the generalized Wilcoxon rank-sum test for time
failure data. Differences between the cumulative proportions of
abnormal markers comparing patients with small, medium, and large
infarcts were calculated with the generalized Mann-Whitney U
test for time failure data. A value of P<.05 was considered
statistically significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion Conclusions References |
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In total, 317 patients were included in the study. Four patients were excluded because of an inability to draw blood from the indwelling catheter. Because of incorrect or incomplete data collection, 4 other patients were excluded. Therefore, 309 patients formed the study group, with 89% of the patients admitted within 6 hours after the onset of symptoms. The median time interval between onset of chest pain and admission was 135 minutes.
Patient Characteristics
Table 1
gives the
patient characteristics. Three
patients had impaired renal function with plasma creatinine
levels >120 µmol/L. Of these, 2 had AMI, and the myoglobin curve
showed a rise above the reference limit and subsequent fall to normal
values. One patient with impaired renal function had no AMI, and the
myoglobin levels in this patient were normal. These 3 patients were
therefore not excluded from analysis.
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Acute Myocardial Infarction
A final diagnosis of AMI was
present in 163 patients. Table 2 summarizes the sizes and
locations of the MIs.
CK-MBact peak value was 30±15 U/L (mean±SD) in the
subgroup with small AMI, 82±21 U/L in the subgroup with medium AMI,
and 211±78 U/L in the subgroup with large AMI.
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Unstable Angina
Fifty-four patients were diagnosed as having
severe unstable
angina (Braunwald class IIIB) and transferred to the CCU.
Twenty-four patients in this group (44%) had at least one troponin
T sample >0.1 ng/mL at some time point during the first 24 hours.
Physician's Estimate of AMI and Time of Onset of
Symptoms
Table 3 shows the estimate of the attending
physician of the probability of the presence of AMI on admission
compared with the final diagnosis of AMI. In 102 patients, the
probability of AMI being present was estimated to be >75%.
Ninety-five of these patients were finally diagnosed as having AMI.
In the remaining 207 patients with intermediate or low probability of
AMI, early marker results may have been helpful in decision making.
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In reconstructing the exact time of t0, the attending physician sometimes interviewed the patients' relatives. The t0 was estimated to be accurate within 15 minutes in 189 patients and between 15 and 60 minutes in 103 patients. In 17 patients, t0 could not be determined accurately within 1 hour.
Test Characteristics
For every time point, the sensitivity,
specificity, PPV, and NPV
of a single sample was calculated for each marker (Table 4).
Specificity and PPV of the CK-MBact do
not reach 100%, although the gold standard for AMI was based on the
CK-MBact results. In the gold standard for AMI, however,
the abnormal CK-MBact result was defined as a typical rise
and fall of the whole CK-MBact curve, and the present
analysis is based on single time points. Some
false-positive CK-MBact results may have resulted from
assay error or the presence of macro-CK. Also, the CK-MBact
level in some patients with small AMI was already falling below 9 U/L
at 20 and 24 hours after the onset of chest pain. This caused the
sensitivity to fall from 96 at 16 hours to 92 at 24 hours and the NPV
to fall from 94 to 86, respectively.
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Table 5 shows the
sensitivity, specificity, NPV, and PPV
of the subgroup of 207 patients who were estimated by the attending
physician to have a probability of AMI of <75% on admission.
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The NPV
of each marker is plotted against time after the onset of
symptoms in Fig 1. Each point represents the
probability of AMI not being present in the presence of a single
test result below the upper reference limit at that time point. The NPV
of myoglobin was significantly different from the other markers at 3,
4, 5, and 6 hours after the onset of symptoms (myoglobin versus
CK-MBact, P<.002; myoglobin versus
CK-MBmass, P<.03; myoglobin versus
troponin T, P<.01). The NPV of CK-MBmass was
significantly different from CK-MBact at 4 and 6 hours
after the onset of symptoms (P<.02) and from troponin T at
6 hours after the onset of symptoms (P<.01). There was no
difference in the NPV of CK-MBact and troponin T at 3, 4,
5, and 6 hours after the onset of symptoms. Fig 2 gives
the NPV in the subgroup of patients with a low probability of the
presence of AMI. As the prevalence of AMI decreases in this subgroup,
the NPV in the early hours is increased for all markers. The NPV of
myoglobin was significantly different from CK-MBact at 4
and 5 hours after the onset of symptoms (P<.008). The NPV
of myoglobin was significantly different from troponin T at 6 hours
after the onset of symptoms (P<.03). There was no
significant difference in the NPVs at all other time points in this
subgroup.
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Cumulative Proportions of Markers Above the Upper Reference
Limit
Because serial samples were taken of all patients, it was
possible
to calculate at what time point the markers rose above the upper
reference limit. Fig 3 shows the cumulative proportion
of patients with AMI with a sample above the upper reference limit,
comparing CK-MBmass, myoglobin, and troponin T. The
cumulative proportion of patients with a myoglobin result above the
upper reference limit was significantly higher in the early hours than
for CK-MBmass and troponin T (P<.0001). At 6
hours, 97% of patients with AMI had a myoglobin result above the upper
reference limit. The cumulative proportion of CK-MBmass was
significantly earlier than troponin T (P<.0001).
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Fig
4 shows for each marker the cumulative proportion of
patients with a sample above the upper reference limit, with the
patients divided into subgroups with small, medium, and large infarcts.
The cumulative proportion of patients with an abnormal myoglobin,
CK-MBmass, and troponin T in the subgroup with small
infarcts was significantly lower than in the subgroup with large
infarcts (myoglobin, P=.04; CK-MBmass,
P=.013; troponin T, P=.016).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion Conclusions References |
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It is estimated that in one third of patients AMI is not recognized by the physician or the patient because chest pain is atypical or absent.21 22 The ECG can be misleading in 8% of all patients with AMI and indeterminate in another 12%.23 As many as 50% of patients with AMI may initially arrive at emergency rooms with nondiagnostic ECGs.24 To rule out AMI on the basis of cardiac markers, some time must elapse after the onset of symptoms. This time is needed for the marker to rise above the upper reference limit of the assay used and the turnaround time of the particular assay. In hospitals with "normal" emergency room facilities, this means that these ruled-out AMI patients will be admitted to the CCU and occupy up to 30% to 50% of the available CCU beds.25 Ruling out AMI early on the basis of cardiac markers may prevent unnecessary CCU admissions.
We demonstrated with frequent serial sampling that the NPVs of
myoglobin, CK-MBmass, and troponin T change rapidly
in the early hours after the onset of symptoms. Several studies report
myoglobin to be a useful marker for MI on
admission.7 9 14 16 With a
turnaround time of 20 minutes,
AMI can be ruled out on a single myoglobin sample with 89% certainty
at 5
hours after t0 (Fig
1
). However, the NPV of
myoglobin declines rapidly after 7 hours in contrast to the other
markers with slower appearance and clearance kinetics. This is
explained by the return to normal values of myoglobin after 7 hours.
The NPV of CK-MBmass increased earlier than that of
CK-MBact and reached 95% at 7 hours. The turnaround time
of this assay was 45 minutes; therefore, AMI can be ruled out with 95%
certainty with CK-MBmass 8 hours after t0. The
NPV of troponin T increased relatively late, comparable to that of
CK-MBact, reaching 92% 12 hours after the onset of
symptoms. An assay with a long turnaround time will delay this even
further. Therefore, we conclude that troponin T appears not to be a
suitable early marker for ruling out AMI. The specificity of troponin T
was <90% after 6 hours owing to 24 patients with unstable angina who
had elevated troponin T, as was described in other
reports.3 17 26 Although these patients
may be at
increased risk of subsequent cardiac events, it currently is unclear
whether a change in management of these patients from current clinical
practice will improve their prognoses.
Table 3 shows that of the 102 patients in whom the attending
physician
estimated the probability of the presence of AMI as >75%, 95 patients
(93%) were confirmed as having AMI. We analyzed the subgroup
of 207 patients with a relatively low probability of AMI in whom
cardiac markers could have influenced patient management. The attending
physician estimated the probability of the presence of AMI as <75%.
The NPV in this subgroup was higher in the early hours than in the
total patient group for all three markers (Fig 2). This occurs
because
patients with obvious (larger) AMI and their early (false-negative)
samples were excluded, and the overall prevalence of AMI decreased.
Thus, the NPV of myoglobin reached 94% at 5 hours and the NPV of
CK-MBmass reached 94% at 6 hours in this subgroup. Again,
the NPVs of troponin T and CK-MBact are comparable in this
subgroup.
The cumulative proportion of patients with AMI with a sample above the
upper reference limit at each time point illustrates the early rise of
myoglobin in AMI patients. The cumulative proportion in the
analysis for the subgroups with small, medium, and large AMI
clearly demonstrates that CK-MBmass and troponin T rise
later in patients with small infarcts, the patients most likely to be
retained in the emergency room for ruling out AMI (Fig 4). This
means
that the size of the infarcts of the patients studied will influence
the sensitivity and specificity in the first 8 hours after the onset of
symptoms for CK-MBmass and troponin T, while this effect is
less obvious for myoglobin.
As reported by Mair et al,15 CK-MBmass increases 1 hour earlier than the total CK or CK-MBact, depending on the upper reference limit of the assay. In that study, however, the size of the infarcts was not reported. Because 35 of 36 AMI patients were eligible for thrombolytic therapy and CK-MBmass values returned to normal a median of 74 hours after the onset of symptoms, these patients probably suffered large infarcts. Their data on the cumulative proportion of first abnormal values show higher proportions at 4 to 7 hours after the onset of symptoms than our data, but the more rapid increase of the CK-MBmass as a result of thrombolytic therapy may explain this difference. Bakker et al19 reported on the value of the CK-MBmass in the early diagnosis of AMI, but they divided the patients into only two groups: admission within 4 hours or between 4 and 12 hours after the onset of chest pain. Our data demonstrate that in the interval between 4 and 12 hours the sensitivity of CK-MBmass ranges from 63% to 99% and the NPV from 69% to 99%, depending on the exact time interval from the onset of symptoms. In the study of Bakker et al,19 infarct size was not reported, but 75 of 154 patients had Q-wave AMI, and 50 received thrombolytic therapy. Katus et al2 and Ravkilde et al27 reported 100% sensitivity of troponin T for the detection of AMI and 28% and 69% specificity. In those studies, plasma was sampled on admission and at 6-hour intervals. Katus et al2 did not report infarct size. In the study of Ravkilde et al,27 average peak CK-MBact was 118 U/L, ranging from 12 to 528 U/L. Therefore, their reported sensitivity for troponin T may have been overestimated by late admission or a predominance of patients with large infarcts.
It is important to take the onset of symptoms as the reference point in time for the evaluation of the rapid changes in diagnostic value of biochemical markers in the early hours. Puleo et al25 showed that patients with MI reach the hospital sooner than patients without MI. This can lead to potential bias if time of admission is taken as the reference time point. To the best of our knowledge, this is the first study that explicitly estimated the accuracy of the reported time of onset of symptoms. The majority of the reported time points in our study are estimated to be accurate within 1 hour.
To decide the clinical usefulness of these markers in ruling out AMI, the turnaround time of the assay should be taken into account.
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Conclusions |
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TopAbstractIntroductionMethods Results Discussion Conclusions References |
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Our data indicate that for the ruling out AMI in the emergency room in the early hours after the onset of symptoms, myoglobin was a better marker than CK-MBmass and troponin T. The NPV of myoglobin was significantly better that those of the other markers 3, 4, 5, and 6 hours after the onset of symptoms. Maximum NPV of myoglobin reached 89% to 94%, depending on the patient population studied. After 7 hours, however, the NPV of CK-MBmass already reached 95%.
For all markers the early NPV was higher in the subgroup of patients with a low probability of the presence of AMI, but the differences between markers were smaller.
All three markers increased earlier in patients with large infarcts, and differences in reported values of sensitivity and specificity in the literature may be explained by differences in infarct size of the patients studied and the time of early sampling relative to t0.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a grant from the Dutch Heart Foundation (grant No. 90-290). Boehringer Mannheim, Behringwerke, and CIBA Corning kindly supplied the reagents used in this study. We thank the physicians and nursing staff of the CCU and CER of the Academic Medical Center for their enthusiasm and efforts to include patients in this study. Special appreciation is due Els van Dongen for secretarial work and Marriette Verstappen and Jan van Straalen for their contributions to data processing and performance of the marker assays.
Received May 22, 1995; revision received July 17, 1995; accepted August 3, 1995.
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