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Figure 1.
Fundus Photographs and Optical Coherence Tomographic (OCT) Images in Patient 1 With Congenital Zika Syndrome
Fundus Photographs and Optical Coherence Tomographic (OCT) Images in Patient 1 With Congenital Zika Syndrome

A, Chorioretinal scar and pigment mottling in the left eye. B, No abnormalities in the right eye. C, Chorioretinal thinning, discontinuation of the ellipsoid zone, and hyperreflectivity underlying the retinal pigment epithelium in the left eye.

Figure 2.
Fundus Photographs and Optical Coherence Tomographic (OCT) Images of Patient 2 With Congenital Zika Syndrome
Fundus Photographs and Optical Coherence Tomographic (OCT) Images of Patient 2 With Congenital Zika Syndrome

A and B, Optic nerve hypoplasia, chorioretinal scar, and pigment mottling in both eyes. C and D, Severe chorioretinal thinning, discontinuation of the ellipsoid zone, and excavation of remaining retina in both eyes.

Figure 3.
Fundus Photographs and Optical Coherence Tomographic (OCT) Images of Patients 3 and 4 With Congenital Zika Syndrome
Fundus Photographs and Optical Coherence Tomographic (OCT) Images of Patients 3 and 4 With Congenital Zika Syndrome

A, Chorioretinal scar in the right eye of patient 3. B, Chorioretinal thinning, discontinuation of the ellipsoid zone, and excavation of remaining retina in the right eye of patient 3. C, Chorioretinal scar and pigmentation in the right eye of patient 4. D, Chorioretinal thinning and discontinuation of the ellipsoid zone in the right eye of patient 4.

Figure 4.
Fundus Photographs and Optical Coherence Tomographic (OCT) Images of Patients 5 and 6 With Congenital Zika Syndrome
Fundus Photographs and Optical Coherence Tomographic (OCT) Images of Patients 5 and 6 With Congenital Zika Syndrome

A, Chorioretinal scars and pigmentation in the left eye of patient 5. B, Hyperreflective dots in the inner retina and retinal thinning in the left eye of patient 5. C, Chorioretinal scar in the left eye of patient 6. D, Discontinuation of the ellipsoid zone and irregular retinal pigment epithelial contour in the left eye of patient 6.

Figure 5.
Fundus Photographs and Optical Coherence Tomographic (OCT) Images of Patients 7 and 8 With Congenital Zika Syndrome
Fundus Photographs and Optical Coherence Tomographic (OCT) Images of Patients 7 and 8 With Congenital Zika Syndrome

A, Chorioretinal scar in the right eye of patient 7. B, Chorioretinal thinning, discontinuation of the ellipsoid zone, and excavation of the remaining retina in the right eye of patient 7. C, Chorioretinal scar and pigmentation in the left eye of patient 8. D, Chorioretinal thinning and discontinuation of the ellipsoid zone in the left eye of patient 8.

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Zanluca  C, Melo  VC, Mosimann  AL, Santos  GI, Santos  CN, Luz  K.  First report of autochthonous transmission of Zika virus in Brazil. Mem Inst Oswaldo Cruz. 2015;110(4):569-572.PubMedArticle
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Yakob  L, Walker  T.  Zika virus outbreak in the Americas: the need for novel mosquito control methods. Lancet Glob Health. 2016;4(3):e148-e149.PubMedArticle
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Dick  GW, Kitchen  SF, Haddow  AJ.  Zika virus, I: isolations and serological specificity. Trans R Soc Trop Med Hyg. 1952;46(5):509-520.PubMedArticle
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Miranda  HA  II, Costa  MC, Frazão  MA, Simão  N, Franchischini  S, Moshfeghi  DM.  Expanded spectrum of congenital ocular findings in microcephaly with presumed Zika infection. Ophthalmology. 2016;123(8):1788-1794.PubMedArticle
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Original Investigation
December 2016

Optical Coherence Tomography of Retinal Lesions in Infants With Congenital Zika Syndrome

Author Affiliations
  • 1Department of Ophthalmology, Altino Ventura Foundation, Recife, Brazil
  • 2Department of Ophthalmology, Pernambuco Eye Hospital, Recife, Brazil
  • 3Department of Ophthalmology and Visual Sciences, Paulista School of Medicine, Federal University of São Paulo, São Paulo, Brazil
  • 4Bascom Palmer Eye Institute, Miami, Florida
  • 5Department of Pediatric Neurology, Barão de Lucena Hospital, Recife, Brazil
JAMA Ophthalmol. 2016;134(12):1420-1427. doi:10.1001/jamaophthalmol.2016.4283
Key Points

Question  What are the optical coherence tomographic (OCT) findings in infants with congenital Zika syndrome who present with chorioretinal scars?

Findings  In this case series of 8 infants with congenital Zika syndrome and associated retinal abnormalities who were born in Pernambuco, Brazil, OCT imaging performed in 9 of the 16 eyes, of which 8 were affected, showed substantial neurosensory retinal thinning with discontinuation of the ellipsoid zone, choroidal thinning, and hyperreflectivity underlying areas of presumed atrophic retinal pigment epithelium.

Meaning  Zika virus can cause substantial damage to the retina, including the internal and external layers, and the choroid.

Abstract

Importance  Zika virus (ZIKV) can cause severe changes in the retina and choroid that may result in marked visual impairment in infants with congenital Zika syndrome (CZS), the term created for a variety of anomalies associated with intrauterine ZIKV infection.

Objective  To evaluate the affected retinal layers in infants with CZS and associated retinal abnormalities using optical coherence tomography (OCT).

Design, Setting, and Participants  This cross-sectional, consecutive case series included 8 infants (age range, 3.0-5.1 months) with CZS. Optical coherence tomographic images were obtained in the affected eyes of 7 infants with CZS who had undergone previous ophthalmologic examinations on March 17, 2016, and in 1 infant on January 1, 2016. An IgM antibody-capture enzyme-linked immunosorbent assay for ZIKV was performed on the cerebrospinal fluid samples of 7 of the 8 infants (88%), and other congenital infections were ruled out.

Main Outcomes and Measures  Observation of retinal and choroidal findings in the OCT images.

Results  Among the 8 infants included in the study (3 male; 5 female; mean [SD] age at examination, 4.1 [0.7] months), 7 who underwent cerebrospinal fluid analysis for ZIKV had positive findings for IgM antibodies. Eleven of the 16 eyes (69%) of the 8 infants had retinal alterations and OCT imaging was performed in 9 (82%) of them. Optical coherence tomography was also performed in 1 unaffected eye. The main OCT findings in the affected eyes included discontinuation of the ellipsoid zone and hyperreflectivity underlying the retinal pigment epithelium in 9 eyes (100%), retinal thinning in 8 eyes (89%), choroidal thinning in 7 eyes (78%), and colobomatouslike excavation involving the neurosensory retina, retinal pigment epithelium, and choroid in 4 eyes (44%).

Conclusions and Relevance  Zika virus can cause severe damage to the retina, including the internal and external layers, and the choroid. The colobomatouslike finding seen in the OCT images relate to the excavated chorioretinal scar observed clinically.

Introduction

Before April 2015, no cases of Zika virus (ZIKV) infection were reported in Brazil. Since that time, ZIKV infection has reached epidemic proportions in the country and affected more than 1 million Brazilians.1,2

Zika virus, a neurotropic flavivirus, was first identified in 1947 among Rhesus monkeys from Africa.3 A few years later, ZIKV was isolated for the first time in Ugandans and Nigerians.4 For more than 50 years, the ZIKV was considered an endemic mosquito-borne disease in Asia and Africa until the Micronesian outbreak occurred in 2007, followed by the French Polynesian outbreak in 2013 to 2014.4 In 2014, the first report of the ZIKV circulating in the Americas was reported on Easter Island.5

Although intrauterine infections had been described during these outbreaks, no cases of microcephaly had been associated with ZIKV in the French Polynesian epidemic.6 In October 2015, the Brazilian Ministry of Health6 reported an unusual increase in cases of microcephaly in northeastern Brazil. By November 2015, the Brazilian Ministry of Health and the World Health Organization6 reported the association of this malformation with intrauterine ZIKV infection. Despite microcephaly being the first clinical feature described in congenital ZIKV intrauterine infection, subsequent studies reported a variety of anomalies associated with this disease, including ocular abnormalities, hearing loss, and limb anomalies, which constitute the clinical features of a syndrome referred to as the congenital Zika syndrome (CZS).711

In 2016, Ventura et al7,8 first reported the ocular findings associated with intrauterine ZIKV infection that involved the optic nerve and retina. The retinal findings include mild to severe macular pigmentary changes and chorioretinal atrophy. Other studies9,10 confirmed the same findings. de Paula Freitas et al9 published a report of similar retinal and optic nerve changes in infants with presumed CZS from the state of Bahia in February 2016, and Miranda et al10 described retinal hemorrhages and peripheral retinal lesions that had not yet been reported and are likely related to the viral infection.

In 1991, Huang et al12 first described optical coherence tomography (OCT), a noninvasive diagnostic imaging tool that provides cross-sectional retinal images. Using low-coherence light (840 nm) associated with an optical reflectivity system, this technology can visualize the retinal layers and therefore plays an important role as an ancillary examination for macular diseases.13 Optical coherence tomography is used to diagnose and follow up congenital and acquired ocular diseases and evaluate the chronicity and activity of these processes. In this case series, we describe the OCT findings of 8 infants with CZS.

Methods

The study inclusion criteria were birth dates from May 1 to December 31, 2015, in the state of Pernambuco, Brazil; negative serologic findings for toxoplasmosis, rubella virus, cytomegalovirus, herpes simplex virus, syphilis, and human immunodeficiency virus; and a previous diagnosis of retinal lesions by indirect ophthalmoscopy followed by documentation using a wide-angle digital fundus camera (RetCam Shuttle; Clarity Medical Systems). After February 2016, serologic testing for ZIKV became available in Brazil, and with the exception of patient 8, the cerebrospinal fluid of all other infants was tested for the ZIKV infection using the IgM antibody-capture enzyme-linked immunosorbent assay.14 The institutional review board of the Altino Ventura Foundation, Recife, Brazil, and the Federal University of São Paulo, São Paulo, Brazil, approved this prospective cross-sectional study, which followed the tenets of the Declaration of Helsinki15 and was conducted at the Altino Ventura Foundation. The patients’ parents provided written informed consent before study enrollment.

Initial Assessment

The patients’ fundus descriptions and images used for this case series are from the patients’ initial assessment that occurred from December 14, 2015, to January 11, 2016, at the Altino Ventura Foundation. The fundus description data were collected from the patients’ medical records. For the present study, increased disc cupping was considered when the cup-disc ratio was 0.5 or greater. Bidigital pressure and corneal diameter were measured in all infants, none of whom presented with abnormal findings.

Some of the patients included in this study have been described previously, and similar fundus images have been published in previous studies.7,8,12,16 Patient 1 has been described in The Lancet7; patients 3 and 5, in the Brazilian Archives of Ophthalmology8; patient 6, in The Lancet14; and patient 7, in JAMA Ophthalmology.16 During the patients’ initial assessment, ocular ultrasonography was performed in both eyes, and no microphthalmia or macular coloboma was detected in any of the 8 patients.

OCT Imaging

Optical coherence tomographic imaging of the retinal lesions was performed in all infants on March 17, 2016, except for patient 2, in whom OCT was performed on January 1, 2016. The examination was performed while the infants were awake with the mothers present. The images were obtained using standard OCT equipment because portable OCT was not available. Seven of the patients underwent imaging using Fourier-domain OCT (FD-OCT) technology with 5-μm axial resolution (RTVue-100 OCT; Optovue).17 Patient 2 underwent imaging using an OCT device that is based on spectral-domain OCT technology with 3-μm axial resolution (Avanti; Optovue).18 Owing to the high level of difficulty in performing the examination, we could not acquire images of both eyes of all 8 infants. The evaluation of optic nerve findings using OCT was not assessed in this study.

Statistical Analysis

We used the statistical software package SPSS for Windows (version 16.0; SPSS, Inc) data analysis. Categorical variables were expressed as relative and absolute frequencies. Continuous variables were expressed as mean (SD) and maximal and minimal values.

Results

eTables 1 and 2 in the Supplement summarize the patients’ characteristics, fundus examination findings, and OCT findings. Among the 8 infants, the mean (SD) age at examination was 4.1 (0.7) months (range, 3.0-5.1 months). Five infants (62%) were female and 3 (38%) were male. Eleven of the 16 eyes (69%) had retinal alterations and OCT scanning was performed in 9 (82%). Optical coherence tomographic imaging was also performed in the unaffected eye of patient 1.

The macular findings included chorioretinal scar in 10 of 16 eyes (63%) and pigment mottling in 7 of 16 eyes (44%). The OCT findings in the 9 affected eyes included discontinuation of the ellipsoid zone and hyperreflectivity underlying the retinal pigment epithelium (RPE) in 9 eyes (100%); retinal thinning in 8 eyes (89%); choroidal thinning in 7 eyes (78%); colobomatouslike excavation of the retina, RPE, and choroid in 4 eyes (44%); possible cleft in 3 eyes (33%); and hyperreflective dots in the inner retinal layers in 1 eye (11%).

Report of Cases
Patient 1

A female infant (age at examination, 5.0 months) with microcephaly (head circumference at birth, 27 cm) was born to a woman in her 30s by cesarean delivery at a gestational age of 37 weeks (weight, 2290 g). The mother denied having symptoms of ZIKV infection during pregnancy.

Results of the fundus examination of the right eye were normal and a chorioretinal scar with pigment mottling was observed in the left eye (Figure 1A). The FD-OCT image of the right eye was unremarkable, with normal retinal and choroidal layers (Figure 1B). The FD-OCT image of the left eye revealed neurosensory retinal thinning with discontinuation of the photoreceptor inner and outer segment junction (ellipsoid zone), choroidal thinning, and hyperreflectivity underlying the RPE (Figure 1C).

Patient 2

A male infant (age at examination, 3.9 months) with microcephaly (head circumference at birth, 28 cm) was delivered vaginally to a woman in her late teens at a gestational age of 37 weeks (weight, 2800 g). The mother reported a rash during the first trimester of pregnancy.

The fundus examination of both eyes revealed optic nerve hypoplasia and a chorioretinal scar with gross pigment mottling in the macular region (Figure 2A and B). The spectral-domain OCT image in both eyes showed severe neurosensory retinal thinning with discontinuation of the ellipsoid zone, a possible cleft, hyperreflectivity underlying the RPE, and choroidal thinning. A colobomatouslike excavation was seen in the affected retina, RPE, and choroid in both eyes (Figure 2C and D).

Patient 3

A female infant (corrected age at examination, 3.0 months) with microcephaly (head circumference at birth, 28 cm) was born to a woman in her 40s by cesarean delivery at a gestational age of 36 weeks (weight, 2765 g). The mother described fever, rash, and generalized malaise during the second trimester of pregnancy.

The fundus examination revealed a unilateral chorioretinal scar in the macular region of the right eye (Figure 3A). The FD-OCT images in the right eye showed severe neurosensory retinal and choroidal thinning with discontinuation of the ellipsoid zone and hyperreflectivity underlying the RPE. A slight excavation with a colobomatous aspect was seen in the affected retina, RPE, and choroid (Figure 3B).

Patient 4

A male infant (age at examination, 4.0 months) with microcephaly (head circumference at birth, 27.5 cm) was delivered vaginally to a woman in her 30s at a gestational age of 40 weeks (weight, 2685 g). The mother described having an itchy rash and fever during the second trimester of pregnancy.

The fundus examination revealed increased optic disc cupping and a chorioretinal scar in the macular region in both eyes and gross pigmentation in the right eye (Figure 3C). The FD-OCT image of the right eye showed neurosensory retinal thinning with discontinuation of the ellipsoid zone, choroidal thinning, and hyperreflectivity underlying the RPE (Figure 3D). Optical coherence tomographic imaging could not be performed in the left eye.

Patient 5

A female infant (age at examination, 4.2 months) with microcephaly (head circumference at birth, 30 cm) was born to a woman in her 40s by cesarean delivery at a gestational age of 39 weeks (weight, 2900 g). The mother reported itchiness alone during the first trimester of pregnancy.

The fundus examination revealed discrete optic disc pallor and gross pigment mottling in both eyes and 2 chorioretinal scars in the macular region in the left eye (Figure 4A). The FD-OCT image of the left eye showed hyperreflective dots in the inner retinal layers, neurosensory retinal thinning with discontinuation of the ellipsoid zone, and discrete hyperreflectivity underlying the RPE. Choroidal alterations could not be evaluated (Figure 4B). Optical coherence tomographic imaging of the right eye could not be performed owing to technical difficulties.

Patient 6

A male infant (age at examination, 4.1 months) with no microcephaly (head circumference at birth, 33 cm) was delivered vaginally to a woman in her late teens at a gestational age of 38 weeks (weight, 3500 g). The mother denied symptoms during pregnancy. At birth, lower and superior limb spasms were noticed. The infant underwent a neurologic assessment that detected cerebral calcifications.

The fundus examination revealed a chorioretinal scar in the fovea of the left eye (Figure 4C). The FD-OCT image of the left eye showed discontinuation of the ellipsoid zone, irregular RPE contour, a possible cleft, and hyperreflectivity underlying the RPE (Figure 4D).

Patient 7

A female infant (age at examination, 3.7 months) with microcephaly (head circumference at birth, 29 cm) was born to a woman in her 30s by cesarean delivery at a gestational age of 39 weeks (weight, 3100 g). The mother reported itchiness, headache, and retroocular pain during the second trimester of pregnancy.

The fundus examination revealed a chorioretinal scar in the macular region of the right eye (Figure 5A). The FD-OCT image of the right eye showed severe neurosensory retinal thinning, with discontinuation of the ellipsoid zone, hyperreflectivity underlying the RPE, and choroidal thinning. A colobomatouslike excavation was seen in the affected retina, RPE, and choroid (Figure 5B).

Patient 8

A female infant (age at examination, 1.1 months) with microcephaly (head circumference at birth, 24 cm) was born to a woman in her 30s by cesarean delivery at a gestational age of 40 weeks (weight, 2925 g). The mother described rash, itchiness, and arthralgia during the second trimester of pregnancy.

The fundus examination revealed a unilateral chorioretinal scar associated with gross pigment mottling in the macular region of the left eye (Figure 5C). The FD-OCT image of the left eye showed severe neurosensory retinal thinning with discontinuation of the ellipsoid zone, choroidal thinning, and hyperreflectivity underlying the RPE (Figure 5D).

Discussion

The present study describes the OCT findings in 8 infants with retinal changes and presumed congenital ZIKV infection, 7 of whom had positive test results for ZIKV in the cerebrospinal fluid. To the best of our knowledge, this study is the first to report the OCT findings in macular lesions of newborns with CZS based on a MEDLINE search on August 28, 2016. These infants were born in the state of Pernambuco in northeastern Brazil, which is considered the epicenter of the ZIKV epidemic, with the highest number of infants with microcephaly in Brazil.19

Until recently, microcephaly was considered the main screening criterion for identifying infants with CZS.79 However, in a recent case report of an infant without microcephaly who presented with other neurologic and ocular findings,16 the infant had positive test results for the ZIKV infection, confirming CZS. This previous report has changed our inclusion criteria; thus the infant without microcephaly from the previous study was included in the present case series.16

Although the ocular findings described by indirect ophthalmoscopy and fundus imaging in infants with CZS from several studies agree,710 none reported the specific retinal layers affected by the ZIKV. The present study used standard OCT devices to better understand the effect of ZIKV on the retina, RPE, and choroid. Despite not acquiring the images with portable devices, the images captured and described have enough quality to perceive in detail the affected retinal layers.

The main OCT findings identified in the present group of infants with CZS included severe neurosensory retinal thinning with discontinuation of the ellipsoid zone associated with choroidal thinning and a hyperreflectivity underlying the atrophic RPE. Although these OCT findings bring new information regarding the severity of the lesions observed clinically in these patients with CZS, they are not unique to CZS. Diseases that cause aggression to the neurosensory retina, such as cytomegalovirus retinitis and toxoplasmic retinochoroiditis, can present with similar OCT findings. These findings include chorioretinal thinning and discontinuation of the ellipsoid zone.2022 In addition, the hyperreflectivity seen underlying the RPE in most of these eyes can be also observed in these other retinal diseases with severe involvement of the RPE, which is simply the signal’s transmission through the atrophic tissue.

We speculate that, according to the severity of the ocular involvement in CZS, the neurosensory retina is solely affected, or in more severe cases, the retina and choroid are affected. The colobomatouslike aspect seen in patients 2, 3, and 7 corresponds to the severe excavated chorioretinal scar observed clinically. Although they simulate macular coloboma, ocular ultrasonographic findings ruled out this possibility in these 3 patients. Furthermore, these colobomatouslike lesions have also been described in other retinal diseases, such as scarred congenital toxoplasmosis lesions and congenital macular coloboma.20,21,23

The possible cleft identified in the OCT images of patients 2 and 6 are also seen in torpedo maculopathy. However, in torpedo maculopathy, the inner retinal structure is not affected, which differs from our cases. Furthermore, the clinical findings of torpedo maculopathy are different from the CZS lesions. Torpedo lesions are typically unilateral, temporal to the fovea, and consequently do not affect visual acuity.24,25

Another interesting OCT finding observed in patient 5 consisted of the hyperreflective dots in the inner retinal layers. We speculated that they corresponded to the retinal pigment mottling seen in the fundus photograph. However, they could also be related to a distortion of the signal.

These OCT findings suggest that the physiopathogenesis of the chorioretinal atrophy is similar to the mechanism by which ZIKV causes microcephaly in these infants. The immense neurotropism of ZIKV could result in a destructive process causing significant necrosis of the retinal tissue. The limitations of the present study included the sample size, lack of newborn cooperation, inability to document bilateral disease systematically, lack of a point-to-point correlation between OCT and fundus findings, and lack of cerebrospinal fluid testing for ZIKV in patient 8.

Conclusions

The use of OCT technology in this case series showed severe involvement of the neurosensory retina, including the internal and external layers, and the choroid. Although these findings provide important new information about this devastating disease, they are not unique to CZS, and therefore OCT cannot be used to differentiate CZS from other retinal diseases. Nevertheless, the OCT findings herein identified confirm the primary involvement of the retina in infants with CZS. They indicate severe visual impairment in newborns; however, further studies should confirm the accuracy of this statement by correlating the findings with visual function in the future.

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Article Information

Corresponding Author: Rubens Belfort Jr, MD, PhD, Department of Ophthalmology and Visual Sciences, Paulista School of Medicine, Federal University of São Paulo, Rua Botucatú, 831, São Paulo, SP, Brazil 04023-062 (clinbelf@uol.com.br).

Accepted for Publication: September 18, 2016.

Published Online: November 10, 2016. doi:10.1001/jamaophthalmol.2016.4283

Author Contributions: Dr C. V. Ventura had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: C. V. Ventura, L. O. Ventura, Berrocal, de Oliveira Dias, Belfort, Maia.

Acquisition, analysis, or interpretation of data: C. V. Ventura, L. O. Ventura, Bravo-Filho, Martins, Gois, de Oliveira Dias, Araujo, Escariao, van der Linden, Maia.

Drafting of the manuscript: C. V. Ventura, L. O. Ventura, Martins, Berrocal, de Oliveira Dias, Araujo, van der Linden, Maia.

Critical revision of the manuscript for important intellectual content: C. V. Ventura, L. O. Ventura, Bravo-Filho, Berrocal, Gois, de Oliveira Dias, Escariao, Belfort, Maia.

Statistical analysis: C. V. Ventura.

Obtained funding: L. O. Ventura, Maia.

Administrative, technical, or material support: L. O. Ventura, Bravo-Filho, Martins, Araujo, van der Linden, Belfort Jr, Maia.

Study supervision: C. V. Ventura, L. O. Ventura, Bravo-Filho, Martins, Berrocal, Gois, de Oliveira Dias, Escariao, Belfort Jr, Maia.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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