Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.

Optic neuropathy is one of the leading causes of irreversible blindness caused by retinal ganglion cell (RGC) degeneration. The development of induced pluripotent stem cell (iPSC)-based therapy opens a therapeutic window for RGC degeneration, and tissue engineering may further promote the efficiency of differentiation process of iPSCs. The present study was designed to evaluate the effects of a novel biomimetic polybenzyl glutamate (PBG) scaffold on culturing iPSC-derived RGC progenitors. The iPSC-derived neural spheres cultured on PBG scaffold increased the differentiated retinal neurons and promoted the neurite outgrowth in the RGC progenitor layer. Additionally, iPSCs cultured on PBG scaffold formed the organoid-like structures compared to that of iPSCs cultured on cover glass within the same culture period. With RNA-seq, we found that cells of the PBG group were differentiated toward retinal lineage and may be related to the glutamate signaling pathway. Further ontological analysis and the gene network analysis showed that the differentially expressed genes between cells of the PBG group and the control group were mainly associated with neuronal differentiation, neuronal maturation, and more specifically, retinal differentiation and maturation. The novel electrospinning PBG scaffold is beneficial for culturing iPSC-derived RGC progenitors as well as retinal organoids. Cells cultured on PBG scaffold differentiate effectively and shorten the process of RGC differentiation compared to that of cells cultured on coverslip. The new culture system may be helpful in future disease modeling, pharmacological screening, autologous transplantation, as well as narrowing the gap to clinical application.

Immunotherapy is a developing but very promising arsenal to treat cancer. Acquiring a more potent and effective approach in cancer immunotherapy is always the ultimate pursuance. CTL-based therapies are highly acclaimed recently due to its direct killing property. However, difficulty in obtaining adequate number of CTLs is still a major obstacle. In previous studies, it is shown that pluripotent stem cell-derived cytotoxic T lymphocytes (CTL)-especially the genetically engineered tumor antigen-specific CTLs-may serve as a good candidate for this goal. Here we introduce a novel approach in generating tumor antigen-specific CTLs from induced pluripotent stem cells (iPSCs) by using both in vitro and in vivo priming mechanisms for the tumor management in a murine melanoma model.

Purpose: People with central vision loss (CVL) often report difficulties watching video. We objectively evaluated the ability to follow the story (using the information acquisition method). Methods: Subjects with CVL (n = 23) or normal vision (NV, n = 60) described the content of 30-second video clips from movies and documentaries. We derived an objective information acquisition (IA) score for each response using natural-language processing. To test whether the impact of CVL was simply due to reduced resolution, another group of NV subjects (n = 15) described video clips with defocus blur that reduced visual acuity to 20/50 to 20/800. Mixed models included random effects correcting for differences between subjects and between the clips, with age, gender, cognitive status, and education as covariates. Results: Compared to both NV groups, IA scores were worse for the CVL group (P < 0.001). IA reduced with worsening visual acuity (P < 0.001), and the reduction with worsening visual acuity was greater for the CVL group than the NV-defocus group (P = 0.01), which was seen as a greater discrepancy at worse levels of visual acuity. Conclusions: The IA method was able to detect difficulties in following the story experienced by people with CVL. Defocus blur failed to recreate the CVL experience. IA is likely to be useful for evaluations of the effects of vision rehabilitation.

Commonly, saccades are thought to be ballistic eye movements, not modified during flight, with a straight path and a well-described velocity profile. However, they do not always follow a straight path and studies of saccade curvature have been reported previously. In a prior study, we developed a real-time, saccade-trajectory prediction algorithm to improve the updating of gaze-contingent displays and found that saccades with a curved path or that deviated from the expected velocity profile were not well fit by our saccade-prediction algorithm (velocity-profile deviation), and thus had larger updating errors than saccades that had a straight path and had a velocity profile that was fit well by the model. Further, we noticed that the curved saccades and saccades with high velocity-profile deviations were more common than we had expected when participants performed a natural-viewing task. Since those saccades caused larger display updating errors, we sought a better understanding of them. Here we examine factors that could affect curvature and velocity profile of saccades using a pool of 218,744 saccades from 71 participants watching "Hollywood" video clips. Those factors included characteristics of the participants (e.g., age), of the videos (importance of faces for following the story, genre), of the saccade (e.g., magnitude, direction), time during the session (e.g., fatigue) and presence and timing of scene cuts. While viewing the video clips, saccades were most likely horizontal or vertical over oblique. Measured curvature and velocity-profile deviation had continuous, skewed frequency distributions. We used mixed-effects regression models that included cubic terms and found a complex relationship between curvature, velocity-profile deviation and saccade duration (or magnitude). Curvature and velocity-profile deviation were related to some video-dependent features such as lighting, face presence, or nature and human figure content. Time during the session was a predictor for velocity profile deviations. Further, we found a relationship for saccades that were in flight at the time of a scene cut to have higher velocity-profile deviations and lower curvature in univariable models. Saccades characteristics vary with a variety of factors, which suggests complex interactions between oculomotor control and scene content that could be explored further.

Enterococcus faecalis are a major cause of nosocomial infection worldwide, and the spread of vancomycin resistant strains (VRE) limits treatment options. Tigecycline-resistant VRE began to be isolated from inpatients at a Brazilian hospital within months following the addition of tigecycline to the hospital formulary. This was found to be the result of a spread of an ST103 E. faecalis clone. Our objective was to identify the basis for tigecycline resistance in this lineage. The genomes of two closely related tigecycline-susceptible (MIC = 0.06 mg/L), and three representative tigecycline-resistant (MIC = 1 mg/L) ST103 isolates were sequenced and compared. Further, efforts were undertaken to recapitulate the emergence of resistant strains in vitro. The specific mutations identified in clinical isolates in several cases were within the same genes identified in laboratory-evolved strains. The contribution of various polymorphisms to the resistance phenotype was assessed by trans-complementation of the wild type or mutant alleles, by testing for differences in mRNA abundance, and/or by examining the phenotype of transposon insertion mutants. Among tigecycline-resistant clinical isolates, five genes contained non-synonymous mutations, including two genes known to be related to enterococcal tigecycline resistance (tetM and rpsJ). Finally, within the in vitro-selected resistant variants, mutation in the gene for a MarR-family response regulator was associated with tigecycline resistance. This study shows that E. faecalis mutates to attain tigecycline resistance through the complex interplay of multiple mechanisms, along multiple evolutionary trajectories.

The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.

Angiogenesis, disruption of the retinal barrier, leukocyte-adhesion and oedema are cardinal signs of proliferative retinopathies that are associated with vision loss. Therefore, identifying factors that regulate these vascular dysfunctions is critical to target pathological angiogenesis. Given the conflicting role of bioactive lipids reported in the current literature, the goal of this review is to provide the reader a clear road map of what has been accomplished so far in the field with specific focus on the role of polyunsaturated fatty acids (PUFAs)-derived metabolites in proliferative retinopathies. This necessarily entails a description of the different retina cells, blood retina barriers and the role of (PUFAs)-derived metabolites in diabetic retinopathy, retinopathy of prematurity and age-related macular degeneration as the most common types of proliferative retinopathies.

AIM: To systematically review whether the increased fluctuation of intraocular pressure (IOP) is a risk factor for open angle glaucoma (OAG) progression. METHODS: Scientific studies relevant to IOP fluctuation and glaucoma progression were retrieved from MEDLINE, EMBASE and CENTRAL databases, and were listed as references in this paper. The hazard ratio (HR) was calculated by using fixed or random-effects models according to the heterogeneity of included studies. RESULTS: Individual data for 2211 eyes of 2637 OAG patients in fourteen prospective studies were included in this Meta-analysis. All studies were longitudinal clinical studies with follow-up period ranging from 3 to 8.5y. The combined HR was 1.23 (95%CI 1.04-1.46, =0.02) for the association between IOP fluctuation and glaucoma onset or progression with the evidence of heterogeneity (<0.1). Subgroup analyses with different types of IOP fluctuation were also evaluated. Results indicated that the summary HR was 0.98 (95%CI 0.78-1.24) in short-term IOP fluctuation group, which showed no statistical significance with heterogeneity, whereas, the combined HR was 1.43 (95%CI 1.13-1.82, =0.003) in long-term IOP fluctuation group without homogeneity. Sensitivity analysis further showed that the pooled HR was 1.10 (95%CI 1.03-1.18, =0.004) for long-term IOP fluctuation and visual function progression with homogeneity among studies (=0.3). CONCLUSION: Long-term IOP fluctuation can be a risk factor for glaucoma progression based on the presented evidence. Thus, controlling the swing of IOP is crucial for glaucoma or glaucoma suspecting patients.

PURPOSE: Introduction of a novel sensory grading system to assess the incidence and long-term recovery of infraorbital hypesthesia following orbital floor and inferior orbital rim fractures. METHODS: Patients who presented for evaluation of orbital floor and/or zygomaticomaxillary complex (ZMC) fractures between January 2015 and April 2016 were analyzed. Two-point subjective infraorbital sensory grading in 5 discrete anatomic areas was performed. Fractures were repaired based on traditional criteria; hypesthesia was not an indication for surgery. The sensory grading system was repeated a mean 21.7 months (range 18-28) after initial fracture. RESULTS: Sixty-two patients (mean 41.8 years) participated in the initial symptom grading, and 42 patients (67.7%) completed the 2-year follow-up. Overall, 20 of 42 patients (47.6%) had some infraorbital hypesthesia. There were fewer with isolated orbital floor fractures versus ZMC fractures (31.8% vs. 68.4%; p = 0.019). Two years postinjury, 9.1% and 40.0% with isolated floor and ZMC fractures, respectively, had persistent sensory disturbance (p = 0.0188). Of patients with sensory disturbance on presentation, 71.4% with isolated floor fractures and 38.5% with ZMC fractures experienced complete sensory recovery (p = 0.1596). Patients with isolated floor fractures had improved recovery after surgery (100% vs. 33.3% recovery; p = 0.0410). Patients with ZMC fractures showed no difference in sensory prognosis between those repaired and observed. CONCLUSIONS: In this pilot study, isolated orbital floor fractures carried a good infraorbital sensory prognosis, further improved by surgical repair. Zygomaticomaxillary complex fractures portended a worse long-term sensory outcome, unaffected by management strategy. This study validates the novel sensory grading system in post-fracture analysis.

PURPOSE OF REVIEW: Continuous curvilinear manual capsulorhexis is currently the standard of cataract surgery. In the past several years, new technologies have been developed to improve the consistency and safety of capsulorhexis creation. This article reviews the most recent technologies in capsulotomy formation and their advantages and disadvantages. RECENT FINDINGS: Guidance devices, femtosecond laser capsulotomy and precision pulse capsulotomy improve the centration, circularity and precision of anterior capsulorhexis and capsulotomy. These developments show particular promise for complex cataract surgeries, though clinical data on the refractive outcomes and complication rates of these technologies are currently limited and warrant additional investigation. SUMMARY: New technological advances in capsulorhexis help surgeons achieve a more ideal capsulotomy geometry. Whether this translates into more predictable refractive outcomes and safer surgeries remains an area of future study.

Importance: Identifying the factors that are associated with the magnitude of treatment benefits from anti-vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME) may help refine treatment expectations. Objective: To identify the baseline factors that are associated with vision and anatomic outcomes when managing DME with anti-VEGF and determine if there are interactions between factors and the agent administered. Design, Setting, and Participants: This post hoc analysis of data from the Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial , Protocol T, was conducted between December 2016 and December 2017. Between August 22, 2012, and August 28, 2013, 660 participants were enrolled with central-involved DME and vision impairment (approximate Snellen equivalent, 20/32-20/320). Interventions: Repeated 0.05-mL intravitreous injections of 2.0-mg aflibercept (201 eyes), 1.25-mg bevacizumab (185 eyes), or 0.3-mg ranibizumab (192 eyes) per protocol. Main Outcomes and Measures: Change in visual acuity (VA) and optical coherence tomography (OCT) central subfield thickness at 2 years and change in VA over 2 years (area under the curve [AUC]). Results: Among 578 participants, the median age (interquartile range) was 61 (54-67) years. Across anti-VEGF treatment groups, each baseline factor was associated with mean improvement in VA and a reduction in central DME compared with the baseline. For every decade of participant age, the mean VA improvement was reduced by 2.1 letters (95% CI, -3.0 to -1.2; P < .001) in the VA and 1.9 letters (95% CI, -2.4 to -1.3; P < .001) in the VA AUC analyses. For each 1% increase in hemoglobin A1c levels, VA improvement was reduced by 1 letter in the VA (95% CI, -1.5 to -0.5; P < .001) and 0.5 letters (95% CI, -0.9 to -0.2; P < .001) in the VA AUC analyses. Eyes with no prior panretinal photocoagulation (PRP) and less than severe nonproliferative diabetic retinopathy had an approximately 3-letter improvement in the VA (95% CI, 0.9-5.4; P = .007) and VA AUC (95% CI, 1.3-4.2; P < .001) analyses compared with eyes with prior PRP. On average, African American participants had greater reductions in central subfield thickness compared with eyes of white participants (-27.3 μm, P = .01), as did eyes with central subretinal fluid compared with eyes without this OCT feature (-22.9 μm, P = .01). There were no interactions between the predictive factors and the specific anti-VEGF agent that was administered for any VA or OCT outcome. Conclusions and Relevance: Lower hemoglobin A1c levels were associated with the magnitude of vision improvement following anti-VEGF therapy, providing further evidence to encourage glycemic control among persons with diabetes. Younger patients and those without prior PRP might expect greater improvement in VA than older patients or those with prior PRP.

An 87-year-old woman not known to have either a lymphoma or leukemia developed a left multinodular, fish-flesh superior epibulbar and forniceal mass. A biopsy disclosed a blastic tumor with scattered multinucleated immature megakaryoblasts. Immunophenotyping of bone marrow cells revealed strong positivity for CD7, CD31, CD43, CD45, CD61, and CD117; CD71, myeloperoxidase, and lysozyme were also positive in scattered cells. Forty percent of the neoplastic cells were Ki-67 positive. Cytogenetic studies indicated a trisomy 8 (associated with worse prognosis) and a t(12; 17) translocation. Desmin, smooth muscle actin, pancytokeratin, CAM 5.2, adipophilin, tryptase, S100, SOX10, MART1, and E-cadherin were negative, ruling out a nonhematopoietic tumor. The conjunctival lesion was diagnosed as a myeloid sarcoma with megakaryoblastic differentiation, a rare variant. It probably arose from a myelodysplastic syndrome. This is the first case of its type to develop in the conjunctiva.

PURPOSE: To evaluate the therapeutic effect of subconjunctival injection of human mesenchymal stromal cells (hMSCs) in the cornea of mice with graft versus host disease (GVHD). METHODS: GVHD was induced in mice after hematopoietic stem cell transplantation (HSCT) between MHC-mismatched mouse strains. Subconjunctival injection of hMSCs was applied at day 10 post-HSCT. Infiltration of CD3 cells in the cornea and epithelial alterations were analyzed by immunofluorescence. Tear was assessed using the PRT test and TearLab Osmolarity System. qPCR was used to evaluate changes in cytokines, Pax6 and Sprr1b expression. To evaluate the effect of irradiation, we analyzed the expression of these genes in TBI mice. RESULTS: Immune cell invasion occurs in mice with GVHD, as shown by the presence of CD3 cells in the cornea. Interestingly, eyes treated with hMSC did not present CD3 cells. Tear osmolarity was increased in GVHD eyes, but not in treated eyes. TNFa expression was highly increased in all corneas except in Control and treated eyes. Pax6 in corneal epithelium showed a similar pattern in GVHD and Control mice, and its gene expression was enhanced in GVHD corneas. In contrast, Pax6 was reduced in GVHD + MSC corneas. We also found an increase in SPRR1B staining in GVHD eyes that was lower in GVHD + MSC mice, demonstrating that corneal keratinization is less frequent after treatment with hMSC. CONCLUSIONS: The treatment with hMSCs by subconjunctival injection is effective in reducing corneal inflammation and squamous metaplasia in ocular GVHD (oGVHD). Local treatment with hMSCs is a promising strategy for oGVHD.

OBJECTIVES: Ocular hypertension is a primary risk factor for glaucoma and results in retinal ganglion cell (RGC) degeneration. Current animal models of glaucoma lack severe RGC cell death as seen in glaucoma, making assessment of physiological mediators of cell death difficult. We developed a modified mouse model of ocular hypertension whereby long-lasting elevation of intraocular pressure (IOP) is achieved, resulting in significant reproducible damage to RGCs. RESULTS: In this model, microbeads are mixed with hyaluronic acid and injected into the anterior chamber of C57BL/6J mice. The hyaluronic acid allows for a gradual release of microbeads, resulting in sustained blockage of Schlemm's canal. IOP elevation was bimodal during the course of the model's progression. The first peak occurred 1 hours after beads injection, with an IOP value of 44.69 ± 6.00 mmHg, and the second peak occurred 6-12 days post-induction, with an IOP value of 34.91 ± 5.21 mmHg. RGC damage was most severe in the peripheral retina, with a loss of 64.1% compared to that of untreated eyes, while the midperiphery exhibited a 32.4% loss, 4 weeks following disease induction. CONCLUSIONS: These results suggest that sustained IOP elevation causes more RGC damage in the periphery than in the midperiphery of the retina. This model yields significant and reproducible RGC degeneration.

Importance: Health care prices may drive differences in health care costs across high-income nations. Adalimumab, ranibizumab, and aflibercept are high-cost medications in the United States and Australia. A comparison of their prices over time may elucidate how ophthalmic medication prices contribute to health care costs. Objective: To compare changes in the prices of adalimumab, ranibizumab, and aflibercept in the United States and Australia, the highest and lowest spenders on health care, respectively, among high-income nations. Design, Setting, and Participants: This retrospective price comparison study examined prices paid by government entities in the United States (Medicare) and Australia (Pharmaceuticals and Benefits Scheme). The analysis and data collection were conducted from March 28 to May 4, 2018, in accordance with guidelines set by the International Society for Pharmacoeconomics and Outcomes Research Task Force on Good Research Practices and prior published studies. No human participants or related data were included in this study. Exposures: The change in mean prices of adalimumab, ranibizumab, and aflibercept in the United States and Australia. Main Outcomes and Measures: Initial, final, and change in medication price annually from 2013 to 2017 in inflation-adjusted 2017 US dollars. Results: The mean prices (US dollar prices unadjusted for inflation) in 2013 and 2017 in the United States were $1114 ($1053) and $1818 ($1818), respectively, for adalimumab; $2102 ($1988) and $1904 ($1904), respectively, for ranibizumab; and $2074 ($1961) and $1956 ($1956), respectively, for aflibercept. The mean (Australian dollar prices unadjusted for inflation) 2013 and 2017 prices in Australia were $1854 (A $1797) and $1206 (A $1574), respectively, for adalimumab; $2157 (A $2090) and $972 (A $1268), respectively, for ranibizumab; and $2030 ($1967) and $996 ($1300), respectively, for aflibercept. The estimated annual change in price for adalimumab was +12.8% (95% CI, 9.1%-16.5%) in the United States compared with -11.1% (95% CI, -15.0% to -7.1%) in Australia, a difference of 23.9% per year (95% CI, 19.7%-28.0%; P < .001). The annual change in price for ranibizumab was -2.6% (95% CI, -3.9% to -1.3%) in the United States compared with -18.5% (95% CI, -29.3% to -7.8%) in Australia, a difference of 15.9% per year (95% CI, 7.6%-24.2%; P = .003). The annual change in price for aflibercept was -1.5% (95% CI, -2.2% to -0.7%) in the United States compared with -16.9% (95% CI, -25.1% to -8.6%) in Australia, a difference of 15.4% (95% CI, 9.1%-21.8%; P = .001). Conclusions and Relevance: Results of this study indicate that the prices of adalimumab, ranibizumab, and aflibercept significantly decreased during the past 5 years in Australia compared with the United States. These data do not indicate why these differences are noted or what actions might affect future pricing in either country.

Age-related declines in both peripheral vision and cognitive resources could contribute to the increased crash risk of older drivers. However, it is unclear whether increases in age and cognitive load result in equal detriments to detection rates across all peripheral target eccentricities (general interference effect) or whether these detriments become greater with increasing eccentricity (tunnel effect). In the current study we investigated the effects of age and cognitive load on the detection of peripheral motorcycle targets (at 5°-30° eccentricity) in static images of intersections. We used a dual-task paradigm in which cognitive load was manipulated without changing the complexity of the central (foveal) visual stimulus. Each image was displayed briefly (250 ms) to prevent eye movements. When no cognitive load was present, age resulted in a tunnel effect; however, when cognitive load was high, age resulted in a general interference effect. These findings suggest that tunnel and general interference effects can co-occur and that the predominant effect varies with the level of demand placed on participants' resources. High cognitive load had a general interference effect in both age groups, but the effect attenuated at large target eccentricities (opposite of a tunnel effect). Low cognitive load had a general interference effect in the older but not the younger group, impairing detection of motorcycle targets even at 5° eccentricity, which could present an imminent collision risk in real driving.

The 2018 Ocular Oncogenesis and Oncology Conference was held through a partnership of the Association for Research in Vision and Ophthalmology (ARVO) and the Champalimaud Foundation. Twenty-one experts from international ocular oncology centers, from the Champalimaud Clinical Centre and the Champalimaud Foundation Cancer Research Program, and from patient advocacy organizations, delivered lectures on subjects that ranged from global ocular oncology, to basic research in mechanisms of ocular malignancy, to clinical research in ocular cancers, and to anticipated future developments in the area. The scientific program of the conference covered a broad range of ocular tumors-including uveal melanoma, retinoblastoma, ocular surface tumors, and adnexal and intraocular lymphomas-and pathogenesis and management were deliberated in the context of the broader systemic cancer discipline. In considering the latest basic and clinical research developments in ocular oncogenesis and oncology, and providing the opportunity for cross-talk between ocular cancer biologists, systemic cancer biologists, ocular oncologists, systemic oncologists, patients, and patient advocates, the forum generated new knowledge and novel insights for the field. This report summarizes the content of the invited talks at the 2018 ARVO-Champalimaud Foundation Ocular Oncogenesis and Oncology Conference.

Purpose: To characterize and compare choroidal neovascularization (CNV) secondary to white dot syndromes (WDS) and age-related macular degeneration (AMD) using optical coherence tomography angiography (OCT-A). Methods: This is a cross-sectional study in which we imaged patients with CNV secondary to WDS and AMD with either the Zeiss Angioplex OCT-A or Optovue AngioVue OCT-A. Relevant demographic and clinical characteristics were collected and analyzed. CNV area and vessel density (VD) were measured by three independent graders, and linear regression analysis was subsequently performed. Results: Three patients with multifocal choroiditis and panuveitis, one patient each with birdshot chorioretinopathy, presumed ocular histoplasmosis syndrome, and persistent placoid maculopathy, and eleven patients with AMD with sufficient image quality were included. CNV associated with WDS was significantly smaller than that secondary to AMD (0.56±0.32 vs 2.79±1.80 mm, =-2.22, =0.01), while no difference in VD was detected (0.46±0.09 vs 0.44±0.09, =0.02, =0.71). Conclusion: CNV networks secondary to WDS appear to be smaller than those secondary to AMD but have similar VD. OCT-A is a powerful tool to investigate properties of CNV from various etiologies. Larger studies are needed for further characterization and understanding of CNV pathogenesis in inflammatory conditions.

Purpose: To detect visual field (VF) progression by analyzing spatial pattern changes. Methods: We selected 12,217 eyes from 7360 patients with at least five reliable 24-2 VFs and 5 years of follow-up with an interval of at least 6 months. VFs were decomposed into 16 archetype patterns previously derived by artificial intelligence techniques. Linear regressions were applied to the 16 archetype weights of VF series over time. We defined progression as the decrease rate of the normal archetype or any increase rate of the 15 VF defect archetypes to be outside normal limits. The archetype method was compared with mean deviation (MD) slope, Advanced Glaucoma Intervention Study (AGIS) scoring, Collaborative Initial Glaucoma Treatment Study (CIGTS) scoring, and the permutation of pointwise linear regression (PoPLR), and was validated by a subset of VFs assessed by three glaucoma specialists. Results: In the method development cohort of 11,817 eyes, the archetype method agreed more with MD slope (kappa: 0.37) and PoPLR (0.33) than AGIS (0.12) and CIGTS (0.22). The most frequently progressed patterns included decreased normal pattern (63.7%), and increased nasal steps (16.4%), altitudinal loss (15.9%), superior-peripheral defect (12.1%), paracentral/central defects (10.5%), and near total loss (10.4%). In the clinical validation cohort of 397 eyes with 27.5% of confirmed progression, the agreement (kappa) and accuracy (mean of hit rate and correct rejection rate) of the archetype method (0.51 and 0.77) significantly (P < 0.001 for all) outperformed AGIS (0.06 and 0.52), CIGTS (0.24 and 0.59), MD slope (0.21 and 0.59), and PoPLR (0.26 and 0.60). Conclusions: The archetype method can inform clinicians of VF progression patterns.

OBJECTIVE: Corneal nerve damage may result in neuropathic corneal pain (NCP). Autologous serum tears (AST) have been shown to results in nerve regeneration and may help alleviate corneal pain. This study aimed to evaluate the efficacy of AST in the treatment of NCP. METHODS: This was a retrospective case-control study. Sixteen patients suffering from severe NCP and no current ocular surface disease were compared to 12 controls. In vivo confocal microscopy (IVCM) (HRT3/RCM; Heidelberg, Germany) of the central corneas was performed bilaterally. Change in pain severity (scale of 0-10), corneal nerve density, tortuosity, reflectivity and presence of beading and microneuromas before and after treatment were recorded. RESULTS: All patients had severe pain of 9.1 ± 0.2 (range 8-10). Before treatment, subbasal nerves were significantly decreased compared to controls, including total nerve length (10,935.5 ± 1264.3 vs. 24,714.4 ± 1056.2 μm/mm; p < 0.0001) and total number of nerves (10.5 ± 1.4 vs. 28.6 ± 2.0; p < 0.0001), respectively. Morphologically, significantly increased reflectivity (2.9 ± 0.2 vs. 1.2 ± 0.1; p = 0.00008) and tortuosity (2.4 ± 0.2 vs. 1.7 ± 0.1; p = 0.001), both graded on a scale of 0-4, were noted. After 3.8 ± 0.5 months (range 1-8 months) of AST treatment, pain severity decreased to 3.1 ± 0.3 (range 0-4), (p < 0.0001). Further, IVCM demonstrated a significant improvement (p < 0.005) in total nerve length (17,351.3 ± 1395.6 μm/mm) and number (15.1 ± 1.6) as well as significant decrease in reflectivity (2.4 ± 0.2; p = 0.001) and tortuosity (2.2 ± 0.2; p = 0.001). CONCLUSION: IVCM demonstrates underlying alterations of the subbasal corneal nerve plexus in patients suffering from debilitating NCP. AST-induced nerve regeneration is seen following treatment with AST, which correlates with improvement in patient symptoms of NCP.

Reactive microglia and infiltrating peripheral monocytes have been implicated in many neurodegenerative diseases of the retina and CNS. However, their specific contribution in retinal degeneration remains unclear. We recently showed that peripheral monocytes that infiltrate the retina after ocular injury in mice become permanently engrafted into the tissue, establishing a proinflammatory phenotype that promotes neurodegeneration. In this study, we show that microglia regulate the process of neuroglia remodeling during ocular injury, and their depletion results in marked upregulation of inflammatory markers, such as , , and in the retina, and abnormal engraftment of peripheral CCR2 CX3CR1 monocytes into the retina, which is associated with increased retinal ganglion cell loss, retinal nerve fiber layer thinning, and pigmentation onto the retinal surface. Furthermore, we show that other types of ocular injuries, such as penetrating corneal trauma and ocular hypertension also cause similar changes. However, optic nerve crush injury-mediated retinal ganglion cell loss evokes neither peripheral monocyte response in the retina nor pigmentation, although peripheral CX3CR1 and CCR2 monocytes infiltrate the optic nerve injury site and remain present for months. Our study suggests that microglia are key regulators of peripheral monocyte infiltration and retinal pigment epithelium migration, and their depletion results in abnormal neuroglia remodeling that exacerbates neuroretinal tissue damage. This mechanism of retinal damage through neuroglia remodeling may be clinically important for the treatment of patients with ocular injuries, including surgical traumas.

PURPOSE: To report the long-term outcome of Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) for delivery of bevacizumab in the treatment of corneal neovascularization (KNV). METHODS: Retrospective, non-comparative, interventional case series of 13 sequential patients treated for KNV at the BostonSight between 2006 and 2017. In all cases, PROSE treatment was initiated for management of ocular surface disease and patients wore PROSE consistently on a daily wear basis prior to bevacizumab treatment. Patients applied a drop of 1% preservative free bevacizumab to the reservoir of PROSE device twice daily. Patients continued with daily wear of the device during treatment and afterwards. RESULTS: 13 patients (8 female and mean age of 45 years) are included with a mean follow-up of 5.1 years (range 6 months-11 years). Underlying ocular diagnoses included Stevens-Johnson syndrome (7), ocular chronic graft-versus-host disease (2), corneal transplant (2), contact lens-related corneal ulcer and limbal stem cell deficiency (1), and familial dysautonomia (1). Median duration of bevacizumab use was 6 months (range 3 months-10 years). Twelve cases (92%) had regression of KNV and 10 cases (77%) had improved best-corrected visual acuity (BCVA) with treatment. Median BCVA improved from -1.1 (LogMAR) at baseline, to -0.66 at end of bevacizumab treatment, and remained -0.63 at last follow-up (P = 0.047). KNV progressed in one eye after discontinuation of bevacizumab. There were no ophthalmic or systemic complications. CONCLUSIONS: Topical bevacizumab used in PROSE is effective in treating KNV and improving vision. Long-term follow-up reveals durable response and no complications.