The Latest Trends in Retinal Vein Occlusions


The Latest Trends in Retinal Vein Occlusions


Occlusive retinal vascular disease is not uncommon. Central retinal vein occlusion (CRVO) is the second most common vision-impairing vascular disorder of the retina following diabetic retinopathy.1 The incidence of CRVO is currently reported as 1.8%.2 Risk factors include older age, male sex, and systemic risk factors, such as hypertension and glaucoma.3 Branched retinal vein occlusions (BRVO) share similar risk factors. At present, there are a number of proposed treatment modalities for retinal vein occlusions (RVOs) aimed at different aspects of the disease process.

While the exact etiology of this condition remains unclear, the early stages of the disease process can be identified by scattered retinal hemorrhages and cotton wool spots. Further evaluation with fluorescein angiography (FA) reveals delayed filling and staining of retinal veins. Macular edema may also be observed in many cases of both BRVO and CRVO. While branch retinal vein occlusions most commonly occur at arteriovenous crossing, pathological examination of patients with CRVO has confirmed the presence of a vascular thrombus within the central retinal vein.4 This thrombosis leads to reduced blood flow from the eye, increased intraluminal pressure, and transudation of blood and plasma into the retina secondary to "liquefaction necrosis of vascular endothelial cells."5 The increased interstitial fluid and protein in turn act as a barrier to capillary perfusion resulting in ischemia.6 Patients with CRVO are often classified into 2 categories: ischemic or nonischemic. However, a spectrum exists along which patients with nonischemic CRVO slowly transition toward ischemia leading to many of the complications of CRVO, including retinal neovascularization, iris neovascularization, and neovascular glaucoma.

The analysis of human pathological specimens has shown that vascular endothelial growth factor (VEGF) concentrations in aqueous fluid are elevated in the presence of neovascularization but are undetectable in the normal human eye.4 In comparison to branch retinal vein occlusion (BRVO), the VEGF load in the aqueous humor has been shown to be approximately 10 times higher in patients with CRVO.7 VEGF is a major stimulator of angiogenesis and promotes proliferation and endothelial cell migration in the eye. The upregulation of VEGF is also associated with breakdown of the blood retinal barrier and increased vascular permeability, resulting in macular edema. This is the most common cause of reduced vision in patients with vein occlusions. However, nonperfusion of the perifoveal capillaries may also be an adjunctive factor. This macular edema can persist and become chronic, lasting months and often years, resulting in degeneration of both Muller cells and adjacent neuronal cells.5 Therefore, it is not surprising that the treatment of patients with RVOs has centered on the management of macular edema.

Alexander J. Brucker is professor of ophthalmology at the Presbyterian Medical Center of Philadelphia, associated with the Scheie Eye Institute of the University of Pennsylvania. Netan Choudhry is a resident at Scheie Institute. Neither author reports any financial interest in any product mentioned in this article. Dr. Brucker can be reached via e-mail at


The Central Vein Occlusion Study (CVOS) was a large, multicenter, prospective, randomized, controlled trial. The primary objective was to compare the efficacy of immediate prophylactic panretinal photocoagulation (PRP; 90 eyes) laser in nonperfused CRVO (with no evidence of neovascularization of the angle or iris) with that of frequent observation (91 eyes).6 The outcome measure was the development of neovascularization of ≥2 clock hours at the iris or angle. Eyes developing neovascularization at the iris or angles were treated with PRP and previously treated eyes had additional PRP. Eyes with intermediate visual acuity (VA), between 20/50 and 20/200 demonstrated variable results. In this cohort, VA improved in 19% of patients, remained stable in 44%, and declined in 33% of patients. Those patients with an initial VA worse than 20/200, visual prognosis was found to be poor (80% remained unchanged or deteriorated).8 Patients with an initial VA of 20/40 were likely to retain good acuity. Thus the CVOS concluded that final visual outcome could be predicted by initial VA.

Furthermore, the group observed no statistically significant difference in the development of iris or angle neovascularization between eyes treated prophylactically with PRP (19 of 90; 20%) and untreated eyes (32 of 91; 35%). Therefore, the CVOS concluded that there is no benefit to early PRP in nonperfused CRVO and that PRP should be reserved until the development of iris or angle neovascularization. The trial also evaluated the benefit of grid macular photocoagulation in patients with macular edema and with a VA between 20/50 and 20/200, secondary to a perfused CRVO (of 3 months duration). The study showed there was no difference in visual outcome between treated and untreated eyes at 1 year in those patients treated with grid pattern laser for macular edema after CRVO. Finally, the CVOS recommended that patients with a CRVO be followed monthly with gonioscopy for the first 6 months (and yearly thereafter), carefully screening for iris and angle neovascularization.


The Branch Vein Occlusion Study (BVOS) was a large, multicenter, prospective, randomized, controlled trial investigating the efficacy of laser photocoagulation in patients with BRVOs. Patients were randomized to 4 groups according to their risk of developing neovascularization, vitreous hemorrhage, and vision loss secondary to macular edema. The groups were: Group 1, major BRVO without neovascularization; Group II, major BRVO with neovascularization of the disc and/or neovascularization at least 1 disc diameter away from the disc; Group III, BRVO with macular edema and reduced vision; and Group X, high risk for neovascularization. Each group was further subdivided into treatment with laser photocoagulation or observation.

This study reported that 22% (35/159) of the control eyes in Group I developed retinal neovascularization, while 12% (19/160) treated eyes treated with scatter-argon photocoagulation developed neovascularization. In group II, eyes treated with peripheral scatter photocoagulation were less likely to develop vitreous hemorrhage (29% vs. 61% of untreated). In Group III, eyes with macular edema and vision 20/40 or worse treated with grid pattern photocoagulation were more likely to have improved vision. In the treated group, 65% gained 2 or more lines of visual acuity from baseline as compared to the control eyes (37%). Finally, eyes in Group X which demonstrated ≥5 DD of nonperfusion showed a greater risk of developing neovascularization. Of these eyes 41% developed neovascularization and met criteria to enter Group II.9

Thus the BVOS concluded that grid pattern laser should be performed in eyes with a BRVO of 3 to 18 months duration if the VA is 20/40 or worse and if FA reveals macular edema as the cause of vision loss without foveal hemorrhage. Furthermore, sector scatter laser is recommended in the treatment of neovascularization, particularly if there is ≥5 DD of nonperfusion.9

Figure 1. Central Retinal Vein Occlusion.


Ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin; Genentech) are recombinant humanized monoclonal antibodies that bind VEGF and inhibit its interaction with receptors found on vascular endothelial cells. Numerous prospective trials have been undertaken to study the effectiveness of bevacizumab in the treatment of both CRVO and BRVO with varying results.7,8,10,11 Treatment of eyes with CRVO with a single injection of 1.25 mg of bevacizumab can have an improvement in VA as early as 1 week, lasting for approximately 4 to 8 weeks.8,11,12 This improvement in VA often correlates with a decrease in macular edema as measured by optical coherence tomography (OCT). Upon cessation of therapy, macular edema may recur and VA can subsequently decline, suggesting the need for repeat injections. In 1 study of patients receiving intravitreal injections of 1.25 mg of bevacizumab, 42% of patients with initial VA worse than 20/200 had improved to ≥20/200, and 93% of patients with an initial VA between 20/200 and 20/50 remained stable or had improved to better than 20/50 vision.11

Recently, the effectiveness of ranibizumab was evaluated in the treatment of both CRVO and BRVO. Campochiaro et al. randomized 20 patients with CRVO and 20 with BRVO to receive 3 monthly injections of either 0.3 mg or 0.5 mg of ranibizumab.7 The primary outcome measure was the percentage of patients who achieved an improvement in VA from baseline of ≥15 letters read on an Early Treatment Diabetic Retinopathy Study (ETDRS) VA chart at 4 m. A number of patients were found to have rapid improvements in center subfield thickness and a greater number of patients had improvements that lasted for a month after the initial injection in the 0.5-mg groups as compared to the 0.3-mg groups.

At the 3-month primary endpoint (1 month after the last injection), approximately 90% of excess central retinal thickness was decreased, i.e., macular edema was significantly reduced following treatment.7 This study concluded that chronic edema from either CRVO or BRVO does not preclude visual improvement, as several patients in both groups with vein occlusions >2 years old gained >15 letters. In addition, no toxicity was demonstrated in any of the injected patients.

Clearly, in a number of these small trials, anti-VEGF therapy is proving to be a safe and effective treatment of macular edema in retinal vein occlusions. However, there is still no clear consensus on the number of treatments needed or the duration of treatment. Furthermore, the issue of the effect of anti-VEGF agents on the development of collateral vessels, which aid in perfusion, remains to be studied in a clinical trial.3 Rebound macular edema following cessation of therapy continues to be problematic and long-term follow-up studies are needed. The CRUISE trial is such a study and is a phase 3, multicenter, randomized, double-masked, sham-injection–controlled study of the efficacy and safety of intravitreal ranibizumab compared with sham injections in subjects with macular edema secondary to CRVO.13 The BRAVO trial is also a phase 3, multicenter, randomized, double-masked, sham-injection–controlled study of the efficacy and safety of intravitreal ranibizumab compared with sham injections in subjects with macular edema secondary to BRVO.13 We hope that the results of these 2 trials will help shed some light on the long-term efficacy of treatment of vein occlusions with ranibizumab and provide information on appropriate dosing schedules.


Corticosteroids for RVOs have been studied for a number of years.14-22 Intravitreal administration of these drugs has attracted particular attention because it allows higher local drug concentrations while minimizing systemic side effects. The mechanism by which intravitreal corticosteroids act to reduce macular edema is not completely understood. In vitro studies have demonstrated inhibition of the expression of the VEGF gene by corticosteroids.14 In addition, corticosteroids have demonstrated the ability to block the induction of VEGF proinflammatory mediators, platelet-derived growth factor, and platelet activating factor in a time- and dose-dependent manner.1 This multifactorial effect decreases retinal vascular permeability and stabilizes the blood-retinal barrier.

Intravitreal triamcinolone acetonide (IVTA) has been shown to successfully decrease macular edema and retinal thickness and improve VA in both CRVO and BRVO.15,16 In comparing patients with ischemic and nonischemic CRVO, both cohorts have shown statistically significant reduction in retinal thickness with IVTA injections; however, nonischemic CRVO patients appear to have a greater improvement in VA.17 In one study, patients receiving 4 mg of IVTA were followed over a 6-month period and those eyes with nonischemic CRVO had an improvement in VA at months 1, 3, and 6, along with decreased retinal thickness, the results of which were statistically significant at each period. However, eyes with an ischemic CRVO only experienced a statistically significant improvement in VA at 6 months, despite improvement in retinal thickness at each time period.17

These results highlight an important fact regarding the nature of the macular edema, which is that reduction in macular thickness does not always correlate with improvement in VA.14 It is speculated that this may be due to degeneration of retinal photoreceptors secondary to ischemia, thereby limiting visual recovery. Prospective analysis has revealed an improvement in VA and decrease in retinal thickness as early as 3 days following injection of 4 mg of triamcinolone.18 These improvements in VA have been shown to last between 3 and 6 months in both CRVO and BRVO, gradually declining thereafter, despite reinjection in a majority of cases.16,19 The 2-year results of eyes with nonischemic CRVO receiving 4 mg of IVTA failed to reveal a statistically significant improvement in VA from baseline. In this study, 55% of patients had a recurrence of macular edema over a mean period of 7.2 months and were subsequently reinjected without significant improvement over this 24 month period.18 This study also concluded that IVTA is more effective in patients with BRVO who are treated earlier.20

The major ocular side effects of intravitreal steroid therapy include the development of cataracts, glaucoma, hemorrhage, and retinal detachment. The long-term 1- and 2-year studies suggest that the cataract formation resulting in these patients receiving intravitreal steroids may be a limiting factor in final VA.18

Although the short-term results of IVTA in the treatment of macular edema associated with CRVO and BRVO appear promising, safety and efficacy of IVTA has yet to be demonstrated in a randomized control trial. Controversies exist in the long-term effectiveness, dosage, timing and need for retreatment. The SCORE (The Standard Care vs. Corticosteroid for Retinal Vein Occlusion) study is a multicenter, phase 3, randomized, controlled trial in which 630 patients with BRVO or CRVO have been randomized to 1 of 3 groups: standard care, IVTA (4 mg), or IVTA (1 mg). Subsequently, patients will be re-examined every 4 months over 3 years. The primary outcome is improvement by 15 or more letters from baseline in best-corrected ETDRS VA score at the 12-month visit. Secondary outcomes include changes from baseline in best-corrected ETDRS VA score, changes in retinal thickness as measured by stereoscopic color fundus photography and optical coherence tomography (OCT), and adverse ocular outcomes.13 The SCORE study completed recruitment in February 2008.


Radial optic neurotomy (RON) in the treatment of CRVO is based on the concept of a "neurovascular compartment syndrome" occurring around the optic nerve within the lamina cribosa.21 Since formation of a thrombus at the level on the lamina cribosa may be the initial step in the development of CRVO, the surgical procedure of radial optic neurotomy attempts to decompress the pressure within the "scleral outlet compartment" (the space containing the scleral canal, cribiform plate, optic nerve, and central retinal artery and vein).21-23 In this procedure a standard 3-port vitrectomy is performed and the intraocular pressure (IOP) raised to minimize potential bleeding. A microvitreoretinal blade is used to perform a radial incision on the nasal side of the disc, thereby avoiding the papillomacular bundle.23 This radial incision approaches the center of the cribiform plate and is thought to allow for an increase in the lumen of the central retinal vein along with venous blood flow.23

The Radial Optic Neurotomy Study was a retrospective study in which 11 consecutive patients with severe hemorrhagic CRVO underwent this procedure. The investigators reported that 7 (63.6%) of the 11 patients with VA of 20/200 or worse at first examination achieved VA of better than 20/200 following the procedure. However, VA in 4 patients (36.4%) remained at 20/200 or worse.21 More modest results in several additional case studies have since been shown, including those reported by Garcia-Arumi et al., where 43% patients improved in VA by 2 or more lines in an uncontrolled study.22

The improvement in VA following RON is thought to result from a more rapid resolution of macular edema in CRVO through the promotion of collateral vessels and subsequent improvement in blood flow.22 However, retinal blood flow analysis following RON in CRVO failed to reveal that either RON or cilioretinal anastamoses improve blood flow.24 In addition, since the difference in the diameter of the prelaminar and retrolaminar optic nerve can be explained by the myelin sheath, the idea of a compartment syndrome at the laminar cribosa may not necessarily be reasonable.25 Furthermore, histopathological examination of RON specimens has also failed to reveal any evidence to support the postulated mechanism by which RON was thought to improve retinal blood flow.26

Finally, the potential complications of this procedure cannot be ignored and include: laceration of the central retinal artery, globe perforation, retinal detachment, and visual field defects. Currently, the surgical success of this procedure has not been met by significant functional improvement in vision.


The vitreous is postulated to have a role in the pathogenesis of neovascularization and macular edema in both BRVO and CRVO.27 An intact vitreous provides a scaffold for neovascularization and allows angiogenic factors to diffuse into it.27 The resultant traction on the Muller cells by vitreous fibers subsequently increases the risk of cystoid macular edema.28 The exact mechanism by which vitrectomy improves macular edema is unknown. One proposed theory for the resolution of the macular edema is improvement in the oxygen supply to the ischemic retina by way of "fluid currents" in the vitreous cavity.29 Another theory is that vitrectomy may relieve traction on the retinal surface as reported in the studies for vitrectomy in diabetic macular edema.30,31

A few retrospective case series have reported improved anatomical and functional outcomes in macular edema associated with CRVO following vitrectomy.32,33 Mandelcorn and Nrusimhadevara prospectively studied 14 consecutive patients with macular edema due to CRVO (8 patients) or BRVO (6 patients) who were not eligible for photocoagulation and were treated with vitrectomy and internal limiting membrane (ILM) peel.34 All patients had an initial Snellen acuity of ≤20/200 and the time between onset of vision loss to surgery ranged from 1 to 7 months (average 4 months). Preoperative VA ranged from 20/1600 to 20/200. Follow-up period ranged from 6 to 20 months (average 9.2 months). This group demonstrated a statistically significant improvement (P = 0.0043) in the VA of 11 of 14 eyes (78.6%), with an average improvement of logMAR 0.507. There were no statistically significant differences in the improvements in VA following vitrectomy and ILM peel between CRVO and BRVO patients nor between ischemic and nonischemic vein occlusions. In addition to improvement in VA, a corresponding decrease in retinal thickness, restoration of foveal contour, and foveal reflex was observed.

The proposed mechanism of this improvement is that in peeling the ILM, the blood and extracellular fluid retained in the retina can be drained, which in turn decompresses the retina.34


Branch retinal vein occlusions are thought to occur at an arteriovenous (AV) crossing site, where the artery and vein share a common adventitial sheath.9 The pathogenesis of this process is thought to be secondary to hypertension and arteriosclerosis of the arterial wall, resulting in compression of the venule. This leads to downstream turbulence, damage to the vascular endothelium, and secondary thrombus formation. Osterloh and Charles were the first to develop a procedure for decompression of an AV crossing.35 In this procedure, a standard pars plana vitrectomy is performed followed by separation of the posterior cortical vitreous from the optic nerve and posterior retina. Next an incision is made in the inner retina approximately 100 to 500 μm proximal to the AV crossing site.21 The incision is extended parallel to the retinal arteriole until a common adventitial sheath is reached, at which point the 2 vessels are separated from each other.

Opremcak and Bruce reported results of 15 cases of sheathotomy in patients with BRVO.36 The patients in the this study had an initial Snellen VA of 20/70 or worse and in all patients decompression was achieved, resulting in clinical improvements in retinal hemorrhages and retinal perfusion. Postoperative VA improved in 10 of 15 patients (67%), with an average of 4 lines of vision gained. Vision did not improve in 3 patients despite surgical success and resolution of fundus changes, which the authors attributed to a rise in IOP.

Mester and Dillinger performed a controlled prospective trial of 43 patients with BRVO treated with VA decompression, while 25 patients served as controls.37 The mean VA improved from 0.35 to 0.16 on the logMAR scale; 26 patients (69%) gained at least 2 lines of vision and 12 patients (28%) gained at least 4 lines of vision. Six weeks following surgery, macular edema and retinal hemorrhages had resolved. Those patients with the greatest improvement also demonstrated angiographic improvements in venous perfusion, whereas 4 patients with completely occluded vessels had worse functional results. Overall visual outcomes were better in patients with AV decompression than in controls and were more successful in patients under age 65.38

Although the preliminary results are encouraging, the success of AV sheathotomy may be partially attributed to the vitrectomy performed at the same time. Recently, Kazuyuki and Mariko et al. published the results of a prospective, randomized series of 36 patients with BRVO who underwent vitrectomy alone or in combination with AV sheathotomy.39 These patients had macular edema from a BRVO of ≤8 weeks in duration and 18 of these patients underwent vitrectomy with sheathotomy and 18 without sheathotomy. The mean preoperative best-corrected VA ranged from 0.03 to 0.7 (median 0.4, mean 0.30) on a logMAR scale. The mean follow-up period was 31 months. Following surgery, both groups showed statistically significant improvement in VA between preoperative and postoperative visits at 3, 6, and 12 months and at the final visit.39 However, there was no significant difference between the 2 groups, as the final median logMAR VA was 0.9 in the vitrectomy group and 1.0 in the sheathotomy group. This study concluded that there is no significant difference between vitrectomy and vitrectomy with sheathotomy in the improvement of visual outcomes and central foveal thickness in patients with macular edema secondary to BRVO.

Han et al. conducted a study of AV sheathotomy in 20 eyes of 20 patients with BRVO and macular dysfunction secondary to macular edema.40 During the attempted separation of the artery and vein in this study, the authors encountered a "strong adhesion" between the 2 vessels which precluded complete separation in 19 of 20 eyes. These patients were followed for a mean period of 10.5 months and an improvement of 2 lines (Snellen acuity) was observed in 16 eyes (80%). VA remained unchanged in 3 eyes (10%) and worsened by at least 2 lines in 3 eyes (10%).40 Furthermore, VA of 20/50 or better was achieved in 50% of patients, averaging 4 lines of improvement. These results are similar to those of Opremacak and Bruce, who reported complete separation of the offending arteriole and venule from each other.36 This finding of an adhesion between the artery and vein is consistent with the histopathological findings of a shared vascular wall observed in cases of BRVO in human cadaver eyes.41 Thus the results of this study performed by Han et al. suggests possible visual improvement following vitrectomy without complete separation of the retinal vessels from each other.

As with any surgical procedure, the potential complications of AV sheathotomy must be considered. These include cataract formation, nerve fiber layer defects, hemorrhage, retinal tear, retinal detachment, and postoperative gliosis. Although there had been much discussion of a surgical trial, at present there is no large, randomized, controlled study to support the use of AV sheathotomy in the treatment of macular edema secondary to BRVO.


The use of anticoagulation and antiplatelet therapy has been proposed for the treatment of RVOs, particularly CRVO. It is thought that by dissolving the thrombus at the level of the lamina cribosa and/or in preventing its reformation, blood flow may be restored to the retina and visual function improved.42 Elman et al. performed a randomized, controlled trial of systemic thrombolytic therapy with tissue-plasminogen activator (tPA) on 96 patients with CRVO.43 These patients were followed for 6 months and best-corrected VA and systemic complications were monitored. At 6 months, it was observed that 89 (42%) of eyes gained 3 or more lines of vision while 37% remained stable and 21% lost 3 or more lines. The subset of patients with pretreatment vision of 20/100 or worse were evaluated further. Of this group, 59% gained 3 or more lines, 31% remained stable, and 9% lost 3 or more lines. Furthermore, one patient had fatal stroke while 3 others developed intraocular bleeds during tPA administration. This group thus concluded that tPA therapy for CRVO was promising; however, there are definite systemic risks that cannot be ignored.43

Figure 2. Branch Retinal Vein Occlusion.

Intravitreal thrombolysis using tPA has been investigated in the treatment of CRVO.42 It is believed that the ILM is permeable to tPA, and in their compromised state (as in CRVO), the retinal capillaries would allow transport of tPA into venous circulation toward the lamina cribosa. This would effectively deliver the drug to the proposed site of obstruction, dissolving the clot and improving retinal blood flow.

Lahey et al. reported a series of 23 patients receiving intravitreal tPA for the treatment of CRVO. Eight (34.8%) of these patients achieved a final VA of 20/40 or better at 3 months following injection.42 Another study of tPA conducted by Glacet-Bernard reported an improvement in VA to at least 20/30 in 36% of eyes.44 The success in both of these studies is not consistent across all patients. Animal studies have shown that the effect of tPA is greatest in more immature clots, and thus in patients with long-standing CRVO, the mature thrombus may not respond as well to tPA treatment.45 Furthermore, poor retinal perfusion may also be a limiting factor, as it has been shown that eyes with nonischemic CRVO have a more pronounced response to tPA.46

In addition to intravitreal thrombolysis, advances in interventional radiology have allowed for cathertization of the ophthalmic artery and delivery of thrombolytic agents at this site. In this approach the internal carotid artery is catheterized via the femoral artery and subsequently a microcatheter is used to catheterize the ophthalmic artery. Urokinase has been infused over a period of 1 hour. Patients undergoing this procedure are given intravenous heparin for 48 hours following the procedure and low molecular weight heparin for 1 month. Oral aspirin is also given for a period of 3 months to prevent further thrombosis.47 Paques et al. reported a series of 26 patients with CRVO undergoing selective ophthalmic artery fibrinolytic therapy. All patients had a baseline pretreatment acuity of ≤20/60. It was observed that in the 48 hours following treatment, 6 patients had improved VA, which was maintained in 5 of 6 patients over the long term.47 Analysis of the patient subgroups revealed that 4 of these 6 patients had a combined CRVO and central retinal artery occlusion (CRAO). In fact, 9 of the 26 patients had a similar fundus appearance of combined CRVO/CRAO. Prospective studies performed on this cohort of patients has revealed similar promising results; however, such studies suffer from lack of control groups.48

To date systemic anticoagulants (oral aspirin, heparin, intravenous thrombolysis) have not been adequately tested or proved to be effective in the treatment of RVOs. Clearly, large, randomized, controlled studies are needed to accurately determine the validity of this treatment modality.


Retinal vein occlusions remain the second most common sight-threatening vascular disorder. The treatment of macular edema in this condition remains challenging and controversial. At the present time, our therapeutic armamentarium for sustained functional improvement remains limited. Despite concerted efforts to treat patients both medically and surgically, no clear consensus on a treatment modality or guidelines have emerged since the BVO and CVO studies.

Currently, a number of large clinical trials are under way to investigate a several of the aforementioned treatment modalities, including the SCORE study and the BRAVO and CRUISE trials. In the near future, it is possible that the treatment of RVOs may involve the use of combination therapy. RP


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