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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

Alice T Epitropoulos,1,2 Sheraz M Daya,3 Cynthia Matossian,4 Alan G Kabat,5,6 Gretchen Blemker,5 Kristen Striffler,5 Laura Hendrix,5 Marian Macsai,5 Andrea Gibson5 1Ophthalmic Surgeons & Consultants of Ohio, the Eye Center of Columbus, Columbus, OH, USA; 2Department of Ophthalmology, the Ohio State University Wexner Medical Center, Columbus, OH, USA; 3Centre for Sight, London, UK; 4Matossian Eye Associates, Pennington, NJ, USA; 5Oyster Point Pharma, Inc, Princeton, NJ, USA; 6Salus University, Elkins Park, PA, USACorrespondence: Andrea Gibson, Oyster Point Pharma, Inc, 202 Carnegie Center, Suite 109, Princeton, NJ, 08540, USA, Tel +1-860-227-1034, Fax +1-856-433-8439, Email agibson@oysterpointrx.comPurpose: To evaluate OC-01 [varenicline solution nasal spray (VNS)] tear production and symptom outcomes in patients with dry eye disease by age, gender, race, ethnicity, and artificial tear use status.Patients and Methods: Adults ≥ 22 years of age diagnosed with dry eye disease, with Ocular Surface Disease Index score ≥ 23, corneal fluorescein staining score ≥ 2 in ≥ 1 region or ≥ 4 for all regions, and baseline Schirmer Test Score (STS) ≤ 10 mm, with no restrictions on eye dryness score (EDS). Efficacy was assessed using integrated data from ONSET-1 and ONSET-2 [vehicle control (VC), n=294; OC-01 VNS 0.03 mg, n=308]. Subgroups included age (≤ 55, 56− 65, > 65 years), gender (male, female), race (White, Black or African American), ethnicity (Hispanic or Latino, Not Hispanic or Latino), and artificial tear use (yes, no). Analysis of covariance models, with the covariates treatment, study site, and baseline severity measures, were used to calculate treatment−VC differences. Consistency of effect among subgroups was evaluated by conducting interaction tests.Results: Consistency of treatment effect across subgroups was observed for all endpoints, with P value for all treatment−subgroup interaction terms > 0.05. For % of patients with ≥ 10mm improvement in STS and least squares (LS) mean change from baseline in STS and EDS, there was improvement in tear production across demographic group categories. Artificial tear use did not change STS or EDS outcomes with OC-01 VNS.Conclusion: OC-01 VNS improved tear production and patient-reported symptom outcomes across a broad range of patients by age, gender, race, and ethnicity, and regardless of artificial tear use status at baseline. OC-01 VNS demonstrated a consistent benefit across an extensive range of patients with dry eye disease.Keywords: bioactivation, dry eye disease, nicotinic acetylcholine receptor, tear production, varenicline nasal spray

Malate, a precursor in the ruminal propionate production pathway, competes with methanogenesis for metabolic hydrogen, offering a way to reduce ruminal methane (CH 4 ) production in ruminants. However, cost considerations hinder widespread use of malate in ruminant diets. An alternative approach involves use of transient malate levels generated during seed germination via the glyoxylate cycle. This study investigated the methane-mitigating potential of malate-containing hydroponic fodder. Fodder samples with peak malate concentrations from alfalfa, forage pea, Italian ryegrass, rye, soybean, triticale, and wheat during germination were subjected to in vitro rumen fermentation using the Hohenheim gas test. The basal diet of in vitro fermentation comprised 40% grass silage, 40% maize silage, 15% hay, and 5% concentrate on a DM basis, with nutritional characteristics including 42.1% NDF, 25.0% ADF, 14.0% starch, 12.7% CP, and 3.5% ether extract, on a DM basis. Experimental treatments were fodder inclusion involving replacing 20% of the basal diet (20R) and, additionally, 100% replacement of the silages with alfalfa d 10 and rye d 9 (SR), the 2 high-malate fodders. Reductions in CH 4 production were observed with soybean (20R, 6.7% reduction), alfalfa (20R, 6.6% reduction), and increased with rye (20R, 6.3% increase). In the setup replacing silages with high-malate fodders (SR), alfalfa decreased CH 4 production (17.7%) but increased ammonia (174%), whereas rye increased CH 4 production (35.8%). Organic matter digestibility increased with SR rye (12.6%). Marginal effects of dietary variables were analyzed in a generalized additive model. A negative relationship between dietary malate content and CH 4 production was observed, whereas dietary NDF and starch content were positively correlated with CH 4 production. In conclusion, malate within the hydroponic fodder could potentially reduce CH 4 emissions in ruminants. However, achieving sufficient efficacy requires high malate content. Additionally, use of hydroponic fodder may increase the risk of nitrogen emissions. Animal studies are required for further investigation., (© 2024, The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the worldwide coronavirus disease 2019 (COVID-19) pandemic. Although the pathophysiology of SARS-CoV-2 infection is still being elucidated, the nicotinic cholinergic system may play a role. To evaluate the interaction of the SARS-CoV-2 virus with human nicotinic acetylcholine receptors (nAChRs), we assessed the in vitro interaction of the spike protein of the SARS-CoV-2 virus with various subunits of nAChRs. Electrophysiology recordings were conducted at α4β2, α3β4, α3α5β4, α4α6β2, and α7 neuronal nAChRs expressed in Xenopus oocytes. In cells expressing the α4β2 or α4α6β2 nAChRs, exposure to the 1 µg/mL Spike-RBD protein caused a marked reduction of the current amplitude; effects at the α3α5β4 receptor were equivocal and effects at the α3β4 and α7 receptors were absent. Overall, the spike protein of the SARS-CoV-2 virus can interact with select nAChRs, namely the α4β2 and/or α4α6β2 subtypes, likely at an allosteric binding site. The nAChR agonist varenicline has the potential to interact with Spike-RBD and form a complex that may interfere with spike function, although this effect appears to have been lost with the omicron mutation. These results help understand nAChR's involvement with acute and long-term sequelae associated with COVID-19, especially within the central nervous system.

Significance: There is a clinical necessity for dry eye disease treatments that perform across a broad range of presenting patient severities. Varenicline solution nasal spray (VNS), a unique cholinergic agonist ocular surface-sparing nasal spray therapy, demonstrated significant improvement in both signs and symptoms of dry eye disease in subjects with mild, moderate, and severe symptoms as the clinical studies enrolled a more real-world patient population., Purpose: This study evaluated efficacy outcomes for VNS in patients with mild-moderate and severe dry eye disease., Methods: An analysis of integrated data from two randomized clinical trials, ONSET-1 (NCT03636061) and ONSET-2 (NCT04036292) (vehicle control [VC], n = 294; VNS 0.03 mg, n = 308), was performed. Adults 22 years or older with dry eye disease, Ocular Surface Disease Index score of ≥23, corneal fluorescein staining score of ≥2 in ≥1 regions/≥4 all regions, and Schirmer Test Score (STS) of ≤10 mm (no restrictions on Eye Dryness Score [EDS]) were included in this study. Efficacy was evaluated using analysis of covariance among pre-specified subgroups of mild-moderate and severe baseline disease severity defined by STS (≤5 vs. >5) and EDS (<60 vs. ≥60). Consistency of effect was evaluated by interaction tests., Results: No treatment-subgroup interactions were observed for all end points ( P > .05). The odds of achieving a ≥10-mm improvement in STS for VNS versus VC for patients with baseline STS ≤5 and >5 were 3.4(95% confidence interval, 2.0 to 5.6) and 2.3(1.3 to 4.0) and for EDS of <60 and ≥60 were 3.4(1.9 to 6.1) and 2.5(1.5 to 4.0). Least-squares mean treatment/VC differences in change from baseline in EDS for patients with baseline STS ≤5 or >5 were -7.4(95% confidence interval, -12.5 to -2.4) and -2.8(-8.7 to 3.1); EDS of <60 and ≥60 were -2.9(-8.3 to 2.5) and -8.1(-13.6 to -2.6)., Conclusions: Compared with VC, VNS improved tear production and patient-reported symptoms in patients with dry eye disease, demonstrating consistency of effect regardless of initial presenting severity., Competing Interests: Conflict of Interest Disclosure: AG, corresponding author, is an employee of and shareholder in Oyster Point Pharma, Inc., the sponsor of this study. The authors report the following conflicts of interest: JDS has consulted for the following companies: AbbVie, Alcon, Aldeyra, Allergan, Alphaeon, ArcScan, Avedro, Bausch & Lomb, BioLayer, Bio-Tissue, Bruder Healthcare, Clearside, Clearview, Clementia Pharma, Dompe, Eleven, Eyedetec, EyeGate Research, EyeRx Research, Eyevance, Glaukos, Hovione, Imprimis Pharma, InSite Vision Inc., Inspire/Merck Pharmaceuticals, Isis Pharmaceuticals, Johnson & Johnson/TearScience/Vistakon, Kala Pharmaceuticals, Kowa, LacriSciences, LayerBio, Lenstatin, Lumenis, Lux Biosciences, Mallinckrodt, Mati Therapeutics, MioTech, Neomedix, NicOx, NovaBay, Novaliq, Novartis, Noveome Biotherapeutics, OcuCure, Ocular Therapeutix, Oculis, Okogen, Omeros, Oyster Point, Parion, Pfizer, Portage, Quidel, Rapid Pathogen Screening, Rutech, Santen, Science Based Health, Senju, Shire, Sun Pharmaceuticals, Surrozen, Synedgen, Takeda, Talia Technology, Tear Solutions, TearLab, Topcon, TopiVert, and Xoma/Servier. LEO, PMK, and WOW are speakers and consultants for Oyster Point Pharma, Inc. GB, MH, LHH, AG, and MM are employees of and shareholders in Oyster Point Pharma, Inc., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Optometry.)

Introduction: The Understanding New Interventions with GBM ThErapy (UNITE) study was designed to assess the effect of prophylaxis for ocular side effects (OSEs) in patients with glioblastoma receiving the antibody-drug conjugate (ADC) depatuxizumab mafodotin. UNITE (NCT03419403) was a phase 3b, open-label, randomized, exploratory study performed at 18 research sites in 5 countries., Methods: The study enrolled adult patients with epidermal growth factor receptor-amplified, histologically confirmed, newly diagnosed supratentorial glioblastoma or grade IV gliosarcoma, and a Karnofsky Performance Status ≥70, receiving depatuxizumab mafodotin. All patients were administered depatuxizumab mafodotin during concurrent radiotherapy and temozolomide and with adjuvant temozolomide. Ninety patients were to be randomized (1:1:1) to OSE prophylactic treatments with each depatuxizumab mafodotin infusion: (a) standard steroid eye drops, (b) standard steroid eye drops plus vasoconstrictor eye drops and cold compress, or (c) enhanced steroids plus vasoconstrictor eye drops and cold compress. A Corneal Epitheliopathy Adverse Event (CEAE) scale was devised to capture symptoms, grade OSEs (scale of 0-5), and inform ADC dose modifications. The primary endpoint was the frequency of a required change in OSE management due to inadequate control of OSEs, defined as decline from baseline in visual acuity (using logarithm of the minimum angle of resolution [LogMAR] scale) or a Grade ≥3 CEAE event, in the worst eye in the first 8 weeks of treatment; unless otherwise specified, the treatment period refers to both the chemoradiation and adjuvant phases., Results: The UNITE study was stopped early after interim analysis of separate phase III trial showed no difference in survival from depatuxizumab mafodotin. Forty patients were randomized (38 received depatuxizumab mafodotin). Overall, 23 patients experienced inadequate control of OSEs that required change in OSE management within 8 weeks of treatment, with 21 (70.0%) experiencing ≥+0.3 change on LogMAR scale in baseline-adjusted visual acuity and 12 reporting a grade ≥3 CEAE. There were no definitive differences among prophylactic treatments., Conclusions: The premature cessation of the study precludes definitive conclusions regarding the OSE prophylaxis strategies. No new clinically significant safety findings were noted. Despite these limitations, this study highlights the need for novel assessment tools to better understand and mitigate OSEs associated with ADCs., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

BACKGROUND: Matching-adjusted indirect comparison (MAIC) is a methodology for cross-study comparisons after adjusting for baseline characteristic imbalances. It is a comparative analytical approach used across therapeutic areas absent head-to-head trial outcomes. OBJECTIVE: To compare the efficacy of OC-01 (varenicline solution) 0.03 mg nasal spray (OC-01 VNS) to lifitegrast 5% ophthalmic solution on tear production and patient-reported eye dryness in patients with dry eye disease (DED) using data from phase 3 clinical trials via MAIC analysis. METHODS: Individual patient data (IPD) from the phase 3 registrational trial of OC-01 VNS and aggregate data from 2 phase 3 trials of lifitegrast in the publicly available XIIDRA New Drug Application were used. Using unanchored MAIC methods, IPD were weighted on clinically relevant baseline variables (age, race, sex, baseline Schirmer's test score [STS], and Eye Dryness Score [EDS]) to produce weighted OC-01 VNS datasets matched to the same lifitegrast datasets' variables. Least-squares (LS) mean change from baseline (CFB) in STS for OC-01 VNS was calculated using the identical analysis of covariance model and covariates used to calculate the same values for lifitegrast in the XIIDRA New Drug Application and was then compared. LS mean EDS (based on a 100- point Visual Analogue Scale) was compared via analysis of covariance in the weighted OC-01 VNS and lifitegrast datasets. OC-01 VNS at 2 and 4 weeks compared to lifitegrast data at 2 and 6 weeks. RESULTS: Data from 511 subjects (n = 260 treated; 251 vehicle control [VC]) in the OC-01 VNS phase 3 trial, 588 (n = 293 treated, 295 VC) in the lifitegrast phase 3 OPUS-1 trial, and 718 (n = 358 treated, 360 VC) in the lifitegrast phase 3 OPUS-2 trial were analyzed. The LS mean STS CFB for OC-01 VNS at 2 and 4 weeks was significantly greater than that for lifitegrast at 2 and 6 weeks in OPUS-1 and OPUS-2 ( P < 0.0001 for all comparisons). The LS mean EDS CFB for OC-01 VNS at 2 and 4 weeks was significantly greater than that for lifitegrast at 2 and 6 weeks in OPUS-1 ( P < 0.0001 for both comparisons) and at 4 weeks vs lifitegrast at 6 weeks in OPUS-2 ( P < 0.0001). CONCLUSIONS: This MAIC analysis demonstrates OC-01 VNS produced significantly greater improvement in mean STS and comparable or greater improvement in EDS compared with lifitegrast in phase 3 trials. These findings suggest a potentially greater magnitude of improvement achieved with OC-01 VNS compared with lifitegrast for the treatment of DED within the conditions of the analysis methodology. DISCLOSURES D White is a consultant for Oyster Point Pharma, Inc. L Hendrix, M Macsai, and A Gibson are employees and shareholders for Oyster Point Pharma, Inc. L Sun was an employee of COEUS, Clinical Research at the time of study conduct and received funding from Oyster Point Pharma, Inc. I Tam is an employee of COEUS, Clinical Research and received funding from Oyster Point Pharma, Inc. Oyster Point Pharma, Inc was involved in the study design, data collection, data analysis, and preparation of the manuscript and is the manufacturer/licensee of OC-01 (varenicline solution) nasal spray. Oyster Point Pharma, Inc., sponsored the phase 3 OC-01 (varenicline solution) clinical study from which analysis data were obtained.

BACKGROUND: Matching-adjusted indirect comparison (MAIC) is a validated and widely accepted statistical method that derives indirect comparisons between treatments when head-to-head studies have not been performed. OBJECTIVE: To compare the efficacy of OC-01 varenicline nasal spray (OC-01 VNS) 0.03 mg to cyclosporine A (CsA) 0.05% ophthalmic emulsion on tear production in patients with dry eye disease based on data from the respective phase 3 clinical trials using the MAIC technique. METHODS: Individual patient data were drawn from the phase 3 registry trial of OC-01 VNS; aggregate data were drawn from 2 phase 3 trials of CsA in the publicly available New Drug Application for CsA 0.05% ophthalmic emulsion (RESTASIS). Using unanchored MAIC methods, the individual patient data were weighted based on 4 clinically relevant baseline variables (age, race, sex, and baseline Schirmer test score [STS]) to produce a weighted OC-01 VNS dataset matched to the key demographics of the CsA dataset. Least-squares mean change from baseline in STS for OC-01 VNS was calculated using the identical analysis of variance model used to calculate the same value for CsA in the RESTASIS New Drug Application, which were then compared. Proportions of subjects with improvement of 10 mm or more from baseline in STS were compared in the weighted OC-01 VNS and CsA dataset. Time points available for comparisons were CsA trials at 3 and 6 months and OC-01 data at 2 and 4 weeks. RESULTS: Data from 511 subjects in the OC-01 VNS phase 3 trial and 585 in the CsA phase 3 trials were analyzed. The least-squares mean STS change from baseline for OC-01 VNS at 2 and 4 weeks was significantly higher than that for CsA at 3 and 6 months ( P < 0.0001 for all comparisons). Mean STS improvements were approximately 6-7 mm for OC-01 VNS and approximately 1 mm for CsA. The proportion of subjects with improvement of 10 mm or more from baseline in STS was significantly higher for OC-01 VNS (50.2%) than CsA (11.7 and 17.1% in the 2 CsA studies; P < 0.0001 for both comparisons). CONCLUSIONS: This MAIC analysis demonstrates OC-01 VNS produces significantly greater improvement in mean STS and results in significantly greater numbers of patients with substantial improvement in STS (percentage ≥ 10 mm) compared with CsA. Together, absent more robust data from head-to-head trials, findings may suggest a potentially greater magnitude of improvement achieved with OC-01 VNS compared with CsA for the treatment of dry eye disease within conditions of the analysis methodology. DISCLOSURES: Dr Visco was a consultant for Novartis, Allergan, and Oyster Point, Inc. Ms Hendrix and Drs Macsai and Gibson are employees and shareholders for Oyster Point Pharma, Inc. Drs Sun and Tam participated in clinical research and received funding from Oyster Point Pharma, Inc. Oyster Point Pharma, Inc sponsored the Phase 3 OC-01 (varenicine solution) clinical study from which analysis data are obtained.

In 2017, a National Rosacea Society Expert Committee developed and published an updated classification of rosacea to reflect current insights into rosacea pathogenesis, pathophysiology, and management. These developments suggest that a multivariate disease process underlies the various clinical manifestations of the disorder. The new system is consequently based on phenotypes that link to this process, providing clear parameters for research and diagnosis as well as encouraging clinicians to assess and treat the disorder as it may occur in each individual. Meanwhile, a range of therapies has become available for rosacea, and their roles have been increasingly defined in clinical practice as the disorder has become more widely recognized. This update is intended to provide a comprehensive summary of management options, including expert evaluations, to serve as a guide for tailoring treatment and care on an individual basis to achieve optimal patient outcomes., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: To diagnose Thiel-Behnke dystrophy, an autosomal dominant disease of the anterior basement membrane/Bowman membrane complex and corneal stroma, currently relies primarily on the overall clinical presentation of patient complaints, inheritance pattern, and physical appearance of the corneal findings on slit-lamp examination. Key challenges to accurately identifying the disease are variable and often obscured morphology caused from secondary scarring, creating phenotypic deviation from the "classical" presentation, and mimicry of characteristics typical of other closely related dystrophies. In this report, we demonstrate the high degree of phenotypic variability that can be found in this disease., Methods: A well-characterized family with an established diagnosis of Thiel-Behnke dystrophy mapped to chromosome 10 was evaluated along with the corresponding pedigree. Each individual was examined under slit lamp, and any apparent lesions were photographed., Results: In total, 4 generations were represented with 20 affected members accounted for, ranging from ages 11 to 86 years. We observed 4 phenotypes in this family: (1) the majority displayed "honeycomb" reticular opacities consistent with Thiel-Behnke dystrophy, (2) several subjects showed more granular-like deposits in a geographic distribution, (3) younger subjects with possible early manifestations of the disease possessed small superficial vesicles, and (4) some eyes exhibited an intermediate form with 2 distinct disease presentations at different regions within the same cornea. Taken together, the pedigree demonstrated a wide continuous spectrum of phenotypes from a supposedly singular genetic disorder that may also vary based on the age of patient., Conclusions: These observations show that the clinical phenotypic appearance alone can result in a variety of different and conflicting diagnoses. With such potential for error, improvement in the diagnostic criteria is necessary.

The standard management options were developed by a consensus committee and review panel of 26 experts to assist in providing optimal patient care based on the standard classification and grading systems for rosacea that were developed to perform research; analyze results and compare data from different sources; and provide a common terminology and reference for the diagnosis, treatment, and assessment of results in clinical practice. We discuss the standard management options for rosacea in 2 parts: (1) overview and broad spectrum of care, and (2) management options according to subtype. The menu of options is considered provisional and may be expanded and updated as appropriate. Managing the various potential signs and symptoms of rosacea calls for consideration of a broad spectrum of care, and a more precise selection of therapeutic options may become increasingly possible as the mechanisms of action of therapies are more definitively established.

The standard management options were developed by a consensus committee and review panel of 26 experts to assist in providing optimal patient care based on the standard classification and grading systems for rosacea that were developed to perform research; analyze results and compare data from different sources; and provide a common terminology and reference for the diagnosis, treatment, and assessment of results in clinical practice. We discuss standard management options for rosacea in 2 parts: (1) overview and broad spectrum of care, and (2) options according to subtype. The options are considered provisional and may be expanded and updated as appropriate. Managing the various potential signs and symptoms of rosacea calls for consideration of a broad spectrum of care, and a more precise selection of therapeutic options may become increasingly possible as the mechanism of action of therapies are more definitively established.

Objective: To examine histopathologic and immunohistochemical features of human corneal buttons from patients who developed keratectasia after laser in situ keratomileusis (LASIK)., Methods: Five corneal buttons were obtained during penetrating keratoplasty from patients who developed keratectasia after LASIK. Histologic features were examined by hematoxylin-eosin staining using paraffin-embedded sections and by transmission electron microscopy. Immunostaining for alpha(1)-proteinase inhibitor, Sp1, and matrix metalloproteinases 1, 2, and 3 was performed with 2 healthy corneas and 2 corneas with keratoconus as controls., Results: Central stromal thinning was observed after hematoxylin-eosin staining in all corneas with keratectasia. No histologic features specific to keratoconus, including Bowman layer disruption, were identified in the corneas with keratectasia. By transmission electron microscopy, collagen fibril thinning and decreased interfibril distance were observed in the stromal bed. Immunostaining intensity and/or pattern for alpha(1)-proteinase inhibitor and Sp1 in the corneas with keratectasia was comparable to that of healthy corneas and differed from that in the corneas with keratoconus. No significant staining with anti-matrix metalloproteinases 1, 2, and 3 antibodies was observed in either the corneas with keratectasia or the healthy corneas., Conclusions: Histologic findings suggest that post-LASIK keratectasia results in collagen fibril thinning and decreased interfibril distance within the residual stromal bed. Discrepant results between keratectasia and keratoconus suggest that the pathogenesis of the 2 conditions differ.

Over the past quarter century, advances in our understanding of corneal anatomy, physiology, and wound healing have all played an integral role in the management of corneal trauma. As the etiologies of corneal trauma have changed, so has our understanding of the impact of injury on corneal function as it relates to visual rehabilitation. Numerous new classes of antibiotics, antiinflammatory agents, and tissue adhesives have emerged. Occlusive therapy has advanced from simple pressure patching bandage soft contact lenses and collagen shields. Surgical instrumentation, operating microscopes, viscoelastic substances, and suture materials have all improved the outcomes of corneal trauma repair. Improved understanding of the refractive properties of the cornea through topography and alternative suture techniques has helped us restore the natural corneal curvature and visual outcomes. Consequently, in the last quarter of this century our therapeutic approaches to cornea trauma, both medical and surgical, have improved.

Purpose: To describe an alternative, novel surgical approach to the repair of a ruptured globe in the second reported patient with keratoglobus, Ehlers-Danlos type VI, and normal lysyl hydroxylase., Methods: Under general anesthesia, a 360 degrees conjunctival peritomy was performed and the epithelium was removed from the keratoglobus cornea. Descemet's membrane and endothelium were removed from a fresh donor corneoscleral ring. An onlay epikeratoplasty was then performed and the entire donor corneoscleral button was secured to the sclera with 9-0 nylon suture. The conjunctiva was brought into position and tacked down over the edge of the donor graft. After 4 months, a full-thickness penetrating keratoplasty was then performed., Results: The patient ultimately had a ruptured globe in the fellow eye and thus required the identical procedure OU. Both eyes were successfully repaired with a final visual acuity OU of 20/100., Conclusion: The described surgical approach allowed successful surgical repair of bilateral ruptured globes in a patient with keratoglobus, Ehlers-Danlos type VI, and normal lysyl hydroxylase levels. In the previous report of such a patient by Judisch et al. (1), the attempt at surgical repair was unsuccessful and ended in enucleation. The described surgical technique may be used to treat advanced keratoglobus or oculus fragilis.

Purpose: We reviewed the clinical data on 10 obese patients to define the role of obesity as a factor for consideration in planning penetrating keratoplasty., Methods: We performed a retrospective case series review of penetrating keratoplasty in obese patients., Results: In our series of 10 patients, spontaneous extrusion of lens and vitreous (three patients) and choroidal hemorrhage (one patient) were intraoperative complications. Wound leakage, wound dehiscence (two patients), iridocorneal synechia formation, and graft rejection (one patient) were postoperative complications. Despite these complications, seven of the 10 patients achieved a final postoperative visual acuity of > or =20/30., Conclusion: Cornea surgeons must consider obesity as a potential risk factor that may be mitigated partially by careful preoperative patient evaluation, anesthesia planning, and meticulous attention to patient positioning and comfort during surgery.

Purpose: To report staphylococcal endophthalmitis following cataract extraction in a patient with Darier' s disease., Methods: A 67-year-old man presented with decreased visual acuity OD and hypopyon 3 days status post-cataract extraction with intraocular lens placement. The patient was hospitalized and placed on topical and intravenous antibiotics. A diagnostic vitreous tap, pars plana vitrectomy, and intravitreal antibiotic installation were performed., Results: Vitreal tap cultures indicated Staphylococcus epidermidis. His clinical status improved after vitrectomy and antibiotic therapy. The same bacteria was cultured from the patient's eyelids., Conclusions: The source of the S. epidermidis was the skin lesions on the patient's face and eyelids. Darier's disease is an exfoliative hyperkeratotic skin disease that affects all areas on the body except the buttocks. Although clean, sterile surgical techniques were followed, the risk of endophthalmitis following intraocular surgery in a patient with Darier's disease may be increased due to his or her dermatologic condition.

Purpose: To report a case of bilateral corneal ulcers and perforations resulting from hypovitaminosis A in an alcoholic patient., Methods: A 38-year-old cachetic man presented with bilateral corneal ulcerations and severe visual loss. He was hospitalized, developed bilateral corneal perforations, and was treated with bilateral corneal transplants., Results: Serum vitamin A level was 0.01 microg/dL (normal, 0.30-0.75). The electroretinogram was consistent with vitamin A deficiency. His clinical status improved after vitamin A replacement., Conclusions: Although rare in developed countries, the ophthalmologist must consider avitaminosis A in the differential diagnosis of corneal ulcerations in cachetic, alcoholic, or chronically ill patients. Early diagnosis and treatment can prevent unwanted outcomes.

Purpose: To report the use of perfluoropropane (C3F8) gas in the repair of Descemet's membrane detachments., Methods: Descemet's membrane detachments after cataract surgery in three eyes and pars plana vitrectomy in a fourth underwent anterior-chamber gas-exchange descemetopexy with an isoexpansile 14% mixture of C3F8 to facilitate reattachment of Descemet's membrane., Results: Descemet's membrane detachment was successfully reattached after anterior-chamber gas exchange with 14% C3F8 in three of the four eyes treated. The fourth eye treated with 14% C3F8 probably failed Descemet's membrane reattachment because of an unrecognized viscoelastic bleb situated anterior to Descemet's membrane. No corneal decompensation or fluctuations in intraocular pressure were believed to be attributable to isoexpansile C3F8 gas exchange., Conclusion: Early recognition and repair of Descemet's membrane detachments may prevent complications, such as corneal decompensation, corneal opacities and edema, and an overall decline in visual acuity. Isoexpansile C3F8 is demonstrated as a safe and efficacious alternative for the repair of Descemet's membrane detachment.

Purpose: To report the association of keratoconus and Turner's syndrome in three patients and to review the ophthalmic manifestations of Turner's syndrome., Methods: Three patients with keratoconus and Turner's syndrome were identified and reported in a retrospective review., Results: These three cases represent the first series of patients with keratoconus and Turner's syndrome. All three patients underwent penetrating keratoplasty with good visual rehabilitation. None of the patients had other ocular features associated with Turner's syndrome., Conclusion: Turner's syndrome is commonly associated with ocular problems. In this series we identify an association of keratoconus with Turner's syndrome. Clearly, a careful ocular examination in this condition with attention to ocular features of Turner's syndrome is important.

Purpose: The purpose of the study is to report the outcome and postoperative topographic analysis of seven patients who underwent small-diameter, round, eccentric penetrating keratoplasty., Methods: Seven patients underwent small-diameter, round, eccentric penetrating keratoplasty for a variety of corneal disorders (cataract wound necrosis and dehiscence or fistula, three patients; penetrating keratoplasty wound infection, two patients; corneal rheumatoid melt and perforation, one patient; localized fungal keratitis, one patient). Full-thickness corneal transplants ranged in size from 3.0 to 5.5 mm. The graft wound and sutures spared the visual axis in all cases. Patients were observed for 7 to 42 months (mean, 21 months). All patients had postoperative topographic analysis. One of these also had preoperative analysis., Results: All grafts tectonically were effective in treating the intended condition. Best-corrected visual acuity was 20/30 or better in the four patients without pre-existing corneal transplants or dry eyes; 20/60 and 5/200 in the patients with previous central penetrating keratoplasties; and 20/40 in the patient with rheumatoid melt. There was no clinically significant regular or irregular astigmatism induced centrally by the eccentric graft in the four patients where visual acuity was 20/30 or better. Irregular astigmatism was noted in the other three patients., Conclusion: Small-diameter, eccentric penetrating keratoplasties may be used successfully to treat various peripheral corneal disorders. In some cases, this can be performed without inducing high or irregular astigmatism or both centrally.

This study was conducted to provide experimental information on the probability of syphilis transmission resulting from corneal transplantation. To determine the effects of commonly employed corneal storage conditions on the survival and infectivity of Treponema pallidum, T. pallidum subsp. pallidum (Nichols) was inoculated into OptiSol storage medium or a T. pallidum survival medium at a concentration of 10(6)/ml and incubated in cornea viewing chambers for 24 h at 4 degrees C. When inoculated intradermally into rabbits (0.1 ml per site), none of the 10 sites developed lesions from suspensions incubated in OptiSol in the presence or absence of 100 microgram/ml gentamicin; T. pallidum incubated in the survival medium yielded lesions at one of 10 sites, whereas freshly extracted organisms produced lesions at all 10 sites. In another set of experiments, the infectivity of corneal tissue from rabbits inoculated intratesticularly with 2 x 10(7) T. pallidum 10 days earlier was determined. Corneas from five T. pallidum-infected rabbits were excised, extracted, and tested for infectivity either immediately after removal or after 24-h storage in OptiSol. Recipient rabbits developed lesions at five of 50 intradermal sites when the corneas were neither stored in OptiSol nor rinsed before extraction. Corneas from 10 donor rabbits that were rinsed with phosphate-buffered saline to remove blood and aqueous humor before extraction did not yield lesions at any of 200 sites in the recipient animals. The results of this study indicate that retention of T. pallidum infectivity is poor under typical corneal storage conditions and that rabbit corneal tissue contains few, if any, infectious T. pallidum organisms under the experimental conditions employed.

X-linked ichthyosis is a relatively common oculodermal disorder. Characteristic corneal opacities are small punctate or filiform lesions and are located in the deep corneal stroma. In an unusual case, a 73-year-old man with X-linked ichthyosis and steroid sulfatase deficiency had superficial corneal opacities. The corneal opacities were granular in nature, involving the subepithelial and anterior stromal layers. The opacities resulted in irregular overlying corneal epithelium and were white-gray in color in direct illumination. Histopathologic and electron microscopic studies demonstrated abnormalities of the corneal epithelial basement membrane. The epithelial basement membrane was thickened with irregular extensions into Bowman's layers. Abnormal depositions of basement membrane protein were seen in the anterior stroma. These abnormalities may have resulted from increased production of basement membrane proteins by the corneal epithelium, resulting from hyperactive turnover of the basal layer.

The administration of prophylaxis against tetanus following a corneal abrasion is routinely performed in many acute care facilities, despite a lack of support in the literature for its necessity. The risk of developing clinical tetanus from three different types of injuries to the eye was evaluated in an animal model. Clinical tetanus was induced in unimmunized mice by injecting Clostridium tetani organisms or toxin into the anterior chamber. Immunized mice injected intracamerally did not develop signs of tetanus. Tetanus was not induced by topical inoculation of either live organisms or toxin following corneal epithelial debridement or stromal scarification of unimmunized and immunized mice. The results of this study support the administration of prophylaxis against tetanus following perforating ocular injuries. However, our results do not support its routine use following uncomplicated corneal abrasions or other types of nonperforating ocular injuries.

We noted opaque deposits in SeeQuence disposable contact lenses in three patients with persistent epithelial defects who were being treated with topical ciprofloxacin and prednisolone acetate. In each patient, the contact lenses with deposits were removed and replaced. High performance liquid chromatography analysis revealed the deposits to be precipitates of ciprofloxacin and prednisolone acetate. We incubated new SeeQuence disposable contact lenses in ciprofloxacin, prednisolone phosphate, and prednisolone acetate alone and in combination. Precipitates did form when ciprofloxacin was combined with either prednisolone acetate or prednisolone phosphate. We recommend removal and replacement of contact lenses should these deposits develop to prevent the possibility of corneal toxicity.

Over a 14-year period from 1974 to 1988, 12 eyes of 11 patients with pellucid marginal corneal degeneration underwent penetrating keratoplasty. Peripheral corneal thinning required a large eccentric graft in each case. Follow-up ranged from one to eight years (mean, three years). One graft failed because of a persistent epithelial defect with keratolysis of the wound. Although endothelial allograft rejection was common, occurring in seven of 11 (64%) clear grafts, no graft failed because of rejection. Other complications included retinal detachment and a bacterial corneal ulcer. Suture erosion and vascularization of the graft were not problems. Postoperative spectacle correction was dispensed an average of 11 months after surgery. Visual acuity in seven patients without amblyopia, retinal disease, or a previous corneal ulcer at the time of spectacle correction ranged from 20/20 to 20/40 (mean, 20/30). Average final keratometric astigmatism in these patients was 2.46 diopters (range, 0.00 to 5.25 diopters). We believe that penetrating keratoplasty offers an excellent surgical result for patients with pellucid marginal corneal degeneration.

We examined, using scanning electron microscopy, the effects of the injection of an isobutyl cyanoacrylate into the rabbit anterior chamber. Injection of the adhesive produced a rapidly polymerized mass that remained in the anterior chamber throughout the course of the study. Additionally, an active inflammatory response was noted in the anterior chamber, characterized by a progressively enlarging "cocoon" of fibrin and inflammatory cells surrounding the polymerized adhesive, as well as inflammatory cells in the trabecular meshwork. Following cyanoacrylate injection, the corneal endothelial cells were noted to be swollen for the first 14 days of the study.

A retrospective review of 398 eyes of 199 patients with keratoconus revealed 106 eyes of 53 patients with an association between contact lens wear and the development of keratoconus. The absence of keratoconus at the time of contact lens fitting was confirmed by slit-lamp examination, keratometry readings, and manifest refraction. Keratoconus was diagnosed after a mean of 12.2 years of contact lens wear. This group was compared with patients with sporadic keratoconus with either no history of contact lens wear or a history of contact lens wear after the diagnosis. They were older at the time of diagnosis, had central vs decentered cones, and had a tendency toward flatter corneal curvatures. We believe that these patients suggest that long-term contact lens wear is a factor that can lead to keratoconus.

We have used an improved protocol to prepare human, human neonatal, rat and frog lenses for examination by stereo scanning electron microscopy. In this manner, complete and accurate images of the changes in lens cell shape, size and surface complexity are revealed as they differentiate and develop from cuboidal epithelial cells into elongate fiber cells. This method also shows that the apical ends of elongating fibers are variably expanded as they interface with the overlying lens epithelium. Apical ends are most expanded as they contact pre-germinative zone epithelial cells and least enlarged as they contact transitional zone cells. By examining the interlocking devices on opposed fibers in frog, rat and human lenses we determined that there are standard types and interlocking patterns in all lens species. Finally, stereo SEM reveals that the ridges previously reported on aged human nuclear fibers are also seen on human neonatal cortical fibers and that these ridges may actually be interlocked villous or fingerlike projections.

We have discovered cell-to-cell fusion between fiber cells of adult frog lenses in situ. Stereo scanning electron microscopy (SEM) revealed fusion between neighboring fiber cells in radial cell columns (RCCs) and in the same growth ring, respectively. Cell-to-cell fusion of fiber cells in the lens produced fusion zones that in cross-section were larger and of different polygonal shapes than unfused fiber cells. The shape and sizes of fiber cells surrounding fusion zones and the alignment of RCCs were also altered. Serial sectioning through fusion zones confirmed that they were areas of cell-to-cell continuity established by the union of neighboring fiber cells as seen by SEM. Fusion zones represent a previously unrecognized intercellular pathway in the adult frog lens. Although numerous fusion zones were seen throughout the lens cortex and nucleus, cell-to-cell fusion was rarely observed to have occurred between elongating fiber cells. Interestingly, communicating junctions with an unusual ultrastructure that closely resembles the appearance of membranes in the process of fusion demonstrated in other systems were frequently seen in the region of the superficial cortex where fusion zones were most numerous. The fact that such unusual communicating junctions were not found in any other region of the lens leads us to speculate that structural changes in fiber cell communicating junctions may herald the formation of fusion zones and that the initial site of cell-to-cell fusion between fiber cells may be within communicating junctional plaques.

The sutures of the crystalline lens have previously been studied by light microscopy (LM). While the gross suture patterns (umbilical, line, y-shaped and star) of lenses are readily visualized by LM, fiber cell shape, curvature, length and the morphology of fiber cell ends cannot be adequately resolved by this technique. We have used scanning electron microscopy (SEM) to examine the sutures of crystalline lenses. SEM has revealed that in lenses with line, y-shaped or umbilical sutures, the anterior and posterior ends of fiber cells curve away in opposite directions from the polar axis of the lens before interlocking at suture branches. The degree of curvature decreases as a function of the number of suture branches. This relationship was not resolved by LM. SEM has revealed that the relationship of fiber cell taper to suture type was underestimated by previous LM studies. The reduction in fiber cell width from the equator to the sutures is 3:1 and 2:1 respectively, in lenses with line and y-shaped sutures. Furthermore, in lenses with star sutures, fiber cells are flared (1:1.7) rather than tapered, a fact not reported by previous LM studies. SEM also revealed that the offsetting of anterior and posterior suture branches does not result in equal fiber cell length in any growth ring as reported by LM studies. Rather, fiber cell length in any one growth ring varies as a sine wave function according to fiber cell location at the equator. Furthermore, the range of fiber cell length decreases as a function of the number of suture branches. Finally, SEM has revealed that the distal ends of fiber cells are expanded in both width and thickness prior to interlocking at suture branches and that these ends overlap rather than simply abut end-to-end to form a three dimensional suture plane extending down from the lens surfaces to the primary fiber cell mass.