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. Author manuscript; available in PMC: 2007 Nov 26.
Published in final edited form as: Chest. 2007 Jun 15;132(3):773–779. doi: 10.1378/chest.07-0116

High-Resolution Chest Computed Tomography Findings Do Not Predict The Presence of Pulmonary Hypertension in Advanced Idiopathic Pulmonary Fibrosis

David A Zisman 1, Arun S Karlamangla 2, David J Ross 1, Michael P Keane 1, John A Belperio 1, Rajan Saggar 1, Joseph P Lynch III 1, Abbas Ardehali 3, Jonathan Goldin 4
PMCID: PMC2093962  NIHMSID: NIHMS33917  PMID: 17573485

Abstract

Background

Reliable, noninvasive approaches to the diagnosis of pulmonary hypertension in idiopathic pulmonary fibrosis are needed. We tested the hypothesis that chest computed tomography-determined extent of pulmonary fibrosis and/or main pulmonary artery diameter can be used to identify the presence of pulmonary hypertension in patients with advanced idiopathic pulmonary fibrosis.

Methods

Cross-sectional study of 65 patients with advanced idiopathic pulmonary fibrosis with available right-heart catheterization and high-resolution chest computed tomography. An expert radiologist scored ground-glass opacity, lung fibrosis, and honeycombing in the computed tomography images on a scale of 0-4. These scores were also summed into a total profusion score. The main pulmonary artery was measured at its widest dimension on the supine full chest sequence. At this same level, the widest aorta diameter was measured.

Results

Chest computed tomography-determined fibrosis score, ground-glass opacity score, honeycombing score, total profusion score, diameter of the main pulmonary artery, and the ratio of the pulmonary artery to aorta diameter did not differ between those with and without pulmonary hypertension. There was no significant correlation between mean pulmonary artery pressure and any of the chest computed tomography-determined measures.

Conclusions

High-resolution chest computed tomography-determined extent of pulmonary fibrosis and/or main pulmonary artery diameter cannot be used to screen for pulmonary hypertension in advanced idiopathic pulmonary fibrosis patients.

Keywords: pressure, pulmonary artery; hypertension, pulmonary; pulmonary fibrosis; high-resolution chest computed tomography; diagnosis

Introduction

Idiopathic pulmonary fibrosis is a specific form of chronic fibrosing interstitial pneumonia associated with the histological appearance of usual interstitial pneumonia (UIP) 1. Pulmonary hypertension (PH) commonly complicates advanced IPF and is associated with worse prognosis 2-6.

Right heart catheterization (RHC) is the “gold standard” test to diagnose PH in IPF. However, RHC is invasive, costly and associated with complications. Although echocardiography is the most commonly used test to screen for PH in patients with ILD, it is not a reliable screening test 5,7. Reliable, noninvasive approaches to the diagnosis of PH in IPF would improve patient safety and reduce cost.

Previous studies in patients with pulmonary vascular disease and diverse lung conditions suggested that chest computed tomography (CT)-determined pulmonary artery diameters can be used to predict PH 8-12. However, this has not been tested in a homogeneous sample of patients with well-characterized IPF. Mechanistically, the severity of lung fibrosis should correlate with the prevalence and degree of PH. However, the relationships between CT assessments of lung fibrosis and pulmonary artery pressure have not been studied in patients with IPF. Therefore, in this study, we examined whether the CT-determined extent and severity of pulmonary fibrosis and diameter of the main pulmonary artery could be used to diagnose PH in advanced IPF patients.

Methods and Materials

Study sample

We retrospectively reviewed the medical records of all patients with IPF who were seen at our institution between July 1999 and June 2006. During their initial visit, all patients prospectively provided written informed consent (approved by the UCLA IRB) to use their clinical and demographic information for research purposes. All patients met accepted diagnostic criteria for IPF and the majority (74%) had histopathologic evidence of usual interstitial pneumonia 1. Three hundred and twenty two patients with well-documented IPF were seen at the center during this period and were candidates for inclusion in this study. To be included in the study, participants had to have had a high-resolution chest computed tomography (HRCT) within one month of the RHC. RHC were performed as part of the lung transplant evaluation (74%) or for participation in a clinical trial (ClinicalTrials.gov identifier: NCT00352482). Sixty-five patients met this entry criterion. Twenty-seven of them had PH.

Measurements

RHC data included measurements of pulmonary arterial pressures with the patient at rest. We defined PH as resting MPAP of > 25 mm Hg 13.

After at least five minutes of rest, pulse oximetry (SpO2) was measured on room air. Standard methodology was used for obtaining pulmonary function tests (PFT) and six-minute walk distance (6MWD) 14-17.

High-resolution Chest Computed Tomography (HRCT) Scoring System

All HRCTs were performed in the prone position acquiring 1.0- or 1.5-mm-thick sections at 1-cm throughout the entire thorax and then in the supine position. Full volume CT scans reconstructed every 3mm were acquired at suspended inspiration. HRCTs were reconstructed with a sharp kernel (Siemens, B50) and field of view (FOV) of widest outer rib to outer rib dimension. All studies were scored by one expert thoracic radiologist (JG) blinded to the patient's clinical and hemodynamic information, using a Likert scale (0 = absent, 1 = 1-25%, 2 = 26-50%, 3 = 51-75% and 4 = 76-100%) for extent of parenchymal abnormality in three categories: ground-glass opacity, lung fibrosis, and honeycombing. These scores were also summed into a total CT profusion score. This scoring system is based on that reported by Kazerooni et al 18. The following radiographic definitions were employed: ground-glass opacity: hazy parenchymal opacity in the absence of reticular opacity or architectural distortion; lung fibrosis: reticular opacification, traction bronchiectasis and bronchiolectasis; honeycombing: clustered air-filled cysts with dense walls. Each lung lobe was scored separately (upper: lung apex to aortic arch, middle: aortic arch to inferior pulmonary veins, and lower: inferior pulmonary veins to diaphragm) and the mean score over all five lobes was computed for each category of parenchymal abnormality: fibrosis (CT-fib), ground glass opacity (CT-alv), honeycombing (CT-hc) and total profusion (CT-tot = CT-fib + CT-alv + CT-hc). Lobe scores were also weighted by typical relative size (right upper lobe: 0.0935; right middle lobe: 0.0935; right lower lobe: 0.363; left upper lobe: 0.155; and left lower lobe: 0.297) and summed to create weighted scores for fibrosis (wCT-fib), ground-glass (wCT-alv), honeycombing (wCT-hc) and total profusion (wCT-tot). We also created a maximum fibrosis score (mCT-fib) based on the most affected lobe.

The main pulmonary artery diameter (MPAD) was measured at its widest dimension on the supine full chest sequence. At this same level, the widest aorta diameter (AD) was measured and the MPAD/AD ratio was calculated. MPAD was also normalized by body surface area (BSA, m2) which was calculated according to the following equation: BSA = 0.00718 × W0.425 × H0.725, where W is body weight (kg), and H is body height (cm) 19.

Statistical Analysis

We compared mean values of all putative predictors of PH in patients with and without PH, using the Student t test. We also examined the Pearson correlation coefficient between MPAP and each of the putative predictors of PH. We then regressed MPAP on CT-fib, wCT-alv, wCT-hc and MPAD/AD in a multivariable linear regression model. The CT-derived scores chosen for the model were the ones with the highest correlation with MPAP in each category (fibrosis, ground glass opacity, honeycombing, and PA size).

All tests were two-tailed, and p values of < 0.05 were required for statistical significance. All statistical analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, N.C., USA).

Power Calculations

Our study was designed to have 80% power to detect 0.75σ or larger differences in putative predictors between the PH and no PH groups (where σ is the common standard deviation in the 2 groups) and to detect correlations of 0.34 or larger between MPAP and putative predictors.

Results

The study sample (n=65) had more advanced pulmonary disease (with lower FVC, DLCO, and room air SpO2) than the rest of the cohort (n=257), but was representative of the cohort with respect to age, gender, and race (Table 1). Mean MPAP in the study sample was similar to the mean MPAP in the 56 patients with RHC data who were excluded from the study because their RHC was more than one month distant from their HRCT.

Table 1.

Descriptive statistics for major characteristics

Characteristic Mean (SD) or % Mean (SD) or %* P-value
Study sample (n=65) Excluded (n=257)
Age (years) 66.7 (8.2) 66.9 (9.6) 0.886
Males (%) 60.0 63.4 0.610
Race (%) 0.663
 Caucasian 78.5 76.1
 Hispanic 16.9 15.7
 Other** 4.6 8.2
FVC (L) 2.0 (0.7) 2.4 (0.9) 0.0008
FVC % predicted 54.3 (16.7) 64.5 (18.8) 0.0002
DLco (mL/mm Hg/min) 7.5 (3.5) 9.7 (4.3) <0.0001
DLco % predicted 31.1 (13.4) 42.1 (18.7) <0.0001
Room air SpO2 (%) 90.8 (4.7) 92.8 (4.9) 0.007
MPAP (mm Hg) 26.1 (8.9) 27.5 (10.8)§ 0.44
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*

Age and gender available in all 322 patients; race available in 320 of 322; forced vital capacity (FVC, absolute and % predicted) available in 304 of 322; diffusing capacity (DLco, absolute and % predicted) available in 293 of 322; Resting room air pulse oximetry (SpO2 %) available in 266 of 322; mean pulmonary artery pressure (MPAP) available in 121 of 322; SD = standard deviation.

§

These 56 patients had RHC data but were excluded because their RHC were not performed within one month of the HRCT.

**

Includes Asian and African-American.

Comparisons of Patients With and Without Pulmonary Hypertension

Patients with and without PH did not differ with respect to age, gender, race and BSA (Table 2). As expected, those with PH had significantly lower DLco, FVC/DLco, 6MWD and resting room air SpO2 and significantly higher MPAP than those without PH, but they did not perform significantly worse on FVC or DLco/VA and had similar CT-derived scores for extent and severity of parenchymal disease and CT-derived MPAD, MPAD/AD and MPAD/BSA. Similarly, CT scores weighted by relative lobar size and the maximum CT-derived fibrosis score over all lobes did not differ between those with or without PH.

Table 2.

Patient Characteristics Based on the Presence or Absence of PH by RHC

Characteristic Mean (SD) or % Mean (SD) or % P-value
MPAP ≤ 25 (n=38) MPAP > 25 (n=27)
Age (years) 65.8 (7.3) 67.9 (9.1) 0.31
Males (%) 60 40 1.00
Race (%) 1.00
 Caucasian 79 78
 Hispanic 16 18
 Other** 5 4
BSA 1.9 (0.2) 1.9 (0.3) 0.60
CT-fib 2.3 (0.6) 2.4 (0.7) 0.80
mCT-fib 2.9 (0.7) 2.9 (0.8) 0.81
wCT-fib 2.4 (0.6) 2.4 (0.7) 0.94
CT-alv 1.7 (0.9) 1.9 (1.0) 0.60
wCT-alv 1.7 (1.0) 1.9 (1.0) 0.50
CT-hc 1.3 (0.4) 1.3 (0.4) 0.80
wCT-hc 1.4 (0.5) 1.4 (0.5) 0.70
CT-tot 5.2 (1.6) 5.5 (1.6) 0.31
wCT-tot 5.5 (1.7) 5.8 (1.5) 0.37
AD (mm) 32.0 (2.6) 32.1 (2.4) 0.71
MPAD (mm) 31.3 (3.7) 33.1 (2.4) 0.19
MPAD/AD 0.98 (0.1) 1.03 (0.1) 0.10
MPAD/BSA 16.8 (2.6) 17.5 (2.7) 0.40
FVC (L) 1.9 (0.6) 2.0 (0.8) 0.81
FVC % predicted 52.3 (14.4) 57.1 (19.7) 0.61
DLco (mL/mm Hg/min) 8.0 (3.4) 6.5 (3.6) 0.06
DLco % predicted 33.5 (13.9) 27.0 (11.7) 0.04
FVC%/DLco% 1.8 (0.8) 2.5 (1.6) 0.04
DLco/VA % predicted 59.4 48.8 0.10
SpO2 (%) 93.3 (2.9) 87.4 (4.6) <.0001
6MWD (m) 229 (163) 61 (30) 0.04
MPAP (mm Hg) 20.5 (3.1) 33.9 (8.6) <.0001
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AD = CT-measured ascending aorta diameter, BSA = body surface area, CT-fib = CT-determined fibrosis score, CT-alv = CT-determined ground-glass score, CT-hc = CT-determined honeycomb score, CT-tot = total profusion score (CT-fib + CT-alv + CT-hc), FVC = forced vital capacity, DLco = diffusing capacity, MPAD = CT-measured main pulmonary artery diameter, mCT-fib = maximum CT-derived fibrosis score over all lobes, MPAP = mean pulmonary artery pressure, SpO2 = resting room air pulse oximetry, wCT-fib = weighted CT-determined fibrosis score, wCT-alv = weighted CT-determined ground-glass score, wCT-hc = weighted CT-determined honeycomb score, wCT-tot = weighted total profusion score, VA = alveolar volume, 6MWD = six-minute walk distance while breathing room air.

**

Includes Asian and African-American. SD = standard deviation.

Correlation Between Mean Pulmonary Artery Pressure and Putative PH Predictors

As shown in table 3, there were strong and statistically significant correlations in the expected directions between MPAP and both 6MWD and resting room air SpO2. We observed a modest and significant correlation between MPAP and DLco, DLco/VA% and FVC%/DLco%. However, there was no correlation between MPAP and FVC, CT-fib, CT-alv, CT-hc, CT-tot, MPAD, AD, MPAD/AD or the MPAD/BSA ratio (Figures 1 and 2). Similarly, there was no correlation between MPAP and CT scores weighted by relative lobar size or the CT-derived maximum fibrosis score. Furthermore, we found no correlation between other RHC-derived measurements (right atrial pressure, pulmonary vascular resistance, cardiac output, cardiac index) and any of the chest computed tomography-determined measures (data not shown).

Table 3.

Pearson correlation coefficients between the mean pulmonary artery pressure (MPAP) and putative predictors of pulmonary hypertension (PH)

Variable n r P-value**
CT-fib 65 0.042 0.74
wCT-fib 65 0.022 0.86
mCT-fib 54 0.004 0.97
CT-alv 65 0.153 0.22
wCT-alv 65 0.171 0.17
CT-hc 65 0.009 0.94
wCT-hc 65 0.025 0.84
CT-tot 65 0.009 0.38
wCT-tot 65 0.119 0.34
MPAD (mm) 65 0.148 0.24
MPAD/AD 65 0.203 0.10
MPAD/BSA 63 0.136 0.29
FVC (L) 64 0.150 0.23
FVC % predicted 64 0.235 0.10
DLco (mL/mm Hg/min) 59 -0.295 0.02
DLco % predicted 59 -0.307 0.02
DLco/VA % predicted 52 -0.408 0.003
FVC%/DLco% 59 0.435 0.0006
SpO2 (%) 59 -0.527 <0.0001
6MWD (m) 17 -0.569 0.002
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AD = CT-measured ascending aorta diameter, BSA = body surface area, CT-fib = CT-determined fibrosis score, CT-alv = CT-determined ground-glass score, CT-hc = CT-determined honeycomb score, CT-tot = total profusion score (CT-fib + CT-alv + CT-hc), FVC = forced vital capacity, DLco = diffusing capacity, mCT-fib = maximum CT-derived fibrosis score over all lobes, MPAD = CT-measured main pulmonary artery diameter, MPAP = mean pulmonary artery pressure, SpO2 = resting room air pulse oximetry, wCT-fib = weighted CT-determined fibrosis score, wCT-alv = weighted CT-determined ground-glass score, wCT-hc = weighted CT-determined honeycomb score, wCT-tot = weighted CT-determined total profusion score, VA = alveolar volume, 6MWD = six-minute walk distance while breathing room air.

**

p value for test of zero correlation

Figure 1. Relationship between CT-determined fibrosis score (CT-fib) and measured mean pulmonary artery pressure (MPAP).

Figure 1

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MPAP = mean pulmonary artery pressure, CT-fib = CT-determined fibrosis score

Figure 2. Relationship between CT-determined main pulmonary artery diameter (MPAD) and measured mean pulmonary artery pressure (MPAP).

Figure 2

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MPAP = mean pulmonary artery pressure, MPAD = CT-determined main pulmonary artery diameter

Multivariable Linear Regression of MPAP on CT-derived Predictors

We regressed the MPAP on the CT scores (one from each category) with the highest correlation with MPAP (namely, CT-fib, wCT-alv, wCT-hc and MPAD/AD) in a multivariable linear regression model. The model adjusted R-square was 0.008 (p=0.35).

Discussion

Pulmonary hypertension is common in patients with advanced IPF and its presence has a significant adverse impact on survival 2,3. Noninvasive approaches to the diagnosis of PH in IPF are needed. In this study, we found that the CT-determined extent and severity of pulmonary fibrosis and main pulmonary artery diameter do not help in identifying PH in advanced IPF patients.

Intuitively, the severity of lung fibrosis should correlate with the prevalence and degree of PH. It seems logical that as the patient's IPF progresses and their lungs become more fibrotic, the cross-sectional area of the pulmonary vascular bed is reduced, the pulmonary vascular resistance rises, and pulmonary hypertension ensues; however, in this study, MPAP did not correlate with CT-based measurements of lung fibrosis and these variables did not differ between those with and without PH. Previously, we and others have shown that MPAP does not correlate with the degree of restrictive physiology (FVC, TLC) in IPF 2-5,20. PH is also disproportionate to the degree of restrictive ventilatory impairment (FVC) in patients with sarcoidosis and pulmonary Langerhan's cell histiocytosis 21,22. This study provides the first radiographic confirmation of the notion that the loss of pulmonary vascular conductance in IPF is not proportional to the extent of fibrosis. Vascular remodeling in IPF has been the subject of intense investigation over the last few years 23-27. There is evidence of regional heterogeneity with some areas demonstrating increased vascularity and other areas demonstrating decreased vascularity 23-27. While fibroblastic foci are notable for the absence of blood vessels, they are surrounded by a rich network of vessels 28. That is probably why there is little correlation between extent of fibrosis and MPAP. Although a higher extent of lung fibrosis on CT has been associated with worse outcome in IPF patients 29-31, our findings suggest that it is unlikely that a higher CT-fibrosis portends poor prognosis in connection with PH in IPF patients. By contrast, hypoxemia is an independent predictor of mortality in IPF 32-34 and it is also strongly linked to PH. This study and previous studies by us and others have consistently observed a strong association between high MPAP and low SpO2, suggesting that vasoconstriction in response to hypoxia is an important factor in the development of PH in IPF 2-5. Although initially reversible, the pathologic changes induced by hypoxia-induced vasoconstriction ultimately result in irreversible vascular remodeling 35,36

Previous studies of the association between pulmonary artery size and pulmonary artery pressure have been inconsistent, with some investigators finding correlations in the expected direction 9,11,37-39, and others reporting no correlation 40-42. Our results support the previous studies that have found no correlation between pulmonary arterial diameter and pulmonary artery pressure 40-42. It should be emphasized that our study population consisted of a homogeneous group of well-characterized IPF patients, whereas other investigators have focused on a wide spectrum of cardiopulmonary diseases 9,12,40,42, with a large proportion of patients with pulmonary vascular disease (PVD) such as idiopathic pulmonary arterial hypertension or chronic thromboembolism 10,11,39,41,42. Although we cannot explain these disparate findings with certainty, it is quite possible that pulmonary artery size and pressure are correlated only in PVD and not in IPF. It is also possible that PH in our patients was not severe enough to cause increase in MPAD. In previous studies that have found associations between pulmonary artery size and PH, the PH cases were predominantly composed of patients with PVD with greater pulmonary artery pressures than our IPF patients with PH 8,11. Haimovici et al observed that when the severe PH cases were omitted by excluding patients with IPAH and patients with Eisenmenger's syndrome, the correlation between CT-measured pulmonary artery size and MPAP dropped 9. In a separate study, inclusion of PVD patients increased the MPAP of the PH group from 35.1 to 45.3 mm Hg. In that study, MPAD increased from 33 to 35 mm when PVD patients were included in the PH group 42, and the sensitivity and specificity of MPAD in predicting PH was lower in the subgroup of patients with parenchymal lung disease when compared to patients with PVD 42. Our study is consistent with these findings and together they suggest that PH due to IPF may not increase MPAD. It is also conceivable that the restrictive lung physiology in IPF may result in a traction effect on the mediastinal vascular structures, distending the pulmonary artery independent of the underlying pulmonary artery pressure; this effect may dampen the influence of the pulmonary artery pressure on the MPAD in patients with IPF. Ng et al showed in multivariable analysis that TLC, a marker of traction on mediastinal structures, independently contributed to MPAD 12. Consistent with this hypothesis, the pulmonary artery diameter in our control group (IPF patients without PH) was greater (31.3 ± 4 mm) than the values reported by others in their controls without cardiopulmonary disease (e.g., 24.2 ± 2 mm 11; 27.2 ± 3 mm 8).

Certain limitations of our study need to be acknowledged. This was a retrospective review of patients evaluated at a single center. Most of our patients underwent evaluation for lung transplantation, reflecting the presence of patients with more advanced IPF; hence, our results may not apply to the general population of IPF patients. However, we and others have shown that PH is more prevalent in patients with severe IPF (defined by reduced DLco and/or SpO2) 2-6; hence, this population is the one in whom identification of PH is more critical. Similar to other studies on this topic 37,39-41, CT scores were read by a single radiologist; however, since interobserver accuracy in measuring MPAD and extent of pulmonary fibrosis has been shown to be good 8,12,18, we do not believe that lack of additional readings by more than one expert radiologist biased our findings. Ours is a cross-sectional study of the association between CT-derived measures and PH in IPF patients. Hence, we cannot conclude that PH secondary to IPF is causally unrelated to changes in CT. That would require a longitudinal study. However, we can say that CT-derived measures of parenchymal disease and MPAD cannot be used to screen for PH in advanced IPF patients. Finally, our sample size may have limited our ability to find a real underlying association between CT-derived measures and PH. Since our study was powered to find correlations of 0.34 or larger, we can infer only that if there are undetected correlations between MPAP and one or more of the CT-derived measures, they are likely to be smaller than 0.34. Since this and previous studies 4,5 have found correlations between MPAP and simple measurements (such as 6MWD, SpO2, and PaO2) of the order of 0.5 and 0.7, we can conclude that HRCT-derived measures cannot distinguish between PH and no PH as well as simple clinical measurements such as oxygenation and the distance walked in six minutes.

In summary, HRCT-determined severity and extent of pulmonary fibrosis and pulmonary artery size cannot be used to screen for PH in advanced IPF patients.

Acknowledgments

This work was supported, in part, by grants from the NIH (5U10HL080411 and 5P50HL67665 to DAZ; HL080206 and HL086491 to JAB; AR055075 to MPK).

Abbreviations

AD

CT-measured diameter of the ascending aorta

BSA

body surface area

CT-alv

CT-determined ground-glass score

CT-fib

CT-determined fibrosis score

CT-hc

CT-determined honeycomb score

CT-tot

CT-determined total profusion score

DLco

diffusing capacity for carbon monoxide

FOV

field of view

FVC

forced vital capacity

ILD

interstitial lung disease

IPF

idiopathic pulmonary fibrosis

IRB

institutional review board

mCT-fib

maximum CT-derived fibrosis score over all lobes

MPAD

CT-measured main pulmonary artery diameter

MPAP

mean pulmonary artery pressure

PaO2

arterial blood oxygen tension

PFT

pulmonary function tests

PH

pulmonary hypertension

RHC

right-heart catheterization

SpO2

resting room air pulse oximetry

wCT-alv

weighted CT-determined ground-glass score

wCT-fib

weighted CT-determined fibrosis score

wCT-hc

weighted CT-determined honeycomb score

wCT-tot

weighted CT-determined total profusion score

VA

alveolar volume

6MWD

six-minute walk distance

Footnotes

All the work was performed at the David Geffen School of Medicine at UCLA.

Author Disclosure Information: David A. Zisman received research grants from Actelion Pharmaceuticals and Cotherix Pharmaceuticals to do multi-center studies. Dr. Zisman is funded by the National Institutes of Health IPF Clinical Research Network, which includes participation in a pulmonary hypertension study with sildenafil.

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