October 2021

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.
Kolomeyer NN, Katz LJ, Hark LA, Wahl M, Gajwani P, Aziz K, Myers JS, Friedman DS. Lessons Learned From 2 Large Community-based Glaucoma Screening Studies. J Glaucoma 2021;30(10):875-877.Abstract
Community-based screening programs have had limited success in preventing vision loss from glaucoma due to overall low prevalence of glaucoma, screening limitations, and barriers to follow-up appointments. This editorial highlights lessons learned from 2 large prospective trials: the Philadelphia Telemedicine Glaucoma Detection and Follow-up Study and the Screening To Prevent Glaucoma Study. While some lessons are specific to ophthalmology, many lessons are applicable to screening for asymptomatic diseases in underserved, vulnerable communities.
Shi L, Yuan T, Fan S, Zheng J, Diao Y, Qin G, Liu D, Zhu G, Qin K, Liu H, Zhang H, Yang A, Meng F, Zhang J. Comparison of cognitive performance between patients with Parkinson's disease and dystonia using an intraoperative recognition memory test. Sci Rep 2021;11(1):20724.Abstract
Neuroscientific studies on the function of the basal ganglia often examine the behavioral performance of patients with movement disorders, such as Parkinson's disease (PD) and dystonia (DT), while simultaneously examining the underlying electrophysiological activity during deep brain stimulation surgery. Nevertheless, to date, there have been no studies comparing the cognitive performance of PD and DT patients during surgery. In this study, we assessed the memory function of PD and DT patients with the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). We also tested their cognitive performance during the surgery using a continuous recognition memory test. The results of the MoCA and MMSE failed to reveal significant differences between the PD and DT patients. Additionally, no significant difference was detected by the intraoperative memory test between the PD and DT patients. The intraoperative memory test scores were highly correlated with the MMSE scores and MoCA scores. Our data suggest that DT patients perform similarly to PD patients in cognitive tests during surgery, and intraoperative memory tests can be used as a quick memory assessment tool during surgery.
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.
Jung J-H, Kurukuti NM, Peli E. Photographic Depiction of the Field of View with Spectacles-mounted Low Vision Aids. Optom Vis Sci 2021;98(10):1210-1226.Abstract
SIGNIFICANCE: Photographic depiction helps to illustrate the primary and secondary field of view effects of low vision devices along with their utility to clinicians, patients, and caretakers. This technique may also be helpful for designers and researchers in improving the design and fitting of low vision devices. PURPOSE: The field of view through spectacles-mounted low vision devices has typically been evaluated using perimetry. However, the perimetric field diagram is different from the retinal image and often fails to represent the important aspects of the field of view and visual parameters. We developed a photographic depiction method to record and veridically show the field of view effects of these devices. METHODS: We used a 3D-printed holder to place spectacles-mounted devices at the same distance from the empirically determined reference point of the field of view in a camera lens (f = 16 mm) as they would be from an eye, when in use. The field of view effects of a bioptic telescope, a minifier (reverse telescope), and peripheral prisms were captured using a conventional camera, representing retinal images. The human eye pupil size (adjusting the F number: f/2.8 to f/8 and f/22 in the camera lens) and fitting parameters (pantoscopic tilt and back vertex distance) varied. RESULTS: Real-world indoor and outdoor walking and driving scenarios were depicted as retinal images illustrating the field of view through low vision devices, distinguishing optical and obscuration scotomas, and demonstrating secondary effects (spatial distortions, viewpoint changes, diplopia, spurious reflection, and multiplexing effects) not illustrated by perimetric field diagrams. CONCLUSIONS: Photographic depiction illustrates the primary and secondary field of view effects of the low vision devices. These images highlight the benefit and possible trade-offs of the low vision devices and may be beneficial in education and training.
Wolff D, Radojcic V, Lafyatis R, Cinar R, Rosenstein RK, Cowen EW, Cheng G-S, Sheshadri A, Bergeron A, Williams KM, Todd JL, Teshima T, Cuvelier GDE, Holler E, McCurdy SR, Jenq RR, Hanash AM, Jacobsohn D, Santomasso BD, Jain S, Ogawa Y, Steven P, Luo ZK, Dietrich-Ntoukas T, Saban D, Bilic E, Penack O, Griffith LM, Cowden M, Martin PJ, Greinix HT, Sarantopoulos S, Socie G, Blazar BR, Pidala J, Kitko CL, Couriel DR, Cutler C, Schultz KR, Pavletic SZ, Lee SJ, Paczesny S. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report. Transplant Cell Ther 2021;27(10):817-835.Abstract
Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.
Hellström A, Pivodic A, Gränse L, Lundgren P, Sjöbom U, Nilsson AK, Söderling H, Hård A-L, Smith LEH, Löfqvist CA. Association of Docosahexaenoic Acid and Arachidonic Acid Serum Levels With Retinopathy of Prematurity in Preterm Infants. JAMA Netw Open 2021;4(10):e2128771.Abstract
Importance: Supplementing preterm infants with long-chain polyunsaturated fatty acids (LC-PUFA) has been inconsistent in reducing the severity and incidence of retinopathy of prematurity (ROP). Furthermore, few studies have measured the long-term serum lipid levels after supplementation. Objective: To assess whether ROP severity is associated with serum levels of LC-PUFA, especially docosahexaenoic acid (DHA) and arachidonic acid (AA), during the first 28 postnatal days. Design, Setting, and Participants: This cohort study analyzed the Mega Donna Mega study, a randomized clinical trial that provided enteral fatty acid supplementation at 3 neonatal intensive care units in Sweden. Infants included in this cohort study were born at a gestational age of less than 28 weeks between December 20, 2016, and August 6, 2019. Main Outcomes and Measures: Severity of ROP was classified as no ROP, mild or moderate ROP (stage 1-2), or severe ROP (stage 3 and type 1). Serum phospholipid fatty acids were measured through gas chromatography-mass spectrometry. Ordinal logistic regression, with a description of unadjusted odds ratio (OR) as well as gestational age- and birth weight-adjusted ORs and 95% CIs, was used. Areas under the curve were used to calculate mean daily levels of fatty acids during postnatal days 1 to 28. Blood samples were obtained at the postnatal ages of 1, 3, 7, 14, and 28 days. Results: A total of 175 infants were included in analysis. Of these infants, 99 were boys (56.6%); the median (IQR) gestational age was 25 weeks 5 days (24 weeks 3 days to 26 weeks 6 days), and the median (IQR) birth weight was 785 (650-945) grams. A higher DHA proportion was seen in infants with no ROP compared with those with mild or moderate ROP or severe ROP (OR per 0.5-molar percentage increase, 0.49 [95% CI, 0.36-0.68]; gestational age- and birth weight-adjusted OR, 0.66 [95% CI, 0.46-0.93]). The corresponding adjusted OR for AA levels per 1-molar percentage increase was 0.83 (95% CI, 0.66-1.05). The association between DHA levels and ROP severity appeared only in infants with sufficient AA levels, suggesting that a mean daily minimum level of 7.8 to 8.3 molar percentage of AA was necessary for a detectable association between DHA level and less severe ROP. Conclusions and Relevance: This cohort study found that higher mean daily serum levels of DHA during the first 28 postnatal days were associated with less severe ROP even after adjustment for known risk factors, but only in infants with sufficiently high AA levels. Further studies are needed to identify LC-PUFA supplementation strategies that may prevent ROP and other morbidities.
Prakalapakorn GS, Weinert MC, Stinnett SS. Photographic assessment of eyelid position using a simple measurement tool paired with cell phone photography in a pediatric population. J AAPOS 2021;Abstract
PURPOSE: This proof-of-concept study evaluates the ability to assess eyelid measurements and the reproducibility of eyelid measurements using a simple measurement tool paired with digital cell phone photography in children. METHODS: Seventy consecutive patients and their siblings, 2-19 years of age, were prospectively enrolled. Participants underwent clinical examination and cell phone photography with a simple measurement tool. An ophthalmologist and nonophthalmologist assessed photographs for interpalpebral fissure distance (IPFD), margin reflex distance-1 (MRD1), and levator function (LF). Clinical examinations and photographs were repeated on the same day in a random sample (n = 20). The agreement of grading photographs compared to clinical examination was assessed using Bland-Altman plots. Intra-grader repeatability of the clinical examination, repeatability of photographic technique, and interobserver reproducibility of photographic assessment was evaluated with intraclass correlation coefficients (ICC). RESULTS: Of photographs acquired, both graders considered quality good/fair in 100% to assess IPFD and MRD1, and 70% to assess LF. The mean difference (limits of agreement) in mm between clinical examination and photographic assessment was 1.1 (-1.5 to 3.8) for IPFD, 0.7 (-1.8 to 3.1) for MRD1, and 1.1 (-3.5 to 5.7) for LF. Intraobserver repeatability on clinical examination was excellent for IPFD (ICC = 0.81), MRD1 (ICC = 0.88), and LF (ICC = 0.94). Repeatability of photographic technique was fair for IPFD (ICC = 0.44) and good for MRD1 (ICC = 0.74) and LF (ICC = 0.77). Interobserver photographic assessment repeatability was excellent for IPFD (ICC = 0.94), MRD1 (ICC = 0.96), and LF (ICC = 0.92). CONCLUSIONS: Photographic assessment of eyelid measurements in children is possible, highly reproducible between graders, and enables documentation for future comparison.
E J-Y, Mihailovic A, Schrack JA, Garzon C, Li T, Friedman DS, West SK, Gitlin LN, Ramulu PY. Longitudinal changes in daily patterns of objectively measured physical activity after falls in older adults with varying degrees of glaucoma. EClinicalMedicine 2021;40:101097.Abstract
Background: Visually impaired older adults have a greater risk of falling, making them particularly susceptible to fall-related health consequences and restricted physical activity. Unclear however, is the relationship between having falls and longitudinal changes in daily patterns of objectively measured physical activity in older adults with visual impairments. Methods: We created a three-year prospective cohort study (Falls in Glaucoma Study) of older adults with primary or suspected glaucoma at the Johns Hopkins Wilmer Eye Institute from 2013 to 2015. Cumulative incidence of falls was determined through self-reported fall calendars over 12 months. Participants were then classified into one of three groups: multiple fallers (≥2 falls), single fallers (1 fall), and non-fallers (0). Daily physical activity was measured over 1 week using a waist-bound accelerometer during baseline and three-year follow-ups. Activity fragmentation was defined as the reciprocal of the mean activity bout length, with higher fragmentation reflecting shorter, more fractured bouts of continuous activity. Multivariate linear mixed-effects models were used to assess three-year longitudinal changes in: 1) activity fragmentation, and 2) accumulation of activity across six three-hour intervals from 5 AM to 11 PM. Findings: In adjusted models accounting for visual field damage and other factors, multiple fallers demonstrated greater annual declines (per year) in daily active bouts (-1.79 bouts/day, 95% confidence interval [CI]: -3.35, -0.22), daily active minutes (-17.15 min/day, 95% CI: -26.35, -7.94), and increased fragmentation (1%, 95% CI: 0, 2%) over the three-year follow-up period as compared to non-fallers; no such changes were seen when comparing single fallers and non-fallers. In time-of-day analyses, multiple fallers experienced greater annual declines in average hourly steps over all periods of the day, though the rate of decline was only significant between 5 PM and 8 PM (-27.07 steps/hour, 95% CI: -51.15, -2.99) compared to non-fallers. Interpretation: In an older population with visual impairment, multiple falls over 12 months were associated with more transient and fragmented activity over a subsequent three-year period, and activity declines during evening hours, compared to non-fallers. These findings suggest that multiple fallers with visual impairment may be at high risk for a decline in physical capacity and endurance, warranting clinical interventions. Funding: The research was supported in part by National Institutes of Health Grant EY022976.
Crespo-Treviño RR, Salinas-Sánchez AK, Amparo F, Garza-Leon M. Comparative of meibomian gland morphology in patients with evaporative dry eye disease versus non-dry eye disease. Sci Rep 2021;11(1):20729.Abstract
Many recent studies have showed that morphological changes are one of the key signs of meibomian gland disease (MGD). These changes can be seen even before symptom onset, potentially underestimating the prevalence of MGD; however, until now, there is no conclusive information about the impact of meibomian gland (MG) morphology in tear film physiology and disease. This study aimed to investigate the prevalence of anatomical and morphological MG alterations between patients with evaporative dry eye disease (DED) and healthy controls. Retrospective chart review of seventy-five patients with evaporative DED and healthy individuals who had dry eye assessments included Ocular Surface Disease Index questionnaire, meibum quality, meibum expressibility, lid margin abnormality, ocular staining, non-invasive tear film break-up time, and meibography. We did not find significant differences in MG alterations in the upper lid between healthy and DED subjects. Patients with evaporative DED presented MG alterations in the lower lid more frequently than healthy subjects (54.8 vs. 30.3%; p = 0.03). The presence of shortened glands was the only MG alteration that was more prevalent in the lower lid in dry-eye patients than in healthy subjects (p < 0.05). Subjects with evaporative DED presented more alterations in the lower lid than healthy subjects.
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.
Bennett CR, Bauer CM, Bex PJ, Bottari D, Merabet LB. Visual search performance in cerebral visual impairment is associated with altered alpha band oscillations. Neuropsychologia 2021;161:108011.Abstract
Individuals with cerebral visual impairment (CVI) often present with deficits related to visuospatial processing. However, the neurophysiological basis underlying these higher order perceptual dysfunctions have not been clearly identified. We assessed visual search performance using a novel virtual reality based task paired with eye tracking to simulate the exploration of a naturalistic scene (a virtual toy box). This was combined with electroencephalography (EEG) recordings and an analysis pipeline focusing on time frequency decomposition of alpha oscillatory activity. We found that individuals with CVI showed an overall impairment in visual search performance (as indexed by decreased success rate, as well as increased reaction time, visual search area, and gaze error) compared to controls with neurotypical development. Analysis of captured EEG activity following stimulus onset revealed that in the CVI group, there was a distinct lack of strong and well defined posterior alpha desynchronization; an important signal involved in the coordination of neural activity related to visual processing. Finally, an exploratory analysis revealed that in CVI, the magnitude of alpha desynchronization was associated with impaired visual search performance as well as decreased volume of specific thalamic nuclei implicated in visual processing. These results suggest that impairments in visuospatial processing related to visual search in CVI are associated with alterations in alpha band oscillations as well as early neurological injury at the level of visual thalamic nuclei.
Neitzel AJ, Wolf B, Guo X, Shakarchi AF, Madden NA, Repka MX, Friedman DS, Collins ME. Effect of a Randomized Interventional School-Based Vision Program on Academic Performance of Students in Grades 3 to 7: A Cluster Randomized Clinical Trial. JAMA Ophthalmol 2021;139(10):1104-1114.Abstract
Importance: Uncorrected refractive error in school-aged children may affect learning. Objective: To assess the effect of a school-based vision program on academic achievement among students in grades 3 to 7. Design, Setting, and Participants: This cluster randomized clinical trial was conducted in Baltimore City Public Schools during school years from 2016 to 2019 among 2304 students in grades 3 to 7 who received eye examinations and eyeglasses. Intervention: Participating schools were randomized 1:1:1 to receive eye examinations and eyeglasses during 1 of 3 school years (2016-2017, 2017-2018, and 2018-2019). Main Outcomes and Measures: The primary outcome was 1-year intervention impact, measured by effect size (ES), defined as the difference in score on an academic test (i-Ready or Partnership for Assessment of Readiness for College and Careers tests on reading and mathematics) between intervention and control groups measured in SD units, comparing cohort 1 (intervention) with cohorts 2 and 3 (control) at the end of program year 1 and comparing cohort 2 (intervention) with cohort 3 (control) at the end of program year 2. The secondary outcome was 2-year intervention impact, comparing ES in cohort 1 (intervention) with cohort 3 (control) at the end of program year 2. Hierarchical linear modeling was used to assess the impact of the intervention. Analysis was performed on an intention-to-treat basis. Results: Among the 2304 students included in the study, 1260 (54.7%) were girls, with a mean (SD) age of 9.4 (1.4) years. The analysis included 964 students (41 schools) in cohort 1, 775 students (41 schools) in cohort 2, and 565 students (38 schools) in cohort 3. There were 1789 Black students (77.6%), 388 Latinx students (16.8%), and 406 students in special education (17.6%). There was an overall 1-year positive impact (ES, 0.09; P = .02) as assessed by the i-Ready reading test during school year 2016-2017. Positive impact was also observed among female students (ES, 0.15; P < .001), those in special education (ES, 0.25; P < .001), and students who performed in the lowest quartile at baseline (ES, 0.28; P < .001) on i-Ready reading and among students in elementary grades on i-Ready mathematics (ES, 0.03; P < .001) during school year 2016-2017. The intervention did not show a sustained impact at 2 years or on Partnership for Assessment of Readiness for College and Careers testing. Conclusions and Relevance: Students in grades 3 to 7 who received eyeglasses through a school-based vision program achieved better reading scores. Students had improved academic achievement over 1 year; however, a sustained impact was not observed after 2 years. Trial Registration: The Registry of Efficacy and Effectiveness Studies Identifier: 1573.1v1.

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