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Comin CH, Tsirukis DI, Sun Y, Xu X. Quantification of retinal blood leakage in fundus fluorescein angiography in a retinal angiogenesis model. Sci Rep 2021;11(1):19903.Abstract
Blood leakage from the vessels in the eye is the hallmark of many vascular eye diseases. One of the preclinical mouse models of retinal blood leakage, the very-low-density-lipoprotein receptor deficient mouse (Vldlr-/-), is used for drug screening and mechanistic studies. Vessel leakage is usually examined using Fundus fluorescein angiography (FFA). However, interpreting FFA images of the Vldlr-/- model is challenging as no automated and objective techniques exist for this model. A pipeline has been developed for quantifying leakage intensity and area including three tasks: (i) blood leakage identification, (ii) blood vessel segmentation, and (iii) image registration. Morphological operations followed by log-Gabor quadrature filters were used to identify leakage regions. In addition, a novel optic disk detection algorithm based on graph analysis was developed for registering the images at different timepoints. Blood leakage intensity and area measured by the methodology were compared to ground truth quantifications produced by two annotators. The relative difference between the quantifications from the method and those obtained from ground truth images was around 10% ± 6% for leakage intensity and 17% ± 8% for leakage region. The Pearson correlation coefficient between the method results and the ground truth was around 0.98 for leakage intensity and 0.94 for leakage region. Therefore, we presented a computational method for quantifying retinal vascular leakage and vessels using FFA in a preclinical angiogenesis model, the Vldlr-/- model.
Gao Q, Ludwig CA, Smith SJ, Schachar IH. Ocular Penetrance and Safety of the Dopaminergic Prodrug Etilevodopa. Transl Vis Sci Technol 2021;10(12):5.Abstract
Purpose: Animal models have demonstrated the role of dopamine in regulating axial elongation, the critical feature of myopia. Because frequent delivery of dopaminergic agents via peribulbar, intravitreal, or intraperitoneal injections is not clinically viable, we sought to evaluate ocular penetration and safety of the topically applied dopaminergic prodrug etilevodopa. Methods: The ocular penetration of dopamine and dopaminergic prodrugs (levodopa and etilevodopa) were quantified using an enzyme-linked immunosorbent assay in enucleated porcine eyes after a single topical administration. The pharmacokinetic profile of the etilevodopa was then assessed in rats. A four-week once-daily application of etilevodopa as a topical eye drop was conducted to establish its safety profile. Results: At 24 hours, the studied prodrugs showed increased dopaminergic derivatives in the vitreous of porcine eyes. Dopamine 0.5% (P = 0.0123) and etilevodopa 10% (p = 0.370) achieved significant vitreous concentrations. Etilevodopa 10% was able to enter the posterior segment of the eye after topical administration in rats with an intravitreal half-life of eight hours after single topical administration. Monthly application of topical etilevodopa showed no alterations in retinal ocular coherence tomography, electroretinography, caspase staining, or TUNEL staining. Conclusions: At similar concentrations, no difference in ocular penetration of levodopa and etilevodopa was observed. However, etilevodopa was highly soluble and able to be applied at higher topical concentrations. Dopamine exhibited both high solubility and enhanced penetration into the vitreous as compared to other dopaminergic prodrugs. Translational Relevance: These findings indicate the potential of topical etilevodopa and dopamine for further study as a therapeutic treatment for myopia.
Whitman MC, Barry BJ, Robson CD, Facio FM, Van Ryzin C, Chan W-M, Lehky TJ, Thurm A, Zalewski C, King KA, Brewer C, Almpani K, Lee JS, Delaney A, FitzGibbon EJ, Lee PR, Toro C, Paul SM, Abdul-Rahman OA, Webb BD, Jabs EW, Moller HU, Larsen DA, Antony JH, Troedson C, Ma A, Ragnhild G, Wirgenes KV, Tham E, Kvarnung M, Maarup TJ, MacKinnon S, Hunter DG, Collins FS, Manoli I, Engle EC. TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy. Hum Genet 2021;140(12):1709-1731.Abstract
Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.
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 2021;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 2021;Abstract
PURPOSE: Evaluate differences in eyecare utilization among glaucoma patients by race and socioeconomic status (SES). DESIGN: Retrospective cohort study. SUBJECTS: Representative 5% sample of Medicare beneficiaries >65 years with continuous part A/B enrollment between 1/1/2014 and 7/1/2014, at least one diagnosis code for glaucoma within that period, and a glaucoma diagnosis in the Chronic Conditions Warehouse before 1/1/2014. 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 two 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 (RR) of eye care utilization among racial groups, stratified by low- and non-low-SES. MAIN OUTCOME MEASURES: Measured from 7/1/2014-12/31/2016: eye examinations and eye care-related office visits; eye care-related inpatient and ED encounters; eye care-related nursing home and home-visit encounters; visual field and retinal nerve fiber optical coherence tomography tests; glaucoma lasers and surgeries. RESULTS: Among 78,526 participants with glaucoma, mean age was 79.1 years (SD 7.9 years), 60.9% were female, 78.4% were non-Hispanic White and 13.8% met enrollment-based criteria for low-SES. Compared to White beneficiaries, Blacks had lower counts of outpatient visits (rate ratio [RR] 0.92, 95% CI 0.90-0.93), 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 1.03-1.7). Hispanics had fewer outpatient visits (RR 0.97, 95% CI 0.95-0.98) and 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 SLT (RR 1.25, 95% CI 1.11-1.42) vs. non-Hispanic Whites. In the non-low-SES group, Black vs. 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 glaucoma patients. These differences persisted among Blacks after stratification by SES, suggesting systemic racism may be an independent driver in this population.
Chinn RN, Raghuram A, Curtiss M, Gehring A, 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 2021;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 of 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 (ICC) 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 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 to 0.45 D; Eye 2: LOA = -0.66 D to 0.67 D). ICC 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 is obtained in amblyopic eyes to improve the precision of measures.
Teran E, Ramírez-Jaime R, Martínez-Gaytán C, Romo-García E, Costela FM. Refractive Error of Students (15- to 18-year-olds) in Northwest Mexico. Optom Vis Sci 2021;98(10):1127-1131.Abstract
SIGNIFICANCE: We assessed the prevalence of refractive error in a sample of children of Northern Mexico using the Refractive Error Study in Children protocol of the World Health Organization, which allows for the comparison with other global studies. PURPOSE: Uncorrected refractive error is the main cause of visual impairment in children. The purpose of this study was to assess the refractive error and visual dysfunctions of students (15 to 18 years old) in the upper-middle school system of Sinaloa, Mexico. METHODS: A total of 3468 students in Sinaloa's high school system participated in the study from 2017 to 2019. Optometrists and student clinicians from the Optometry Program of the Autonomous University of Sinaloa conducted the testing. Tests included visual acuities and static retinoscopy. We did not use a cycloplegic agent. RESULTS: The results showed a high prevalence of uncorrected refractive errors. Myopia, defined as a refractive error ≤-0.50 D, had a prevalence of 36.11% (95% confidence interval, 33.47 to 38.83%); hyperopia, defined as a refractive error ≥+2.00 D, had a prevalence of 1.49% (95% confidence interval, 0.09 to 2.33%); and astigmatism, defined as a refractive error with a cylinder ≥0.75 D, had a prevalence of 29.17% (95% confidence interval, 26.60 to 31.76%). We found a significant effect of sex on visual acuity. CONCLUSIONS: Our results are consistent with a high prevalence of myopia reported in adolescents worldwide and in Mexico's northern regions. The results suggest that students attending high school and entering universities should be required to have an optometric eye examination. Additional studies are needed to investigate the prevalence of refractive errors in children in Mexico.
Cui Y, Zhu Y, Lu ES, Le R, Laíns I, Katz R, Wang JC, Garg I, Lu Y, Zeng R, Eliott D, Vavvas DG, Husain D, Miller JW, Kim LA, Wu DM, Miller JB. Widefield Swept-Source OCT Angiography Metrics Associated with the Development of Diabetic Vitreous Hemorrhage: A Prospective Study. Ophthalmology 2021;128(9):1312-1324.Abstract
PURPOSE: To investigate the association among widefield swept-source (SS) OCT angiography (OCTA) metrics and systemic parameters and vitreous hemorrhage (VH) occurrence in eyes with proliferative diabetic retinopathy (PDR). DESIGN: Prospective, observational study. PARTICIPANTS: Fifty-five eyes from 45 adults with PDR, with no history of VH, followed up for at least 3 months. METHODS: All patients underwent widefield SS OCTA (Montage 15 × 15 mm and high-definition (HD)-51 line scan) imaging. Images were evaluated independently by 2 graders for quantitative and qualitative widefield SS OCTA metrics defined a priori. Systemic and ocular parameters and widefield SS OCTA metrics were screened using least absolute shrinkage and selection operator and logistic or Cox regression for variable selection. Firth's bias-reduced logistic regression models (outcome, occurrence of VH) and Cox regression models (outcome, time to occurrence of VH) were used to identify parameters associated with VH occurrence. MAIN OUTCOME MEASURES: Occurrence of VH. RESULTS: Over a median follow-up of 363 days (range, 28-710 days), 13 of 55 PDR eyes (24%) demonstrated VH during the follow-up period. Presence of extensive neovascularizations (odds ratio, 8.05; 95% confidence interval [CI], 1.43-58.56; P = 0.02), defined as neovascularizations with total area of more than 4 disc diameters, and forward neovascularizations (odds ratio, 5.42; 95% CI, 1.26-35.16; P = 0.02) that traversed the posterior hyaloid face into the vitreous were associated with the occurrence of VH. The presence of flat neovascularizations (odds ratio, 0.25; 95% CI, 0.04-1.01; P = 0.05) confined to the posterior hyaloid face was associated with a lower risk of VH with borderline significance. Similarly, presence of extensive neovascularizations (hazard ratio, 18.24; 95% CI, 3.51-119.47; P < 0.001) and forward neovascularizations (hazard ratio, 9.60; 95% CI, 2.07-68.08; P = 0.002) was associated significantly with time to development of VH. CONCLUSIONS: Widefield SS OCTA is useful for evaluating neovascularizations and their relationship with the vitreous. The presence of forward and extensive neovascularizations was associated with the occurrence of VH in patients with PDR. Larger samples and longer follow-up are needed to verify the risk factors and imaging biomarkers for diabetic VH.
Bannai D, Adhan I, Katz R, Kim LA, Keshavan M, Miller JB, Lizano P. Quantifying Retinal Microvascular Morphology in Schizophrenia Using Swept-Source Optical Coherence Tomography Angiography. Schizophr Bull 2021;Abstract
BACKGROUND: Retinovascular changes are reported on fundus imaging in schizophrenia (SZ). This is the first study to use swept-source optical coherence tomography angiography (OCT-A) to comprehensively examine retinal microvascular changes in SZ. METHODS: This study included 30 patients with SZ/schizoaffective disorder (8 early and 15 chronic) and 22 healthy controls (HCs). All assessments were performed at Beth Israel Deaconess Medical Center and Massachusetts Eye and Ear. All participants underwent swept-source OCT-A of right (oculus dextrus [OD]) and left (oculus sinister [OS]) eye, clinical, and cognitive assessments. Macular OCT-A images (6 × 6 mm) were collected with the DRI Topcon Triton for superficial, deep, and choriocapillaris vascular regions. Microvasculature was quantified using vessel density (VD), skeletonized vessel density (SVD), fractal dimension (FD), and vessel diameter index (VDI). RESULTS: Twenty-one HCs and 26 SZ subjects were included. Compared to HCs, SZ patients demonstrated higher overall OD superficial SVD, OD choriocapillaris VD, and OD choriocapillaris SVD, which were primarily observed in the central, central and outer superior, and central and outer inferior/superior, respectively. Early-course SZ subjects had significantly higher OD superficial VD, OD choriocapillaris SVD, and OD choriocapillaris FD compared to matched HCs. Higher bilateral (OU) superficial VD correlated with lower Positive and Negative Syndrome Scale (PANSS) positive scores, and higher OU deep VDI was associated with higher PANSS negative scores. CONCLUSIONS AND RELEVANCE: These results suggest the presence of microvascular dysfunction associated with early-stage SZ. Clinical associations with microvascular alterations further implicate this hypothesis, with higher measures being associated with worse symptom severity and functioning in early stages and with lower symptom severity and better functioning in later stages.
Patel NA, Yannuzzi NA, Lin J, Smiddy WE. A Cost Effectiveness Analysis of Intravitreal Aflibercept for the Prevention of Progressive Diabetic Retinopathy. Ophthalmol Retina 2021;Abstract
PURPOSE: To calculate costs required to prevent center-involved diabetic macular edema (CI-DME) or proliferative diabetic retinopathy (PDR), and to improve the diabetic retinopathy severity score (DRSS) with intravitreal anti-VEGF injections as reported for aflibercept in two randomized control trials. DESIGN: Cost-effectiveness analysis modeling based on published data SUBJECTS: None METHODS: Results from PANORAMA and the Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol W were analyzed. Parameters collected included DRSS score, risk reduction of PDR, risk reduction of CI-DME, and number of treatments required. Costs were modeled based on 2020 Medicare reimbursement data practice settings of hospital-based facility and non-facility. MAIN OUTCOME MEASURE: Cost to prevent case of PDR and CI-DME, and to improve DRSS stage RESULTS: Over 2 years in Protocol W, the cost required to prevent 1 case of PDR was $83,000 ($72,400) in the facility (non-facility) setting; in PANORAMA, the corresponding 2 year costs were $89,400 ($75,000) for the 2Q16 arm, and $91,200 ($89,900) for the 2Q8PRN arm. To prevent 1 case of CI-DME with vision loss in Protocol W, the cost was $154,000 ($133,000). For all CI-DME, with and without vision loss; in PANORAMA, the costs to prevent a case were $70,900 ($59,500) for the 2Q16 arm, and $90,000 ($88,800) for the 2Q8PRN arm. In Protocol W, the overall accumulated total for cost /DRSS unit change at the 2 year point for facility (non-facility) setting was $2700 ($2400)/DRSS. In the first year alone, it was $2100 ($1800)/DRSS and in the second year alone, $6100 ($5300)/DRSS. CONCLUSION: There is a considerable cost associated with the prevention of PDR and CI-DME with intravitreal aflibercept injections. A price per unit of change in diabetic retinopathy severity score is a new parameter which might serve as a benchmark in future utility analyses that could be used to bring perspective to cost-utility considerations.
Townes-Anderson E, Halasz E, Wang W, Zarbin M. Coming of Age for the Photoreceptor Synapse. Invest Ophthalmol Vis Sci 2021;62(12):24.Abstract
Purpose: To discuss the potential contribution of rod and cone synapses to the loss of visual function in retinal injury and disease. Methods: The published literature and the authors' own work were reviewed. Results: Retinal detachment is used as a case study of rod spherule and cone pedicle plasticity after injury. Both rod and cone photoreceptors terminals are damaged after detachment although the structural changes observed are only partially overlapping. For second-order neurons, only those associated with rod spherules respond consistently to injury by remodeling. Examination of signaling pathways involved in plasticity of conventional synapses and in neural development has been and may continue to be productive in discovering novel therapeutic targets. Rho kinase (ROCK) inhibition is an example of therapy that may reduce synaptic damage by preserving normal synaptic structure of rod and cone cells. Conclusions: We hypothesize that synaptic damage contributes to poor visual restoration after otherwise successful anatomical repair of retinal detachment. A similar situation may exist for patients with degenerative retinal disease. Thus, synaptic structure and function should be routinely studied, as this information may disclose therapeutic strategies to mitigate visual loss.

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