Bispecific VEGF-A and Angiopoietin-2 Antagonist RO-101 Preclinical Efficacy in Model of Neovascular Eye Disease.

Objective: To investigate preclinical data regarding the efficacy and biocompatibility of a bispecific protein, RO-101, with effects on VEGF-A and angiopoietin-2 (Ang-2) for use in retinal diseases. Design: Experimental study. Subjects: Brown Norway rats and New Zealand White Cross rabbits. Methods: Preclinical study data of RO-101 in terms of target-specific enzyme-linked immunosorbent assay binding affinity to VEGF-A and Ang-2, vitreous half-life, inhibition of target-receptor interaction, laser choroidal neovascular membrane animal model, human umbilical vein endothelial cell migration, and biocompatibility was obtained. Where applicable, study data were compared with other anti-VEGF agents. Main Outcome Measures: Binding affinity, half-life, biocompatibility, and efficacy of RO-101. Neovascularization prevention by RO-101. Results: RO-101 demonstrated a strong binding affinity for VEGF-A and Ang-2 and in vitro was able to inhibit binding to the receptor with higher affinity than faricimab. The half-life of RO-101 is comparable to or longer than current VEGF inhibitors used in retinal disease. RO-101 was found to be biocompatible with retinal tissue in Brown Norway rats. RO-101 was as effective or more effective than current anti-VEGF therapeutics in causing regression of neovascular growth in vivo. Conclusions: RO-101 is a promising candidate for use in retinal diseases. In preclinical models, RO-101 demonstrated similar or higher regression of neovascular growth to current anti-VEGF therapeutics with comparable or longer half-life. It also demonstrates a strong binding affinity for VEGF-A and Ang-2. It also was shown to be biocompatible with retinal tissue in animal studies, indicating potential compatibility for use in humans. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

ALTERNATIVE INTRAVITREAL ANTIBIOTICS: A Systematic Review for Consideration in Recalcitrant or Resistant Endophthalmitis.

PURPOSE: To organize, categorize, and create a quick reference guide for the use of intravitreal antibiotic alternatives to the standard combination of vancomycin and ceftazidime for the treatment of endophthalmitis. METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. The authors searched for all available information regarding intravitreal antibiotics in the last 21 years. Manuscripts were selected according to relevance, level of information, and the available data regarding intravitreal dose, potential adverse effects, bacterial coverage, and relevant pharmacokinetic information. RESULTS: The authors included 164 of 1810 manuscripts. The antibiotics were classified according to their class into fluoroquinolones, cephalosporins, glycopeptide and lipopeptide, penicillins and beta-lactams, tetracyclines, and miscellaneous. The authors also included information regarding intravitreal adjuvants for the treatment of endophthalmitis and one ocular antiseptic. CONCLUSION: The treatment of infectious endophthalmitis is a therapeutic challenge. The current review summarizes the properties of possible intravitreal antibiotic alternatives that should be considered in cases of suboptimal response to initial treatment.

Preventable risk factors for type 2 diabetes can be detected using noninvasive spontaneous electroretinogram signals.

Given the ever-increasing prevalence of type 2 diabetes and obesity, the pressure on global healthcare is expected to be colossal, especially in terms of blindness. Electroretinogram (ERG) has long been perceived as a first-use technique for diagnosing eye diseases, and some studies suggested its use for preventable risk factors of type 2 diabetes and thereby diabetic retinopathy (DR). Here, we show that in a non-evoked mode, ERG signals contain spontaneous oscillations that predict disease cases in rodent models of obesity and in people with overweight, obesity, and metabolic syndrome but not yet diabetes, using one single random forest-based model. Classification performance was both internally and externally validated, and correlation analysis showed that the spontaneous oscillations of the non-evoked ERG are altered before oscillatory potentials, which are the current gold-standard for early DR. Principal component and discriminant analysis suggested that the slow frequency (0.4-0.7 Hz) components are the main discriminators for our predictive model. In addition, we established that the optimal conditions to record these informative signals, are 5-minute duration recordings under daylight conditions, using any ERG sensors, including ones working with portative, non-mydriatic devices. Our study provides an early warning system with promising applications for prevention, monitoring and even the development of new therapies against type 2 diabetes.

Treatment of Demodex Blepharitis: A Prospective, Randomized, Controlled, Double-Masked Clinical Trial Comparing Topical Lotilaner Ophthalmic Solution, 0.25% Eyedrops to Vehicle.

PURPOSE: To evaluate the efficacy and safety of lotilaner ophthalmic solution, 0.25% eyedrops compared to vehicle for the treatment of Demodex blepharitis. METHODS: In this randomized, controlled, double-masked clinical trial, 54 participants were randomly assigned in a 1:1 ratio to receive either lotilaner ophthalmic solution, 0.25% (study group) or the vehicle (control group) bilaterally, twice daily for 42 days. Outcome measures were collarette cure (collarette grade 0, upper eyelid), mite eradication (mite density of 0 mites/lash), and composite cure (grade 0 for collarettes and erythema). RESULTS: The proportion of participants achieving collarette cure (80.0% vs 15.8%; p < .001), mite eradication (73.3% vs 21.1%, p = .003) and composite cure (73.3% vs 10.5%, p < .001) at Day 42 was statistically significantly higher in the study group than the control group. CONCLUSION: Twice-daily 42-day treatment with novel lotilaner ophthalmic solution, 0.25% is safe and effective for the treatment of Demodex blepharitis compared to the vehicle control. (Registry number: ACTRN12620000320954, dated 09/03/2020).

Color Vision and Microperimetry Changes in Nonexudative Age-Related Macular Degeneration After Risuteganib Treatment: Exploratory Endpoints in a Multicenter Phase 2a Double-Masked, Randomized, Sham-Controlled, Crossover Clinical Trial.

BACKGROUND AND OBJECTIVE: To explore the association between best-corrected visual acuity (BCVA) improvement and changes in microperimetry (MP) and color vision in patients with nonexudative age-related macular degeneration following administration of two 1.0-mg intravitreal doses of risuteganib. PATIENTS AND METHODS: In a phase 2a, prospective, double-masked, sham-controlled study, eyes with nonexudative age-related macular degeneration and Early Treatment Diabetic Retinopathy Study BCVA between 20/40 and 20/200 were randomized to intravitreal risuteganib (1.0 mg) or sham injection. The risuteganib group received a second 1.0-mg dose, and patients in the sham group crossed over to receive 1.0 mg of risuteganib at week 16. Exploratory endpoints included changes in color vision and mesopic MP. RESULTS: Thirty-nine patients (risuteganib, n = 25; sham, n = 14) completed the study. There was a significant (P < .05) correlation between BCVA and the total error score (TES) for both Lanthony and Hue Style. Confusion index was close to the criterion for significance (P = .056) in the risuteganib group. All color vision metrics demonstrated a trend toward improvement in risuteganib responders (BCVA letter gain ≥8 letters) and no change in the nonresponders, with significant differences seen in confusion index between the risuteganib and control group (P = .0493) and between responders and nonresponders (P = .0478). MP showed that risuteganib responders improved in mean sensitivity and change in number of loci ≤11 dB and ≤0 dB, whereas nonresponders worsened. CONCLUSION: All color vision and MP parameters tested trended toward improvement in risuteganib-treated patients and risuteganib responders. Statistically significant improvement was evident in two metrics: confusion index (in risuteganib-treated patients and responders) and number of loci with decreased sensitivity (in responders). A significant correlation between BCVA and both TES Lanthony and TES Hue Style in risuteganib patients provides concurrent evidence of objective and subjective improvement of retinal function. [Ophthalmic Surg Lasers Imaging Retina 2022;53:430-438.].

Correlation of Complement Activation in Aqueous and Vitreous in Patients With Proliferative Diabetic Retinopathy.

Purpose: 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. Methods: 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. Results: 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 values < 0.0001). 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; P < 0.0001) were significantly correlated. Conclusions: A strong correlation exists between aqueous and vitreous complement levels in diabetic eye disease. Translational Relevance: 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.

Safety and efficacy of lotilaner ophthalmic solution, 0.25% for the treatment of blepharitis due to demodex infestation: A randomized, controlled, double-masked clinical trial.

PURPOSE: To evaluate the safety and efficacy of lotilaner ophthalmic solution, 0.25% for the treatment of blepharitis due to Demodex infestation compared to vehicle control. METHODS: In this phase II, randomized, controlled, double-masked clinical trial, 60 eligible participants with Demodex blepharitis were randomly assigned in a 1:1 ratio to receive either topical lotilaner ophthalmic solution, 0.25% (Tarsus Pharmaceuticals, Inc., Irvine, CA) (study group) or the vehicle without lotilaner (control group) bilaterally twice a day for 28 days. Participants were followed at Days 7, 14, 28, 60 and 90. The efficacy parameters were change in collarette grade and Demodex density at Day 28. Safety parameters were adverse events, changes in corrected distance visual acuity (CDVA), intraocular pressure (IOP) and slit-lamp biomicroscopy. RESULTS: The study group showed a statistically significant decrease in collarette grade compared to the control group beginning at Day 14 (p = 0.003) in the upper eyelid and at Day 28 (p = 0.003) in the lower eyelid. Decreases in both lids were maintained through Day 90 (p < 0.001). At Day 28, mite eradication was achieved in 66.7% and 25.9% of eyes in the study and control group (p = 0.005); at Day 90, these proportions were 68.2% and 18.5% (p = 0.001), respectively. No serious adverse events or clinically significant changes in CDVA and IOP were observed. CONCLUSION: For Demodex blepharitis, treatment with lotilaner ophthalmic solution, 0.25% for 4 weeks is safe and effective. The improvement in collarette grade and mite density observed during the treatment period persisted for at least two months following treatment cessation.

A phase II randomized trial to evaluate the long-term (12-week) efficacy and safety of OC-01 (varenicline solution) nasal spray for dry eye disease: The MYSTIC study.

PURPOSE: Dry eye disease is characterized by loss of tear film stability. OC-01 (varenicline solution) is a small-molecule nicotinic acetylcholine receptor agonist administered as a nasal spray that stimulates tear production. METHODS: In MYSTIC (NCT03873246) patients aged ≥22 years with dry eye disease were randomized 1:1:1 to OC-01 0.03 mg, OC-01 0.06 mg, or vehicle (n = 41 per group), administered twice daily via intranasal spray, for 12 weeks (84 days). Primary efficacy endpoint was mean change from baseline in anesthetized Schirmer's test score (STS) in study eye at day (D) 84. RESULTS: Patients receiving OC-01 0.03 and 0.06 mg had statistically significantly increased tear production at D84 versus vehicle; least squares mean changes from baseline in STS were 10.8 mm and 11.0 mm for OC-01 0.03 and 0.06 mg, respectively. A trend toward a higher proportion of patients experiencing ≥10-mm improvement in STS from baseline was observed with OC-01 0.03 mg (36.6%; p > 0.05), and was significant for OC-01 0.06 mg (48.8%; p = 0.024), versus vehicle (24.4%). Non-ocular treatment-emergent adverse events (TEAEs) were reported by 21 patients; the most common was sneezing (OC-01 0.03 mg, 2 [4.9%]; OC-01 0.06 mg, 3 [7.3%]), with similar frequencies between treatment groups. No severe or serious TEAEs were reported. CONCLUSIONS: OC-01 (varenicline solution) nasal spray improved tear production in patients with dry eye disease over a long-term (12-week) period, and represents a receptor neuro-activator with a nasal route of administration that spares the ocular surface to stimulate tear production.

Safety and Efficacy of Topical Lotilaner Ophthalmic Solution 0.25% for the Treatment of Demodex Blepharitis: A Pilot Study.

PURPOSE: Evaluate safety and efficacy of topical lotilaner ophthalmic solution, 0.25% for the treatment of Demodex blepharitis. Patients and Methods. 15 patients with Demodex blepharitis, defined as >10 collarettes on the upper lid, lid margin erythema, and Demodex density of ≥1.5 mites/lash on microscopy, were treated bid for 28 days with lotilaner ophthalmic solution, 0.25%. Contact lens wear, artificial eyelashes, and lid structural abnormalities were among the exclusion criteria. No other antibacterial, antiparasitic, or anti-inflammatory treatment or lid hygiene products were permitted. Patients were assessed on Days 7, 14, 28, 60, and 90. Outcome measures were changes in collarette grade and mite density on Day 28. Adverse events and changes in intraocular pressure (IOP), corrected distance visual acuity (CDVA), and slit-lamp biomicroscopy were assessed. RESULTS: Mean collarette grade (upper lids) improved from 3.07 ± 0.21 to 0.79 ± 0.19 on Day 28; the change was statistically significant for both upper and lower lids from Day 14 on. Mean mite density per lash decreased from 2.28 ± 0.16 at baseline to 0.14 ± 0.05 at Day 28 (p < 0.0001). Mite eradication (0 mites) was documented in 57.1% of eyes. The effects were durable through Day 90. There were no adverse events and little to no change in CDVA or IOP. The drop was well tolerated, with no discontinuations due to ocular irritation. CONCLUSION: Topical lotilaner ophthalmic solution, 0.25% for 4 weeks, showed promising efficacy for the treatment of Demodex blepharitis. This novel treatment appears to be safe and well tolerated. Randomized controlled studies are needed to confirm the results.

Screening Diabetic Retinopathy Using an Automated Retinal Image Analysis System in Independent and Assistive Use Cases in Mexico: Randomized Controlled Trial.

BACKGROUND: The automated screening of patients at risk of developing diabetic retinopathy represents an opportunity to improve their midterm outcome and lower the public expenditure associated with direct and indirect costs of common sight-threatening complications of diabetes. OBJECTIVE: This study aimed to develop and evaluate the performance of an automated deep learning-based system to classify retinal fundus images as referable and nonreferable diabetic retinopathy cases, from international and Mexican patients. In particular, we aimed to evaluate the performance of the automated retina image analysis (ARIA) system under an independent scheme (ie, only ARIA screening) and 2 assistive schemes (ie, hybrid ARIA plus ophthalmologist screening), using a web-based platform for remote image analysis to determine and compare the sensibility and specificity of the 3 schemes. METHODS: A randomized controlled experiment was performed where 17 ophthalmologists were asked to classify a series of retinal fundus images under 3 different conditions. The conditions were to (1) screen the fundus image by themselves (solo); (2) screen the fundus image after exposure to the retina image classification of the ARIA system (ARIA answer); and (3) screen the fundus image after exposure to the classification of the ARIA system, as well as its level of confidence and an attention map highlighting the most important areas of interest in the image according to the ARIA system (ARIA explanation). The ophthalmologists' classification in each condition and the result from the ARIA system were compared against a gold standard generated by consulting and aggregating the opinion of 3 retina specialists for each fundus image. RESULTS: The ARIA system was able to classify referable vs nonreferable cases with an area under the receiver operating characteristic curve of 98%, a sensitivity of 95.1%, and a specificity of 91.5% for international patient cases. There was an area under the receiver operating characteristic curve of 98.3%, a sensitivity of 95.2%, and a specificity of 90% for Mexican patient cases. The ARIA system performance was more successful than the average performance of the 17 ophthalmologists enrolled in the study. Additionally, the results suggest that the ARIA system can be useful as an assistive tool, as sensitivity was significantly higher in the experimental condition where ophthalmologists were exposed to the ARIA system's answer prior to their own classification (93.3%), compared with the sensitivity of the condition where participants assessed the images independently (87.3%; P=.05). CONCLUSIONS: These results demonstrate that both independent and assistive use cases of the ARIA system present, for Latin American countries such as Mexico, a substantial opportunity toward expanding the monitoring capacity for the early detection of diabetes-related blindness.

Collarette Elimination and Demodex Mite Eradication with Topical Lotilaner Ophthalmic Solution, 0.25.

Purpose: To evaluate the efficacy of topical lotilaner ophthalmic solution, 0.25%, in patients with Demodex blepharitis. Methods: Eighteen adults with Demodex blepharitis, defined as >10 collarettes on the upper lid and/or mite density of ≥1.5 mites per lash (upper and lower), were treated bid for 42 days with the topical lotilaner ophthalmic solution, 0.25%. Contact lens wear, artificial eyelashes, and lid structural abnormalities were among the exclusion criteria. No other antibacterial, antiparasitic, or anti-inflammatory treatment or lid hygiene products were permitted. One eye of each patient was selected for analysis and assessed on day 7, 14, 28, and 42. Collarettes were graded at each visit, and mite density was evaluated by microscopy at each visit except day 7. Outcome measures were collarette elimination (≤2 lashes with collarettes) and mite eradication (0 mites). Drop tolerability, adverse events, visual acuity, and slit-lamp biomicroscopy were assessed. Results: Collarette elimination was achieved in 13/18 participants (72.2%) by day 42. Mean collarette grade (upper lid) declined from 3.56 ± 0.17 to 0.28 ± 0.11. Mite eradication was achieved in 14/18 participants (77.8%) by day 42. Mean mite density decreased from 2.63 ± 0.39 to 0.12 ± 0.08 mites/lash. Participants reported good tolerability. Adverse events were mild and transient and did not result in treatment discontinuation. Conclusion: Six weeks of at-home topical therapy with the lotilaner ophthalmic solution, 0.25%, was effective in eliminating the most common objective signs of Demodex blepharitis, with a collarette elimination rate of 72% and mite eradication in 78% of eyes by day 42. ISRCTN registration #: 24398865.

Safety and Efficacy of Intravitreal Risuteganib for Non-Exudative AMD: A Multicenter, Phase 2a, Randomized, Clinical Trial.

BACKGROUND AND OBJECTIVE: To evaluate the safety and efficacy of 1.0 mg risuteganib in subjects with nonexudative age-related macular degeneration (AMD). PATIENTS AND METHODS: This was a phase 2a, prospective, double-masked, sham-controlled study. Eyes with nonexudative (dry) AMD and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/40 and 20/200 were included. Subjects were randomized to intravitreal 1.0 mg risuteganib or sham injection. At Week 16, subjects in the risuteganib group received a second 1.0-mg dose and the sham group crossed over to receive a dose of 1.0 mg risuteganib and were evaluated at Week 28. The primary endpoint was proportion of subjects with 8 letters ETDRS or more BCVA gain from baseline to Week 28 in the risuteganib group versus baseline to Week 12 for the sham group. BCVA was tested and subjects were observed for adverse events (AEs) every 4 weeks until completion of the study at 32 weeks. RESULTS: Forty-five subjects (risuteganib, n = 29; sham, n = 16) were enrolled in the study, of whom 39 (risuteganib, n = 25; sham, n = 14) completed the study and were included in the per protocol efficacy analysis. At baseline, mean age was 78.8 and 75.9 years and mean BCVA was 67.1 and 64.4 letters in the sham and risuteganib groups, respectively. The primary endpoint was met by 48% of the risuteganib group at Week 28 and 7% of the sham group at Week 12 (P = .013). Of the risuteganib subjects, 20% gained 15 letters or more at Week 28, whereas no patients in the sham group at Week 12 achieved this visual acuity gain. The only ocular treatment-related treatment-emergent AE was vitreous floaters, which spontaneously recovered without sequelae. No drug-related serious AE was reported. CONCLUSIONS: Risuteganib demonstrated significant BCVA improvement in patients with non-exudative AMD. No drug-related AEs were seen during a 32-week observation period. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:327-335.].

Fundus autofluorescence in premature infants.

To describe fundus autofluorescence (FAF) patterns in premature infants and to determine whether FAF increases gradually with increasing post-gestational age. This was a cross-sectional, observational and descriptive case series. FAF images were obtained from patients screened for Retinopathy of Prematurity. The presence of the following hypo-autofluorescence areas/structures was graded and ranked: macular pigment (foveal centre), optic nerve head, peripapillary vessels/vascular arcade (PP/VA), and equatorial vessels (EqV). Ranks were attributed to the number of structures visualized from the posterior pole towards the periphery. The rank of FAF could then be analysed by Spearman's correlation against age. Additionally, patients were divided by age into group 1 (< 40 weeks of corrected gestational age (WCGA)) and group 2 (> 40 WCGA). Differences between groups were tested with the Mann-Whitney U test. Thirteen patients were analysed. The mean WCGA at examination was 47.85 weeks. Spearman's correlation showed a strong positive correlation (r = 0.714) (P = 0.006) of FAF and WCGA. The Mann-Whitney U test revealed that the PP/VA and EqV were significantly more visible at > 40 WCGA than at < 40 WCGA (8.0 [P = 0.016] and 7.5 [P = 0.03], respectively). Patterns of FAF are described for the first time in premature infants. FAF increases gradually with age and centrifugally from the posterior pole towards the equator in premature infants.

Short-term Evaluation of Negative Pressure Applied by the Multi-Pressure Dial System to Lower Nocturnal IOP: A Prospective, Controlled, Intra-subject Study.

INTRODUCTION: The purpose of this study was to investigate the short-term safety and feasibility of negative pressure application by the Multi-Pressure Dial (MPD) System to lower nocturnal intraocular pressure (IOP) in subjects with open-angle glaucoma (OAG). METHODS: A prospective, controlled, intra-subject study of 22 eyes from 11 subjects at a single site was performed. All subjects had a history of OAG and were currently using a topical prostaglandin. For each subject, the eye with the highest IOP in the supine position was selected as the treatment eye (TE) and the contralateral eye served as the control eye (CE). The negative pressure for the TE was set to 60% of the baseline IOP value with no negative pressure in the CE. IOP measurements were collected at three prespecified time points overnight in the supine position with active negative pressure. The primary outcome measure was mean IOP with the application of negative pressure. RESULTS: At the three overnight time points, the mean (± standard deviation) baseline IOP prior to negative pressure application was 22.2 ± 2.5 mmHg in the TE and 21.8 ± 2.5 mmHg in the CE. With the application of 60% negative pressure to the TE and no active negative pressure to the CE, the mean IOP was 14.2 ± 2.2 and 19.5 ± 2.4 mmHg, respectively. The mean percentage IOP reduction in the TE was 35% (p < 0.001). There were two minor adverse events, both unrelated to device wear, and there were no IOP spikes ≥ 10 mmHg. CONCLUSION: The MPD can safely and effectively lower nocturnal IOP in the supine position. The MPD holds promise as a potential new, non-invasive treatment option for the control of nocturnal IOP.

Abnormal N-Glycosylation of Human Lens Epithelial Cells in Type-2 Diabetes May Contribute to Cataract Progression.

PURPOSE: In order to better understand cataract development, we analyzed the glycosylation profile of human lens epithelial cells (HLECs) from anterior lens capsules of type 2 diabetes mellitus (T2DM) and non-diabetic (ND) patients undergoing routine cataract surgery. SETTING: Research Department of the Asociación para Evitar la Ceguera, Hospital "Dr. Luis Sánchez Bulnes", Mexico. DESIGN: Experimental study. METHODS: Evaluation of anterior lens capsules from T2DM and ND patients undergoing phacoemulsification and free from other ocular diseases. RESULTS: Hematoxylin-eosin staining revealed HLECs alterations in T2DM samples. From lectins with different sugar specificities used, concanavalin A showed significant differences, labeling homogeneously both in the cytoplasm and in cell membranes in ND capsules, while in T2DM capsules, in addition to membrane and cytoplasm labeling, there were perinuclear vesicles with high concanavalin A labeling. Two-dimensional gel electrophoresis showed that T2DM patients have a ~65-kDa spot with an isoelectric point of 5.5 with a higher density compared to ND capsules, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed 62% homology with type-1 cytokeratin. Immunohistochemistry using anti-pan cytokeratin antibody revealed co-localization with concanavalin A, and a lectin blot revealed with concanavalin A showed a band of ~65 kDa, a molecular weight that corresponds to human type 1 cytokeratin. CONCLUSION: These results suggest that over-expression of N-glycosidically linked human type 1 cytokeratin may induce capsule disruption and affect selective permeability, allowing the entry of different molecules to the lens that facilitate cataract progression.

Intravitreal quantum dots for retinitis pigmentosa: a first-in-human safety study.

Background: Studies indicate that electrical stimulation of retinitis pigmentosa (RP) retina is beneficial. Quantum dots (QDs) can convert light to electrical stimulus and therefore may have therapeutic potential for RP. Methods: This was an open-label, fellow eye-controlled, first-in-human safety study. Five adults with end-stage (arm A) and 15 with severe (arm B) RP received one or two intravitreal injections of 0.2 or 2µM cadmium/selenium 655 Alt QDs. Results: No adverse events were attributed to QDs. In arm A, median best corrected visual acuity was unchanged. In arm B, mean best corrected visual acuity improved from 6/398 to 6/177, versus 6/147 to 6/144 in the fellow eye. Conclusion: Intravitreal QDs can be safely administered to patients with RP. Vision appears to benefit and further validating studies are justified.

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.

Complement Activation in the Vitreous of Patients With Proliferative Diabetic Retinopathy.

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.

Oculocardiac Reflex During Intravitreal Injection.

Oculocardiac reflex (OCR) has been described to occur with mechanical manipulation of the eye, eyelids or orbit. There are no reports in the literature of OCR during intravitreal injection (IVI). This may be due to the fact that heart rate is not monitored during the procedure. We aimed to evaluate OCR during IVI. A total of 532 patients were enrolled in the study at Asociacion para Evitar la Ceguera en Mexico. Mexico City, Mexico. IVI was performed on one eye in every patient with diabetic retinopathy (DR), age related macular degeneration (AMD) or choroidal neovascularization (CNV) secondary to pathological myopia. Heart rate was monitored with a pulse oximeter before, during and after injection. OCR was defined as a 20% decrease or more of basal heart rate. The population enrolled included 270 females and 262 males with mean age of 63.8 years. A decrease in heart rate of 20% or more occurred in 18 patients during IVI (3.3%; 95% confidence interval 1.85% and 4.92%). OCR was asymptomatic in these patients. OCR occurred in 3.3% of our patients during IVI. Hence, OCR must be considered when performing IVI.

Interplay between Oxidative Stress, Inflammation, and Amyloidosis in the Anterior Segment of the Eye; Its Pathological Implications.

There are different pathologies associated with amyloidogenic processes caused by the increase of reactive oxygen species (ROS) and the overactivation of inflammatory responses. These alterations are present in different regions of the anterior segment of the eye, and they have been associated with the development and progression of ocular pathologies, such as glaucoma, dry eye syndrome, keratitis, and cataracts among other pathologies. Aim. To discuss briefly the anatomical characteristics of the anterior segment of the eye and describe the interaction between oxidative stress (OS) and inflammatory responses, emphasizing the misfolding of several proteins leading to amyloidogenic processes occurring in the anterior segment and their implications in the development of ocular diseases. We performed a search on PubMed, CINAHL, and Embase using the MeSH terms "eye," "anterior segment", "inflammation", "oxidative stress", and "amyloidosis". The search encompassed manuscripts published up to April 2019. A hundred forty-four published studies met the inclusion criteria. We present the current knowledge regarding the interaction between OS and the activation of inflammatory processes and how both can cause conformational changes in several peptides and proteins in each compartment of the anterior segment. However, we found that there is no consensus about which factor is the first to cause amyloidosis. Our conclusions suggest that there is an interplay among these factors forming a vicious cycle that leads to the loss of protein structure in ocular pathologies, and multifactorial therapies should be developed to avoid protein misfolding and to stop the progression of ocular pathologies.

A Teleophthalmology Support System Based on the Visibility of Retinal Elements Using the CNNs.

This paper proposes a teleophthalmology support system in which we use algorithms of object detection and semantic segmentation, such as faster region-based CNN (FR-CNN) and SegNet, based on several CNN architectures such as: Vgg16, MobileNet, AlexNet, etc. These are used to segment and analyze the principal anatomical elements, such as optic disc (OD), region of interest (ROI) composed by the macular region, real retinal region, and vessels. Unlike the conventional retinal image quality assessment system, the proposed system provides some possible reasons about the low-quality image to support the operator of an ophthalmoscope and patient to acquire and transmit a better-quality image to central eye hospital for its diagnosis. The proposed system consists of four steps: OD detection, OD quality analysis, obstruction detection of the region of interest (ROI), and vessel segmentation. For the OD detection, artefacts and vessel segmentation, the FR-CNN and SegNet are used, while for the OD quality analysis, we use transfer learning. The proposed system provides accuracies of 0.93 for the OD detection, 0.86 for OD image quality, 1.0 for artefact detection, and 0.98 for vessel segmentation. As the global performance metric, the kappa-based agreement score between ophthalmologist and the proposed system is calculated, which is higher than the score between ophthalmologist and general practitioner.