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Rheumatology 2004;43:461466 doi:10.

1093/rheumatology/keh067
Advance Access publication 6 January 2004

Echocardiography and pulmonary function as


screening tests for pulmonary arterial hypertension in
systemic sclerosis
D. Mukerjee, D. St. George1, C. Knight, J. Davar2, A. U. Wells3,
R. M. Du Bois3, C. M. Black and J. G. Coghlan2

Objective. A prospective study to evaluate echocardiography and gas transfer (DLCO) by comparison with cardiac
catheterization in discriminating between patients with and without systemic sclerosis-associated pulmonary arterial
hypertension (SScPAH).
Method. A total of 137 (52 with and 85 without pulmonary brosis) had echocardiography and lung function tests within
3 months of their denitive invasive study.
Results. At cardiac catheterization 99 of these patients were found to have PAH, while PAH was excluded in 38.
Echocardiographically estimated tricuspid gradient (TG) showed a moderate positive correlation (r2 0.44, P<0.005) with
both mean pulmonary pressure and invasively determined tricuspid gradient. DLCO showed a weak correlation (r2 0.09,
P 0.006), when compared with mean pulmonary arterial pressure. In total, 97% of patients with an echocardiographically
determined TG of >45 mmHg were found to have pulmonary hypertension at catheterization. However, no threshold could be
dened with either screening test that safely excluded PAH.
Conclusions. The positive predictive accuracy of currently used non-invasive tests are adequate for the diagnosis of advanced
PAH provided sufciently high thresholds (TG >45 mmHg or DLCO <55% predicted) are used. These tests cannot be relied
upon to exclude pulmonary hypertension where pre-test probability is high.
KEY WORDS: Pulmonary arterial hypertension, Echocardiography, Tricuspid gradient, DLCO, Cardiac catheterization, Systemic
sclerosis.

Idiopathic pulmonary hypertension (IPH), previously known advanced PAH related to systemic sclerosis (SScPAH). There is
as primary pulmonary hypertension, is a progressive disorder a scarcity of published data on the reliability of these techniques
historically associated with a poor prognosis [1]. In the setting of in instances where PAH is not clinically evident. In the context of
systemic sclerosis (SSc) the outlook for patients with pulmonary SScPAH, Denton et al. [18] performed Doppler echocardiography
arterial hypertension (PAH) was reported to be even worse [2] than to estimate the tricuspid gradient (TG), an indirect and observer-
IPH. Recently, effective therapies have become available [37] and dependent measure of pulmonary artery pressure elevation, on 33
recent registries suggest that with treatment the prognosis has consecutive SSc patients clinically suspected to have PAH. They
improved relative to historical controls [8, 9]. subsequently conrmed the diagnosis in 21 of these patients (64%)
Most authorities recommend non-invasive testing as part of on cardiac catheterization (where the mean pulmonary artery
a screening programme for those at risk of developing PAH [10]. pressure was directly measured). Echocardiography correctly
SSc is the best known example of an at-risk group with a identied 19 of these patients, giving a sensitivity of 90% and
prevalence of PAH of up to 1015% [11]. Other at-risk popula- specicity of 75%. Interestingly, they noted a difference of up to
tions are known to exist. These include relatives of patients with 29 mmHg between echo and catheter ndings, the authors
familial PAH [12], patients with other connective tissue diseases concluded that echocardiography is a useful non-invasive, initial
[13, 14] and patients with pulmonary embolic disease [15], all of screening tool. The role of carbon monoxide diffusing capacity
whom may benet from regular screening. The accuracy of (DLCO) as a non-invasive measure of PAH is less certain. Stupi
echocardiography or pulmonary function testing has not been et al. [16] and Ungerer et al. [17] have demonstrated an association
formally assessed against the gold standard diagnostic technique between DLCO <4055% and isolated SSc PAH in a total of 87
of cardiac catheterization in any of these at-risk populations. patients. Steen et al. [19] found that an isolated reduction in DLCO
Although echocardiography has been evaluated in populations is a frequent abnormality in SSc. Of their 73 patients followed-up
where the diagnosis of pulmonary hypertension has already been for a mean 5.4 yr, ve developed PAH. In a smaller population of
established, these are very different groups from ones where mild predominantly IPH patients, Burke et al. [20] and Jezek and
pulmonary hypertension may or may not be present. Widimsky [21] were unable to conrm a clear link between a low
Both echocardiography [16] and pulmonary function testing [17] DLCO and PAH. Krowka [22] and Capomolla et al. [23] have
appear to perform adequately in identifying patients with recommended that DLCO should be added to echocardiography

Department of Rheumatology, 1Clinical Information Centre and 2Department of Cardiology, Royal Free Hospital, Pond Street, London NW32QG and
3
Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK.

Submitted 3 December 2002; revised version accepted 13 October 2003.


Correspondence to: J. G. Coghlan. E-mail: gerry.coghlan@royalfree.nhs.uk
461
Rheumatology Vol. 43 No. 4 British Society for Rheumatology 2004; all rights reserved
462 D. Mukerjee et al.

as the initial diagnostic screen for PAH. These authors had small Clinical review
cohorts of patients with PAH resulting from a mixture of causes
(including SSc, systemic lupus erythematosus, IPH and chronic At the RFH site, annual clinical review was performed in clinics
thromboembolism). They found that a fall in DLCO in addition to directed by CB, using a standard proforma. The presence or
a rise in echo TG correlated with the onset of PAH at cardiac absence and grade of dyspnoea [modied New York Heart
catheterization. Association (NYHA) grading] were established at each review.
Thus, though widely used in screening programmes, the positive Patients were identied as having unexplained dyspnoea if severe
and negative predictive values and thresholds for diagnosis on pulmonary brosis on high-resolution CT (HRCT) or signicant
echocardiography and pulmonary function testing are unknown. airway disease on pulmonary function testing were not found.
Establishing the accuracy of non-invasive tests in the setting of SSc Patients from either site (RFH, RBH) meeting the criteria for
is important. It will facilitate the development of robust PAH catheterization were formally reviewed in the pulmonary hyperten-
screening programmes in the SSc population, while providing sion clinic led by JC, and the dyspnoea grade, clinical ndings and
insights to the limits of these techniques when applied to other results of investigations evaluated. Catheterization was scheduled
disease states where the prevalence of PAH is lower. for all patients within 1 month of review, where possible, if the
The aims of this study, therefore, were: (i) to evaluate the patient agreed and was considered t for the procedure.
reliability of echo-estimated TG or DLCO in predicting the
presence of pulmonary hypertension at cardiac catheterization;
(ii) to determine threshold values which reliably establish or Pulmonary function testing
exclude the diagnosis of pulmonary hypertension; and (iii) to
Annual pulmonary function testing was performed in the two
determine whether echocardiography or DLCO abnormalities
institutions (Dr P. Dillworth at RFH and Prof. Du Bois at RBH).
were predictive of the severity of SScPAH in terms of the degree
Patients with a total lung capacity (TLC) of <70% underwent
of haemodynamic impairment abnormality seen at catheterization.
high-resolution CT unless they were already known to have
advanced interstitial lung disease. Patients with a corrected
DLCO of <50% in the absence of advanced interstitial lung
disease were invited for cardiac catheterization irrespective of
Patients and methods
echocardiographic ndings. All patients in whom DLCO had
An active screening programme for the early identication of fallen by more than 20% since the previous examination were
SScPAH has been in operation at the Royal Free Hospital (RFH) invited for catheterization, unless active brosis (falling lung
since 1998. To evaluate the efcacy of this programme, standard- volumes or ground-glass appearance on high-resolution CT)
ized criteria for invasive evaluation were instituted in 1998. Cardiac explained the change.
catheterization was performed in all patients in a background SSc
population who met the following criteria:
(1) The tricuspid gradient on transthoracic echocardiography Echocardiography
exceeded 35 mmHg or, if the gradient could not be Annual echocardiography was performed either at the Royal Free
determined, the pulmonary acceleration time was less than Hospital (under the direction of JD) or at the Royal Brompton
100 ms. Hospital (under the direction of Dr Henein) using standardized
(2) The corrected DLCO was less than 50% of predicted in templates for the evaluation of right ventricular dimensions,
patients without advanced (grade 3 or 4 on high-resolution tricuspid gradients (TG) and, more recently, pulmonary accelera-
CT) pulmonary brosis, or any patient in whom the corrected tion times. All patients in whom a TG of greater than 35 mmHg, or
DLCO fell by more than 20% in the previous 2 yr. in whom right ventricular dilatation or shortened pulmonary
(3) Any patient with unexplained exercise limitation. acceleration times were found, were invited for cardiac catheter-
ization, irrespective of symptoms or pulmonary function test
Patients were drawn from the population attending the Royal
ndings.
Free Scleroderma Unit, the Interstitial Lung Disease Unit at the
Royal Brompton Hospital (RBH) and from external referral
sources. Full written informed consent was obtained from all
patients who underwent invasive cardiac catheterization. Cardiac catheterization
Right heart catheterization was performed from a right femoral
approach using a 7 French Bard thermodilution catheter under
local anaesthesia. Patients were allowed to rest for 5 min after
Population
catheter insertion, and then baseline haemodynamics were per-
Between 1998 and 2002, 219 patients have met these criteria and formed on two occasions over a period of 5 min. If pulmonary
proceeded to cardiac catheterization; 148 were found to have arterial pressure, heart rate or pulmonary vascular resistance
pulmonary arterial hypertension and in 71 patients the diagnosis varied by more than 10%, further assessments were performed
was excluded. These patients are considered in another publication until stability was established. Patients with a mean pulmonary
[11]. However, not all these patients had pulmonary function pressure of less than 25 mmHg underwent benchy exercise
testing and echocardiography prior to catheterization and in many for 2 min if the resting pulmonary vascular resistance exceeded
(especially asymptomatic patients) the investigation leading to 200 dynes per cm5. Where exercise mean pulmonary pressure
catheterization had been performed more than 3 months prior exceeded 30 mmHg, patients were dened as having PAH. Patients
to invasive evaluation. with PAH underwent vasodilator testing using a graded iloprost
From this population we identied all patients in whom infusion regime (2, 6 and 12 ng/kg per min at 5-min intervals).
pulmonary function testing and echocardiography had been Pulmonary angiography was performed in patients with non-
performed in the 3 months before cardiac catheterization. We low risk ventilation perfusion scans unless CT pulmonary
examined the predictive power of these non-invasive tests for the angiography had already excluded pulmonary embolic disease.
identication of patients who are found to have pulmonary Left heart catheterization was additionally performed in all
hypertension on catheterization. For the purposes of standardiza- patients with angina-like chest pain, or in whom dyspnoea
tion we only included patients whose tests had been performed at remained unexplained on the basis of pulmonary function testing
the RFH or RBH. and right heart pressures. The catheterization operators were not
Performance of non-invasive screening tests for SScPAH 463

blinded to the echocardiographic and lung function test informa- Patients without pulmonary brosis
tion as these investigations were performed prior to this procedure.
Indications for catheterization included unexplained dyspnoea in
74 out of 85 (as an isolated abnormality in 26 patients, of whom 12
had PAH). The echo-estimated TG was over 35 mmHg in 49 out of
Statistical analysis 85 (as an isolated abnormality in six of whom one had PAH). The
The statistical software package Microsoft Excel was used. The corrected DLCO was <50% in 25 out of 85 patients (isolated
echo-estimated tricuspid gradients (otherwise known as the pul- abnormality in none). Eight patients had a fall in their corrected
monary artery systolic pressures) were correlated with the baseline DLCO >20% over the previous 2 yr as their reason for cardiac
mean systolic pulmonary artery pressure (mPAP) minus the right catheterization (this was an isolated nding in two patients). None
atrial pressure (RAP) on cardiac catheterization. The mean PAP of these eight patients had PAH. A single patient was catheterized
was correlated with the DLCO and an r2 value derived for patients based only on pulmonary acceleration time and PAH was
with no pulmonary brosis. The patients with advanced brosis excluded.
were not included in the DLCO correlation as it was felt that the PAH was found in 54 of the 85 studied, 33 had NYHA grade 3
presence of brosis might be a confounding factor. or 4 dyspnoea. Two patients were NYHA grade 1, and identied
To determine the predictive capacity of the screening tests for purely on the basis of the screening tests (TG >35 mmHg in both,
the diagnosis of PAH, threshold tricuspid gradient levels (30, 35, 40 plus a falling DLCO in one). However, 11 patients with mild
and 45 mmHg) and corrected %DLCO (50, 55 and 60%) were dyspnoea (NYHA grade 2) had not been identied as symptomatic
analysed for positive and negative predictive values; 44 tables until rigorously questioned.
were constructed for each threshold and the sensitivity, specicity, Twenty two of the 31 patients in whom PAH was excluded were
positive and negative predictive values calculated. also symptomatic. Eight of these patients were NYHA grade 3.
Specic diagnoses (diastolic dysfunction and coronary disease)
were found in ve of these patients. Thus, with rigorously applied
questioning most patients in whom isolated PAH was found were
Results symptomatic. However, a third of symptomatic patients did not
During the 4-yr period of the study serial echocardiography, have PAH.
pulmonary function testing and clinical evaluation were performed The tricuspid gradient exceeded 45 mmHg in 21 of the 54
on 574 patients at either the RFH or RBH. patients with isolated PAH, while only one patient in whom PAH
During this period 137 patients had cardiac catheterization was excluded at catheterization had a TG of >45 mmHg. Eighteen
performed within 3 months of screening; 85 of these patients had patients who had isolated PAH had a TG of <35 mmHg, and eight
no or mild brosis, while 52 had grade III or IV brosis on high- patients with a TG of <30 mmHg on echocardiography had
resolution CT scanning. Table 1 shows the differences between the pulmonary hypertension at catheterization.
populations with and without pulmonary brosis. The corrected DLCO was <50% predicted in 21 of the 54
patients with isolated PAH, and less than 55% in 31, while
similarly impaired gas transfer was found in only three and nine,
respectively, of the 31 patients in whom PAH was excluded.
Total population Nevertheless, PAH was found in 23 patients with a predicted
As pulmonary brosis does not inuence the accuracy of corrected DLCO of greater than 55%, again suggesting that
echocardiography, the whole population was considered in asses-
sing the accuracy of tricuspid gradient in identifying patients with
TABLE 2. Relationship between echo tricuspid gradient thresholds of 30,
PAH (Table 2). Echocardiography showed good specicity at high
35, 40 and 45 mmHg and sensitivity, specicity, negative and positive
thresholds (TG 45 mmHg) associated with a high false-negative predictive values in 137 SSc patients suspected to have PAH
rate, and poor specicity at lower thresholds.
These ndings suggest that echocardiography using TG and Positive Negative
pulmonary acceleration time lacks the sensitivity required to Echo TG thresholds Sensitivity Specicity predictive predictive
exclude PAH. A positive correlation was found between TG and in mmHg (%) (%) value (%) value (%)
mean PAP (Fig. 1), and additional abnormalities on echocardio-
<30 vs 30 88 42 73 57
graphy (right ventricular dilation in 23, reversed septal motion in
<35 vs 35 75 66 85 50
16) were found only in those with a TG of >40 mmHg, thus <40 vs 40 58 87 92 44
abnormal echocardiographic ndings are increasingly found as <45 vs 45 47 97 98 41
pulmonary hypertension reaches advanced stages.

TABLE 1. Characteristics of 137 SSc patients undergoing cardiac catheterization for suspected PAH within the 3-month period after screening with
echocardiography and lung function tests, including DLCO estimation, between 1998 and 2002

SSc with no pulmonary brosis


(excluded on HRCT chest) SSc with pulmonary brosis

Number of patients 85 52
Mean age (yr) 62  11 64  7
Duration of SSc (yr) 12  8 14  7
Autoantibodies ACA 41, SCL70 8, ANA 22, other ENA 14, SCL70 28, ANA 24
mPAP on catheter (mmHg) 39  12 36  11
PASP - RAP on catheter (mmHg) 45  22 49  19
PASP on echo (mmHg) 39  15 46  18
Corrected DLCO 57  12% 39  12%

Corrected DLCO, % corrected transfer factor for carbon monoxide; mPAP, mean pulmonary artery pressure; PASP, pulmonary artery systolic
pressure; RAP, right atrial pressure.
464 D. Mukerjee et al.

FIG. 1. Relationship between systolic pulmonary pressures on cardiac catheter and echocardiographically determined tricuspid
gradient (echo TG) in 137 patients. A clear positive correlation is evident (r2 0.45); however, PAH is evident in many patients with
low tricuspid gradients.

FIG. 2. Relationship between mean pulmonary pressures (mPAP) on cardiac catheter and corrected DLCO in 85 SSc patients without
signicant pulmonary brosis. A weak negative correlation is seen (r2 0.09), but few patients with very low gas transfer do not have
PAH.

TABLE 3. Relationship between falling DLCO thresholds and sensitivity, associated with more advanced PAH. The average mPAP was
specicity, negative and positive predictive values in 85 SSc patients, in 42 mmHg in patients with a DLCO of less than 55%, but only
whom signicant pulmonary brosis had been excluded, undergoing 32 mmHg in patients with PAH and a DLCO of greater than 55%.
cardiac catheterization for suspected PAH However, the strength of the relationship between mPAP and
DLCO is weak (Fig. 2) with an r2 value of 0.09. Thus, as with
Positive Negative
% DLCO Sensitivity Specicity predictive predictive echocardiography, the test performs best in advanced rather than
thresholds (%) (%) value (%) value (%) early PAH, but the relationship with severity is less secure.

>60 vs 60 74 45 70 50
>55 vs 55 57 71 78 49
>50 vs 50 39 90 88 46 Patients with pulmonary brosis
Thirty-eight of the 52 patients with pulmonary brosis had
a tricuspid gradient of 35 mmHg. All but one were breathless
on exertion. Fourteen patients with TG <35 mmHg were studied,
preserved gas transfer is insufciently sensitive for the exclusion of six because of a falling DLCO, and eight with increasing dyspnoea
PAH. Table 3 demonstrates the relationship between lower unexplained on lung function tests and high-resolution CT
thresholds of DLCO (60, 55 and 50%) and the positive and changes. Five of the eight with increasing symptoms had PAH
negative predictive values at each threshold in this group of 85 on catheterization, while two of the six whose symptoms had not
SSc patients. Among patients with PAH, a lower DLCO was deteriorated had PAH.
Performance of non-invasive screening tests for SScPAH 465

The tricuspid gradient exceeded 45 mmHg in 25 of the 45 Echocardiographic assessment of TG is traditionally regarded
patients with pulmonary brosis-associated PAH, while no patient as an extremely accurate technique [29]. However, under- and
in whom PAH was excluded had a TG of >35 mmHg. Pulmonary overestimations of TGs are well known to occur. Overestimates are
hypertension was found in seven of the 14 patients with a TG of rarely reported [30]. Underestimation of the pressure difference is
<35 mmHg. Fewer patients with low tricuspid gradients were expected in a minority of cases, due either to the absence of
studied in the pulmonary brosis group, as breathlessness alone tricuspid regurgitation or inability to obtain full alignment with the
was rarely considered unexplained in this population. regurgitant jet [31, 32]. Not surprisingly, therefore, the bulk of the
inaccuracy associated with echocardiographic estimation is due to
underdiagnosis of mild to moderate PAH. The frequency of
Discussion overestimation of the pressure difference identied in this study is
not currently well recognized, though this has been reported by
The main ndings of this study are that echo-estimated TG (or other investigators [3133]. Hinderleiter [32] found that Doppler
systolic pulmonary artery pressure) and DLCO, the most com- echo estimates and invasive catheter measurements of pulmonary
monly used screening tools for SScPAH, perform well only in the artery systolic pressure were signicantly correlated (r 0.57,
diagnosis of advanced pulmonary hypertension. Using conserva- P<0.001) in 70 out of 81 patients with IPH. However, where
tive thresholds (TG >40 mmHg or DLCO <55%) nearly half the regurgitant velocity was measurable, Doppler estimates exceeded
patients with symptomatic PAH are left without a rm diagnosis. invasive measurements in 35% of cases. These investigators
With lower echo TGs or higher DLCO thresholds the number of concluded that echocardiography is useful in estimating the
false-positive diagnoses increases progressively. severity of PAH, but may not quantify small changes in tricuspid
The importance of screening programmes for SScPAH has long gradients in individual patients. The reason for this discrepancy is
been recognized [10]. With advances in our understanding of unknown, but several explanations have been proposed. Valchiery
genetics [24], and the ability to undertake complex procedures et al. [34] explained the lack of agreement between catheter and
in patients at risk of PAH [25], it is increasingly important that echo measurements by a variety of factors. These include clinical
we understand the strengths and limitations of our diagnostic estimate instead of direct measurement of right atrial pressure, an
and screening tools. From our data it would appear that echo- unavoidable discrepancy between sonic beam to ow angle, and
estimated TG and DLCO cannot be regarded as adequate for the uncertainty in the assignment of the maximum velocity of the
exclusion of pulmonary hypertension in breathless patients. How regurgitant signal. Similarly, Rich et al. [35] and Richards et al.
these tests perform in asymptomatic populations cannot be [36] have demonstrated variations of up to 30% within 24 h
determined from this study as very few patients had asymptomatic in pulmonary artery pressures. Again, they concluded that
pulmonary hypertension. this variation might lead to the overestimation recorded by the
Contrary to previous authors [26], we did not nd that DLCO one-off echo measurement.
was a useful method of identifying patients with early pulmonary
vasculopathy associated with SSc. Rather, this technique appeared
to identify patients with advanced PAH. Limitations
SScPAH patients are unusual in that they become symptomatic Our study had several limitations. Only one aspect of the
and develop reduced cardiac output at relatively low pulmonary echocardiographic study has been considered in detail. During
pressures. As a consequence we have been able to analyse the evaluation pulmonary artery acceleration times, right ventricular
impact of using lower thresholds of TG on false-positive rates of diameters and estimates of left ventricular diastolic dysfunction
diagnosis of pulmonary hypertension. As one uses TG thresholds were also recorded. The former two are essentially conrmatory
below 40 mmHg the issue of false positives becomes prohibitive, measures for advanced pulmonary hypertension rather than useful
and thus we cannot recommend resting echocardiographic exam- in diagnosing early PAH, the latter only important for excluding
ination as a method for identifying populations with early PAH in post-capillary causes of PAH.
the setting of SSc. In addition it is evident from our data that Multiple operators in two institutions performed the echocar-
resting echocardiography may not reliably exclude PAH in diograms and despite strict quality control at both institutions there
breathless patients. Whether modications such as exercise may be signicant intra-observer variability between operators
echocardiography [12], pulmonary vascular resistance estimation results. This may explain some of the spread of results obtained.
by colour-ow Doppler [27], or the use of new contrast media such There was a maximum 3-month delay between the screening tests
as sonicated albumin [28] can ll this role requires further study. and cardiac catheterization. This may have caused bias towards the
Echocardiography performed better in identifying patients who null, but none of the patients deteriorated in their functional state
require urgent referral and treatment for advanced disease. Patients during this time period, suggesting disease stability. This limitation
suspected of having advanced IPH (formerly known as PPH represents real-life screening rather than the ideal, which can only
modied NYHA grade III/IV, cardiac index <2.1l/min per m2, be occasionally achieved outside research situations.
right atrial pressure >11 mmHg) have a 35% annual mortality We did not routinely investigate patients with a DLCO of
without therapy [1]. In SSc the annual mortality in this PAH 5055% in the absence of symptoms or echocardiographic
population is 40% even with therapy [11]. Patients in this group abnormalities. The signicant number of symptomatic patients
need urgent invasive assessment and institution of effective therapy with PAH whose DLCO exceeded 5055% strongly suggests that
as proposed by Gibbs [10]. Relying on echocardiography alone a sizeable asymptomatic population of patients with PAH and
to identify these patients results in a false-negative rate of a DLCO of 5055% has not been overlooked.
42% (patients with PAH and echo TG <45 mmHg). However,
combining echocardiography and clinical ndings (modied
NYHA dyspnoea grade) identies >90% of patients with Conclusion
advanced PAH. Thus, any patient with SSc who has developed Resting echocardiography and pulmonary function testing are less
breathlessness while walking on the at at a normal pace within the sensitive than clinical history in identifying patients with early
preceding 612 months should be regarded as potentially having pulmonary hypertension in SSc patients. Both techniques identify
advanced pulmonary hypertension irrespective of echocardio- patients with advanced PAH with moderate specicity in the
graphic ndings. Many of these patients will have lung brosis or setting of SSc, though echocardiography correlates better with
other cardiac diseases as the cause of their symptoms, but urgent severity of pulmonary hypertension. Neither technique has the
investigation is mandatory. characteristics that make it a good screening test for early
466 D. Mukerjee et al.

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