OBJECTIVE: Pathological ocular neovascularization is a major cause of blindness. Increased dietary intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces retinal neovascularization and choroidal neovascularization (CNV), but ω-3 LCPUFA metabolites of a major metabolizing pathway, cytochrome P450 oxidase (CYP) 2C, promote ocular pathological angiogenesis. We hypothesized that inhibition of CYP2C activity will add to the protective effects of ω-3 LCPUFA on neovascular eye diseases. APPROACH AND RESULTS: The mouse models of oxygen-induced retinopathy and laser-induced CNV were used to investigate pathological angiogenesis in the retina and choroid, respectively. The plasma levels of ω-3 LCPUFA metabolites of CYP2C were determined by mass spectroscopy. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of CYP2C inhibition and ω-3 LCPUFA-derived CYP2C metabolic products on angiogenesis ex vivo. We found that inhibition of CYP2C activity by montelukast added to the protective effects of ω-3 LCPUFA on retinal neovascularization and CNV by 30% and 20%, respectively. In CYP2C8-overexpressing mice fed a ω-3 LCPUFA diet, montelukast suppressed retinal neovascularization and CNV by 36% and 39% and reduced the plasma levels of CYP2C8 products. Soluble epoxide hydrolase inhibition, which blocks breakdown and inactivation of CYP2C ω-3 LCPUFA-derived active metabolites, increased oxygen-induced retinopathy and CNV in vivo. Exposure to selected ω-3 LCPUFA metabolites of CYP2C significantly reversed the suppression of both angiogenesis ex vivo and endothelial cell functions in vitro by the CYP2C inhibitor montelukast. CONCLUSIONS: Inhibition of CYP2C activity adds to the protective effects of ω-3 LCPUFA on pathological retinal neovascularization and CNV.

The nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) enzyme is essential for regenerating the nuclear pool of NAD(+) in all nucleated cells in the body, and mounting evidence also suggests that it has a separate role in neuroprotection. Recently, mutations in the NMNAT1 gene were associated with Leber congenital amaurosis, a severe retinal degenerative disease that causes blindness during infancy. Availability of a reliable mammalian model of NMNAT1-Leber congenital amaurosis would assist in determining the mechanisms through which disruptions in NMNAT1 lead to retinal cell degeneration and would provide a resource for testing treatment options. To this end, we identified two separate N-ethyl-N-nitrosourea-generated mouse lines that harbor either a p.V9M or a p.D243G mutation. Both mouse models recapitulate key aspects of the human disease and confirm the pathogenicity of mutant NMNAT1. Homozygous Nmnat1 mutant mice develop a rapidly progressing chorioretinal disease that begins with photoreceptor degeneration and includes attenuation of the retinal vasculature, optic atrophy, and retinal pigment epithelium loss. Retinal function deteriorates in both mouse lines, and, in the more rapidly progressing homozygous Nmnat1(V9M) mutant mice, the electroretinogram becomes undetectable and the pupillary light response weakens. These mouse models offer an opportunity for investigating the cellular mechanisms underlying disease pathogenesis, evaluating potential therapies for NMNAT1-Leber congenital amaurosis, and conducting in situ studies on NMNAT1 function and NAD(+) metabolism.

Neurons in the cerebral cortex respond inconsistently to a repeated sensory stimulus, yet they underlie our stable sensory experiences. Although the nature of this variability is unknown, its ubiquity has encouraged the general view that each cell produces random spike patterns that noisily represent its response rate. In contrast, here we show that reversibly inactivating distant sources of either bottom-up or top-down input to cortical visual areas in the alert primate reduces both the spike train irregularity and the trial-to-trial variability of single neurons. A simple model in which a fraction of the pre-synaptic input is silenced can reproduce this reduction in variability, provided that there exist temporal correlations primarily within, but not between, excitatory and inhibitory input pools. A large component of the variability of cortical neurons may therefore arise from synchronous input produced by signals arriving from multiple sources.

PURPOSE: Purinergic receptors play a key role in the function of the lacrimal gland (LG) as P1 purinergic receptors A1, A2A, and A2B, P2X1-7 receptors, and many of the P2Y receptors are expressed. METHODS: This review examines the current knowledge of purinergic receptors in the LG as well as the signaling pathways activated by these receptors. RESULTS: These receptors are expressed on the acinar, ductal, and myoepithelial cells. Considerable crosstalk exists between the pathways activated by P2X7 receptors with those activated by M3 muscarinic or α1D adrenergic receptors. The mechanism of the crosstalk between P2X7 and M3 muscarinic receptors differs from that of the crosstalk between P2X7 and α1D adrenergic receptors. CONCLUSIONS: Understanding purinergic receptors and how they modulate protein secretion could play a key role in normal and pathological responses of the LG.

To compare the surgical duration and clinical outcomes of nasolacrimal recanalization versus external dacryocystorhinostomy (DCR) in the treatment of failed nasolacrimal duct intubation.This is a retrospective, comparative, and interventional study. We evaluated the outcomes of 66 consecutive patients undergoing either nasolacrimal recanalization (n = 32) or DCR (n = 34) in a tertiary lacrimal disease referral center. Length of surgical duration, clinical outcomes, and rate of recurrence at 18 months postoperatively were compared.The mean surgical duration was 18.5 minutes (range, 15-25 minutes) for nasolacrimal recanalization and 48.2 minutes (range, 45-61 minutes) for DCR, respectively (P < 0.001). The rate of success was 84.4% in the recanalization group and 85.3% in the DCR group, respectively (P = 0.91). The time to recurrence was 2.6 ± 1.1 months in the recanalization group and 5.6 ± 2.1 months in the DCR group (P < 0.001). Five failed cases in each group received a secondary DCR surgery with the same resolution rate (40%). The absence of ocular discharge at baseline was a significant predictor for a successful outcome in the recanalization group (P = 0.04) but not in the DCR group (P = 0.63).Nasolacrimal recanalization is an effective, safe, and time-saving alternative to DCR for the treatment of failed nasolacrimal duct intubation. Clinicians should be cautious in patients with discharge.

The Illumina HumanExome BeadChip and other exome-based genotyping arrays offer inexpensive genotyping of some 240,000 mostly nonsynonymous coding variants across the human genome. The HumanExome chip, with its highly non-uniform distribution of markers and emphasis on rare coding variants, presents some unique challenges for quality control (QC) and data cleaning. Here, we describe QC procedures for HumanExome data, with examples of challenges specific to exome arrays from our experience cleaning a data set of ∼7,500 samples from the NEIGHBORHOOD Consortium. We focus on standard procedures for QC of genome-wide array data including genotype calling, sex verification, sample identity verification, relationship checking, and population structure that are complicated by the HumanExome panel's enrichment in rare, exonic variation. © 2016 by John Wiley & Sons, Inc.

Human adenoviruses (HAdVs) contain seven species (HAdV-A to -G), each associated with specific disease conditions. Among these, HAdV-D includes those viruses associated with epidemic keratoconjunctivitis (EKC), a severe ocular surface infection. The reasons for corneal tropism for some but not all HAdV-Ds are not known. The fiber protein is a major capsid protein; its C-terminal "knob" mediates binding with host cell receptors to facilitate subsequent viral entry. In a comprehensive phylogenetic analysis of HAdV-D capsid genes, fiber knob gene sequences of HAdV-D types associated with EKC formed a unique clade. By proteotyping analysis, EKC virus-associated fiber knobs were uniquely shared. Comparative structural modeling showed no distinct variations in fiber knobs of EKC types but did show variation among HAdV-Ds in a region overlapping with the known CD46 binding site in HAdV-B. We also found signature amino acid positions that distinguish EKC from non-EKC types, and by in vitro studies we showed that corneal epithelial cell tropism can be predicted by the presence of a lysine or alanine at residue 240. This same amino acid residue in EKC viruses shows evidence for positive selection, suggesting that evolutionary pressure enhances fitness in corneal infection, and may be a molecular determinant in EKC pathogenesis. IMPORTANCE: Viruses adapt various survival strategies to gain entry into target host cells. Human adenovirus (HAdV) types are associated with distinct disease conditions, yet evidence for connections between genotype and cellular tropism is generally lacking. Here, we provide a structural and evolutionary basis for the association between specific genotypes within HAdV species D and epidemic keratoconjunctivitis, a severe ocular surface infection. We find that HAdV-D fiber genes of major EKC pathogens, specifically the fiber knob gene region, share a distinct phylogenetic clade. Deeper analysis of the fiber gene revealed that evolutionary pressure at crucial amino acid sites has a significant impact on its structural conformation, which is likely important in host cell binding and entry. Specific amino acids in hot spot residues provide a link to ocular cell tropism and possibly to corneal pathogenesis.

Stevens-Johnson syndrome (SJS) is an acute blistering disease of the skin and mucous membranes. Acute SJS leads to the acute inflammation of the ocular surface and chronic conjunctivitis. If not properly treated, it causes chronic cicatricial conjunctivitis and cicatricial lid margin abnormalities. Persistent inflammation and ulceration of the ocular surface with cicatricial complications of the lids leads to chronic ocular sequelae, ocular surface damage, and corneal scarring. The destruction of the glands that secrete the tear film leads to a severe form of dry eye that makes the management of chronic SJS difficult. The option that is routinely used for corneal visual rehabilitation, keratoplasty, is best avoided in such cases. We describe the management strategies that are most effective during the acute and chronic stages of SJS. Although treatments for acute SJS involve immunosuppressive and immunomodulatory therapies, amniotic membrane transplantation is also useful. The options for visual rehabilitation in patients with chronic SJS are undergoing radical change. We describe the existing literature regarding the management of SJS and highlight recent advances in the management of this disorder.

A 24-year-old man with a painful, recurrent left upper eyelid nodule underwent an excision. Histopathologic evaluation disclosed a granulomatous process, most likely in response to a ruptured epidermoid cyst. In the vicinity of the nodule were multiple eccrine sweat glands displaying a curious clear-cell appearance in the adlumenal cells, the first example of such a phenomenon in the eyelids. Alcian blue, periodic acid Schiff, and documented staining failed to disclose, respectively, any cytoplasmic mucosubstances, glycogen accumulation, or lipid in the adlumenal secretory cells. Cytokeratin 7 immunostained the adlumenal cells of the eccrine secretory coil, while cytokeratin 5/6 stained the ablumenal myoepithelial and ductular cells. Gross cystic disease fluid protein 15, normally demonstrable in the eccrine secretory cells, was not detectable. Clear-cell transformation should not be confused with syringoma of the lower eyelids, in which glycogen is responsible for the ablumenal clear-cell change.

PURPOSE: To investigate the association between sleep duration and diabetic retinopathy (DR). METHODS: A population-based cross-sectional study using a nation-wide, systemically stratified, multistage, clustered sampling method included a total of 1670 subjects aged ≥40 years with diabetes who participated in the Korean National Health and Nutrition Examination Survey during 2008-2012. All participants performed standardized interviews, including self-reported sleep duration, and comprehensive ophthalmic examinations. Seven standard retinal fundus photographs were obtained from both eyes after pupil dilatation. Diabetic retinopathy (DR) was graded and classified as any DR and vision-threatening DR. Participants were stratified into men and women. RESULTS: The mean sleep duration was 6.71 hr/day. In men, adjusted OR of any DR was 1.88 [95% confidence interval (OR), 1.01-3.59] in those with ≤5 hr sleep, and 2.19 (95% CI, 1.01-4.89) in those with ≥9 hr sleep, compared to in subjects with 6-8 hr sleep, after adjusting for potential confounders including age, body mass index (BMI), diabetes duration, fasting glucose level, haemoglobin A1c levels and hypertension. In women, however, no significant association between sleep duration and DR was found. The vision-threatening DR was not significantly associated with sleep duration in either men or women. CONCLUSIONS: Short and long sleep was associated with high prevalence of DR in men. Sleep deprivation may be involved in the pathogenesis of DR development.

BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls. RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse. CONCLUSIONS: In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.

OBJECTIVES: To review the contribution of the Nurses' Health Study (NHS) to understanding the genetic and lifestyle factors that influence the risk of cataract, age-related macular degeneration, and glaucoma. METHODS: We performed a narrative review of the publications of the NHS between 1976 and 2016. RESULTS: The NHS has helped to elucidate the roles of genetics, lifestyle factors (e.g., cigarette smoking associated with cataract extraction and age-related macular degeneration), medical conditions (e.g., diabetes associated with cataract extraction and glaucoma), and dietary factors (e.g., greater carotenoid intake and lower glycemic diet associated with lower risk of age-related macular degeneration) in the etiology of degree and progression of lens opacities, cataract extraction, age-related macular degeneration, primary open-angle glaucoma, and exfoliation glaucoma. CONCLUSIONS: The findings from the NHS, combined with those of other studies, have provided compelling evidence to support public health recommendations for helping to prevent age-related eye diseases: abstinence from cigarette smoking, maintenance of healthy weight and diabetes prevention, and a healthy diet rich in fruits and vegetables.

Abnormal blood vessel growth in the retina is a hallmark of many retinal diseases, such as retinopathy of prematurity (ROP), proliferative diabetic retinopathy, and the wet form of age-related macular degeneration. In particular, ROP has been an important health concern for physicians since the advent of routine supplemental oxygen therapy for premature neonates more than 70 years ago. Since then, researchers have explored several animal models to better understand ROP and retinal vascular development. Of these models, the mouse model of oxygen-induced retinopathy (OIR) has become the most widely used, and has played a pivotal role in our understanding of retinal angiogenesis and ocular immunology, as well as in the development of groundbreaking therapeutics such as anti-vascular endothelial growth factor injections for wet age-related macular degeneration. Numerous refinements to the model have been made since its inception in the 1950s, and technological advancements have expanded the use of the model across multiple scientific fields. In this review, we explore the historical developments that have led to the mouse OIR model utilized today, essential concepts of OIR, limitations of the model, and a representative selection of key findings from OIR, with particular emphasis on current research progress.

PURPOSE: We determined the receiver operating characteristic (ROC) curves for Peristat online perimetry at detecting varying degrees of glaucoma and the correlation between Peristat online perimetry and Humphrey visual field. METHODS: A prospective, comparative study of Peristat online perimetry (an achromatic static computer threshold testing program) and Humphrey visual field (HVF) 24-2 SITA standard testing was performed by 63 glaucoma patients and 30 healthy controls in random order. The number of total adjacent abnormal test points were identified for each test, and compared with Spearman correlation. Receive operating characteristic curves were generated for Peristat online perimetry detection of mild and moderate-severe glaucoma patients using contrast sensitivity thresholds of -16.7, -21.7, and -26.7 dB. RESULTS: The area under the ROC curve for glaucoma detection ranged from 0.77 to 0.81 for mild disease (mean deviation [MD], >-6 dB on HVF) and 0.85 to 0.87 for moderate to severe disease (MD, <-6 dB on HVF) depending on contrast threshold. Peristat online perimetry and Humphrey visual field abnormal points were highly correlated with Spearman rank correlations ranging from 0.55 to 0.77 (all P < 0.001). CONCLUSIONS: Peristat online perimetry exhibits a reasonable ROC curve without specialized equipment and exhibited significant correlation with the conventional 24° Humphrey visual field test. TRANSLATIONAL RELEVANCE: Low cost widely available internet-based visual fields may complement traditional office-based visual field testing.

PURPOSE: The purpose of this study was to assess whether clinically useful measures of fixation instability and eccentricity can be derived from retinal tracking data obtained during optical coherence tomography (OCT) in patients with optic neuropathy (ON) and to develop a method for relating fixation to the retinal ganglion cell complex (GCC) thickness. METHODS: Twenty-nine patients with ON underwent macular volume OCT with 30 seconds of confocal scanning laser ophthalmoscope (cSLO)-based eye tracking during fixation. Kernel density estimation quantified fixation instability and fixation eccentricity from the distribution of fixation points on the retina. Preferred ganglion cell layer loci (PGCL) and their relationship to the GCC thickness map were derived, accounting for radial displacement of retinal ganglion cell soma from their corresponding cones. RESULTS: Fixation instability was increased in ON eyes (0.21 deg2) compared with normal eyes (0.06982 deg2; P < 0.001), and fixation eccentricity was increased in ON eyes (0.48°) compared with normal eyes (0.24°; P = 0.03). Fixation instability and eccentricity each correlated moderately with logMAR acuity and were highly predictive of central visual field loss. Twenty-six of 35 ON eyes had PGCL skewed toward local maxima of the GCC thickness map. Patients with bilateral dense central scotomas had PGCL in homonymous retinal locations with respect to the fovea. CONCLUSIONS: Fixation instability and eccentricity measures obtained during cSLO-OCT assess the function of perifoveal retinal elements and predict central visual field loss in patients with ON. A model relating fixation to the GCC thickness map offers a method to assess the structure-function relationship between fixation and areas of preserved GCC in patients with ON.

PURPOSE: Previous studies have shown that vitreous stimulates degradation of the tumor suppressor protein p53 and that knockdown of phosphatidylinositol 5-phosphate 4-kinases (PI5P4Kα and -β) abrogates proliferation of p53-deficient cells. The purpose of this study was to determine whether vitreous stimulated expression of PI5P4Kα and -β and whether suppression of PI5P4Kα and -β would inhibit vitreous-induced cellular responses and experimental proliferative vitreoretinopathy (PVR). METHODS: PI5P4Kα and -β encoded by PIP4K2A and 2B, respectively, in human ARPE-19 cells were knocked down by stably expressing short hairpin (sh)RNA directed at human PIP4K2A and -2B. In addition, we rescued expression of PI5P4Kα and -β by re-expressing mouse PIP4K2A and -2B in the PI5P4Kα and -β knocked-down ARPE-19 cells. Expression of PI5P4Kα and -β was determined by Western blot and immunofluorescence. The following cellular responses were monitored: cell proliferation, survival, migration, and contraction. Moreover, the cell potential of inducing PVR was examined in a rabbit model of PVR effected by intravitreal cell injection. RESULTS: We found that vitreous enhanced expression of PI5P4Kα and -β in RPE cells and that knocking down PI5P4Kα and -β abrogated vitreous-stimulated cell proliferation, survival, migration, and contraction. Re-expression of mouse PIP4Kα and -β in the human PI5P4Kα and -β knocked-down cells recovered the loss of vitreous-induced cell contraction. Importantly, suppression of PI5P4Kα and -β abrogated the pathogenesis of PVR induced by intravitreal cell injection in rabbits. Moreover, we revealed that expression of PI5P4Kα and -β was abundant in epiretinal membranes from PVR grade C patients. CONCLUSIONS: The findings from this study indicate that PI5P4Kα and -β could be novel therapeutic targets for the treatment of PVR.

PURPOSE: To design chart-based vision screening for preschool-aged children. METHODS: Our program consisted of educational sessions for providers as well as hands-on training for practice staff. We evaluated the intervention through pre- and post-intervention review of medical records. RESULTS: Completion of full vision screening (distance visual acuity in each eye plus stereovision beginning at 3 years of age, as recommended at the time of the project) at well-child visits improved for 5-year-olds (45.0% to 58.2%; risk difference +13.2% [95% CI, 1.7-24.7]) and 4-year-olds (39.3% to 51.4%; risk difference +12.0% [95% CI, 0.7-23.4]) but declined somewhat among 3-year-olds (23.1% to 14.3%; risk difference, -8.8% [95% CI, -17.7 to 0.0]). Risk factors for not being fully screened included being 3 years old (risk ratio of 4.1 compared to 5-year-olds) and being a patient of a small practice (risk ratio of 1.9 compared to large practices). CONCLUSIONS: This quality improvement project showed that screening for visual acuity and stereovision among preschool-aged children using chart-based techniques is difficult to accomplish and unlikely to be consistently successful, especially among 3-year-olds.

PURPOSE: To present cases of endophthalmitis following intravitreal injections where povidone-iodine (PI) was not used as part of the surgical preparation. DESIGN: Retrospective case series. METHODS: All cases of presumed injection-related endophthalmitis presenting to the Massachusetts Eye and Ear Infirmary between June 2008 and November 2014 and Dean McGee Eye Institute between January 2010 and January 2015 were identified. Patients who did not receive PI preparation owing to documented self-reported allergy to iodine, iodine-containing contrast material, or shellfish were identified and their injection histories and clinical courses reviewed. RESULTS: The combined rate of postinjection endophthalmitis at these 2 centers was 0.019%. Among 42 patients with postinjection endophthalmitis, 5 (11.9%) did not receive PI prophylaxis. The mean number of intravitreal injections without PI before the development of endophthalmitis was 10.6 with a 9.4% rate of endophthalmitis (5 cases per 53 injections). All patients underwent tap-and-inject procedures with vancomycin 1 mg and ceftazidime 2 mg. Two patients did not receive PI at the time of tap and inject; 1 of these patients required subsequent pars plana vitrectomy for worsening clinical course. Cultures were positive in 4 of 5 cases; all positive cultures grew coagulase-negative Staphylococcus. All patients who received subsequent intravitreal injections received PI prophylaxis without allergic reactions, thus demonstrating a lack of true PI allergy. CONCLUSIONS: Avoiding PI owing to self-reported iodine "allergy" risks substantial ocular morbidity. Allergy testing can be pursued per patient request or in rare cases of suspected true PI allergy; however, in cases where delayed treatment would adversely affect visual outcome, the clinician should feel confident that minimal allergic risk exists.

PURPOSE: To explore the association of American Society of Anesthesiologists (ASA) classification with cataract surgery outcomes. SETTING: Five Veterans Affairs Medical Centers, United States. DESIGN: Retrospective observational cohort study. METHODS: The study analyzed the outcomes of cataract surgery cases. Corrected distance visual acuity (CDVA), unanticipated events, and vision-related quality of life (VRQL) were assessed using the National Eye Institute Visual Function Questionnaire (NEI-VFQ), comparing ASA classes I through IV. For some analyses, ASA classes I and II were designated as Group A and ASA classes III and IV were designated Group B. RESULTS: Of the 4923 cases, 875 (17.8%) were in Group A, 4032 (81.9%) were in Group B, and 16 (0.3%) had missing data. The mean CDVA and mean composite NEI-VFQ score improved after cataract surgery in both groups (P < .0001); however, Group A had a better mean postoperative CDVA and postoperative VFQ composite scores than Group B (P < .0001, both outcomes). A higher ASA class was associated with an increased risk for 2 unanticipated events; that is, clinically significant macular edema (CSME) (Group A: 4 [0.47%] versus Group B: 50 [1.28%]; adjusted odds ratio [OR], 3.02; 95% confidence interval [CI], 1.02-13.05; P = 0.04) and readmission to the hospital within 30 days (2 [0.23%] versus 56 [1.41%]; OR, 8.26; 95% CI, 1.71-148.62; P = .004) CONCLUSIONS: Among United States veterans, the ASA classification could be an important predictor of VRQL and visual outcomes. In this cohort, it was associated with an increased risk for 2 serious unanticipated events-CSME and readmission to the hospital-both costly, unwanted outcomes. FINANCIAL DISCLOSURE: Dr. Vollman is a consultant to Forsight Vision5. None of the authors has a financial or proprietary interest in any material or method mentioned.

PURPOSE: To validate the Ocular Pain Assessment Survey (OPAS), specifically designed to measure ocular pain and quality of life for use by eye care practitioners and researchers. DESIGN: A single-center cohort study was conducted among patients with and without corneal and ocular surface pain at initial and follow-up visits over a 6-month period. The content of the OPAS was guided by literature review, a body of experts, and incorporating conceptual frameworks from existing pain questionnaires. The Wong-Baker FACES Pain Rating Scale served as the gold standard for measuring the intensity of ocular pain. PARTICIPANTS: A total of 102 patients aged 18 to 80 years completed the OPAS at the initial visit. A total of 21 patients were followed up after treatment. METHODS: Indices of validity and internal consistency (Spearman's rank-order, rs, or Pearson's correlation coefficients, rp), and coefficient of reliability (Cronbach's α) were determined in addition to equivalence testing, exploratory factor analysis (EFA), and diagnostic analysis. MAIN OUTCOME MEASURES: Eye pain intensity was the primary outcome measure, and interference with quality of life (QoL), aggravating factors, associated factors, associated non-eye pain intensity, and self-reported symptomatic relief were the secondary outcome measures. RESULTS: The OPAS had criterion validity at both initial (rs = 0.71; n = 102; P < 0.01) and follow-up visits (rs = 0.97; n = 21; P < 0.01). Equivalence tests yielded OPAS and gold standard equivalence for both the initial and follow-up visits. The EFA supported 6 subscales (eye pain intensity at 24 hours and 2 weeks, non-eye pain intensity, QoL, aggravating factors, and associated factors) confirming multidimensionality. Cronbach's α >0.83 for all subscales established strong internal consistency, which correlated with the gold standard, including 24-hour eye pain intensity and QoL interference scores (rp = 0.81, 0.64, respectively P < 0.001). At follow-up, reduction in pain scores was accompanied by improvement in all dimensions of the OPAS. Percentage change in QoL correlated to percentage change in the gold standard (rp = 0.53; P < 0.05). The OPAS was sensitive (94%), specific (81%), and accurate (91%), with a diagnostic odds ratio >50. CONCLUSIONS: The OPAS is a valid, reliable, and responsive tool with strong psychometric and diagnostic properties in the multidimensional quantification of corneal and ocular surface pain intensity, and QoL.

PURPOSE: To investigate the tear levels of matrix metalloproteinases (MMPs), myeloperoxidase (MPO), and tissue inhibitor of metalloproteinase-1 in eyes after Boston keratoprosthesis type I (B-KPro) implantation and to correlate these markers with the established B-KPro prognostic categories. METHODS: Tear washes were collected from 40 patients (7 with autoimmune disease, 2 with chemical burn, and 31 with other noncicatrizing diagnoses). Tear levels of MMPs, MPO, and tissue inhibitor of metalloproteinase-1 were quantified using multianalyte bead-based enzyme-linked immunosorbent assays. The total MMP activity was determined using a fluorimetric assay. The analytes were compared to the underlying diagnosis and other clinical factors. RESULTS: The MMP-8, MMP-9, and MPO levels were markedly elevated in the eyes with B-KPro (80 ± 31, 291 ± 77, and 244 ± 33 pg/μg, respectively). Chemical burn was associated with significantly higher tear MMP-8 (474 ± 376 pg/μg) and MMP-9 levels (1300 ± 635 pg/μg) compared with noncicatrizing diseases (MMP-8: 41 ± 15 pg/μg, P = 0.02 and MMP-9: 196 ± 57 pg/μg, P = 0.02) and higher MMP-9 levels compared with autoimmune diseases (MMP-8: 96 ± 65 pg/μg, P = 0.21 and MMP-9: 306 ± 196 pg/μg, P = 0.04). Similar analyte levels were observed in the B-KPro eye and the contralateral non-B-KPro eye of patients with bilateral diseases. MMP-8, MMP-9, and total MMP activities correlated strongly with each other. CONCLUSIONS: In the eyes with B-KPro, tear MMP-8 and MMP-9 levels seem to be related to the underlying ocular surface pathology and not significantly influenced by the presence of the prosthesis.

PURPOSE: To report the occurrence of corneal ectasia (ECT) in patients with history of Stevens-Johnson syndrome (SJS), and to make the case for an association between these 2 diagnoses. We also report the impact of prosthetic replacement of the ocular surface ecosystem (PROSE) treatment on visual acuity (VA) in these patients. DESIGN: Retrospective cohort study. METHODS: A manufacturing database of PROSE patients from 2002 to 2014 at Boston Foundation for Sight (BFS), a single-center clinical practice, was reviewed to identify patients with diagnoses of both SJS and ECT. RESULTS: Nine patients were identified with diagnoses of both SJS and ECT. In each case, review of the medical record revealed that diagnosis of SJS preceded that of ECT. The prevalence of ECT in this population exceeded that in the general population (P < .0001). Videokeratography was available for 13 eyes in 7 patients; using Krumeich's classification of keratoconus, 3 eyes were found to be at stage 1, 3 at stage 2, 1 at stage 3, and 6 at stage 4. Sixteen of 18 eyes underwent PROSE treatment. Of these 16 eyes, initial median VA was 20/200 (range, count fingers to 20/20; logMAR 1.0). Median VA after PROSE customization was 20/30 (range, 20/60-20/15; logMAR 0.1761, P < .0025). CONCLUSIONS: ECT occurs at a higher-than-expected rate in patients with a history of SJS. PROSE treatment improves VA in these patients. The basis of the association between SJS and ECT is considered, as well as the role of plausible contributory factors such as corneal microtrauma and matrix metalloproteinases.

PURPOSE: We assessed the long-term efficacy and safety of human retinal progenitor cells (hRPC) using established rodent models. METHODS: Efficacy of hRPC was tested initially in Royal College of Surgeons (RCS) dystrophic rats immunosuppressed with cyclosporine/dexamethasone. Due to adverse effects of dexamethasone, this drug was omitted from a subsequent dose-ranging study, where different hRPC doses were tested for their ability to preserve visual function (measured by optokinetic head tracking) and retinal structure in RCS rats at 3 to 6 months after grafting. Safety of hRPC was assessed by subretinal transplantation into wild type (WT) rats and NIH-III nude mice, with analysis at 3 to 6 and 9 months after grafting, respectively. RESULTS: The optimal dose of hRPC for preserving visual function/retinal structure in dystrophic rats was 50,000 to 100,000 cells. Human retinal progenitor cells integrated/survived in dystrophic and WT rat retina up to 6 months after grafting and expressed nestin, vimentin, GFAP, and βIII tubulin. Vision and retinal structure remained normal in WT rats injected with hRPC and there was no evidence of tumors. A comparison between dexamethasone-treated and untreated dystrophic rats at 3 months after grafting revealed an unexpected reduction in the baseline visual acuity of dexamethasone-treated animals. CONCLUSIONS: Human retinal progenitor cells appear safe and efficacious in the preclinical models used here. TRANSLATIONAL RELEVANCE: Human retinal progenitor cells could be deployed during early stages of retinal degeneration or in regions of intact retina, without adverse effects on visual function. The ability of dexamethasone to reduce baseline visual acuity in RCS dystrophic rats has important implications for the interpretation of preclinical and clinical cell transplant studies.

PURPOSE: Describe the presentation and management of superior limbic keratoconjunctivitis (SLK)-like inflammation and secondary limbal stem cell dysfunction in the setting of ocular chronic graft-versus-host disease (cGVHD). METHODS: Retrospective observational case series in a multicenter clinical practice. Participants were 13 patients (26 eyes) with ocular cGVHD and SLK-like inflammation presenting to the University of Illinois at Chicago and BostonSight® between January 1, 2009 and July 1, 2013. MAIN OUTCOME MEASURES: 1) Reversal or worsening of SLK, and 2) development of limbal stem cell dysfunction. RESULTS: All eyes showed evidence of SLK-like inflammation and superior limbal stem cell dysfunction manifested by conjunctival injection and superior conjunctival and corneal staining. In addition to aggressive lubrication, management strategies for SLK included topical steroids (20/26), punctal occlusion (18/26), topical cyclosporine (24/26), autologous serum tears (12/26), therapeutic soft contact lens (13/26 eyes) and scleral lenses (4/26 eyes). SLK and limbal stem cell dysfunction were reversed in 23/26 eyes. Three eyes of two patients with long-standing disease demonstrated frank limbal stem cell deficiency (LSCD) and corneal pannus, with one patient requiring multiple reconstructive surgical procedures. CONCLUSIONS: SLK-like inflammation is an under-recognized condition in patients with severe dry eyes secondary to ocular cGVHD. Untreated SLK can potentially lead to permanent LSCD over time. Early recognition and management of SLK in ocular cGVHD can improve vision, reverse signs, and may prevent these long-term consequences.