Platelet activating factor antagonist enhances lung preservation

JOURNAL

OF SURGICAL

RESEARCH

52,615-620

Platelet Activating PHILIP

C.

CORCOFLAN,

FOEGH, M.D.,*

Factor Antagonist

Enhances Lung Preservation

M.D.,* YINING WANG, M.D.,* NEVIN M. KATZ, M.D.,* JAMES D. ST. LOUIS, B.S.,* MARIE SUNDER S. RAJAN, PH.D.,? ALI R. ANALOUEI, PH.D.,* AND ROBERT B. WALLACE, M.D.*

Departments Presented

(19%‘)

at the Annual

of *Surgery Meeting

and tRadiology, of the Association

Georgetown

University

for Academic

Surgery,

Medical

Center,

Colorado

Washington,

Springs,

Colorado,

D.C.

L.

20007

November

20-23,

1991

procurement of lung tissue for transplantation 111. Current clinically employed techniques of organ preservation are limited to 4 to 6 hr of safe cold ischemia [2,3]. Extension of this limited period would expand the diminishing donor supply and potentially extend graft survival. Platelet activating factor (PAF) is a potent phospholipid mediator of the immune and inflammatory responses [4-71. The physiologic effects of PAF resemble post-transplant pulmonary dysfunction: pulmonary edema, pulmonary vascular hypertension, increased tracheobronchial secretions, and bronchoconstriction [811]. This study investigates the hypothesis that a specific PAF receptor antagonist, BN 52021, would enhance oxygenation and pulmonary hemodynamics in the early post-transplant period in an acute canine model of left lung allotransplantation when added to hypothermic pulmonary artery flush solution [12].

Platelet activating factor (PAF) is a potent phospholipid mediator of the immune and inflammatory responses, which causes physiologic effects similar to post-transplant pulmonary dysfunction. This study investigates the hypothesis that the use of a specific PAF antagonist (PAFA), BN 52021, in canine lung transplantation improves lung preservation. Twelve pairs of canines underwent left lung allotransplantation after pulmonary artery flushing with modified Euro-Collins (EC) solution (40 ml/kg). The experimental group (IV = 6) received EC with BN 5202 l(l0 mg/kg). BN 52021 was administered to donors prior to harvest and to recipients prior to reperfusion. The preservation interval was 20 hr and the study period was 12 hr post-transplant. Differential pulmonary function and hemodynamics were monitored, comparing the transplanted left lung and the native right lung. Recipients were ventilated on 100% 0,. Administration of the platelet activating factor antagonist, BN 52021, was associated with improvement in transplant lung oxygenation, pulmonary vascular resistance, and compliance. At 12 hr, transplant lung pulmonary venous oxygen tension in the treatment group (EC + BN 52021) was 154 * 21 mm Hg versus 87 + 10 mm Hg in the control group (EC) (P < 0.05). Pulmonary vascular resistance of the transplant lung at 12 hr was 146 + 24 Dynes - set * cm-’ in the EC + BN 52021 group as compared to 320 f 51 Dynes - sec. crnm6 in the EC group (P < 0.05). Dynamic pulmonary compliance of the transplant lung at 12 hr was 32 + 2.9 ml/cm Ha0 in the EC + BN 5202 1 group versus 13 + 2.0 ml/cm H,O in the EC group (P < 0.05). Total lung water for the EC group was 88.6 + 14% versus 67.3 + 11% for the EC + BN 52021 group (P < 0.05), as determined by proton magnetic resonance spectroscopy. From these data, we conclude that the specific PAFA, BN 5202 1, enhances lung preservation at 20 hr of ischemia in a canine model of 0 1992 Academic press, k. left lung allotransplantation.

METHODS

AND

MATERIALS

Twenty-four size- and weight-matched adult male mongrel canines (20-30 kg) were used in the study. Experimental donor animals were randomly assigned to receive either modified Euro-Collins (EC) solution (Baxter Healthcare Corp., Deerfield, IL) as the hypothermic pulmonary artery flush solution at the time of left lung allotransplantation (N = 6) or EC solution with the specific PAF receptor antagonist, BN 52021 (L’Institut Henri Beaufour, Le Plessis Robinson, France) in a dose of 10 mg/kg (N = 6). BN 52021 was administered to donors via slow intravenous central infusion 30 min prior to harvest (10 mg/kg) and to recipients 30 min prior to implantation and reperfusion (10 mg/kg). The PAF antagonist was obtained as a fine, white microcrystalline powder which was stored at 4°C and reconstituted prior to administration in 3 ml of sterile 0.9% NaCl. The cold ischemic period of organ preservation was 20 hr and the period of monitoring post-transplant was 12 hr. After hypothermic roller-pump flushing of the main pulmonary artery at 4”C, the left lung was stored at 10°C immersed in the preservation solution and sterile 0.9% NaCl. Experimental animals used in this study

INTRODUCTION

Considerable research has been directed toward the extension of the safe ischemic interval to allow distant 615

All

0022-4804/92 $4.00 Copyright 0 1992 by Academic Press, Inc. rights of reproduction in any form reserved.

616

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received humane and compassionate care in accordance with the guidelines set forth in Principles of Laboratory Animal Care, as formulated by the National Society for Medical Research, and in the Guide for the Care and Use of Laboratory Animals, prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication 80-23, revised edition, 1978). Donor operation. Twelve donor animals were anesthetized with thiopental sodium solution (1 ml/kg) and pancuronium bromide (0.2-0.4 mg/kg). General anesthesia was maintained with Halothane (0.5-1.25%) and experimental animals were ventilated with 100% 0, with tidal volume of 15 ml/kg at a rate of 14 breaths/min. A primary median sternotomy was performed and the heart-lung bloc was removed [ 131. Prior to removal, plunge thermistor temperature probes were placed in the donor right upper lobe, right lower lobe, main pulmonary artery, perfusion line, preservation solution reservoir, and right costophrenic recess to monitor organ cooling. The pulmonary artery flush was administered through the main pulmonary artery with a pressure monitoring catheter in the distal main pulmonary artery. The preservation solution was administered (40 ml/kg over 4 min) at a perfusion pressure below that of the animal’s baseline main pulmonary artery pressure with a roller-pump device (Cobe Instruments, Inc.) [ 141. The left lung was dissected from the heart-lung bloc prior to the period of cold ischemic storage, with final trimming of the left atria1 cuff, the left pulmonary artery, and the left main bronchus two rings below the carina at the time of implantation. The organs were stored immersed in the preservation solution and saline at 10°C for a period of 20 hr. The lung was stored at 75% of inflation with a noncrushing vascular clamp across the left main bronchus to prevent atelectasis. Hypothermic, hypovolemic arrest was achieved by inflow occlusion and topical slush. No cardioplegic agents were administered. Donors were systemically heparinized with 5000 U of heparin sodium intravenously. Recipient operation. The following day, recipients were anesthetized and mechanically ventilated in an analogous fashion to donors. Dual lumen endotracheal intubation was employed for all recipient animals. Recipient pneumonectomy was performed through a left posterolateral thoracotomy. Left lung allotransplantation was then performed and the animals were maintained in the right lateral decibitus, open-chested position [ 141. The left atria1 anastomosis was performed with running horizontal mattress 4-O polypropylene suture. All atria1 tissue was everted from the suture line in order to avoid thrombotic complications. The left pulmonary artery anastomosis was fashioned with running continuous 50 polypropylene suture. The left bronchial anastomosis was performed using a running 3-O polypropylene suture initiated at the cartilaginous-membranous junction

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with the telescoping technique. The allograft was deaired retrograde through the pulmonary artery anastomosis after unclamping the left atrium. As we have previously described, recipient animals were instrumented for the 12-hr period of observation with bilateral balloon-tipped, flow-directed catheters in the pulmonary arteries (Edwards Laboratories, Inc.) and bilateral dual angle ultrasonic flow probes around the pulmonary arteries (Transonic Systems, Inc.) [15]. High fidelity, solid state micromanometers (Millar Instruments, Inc.) were placed into the left atrium, the left ventricle, and the aortic root to record pressures. Sampling catheters were placed in the common femoral artery and the right and left inferior pulmonary veins. Bilateral inferior pulmonary venous blood samples as well as femoral arterial and mixed venous blood samples were analyzed at baseline for the donors and at baseline and 1, 2, 4, 6, 8, 10, and 12 hr post-transplant. Blood sample analysis was performed by Gem-Stat (Mallinckrodt Sensor Systems, Inc.) and by co-oximetry (Cobe Instruments, Inc.) Hemodynamic data were analyzed at baseline and hourly post-transplant. Analog signals were digitized and stored on a PDP 11-73 microcomputer-based data acquisition system with the use of customized interactive software. After conclusion of the 12-hr study period, experimental animals were euthanized. Proton (‘H) magnetic resonance spectroscopy (SIS Systems, Inc.) was performed on corresponding wedge segments of upper and lower lobes from the transplanted left lungs and native right lungs of all experimental animals for the determination of total lung water as a measure of pulmonary edema post-transplant [16]. Parameters for spectral analysis included a field strength of 4.7 Tesla operating at 200 MHz, a spectral width of 4000 Hz, an acquisition time of 0.5 set, a recycle time of 2 set, line broadening of 5 Hz with a total of 64 acquisitions. For standardization, samples of fresh, perfused, and perserved lung tissue were analyzed. Light microscopic hematoxalin and eosin-stained sections of transplanted left and native right lungs from both groups were independently examined and graded for evidence of pulmonary edema. Differential oxygenation and pulmonary hemodynamic calculations were derived from right and left lung inferior pulmonary venous blood sample analysis and differential pulmonary artery flow and pressure measurements. Parameters of investigation included inferior pulmonary venous oxygen tension (P,O, in mm Hg), alveolar-arterial oxygen difference (A-a DO, in mm Hg), intrapulmonary shunt fraction ( Qs/Qt in percentage), pulmonary vascular resistance (PVR in Dynes. set * cmA5) and dynamic pulmonary compliance (DPC in ml/ cm H,O). Statistical analysis was performed using the paired two-tailed Student’s t statistic and one-way analysis of variance where appropriate. Differences of stastical significance were indicated by P < 0.05. All values were reported as means f SEM.

CORCORAN

TABLE Donor

End-Perfusion

ET

AL.:

PAF

ANTAGONIST

ENHANCES

LUNG

1

TABLE

Temperatures

EC

(“C)

617

PRESERVATION

Transplanted

2

Lung Data at 2,8, and 12 Hr Post-Transplant

EC + BN 52021

P,O, (mm Hg) MPA RUL RLL PL PS RCR

10.6 12.4 12.9 4.4 1.3 16.4

+ -+ f + + t

2.2”C 2.8”C 3.4”C 0.8”C 0.4”C 4.1”C

11.1 13.3 13.4 4.8 1.8 17.0

+ -c * + + +

3.0°c* 3.0°c* 2.5”c* 0.6”C* 0.5”C* 4.8”C*

TLC2 W8) TL(12)

Note. MPA, main pulmonary artery; RUL, right right lower lobe; PL, perfusion line; PS, preservation voir; RCR, right costophrenic recess. * P = NS as compared to the EC Group.

EC+BN 52021

EC

upper lobe; RLL, solution reser-

109 f 34 127 + 36 87 -c 10 PVR

141* 43t 184 t 63t 154 * 21t

(Dynes

EC RESULTS

All recipient animals survived the period of instrumentation and post-transplant monitoring. Donor main pulmonary artery, right upper and lower lobe, perfusion line, preservation solution reservoir, and right costophrenic recess temperatures did not differ between the two study groups (Table 1). The mean perfusion pressure for the distal main pulmonary artery was 10.4 f 3.3 mm Hg for the EC group and 11.2 + 2.9 mm Hg for the EC + BN 52021 group (P = NS). The mean donor and recipient body weights were 23.4 -t 1.5 kg and 21.7 t 2.2 kg for the EC group as compared to 24.6 + 3.1 kg and 22.8 rfr: 2.8 kg for the EC + BN 52021 group (P = NS). Pulmonary artery flush duration for the EC group was 4.6 * 0.8 min as compared to 4.1 f 0.7 min for the EC + BN 52021 group (P = NS). Preservation interval of cold ischemia for the EC group was 20.6 t- 0.4 hr as compared to 21.0 f 0.6 hr for the EC + BN 52021 group (P = NS). Transplant lung postoperative 2-, 8-, and 12hr data are seen in Table 2. Pulmonary

TW) Tw3) TL(12)

304 + 44 299 + 61 320 + 51

A-aD0,

340 -+ 46 350 * 30 348 + 38 DPC

EC+BN 52021

EC

Hg)

EC+BN 52021

EC

* sec. cm-“)

145 * 22t 171 * 44t 146 t 24t

(mm

291 f 31t 266 t 28t 265 k 24t (ml/cm

16 + 0.9 15 + 1.0 13 -c 2.0

H,O) EC+BN 52021 30 + 1.zt 28 zk 2.Ot 32 k 2.9t

Note. P,O,, pulmonary venous oxygentension (mm Hg); A-aDO,, alveolar-arterial oxygen difference (mm Hg); QJQt, intrapulmonary shunt fraction (W); PVR, pulmonary vascular resistance (Dynes * sec. cm-5); DPC, dynamic pulmonary compliance (ml/cm H,O); TL, transplanted left lung. t P < 0.05 as compared to the EC Group.

tion. At 12 hr post-transplant, the A-aD0, for the EC group was 348 + 38 mm Hg as compared to 265 + 24 mm Hg (P < 0.05) (Fig. 2). There were no differences between the native lung A-aD0, data during the 12 hr of observation post-transplant: 413 + 44 mm Hg for the EC group and 428 * 51 mm Hg for the EC + BN 52021 group (P = NS).

Venous Oxygen Tension

Mean baseline recipient transplant lung pulmonary venous oxygen tension values for the EC group were consistently lower throughout the period of post-transplant monitoring as compared to the EC + BN 52021 group. At 12 hr post-transplant, the mean pulmonary venous oxygen tension for the left lung of the EC group was 87 * 10 mm Hg versus 154 f 21 mm Hg for the EC + BN 52021 group (P < 0.05) (Fig. 1). Native right lung pulmonary venous oxygen tension values at 12 hr posttransplant for the EC group were 213 f 21 mm Hg versus 205 f 29 mm Hg for the EC + BN 52021 group (P = NS). Alveolar-Arterial

Oxygen Difference

Baseline left lung alveolar-arterial oxygen difference data were similar for the two groups. A-aD0, data were consistently lower for the EC + BN 52021 Group throughout the 12-hr post-transplant period of observa-

0

2

4 TIME

6 6 POST-TRANSPLANT

1012 (Hours)

FIG. 1. Transplant lung pulmonary venous oxygen tension (mm Hg) versus time post-transplant (hours). The control group received the modified EuroCollins (EC) solution as the pulmonary artery flush solution while the BN 52021 group received the PAF antagonist (10 mg/kg) in addition to the EC Solution. Donors were pretreated 30 min prior to harvest and recipients were pretreated 30 min prior to reperfusion with BN 52021 (10 mg/kg iv).

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I I ~~~~~fl’~‘LK’LJ 0

2

4 TIME

I I

I

6 6 POST-TRANSPLANT

I I § IdJ.oj) 1012 (Hours)

Transplant lung alveolar-arterial oxygen difference (mm Hg) vs time post-transplant (hours): Control-modified Euro-Collins solution as the pulmonary artery flush solution. BN 52021-specific platelet activating factor antagonist added to the modified Euro-Collins solution used for pulmonary artery flushing. BN 52021 was administered to donors 30 min prior to harvest and to recipients 30 min prior to reperfusion.

Intrapulmonary

Shunt Fraction

There were no differences between the mean left lung intrapulmonary shunt fraction values for the two groups at baseline. However, immediately post-transplant, the EC group demonstrated an elevated intrapulmonary shunt fraction. This persisted throughout the posttransplant period of observation. By 12 hr, the intrapulmonary shunt fraction for the EC group was 0.44 + 0.18% as compared to 0.29 + 0.09% for the EC + BN 52021 group (P < 0.05) (Fig. 3). Native right lung intrapulmonary shunt fraction calculations demonstrated no

2

4 TIME

6 8 POST-TRANSPLANT

1012 (Hours)

FIG. 3. Transplant lung intrapulmonary shunt fraction (W) vs time (hours): Control-modified Euro-Collins solution as the pulmonary artery flush solution. BN 52021-specific platelet activating factor antagonist added to the modified Euro-Collins solution used for pulmonary artery flushing. BN 52021 was administered to donors 30 min prior to harvest and recipients 30 min prior to reperfusion.

1012 (Hours)

FIG. 4. Transplant lung pulmonary vascular resistance (Dynes * set * cme5) vs time (hours): Control-modified Euro-Collins solution as the pulmonary artery flush solution. BN 52021-specific platelet activating factor antagonist added to the modified Euro-Collins solution used for pulmonary artery flushing. BN 52021 was administered to donors 30 min prior to harvest and recipients 30 min prior to reperfusion.

differences between the two groups at 12 hr post-transplant: 0.519 + 0.04% for the EC group as compared to 0.511 I~I 0.06% for the EC + BN 52021 group (P = NS). Pulmonary

Vascular

Resistance

Baseline pulmonary vascular resistances pretransplant were similar for the two groups. The EC groups demonstrated persistently a higher pulmonary vascular resistance during the period of observation and investigation. By 12 hr post-transplant, the pulmonary vascular resistance for the EC group was 320 + 51 Dynes * set - cmm5 as compared to 146 k 24 Dynes. set * cmm5 for the EC + BN 52021 group (P < 0.05). The pulmonary vascular resistance was reduced by greater than 50% with the addition of BN 52021 (Fig. 4). The right lung data did not differ, with the 12-hr values being 326 + 91 Dynes. set * crne5 for the EC group and 415 f 88 Dynes. set - cmV5 for the EC + BN 52021 group (P = NS). Dynamic

0

4 6 8 POST-TRANSPLANT

Pulmonary

Compliance

Transplant lung dynamic pulmonary compliance as determined through differential pressure transducers in each lumen of the dual lumen endotracheal tube were consistently lower for the EC group as compared to the EC + BN 52021 group (Fig. 5). After 12 hr post-transplant, the EC group’s mean value was 13 zk 1.5 ml/cm Hz0 as compared to 32 f 3.9 ml/cm H,O for the EC + BN 52021 group (P < 0.05). Histology

Light microscopic sections of upper and lower lobes from both experimental groups were examined indepen-

CORCORAN

ET

AL.:

PAF

ANTAGONIST

ENHANCES

LUNG

PRESERVATION

619

nary compliance, and lower total lung water as determined by proton (‘H) magnetic resonance spectroscopy. Native lung function was similar between the two groups during the course of the post-transplant period of observation, with no differences in pulmonary venous oxygen tension, alveolar-arterial oxygen difference, intrapulmonary shunt fraction, and pulmonary vascular resistance. Differential pulmonary function and hemodynamics were monitored and served as added internal controls within each group and each animal. The animals were maintained in the open-chested lateral decubitus position for the entire period of post-transplant observation. 0 The flow dynamics of maintaining the native right lung 0 2 4 6 8 1012 in the dependent position and the transplant lung in the TIME POST-TRANSPLANT (Hours) superior position resulted in the predictable deterioraFIG. 5. Transplant lung dynamic pulmonary compliance (ml/cm tion of native right lung function over the course of the H,O) vs time (hours): Control-modified Euro-Collins solution as the post-transplant period, despite the use of a dual lumen pulmonary artery flush solution. BN 52021specific platelet activating factor antagonist added to the modified Euro-Collins solution used for endotracheal tube. This problem has been rectified in pulmonary artery flushing. BN 52021 was administered to donors 30 our laboratory by closing the chest and returning the min prior to harvest and recipients 30 min prior to reperfusion. experimental animals to the supine position. This preserves the native right lung function over the course of the post-transplant period of observation. dently at termination of the post-transplant period of Current clinically employed techniques of lung preserobservation in efforts to determine cellular integrity and vation provide adequate organ protection for a cold ischgrade pulmonary edema. There were no differences seen emit preservation interval of 4 to 6 hr. Extending the between the two groups. Severe alveolar edema, pareninterval beyond this time limit produces progressive hypchymal hemorrhage, and the presence of PMN’s and oxemia, pulmonary edema, loss of compliance, elevation macrophages were consistent findings in both experiin pulmonary vascular resistance, and pulmonary hymental groups. pertension [2-191. Ischemic injury during preservation and reperfusion-mediated injury are the two principal Total Lung Water mechanisms which cause this pulmonary dysfunction. Total lung water as determined by proton (‘H) mag- Oxygen-derived free radicals are believed to be the medinetic resonance spectroscopy of corresponding wedge ators of direct tissue injury at the time of reperfusion segments of upper and lower lobes from donors and recip[20]. PAF can produce just this picture of post-transients was performed to measure pulmonary edema post- plant pulmonary dysfunction. Therefore, this study intransplant. Fresh wedge excisions from donor animals vestigates the hypothesis that the use of a specific PAF prior to pulmonary artery flushing contained a total lung antagonist, BN 52021, would improve pulmonary function and hemodynamics in the early post-transplant pewater content of 41.4 + 9%. Donor lung specimens after flush perfusion with either preservation solution con- riod in a canine model of single lung allotransplantation. PAF promotes the generation of oxygen-derived free tained 48.6 + 11% total lung water while after flush preservation and cold storage for 20 hr the mean value was radicals by two different proposed mechanisms. PAF, 52.3 f 12%. After the post-transplant period of observa- which is released by leukocytes, endothelial cells, macrotion, the EC group had a total lung water content of 88.6 phages, and other phagocytic cells, promotes the formaf 14% as compared to the EC + BN 52021 group’s 67.3 f tion of arachidonic acid via the cycle-oxygenase path11% (P < 0.05). way and also potentiates the respiratory burst phenomenon by generating the superoxide radical from oxygen with the reduction of NADPH via the hexose monophosDISCUSSION phate shunt [12, 211. The direct mechanism of specific In this study, the addition of the specific PAF antagoPAF antagonists’ protective action in canine single lung nist, BN 52021, to a canine model of single lung allo- transplantation remains a matter of debate. In addition transplantation with a cold ischemic preservation interto blocking the deleterious effects of PAF directly, they val of 20 hr enhanced post-transplant pulmonary funcmay indirectly reduce oxygen-derived free radical genertion, as evidenced by higher transplant lung pulmonary ation at the time of organ reperfusion. PAF promotes venous oxygen tension, lower alveolar-arterial oxygen arachidonic acid release and the generation of prostadifference, lower intrapulmonary shunt fraction, lower glandins via the cycle-oxygenase pathway and leukopulmonary vascular resistance, higher dynamic pulmotrienes via the lipoxygenase pathway. Reduction in the

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generation of these vasoactive substances may reduce potential injury at the time of organ reperfusion [12]. Platelet activating factor is a potent phospholipid mediator of the immune and inflammatory responses with direct physiologic effects similar to post-transplant pulmonary dysfunction. The addition of a specific PAF antagonist to the organ preservation solution as well as administering it to donors prior to harvest and recipients prior to reperfusion in a canine model of single lung allotransplantation produced better pulmonary function and hemodynamics in the early post-transplant period. This effect holds promise as a potential strategy for safely extending the cold ischemic period of preservation in lung transplantation and merits further investigation.

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Handley, D. A., Van Valen, R. G., Melden, M. K., et al. Evaluation of dose and route effects of platelet activating factor-induced extravasation in the guinea pig. Thromb. Haemost. 52: 34, 1984.

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Conte, J. V., Ramwell, P. W., and Foegh, M. L. Lung presewation: a new indication for a PAF antagonist, BN 52021. In J. P. O’Flaherty and P. W. Ramwell (Eds.), PAP Antagonists: New Developments for Clinical Application. Woodlands, TX: Portfolio Publishing Co., 1990. Pp. 129-137.

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Veith, F. J., and lung transplantation.

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Corcoran, P. C., Wang, Y. N., Katz, N. M., etal. Platelet activating factor antagonist enhances lung preservation in a canine model of single lung allotransplantation. J. Thorac. Cardiovasc. Surg., (in press).

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