April 2021

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Sharifi S, Islam MM, Sharifi H, Islam R, Huq TN, Nilsson PH, Mollnes TE, Tran KD, Patzer C, Dohlman CH, Patra HK, Paschalis EI, Gonzalez-Andrades M, Chodosh J. Electron Beam Sterilization of Poly(Methyl Methacrylate)-Physicochemical and Biological Aspects. Macromol Biosci 2021;21(4):e2000379.Abstract
Electron beam (E-beam) irradiation is an attractive and efficient method for sterilizing clinically implantable medical devices made of natural and/or synthetic materials such as poly(methyl methacrylate) (PMMA). As ionizing irradiation can affect the physicochemical properties of PMMA, understanding the consequences of E-beam sterilization on the intrinsic properties of PMMA is vital for clinical implementation. A detailed assessment of the chemical, optical, mechanical, morphological, and biological properties of medical-grade PMMA after E-beam sterilization at 25 and 50 kiloGray (kGy) is reported. Fourier transform infrared spectroscopy, thermogravimetric analysis, and differential scanning calorimetry studies indicate that E-beam irradiation has minimal effect on the chemical properties of the PMMA at these doses. While 25 kGy irradiation does not alter the mechanical and optical properties of the PMMA, 50 kGy reduces the flexural strength and transparency by 10% and 2%, respectively. Atomic force microscopy demonstrates that E-beam irradiation reduces the surface roughness of PMMA in a dose dependent manner. Live-Dead, AlamarBlue, immunocytochemistry, and complement activation studies show that E-beam irradiation up to 50 kGy has no adverse effect on the biocompatibility of the PMMA. These findings suggest that E-beam irradiation at 25 kGy may be a safe and efficient alternative for PMMA sterilization.
Shuldiner SR, Boland MV, Ramulu PY, De Moraes GC, Elze T, Myers J, Pasquale L, Wellik S, Yohannan J. Predicting eyes at risk for rapid glaucoma progression based on an initial visual field test using machine learning. PLoS One 2021;16(4):e0249856.Abstract
OBJECTIVE: To assess whether machine learning algorithms (MLA) can predict eyes that will undergo rapid glaucoma progression based on an initial visual field (VF) test. DESIGN: Retrospective analysis of longitudinal data. SUBJECTS: 175,786 VFs (22,925 initial VFs) from 14,217 patients who completed ≥5 reliable VFs at academic glaucoma centers were included. METHODS: Summary measures and reliability metrics from the initial VF and age were used to train MLA designed to predict the likelihood of rapid progression. Additionally, the neural network model was trained with point-wise threshold data in addition to summary measures, reliability metrics and age. 80% of eyes were used for a training set and 20% were used as a test set. MLA test set performance was assessed using the area under the receiver operating curve (AUC). Performance of models trained on initial VF data alone was compared to performance of models trained on data from the first two VFs. MAIN OUTCOME MEASURES: Accuracy in predicting future rapid progression defined as MD worsening more than 1 dB/year. RESULTS: 1,968 eyes (8.6%) underwent rapid progression. The support vector machine model (AUC 0.72 [95% CI 0.70-0.75]) most accurately predicted rapid progression when trained on initial VF data. Artificial neural network, random forest, logistic regression and naïve Bayes classifiers produced AUC of 0.72, 0.70, 0.69, 0.68 respectively. Models trained on data from the first two VFs performed no better than top models trained on the initial VF alone. Based on the odds ratio (OR) from logistic regression and variable importance plots from the random forest model, older age (OR: 1.41 per 10 year increment [95% CI: 1.34 to 1.08]) and higher pattern standard deviation (OR: 1.31 per 5-dB increment [95% CI: 1.18 to 1.46]) were the variables in the initial VF most strongly associated with rapid progression. CONCLUSIONS: MLA can be used to predict eyes at risk for rapid progression with modest accuracy based on an initial VF test. Incorporating additional clinical data to the current model may offer opportunities to predict patients most likely to rapidly progress with even greater accuracy.
Singh RB, Blanco T, Mittal SK, Alemi H, Chauhan SK, Chen Y, Dana R. Pigment Epithelium-Derived Factor Enhances the Suppressive Phenotype of Regulatory T Cells in a Murine Model of Dry Eye Disease. Am J Pathol 2021;191(4):720-729.Abstract
Pigment epithelium-derived factor (PEDF) is a widely expressed 50-kDa glycoprotein belonging to the serine protease inhibitor family, with well-established anti-inflammatory functions. Recently, we demonstrated the immunoregulatory role played by PEDF in dry eye disease (DED) by suppressing the maturation of antigen-presenting cells at the ocular surface following exposure to the desiccating stress. In this study, we evaluated the effect of PEDF on the immunosuppressive characteristics of regulatory T cells (Tregs), which are functionally impaired in DED. In the presence of PEDF, the in vitro cultures prevented proinflammatory cytokine (associated with type 17 helper T cells)-induced loss of frequency and suppressive phenotype of Tregs derived from normal mice. Similarly, PEDF maintained the in vitro frequency and enhanced the suppressive phenotype of Tregs derived from DED mice. On systemically treating DED mice with PEDF, moderately higher frequencies and significantly enhanced suppressive function of Tregs were observed in the draining lymphoid tissues, leading to the efficacious amelioration of the disease. Our results demonstrate that PEDF promotes the suppressive capability of Tregs and attenuates their type 17 helper T-cell-mediated dysfunction in DED, thereby playing a role in the suppression of DED.
Singh N, Singh R, Bowen RC, Abdel-Rahman MH, Singh AD. Uveal Melanoma in BAP1 Tumor Predisposition Syndrome: Estimation of Risk. Am J Ophthalmol 2021;224:172-177.Abstract
PURPOSE: To estimate point prevalence of uveal melanoma in the patients with germline BAP1 pathogenic variant. DESIGN: Cohort study with risk assessment using Bayesian analysis. METHODS: The point prevalence estimate was obtained by Bayes's rule of reverse conditional probabilities. The probability of uveal melanoma given that BAP1 mutation exists was derived from the prevalence of uveal melanoma, prevalence of germline BAP1 pathogenic variants, and the probability of germline BAP1 pathogenic variant given that uveal melanoma is present. Confidence intervals (CIs) for each variable were calculated as the mean of Bernoulli random variables and for the risk estimate, by the delta method. The age at diagnosis and the gender of the uveal melanoma patients with BAP1 germline pathogenic variants obtained from previous publications or from authors' unpublished cohort was compared with those in the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: The point prevalence of uveal melanoma in patients with the germline BAP1 pathogenic variants in the US population was estimated to be 2.8% (95% CI, 0.88%-4.81%). In the SEER database, the median age at diagnosis of uveal melanomas was 63 (range 3-99 years) with a male-to-female ratio of 1.01:1. In comparison, uveal melanoma cases with BAP1 germline pathogenic variants from the US population (n = 27) had a median age at diagnosis of 50.5 years (range 16-71). CONCLUSIONS: Quantification of the risk of developing uveal melanoma can enhance counseling regarding surveillance in patients with germline BAP1 pathogenic variant.
Stern-Ascher CN, North VS, Garg A, Ananth CV, Wapner RJ, Bearelly S. Subfoveal Choroidal Thickness and Associated Changes of Angiogenic Factors in Women with Severe Preeclampsia. Am J Perinatol 2021;38(5):482-489.Abstract
OBJECTIVE:  Severe preeclampsia complicates roughly 1% of all pregnancies. One defining feature of severe preeclampsia is new onset visual disturbance. The accessibility of the choroid to high-resolution, noninvasive imaging makes it a reasonable target of investigation for disease prediction, stratification, or monitoring in preeclampsia. This study aimed to compare subfoveal choroidal thickness between women with severe preeclampsia and those with normotensive pregnancies, and to investigate associations between such findings and other indicators of disease severity, including gestational age and serum angiogenic factors. STUDY DESIGN:  We designed a case-control study comprised of 36 women diagnosed with severe preeclampsia (cases) matched to 37 normotensive women (controls) by race/ethnicity and parity, all diagnosed in the postpartum period. All patients underwent enhanced depth imaging spectral-domain optical coherence tomography and serum analysis. RESULTS:  Cases showed no difference in subfoveal choroidal thickness compared with controls ( = 0.65). Amongst cases, subfoveal choroidal thickness and gestational age at delivery were inversely related ( = 0.86,  < .001). There was a positive association of placental growth factor with subfoveal choroidal thickness amongst cases ( = 0.54,  = 0.002). CONCLUSION:  This study suggests a relationship between the degree of disease severity and the magnitude of choroidal thickening. We also show an association between this index and placental growth factor level in the postpartum period.
Subburaman G-BB, Kempen JH, Duraisamy S, Vijayakumar B, Valaguru V, Namperumalsamy VP, Ravilla TD, Gupta S. Response to comments: Making the decision to donate eye organs: Perspectives from the families of the deceased in Madurai, India. Indian J Ophthalmol 2021;69(4):1020-1021.
Swan G, Goldstein RB, Savage SW, Zhang L, Ahmadi A, Bowers AR. Automatic processing of gaze movements to quantify gaze scanning behaviors in a driving simulator. Behav Res Methods 2021;53(2):487-506.Abstract
Eye and head movements are used to scan the environment when driving. In particular, when approaching an intersection, large gaze scans to the left and right, comprising head and multiple eye movements, are made. We detail an algorithm called the gaze scan algorithm that automatically quantifies the magnitude, duration, and composition of such large lateral gaze scans. The algorithm works by first detecting lateral saccades, then merging these lateral saccades into gaze scans, with the start and end points of each gaze scan marked in time and eccentricity. We evaluated the algorithm by comparing gaze scans generated by the algorithm to manually marked "consensus ground truth" gaze scans taken from gaze data collected in a high-fidelity driving simulator. We found that the gaze scan algorithm successfully marked 96% of gaze scans and produced magnitudes and durations close to ground truth. Furthermore, the differences between the algorithm and ground truth were similar to the differences found between expert coders. Therefore, the algorithm may be used in lieu of manual marking of gaze data, significantly accelerating the time-consuming marking of gaze movement data in driving simulator studies. The algorithm also complements existing eye tracking and mobility research by quantifying the number, direction, magnitude, and timing of gaze scans and can be used to better understand how individuals scan their environment.
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Ung L, Jonas JB, Lietman TM, Chodosh J. COVID-19 and the Unfinished Agenda of VISION 2020. Am J Ophthalmol 2021;224:30-35.Abstract
PURPOSE: To critically evaluate the potential impact of the coronavirus disease (COVID-19) pandemic on global ophthalmology and VISION 2020. DESIGN: Perspective supplemented with epidemiologic insights from available online databases. METHODS: We extracted data from the Global Vision Database (2017) and Global Burden of Disease Study (2017) to highlight temporal trends in global blindness since 1990, and provide a narrative overview of how COVID-19 may derail progress toward the goals of VISION 2020. RESULTS: Over 2 decades of VISION 2020 advocacy and program implementation have culminated in a universal reduction of combined age-standardized prevalence of moderate-to-severe vision impairment (MSVI) across all world regions since 1990. Between 1990 and 2017, low-income countries observed large reductions in the age-standardized prevalence per 100,000 persons of vitamin A deficiency (25,155 to 19,187), undercorrected refractive disorders (2,286 to 2,040), cataract (1,846 to 1,690), onchocerciasis (5,577 to 2,871), trachoma (506 to 159), and leprosy (36 to 26). Despite these reductions, crude projections suggest that more than 700 million persons will experience MSVI or blindness by 2050, principally owing to our growing and ageing global population. CONCLUSIONS: Despite the many resounding successes of VISION 2020, the burden of global blindness and vision impairment is set to reach historic levels in the coming years. The impact of COVID-19, while yet to be fully determined, now threatens the hard-fought gains of global ophthalmology. The postpandemic years will require renewed effort and focus on vision advocacy and expanding eye care services worldwide.
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Webb BD, Manoli I, Engle EC, Jabs EW. A framework for the evaluation of patients with congenital facial weakness. Orphanet J Rare Dis 2021;16(1):158.Abstract
There is a broad differential for patients presenting with congenital facial weakness, and initial misdiagnosis unfortunately is common for this phenotypic presentation. Here we present a framework to guide evaluation of patients with congenital facial weakness disorders to enable accurate diagnosis. The core categories of causes of congenital facial weakness include: neurogenic, neuromuscular junction, myopathic, and other. This diagnostic algorithm is presented, and physical exam considerations, additional follow-up studies and/or consultations, and appropriate genetic testing are discussed in detail. This framework should enable clinical geneticists, neurologists, and other rare disease specialists to feel prepared when encountering this patient population and guide diagnosis, genetic counseling, and clinical care.
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Xue Y, Wang SK, Rana P, West ER, Hong CM, Feng H, Wu DM, Cepko CL. AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa. Elife 2021;10Abstract
Retinitis pigmentosa (RP) is an inherited retinal disease affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high-acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a disease gene-agnostic therapy, we screened 20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb) and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism.
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Yang S, Kam WR, Liu Y, Ding J, Li Y, Sullivan DA. Comparative influence of differentiation and proliferation on gene expression in human meibomian gland epithelial cells. Exp Eye Res 2021;205:108452.Abstract
We recently discovered that by changing environmental signals, differentiated immortalized human meibomian gland epithelial cells (IHMGECs) de-differentiate into proliferating cells. We also discovered that following exposure to appropriate stimuli, these proliferative cells re-differentiate into differentiated IHMGECs. We hypothesize that this plasticity of differentiated and proliferative IHMGECs is paralleled by very significant alterations in cellular gene expression. To begin to test this hypothesis, we compared the gene expression patterns of IHMGECs during differentiation and proliferation. IHMGECs were cultured for four days in either differentiating or proliferating media. After four days of culture, cells were processed for the analysis of gene expression by using Illumina BeadChips and bioinformatic software. Our study identified significant differences in the expression of more than 9200 genes in differentiated and proliferative IHMGECs. Differentiation was associated with significant increases in the expression of specific genes (e.g. S100 calcium binding protein P; 7,194,386-fold upregulation) and numerous ontologies (e.g. 83 biological process [bp] ontologies with ≥100 genes were upregulated), such as those related to development, transport and lysosomes. Proliferation also led to a significant rise in specific gene expressions (e.g. cathelicidin antimicrobial peptide; 859,100-fold upregulation) and many ontologies (115 biological process [bp] ontologies with ≥100 genes were upregulated), with most of the highly significant ontologies related to cell cycle (z scores > 13.9). Our findings demonstrate that gene expression in differentiated and proliferative IHMGECs is extremely different. These results may have significant implications for the regeneration of HMGECs and the reversal of MG dropout in MG dysfunction.
Yoon MK, Kelly HR, Freitag SK, Marneros AG, Barshak MB, Brackett DG. Case 12-2021: A 78-Year-Old Man with a Rash on the Scalp and Face. N Engl J Med 2021;384(16):1553-1562.

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