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To examine gender differences in visual functioning using the National Eye Institute Visual Functioning Questionnaire-25 (VFQ-25) in a Colorado cohort of patients with age-related macular degeneration (AMD).A retrospective cohort study was conducted using a registry of AMD patients who attended the Sue Anschutz-Rodgers Eye Center (2014 to 2019). Demographic, clinical, and image data were collected, and AMD was categorized as Early/Intermediate AMD, or unilateral/bilateral neovascular (NV) AMD, geographic atrophy (GA), or Both Advanced using the Beckman Classification. Each patient completed the VFQ-25, which evaluates visual functioning, generating a composite score and subscale scores for vision-specific activities. Univariate and multivariable general linear models were used to estimate the associations between gender and VFQ-25 scores with parameter estimates (PE) and standard errors (SE).Among 739 patients with AMD, 294 (39.8%), 115 (15.6%), 168 (22.7%), and 162 (21.9%) were diagnosed with Early/Intermediate AMD, GA, NV AMD, and Both Advanced, respectively. Adjusted for AMD classification, age and habitual visual acuity in the better-seeing and worse-seeing eyes, female gender was not significantly associated with lower composite VFQ-25 scores (PE (SE): -1.2 (0.9), p = .193), and was significantly associated with reportedly worse ocular pain and driving subscale scores (PE (SE): -4.6 (1.0), p .0001 and -9.1 (2.1), p .0001, respectively).Gender plays a role in reported driving activities and ocular pain among patients with AMD. This may need to be accounted for in future research related to the use of VFQ-25 for AMD.

Unrecognized neurodegenerative diseases (NDD) in age-related eye disease research studies have the potential to confound vision-specific quality of life and retinal optical coherence tomography (OCT) outcome measures. The aim of this exploratory study was to investigate relationships between NDD screening tools and visual outcome measures in a small cohort of controls from the Colorado Age-Related Macular Degeneration Registry (CO-AMD), to consider the utility of future studies.Twenty-nine controls from the CO-AMD were screened using the Montreal Cognitive Assessment (MoCA), a Colorado Parkinsonian Checklist, and the Lewy Body Composite Risk Score. Univariate and multivariable linear regression modeling was used to assess associations between screening tools and the National Eye Institute Visual Function Questionnaire-25 (VFQ-25) and macular OCT outcome measures, and t tests were used to evaluate outcome measure differences between those with normal vs abnormal MoCA scores.One patient withdrew. The average age was 72.8 years, and 68% were female patients. Ten participants (36%) had abnormal MoCA scores, and their VFQ-25 scores were only 1 point less and not statistically different than those with normal MoCA scores. Macular OCT volumes and thicknesses for retinal nerve fiber layer (RNFL) and retinal ganglion cell layer were consistently and moderately lower for those with abnormal MoCA scores, and a positive association between MoCA and macular RNFL volume was observed, although differences and regression were not significant. Parkinson screening tests were abnormal for only 4 participants and were not associated with OCT or VFQ-25 measures by regression modeling.Given the degree and direction of observed differences, further investigation is warranted regarding the relationship between cognitive screening tools and macular OCT measures in age-related eye disease research, but future investigations regarding the relationship between NDD screening tools and VFQ-25 seem unwarranted.

PURPOSE: Sparse data exist regarding low vision (LV) services referral patterns. We retrospectively examined our institution’s intermediate age-related macular degeneration (iAMD) patients to determine factors influencing referral. METHODS: We compared visual acuity (VA) and Visual Function Questionnaire (VFQ-25) composite and subscale scores for referred and non-referred iAMD patients. VA was collected at time of referral or most recent visit, and VFQ-25 was taken upon enrollment into the registry. RESULTS: Thirty-six (15.5%) of the 232 iAMD patients were referred to LV. Referred patients were more likely to have older age, worse VA in both eyes, and lower VFQ-25 scores. Univariate analysis of VFQ-25 subscales demonstrated worse scores in general vision, near, distance, mental health, role limitations, dependency, and driving. Multivariable analysis revealed lower scores in general health, general vision, and driving. Forty-eight percent of non-referred patients had VA or VFQ-25 composite scores at least as poor as the median for referred patients. Two-thirds of patients who were not referred had no discernable obstacle to referral. CONCLUSIONS: Our institution refers patients with worse objective and functioning vision, but more patients may benefit from referral. Future studies should identify metrics to prompt referral and evaluate this approach.

Age-related macular degeneration (AMD) is an acquired degenerative disease of the retina classified into early, intermediate, and advanced AMD. A key factor in the pathogenesis of AMD is the complement system. The interaction of age and sex with the complement system may affect the risk of developing AMD. The purpose of this study was to determine if there were sex-specific differences in levels of complement factors among patients with the intermediate phenotype of AMD (iAMD) and explore the correlation between age and complement proteins.We studied complement factors in patients with iAMD and controls without AMD. Nonparametric, rank-based linear regressions including a sex by AMD interaction were used to compare levels for each analyte. Correlations between age and complement proteins were evaluated using the Spearman rank correlation coefficient.We found significantly higher levels of factor B and factor I in females compared with males with iAMD, whereas no differences were seen in complement levels in male and female controls. The ratios of Ba/factor B, C3a/C3, C4b/C4, and C5a/C5 were not different in males and females with iAMD.We demonstrate disparities in a subset of systemic complement factors between females and males with iAMD, but apparent complement turnover as measured by ratios of activation fragments to intact molecules was not different between these groups. The results suggest that complement system levels, including complement regulator factor I, exhibits sex-related differences in patients with iAMD and highlights that stratification by sex might be helpful in the interpretation of clinical trials of anticomplement therapy.

To examine the risk of posterior capsule rupture (PCR) during phacoemulsification cataract surgery in patients who received intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections prior to surgery.A retrospective study was conducted of cataract surgeries at the Sue Anschutz-Rodgers UCHealth Eye Center from January 1, 2014, through December 31, 2018. The primary outcome was the occurrence of PCR during surgery. Other variables of interest included age, race, sex, ocular comorbidities, diabetes, mature cataract, primary surgeon, injection frequency and type, and date of most recent injection. Predictors of PCR were assessed using logistic regression with generalized estimating equations to account for correlation between patient eyes. Additional sub-analysis was performed on eyes with PCR with and without anti-VEGF injection history to compare intraoperative characteristics, post-operative complications, and visual outcomes.In total 10,327 cataract surgeries were included in the analysis, and 308 of these eyes received anti-VEGF injections prior to surgery. Of the 308 eyes that received anti-VEGF injections, eight (2.6%) had a PCR during surgery compared to 45 of 10,019 eyes (0.5%) that did not receive injections (unadjusted OR = 5.9, 95% CI: 2.8-12.7,History of intravitreal anti-VEGF injections was associated with higher odds of PCR during cataract surgery.

A growing body of evidence suggests complement dysregulation is present in the vitreous of patients with diabetic eye disease. Further translational study could be simplified if aqueous-as opposed to vitreous-were used to sample the intraocular complement environment. Here, we analyze aqueous samples and assess whether a correlation exists between aqueous and vitreous complement levels.We collected aqueous, vitreous, and plasma samples from patients with and without proliferative diabetic retinopathy (PDR) undergoing vitrectomy. We assessed correlation between complement levels in aqueous and vitreous samples after using a normalizing ratio to correct for vascular leakage. Spearman correlation coefficients were used to assess the correlation between complement levels in the aqueous and vitreous.Aqueous samples were obtained from 17 cases with PDR and 28 controls. In all patients, aqueous Ba, C3a, and albumin levels were strongly correlated with vitreous levels (Spearman correlation coefficient of 0.8 for Ba and C3a and 0.7 for albumin; all P values0.0001). In PDR eyes only, aqueous and vitreous C3a levels were significantly correlated (Spearman correlation coefficient 0.7; P = 0.002), whereas in control eyes, both Ba and C3a (Spearman correlation coefficients of 0.7; P0.0001) were significantly correlated.A strong correlation exists between aqueous and vitreous complement levels in diabetic eye disease.The results establish that accurate sampling of the intraocular complement can be done by analyzing aqueous specimens, allowing for the rapid and safe measurement of experimental complement targets and treatment response.

Purpose: To determine the relationship between plasma concentrations of the C-C chemokines CCL2, CCL3, CCL4, and CCL5 and intermediate age-related macular degeneration (iAMD) patients compared with control inidividuals to further define the inflammatory pathways associated with age-related macular degeneration.Methods: The concentrations of CCL2, CCL3, CCL4, and CCL5 were measured using multiplex assays in plasma collected from 210 patients with iAMD and 102 control individuals with no macular degeneration as defined by multi-modal imaging. Non-inflammatory data included in the analysis were: age, sex, family history of AMD, history of smoking, body mass index, presence of reticular pseudo-drusen and cardiovascular disease. Median concentrations as well as a cutoff value for each chemokine were compared between the two groups.Results: The median concentrations of CCL2 and CCL4 did not differ between control and iAMD groups, however, CCL2 was elevated in iAMD when a cutoff comparison was used (p < 0.05). Median CCL3 and CCL5 concentrations were significantly decreased in the macular degeneration group compared with controls (p < 0.001) as well as when a cutoff value comparison was used. CCL3 and CCL5 were negatively correlated in cases and positively correlated in controls.Conclusions: Plasma CCL3 and CCL5 concentrations were significantly decreased and CCL2 concentrations were increased in patients with iAMD compared with controls, suggesting a role for C-C chemokines in the systemic inflammatory processes associated with disease development.

Purpose To determine the effect of metformin on early Nd:YAG laser treatment for posterior capsule opacification (PCO) and to explore a molecular mechanism to explain a possible protective effect of metformin against PCO. Methods We conducted: 1) a retrospective cohort study of patient eyes undergoing phacoemulsification at our institution; and 2) laboratory investigation of the effect of metformin on the behavior of lens epithelial cells in the context of an animal model for PCO. Population-averaged Cox proportional hazards modeling was used to estimate risk for time to Nd:YAG. For laboratory studies, expression of markers for epithelial-to-mesenchymal transition (EMT) implicated in PCO pathogenesis was measured in tissue culture and following extracapsular lens extraction in a mouse model. Results The rate of Nd:YAG laser capsulotomy was 13.1% among the 9798 eyes. Both metformin use and diabetes were protective factors for Nd:YAG laser capsulotomy in univariate analysis. However, in multivariable analysis with nondiabetics as the reference group, only metformin use among diabetics was significantly protective of Nd:YAG (hazard ratio: 0.68, 95% CI: 0.54-0.85, P = 0.0008), while eyes of patients with diabetes without metformin use did not significantly differ (P = 0.5026). Treatment of lens epithelial cells with metformin reduced the level of the EMT markers ⍺-SMA and pERK induced by TGF-β2. Similarly, metformin treatment reduced ⍺-SMA expression in lens epithelial cells following extracapsular lens extraction in a mouse model. Conclusions The protective effect of metformin against early Nd:YAG may relate to its ability to downregulate EMT in residual lens epithelial cells that otherwise trend toward myofibroblast development and PCO.

Purpose: The purpose of this study was to determine if the use of menopausal hormone therapy (HT) is related to the development of neovascular (NV) age-related macular degeneration (AMD), geographic atrophy (GA) and/or early/intermediate AMD.Methods: A case-control study was conducted from patients prospectively recruited from July 2014 to June 2019. Cases were females with AMD recruited into a registry and controls were females with age-related cataract and no AMD. Age-related macular degeneration was categorized into NV-AMD, GA, and early/intermediate. Hormone therapy (historic and current) was self-reported by the patient and categorized as ever/never use. Adjusted odds ratios (ORs) from multinomial logistic regressions are presented for each AMD group.Results: Female AMD case patients (n = 409) and controls (n = 132) were included in the analytic database. Almost half (45.5%) of the female AMD patients had NV-AMD, 14.9% had GA, and 39.6% had early/intermediate AMD. Among all study participants, 285 (52.7%) reported historic and/or current use of HT. Controls were significantly more likely to have any HT use (71.2%), compared to 43.0% (p ≤ 0.001) of NV-AMD patients, 47.5% (p = .002) of GA patients, and 50.6% (p ≤ 0.001) of early/intermediate AMD patients. Adjusted for potential confounders of age and Caucasian race, cases were significantly more likely to have lower HT use compared to controls: NV-AMD, OR = 0.31 (95%CI: 0.18-0.54), GA, OR = 0.40 (95%CI: 0.20-0.80), and early/intermediate AMD, OR = 0.36 (95%CI: 0.22-0.61).Conclusion: Our case-control study found that the use of HT was associated with a lower odds of all AMD stages studied: NV-AMD, GA and early/intermediate.

Purpose To study new and existing risk factors related to age-related macular degeneration (AMD) phenotypes in a Colorado cohort. Methods Age-related macular degeneration was categorized into early, intermediate, or advanced forms. Controls (n = 180) were patients with cataract and no AMD. Demographic and clinical data were gathered by patient interview and verified by chart review. Image data were reviewed by vitreoretinal specialists. Statistical analysis included univariable and multivariate logistic regression analysis (P Results Among the 456 patients with AMD, 157 (34.4%), 80 (17.6%), and 219 (48.0%) had the early/intermediate, geographic atrophy, and neovascular forms of the disease, respectively. Adjusted for age, African-American race was associated with a reduced risk of early/intermediate (adjusted odds ratio [AOR] = 0.08, confidence interval [CI] = 0.01-0.67) and neovascular AMD (AOR = 0.15, CI = 0.03-0.72). A family history of AMD was a risk factor for early/intermediate (AOR = 4.08, CI = 2.30-7.25), geographic atrophy (AOR = 8.62, CI = 3.77-19.7), and neovascular AMD (AOR = 3.76, CI = 2.16-6.56). A history of asthma was related to the early/intermediate form of AMD (AOR = 2.34, CI = 1.22-4.46). Conclusion Studying AMD in specific populations may reveal novel risk factors such as our finding of a relationship between asthma history and AMD.

AIM: To determine whether the prevalence of treated hypertension is higher among males or females with early/intermediate (e/i) age-related macular degeneration (AMD) with and without bilateral reticular pseudodrusen (RPD). METHODS: Retrospective review of the records of patients with e/iAMD who were recruited into the University of Colorado AMD registry between July 2014 and November 2019. Images were classified using the Beckman Initiative criteria and presence/absence of RPD. Patients were categorized into three groups: 1) e/iAMD with RPD; 2) e/iAMD without RPD; 3) control patients who did not have AMD. Multinomial logistic regression analysis was used for adjusted analysis with odds ratios (OR) and confidence intervals (CI). RESULTS: There were 260 patients with e/iAMD of which 101 had bilateral RPD and 159 had no RPD, and 221 controls. Overall, 62% of patients were female and the three groups did not differ by gender. When stratified by gender, the female e/iAMD/RPD group had a higher prevalence of hypertension, 64.1% vs 45.2% for controls, OR=2.2 (95%CI: 1.2-4.0). The frequency of hypertension in the e/iAMD/no RPD group was 54.1% and did not significantly differ from the control group. Among males, prevalence rates of treated hypertension did not differ. There is a significant interaction of hypertension and gender for the e/iAMD/RPD group such that women with e/iAMD who had RPD were significantly more likely to have hypertension (P=0.042). This relationship was not significant in the e/iAMD/no RPD group (P=0.269). CONCLUSION: Among females treated hypertension is significantly higher among e/iAMD/RPD patients, whereas for males there is no significant association.

PURPOSE: Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly. The role of systemic inflammation in AMD remains unclear specifically in patients with intermediate AMD (iAMD). We sought to determine whether systemic inflammation was associated with future iAMD progression. METHODS: Combinations of 27 circulating inflammatory markers including complement factors, cytokines, chemokines, and high-sensitivity C-reactive protein (hsCRP) were evaluated in iAMD patients recruited into a Colorado AMD registry. Systemic inflammatory markers were combined using principal component analysis. Risk factors for AMD progression were evaluated using Cox regression models. RESULTS: This study included 99 subjects with iAMD, 21 of which progressed to advanced AMD. Two principal components (PCs) were identified that contributed to risk for progression to advanced AMD, after adjusting for age and bilateral reticular pseudodrusen. The strongest associated PC was explained largely by the pro-inflammatory cytokine TNFα and the anti-inflammatory IL1ra antagonist of IL1. The additional PC was largely explained by IL6, IL8, C3 and factor D in the positive direction and CRP, MCP1, factor B and factor I in the negative direction. CONCLUSION: When evaluated through multivariate analyses, combinations of biomarkers distinguished patients who did and did not progress to future advanced AMD. Increased risk could result from different combinations of analyte levels indicating a complex relationship rather than a simple increase in a few markers. This suggests that studying systemic inflammation in iAMD can provide insights into early pathologic events and potentially identify patients at highest risk for the development of severe AMD.

Lay abstract This study investigated the use of quantum dots (QDs) to treat very advanced retinitis pigmentosa (RP), a disease characterized by progressive loss of peripheral and then central vision. QDs are sometimes called ‘artificial atoms’. If they are injected into the eye, they settle in the retina, the light-sensing layer of cells that is damaged by RP. When light enters the eye, it is absorbed by the QDs in the retina, and the light energy is converted to electrical energy. Electrical stimulation has been shown to benefit degenerating retina, as occurs in RP, and hence QDs may have the potential to improve or preserve vision in people with RP. This preliminary study recruited 20 people with very severe RP and injected QDs into their eyes. We aimed to see whether the QDs were safe. No adverse reactions were attributed to the QDs, and the average vision of treated eyes improved, whereas the participants’ untreated fellow eyes showed no real change in vision. Although encouraging, these results are only preliminary, and a larger study is planned to explore these findings.

Purpose A growing body of evidence points to complement dysregulation in diabetes. Early studies have indicated the presence of complement components inside the eye in patients with diabetic retinopathy, but these data have been confounded by leakage of proteins from the systemic circulation into the vitreous cavity. Methods We took samples of plasma and vitreous from patients with and without proliferative diabetic retinopathy (PDR) and measured levels of 16 complement components as well as albumin. We employed a normalized ratio using local and systemic complement and albumin levels to control for vascular leakage into the vitreous cavity. Results Before normalizing, we found significantly higher levels of 16 complement components we measured in PDR eyes compared to controls. After normalizing, levels of C4, factor B, and C5 were decreased compared to controls, while C3a and Ba levels were elevated compared to controls. We also found higher ratios of C3a/C3, C5a/C5, and Ba/factor B in PDR eyes compared to controls. Conclusions We found evidence of local, intraocular activation of C3, C5, and factor B. The normalized data suggest involvement of the alternative complement pathway. By showing activation of specific complement components in PDR, this study identifies targets for diagnostic and therapeutic potential.

To determine trends in retinopathy of prematurity (ROP) in a Colorado cohort between 2006 and 2017 and compare trends in risk factors between our cohort and statewide data.A retrospective cohort study was conducted by the use of records from two registry databases: 1) an academic center's ROP registry, and 2) vital statistics birth data from the Colorado Department of Public Health and Environment (CDPHE). ROP was categorized as severe (type 1 or type 2), low grade (not type 1 or type 2), or no ROP. Other variables included in the analyses were gestational age and birth weight at delivery, and infant mortality. Trends over time were evaluated for both registry databases using generalized linear models.In our ROP registry cohort of 1,267 eligible infants, 134 (10.6%) developed severe ROP and 279 (22%) developed low-grade ROP. We found no overall trend in severe ROP rates (The rate of severe ROP in our ROP registry cohort did not change over time. There was evidence of a decreasing trend in low grade ROP during the 12-year study period that was not explained by a change in the primary ROP risk factors in either the ROP registry cohort or the Colorado statewide data.

Purpose To determine, using an aptamer-based technology in patients with intermediate age-related macular degeneration (AMD), (1) if there is a difference in plasma levels of 4979 proteins in patients with and without reticular pseudodrusen (RPD), and (2) if plasma levels of proteins are related to time to conversion to advanced AMD. Methods Patients with intermediate AMD and RPD were identified from an AMD registry. Relative concentrations of each protein were log (base 2) transformed and compared between patients with and without RPD using linear regression. A Cox proportional hazards survival model was fit to each aptamer to quantify associations with time to conversion. A pathway analysis was conducted in converters versus non-converters using the Reactome database. Results Of the 109 intermediate AMD patients, 39 had bilateral RPD (36%). Two proteins, TCL1A and CNDP1, were lower in patients in the intermediate AMD group with RPD. Twenty-one patients converted to advanced AMD with a median time to conversion of 25.2 months (range, 2.3-48.5 months) and median follow-up time in non-converters of 26.4 months (range, 0.03-49.7 months). Several proteins (lysozyme C, TFF3, RNAS6, and SAP3) distinguished patients who converted from those who did not convert to advanced AMD. The top conversion pathways included tumor necrosis factors bind their physiological receptors, digestion and absorption, signaling by activin, and signaling by TGF-β family members. Conclusions We identified a protein signature related to RPD, as well as to conversion to advanced AMD. The pathway analysis suggests that dysfunction of critical systemic pathways may have links to conversion to advanced AMD. Translational relevance Biomarkers identified in plasma likely reflect systemic alterations in protein expression in patients with intermediate AMD.

PURPOSE: To assess the retinal anatomy and array position in the Argus II Retinal Prosthesis recipients. DESIGN: Prospective, non-comparative cohort study METHODS: Setting: international multicenter study Patients: Argus II recipients enrolled in the Post-Market Surveillance Studies. Procedures: Spectral-domain Optical Coherence Tomography images collected for the Surveillance Studies (NCT01860092 and NCT01490827) were reviewed. Baseline and postoperative macular thickness, electrode-retina distance (gap), optic disc-array overlap, and preretinal membrane presence were recorded at 1, 3, 6, and 12 months. Main Outcome Measures: Axial retinal thickness and axial gap along the array’s long axis (a line between the tack and handle), maximal retinal thickness and maximal gap along a B-scan near the tack, midline, and handle. RESULTS: Thirty-three patients from 16 surgical sites in the United States and Germany were included. Mean axial retinal thickness increased from month 1 through month 12 at each location, but reached statistical significance only at the array midline (p- value=0.007). The rate of maximal thickness increase was highest near the array midline (slope=6.02, p=0.004), compared to the tack (slope=3.60, p

Purpose C-reactive protein (CRP) and decreased choroidal thickness (CT) are risk factors for progression to advanced age-related macular degeneration (AMD). We examined the association between systemic levels of CRP and CT in patients with intermediate AMD (iAMD). Methods Patients with iAMD in the Colorado AMD Registry were included. Baseline serum samples and multimodal imaging including spectral domain–optical coherence tomography (SD-OCT), fundus photography, and autofluorescence were obtained. Medical and social histories were surveyed. CT was obtained by manual segmentation of OCT images. High-sensitivity CRP levels were quantified in serum samples. Univariate and multivariable linear regression models accounting for the intrasubject correlation of two eyes were fit using log-transformed CT as the outcome. Results The study included 213 eyes from 107 patients with a mean age of 76.8 years (SD, 6.8). Median CT was 200.5 µm (range, 86.5–447.0). Median CRP was 1.43 mg/L (range, 0.13–17.10). Higher CRP was associated with decreased CT in the univariate model (P = 0.01). Older age and presence of reticular pseudodrusen (RPD) were associated with decreased CT (P < 0.01), whereas gender, body mass index, and smoking were not associated with CT. Higher CRP remained significantly associated with decreased CT after adjustment for age and RPD (P = 0.01). Conclusions Increased CRP may damage the choroid, leading to choroidal thinning and increased risk of progression to advanced AMD. Alternatively, CRP may be a marker for inflammatory events that mediate ocular disease. The results of this study further strengthen the association between inflammation and AMD. Translational Relevance Increased CRP is associated with choroidal thinning, a clinical risk factor for AMD.

ObjectiveSystemic activation of the complement system in intermediate age-related macular degeneration (AMD) is understudied. Moreover, links between the presence of reticular pseudodrusen (RPD) and systemic complement dysregulation have not been studied. The aim of this study was to determine if there is a difference in plasma complement factor levels in intermediate AMD compared with controls, and if complement levels are related to the presence of RPD.Methods and analysisLevels of complement factors C1q (µg/mL), C4 (µg/mL), C2 (µg/mL), Mannose Binding Lectin (ng/mL), C4b (µg/mL), C3 (µg/mL), factor B (µg/mL), factor D (µg/mL), properdin (µg/mL), C3a (ng/mL), iC3b/C3b (ng/mL), Ba (ng/mL), factor H (µg/mL), factor I (µg/mL), C5 (µg/mL), C5a (pg/mL) and SC5b-9 (ng/mL) were measured in plasma.Results109 cases and 65 controls were included in the study. Thirty-nine (36%) cases had RPD. Significantly lower systemic levels of: C1q (OR 0.96, 95% CI 0.94 to 0.98), factor B (OR 0.98, 95% CI 0.96 to 0.99), iC3b/C3b (OR 0.97, 95% CI 0.95 to 0.98), factor H (OR 0.99, 95% CI 0.98 to 0.99), factor I (OR 0.83, 95% CI 0.77 to 0.89) and C5 (OR 0.94, 95% CI 0.90 to 0.98) were found in cases versus controls. Significantly elevated levels of: C2 (OR 1.29, 95% CI 1.07 to 1.59), C3a (OR 1.03, 95% CI 1.01 to 1.05) Ba (OR 1.03, 95% CI 1.01 to 1.05) and C5a (OR 1.04, 95% CI 1.02 to 1.07) were found in cases versus controls. Systemic levels of complement factors measured were not related to the presence of RPD.ConclusionsLevels of several systemic complement pathway factors were found to be altered in intermediate AMD. Systemic levels of complement factors were not related to RPD.

To determine predictors of best-corrected postoperative visual acuity (VA) in patients who underwent surgical intervention for macula-off rhegmatogenous retinal detachment. Primary macula-off retinal detachments from the University of Colorado Primary Rhegmatogenous Retinal Detachment Database (2012–2017) were reviewed. The primary outcome measure was a postoperative VA of 20/40 or better at least 6 months after surgery. Patient demographics, medical history, duration of central vision loss before surgery, examination findings, operative technique, and postoperative findings were analyzed as possible predictors of postoperative visual recovery to 20/40 or better. Chi-square or Fisher’s exact test was used to compare categorical variables, and Wilcoxon rank sum test was used for continuous variables. A multivariable logistic regression analysis was used to determine the adjusted odds ratios and 95% confidence intervals for variables that were significant in the univariable analyses. Statistical significance was set at p

Purpose: To examine the role of systemic activation of the complement system (assessed by levels of circulating C3a, Ba, and sC5b-9) in patients (n = 122) with advanced age-related macular degeneration, geographic atrophy, and neovascular age-related macular degeneration, compared with cataract controls (n = 27). Methods: Plasma complement factors were measured using enzyme-linked immunosorbent assays. Statistical analysis included univariate and multivariate logistic regression (p Results: Adjusted for age, the odds ratios of C3a and sC5b-9 for any advanced age-related macular degeneration were 1.78 (95% confidence interval = 1.16–2.73, p Conclusion: We suggest a role for elevated plasma levels of C3a and sC5b-9 in patients with neovascular age-related macular degeneration. The study’s results reinforce the need for more investigation to assess the impact of therapeutic interventions targeted at the complement signaling pathways in age-related macular degeneration.

Background/purpose To report a case of simultaneous endophthalmitis and anterior segment ischemia (ASI) that occurred in a patient after strabismus surgery. This is the first known case of both complications occurring at the same time. Methods Case report. Results A 60-year-old woman presented with eye pain and loss of vision 6 days after uncomplicated strabismus surgery for thyroid eye disease. On examination, she had corneal edema, anterior segment fibrin, an atonic iris, and no view to the posterior segment. On fluorescein angiography of the anterior segment, a large portion of the iris was nonperfused. Posterior segment ultrasound showed dense vitritis and a choroidal abscess. Intraoperative cultures grew methicillin-resistant Staphylococcus aureus. Conclusions Endophthalmitis and anterior segment ischemia are both exceedingly rare complications of strabismus surgery. It is possible that each one occurred independently, but more likely one process potentiated the other. One possible mechanism is inflammation-induced thrombosis.

To assess driving status, habitual visual acuity (VA) in the better-seeing eye, and self-reported driving difficulty among patients diagnosed with age-related macular degeneration (AMD).Cross-sectional cohort study of 553 AMD patients' habitual VA, self-reported driving status, and driving difficulty at time of interview.Patients diagnosed with AMD and recruited into the University of Colorado registry.Measurement of habitual VA by median logarithm of the minimum angle of resolution (logMAR) and Snellen equivalent, as well as 3 categories: 20/40 or better, 20/50 or 20/60, and worse than 20/60. Driving difficulty was self-reported on the 25-item National Eye Institute Visual Function Questionnaire.Self-reported driving status and driving difficulty.A total of 394 patients (71.2%) reported currently driving at time of study interview. Drivers were significantly younger than nondrivers (mean age, 76.7 years vs. 83.9 years; P0.0001) and were more likely to be men (42.6% vs. 25.8%; P = 0.0002). Median habitual VA in the better-seeing eye was better among drivers: 0.097 logMAR (Snellen equivalent, 20/25) versus 0.301 logMAR (Snellen equivalent, 20/40) for nondrivers (P0.0001). Among drivers, habitual VA was 20/40 or better for 87.6% of patients, 20/50 to 20/60 for 9.6% of participants, and worse than 20/60 for 2.8% of participants. Driving patients with habitual VA in the better-seeing eye of 20/40 or better reported less difficulty driving compared with patients with 20/50 or worse VA.In our study, most patients with AMD who were currently driving had at least 20/40 VA in the better-seeing eye. However, 12.4% of patients had VA of 20/50 or worse and reported more difficulties with driving. As the aging population continues to grow with increasing lifespan, the number of patients with AMD will increase, and discussion of driving and VA will become more clinically and legally pertinent.

We introduce a new method to observe the morphologic features of the vitreous with spectral-domain optical coherence tomography (SD-OCT) by evaluating and describing the posterior vitreous structure of various selected cases using enhanced high-density (HD) line mode.This is a descriptive case series of SD-OCT images with enhanced HD line at Denver Health Medical Center, University of Colorado School of Medicine, in 2014. The medical records with ocular images for these patients were analyzed.Enhanced HD line in vitreoretinal mode with SD-OCT offered wide images with well-visible vitreoretinal interface. The posterior precortical vitreous pocket (PPVP), often mistaken as a posterior vitreous detachment on standard retina-based cross line mode, was easily identified. Vitreomacular adhesion and traction, absence or presence of connecting channels between PPVP and Cloquet's canal, liquefied vitreous lacuna, and emulsified silicone oil droplet-layer could be observed.SD-OCT using enhanced HD line in vitreoretinal mode enables clear visualization of the posterior vitreous structure and often reclassifies patients previously thought to have a posterior vitreous detachment.

BACKGROUND AND OBJECTIVE: To evaluate the role of nonmydriatic ultrawide-field (UWF) color retinal imaging as a screening tool in the follow-up of asymptomatic patients after cataract extraction surgeries. PATIENTS AND METHODS: A retrospective, observational case series. A review of electronic medical records identified patients after cataract extraction followed with UWF retinal imaging (Optos 200Tx; Optos, Dunfermline, Scotland). Images were graded and reviewed by a retina specialist. Outcome measures included image quality, the detection of peripheral lesions, and association with perioperative risk factors. RESULTS: Seventy-six eyes of 58 consecutive patients were enrolled. A good visualization of the peripheral retina was accomplished in more than 90% of patients. Peripheral lesions were identified in 40 eyes (52.6%) with no surgery-related retinal breaks and/or detachments. Additional pathologies were found in 35 eyes (46.1%). CONCLUSION: Nonmydriatic UWF color retinal imaging was found to be a useful screening tool in the follow-up of asymptomatic patients after cataract extraction in this series. [ Ophthalmic Surg Lasers Imaging Retina . 2015;46:50–55.]

To purpose if this study was to determine whether the horizontal rectus muscle tendons (HRMTs) can be observed using anterior segment optical coherence tomography (AS-OCT) and to determine the repeatability of its measurements. Also, this study aimed to observe and measure the different external ocular structures at the level of the horizontal rectus muscle (HRM) insertion. This was a retrospective, observational, descriptive and comparative study. Images were obtained utilizing the RTVue 100 CAM system. Eyes were analyzed at the three and nine o’clock position. Scans were performed for three different locations: the limbus, the ciliary body and the equator. All scans were analyzed by two graders, separately and blinded. Measurements were performed for: HRMT length; HRM thickness; conjunctival epithelium thickness; conjunctiva and Tenon’s capsule thickness; scleral thickness; and external ocular thickness. Results were obtained from twenty eyes of ten volunteers. The conjunctival epithelium thickness was 52.33 μm, the total conjunctiva/Tenon’s capsule thickness was 313.54 μm, the medial rectus (MR) thickness was 136.63 μm and the lateral rectus (LR) thickness was 181.65 μm. The MR tendon length was 1,426.88 μm, the LR tendon length was 1,433.65 μm, the scleral thickness was 489.91 μm and the total external ocular structure thickness was 785.17 μm. Intra-observer reproducibility (intraclass correlation coefficient [ICC]) for tendon length was 0.993 for grader #1, 0.989 for grader #2; the muscle thickness ICC was 0.990 for grader #1 and 0.981 for grader #2. The inter-observer reproducibility ICC for tendon length was 0.557; the ICC for muscle thickness was 0.834. It is possible to visualize and measure HRMTs using AS-OCT. Measurements of the HRM, as well as the surrounding external ocular tissues, can be achieved.

To address the most dynamic and current issues concerning human genetics, risk factors, pharmacoeconomics, and prevention regarding age-related macular degeneration.An online review of the database Pubmed and Ovid was performed, searching for the key words: age-related macular degeneration, AMD, pharmacoeconomics, risk factors, VEGF, prevention, genetics and their compound phrases. The search was limited to articles published since 1985 to date. All returned articles were carefully screened and their references were manually reviewed for additional relevant data. The webpage www.clinicaltrials.gov was also accessed in search of relevant research trials.A total of 366 articles were reviewed, including 64 additional articles extracted from the references and 25 webpages and online databases from different institutions. At the end, only 244 references were included in this review.Age-related macular degeneration is a complex multifactorial disease that has an uneven manifestation around the world but with one common denominator, it is increasing and spreading. The economic burden that this disease poses in developed nations will increase in the coming years. Effective preventive therapies need to be developed in the near future.

Purpose: To describe the long-term outcome of a patient with multifocal choroiditis, who underwent surgical removal of a type 2 choroidal neovascular membrane employing 23 G pars plana vitrectomy. Observations: A 50-year-old man was treated with 3 monthly intravitreal bevacizumab injections, but despite treatment, visual acuity continued to worsen from 20/40 to 20/100, and bleeding was not receding. A minimal invasive pars plana vitrectomy was performed for surgical removal of the neovascular complex without any complicating incident. Subsequent visual acuity was 20/25 for more than eleven years. Conclusions and Importance: Surgical removal of choroidal neovascular membranes employing minimal invasive surgery in addition to anti-VEGF therapy, and OCT evaluation can be a viable approach for selected cases of juxtafoveal type 2 CNV. Keywords: Choroidal neovascular membrane, Spectral-domain optical coherence tomography, Pars plana vitrectomy, Anti-VEGF therapy

While the Endophthalmitis Vitrectomy Study (EVS) included only post-cataract surgery patients, the methods and data from that study are widely applied in the management of endophthalmitis of all types. We sought to examine how our experience with in-office vitreous aspiration differed from the EVS in two ways: first, by reviewing microbiological culture yields from vitreous aspirates obtained using 30-gauge needles versus 25-27-gauge needles and second, by reviewing culture yields in cases of endogenous versus non-endogenous endophthalmitis.Cases of endophthalmitis over a 14-year period were reviewed when vitreous tap was the initial diagnostic procedure. The data included infection source, needle size used to obtain a vitreous aspirate, organism cultured and rates of unsuccessful attempts at vitreous aspiration or dry taps.10 cases were endogenous endophthalmitis, while 36 cases were a mix of postoperative, post-traumatic, post-intravitreal injection and miscellaneous patients. A positive microbiological culture was obtained in 11/36 (31%) of vitreous taps using a 25-27-gauge needle and in 8/10 (80%) taps using a 30-gauge needle (p0.01). A positive vitreous culture was obtained in 18/36 (50%) of all non-endogenous cases, while a positive result was obtained in 0/10 (0%) cases of endogenous endophthalmitis (p0.01).The use of a smaller needle in obtaining vitreous samples in endophthalmitis did not lower the microbiological yield. A positive microbiological yield was significantly less likely in cases of endogenous endophthalmitis compared with non-endogenous cases. Vitreous tap as a method for identifying the causative organism in endogenous endophthalmitis was of limited utility.

Simultaneous spatial temporal focusing (SSTF) is used to deliver microjoule femtosecond pulses with low numerical aperture geometries (

Background Retinopathy of prematurity is an adverse outcome of preterm birth and is a leading cause of childhood blindness. The relationship between the subtypes of preterm birth with retinopathy of prematurity is understudied. Objective To investigate whether there is a difference in the incidence of type 1 or type 2 retinopathy of prematurity in infants with preterm birth resulting from spontaneous preterm labor, a medical indication of preterm birth, or preterm premature rupture of the membranes. Study Design A retrospective cohort study was conducted of 827 infants screened for retinopathy of prematurity who were delivered at a single tertiary care center in Colorado. All infants fulfilled the American Academy of Pediatrics 2013 screening criteria for retinopathy of prematurity defined as "infants with a birth weight of ≤1500 g or gestational age of 30 weeks or less (as defined by the attending neonatologist) and selected infants with a birth weight between 1500 and 2000 g or gestational age of >30 weeks with an unstable clinical course, including those requiring cardiorespiratory support and who are believed by their attending pediatrician or neonatologist to be at high risk for retinopathy of prematurity." Two independent reviewers masked to retinopathy of prematurity outcomes determined whether preterm birth resulted from spontaneous preterm labor, medical indication of preterm birth, or preterm premature rupture of the membranes. Discrepancies were resolved by a third reviewer. Data were analyzed with univariate and multivariable logistic regression. Results In our cohort, the frequency of preterm birth resulting from spontaneous preterm labor, medical indication of preterm birth, or preterm premature rupture of the membranes was 34%, 40%, and 26%, respectively. The mean gestational age (weeks, days) ± SD (range) in the cohort and across the preterm birth subtypes was as follows: entire cohort, 28 weeks, 6 days ± 2 weeks, 3 days (23 weeks, 3 days – 36 weeks, 4 days); spontaneous preterm labor, 28 weeks 1 day ± 2 weeks, 3 days (23 weeks, 3 days – 33 weeks, 4 days); medical indication of preterm birth, 29 weeks, 1 day ± 2 weeks, 2 days (24–36 weeks, 4 days); preterm premature rupture of the membranes, 28 weeks, 4 days ± 2 weeks, 1 day (24–33 weeks, 1 day). Among infants with type 1, type 2, or no retinopathy of prematurity, the incidence of type 1 or type 2 retinopathy of prematurity in births from spontaneous preterm labor, medical indication of preterm birth, and preterm premature rupture of the membranes was 37 of 218 (17%), 27 of 272 (10%), and 10 of 164 (6%), respectively. Adjusted for gestational age, birth weight, and multiparity and compared with the preterm premature rupture of the membranes group, the odds ratios of spontaneous preterm labor and medical indication of preterm birth for type 1 or type 2 retinopathy of prematurity were 6.1 (95% confidence interval, 1.8 to 20, P = .003) and 5.5 (95% confidence interval, 1.4 to 21, P = .01), respectively. Among neonates born after preterm premature rupture of the membranes, the probability of developing type 1 or type 2 retinopathy of prematurity was greatest in infants with rupture of membrane duration of up to 24 hours. After 24 hours, the probability of developing type 1 or type 2 retinopathy of prematurity declined. The odds of developing type 1 or type 2 retinopathy of prematurity was 9.0 (95% confidence interval 2.3 to 34, P = .002) in infants who had preterm premature rupture of the membranes ≤ 24 hours compared with infants who had preterm premature rupture of the membranes > 24 hours. Conclusion Type 1 or type 2 retinopathy of prematurity are adverse ocular outcomes linked with not only lower gestational age and birth weight at delivery but also with events in the intrauterine environment that trigger a preterm birth. The reduced incidence of type 1 or type 2 retinopathy of prematurity in the preterm premature rupture of the membranes group compared with other causes of preterm birth may be related to the perinatal therapies associated with preterm premature rupture of the membranes (such as corticosteroids, antibiotics, maternal–fetal surveillance), which may have an inhibitory effect on the development of retinopathy of prematurity. We suggest that the physiologic events that predispose infants to type 1 or type 2 retinopathy of prematurity begin before delivery.

Purpose Retinopathy of prematurity (ROP) is a vision-threatening disease associated with abnormal retinal vascular development. Proteins from the insulin-like growth factor pathway are related to ROP. However, there is a paucity of research on the role of other proteins in ROP. The aim of this study was to identify plasma proteins related to clinically significant ROP. Methods We measured 1121 plasma proteins in the early neonatal period in infants at risk for ROP using an aptamer-based proteomic technology. The primary aim of the study was to compare plasma protein concentrations in infants who did (n = 12) and did not (n = 23) subsequently develop clinically significant ROP using logistic regression. As a secondary aim, we examined patterns in the proteins across categories of clinically significant, low-grade, and no ROP groups. Results Lower levels of 16 proteins were associated with an increased risk of clinically significant ROP. In this group, superoxide dismutase (Mn), mitochondrial (MnSOD), and chordin-like protein 1 (CRDL1) were highly ranked. Other proteins in this group included: C-C motif chemokine 14 (HCC-1), prolactin, insulin-like growth factor-binding protein 7 (IGFBP-7), and eotaxin. Higher levels of 12 proteins were associated with a higher risk for ROP. Fibroblast growth factor 19 (FGF-19) was the top-ranked protein target followed by hepatocyte growth factor-like protein (MSP), luteinizing hormone (LH), cystatin M, plasminogen, and proprotein convertase subtilisin/kexin type 9 (PCSK9). We also noted different patterns in the trend of concentrations of proteins across the clinically significant, low-grade, and no ROP groups. Conclusions We discovered plasma proteins with novel associations with clinically significant ROP (MnSOD, CRDL1, PCSK9), proteins with links to established ROP signaling pathways (IGFBP-7), and proteins such as MnSOD that may be a target for future therapeutic interventions.

Purpose To explore top-ranked plasma proteins related to neovascular age-related macular degeneration (AMD) and geographic atrophy (GA), and explore pathways related to neovascular AMD and GA. Methods We conducted a pilot study of patients with neovascular AMD (n = 10), GA (n = 10), and age-matched cataract controls (n = 10) who were recruited into an AMD registry. We measured 4001 proteins in ethylenediaminetetraacetic acid plasma samples using an aptamer-based proteomic technology. Relative concentrations of each of 4001 proteins were log (base 2) transformed and compared between cases of neovascular AMD and GA versus controls using linear regression. Pathway analysis was conducted using pathways downloaded from Reactome. Results In this pilot study, higher levels of vinculin and lower levels of CD177 were found in patients with neovascular AMD compared with controls. Neuregulin-4 was higher and soluble intercellular adhesion molecule-1 was lower in patients with GA compared with controls. For neovascular AMD, cargo trafficking to the periciliary membrane, fibroblast growth factor receptor 3b ligand binding and activation, and vascular endothelial growth factor-related pathways were in the top ranked pathways. The top-ranked pathways for GA included several related to ErbB4 signaling. Conclusions We found different proteins and different pathways associated with neovascular AMD and GA. Vinculin and some of the top-ranked pathways have been previously associated with AMD, whereas others have not been described. Translational relevance Biomarkers identified in plasma likely reflect systemic alterations in protein expression and may improve our understanding of the mechanisms leading to AMD.

Problem There is a paucity of research on the contribution of placental inflammation to severe retinopathy of prematurity (ROP). Method of study A retrospective cohort study (n = 1217) was conducted of infants screened for ROP (2006-2016). The outcomes of the study were severe ROP (type 1 or type 2 ROP) and low grade ROP. We categorized the placental pathology as the presence of (i) maternal plus fetal inflammatory response, (ii) maternal inflammatory response only, (iii) fetal inflammatory response only and, (iv) no evidence of a maternal or fetal inflammatory response. The data were analyzed using univariate and multivariate logistic regression analyses (P Results In this cohort, the number of infants with the maternal plus fetal inflammatory response, the maternal inflammatory response only, the fetal inflammatory response only, and no maternal or fetal inflammatory response was 305 (25%), 82 (7%), 8 (1%), and 822 (67%), respectively. Adjusted for covariates, the maternal plus fetal inflammatory response was a significant risk factor for severe ROP (AOR = 2.6, 95% CI 1.1-5.9, P = .03). None of the categories of placental inflammation were significantly associated with low grade ROP. Conclusion Placental pathology distinguished by the maternal plus fetal inflammatory response was a significant risk factor for severe ROP. Our study supports a link between intrauterine inflammatory events and the subsequent development of severe ROP.

Purpose: To determine the effect of intravitreal anakinra on choroidal neovascularization (CNV) in an animal model.Methods: Laser photocoagulation used to rupture Bruch’s membrane; animals then assigned to groups based on varying frequency of intravitreal anakinra injections. At day 30, digital angiography was used to measure the CNV area. Result: Intravitreal anakinra dose-dependently inhibited CNV growth. Injections given one time resulted in a 26% reduction in CNV; in the once weekly group, a 41% reduction was seen; in the twice-weekly group, a 62% reduction was seen (all p < .001). Conclusion: Suppressing IL-1 function may provide another therapeutic avenue in exudative AMD.

Ischemic optic neuropathy is the most frequent cause of vision loss in middle age. Clinical and laboratory research studies have begun to clarify the natural history, clinical presentation, diagnostic criteria and pathogenesis of various ischemic nerve injuries. As a result, physicians are acquiring new tools to aid in the diagnosis and potential treatment of ischemic nerve injury. The aim of this review is to examine recent data on anterior and posterior ischemic optic neuropathy and to provide a framework for physicians to manage and counsel affected individuals.