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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 56  |  Issue : 4  |  Page : 226-231

Ophthalmological and medical long-term follow-up of patients with central retinal vein occlusion


1 Department of Oto-Neuro-Ophthalmological Surgical Sciences, Eye Clinic, Careggi University Hospital, Florence, Italy
2 Department of Experimental and Clinical Medicine, Careggi University Hospital, University of Florence, Florence, Italy

Date of Web Publication19-Feb-2019

Correspondence Address:
Dr. Shadi Alashwal
Ministry of Public Health, First Floor, W1-07, Doha, Qatar

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tjosr.tjosr_97_18

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  Abstract 


Purpose: The purpose of this study was to evaluate the ophthalmological and medical aspects of patients with a history of central retinal vein occlusion (CRVO) after a long-term follow-up. Design: This was a retrospective case–control study. Materials and Methods: Twenty-seven consecutive CRVO patients (29 eyes) were enrolled between April 2011 and April 2012, each participant underwent a comprehensive and detailed interview and also they had an ophthalmic examination with investigations such as color retinography and optical coherence tomography. Finally, medical and cardiologic examinations, including the laboratory analysis of blood specimens, were performed to all participants. Results: Our data confirm the significant association of CRVO with age (P = 0.025) and with ischemia (P = 0.022) and also treatment with low-molecular-weight heparin. Main risk factors of developing CRVO were as follows: hypertension (59.0%), dyslipidemia (48.0%), blood diseases (15.0%), and high body mass index (15.0%). There was no any significant association between all of the thrombophilic factors (laboratory parameters) and visual acuity (VA), except IgG anticardiolipin antibodies (P = 0.004). Two patients had myocardial infarction during the follow-up period. There was a parallel reduction of VA and foveal thickness during a long follow-up period. Conclusions: VA and central foveal thickness decreased during the follow-up period probably because of a progressive atrophy of the central retinal area, which suggest an early treatment of the macular edema prior an unfavorable evolution of the clinical situation, only one laboratory parameter had association with VA, small minority of patients developed serious cardiovascular events during the follow-up period after CRVO; these data suggest no overall association of CRVO with cardiovascular events.

Keywords: Central retinal vein occlusion, follow-up, medical, ophthalmological


How to cite this article:
Alashwal S, Murro V, Sodi A, Virgili G, Marcucci R. Ophthalmological and medical long-term follow-up of patients with central retinal vein occlusion. TNOA J Ophthalmic Sci Res 2018;56:226-31

How to cite this URL:
Alashwal S, Murro V, Sodi A, Virgili G, Marcucci R. Ophthalmological and medical long-term follow-up of patients with central retinal vein occlusion. TNOA J Ophthalmic Sci Res [serial online] 2018 [cited 2019 Mar 24];56:226-31. Available from: http://www.tnoajosr.com/text.asp?2018/56/4/226/252504




  Introduction Top


Retinal vein occlusion (RVO), one of the most frequently occurring retinal vascular disorders in elderly patients, develops predominantly in individuals over the age of 65 years.[1] It is an important cause of significant loss of vision in elderly populations in developed countries;[2] moreover, considered to be the second most common retinal vascular disease after diabetic retinopathy.[3] RVO is presented with painless visual loss, and a combination of fundoscopic findings consisting of retinal vascular tortuosity, retinal hemorrhages (blot and flame shaped), cotton wool spots, optic disc swelling, and macular edema. In a central RVO (CRVO), retinal hemorrhages will be found in all four quadrants of the fundus, while these are restricted to either the superior or inferior fundal hemisphere in a hemicentral RVO (HRVO).

RVO is generally classified into CRVO and branch RVO (BRVO) according to the site of blockage in the retinal vein. CRVO is divided further into nonischemic and ischemic types according to the perfusion status based on an investigation called fundus fluorescein angiography (FFA).[4] Of note, the ischemic pattern of CRVO is associated with >10 disc areas in diameter of retinal capillary nonperfusion on FFA.[5]

CRVO, in many cases, occurs in young adults with no other systemic disease; both local and systemic risk factors have been associated with CRVO, however, the cause of CRVO remains multifactorial.[6],[7] The epidemiology of RVO in a population as a whole is difficult to establish, perhaps many RVOs are silent where the condition is mild, the patient is asymptomatic, and it is only detected incidentally.

Studies among older population-based samples reported that the prevalence of RVO ranges from 0.3% in the pooling of two large population-based cardiovascular studies (the Atherosclerosis Risk in Communities Study and Cardiovascular Health Study).[8] On the other hand, the Blue Mountains Study was significantly associated with increasing age; over the age of 70 years, the prevalence of RVO was high about 1.6%.[9]

The incidence of RVO was evaluated in different longitudinal studies. In Hiroshima, Japan, the 5-year incidence of RVO was 0.6% at a general outpatient clinic but was 4.2% in the glaucoma clinic.[10] The 4-year incidence of RVO in an Israeli study of persons aged 40 years and older was 2.14 cases (0.2%) per 1000 people.[11]

The Beaver Dam Eye Study[12] reported a 15-year cumulative incidence of CRVO of 0.5%; for a BRVO, this was approximately three times more at 1.8%. Applying this to the United Nations projected UK population figures for 2010 gives approximately 47,000 new cases annually;[13] this figure is >150,000 for the United States.[14]

At present, the long-term natural history of patients with CRVO is still unclear as not many studies report on the evolution of the clinical picture and the possible recurrence of the disease in the same eye or in the fellow one. Moreover, there is no agreement on the association of CRVO with an increased risk of severe cardiovascular disorders (such as stroke or myocardial infarction) in the years following CRVO.

The main purpose of this study is to evaluate patients with CRVO in a long-term way of both ophthalmological and medical aspects.

In the present research, we reexamined a group of available patients who developed CRVO at least 5 years ago, evaluating their ophthalmological clinical history and their systemic health conditions. We also took into account the compliance of the patient and his/her adherence to the therapeutic regimen established at baseline.

Almost all patients with CRVO were subsequently addressed to thrombosis center for cardiovascular evaluation and to find the presence of thrombophilic risk factors occurred during the follow-up period.


  Materials and Methods Top


In this retrospective randomized controlled study, 27 consecutive CRVO participants (29 eyes) were enrolled between April 2011 and April 2012. Inclusion criteria for participants' recruitment were the central location of the occlusion, and the time of thrombosis has to be at least 5 years before to evaluate the clinical evolution and the long-term outcomes.

Each participant underwent a comprehensive interview, followed by ophthalmic and cardiologic examinations. A record sheet was used during the interview to obtain data of age, gender, the date of CRVO incident, signs and symptoms, and all previous measurements of VA or intraocular pressure (IOP). The sheet contained further information about risk factors, complications (macular edema and neovascular glaucoma), and management (retinal laser photocoagulation, anti-vascular endothelial growth factor [anti-VEGF], and surgery). Recurrence of the thrombotic episode (relapse) either on the same eye or in the contralateral eye and systemic diseases with their medication (heparin subcutaneous [SC], aspirin and oral steroids) were considered too. The participants were asked to bring all previous ophthalmological investigations (fluorescein angiographies and optical coherence tomographies [OCTs]) and also medical documentations (ECHO, carotid Doppler ultrasound, and blood tests). Due to the reason that all participants were examined in our department; hence, we reconsidered their stored clinical files.

Then, the participants were asked to receive an ophthalmic examination, including a best-corrected visual acuity (VA) measurement using the Snellen decimal method, slit-lamp examination of anterior segment, fundus examination with a Volk 90 lens after pupil dilation, and IOP measurement through slit-lamp Goldmann method. All participants had underwent further investigations to evaluate the presence of macular edema such as color retinography by means of Zeiss Retinal Camera and OCT examination by means of Topcon-1000 three-dimensional.

The thickness of the central fovea was defined as the distance between the inner limiting membrane and the retinal pigment epithelium (including any serous retinal detachment). The severity of macular edema was determined from the measured retinal thickness, and all measurements were obtained automatically by computer analysis. Finally, the participants underwent a cardiovascular evaluation performed by an internal medicine specialist to assess the possibility of cardiovascular risk factors.

The large majority of participants lived in Florence (Italy) and gave their informed consent for the study, which was approved by the Institutional Review Board.

The influences of the ocular and systemic risk factors were considered in the analysis of the results with evaluation of the progress of VA and OCT foveal thickness. A special focus on the final value was obtained at the end of the follow-up period. All analysis was done using Stata 10.2 (College Station, TX, USA). In short, linear mixed models were used to model change of VA with time, with time as a random coefficient at the individual level. The same model was used to investigate the change of retinal thickness measured with OCT. The effect of several covariates was assessed using linear regression on change of VA at 24 months, which was the most consistently reported time point. A Student's t-test was used for this purpose.


  Results Top


Twenty-seven participants were included in this study, two participants of them have a relapse in the contralateral eyes. A total of 29 eyes were included in this study (16 left eyes and 13 right eyes). The follow-up period ranged from 5 to 9 years, which depends on the period when participants had the attack of CRVO.

Regarding the systemic aspect of the participants, hypertension was the most important risk factor, in fact 16 participants (59.0%) suffered from high blood pressure; among them, 12 participants (44.0%) whom hypertension was already diagnosed at the time when CRVO was manifested, whereas the other four participants (15.0%) discovered it during the follow-up period.

Dyslipidemia conditions such as hypercholesterolemia, hyperlipidemia, and similar disorders had a raised important as well. Thirteen participants out of 27 (48.0%) had suffered from one of these disorders and were taking statin in a regular basis; only 19.0% of participants were already diagnosed at the moment of CRVO while the other 29% of participants were diagnosed after the ophthalmologic disorder.

Age was taken into account as an important risk factor; of note, there were 59% of the participants aged more than 60 years, approximately 26% aged between 50 and 60 years, while the prevalence of participants younger than 50 years was 15%. The mean age was 67 years (standard deviation: 16, range 27–87).

Hematological diseases and hypercoagulability conditions were detected in four participants (15.0%), of which 2 had hyperhomocysteinemia, one had anemia, and the last patient had a high level of lipoprotein(a), of notice all of them are young females.

In this study, diabetes mellitus showed a weak association with CRVO: in our series, there were only two participants (7.0%) with type 2 diabetes, one of them was taking the oral hypoglycemic therapy, while another was under insulin therapy.

High body mass index (BMI) has also been implicated in RVO; BMI higher than 25 was found in four participants (15.0%), our series has involved five participants (19%) suffered from ocular risk factor which is chronic primary open-angle glaucoma and has been receiving antiglaucomatous drops regularly. On the other side, neovascular glaucoma, which is a horrible complication of ischemic CRVO, was detected in three participants (11.0%), unlikely associated with rubeosis iridis and poor vision.

We considered five (VA) measurements during the follow-up period. [Table 1] and [Table 2] summarize the behavior of VA with time (shown in months); more specifically number and percentage of eyes which remained stable or presented a gain or loss of VA of three lines. The term “final” indicates the last VA measurement during the interview.
Table 1: Number of eyes according to visual acuity change (in Snellen lines)

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Table 2: Percentage of eyes with visual acuity change during the follow-up period

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One of the interesting findings is the change of VA in logarithm of the minimum angle of resolution (logMAR). [Figure 1] shows the change of VA been presented as box plots, where the horizontal line is the median, boxes margins are quartiles and whiskers are extreme observations within 2.5 boxes of the median, with further observations presented as dots. The mean change was stable; however, there was a lot of variation regarding visual changes with some participants improving vision and more participants losing it.
Figure 1: Change of visual acuity in logarithm of the minimum angle of resolution

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[Table 3] shows changes in central retinal thickness (CRT) measured by means of OCT scan during the follow-up period, OCT 0 refers to the value measured at the time of CRVO diagnosis, the following values refer to the measurements performed during the follow-up period at 6, 12, 24 months, and final during the interview, supporting this result. [Figure 2] shows the changes of CRT measured by OCT scan presented as boxplots were the horizontal line is the median, boxes margins are quartiles and whiskers are extreme observations within 2.5 boxes of the median, with further observations presented as dots. The mean change of logMAR VA and retinal thickness by OCT from baseline has been demonstrated in [Table 4].
Table 3: Optical coherence tomography retinal thickness measurements during the follow-up period (μm)

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Figure 2: Changes of central retinal thickness

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Table 4: The mean change of logarithm minimum angle of resolution visual acuity and retinal thickness by optical coherence tomography from baseline

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Ischemic cases have been detected by the presence of nonperfused areas on FFA; surprisingly, there were 12 participants with ischemic features (44.0%), out of which eight cases had few ischemic areas and the other four had developed extensive ischemic areas distributed in all quadrants. The P value resulting from a correlation between ischemia and VA in the 24 months was statistically significant (0.022). To be noted that, 3 (11.0%) participants complicated with neovascular glaucoma and rubeosis iridis (new vessel in the iris).

Discussing further consequences of CRVO, it is important to state that all participants have developed macular edema in the course of this disease, there were 19 participants (70%) already present with the macular edema during the period of occlusion.

Reoccurrence (relapse) occurred in five participants (18%), in three of them were in the same eye and in the other two participants in the contralateral eye. [Table 5] illustrates age-sex-adjusted univariate regression coefficient of each risk factor on change of VA at final VA, and there was no significant association between all the considered parameters and VA after 24 months with the only exception of IgG anticardiolipin antibodies (P = 0.004) the small number of participants included in the study does not allow definite statements; however, this finding is interesting and is in agreement with previous reports of an association between thrombophilic risk factors and the development of an ischemic (more severe) type of CRVO.[15]
Table 5: Age-sex-adjusted univariate regression coefficient of each risk factor on change of visual acuity at final visual acuity

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Twenty-four out of 27 participants (88%) received subcutaneous low-molecular-weight heparin 0.4 IU, for at least 2 months, according to the protocols shared between the Eye Clinic and the Thrombosis Center of our Hospital. After the acute phase and during the follow-up period, some participants were assuming more than one medication in different periods, 23 were on aspirin (85%), and three participants were assuming warfarin while only one patient was on ticlopidine. It has been found no any significant association between VA at 24 months and management methods [Table 6].
Table 6: The possible association of treatment variables with the visual acuity at 24 months

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In our series, only two participants showed a major cardiovascular event (myocardial infarction) during the follow-up period after the CRVO. These two participants did not show any particular clinical ophthalmologic feature suggesting a predictive value for major cardiovascular complications.


  Discussion Top


In this study, it has been considered a group of 29 eyes which were affected by CRVO. It is reported the main risk factors for this disease and the ophthalmological and medical features of the patients during a long-term follow-up period.

The most important risk factor was hypertension with a prevalence of 59.0%. Among the hypertensive participants, 44.0% were hypertensive when they developed the CRVO, whereas the remaining 15.0% developed the disease during the follow-up period.

The prevalence of hypertension within participants group was lower than been published in some previous studies, as in the Beaver Dam Eye Study, with a reported value of 89.2% and in the Blue Mountains Eye Study with a reported prevalence of 89.7%.[9] In contrast to some researches in the literature, our value was slightly higher than in Hisayama Study (56%). It is assumed that these results discrepancies might be influenced by ethnic or methodological differences, and by the low number of participants, we were able to recruit for the present study.

Dyslipidemia was another important risk factor as 48% of participants suffered from it, out of which 19.0% were already diagnosed at the moment of CRVO while the rest (>29%) discovered it later on.

Our data confirm the known association of age with CRVO (P = 0.025), only 15% of our participants were younger than 50 years, and all of them recover a good vision with VA ≥0.8 logMAR. This figure is approximately similar to that reported by Hayreh et al.[1] which mentioned that of 99 of 620 RVO participants (16%) were younger than 45 years.

As for ophthalmological follow-up, we have found that 52% of our participants have lost three lines of VA logMAR during the final vision measurement in comparison with the baseline. This could be due to the natural progression of CRVO, relapsing of this occlusion, or duo to serious complications of the CRVO, such as macular edema, vitreous hemorrhage, or neovascular glaucoma; of course, we cannot exclude the influence of ocular diseases other than CRVO such as senile cataract and chronic glaucoma, another logical explanation may explain that before 2006, there was not available treatment with the anti-VEGF.

As for OCT measurements, we found at baseline an increased foveal thickness associated with the presence of macular edema; with time the CRT values tend to reduce significantly. The parallel reduction of VA and foveal thickness during our relatively long follow-up period suggests that the final poor VA is mainly due to a progressive macular atrophy.

Recurrence in the same eye took place in three participants (11.0%), and all of them had the first episode at least 5 years before. This figure is higher than that of Hayreh et al.,[1] which was 0.9% within 2 years and 2.5% within 4 years.

Two participants (7.4%) have manifested recurrence features in the contralateral eye, while it is reported by Hayreh et al.[1] that 7.7% of participants with CRVO developed the second episode of thrombosis in the contralateral eye within 2 years and 11.9%, within 4 years.

Many studies concerning antiphospholipid antibodies (aPL) and occlusive retinal vascular disease have been published; however, many questions remain unanswered. The prevalence of anticardiolipin antibodies (which is the marker of antiphospholipid syndrome [APS]) in our study was 14.8% with no patient with APS. In a prospective study of consecutively admitted patients in a department of internal medicine, 20 patients (1.9%) fulfilled the criteria for APS. Isotype IgG of anticardiolipin was the most frequently identified antibody associated with the event consistent with previous studies. Among 40 patients with retinal vascular disease, Cobo-Soriano et al.[16] reported only three patients (7.5%) with APS. However, that study combined retinal venous and artery occlusion, which have different pathogeneses and risk factors.

Lifelong anticoagulation is the international standard of care for patients with APS and warfarin is more effective than aspirin in preventing further thrombotic events. However, 85% of patients with thrombotic event related to APS are under 50 years of age and patients with RVO are not included in such studies. It is probably a confounding factor to apply the findings on pathogenesis and risk factors from deep vein thrombosis to RVO. The two are very different diseases with different pathogenesis. The role of aPL in predicting ischemic stroke recurrence and treatment management also remains controversial.

In this study, no participants had an APS. Since no recurrent event occurred during follow-up, we believe that Virchow's triad plays a major role and that RVOs are multifactorial in origin.

As some of our participants suffered from vascular risk factors, RVO might be attributed to the degenerative change of the vessel wall. Aspirin may be sufficient to prevent further thrombotic event after RVO, and it would carry less risk of hemorrhage than anticoagulants, particularly in the elderly. Besides antiplatelet properties, it has been shown that aspirin exerts a protective effect toward aPL at the endothelial cell level.

A long follow-up would also be interesting to better assess the risk of recurrence of thrombosis. Until the role of aPL antibodies in relation to causation of RVO is better defined, we recommend a routine screening for aPL in patients with the first episode of RVO and no past thrombotic event.

Our study has some significant limitations; the most important is the small number of participants, which does not allow a reliable epidemiological evaluation. Another bias may be represented by the selection of participants who were available for coming to the hospital for the interview and the clinical evaluation, with the exclusion of the participants with more severe systemic troubles.


  Conclusion Top


In this study, both visual acuity and OCT foveal thickness decreased during the follow-up period probably because of a progressive atrophy of the central retinal area; we speculate that the underlying pathological mechanism is the absorption of intraretinal edema with the development of macular atrophy. These findings suggest an early treatment of the macular edema prior to an unfavorable evolution of the clinical situation. In our series, different clinical pictures and various therapeutic approaches seem poorly related with the visual outcome; however, it was assumed to be correlated to a small number of which makes it difficult to highlight possible associations. The detection of a possible thrombophilic state may represent a valuable clinical tool not only for the investigation of the pathogenic mechanisms of the vascular occlusion, but also for a possible prognostic long-term evaluation of the patients. In our series, only a small minority of patients developed serious cardiovascular events during the follow-up period after CRVO; therefore, data suggests a poor predictive value of CRVO for incoming cardiovascular complications, but our series is too small to allow a reliable prognostic evaluation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
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2.
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3.
Wong TY, Scott IU. Clinical practice. Retinal-vein occlusion. N Engl J Med 2010;363:2135-44.  Back to cited text no. 3
    
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6.
Lattanzio R, Sampietro F, Ramoni A, Fattorini A, Brancato R, D'Angelo A, et al. Moderate hyperhomocysteinemia and early-onset central retinal vein occlusion. Retina 2006;26:65-70.  Back to cited text no. 6
    
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Yildirim C, Yaylali V, Tatlipinar S, Kaptanoǧlu B, Akpinar S. Hyperhomocysteinemia: A risk factor for retinal vein occlusion. Ophthalmologica 2004;218:102-6.  Back to cited text no. 7
    
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Wong TY, Larsen EK, Klein R, Mitchell P, Couper DJ, Klein BE, et al. Cardiovascular risk factors for retinal vein occlusion and arteriolar emboli: The atherosclerosis risk in communities and cardiovascular health studies. Ophthalmology 2005;112:540-7.  Back to cited text no. 8
    
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Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in Australia. The blue mountains eye study. Arch Ophthalmol 1996;114:1243-7.  Back to cited text no. 9
    
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11.
David R, Zangwill L, Badarna M, Yassur Y. Epidemiology of retinal vein occlusion and its association with glaucoma and increased intraocular pressure. Ophthalmologica 1988;197:69-74.  Back to cited text no. 11
    
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Klein R, Moss SE, Meuer SM, Klein BE. The 15-year cumulative incidence of retinal vein occlusion: The beaver dam eye study. Arch Ophthalmol 2008;126:513-8.  Back to cited text no. 12
    
13.
Anon. Advance notification document: Dexamethasone 700 μg intravitreal implant in applicator (OZURDEX™) for retinal vein occlusion. Allergan; 2009.  Back to cited text no. 13
    
14.
Dexamethasone Intravitreal Implant Approved for Retinal Vein Occlusion. Medscape Medical News. Available from: http://www.medscape.com/viewarticle/704854. [Last accessed on 2010 Mar 01].  Back to cited text no. 14
    
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Sodi A, Giambene B, Marcucci R, Sofi F, Fedi S, Abbate R, et al. Atherosclerotic and thrombophilic risk factors in patients with ischemic central retinal vein occlusion. Retina 2011;31:724-9.  Back to cited text no. 15
    
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Cobo-Soriano R, Sánchez-Ramón S, Aparicio MJ, Teijeiro MA, Vidal P, Suárez-Leoz M, et al. Antiphospholipid antibodies and retinal thrombosis in patients without risk factors: A prospective case-control study. Am J Ophthalmol 1999;128:725-32.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

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



 

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