Translational Vision Science & Technology最新文献

Purpose: The purpose of this study was to introduce SLOctolyzer: an open-source analysis toolkit for en face retinal vessels in infrared reflectance scanning laser ophthalmoscopy (SLO) images.

Methods: SLOctolyzer includes two main modules: segmentation and measurement. The segmentation module uses deep learning methods to delineate retinal anatomy, and detects the fovea and optic disc, whereas the measurement module quantifies the complexity, density, tortuosity, and caliber of the segmented retinal vessels. We evaluated the segmentation module using unseen data and measured its reproducibility.

Results: SLOctolyzer's segmentation module performed well against unseen internal test data (Dice for all-vessels = 0.91; arteries = 0.84; veins = 0.85; optic disc = 0.94; and fovea = 0.88). External validation against severe retinal pathology showed decreased performance (Dice for arteries = 0.72; veins = 0.75; and optic disc = 0.90). SLOctolyzer had good reproducibility (mean difference for fractal dimension = -0.001; density = -0.0003; caliber = -0.32 microns; and tortuosity density = 0.001). SLOctolyzer can process a 768 × 768 pixel macula-centered SLO image in under 20 seconds and a disc-centered SLO image in under 30 seconds using a laptop CPU.

Conclusions: To our knowledge, SLOctolyzer is the first open-source tool to convert raw SLO images into reproducible and clinically meaningful retinal vascular parameters. It requires no specialist knowledge or proprietary software, and allows manual correction of segmentations and re-computing of vascular metrics. SLOctolyzer is freely available at https://github.com/jaburke166/SLOctolyzer.

Translational relevance: SLO images are captured simultaneous to optical coherence tomography (OCT), and we believe SLOctolyzer will be useful for extracting retinal vascular measurements from large OCT image sets and linking them to ocular or systemic diseases.

Purpose: To evaluate the ocular distribution of omidenepag isopropyl (OMDI) and its active form omidenepag (OMD), an EP2 receptor agonist, after topical administration of OMDI into rabbit and monkey eyes, and to determine whether OMDI and OMD interact with target receptors or enzymes of other antiglaucoma agents.

Methods: Both eyes of six rabbits and of 14 monkeys were topically instilled with 0.03% [14C]-OMDI. Rabbits were sacrificed after one to four hours, and ocular tissues were collected. Monkeys were sacrificed after 0.25 to 24 hours, and blood and ocular tissues were collected. Radioactivity was measured in each sample. The interactions of OMDI and OMD with the receptors and enzymes associated with the mechanisms of action of other antiglaucoma agents were evaluated.

Results: Most radioactivity applied to rabbit eyes was recovered as OMD from the cornea, aqueous humor, and iris-ciliary body. Similarly, high concentrations of radioactivity were observed in monkey cornea, bulbar/palpebral conjunctiva, and trabecular meshwork. OMD bound to EP2 receptors, but neither OMD nor OMDI bound to α2A, β1, and β2 adrenergic receptors or inhibited enzymatic activities of CA1 and CA2. OMD and OMDI had little or no effect on ROCK1 and ROCK2.

Conclusions: OMDI rapidly permeates rabbit and monkey corneas and is converted to OMD, which distributes into anterior ocular tissues. Neither OMD nor OMDI interacted with the target receptors or enzymes of other antiglaucoma agents, suggesting that OMD interacts highly selectively with EP2 receptors.

Translational relevance: OMDI is a specific antiglaucoma agent that interacts selectively with ocular EP2 receptors.

Purpose: This study aimed to investigate the causal effect of plasma proteins on diabetic retinopathy (DR) risk and identify potential drug targets for this disease.

Methods: Two-sample Mendelian randomization was performed to explore potential drug targets for DR. A total of 734 proteins were selected as instrumental variables. The Steiger filtering test and colocalization analysis were conducted to determine the causal direction and genetic pleiotropy. Plasma proteins from the decode study were used to validate the findings.

Results: Eleven plasma proteins were associated with DR risk. Genetically predicted high levels of CCL3L1 (odds ratio [OR] = 0.582; 95% confidence interval [CI], 0.343-0.986; P = 0.044), PAM (OR = 0.782; 95% CI, 0.652-0.937; P = 0.008), GP1BA (OR = 0.793; 95% CI, 0.632-0.994; P = 0.044), GALNT16 (OR = 0.832; 95% CI, 0.727-0.952; P = 0.008), POGLUT1 (OR = 0.836; 95% CI = 0.703-0.995; P = 0.043), and DKK3 (OR = 0.859; 95% CI, 0.777-0.950; P = 0.003) have the protective effect on DR risk. Genetically predicted high levels of GFRA2 (OR = 1.104; 95% CI, 1.028-1.187; P = 0.007), PATE4 (OR = 1.405; 95% CI, 1.060-1.860; P = 0.018), GSTA1 (OR = 1.464; 95% CI, 1.163-1.842; P = 0.001), SIRPG (OR = 1.600, 95% CI, 1.244-2.057; P = 2.51E-04), and MAPK13 (OR = 1.731; 95% CI, 1.233-2.431; P = 0.002) were associated with an increased risk of DR. However, the colocalization analysis results suggested that SIRPG and GP1BA have a shared causal variant with DR.

Conclusions: CCL3L1, PAM, GALNT16, POGLUT1, DKK3, GFRA2, PATE4, GSTA1, and MAPK13 were associated with DR risk and were identified as potential drug targets for DR.

Translational relevance: The present study has highlighted the role of CCL3L1, PAM, GALNT16, POGLUT1, DKK3, GFRA2, PATE4, GSTA1, and MAPK13 in the development of DR.

Purpose: To examine whether time of year (relative to hibernation emergence) influences the retinal degenerative effects of intravitreal injection of adenosine triphosphate (ATP) in the 13-lined ground squirrel (13-LGS).

Methods: Eighteen (9 male, 9 female) 13-LGS in three experimental cohorts (early season, mid-season, late season) (n = 6 each) underwent baseline imaging using scanning light ophthalmoscopy (SLO) and optical coherence tomography (OCT). Animals then received a 10-µL intravitreal injection of 0.723 M ATP, followed by OCT and SLO imaging at 3, 10, and 21 days. Adaptive optics SLO (AOSLO) was performed in animals without retinal damage after the 21-day follow-up. Retinal thickness, choroidal thickness, and cone density measures were compared to values from wild-type controls (n = 12).

Results: Five animals (four early season, one late season) showed retinal damage post-ATP injection (Fisher's exact test, P = 0.065). Animals with retinal damage displayed areas of disrupted retinal lamination on OCT. Any changes in OCT thickness were generally present on initial follow-up and resolved at later time points. Follow-up imaging with AOSLO on animals without retinal damage showed no significant differences in the cone mosaic topography from control eyes. Axial length was increased in mid-/late-season cohorts relative to early season (P = 0.0025 and P = 0.0007).

Conclusions: In this pilot study, the 13-LGS appears more susceptible to ATP-induced retinal damage during the early season. Future studies adjusting dose based on ocular biometry may help elucidate the impact of time of year on chemical response.

Translational relevance: Consideration of ocular biometry in this and other animal models is merited when using intravitreal methods of chemical administration.

Purpose: Lifestyle risk factors are implicated in driving the current surge in myopia prevalence yet, paradoxically, known risk factors explain little of the variation in refractive error in the population. Here, we applied "instrumental variable" (IV) methods designed to avoid reverse causation and decrease confounding bias, to gauge lifestyle risk factor effect sizes.

Methods: Three myopia risk factors (time outdoors, time reading, and sleep duration) were assessed in participants of the Avon Longitudinal Study of Parents and Children: a cross-sectional sample of 2302 children aged 15 years old and a longitudinal sample of 3086 children followed from age 7 to 15 years. Seven IVs were considered jointly: dog ownership, cat ownership, bedtime variability, birth order, and polygenic scores quantifying genetic predisposition to spend additional time outdoors, years in fulltime education, and time asleep overnight.

Results: Risk factor effect sizes were 4-fold to 9-fold higher in the IV analyses compared with conventional regression analyses. In IV analyses, one extra hour spent outdoors every day during childhood was associated with a shift toward hyperopia of +0.53 to +0.94 diopters (D), whereas 1 extra hour spent reading every day was associated with a shift toward myopia of -0.44 to -0.88 D. There was inconsistent evidence that sleep duration influenced refractive error.

Conclusions: Myopia risk factor effects were underestimated up to 9-fold in conventional analyses in this sample, compared with IV analyses.

Translational relevance: We speculate that the effects of lifestyle risk factors for myopia have been underestimated in past studies.

Purpose: To test on humans an eye tracker based on the use of a contact lens with active infrared sources and to evaluate whether this system can track the eye behind the eyelid.

Methods: The system is made up of a scleral contact lens embedding two vertical cavity self-emitting lasers (VCSELs) remotely driven by eyewear comprised of electronics and cameras. Tests on humans were carried out on five subjects to assess performance and to determine whether the VCSEL spot could be detected behind the eyelid.

Results: The lens was worn and used without difficulty. The device allowed accurate tracking of the eye (0.83° ± 0.59°), and the VCSELs can be detected behind closed eyelids.

Conclusions: These results confirm those previously obtained in terms of tracking and demonstrate that the device can be used safely to monitor eye movements even when the eyelids are closed.

Translational relevance: The VCSELs could be useful for a variety of applications to reduce data missed due to blinks, particularly with regard to interactive systems, fundamental studies on closed eye movements, or finding ways to improve clinical diagnostic precision for disorders of consciousness.

Purpose: To characterize faricimab ocular and systemic pharmacokinetics (PK) in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) and to assess the effect of faricimab ocular exposure on clinical endpoints.

Methods: A population PK (popPK) model was developed using pooled data from phase 1 to 3 studies in patients with nAMD/DME. The dataset included 1095 faricimab aqueous humor (AH) concentrations from 284 patients and 8372 faricimab plasma concentrations from 2246 patients.

Results: Following intravitreal administration, faricimab PK was accurately described by a linear three-compartment model with sequential vitreous humor (VH), AH, and plasma compartments. Faricimab VH elimination to AH is the slowest process, with an estimated half-life (t1/2) of 7.5 days. Due to flip-flop kinetics, plasma, AH, and VH concentrations declined in parallel. Disease had no effect on faricimab PK. Plasma exposure was ∼6000-fold lower than VH exposure. Age, anti-drug antibodies, body weight, and sex statistically significantly influenced PK parameters but had no clinically meaningful effect on ocular and systemic exposure. VH t1/2 alone could not explain faricimab dosing frequency. Exposure-response analyses showed similar gains in best-corrected visual acuity across faricimab exposure ranges and dosing regimens.

Conclusions: Faricimab ocular and systemic pharmacokinetics were quantified and accurately described by the popPK model, developed using a large dataset from patients with nAMD/DME. Exposure-response analyses suggest that faricimab phase 3 dosing algorithms are appropriate to select the most suitable dosing regimen.

Translational relevance: The popPK analysis suggested that faricimab dosing frequency was influenced by several factors and not by VH t1/2 alone.

Purpose: Retinal ganglion cell (RGC) apoptosis and axon regeneration are the principal obstacles challenging the development of successful whole eye transplantation (WET). The purpose of this study was to create a neuroprotective cocktail that targets early events in the RGC intrinsic apoptotic program to stabilize RGCs in a potential donor eye.

Methods: University of Wisconsin (UW) solution was augmented with supplements known to protect RGCs. Supplements targeted tyrosine kinase signaling, histone deacetylase activity, K+ ion efflux, macroglial stasis, and provided energy support. Modified UW (mUW) solutions with individual supplements were injected into the vitreous of enucleated mouse eyes, which were then stored in cold UW solution for 24 hours. Histopathology, immunostaining of individual retinal cell types, and analysis of cell-specific messenger RNAs (mRNAs) were used to identify supplements that were combined to create optimal mUW solution.

Results: UW and mUW solutions reduced ocular edema and focal ischemia in globes stored in cold storage. Two major issues were noted after cold storage, including retinal detachment and reduction in glial fibrillary acidic protein staining in astrocytes. A combination of supplements resolved both these issues and performed better than the individual supplements alone. Cold storage resulted in a reduction in cell-specific mRNAs, even though it preserved the corresponding protein products.

Conclusions: Eyes treated with optimal mUW solution exhibited preservation of retinal and cellular architecture, but did display a decrease in mRNA levels, suggesting that cold storage induced cellular stasis.

Translational relevance: Application of optimal mUW solution lowers an important barrier to the development of a successful whole eye transplantation procedure.

Purpose: To assess whether the Humphrey Visual Field Analyzer (HFA) and the Macular Integrity Assessment instrument (MAIA) provide equivalent estimates of visual deficit size, severity, and progression in cortically blinded participants.

Methods: Reliable, monocular 10-2 HFA and MAIA fields were collected at baseline, and after a blind-field training intervention (n = 54) or no intervention (n = 6) in adult participants with occipital strokes. Binocular HFA and MAIA mean sensitivities (MS) were first computed, before creating binocular maps of visual sensitivity for each perimetry system to calculate deficit areas, using a unitary, published, less than 10 dB criterion to define blindness. We contrasted HFA/MAIA MS and deficit area at individual study visits, together with change in these measures between visits.

Results: At individual visits, MS and deficit areas were well-correlated, but there were systematic differences between machines, greater for the intact than impaired hemifields, with the MAIA overestimating areas of visual deficit relative to the HFA. Between visits, the two perimeters' assessment of change in MS was correlated, but change in the deficit area was not, despite good test reliability.

Conclusions: Reliable HFA and MAIA tests produce well-correlated but systematically offset estimates of visual sensitivity and deficit area in patients with homonymous field defects, which can impact assessment of progression.

Translational relevance: Cortically blinded patients exhibited comparable changes in sensitivity (spontaneous and training induced) when assessed using Humphrey and fundus-controlled MAIA perimetry. However, the photopic vs. mesopic nature of these tests impacted participant performance and suggests that custom, machine-specific criteria are needed to comparably define blindness on both systems.

Purpose: This study aimed to develop an algorithm for automated detection of drusenoid pigment epithelial detachments (DPEDs) in optical coherence tomography (OCT) volumes of patients with age-related macular degeneration (AMD) and to compare its performance against traditional reading center grading on color-fundus photographs (CFPs).

Methods: Eyes with a range of AMD severities, excluding neovascular disease, were imaged using spectral-domain OCT (SD-OCT) and paired CFPs and were followed annually for up to 5 years. DPEDs were automatically identified by segmenting the retinal pigment epithelium (RPE) and Bruch's membrane (BM) layers from the SD-OCT volumes and imposing both a minimum RPE BM height (>75 µm) and a two-dimensional length requirement (>433 µm). Comparisons in detection rates and contoured areas were made between the algorithmic SD-OCT detections and manually graded and contoured CFPs.

Results: Of the 1602 visits for the 323 eyes, the automated OCT algorithm identified 139 visits (8.7%) from 50 eyes with DPED, but a reading center review of paired CFPs identified 23 visits (1.4%) from nine eyes as having DPEDs. Eyes identified with DPEDs on OCT received nine-step AMD severity scores ranging from 6 to 10, and those scores had occurrence ratios of 23/160 (14%), 89/226 (39%), 24/99 (24%), 2/63 (3%), and 1/29 (3%), respectively. On a subset of 25 visits that also underwent manual contouring of DPED lesions in CFP, the Pearson correlation coefficient for DPED areas observed by OCT and CFP was 0.85.

Conclusions: Our analysis shows the feasibility of using OCT scans to objectively detect features that historically have been detected qualitatively by expert graders on CFPs.

Translational relevance: Automated detection and quantitation of high-risk features can facilitate screening patients for clinical-trial enrollment and could serve as an outcome metric [T1 (Translation-to-Humans) and T4 (Translation-to-Population-Health)].