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ORIGINAL ARTICLE
Year : 2019  |  Volume : 10  |  Issue : 1  |  Page : 63-68  

Impact of hormonal replacement therapy on macula and retinal nerve fiber layer in postmenopausal women


1 Department of Ophthalmology, Hospital Melaka, Melaka; Pusat Perubatan Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
2 Department of Ophthalmology, Hospital Melaka, Melaka, Malaysia
3 Department of Ophthalmology, Pusat Perubatan Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia

Date of Web Publication22-Aug-2019

Correspondence Address:
Jemaima Che Hamzah
Department of Ophthalmology, Pusat Perubatan Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Batu 9 Cheras, Wilayah Persekutuan Kuala Lumpur
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpnr.JPNR_16_18

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   Abstract 


Objective: The objective of this study was to investigate the effect of hormonal replacement therapy (HRT) in postmenopausal women on peripapillary retinal nerve fiber layer (RNFL) and macular thickness and macular volume and to compare them with postmenopausal women who are not on hormonal replacement therapy. Materials and Methods: The study population included postmenopausal women who are taking HRT (n = 50) and postmenopausal women who are not taking HRT (n = 50). Peripapillary retinal nerve fiber layer and macular thickness and macular volume were evaluated using spectral domain-optical coherence tomography. Results: There was no statistically significant difference in all peripapillary RNFL thickness and macular thickness and volume parameters between the two groups, HRT and non-HRT groups, except for superior outer macular thickness and volume were significantly thicker in postmenopausal women who are taking hormonal replacement therapy, P = 0.036 and P = 0.037, respectively. There was a positive correlation between duration on HRT with most of peripapillary RNFL and macular thickness and macular volume, but the correlation was only significant at superotemporal peripapillary RNFL. Conclusion: Our result does not provide strong evidence for a protective effect of postmenopausal HRT usage against ocular diseases. However, the increased macular thickness in superior outer macula and positively correlated peripapillary retinal nerve fiber layer at superotemporal encouraged us to think of promising positive effect of HRT on ocular structure.

Keywords: Hormonal replacement therapy, macula, peripapillary nerve fiber layer, postmenopausal women, spectral domain-optical coherence tomography


How to cite this article:
Tharek S, Omar RN, Hamzah JC. Impact of hormonal replacement therapy on macula and retinal nerve fiber layer in postmenopausal women. J Pharm Negative Results 2019;10:63-8

How to cite this URL:
Tharek S, Omar RN, Hamzah JC. Impact of hormonal replacement therapy on macula and retinal nerve fiber layer in postmenopausal women. J Pharm Negative Results [serial online] 2019 [cited 2019 Sep 23];10:63-8. Available from: http://www.pnrjournal.com/text.asp?2019/10/1/63/265146




   Introduction Top


Hormonal replacement therapy (HRT) usage was associated with reducing risk of primary open-angle glaucoma (POAG). A large, retrospective, longitudinal cohort study in the United States showed that the proportions of women taking estrogen, estrogen with a combination of progesterone, and estrogen with combination of androgen who developed POAG were 1.7%, 1.9%, and 1.4%, respectively. By comparison, 2.1% of those non-HRT users developed POAG. This study also showed that each additional month use of HRT containing estrogen only was associated with 0.4% reduced risk for POAG. However, the risk did not differ in combination estrogen and progesterone group or combination estrogen and androgen group.[1]

There are increasing evidence suggesting that sex hormones may play a role in the development of glaucoma. Retinal ganglion cells (RGCs) were found to express estrogen receptors by several investigators.[2] In a rat model of retinal ischemia, oral estrogen administration had a protective effect on RGCs that was mediated by these receptors.[3],[4] Several observational studies have shown that usage of HRT was associated with a modestly reduced intraocular pressure (IOP).[5],[6],[7],[8] HRT was also found to cause increased blood flow in retinal arteries in postmenopausal women treated with HRT.[9],[10],[11],[12] These data suggest that sex hormones may influence the pathogenesis of POAG through lowering of IOP, protection of RGCs, and improvement of ocular blood flow.

Retinal nerve fiber layer (RNFL) thinning and characteristic visual field defects are the most common signs of glaucoma.[13] Accumulating evidence indicates that both structural and functional macular involvements are present throughout the spectrum of glaucoma as RGCs are most densely populated in the macular region.[14] Since HRT usage has been associated with reduced incidence of glaucoma, we performed peripapillary RNFL and macular thickness and macular volume measurements using spectral domain-optical coherence tomography (SD-OCT) in postmenopausal women to determine the preservation of RNFL and macular thickness and macular volume in postmenopausal women on HRT as compared to postmenopausal women who are not on HRT.

The objective of this study was to investigate the relationship between RNFL and macular thickness and macular volume in postmenopausal women with and without HRT. The second objective of this study was to investigate the correlation between duration of HRT usage with peripapillary RNFL and macular thickness and macular volume.


   Materials and Methods Top


Study design

This cross-sectional comparative study was performed at Ophthalmology and Obstetrics and Gynecology Clinic, Hospital Melaka, from March 2016 to May 2018. The study was approved by the Medical Research and Ethics Committee, Ministry of Health (NMRR-16-1941-32894) and Medical Research and Ethics Committee, Universiti Kebangsaan Malaysia (FF-2017-041). Each participant was treated in accordance with the Declaration of Helsinki and written informed consent was obtained from all the participants.

Sample size

The sample size was calculated using Power and Sample Size Calculation software version 3.1.2, 2014, by William D. Dupont and Walton D. Plummer. The calculated sample size has at least 80% power to detect a difference of macular volume and thickness and peripapillary nerve fiber layer thickness between postmenopausal women with and without HRT at a 5% statistical significance level using t-test. The standard deviation used is based on a similar study done by Deschênes et al.[11] Thus, the calculated minimum sample size is 50 participants in each group. In this study, a total of 100 participants were therefore recruited.

Participants

A total of 100 participants were recruited and divided into two equal groups. The first group (HRT) comprised 50 postmenopausal women on HRT either estrogen hormonal therapy or combination estrogen and progesterone hormonal therapy for at least 1 year before enrollment in the study. The second group (non-HRT) comprised 50 postmenopausal women who never receive any HRT. These postmenopausal women were aged between 50 and 60 years old and either naturally or surgically menopaused.

We excluded postmenopausal women who had a history of smoking, previous ocular surgery, previous ocular trauma, cloudy ocular media such as dense cataract, and other concomitant ocular diseases such as diabetic or hypertensive retinopathy, retinal or macular edema, ocular inflammation or infection, age-related macular degeneration and glaucoma at the time of OCT measurement, and long axial length of eyeball more than 24.5 mm or shorter axial length <22 mm. Those who had underlying obstructive airway disease, cardiovascular and central nervous system diseases, uncontrolled diabetes mellitus, uncontrolled hypertension, and poor OCT signal strength <25 decibels were also excluded from the study.

Study protocol

Demographic, medical, obstetrics, and gynecologic as well as ocular history were obtained from each participant. The systolic and diastolic blood pressure (BP) was measured using digital automatic BP monitor after the patient rested for 10 min. Five milliliters of nonfasting venous blood sample was taken for glycosylated hemoglobin (HbA1c) and random blood glucose. Each participant underwent a comprehensive ophthalmologic examination. Visual acuity was taken using the Snellen chart. Axial length measurement was done using IOL Master 700 (Carl Zeiss, Germany). IOP was measured using Goldmann applanation tonometer. Fundus examination through a dilated pupil was performed using a 78 D lens.

Following this examination, OCT scanning was done by a single experienced optometrist using the third-generation spectralis OCT (OCT Heidelberg Engineering, Germany) with software version of 1.9.10.0 for the measurement of peripapillary RNFL and macular thickness and macular volume. The fast macular thickness scanning protocol was used for measurement of macular thickness and volume, while the peripapillary RNFL was measured using the fast RNFL thickness scanning protocol. Only one eye of each participant was selected as the study eye and laterality was randomly chosen. The macular thickness and volume was automatically calculated by the built-in software for all nine macular regions as defined by the Early Treatment Diabetic Retinopathy Study [15] which consists of central subfield (CSF), inferior inner macula (IIM), inferior outer macula (IOM), nasal inner macula (NIM), nasal outer macula (NOM), superior inner macula (SIM), superior outer macula (SOM), temporal inner macula (TIM), and temporal outer macula (TOM) [Figure 1]. The peripapillary RNFL thickness was automatically segmented and calculated using the built-in software for all regions included temporal quadrant (T), temporal superior quadrant (TS), nasal superior quadrant (NS), nasal quadrant (N), nasal inferior quadrant (NI), temporal inferior quadrant (TI), and average (G) [Figure 2].
Figure 1: (a-d) Diagram showing macular thickness and volume map provided by spectral domain-optical coherent tomography

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Figure 2: (a-d) Peripapillary retinal nerve fiber layer thickness map provided by spectral domain-optical coherence tomography

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As shown in [Figure 1], [Figure 1]a is a volume scan, centered on the macula. The scan consists of multiple aligned scans of which the black arrow indicates one. For orientation, a small black line is inserted (asterisk). In [Figure 1]b, circles on the plots represent 1-, 3-, and 6-mm scan diameters. The innermost circle defines the fovea, an area with few RGCs. Data in black represent macular thickness, which are expressed in μm and data in gray represent macular volume expressed in mm3. [Figure 1]c is a cross-sectional image of macula, in which the vertical gray line corresponds to the position of the asterisk shown in [Figure 1]a. [Figure 1]d is the three-dimensional image of the macula, visualizing the retinal layers. The black line corresponds to the position of the asterisk shown in [Figure 1]a and [Figure 1]c.

[Figure 2]a is a circular scan centered on the optic nerve head (ONH). The ring scan starts at the arrowhead seen to the right of the circle (nasal sector). For orientation, a small black line is inserted (asterisk). In [Figure 2]b, the data are expressed in μm of RNFL thickness for each retinal sector. [Figure 2]c is a cross-sectional image of RNFL (B-scan, averaged from approximately 200 A-scans). The vertical gray line corresponds to the position of the asterisk shown in A, next to the superior temporal retinal artery and vein. In [Figure 2]d, the RNFL thickness is measured across 768 locations. Baseline data are shown by a black line. Normative data represent by the line of gray shades, where the whitish layer in the middle corresponds to the 95% normal range, and the darker gray and lighter gray areas represent values outside the 99% confidence interval of the normal distribution, indicating outside normal limits. The vertical gray line corresponds to the position of the asterisks shown in [Figure 2]a and [Figure 2]c.

Statistical analysis

Statistical analysis was conducted using IBM SPSS software package version 22.0. Shapiro–Wilk test, skewness, kurtosis, and box plot were used to assess data normality. Levene's test was used to assess the variance homogeneity. Values are expressed as mean ± standard deviation and frequencies in number and percentage.

Comparison between HRT and non-HRT groups was made with independent sample t-test for continuous data (age, HbA1c, random blood sugar, diastolic and systolic BP, parity, duration menopause, age menarche, history of oophorectomy, IOP, axial length, peripapillary RNFL, and macular thickness and macular volume). Chi-square test was used for categorical data (race, diabetes mellitus, hypertension, usage of oral contraceptive, and history of oophorectomy).

Pearson's correlation test was used to test the correlation between duration of HRT usage, duration of menopause, and age with peripapillary RNFL and macular thickness and macular volume.


   Results Top


Demographic data

The HRT group comprised 50 eyes of 50 postmenopausal women who are taking HRT and the non-HRT consists of 50 eyes of 50 postmenopausal women who are not taking HRT. The mean age was 53.3 ± 3.2 years and 54.4 ± 2.8 years in HRT and non-HRT groups, respectively, which was statistically not significant (P = 0.08). Majority of the participants are Malay, followed by Chinese and Indians in both groups but not statistically significant (P = 0.08). Other systemic comorbidities were comparable between both groups [Table 1] except the history of diabetes mellitus was more in the HRT group compared to non-HRT group, (P = 0.01). Mean IOP was 16.04 ± 1.60 mmHg in the HRT group, while mean IOP in the non-HRT group was 15.90 ± 2.16 mmHg, which was not statistically significant (P = 0.71).
Table 1: Demographic characteristics of the study population

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The mean duration of menopause was 3.0 ± 3.0 years in HRT group compared to 4.0 ± 5.0 years in non-HRT group, which was not statistically significant difference (P = 0.259). Duration of treatment with HRT in the HRT group was 2.0 ± 3.25 years. Among these participants, 34 (68%) postmenopausal women on HRT group were surgically menopause compared to 11 (2%) in the non-HRT group, which was statistically significant (P = 0.00) [Table 2].
Table 2: Gynecologic data for the study population

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Comparison of peripapillary retinal nerve fiber layer thickness between hormonal replacement therapy group and nonhormonal replacement therapy group

The peripapillary RNFL thickness analysis obtained by SD-OCT is summarized in [Table 3]. Most of the peripapillary RNFL quadrant thicknesses were thinner in the HRT group compared to non-HRT except the nasal quadrant and temporal inferior quadrant, but this was not statistically significant.
Table 3: Peripapillary retinal nerve fiber layer thickness among postmenopausal women on hormonal replacement therapy and not on hormonal replacement therapy

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Comparison of macular thickness and volume between hormonal replacement therapy group and non-hormonal replacement therapy group

The macular thickness and volume analysis obtained by SD-OCT is summarized in [Table 4] and [Table 5], respectively. Mean macular thickness and volume at SOM were significantly thicker in HRT group compared to non-HRT group with P = 0.04. SIM, IIM, NIM, TOM, IOM, NOM thickness, and volume were observed to be thicker in HRT group compared to non-HRT group, although these were not statistically significant. Only CSF and TIM thickness were thinner in HRT group compared to non-HRT group, but it was not statistically significant.
Table 4: Macular thickness among postmenopausal women on hormonal replacement therapy and not on hormonal replacement therapy

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Table 5: Macular volume among postmenopausal women on hormonal replacement therapy and not on hormonal replacement therapy

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Correlation between duration of hormonal replacement therapy usage with peripapillary retinal nerve fiber layer thickness, macular thickness, and volume

The Pearson's correlation test was used to assess the correlation between duration of HRT usage with peripapillary RNFL thickness, macular thickness, and volume, and the result is shown in [Table 6], [Table 7], [Table 8], respectively. TS peripapillary RNFL thickness was significant but weakly correlated with duration of HRT usage (r = 318, P = 0.02). Positive correlation was also observed between duration of taking HRT and all peripapillary and macular thickness and macular volume except N peripapillary RNFL thickness, TI peripapillary RNFL thickness, SOM thickness, and volume, which have negative correlation. However, the correlation was not statistically significant.
Table 6: Correlation between duration of hormonal replacement therapy usage with peripapillary retinal nerve fiber layer thickness

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Table 7: Correlation between duration of hormonal replacement therapy usage with macular thickness

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Table 8: Correlation between duration of hormonal replacement therapy usage with macular volume

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   Discussion Top


Several studies have shown that HRT usage was associated with a modestly reduced IOP,[5],[6],[7],[8] improvement of ocular blood flow,[9],[10],[11],[12] and neuroprotection of RGCs.[3],[4] Thus, HRT may help in delaying the development or progression of glaucoma. Hence, RNFL and macular thickness and volume were investigated in this study to assess the protective effect of HRT against glaucoma.

In this study, most of the peripapillary RNFL thickness and macular thickness and volume parameters were higher in HRT group; however, only macula SOM thickness showed significant difference in between the two groups. Yoshida et al. observed that blood flow in the superior temporal artery was higher than the inferior temporal artery.[16] Harris-Yitzhak et al. found that posterior ciliary vessels which supplied ONH resistance index was unchanged by either age or estrogen replacement therapy while studying the effects of estrogen replacement therapy on retrobulbar hemodynamics.[12] This result may explain the significant result at macula SOM and insignificant result on the peripapillary RNFL.

Our findings are in contrast with an observational study by Deschênes et al.[11] where they found in postmenopausal women who are taking HRT, they have significantly greater rim volume for the entire ONH. For the inferotemporal RNFL of the ONH region, rim volume, height variation contour, mean thickness, and cross-sectional area were also significantly greater in postmenopausal women who are taking HRT.

The discrepancy in the results might be due to shorter duration of use of HRT in our study (3.64 ± 3.24 years) compared to their study (8.3 ± 6.1 years). Imtiaz et al. showed a protective effect of long-term use of HRT (>10 years) against Alzheimer disease in postmenopausal women.[17] Our study observed positive correlation between peripapillary RNFL thickness and macular thickness and volume parameters with duration of HRT usage, but only TS peripapillary RNFL thickness was statistically significant. However, there is no other study on the effects of duration of HRT on ocular structures available at this current time.

Deschênes et al. used confocal scanning laser ophthalmoscopy [11] while assessing the ONH topography as compared to our study which used SD-OCT to measure the RNFL and macular thickness and volume. A few studies showed that there was a poor correlation between ONH parameter measured with SD-OCT and CSLO.[13],[18] Hence, the result of ONH parameter in this study cannot be directly compared with the result of a study by Deschênes et al., in which is the only study to the best of our knowledge comparing ONH parameter in between postmenopausal women on HRT and non-HRT.

The strength of this study is the usage of SD-OCT, which provides quantitative measurement of retinal structure with enhanced image resolution, decreased scan acquisition time, and better measurement reproducibility which increase its clinical usefulness for detection of several retinal diseases.[19] To the best of our knowledge, this is the first observational study that investigates the influence of HRT on peripapillary RNFL and macular thickness and macular volume in postmenopausal women with SD-OCT.

Limitations of this study are short duration of HRT usage and effects of different types of HRT usage were not studied in this study. Further studies may be needed to look at the effects of different types of HRT with longer duration of HRT usage in postmenopausal women on the macula and RNFL.


   Conclusion Top


Our results did not provide a strong evidence of the protective effect of HRT usage in postmenopausal women as a modifiable risk factor in the prevention development of age-related vision-threatening ocular diseases such as glaucoma. However, the increased macular thickness in SOM and positively collerated peripapillar RNFL at ST after taking HRT may be a promising positive effect of HRT on ocular structures, which should be further investigated.

Acknowledgment

The authors would like to thank Dana Fundamental PPUKM for financial support.

Financial support and sponsorship

The study was financially supported by Dana Fundamental PPUKM.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Newman-Casey PA, Talwar N, Nan B, Musch DC, Pasquale LR, Stein JD, et al. The potential association between postmenopausal hormone use and primary open-angle glaucoma. JAMA Ophthalmol 2014;132:298-303.  Back to cited text no. 1
    
2.
Munaut C, Lambert V, Noël A, Frankenne F, Deprez M, Foidart JM, et al. Presence of oestrogen receptor type beta in human retina. Br J Ophthalmol 2001;85:877-82.  Back to cited text no. 2
    
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Prokai-Tatrai K, Xin H, Nguyen V, Szarka S, Blazics B, Prokai L, et al. 17β-estradiol eye drops protect the retinal ganglion cell layer and preserve visual function in an in vivo model of glaucoma. Mol Pharm 2013;10:3253-61.  Back to cited text no. 3
    
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Tint NL, Alexander P, Tint KM, Vasileiadis GT, Yeung AM, Azuara-Blanco A, et al. Hormone therapy and intraocular pressure in nonglaucomatous eyes. Menopause 2010;17:157-60.  Back to cited text no. 7
    
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Ciccone MM, Cicinelli E, Giovanni A, Scicchitano P, Gesualdo M, Zito A, et al. Ophthalmic artery vasodilation after intranasal estradiol use in postmenopausal women. J Atheroscler Thromb 2012;19:1061-5.  Back to cited text no. 9
    
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Atalay E, Karaali K, Akar M, Ari ES, Simsek M, Atalay S, et al. Early impact of hormone replacement therapy on vascular hemodynamics detected via ocular colour Doppler analysis. Maturitas 2005;50:282-8.  Back to cited text no. 10
    
11.
Deschênes MC, Descovich D, Moreau M, Granger L, Kuchel GA, Mikkola TS, et al. Postmenopausal hormone therapy increases retinal blood flow and protects the retinal nerve fiber layer. Invest Ophthalmol Vis Sci 2010;51:2587-600.  Back to cited text no. 11
    
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Harris-Yitzhak M, Harris A, Ben-Refael Z, Zarfati D, Garzozi HJ, Martin BJ, et al. Estrogen-replacement therapy: Effects on retrobulbar hemodynamics. Am J Ophthalmol 2000;129:623-8.  Back to cited text no. 12
    
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Leung CK, Lam S, Weinreb RN, Liu S, Ye C, Liu L, et al. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: Analysis of the retinal nerve fiber layer map for glaucoma detection. Ophthalmology 2010;117:1684-91.  Back to cited text no. 13
    
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Hood DC, Raza AS, de Moraes CG, Liebmann JM, Ritch R. Glaucomatous damage of the macula. Prog Retin Eye Res 2013;32:1-21.  Back to cited text no. 14
    
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Early treatment diabetic retinopathy study design and baseline patient characteristics. ETDRS report number 7. Ophthalmology 1991;98:741-56.  Back to cited text no. 15
    
16.
Yoshida A, Feke GT, Ogasawara H, Goger DG, McMeel JW. Retinal hemodynamics in middle-aged normal subjects. Ophthalmic Res 1996;28:343-50.  Back to cited text no. 16
    
17.
Imtiaz B, Tuppurainen M, Rikkonen T, Kivipelto M, Soininen H, Kröger H, et al. Postmenopausal hormone therapy and Alzheimer disease: A prospective cohort study. Neurology 2017;88:1062-8.  Back to cited text no. 17
    
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Kremmer S, Ayertey HD, Selbach JM, Steuhl KP. Scanning laser polarimetry, retinal nerve fiber layer photography, and perimetry in the diagnosis of glaucomatous nerve fiber defects. Graefes Arch Clin Exp Ophthalmol 2000;238:922-6.  Back to cited text no. 18
    
19.
Povazay B, Hofer B, Torti C, Hermann B, Tumlinson AR, Esmaeelpour M, et al. Impact of enhanced resolution, speed and penetration on three-dimensional retinal optical coherence tomography. Opt Express 2009;17:4134-50.  Back to cited text no. 19
    


    Figures

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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