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1.  [No title available] 
PMCID: PMC3918479  PMID: 24211172
2.  [No title available] 
PMCID: PMC3937766  PMID: 24572674
3.  [No title available] 
PMCID: PMC3946572  PMID: 24289917
4.  [No title available] 
PMCID: PMC3946576  PMID: 24332536
5.  [No title available] 
PMCID: PMC3946613  PMID: 24183341
6.  [No title available] 
PMCID: PMC3946650  PMID: 24268861
7.  [No title available] 
PMCID: PMC4031747  PMID: 24289916
8.  Neutrophil Collagenase, Gelatinase and Myeloperoxidase in Tears of Stevens-Johnson Syndrome and Ocular Cicatricial Pemphigoid Patients 
Ophthalmology  2013;121(1):79-87.
Objective
To investigate the levels of matrix metalloproteinases (MMPs), myeloperoxidase (MPO) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in tears of patients with Stevens-Johnson syndrome (SJS) and ocular cicatricial pemphigoid (OCP).
Design
Prospective non-interventional cohort study.
Participants
Four SJS patients (7 eyes), 19 OCP patients (37 eyes) and 20 post-phacoemulsification healthy controls (40 eyes).
Methods
Tear washes were collected from all patients and were analyzed for levels of MMP-2, -3, -7, -8, -9, -12, MPO and TIMP-1 using multi-analyte bead-based enzyme-linked immunosorbent assays (ELISA). Total MMP activity was determined using a fluorimetric assay. Correlation studies were performed between the various analytes within study groups.
Main Outcome Measures
Levels of MMP-2, -3, -7, -8, -9, -12, MPO and TIMP-1 (in ng/µg protein), total MMP activity (in relative fluorescent units/min/µg protein) in tears, MMP-8/TIMP-1, MMP-9/TIMP-1 ratios and the correlations between MMP-8 and MMP-9 and each MMP and MPO.
Results
MMP-8, MMP-9 and MPO levels were significantly elevated in SJS and OCP tears (SJS > OCP) when compared to controls. MMP activity was highest in SJS while OCP and controls showed lower and similar activities. TIMP-1 levels were decreased in SJS and OCP when compared to controls with OCP levels reaching significance. MMP-8/TIMP-1 and MMP-9/TIMP-1 ratios were markedly elevated in SJS and OCP tears (SJS > OCP) when compared to controls. Across all study groups, MMP-9 levels correlated strongly with MMP-8 and MPO levels and MMP-8 correlated with MPO but did not reach significance in SJS. There was no relationship between MMP-7 and MPO.
Conclusions
Since MMP-8 and MPO are produced by inflammatory cells, particularly neutrophils, the correlation data indicate that they may be the common source of elevated enzymes including MMP-9 in SJS and OCP tears. Elevated MMP/TIMP ratios and MMP activity suggest an imbalance in tear MMP regulation that may explain the predisposition of these patients to develop corneal melting and chronic complications associated with persistent inflammation. MPO in tears may be a sensitive and specific marker for the quantification of ocular inflammation.
doi:10.1016/j.ophtha.2013.06.049
PMCID: PMC3920830  PMID: 23962653
9.  Changing Incidence of Lens Extraction Over Twenty Years: the Beaver Dam Eye Study 
Ophthalmology  2013;121(1):10.1016/j.ophtha.2013.06.006.
Objective
Investigate trends in incidence of lens extraction over the past twenty years.
Design
Longitudinal population-based cohort study.
Participants
Persons who participated in the Beaver Dam Eye Study.
Methods
Eligible persons 43–84 years of age living in the city or township of Beaver Dam, Wisconsin were recruited in 1987–1988. Participants were followed up every five years in 1993–1995, 1998–2000, 2003–2005, and 2008–2010 after the baseline examination in 1988–1990. Examinations consisted of ocular examination with lens photography and grading, medical history, measurements of blood pressure, height, and weight. Adjustments were made for age and sex. Values of risk variables were updated, and incidence of cataract surgery was calculated in each 5-year interval.
Main Outcome Measure
Incidence of lens extraction with regard to presence of clinically significant lens opacity and visual function.
Results
Age- and sex-adjusted incidence of lens extraction increased over the four 5-year intervals from 1.8% (95% confidence interval [CI] 1.3% to 2.5%) in the interval between the first and second study examinations to 11.7% (95% CI 9.9% to 13.8%) in the most recent study interval. The increase in incidence of surgery was significantly higher at successive intervals in persons without clinically significant lens opacity at each preceding examination (interval 1: 0.8% [95% CI 0.6% to 1.1%]; interval 4: 9.4% [7.8% to 11.2%]) compared with persons with at least one detectable type of opacity (interval 1: 9.2% [95% CI 6.4% to 13.2%]; interval 4: 16.5% [13.4% to 20.0%]). Recency of examination was not attenuated by adjusting for additional risk factors. There was no evidence that the increased incidence in surgery was preceded by poorer visual acuity, near vision, or contrast sensitivity at the beginning of each interval.
Conclusion
The incidence of lens extraction has increased over the past 20 years in persons older than the age of 65. The relative increase of surgery is higher in those without any clinically significant lens opacity, and in persons with visual acuity better than 20/40 at an exam as measured five years prior to observed incidence of lens extraction.
doi:10.1016/j.ophtha.2013.06.006
PMCID: PMC3830736  PMID: 23932514
10.  Evaluation of Progressive Neuroretinal Rim Loss as a Surrogate Endpoint for Development of Visual Field Loss in Glaucoma 
Ophthalmology  2013;121(1):10.1016/j.ophtha.2013.06.026.
Purpose
To evaluate the validity of using progressive neuroretinal rim area loss as a surrogate endpoint for development of visual field loss in glaucoma.
Design
Prospective observational cohort study.
Participants
The study group included 492 eyes of 328 patients classified as suspected of having glaucoma at the baseline visit. These eyes had an average of 7.4 ± 2.8 confocal scanning laser ophthalmoscopy (CSLO) images during a mean follow-up time of 6.6 ± 1.6 years.
Methods
Rim area measurements were acquired with CSLO during follow-up. The visual field endpoint was considered as development of 3 consecutive abnormal visual fields on standard automated perimetry. Strong predictive ability and large proportion of treatment effect explained (PTE) are requisites for a suitable surrogate endpoint. A joint longitudinal survival model was used to evaluate the ability of rates of rim area loss in predicting visual field development, adjusting for confounding variables (baseline age, race and corneal thickness, and follow-up measurements of intraocular pressure [IOP] and pattern standard deviation). The PTE was calculated comparing the effect of IOP on the risk of development of visual field loss when incorporating rim area loss in the same model versus the effect of IOP in the model excluding rim area measurements.
Main Outcome Measures
Predictive strength measured by survival-adapted R2 and PTE.
Results
Sixty-two of 492 (13%) eyes developed visual field loss during follow-up. The mean rate of rim area change in eyes that developed visual field loss was −0.011mm2/year versus −0.003mm2/year in those that did not (P <0.001). In the multivariable model, each 0.01mm2/year faster rate of rim area loss was associated with a 2.94 higher risk of visual field loss (hazard ratio = 2.94; 95% confidence interval: 1.38 – 6.23; P = 0.005). R2 values were 62% and 81% for univariable and multivariable models, respectively. The PTE was 65%.
Conclusion
Progressive rim area loss was highly predictive of development of visual field loss in glaucoma and explained a significant proportion of treatment effect on the clinically relevant outcome. These findings suggest that rim area measurements may be suitable surrogate endpoints in glaucoma clinical trials.
doi:10.1016/j.ophtha.2013.06.026
PMCID: PMC3852019  PMID: 23948465
11.  Retinal detachment after open globe injury 
Ophthalmology  2013;121(1):10.1016/j.ophtha.2013.06.045.
Purpose
To characterize the development of retinal detachment after open globe trauma.
Design
Case-control study
Participants
892 patients comprising 893 open globe injuries, of which 255 were ultimately diagnosed with retinal detachment, with the remaining eyes serving as controls.
Methods
Retrospective chart review of open globe injuries presenting to the Massachusetts Eye and Ear Infirmary between 1999 and 2011. Kaplan-Meier analysis was used to estimate time to detachment and multivariable logistic regression was used to define clinical factors associated with retinal detachment after open globe injury.
Main Outcome Measures
Demographic and clinical characteristics at the time of presentation after open globe injury, date of retinal detachment diagnosis, and last date of follow-up.
Results
Primary repair of the open globe was typically undertaken within hours of presentation. 255 eyes were ultimately diagnosed with retinal detachment after open globe trauma, yielding an incidence of 29% (95% confidence interval: 26%-32%). For eyes that developed retinal detachment, 27% (69/255) detached within 24 hours of primary open globe repair, 47% (119/255) detached within one week, 72% (183/255) within one month. Multivariable regression analysis revealed presence of vitreous hemorrhage (odds ratio: 7.29, p<0.001), higher zone of injury (odds ratio: 2.51 per integer increase in zone number, odds ratio: 1.00-6.30, p<0.001), and poorer Logarithm of the Minimum Angle of Resolution visual acuity at the time of presentation after open globe injury (odds ratio: 2.41 per integer increase in Logarithm of the Minimum Angle of Resolution visual acuity, odds ratio: 1.00-81.30, p<0.001) to be associated with retinal detachment. A screening tool, named herein the Retinal Detachment after Open Globe Injury (RD-OGI) score, was created.
Conclusions
Retinal detachment is common after open globe trauma, though often not appearing until days to weeks after the initial traumatic event. Several clinical variables at the time of initial presentation can predict the future risk of detachment.
doi:10.1016/j.ophtha.2013.06.045
PMCID: PMC3867520  PMID: 24011994
12.  Risk of Geographic Atrophy in the Comparison of Age-related Macular Degeneration Treatments Trials 
Ophthalmology  2013;121(1):150-161.
Purpose
To describe risk factors for geographic atrophy (GA) in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).
Design
Cohort within a randomized clinical trial.
Participants
We analyzed 1024 CATT patients with no GA visible on color fundus photographs (CFPs) and/or fluorescein angiograms (FAs) at enrollment.
Methods
Eyes were assigned to ranibizumab (0.5 mg) or bevacizumab (1.25 mg) treatment and to a 2-year monthly or pro re nata (PRN) injection regimen, or monthly injections for 1 year and PRN for 1 year. Demographic, genetic, and baseline ocular characteristics and lesion features of CFP/FA and optical coherence tomography (OCT) were evaluated as risk factors for GA through 2 years of follow-up. Time-dependent Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs).
Main Outcome Measures
Development of GA.
Results
By 2 years, GA developed in 187 of 1024 patients (18.3%). Baseline risk factors for GA development included baseline visual acuity (VA) ≤20/200 (aHR, 2.65; 95% confidence interval [CI], 1.43–4.93), retinal angiomatous proliferation (RAP; aHR, 1.69; 95% CI, 1.16–2.47), GA in the fellow eye (aHR, 2.07; 95% CI, 1.40–3.08), and intraretinal fluid at the foveal center (aHR, 2.10; 95% CI, 1.34–3.31). Baseline factors associated with lower risk for GA development included blocked fluorescence (aHR, 0.49; 95% CI, 0.29–0.82), OCT measurements of subretinal fluid thickness of >25 μ (aHR, 0.52; 95% CI, 0.35–0.78), subretinal tissue complex thickness of >275 compared with ≤75 μ (aHR, 0.31; 95% CI, 0.19–0.50), and vitreomacular attachment (aHR, 0.55; 95% CI, 0.31–0.97). Ranibizumab compared with bevacizumab had a higher risk (aHR, 1.43; 95% CI, 1.06–1.93), and monthly dosing had a higher risk (aHR, 1.59; 95% CI, 1.17–2.16) than PRN dosing. There were no strong associations between development of GA and the presence of risk alleles for CFH, ARMS 2, HTRA1, C3, or TLR3.
Conclusions
Approximately one fifth of CATT patients developed GA within 2 years of treatment. Independent baseline risk factors included poor VA, RAP, foveal intraretinal fluid, monthly dosing, and treatment with ranibizumab. Anti-vascular endothelial growth factor therapy may have a role in the development of GA.
doi:10.1016/j.ophtha.2013.08.015
PMCID: PMC3892560  PMID: 24084496
13.  Retinal Structure and Function in Achromatopsia: Implications for Gene Therapy 
Ophthalmology  2013;121(1):234-245.
Purpose
To characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical trials of gene therapy.
Design
Cross-sectional study.
Participants
Forty subjects with ACHM.
Methods
All subjects underwent spectral domain optical coherence tomography (SD-OCT), microperimetry, and molecular genetic testing. Foveal structure on SD-OCT was graded into 5 distinct categories: (i) continuous inner segment ellipsoid (ISe), (ii) ISe disruption, (iii) ISe absence, (iv) presence of a hyporeflective zone (HRZ), and (v) outer retinal atrophy including retinal pigment epithelial (RPE) loss. Foveal and outer nuclear layer (ONL) thickness was measured, and presence of hypoplasia determined.
Main Outcome Measures
Photoreceptor appearance on SD-OCT imaging; foveal and ONL thickness; presence of foveal hypoplasia; retinal sensitivity and fixation stability; and association of these parameters with age and genotype.
Results
Forty subjects with mean age of 24.9 years (range 6 to 52) were included. Disease-causing variants were found in CNGA3 (n=18), CNGB3 (n=15), GNAT2 (n=4), and PDE6C (n=1). No variants were found in 2 individuals. 22.5% of subjects had a continuous ISe layer at the fovea; 27.5% had ISe disruption; 20% had an absent ISe layer; 22.5% had a HRZ; and 7.5% had outer retinal atrophy. No significant differences in age (p=0.77), mean retinal sensitivity (p=0.21) or fixation stability (p=0.34) across the 5 SD-OCT categories were evident. No significant correlation was found between age and foveal thickness (p=0.84), or between age and foveal ONL thickness (p=0.12).
Conclusions
The lack of clear association of disruption of retinal structure or function in ACHM with age suggests that the window of opportunity for intervention by gene therapy is wider in some individuals than previously indicated. Therefore the potential benefit for a given subject is likely to be better predicted by specific measurement of photoreceptor structure rather than simply by age. The ability to directly assess cone photoreceptor preservation with SD-OCT and/or adaptive optics imaging is likely to prove invaluable in selecting subjects for future trials and measuring their impact.
doi:10.1016/j.ophtha.2013.08.017
PMCID: PMC3895408  PMID: 24148654
14.  Quantitative Classification of Eyes with and without Intermediate Age-related Macular Degeneration Using Optical Coherence Tomography 
Ophthalmology  2013;121(1):162-172.
Objective
To define quantitative indicators for the presence of intermediate age-related macular degeneration (AMD) via spectral-domain optical coherence tomography (SD-OCT) imaging of older adults.
Design
Evaluation of diagnostic test and technology.
Participants and Controls
One eye from 115 elderly subjects without AMD and 269 subjects with intermediate AMD from the Age-Related Eye Disease Study 2 (AREDS2) Ancillary SD-OCT Study.
Methods
We semiautomatically delineated the retinal pigment epithelium (RPE) and RPE drusen complex (RPEDC, the axial distance from the apex of the drusen and RPE layer to Bruch's membrane) and total retina (TR, the axial distance between the inner limiting and Bruch's membranes) boundaries. We registered and averaged the thickness maps from control subjects to generate a map of “normal” non-AMD thickness. We considered RPEDC thicknesses larger or smaller than 3 standard deviations from the mean as abnormal, indicating drusen or geographic atrophy (GA), respectively. We measured TR volumes, RPEDC volumes, and abnormal RPEDC thickening and thinning volumes for each subject. By using different combinations of these 4 disease indicators, we designed 5 automated classifiers for the presence of AMD on the basis of the generalized linear model regression framework. We trained and evaluated the performance of these classifiers using the leave-one-out method.
Main Outcome Measures
The range and topographic distribution of the RPEDC and TR thicknesses in a 5-mm diameter cylinder centered at the fovea.
Results
The most efficient method for separating AMD and control eyes required all 4 disease indicators. The area under the curve (AUC) of the receiver operating characteristic (ROC) for this classifier was >0.99. Overall neurosensory retinal thickening in eyes with AMD versus control eyes in our study contrasts with previous smaller studies.
Conclusions
We identified and validated efficient biometrics to distinguish AMD from normal eyes by analyzing the topographic distribution of normal and abnormal RPEDC thicknesses across a large atlas of eyes. We created an online atlas to share the 38 400 SD-OCT images in this study, their corresponding segmentations, and quantitative measurements.
Financial Disclosure(s)
Proprietary or commercial disclosure may be found after the references.
doi:10.1016/j.ophtha.2013.07.013
PMCID: PMC3901571  PMID: 23993787
15.  Defects of the lamina cribrosa in eyes with localized retinal nerve fiber layer loss 
Ophthalmology  2013;121(1):110-118.
Objective
To determine whether focal abnormalities of the lamina cribrosa (LC) are present in glaucomatous eyes with localized retinal nerve fiber layer (RNFL) defects.
Design
Cross-sectional observational study.
Participants
20 eyes of 14 subjects with localized RNFL defects detected by masked grading of stereophotographs and 40 eyes of 25 age-matched healthy subjects recruited from the Diagnostic Innovations in Glaucoma Study (DIGS) at the University of California, San Diego.
Methods
All eyes had stereoscopic optic disc photography and in vivo LC imaging using enhanced depth optical coherence tomography (EDI-OCT). Two masked graders identified focal LC defects defined by a standardized protocol using 48 radial scan EDI-OCT images. The Kappa coefficient was calculated as a measure of the reliability of interobserver agreement.
Main Outcome Measures
The number of focal LC defects and the relationship between the location of LC defects and the location of localized RNFL defects.
Results
15 of 20 eyes with a localized RNFL defect (75%) had at least one LC defect compared to only 1 of 40 healthy eyes (3%). 13 eyes with localized RNFL defects had 1 LC defect, 1 eye had 2 LC defects and 1eye had 3 LC defects. The largest area LC defect was present in a radial line EDI-OCT scan corresponding to a localized RNFL defect in 13/15 (87%) of eyes. There was good agreement between graders as to whether an eye had a LC defect (Kappa=0.87, 95% CI 0.73–1.00, P<0.001) and the location of the largest defect (Kappa=0.72, 95% CI 0.44–1.00, P<0.001).
Conclusions
Focal defects of the lamina cribrosa were frequently visible in glaucomatous eyes with localized RNFL defects. Focal abnormalities of the LC may be associated with focal retinal nerve fiber damage.
doi:10.1016/j.ophtha.2013.08.018
PMCID: PMC3947348  PMID: 24144452
16.  Long-Term Trends in Glaucoma-Related Blindness in Olmsted County, Minnesota 
Ophthalmology  2013;121(1):134-141.
Objective
To determine the longitudinal trends in the probability of blindness due to open-angle glaucoma (OAG) in Olmsted County, Minnesota from 1965 to 2009.
Design
Retrospective, population-based cohort study.
Participants
All residents of Olmsted County, Minnesota (40 years of age and over) who were diagnosed with OAG between January 1, 1965 to December 31, 2000.
Methods
All available medical records of every incident case of OAG were reviewed until December 31, 2009 to identify progression to blindness, defined as visual acuity of 20/200 or worse, and/or visual field constriction to 20° or less. Kaplan–Meier analysis was used to estimate the cumulative probability of glaucoma-related blindness. Population incidence of blindness within 10 years of diagnosis was calculated using United States Census data. Rates for subjects diagnosed in the period 1965–1980 were compared with rates for subjects diagnosed in the period 1981–2000 using logrank tests and Poisson regression models.
Main Outcome Measures
Cumulative probability of OAG-related blindness, and population incidence of blindness within 10 years of diagnosis.
Results
Probability of glaucoma-related blindness in at least one eye at 20 years decreased from 25.8 % (95% Confidence interval [CI]: 18.5–32.5) for subjects diagnosed in 1965–1980, to 13.5% (95% CI: 8.8–17.9) for subjects diagnosed in 1981–2000 (P=0.01). The population incidence of blindness within 10 years of the diagnosis decreased from 8.7 per 100,000 (95% CI: 5.9–11.5) for subjects diagnosed in 1965–1980, to 5.5 per 100,000 (95% CI: 3.9–7.2) for subjects diagnosed in 1981–2000 (P=0.02). Higher age at diagnosis was associated with increased risk of progression to blindness (P< 0.001).
Conclusions
The 20-year probability and the population incidence of blindness due to OAG in at least one eye have decreased over a 45 year period from 1965 to 2009. However, a significant proportion of patients still progress to blindness despite recent diagnostic and therapeutic advancements.
doi:10.1016/j.ophtha.2013.09.003
PMCID: PMC4038428  PMID: 24823760
17.  Phase-Contrast Optical Coherence Tomography: A New Technique for Non-Invasive Angiography 
Ophthalmology  2013;121(1):180-187.
Purpose
Phase-contrast optical coherence tomography (PC-OCT) provides volumetric imaging of the retinal vasculature without the need for intravenous injection of a fluorophore. Here, we compare images from PC-OCT and fluorescein angiography (FA) for normal individuals and patients with age-related macular degeneration and diabetic retinopathy.
Design
This is an evaluation of a diagnostic technology.
Participants
4 patients underwent comparative retinovascular imaging using FA and PC-OCT. Imaging was performed on 1 normal individual, 1 patient with dry age-related macular degeneration, 1 patient with exudative age-related macular degeneration and 1 patient with non-proliferative diabetic retinopathy.
Methods
FA imaging was performed using a Topcon (TRC-50IX) camera having resolution of 1280 (H) x 1024 (V) pixels. PC-OCT images were generated by software data processing of the entire cross-sectional image from consecutively acquired B-scans. Bulk axial motion was calculated and corrected for each transverse location, reducing the phase noise introduced from eye motion. Phase contrast was calculated through the variance of the motion-corrected phase changes acquired within multiple B-scans at the same position. Repeating these calculations over the entire volumetric scan produced a three-dimensional PC-OCT representation of the vasculature.
Main Outcome Measures
Feasibility of rendering retinal and choroidal microvasculature using PC-OCT was compared qualitatively to FA, the current gold standard for retinovascular imaging.
Results
PC-OCT rendered a two-dimensional depth color-coded vasculature map of the retinal and choroidal vasculature non-invasively. The choriocapillaris was imaged with better resolution of microvascular detail using PC-OCT. Areas of geographic atrophy and choroidal neovascularization imaged by FA were depicted by PC-OCT. Regions of capillary non-perfusion from diabetic retinopathy were shown by both imaging techniques; there was not complete correspondence between microaneurysms shown on FA and PC-OCT images.
Conclusion
PC-OCT yields high resolution imaging of the retinal and choroidal microvasculature that compares favorably to FA.
doi:10.1016/j.ophtha.2013.09.002
PMCID: PMC4190463  PMID: 24156929
18.  A Randomized, Clinical Trial Evaluating Ready-Made and Custom Spectacles Delivered Via a School-Based Screening Program in China 
Ophthalmology  2009;116(10):1839-1845.
Purpose
We sought to evaluate visual performance and satisfaction with ready-made spectacles (RMS) in Chinese school-aged children with uncorrected refractive error.
Design
Randomized, double-blind, clinical trial.
Participants
Junior high school students from urban Guangzhou, China, aged approximately 12 to 15 years with ≥1 diopter (D) of uncorrected spherical equivalent (SE) refractive error. Students were excluded with ≥2.00 D astigmatism, ≥2 D myopic anisometropia, and ≥1 D hyperopic anisometropia and ocular disease affecting vision.
Methods
Refractive error was determined by cycloplegic subjective refraction. Students were randomly assigned to receive RMS or custom spectacles (CS) and assessed after 1 month of use. We required 175 students to complete in each arm to be able to measure a 15% difference in compliance.
Main Outcome Measures
Compliance with spectacles lens wear, patterns of use, vision, symptoms, and perceived value.
Results
Screening identified 965 of 4607 (20.9%) students with reduced distance vision; 212 of the 965 (22.0%) refused evaluation and 187 of the 965 (20.8%) had <1 D of SE refractive error. Sixty-one (6.3%) were referred for further evaluation and the remaining 495 (51.3%) participated. Social, demographic, and ocular parameters were similar in the 2 groups. Average SE refractive error was −2.57±1.31 (mean value ± standard deviation [SD]). Spectacle vision (Snellen acuity, mean ± SD) was worse with RMS in the eye with lower SE (20/25−0.5±0.9 lines vs 20/25+1±0.7 lines; P = 0.004) and higher SE (20/25−2±1.2 lines vs 20/25+1±0.8; P<0.001). There were no differences (P>0.05) in the rate of use (94.3% vs 92.2%), wearing to the 1-month visit (46.9% vs 51.5%), planned use (93.3% vs 93.7%), value (89.5% vs 91.7% “moderate or high value or most valued possession”), or symptoms (blur, 21.1% vs 19.4% [P = 0.8] and other symptoms [P>0.2]).
Conclusions
Although visual acuity was better with CS, no difference was found in acceptability in this population of students with predominantly simple myopic refractive error. This study supports the use of RMS in a school-based refractive services program, saving costs and improving the logistics of service delivery.
doi:10.1016/j.ophtha.2009.04.004
PMCID: PMC4252048  PMID: 19592103
19.  Validity of Self Report in Type 1 Diabetic Subjects for Laser Treatment of Retinopathy 
Ophthalmology  2013;120(12):10.1016/j.ophtha.2013.06.002.
Purpose
This study sought to determine the validity of self report of prior pan-retinal photocoagulation (PRP) and focal photocoagulation (FP) compared to fundus photography.
Design
Prospective cohort study.
Participants
1363 type 1 diabetic subjects from the Epidemiology of Diabetes Interventions and Complications (EDIC) Study, a subset of the 1441 subjects originally enrolled in the multi-center Diabetes Control and Complications Trial.
Methods
At each annual visit, subjects were asked by EDIC staff whether they had PRP and/or FP since the last completed annual clinic visit. Fundus photographs were collected in one quarter of the cohort each year and in the whole cohort at EDIC years 4 and 10. Photographs were graded for the presence and extent of PRP and FP. Seventeen years of subject reporting and photograph grading of PRP and FP were compared in EDIC subjects.
Main Outcome Measures
Kappa, sensitivity, specificity, and positive and negative predictive values were calculated for subject-reported PRP and FP. Factors influencing subject misreporting were investigated.
Results
For subject reporting, 1244 (96%) of 1296 subjects with gradable photographs accurately reported whether they had a history of PRP in one or both eyes, and 1259 (97.5%) of 1291 with valid photographs correctly reported their history of FP. Sensitivities for PRP and FP were 90.4 and 74.0%; specificities, 96.0 and 98.8%; positive predictive values, 75.9 and 80.3%; negative predictive values, 98.9 and 98.4%; and kappa 0.80 and 0.76. Risk factors associated with misreporting include prior laser for diabetic retinopathy and prior ocular surgery (each p <0.04).
Conclusions
For subjects with type 1 diabetes, in the absence of a clinical exam or fundus photographs, subject self report could be a reliable tool in a well-monitored study for assessing laser treatment type in diabetic retinopathy.
doi:10.1016/j.ophtha.2013.06.002
PMCID: PMC3818390  PMID: 23890420
20.  Assessment of Choroidal Thickness and Volume During the Water Drinking Test By Swept-Source Optical Coherence Tomography 
Ophthalmology  2013;120(12):10.1016/j.ophtha.2013.07.040.
Objective
To evaluate changes in peripapillary and macular choroidal thickness and volume after the water-drinking test (WDT) using swept-source optical coherence tomography (SS-OCT).
Design
Prospective, cross-sectional observational study.
Participants
Fifty-six eyes of 28 healthy volunteers.
Methods
Participants underwent a 3-dimensional optic disc and macula scanning protocol with a prototype SS-OCT (Topcon Inc., Tokyo, Japan) at baseline and 15, 30, 45, and 120 minutes after the start of the WDT. The WDT consisted of drinking 1000mL of water within five minutes. Objective measurements of the choroid were obtained with automated segmentation of the choroidal boundaries.
Main Outcome Measures
Choroidal thickness and volume.
Results
Mean (standard deviation) age of participants was 35.6 ± 9.1 years. Intraocular pressure (IOP) increased from 14.9 ± 2.7 mmHg at baseline to a peak of 16.8 ± 3.0 mmHg at 15 minutes after the WDT (p<0.001). Mean baseline choroidal thickness and volume were 181.3 ± 50.8 μm and 6.19 ± 1.80 mm3 at the optic disc and 217.4 ± 43.6 μm and 7.83 ± 1.55 mm3 at the macula. Following the WDT, peripapillary and macular choroidal thickness increased by a maximum of 5.7% (P < 0.001) and 4.3% (P < 0.001) respectively. Choroidal volumes increased by 6.4% (P < 0.001) and 3.9% (P < 0.001), respectively. There was no association between change in IOP and peripapillary (P = 0.27) or macular (P = 0.09) choroidal thickness.
Conclusions
Using automated segmentation of SS-OCT measurements, significant increases in choroidal thickness and volume are observed after the WDT in healthy subjects.
doi:10.1016/j.ophtha.2013.07.040
PMCID: PMC3833954  PMID: 24021895
21.  Donor age and factors related to endothelial cell loss ten years after penetrating keratoplasty: Specular Microscopy Ancillary Study 
Ophthalmology  2013;120(12):10.1016/j.ophtha.2013.08.044.
Objective
To examine the effect of donor age and other perioperative factors on long term endothelial cell loss after penetrating keratoplasty (PKP)
Design
Multi-center, prospective, double-masked clinical trial
Participants
176 participants from the Cornea Donor Study cohort who had not experienced graft failure 10 or more years after PKP for a moderate risk condition (principally Fuchs’ dystrophy or pseudophakic/aphakic corneal edema)
Methods
Corneas from donors 12 to 75 years old were assigned to participants using a randomized approach, without respect to recipient factors. Surgery and post-operative care were performed according to the surgeons’ usual routines. Images of the central endothelium were obtained preoperatively and at intervals for ten years postoperatively. Images were analyzed by a central image analysis reading center to determine endothelial cell density (ECD).
Main Outcome Measure
Endothelial cell density at 10 years
Results
Among study participants with a clear graft at 10 years, the 125 who received a cornea from a donor 12 to 65 years old experienced a median cell loss of 76%, resulting in a 10-year median ECD of 628 cells/mm2 (interquartile range, 522-850), whereas the 51 who received a cornea from a donor 66 to 75 years old experienced a cell loss of 79%, resulting in a median 10-year ECD of 550 cells/mm2 (interquartile range, 483-694) (P adjusted for baseline ECD=0.03). In addition to younger donor age, higher ECD values were significantly associated with higher baseline ECD (P<0.001) and larger donor tissue size (P<0.001). Forty-two (24%) of the 176 participants had an ECD below 500 cells/mm2 at 10 years and only 24 (14%) had an ECD above 1,000 cells/mm2.
Conclusions
Substantial cell loss occurs in eyes with a clear graft 10 years after PKP, with the rate of cell loss being slightly higher with older donor age. Higher pre-operative ECD and larger donor tissue size are associated with higher ECD at 10 years.
Trial Registration
NCT00006411
doi:10.1016/j.ophtha.2013.08.044
PMCID: PMC3835371  PMID: 24246826
22.  The Effect of Donor Age on Penetrating Keratoplasty for Endothelial Disease: Graft Survival after 10 Years in the Cornea Donor Study 
Ophthalmology  2013;120(12):10.1016/j.ophtha.2013.08.026.
Objective
To determine whether the 10-year success rate of penetrating keratoplasty for corneal endothelial disorders is associated with donor age.
Design
Multi-center, prospective, double-masked clinical trial
Participants
1090 participants undergoing penetrating keratoplasty at 80 sites for Fuchs’ dystrophy (62%), pseudophakic/aphakic corneal edema (34%) or another corneal endothelial disorder (4%) and followed for up to 12 years.
Methods
Forty-three eye banks provided corneas from donors 12 to 75 years old, using a randomized approach to assign donor corneas to study participants, without respect to recipient factors. Surgery and postoperative care were performed according to the surgeons’ usual routines.
Main Outcome Measure
Graft failure defined as a regraft or in the absence of a regraft, a cloudy cornea that was sufficiently opaque to compromise vision for 3 consecutive months.
Results
In the primary analysis, the 10-year success rate was 77% for 707 corneas from donors 12 to 65 years old compared with 71% for 383 donors 66 to 75 years old (difference = +6%, 95% confidence interval = −1% to +12%, P=0.11). When analyzed as a continuous variable, higher donor age was associated with lower graft success after the first 5 years (P<0.001). Exploring this association further, we observed that the 10-year success rate was relatively constant for donors 34 to 71 years old (75%). The success rate was higher for 80 donors 12 to 33 (96%) and lower for 130 donors 72 to 75 years old (62%). The relative drop in the success rate with donor ages 72 to 75 years was not observed until after year 6.
Conclusions
Although the primary analysis did not show a significant difference in 10-year success rates comparing donor ages 12 to 65 and 66 to 75 years, there was evidence of a donor age effect at the extremes of the age range. Since we observed a fairly constant 10-year success rate for donors age 34 to 71 years, which account for approximately 75% of corneas in the United States available for transplant, the Cornea Donor Study results indicate that donor age is not an important factor in most penetrating keratoplasties for endothelial disease.
doi:10.1016/j.ophtha.2013.08.026
PMCID: PMC3885822  PMID: 24246825
23.  Prediction of Age-related Macular Degeneration in the General Population 
Ophthalmology  2013;120(12):2644-2655.
Purpose
Prediction models for age-related macular degeneration (AMD) based on case-control studies have a tendency to overestimate risks. The aim of this study is to develop a prediction model for late AMD based on data from population-based studies.
Design
Three population-based studies: the Rotterdam Study (RS), the Beaver Dam Eye Study (BDES), and the Blue Mountains Eye Study (BMES) from the Three Continent AMD Consortium (3CC).
Participants
People (n = 10106) with gradable fundus photographs, genotype data, and follow-up data without late AMD at baseline.
Methods
Features of AMD were graded on fundus photographs using the 3CC AMD severity scale. Associations with known genetic and environmental AMD risk factors were tested using Cox proportional hazard analysis. In the RS, the prediction of AMD was estimated for multivariate models by area under receiver operating characteristic curves (AUCs). The best model was validated in the BDES and BMES, and associations of variables were re-estimated in the pooled data set. Beta coefficients were used to construct a risk score, and risk of incident late AMD was calculated using Cox proportional hazard analysis. Cumulative incident risks were estimated using Kaplan–Meier product-limit analysis.
Main Outcome Measures
Incident late AMD determined per visit during a median follow-up period of 11.1 years with a total of 4 to 5 visits.
Results
Overall, 363 participants developed incident late AMD, 3378 participants developed early AMD, and 6365 participants remained free of any AMD. The highest AUC was achieved with a model including age, sex, 26 single nucleotide polymorphisms in AMD risk genes, smoking, body mass index, and baseline AMD phenotype. The AUC of this model was 0.88 in the RS, 0.85 in the BDES and BMES at validation, and 0.87 in the pooled analysis. Individuals with low-risk scores had a hazard ratio (HR) of 0.02 (95% confidence interval [CI], 0.01–0.04) to develop late AMD, and individuals with high-risk scores had an HR of 22.0 (95% CI, 15.2–31.8). Cumulative risk of incident late AMD ranged from virtually 0 to more than 65% for those with the highest risk scores.
Conclusions
Our prediction model is robust and distinguishes well between those who will develop late AMD and those who will not. Estimated risks were lower in these population-based studies than in previous case-control studies.
doi:10.1016/j.ophtha.2013.07.053
PMCID: PMC3986722  PMID: 24120328
24.  Alleles in the HtrA Serine Peptidase 1 Gene Alter the Risk of Neovascular Age-Related Macular Degeneration 
Ophthalmology  2007;115(7):1209-1215.e7.
Objective
To examine if the genes encoding the pleckstrin homology domain–containing protein gene (PLEKHA1), hypothetical LOC387715/ARMS2 gene, and HtrA serine peptidase 1 gene (HTRA1) located on the long arm of chromosome 10 (10q26 region) confer risk for neovascular age-related macular degeneration (AMD) in an independent or interactive manner when controlling for complement factor H gene (CFH) genotype and smoking exposure.
Design
Retrospective matched-pair case– control study.
Participants
Hospital clinic-based sample of 134 unrelated patients with neovascular AMD who have a sibling with normal maculae (268 subjects).
Methods
Disease status was ascertained by at least 2 investigators by review of fundus photographs and/or fluorescein angiography according to the Age-Related Eye Disease Study grading scale. If necessary, a home retinal examination was performed (n = 6). A combination of direct sequencing and analysis of 8 highly polymorphic microsatellite markers was used to genotype 33 megabases of the 10q26 region on leukocyte DNA. Smoking history was obtained via a standardized questionnaire and measured in pack-years. The family-based association test, haplotype analysis, multiple conditional logistic regression, and linkage analysis were used to determine significant associations.
Main Outcome Measure
Neovascular AMD status.
Results
Of the 23 variants we identified in the 10q26 region, 6 were significant. Four of the 6 were novel and included 2 genotypes that reduced risk of AMD. Many single-nucleotide polymorphisms (SNPs), including the previously reported variants rs10490924 (hypothetical LOC387715/ARMS2) and rs11200638 (HTRA1), defined 2 significant haplotypes associated with increased risk of neovascular AMD. The coding HTRA1 SNP rs2293870, not part of the significant haplotypes containing rs10490924 and rs11200638, showed as strong an association with increased susceptibility to neovascular AMD. Linkage analysis supported our findings of SNP association (P<10−15). No significant interactions were found between any of the SNPs in the 10q26 and smoking or between these SNPs and CFH genotype.
Conclusions
Independent of CFH genotype or smoking history, an individual’s risk of AMD could be increased or decreased, depending on their genotype or haplotype in the 10q26 region.
doi:10.1016/j.ophtha.2007.10.032
PMCID: PMC4242506  PMID: 18164066
25.  Accuracy of Pupil Assessment for the Detection of Glaucoma 
Ophthalmology  2013;120(11):10.1016/j.ophtha.2013.04.012.
Objective
To assess the accuracy of using pupillary light reflex (PLR) in detecting glaucoma.
Clinical Relevance
Glaucoma is a specific disease of the optic nerve and is often more severe in 1 eye. When large enough, this asymmetry in disease severity can cause a relative afferent pupillary defect (RAPD). Better detection of RAPDs may be one way to identify persons with glaucoma.
Methods
We searched Medline and Embase through June 2012 and searched bibliographies for relevant studies for additional references. Two authors independently reviewed all articles and selected studies that assessed PLRs in patients with glaucoma. We analyzed data using mixed-effect bivariate summary receiver operating characteristic meta-analysis models.
Results
A total of 30 studies were included in this review. An RAPD was observed in 9% to 82% of patients with glaucoma. Eleven studies with a total of 7271 participants were included in the analysis, and the pooled estimate corresponded to a sensitivity of 0.63 (95% confidence interval [CI], 0.43–0.80) and a specificity of 0.93 (95% CI, 0.85–0.97). After excluding 2 studies that used the swinging flashlight test, the sensitivity increased to 0.74 (95% CI, 0.59–0.85) with a specificity of 0.85 (95% CI, 0.77–0.90). Study designs and different pupil measurement techniques explained part of the heterogeneity between studies.
Conclusions
Patients with glaucoma frequently have an abnormal PLR and comparing the responses between the 2 eyes can in part distinguish between those with glaucoma and those without the disease. Newer instruments and analytic approaches to assess pupil function may improve the performance of pupil screening.
doi:10.1016/j.ophtha.2013.04.012
PMCID: PMC3818414  PMID: 23809274

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