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Scott HA, Larson A, Rong SS, Mehrotra S, Butcher R, Chao KR, Wiggs JL, Place EM, Pierce EA, Bujakowska KM. A hidden structural variation in a known IRD gene: a cautionary tale of two new disease candidate genes. Cold Spring Harb Mol Case Stud 2022;8(2)Abstract
Rod-cone dystrophy (RCD), also known as retinitis pigmentosa, is an inherited condition leading to vision loss, affecting 1 in 3500 people. More than 270 genes are known to be implicated in the inherited retinal degenerations (IRDs), yet genetic diagnosis for ∼30% of IRD of patients remains elusive despite advances in sequencing technologies. The goal of this study was to determine the genetic causality in a family with RCD. Family members were given a full ophthalmic exam at the Retinal Service at Massachusetts Eye and Ear and consented to genetic testing. Whole-exome sequencing (WES) was performed and variants of interest were Sanger-validated. Functional assays were conducted in zebrafish along with splicing assays in relevant cell lines to determine the impact on retinal function. WES identified variants in two potential candidate genes that segregated with disease: GNL3 (G Protein Nucleolar 3) c.1187 + 3A > C and c.1568-8C > A; and PDE4DIP (Phosphodiester 4D Interacting Protein) c.3868G > A (p.Glu1290Lys) and c.4603G > A (p.Ala1535Thr). Both genes were promising candidates based on their retinal involvement (development and interactions with IRD-associated proteins); however, the functional assays did not validate either gene. Subsequent WES reanalysis with an updated bioinformatics pipeline and widened search parameters led to the detection of a 94-bp duplication in PRPF31 (pre-mRNA Processing Factor 31) c.73_266dup (p.Asp56GlyfsTer33) as the causal variant. Our study demonstrates the importance of thorough functional characterization of new disease candidate genes and the value of reanalyzing next-generation sequencing sequence data, which in our case led to identification of a hidden pathogenic variant in a known IRD gene.
Xu J, Emmermann B, Bowers AR. Auditory Reminder Cues to Promote Proactive Scanning on Approach to Intersections in Drivers With Homonymous Hemianopia: Driving With Hemianopia, IX. JAMA Ophthalmol 2022;140(1):75-78.Abstract
Importance: Individuals with homonymous hemianopia (HH) are permitted to drive in some jurisdictions. They could compensate for their hemifield vision loss by scanning toward the blind side. However, some drivers with HH do not scan adequately well to the blind side when approaching an intersection, resulting in delayed responses to hazards. Objective: To evaluate whether auditory reminder cues promoted proactive scanning on approach to intersections. Design, Setting, and Participants: This cross-sectional, single-visit driving simulator study was conducted from October 2018 to May 2019 at a vision rehabilitation research laboratory. A volunteer sample of individuals with HH without visual neglect are included in this analysis. This post hoc analysis was completed in July and August 2020. Main Outcomes and Measures: Participants completed drives with and without scanning reminder cues (a single tone from a speaker on the blind side). Scanning was quantified by the percentage of intersections at which an early large scan was made (a scan with a head movement of at least 20° made before 30 m from the intersection). Responses to motorcycle hazards at intersections were quantified by the time to the first fixation and the time to the horn-press response. Results: Sixteen individuals were recruited and completed the study. Two were subsequently excluded from analyses. Thus, data from 14 participants (median [IQR] age, 54 [36-66] years; 13 men [93%]) were included. Stroke was the primary cause of the HH (10 participants [71%]). Six (43%) had right-sided HH. Participants were more likely to make an early large scan to the blind side in drives with vs without cues (65% vs 45%; difference, 20% [95% CI, 5%-37%]; P < .001). When participants made an early large scan to the blind side, they were faster to make their first fixation on blind-side motorcycles (mean [SD], 1.77 [1.34] vs 3.88 [1.17] seconds; difference, -2.11 [95% CI, -2.46 to -1.75] seconds; P < .001) and faster to press the horn (mean [SD], 2.54 [1.19] vs 4.54 [1.37] seconds; difference, -2.00 [95% CI, -2.38 to -1.62] seconds; P < .001) than when they did not make an early scan. Conclusions and Relevance: This post hoc analysis suggests that auditory reminder cues may promote proactive scanning, which may be associated with faster responses to hazards. This hypothesis should be considered in future prospective studies.
Zekavat SM, Raghu VK, Trinder M, Ye Y, Koyama S, Honigberg MC, Yu Z, Pampana A, Urbut S, Haidermota S, O'Regan DP, Zhao H, Ellinor PT, Segrè AV, Elze T, Wiggs JL, Martone J, Adelman RA, Zebardast N, Del Priore L, Wang JC, Natarajan P. Deep Learning of the Retina Enables Phenome- and Genome-Wide Analyses of the Microvasculature. Circulation 2022;145(2):134-150.Abstract
BACKGROUND: The microvasculature, the smallest blood vessels in the body, has key roles in maintenance of organ health and tumorigenesis. The retinal fundus is a window for human in vivo noninvasive assessment of the microvasculature. Large-scale complementary machine learning-based assessment of the retinal vasculature with phenome-wide and genome-wide analyses may yield new insights into human health and disease. METHODS: We used 97 895 retinal fundus images from 54 813 UK Biobank participants. Using convolutional neural networks to segment the retinal microvasculature, we calculated vascular density and fractal dimension as a measure of vascular branching complexity. We associated these indices with 1866 incident International Classification of Diseases-based conditions (median 10-year follow-up) and 88 quantitative traits, adjusting for age, sex, smoking status, and ethnicity. RESULTS: Low retinal vascular fractal dimension and density were significantly associated with higher risks for incident mortality, hypertension, congestive heart failure, renal failure, type 2 diabetes, sleep apnea, anemia, and multiple ocular conditions, as well as corresponding quantitative traits. Genome-wide association of vascular fractal dimension and density identified 7 and 13 novel loci, respectively, that were enriched for pathways linked to angiogenesis (eg, vascular endothelial growth factor, platelet-derived growth factor receptor, angiopoietin, and WNT signaling pathways) and inflammation (eg, interleukin, cytokine signaling). CONCLUSIONS: Our results indicate that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease and provide insights into genes and biological pathways influencing microvascular indices. Moreover, such a framework highlights how deep learning of images can quantify an interpretable phenotype for integration with electronic health record, biomarker, and genetic data to inform risk prediction and risk modification.
Warkad VU, Hunter DG, Dagi AF, MacKinnon S, Kazlas MA, Heidary G, Staffa SJ, Dagi LR. Impact of Adding Augmented Superior Rectus Transpositions to Medial Rectus Muscle Recessions When Treating Esotropic Moebius Syndrome. Am J Ophthalmol 2022;237:83-90.Abstract
PURPOSE: To describe outcomes after treatment of Moebius syndrome (MBS) esotropia by adjustable bilateral medial rectus recession (BMR) with and without augmented superior rectus transposition (SRT). DESIGN: Retrospective case series. METHODS: Patients meeting 2014 diagnostic criteria for MBS and treated at Boston Children's Hospital between 2003 and 2019 were identified via billing records and chart review. Visual acuity, sensorimotor evaluations, strabismus procedures, and other clinical features were recorded. Surgical outcomes for patients treated with strabismus surgery (excluding those with prior surgery elsewhere) were evaluated. The primary outcome measure was postoperative alignment comparing treatment by adjustable BMR vs adjustable BMR+SRT. RESULTS: A total of 20 patients had MBS, and 12 of these (60%) were male. Fifteen patients (75%) had primary position esotropia, and all had bilateral abduction deficit. Eight of 20 patients met inclusion criteria for primary strabismus surgery outcome. Five had undergone adjustable BMR ranging from 4.5 to 6.5 mm. Three had undergone adjustable BMR+SRT, all with 4-mm medial rectus muscle recessions. Mean preoperative esotropia before treatment by BMR was 39.5 PD (± 15 PD) with mean postoperative esotropia 9 PD (± 7.9 PD) at 6 months. Mean preoperative esotropia before treatment by BMR+SRT was 70.8 PD (± 5.9 PD) with mean postoperative esotropia 2.5 PD (± 3.5 PD) at 6 months. Significantly greater reduction in esotropia resulted from BMR+SRT than from BMR (P = .036). CONCLUSIONS: BMR proved sufficient to treat esotropia <50 PD and BMR+SRT for greater esotropia in patients with MBS-associated abduction limitation.
Brown EE, Scandura MJ, Mehrotra S, Wang Y, Du J, Pierce EA. Reduced nuclear NAD+ drives DNA damage and subsequent immune activation in the retina. Hum Mol Genet 2022;31(9):1370-1388.Abstract
Mutations in NMNAT1, a key enzyme involved in the synthesis of NAD+ in the nucleus, lead to an early onset severe inherited retinal degeneration (IRD). We aimed to understand the role of nuclear NAD+ in the retina and to identify the molecular mechanisms underlying NMNAT1-associated disease, using a mouse model that harbors the p.V9M mutation in Nmnat1 (Nmnat1V9M/V9M). We identified temporal transcriptional reprogramming in the retinas of Nmnat1V9M/V9M mice prior to retinal degeneration, which begins at 4 weeks of age, with no significant alterations in gene expression at 2 weeks of age and over 2600 differentially expressed genes by 3 weeks of age. Expression of the primary consumer of NAD+ in the nucleus, PARP1, an enzyme involved in DNA damage repair and transcriptional regulation, as well as 7 other PARP family enzymes, was elevated in the retinas of Nmnat1V9M/V9M. This was associated with elevated levels of DNA damage, PARP-mediated NAD+ consumption and migration of Iba1+/CD45+ microglia/macrophages to the subretinal space in the retinas of Nmnat1V9M/V9M mice. These findings suggest that photoreceptor cells are especially sensitive to perturbation of genome homeostasis, and that PARP-mediated cell death may play a role in other genetic forms of IRDs, and potentially other forms of neurodegeneration.
Shah YS, Fliotsos MJ, Alaqeel A, Boland MV, Zafar S, Srikumaran D, Woreta FA. Use of Teleophthalmology for Evaluation of Ophthalmic Emergencies by Ophthalmology Residents in the Emergency Department. Telemed J E Health 2022;28(6):858-864.Abstract
Background: Utilizing telemedicine is one approach to reduce the ever-increasing burden of patients on emergency departments (EDs) and consulting physicians. Utilization of telemedicine services in the ED may also benefit resident education. Materials and Methods: Ten first-year ophthalmology residents were trained to use a Topcon 3D Optical Coherence Tomography (OCT)-1 Maestro to capture OCT images and fundus photos in patients presenting to the ED with urgent ophthalmic concerns. Findings were communicated to the supervising ophthalmologist. Retrospective chart review was conducted to obtain patient characteristics and final ophthalmologist diagnosis. Residents rated ease of use, technical reliability, and educational value through a survey. Results: From December 1, 2019, to December 1, 2020, the device was used in 109 patient encounters, capturing 887 images (average 8.1 images per encounter). Patients on whom the device was used were on average 48.5 years old (±17.2, range 17-90) and 59.6% were female. The imaging device was utilized most commonly for evaluating papilledema (n = 21, 18.6%), new-onset visual acuity/visual field defects (n = 12, 10.6%), retinal detachment/tear (n = 8, 7.1%), and ophthalmic trauma workup (n = 8, 7.1%). Eight residents completed the survey and most (n = 7) agreed or strongly agreed that the device helped them diagnose patients more accurately. Technical issues such as machine malfunction, image artifacts, and problems syncing with the electronic health record and computer were noted by survey respondents. Conclusions: The most common use of teleophthalmology in the ED setting was evaluation of papilledema; the majority of residents perceived an educational benefit from this tool. Efforts should be made to address the technical challenges to increase the utility of this device.
Kim JE, Glassman AR, Josic K, Melia M, Aiello LP, Baker C, Eells JT, Jampol LM, Kern TS, Marcus D, Salehi-Had H, Shah SN, Martin DF, Stockdale CR, Sun JK, Sun JK. A Randomized Trial of Photobiomodulation Therapy for Center-Involved Diabetic Macular Edema with Good Visual Acuity (Protocol AE). Ophthalmol Retina 2022;6(4):298-307.Abstract
PURPOSE: To determine if treatment with a photobiomodulation (PBM) device results in greater improvement in central subfield thickness (CST) than placebo in eyes with center-involved diabetic macular edema (CI-DME) and good vision. DESIGN: Phase 2 randomized clinical trial. PARTICIPANTS: Participants had CI-DME and visual acuity (VA) 20/25 or better in the study eye and were recruited from 23 clinical sites in the United States. METHODS: One eye of each participant was randomly assigned 1:1 to a 670-nm light-emitting PBM eye patch or an identical device emitting broad-spectrum white light at low power. Treatment was applied for 90 seconds twice daily for 4 months. MAIN OUTCOME MEASURES: Change in CST on spectral-domain OCT at 4 months. RESULTS: From April 2019 to February 2020, 135 adults were randomly assigned to either PBM (n = 69) or placebo (n = 66); median age was 62 years, 37% were women, and 82% were White. The median device compliance was 92% with PBM and 95% with placebo. OCT CST increased from baseline to 4 months by a mean (SD) of 13 (53) μm in PBM eyes and 15 (57) μm in placebo eyes, with the mean difference (95% confidence interval [CI]) being -2 (-20 to 16) μm (P = 0.84). CI-DME, based on DRCR Retina Network sex- and machine-based thresholds, was present in 61 (90%) PBM eyes and 57 (86%) placebo eyes at 4 months (adjusted odds ratio [95% CI] = 1.30 (0.44-3.83); P = 0.63). VA decreased by a mean (SD) of -0.2 (5.5) letters and -0.6 (4.6) letters in the PBM and placebo groups, respectively (difference [95% CI] = 0.4 (-1.3 to 2.0) letters; P = 0.64). There were 8 adverse events possibly related to the PBM device and 2 adverse events possibly related to the placebo device. None were serious. CONCLUSIONS: PBM as given in this study, although safe and well-tolerated, was not found to be effective for the treatment of CI-DME in eyes with good vision.
Jumelle C, Yung A, Shirzaei Sani E, Taketani Y, Gantin F, Bourel L, Wang S, Yüksel E, Seneca S, Annabi N, Dana R. Development and characterization of a hydrogel-based adhesive patch for sealing open-globe injuries. Acta Biomater 2022;137:53-63.Abstract
Full-thickness wounds to the eye can lead to serious vision impairment. Current standards of care (from suturing to tissue transplantation) usually require highly skilled surgeons and use of an operating theater. In this study, we report the synthesis, optimization, and in vitro and ex vivo testing of photocrosslinkable hydrogel-based adhesive patches that can easily be applied to globe injuries or corneal incisions. According to the type and concentration of polymers used in the adhesive formulations, we were able to finely tune the physical properties of the bioadhesive including viscosity, elastic modulus, extensibility, ultimate tensile strength, adhesion, transparency, water content, degradation time, and swellability. Our in vitro studies showed no sign of cytotoxicity of the hydrogels. Moreover, the hydrogel patches showed higher adhesion on freshly explanted pig eyeballs compared to a marketed ocular sealant. Finally, ex vivo feasibility studies showed that the hydrogel patches could seal complex open-globe injuries such as large incision, cruciform injury, and injury associated with tissue loss. These results suggest that our photocrosslinkable hydrogel patch could represent a promising solution for the sealing of open-globe injuries or surgical incisions. STATEMENT OF SIGNIFICANCE: Current management of severe ocular injuries require advanced surgical skills and access to an operating theater. To address the need for emergent management of wounds that cannot be handled in the operating room, surgical adhesives have gained popularity, but none of the currently available adhesives have optimal bioavailability, adhesive or mechanical properties. This study describes the development, optimization and testing of a light-sensitive adhesive patch that can easily be applied to the eye. After solidification using visible light, the patch shows no toxicity and is more adherent to the tissue than a marketed sealant. Thus this technology could represent a promising solution to stabilize ocular injuries in emergency settings before definitive surgical repair.
Halawa OA, Kolli A, Oh G, Mitchell WG, Glynn RJ, Kim DH, Friedman DS, Zebardast N. Racial and Socioeconomic Differences in Eye Care Utilization among Medicare Beneficiaries with Glaucoma. Ophthalmology 2022;129(4):397-405.Abstract
PURPOSE: Evaluate differences in eye care utilization among patients with glaucoma by race and socioeconomic status (SES). DESIGN: Retrospective cohort study. PARTICIPANTS: Representative 5% sample of Medicare beneficiaries aged > 65 years with continuous part A/B enrollment between January 1, 2014, and July 1, 2014, at least 1 diagnosis code for glaucoma within that period, and a glaucoma diagnosis in the Chronic Conditions Warehouse before January 1, 2014. METHODS: The following race/ethnicity categories were defined in our cohort: non-Hispanic White, Black/African American, Hispanic, and Asian/Pacific Islander. Low SES was defined as having 2 or more enrollment-based low-income indicators (dual eligibility for Medicare/Medicaid, Part D limited income subsidies, and eligibility for Part A and B State buy-in). Negative binomial regression analyses were carried out to compare relative rate ratios (RRs) of eye care utilization among racial groups stratified by low and non-low SES. MAIN OUTCOME MEASURES: Measured from July 1, 2014, to December 31, 2016: eye examinations and eye care-related office visits; eye care-related inpatient and emergency department (ED) encounters; eye care-related nursing home and home-visit encounters; visual field and retinal nerve fiber OCT tests; glaucoma lasers and surgeries. RESULTS: Among 78 526 participants with glaucoma, mean age was 79.1 years (standard deviation, 7.9 years), 60.9% were female, 78.4% were non-Hispanic White, and 13.8% met enrollment-based criteria for low-SES. Compared with White beneficiaries, Blacks had lower counts of outpatient visits (RR, 0.92; 95% confidence interval [CI], 0.90-0.93), visual field (VF) tests (RR, 0.92; 95% CI, 0.90-0.94), but more inpatient/ED encounters (RR, 2.42; 95% CI, 1.55-3.78) and surgeries (RR, 1.14; 95% CI, 1.03-1.27). Hispanics had fewer outpatient visits (RR, 0.97; 95% CI, 0.95-0.98) and retinal nerve fiber layer (RNFL) OCT tests (RR, 0.89; 95% CI, 0.86-0.93), but more inpatient/ED encounters (RR, 2.32; 95% CI, 1.18-4.57) and selective laser trabeculoplasty (SLT) (RR, 1.25; 95% CI, 1.11-1.42) versus non-Hispanic Whites. In the non-low SES group, Black versus White disparities persisted in outpatient visits (RR, 0.93; 95% CI, 0.92-0.95), VF (RR, 0.96; 95% CI, 0.94-0.98), RNFL OCT (RR, 0.81; 95% CI, 0.78-0.83), and inpatient/ED encounters (RR, 2.57; 95% CI, 1.55-4.26). CONCLUSIONS: Disparities were found in eye care utilization among Black and Hispanic patients with glaucoma. These differences persisted among Blacks after stratification by SES, suggesting that systemic racism may be an independent driver in this population.
Chinn RN, Raghuram A, Curtiss MK, Gehring AM, De Paula AJ, Roberts TL. Repeatability of the Accommodative Response Measured by the Grand Seiko Autorefractor in Children With and Without Amblyopia and Adults. Am J Ophthalmol 2022;236:221-231.Abstract
PURPOSE: To assess test-retest repeatability of the accommodative response (AR) in children with and without amblyopia and adults using the Grand Seiko autorefractor. DESIGN: Prospective reliability assessment. METHODS: Test-retest of accommodation was obtained while participants viewed 20/150 sized letters at 33 cm using the Grand Seiko autorefractor in children 5 to <11 years with amblyopia (n=24) and without amblyopia (n=36), and adults 18 to <35 years (n=34). Bland-Altman 95% limits of agreement (LOA) and intraclass correlation coefficients (ICCs) were used to assess repeatability and reliability. The AR between the fellow and amblyopic eyes of children with amblyopia and eye 1 and eye 2 of the visually normal participants was assessed using group comparisons. RESULTS: The 95% LOA of the AR was greatest in the amblyopic eyes (-1.25 diopters [D], 1.62 D) of children with amblyopia. The 95% LOA were similar between the fellow eyes (-0.88 D, 0.74 D) of children with amblyopia and both eyes of the children without amblyopia (eye 1: -0.68 D, 0.71 D; eye 2: -0.59 D, 0.70 D) and the adults (eye 1: 95% LOA = -0.49 D, 0.45 D; eye 2: LOA = -0.66 D, 0.67 D). ICCs revealed the Grand Seiko autorefractor as a reliable instrument for measuring AR. CONCLUSIONS: The Grand Seiko autorefractor was more repeatable and reliable when measuring the AR in children and adults without amblyopia than in the amblyopic eye in children with amblyopia. It is recommended that multiple measures of the AR be obtained in amblyopic eyes to improve the precision of measures.
Fjaervoll H, Fjaervoll K, Magno M, Moschowits E, Vehof J, Dartt DA, Utheim TP. The association between visual display terminal use and dry eye: a review. Acta Ophthalmol 2022;100(4):357-375.Abstract
BACKGROUND: Dry eye disease (DED) is a multifactorial disease of the tear film and ocular surface. It causes ocular symptoms, reduced quality of life and a considerable economic burden on society. Prolonged use of visual display terminals (VDTs) has been suggested as an important risk factor for DED. PURPOSE: This review aims to study the association between DED and VDT use with an emphasis on the prevalence of DED among VDT users and harmful daily duration of VDT use. METHODS: A PubMed search was conducted and yielded 57 relevant articles based on a set of inclusion and exclusion criteria. The studies were subclassified according to study design. RESULTS: The far majority of the studies showed an association between VDT use and DED or DED-related signs and symptoms. The prevalence of definite or probable DED in VDT and office workers ranged from 26% to 70%, with as few as 1-2 hr of VDT exposure per day being associated with DED. CONCLUSION: VDT use is strongly associated with DED. VDT-associated DED is prevalent, but the exact prevalence needs to be further elucidated using standardized DED diagnosis criteria. Furthermore, a safe lower limit of daily VDT use has yet to be established. More research is needed on the effect of digitalization and digital transformation, which are particularly high during the time of the COVID-19 pandemic.
Xu BY, Friedman DS, Foster PJ, Jiang Y, Porporato N, Pardeshi AA, Jiang Y, Munoz B, Aung T, He M. Ocular Biometric Risk Factors for Progression of Primary Angle Closure Disease: The Zhongshan Angle Closure Prevention Trial. Ophthalmology 2022;129(3):267-275.Abstract
PURPOSE: To assess baseline ocular biometric risk factors for progression from primary angle closure suspect (PACS) to primary angle closure (PAC) or acute angle closure (AAC). DESIGN: Prospective, observational study. PARTICIPANTS: Six hundred forty-three mainland Chinese with untreated PACS. METHODS: Participants underwent baseline clinical examinations, including gonioscopy, anterior segment OCT (AS-OCT) imaging, and A-scan ultrasound biometry as part of the Zhongshan Angle Closure Prevention (ZAP) Trial. Primary angle closure suspect was defined as an inability to visualize pigmented trabecular meshwork in 2 or more quadrants based on static gonioscopy. Primary angle closure was defined as development of intraocular pressure above 24 mmHg or peripheral anterior synechiae. Progression was defined as development of PAC or an AAC attack. Multivariable logistic regression models were developed to assess biometric risk factors for progression. MAIN OUTCOME MEASURES: Six-year progression from PACS to PAC or AAC. RESULTS: Six hundred forty-three untreated eyes (609 nonprogressors, 34 progressors) of 643 participants were analyzed. In a multivariable model with continuous parameters, narrower horizontal angle opening distance of 500 μm from the scleral spur (AOD500; odds ratio [OR], 1.10 per 0.01-mm decrease; P = 0.03), flatter horizontal iris curvature (IC; OR, 1.96 per 0.1-mm decrease; P = 0.01), and older age (OR, 1.11 per 1-year increase; P = 0.01) at baseline were associated significantly with progression (area under the receiver operating characteristic curve [AUC], 0.73). Smaller cumulative gonioscopy score was not associated with progression (OR, 1.03 per 1-modified Shaffer grade decrease; P = 0.85) when replacing horizontal AOD500 in the multivariable model. In a separate multivariable model with categorical parameters, participants in the lowest quartile of horizontal AOD500 (OR, 3.10; P = 0.002) and IC (OR, 2.48; P = 0.014) measurements and 59 years of age or older (OR, 2.68; P = 0.01) at baseline showed higher odds of progression (AUC, 0.72). CONCLUSIONS: Ocular biometric measurements can help to risk-stratify patients with early angle closure for more severe disease. Anterior segment OCT measurements of biometric parameters describing the angle and iris are predictive of progression from PACS to PAC or AAC, whereas gonioscopy grades are not.

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