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Prcis: About one-fourth of survey respondents from an ASCRS database initiate treatment for primary open angle glaucoma (POAG) with laser trabeculoplasty. Factors impacting physicians' choice of laser versus topical treatment for POAG were explored., Purpose: To characterize primary treatment preferences (topical medication versus laser trabeculoplasty or intracameral sustained release implants) in primary open angle glaucoma (POAG) patients and determine factors related to primary intervention selection., Methods: A 33-question survey was distributed to an American Society of Cataract and Refractive Surgery database on treatment choices made by ophthalmologists for POAG. Data collected included country of practice, years of practice, completion of glaucoma fellowship training, type of practice, and preference for the first line of treatment for POAG. Multiple logit regression was used to compare the effect of covariates on physicians' choice of either topical medication or laser trabeculoplasty for POAG., Results: A total of 252 of 19,246 (1.3%) surveys were returned. Almost three-quarters of respondents used topical medication as the first line of treatment for POAG (73.6%), whereas 26.4% preferred to start with laser treatment. Significant variables associated with the selection of laser (vs. drops) are practicing in the United States (odds ratio [OR] 2.85; 95% CI, 1.33-6.10), the more recent completion of ophthalmology residency (OR 1.95; 95% CI, 1.00-3.77), the greater volume of minimally invasive glaucoma surgeries (MIGS) (OR 1.68; 95% CI, 1.18-2.40), and a glaucoma patient base greater than 25% (OR 2.21; 95% CI, 1.09-4.48)., Conclusions: For the first-line treatment of POAG, laser trabeculoplasty is more likely to be preferred, over topical drops, by U.S. physicians who are relatively new in practice, who have a larger glaucoma patient base, and who perform more MIGS., Competing Interests: Disclosure: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Contact lenses are a safe and effective method for correction of refractive error and worn by an estimated 45 million Americans. Because of the widespread availability and commercial popularity of contact lenses, it is not well appreciated by the public that contact lenses are U.S. Food and Drug Administration (FDA)-regulated medical devices. Contact lenses are marketed in numerous hard and soft materials that have been improved over decades, worn in daily or extended wear, and replaced in range of schedules from daily to yearly or longer. Lens materials and wear and care regimens have impact on the risks of contact lens-related corneal inflammatory events and microbial keratitis. This article reviews contact lens safety, with specific focus on the correction of refractive error in healthy eyes., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Contact Lens Association of Opthalmologists.)

Competing Interests: The author has no conflicts of interest to disclose.

The medical use of contact lenses is a solution for many complex ocular conditions, including high refractive error, irregular astigmatism, primary and secondary corneal ectasia, disfiguring disease, and ocular surface disease. The development of highly oxygen permeable soft and rigid materials has extended the suitability of contact lenses for such applications. There is consistent evidence that bandage soft contact lenses, particularly silicone hydrogel lenses, improve epithelial healing and reduce pain in persistent epithelial defects, after trauma or surgery, and in corneal dystrophies. Drug delivery applications of contact lens hold promise for improving topical therapy. Modern scleral lens practice has achieved great success for both visual rehabilitation and therapeutic applications, including those requiring retention of a tear reservoir or protection from an adverse environment. This report offers a practical and relevant summary of the current evidence for the medical use of contact lenses for all eye care professionals including optometrists, ophthalmologists, opticians, and orthoptists. Topics covered include indications for use in both acute and chronic conditions, lens selection, patient selection, wear and care regimens, and recommended aftercare schedules. Prevention, presentation, and management of complications of medical use are reviewed., (Copyright © 2021 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Significance: Standardized guidelines that are clinically practical are needed to assist the prescriber in minimizing the risk of conveying infection through multiuse diagnostic contact lens use and reuse.Contact lens prescribers face the specter of transferring potential pathogens from one patient to another when reusing diagnostic (trial) contact lenses on multiple patients because infectious organisms have been recovered from worn contact lenses, although there is no evidence of transmission through this mechanism. These pathogens can be introduced into the system from one patient to another, or they may be introduced by clinician lens handling, storage, or both. These pathogens can cause acute or chronic systemic or ocular infection that can lead to significant morbidity (temporary or permanent) that includes vision loss.

Significance: Lotrafilcon B lenses packaged in and cared for with block copolymer-containing (polyoxyethylene-polyoxybutylene; EOBO) lens care solutions resulted in lower cholesterol extraction than each of the habitual silicone hydrogel lens/multipurpose solution (MPS) regimens tested., Purpose: This study aimed to compare the extracted cholesterol of lotrafilcon B lenses packaged in and cared for with EOBO-containing lens care solutions with the extracted cholesterol of habitual silicone hydrogel lenses cared for with MPS not containing EOBO., Methods: In this prospective, randomized, observer-masked parallel study, habitual wearers of senofilcon C, senofilcon A, comfilcon A, and samfilcon A contact lenses using a non-EOBO MPS were randomized 1:1 to lotrafilcon B lenses packaged in and cared for with EOBO-containing solutions or to their habitual lenses and MPS. Subjects randomized to lotrafilcon B were further randomized to one of two EOBO-containing lens care solutions, OPTI-FREE PUREMOIST or CLEAR CARE PLUS with HydraGlyde (Alcon Laboratories, Inc., Fort Worth, TX). A subset of right eye lenses was collected after wear, and total cholesterol was extracted and measured using a fluorometric enzymatic assay., Results: Of 143 lenses analyzed, 95 were from subjects randomized to their habitual lenses/MPS and 48 to lotrafilcon B + EOBO lenses plus CLEAR CARE PLUS with HydraGlyde or OPTI-FREE PUREMOIST. The mean amounts of cholesterol extracted from lotrafilcon B + EOBO lenses cared for with CLEAR CARE PLUS with HydraGlyde (0.28 ± 0.18 μg/lens) and OPTI-FREE PUREMOIST (0.28 ± 0.48 μg/lens) were significantly lower than those extracted from senofilcon C (4.18 ± 3.25 μg/lens), senofilcon A (2.19 ± 2.69 μg/lens), comfilcon A (2.17 ± 1.47 μg/lens), and samfilcon A (2.07 ± 1.48 μg/lens) lenses used with MPS (P < .0001 each)., Conclusions: Cholesterol sorption was significantly lower in wearers of lotrafilcon B lenses cared for with polyoxyethylene-polyoxybutylene-containing lens care solutions than in users of habitual silicone hydrogel lenses cared for with non-polyoxyethylene-polyoxybutylene MPS.

Purpose: This study assessed microbiome adherent to contact lenses and defined the bacterial communities associated with use of lens care solutions., Methods: Among 84 lenses screened for adherent ocular surface bacterial microbiome using 16S rRNA molecular amplification, 63 (75%) generated bacterial-specific amplicons processed using the Ion Torrent Personal Genome Machine workflow. Data were stratified by solution use (peroxide vs. polyhexamethylene biguanide [PHMB]-preserved multipurpose solution [MPS]). Diversity of lens-adherent microbiome was characterized using Shannon diversity index and richness index. Data were analyzed using principal components analysis and Kruskal-Wallis tests., Results: We identified 19 phyla and 167 genera of bacteria adherent to the lenses. Proteobacteria was the most abundant phyla, followed by Firmicutes and Actinobacteria. The most abundant bacterial genera (>1% abundance) were Ralstonia, Enterococcus, Streptococcus, Halomonas, Corynebacterium, Staphylococcus, Acinetobacter, Shewanella, Rhodococcus, and Cobetia. Sixteen of 20 lenses (80%) negative for bacterial DNA were worn by participants using peroxide solutions while only 4 (20%) were MPS-treated lenses (P=0.004). Genera diversity of lens-adherent microbiome showed a significant increase in MPS-treated lenses compared with peroxide (P=0.038). Abundance of Corynebacterium, Haemophilus, and Streptococcus were increased 4.3-, 12.3-, and 2.7-fold, respectively, in the MPS group compared with peroxide (P=0.014, 0.006, 0.047, respectively)., Conclusions: Commensal, environmental, and pathogenic bacteria known to be present in the conjunctival microbiome can be detected on worn contact lenses. Although most contact lenses worn by asymptomatic wearers harbor bacterial DNA, compared with peroxide, lenses stored in a PHMB-preserved MPS have more quantifiable, abundant, and diverse bacterial communities adherent to them.

Despite their established disinfection and safety benefits, the use of hydrogen peroxide (H2O2) lens care systems among today's wearers of reusable contact lenses remains low in comparison with multipurpose solution (MPS) use. Multipurpose solution systems, however, present several potential drawbacks that may impact patient outcomes, including the use of chemical preservatives for disinfection, biocompatibility issues, and challenges with respect to lens care compliance. Given their unique composition and mechanism of action, one-step H2O2 systems offer the opportunity to avoid many of the challenges associated with MPS use. This article reviews the evolution of H2O2 lens care systems and examines the current scientific and clinical evidence regarding the relative ease of use, lens and tissue compatibility, disinfection efficacy, and ocular surface safety of H2O2 systems. Evaluation of the available data indicates that in comparison with MPS, one-step H2O2 systems tend to promote more favorable compliance, efficacy, comfort, and ocular surface outcomes for a wide range of contact lens-wearing patients. Based on the current published evidence, the authors recommend that eye care practitioners consider making one-step H2O2 systems their first-line contact lens care recommendation for most wearers of reusable lenses.

Corneal infiltrative events (CIEs) are well established as a risk associated with soft contact lens wear. The incidence of symptomatic CIEs during extended soft lens wear ranges from 2.5 to six per cent; when asymptomatic CIEs are included, the incidence can be as high as 20-25 per cent. In daily soft lens wear, the annual incidence of symptomatic CIEs is about three per cent. There are various accepted methods of categorising CIEs, and a scoring system based on clinical signs and symptoms is a good approach to grade severity. Lens-related risk factors include extended wear, silicone hydrogel material, the use of multipurpose solutions, bacterial bioburden and reusable lenses. Recent studies report that daily disposable lenses reduce the risk of CIEs., (© 2017 Optometry Australia.)

Purpose: To assess corneal epithelial microstructure via confocal microscopy and determine if cellular changes are associated with lens care solutions during daily wear of silicone hydrogel contact lenses., Methods: Corneal in vivo confocal microscopy with the Nidek ConfoScan4 was performed at baseline and after 5 months of lotrafilcon A daily contact lens wear. Enrolled participants were randomized to use either a polyhexamethylene biguanide (PHMB) preserved multipurpose care solution (MPS) or a peroxide based solution system. Lens and storage case bioburden were assessed with aerobic culture methods. Univariate and multivariable analyses were done to evaluate the association between solution use, or solution-related clinical covariates, and morphologic differences (hyper-reflectivity) in the superficial epithelial cells and epithelial basal cell density., Results: Data on 139 participants were available for analysis of superficial epithelial cells while data on 92 participants were available for epithelial basal cell density. Five months after randomization to the solution groups, 33% of participants had visible hyper-reflective cells. More participants using MPS had ≥1 hyper-reflective cells compared to peroxide users at 5 months (44% vs. 22%; p=0.006). Similarly at 5 months, more participants with solution-induced corneal staining (SICS) had ≥1 hyper-reflective cells compared to non-SICS participants (57% vs. 29%; p=0.010). The adjusted odds ratios (ORs) for risk of presenting with hyper-reflective cells in MPS users or SICS participants was 2.7 (95% CI; 1.27-5.65) and 3.4 (95% CI; 1.29-8.97), respectively. Basal cell density decreased by over 350 cells/mm 2 over time (about 6%) in participants who had substantial bioburden on their lenses or in their storage case., Conclusion: The confocal microscope can detect epithelial cellular changes in vivo during contact lens wear. Hyper-reflective superficial epithelial cells are associated with a PHMB preserved solution and decreases in basal epithelial cell density may be associated with bacterial bioburden., (Copyright © 2016 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this study was to assess risk factors associated with soft contact lens (SCL)-related corneal infiltrative events (CIEs)., Methods: This was a single-visit, case-control study conducted at five academic centers in North America. Cases were defined as current SCL wearers with a symptomatic CIE. For each case, three age- and sex-matched controls were enrolled. Subjects completed the Contact Lens Risk Survey (CLRS), a standardized scripted medical interview, supplied a recent health history, and underwent an ocular examination. Microbial culturing of the ocular surface, SCL, and lens storage case was conducted for all cases and one of the three matched controls. Univariate and multivariate logistic regression modeling were used to assess the risk of developing a CIE., Results: Thirty cases and 90 controls 13 to 31 years of age completed the study. Corneal infiltrative event diagnosis included contact lens-associated red eye, infiltrative keratitis, and contact lens peripheral ulcer. Subjects with symptomatic CIEs were more likely to harbor substantial levels of gram-negative bioburden on the ocular surface and contact lens. Significant risk factors for developing a CIE were overnight wear of SCLs, use of multipurpose solution, rinsing SCLs with water, lens storage case older than 6 months, previous "red eye" event, use of ocular drops in the past week, and illness during the past week., Conclusions: This pilot study demonstrated feasibility of enrolling a representative pool of SCL wearers with an untreated, symptomatic CIE and assessing CIE risk factors by using standardized methods. A larger sample size is needed to determine relationships between patient-reported behaviors and exposures, microbial bioburden, and CIE development.

Phototherapy is an effective treatment option for a variety of dermatologic disorders, and the list of indications for its use continues to grow with advances in technology and our understanding of disease processes. Commonly used types of phototherapy include PUVA, broadband UVB, narrowband UVB, photodynamic therapy, and intense pulsed light therapy. Each therapeutic modality can have adverse acute and chronic effects on periocular and ocular structures, including the conjunctiva, cornea, crystalline lens, and retina. There are many types of protective eyewear options available, including goggles and contact lenses that can be used to prevent damage to ocular structures during phototherapy, particularly if eyelid closure is incomplete., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to determine the probability and risk factors for developing a corneal inflammatory event (CIE) during daily wear of lotrafilcon A silicone hydrogel contact lenses., Methods: Eligible participants (n = 218) were fit with lotrafilcon A lenses for daily wear and followed up for 12 months. Participants were randomized to either a polyhexamethylene biguanide-preserved multipurpose solution or a one-step peroxide disinfection system. The main exposures of interest were bacterial contamination of lenses, cases, lid margins, and ocular surface. Kaplan-Meier (KM) plots were used to estimate the cumulative unadjusted probability of remaining free from a CIE, and multivariate Cox proportional hazards regression was used to model the hazard of experiencing a CIE., Results: The KM unadjusted cumulative probability of remaining free from a CIE for both lens care groups combined was 92.3% (95% confidence interval [CI], 88.1 to 96.5%). There was one participant with microbial keratitis, five participants with asymptomatic infiltrates, and seven participants with contact lens peripheral ulcers, providing KM survival estimates of 92.8% (95% CI, 88.6 to 96.9%) and 98.1% (95% CI, 95.8 to 100.0%) for remaining free from noninfectious and symptomatic CIEs, respectively. The presence of substantial (>100 colony-forming units) coagulase-negative staphylococci bioburden on lid margins was associated with about a five-fold increased risk for the development of a CIE (p = 0.04)., Conclusions: The probability of experiencing a CIE during daily wear of lotrafilcon A contact lenses is low, and symptomatic CIEs are rare. Patient factors, such as high levels of bacterial bioburden on lid margins, contribute to the development of noninfectious CIEs during daily wear of silicone hydrogel lenses.

Background: UV-blocking contact lenses were evaluated to determine if they could provide adequate ocular protection during narrowband UVB phototherapy treatment. Theoretical safe exposure durations for the crystalline lens, cornea and conjunctiva were determined., Methods: A Cary 500 spectrophometer generated transmittance data for six UV-blocking and two non-UV-blocking contact lenses. An IL-1700 radiometer measured the lenses' radiation transmittance within the NB-UVB phototherapy unit. The lenses were exposed to a 1500-mJ/cm(2) dose of radiation from a 308-nm excimer laser to determine if the radiation would alter their protective properties. Theoretical safe exposure durations for eye structures were calculated using previous human and animal study data., Results: All UV-blocking contact lenses showed less than 1E-7 W/cm(2) of radiation transmittance within the narrowband phototherapy unit. The excimer laser did not significantly alter the lenses' UV-blocking capabilities. The safe exposure durations for the cornea and crystalline lens were greater than 11 min with UV-blocking lenses, and that for the unprotected conjunctiva was approximately 11 s., Conclusion: Some UV-blocking contact lenses potentially provide sufficient ocular protection during narrowband UVB phototherapy treatment, as the crystalline lens and cornea are adequately protected should a patient open his or her eyes for a short time., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Keratoconus (KC) is a genetically heterogeneous corneal dystrophy. Previously, we performed 2 genome-wide linkage scans in a 4-generation autosomal dominant pedigree and repeatedly mapped a KC locus to a genomic region located on chromosome 5q overlapping the gene encoding the inhibitor of calpains, calpastatin (CAST). To test whether variants in CAST gene are involved in genetic susceptibility to KC, we performed genetic testing of polymorphic markers in CAST gene in family and case-control panels of patients with KC., Methods: We genotyped single-nucleotide polymorphisms (SNPs) located in CAST gene in 262 patients in 40 white KC families and in a white case-control panel with 304 cases and 518 controls. Generalized estimating equation models accounting for familial correlations implemented in GWAF program were used for association testing in families. Logistic regression models implemented in PLINK were performed to test the associations in case-control samples., Results: Genetic testing of the first set of 7 SNPs in familial samples revealed 2 tentative nominally significant markers (rs4869307, P = 0.03; rs27654, P = 0.07). Additional genotyping of 12 tightly spaced SNPs identified CAST SNP rs4434401 to be associated with KC in both familial and case-control panels with P values of 0.005 and 0.05, respectively, and with combined meta P value of familial and case-control cohorts of 0.002 or after Bonferroni correction of 0.04., Conclusions: Linkage analysis and genetic association support involvement of CAST gene in the genetic susceptibility to KC. In silico analysis of CAST expression suggests differential regulation of calpain/calpastatin system in cornea as a potential mechanism of functional defect.

Purpose: Single nucleotide polymorphisms (SNPs) located near or within the COL5A1 gene, at 9q34.2-q34.3 chromosomal region have been reported in association with central corneal thickness (CCT). Using family linkage analysis, we identified a keratoconus susceptibility locus at 9q34. These findings led us to perform an association study between COL5A1 variation and keratoconus susceptibility., Methods: A Caucasian case-control cohort of 222 keratoconus patients and 3324 controls was selected as the discovery panel. An independent case-control panel of 304 cases and 518 controls and a family panel of 186 subjects were replicated for genotyping and association. Forty-four SNPs (21 for discovery and 23 for fine-mapping) spanning 300 kilobases in and around COL5A1 were genotyped and tested for genetic association. Logistic regression models implemented in PLINK were used to test for association in case controls. Generalized estimating equation models accounting for familial correlations implemented in genome-wide interaction analyses with family data were used for association testing in families., Results: Two CCT associated SNPs (rs1536482 and rs7044529 near and within COL5A1) were identified in the keratoconus discovery cohort (P values of 6.5 × 10(-3) and 7.4 × 10(-3)). SNP rs1536482 was replicated in the second case-control sample (P = 0.02), and SNP rs7044529 was replicated in a keratoconus family panel (P = 0.03). Meta P values of rs1536482 and rs7044529 in the keratoconus cohorts were 1.5 × 10(-4) (odds ratio [OR] = 1.30) and 2.9 × 10(-3) (OR = 1.39). After Bonferroni correction, the association of SNP rs1536482 remained significant (P = 6.5 × 10(-3))., Conclusions: SNPs in the COL5A1 region, which regulate normal variation in CCT, may play a role in the thinning associated with keratoconus.

Microbial infections of the cornea frequently cause painful, blinding and debilitating disease that is often difficult to treat and may require corneal transplantation. In addition, sterile corneal infiltrates that are associated with contact lens wear cause pain, visual impairment and photophobia. In this article, we review the role of Toll-Like Receptors (TLR) in bacterial keratitis and sterile corneal infiltrates, and describe the role of MD-2 regulation in LPS responsiveness by corneal epithelial cells. We conclude that both live bacteria and bacterial products activate Toll-Like Receptors in the cornea, which leads to chemokine production and neutrophil recruitment to the corneal stroma. While neutrophils are essential for bacterial killing, they also cause tissue damage that results in loss of corneal clarity. These disparate outcomes, therefore, represent a spectrum of disease severity based on this pathway, and further indicate that targeting the TLR pathway is a feasible approach to treating inflammation caused by live bacteria and microbial products. Further, as the P. aeruginosa type III secretion system (T3SS) also plays a critical role in disease pathogenesis by inducing neutrophil apoptosis and facilitating bacterial growth in the cornea, T3SS exotoxins are additional targets for therapy for P. aeruginosa keratitis.

Contact lenses and lens care regimens are an important part of eyecare practices and vital to lens-wearing patients. New contact lens materials and cleaning options continue to come to market and affect how patients wear and care for their lenses. In this section we look at how the contact lens and lens solution revolution started, how it has evolved over the last 40 years, and how standards have evolved and impacted these new offerings., (Copyright © 2013 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Contact lens-associated corneal infiltrative events (CIEs) are presumed sterile events that have complicated contact lens wear for more than 30 years. There is consistent evidence that silicone hydrogel soft contact lenses increase CIE risk by twofold compared with low Dk hydrogel materials. The incidence of CIEs during silicone hydrogel extended wear ranges from 2% to 6% for symptomatic events and from 6% to 25% when asymptomatic events are included. For daily wear, with silicone hydrogels, the incidence of CIEs ranges from 2% to 3% for symptomatic events and from 7% to 20% when asymptomatic events are included. Despite the increased rate of CIEs with silicone hydrogels, the benefits of these lenses largely outweigh this risk for many patients. Most risk factors for CIEs observed with silicone hydrogels are consistent with CIE risk factors reported earlier with hydrogel lenses, such as bacterial bioburden on lens surfaces, and young age among others. Limiting the transfer of bacterial bioburden from the skin to lenses, lens cases and eventually to the eye is an obvious step forward for the prevention of CIEs across all lens types.

Purpose: Serratia marcescens is frequently isolated from lenses of patients with contact lens-associated corneal infiltrates. In the current study, we examined the role of toll-like receptors (TLRs) and interleukin-1 receptor type 1 (IL-1R1) in S. marcescens-induced corneal inflammation and infection., Methods: The central corneal epithelium of C57BL/6 and gene knockout mice was abraded, and 1 × 10(7) S. marcescens were added in the presence of a silicone hydrogel contact lens, and we examined corneal inflammation by confocal microscopy and neutrophil enumeration. Viable bacteria were quantified by colony-forming units (CFU)., Results: S. marcescens induced neutrophil recruitment to the corneal stroma, and increased corneal thickness and haze in C57BL/6 mice. Conversely, CFU was significantly lower by 48 hours post infection. In contrast, MyD88(-/-), IL-1R(-/-), TLR4(-/-), and TLR4/5(-/-) corneas infected with S. marcescens had significantly increased CFU, indicating impaired clearance. However, there was no significant difference in CFU among C57BL/6, TIRAP(-/-), and TRIF(-/-) mice. Tobramycin-killed S. marcescens induced corneal inflammation in C57BL/6 mice, which was impaired significantly in MD-2(-/-) mice and in C57BL/6 mice pretreated topically with the MD-2 antagonist eritoran tetrasodium., Conclusions: S. marcescens induces corneal inflammation by activation of TLR4/MD-2/MyD88 and the IL-1R1/MyD88 pathways, which are potential therapeutic targets for inhibition of S. marcescens-induced corneal inflammation.

Purpose: Keratoconus is a bilateral noninflammatory progressive corneal disorder with complex genetic inheritance and a common cause for cornea transplantation in young adults. A genomewide linkage scan in keratoconus families identified a locus at 5q23.2, overlapping the gene coding for the lysyl oxidase (LOX). LOX encodes an enzyme responsible for collagen cross-linking in a variety of tissues including the cornea. Corneal collagen cross-linking with long-wave ultraviolet light and riboflavin is a promising new treatment for keratoconus. To determine whether LOX is a genetic determinant of the pathogenesis of keratoconus, we analyzed association results of LOX polymorphisms in two independent case-control samples and in keratoconus families., Methods: Association results were analyzed of single-nucleotide polymorphisms (SNPs) in the LOX gene from a Genome-Wide Association Study (GWAS) investigation in two independent panels of patients with keratoconus and controls and in keratoconus families., Results: Evidence of association was found at SNPs rs10519694 and rs2956540 located in intron 4 of LOX in the GWAS discovery case-control panel with P values of 2.3×10(-3) and 7×10(-3), respectively. The same two SNPs were found to be associated with keratoconus by family-based association testing with P values of 2.7×10(-3) and 7.7×10(-4), respectively. Meta P values of 4.0×10(-5) and 4.0×10(-7) were calculated for SNPs rs10519694 and rs2956540 by analyzing case-control and family samples simultaneously. Sequencing of LOX exons in a subset of keratoconus patients identified two polymorphisms, rs1800449 and rs2288393, located in LOX transcripts I and II, associated with keratoconus in case-control and family samples with a meta P value of 0.02., Conclusions: Results provided strong genetic evidence that LOX variants lead to increased susceptibility to developing of keratoconus.

Keratoconus is a condition in which the cornea progressively thins over time, and is a major cause for cornea transplantation. To identify keratoconus susceptibility regions, we performed a comprehensive genome-wide association study (GWAS) using a discovery and replication design. A discovery panel of 222 keratoconus Caucasian patients and 3324 Caucasian controls was genotyped using Illumina 370K beadchips. Further associated and fine-mapping single nucleotide polymorphisms (SNPs) (n= 4905) were genotyped in an independent replication case-control panel of 304 cases and 518 controls and a family panel of 307 subjects in 70 families. Logistic regression models implemented in PLINK were performed to test associations in case-control samples with and without principal component (PC) adjustments. Generalized estimation equation models accounting for familial correlations implemented in GWAF were used for association testing in families. No genome-wide associations were identified in the discovery GWAS panel. From the initial testing without adjustments for PCs, the top three SNPs located at 3p26 (rs6442925), 2q21.3 (rs4954218) and 19q13.3 (rs1428642) were identified with unadjusted P-values of 6.5 × 10(-8), 2.4 × 10(-7) and 3.1 × 10(-7), respectively. After adjustments for PCs, rs1428642 became the most significant through the genome with a P-value of 1.4 × 10(-6), while rs6442925 and rs4954218 were less significant (P= 1.9 × 10(-5) and 2.6 × 10(-4)). SNP rs4954218 was confirmed in two independent replication panels with P-values of 0.004 and 0.009, respectively. Meta-analysis revealed a highest association at rs4954218 with adjusted P= 1.6 × 10(-7) (unadjusted P= 1.2 × 10(-9)). These findings suggest SNP rs4954218, located near the RAB3GAP1 gene, previously reported to be associated with corneal malformation, is a potential susceptibility locus for keratoconus., (© The Author 2011. Published by Oxford University Press. All rights reserved.)

Purpose: Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease., Methods: Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype., Results: The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10(-7)) and rs17501108 (P = 9.9 × 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036)., Conclusions: Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.

Purpose: To determine the association between mucin ball formation and corneal infiltrative events (CIEs) during continuous wear with lotrafilcon A silicone hydrogel contact lenses., Methods: Subjects (n = 205) in the Longitudinal Analysis of Silicone Hydrogel Contact Lens Study wore lotrafilcon A contact lenses for 12 months of continuous wear. The primary outcome was a CIE. Kaplan-Meier methods were used to estimate the unadjusted cumulative incidence of remaining CIE free stratified by mucin ball presence. Cox proportional hazards regression was used to model the hazard of developing a CIE as a function of mucin ball formation and other covariates., Results: Over half (54.2%) of the subjects displayed some presence of mucin balls during at least 1 visit and about one third (32.8%) displayed repeated episodes. Mucin ball scores were correlated between the 2 eyes and weakly correlated with corneal curvature (P ≤ 0.005). Univariate analyses revealed that the relative hazard for a CIE was 0.35 [95% confidence interval (CI), 0.19-0.68] if a single episode of mucin balls was detected and 0.17 (95% CI, 0.06-0.43) if repeated episodes were detected. Upon multivariate analysis, repeated presence of mucin balls was associated with an 84% decreased hazard of experiencing a CIE (hazard ratio: 0.16; 95% CI, 0.06-0.44)., Conclusions: The presence of mucin balls is significantly associated with a decreased incidence of CIEs, and the effect is greatest when they are repeatedly present over time. We hypothesize that the mucin ball presence represents a more concentrated or viscous mucus layer, which prevents upregulation of the immune response against bacterial ligands.

Purpose: To investigate the relationships between ophthalmology resident performance on the United States Medical Licensing Examination (USMLE), the Ophthalmic Knowledge Assessment Program (OKAP) exam and the American Board of Ophthalmology written qualifying examination (ABO-WQE)., Design: Cohort study., Participants: We included 76 residents from 15 consecutive training classes (1991-2006) at 1 ophthalmologic residency training program., Methods: Numeric scores on the USMLE Step 1 and OKAP examinations during the 3 years of residency, and first attempt pass rate on the ABO-WQE were recorded for 76 residents. Age and gender were also noted. Spearman's rank correlations and univariate and multivariate logistic analyses were performed to determine relevant associations., Main Outcome Measures: First-time attempt pass rate on the ABO-WQE and/or successful completion of the ABO-WQE within 3 years of graduation from the residency program., Results: The ABO-WQE first-attempt pass rate was 72.6%, consistent with the national average. Resident USMLE scores were not significantly associated with ABO-WQE performance. The ABO-WQE pass rate was significantly associated with OKAP examination scores during the 3 residency years (year 1: odds ratio [OR], 8.85 and 95% confidence interval [CI] 1.82-42.79; year 2: OR, 5.28 and 95% CI, 1.15-25.27; year 3: OR, 11.08 and 95% CI, 1.86-68.96). Passing the OKAP examinations in all 3 years during residency training was associated with 5.43-fold increased odds of passing the ABO-WQE and failing all 3 OKAP examinations was associated with >9-fold lower odds of passing the ABO-WQE on the first attempt., Conclusions: Our results suggest that OKAP examination performance is a predictor of a resident's success in passing the ABO-WQE on the first attempt, as well as within 3 years of graduation from an ophthalmologic training program. Awareness of this association may permit identification of residents at risk for failing the ABO-WQE and encourage educational remediation to prevent this failure., (Copyright © 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: This study determined which microbiologic, clinical, demographic, and behavioral factors are associated with corneal infiltrative events (CIEs) during continuous wear of silicone hydrogel (SH) contact lenses., Methods: Subjects (n = 205) were fitted with lotrafilcon A lenses for continuous wear and observed for 1 year. The main exposures of interest were corneal staining and bacterial lens contamination. Kaplan-Meier (KM) plots were used to estimate the cumulative unadjusted probability of remaining CIE free, and Cox proportional hazards regression was used to model the hazard of having a CIE, as a function of key predictor variables., Results: The KM-unadjusted cumulative probability of remaining CIE free was 73.3%. Approximately 53% of subjects had repeated episodes of corneal staining (mild or greater), and 11.3% had repeated episodes of moderate or greater corneal staining. Corneal staining was not associated with the development of a CIE. The frequency of substantial bacterial bioburden on worn lenses at the time of a CIE was 64.7%, compared with only 12.2% during uncomplicated wear. The presence of substantial lens bacterial bioburden was associated with the development of a CIE (adjusted hazards ratio [HR], 8.66; 95% confidence interval [CI], 2.88-26.01). Smoking was also associated with a CIE (adjusted HR, 4.13; 95% CI, 1.27-13.45)., Conclusions: Corneal staining is common during continuous wear of SH lenses, but it is not associated with the development of a CIE. Smoking and substantial lens bacterial bioburden pose prominent risks of a CIE. In this study, more than 70% of the total risk of CIE in those with substantial lens bioburden is attributable to this exposure. (ClinicalTrials.gov number, NCT00727402).

Purpose: Fusarium solani and F. oxysporum were the causative organisms of the 2005/2006 outbreak of contact lens-associated fungal keratitis in the United States. The present study was an investigation of the ability of F. oxysporum grown as a biofilm on silicone hydrogel contact lenses to induce keratitis., Methods: A clinical isolate of F. oxysporum was grown as a biofilm on lotrafilcon A contact lenses, and a 2-mm diameter punch was placed on the abraded corneal epithelium of either untreated or cyclophosphamide-treated C57BL/6 mice or of IL-1R1(-/-), MyD88(-/-), TLR2(-/-), or TLR4(-/-) mice. After 2 hours, the lens was removed, and corneal opacification, colony forming units (CFUs), and histopathology were evaluated., Results: C57BL/6 mice developed severe corneal opacification within 24 hours and resolved after four days. In contrast, corneal opacification progressed in cyclophosphamide-treated mice, and was associated with unimpaired fungal growth in the cornea, and with hyphae penetrating into the anterior chamber. The phenotype of MyD88(-/-) and IL-1R(-/-) mice was similar to that of cyclophosphamide-treated animals, with significantly impaired cellular infiltration and fungal clearance. Although TLR4(-/-) mice developed a cellular infiltrate and corneal opacification similar to C57BL/6 mice, the CFU count was significantly and consistently higher., Conclusions: Fusarium grown as a biofilm on silicone hydrogel contact lenses can induce keratitis on injured corneas, with disease severity and fungal killing dependent on the innate immune response, including IL-1R1, MyD88, and TLR4.

Purpose: In 1995, Myers and Weiss published an article comparing the risk of ulcerative keratitis related to low oxygen permeability (Dk) extended contact lens wear to other life risks. This article updates the risks associated with silicone hydrogel (SH) extended wear contact lens use and some comparative life risks, to provide a current perspective within the hierarchy of life risks., Methods: A comparative ratio was defined as the incidence of microbial keratitis in a population of SH extended wear contact lens users divided by the incidence of other disease or occurrence in a given population at risk., Results: The risk of SH lens-related microbial keratitis is about 1.5 to 16 times less risky than certain nonfatal disruptive occurrences in the general population, and about the same as the risk of developing breast cancer. Compared with other ocular conditions, the risk of microbial keratitis with SH lenses is about the same as developing late-stage age-related macular degeneration or retinal detachment after cataract extraction on an annual basis; it is over 200 times greater than developing eye or orbit cancer; it is about 7, 20, or more than 30 times less than proceeding to penetrating keratoplasty in keratoconus, developing nuclear cataract, or experiencing a corneal inflammatory event during low-Dk extended wear, respectively., Conclusions: Although the risk of microbial keratitis with modern day SH contact lens extended wear has not changed since the 1980s, when put in perspective with other life risks, it is a relatively rare occurrence.

Purpose: High Dk silicone hydrogel (SH) lenses have been shown to significantly decrease the risk of hypoxic complications compared to traditional low Dk hydrogels. However, the risks of inflammatory complications with SH compared to low Dk lenses are not as clear. A meta-analysis was performed to combine the relevant literature to evaluate the risks of corneal inflammatory events in users of SH and low Dk hydrogel extended wear lenses., Methods: A systematic search was conducted using online databases, unpublished meeting abstracts, and retrieval of other cited references presented or published between 1990 and February 2006. Each study was evaluated for quality in terms of the research question, and these quality assessments were used to determine which studies should be used in subgroup analyses. A generalized linear mixed model framework with an underlying Poisson distribution for the occurrence of events was employed to combine information from the included studies., Results: Twenty-three studies published or presented on either or both arms by February 2006 were selected for analysis. A total of 9,336 subjects and 18,537 eyes comprised the entire sample. Seven studies were published in the 1990s. Eighteen studies (78%) were prospective, and 11 (48%) used randomization. The follow-up ranged from 4 to 36 months, with a median of 12 months. The rates of infiltrates for low Dk hydrogels and SH lenses were 7.7 (2.2, 26.7) and 14.4 (4.3, 48.2) per 100 eye-years, respectively. In the subset of five best quality studies, the unadjusted risk ratio for corneal inflammatory events for SH lenses compared to low Dk lenses was 2.18 (p < 0.005). Across studies, adjusted risk ratios ranged from 2.18 to 2.23 (p < 0.05), with strong confounding between material and length of wear., Conclusions: Based on published or presented studies between 1991 and 2006, there is approximately a twofold higher risk for corneal inflammatory events in users of SH lenses when typically worn for up to 30 days extended wear when compared with low Dk extended wear lenses when typically worn for 7 days extended wear. The increased risk cannot be definitively linked to SH lens materials because the effect of material on outcome is confounded by length of wear.

Objective: To estimate the cumulative probability and risk factors for developing corneal infiltrates after up to 3 years of continuous wear (CW) with lotrafilcon A lenses., Methods: Patients were fitted with lotrafilcon A lenses and followed up for 3 years. The main outcome variable was the first occurrence of any infiltrative event in either eye. Cox proportional hazards regression was used to model the probability of developing infiltrates as a function of demographic and biomicroscopy findings., Results: A total of 317 patients participated in this study. The Kaplan-Meier unadjusted cumulative incidence of a corneal infiltrate after CW was 5.7% (95% confidence interval [CI], 3.0%-8.4%) at the end of 1 year, 8.5% (95% CI, 5.2%-11.9%) at the end of 2 years, and 10.3% (95% CI, 6.6%-13.9%) at the end of 3 years. Corneal staining and limbal redness present in the affected eye on a previous visit were significantly associated with the development of an infiltrative event (hazard ratios, 7.23 and 3.18; P<.001 and P = .02, respectively)., Conclusions: Corneal staining and limbal redness may predict the subsequent development of an infiltrative event among CW contact lens patients. The probability of remaining free of any corneal infiltrates at the end of 3 years of CW of contact lenses was 89.7% (95% CI, 86.1%-93.4%).

Purpose: To identify baseline demographic and clinical factors associated with undergoing penetrating keratoplasty (PK) in a prospective cohort of 1,065 keratoconus patients followed for eight years in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study., Design: Multicenter, prospective, observational cohort study., Methods: We report the rate of PK over eight years and baseline factors predictive of PK in 1,065 patients who, at the time of study enrollment, had not undergone PK in either eye., Results: Eighty-two percent of patients completed the eight-year close-out visit. Twelve percent (126 of 1,065) had PK in one (9.3%) or both eyes (2.5%). Baseline factors associated with increased likelihood of PK included younger age, steeper keratometric values, worse visual acuity, corneal scarring, poorer contact lens comfort, and poorer vision-related quality of life. The percent of eyes undergoing PK was 15% for patients 40 years old and younger, 28% for eyes with a steep keratometric value greater than 52 diopters, 33% for visual acuity less than 20/40, and 24% for eyes with corneal scarring., Conclusions: The CLEK Study confirmed previous reports of the increased likelihood of PK associated with corneal scarring, steeper keratometry values, poorer visual acuity, and poorer contact lens comfort. The CLEK Study is among the first to report an increased risk of PK associated with younger age, worse vision-related quality of life, and flatter contact lens fits. Knowledge of these factors is beneficial to clinicians in patient education and may be useful in disease management.

Purpose: To define a new method for grading severity of keratoconus, the Keratoconus Severity Score (KSS)., Methods: A rationale for grading keratoconus severity was developed using common clinical markers plus 2 corneal topographic indices, creating a 0 to 5 severity score. An initial test set of 1012 eyes, including normal eyes, eyes with abnormal corneal and topographic findings but not keratoconus, and eyes with keratoconus having a wide range of severity, was used to determine cutpoints for the KSS. Validation set 1, comprising data from 128 eyes, was assigned a KSS and compared with a clinician's ranking of severity termed the "gold standard" to determine if the scale fairly represented how a clinician would grade disease severity. kappa statistics, sensitivity, and specificity were calculated. A program was developed to automate the determination of the score. This was tested against a manual assignment of KSS in 2121 (validation set 2) eyes from the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study, as well as normal eyes and abnormal eyes without keratoconus. Ten percent of eyes underwent repeat manual assignment of KSS to determine the variability of manual assignment of a score., Results: From initial assessments, the KSS used 2 corneal topography indices: average corneal power and root mean square (RMS) error for higher-order Zernike terms derived from the first corneal surface wavefront. Clinical signs including Vogt striae, Fleischer rings, and corneal scarring were also included. Last, a manual interpretation of the map pattern was included. Validation set 1 yielded a kappa statistic of 0.904, with sensitivities ranging from 0.64 to 1.00 and specificities ranging from 0.93 to 0.98. The sensitivity and specificity for determining nonkeratoconus from keratoconus were both 1.00. Validation set 2 showed kappa statistics of 0.94 and 0.95 for right and left eyes, respectively. Test-retest analysis yielded kappa statistics of 0.84 and 0.83 for right and left eyes, respectively., Conclusion: A simple and reliable grading system for keratoconus was developed that can be largely automated. Such a grading scheme could be useful in genetic studies for a complex trait such as keratoconus requiring a quantitative measure of disease presence and severity.

Purpose: This study was designed to identify factors that predict longitudinal increases in corneal curvature as measured by the First Definite Apical Clearance Lens (FDACL) and flatter keratometric reading (Flat K) in keratoconus., Methods: The Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study is a long-te rm evaluation of the natural history of keratoconus involving 1209 patients. This report uses 8 years of follow-up data from 1032 patients who had penetrating keratoplasty in neither eye at baseline and who provided enough data to compute the slope of the change with time in the FDACL or the Flat K. Outcome measures included the aforementioned slopes and whether the FDACL or the Flat K increased by 3.00 or more diopters (D) in at least 1 eye., Results: At CLEK Study entry, patients were aged 38.9 +/- 10.8 years. Overall, 44.3% of them were women, and 69.3% of them were white. The slope of the change in FDACL (0.18 +/- 0.60 D/y) and Flat K (0.20 +/- 0.80 D) during 8 years translates into expected 8-year increases of 1.44 D in FDACL and 1.60 D in Flat K. Increases of > or = 3.00 D in either eye had an 8-year incidence of 24.8% for FDACL and 24.1% for Flat K. Independent predictors of increased FDACL included younger age, poorer baseline high-contrast manifest refraction visual acuity, and non-white race. Younger age and poorer high-contrast manifest refraction visual acuity were independent predictors of a >3.00-D increase for both FDACL and Flat K., Conclusion: CLEK patients exhibited a slow but clear increase in corneal curvature. Younger age and poorer high-contrast manifest refraction visual acuity at baseline predicted the rate of change in corneal curvature.

Purpose: Computerized videokeratography (CVK) has become the standard method for measuring the corneal curvature after refractive surgery. However, few resources exist on the use of CVK data for postoperative contact lens fitting, and no recommendations exist on the selection of the best topographic algorithm relevant to gas-permeable (GP) lens fitting. This study assessed the optimal use of topographic data to fit spherical GP contact lenses on patients who have undergone laser in situ keratomileusis., Methods: A retrospective analysis of CVK maps from eight post-LASIK eyes fitted with spherical GP lenses was performed in the Contact Lens Service of the Department of Ophthalmology at Case Western Reserve University and University Hospitals of Cleveland. Axial and tangential maps from the Dicon CT 200 (version 3.50) or Humphrey Atlas (version A8) topographer were analyzed. Averaged dioptric curvatures from different locations (inferior, superior, and temporal) at various distances (2.0 mm, 2.5 mm, 3.0 mm, 3.5 mm, and 4.0 mm) from the vertex normal of each eye were compared with the base curves of the prescribed GP contact lenses., Results: One-way analysis of variance, Pearson correlation analysis, and paired t tests showed that the best topographic predictors of a successful GP base curve were the average curvatures at the 4.0 mm distance on the axial maps (r=0.8078, P=0.05) and at the 2.0 mm distance on the tangential maps (r=0.9738, P=0.0002). The mean dioptric powers of the GP base curve, axial map 4.0 mm curvature, and tangential map 2.0 mm curvature were 41.50 diopters (D), 42.65 D, and 42.67 D, respectively., Conclusion: To simplify and guide GP fitting after LASIK, the average dioptric curvature 4.0 mm from the vertex normal on axial maps or 2.0 mm from the vertex normal on tangential maps are the best predictors of accurate GP base curve selection.

The shape of a cornea, as measured by corneal topography, can be influenced by a variety of factors. Direct and obvious influences on corneal shape include corneal pathology, corneal surgery, and contact lenses. With the modern and widespread use of computerized videokeratoscopy, subtle topographic changes from other external and systemic influences can now be detailed. The purpose of this review is to examine ocular surface influences and indirect surgical, pathological, and pharmacological factors that affect the corneal shape and acquired topographic maps. The clinical consequences of altered corneal topography will be highlighted throughout.

Purpose: Progressive corneal astigmatism occurring at least 10 years after penetrating keratoplasty for keratoconus is a late-phase complication of surgery. This report characterizes this condition in a series of patients from three corneal referral centers in the United States., Methods: Charts were retrospectively reviewed which met the following criteria: penetrating keratoplasty performed for keratoconus at least 10 years ago, keratometry or simulated keratometry from topography as well as manifest refraction recorded at least 6 months after the last suture removal ("baseline"), and an increase in corneal astigmatism of at least three D over baseline recorded at least 5 years later. Patients who had any other corneal or intraocular surgery performed were excluded., Results: Data from 15 patients (11 males and 4 females) who had penetrating keratoplasties performed by 8 different surgeons are included in this descriptive series. Postoperative follow-up averaged 17.27 years (range 11-24 years). The average donor button size was 7.83 mm (range 7.25-8.5 mm). Baseline corneal astigmatism was obtained an average of 5.2 years after penetrating keratoplasty (range 1.5-16 years) and was on average 3.57 +/- 1.8 D (10 with-the-rule [WTR], 3 against-the-rule [ATR], 2 oblique). Corneal astigmatism significantly increased to an average of 11.23 +/- 3.56 D (range 8.00-19.37 D, P < 0.0001) and most astigmatism was regular and WTR (9 WTR, 3 ATR, 3 oblique) 15.3 years (range 10-22 years) after surgery. Inferior steepening on topography was often noted, even those with oblique and ATR axes., Conclusions: High, late-stage, regular astigmatism after penetrating keratoplasty for keratoconus is described in a series of patients occurring at least 10 years after surgery. Possible mechanisms of this progressive astigmatism are recurrence of keratoconus in the graft, progressive corneal thinning of the host cornea, or progressive misalignment of the graft-host interface over time.