A Dosing Study of Bevacizumab for Retinopathy of Prematurity: Late Recurrences and Additional Treatments.

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

Communication Predicts Medication Self-Efficacy in Glaucoma Patients.

PURPOSE: Medication self-efficacy, or patients' confidence that they can perform medication-related behaviors, is associated with better glaucoma medication adherence. Little is known about how to enhance glaucoma patients' medication self-efficacy. Our purpose is to examine whether patient-provider communication increases glaucoma patients' medication self-efficacy. METHODS: During an 8-month cohort study of 279 glaucoma patients and 15 providers, two office visits were videotape-recorded, transcribed, and coded for six patient-provider communication behaviors. A validated scale was used at baseline and 8-month follow-up to assess patients' confidence in overcoming adherence barriers (adherence barriers self-efficacy) and carrying out tasks to use eye drops correctly (eye drop task self-efficacy). We ran two generalized estimating equations to examine whether more frequent patient-provider communication during office visits predicted increased patient adherence barriers self-efficacy and eye drop task self-efficacy at 8-month follow-up. RESULTS: For each additional topic providers educated about, patients reported an average increase of 0.35 in self-efficacy in overcoming adherence barriers (p < 0.001). Patients also reported an average increase of 1.01 points in eye drop task self-efficacy when providers asked about patients' views of glaucoma and its treatment versus not (p < 0.001). Patients who asked more medication questions (p < 0.001) and African-American patients (p < 0.05) reported lower adherence barriers self-efficacy by 0.30 and 2.15 points, respectively. Women had a 0.63 lower eye drop task self-efficacy than men (p < 0.05). CONCLUSIONS: When providers educate glaucoma patients and assess patient views about glaucoma and its treatment, patients report higher medication self-efficacy. Providers should be aware that patients who ask more medication questions may have less confidence in their ability to overcome barriers to adherence.

The Effect of Eye Drop Technique Education in Patients With Glaucoma.

Education about how to administer eye drops may improve a patient's ability to instill his or her eye drops correctly. Our objectives were to (a) document the methods providers use to educate glaucoma patients about eye drop technique; (b) determine whether eye drop technique education varies by provider and patient characteristics; and (c) evaluate whether education predicts improved patient technique. We conducted an 8-month longitudinal study of 279 glaucoma patients and 15 providers in which we recorded on videotape the content of glaucoma office visits at two time points (baseline and 4- to 6-week follow-up) and videotaped patient eye drop technique at three time points (baseline, 4- to 6-week follow-up, and 8-month follow-up). Mann-Whitney rank sum tests were used to determine whether education was associated with improved patient eye drop technique over time. Ninety-four patients (34%) received technique education at either visit; 31% received verbal education and 10% received a technique demonstration. Only 24 patients (47%) who were new to eye drops received technique education at the baseline visit. Patients who were new to drops at baseline (p = .008) and patients who asked a question about drops (p < .001) were more likely to receive technique education. Education was not associated with improved technique. Eye drop technique education occurs infrequently during glaucoma office visits. Future studies should compare the effectiveness of different educational methods, such as patient demonstration versus provider verbal instruction, to determine which method is best at improving patient eye drop technique.

Ophthalmologist-patient communication, self-efficacy, and glaucoma medication adherence.

OBJECTIVE: To examine the associations of provider-patient communication, glaucoma medication adherence self-efficacy, and outcome expectations with glaucoma medication adherence. DESIGN: Prospective, observational cohort study. PARTICIPANTS: Two hundred seventy-nine patients with glaucoma who were newly prescribed or taking glaucoma medications were recruited at 6 ophthalmology clinics. METHODS: Patients' visits were video recorded and communication variables were coded using a detailed coding tool developed by the authors. Adherence was measured using Medication Event Monitoring Systems for 60 days after their visits. MAIN OUTCOME MEASURES: The following adherence variables were measured for the 60-day period after their visits: whether the patient took 80% or more of the prescribed doses, percentage of the correct number of prescribed doses taken each day, and percentage of the prescribed doses taken on time. RESULTS: Higher glaucoma medication adherence self-efficacy was associated positively with better adherence with all 3 measures. Black race was associated negatively with percentage of the correct number of doses taken each day (ß = -0.16; P < 0.05) and whether the patient took 80% or more of the prescribed doses (odds ratio, 0.37; 95% confidence interval, 0.16-0.86). Physician education about how to administer drops was associated positively with percentage of the correct number of doses taken each day (ß = 0.18; P < 0.01) and percentage of the prescribed doses taken on time (ß = 0.15; P < 0.05). CONCLUSIONS: These findings indicate that provider education about how to administer glaucoma drops and patient glaucoma medication adherence self-efficacy are associated positively with adherence.

Glaucoma patient expression of medication problems and nonadherence.

PURPOSE: The purpose of this study was to examine if patient demographic factors influenced self-reporting of medication side effects, difficulty with drop instillation, and nonadherence to glaucoma therapy. METHODS: English-speaking adult glaucoma patients (n = 279) from six ophthalmology clinics were enrolled. Patients' medical visits were videotaped and patients were interviewed immediately afterward by research assistants. The videotapes were transcribed verbatim and coded to identify patients who expressed problems with medication side effects, eye drop administration, and nonadherence during the glaucoma office visits. Generalized estimating equations were performed to identify whether patient characteristics were associated with expression of problems with glaucoma medication and medication nonadherence during the office visit. RESULTS: Patients with lower health literacy were significantly less likely to express problems with side effects (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.25 to 0.88) and eye drop administration (OR, 0.26; 95% CI, 0.11 to 0.63) during the visit. Patients who reported eye drop administration and side effect problems during the interview were significantly more likely to express these problems to their ophthalmologist (OR, 3.13; 95% CI, 1.82 to 5.37 and OR, 1.86; 95% CI, 1.12 to 3.08, respectively). Patients who expressed a problem with eye drop administration and with side effects were significantly more likely to express medication nonadherence to their ophthalmologist (OR, 2.89; 95% CI, 1.44 to 5.80 and OR, 2.03; 95% CI, 1.16 to 3.54, respectively). Patients who reported greater than 80% medication adherence during the interview were significantly less likely to express nonadherence to their ophthalmologist (OR, 0.22; 95% CI, 0.12 to 0.40). CONCLUSIONS: Eye care providers should be aware that glaucoma patients with lower health literacy are less likely to express problems with side effects and eye drop administration. Providers should work with patients to assess medication-related problems to mitigate potential barriers to medication adherence because patients who expressed medication problems were also more likely to express nonadherence.

Determinants of Self-Reported Barriers to Glaucoma Medicine Administration and Adherence: A Multisite Study.

BACKGROUND: Many factors influence glaucoma medication adherence. A better understanding of the relationships between health literacy, depressive symptoms, and patient-reported problems in using glaucoma medications may reveal opportunities for intervention that could improve patients' clinical outcomes. OBJECTIVE: To examine the relationship between patient characteristics (demographics, health literacy, and depressive symptoms) and patient-reported problems in using glaucoma medications and to assess factors related to patients' self-reported adherence to glaucoma medications. METHODS: Patients diagnosed with primary open-angle glaucoma (n = 228) currently taking intraocular pressure-lowering medications were recruited at 6 ophthalmology clinics. Patients were interviewed to identify problems using glaucoma medications, and self-reported medication adherence was determined using a Visual Analog Scale. Questionnaires were administered to assess health literacy, depressive symptoms, outcome expectations, and medication self-efficacy. RESULTS: Younger patients (P = 0.03), patients with depressive symptoms (P = 0.02), and patients who reported more medication problems (P = 0.005) were significantly less adherent to their glaucoma medications. Patients with higher glaucoma medication self-efficacy adherence scores (P = 0.003) and higher outcome expectations (P = 0.03) were significantly more adherent. CONCLUSIONS: Providers should consider using tools to screen glaucoma patients for depressive symptoms and for problems in using medications to identify patients who are at higher risk of nonadherence to treatment and who might benefit from follow-up with primary care providers.

Provider use of collaborative goal setting with glaucoma patients.

PURPOSE: The purpose of this preliminary study was to describe the extent to which providers used collaborative goal setting and individualized assessment with patients who were newly prescribed glaucoma medications. METHODS: English-speaking glaucoma suspect patients from six ophthalmology clinics who were newly prescribed glaucoma medications had their medical visits videotaped and were interviewed after the visits. The videotapes were transcribed and coded to examine provider use of collaborative goal setting and individualized assessment. RESULTS: Fifty-one patients seeing 12 ophthalmologists participated. Providers gave patients glaucoma treatment options during 37% of the visits; only five providers gave patients treatment options Providers asked for patient treatment preferences in less than 20% of the visits; only two providers asked for patient treatment preferences. Providers were significantly more likely to ask African American patients for their preferences or ideas concerning treatment than non-African American patients (Pearson χ² = 4.1, p = 0.04). Providers were also significantly more likely to ask African American patients about their confidence in using glaucoma medication regularly than non-African American patients (Pearson χ² = 8.2, p = 0.004). Providers asked about patient views about glaucoma in less than 20% of the visits; five providers asked patients their views on glaucoma and its treatment. Providers were significantly more likely to ask African American patients about their views on glaucoma than non-African American patients (Pearson χ² = 5.62, p = 0.02). CONCLUSIONS: Eye care providers often did not use collaborative goal setting or conduct individualized assessments of patient views on glaucoma when prescribing treatment for the first time.

Prenatal Carotenoid Supplementation With Lutein or Zeaxanthin Ameliorates Oxygen-Induced Retinopathy (OIR) in Bco2-/- Macular Pigment Mice.

Purpose: Premature infants at risk of retinopathy of prematurity (ROP) miss placental transfer of the carotenoids lutein (L) and zeaxanthin (Z) during the third trimester. We previously demonstrated that prenatal L and Z supplementation raised carotenoid levels in infants at birth in the Lutein and Zeaxanthin in Pregnancy (L-ZIP) study (NCT03750968). Based on their antioxidant effects and bioavailability, we hypothesized that prenatal maternal supplementation with macular carotenoids would reduce the risk of ROP. To test this hypothesis, we utilized "macular pigment mice" genetically engineered to take up L and Z into the retina in a model of oxygen-induced retinopathy (OIR). Methods: Pregnant Bco2-/- mice were divided into nine experimental subgroups based on the type of supplementation (L, Z, or placebo) and on the maternal supplementation start date corresponding to the three trimesters of human fetal development (E0, E11, and P1). Pups and nursing mothers were exposed to 75% O2 for 5 days (P7-P12) and returned to room air for 5 days (P12-P17). Pups were killed at P12 and P17, and their retinas were analyzed for vaso-obliteration and intravitreal neovascularization. Results: Pups of pregnant mice supplemented with L or Z had significant reductions in areas of vaso-obliteration and intravitreal neovascularization compared to placebo. Prenatal carotenoid supplementation starting at E0 or E11 was significantly more protective against OIR than postnatal supplementation starting at P1. Conclusions: Prenatal supplementation with L and Z was beneficial in a mouse OIR model. We recommend testing prenatal L and Z supplementation in future human clinical trials to prevent ROP.

Bone morphogenetic protein endothelial cell precursor-derived regulator regulates retinal angiogenesis in vivo in a mouse model of oxygen-induced retinopathy.

OBJECTIVE: Bone morphogenetic proteins (BMPs) are potently proangiogenic; however, the mechanisms underlying the regulation of vessel development by BMPs are not fully understood. To assess the significance of BMP endothelial cell precursor-derived regulator (BMPER) in blood vessel formation in vivo, we investigated its role in retinal angiogenesis. METHODS AND RESULTS: In a model of oxygen-induced retinopathy, Bmper mRNA expression and protein levels are downregulated, correlating with the initiation of Sma and Mad related protein phosphorylation in endothelial cells. Moreover, Bmper haploinsufficiency results in an increased rate of retinal revascularization, with retinas from Bmper+/- mice displaying increased numbers of branching points and angiogenic sprouts at the leading edge of the newly formed vasculature. Furthermore, although Bmper haploinsufficiency does not alter Bmp expression, it does lead to an increase in BMP signaling, as evidenced by increased phosphorylated Sma and Mad related protein levels in endothelial cells and increased expression of known BMP target genes. CONCLUSIONS: These observations provide compelling evidence that BMPER is important in the regulation of BMP signaling and revascularization in the hypoxic retina. These bring forth the possibility of novel therapeutic approaches for pathological angiogenesis based on manipulation of BMP signaling.

The Male to Female Ratio in Treatment-Warranted Retinopathy of Prematurity: A Systematic Review and Meta-analysis.

Importance: Literature and anecdotal evidence suggest a relationship between male sex and retinopathy of prematurity (ROP). It is not known whether a difference, if present, is sex-related pathophysiologic predisposition or sex difference in meeting ROP screening criteria. Objective: To evaluate the association of sex with the development of treatment-warranted ROP. Data Sources: PubMed, Embase, and Web of Science databases were searched from 2000 to 2022. The search strategy used keywords including retinopathy of prematurity or ROP or retrolental fibroplasia and treatment or anti-VEGF or bevacizumab or ranibizumab or aflibercept or conbercept or laser or cryotherapy and gender or sex or male or female and medical subject headings terms. Study Selection: All studies reporting on treatment with anti-vascular endothelial growth factor, laser photocoagulation, and/or cryotherapy for ROP were identified. Studies reporting sex distribution in the treatment group were included in the meta-analysis. Exclusion criteria included case reports, case series of fewer than 10 treated patients, systematic reviews, conference abstracts, letters to the editor, animal studies, and non-English records. Data Extraction and Synthesis: Two reviewers independently screened and extracted the data following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The proportions of treated male and female infants were combined using random-effects meta-analysis. Main Outcomes and Measures: Numbers and percentages of male and female infants treated for ROP. Results: Of 11 368 identified studies, 316 met inclusion criteria, yielding a total of 31 026 treated patients. A higher percentage of male infants were treated for ROP (55% [95% CI, 0.54%-0.55%]), with low heterogeneity between studies (I2 = 34%; P < .001). Thirty-eight studies reported sex distribution in the screened population (170 053 patients; 92 612 [53%] male vs 77 441 [47%] female). There was no significant difference in the odds of receiving treatment between screened male and female infants (pooled odds ratio, 1.04 [95% CI, 0.91-1.18]; P = .67). Conclusions and Relevance: More male infants are treated for ROP than female infants. This could be due to a known relative pathophysiological fragility of preterm male infants in addition to a difference in ROP screening rates, with more male infants meeting the criteria than female infants. These findings have implications for future studies and may prompt more careful clinical monitoring of male neonates.

Baseline predictors of visual acuity and retinal thickness outcomes in patients with retinal vein occlusion: Standard Care Versus COrticosteroid for REtinal Vein Occlusion Study report 10.

OBJECTIVE: To investigate baseline factors associated with visual acuity and central retinal thickness outcomes in patients with macular edema secondary to retinal vein occlusion in the Standard Care versus COrticosteroid for REtinal Vein Occlusion (SCORE) Study. DESIGN: Two multicenter, randomized clinical trials: one evaluating participants with central retinal vein occlusion (CRVO) and one evaluating participants with branch retinal vein occlusion (BRVO). PARTICIPANTS: Participants with follow-up data of 1 year or more, including 238 with CRVO and 367 with BRVO. METHODS: Visual acuity was measured by the electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) method, and central retinal thickness was measured by optical coherence tomography (OCT). Regression analysis related these outcomes to 20 baseline measures. Multiple P values were adjusted to control the false discovery rate. MAIN OUTCOME MEASURES: Outcome measures of visual acuity letter score included absolute change from baseline, a gain of ≥ 15 from baseline, and a loss of ≥ 15 from baseline. Outcome measures of center point thickness included absolute change from baseline, a measurement of ≤ 250 µm, and a measurement of ≥ 500 µm. Outcomes were assessed at 1 and 2 years. RESULTS: For CRVO and BRVO, younger age was associated with improved visual acuity and central retinal thickness outcomes. For CRVO, triamcinolone treatment and less severe anatomic abnormalities of the retina (center point thickness and areas of retinal hemorrhage, thickening, and fluorescein leakage) were predictive of better visual acuity outcomes. For BRVO, no history of coronary artery disease was predictive of improved visual acuity outcomes. For center point thickness outcomes, shorter duration of macular edema was associated with improvement in both disease entities. For CRVO, higher baseline visual acuity letter score was predictive of favorable OCT outcomes. For BRVO, lower baseline visual acuity letter score, presence of dense macular hemorrhage, and no prior grid photocoagulation were predictive of favorable OCT outcomes. CONCLUSIONS: Several factors were predictive of better visual acuity outcomes and more favorable OCT outcomes, including younger age and shorter duration of macular edema, respectively. These factors may assist clinicians in predicting disease course for patients with CRVO and BRVO.

Stanniocalcin-1 is a Modifier of Oxygen-Induced Retinopathy Severity.

Purpose/Aim: Abnormal activation of signaling pathways related to angiogenesis, inflammation, and oxidative stress has been implicated in the pathophysiology of retinopathy of prematurity (ROP), a leading cause of blindness in pre-term infants. Therapies for ROP include laser and anti-vascular endothelial growth factor agents. However, these therapies have side effects, and even with adequate treatment, visual acuity can be impaired. Novel therapeutic options are needed. Stanniocalcin-1 (STC-1) is a neuroprotective protein with anti-inflammatory and anti-oxidative stress properties. Rodent models of oxygen-induced retinopathy (OIR) were selected to determine whether STC-1 plays a role in the development of OIR.Materials and methods: STC-1 gene and protein expression was first evaluated in the Sprague Dawley rat OIR model that is most similar to human ROP. OIR was then induced in wild-type and Stc-1-/- mice. Retinas were isolated and evaluated for avascular and neovascular area on retinal flat mounts. Quantification of gene expression by quantitative real-time PCR was performed. VEGF was assayed by ELISA in media obtained from induced pluripotent stem-cell-derived retinal pigment epithelial (iPS-RPE) cells following treatment with recombinant STC-1.Results: STC-1 was significantly upregulated in a rat model of OIR compared to room air controls at the gene (P < .05) and protein (P < .001) level. Stc-1-/- OIR mice showed significantly worse ROP compared to wild-type mice as assessed by avascular (20.2 ± 2.4% vs 15.2 ± 2.5%; P = .02) and neovascular area (14.3 ± 2.7% vs 8.8 ± 3.7%; P < .05). Transcript levels of vascular endothelial growth factor-A were significantly higher in Stc-1-/- OIR mice compared to wild-type controls (P = .03). STC-1 reduced VEGF production in iPS-RPE cells (P = .01).Conclusions: STC-1 plays a role in the OIR stress response and development of pathologic vascular features in rodent OIR models by regulating VEGF levels.

Systemic Disease and Ocular Comorbidity Analysis of Geographically Isolated Federally Recognized American Indian Tribes of the Intermountain West.

BACKGROUND: The American Indian Navajo and Goshute peoples are underserved patient populations residing in the Four Corners area of the United States and Ibupah, Utah, respectively. METHODS: We conducted a cross-sectional study of epidemiological factors and lipid biomarkers that may be associated with type II diabetes, hypertension and retinal manifestations in tribal and non-tribal members in the study areas (n = 146 participants). We performed multivariate analyses to determine which, if any, risk factors were unique at the tribal level. Fundus photos and epidemiological data through standardized questionnaires were collected. Blood samples were collected to analyze lipid biomarkers. Univariate analyses were conducted and statistically significant factors at p < 0.10 were entered into a multivariate regression. RESULTS: Of 51 participants for whom phenotyping was available, from the Four Corners region, 31 had type II diabetes (DM), 26 had hypertension and 6 had diabetic retinopathy (DR). Of the 64 participants from Ibupah with phenotyping available, 20 had diabetes, 19 had hypertension and 6 had DR. Navajo participants were less likely to have any type of retinopathy as compared to Goshute participants (odds ratio (OR) = 0.059; 95% confidence interval (CI) = 0.016-0.223; p < 0.001). Associations were found between diabetes and hypertension in both populations. Older age was associated with hypertension in the Four Corners, and the Navajo that reside there on the reservation, but not within the Goshute and Ibupah populations. Combining both the Ibupah, Utah and Four Corners study populations, being American Indian (p = 0.022), residing in the Four Corners (p = 0.027) and having hypertension (p < 0.001) increased the risk of DM. DM (p < 0.001) and age (p = 0.002) were significantly associated with hypertension in both populations examined. When retinopathy was evaluated for both populations combined, hypertension (p = 0.037) and living in Ibupah (p < 0.001) were associated with greater risk of retinopathy. When combining both American Indian populations from the Four Corners and Ibupah, those with hypertension were more likely to have DM (p < 0.001). No lipid biomarkers were found to be significantly associated with any disease state. CONCLUSIONS: We found different comorbid factors with retinal disease outcome between the two tribes that reside within the Intermountain West. This is indicated by the association of tribe and with the type of retinopathy outcome when we combined the populations of American Indians. Overall, the Navajo peoples and the Four Corners had a higher prevalence of chronic disease that included diabetes and hypertension than the Goshutes and Ibupah. To the best of our knowledge, this is the first study to conduct an analysis for disease outcomes exclusively including the Navajo and Goshute tribe of the Intermountain West.

Late-Onset Retinal Findings and Complications in Untreated Retinopathy of Prematurity.

PURPOSE: To investigate late retinal findings and complications of eyes with a history of retinopathy of prematurity (ROP) that did not meet treatment criteria and did not receive treatment during infancy. DESIGN: Retrospective, nonconsecutive, noncomparative, multicenter case series. PARTICIPANTS: Three hundred sixty-three eyes of 186 patients. METHODS: Data were requested from multiple providers on premature patients with a history of ROP and no treatment during infancy who demonstrated late retinal findings or complications and included age, gender, gestational age and weight, zone and stage at infancy, visual acuity, current retina vascularization status, vitreous character, presence of peripheral retinal findings such as lattice retinal tears and detachments (RDs), retinoschisis, and fluorescein findings. MAIN OUTCOME MEASURES: Rate of RDs and factors conferring a higher risk of RDs. RESULTS: The average age was 34.5 years (range, 7-76 years), average gestational age was 26.6 weeks (range, 23-34 weeks), and average birth weight was 875 g (range, 425-1590 g). Findings included lattice in 196 eyes (54.0%), atrophic holes in 126 eyes (34.7%), retinal tears in 111 eyes (30.6%), RDs in 140 eyes (38.6 %), tractional retinoschisis in 44 eyes (11.9%), and visible vitreous condensation ridge-like interface in 112 eyes (30.5%). Fluorescein angiography (FA) was performed in 113 eyes, of which 59 eyes (52.2%) showed leakage and 16 eyes (14.2%) showed neovascularization. Incomplete vascularization posterior to zone 3 was common (71.6% of eyes). Retinal detachments were more likely in patients with a gestational age of 29 weeks or less (P < 0.05) and in eyes with furthest vascularization to posterior zone 2 eyes compared with zone 3 eyes (P = 0.009). CONCLUSIONS: Eyes with ROP not meeting the treatment threshold during infancy showed various late retinal findings and complications, of which RDs were the most concerning. Complications were seen in all age groups, including patients born after the Early Treatment for Retinopathy of Prematurity Study. Contributing factors to RDs included atrophic holes within peripheral avascular retina, visible vitreous condensation ridge-like interface with residual traction, and premature vitreous syneresis. We recommend regular examinations and consideration of ultra-widefield FA examinations. Prospective studies are needed to explore the frequency of complications and benefit of prophylactic treatment and if eyes treated with anti-vascular endothelial growth factor therapy are at risk of similar findings and complications.

Reduction in endothelial tip cell filopodia corresponds to reduced intravitreous but not intraretinal vascularization in a model of ROP.

To determine the effect of a vascular endothelial growth factor receptor 2 tyrosine kinase (VEGFR2) inhibitor on intravitreous neovascularization (IVNV), endothelial tip cell filopodia, and intraretinal vascularization in a rat model of retinopathy of prematurity (ROP). Within 4h of birth, newborn Sprague-Dawley rat pups and their mothers were cycled between 50% and 10% oxygen daily until postnatal day (p)12. Pups were given intravitreous injections of VEGFR2 inhibitor, SU5416, or control (dimethyl sulfoxide, DMSO) and returned to oxygen cycling until p14, then placed into room air. Intravitreous neovascularization (IVNV), avascular/total retinal areas, and endothelial tip cell filopodial number and length were determined in lectin-labeled neurosensory retinal flat mounts. Cryosections or fresh tissue were analyzed for phospho-VEGFR1, phospho-VEGFR2, activated caspase-3, or phospho-beta3 integrin. Human umbilical venous (HUVECs) and human choroidal endothelial cells (ECs) were treated with VEGFR2 inhibitor to determine effect on VEGFR2 phosphorylation and on directed EC migration toward a VEGF gradient. Filopodial length and number of migrated ECs were also measured. Compared to control, the VEGFR2 inhibitor reduced VEGFR2 phosphorylation in HUVECs in vitro and clock hours and areas of IVNV but not percent avascular retina in vivo. Filopodial length and number of filopodia/EC tip cell were reduced in retinal flat mounts at doses that inhibited IVNV, whereas at lower doses, only a reduction in filopodial length/EC tip cell was found. There was no difference in phosphorylated beta3 integrin and cleaved caspase-3 labeling in VEGFR2 inhibitor-treated compared to control in vivo. Doses of the VEGFR2 inhibitor that reduced filopodial length and number of filopodia/migrating EC corresponded to reduced EC migration in in vitro models. VEGFR2 inhibitor reduced IVNV and filopodial number and length/EC tip cell without interfering with intraretinal vascularization. Reducing the number and length of filopodia/endothelial tip cell may reduce guidance cues for endothelial cells to migrate into the vitreous without interfering with migration into the retina toward a VEGF gradient.

Experimental Evidence Behind Clinical Trial Outcomes in Retinopathy of Prematurity.

Treatment of severe retinopathy of prematurity (ROP) has evolved over the last decade. This article reviews recent clinical trials and experimental evidence that supports clinical outcomes and observations, including the efficacy of anti-vascular endothelial growth factor (VEGF) agents in reducing the vascular activity of severe ROP, and the mechanisms behind recurrent stage 3 ROP and plus disease in some infants treated with anti-VEGF agents. Also discussed will be current imaging modalities that link experimental models of ROP with longitudinal human studies and which provide exciting future opportunities to enhance the understanding of pathophysiology of ROP and improve treatments. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:228-234.].

Genetic Epidemiologic Analysis of Hypertensive Retinopathy in an Underrepresented and Rare Federally Recognized Native American Population of the Intermountain West.

Understanding disease risk is challenging in multifactorial conditions as it can differ by environment, ethnicity and race. The Confederated Tribes of the Goshute Reservation are one of the most isolated populations in the United States. Retinal changes are a reliable indicator for systemic disease. We conducted a cross-sectional study to identify correlations between genetic data and epidemiological risk factors for blinding retinal disease in this tribe. As part of the "Supporting Prediction and Prevention Blindness Project (SPBPP)" in the Native American Population of the Intermountain West, we found that hypertensive retinopathy was the most prevalent retinal disease. We found that forty-two percent of the Goshute population was affected. Blood samples, fundus photos and intraocular pressure were obtained for all participants. In addition, a standardized questionnaire was administered. DNA and total cholesterol, HDL, LDL, VLDL, triglycerides and HbA1c were also evaluated. Our study interrogated genetic variants from the PAGE study (ARMS2 rs10490924, CFH rs800292, rs1061170) and additional studies that looked at previously associated genetic variants with retinal disease associated with cardiovascular disease. We conducted univariate and multivariate logistic regression in Stata v15.0. We found an association between hypertriglyceridemia and HTR (adjp = .05) within the Goshute population. To the best of our knowledge, this is the first study to demonstrate the prevalence of hypertensive retinopathy in a Native American population. Moreover, our study is the first to demonstrate an independently predictive relationship between hypertriglyceridemia and hypertensive retinopathy in an American Indian population. This study furthers our knowledge about prevalent blinding eye disease within the most geographically isolated federally recognized native United States American tribe, for which nothing has been published with respect to any disease. Although, this study furthers our understanding about the prevalence of genetic epidemiological risk factors within this population, it has greater implications for the screening of blinding diseases in underserved populations in general. This study can inform public health on planning and delivering of quality, accessible and relevant care to this population.

Longitudinal Examination of Fellow-Eye Vascular Anomalies in Coats' Disease With Widefield Fluorescein Angiography: A Multicenter Study.

BACKGROUND AND OBJECTIVE: Retinovascular anomalies in the fellow eyes of patients with Coats' disease have been described, but the clinical significance is unknown, as well as whether these lesions progress over time. PATIENTS AND METHODS: This is an international, multicenter, retrospective, observational cohort study of fellow-eye abnormalities on widefield fluorescein angiography in patients with Coats' disease. RESULTS: Three hundred fifty eyes of 175 patients with Coats' disease were analyzed. A total of 33 patients (18.8%) demonstrated abnormal fellow-eye findings: 14 (42.4%) telangiectasias, 18 (54.5%) aneurysms, six (18.2%) segmental non-perfusion, six (18.2%) leakage, and two (6.0%) vascular tortuosity. All eyes were asymptomatic, and none of the lesions progressed over time. There was no association between fellow-eye findings with severity of Coats' disease (P = .16), patient age (P = .16), or presence of systemic vascular disease (P = .16). CONCLUSIONS: The vascular abnormalities in fellow eyes of patients with Coats' disease did not progress over time. Observation is a reasonable initial management strategy. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:221-227.].

Comparison of time-domain OCT and fundus photographic assessments of retinal thickening in eyes with diabetic macular edema.

PURPOSE: To explore the correlation between optical coherence tomography (OCT) and stereoscopic fundus photographs (FP) for the assessment of retinal thickening (RT) in diabetic macular edema (DME) within a clinical trial. METHODS: OCT, FP, and best corrected visual acuity (VA) measurements were obtained in both eyes of 263 participants in a trial comparing two photocoagulation techniques for DME. Correlation coefficients (r) were calculated comparing RT measured by OCT, RT estimated from FP, and VA. Principal variables were central subfield retinal thickness (CSRT) obtained from the OCT fast macular map and DME severity assessed by a reading center using a seven-step photographic scale combining the area of thickened retina within 1 disc diameter of the foveal center and thickening at the center. RESULTS: Medians (quartiles) for retinal thickness within the center subfield by OCT at baseline increased from 236 (214, 264) microm in the lowest level of the photographic scale to 517 (455, 598) microm in the highest level (r = 0.67). However, CSRT interquartile ranges were broad and overlapping between FP scale levels, and there were many outliers. Correlations between either modality and VA were weaker (r = 0.57 for CSRT, and r = 0.47 for the FP scale). OCT appeared to be more reproducible and more sensitive to change in RT between baseline and 1 year than was FP. CONCLUSIONS: There was a moderate correlation between OCT and FP assessments of RT in patients with DME and slightly less correlation of either measure with VA. OCT and FP provide complementary information but neither is a reliable surrogate for VA.