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Femtosecond-assisted intrastromal corneal cross-linking for
early and moderate keratoconus

M. Balidis,1,2 V.E. Konidaris,2 G. Ioannidis,1,3 A.J. Kanellopoulos4,5 months. Our study demonstrates the safety and efficacy ofthe proposed method.
Purpose: To evaluate the effect of Femtosecond-assisted
Key words: keratoconus, femtosecond, cross-linking.
intrastromal corneal cross-linking to stabilize early and mod-erate keratoconus.
Methods: Twelve eyes of 9 consecutive patients (6 male),
with early keratoconus (K > 48.00 D, Skewed Steepest Ra-dial > 22º, superior–inferior difference on the 5 mm circle > Keratoconus is a bilateral, non symmetric and nonin- 2.5 D, inferior– superior difference > 1.5 D), minimum flammatory progressive corneal degeneration. It is charac- corneal thickness > 380 μm, age < 50 years included in the terized by progressive thinning and steepening of the central study studied.
cornea, resulting in increasing myopia, irregular astigma- Results: Stabilization of keratoconus during the 1 year fol-
tism, and eventual loss of spectacle-corrected visual acuity.
low-up period, with Kmax remaining unchanged and Kmax- Its incidence has been estimated to be 1 in 2000 in the gen- Kmin difference reduced after the first postoperative month eral population, but the increased number of eyes undergo- (p < 0.05). There was statistically significant difference in ing screening for laser refractive surgery suggests that the preoperative and 1 year postoperative value of eccentric- prevalence may be higher.1 Rigid contact lenses can be used ity (Topolyser, Oculus Instruments), thinnest corneal point to improve visual acuity in many patients,2 but keratoconus and irregularity in 3mm (Orbscan imaging) (p < 0.05). Cor- frequently progresses to the point that corneal transplanta- rected distant visual acuity, initially decreased (p = 0.157), tion is required to restore useful vision.3 Until recently, there followed by improvement in 3 and 12 months (p = 0.042).
was no effective way to stop progressive keratoconus so that Conclusions: Riboflavin injected intrastromal in a pre-
eventually about 21% of keratoconus patients required cisely designed corneal pocket is a painless procedure. This corneal transplantation. Also keratoconus may recur follow- surgical approach provokes topographic stability of the ing corneal transplantation and require further transplant sur- ectatic disease and improvement of CDVA even after 12 More than ten years ago, corneal collagen cross-linking by means of Ultraviolet A light and riboflavin was proposed 1. Thessaloniki Eye Foundation Private Eye clinic, as a therapeutic approach to improve biomechanical and bio- chemical properties of the cornea. Since then the manage- 2. 1st Ophthalmology Clinic, AHEPA University Hospital, ment of keratoconus with collagen cross linking (CXL) has 3. Eye Clinic, Ippocration General Hospital, Thessaloniki, been studied at length both in the laboratory as well as clin- ically and received CE marking in December 2006 for clin- 4. New York University Medical College and Manhattan Eye, ical use in the European Union countries.5 Ear and Throat Hospital, New York NY The proposed treatment counteracts progressive thinning and ectasia by photosensitized oxidation, increasing intra 5. Laservision.gr Institute, Athens Greece. and interfibrillar covalent bonds, while minimizing exposureto the surrounding structures of the eye.6 UVA CXL assisted Corresponding author: Miltiadis Balidis by the photo sensitizer riboflavin, leads to a significant in- Panoptis Volume 26Issue 1 June 2014 crease in corneal collagen diameter in rabbit eyes. This mor- more in two consecutive Orbscan topographies. The research phologic alteration is leading to an increase in biomechanical followed the tenets of the Declaration of Helsinki and writ- stability. Cross linking effect is strongest in the anterior half ten informed consent was obtained from the subjects after of the stroma due to rapid decrease in UVA irradiance as a explanation of the nature and possible consequences of the result of riboflavin-enhanced absorption.7 study. The mean cohort age was 29.75 years (Std deviation The standard technique involves application of a photo- ± 9.3). The preoperative CDVA for each patient was better sensitizing agent containing riboflavin to the corneal surface than 0.15 Log MAR. The mean preoperative CDVA was 0.1 at regular time intervals for a total time of 30 minutes fol- ± 0.09, with mean sphere -4.1 ± 2.9 diopters and cylinder - lowed by continuous application of a broad ultraviolet (UV- 3.23 ± 3.2 diopters. The mean corneal pachymetry was 445.1 A) beam for another 30 minutes.1,8,9 Before riboflavin is ± 38.7 μm. One year after CXL with Femtosecond laser, applied, the epithelium is typically removed from the central CDVA was 0.05 ± 0.06, mean sphere was -3.6 ± 3.1 and 5- to 7-mm-diameter zone of the cornea to facilitate pene- mean cylinder was -3.1 ± 1.2. Mean corneal pachymetry was tration of riboflavin into the stroma.1,8,10 During epithelial 425.3 ± 39.8 μm.
healing patients experience significant discomfort and pain.
Postoperative medications included topical ciprofloxacin Sterile corneal infiltrates and melting after CXL for kerato- HCL 0.3% four times a day for 5 days and 1% prednisolone conus have been reported after epithelium-off procedures.11 acetate four times a day for 4 weeks. Patients were evaluated An alternative technique was described by Wachler et al.12 at postoperative day 1, month 1 and 3, and every 6 months Epithelium is not removed offering patients a less invasive, thereafter to last follow-up.
faster and painless CXL, while retaining the efficacy of the Preoperative and postoperative examinations included standard technique. This technique applies a riboflavin so- slit lamp evaluation, corrected distance visual acuity lution containing benzalkonium chloride (BAK) directly (CDVA), corneal topography [three consecutive measure- onto intact epithelium. Riboflavin is hydrophilic and epithe- ments using Oculus Instruments Wetzlar (Germany), lium is hydrophobic. However, underneath the epithelium, equipped with Topolyser software, Wavelight (Erlangen, stroma is highly hydrophilic. Thus epithelium with its tight Germany), comparison charts, Orbscan corneal topographer junctions is considered to be the most important barrier for (Bausch and Lomb Orbscan II Corneal Analysis System)], permeability of riboflavin. So far riboflavin solutions used and corneal thickness at the thinnest point. Specular mi- (Sooft, EDTA and Benzalkonium chloride) are thought to croscopy was performed preoperatively and 3 months post- loosen and open up tight junction of epithelial barrier. BAK, operatively (Tomey EM-3000 Specular Microscope).
an effective tensioactive substance, alters surface tension The studied parameters including mean endothelial cell value, and hence facilitates penetration of other substances density (MCD) and mean cell area (MCA) of the central through biological membranes. Therefore, BAK promote ri- cornea were analyzed. Anterior Optical Coherence Tomog- boflavin penetration into corneal stroma, without the need raphy scans (SOCT Copernicus OPTOPOL Technology of de- epitheliazation. As an alternative to the above ap- S.A.) were also performed.
proaches, we developed a Femtosecond assisted intrastromal It is well known from refractive surgery, that regular use pocket to introduce riboflavin, and evaluate its safety and of contact lenses, especially hard gas permeable, introduce a mechanical effect on corneal surface and as a consequencealtered refractive status and corneal topography. Therefore Patients and Methods
all our patients refrained from contact lens use one monthpreoperatively and during the follow up period (up to 2 Twelve eyes of 9 consecutive patients, 6 male and 3 fe- years). Patients entering the project have been informed to male, with early progressive keratoconus were included in avoid contact lens use. Warpage after rigid contact lenses the study. Early and moderate keratoconic corneas were se- may need more than a month to regress. Thus we can assume lected with the following criteria: topographic evidence of that changes documented in a 3 monthly corneal topography keratoconus (K-readings > 48 D, Skewed Steepest Radial examination were due to treatment effect or disease progres- Axis (SRAX) >22º, superior–inferior difference (S-I) on the 5 mm circle > 2.5 D, inferior–superior difference (I-S) >1.5 Intrastromal Pocket Creation. The Femtosecond laser
D.), minimum corneal thickness > 380 μm, and patient age used to create stromal pockets was the Technolas Femtec younger than 50 years.
520 (Technolas Perfect Vision GmbH). This Femtosecond Progression was confirmed by documenting K – reading Diode pumped solid state laser had the following technical increase of 1 or more diopters in two consecutive corneal characteristics Laser Wavelength 1040 nm; Pulse Rate 40 topographies, or minimum thickness decrease of 5 μm or kHz; Laser Pulse Duration: 400 – 800 femtoseconds; Pulseenergy 1-4 μJ. For this treatment the distance between spots Femtosecond-assisted intrastromal corneal cross-linking for early and moderate keratoconus was 5μm. The Femtec laser works in a spiral pattern. Spiralpattern is applied when laser pulses begin centrally and ex-pand centrifugally out to the periphery. Also we used acurved applanation docking system, which generate less in-traocular pressure (IOP) increase and more physiologic in-terface between the eye and the laser.
Under topical 1% proparacaine anesthesia (Alcaine; Alcon Laboratories Inc, Ft Worth, Texas) a 6 mm diameterdoughnut-shaped intrastromal pocket was created by theFemtosecond laser leaving a clear central optical zone of 3mm (Fig. 1.1 upper left). The outer diameter of the pocketwas 6mm and the inner diameter 3mm. Thus a doughnutshape pocket at 200μ depth and 1.5 mm width was created.
Then two 0.5 x 0.5 mm entry channels were created 180 de-grees apart. From the fashioned channels, one is facilitatingfor riboflavin infusion and the contra latera depressurization.
Following the pocket creation, a tapered Intacs spatula mall Jameson muscle hook (Storz Bausch & Lomb GmbH)was used to open, enter and bluntly dissect the pocket (Fig.
1.2).
0.1% Riboflavin solution Infusion. 0.3 mL of 0.1% ri-
boflavin in 20% dextran solution was infused into the pocketwith 2 injections one at the upper half and one at the lower,using Intacs stromal channel Irrigation cannula (StorzBausch & Lomb GmbH). Infusion continued until the entirepocket was colored bright yellow from riboflavin and the Figure 1: 1. Creation of a 6 mm diameter circular in- solution was overflowing from the opposite incision (Fig.
trastromal pocket, by means of the femtosecond laser, 1.3 lower left). When corneal stroma colored yellow we start leaving a clear optical zone of 3 mm. preparing the UVA radiation device. Time interval between 2. Creation of two 0.5 mm width entry channels 180 de- the two stages was 5 minutes, during that period riboflavin grees apart. Following the pocket creation, a tapered In- was allowed to diffuse into stroma (Fig. 1.3) tacs spatula mall Jameson muscle hook was used to enter Collagen Cross-linking. We use the UVX-PESCHKE
and bluntly dissect the pocket. (Meditrate GmbH Hunenberg, Switzerland) device. Cornea 3. Infusion of 0.3 mL of 0.1% riboflavin solution into the was irradiated with UVA 365 -375nm light at an irradiance pocket using an Intacs stromal channel Irrigation cannula. of 3 mW/ cm2 for 30 minutes. During irradiation corneal Infusion continued until the entire pocket was colored epithelium was moistened twice (one drop at 10 and one at bright yellow from the presence of the riboflavin solution. 20 minutes after the beginning of irradiation) with riboflavin 4. A UVA irradiation source of 370 nm wavelength (365 0.1% solution. The total fluency at the 6 mm diameter to 375 nm) was used for corneal surface irradiation. corneal plane was 5.4 J/cm2. During UVA emission we ap-plied one drop of riboflavin every 10 minutes (total 2 drops)to moist and protec 156 t epithelium. Riboflavin solution used could not cross the epithelial barrier.
Statistical methods: Statistical Package for the Social
Specular microscopy was performed preoperatively and Sciences 17 (SPSS, inc., Chicago, IL) was used for the sta- 3 months postoperatively. Mean endothelial Cell Density tistical analysis of the data collected. Due to the small num- MCD preoperatively was 2543.83 ± 241 cells / mm2 and ber of patients, Shapiro Wilk test (appropriate for small MCA was 501.0 ± 137.4 μm2. 3 months postoperatively sample sizes) was performed in order to test normality of MCD was 2495.1 ± 227.4 cells / mm2 and MCA was 527.0 distributions. Wilcoxon signed-rank test for non-parametric ± 114 μm2. There was no statistically significant difference data was used to compare the pre- and postoperative param- in MCD and MCA. According to Shapiro Wilk test, the stud- eters. Values of p < 0.05 were considered to differ statisti- ied parameters demonstrate non parametric distribution.
cally importantly.
Corrected distance visual acuity, although decreased in 1st Panoptis Volume 26Issue 1 June 2014 Kmin and eccentricity (Ecc) (Topolyser, Oculus Instru- ments), corneal pachymetry (in μm) (Tomey), and thinnest corneal point (in μm) (thinn) and irregularity in 3mm (Irreg) (Orbscan imaging). Statistically important differences are marked as: ¥: Preoperative vs 1 year (p<0.05) *: 1 month vs 1 year (p<0.05) ‡: 3 months vs 1 year (p<0.05) : 3 months vs 1 month (p<0.05)to 375 nm) was used for
corneal surface irradiation. Comparison charts demonstrate the postoperative effect of the procedure in anterior corneal curvature. Comparingpre and 1 184 year postoperative topographies we identify Figure 2: Change in Corrected Distance Visual Acuity. the highest curvature difference in the periphery and the cen-ter of the topographic map. Safety and efficacy of the pro- month (p = 0.157), increased in 3rd and 12th months postop- cedure is displayed on the Figure 3. There was no CDVA eratively. There was a statistically significant difference in line loss in our study group. Slit-lamp biomicroscopy re- CDVA between the preoperative and one year postoperative vealed minimal diffuse light scattering at the level of mid- examination (p = 0.042) (Fig. 2). Additionally statistically stroma, delineating the annular pocket. Haze formation significant difference confirmed in the preoperative and 1 resolved within 3 months. Haze after cross linking differs in year postoperative value of astigmatic power (p = 0.016), appearance compare to sub-Bowman scaring after PRK. In eccentricity (Topolyser, Oculus Instruments) (p= 0.044), and the 2 year follow up, slit lamp examination haze disappeared thinnest point of corneal thickness (p = 0.043) (Orbscan im- in almost all cases.
aging). The effect observed in difference maps was a centralflattening and circular midperipheral steepening at the areaof the intrastromal treatment. We did not notice any induc-tion of astigmatism as a result of these negligible incisions.
Moreover, keratoconus remained unchanged even after 12 months postoperatively, Kmax remaining unchanged andKmin increased after the first postoperative month (p =0.034). The values of CDVA, Kmax, Kmin, eccentricity,corneal pachymetry, thinnest point and irregularity in 3 mmas well as the statistically significant differences are shownon table 1.
Figure 3: Safety and efficacy of the procedure. Keratoconus is the second most frequent indication for corneal transplantation, accounting for about 15% of thecorneal transplants performed in the United States.13 Cornealtransplantation has inherent risks that could result in perma-nent loss of vision and significantly impact the patient'squality of life during the surgical recovery phase.14 Any Table 1: Preoperative, 1, 3 and 12 postoperative month modality, such as CXL, that can delay or prevent corneal follow-up mean values and standard deviation for Cor- transplantation in patients with these conditions is of great rected Distant Visual Acuity (CDVA) (logMAR), Kmax, benefit. CXL using UVA light with riboflavin photo sensi- Femtosecond-assisted intrastromal corneal cross-linking for early and moderate keratoconus tizer to strengthen corneal tissue has shown promising re- deep. Treatment is aimed in order to achieve greatest ab- sults internationally, in stabilizing corneal curvature and sorbed irradiation in mid- corneal stoma. Concerns regarding slowing or even arresting progression of keratoconus and safety and UV absorption through intact epithelium were ad- post-refractive ectasia.1 Experimental studies in rabbit and dressed in this study. Corneal stroma, due to its thickness porcine eyes have shown an approximate increase in corneal (10fold thicker than that of the other layers) absorbs UVA rigidity by 70% after CXL.15 A clinical study of 22 cases light more than the other corneal structures.21,22 UV filtering demonstrated stabilization of keratoconus with 4-year fol- ability of the epithelium and Bowman layer may be due to low-up, with mean keratometric regression of 2 D in 70% their special molecular composition and higher dry mass of cases, and manifest spherical equivalent refractive error content of the Bowman layer, resulting in a higher absorp- regression of 1.14 D. Corneal and lens transparency, as well tion coefficient. Concentration of riboflavin with this tech- as endothelial cell density and intraocular pressure, remained nique was expected to be activated by stray UVA light at the unchanged, whereas visual acuity improved slightly in 65% mid stromal level.23 As confirmation of the safety of the pro- of the eyes.8,15-17 Corneal stabilization, followed by full vi- cedure pre- and one year postoperative endothelial cell den- sual rehabilitation, leads us to believe that this combined ap- sity and morphology show no significant difference in our proach may have wider applications and become a cases. Concerns about biomechanical instability from the temporizing alternative to corneal transplantation.
femto ring, the 6 mm diameter doughnut-shaped intrastro- In the standard technique, involving central epithelial re- mal femtosecond ring, with a clear central optical zone of 3 moval to achieve intrastromal penetration, extended healing mm, have been countered by Kanellopoulos in his paper on time causes significant discomfort and pain.18 Angunawela the same subject.5 et al11 present a case of sterile corneal infiltrates and melting In our prospective study, there was a statistically impor- after CXL for keratoconus. Staphylococcal antigens, de- tant improvement in CDVA. Moreover, stabilization of ker- posited at high concentrations in static tear pools beneath atoconus was established for 12 months. Kmax remained the bandage contact lens, triggered an enhanced cell-medi- unchanged and Kmin regressed after the first postoperative ated immune reaction, as proposed by the authors. Regard- month. Limitation of our study is the small cohort. The fol- ing post-CXL haze, Raiskup et al.19 reported in their low up period is long enough to disclose failure of stabiliza- retrospective survey that 8.6% of the KC eyes that under- went CXL treatment developed clinically significant perma- This surgical approach merits further exploration. Ri- nent stromal haze. Disadvantage of standard epithelium off boflavin injected intrastromally in a precisely designed CXL include prolonged surgical time, increased incidence pocket is a painless procedure, lacking epithelialization pe- of herpetic activation and haze development, corneal edema, riod. A faster and longer saturation period and possibly more postoperative pain and discomfort, and reduced visual acuity effective diffusion of riboflavin (as the large molecule, in (until epithelialization is complete and corneal edema is re- regard to the Bowman's layer barrier is directly injected at depth via the intrastromal pocket), provide greater shielding We have been motivated to develop a alternative tech- near the endothelium. In cases of central or paracentral nique in which the epithelium is not removed. Riboflavin cones the cross linking effect treatment is augmented. Flat- placed intrastromally in a pre-formed pocket will absorb and tening of the cone, surrounded by mid peripheral steepening activate UVA light and achieve CXL in a more controlled has been shown in topographic comparison maps. Introduc- method. Kanellopoulos presented a novel epithelium-spar- ing cross linking in the mid peripheral annulus rather than ing, rapid soak-and-treat method of intrastromal riboflavin central cornea may increase the biomechanical effect fur- instillation, creating a femtosecond assisted pocket and uti- lizing higher fluence UVA light for CXL.5 The effect is augmented in central topographic cones. It The effect of UVA light is at the area of maximal ab- is possible to further customize the procedure, by fitting the sorbance and its close vicinity. Using hand-held spectral do- femto - created ring pocket to encircle the cone. Riboflavin main optical coherence tomography, Malhotra et al.
concentrated at the ring will maximize the cross linking ef- measured riboflavin penetration during collagen cross-link- fect at the mid - stromal around the protrusion, probably flat- ing (CXL) in vivo.20 In the epithelium-off cases the hyper- tening the cone. This novel technique may become an reflectivity band of riboflavin was measured 54.2 +/- 5.2 μm alternative for the prevention of cornea transplantation in (mean) at the end of 30 minute drop administration period.
corneal ecstasies. Further studies and longer follow-up are At the end of the procedure (total 60 minutes of riboflavin needed to validate these data.
penetration) mean band thickness was 72.4 +/- 7.1 μm. Sothe greatest concentration of Riboflavin is expected to be 55μm from the area of injection, which in our method is 200μm Panoptis Volume 26Issue 1 June 2014 13. Binder PS, Lindstrom RL, Stulting RD, Donnenfeld 1. Wollensak G. Crosslinking treatment of progressive E, Wu H, McDonnell P, et al. Keratoconus and corneal ec- keratoconus: New hope. Curr Opin Ophthalmol 2006; tasia after lasik. J Refract Surg 2005; 21:749-752.
14. Price FW, Price MO. Adult keratoplasty. Ha 290 s 2. Barnett M, Mannis MJ. Contact lenses in the manage- the prognosis improved in the last 25 years? Int Ophthalmol ment of keratoconus. Cornea 2011; 30:1510-1516.
2008; 28:141-146.
3. Jhanji V, Sharma N, Vajpayee RB. Management of 15. Wollensak G, Spoerl E, Seiler T. Stress-strain meas- keratoconus: Current scenario. Br J Ophthalmol 2011; urements of human and porcine corneas after riboflavin-ul- traviolet-a-induced cross-linking. J Cataract Refract Surg 4. Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998; 2003; 29:1780-1785.
16. Sporl E, Schreiber J, Hellmund K, Seiler T, 5. Kanellopoulos AJ. Collagen cross-linking in early ker- Knuschke P. Studies on the stabilization of the cornea in rab- atoconus with riboflavin in a femtosecond laser-created bits]. Ophthalmologe 2000; 97:203-206.
pocket: Initial clinical results. J Refract Surg 2009; 25:1034- 17. Wollensak G, Spoerl E, Wilsch M, Seiler T. Kerato- cyte apoptosis after corneal collagen cross-linking using ri- 6. Kohlhaas M, Spoerl E, Schilde T, Unger G, Wittig C, boflavin/uva treatment. Cornea 2004; 23:43-49.
Pillunat LE. Biomechanical evidence of the distribution of 18. Vicente LL, Boxer Wachler BS. Factors that correlate cross-links in corneas treated with riboflavin and ultraviolet with improvement in vision after combined intacs and trans- a light. J Cataract Refract Surg 2006; 32:279-283.
epithelial corneal crosslinking. Br J Ophthalmol 2010; 7. Wollensak G, Wilsch M, Spoerl E, Seiler T. Collagen fiber diameter in the rabbit cornea after collagen crosslinking 19. Raiskup F, Hoyer A, Spoerl E. Permanent corneal by riboflavin/UVA. Cornea 2004; 23:503-507.
haze after riboflavin-uva-induced cross linking in kerato- 8. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultravio- conus. J Refract Surg 2009; 25:824-828.
let-a-induced collagen crosslinking for the treatment of ker- 20. Malhotra C, Shetty R, Kumar R, Veluri H, Nagaraj atoconus. Am J Ophthalmol 2003; 135:620-627.
H, Shetty KB. In Vivo Imaging of Riboflavin Penetration 29. Tu KL, Aslanides IM. Orbscan ii anterior elevation During Collagen Cross-linking With Hand-held Spectral Do- changes following corneal collagen cross-linking treatment main Optical Coherence Tomography. J Refract Surg 2012; for keratoconus. J Refract Surg 2009; 25:715-722.
10. Baiocchi S, Mazzotta C, Cerretani D, Caporossi T, 21. Schnitzler E, Sporl E, Seiler T. [Irradiation of cornea Caporossi A. Corneal crosslinking: Riboflavin concentration with ultraviolet light and riboflavin administration as a new in corneal stroma exposed with and without epithelium. J treatment for erosive corneal processes, preliminary results Cataract Refract Surg 2009; 35:893-899.
in four patients]. Klin Monbl Augenheilkd 2000; 217:190- 11. Angunawela RI, Arnalich-Montiel F, Allan BD. Pe- ripheral sterile corneal infiltrates and melting after collagen 22. Wollensak G, Spoerl E, Reber F, Seiler T. Keratocyte crosslinking for keratoconus. J Cataract Refract Surg 2009; cytotoxicity of riboflavin/uva-treatment in vitro. Eye (Lond) 2004; 18:718-722.
12. Boxer Wachler BS, Pinelli R, Ertan A, Chan CC.
23. Kolozsvari L, Nogradi A, Hopp B, Bor Z. UV ab- Safety and efficacy of transepithelial crosslinking (c3-r/cxl).
sorbance of the human cornea in the 240- to 400-nm range.
J Cataract Refract Surg 2010; 36:186-188; author reply 188- Invest Ophthalmol Vis Sci 2002; 43:2165-2168.

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Eradication of norway rats (rattus norvegicus) from hawea island, fiordland, using brodifacoum

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