August 2019

PURPOSE: To evaluate outcomes of unilateral cataract surgery in children 7 to 24 months of age. DESIGN: Retrospective case series at 10 Infant Aphakia Treatment Study (IATS) sites. PARTICIPANTS: The Toddler Aphakia and Pseudophakia Study is a registry of children treated by surgeons who participated in the IATS. METHODS: Children underwent unilateral cataract surgery with or without intraocular lens (IOL) placement during the IATS enrollment years of 2004 and 2010. MAIN OUTCOME MEASURES: Intraoperative complications, adverse events (AEs), visual acuity, and strabismus. RESULTS: Fifty-six children were included with a mean postoperative follow-up of 47.6 months. Median age at cataract surgery was 13.9 months (range, 7.2-22.9). Ninety-two percent received a primary IOL. Intraoperative complications occurred in 4 patients (7%). At 5 years of age, visual acuity of treated eyes was very good (≥20/40) in 11% and poor (≤20/200) in 44%. Adverse events were identified in 24%, with a 4% incidence of glaucoma suspect. An additional unplanned intraocular surgery occurred in 14% of children. Neither AEs nor intraocular reoperations were more common for children with surgery at 7 to 12 months of age than for those who underwent surgery at 13 to 24 months of age (AE rate, 21% vs. 25% [P = 0.60]; reoperation rate, 13% vs. 16% [P = 1.00]). CONCLUSIONS: Although most children underwent IOL implantation concurrent with unilateral cataract removal, the incidence of complications, reoperations, and glaucoma was low when surgery was performed between 7 and 24 months of age and compared favorably with same-site IATS data for infants undergoing surgery before 7 months of age. Our study showed that IOL implantation is relatively safe in children older than 6 months and younger than 2 years.

The precision of the delivery of therapeutics to the desired injection site by syringes and hollow needles typically depends on the operator. Here, we introduce a highly sensitive, completely mechanical and cost-effective injector for targeting tissue reliably and precisely. As the operator pushes the syringe plunger, the injector senses the loss-of-resistance on encountering a softer tissue or a cavity, stops advancing the needle and delivers the payload. We demonstrate that the injector can reliably deliver liquids to the suprachoroidal space-a challenging injection site that provides access to the back of the eye-for a wide range of eye sizes, scleral thicknesses and intraocular pressures, and target sites relevant for epidural injections, subcutaneous injections and intraperitoneal access. The design of this simple and effective injector can be adapted for a broad variety of clinical applications.

The provided database of tracked eye movements was collected using an infra-red, video-camera Eyelink 1000 system, from 95 participants as they viewed 'Hollywood' video clips. There are 206 clips of 30-s and eleven clips of 30-min for a total viewing time of about 60 hours. The database also provides the raw 30-s video clip files, a short preview of the 30-min clips, and subjective ratings of the content of the videos for each in categories: (1) genre; (2) importance of human faces; (3) importance of human figures; (4) importance of man-made objects; (5) importance of nature; (6) auditory information; (7) lighting; and (8) environment type. Precise timing of the scene cuts within the clips and the democratic gaze scanpath position (center of interest) per frame are provided. At this time, this eye-movement dataset has the widest age range (22-85 years) and is the third largest (in recorded video viewing time) of those that have been made available to the research community. The data-acquisition procedures are described, along with participant demographics, summaries of some common eye-movement statistics, and highlights of research topics in which the database was used. The dataset is freely available in the Open Science Framework repository (link in the manuscript) and can be used without restriction for educational and research purposes, providing that this paper is cited in any published work.

Importance: Genetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations. Objective: To investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis. Design, Setting, and Participants: A cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018. Main Outcomes and Measures: Association of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression. Results: The GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10-66). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (β = -0.36; 95% CI, -0.56 to -0.16; P = 4.0 × 10-4). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10-4). Conclusions and Relevance: A higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.

SUMMARY is a diverse and rugged genus colonizing the gastrointestinal tract of humans and numerous hosts across the animal kingdom. Enterococci are also a leading cause of multidrug-resistant hospital-acquired infections. In each of these settings, enterococci must contend with changing biophysical landscapes and innate immune responses in order to successfully colonize and transit between hosts. Therefore, it appears that the intrinsic durability that evolved to make enterococci optimally competitive in the host gastrointestinal tract also ideally positioned them to persist in hospitals, despite disinfection protocols, and acquire new antibiotic resistances from other microbes. Here, we discuss the molecular mechanisms and regulation employed by enterococci to tolerate diverse stressors and highlight the role of stress tolerance in the biology of this medically relevant genus.

Importance: Some marketing materials for yellow-lens night-driving glasses claim that they increase nighttime road visibility and reduce oncoming headlight glare (HLG). However, there is no scientific evidence to support these claims. Objective: To measure the association between yellow-lens glasses and the detection of pedestrians with and without an oncoming HLG, using a driving simulator equipped with a custom HLG simulator. Design, Setting, and Participants: A single-center cohort study was conducted between September 8, 2016, and October 25, 2017, at the Schepens Eye Research Institute. A total of 22 individuals participated in the study, divided into groups to determine response to a pedestrian wearing a navy blue shirt by younger individuals and, to control for participant's age and the interaction of the shirt color with the filter, response to a pedestrian wearing an orange shirt by a group of younger and older participants. Exposures: Participants drove scripted night-driving scenarios, 3 times with 3 commercially available yellow-lens glasses and once with clear-lens glasses, with the HLG simulator turned on and off. A total of 8 conditions were used for each participant. Main Outcomes and Measures: Pedestrian detection response time. Results: The 22 participants who completed the study included 12 younger (mean [SD] age, 28 [7] years; 6 men) individuals who responded to a pedestrian wearing a dark navy blue shirt, as well as 6 younger (mean [SD] age, 27 [4] years; 4 men) and 4 older (mean [SD], 70 [11] years; all men) participants who responded to a pedestrian in an orange shirt. All participants had normal visual acuity (mean [SD], -0.05 [0.06] logMAR). No significant difference in response time with yellow lens was found in all experiment conditions; younger participants for dark navy blue shirt pedestrians (F1,33 = 0.59; P = .45), orange shirt pedestrians (F1,15 = 0.13; P = .72), and older participants for orange shirt pedestrians (F1,9 = 0.84; P = .38). Among all participants (n = 22), no significant main effect of yellow lenses was found (F1,63 = 0.64; P = .42). In all measuring conditions, the response times with the yellow lenses were not better than with the clear lenses. Significant main effects of HLG were found with dark navy blue shirt pedestrian condition for young participants (F1,33 = 7.34; P < .001) and with orange shirt pedestrian condition for older individuals (F1,9 = 75.32; P < .001), where the difference in response time between with and without HLG was larger for older (1.5 seconds) than younger (0.3 seconds) participants. Conclusions and Relevance: Using a driver simulator equipped with an HLG simulator, yellow-lens night-driving glasses did not appear to improve pedestrian detection at night or reduce the negative effects of HLG on pedestrian detection performance. These findings do not appear to support having eye care professionals advise patients to use yellow-lens night-driving glasses.

PRECIS: Three-dimensional (3D) spectral domain optical coherence tomography (OCT) volume scans of the optic nerve head (ONH) and the peripapillary area are useful in the management of glaucoma in patients with a type I or II Boston Keratoprosthesis (KPro). PURPOSE: The purpose of this study was to report the use of spectral domain OCT in the management of glaucoma in patients with a type I or II Boston KPro. MATERIALS AND METHODS: This study is an observational case series. Four consecutive patients with KPro implants were referred for glaucoma evaluation. A comprehensive eye examination was performed which included disc photography, visual field testing, and high-density spectral domain OCT volume scans of the ONH and the peripapillary area. 2D and 3D parameters were calculated using custom-designed segmentation algorithms developed for glaucoma management. RESULTS: Spectral domain OCT parameters provided useful information in the diagnosis and management of 4 KPro patients. OCT parameters which can be used in KPro patients included 2D retinal nerve fiber layer (RNFL) thickness, 3D peripapillary RNFL volume, 3D peripapillary retinal thickness and volume, 3D cup volume, and 3D neuroretinal rim thickness and volume. In 3 of 4 cases where the traditional 2D RNFL thickness scan was limited by artifacts, 3D spectral domain OCT volume scans provided useful quantitative objective measurements of the ONH and peripapillary region. Therefore, 3D parameters derived from high-density volume scans as well as radial scans of the ONH can be used to overcome the limitations and artifacts associated with 2D RNFL thickness scans. CONCLUSIONS: Spectral domain OCT volume scans offer the possibility to enhance the evaluation of KPro patients with glaucoma by using both 2D and 3D diagnostic parameters that are easily obtained in a clinic setting.

We have previously shown that knockdown of endomucin (EMCN), an integral membrane glycocalyx glycoprotein, prevents VEGF-induced proliferation, migration, and tube formation and angiogenesis . In the endothelium, VEGF mediates most of its angiogenic effects through VEGF receptor 2 (VEGFR2). To understand the role of EMCN, we examined the effect of EMCN depletion on VEGFR2 endocytosis and activation. Results showed that although VEGF stimulation promoted VEGFR2 internalization in control endothelial cells (ECs), loss of EMCN prevented VEGFR2 endocytosis. Cell surface analysis revealed a decrease in VEGFR2 following VEGF stimulation in control but not siRNA directed against EMCN-transfected ECs. EMCN depletion resulted in heightened phosphorylation following VEGF stimulation with an increase in total VEGFR2 protein. These results indicate that EMCN modulates VEGFR2 endocytosis and activity and point to EMCN as a potential therapeutic target.-LeBlanc, M. E., Saez-Torres, K. L., Cano, I., Hu, Z., Saint-Geniez, M., Ng, Y.-S., D'Amore, P. A. Glycocalyx regulation of vascular endothelial growth factor receptor 2 activity.

PURPOSE: Epiretinal proliferation is a distinct clinical entity from epiretinal membrane that classically is associated with lamellar macular holes, but its prevalence and association with full-thickness macular holes (FTMH) have not been well described. We characterized macular hole-associated epiretinal proliferation (MHEP) and its effects on long-term surgical outcomes. DESIGN: Multicenter, interventional, retrospective case-control study. PARTICIPANTS: Consecutive eyes that underwent surgery for FTMH with a minimum of 12 months follow-up. METHODS: All eyes underwent pars plana vitrectomy, removal of any epiretinal membranes, and gas tamponade, with or without internal limiting membrane (ILM) peeling. Spectral-domain OCT imaging was obtained before and after surgery. MAIN OUTCOME MEASURES: Improvement in visual acuity and single-surgery hole closure rates in eyes with, versus without, MHEP at 12 months. RESULTS: Seven hundred twenty-five charts were analyzed, and 113 patients met inclusion criteria. Of 113 eyes with FTMH, 30 (26.5%) showed MHEP. Patients with FTMH and MHEP were older (P < 0.002) and more often men (P = 0.001), and showed more advanced macular hole stages than those without MHEP (P = 0.010). A full posterior vitreous detachment was more common in eyes with MHEP (P < 0.004). Twelve months after surgery, FTMH with MHEP patients showed significantly less improvement in visual acuity (P = 0.019) with higher rates of ellipsoid and external limiting membrane defects (P < 0.05) and with a higher rate of failure to close with 1 surgery compared to FTMH without MHEP (26.7% vs. 4.8%; P = 0.002]). Peeling the ILM was associated with improved rates of hole closure in FTMH with MHEP (P < 0.001). Multivariate testing confirmed that the presence of MHEP was an independent risk factor for less visual improvement (P = 0.031) and for single-surgery nonclosure (P = 0.009) and that ILM peeling improved single-surgery closure rates (P = 0.026). CONCLUSIONS: We found that FTMH with MHEP showed poorer anatomic and visual outcomes after vitrectomy compared with FTMH without MHEP. Internal limiting membrane peeling was associated with improved closure rates and should be considered when MHEP is detected before surgery.

PRéCIS:: The diagnostic capability of peripapillary retinal volume is similar to peripapillary retinal nerve fiber layer thickness for diagnosing glaucoma, but with fewer artifacts. PURPOSE: To compare the diagnostic capability of 3-dimensional peripapillary retinal volume (RV) versus 2-dimensional peripapillary retinal nerve fiber layer (RNFL) thickness for open-angle glaucoma. PATIENTS AND METHODS: A retrospective cross-sectional analysis was conducted. A total of 180 subjects (113 open-angle glaucoma, 67 normal participants) had spectral domain optical coherence tomography volume scans and RNFL thickness measurements. Peripapillary RV values were calculated using a custom-designed program with 4 circumpapillary annuli (CA): CA1 had circle diameters of 2.5 and 3.5 mm; CA2, 3 and 4 mm; CA3, 3.5 and 4.5 mm; and CA4, 4 and 5 mm. Area under the receiver operating characteristic curves were calculated for global, quadrant, and octant regions for RV (CA1 to CA4) and RNFL thickness. Pair-wise comparisons were conducted. Artifacts rates were determined. RESULTS: Mean age was 62.7±15.4 years, and 47.8% (86/180) were male. Among RV measurements, best diagnostic performances were for the smallest 2 annuli for inferior RV (CA1: 0.964, CA2: 0.955). Of the 4 annuli, CA1 had the highest diagnostic performance. Of specific regions, the inferior RV quadrant had the highest performance across CA1 to CA4. Peripapillary RV had similar diagnostic capability compared with RNFL thickness (P>0.05). The artifact rate per B-scan for RV was 6.0%, which was significantly lower compared with 2-dimensional RNFL thickness in the same patient population (32.2%, P<0.0001). CONCLUSIONS: The diagnostic capability of RV is similar to RNFL thickness for perimetric open-angle glaucoma, but RV had fewer artifacts compared with RNFL thickness.

BACKGROUND: Preterm infants with anaemia are treated with recombinant human erythropoietin (rhEPO). It is debated whether rhEPO treatment is a risk factor for retinopathy of prematurity (ROP). We evaluated longitudinal EPO and haemoglobin levels, blood transfusions and neonatal morbidities as risk factors for severe ROP. METHOD: This prospective study included 78 Swedish infants, born <28 weeks gestational age (GA), screened for ROP. We tested serum EPO levels on postnatal days 1, 7, 14 and 28 and at postmenstrual ages 32, 36 and 40 weeks. Haemoglobin levels and blood transfusions were recorded during postnatal weeks 1-4. Anaemia was defined as haemoglobin ≤110 g/L. RESULTS: During postnatal week 1, infants with severe ROP requiring treatment (28%) more frequently developed anaemia (42.9% versus 8.0%, P = 0.003) and had higher mean EPO levels (postnatal day 7: 14.2 versus 10.8 mIU/mL, P = 0.003) compared to infants with no or less severe ROP not requiring treatment. In multivariable analyses, GA and anaemia during week 1 remained significant risk factors, but elevated EPO level postnatal day 7 was no longer significant. CONCLUSIONS: Among infants born <28 weeks GA, anaemia during week 1 was a significant risk factor for severe ROP requiring treatment but not elevated EPO levels.

Tree shrews are small mammals with excellent vision and are closely related to primates. They have been used extensively as a model for studying refractive development, myopia, and central visual processing and are becoming an important model for vision research. Their cone dominant retina (∼95% cones) provides a potential avenue to create new damage/disease models of human macular pathology and to monitor progression or treatment response. To continue the development of the tree shrew as an animal model, we provide here the first measurements of higher order aberrations along with adaptive optics scanning light ophthalmoscopy (AOSLO) images of the photoreceptor mosaic in the tree shrew retina. To compare intra-animal in vivo and ex vivo cone density measurements, the AOSLO images were matched to whole-mount immunofluorescence microscopy. Analysis of the tree shrew wavefront indicated that the optics are well-matched to the sampling of the cone mosaic and is consistent with the suggestion that juvenile tree shrews are nearly emmetropic (slightly hyperopic). Compared with in vivo measurements, consistently higher cone density was measured ex vivo, likely due to tissue shrinkage during histological processing. Tree shrews also possess massive mitochondria ("megamitochondria") in their cone inner segments, providing a natural model to assess how mitochondrial size affects in vivo retinal imagery. Intra-animal in vivo and ex vivo axial distance measurements were made in the outer retina with optical coherence tomography (OCT) and transmission electron microscopy (TEM), respectively, to determine the origin of sub-cellular cone reflectivity seen on OCT. These results demonstrate that these megamitochondria create an additional hyper-reflective outer retinal reflective band in OCT images. The ability to use noninvasive retinal imaging in tree shrews supports development of this species as a model of cone disorders.

Searching for a "Q" among "O"s is easier than the opposite search (Treisman & Gormican in Psychological Review, 95, 15-48, 1988). In many cases, such "search asymmetries" occur because it is easier to search when a target is defined by the presence of a feature (i.e., the line terminator defining the tail of the "Q"), rather than by its absence. Treisman proposed that features that produce a search asymmetry are "basic" features in visual search (Treisman & Gormican in Psychological Review, 95, 15-48, 1988; Treisman & Souther in Journal of Experimental Psychology: General, 114, 285-310, 1985). Other stimulus attributes, such as color, orientation, and motion, have been found to produce search asymmetries (Dick, Ullman, & Sagi in Science, 237, 400-402, 1987; Treisman & Gormican in Psychological Review, 95, 15-48, 1988; Treisman & Souther in Journal of Experimental Psychology: General, 114, 285-310, 1985). Other stimulus properties, such as facial expression, produce asymmetries because one type of item (e.g., neutral faces) demands less attention in search than another (e.g., angry faces). In the present series of experiments, search for a rolling target among spinning distractors proved to be more efficient than searching for a spinning target among rolling distractors. The effect does not appear to be due to differences in physical plausibility, direction of motion, or texture movement. Our results suggest that the spinning stimuli demand less attention, making search through spinning distractors for a rolling target easier than the opposite search.

PURPOSE: To evaluate the changes in anterior corneal topography induced by short-time wear of scleral contact lenses (SLs) in keratoconic subjects with and without a history of corneal cross-linking (CXL). METHODS: Nine keratoconic patients (14 eyes) were fitted with 18.5 mm SLs for optical rehabilitation. Subjects were divided into 2 groups: 7 eyes without a history of CXL (Non-CXL group) and 7 with a history of CXL (CXL group). Corneal topography was performed at baseline and after 2 and 5 hours of lens wear. The differences for simulated flat (Kflat), steep (Ksteep) and maximal (Kmax) corneal curvatures, central corneal astigmatism (CCA), and central cornea thickness were evaluated. RESULTS: No statistically significant difference was detected between Non-CXL and CXL groups in any of these measures. Statistically significant flattening was detected in Ksteep Repeated measures analysis of variance ([RM-ANOVA), F (2,24) = 11.32, P < 0.0001], CCA [RM-ANOVA, F (2,24) = 15.34, P < 0.0001], and Kmax [RM-ANOVA, F (2,24) = 19.10, P < 0.0001). From baseline to 5 hours of SL wear, Ksteep decreased on average from 53.1 to 52.4 D, Kmax decreased from 56.7 to 55.8 D, and CCA decreased from 7.2 to 6.3 D. Kmax showed a trend toward more flattening in the Non-CXL group. Central cornea thickness showed significant thickening over time from baseline (451 μm) to 5 hours (458 μm) of SL wear [RM-ANOVA, F (1,12) = 319.3, P < 0.0001]. CONCLUSIONS: Short-term scleral lens wear in keratoconic patients may cause flattening of the anterior cornea. A history of CXL treatment does not guarantee corneal shape stability after scleral lens wear. Practitioners should be aware of these changes because scleral lens wear may mask the signs of keratoconus progression.

PURPOSE: To describe the clinical spectrum, clinicopathological correlation and outcomes of different surgical strategies in the management of acquired implantation iris cysts. METHODS: From 1 January 1989 to 31 December 2015, 27 patients (27 eyes) with acquired implantation iris cysts underwent surgery. The charts were reviewed for demographics, preoperative characteristics, surgical approach, histopathological records of excised cyst and postoperative outcomes. RESULTS: The median age at presentation was 5 years (IQR: 1.3-14 years). Out of 27 patients, 21 (78%) were aged≤18 years. Almost two-third (17/27, 63%) patients had history of penetrating ocular trauma prior to surgery. All patients underwent cyst aspiration combined with complete cyst excision with additional surgical procedures when necessary. Along with complete cyst excision, sector iridectomy was performed in 20/27 (74%) eyes. At a median postoperative follow-up period of 8 months (range: 1-72 months), recurrence was noted in 3/27 (11%) cases at a mean follow-up period of 2.3±1.5 months postsurgery. Eyes in which sector iridectomy was performed had lower incidence of recurrence, and this was statistically significant (p=0.03). However, the improvement in best-corrected visual acuity postoperatively was not statistically significant (p=0.15). CONCLUSION: Acquired implantation iris cysts are associated with significant ocular morbidity. Complete excision of the cyst with sector iridectomy is an effective treatment option if other less invasive surgical approaches fail. Visual acuity can be significantly improved but is typically limited due to associated comorbidities.

Keratoconus (KC) is a multi-factorial corneal ectasia with unknown etiology affecting approximately 1:2000 people worldwide. Dysregulated gene expression, using RNA-Seq technology, have been reported in KC corneal tissue. However, the differential expression of genes, in KC corneal stromal cells have been widely ignored. We utilized mRNA-Seq to analyze gene expression in primary human corneal stromal cells derived from five non-Keratoconus healthy (HCF) and four Keratoconus (HKC) donors. Selected genes were further validated using real time PCR (RT-PCR). We have identified 423 differentially expressed genes with 187 down- and 236 up-regulated in KC-affected corneal stromal cells. Gene ontology analysis using WebGestalt indicates the enrichment of genes involved in cell migration, extracellular matrix, adherens junction, and MAPK signaling. Our protein-protein interaction network analysis identified several network seeds, such as EGFR, NEDD4, SNTA1, LGALS3BP, HSPB1, SDC2, MME, and HIF1A. Our work provides an otherwise unknown information on the transcriptional changes in HKCs, and reveals critical mechanisms of the cellular compartment. It also highlights the importance of human-based in vitro studies on a disease that currently lacks strong biomarkers and animal models.