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Brian J Nguyen,1 Angela S Gupta,1 Jocelyn He,1,2 Gui-Shuang Ying,1,2 Vatinee Y Bunya,1 Ilaria Macchi,1 Mina Massaro-Giordano1 1Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Ophthalmology, Center for Preventive Ophthalmology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USACorrespondence: Mina Massaro-Giordano, Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, 51 North 39th St, Philadelphia, PA, 19104, USA, Email mina@pennmedicine.upenn.eduPurpose: This study was to assess corneal epithelial thickness (CET) in patients with Sjogren’s disease (SjD).Methods: A retrospective chart review was conducted of SjD patients from September 2021 to January 2022. Patient demographics, unanesthetized Schirmer’s test, serologic markers, and symptoms as measured by the Ocular Surface Disease Index (OSDI) were reviewed. Epithelial thickness from both eyes was measured using anterior segment OCT at the central 3mm and concentric 5mm, 7mm, and 9mm zones for the superior, temporal, inferior, and nasal corneal quadrants. Associations between corneal epithelial thickness with patient demographics, clinical characteristics, and symptoms were evaluated using regression models.Results: Fifteen SjD patients (100% female) were included with a mean age of 58.4 years. Patients with Sjogren’s disease had a significantly thinner superior corneal epithelium compared to the inferior epithelium (mean 47.7mm vs 53.1mm, p = 0.001). The epithelial thickness mean standard deviation (MSD) was significantly inversely correlated with the unanesthetized Schirmer test (r=− 0.39, p = 0.005), suggesting that an overall variability of CET correlates with decreased aqueous tear production. SS-A, SS-B, ANA, and RF positivity were not associated with any measures of CET.Conclusion: This pilot study suggests that there is significant superior versus inferior thinning of corneal epithelium in Sjogren’s patients. There was a significant correlation between variability of corneal epithelial thickness and decreased tear production in Sjogren’s patients. Further larger studies are needed to understand the relationship of CET with objective and subjective measurements of ocular surface disease.Keywords: Sjogren’s disease, corneal epithelial thickness, anterior segment OCT

Julie M Schallhorn,1 Selina McGee,2 Jeffrey Nau,3 Marian Macsai,3 Andrea Gibson,3 Gretchen Blemker,3 Laura H Hendrix,3 Mina Massaro-Giordano4 1Department of Ophthalmology and Francis I, Proctor Foundation, University of California, San Francisco, CA, USA; 2BeSpoke Vision, Edmond, OK, USA; 3Oyster Point Pharma, Princeton, NJ, USA; 4Scheie Eye Institute, Penn Dry Eye and Ocular Surface Center, University of Pennsylvania Health System, Philadelphia, PA, USACorrespondence: Mina Massaro-Giordano, Scheie Eye Institute, 51 N 39th Street, Philadelphia, PA, 19104, USA, Tel +1 216 662-9903, Email mina@pennmedicine.upenn.eduPurpose: We evaluate the treatment effect of OC-01 (varenicline solution) nasal spray (VNS) in dry eye disease (DED) subjects from two randomized trials who self-reported autoimmune disease (AID).Patients and Methods: Post hoc subgroup analysis of subjects reporting a history of AID from the integrated OC-01 VNS 0.03 or 0.06 mg and vehicle control (VC) treatment groups of the ONSET-1 and ONSET-2 trials. Mean change in Schirmer test with anesthesia score (STS, mm) and Eye Dryness Score (EDS) from baseline to 28 days was compared between OC-01 VNS and VC groups. Consistency of treatment effect in subjects with and without AID was evaluated using treatment–subgroup interaction terms in ANCOVA models for mean changes from baseline STS and EDS, and in a logistic regression model for proportion achieving ≥ 10 mm STS improvement.Results: Of the 891 participants, 31 reported comorbid AID. In all models, the treatment–subgroup interaction terms were not significant (p> 0.05), indicating consistency of therapeutic effect of OC-01 VNS in subjects with and without AID. In subjects with AID, the treatment difference for STS was 11.8 mm and − 9.3 for EDS and difference for proportion of subjects with ≥ 10 mm STS improvement was 61.1%. The most common adverse event was sneeze (82– 84%), graded as mild by 98% of subjects.Conclusion: OC-01 VNS demonstrated consistency in improving both tear production and patient-reported symptoms in subjects with AID, consistent with pivotal ONSET-1 and 2 trial results. Further investigation is warranted, and results may further support use of OC-01 VNS for DED in AID patients.Keywords: dry eye disease, autoimmune disease, Eye Dryness Score, nicotinic acetylcholine receptor, Schirmer test score, varenicline nasal spray, Tyrvaya

Jennifer B Nadelmann,1,2 Vatinee Y Bunya,1 Gui-Shuang Ying,3 Peiying Hua,3 Mina Massaro-Giordano1 1Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Ophthalmology, Weill Cornell Medicine, New York, NY, USA; 3Center for Preventive Ophthalmology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USACorrespondence: Mina Massaro-Giordano, Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, Tel +1-215-662-8100, Email mina@pennmedicine.upenn.eduPurpose: Platelet rich plasma (PRP) is an autologous preparation that concentrates platelets in a small volume of plasma. The purpose of this study was to determine if PRP eye drops improved the symptoms and signs of ocular surface disease.Patients and Methods: A retrospective case series was conducted of patients who were prescribed PRP eye drops. Subjects were excluded if they did not have follow-up, underwent intraocular surgery prior to follow-up, received nerve growth factor treatments, or did not have a baseline examination with photography. Symptoms were assessed using the Ocular Surface Disease Index (OSDI). Patients also underwent a slit lamp exam, ocular surface staining with fluorescein and lissamine green, and Schirmer testing.Results: The charts of 47 patients treated with PRP drops for ocular surface disease were reviewed. Sixty-four eyes of 32 patients were included in the study who had photographs of lissamine green staining taken at baseline and at follow-up. Thirteen patients (28%) had ocular graft-versus-host disease, 16 patients (34%) had Sjögren’s syndrome, and 4 patients (8.5%) had rheumatoid arthritis. There was a statistically significant decrease in OSDI score from baseline to follow-up (39.5 vs 30.8 points, p = 0.02). Among the 64 eyes included, 9 (14%) had an improvement in conjunctival lissamine green staining, while 6 (9%) had an increase in staining at follow-up. Among the 20 eyes with Schirmer testing, there was a borderline significant increase in score from baseline to follow-up (5.9 vs 9.7, p = 0.06). Among the 44 eyes that had corneal fluorescein staining (CFS) reported, 8 (18.2%) had decreased staining and 2 (4.5%) had increased staining at follow-up.Conclusion: Treatment with PRP drops was associated with a significant improvement in symptoms in patients with ocular surface disease. Future larger prospective studies are needed to further evaluate the efficacy of PRP drops for treating ocular surface disease.Keywords: ocular surface disease, cornea, lissamine green, Ocular Surface Disease Index, platelet-rich plasma

Zujaja Tauqeer,1 Stephanie E Jinno,1,2 Caroline W Chung,1 Mina Massaro-Giordano,1 Vatinee Y Bunya1 1Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Drexel University School of Medicine, Philadelphia, PA, USACorrespondence: Vatinee Y Bunya, Tel +1-215-662-8100, Email Vatinee.Bunya@pennmedicine.upenn.eduPurpose: Ocular adverse events have been reported in association with dupilumab, a monoclonal antibody to treat allergic diseases including atopic dermatitis (AD). We describe clinical findings and treatment of dupilumab-related ocular complications.Patients and Methods: Retrospective study of 19 dupilumab-treated AD patients seen for a new ocular complaint. Primary outcomes were specific ocular exam findings (conjunctival injection, corneal fluorescein staining, blepharitis, meibomian gland dysfunction (MGD)), treatments, and follow-up.Results: Nineteen dupilumab-treated AD patients were included. Median age was 47 years (range 18– 73). Over half were women (11/19) and majority were Caucasian (13/19). Symptom onset occurred at a mean of 99 days (range 23– 520 days) from first dupilumab dose. The most common symptoms were redness (63%), tearing (47%), and pruritus (37%). Most common ocular findings were conjunctival injection (75%) and corneal staining (60%). Blepharitis was seen in about a third (30%), and 25% had MGD. Initially, 10% were observed without treatment, while 15% were treated with artificial tears alone. Other treatments included antihistamine drops (20%) and steroid drops alone (15%). In 40% of patients, a combination of steroids and various other topical eye drops were prescribed. Eighty-four percent (16/19) of patients were seen for follow-up. Steroid drops were required at follow-up in 3 out of 4 patients initially treated with antihistamines alone and in two-thirds of patients initially treated with artificial tears only. Mean follow-up period was 88 days (range 5– 369). Dupilumab was discontinued in 31.5% (6/19) of patients; of those who discontinued, 3 restarted it later.Conclusion: Conjunctival injection was the most frequent dupilumab-related ocular symptom and most common exam finding followed by corneal staining. Most patients initially treated with antihistamine drops or artificial tears alone subsequently required steroid drops to control symptoms. Some patients who discontinued dupilumab restarted the medication after achieving adequate control of ocular symptoms.Keywords: dupilumab, atopic dermatitis, conjunctivitis, cornea, dry eye

Jonathan Lilley,1 Erin C O’Neil,1 Vatinee Y Bunya,1 Kennedy Johnson,1 Gui-Shuang Ying,2 Peiying Hua,2 Mina Massaro-Giordano1 1Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; 2Center for Preventive Ophthalmology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USACorrespondence: Mina Massaro-GiordanoDepartment of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 51 N. 39th Street, Philadelphia, PA, 19104, USATel +1 215-662-9393Email mina@pennmedicine.upenn.eduPurpose: To assess the efficacy and safety of an intranasal tear neurostimulator (ITN) device in Sjögren syndrome (SS) patients.Methods: This was a two-visit prospective, randomized, controlled, same-day crossover study in participants with SS. Inclusion criteria were assessed at a baseline screening visit and included an Ocular Surface Disease Index (OSDI) score ≥ 13, and a Schirmer with anesthesia ≤ 10 mm/5 min (in at least one eye), with a cotton swab stimulation induced increase of ≥ 4 mm in the same eye. Participants returned for the application visit, where they received intranasal and extranasal applications of the ITN in random sequence, separated by at least 60 min. Schirmer scores were measured in both eyes after each application and compared to baseline values. Generalized linear models were performed to compare the change in Schirmer scores from baseline, and generalized estimating equations were used to account for correlations from repeated measurements in the same eye and measurements from two eyes of the same patient.Results: Fifty-five participants were screened and 35 were enrolled (all female), ranging in age from 31 to 72 years (mean, 57 years). The baseline OSDI score ranged from 14 to 91 (mean, 50.5), and the baseline Schirmer score had a mean (SD) of 6.4 (3.5) ranging from 0 to 20 (mm/5min). Improvement in Schirmer scores was significantly greater for intranasal device application (13.5 mm/5min, 95% CI: 10.4, 16.5) compared to extranasal device application (0.8mm/5min, 95% CI: − 0.9, 2.4) (p< 0.0001). The effects of the intranasal device application were significant regardless of the participant’s baseline Schirmer score and systemic SS medication usage (p< 0.05).Conclusion: Intranasal application of the ITN device significantly increased tear production in a subset of SS patients compared to baseline and was more effective than extranasal application. While production of the ITN device was recently discontinued, our findings suggest that other therapies that neurostimulate the lacrimal function unit may be effective in a subset of SS patients.Keywords: Sjögren syndrome, intranasal tear neurostimulation, tear production

Marco Marenco,1,* Ilaria Macchi,2,* Iacopo Macchi,3 Emilio Galassi,4 Mina Massaro-Giordano,5 Alessandro Lambiase1 1Department of Sense Organs, University of Rome “Sapienza”, 2Department of Ophthalmology, Campus Bio-Medico University of Rome, Rome, 3Department of Ophthalmology, University of Catania, Catania, 4Ophthalmic Clinic, Department of Ophthalmology, University of L’Aquila, L’Aquila, Italy; 5Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA *These authors contributed equally to this work Abstract: Congenital ptosis is a rare condition characterized by lower positioning of the upper eyelid that is present at birth and is a clinical condition that is persistent if not treated. It may be unilateral or bilateral and may be associated with other ocular disorders or systemic conditions, including Marcus Gunn, Horner, and Duane syndromes. It is a benign condition but causes functional, cosmetic, and psychological problems in children. However, not all patients need to undergo surgery, and usually only patients at risk of amblyopia need a prompt surgical correction, while in other cases, surgery can be postponed. The grade of ptosis, the eyelid function, and the amblyopic risk are the parameters that affect the ophthalmologist’s decision on timing of surgery and the surgical technique to be used. In fact, there are several types of surgical techniques to correct a congenital ptosis, although very often more than one is needed to obtain an acceptable result. This paper reviews the causes of congenital ptosis and associated diseases. Particular emphasis is given to surgical management and different procedures available to correct the upper eyelid anomaly and avoid permanent damage to visual function. Keywords: ptosis, extraocular muscle development, neurologic dysfunction, surgical approach

Nicole Fuerst,1 Nicole Langelier,1 Mina Massaro-Giordano,1 Maxwell Pistilli,1 Kalliopi Stasi,1 Carrie Burns,2 Serena Cardillo,2 Vatinee Y Bunya1 1Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Purpose: To assess the relationship between tear osmolarity and dry eye symptoms in patients with diabetes. Patients and methods: Fifty patients with diabetes were enrolled. Demographic information and past medical history were recorded. Symptoms were assessed using the ocular surface disease index (OSDI). Tear osmolarity of each eye was measured with the TearLab® Osmolarity System. Results: The majority of the subjects were female (76%), African American (56%), and/or had a diagnosis of type 2 diabetes (82%). The mean ± standard deviation (SD) for age was 54.6±13.4, and maximum tear osmolarity was 304.6±12.7 mOsm/L. Men had higher osmolarity than women (mean ± standard error (SE) 311.8±4.0 mOsm/L versus 302.3±1.9 mOsm/L, P=0.02). Age, race, use of artificial tears, years of diabetes, and hemoglobin A1c did not have a statistically significant association with tear osmolarity. Longer duration of diabetes was associated with lower (less severe) OSDI scores (r=-0.35, P=0.01). Higher tear osmolarity was associated with lower (less severe) OSDI scores (r=-0.29, P=0.04). Conclusion: Approximately half of the diabetic subjects in our study had elevated tear osmolarity, and half of our population also reported symptoms consistent with dry eye disease. However, the two were slightly inversely related in that those with higher osmolarity reported fewer symptoms. Subjects with a longer duration of diabetes also reported fewer dry eye symptoms. Therefore, health care providers should be aware that patients who are most likely to have ocular surface disease, including those with long-standing diabetes, may not experience symptoms and seek care in a timely manner. Keywords: dry eye, osmolarity, diabetes

Purpose: The purpose of this study was to provide relative citation ratio (RCR) benchmark data for cornea and external diseases specialists., Design: This is a cross-sectional bibliometric analysis., Subjects: Subjects included were fellowship-trained cornea and external diseases faculty at Accreditation Council for Graduate Medical Education-accredited institutions in the United States., Methods: Academic specialists were indexed using the National Institutes of Health iCite Web site. Publication count, mean RCR score, and weighted RCR score were obtained between October 2022 and January 2023 by examining PubMed-listed publications from 1980 to 2022. Data were compared by sex, career duration, academic rank, and acquisition of a Doctor of Philosophy., Main Outcome Measures: The main outcome measures were publication count, mean RCR value, and weighted RCR value., Results: The cohort included 602 specialists from 112 Accreditation Council for Graduate Medical Education-accredited institutions. These clinician-scientists produced highly impactful research with a median publication count of 15 (interquartile ranges 4-41), median RCR of 1.4 (interquartile ranges 0.91-1.88), and median-weighted RCR of 20.28 (5.3-66.69). Both academic rank and career length were associated with greater publication count and RCR values. Male sex was also associated with greater publications counts and RCR scores compared with female faculty. Acquisition of a Doctor of Philosophy was associated with greater publication counts and weighted RCR scores but no difference in mean RCR scores., Conclusions: Academic cornea and external diseases specialists conduct high-impact research, with a median RCR of 1.4, exceeding the NIH standard value of 1. These data provide RCR benchmark data for the field to inform self, institutional, and departmental evaluations. These results also highlight a significant gender disparity in the field necessitating efforts to increase female representation and ensure equal opportunities., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Cenegermin is approved for treatment of neurotrophic keratopathy (NK) and has been studied in patients with stage 2 or 3 NK. This study evaluated the efficacy and safety of cenegermin in adults with stage 1 NK., Methods: This was a phase IV, multicenter, prospective, open-label, uncontrolled trial. Adults with stage 1 NK (Mackie criteria) and decreased corneal sensitivity (≤ 4 cm) received 1 drop of cenegermin 20 mcg/ml in the affected eye(s) 6 times/day for 8 weeks with a 24-week follow-up., Results: Of 37 patients, corneal epithelial healing was observed in 84.8% (95% confidence interval [CI] 68.1-94.9%; P < 0.001) at week 8; 95.2% (95% CI 76.2-99.9%; P < 0.001) of those patients remained healed at the end of the 24-week follow-up (week 32). At week 8, 91.2% (95% CI 76.3-98.1%; P < 0.001) of patients experienced improved corneal sensitivity; this improvement was observed in 82.1% (95% CI 63.1-93.9%; P < 0.001) of patients at week 32. Mean best-corrected distance visual acuity change from baseline at week 8 was - 0.10 logMAR (standard deviation [SD], 0.15; 95% CI - 0.16 to - 0.05; P < 0.001) and at week 32 was - 0.05 logMAR (SD, 0.16; 95% CI - 0.11 to 0.01; P = 0.122). At weeks 8 and 32, 15.2% (95% CI 5.1-31.9%; P < 0.001) and 10.7% (95% CI 2.3-28.2%; P < 0.001) of patients, respectively, had a 15-letter gain from baseline. At least one adverse event (AE) was reported by 73.0% and 45.7% of patients during the treatment and follow-up periods, respectively. The most common treatment-related, treatment-emergent AEs were eye pain (37.8%), blurred vision (10.8%), and eyelid pain (8.1%); these were mostly mild or moderate and were only reported during the treatment period., Conclusions: These results support the potential use of cenegermin for treating patients with stage 1 NK, and future confirmatory studies would be beneficial to elaborate on these findings., Trial Registration: DEFENDO; NCT04485546., (© 2024. The Author(s).)

Objective: Sjögren's syndrome (SS) is frequently undetected or misdiagnosed as other rheumatologic diseases. We aimed to develop an SS screening questionnaire for the rheumatology practice., Methods: We developed the Sjögren's Syndrome Screening Questionnaire (SSSQ) via secondary analysis of data from 974 participants referred by rheumatologists to the Sjögren's International Collaborative Clinical Alliance (SICCA) study. Participants answered 88 questions regarding symptoms, medical history, and demographics. They underwent ocular, dental, and serologic tests and were classified as SS or non-SS using the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria. We conducted univariate and multivariate logistic regression to identify questions most discriminative of SS, from which we derived an individual's likelihood of SS ("SSSQ score")., Results: Five questions were significantly discriminative of SS in the multivariate analysis (p < 0.05): (1) Can you eat a cracker without drinking a fluid/liquid? (no: odds ratio [OR], 1.39; 95% confidence interval [CI], 1.06-1.82]); (2) How would you describe your dental and oral health in general? (fair/poor: OR, 1.68; 95% CI, 1.04-2.75); (3) During the last week, have you experienced tearing? (none of the time: OR, 2.26; 95% CI, 1.23-4.34); (4) Are you able to produce tears? (no: OR, 1.62; 95% CI, 1.12-2.37); and (5) Do you currently smoke cigarettes? (no: OR, 2.83; 95% CI, 1.69-4.91). SSSQ score ≥7 (possible range, 0-11) distinguishes SS from non-SS patients with 64% sensitivity and 58% specificity (area under receiver operating characteristic curve, 0.65)., Conclusions: The SSSQ is a simple 5-item questionnaire designed to screen for SS in clinical practice, with a potential impact to reduce delays in diagnosis., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Topical administration is the most convenient route for ocular drug delivery, but only a minor fraction is retained in the precorneal pocket. To overcome this limitation, numerous drug delivery systems (DDS) have been developed. The protein corona (PC) is the layer of biomolecules (e.g., proteins, sugars, lipids, etc.) that forms around DDS in physiological environments by non-covalent interaction. The PC changes the DDS physical-chemical properties, providing them with a completely novel biological identity. The specific involvement of PC in ocular drug delivery has not been addressed so far. To fulfill this gap, here we explored the interaction between a library of four cationic liposome-DNA complexes (lipoplexes) and mucin (MUC), one of the main components of the tear film. We demonstrate that MUC binds to the lipoplex surface shifting both their size and surface charge and reducing their absorption by primary corneal epithelial cells. To surpass such restrictions, we coated lipoplexes with two different artificial PCs made of Fibronectin (FBN) and Val-Gly-Asp (VGA) tripeptide that are recognized by receptors expressed on the ocular surface. Both these functionalizations remarkedly boosted internalization in corneal epithelial cells with respect to pristine (i.e., uncoated) lipoplexes. This opens the gateway for the exploitation of artificial protein corona in targeted ocular delivery, which will significantly influence the development of novel nanomaterials.

The purpose of this review is to delve into the clinical and research understanding of the pathophysiology and presentation of Sjögren's-related keratoconjunctivitis sicca in order address the diagnostic and management challenge that it represents, as well as to provide a basis for appreciating the pharmacotherapies designed to treat the ophthalmic symptoms of Sjögren's disease.

Background: Although dupilumab has been associated with the development of conjunctivitis, little is known about other ocular surface disorders such as dry eye and how these side effects are managed., Objective: To evaluate the incidence and management of ocular surface disorders, including dry eye and conjunctivitis, among patients treated with dupilumab., Methods: Using US claims data, we evaluated the incidence of encounters for ocular surface disorders among patients treated with dupilumab. Secondary outcomes included ophthalmic medication use. A propensity score matched, active-comparator, new-user cohort design was used to compare the incidence of ocular surface disorders between those starting dupilumab versus methotrexate., Results: Among those with a history of atopic dermatitis, encounters for ocular surface disorders were more common in the 6 months after starting dupilumab than in the 6 months prior (11.7% versus 8.7%, P  < .001); 59.7% of those with a new ocular surface disorder diagnosis filled a prescription for an ophthalmic medication. The incidence of ocular surface disorders was higher among those treated with dupilumab than that in those treated with methotrexate (odds ratio 1.64; 95% confidence interval 1.17-2.30)., Limitations: Observational design., Conclusions: Dupilumab use for atopic dermatitis was associated with an increased risk of ocular surface disorders. Most patients who developed an ocular surface disorder received a prescription for an ophthalmic medication., Competing Interests: Dr Margolis was a member of joint Sanofi/Regeneron Data Safety and Monitoring Board for studies of dupilumab; he left the Data Safety and Monitoring Board about 2 years ago. He receives research funding to the Trustees of the University of Pennsylvania from the NIH-NIAMS and Valiant for unrelated studies of atopic dermatitis. He was on an advisory board sponsored by Leo, which disbanded about 2 years ago, and is currently a consultant for Leo both with respect to atopic dermatitis. Dr Bunya has served as a consultant for Verily and receives grant funding from 10.13039/100007489Bausch and Lomb for an unrelated study. Dr Massaro-Giordano has served as a consultant for Verily and was on advisory boards sponsored by Dompe and Lynthera. Author Barbieri has no conflicts of interest to declare. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication., (© 2021 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

Purpose: This systematic review examines the specific effects of pingueculum and pterygium on the ocular surface and evaluates the efficacy of surgical excision in reversing those effects., Methods: A systematic review was performed according to the Preferred Reporting Items for the Systematic Review and Meta-Analyses statement and included 59 articles studying the effects of pterygium and pingueculum on the ocular surface as measured by tear break-up time (TBUT), Schirmer testing, tear osmolarity, Ocular Surface Disease Index (OSDI), and the effects of surgical removal on these ocular surface parameters., Results: In most studies, eyes with pterygium or pingueculum when compared with control eyes had a statistically significantly lower TBUT (average 3.72 s), lower Schirmer I without anesthesia (average 3.01 mm), lower Schirmer II (average 4.10 mm), higher tear osmolarity (average 12.33 mOsm/L), and higher OSDI (average 6.82 points). Moreover, excision of pterygium and pingueculum led to a statistically significantly higher TBUT (average 3.15 s higher at 1 mo postexcision), lower tear osmolarity (average 3.10 mOsm/L lower at 3 mo postexcision), and lower OSDI score (average 2.86 points lower 1 mo postexcision) in most of the studies. The effect of excision on Schirmer test scores was equivocal because most studies did not reach significance., Conclusions: Our data confirm the relationship between pterygium and pingueculum and abnormal tear function and symptoms of dry eye disease. Furthermore, the data suggest that tear film parameters might improve after surgical removal of pterygium or pingueculum. Future studies would be helpful in exploring the potential role of pterygium and pingueculum excision in the management of dry eye disease., Competing Interests: V. Y. Bunya is a consultant for Verily and has received funding from the National Eye Institute (R01 EY026972), Research to Prevent Blindness, and Bausch & Lomb. M. M.-Giordano is a consultant for Dompe, Lynthera, and PRN. The remaining authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To develop a screening questionnaire to identify patients with dry eye with a high likelihood of having underlying Sjögren syndrome (SS)., Methods: This was a cross-sectional study of participants with dry eye complaints who were self-referred or referred by an ophthalmologist to the Sjögren's International Collaborative Clinical Alliance study. Symptoms and ocular surface examination findings were candidate predictors. Univariable and multivariable logistic regression analyses were performed to estimate odds ratios (ORs) and 95% confidence intervals (95% CI) for the association of a symptom and/or ocular sign with SS. Area under the receiver operating characteristic curve (AUC) was used to summarize the predictive ability of different regression models and the derived likelihood score., Results: Four questions were statistically significant in the final multivariable model: 1) Is your mouth dry when eating a meal? [Yes = OR 1.63 (1.18-2.26)]; 2) Can you eat a cracker without drinking a fluid or liquid? [No = OR 1.46 (1.06-2.01)]; 3) How often do you have excessive tearing? [None of the time = OR 4.06 (1.81-9.10)]; and 4) Are you able to produce tears? [No = OR 2.24 (1.62-3.09)]. The SS likelihood score had an AUC of 0.70 (95% CI, 0.66-0.73), and when including tear break-up time and conjunctival staining, it yielded an AUC of 0.79 (95% CI, 0.77-0.82)., Conclusions: This questionnaire can be used to identify patients with dry eye with a high likelihood of having SS. With future refinement and validation, this screening tool could be used alone or in combination with examination findings to identify patients with SS earlier, thereby facilitating better clinical outcomes., Competing Interests: V. Y. Bunya: Bausch & Lomb (funding for research study); Celularity (consultant); Verily (consultant). E. K. Akpek: Allergan Inc. (institutional support), Novalique Gmb. (consultant), Regeneron (consultant), Sjogren's Syndrome Foundation (unpaid board member). M. Massaro-Giordano: Celularity (consultant); PRN (personal financial interest); Verily (consultant). F. B. Vivino: Novartis (consultant), Biogen-Idec (consultant), Celularity (consultant), Boston Pharmaceuticals (consultant) Bristol-Myers Squibb (consultant), Immco Diagnostics (consultant). A. N. Baer: Bristol-Myers Squibb (consultant), Abbvie (consultant), Sanofi (consultant). The remaining authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To describe associations between symptoms and signs of dry eye disease (DED) and meibomian gland (MG) morphology., Methods: Cross-sectional study utilizing data from the Dry Eye Assessment and Management (DREAM) Study. Readers graded MG features in the middle third of upper and lower lids on infrared meibography images. Associations with signs and symptoms of DED were evaluated with adjustment for age and sex., Results: Among 268 patients, no MG features were associated with symptom scores (p > 0.08). Among 394 upper eyelids, better tear break-up times (<2, >2- <3.2and ≥ 3.2 s) were associated with more tortuous glands (mean (SD) 0.58(0.95), 0.83(1.2) and 1.14 (1.4), p = 0.01) and with higher scores on a composite score of MG features (21.90 (9.76), 23.29 (9.50), 26.26 (10.27); p = 0.02). Longer Schirmer test wetting lengths (0-5, >5-10, and >10 mm) were associated with increasing composite scores (22.02 (9.29), 23.80 (10.34), 24.96 (9.96), p = 0.03). Patients with Sjogren syndrome compared to other patients had fewer distorted MGs (mean 3.4 (2.3) vs 4.3 (2.3), p = 0.03) and fewer ghost glands (mean 0.33 (0.88) vs 0.89 (1.8), p = 0.006) in the upper lid., Conclusion: In the DREAM study, most MG morphologic features were not associated with the severity of DED symptoms or signs. Tortuous glands and a higher composite score for MG features were associated with longer tear break-up times and longer Schirmer test length in the upper eyelid only. Patients with Sjogren syndrome had fewer distorted and ghost glands., (Copyright © 2020. Published by Elsevier Inc.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Purpose: To evaluate the efficacy and safety of topical cenegermin (recombinant human nerve growth factor) in patients with neurotrophic keratopathy., Design: Multicenter, randomized, double-masked, vehicle-controlled trial., Participants: Patients with neurotrophic persistent epithelial defect with or without stromal thinning., Methods: The NGF0214 trial, conducted among 11 sites in the United States, randomized 48 patients 1:1 to cenegermin 20 μg/ml or vehicle eye drops, 6 drops daily for 8 weeks of masked treatment. Follow-up was 24 weeks. Safety was assessed in all patients who received study drug. Efficacy was assessed by intention to treat., Main Outcome Measures: The primary end point was healing of the neurotrophic lesion (persistent epithelial defect or corneal ulcer) after 8 weeks of masked treatment. Masked central readers measured neurotrophic lesions in randomized clinical pictures, then assessed healing status conventionally (<0.5 mm of fluorescein staining in the greatest dimension of the lesion area) and conservatively (0-mm lesion staining and no other residual staining). Secondary variables included corneal healing at 4 weeks of masked treatment (key secondary end point), overall changes in lesion size, rates of disease progression, and changes in visual acuity and corneal sensitivity from baseline to week 8., Results: Conventional assessment of corneal healing showed statistically significant differences at week 8: compared to 7 of 24 vehicle-treated patients (29.2%), 16 of 23 cenegermin-treated patients (69.6%) achieved less than 0.5 mm of lesion staining (+40.4%; 95% confidence interval [CI], 14.2%-66.6%; P = 0.006). Conservative assessment of corneal healing also reached statistical significance at week 8: compared to 4 of 24 vehicle-treated patients (16.7%), 15 of 23 cenegermin-treated patients (65.2%) achieved 0 mm of lesion staining and no other residual staining (+48.6%; 95% CI, 24.0%-73.1%; P < 0.001). Moreover, the conservative measure of corneal healing showed statistical significance at week 4 (key secondary end point). Compared to vehicle, cenegermin-treated patients showed statistically significant reductions in lesion size and disease progression rates during masked treatment. Cenegermin was well tolerated; adverse effects were mostly local, mild, and transient., Conclusions: Cenegermin treatment showed higher rates of corneal healing than vehicle in neurotrophic keratopathy associated with nonhealing corneal defects., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the prevalence of novel candidate autoantibodies associated with Sjögren syndrome (SS) and their ability to identify those with SS among participants with dry eye enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) study at the University of Pennsylvania (Penn)., Methods: All participants previously underwent a full ocular and systemic evaluation for possible SS as part of the SICCA study. An enzyme-linked immunosorbent assay was used to detect IgG, IgA, and IgM autoantibodies to salivary protein 1 (SP-1), parotid secretory protein (PSP), and carbonic anhydrase 6 from previously banked baseline serum samples from SICCA study participants enrolled at Penn. The prevalence rate of each autoantibody, calculated by considering the presence of any isotype as antibody positive, was compared between participants with dry eye with SS (n = 81) or without SS (n = 129) using the Fisher exact test., Results: The prevalence of SP-1 IgM autoantibodies was higher in those with SS compared with those without SS (14% vs. 5%; P = 0.03). Similarly, the prevalence of PSP IgA autoantibodies was higher in those with SS compared with non-SS dry eye participants (21% vs. 11%; P = 0.048). There was no statistically significant difference in the prevalence of carbonic anhydrase 6 autoantibodies between those with or without SS (15% vs. 20%; P = 0.36)., Conclusions: In the Penn SICCA cohort, SP-1 IgM and PSP IgA autoantibodies were more prevalent in the serum of SS-related dry eye participants compared with those without SS. Further longitudinal studies are needed to determine the clinical significance of these findings.

Here we present a miniaturized analog of a blinking human eye to reverse engineer the complexity of the interface between the ocular system and the external environment. Our model comprises human cells and provides unique capabilities to replicate multiscale structural organization, biological phenotypes and dynamically regulated environmental homeostasis of the human ocular surface. Using this biomimetic system, we discovered new biological effects of blink-induced mechanical forces. Furthermore, we developed a specialized in vitro model of evaporative dry-eye disease for high-content drug screening. This work advances our ability to emulate how human physiological systems interface with the external world, and may contribute to the future development of novel screening platforms for biopharmaceutical and environmental applications.

Purpose: To determine whether signs and symptoms of ocular surface disease improve after placement of a self-retained, cryopreserved amniotic membrane (CAM) in patients with Sjögren syndrome (SS)., Methods: The medical records of SS patients who received a self-retained CAM implant (Prokera or Prokera Slim; TissueTech Inc, Doral, FL) for the treatment of ocular surface disease between August 2012 and August 2016 at a single, large academic institution were reviewed retrospectively. Visual acuity, results of slit-lamp examination of the cornea and conjunctiva, and dry eye symptoms, were evaluated before and after CAM insertion., Results: A total of 6 eyes of 6 patients (all female; mean age, 62.5 ± 13.0 years [range, 49-86 years]) were included. All patients were on topical medications at the time of the study and had signs of ocular surface dryness. There were reductions in corneal and/or conjunctival staining in 5 eyes (83%) after the CAM dissolved. All patients who completed therapy (5/5) experienced a relapse in their signs and symptoms within 1 month of removal of the CAM, with an average time to relapse of 24.6 days. Mean follow-up time was 54.5 days. Foreign body sensation and blurred vision were the most common complaints associated with the CAM implant., Conclusions: In this small case series, self-retained CAM implantation was found to be beneficial in SS patients with ocular surface disease that is refractory to standard therapies; however, we found that the effects were temporary. Future larger studies are needed to confirm these benefits.

Purpose of Review: The prevalence and burden of dry eye disease continues to grow at a rapid pace, creating an increased need for new therapies. In a sector once limited to only a handful of treatments, clinicians now have multiple options available for patients who fail traditional therapies. This review summarizes the various treatment options available to clinicians treating complex dry eye disease patients., Recent Findings: As we better understand the multifactorial mechanisms leading to dry eye disease, treatments increasingly focus on the amelioration of the underlying deficiencies and inflammation, rather than on transient symptomatic relief alone. Most topical medications seek to replace deficient growth factors and/or decrease inflammation on the ocular surface. The majority of new devices and procedures seek to treat meibomian gland dysfunction, with one new device stimulating tear production through utilizing the nasolacrimal reflex pathway., Summary: Clinicians have more options at their disposal in the treatment of dry eye disease than ever before, including topical medications and devices.

Objective: To survey ophthalmologists about current practice patterns regarding the evaluation of dry eye patients and referrals for a Sjogren syndrome (SS) workup., Methods: An online survey was sent to ophthalmologists affiliated with the Scheie Eye Institute or Wills Eye Hospital using REDCap in August 2015. Descriptive statistics were used to summarize the data., Results: Four hundred seventy-four survey invitations were sent out and 101 (21%) ophthalmologists completed the survey. The common traditional dry eye test performed was corneal fluorescein staining (62%) and the most common newer dry eye test performed was tear osmolarity (18%). Half of respondents (51%) refer fewer than 5% of their dry eye patients for SS workups, with 18% reporting that they never refer any patients. The most common reasons for referrals included positive review of systems (60%), severe dry eye symptoms (51%) or ocular signs (47%), or dry eye that is refractory to treatment (42%). The majority (83%) felt that there is a need for an evidence-based standardized screening tool for dry eye patients to decide who should be referred for evaluation for SS., Conclusions: Ophthalmologists continue to prefer the use of traditional dry eye tests in practice, with the most common test being corneal fluorescein staining. There is an underreferral of dry eye patients for SS workups, which is contributing to the continued underdiagnosis of the disease. Most respondents felt that there was a need for an evidence-based standardized screening tool to decide which dry eye patients should be referred for SS evaluations.

Purpose: Current scales for assessment of bulbar conjunctival redness have limitations for evaluating digital images. We developed a scale suited for evaluating digital images and compared it to the Validated Bulbar Redness (VBR) scale., Methods: From a digital image database of 4889 color corrected bulbar conjunctival images, we identified 20 images with varied degrees of redness. These images, ten each of nasal and temporal views, constitute the Digital Bulbar Redness (DBR) scale. The chromaticity of these images was assessed with an established image processing algorithm. Using 100 unique, randomly selected images from the database, three trained, non-physician graders applied the DBR scale and printed VBR scale. Agreement was assessed with weighted Kappa statistics (K w )., Results: The DBR scale scores provide linear increments of 10 from 10-100 when redness is measured objectively with an established image processing algorithm. Exact agreement of all graders was 38% and agreement with no more than a difference of ten units between graders was 91%. K w for agreement between any two graders ranged from 0.57 to 0.73 for the DBR scale and from 0.38 to 0.66 for the VBR scale. The DBR scale allowed direct comparison of digital to digital images, could be used in dim lighting, had both temporal and nasal conjunctival reference images, and permitted viewing reference and test images at the same magnification., Conclusion: The novel DBR scale, with its objective linear chromatic steps, demonstrated improved reproducibility, fewer visualization artifacts and improved ease of use over the VBR scale for assessing conjunctival redness., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Gender-based differences may influence the occurrence of several ocular conditions suggesting the possibility that fluctuations in sex steroid homeostasis may have direct effects on the eye physiology. Here, we evaluated the effect of sex steroid hormone fluctuations in male retinal pigment epithelial cells, RPEs (ARPE-19). To mimic hormonal fluctuations occurring during aging, we exposed ARPE-19 to acute, prolonged or chronic estradiol, and progesterone challenges. We found that chronic estradiol treatment promotes a remarkable necrosis of RPE cells, and does not affect pRb2/p130 or PAI-2 sub-cellular localization. In contrast, chronic progesterone exposure induces nuclear subcellular rearrangement of pRb2/p130, co-immunolocalization of pRb2/p130 with PAI-2, and accumulation of cells in G2/M phase, which is accompanied by a remarkable reduction of necrosis in favour of apoptosis activation. This study has a high clinical significance since it considers sex steroid fluctuations as inducers of milieu change in the retina able to influence pathological situations occurring with aging in non-reproductive systems such as the eye. Exogenous administration of physiologically significant amounts of sex hormones for long periods of time is a common clinical practice for transgender patients seeking sex reassignment. In particular, our study offers the unique opportunity to unravel the effects of sex hormones, not only in determining gender differences but also in affecting the physiology of non-reproductive systems, such as the eye, in the underserved transgender community., (© 2018 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals.)

Importance: Lissamine green (LG) staining of the conjunctiva is a key biomarker in evaluating ocular surface disease. The disease currently is assessed using relatively coarse subjective scales. Objective assessment would standardize comparisons over time and between clinicians., Objective: To develop a semiautomated, quantitative system to assess lissamine green staining of the bulbar conjunctiva on digital images., Design, Setting, and Participants: Using a standard photography protocol, 35 digital images of the conjunctiva of 11 patients with a diagnosis of dry eye disease based on characteristic signs and symptoms were obtained after topical administration of preservative-free LG, 1%, solution. Images were scored independently by 2 masked ophthalmologists in an academic medical center using the van Bijsterveld and National Eye Institute (NEI) scales. The region of interest was identified by manually marking 7 anatomic landmarks on the images. An objective measure was developed by segmenting the images, forming a vector of key attributes, and then performing a random forest regression. Subjective scores were correlated with the output from a computer algorithm using a cross-validation technique. The ranking of images from least to most staining was compared between the algorithm and the ophthalmologists. The study was conducted from April 26, 2012, through June 2, 2016., Main Outcomes and Measures: Correlation and level of agreement among computerized algorithm scores, van Bijsterveld scale clinical scores, and NEI scale clinical scores., Results: The scores from the automated algorithm correlated well with the mean scores obtained from the gradings of 2 ophthalmologists for the 35 images using the van Bijsterveld scale (Spearman correlation coefficient, rs = 0.79), and moderately with the NEI scale (rs = 0.61) scores. For qualitative ranking of staining, the correlation between the automated algorithm and the 2 ophthalmologists was rs = 0.78 and rs = 0.83., Conclusions and Relevance: The algorithm performed well when evaluating LG staining of the conjunctiva, as evidenced by good correlation with subjective gradings using 2 different grading scales. Future longitudinal studies are needed to assess the responsiveness of the algorithm to change of conjunctival staining over time.

Purpose: The aim of this study was to examine the tolerability of topical tocilizumab eyedrops in normal dogs and to assess whether this preparation alters tear film cytokine levels or conjunctival cytokine mRNA expression., Methods: Two percent tocilizumab eyedrops were administered to the right eyes and artificial tears to the left eyes of 10 dogs with no anterior segment pathology 3 times daily for 4 weeks. Portable slit-lamp examinations and Schirmer tear testing were performed at baseline and day 1 week 4, as well as 2 weeks after treatment (week 6). Schirmer strips were also used to collect tears for analyses of cytokine levels using multiplex bead array. Median levels of 8 cytokines in the tear film [interferon gamma (IFN-γ), tumor necrosis factor (TNF)-α, interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-8, and IL-10] were compared among tocilizumab-treated and control eyes. Conjunctival biopsies from both eyes were collected at week 4, and mRNA levels of cytokines were also evaluated. Blood samples were collected at baseline and at the end of treatment to monitor for changes in complete blood count, basic metabolic panel, or liver function tests., Results: At week 4, conjunctival biopsies and tear samples showed no significant differences in either tear cytokine or mRNA levels for IFN-γ, TNF-α, IL-2, IL-6, IL-8, and IL-10. There was no evidence of local irritation or changes in bloodwork results from the topical tocilizumab formulation., Conclusions: Topical application of tocilizumab eyedrops was well tolerated when used on healthy dog eyes in this pilot study.

Purpose: To describe imaging of the external eye with Crossed Polarizers to enhance clinically important features in digital photographs of the eyelids., Methods: External photographs with and without crossed polarizing filters were taken of patients with blepharitis and controls with no clinical eye pathology., Results: Photographing eyelid skin through Crossed Polarizers decreased reflections on the skin surface and improved visualization of eyelid telangiectasias and blood vessels in patients with a broad range of skin pigmentation and ethnicities., Conclusions: The use of Crossed Polarizers in imaging the external eye reduces reflections and glare from the eyelid skin and margins, thereby allowing for a more detailed evaluation of underlying structures and analysis of images. These findings suggest that including Crossed Polarizers in clinical photography has informative applications for assessing eyelid disease.

Cell cycle reactivation in adult neurons is an early hallmark of neurodegeneration. The lipopolysaccharide (LPS) is a well-known pro-inflammatory factor that provokes neuronal cell death via glial cells activation. The retinoblastoma (RB) family includes RB1/p105, retinoblastoma-like 1 (RBL1/p107), and retinoblastoma-like 2 (Rb2/p130). Several studies have indicated that RB proteins exhibit tumor suppressor activities, and play a central role in cell cycle regulation. In this study, we assessed LPS-mediated inflammatory effect on cell cycle reactivation and apoptosis of neuronally differentiated cells. Also, we investigated whether the LPS-mediated inflammatory response can influence the function and expression of RB proteins. Our results showed that LPS challenges triggered cell cycle reactivation of differentiated neuronal cells, indicated by an accumulation of cells in S and G2/M phase. Furthermore, we found that LPS treatment also induced apoptotic death of neurons. Interestingly, we observed that LPS-mediated inflammatory effect on cell cycle re-entry and apoptosis was concomitant with the aberrant expression of RBL1/p107 and RB1/p105. To the best of our knowledge, our study is the first to indicate a role of LPS in inducing cell cycle re-entry and/or apoptosis of differentiated neuronal cells, perhaps through mechanisms altering the expression of specific members of RB family proteins. This study provides novel information on the biology of post-mitotic neurons and could help in identifying novel therapeutic targets to prevent de novo cell cycle reactivation and/or apoptosis of neurons undergoing neurodegenerative processes.

Purpose: To identify a screening strategy for dry eye patients with a high likelihood of having Sjogren syndrome (SS) through the evaluation of the association of ocular surface tests with the extraocular signs used for the diagnosis of SS., Design: Multicenter cross-sectional study., Methods: The Sjogren's International Clinical Collaborative Alliance (SICCA) registry enrolled 3514 participants with SS or possible SS from 9 international academic sites. Ocular surface evaluation included Schirmer I testing, tear breakup time (TBUT), and staining of the cornea (0-6 points) and conjunctiva (0-6 points). Multivariate logistic regression analysis was performed to identify predictive factors for (1) histopathologic changes on labial salivary gland (LSG) biopsies (positive = focus score of ≥1 focus/4 mm 2 ) and (2) positive anti-SSA/B serology., Results: The adjusted odds of having a positive LSG biopsy were significantly higher among those with an abnormal Schirmer I test (adjusted OR = 1.26, 95% CI 1.05-1.51, P = .014) and positive conjunctival staining (for each additional unit of staining 1.46; 95% CI 1.39-1.53, P < .001) or corneal staining (for each additional unit of staining 1.14; 95% CI 1.08-1.21, P < .001). The odds of having a positive serology were significantly higher among those with an abnormal Schirmer I test (adjusted OR = 1.3; 95% CI 1.09-1.54, P = .004) and conjunctival staining (adjusted OR = 1.51; 95% CI 1.43-1.58, P < .001)., Conclusions: In addition to corneal staining, which was associated with a higher likelihood of having a positive LSG biopsy, conjunctival staining and abnormal Schirmer I testing are of critical importance to include when screening dry eye patients for possible SS, as they were associated with a higher likelihood of having a positive LSG biopsy and serology., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Importance: Knowledge about the variability of measurements using the TearLab Osmolarity System is necessary when evaluating the clinical utility of readings., Objective: To examine the variability of tear osmolarity measured by the TearLab Osmolarity System in patients with Sjögren syndrome (SS), patients with blepharitis, and control participants., Design, Setting, and Participants: Cross-sectional study at a tertiary care academic center from June 13, 2012, to March 21, 2013. Participants included 74 eyes of 37 patients from a volunteer sample (18 patients with SS, 11 patients with blepharitis, and 8 control participants) who were evaluated using the TearLab Osmolarity System, with 3 consecutive osmolarity measurements taken at 1-minute intervals in a session; 15 of these patients had the same measurements taken by the same examiner in 2 additional sessions on the same day (9 AM-10 AM, 12 PM-1 PM, or 3 PM-4 PM). Most patients with SS and patients with blepharitis were taking systemic or topical dry eye medications at the time of enrollment., Main Outcomes and Measures: Mean osmolarity and its variability calculated from a linear mixed model for each disease group that accounts for the variations attributable to different patients, eyes, and sessions and measurement error specific to each disease group., Results: Mean tear osmolarity was 307 mOsm/L, 304 mOsm/L, and 301 mOsm/L in the SS, blepharitis, and control groups, respectively (P = .46). The error associated with repeated measurements within a session in the patients without dry eye (10.5 mOsm/L [95% CI, 9.0-12.4]) was significantly lower than in the patients with blepharitis (14.6 mOsm/L [95% CI, 12.5-17.5]; P = .006) and patients with SS (15.8 mOsm/L [95% CI, 14.2-17.8]; P < .001) but a difference in the error of repeated measurements between patients with blepharitis and patients with SS was not identified (P = .46)., Conclusions and Relevance: There was increased variability attributable to error in repeated measurements in patients with SS and patients with blepharitis compared with control participants. The high variability of TearLab osmolarity readings in all groups makes the clinical interpretation of measurements unclear.

Nerve growth factor (NGF) is an endogenous neurotrophin involved in the development, maintenance and regeneration of mammalian sympathetic and sensory neurons. Additionally, NGF is known to have trophic and differentiating activity on several populations of cholinergic neurons of the central nervous system (CNS), and to act as a differentiation factor in the development of the visual cortex. The paramount functions of NGF in the visual system are also highlighted by the presence of this neurotrophin and both its receptors TrkA and p75 in most intra-ocular tissues, including lens, vitreous, choroid, iris, and trabecular meshwork. In the retina, NGF is produced and utilized specifically by retinal ganglion cells (RGC), bipolar neurons and glial cells, and is thought to have crucial protective effects in several disease states. Studies on the role of NGF on RGCs survival following optic nerve transection, ischemic injury, ocular hypertension and glaucoma are discussed in this review., (© 2014 Wiley Periodicals, Inc.)

Purpose: To describe a standardized technique for acquiring and viewing photographic images of eyelids, assess the reproducibility and validity of a grading protocol for signs of anterior blepharitis, and to explore whether the signs depend on the eyelid or the area of the eyelid assessed., Methods: Subjects with anterior blepharitis ranging from none to severe were examined by ophthalmologists at clinical sites. Digital images of the eyelids of subjects were acquired using a protocol that allowed for the calibration of color and luminance. Three ophthalmologists at a centralized reading center applied a novel protocol for grading features of anterior blepharitis from the digital images viewed on color-calibrated monitors. The agreement among graders was assessed using percent agreement and weighted kappa statistics (Kw), and the correlation of photographic and clinical gradings was assessed using Spearman correlation coefficients., Results: Agreement among graders was excellent (Kw > 0.80) on the number of eyelid margin vessels and was substantial (Kw between 0.61 and 0.80) for erythema, collarettes, number of engorged vessels, and number of lashes. Grading of the photographic images and the clinical assessments of erythema and lid debris were moderately correlated (r = 0.27-0.45). The grades for different features depended on whether the upper or lower eyelid, eyelid skin or lid margin, and central or lateral lid were assessed., Conclusions: The application of a protocol to obtain and display calibrated digital images of eyelids supports the standardized assessment of anterior blepharitis in clinical care and research studies.

Stem cell technology has evoked considerable excitement among people interested in the welfare of animals, as it has suggested the potential availability of new tools for several pathologies, including eye disease, which in many cases is considered incurable. One such example is ulcerative keratitis, which is very frequent in horses. Because some of these corneal ulcers can be very severe, progress rapidly and, therefore, can be a possible cause of vision loss, it is important to diagnose them at an early stage and administer an appropriate treatment, which can be medical, surgical, or a combination of both. The therapeutic strategy should eradicate the infection in order to reduce or stop destruction of the cornea. In addition, it should support the corneal structures and control the uveal reaction, and the pain associated with it, in order to minimize scarring. In this study, we address how stem cells derived from peripheral blood can be used also in ophthalmological pathologies. Our results demonstrate that this treatment protocol improved eye disease in four horse cases, including corneal ulcers and one case of retinal detachment. In all cases, we detected a decrease in the intense inflammatory reaction as well as the restoration of the epithelial surface of the central cornea., (Copyright © 2011 Wiley Periodicals, Inc.)

Iron is essential for many metabolic processes but can also cause damage. As a potent generator of hydroxyl radical, the most reactive of the free radicals, iron can cause considerable oxidative stress. Since iron is absorbed through diet but not excreted except through menstruation, total body iron levels buildup with age. Macular iron levels increase with age, in both men and women. This iron has the potential to contribute to retinal degeneration. Here we present an overview of the evidence suggesting that iron may contribute to retinal degenerations. Intraocular iron foreign bodies cause retinal degeneration. Retinal iron buildup resulting from hereditary iron homeostasis disorders aceruloplasminemia, Friedreich's ataxia, and panthothenate kinase-associated neurodegeneration cause retinal degeneration. Mice with targeted mutation of the iron exporter ceruloplasmin have age-dependent retinal iron overload and a resulting retinal degeneration with features of age-related macular degeneration (AMD). Post mortem retinas from patients with AMD have more iron and the iron carrier transferrin than age-matched controls. Over the past 10 years much has been learned about the intricate network of proteins involved in iron handling. Many of these, including transferrin, transferrin receptor, divalent metal transporter-1, ferritin, ferroportin, ceruloplasmin, hephaestin, iron-regulatory protein, and histocompatibility leukocyte antigen class I-like protein involved in iron homeostasis (HFE) have been found in the retina. Some of these proteins have been found in the cornea and lens as well. Levels of the iron carrier transferrin are high in the aqueous and vitreous humors. The functions of these proteins in other tissues, combined with studies on cultured ocular tissues, genetically engineered mice, and eye exams on patients with hereditary iron diseases provide clues regarding their ocular functions. Iron may play a role in a broad range of ocular diseases, including glaucoma, cataract, AMD, and conditions causing intraocular hemorrhage. While iron deficiency must be prevented, the therapeutic potential of limiting iron-induced ocular oxidative damage is high. Systemic, local, or topical iron chelation with an expanding repertoire of drugs has clinical potential.

Human retinoblastoma occurs in two forms (familial and sporadic) both due to biallelic mutation of the RB1/p105 gene even if its loss is insufficient for malignancy. We have recently reported that loss of expression of the retinoblastoma-related protein pRb2/p130 correlates with low apoptotic index, suggesting that RB2/p130 gene could be involved in retinoblastoma. Mutational analysis of RB2/p130 in primary tumors showed a tight correlation between Exon 1 mutations and pRb2/p130 expression level in sporadic retinoblastoma. These mutations are located within a CpG-enriched region prone to de novo methylation. Analysis of RB2/p130 methylation status revealed that epigenetic events, most probably consequent to the Exon 1 mutations, determined the observed phenotype. Treatment of Weri-Rb1 cell line by 5-Aza-dC induced an increase in expression level of pRb2/p130, E2F1, p73 and p53. Overall, our results highlight a crucial role of epigenetic events in sporadic retinoblastoma, which opens a perspective for new therapeutic approaches.