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Moein H-R, Akhlaq A, Dieckmann G, Abbouda A, Pondelis N, Salem Z, Müller RT, Cruzat A, Cavalcanti BM, Jamali A, Hamrah P. Visualization of micro-neuromas by using in vivo confocal microscopy: An objective biomarker for the diagnosis of neuropathic corneal pain?. Ocul Surf 2020;Abstract
PURPOSE: The diagnosis of neuropathic corneal pain (NCP) is challenging, as it is often difficult to differentiate from conventional dry eye disease (DED). In addition to eye pain, NCP can present with similar signs and symptoms of DED. The purpose of this study is to find an objective diagnostic sign to identify patients with NCP, using in vivo confocal microscopy (IVCM). METHODS: This was a comparative, retrospective, case-control study. Patients with clinical diagnosis of NCP (n = 25), DED (n = 30), and age and sex-matched healthy controls (n = 16), who underwent corneal imaging with IVCM (HRT3/RCM) were included. Central corneal IVCM scans were analyzed by 2 masked observers for nerve density and number, presence of micro-neuromas (terminal enlargements of subbasal corneal nerve) and/or nerve beading (bead-like formation along the nerves), and dendritiform cell (DC) density. RESULTS: There was a decrease in total nerve density in both NCP (14.14 ± 1.03 mm/mm) and DED patients (12.86 ± 1.04 mm/mm), as compared to normal controls (23.90 ± 0.92 mm/mm; p < 0.001). However, total nerve density was not statistically different between NCP and DED patients (p = 0.63). Presence of nerve beading was not significantly different between patients and normal controls (p = 0.15). Interestingly, micro-neuromas were observed in all patients with NCP, while they were not present in any of the patients with DED (sensitivity and specificity of 100%). DC density was increased significantly in both NCP (71.89 ± 16.91 cells/mm) and DED patients (111.5 ± 23.86 cells/mm), as compared to normal controls (24.81 ± 4.48 cells/mm (Colloca et al., 2017) [2]; p < 0.05). However, there was no significant difference in DC density between DED and NCP patients (p = 0.31). CONCLUSION: IVCM may be used as an adjunct diagnostic tool for the diagnosis of NCP in the presence of neuropathic symptoms. Micro-neuromas may serve as a sensitive and specific biomarker for the diagnosis of NCP.
Ashofteh Yazdi A, Melchor J, Torres J, Faris I, Callejas A, Gonzalez-Andrades M, Rus G. Characterization of non-linear mechanical behavior of the cornea. Sci Rep 2020;10(1):11549.Abstract
The objective of this study was to evaluate which hyperelastic model could best describe the non-linear mechanical behavior of the cornea, in order to characterize the capability of the non-linear model parameters to discriminate structural changes in a damaged cornea. Porcine corneas were used, establishing two different groups: control (non-treated) and NaOH-treated (damaged) corneas (n = 8). NaOH causes a chemical burn to the corneal tissue, simulating a disease associated to structural damage of the stromal layer. Quasi-static uniaxial tensile tests were performed in nasal-temporal direction immediately after preparing corneal strips from the two groups. Three non-linear hyperelastic models (i.e. Hamilton-Zabolotskaya model, Ogden model and Mooney-Rivlin model) were fitted to the stress-strain curves obtained in the tensile tests and statistically compared. The corneas from the two groups showed a non-linear mechanical behavior that was best described by the Hamilton-Zabolotskaya model, obtaining the highest coefficient of determination (R > 0.95). Moreover, Hamilton-Zabolotskaya model showed the highest discriminative capability of the non-linear model parameter (Parameter A) for the tissue structural changes between the two sample groups (p = 0.0005). The present work determines the best hyperelastic model with the highest discriminative capability in description of the non-linear mechanical behavior of the cornea.
Nartker MS, Alaoui-Soce A, Wolfe JM. Visual search errors are persistent in a laboratory analog of the incidental finding problem. Cogn Res Princ Implic 2020;5(1):32.Abstract
When radiologists search for a specific target (e.g., lung cancer), they are also asked to report any other clinically significant "incidental findings" (e.g., pneumonia). These incidental findings are missed at an undesirably high rate. In an effort to understand and reduce these errors, Wolfe et al. (Cognitive Research: Principles and Implications 2:35, 2017) developed "mixed hybrid search" as a model system for incidental findings. In this task, non-expert observers memorize six targets: half of these targets are specific images (analogous to the suspected diagnosis in the clinical task). The other half are broader, categorically defined targets, like "animals" or "cars" (analogous to the less well-specified incidental findings). In subsequent search through displays for any instances of any of the targets, observers miss about one third of the categorical targets, mimicking the incidental finding problem. In the present paper, we attempted to reduce the number of errors in the mixed hybrid search task with the goal of finding methods that could be deployed in a clinical setting. In Experiments 1a and 1b, we reminded observers about the categorical targets by inserting non-search trials in which categorical targets were clearly marked. In Experiment 2, observers responded twice on each trial: once to confirm the presence or absence of the specific targets, and once to confirm the presence or absence of the categorical targets. In Experiment 3, observers were required to confirm the presence or absence of every target on every trial using a checklist procedure. Only Experiment 3 produced a marked decline in categorical target errors, but at the cost of a substantial increase in response time.
Chodosh J, Ung L. Adoption of Innovation in Herpes Simplex Virus Keratitis. Cornea 2020;39 Suppl 1:S7-S18.Abstract
Herpes simplex keratitis, caused primarily by human herpes simplex virus type 1 (HSV-1), remains the most common infectious cause of unilateral blindness and vision impairment in the industrialized world. Major advances in the care of HSV keratitis have been driven in large part by the landmark Herpetic Eye Disease Study randomized clinical trials, which were among the first in ophthalmology to reflect emerging trial conventions, including multicenter subject enrollment, double-masking, placebo controls, and a priori sample size determinations. The results of these trials now form much of the evidence basis for the management of this disease. However, management patterns in clinical practice often deviate from evidence-based care. These perceived quality gaps have given rise to the evolving field of implementation science, which is concerned with the methods of promoting the application of evidence-based medicine within routine care. To overcome variations in the quality and consistency of care for HSV keratitis, a range of clinical- and technology-based innovations are proposed. The most pressing needs include the following: a rational and tractable disease classification scheme that provides an immediate link between the anatomical localization of disease (corneal epithelial, stromal, or endothelial) and the appropriate treatment, and the actualization of an electronic medical record system capable of providing evidence-based treatment algorithms at relevant points of care. The latter would also input data to population-wide disease registries to identify implementation-rich targets for quality improvement, education, and research. These innovations may allow us to reduce the human and economic burdens of this highly morbid, and often blinding, disease.
Wolkow N, Jakobiec FA, Afrogheh AH, Pai SI, Faquin WC. High Expression of Programmed Death Ligand 1 and Programmed Death Ligand 2 in Ophthalmic Sebaceous Carcinoma: The Case for a Clinical Trial of Checkpoint Inhibitors. Am J Ophthalmol 2020;220:128-139.Abstract
PURPOSE: To evaluate the expression of programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2) in ocular adnexal sebaceous carcinoma (OASC), and to appraise these findings within the context of recent comparable studies. DESIGNS: Retrospective case series. METHODS: Twenty cases of primary OASC were immunostained for PD-L1, PD-L2 and CD8. PD-L1 and PD-L2 expression were graded with both the combined positive score (CPS) and the tumor proportion score (TPS). Both raw CPS and TPS were reported, as well as positivity with TPS and CPS ≥1. CD8 expression was graded on a 0-3 scale. Charts were reviewed for clinical correlations. The results of the current study were compared with results of similar recent investigations. RESULTS: For the 20 cases, mean expression of PD-L1 with CPS was 29.7 (range 0-101.5) and with TPS was 12.2 (range 0-95.8); mean expression of PD-L2 with CPS was 7.9 (range 0-37.3) and with TPS was 1.9 (range 0-12.9). PD-L1 CPS ≥1 was detected in 95% of OASC, while PD-L1 TPS ≥1 was found in 75%. PD-L2 CPS ≥1 was present in 60%, while only 20% had PD-L2 TPS ≥1. Immune cells appeared to contribute to a substantial proportion of PD-L1 and PD-L2 positivity, and a conspicuous CD8-positive T-lymphocytic infiltrate was present in most tumors. Significant correlations were identified between tissue expression of PD-L1, PD-L2, and CD8. Tissues with greater levels of PD-L1 tended to express higher levels of PD-L2 and CD8. The degree of PD-L1 and PD-L2 expression was also associated with the area in millimeters squared of the immunostained tumor, suggesting that tumor sampling may influence interpretation of PD-L1 and PD-L2 expression in ocular adnexal tumors. CONCLUSIONS: The current and preceding studies confirm that PD-L1 and PD-L2 are expressed in a high percentage of OASCs. These results support the premise that checkpoint inhibitor drugs hold considerable therapeutic promise for patients with OASC and stimulate the institution of clinical trials.
Deng SX, Kruse F, Gomes JAP, Chan CC, Daya S, Dana R, Figueiredo FC, Kinoshita S, Rama P, Sangwan V, Slomovic AR, Tan D, and Group TILSCDW. Global Consensus on the Management of Limbal Stem Cell Deficiency. Cornea 2020;39(10):1291-1302.Abstract
PURPOSE: In recent decades, the medical and surgical treatment of limbal stem cell deficiency (LSCD) has evolved significantly through the incorporation of innovative pharmacological strategies, surgical techniques, bioengineering, and cell therapy. With such a wide variety of options, there is a need to establish a global consensus on the preferred approaches for the medical and surgical treatment of LSCD. METHODS: An international LSCD Working Group was established by the Cornea Society in 2012 and divided into subcommittees. Four face-to-face meetings, frequent email discussions, and teleconferences were conducted since then to reach agreement on a strategic plan and methods after a comprehensive literature search. A writing group drafted the current study. RESULTS: A consensus in the medical and surgical management of LSCD was reached by the Working Group. Optimization of the ocular surface by eyelid and conjunctival reconstruction, antiinflammatory therapy, dry eye and meibomian gland dysfunction treatment, minimization of ocular surface toxicity from medications, topical medications that promote epithelialization, and use of a scleral lens is considered essential before surgical treatment of LSCD. Depending on the laterality, cause, and stage of LSCD, surgical strategies including conjunctival epitheliectomy, amniotic membrane transplantation, transplantation of limbal stem cells using different techniques and sources (allogeneic vs. autologous vs. ex vivo-cultivated), transplantation of oral mucosal epithelium, and keratoprosthesis can be performed as treatment. A stepwise flowchart for use in treatment decision-making was established. CONCLUSIONS: This global consensus provides an up-to-date and comprehensive framework for the management of LSCD.
Ibrahim AS, Hussein K, Wang F, Wan M, Saad N, Essa M, Kim I, Shakoor A, Owen LA, Deangelis MM, Al-Shabrawey M. Bone Morphogenetic Protein (BMP)4 But Not BMP2 Disrupts the Barrier Integrity of Retinal Pigment Epithelia and Induces Their Migration: A Potential Role in Neovascular Age-Related Macular Degeneration. J Clin Med 2020;9(7)Abstract
Disruption of retinal pigment epithelial (RPE) barrier integrity and RPE migration are hallmark features in neovascular age-related macular degeneration (nAMD), but the underlying causes and pathophysiology are not completely well-defined. Herein, we aimed to evaluate the effect of bone morphogenetic proteins (BMPs) on the barrier function and migration of RPE. In particular, we investigated the role of BMP2 and BMP4 in these processes as our analysis of RNA-sequencing (seq) data from human donor eyes demonstrated that they are highly differentially expressed BMP members in macular RPE/choroid versus macular retina. We used electrical cell-substrate impedance sensing (ECIS) system to monitor precisely in real time the barrier integrity and migration of ARPE-19 after treatment with various concentrations of BMP2 or BMP4. Immunofluorescence was also used to assess the changes in the expression and the organization of the key tight junction protein, zona occludens (ZO)-1, in ARPE-19 cells under BMP2 or BMP4 treatment. This was followed by measuring the activity of matrix metalloproteinases (MMPs). Finally, RNA-seq and ELISA were used to determine the local and circulating levels of BMP2 and BMP4 in retinas and serum samples from nAMD donors. Our ECIS results showed that BMP4 but not BMP2 decreased the transcellular electrical resistance (TER) of ARPE-19 and increased their migration in comparison with control (vehicle-treated cells). Furthermore, immunofluorescence showed a disorganization of ZO-1 in BMP4-treated ARPE-19 not in BMP2-treated cells or vehicle-treated controls. This effect of BMP4 was associated with significant increases in the activity of MMPs, specifically MMP2. Lastly, these results were corroborated by additional findings that circulating but not local BMP4 levels were significantly higher in nAMD donor samples compared to controls. Collectively, our results demonstrated unreported effects of BMP4 on inducing RPE dysfunction and suggest that BMP4 but not BMP2 may represent a potential therapeutic target in nAMD.
Liebman DL, McKay KM, Haviland MJ, Moustafa GA, Borkar DS, Kloek CE. Quantifying the educational benefit of additional cataract surgery cases in ophthalmology residency. J Cataract Refract Surg 2020;46(11):1495-1500.Abstract
PURPOSE: To quantify the resident learning curve for cataract surgery using operative time as an indicator of surgical competency, to identify the case threshold at which marginal additional educational benefit became equivocal, and to characterize heterogeneity in residents' pathways to surgical competency. SETTING: Academic medical center. DESIGN: Large-scale retrospective consecutive case series. METHODS: All cataract surgery cases performed by resident physicians as primary surgeon at Massachusetts Eye and Ear from July 1, 2010, through June 30, 2015, were reviewed. Data were abstracted from Accreditation Council for Graduate Medical Education case logs and operative time measurements. A linear mixed-methods analysis was conducted to model changes in residents' cataract surgery operative times as a function of sequential case number, with resident identity included as a random effect in the model to normalize between-resident variability. RESULTS: A total of 2096 cases were analyzed. A marked progressive decrease in operative time was noted for resident cases 1 to 39 (mean change -0.17 minutes per additional case, 95% CI, -0.21 to -0.12; P < .001). A modest, steady reduction in operative time was subsequently noted for case numbers 40 to 149 (mean change -0.05 minutes per additional case, 95% CI, -0.07 to -0.04; P < .001). No statistically significant improvement was found in operative times beyond the 150th case. CONCLUSIONS: Residents derived educational benefit from performing a greater number of cataract procedures than current minimum requirements. However, cases far in excess of this threshold might have diminishing educational return in residency. Educational resources currently used for these cases might be more appropriately devoted to other training priorities.
Liou VD, Yoon MK. Advances in steroid sparing medical management of active thyroid eye disease. Semin Ophthalmol 2020;:1-8.Abstract
Thyroid eye disease (TED) is an autoimmune inflammatory disease of the orbit and the most common extrathyroidal manifestation of Graves disease. The release of pro-inflammatory cytokines is associated with inflammation of the ocular surface and lacrimal gland along with periorbital skin erythema and edema. Resultant tissue remodeling, fibrosis, and fat deposition can impart permanent physical changes to the ocular adnexa with effects on function and cosmesis. These changes occur in the active phase of disease, and it is during this time that steroids are often relied on to help alleviate symptoms. Due to the common and predictable side effects of long-term and high-dose steroid use, there has been a continuous effort to find alternative steroid-sparing medical management options for TED. This review highlights the various research studies that support the use of these medications.
Chen X, Lei F, Zhou C, Chodosh J, Wang L, Huang Y, Dohlman CH, Paschalis EI. Glaucoma after Ocular Surgery or Trauma: The Role of Infiltrating Monocytes and Their Response to Cytokine Inhibitors. Am J Pathol 2020;190(10):2056-2066.Abstract
Glaucoma is a frequent and devastating long-term complication following ocular trauma, including corneal surgery, open globe injury, chemical burn, and infection. Postevent inflammation and neuroglial remodeling play a key role in subsequent ganglion cell apoptosis and glaucoma. To this end, this study was designed to investigate the amplifying role of monocyte infiltration into the retina. By using three different ocular injury mouse models (corneal suture, penetrating keratoplasty, and globe injury) and monocyte fate mapping techniques, we show that ocular trauma or surgery can cause robust infiltration of bone marrow-derived monocytes into the retina and subsequent neuroinflammation by up-regulation of Tnf, Il1b, and Il6 mRNA within 24 hours. This is accompanied by ganglion cell apoptosis and neurodegeneration. Prompt inhibition of tumor necrosis factor-α or IL-1β markedly suppresses monocyte infiltration and ganglion cell loss. Thus, acute ocular injury (surgical or trauma) can lead to rapid neuroretinal inflammation and subsequent ganglion cell loss, the hallmark of glaucoma. Infiltrating monocytes play a central role in this process, likely amplifying the inflammatory cascade, aiding in the activation of retinal microglia. Prompt administration of cytokine inhibitors after ocular injury prevents this infiltration and ameliorates the damage to the retina-suggesting that it may be used prophylactically for neuroprotection against post-traumatic glaucoma.
Shah DN, Al-Moujahed A, Newcomb CW, Kaçmaz OR, Daniel E, Thorne JE, Foster SC, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Sen NH, Suhler EB, Bhatt NP, Kempen JH, for Group SITEDR. Exudative Retinal Detachment in Ocular Inflammatory Diseases: Risk and Predictive Factors. Am J Ophthalmol 2020;218:279-287.Abstract
PURPOSE: This study evaluated the risk and risk factors for exudative retinal detachment (ERD) in ocular inflammatory diseases. DESIGN: Retrospective cohort study. METHODS: Patients with noninfectious ocular inflammation had been followed longitudinally between 1978 and 2007 at 4 US subspecialty uveitis centers. The main outcome measurements were occurrences of ERD and predictive factors. RESULTS: A total of 176 of 14,612 eyes with ocular inflammation presented with ERD. Among uveitis cases, Vogt-Koyanagi-Harada syndrome (VKH) (odds ratio [OR] = 109), undifferentiated choroiditis (OR = 9.18), sympathetic ophthalmia (OR = 8.43), primary or secondary panuveitis (OR = 7.09), multifocal choroiditis with panuveitis (OR = 4.51), and "other" forms of posterior uveitis (OR = 16.9) were associated with a higher prevalence of ERD. Among the 9,209 uveitic or scleritic eyes initially free of ERD and followed, 137 incident ERD cases were observed over 28,949 eye-years at risk (incidence rate = 0.47% [0.40%-0.56%/eye-year]). VKH (HR = 13.2), sympathetic ophthalmia (HR = 5.82), undifferentiated choroiditis (HR = 6.03), primary or secondary panuveitis (HR = 4.21), and rheumatoid arthritis (HR = 3.30) were significantly associated with incident ERD. A significant dose-response relationship with the prevalence and incidence of ERD were observed for AC cells and vitreous cell activity. African Americans had significantly higher prevalence and incidence of ERD. CONCLUSIONS: Other ocular inflammatory conditions in addition to VKH syndrome and posterior scleritis were associated with increased risk of ERD, indicating that ERD does not necessarily dictate a diagnosis of VKH or posterior scleritis. In addition, the relationship between ERD and inflammatory severity factors implies that inflammation is a key predictive factor associated with developing ERD and requires early and vigorous control.
Yang M, Lippestad M, Hodges RR, Fjærvoll HK, Fjærvoll KA, Bair JA, Utheim TP, Serhan CN, Dartt DA. RvE1 uses the LTB receptor BLT1 to increase [Ca] and stimulate mucin secretion in cultured rat and human conjunctival goblet cells. Ocul Surf 2020;18(3):470-482.Abstract
PURPOSE: Specialized pro-resolving lipid mediator resolvin (Rv) E1 stimulates secretion including mucins from conjunctival goblet cells. RvE1 can use both its ChemR23 receptor and the LTB receptor BLT1 to increase [Ca]. The purpose of this study was to determine the expression of ChemR23 and BLT1 and receptors on conjunctival goblet cells and the respective roles these two receptors play in goblet cell responses to RvE1. METHODS: Goblet cells were cultured from male rat or human conjunctiva from both sexes. Western blotting analysis, reverse transcription PCR and immunofluorescence microscopy were used to demonstrate the expression of ChemR23 and BLT1 in conjunctival goblet cells. High molecular weight glycoprotein secretion was determined using an enzyme-linked lectin assay. Signaling pathways were studied by measuring the increase in [Ca] using fura 2/AM. RESULTS: ChemR23 and BLT1 and receptors were present on both rat and human conjunctival goblet cells. The BLT1 inhibitors LY293111 and U75302 significantly blocked RvE1-and LTB-stimulated [Ca] increase. RvE1-and LTB-stimulated [Ca] and secretion increases were blocked by BLT1-targeted siRNA. RvE1-stimulated [Ca] and secretion increases were also blocked by ChemR23-targeted siRNA. Addition of RvE1 2 min before or simultaneously with LTB desensitized the LTB [Ca] response. Addition of RvE1 and LTB simultaneously caused secretion that was decreased compared to either response alone. CONCLUSION: RvE1, in addition to the ChemR23 receptor, uses the BLT1 receptor to increase [Ca] and stimulate secretion in both rat and human cultured conjunctival goblet cells.
Chen EM, Armstrong GW, Cox JT, Wu DM, Hoover DR, Del Priore LV, Parikh R. Association of the Affordable Care Act Medicaid Expansion with Dilated Eye Examinations among the United States Population with Diabetes. Ophthalmology 2020;127(7):920-928.Abstract
PURPOSE: To evaluate the association between Medicaid expansion and diabetic dilated eye examinations. DESIGN: A retrospective difference in differences (DiD) analysis using individual-level survey response data from January 1, 2009, to December 31, 2017. PARTICIPANTS: A total of 52 392 survey responses from 50 states and the District of Columbia between 2009 and 2017. Responders were adults aged 18 to 64 years reporting a previous diagnosis of diabetes and a household income below 138% of the US federal poverty line (FPL). METHODS: The Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System data were used to identify survey responders who were asked about the presence of dilated eye examinations from years before and after Medicaid expansion implementation. MAIN OUTCOME MEASURES: The DiD in proportion of dilated eye examinations among diabetic persons aged 18 to 64 years with household incomes below 138% of the FPL between states that did and did not implement Medicaid expansion. RESULTS: Implementation of Medicaid expansion policies was associated with a 1.3% (95% confidence interval [CI], -3.8 to 6.4; P = 0.61), 6.3% (95% CI, 1.3-11.3; P = 0.016), 4.1% (95% CI, -0.8 to 9.0; P = 0.11), and 2.3% (95% CI, -1.6 to 6.2; P = 0.23) increase in the proportion of diabetic persons aged 18 to 64 years with incomes below 138% of the FPL receiving a dilated eye examination within the past year due to Medicaid expansion 1, 2, 3, and 4 cumulative years after expansion, respectively. CONCLUSIONS: Medicaid expansion policies were significantly associated with an increase in dilated eye examination rates within the first 2 years after implementation. However, this increase did not persist beyond this period, with nonsignificant increases 3 and 4 cumulative years after implementation. Healthcare policymakers should be aware that additional measures beyond expanding insurance coverage may be necessary to increase and sustain the rate of dilated eye examinations among diabetic populations.
Singh RB, Sinha S, Saini C, Elbasiony E, Thakur S, Agarwal A. Recent advances in the management of non-infectious posterior uveitis. Int Ophthalmol 2020;40(11):3187-3207.Abstract
PURPOSE: To review the current regimens and novel therapeutic modalities in various stages of research and development for the management of non-infectious posterior uveitis (NIPU). METHODS: We performed a thorough review of current literature using PubMed, Google Scholar and Clinicaltrials.gov to identify the published literature about the available therapeutics and novel drugs/therapies in different stages of clinical trials. RESULTS: The current management regimen for non-infectious posterior uveitis includes corticosteroids, immunomodulatory therapies and anti-metabolites. However, NIPU requires long-term management for efficacious remission of the disease and to prevent disease relapse. Long-term safety issues associated with steroids have led to efforts to develop novel therapeutic agents including biological response modulators and immunosuppressants. The current therapeutic agents in various stages of development include calcineurin inhibitors, biologic response modifiers and a more a comprehensive modalities like ocular gene therapy as well as novel drug delivery mechanisms for higher bioavailability to the target tissues, with minimal systemic effects. CONCLUSION: Novel efficacious therapeutic modalities under development will help overcome the challenges associated with the traditional therapeutic agents.

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