An agnostic high throughput search of the genome revealed a robust association between LOXL1 genetic polymorphisms and exfoliation syndrome (XFS), a discovery that likely would not have been possible with candidate or family-based gene search strategies. While questions remain regarding how LOXL1 gene variants contribute to XFS pathogenesis, it is clear that the frequencies of disease-related alleles do not track with the varying disease burden throughout the world, prompting a search for environmental risk factors. A geo-medicine approach revealed that disease load seemed to increase as a function of the distance from the equator. The exact reason for this extraequatorial disease distribution pattern remains unclear, but a greater amount of time spent outdoors is a robust risk factor for XFS, suggesting climatic factors such as ocular solar exposure and colder ambient temperature may be involved in disease pathogenesis. Prospective studies have also implicated higher coffee consumption and lower dietary folate intake in association with incident XFS. The discovery of environmental risk factors for XFS suggests that preventive measures may help to reduce ocular morbidity from XFS.

Importance: Developmental dyslexia (DD) is a specific learning disability of neurobiological origin whose core cognitive deficit is widely believed to involve language (phonological) processing. Although reading is also a visual task, the potential role of vision in DD has been controversial, and little is known about the integrity of visual function in individuals with DD. Objective: To assess the frequency of visual deficits (specifically vergence, accommodation, and ocular motor tracking) in children with DD compared with a control group of typically developing readers. Design, Setting, and Participants: A prospective, uncontrolled observational study was conducted from May 28 to October 17, 2016, in an outpatient ophthalmology ambulatory clinic among 29 children with DD and 33 typically developing (TD) children. Main Outcomes and Measures: Primary outcomes were frequencies of deficits in vergence (amplitude, fusional ranges, and facility), accommodation (amplitude, facility, and accuracy), and ocular motor tracking (Developmental Eye Movement test and Visagraph eye tracker). Results: Among the children with DD (10 girls and 19 boys; mean [SD] age, 10.3 [1.2] years) and the TD group (21 girls and 12 boys; mean [SD] age, 9.4 [1.4] years), accommodation deficits were more frequent in the DD group than the TD group (16 [55%] vs 3 [9%]; difference = 46%; 95% CI, 25%-67%; P < .001). For ocular motor tracking, 18 children in the DD group (62%) had scores in the impaired range (in the Developmental Eye Movement test, Visagraph, or both) vs 5 children in the TD group (15%) (difference, 47%; 95% CI, 25%-69%; P < .001). Vergence deficits occurred in 10 children in the DD group (34%) and 5 children in the TD group (15%) (difference, 19%; 95% CI, -2.2% to 41%; P = .08). In all, 23 children in the DD group (79%) and 11 children in the TD group (33%) had deficits in 1 or more domain of visual function (difference, 46%; 95% CI, 23%-69%; P < .001). Conclusions and Relevance: These findings suggest that deficits in visual function are far more prevalent in school-aged children with DD than in TD readers, but the possible cause and clinical relevance of these deficits are uncertain. Further study is needed to determine the extent to which treating these deficits can improve visual symptoms and/or reading parameters.

PURPOSE: To evaluate the standards of harm reporting for glaucoma surgical trials and to develop a classification system for reporting surgical complication severity. DESIGN: Systematic review and Delphi consensus method. METHODS: Systematic review of glaucoma surgical trials published from January 2010 until July 2017 with a quality assessment against the CONSORT checklist for harm. A Delphi method was employed to generate consensus grading (interquartile range ≤ 2) among international glaucoma experts (n = 43) on severity of glaucoma surgical complications, and specifically for trabeculectomy and aqueous shunt complications, from 1 (no clinical significance) to 10 (most severe complication). RESULTS: Forty-seven studies were eligible. The items of the CONSORT checklist for harm that were most frequently missing were use of a validated instrument to report severity (0%), withdrawals due to harm, and subgroup analyses, both reported in 3 publications (6.4%). Most glaucoma experts participating in the Delphi process (80%) completed the second round, and consensus was achieved for all but 1 complication. The least severe complications (graded 2) were "transient loss of vision," "early low intraocular pressure," "choroidal detachment anterior to equator," "small layered hyphema < 1 mm," and "increased lens opacity not clinically significant." The most severe complications (graded 10) were "endophthalmitis" and "permanent severe loss of vision (hand movements or worse)." CONCLUSIONS: Glaucoma surgical randomized controlled trials report frequency of complications, but their severity is rarely reported. The quality of harm reporting is poor. We propose the use of a newly developed system of classification for assessing the severity of surgical complications based on consensus.

PURPOSE: In this study, we examine the expression of corneal epithelium-derived thrombospondin-1 (TSP-1) and its immunomodulatory functions in a validated murine model of dry eye disease (DED). METHODS: DED was induced in female C57BL/6 using a controlled environment chamber (CEC) for 14 days. mRNA and protein expression of TSP-1 by corneal epithelial cells was quantified using real-time PCR and flow cytometry. Corneal epithelial cells from either naïve or DED mice were cultured with bone marrow derived dendritic cells (BMDCs) in the presence of IFNγ for 48 h, and BMDC expression of MHC-II and CD86 was determined using flow cytometry. Next, either recombinant TSP-1 or anti-TSP-1 antibody was added to the co-culture, and BMDC expression of above activation markers was evaluated. Finally, either DED mice were topically treated with either recombinant TSP-1 or human serum albumin (HSA), and maturation of corneal DCs, expression of inflammatory cytokines, and DED severity were investigated. RESULTS: mRNA expression of TSP-1 by the corneal epithelium was upregulated in DED. Corneal epithelial cells derived from mice with DED demonstrated an enhanced capacity in suppressing BMDC expression of MHC-II and CD86 relative to wild type mice, and this effect was abrogated by TSP-1 blockade and potentiated by recombinant TSP-1. Finally, topical application of recombinant TSP-1 significantly suppressed corneal DC maturation and mRNA expression of pro-inflammatory cytokines, and ameliorated disease severity in mice with DED. CONCLUSIONS: Our study elucidates the function of epithelium-derived TSP-1 in inhibiting DC maturation and shows its translational potential to limit corneal epitheliopathy in DED.

Retinal detachment (RD) leads to photoreceptor cell death secondary to the physical separation of the retina from the underlying retinal pigment epithelium. Intensifying photoreceptor survival in the detached retina could be remarkably favorable for many retinopathies in which RD can be seen. BNN27, a blood-brain barrier (BBB)-permeable, C17-spiroepoxy derivative of dehydroepiandrosterone (DHEA) has shown promising neuroprotective activity through interaction with nerve growth factor receptors, TrkA and p75. Here, we administered BNN27 systemically in a murine model of RD. TUNEL photoreceptors were significantly decreased 24 hours post injury after a single administration of 200 mg/kg BNN27. Furthermore, BNN27 increased inflammatory cell infiltration, as well as, two markers of gliosis 24 hours post RD. However, single or multiple doses of BNN27 were not able to protect the overall survival of photoreceptors 7 days post injury. Additionally, BNN27 did not induce the activation/phosphorylation of TrkA in the detached retina although the mRNA levels of the receptor were increased in the photoreceptors post injury. Together, these findings, do not demonstrate neuroprotective activity of BNN27 in experimentally-induced RD. Further studies are needed in order to elucidate the paradox/contradiction of these results and the mechanism of action of BNN27 in this model of photoreceptor cell damage.

Limbal stem cell deficiency can be treated with transplantation of cultured human limbal epithelial cells (LEC). It can be advantageous to produce LEC in centralized labs and thereafter ship them to eye clinics. The present study used transport simulations of LEC to determine if vigorous shaking during transport altered the viability, morphology and phenotype during a 4 day-long storage of LEC with a previously described serum-free storage method. Inserts with LEC cultured on amniotic membranes were sutured to caps inside air-tight containers with generous amounts of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)-buffered minimal essential medium (MEM). The containers were distributed among the following testing conditions: 6 hours with full containers, 36 hours with full containers, 36 hours with container three quarters full of medium, and 36 hours with container full of medium containing a shear-protecting agent (Pluronic-F68). Compared to stored, but non-transported controls, no statistically significant changes in viability and immunohistochemical staining were observed. The epithelial sheets remained intact. However, an air-liquid interface in the containers reduced the number of desmosomes and hemi-desmosomes compared to the controls. In conclusion, cultured LEC sheets appear to endure vigorous shaking for at least 36 hours if the container is full.

The multifunctional protein clusterin (CLU) is a secreted glycoprotein ubiquitously expressed throughout the body, including in the eye. Its primary function is to act as an extracellular molecular chaperone, preventing the precipitation and aggregation of misfolded extracellular proteins. Clusterin is commonly identified at fluid-tissue interfaces, and has been identified in most body fluids. It is a component of exfoliation material, and CLU mRNA is reduced in eyes with exfoliation syndrome compared with controls. SNPs located in the CLU genomic region have been associated with Alzheimer disease (AD) at the genome-wide level and several CLU SNPs located in an apparent regulatory region have been nominally associated with XFS/XFG in Caucasians with European ancestry and in south Indians. Interestingly, clusterin associates with altered elastic fibers in human photoaged skin and prevents UV-induced elastin aggregation in vitro. In light of the known geographic risk factors for XFS/XFG, which could include UV light, investigations of CLU-geographic interactions could be of interest. Future studies investigating rare CLU variation and other complex interactions including gene-gene interactions in XFS/XFG cases and controls may also be fruitful. Although CLU has been considered as a therapeutic target in AD, cancer and dry eye, a role for clusterin in XFS/XFG needs to be better defined before therapeutic approaches involving CLU can be entertained.

PURPOSE: To describe outcomes of globe-preserving surgery combined with high-dose proton beam radiation (PBR) in treating primary adenoid cystic carcinoma (ACC) of the lacrimal gland. DESIGN: Retrospective case series. METHODS: Twenty-nine patients with primary ACC of the lacrimal gland were identified in the records of a single institution between 1990 and 2017. Patients with nonorbital primary tumor origins or with inadequate follow-ups were excluded. Eighteen patients met inclusion criteria. Clinical data, imaging studies, histopathology, treatment modality, local recurrences, visual outcomes, metastases, and survivals were assessed. Disease-free survivals for the current patients were measured and compared to those of other studies. RESULTS: The eighteen patients (14 female, 4 male) were followed for a median of 12.9 years (range 0.6-22.3 years) after treatment completion. Their median age was 40 years. Four were children (median age 12 years). All were treated with globe-preserving tumor resection and radiation (median dose of 72 cobalt gray equivalents). Three adult patients died of metastatic disease (median of 4.2 years after treatment). Four had local recurrences. Useful vision (20/40 or better) was retained for a median 3 years (range 1-12.9 years). Radiation morbidity included brain injury, retinopathy, optic neuropathy, keratopathy, and cataract. Overall and disease-free survivals were significantly better compared to historical treatments, but did not differ statistically from other modern approaches. CONCLUSIONS: Globe-preserving surgery with PBR, although imperfect, has a favorable long-term survival compared to other modern modalities, and offers a variable period of useful vision.

PURPOSE: Intravitreal bevacizumab is increasingly used to treat severe retinopathy of prematurity (ROP), but it enters the bloodstream, and there is concern that it may alter development of other organs. Previously we reported short-term outcomes of 61 infants enrolled in a dose de-escalation study, and we report the late recurrences and additional treatments. DESIGN: Masked, multicenter, dose de-escalation study. PARTICIPANTS: A total of 61 premature infants with type 1 ROP. METHODS: If type 1 ROP was bilateral at enrollment, then the study eye was randomly selected. In the study eye, bevacizumab intravitreal injections were given at de-escalating doses of 0.25 mg, 0.125 mg, 0.063 mg, or 0.031 mg; if needed, fellow eyes received 1 dose level higher: 0.625 mg, 0.25 mg, 0.125 mg, or 0.063 mg, respectively. After 4 weeks, additional treatment was at the discretion of the investigator. MAIN OUTCOME MEASURES: Early and late ROP recurrences, additional treatments, and structural outcomes after 6 months. RESULTS: Of 61 study eyes, 25 (41%; 95% confidence interval [CI], 29%-54%) received additional treatment: 3 (5%; 95% CI, 1%-14%) for early failure (within 4 weeks), 11 (18%; 95% CI, 9%-30%) for late recurrence of ROP (after 4 weeks), and 11 (18%; 95% CI, 9%-30%) for persistent avascular retina. Re-treatment for early failure or late recurrence occurred in 2 of 11 eyes (18%; 95% CI, 2%-52%) treated with 0.25 mg, 4 of 16 eyes (25%; 95% CI, 7%-52%) treated with 0.125 mg, 8 of 24 eyes (33%; 95% CI, 16%-55%) treated with 0.063 mg, and 0 (0%; 95% CI, 0%-31%) of 10 eyes treated with 0.031 mg. By 6 months corrected age, 56 of 61 study eyes had regression of ROP with normal posterior poles, 1 study eye had developed a Stage 5 retinal detachment, and 4 infants had died of preexisting medical conditions. CONCLUSIONS: Retinal structural outcomes are very good after low-dose bevacizumab treatment for ROP, although many eyes received additional treatment.