Ashofteh Yazdi A, Melchor J, Torres J, Faris I, Callejas A, Gonzalez-Andrades M, Rus G. Characterization of non-linear mechanical behavior of the cornea. Sci Rep 2020;10(1):11549.Abstract
The objective of this study was to evaluate which hyperelastic model could best describe the non-linear mechanical behavior of the cornea, in order to characterize the capability of the non-linear model parameters to discriminate structural changes in a damaged cornea. Porcine corneas were used, establishing two different groups: control (non-treated) and NaOH-treated (damaged) corneas (n = 8). NaOH causes a chemical burn to the corneal tissue, simulating a disease associated to structural damage of the stromal layer. Quasi-static uniaxial tensile tests were performed in nasal-temporal direction immediately after preparing corneal strips from the two groups. Three non-linear hyperelastic models (i.e. Hamilton-Zabolotskaya model, Ogden model and Mooney-Rivlin model) were fitted to the stress-strain curves obtained in the tensile tests and statistically compared. The corneas from the two groups showed a non-linear mechanical behavior that was best described by the Hamilton-Zabolotskaya model, obtaining the highest coefficient of determination (R > 0.95). Moreover, Hamilton-Zabolotskaya model showed the highest discriminative capability of the non-linear model parameter (Parameter A) for the tissue structural changes between the two sample groups (p = 0.0005). The present work determines the best hyperelastic model with the highest discriminative capability in description of the non-linear mechanical behavior of the cornea.
Ashok A, Pooranawattanakul S, Tai WL, Cho KS, Utheim TP, Cestari DM, Chen DF. Epigenetic Regulation of Optic Nerve Development, Protection, and Repair. Int J Mol Sci 2022;
Ashraf M, Sampani K, AbdelAl O, Fleming A, Cavallerano J, Souka A, El Baha SM, Silva PS, Sun J, Aiello LP. Disparity of microaneurysm count between ultrawide field colour imaging and ultrawide field fluorescein angiography in eyes with diabetic retinopathy. Br J Ophthalmol 2020;104(12):1762-1767.Abstract
AIMS: To compare microaneurysm (MA) counts using ultrawide field colour images (UWF-CI) and ultrawide field fluorescein angiography (UWF-FA). METHODS: Retrospective study including patients with type 1 or 2 diabetes mellitus receiving UWF-FA and UWF-CI within 2 weeks. MAs were manually counted in individual Early Treatment Diabetic Retinopathy Study (ETDRS) and extended UWF zones. Fields with MAs ≥20 determined diabetic retinopathy (DR) severity (0 fields=mild, 1-3=moderate, ≥4=severe). UWF-FA and UWF-CI agreement was determined and UWF-CI DR severity sensitivity analysis adjusting for UWF-FA MA counts performed. RESULTS: In 193 patients (288 eyes), 2.4% had no DR, 29.9% mild non-proliferative DR (NPDR), 32.6% moderate (NPDR), 22.9% severe NPDR and 12.2% proliferative DR. UWF-FA MA counts were 3.5-fold higher (p<0.001) than UWF-CI counts overall, 3.2x-fold higher in ETDRS fields (p<0.001) and 5.3-fold higher in extended ETDRS fields (p<0.001) and higher in type 1 versus type 2 diabetes (p<0.001). In eyes with NPDR on UWF-CI (n=246), UWF-FA images had 1.6x-3.5x more fields with ≥20 MAs (p<0.001). Fair agreement existed between imaging modalities (k=0.221-0.416). In ETDRS fields, DR severity agreement increased from k=0.346 to 0.600 when dividing UWF-FA counts by a factor of 3, followed by rapid decline in agreement thereafter. Total UWF area agreement increased from k=0.317 to 0.565 with an adjustment factor of either 4 or 5. CONCLUSIONS: UWF-FA detects threefold to fivefold more MAs than UWF-CI and identifies 1.6-3.5-fold more fields affecting DR severity. Differences exist at all DR severity levels, thus limiting direct comparison between the modalities. However, correcting UWF-FA MA counts substantially improves DR severity agreement between the modalities.
Ashraf M, Sampani K, Rageh A, Silva PS, Aiello LP, Sun JK. Interaction Between the Distribution of Diabetic Retinopathy Lesions and the Association of Optical Coherence Tomography Angiography Scans With Diabetic Retinopathy Severity. JAMA Ophthalmol 2020;138(12):1291-1297.Abstract
Importance: Studies have not yet determined whether the distribution of lesions in the retinal periphery alters the association between the severity of diabetic retinopathy (DR) and macular vessel density. Objective: To evaluate the association of DR lesion distribution with optical coherence tomography angiography (OCTA) metrics and DR severity. Design, Setting, and Participants: This cross-sectional observational study was conducted at a tertiary care center for diabetic eye disease among 225 patients with type 1 or 2 diabetes who had undergone imaging between February 15, 2016, and December 31, 2019. Exposures: Optical coherence tomography angiography 3 × 3-mm macular scans and ultra-widefield color imaging. Main Outcomes and Measures: Optical coherence tomography angiography vessel density in the superficial capillary plexus, intermediate capillary plexus, and deep capillary plexus and choriocapillaris flow density. The severity of DR and the predominantly peripheral lesions (PPL) were evaluated from ultra-widefield color imaging. Results: The study evaluated 352 eyes (225 patients; 125 men [55.6%]; mean [SD] age, 52.1 [15.1] years), of which 183 eyes (52.0%) had mild nonproliferative diabetic retinopathy (NPDR), 71 eyes (20.2%) had moderate NPDR, and 98 eyes (27.8%) had severe NPDR or proliferative diabetic retinopathy (PDR). In eyes with no PPL (209 [59.4%]), the mean (SD) vessel density in the superficial capillary plexus (mild NPDR, 38.1% [4.7%]; moderate NPDR, 36.4% [4.6%]; severe NPDR or PDR, 34.1% [4.1%]; P < .001) and the deep capillary plexus (mild NPDR, 45.8% [3.0%]; moderate NPDR, 45.8% [2.2%]; severe NPDR or PDR, 44.5% [1.9%]; P = .002), as well as the mean (SD) choriocapillaris flow density (mild NPDR, 69.7% [6.2%]; moderate NPDR, 67.6% [5.6%]; severe NPDR or PDR, 67.1% [5.6%]; P = .01), decreased with increasing DR severity. These associations remained statistically significant even after correcting for age, signal strength index, spherical equivalent, duration of diabetes, type of diabetes, and correlation between eyes of the same patient. In eyes with PPL (143 [40.6%]), mean (SD) vessel density in the superficial capillary plexus (mild NPDR, 34.1% [4.1%]; moderate NPDR, 35.2% [4.1%]; severe NPDR or PDR, 36.0% [4.3%]; P = .42) and the deep capillary plexus (mild NPDR, 44.5% [1.7%]; moderate NPDR, 45.4% [1.4%]; severe NPDR or PDR, 44.9% [1.5%]; P = .81), as well as the mean (SD) choriocapillaris flow density (mild NPDR, 67.1% [5.6%]; moderate NPDR, 69.3% [4.6%]; severe NPDR or PDR, 68.3% [5.6%]; P = .49), did not appear to change with increasing DR severity. Conclusions and Relevance: These results suggest that central retinal vessel density is associated with DR severity in eyes without, but not with, PPL. These findings suggest a potential need to stratify future optical coherence tomography angiography studies of eyes with DR by the presence or absence of PPL. If DR onset and worsening are associated with the location of retinal nonperfusion, assessment of global retinal nonperfusion using widefield angiography may improve the ability to evaluate DR severity and risk of DR worsening over time.
Ashraf M, Shokrollahi S, Salongcay RP, Aiello LP, Silva PS. Diabetic retinopathy and ultrawide field imaging. Semin Ophthalmol 2020;35(1):56-65.Abstract
The introduction of ultrawide field imaging has allowed the visualization of approximately 82% of the total retinal area compared to only 30% using 7-standard field Early Treatment Diabetic Retinopathy (ETDRS) photography. This substantially wider field of view, while useful in many retinal vascular diseases, is particularly important in diabetic retinopathy where eyes with predominantly peripheral lesions or PPL have been shown to have significantly greater progression rates compared to eyes without PPL. In telemedicine settings, ultrawide field imaging has substantially reduced image ungradable rates and increased rate of disease identification allowing care to be delivered more effectively. Furthermore, the use of ultrawide field fluorescein angiography allows the visualization of significantly more diabetic retinal lesions and allows more accurate quantification of total retinal nonperfusion, with potential implications in the management of diabetic retinopathy and diabetic macular edema. The focus of this paper is to review the current role of ultrawide field imaging in diabetic retinopathy and its possible future role in innovations for retinal image analysis such as artificial intelligence and vessel caliber measurements.
Ashraf M, Rageh A, Gilbert M, Tolls D, Fleming A, Souka A, El-Baha S, Cavallerano JD, Sun JK, Aiello LP, Silva PS. Factors Affecting Predominantly Peripheral Lesion Identification and Grading. Transl Vis Sci Technol 2021;10(7):6.Abstract
Purpose: The purpose of this study was to determine factors affecting predominantly peripheral lesion (PPL) grading, such as qualitative versus quantitative assessment, device type, and severity of diabetic retinopathy (DR) in ultrawide field color images (UWF-CIs). Methods: Patients with DR had UWF-CI qualitatively graded for PPL using standardized techniques and had hemorrhages/microaneurysms (H/Mas) individually annotated for quantitative PPL grading on two different ultrawide field devices. Results: Among 791 eyes of 481 patients, 38.2% had mild nonproliferative DR (NPDR), 34.7% had moderate NPDR, and 27.1% had severe NPDR to proliferative DR (PDR). The overall agreement between qualitative and quantitative PPL grading was moderate (ĸ = 0.423, P < 0.001). Agreement rates were fair in eyes with mild NPDR (ĸ = 0.336, P < 0.001) but moderate in eyes with moderate NPDR (ĸ = 0.525, P < 0.001) and severe NPDR-PDR (ĸ = 0.409, P < 0.001). Increasing thresholds for quantitative PPL determination improved agreement rates, with peak agreements at H/Ma count differences of six for mild NPDR, five for moderate NPDR, and nine for severe NPDR-PDR. Based on ultrawide field device type (California = 412 eyes vs. 200Tx = 379 eyes), agreement between qualitative and quantitative PPL grading was moderate for all DR severities in both devices (ĸ = 0.369-0.526, P < 0.001) except for mild NPDR on the 200Tx, which had poor agreement (ĸ = 0.055, P = 0.478). Conclusions: Determination of PPL varies between standard qualitative and quantitative grading and is dependent on NPDR severity, device type, and magnitude of lesion differences used for quantitative assessment. Translational Relevance: Prior UWF studies have not accounted for imaging and grading factors that affect PPL, such factors need to be reviewed when assessing thresholds for DR progression rates.
Ashraf M, Shokrollahi S, Pisig AU, Sampani K, AbdelAl O, Cavallerano JD, Robertson G, Fleming A, van Hemert J, Pitoc CM, Sun JK, Aiello LP, Silva PS. Retinal Vascular Caliber Association with Nonperfusion and Diabetic Retinopathy Severity Depends on Vascular Caliber Measurement Location. Ophthalmol Retina 2021;5(6):571-579.Abstract
PURPOSE: To evaluate the association of retinal nonperfusion and diabetic retinopathy (DR) severity with location of vascular caliber measurement using ultrawide field (UWF) imaging. DESIGN: Retrospective image review. PARTICIPANTS: Adults with diabetes mellitus. METHODS: All images from subjects with same-day UWF fluorescein angiography (FA) and color imaging were evaluated. Predominantly peripheral lesions (PPL) and DR severity were graded from UWF color images. Nonperfusion was quantified using UWF-FA in defined retinal regions [posterior pole (PP), mid-periphery (MP), far-periphery (FP)]. Retinal vessel calibers were measured at an optic disc centered inner and outer zone. MAIN OUTCOME MEASURES: Nonperfusion index (NPI) in the PP, MP and FP. Mean arteriole and venule diameter in the inner and outer zones. RESULTS: Two hundred eighty-five eyes of 193 patients (24.9% mild nonproliferative DR [NPDR], 22.8% moderate NPDR, 37.5% severe NPDR and 14.7% proliferative DR [PDR]) were reviewed. No significant associations between inner zone arteriolar diameter and retinal NPI overall or in any retinal region. In the outer zone, eyes with thinnest arteriolar calibers (quartile 1) were associated with a 1.7- to 2.4-fold nonperfusion increase across all retinal regions compared to the remaining eyes (P = 0.002 [PP] to 0.048 [FP]). In the outer zone, the percentage of eyes in the thinnest quartile of retinal arteriolar diameter increased with worsening DR severity (mild NPDR: 10% vs PDR: 31%, P = 0.007). This association was not observed when measured within the inner zone (P = 0.129). All venular caliber associations were not statistically significant when corrected for potentially confounding factors. Thinner outer zone retinal arteriolar caliber (quartile 1) was more common in eyes with PPL compared to eyes without PPL (34.1% vs 20.8%, P = 0.017) as were thicker outer venular calibers (quartile 4) (33% vs 21.3%, P = 0.036). Presence of PPL was associated with thinner outer zone arteriolar caliber (109.7 ± 26.5μm vs 123.0 ± 29.5μm, P = 0.001). CONCLUSIONS: The association of vascular caliber with nonperfusion and DR severity differs based upon the retinal location at which vascular caliber is measured. Peripheral arterial narrowing is associated with increasing nonperfusion, worsening DR severity and presence of PPL. In contrast, inner zone retinal arteriolar caliber is not associated with these findings.
Au ED, Fernandez-Godino R, Kaczynksi TJ, Sousa ME, Farkas MH. Characterization of lincRNA expression in the human retinal pigment epithelium and differentiated induced pluripotent stem cells. PLoS One 2017;12(8):e0183939.Abstract
Long intervening non-coding RNAs (lincRNAs) are increasingly being implicated as important factors in many aspects of cellular development, function, and disease, but remain poorly understood. In this study, we examine the human retinal pigment epithelium (RPE) lincRNA transcriptome using RNA-Seq data generated from human fetal RPE (fRPE), RPE derived from human induced pluripotent stem cells (iPS-RPE), and undifferentiated iPS (iPS). In addition, we determine the suitability of iPS-RPE, from a transcriptome standpoint, as a model for use in future studies of lincRNA structure and function. A comparison of gene and isoform expression across the whole transcriptome shows only minimal differences between all sample types, though fRPE and iPS-RPE show higher concordance than either shows with iPS. Notably, RPE signature genes show the highest degree of fRPE to iPS-RPE concordance, indicating that iPS-RPE cells provide a suitable model for use in future studies. An analysis of lincRNAs demonstrates high concordance between fRPE and iPS-RPE, but low concordance between either RPE and iPS. While most lincRNAs are expressed at low levels (RPKM < 10), there is a high degree of concordance among replicates within each sample type, suggesting the expression is consistent, even at levels subject to high variability. Finally, we identified and annotated 180 putative novel genes in the fRPE samples, a majority of which are also expressed in the iPS-RPE. Overall, this study represents the first characterization of lincRNA expression in the human RPE, and provides a model for studying the role lincRNAs play in RPE development, function, and disease.
Aung T, Ozaki M, Lee MC, Schlötzer-Schrehardt U, Thorleifsson G, Mizoguchi T, Igo RP, Haripriya A, Williams SE, Astakhov YS, Orr AC, Burdon KP, Nakano S, Mori K, Abu-Amero K, Hauser M, Li Z, Prakadeeswari G, Bailey JCN, Cherecheanu AP, Kang JH, Nelson S, Hayashi K, Manabe S-I, Kazama S, Zarnowski T, Inoue K, Irkec M, Coca-Prados M, Sugiyama K, Järvelä I, Schlottmann P, Lerner FS, Lamari H, Nilgün Y, Bikbov M, Park KH, Cha SC, Yamashiro K, Zenteno JC, Jonas JB, Kumar RS, Perera SA, Chan ASY, Kobakhidze N, George R, Vijaya L, Do T, Edward DP, de Juan Marcos L, Pakravan M, Moghimi S, Ideta R, Bach-Holm D, Kappelgaard P, Wirostko B, Thomas S, Gaston D, Bedard K, Greer WL, Yang Z, Chen X, Huang L, Sang J, Jia H, Jia L, Qiao C, Zhang H, Liu X, Zhao B, Wang Y-X, Xu L, Leruez S, Reynier P, Chichua G, Tabagari S, Uebe S, Zenkel M, Berner D, Mossböck G, Weisschuh N, Hoja U, Welge-Luessen U-C, Mardin C, Founti P, Chatzikyriakidou A, Pappas T, Anastasopoulos E, Lambropoulos A, Ghosh A, Shetty R, Porporato N, Saravanan V, Venkatesh R, Shivkumar C, Kalpana N, Sarangapani S, Kanavi MR, Beni AN, Yazdani S, Lashay A, Naderifar H, Khatibi N, Fea A, Lavia C, Dallorto L, Rolle T, Frezzotti P, Paoli D, Salvi E, Manunta P, Mori Y, Miyata K, Higashide T, Chihara E, Ishiko S, Yoshida A, Yanagi M, Kiuchi Y, Ohashi T, Sakurai T, Sugimoto T, Chuman H, Aihara M, Inatani M, Miyake M, Gotoh N, Matsuda F, Yoshimura N, Ikeda Y, Ueno M, Sotozono C, Jeoung JW, Sagong M, Park KH, Ahn J, Cruz-Aguilar M, Ezzouhairi SM, Rafei A, Chong YF, Ng XY, Goh SR, Chen Y, Yong VHK, Khan MI, Olawoye OO, Ashaye AO, Ugbede I, Onakoya A, Kizor-Akaraiwe N, Teekhasaenee C, Suwan Y, Supakontanasan W, Okeke S, Uche NJ, Asimadu I, Ayub H, Akhtar F, Kosior-Jarecka E, Lukasik U, Lischinsky I, Castro V, Grossmann RP, Megevand GS, Roy S, Dervan E, Silke E, Rao A, Sahay P, Fornero P, Cuello O, Sivori D, Zompa T, Mills RA, Souzeau E, Mitchell P, Wang JJ, Hewitt AW, Coote M, Crowston JG, Astakhov SY, Akopov EL, Emelyanov A, Vysochinskaya V, Kazakbaeva G, Fayzrakhmanov R, Al-Obeidan SA, Owaidhah O, Aljasim LA, Chowbay B, Foo JN, Soh RQ, Sim KS, Xie Z, Cheong AWO, Mok SQ, Soo HM, Chen XY, Peh SQ, Heng KK, Husain R, Ho S-L, Hillmer AM, Cheng C-Y, Escudero-Domínguez FA, González-Sarmiento R, Martinon-Torres F, Salas A, Pathanapitoon K, Hansapinyo L, Wanichwecharugruang B, Kitnarong N, Sakuntabhai A, Nguyn HX, Nguyn GTT, Nguyn TV, Zenz W, Binder A, Klobassa DS, Hibberd ML, Davila S, Herms S, Nöthen MM, Moebus S, Rautenbach RM, Ziskind A, Carmichael TR, Ramsay M, Álvarez L, García M, González-Iglesias H, Rodríguez-Calvo PP, Cueto LF-V, Oguz Ç, Tamcelik N, Atalay E, Batu B, Aktas D, Kasım B, Wilson RM, Coleman AL, Liu Y, Challa P, Herndon L, Kuchtey RW, Kuchtey J, Curtin K, Chaya CJ, Crandall A, Zangwill LM, Wong TY, Nakano M, Kinoshita S, den Hollander AI, Vesti E, Fingert JH, Lee RK, Sit AJ, Shingleton BJ, Wang N, Cusi D, Qamar R, Kraft P, Pericak-Vance MA, Raychaudhuri S, Heegaard S, Kivelä T, Reis A, Kruse FE, Weinreb RN, Pasquale LR, Haines JL, Thorsteinsdottir U, Jonasson F, Allingham RR, Milea D, Ritch R, Kubota T, Tashiro K, Vithana EN, Micheal S, Topouzis F, Craig JE, Dubina M, Sundaresan P, Stefansson K, Wiggs JL, Pasutto F, Khor CC. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. Nat Genet 2017;Abstract
Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10(-14)) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10(-8)). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.
Aung T, Ozaki M, Mizoguchi T, Allingham RR, Li Z, Haripriya A, Nakano S, Uebe S, Harder JM, Chan ASY, Lee MC, Burdon KP, Astakhov YS, Abu-Amero KK, Zenteno JC, Nilgün Y, Zarnowski T, Pakravan M, Safieh LA, Jia L, Wang YX, Williams S, Paoli D, Schlottmann PG, Huang L, Sim KS, Foo JN, Nakano M, Ikeda Y, Kumar RS, Ueno M, Manabe S-I, Hayashi K, Kazama S, Ideta R, Mori Y, Miyata K, Sugiyama K, Higashide T, Chihara E, Inoue K, Ishiko S, Yoshida A, Yanagi M, Kiuchi Y, Aihara M, Ohashi T, Sakurai T, Sugimoto T, Chuman H, Matsuda F, Yamashiro K, Gotoh N, Miyake M, Astakhov SY, Osman EA, Al-Obeidan SA, Owaidhah O, Al-Jasim L, Shahwan SA, Fogarty RA, Leo P, Yetkin Y, Oğuz Ç, Kanavi MR, Beni AN, Yazdani S, Akopov EL, Toh K-Y, Howell GR, Orr AC, Goh Y, Meah WY, Peh SQ, Kosior-Jarecka E, Lukasik U, Krumbiegel M, Vithana EN, Wong TY, Liu Y, Koch AAE, Challa P, Rautenbach RM, Mackey DA, Hewitt AW, Mitchell P, Wang JJ, Ziskind A, Carmichael T, Ramakrishnan R, Narendran K, Venkatesh R, Vijayan S, Zhao P, Chen X, Guadarrama-Vallejo D, Cheng CY, Perera SA, Husain R, Ho S-L, Welge-Luessen U-C, Mardin C, Schloetzer-Schrehardt U, Hillmer AM, Herms S, Moebus S, Nöthen MM, Weisschuh N, Shetty R, Ghosh A, Teo YY, Brown MA, Lischinsky I, Lischinsky I, Lischinsky I, Crowston JG, Coote M, Zhao B, Sang J, Zhang N, You Q, Vysochinskaya V, Founti P, Chatzikyriakidou A, Lambropoulos A, Anastasopoulos E, Coleman AL, Wilson RM, Rhee DJ, Kang JH, May-Bolchakova I, Heegaard S, Mori K, Alward WLM, Jonas JB, Xu L, Liebmann JM, Chowbay B, Schaeffeler E, Schwab M, Lerner F, Wang N, Yang Z, Frezzotti P, Kinoshita S, Fingert JH, Inatani M, Tashiro K, Reis A, Edward DP, Pasquale LR, Kubota T, Wiggs JL, Pasutto F, Topouzis F, Dubina M, Craig JE, Yoshimura N, Sundaresan P, John SWM, Ritch R, Hauser MA, Khor C-C. A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. Nat Genet 2015;47(4):387-92.Abstract

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: ORA allele = 9.87, P = 2.13 × 10(-217); non-Japanese: ORA allele = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Avedschmidt SE, Stagner AM, Eagle RC, Harocopos GJ, Dou Y, Rao RC. The Targetable Epigenetic Tumor Protein EZH2 is Enriched in Intraocular Medulloepithelioma. Invest Ophthalmol Vis Sci 2016;57(14):6242-6246.Abstract

Purpose: Intraocular medulloepithelioma (IM), the second most common primary neuroepithelial tumor of the eye, can lead to blindness in the affected eye and in rare cases, is deadly. Intraocular medulloepithelioma lacks targetable biomarkers for potential pharmacologic therapy. The purpose of this study was to identify actionable, tumor-specific proteins for potential diagnostic or therapeutic strategies. We hypothesize that the tumor-specific epigenetic enzyme EZH2 is selectively expressed in IM. Methods: We conducted a retrospective case series study of five IM from five eyes of four children and one adult. Hematoxylin and eosin (H&E) stains of sections from formalin-fixed, paraffin-embedded blocks of IM tumors were used to localize IM tumor cells in each case. Using an EZH2-specific antibody for immunohistochemistry, we semiquantitatively calculated the proportion of IM tumor cells positive for EZH2, and also assayed for EZH2 staining intensity. Results: We found that EZH2 was expressed in all IM cases but this protein was absent in nontumor ciliary body or retinal tissues. However, not all IM tumor cells expressed EZH2. Similar to retinoblastoma, moderately to poorly differentiated (primitive appearing) IM tumor cells strongly expressed EZH2; expression was weaker or absent in areas of well-formed neuroepithelial units. Conclusions: To our knowledge, this is the first study to identify an actionable tumor-specific maker, EZH2, in IM. Our findings point to the possibility of exploring the potential of EZH2 inhibitors, already in clinical trials for other cancers, for IM.

Avery RA, Katowitz JA, Fisher MJ, Heidary G, Dombi E, Packer RJ, Widemann BC, Widemann BC. Orbital/Periorbital Plexiform Neurofibromas in Children with Neurofibromatosis Type 1: Multidisciplinary Recommendations for Care. Ophthalmology 2017;124(1):123-132.Abstract

TOPIC: Children and adults with neurofibromatosis type 1 (NF1), a common autosomal dominant condition, manifest a variety of ophthalmologic conditions. Plexiform neurofibromas (PNs) involving the eyelid, orbit, periorbital, and facial structures (orbital-periorbital plexiform neurofibroma [OPPN]) can result in significant visual loss in children. Equally important, OPPNs can cause significant alteration in physical appearance secondary to proptosis, ptosis, and facial disfigurement, leading to social embarrassment and decreased self-esteem. CLINICAL RELEVANCE: Although NF1 is a relatively common disease in which routine ophthalmologic examinations are required, no formal recommendations for clinical care of children with OPPNs exist. Although medical and surgical interventions have been reported, there are no agreed-on criteria for when OPPNs require therapy and which treatment produces the best outcome. METHODS: Because a multidisciplinary team of specialists (oculofacial plastics, pediatric ophthalmology, neuro-ophthalmology, medical genetics, and neuro-oncology) direct management decisions, the absence of a uniform outcome measure that represents visual or aesthetic sequelae complicates the design of evidence-based studies and feasible clinical trials. RESULTS: In September 2013, a multidisciplinary task force, composed of pediatric practitioners from tertiary care centers experienced in caring for children with OPPN, was convened to address the lack of clinical care guidelines for children with OPPN. CONCLUSIONS: This consensus statement provides recommendations for ophthalmologic monitoring, outlines treatment indications and forthcoming biologic therapy, and discusses challenges to performing clinical trials in this complicated condition.

Avraham D, Jung J-H, Yitzhaky Y, Peli E. Retinal prosthetic vision simulation: temporal aspects. J Neural Eng 2021;18(4)Abstract
Objective. The perception of individuals fitted with retinal prostheses is not fully understood, although several retinal implants have been tested and commercialized. Realistic simulations of perception with retinal implants would be useful for future development and evaluation of such systems.Approach.We implemented a retinal prosthetic vision simulation, including temporal features, which have not been previously simulated. In particular, the simulation included temporal aspects such as persistence and perceptual fading of phosphenes and the electrode activation rate.Main results.The simulated phosphene persistence showed an effective reduction in flickering at low electrode activation rates. Although persistence has a positive effect on static scenes, it smears dynamic scenes. Perceptual fading following continuous stimulation affects prosthetic vision of both static and dynamic scenes by making them disappear completely or partially. However, we showed that perceptual fading of a static stimulus might be countered by head-scanning motions, which together with the persistence revealed the contours of the faded object. We also showed that changing the image polarity may improve simulated prosthetic vision in the presence of persistence and perceptual fading.Significance.Temporal aspects have important roles in prosthetic vision, as illustrated by the simulations. Considering these aspects may improve the future design, the training with, and evaluation of retinal prostheses.
Awh CC, Lane AM, Hawken S, Zanke B, Kim IK. Author reply: To PMID 23972322. Ophthalmology 2014;121(8):e39.
Azad AD, Chen EM, Hinkle J, Rayess N, Wu D, Eliott D, Mruthyunjaya P, Parikh R. Anti-Vascular Endothelial Growth Factor and Panretinal Photocoagulation Use after Protocol S for Proliferative Diabetic Retinopathy. Ophthalmol Retina 2021;5(2):151-159.Abstract
PURPOSE: To characterize the rates of panretinal photocoagulation (PRP) and anti-vascular endothelial growth factor (VEGF) medications before and after publication of the Diabetic Retinopathy Clinical Research Network protocol S. DESIGN: A retrospective, cross-sectional study from January 2012, through September 2019, using a nationally representative claims-based database, Clinformatics Data Mart Database (OptumInsight, Eden Prairie, MN). PARTICIPANTS: Eyes newly diagnosed with proliferative diabetic retinopathy (PDR), continuous enrollment, and no prior treatment with PRP or anti-VEGF agents. METHODS: Interrupted time series regression analysis was performed to identify the annual change in treatment rates before and after the publication of Protocol S (November 2015). MAIN OUTCOME MEASURES: Annual rates of anti-VEGF or PRP treatments per 1000 treated eyes with PDR. RESULTS: From 2012 through 2019, 10 035 PRP or anti-VEGF treatments were administered to 3685 PDR eyes. Of these, 63.6% (n = 6379) were anti-VEGF agents, and 36.4% (n = 3656) were PRP treatments. Throughout treatment, 88.7% of eyes treated with anti-VEGF received the same agent and 7.7% were treated with both PRP and anti-VEGF agents. Panretinal photocoagulation rates declined from 784/1000 treated eyes in 2012 to 566/1000 in 2019 (pre-Protocol S: β = -32 vs. post-Protocol S: -77; P = 0.005), whereas anti-VEGF rates increased from 876/1000 in 2012 to 1583/1000 in 2019 (β = -48 vs. 161, respectively; P = 0.001). Panretinal photocoagulation rates in diabetic macular edema (DME) eyes did not significantly differ from 474/1000 in 2012 to 363/1000 in 2019 (β = -9 vs. -58 respectively; P = 0.091), and anti-VEGF rates increased from 1533/1000 in 2012 to 2096/1000 in 2019 (β = -57 vs. 187; P = 0.043). In eyes without DME, PRP use declined from 1017/1000 in 2012 to 707/1000 in 2019 (β = -31 vs. -111, respectively; P < 0.001), and anti-VEGF use increased from 383/1000 in 2012 to 1226/1000 in 2019 (β = -48 vs. 140, respectively; P < 0.001). CONCLUSIONS: Following the publication of Protocol S, PRP rates decreased, while anti-VEGF rates increased. Panretinal photocoagulation rates did not significantly change among eyes with DME. Our findings indicate the impact that randomized controlled trials can have on real-world practice patterns.
Azad AD, Chen EM, Hinkle J, Rayess N, Wu D, Eliott D, Mruthyunjaya P, Parikh R. Trends in Anti-Vascular Endothelial Growth Factor Agents and Panretinal Photocoagulation Use in Diabetic Retinopathy. Ophthalmol Retina 2021;5(4):390-392.
Azad AD, Chandramohan A, Li AS, Rosenblatt TR, Reeves M-GR, Veerappan-Pasricha M, Ludwig CA, Nguyen A, Winges KM, Wang SY, Pan CK, Moss HE, Do DV, Fountain TR, Kossler AL. Representation of Women in Ophthalmology Subspecialty Societies over 20 Years. Ophthalmology 2022;129(5):587-590.
Aziz K, Moon JY, Parikh R, Lorch AC, Friedman DS, Miller JB, Armstrong GW. Association of Patient Characteristics With Delivery of Ophthalmic Telemedicine During the COVID-19 Pandemic. JAMA Ophthalmol 2021;139(11):1174-1182.Abstract
Importance: Telemedicine has been shown to have had reduced uptake among historically marginalized populations within multiple medical specialties during the COVID-19 pandemic. An evaluation of health disparities among patients receiving ophthalmic telemedical care during the pandemic is needed. Objective: To evaluate disparities in the delivery of ophthalmic telemedicine at Massachusetts Eye and Ear (MEE) during the COVID-19 pandemic. Design, Setting, and Participants: This retrospective, cross-sectional study analyzed clinical visits at a single tertiary eye care center (MEE) from January 1 to December 31, 2020. Patients who had ophthalmology and optometry clinical visits at the MEE during the study period were included. Exposures: Telemedicine vs in-person clinical encounters. Main Outcomes and Measures: Variables associated with use of ophthalmic telemedicine during the study period. Results: A total of 2262 telemedicine ophthalmic encounters for 1911 patients were included in the analysis. The median age of the patients was 61 (interquartile range, 43-72) years, and 1179 (61.70%) were women. With regard to race and ethnicity, 87 patients (4.55%) identified as Asian; 128 (6.70%), as Black or African American; 23 (1.20%), as Hispanic or Latino; and 1455 (76.14%), as White. On multivariate analysis, factors associated with decreased receipt of telemedical care included male sex (odds ratio [OR], 0.86; 95% CI, 0.77-0.96), Black race (OR, 0.69; 95% CI, 0.56-0.86), not speaking English (OR, 0.63; 95% CI, 0.48-0.81), educational level of high school or less (OR, 0.83; 95% CI, 0.71-0.97), and age (OR per year of age, 0.99; 95% CI, 0.989-0.998). When comparing telephone- and video-based telemedicine visits, decreased participation in video-based visits was associated with age (OR per year of age, 0.96; 95% CI, 0.94-0.98), educational level of high school or less (OR, 0.54; 95% CI, 0.29-0.99), being unemployed (OR, 0.28; 95% CI, 0.12-0.68), being retired (OR, 0.22; 95% CI, 0.10-0.42), or having a disability (OR, 0.09; 95% CI, 0.04-0.23). Conclusions and Relevance: The findings of this cross-sectional study, though limited to retrospective data from a single university-based practice, suggest that historically marginalized populations were less likely to receive ophthalmic telemedical care compared with in-person care during the first year of the COVID-19 pandemic in the US. Understanding the causes of these disparities might help those who need access to virtual care.
Ba-Abbad R, Leys M, Wang X, Chakarova C, Waseem N, Carss KJ, Raymond LF, Bujakowska KM, Pierce EA, Mahroo OA, Mohamed MD, Holder GE, Hummel M, Arno G, Webster AR. Clinical Features of a Retinopathy Associated With a Dominant Allele of the RGR Gene. Invest Ophthalmol Vis Sci 2018;59(12):4812-4820.Abstract
Purpose: We describe the clinical features in two pedigrees with dominantly inherited retinopathy segregating the previously reported frameshifting mutation, c.836dupG (p.Ile280Asn*78) in the terminal exon of the RGR gene, and compare their haplotypes to that of the previously reported pedigree. Methods: The probands were ascertained at West Virginia University Eye Institute (WVU) and Moorfields Eye Hospital (MEH) through next generation sequencing (NGS) and whole genome sequencing (WGS) respectively. Clinical data included visual acuity (VA), visual fields, fundus autofluorescence (FAF), optical coherence tomography (OCT), and electroretinography (ERG). Haplotype analysis was performed using Sanger sequencing of the DNA from the molecularly ascertained individuals from the three pedigrees. Results: Nine heterozygous mutation carriers were identified in two families. Four carriers were asymptomatic; five carriers had variable VA reduction, visual field constriction, and experienced difficulty under dim illumination. Fundus examination of the asymptomatic carriers showed diffuse or reticular pigmentation of the retina; the symptomatic carriers had chorioretinal atrophy. FAF imaging showed widespread signal loss in advanced retinopathy, and reticular hyperautofluorescence in mild cases. OCT showed loss of outer retinal lamina in advanced disease. ERG showed moderate-to-severe rod-cone dysfunction in two symptomatic carriers; and was normal in three asymptomatic carriers. A shared haplotype flanking the mutation of up to 6.67 Mb was identified in both families. Within this region, 1.27 Mb were shared with the first family reported with this retinopathy. Conclusions: The clinical data suggest a variable and slow degeneration of the RPE. A shared chromosomal segment surrounding the RGR gene suggests a single ancestral mutational event underlying all three families.
Bagdonaite-Bejarano L, Hansen RM, Fulton AB. Microperimetry in Three Inherited Retinal Disorders. Semin Ophthalmol 2019;:1-6.Abstract
Microperimetry (MP) is used to assess visual sensitivity mediated by the central retina. As such, MP performance is a candidate outcome measure for gene therapy trials. Herein, we review MP results in three inherited retinal disorders for which gene therapy trials have been initiated-choroideremia, Stargardt disease, and X-linked juvenile retinoschisis. Each of these disorders typically presents in childhood and each has distinct effects on the central retina. Our review indicates that microperimetry is feasible in each of these conditions. The MP sensitivity maps vary among conditions consistent with known effects of each of the three conditions. There is, however, within each of the three disorders considerable variability in fixation stability and in the pattern of sensitivity loss. Microperimetry is a valuable tool for monitoring functional aspects of central retina in an individual patient, especially in combination with other modalities such as OCT, autofluorescence, and acuity and thus may contribute to evaluating the efficacy of gene treatments. Variability of the MP parameters raises some cautions in application of MP as an outcome measure in treatment trials that may have small sample sizes. Nonetheless, we suspect that MP will continue to have a rightful place in future gene therapy trials.