Parapapillary Diffuse Choroidal Atrophy in Children Is Associated With Extreme Thinning of Parapapillary

Tae Yokoi,1 Dan Zhu,2 Hong Sheng Bi,3 Jost B. Jonas,4 Rahul A. Jonas,5 Natsuko Nagaoka,1 Muka Moriyama,1 Takeshi Yoshida,1 and Kyoko Ohno-Matsui1

1Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan 2The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China 3Eye Institute of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China 4Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany 5Department of Ophthalmology, Friedrich-Alexander-University Erlangen-Nurnberg,¨ Germany

Correspondence: Kyoko Ohno-Mat- PURPOSE. To analyze morphologic features of segmental parapapillary diffuse choroidal sui, Department of Ophthalmology atrophy (PDCA) in children. and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yush- METHODS. The study group included children (age 15 years) with high myopia who attended ima, Bunkyo-ku, Tokyo 1138510, the Tokyo High Myopia Clinic. Control groups comprised participants of the population-based Japan; Gobi Desert Children Study (GobiDCES). photographs were examined for [email protected]. presence of PDCA and choroidal thickness (CT) was measured by optical coherence tomography. TY and DZ contributed equally to the work presented here and should RESULTS. The study group included 41 of 21 children with PDCA (mean age: 9.4 6 3.7 therefore be regarded as equivalent years; mean : 11.5 6 3.1 diopters) and the GobiDCES included 1463 authors. children (age: 11.8 6 3.5 years). In the study group, all eyes showed an extreme and abrupt Submitted: August 31, 2016 thinning of the temporal parapapillary choroid. At 2500 lm nasal to the foveola, CT was <60 Accepted: December 12, 2016 lm in 31 (76%) eyes of the study group but in none (0/1463) of the GobiDCES (P < 0.001), except for one child with PDCA. Citation: Yokoi T, Zhu D, Bi HS, et al. Parapapillary diffuse choroidal atro- CONCLUSIONS. Parapapillary diffuse choroidal atrophy in children is associated with abrupt phy in children is associated with segmental thinning of the choroid in the temporal parapapillary region, in addition to the extreme thinning of parapapillary thinning of the subfoveal choroid after adjusting for refractive error and age. choroid. Invest Ophthalmol Vis Sci. Keywords: parapapillary diffuse choroidal atrophy, optical coherence tomography, choroidal 2017;58:901–906. DOI:10.1167/ iovs.16-20652 thickness, pathologic myopia

athologic myopia has become one of the most common optic nerve head outside of the parapapillary alpha, beta, P causes of loss of best-corrected (BCVA), gamma, or delta zones.16 The study suggested that the presence particularly in East Asian countries.1–6 ‘‘Pathologic myopia’’ of PDCA in children with high axial myopia might be a has been characterized by specific myopia-related complica- biomarker for eventually developing pathologic myopia in tions occurring in the posterior fundus, such as myopic adulthood. maculopathy or posterior staphyloma.7–10 In East Asian Since that previous retrospective longitudinal study started populations, the prevalence of high myopia, parallel to the more than 25 years ago when optical coherence tomography increase in the prevalence of myopia in general, has markedly (OCT) was not yet available—and since it is of interest to know increased in the last 50 years.11–14 To cite an example, Morgan more about the anatomy of PDCA in children that up to now and colleagues13 in their recent review article noted the trend has only been defined upon ophthalmoscopy—we conducted that a higher frequency of myopia increases the prevalence of the present study. Using OCT, we examined the morphologic high myopia. It has remained unclear so far whether an features of PDCA detected in children attending third-referral increased prevalence of ‘‘high myopia’’ will eventually cause an high myopia clinics. We additionally compared the OCT increased prevalence of ‘‘pathologic myopia (which is defined findings between the hospital-based study group of children by the presence of its specific complications in the posterior with PDCA and control groups formed on the basis of a 9,15 fundus). population-based recruitment of study participants. In a recent longitudinal study on 35 eyes of adult patients with signs of myopic maculopathy, who were aged 37.0 6 5.1 years (range, 33–42 years), 29 of the 35 eyes (83%) showed a METHODS parapapillary diffuse choroidal atrophy (PDCA) at the initial visit (age 10.5 6 2.6 years; range, 5–15 years), with a mean Medical records of children with high axial myopia, aged 15 axial length of 27.8 6 1.2 mm (range, 25.5–29.7 mm).16 Results years, and who visited the high myopia clinic at Tokyo Medical indicated that PDCA was confined to the area temporal to the and Dental University between April 2014 and March 2016

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were retrospectively analyzed. Approval for the study was obtained from the ethics committee of the Tokyo Medical and Dental University. The procedures applied during the exami- nations conformed to the tenets of the Declaration of Helsinki. Applying the criteria formulated by the Ministry of Health and Welfare in Japan, high myopia was defined as a myopic refractive error of >4.0 diopters (D) for children aged 5 years, a myopic refractive error of >6.0 D for children aged between 6 and 8 years, and a myopic refractive error of >8.0 D for children aged >9 years. Exclusion criteria were systemic and ocular diseases that caused or were associated with high myopia; (e.g., congenital stationary night blindness, congenital glaucoma, a history of prematurity and chromosomal abnor- malities, and presence of intrachoroidal cavitation). Patients with presence of intrachoroidal cavitation were excluded because it was associated with secondary widening of the peripapillary suprachoroidal space.17–20 All patients underwent a detailed ophthalmologic examina- tion including refractometry; ocular biometry with measure- ment of axial length (IOLMaster; Carl Zeiss, Oberkochen, Germany); slit-lamp based examination of the anterior segment and posterior segment under medical mydriasis; color (fundus camera: Topcon TRC 50DX; Topcon, Tokyo, Japan, or Kowa Pro 1 or VX-10; Kowa, Tokyo, Japan); and optical coherence tomography (DRI-OCT-1; Topcon, Tokyo, Japan). The presence of PDCA was identified by two retina specialists (TY, KOM). Lastly, the children with PDCA were enrolled in the study group. The study group was compared with a control group formed by the Gobi Desert Children Eye Study (GobiD- CES)21,22: a cross-sectional, school-based study performed in the city oasis of Ejina in the Gobi desert. The ethics board of the Inner Mongolia Medical University Affiliated Hospital, Hohhot and the local administration of the School Board of Education of Ejina approved the study and informed written FIGURE 1. Extreme and sudden thinning of the peripapillary choroid consent was obtained from the parents or guardians of all in a child with PDCA. (A) Left fundus of an 11-year-old child with children. The study included all three schools in Ejina with an refractive error of –9.0 D (spherical equivalent) and with axial length of overall 1911 eligible children, out of whom 1565 (81.9%) 27.1 mm shows yellowish diffuse atrophy temporal to the gamma zone. children with a mean age of 11.9 6 3.5 years (range, 6–21 (B) A horizontal section of OCT shows extreme thinning of choroid years) participated. Refractometry was performed under temporal to the optic nerve. Almost the entire thickness of the choroid cycloplegic conditions, and fundus photography was carried has disappeared in the area of PDCA nasal to the central fovea, out. Spectral domain OCT (Spectralis, wavelength: 870 nm; although the choroid seems to maintain its thickness temporal to the fovea. The transition from relatively normal choroid around the fovea Heidelberg Engineering Co., Heidelberg, Germany) with to almost absent choroid in the area of PDCA is sudden. enhanced depth imaging (EDI) modality was performed after dilation. The horizontal section running through the center of the fovea was selected for measurement of choroidal b and the nonstandardized regression coefficient b and its 95% thickness (CT). Choroidal thickness was defined as the confidence interval (CI). distance from the outer surface of the hyperreflective line referred to Bruch’s membrane to the hyperreflective line of the inner border. Presence of PDCA was assessed on the RESULTS color fundus photographs and PDCA was identified as ill- Between April 2014 and March 2016, 34 children visiting the defined yellowish atrophy with decreased pigmentation and Tokyo High Myopia Clinic met the criteria of a highly myopic 16 bright fundus reflex (Figs. 1, 2). refractive error as defined by the Japanese Ministry of Health Statistical analysis was carried out using a commercially and Welfare. One patient was excluded because he was available statistical software package (SPSS for Windows, diagnosed with congenital stationary night blindness due to version 22.0; SPSS, Inc., Chicago, IL, USA). We calculated the characteristic findings in the electroretinogram. Four patients mean and the standard deviations of the thickness of the had unilateral high myopia, and their nonhighly myopic eyes choroid at the various measurement locations. In univariate were not included in the study. Another patient was excluded analysis, we assessed the associations between choroidal due to parapapillary suprachoroidal cavitation. Out of the thickness and other ocular and general parameters. A remaining 60 eyes of 32 children (mean age: 7.7 6 4.1 years, multivariate analysis included choroidal thickness as a depen- mean refractive error: 9.3 6 3.0 D, mean axial length: 26.5 6 dent variable and all variables as independent parameters that 1.7 mm), 41 eyes of 21 patients showed PDCA and were were significantly correlated with choroidal thickness in the included in the study group of our investigation. The mean age univariate analysis. We then dropped all those parameters that was 9.4 6 3.7 years (range, 3–15 years); mean refractive error either showed a high collinearity or were no longer (spherical equivalent) was 11.5 6 3.1 D (range, 18.5 to significantly associated with choroidal thickness, in a stepwise 6.75 D); and mean axial length was 27.5 6 1.4 mm (range, fashion. We calculated the standardized regression coefficient 24.2–30.5 mm; Table 1).

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FIGURE 3. Boxplots showing the distribution of CT (lm) as measured at 2500 lm nasal to the foveola in the children with PDCA (study group) and in children from the GobiDCES.

Out of 1911 primarily eligible children in the GobiDCES, 1565 (81.9%) children participated in the study, among which 1463 (93.5%) children had EDI-OCT images available for measuring choroidal thickness. Their mean age was 11.8 6 3.5 years and their mean refractive error was 1.20 6 2.03 D (Table 1). In all 41 eyes of the study group with PDCA, OCT images showed an extreme and abrupt thinning of the temporal parapapillary choroid (Figs. 1, 2). At 2500 lm nasal to the foveola, CT was <60 lm in 31 of the 41 eyes (76%); 50 lmin 25 of the 41 eyes (61%); and 25 lm in 11 eyes (27%). In contrast, none of the participants of the GobiDCES, except for the child with PDCA, had a CT as measured at 2500 lm nasally to the foveola of <60 lm (Fig. 3). Choroidal thickness in the macular region was also thinner (P < 0.001) in the study group FIGURE 2. Extreme and sudden thinning of the peripapillary choroid than in the GobiDCES after adjusting for age, refractive error, in children with PDCA. (A) Right fundus of a 9-year-old child with and corneal refractive power (Table 2). Thicker CT at 2500 lm refractive error of 10.25 D (spherical equivalent) and with an axial nasal to the fovea was significantly associated ( 2 0.30) with length of 26.4 mm shows yellowish diffuse atrophy temporal to the r ¼ gamma zone. (B) A horizontal section of OCT shows extreme thinning the control group versus study group (P < 0.001) after of the choroid in the area of diffuse atrophy. Almost the entire adjusting for younger age (P ¼ 0.002); higher hyperopic thickness of the choroid has disappeared in the area of PDCA nasal to refractive error (P < 0.001); and higher corneal refractive the central fovea, although the subfoveal choroid seems to maintain its power (P < 0.001; Table 3; Fig. 3). Thicker CT at 2500 lm thickness. The transition from relatively normal choroid around the temporal to the fovea was significantly associated (r2 ¼ 0.16) fovea to almost absent choroid in the area of PDCA is relatively sudden. with the control group versus study group (P < 0.001) after

TABLE 1. General and Eye Characteristics of the Children With PDCA and Children From the GobiDCES

Study Group Control Group (Children PCDA, n ¼ 41) (GobiDCES, n ¼ 1463) P Value

Age, y (range) 9.4 6 3.7 (3–15) 11.8 6 3.5 (6.0–20.7) 0.54 Boys/Girls 23/18 747/716 <0.001 Refractive error, D (range) 11.5 6 3.6 (18.5 to 6.75) 1.31 6 1.92 (12.75 to þ5.75) <0.001 Corneal refractive power, D 43.1 6 1.6 43.1 6 1.6 0.77 CT, lm Subfoveal region 282 6 49 (91–417) 129 6 59 (40–282) <0.001 1000 lm nasal to the foveola 254 6 49 (87–407) 95 6 50 (8–207) <0.001 2500 lm nasal to the foveola 197 6 50 (60–388) 43 6 22 (7–88) <0.001 1000 lm temporal to the foveola 286 6 49 (117–430) 149 6 61 (57–313) <0.001 2500 lm temporal to the foveola 278 6 49 (111–431) 174 6 62 (66–335) <0.001 1000 lm nasal to the foveola/subfoveal 0.73 6 0.23 (0.11–1.26) 0.90 6 0.06 (0.66–1.23) <0.001 2500 lm nasal to the foveola/subfoveal 0.39 6 0.29 (0.08–1.56) 0.70 6 0.13 (0.28–1.23 <0.001 1000 lm temporal to the foveola/subfoveal 1.20 6 0.25 (0.88–2.22) 1.02 6 0.06 (0.56–1.37) <0.001 2500 lm temporal to the foveola/subfoveal 1.49 6 0.61 (0.74–3.47) 0.99 6 0.11 (0.54–1.84) <0.001

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TABLE 2. Multivariate Analysis of Associations Between Subfoveal CT and Ocular and General Parameters in Children With PDCA and Children From the GobiDCES

Standardized Regression Nonstandardized Regression Parameter P Value Coefficient b Coefficient 95% CI of B

Age, y 0.001 0.08 1.29 2.02, 0.55 Refractive error, D <0.001 0.38 8.12 6.79, 9.45 Corneal refractive power, D <0.001 0.09 3.24 1.73, 4.76 Study vs. control group <0.001 0.22 73.5 93.8, 53.3

adjusting for higher hyperopic refractive error (P < 0.001) and The observations made in our study are new and cannot higher corneal refractive power (P < 0.001), while it was not directly be compared with results of other investigations. The significantly associated with age (P ¼ 0.17; Table 4). finding of a general thinning of the choroid at the posterior The mean ratio of CT at 2500 lm nasal to the fovea to pole in axially elongated eyes has been reported in several subfoveal CT was significantly lower (r2 ¼ 0.16) in the study previous studies.23–27 A study examining choroidal thickness in group than in the GobiDCES (P < 0.001; b: 0.25; B: 0.22; children in the fovea and in a circle of 1 mm diameter around 95% CI: 0.27, 0.17) after adjusting for higher refractive error the fovea showed that the choroid was thinnest at 500 lm (P < 0.001; b: 0.15; B: 0.08; 95% CI: 0.005, 0.012; Fig. 4). Age nasal of the fovea (268 lm) and thickest at 500 lm temporal to was not significantly associated in that model (P ¼ 0.30). Mean the foveal region (290 lm).23–27 It indicated that in children in ratio of CT at 1000 lm nasal to the fovea to subfoveal CT was general, the choroid is thinner in the region nasal to the fovea significantly lower (r2 ¼ 0.16) in the study group than in the than temporal to the fovea. While most of the previous control group (P < 0.001; b: 0.26; B: 0.12; 95% CI: 0.15, investigations included adults, Read and colleagues recently 0.10) after adjusting for higher refractive error (P < 0.001; b: reported on the peripapillary choroidal thickness in children.28 0.18; B: 0.005; 95% CI: 0.003, 0.007). Age was not significantly They examined 93 children (37 myopes and 56 nonmyopes) associated (P ¼ 0.47). aged between 11 and 16 years and measured the choroidal In contrast, the mean ratio of CT at 2500 lm temporal to the thickness in five concentric annuli with a distance of 250 lm fovea to subfoveal CT was higher (r2 ¼ 0.26) in the study group between each annulus and starting at the edge of parapapillary than in the GobiDCES (P < 0.001; b: 0.36; B: 0.37; 95% CI: gamma zone. The mean CT at a distance of 250 lm from the 0.31, 0.43) after adjusting for lower refractive error (P < 0.001; edge of the gamma zone was 77 6 16 lm. This value was b: 0.20; B: 0.01; 95% CI: 0.02, 0.01). Also, the mean ratio higher than the mean CT at the same location measured in our of CT at 1000 lm temporal to the fovea to subfoveal CT was study population with 46 lm, confirming the finding of an higher (r2 ¼ 0.18) in the study group than in the GobiDCES (P extreme thinning of parapapillary choroid in our study group < 0.001; b: 0.28; B: 0.13; 95% CI: 0.10, 0.15) after adjusting for with PDCA. lower refractive error (P < 0.001; b: 0.20; B: 0.006; 95% CI: Since the ophthalmoscopic assessment of PDCA is subjec- 0.007, 0.004). tive and depends on the experience of the examiner, the present study showed the usefulness of OCT to detect a PDCA by measuring choroidal thickness and assessing the pattern of DISCUSSION choroidal thickness including the observation of an abrupt change in choroidal thickness in the temporal parapapillary Parapapillary diffuse choroidal atrophy in the children of our region. A potentially useful cutoff value for the CT at a distance study group was characterized by a profound segmental and of 2500 lm nasal to the foveola may be the value of <60 lm, abrupt thinning of the choroid in the temporal parapapillary since it is significantly differentiated in the group of children region, in addition to a thinning of the subfoveal choroid. The with PDCA versus those without PDCA. parapapillary segmental thinning of the choroid with an abrupt A recent longitudinal study suggested that the presence of border in direction to the slightly thicker macular choroid was PDCA in children with high axial myopia might potentially be a an OCT feature of PDCA. Using a CT cutoff value of <60 lmat biomarker for eventual pathologic myopia in adulthood in 2500 lm nasal to the foveola, 31 of the 41 eyes with PDCA and some individuals.16 The reasons for this potential association none of the eyes in the GobiDCES—except for the child with have remained inconclusive. Recent histologic studies have PDCA—were positive for this sign. The preferential and suggested that myopic axial elongation of the eye is associated segmental thinning of the choroid in the parapapillary region with thinning of the sclera and choroid most marked at the in the eyes with PDCA also explained that the choroid in the posterior pole while the thickness of Bruch’s membrane in all temporal area of the macula compared with the subfoveal regions of the eye did not decrease significantly with longer region was relatively thicker in children with PDCA compared axial length.29,30 It has remained unclear which of these three with the children of the control group after adjusting for age layers, sclera, choroid, Bruch’s membrane, or a combination, is and refractive error. involved in the etiology of PDCA as a potential precursor of

TABLE 3. Multivariate Analysis of Associations Between CT, as Measured at 2500 lm Nasal to the Foveola, and Ocular and General Parameters in Children With PDCA and Children From the GobiDCES

Standardized Regression Nonstandardized Regression Parameter P Value Coefficient b Coefficient 95% CI of B

Age, y 0.002 0.07 1.15 1.90, 0.41 Refractive error, D <0.001 0.36 7.75 6.41, 9.09 Corneal refractive power, D <0.001 0.10 3.38 1.85, 4.91 Study vs. control group <0.001 0.23 77.7 98.2, 57.2

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TABLE 4. Multivariate Analysis of Associations Between CT, as Measured at 2500 lm Temporal to the Foveola, and Ocular and General Parameters in Children With PDCA and Children From the GobiDCES

Standardized Regression Nonstandardized Regression Parameter P Value Coefficient b Coefficient 95% CI of B

Refractive error, D <0.001 0.29 5.82 4.58, 7.06 Corneal refractive power, D 0.02 0.06 1.82 0.26, 3.37 Study vs. control group <0.001 0.14 45.1 64.6, 25.7

pathologic myopia in some patients. Future studies may mostly Chinese, thus interethnic differences may have address which morphologic signs of the fundus occur first in confounded a difference between the populations. However, eyes developing pathologic myopia, and the sequence of previous studies have shown that in all ethnic groups changes could further elucidate the mechanism leading to examined, the choroid thickness decreased with longer axial myopic maculopathy. length and older age, and that overall the mean choroidal Potential limitations of our study should be mentioned. thickness measurements did not markedly differ between First, it was a cross-sectional study, so any conclusions drawn Japanese and Chinese patients. on the longitudinal development of pathologic myopia have to In conclusion, PDCA in children was associated with a be cautiously interpreted. Second, the children of our study profound segmental abrupt choroidal thinning in the temporal group were highly selected from specialized third-referral parapapillary region, in addition to a generalized thinning of clinics. It remains unclear just how representative they are of the choroid in the macular region overall. A potentially useful myopic children in general. Third, based on the marked cutoff value of CT at a distance of 2500 lm nasal to the foveola selection of the children of the hospital-based study group in may be the value of <60 lm, which may be helpful for the the present investigation and in particular in the previous detection and diagnosis of PDCA in myopic children. study underlying the present investigation, it cannot be concluded that PDCA was a predictor of all or, ultimately, Acknowledgments pathologic myopia. It is possible that PDCA represented only one (if at all) out of several biomarkers in children for eventual Disclosure: T. Yokoi, None; D. Zhu, None; H.S. Bi, None; J.B. pathologic myopia in adulthood. This assumption is supported Jonas, Mundipharma Co. (C), P; R.A. Jonas, None; N. Nagaoka, by results of a recent population-based study in which the None; M. Moriyama, None; T. Yoshida, None; K. Ohno-Matsui, prevalence of PDCA in children was considerably lower than None the prevalence of pathologic myopia in adults.21 It is also possible that there is no biomarker of later myopic pathology References at the young age at all. Fourth, a recent study showed that high myopia in children 1. Foster PJ, Jiang Y. Epidemiology of myopia. Eye (Lond). 2014; and teenage cohorts from East and Southeast Asia showed 28:202–208. associations with the level of education, whereas cohorts of 2. Morgan IG, Ohno-Matsui K, Saw SM. Myopia. Lancet. 2012; adults did not.22 Since the children of our study group were 379:1739–1748. relatively young (mean age: 9.4 6 3.7 years), it may be that 3. Wong TY, Ohno-Matsui K, Leveziel N, et al. Myopic choroidal these children with PDCA consisted of a genetic, very early neovascularisation: current concepts and update on clinical onset, highly myopic group, whereas those who develop high management. Br J Ophthalmol. 2015;99:289–296. myopia after the ages of 10 to 13 are predominantly 4. Iwase A, Araie M, Tomidokoro A, et al. Prevalence and causes environmental in origin. Fifth, while the children of our study of low vision and blindness in a Japanese adult population: group were Japanese, the children of the control group were the Tajimi Study. Ophthalmology. 2006;113:1354–1362. 5. Xu L, Wang Y, Li Y, et al. Causes of blindness and visual impairment in urban and rural areas in Beijing: the Beijing Eye Study. Ophthalmology. 2006;113:1134. 6. Ohno-Matsui K, Lai TYY, Cheung CMG, Lai CC. Updates of pathologic myopia. Prog Retin Eye Res. 2016;52:156–187. 7. Curtin BJ. Basic science and clinical management. In: Curtin BJ, ed. The Myopias. New York, NY: Harper and Row; 1985: 177. 8. Curtin BJ. The posterior staphyloma of pathologic myopia. Trans Am Ophthalmol Soc. 1977;75:67–86. 9. Ohno-Matsui K, Kawasaki R, Jonas JB, et al. International photographic classification and grading system for myopic maculopathy. Am J Ophthalmol. 2015;159:877–883.e7. 10. Ohno-Matsui K, Lai TY, Lai CC, Cheung CM. Updates of pathologic myopia. Prog Retin Eye Res. 2016;52:156–187. 11. Lin LL, Shih YF, Hsiao CK, Chen CJ. Prevalence of myopia in Taiwanese schoolchildren: 1983 to 2000. Ann Acad Med Singapore. 2004;33:27–33. 12. Rudnicka AR, Kapetanakis VV, Wathern AK, et al. Global FIGURE 4. Boxplots showing the distribution of the ratio of CT as variations and time trends in the prevalence of childhood measured at 2500 lm nasal to the foveola divided by subfoveal CT in myopia, a systematic review and quantitative meta-analysis: the children with PDCA (study group) and in children from the implications for aetiology and early prevention. Br J GobiDCES. Ophthalmol. 2016;100:882–890.

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