OCT Angiography Artifacts in Glaucoma.

PURPOSE: To determine the prevalence of different types of artifacts seen in OCT angiography (OCTA) images of healthy and glaucoma eyes and evaluate the characteristics associated with poor-quality images. DESIGN: Retrospective study. PARTICIPANTS: A total of 649 eyes of 368 healthy, glaucoma suspect, and glaucoma patients. METHODS: Angiovue (Optovue Inc) high-density (HD) and non-HD optic nerve head and macula OCTA images of participants were evaluated by 4 expert reviewers for the presence of different artifacts, including eye movement, defocus, shadow, decentration, segmentation error, blink, and Z offset in the superficial vascular layer. Each OCTA scan was designated to have good or poor quality based on the presence of artifacts. The association of demographic and ocular characteristics with the likelihood of obtaining poor-quality OCTA images was evaluated. MAIN OUTCOME MEASURES: The prevalence of OCTA artifacts and the factors associated with increased likelihood of capturing poor-quality OCTA images. RESULTS: A total of 5263 OCTA images were evaluated. Overall, 33.9% of the OCTA images had poor quality. The majority of images with acceptable quality scores (QS ≥ 4) had no artifacts (76.6%). Other images had 1 (13.6%) or 2 or more artifacts (9.8%). Older age (P < 0.001), male gender (P = 0.045), worse visual field mean deviation (P < 0.001), absence of eye tracking (P < 0.001), and macular scan area (P < 0.001) were associated with a higher likelihood of obtaining poor-quality images. In images with acceptable QS, the commercially available quality measures including QS and signal strength index had the area under the receiver operating characteristic curves of 0.65 (95% confidence interval [CI], 0.62-0.69) and 0.70 (95% CI, 0.68-0.73) to detect good-quality images, respectively. CONCLUSIONS: OCTA artifacts associated with poor-quality images are frequent, and their prevalence is affected by ocular and patient characteristics. One should not rely solely on the quantitative assessments that are provided automatically by OCTA instruments. A systematic scan review should be conducted to ensure appropriate interpretation of OCTA images. Given the high prevalence of poor-quality OCTA images, the images should be reacquired whenever an apparent and correctable artifact is present on a captured image.

Ganglion Cell Complex Thickness and Macular Vessel Density Loss in Primary Open-Angle Glaucoma.

PURPOSE: To characterize the change rate of ganglion cell complex (GCC) thickness and macular vessel density in healthy, preperimetric glaucoma and primary open-angle glaucoma (POAG) eyes. DESIGN: Prospective, longitudinal study. PARTICIPANTS: One hundred thirty-nine eyes (23 healthy eyes, 36 preperimetric glaucoma eyes, and 80 POAG eyes) of 94 patients who had at least 3 visits were included from the Diagnostic Innovations in Glaucoma Study. The mean follow-up was 2.0 years for healthy eyes, 2.6 years for preperimetric glaucoma eyes, and 2.6 years for POAG eyes. METHODS: OCT angiography (OCTA)-based vessel density and OCT-based structural thickness of the same 3×3-mm2 GCC scan slab were evaluated. The dynamic range-based normalized rates of vessel density and thickness change were calculated and compared within each diagnostic group. The association between the rates of thickness and vessel density change and potential factors were evaluated. MAIN OUTCOME MEASURES: The rates of GCC thinning and macular vessel density loss. RESULTS: Significant rates of GCC thinning and macular vessel density decrease were detectable in all diagnostic groups (all P < 0.05). In healthy eyes and preperimetric glaucoma eyes, the normalized rates of GCC thinning and macular vessel density decrease were comparable (all P > 0.1). In contrast, the normalized rate (mean, 95% confidence interval) of macular vessel density decrease in the POAG eyes (-7.12 [-8.36, -5.88]%/year) was significantly faster than GCC thinning (-2.13 [-3.35, -0.90]%/year; P < 0.001). In the POAG group, more than two thirds of the eyes showed faster macular vessel density decrease than GCC thinning; faster macular vessel density decrease rate was associated significantly with worse glaucoma severity (P = 0.037). The association between GCC thinning rate and glaucoma severity was not significant (P = 0.586). Intraocular pressure during follow-up significantly affected the rate of GCC thinning in all groups (all P < 0.05) but showed no association with the rate of macular vessel density decrease. CONCLUSIONS: Both GCC thinning and macular vessel density decrease were detectable over time in all diagnostic groups. In POAG eyes, macular vessel density decrease was faster than GCC thinning and was associated with severity of disease. Macular vessel density is useful for evaluating glaucoma progression, particularly in more advanced disease.

Measurement Floors and Dynamic Ranges of OCT and OCT Angiography in Glaucoma.

PURPOSE: To determine if OCT angiography (OCTA)-derived vessel density measurements can extend the available dynamic range for detecting glaucoma compared with spectral-domain (SD) OCT-derived thickness measurements. DESIGN: Observational, cross-sectional study. PARTICIPANTS: A total of 509 eyes from 38 healthy participants, 63 glaucoma suspects, and 193 glaucoma patients enrolled in the Diagnostic Innovations in Glaucoma Study. METHODS: Relative vessel density and tissue thickness measurement floors of perifoveal vessel density (pfVD), circumpapillary capillary density (cpCD), circumpapillary retinal nerve fiber (cpRNFL) thickness, ganglion cell complex (GCC) thickness, and visual field (VF) mean deviation (MD) were investigated and compared with a previously reported linear change point model (CPM) and locally weighted scatterplot smoothing curves. MAIN OUTCOME MEASURES: Estimated vessel density and tissue thickness measurement floors and corresponding dynamic ranges. RESULTS: Visual field MD ranged from -30.1 to 2.8 decibels (dB). No measurement floor was found for pfVD, which continued to decrease constantly until very advanced disease. A true floor (i.e., slope of approximately 0 after observed CPM change point) was detected for cpRNFL thickness only. The post-CPM estimated floors were 49.5±2.6 µm for cpRNFL thickness, 70.7±1.0 µm for GCC thickness, and 31.2±1.1% for cpCD. Perifoveal vessel density reached the post-CPM estimated floor later in the disease (VF MD, -25.8±3.8 dB) than cpCD (VF MD, -19.3±2.4 dB), cpRNFL thickness (VF MD, -17.5±3.3 dB), and GCC thickness (VF MD, -13.9±1.8 dB; P < 0.001). The number of available measurement steps from normal values to the CPM estimated floor was greatest for cpRNFL thickness (8.9), followed by GCC thickness (7.4), cpCD (4.5), and pfVD (3.8). CONCLUSIONS: In late-stage glaucoma, particularly when VF MD is worse than -14 dB, OCTA-measured pfVD is a promising tool for monitoring progression because it does not have a detectable measurement floor. However, the number of steps within the dynamic range of a parameter also needs to be considered. Although thickness parameters reached the floor earlier than OCTA-measured pfVD, there are more such steps with thickness than OCTA parameters.

Macular and Optic Nerve Head Vessel Density and Progressive Retinal Nerve Fiber Layer Loss in Glaucoma.

PURPOSE: To investigate prospectively the relationship between macular and peripapillary vessel density and progressive retinal nerve fiber layer (RNFL) loss in patients with mild to moderate primary open-angle glaucoma. DESIGN: Prospective, observational study. PARTICIPANTS: One hundred thirty-two eyes of 83 patients with glaucoma followed up for at least 2 years (average: 27.3±3.36 months). METHODS: Measurements of macular whole image vessel density (m-wiVD) and optic nerve head whole image vessel density (onh-wiVD) were acquired at baseline using OCT angiography. RNFL, minimum rim width (MRW), and ganglion cell plus inner plexiform layer (GCIPL) thickness were obtained semiannually using spectral-domain OCT. Random-effects models were used to investigate the relationship between baseline vessel density parameters and rates of RNFL loss after adjusting for the following confounding factors: baseline visual field mean deviation, MRW, GCIPL thickness, central corneal thickness (CCT), and mean intraocular pressure during follow-up and disc hemorrhage, with or without including baseline RNFL. MAIN OUTCOME MEASURES: Effects of m-wiVD and onh-wiVD on rates of RNFL loss over time. RESULTS: Average baseline RNFL thickness was 79.5±14.8 µm, which declined with a mean slope of -1.07 µm/year (95% confidence interval, -1.28 to -0.85). In the univariate model, including only a predictive factor and time and their interaction, each 1% lower m-wiVD and onh-wiVD was associated with a 0.11-µm/year (P < 0.001) and 0.06-µm/year (P = 0.031) faster rate of RNFL decline, respectively. A similar relationship between low m-wiVD and onh-wiVD and faster rates of RNFL loss was found using different multivariate models. The association between vessel density measurements and rate of RNFL loss was weak (r2 = 0.125 and r2 = 0.033 for m-wiVD and onh-wiVD, respectively). Average CCT also was a predictor for faster RNFL decline in both the univariate (0.11 µm/year; P < 0.001) and multivariate models. CONCLUSIONS: Lower baseline macular and optic nerve head (ONH) vessel density are associated with a faster rate of RNFL progression in mild to moderate glaucoma. Assessment of ONH and macular vessel density may add significant information to the evaluation of the risk of glaucoma progression and prediction of rates of disease worsening.

MicroRNA-188-5p regulates contribution of bone marrow-derived cells to choroidal neovascularization development by targeting MMP-2/13.

Our previous investigations have shown that bone marrow-derived cells (BMCs), including mesenchymal stem cells (MSCs), contribute to the development of choroidal neovascularization (CNV) as sources of cells and angiogenic factors. Two main steps for circulating BMCs to integrate into CNV lesions are extracellular matrix remodeling and consequential cell migration. MicroRNAs (miRNAs) were found to be involved in CNV development; however, little is known about whether miRNAs regulate the contribution of BMCs to CNV. In the present study, we found that the expression of miR-188-5p was decreased in cultured hypoxic MSCs and BMCs within laser-induced CNV in mice. Matrix metalloproteinase 2 (MMP-2) and MMP-13 were both discovered as targets of miR-188-5p by bioinformatics predictions and dual-luciferase reporter system. Accordingly, increased expression of MMP-2/13 was found in hypoxic MSCs and BMCs in CNV lesions. Furthermore, miR-188-5p mimic transfection caused downregulation of MMP-2/13 in hypoxic MSCs and decreased tube formation of co-cultured vascular endothelial cells. Intravitreal injections of a miR-188-5p agomir attenuated the severity of CNV and inhibited the migration of BMCs into CNV lesions in mice. Our study suggests that miR-188-5p regulates the contribution of BMCs to CNV development by targeting MMP-2/13-mediated extracellular matrix degeneration, and miR-188-5p serves as a therapeutic target to treat CNV-related diseases.

Animal Models of Proliferative Vitreoretinopathy and Their Use in Pharmaceutical Investigations.

Animal models are indispensable for pharmaceutical investigations. However, investigators often have difficulty choosing the appropriate modal for their research. To provide a comprehensive and convenient source of information about animal models of proliferative vitreoretinopathy (PVR), the current review sorted and analyzed representative animal models for pharmacotherapy of PVR since 1976.

Bone marrow-derived cells in ocular neovascularization: contribution and mechanisms.

Ocular neovascularization often leads to severe vision loss. The role of bone marrow-derived cells (BMCs) in the development of ocular neovascularization, and its significance, is increasingly being recognized. In this review, we discuss their contribution and the potential mechanisms that mediate the effect of BMCs on the progression of ocular neovascularization. The sequence of events by which BMCs participate in ocular neovascularization can be roughly divided into four phases, i.e., mobilization, migration, adhesion and differentiation. This process is delicately regulated and liable to be affected by multiple factors. Cytokines such as vascular endothelial growth factor, granulocyte colony-stimulating factor and erythropoietin are involved in the mobilization of BMCs. Studies have also demonstrated a key role of cytokines such as stromal cell-derived factor-1, tumor necrosis factor-α, as well as vascular endothelial growth factor, in regulating the migration of BMCs. The adhesion of BMCs is mainly regulated by vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and vascular endothelial cadherin. However, the mechanisms regulating the differentiation of BMCs are largely unknown at present. In addition, BMCs secrete cytokines that interact with the microenvironment of ocular neovascularization; their contribution to ocular neovascularization, especially choroidal neovascularization, can be aggravated by several risk factors. An extensive regulatory network is thought to modulate the role of BMCs in the development of ocular neovascularization. A comprehensive understanding of the involved mechanisms will help in the development of novel therapeutic strategies related to BMCs. In this review, we have limited the discussion to the recent progress in this field, especially the research conducted at our laboratory.

Macrophages promote vasculogenesis of retinal neovascularization in an oxygen-induced retinopathy model in mice.

To investigate the role of macrophages in oxygen-induced retinal neovascularization (NV) in mice, particularly the involvement of bone marrow-derived cells (BMCs) and the underlying mechanisms, BMCs from green fluorescent protein (GFP) transgenic mice were transplanted into postnatal day (P) 1 mice after irradiation. The mice were exposed to 75 % oxygen from P7 to P12 to initiate oxygen-induced retinopathy (OIR). The macrophages were depleted by injection of clodronate-liposomes (lip) intraperitoneally. The eyes were collected at P12 and P17. Retinal flatmounts and histopathological cross-sections were performed to analyze the severity of retinal NV and BMC recruitment. BMCs immunopositive for CD31 (PECAM-1; endothelial cell marker) and α-SMA (smooth muscle cell marker) antigens were detected using a confocal microscope. Expression of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) mRNA was detected by RT-PCR. The VEGF, SDF-1, CXCR4 and CD45 protein expression was detected by western blot examination. The retinal avascular area in OIR mice at P12 was unaffected after macrophage depletion carried out twice (38.27 ± 1.92 % reduction) using clodronate-lip. The retinal avascular area and the NV area at P17 were reduced after macrophage depletion four times (79.53 ± 1.02 % reduction); these findings were supported by retinal flatmounts and histopathological cross-sections. Macrophage depletion led to significant inhibition of BMC recruitment into the NV tufts at P17, with decreased expression of retinal VEGF, SDF-1, CXCR4 and CD45. The recruited BMCs differentiated primarily into CD31-positive endothelial cells (ECs) and α-SMA-positive smooth muscle cells (SMCs). This study suggested that macrophages promoted the vasculogenesis of retinal NV, particularly the contribution of BMCs in the mouse OIR model, which might be triggered by VEGF and SDF-1 production.

MicroRNA-195a-3p inhibits angiogenesis by targeting Mmp2 in murine mesenchymal stem cells.

MicroRNAs (miRNAs) modulate complex physiological and pathological processes, including the regulation of angiogenesis. Our previous study reported that bone marrow-derived mesenchymal stem cells (MSCs) are recruited into choroidal neovascularization lesions. miRNA-195 is highly expressed in MSCs, but its function remains unknown. In the present study, miR-195a-3p abundance was significantly decreased in hypoxia-treated murine MSCs; on the other hand, its overexpression reduced MSC proliferation and migration while increasing the activation of anti-angiogenic factor pigment epithelium-derived factor (PEDF). We further discovered that matrix metalloproteinase 2 (Mmp2) transcript is a target of miR-195a-3p, and that silencing Mmp2 phenocopied the reduced proliferation and migration of MSCs. The therapeutic potential of miR-195a-3p as an angiogenesis inhibitor was also demonstrated in a laser-induced choroidal neovascularization mouse model. These findings collectively indicate that miR-195a-3p is a negative modulator of angiogenesis, and could be used as an angiogenesis inhibitor. Mol. Reprod. Dev. 83: 413-423, 2016. © 2016 Wiley Periodicals, Inc.

The roles of nanocarriers on pigment epithelium-derived factor in the differentiation of human cardiac stem cells.

Over the past decade, adult stem cells have attracted great attention because of their ability to potentially regenerate desired tissues or entire organs. With the emergence of nanomaterial-based gene therapy, adult stem cells have been considered as a proper tool for the biomedical field. In this study, we utilized organically modified silica (ORMOSIL) nanoparticles to deliver small interfering RNA (siRNA) against pigment epithelium-derived factor (PEDF) and induce the differentiation of human cardiac stem cells (CSCs). We found that the down-regulation of PEDF can inhibit the proliferation of human CSCs and induce cell differentiation. To further study the mechanism, we have tested the Notch signalling pathway genes, Hes1 and Hes5, and found that their expressions were inhibited by the PEDF down-regulation. Furthermore, with the restoration of PEDF, both the proliferation of human CSCs and expressions of Hes1 and Hes5 were recovered. Our results suggest for the first time the use of ORMOSIL as nanocarriers for the delivery of PEDF siRNA in human CSCs, and demonstrated the cooperation between PEDF and the Notch signalling pathway in maintaining the self-renewal and pluripotency of stem cells. PEDF as the essential controller in differentiation may be a promising target for the regulation of cardiac homeostasis and damage repair, which opens new treatment strategies using nanomaterials for heart disease therapy.

Intravitreal controlled release of dexamethasone from engineered microparticles of porous silicon dioxide.

Dexamethasone is a glucocorticoid that is widely used in the ophthalmic arena. The recent FDA approved dexamethasone implant can provide a three month efficacy but with high rate of drug related cataract and high intraocular pressure (IOP). It seems that higher steroid in aqueous humor and around lens may be associated with these complications based on clinical fact that higher IOP was observed with intravitreal triamcinolone acetonide (TA) than with subtenon TA. We hypothesize that placing a sustained dexamethasone release system near back of the eye through a fine needle can maximize efficacy while mitigate higher rate of IOP rise and cataract. To develop a sustained intravitreal dexamethasone delivery system, porous silicon dioxide (pSiO2) microparticles were fabricated and functionalized with amines as well as carboxyl groups. Dexamethasone was conjugated to pSiO2 through the Steglich Esterification Reaction between hydroxyl of dexamethasone and carboxyl groups on the pSiO2. The drug loading was confirmed by Fourier transform infrared spectroscopy (FTIR) and loading efficiency was quantitated using thermogravimetric analysis (TGA). In vitro release was conducted for three months and dexamethasone was confirmed in the released samples using liquid chromatography-tandem mass spectrometry (LC/MS/MS). A pilot ocular safety and determination of vitreous drug level was performed in rabbit eyes. The drug loading study demonstrated that loading efficiency was from 5.96% to 10.77% depending on the loading reaction time, being higher with longer loading reaction time before reaching saturation around 7 days. In vitro drug release study revealed that dexamethasone release from pSiO2 particles was sustainable for over 90 days and was 80 days longer than free dexamethasone or infiltration-loaded pSiO2 particle formulation in the same setting. Pilot in vivo study demonstrated no sign of ocular adverse reaction in rabbit eyes following a single 3 mg intravitreal injection and free drug level at 2-week was 107.23 ± 10.54 ng/mL that is well above the therapeutic level but only around 20% level of dexamethasone released from OZURDEX(®) (dexamethasone intravitreal implant) in a rabbit eye model. In conclusion, dexamethasone is able to covalently load to the pSiO2 particles and provide sustained drug release for at least 3 months in vitro. Intravitreal injection of these particles were well tolerated in rabbit eyes and free drug level in vitreous at 2-week was well above the therapeutic level.

Hyperglycemia promotes vasculogenesis in choroidal neovascularization in diabetic mice by stimulating VEGF and SDF-1 expression in retinal pigment epithelial cells.

To investigate the influence of hyperglycemia on the severity of choroidal neovascularization (CNV) in diabetic mice, especially the involvement of bone marrow-derived cells (BMCs) and underlying molecular mechanisms. The mice were randomly divided into control group, diabetes group and diabetes treated with insulin group, which were laser treated to induce CNV. The CNV severity was evaluated by fundus fluorescein angiography, HE staining and choroidal flatmount. The BMCs recruitment and differentiation in CNV were examined in GFP chimeric mice by choroidal flatmount and immunofluorescence. The bone marrow-derived mesenchymal stem cells (BMSCs) recruitment and migration were tested in vivo and in vitro. VEGF and SDF-1 production in vivo and in vitro were tested by realtime PCR and ELISA. The CNV severity and expression of VEGF and SDF-1 were enhanced in DM mice compared with control mice and that insulin treatment decreased CNV severity in DM mice. The DM mice demonstrated more BMCs and bone marrow-derived mesenchymal stem cells (BMSCs) recruited and incorporated into CNV, increased ratio of BMCs expressing endothelial cell marker or macrophage marker, and up-regulated expression of VEGF and SDF-1 in CNV. Human BMSCs migration and expression of VEGF and SDF-1 in retinal pigment epithelial (RPE) cells increased when cultured under high glucose. This study suggested that hyperglycemia enhanced the expression of VEGF and SDF-1 in RPE cells, and promoted recruitment and incorporation of BMCs and affected differentiation of BMCs in CNV, which led to more severe CNV in diabetic mice.

Macular choroidal volume variations in highly myopic eyes with myopic traction maculopathy and choroidal neovascularization.

PURPOSE: To compare the choroidal volume (CV) between emmetropic and highly myopic eyes, and to assess if the presence of myopic fundus abnormalities, myopic traction maculopathy, or choroidal neovascularization affects the CV. METHODS: We retrospectively reviewed imaging studies of 98 eyes of 98 patients who underwent CV measurement on optical coherence tomography. We included 31 emmetropic eyes (Group 1), 36 highly myopic eyes without vitreoretinal or choroidal pathologies (Group 2), 21 highly myopic eyes with traction maculopathy (Group 3), and 10 highly myopic eyes with history of choroidal neovascularization (Group 3). Eyes with chorioretinal atrophy were excluded. Regression analysis was performed to evaluate the correlation between CV and multiple variables. RESULTS: Choroidal volume was lower in Group 2 than in Group 1 (P < 0.001), and in Groups 3 and 4 than in Group 2 (P < 0.001 and P = 0.002, respectively). Age (P = 0.002), axial length (P < 0.001), sex (P = 0.047), staphyloma (P < 0.001), and myopic group (P = 0.05) were independent predictors for the final CV (R = 0.645). In highly myopic eyes, CV decreased by 0.32 mm for every 10 years and by 0.49 mm per millimeter of axial length. CONCLUSION: Choroidal thinning is present in highly myopic eyes compared with emmetropic eyes, and is related to age, axial length, sex, and staphyloma. However, myopic eyes with coexisting myopic traction maculopathy or history of choroidal neovascularization have more severe thinning, likely leading to insufficient metabolic supplementation for the macula.

Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury.

AIMS: Mesenchymal stem cells (MSCs) can ameliorate myocardial infarction (MI) injury. However, older-donor MSCs seem less efficacious than those from younger donors, and the contributing underlying mechanisms remain unknown. Here, we determine how age-related expression of pigment epithelium-derived factor (PEDF) affects MSC therapeutic efficacy for MI. METHODS AND RESULTS: Reverse transcriptase-polymerized chain reaction  and enzyme-linked immunosorbent assay analyses revealed dramatically increased PEDF expression in MSCs from old mice compared to young mice. Morphological and functional experiments demonstrated significantly impaired old MSC therapeutic efficacy compared with young MSCs in treatment of mice subjected to MI. Immunofluorescent staining demonstrated that administration of old MSCs compared with young MSCs resulted in an infarct region containing fewer endothelial cells, vascular smooth muscle cells, and macrophages, but more fibroblasts. Pigment epithelium-derived factor overexpression in young MSCs impaired the beneficial effects against MI injury, and induced cellular profile changes in the infarct region similar to administration of old MSCs. Knocking down PEDF expression in old MSCs improved MSC therapeutic efficacy, and induced a cellular profile similar to young MSCs administration. Studies in vitro showed that PEDF secreted by MSCs regulated the proliferation and migration of cardiac fibroblasts. CONCLUSIONS: This is the first evidence that paracrine factor PEDF plays critical role in the regulatory effects of MSCs against MI injury. Furthermore, the impaired therapeutic ability of aged MSCs is predominantly caused by increased PEDF secretion. These findings indicate PEDF as a promising novel genetic modification target for improving aged MSC therapeutic efficacy.

Development and validation of a deep-learning model to predict 10-year atherosclerotic cardiovascular disease risk from retinal images using the UK Biobank and EyePACS 10K datasets.

Background: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death globally, and early detection of high-risk individuals is essential for initiating timely interventions. The authors aimed to develop and validate a deep learning (DL) model to predict an individual's elevated 10-year ASCVD risk score based on retinal images and limited demographic data. Methods: The study used 89,894 retinal fundus images from 44,176 UK Biobank participants (96% non-Hispanic White, 5% diabetic) to train and test the DL model. The DL model was developed using retinal images plus age, race/ethnicity, and sex at birth to predict an individual's 10-year ASCVD risk score using the pooled cohort equation (PCE) as the ground truth. This model was then tested on the US EyePACS 10K dataset (5.8% non-Hispanic White, 99.9% diabetic), composed of 18,900 images from 8969 diabetic individuals. Elevated ASCVD risk was defined as a PCE score of ≥7.5%. Results: In the UK Biobank internal validation dataset, the DL model achieved an area under the receiver operating characteristic curve of 0.89, sensitivity 84%, and specificity 90%, for detecting individuals with elevated ASCVD risk scores. In the EyePACS 10K and with the addition of a regression-derived diabetes modifier, it achieved sensitivity 94%, specificity 72%, mean error -0.2%, and mean absolute error 3.1%. Conclusion: This study demonstrates that DL models using retinal images can provide an additional approach to estimating ASCVD risk, as well as the value of applying DL models to different external datasets and opportunities about ASCVD risk assessment in patients living with diabetes.

Ocular silicon distribution and clearance following intravitreal injection of porous silicon microparticles.

Porous silicon (pSi) microparticles have been investigated for intravitreal drug delivery and demonstrated good biocompatibility. With the appropriate surface chemistry, pSi can reside in vitreous for months or longer. However, ocular distribution and clearance pathway of its degradation product, silicic acid, are not well understood. In the current study, rabbit ocular tissue was collected at different time point following fresh pSi (day 1, 5, 9, 16, and 21) or oxidized pSi (day 3, 7, 14, 21, and 35) intravitreal injection. In addition, dual-probe simultaneous microdialysis of aqueous and vitreous humor was performed following a bolus intravitreal injection of 0.25 mL silicic acid (150 µg/mL) and six consecutive microdialysates were collected every 20 min. Silicon was quantified from the samples using inductively coupled plasma-optical emission spectroscopy. The study showed that following the intravitreal injection of oxidized pSi, free silicon was consistently higher in the aqueous than in the retina (8.1 ± 6.5 vs. 3.4 ± 3.9 µg/mL, p = 0.0031). The area under the concentration-time curve (AUC) of the retina was only about 24% that of the aqueous. The mean residence time was 16 days for aqueous, 13 days for vitreous, 6 days for retina, and 18 days for plasma. Similarly, following intravitreal fresh pSi, free silicon was also found higher in aqueous than in retina (7 ± 4.7 vs. 3.4 ± 4.1 µg/mL, p = 0.014). The AUC for the retina was about 50% of the AUC for the aqueous. The microdialysis revealed the terminal half-life of free silicon in the aqueous was 30 min and 92 min in the vitreous; the AUC for aqueous accounted for 38% of the AUC for vitreous. Our studies indicate that aqueous humor is a significant pathway for silicon egress from the eye following intravitreal injection of pSi crystals.

[Identification and early diagnosis of choroideremia and gyrate atrophy].

Choroideremia and gyrate atrophy are two kinds of heritage primary retino-choroidal atrophy diseases. At advanced stage, their typical fundus lesions are conductive to identification. However, early diagnosis and intervention, which lead to improved prognosis and genetic benefits, are hindered by some similar clinical manifestation and optical examine results. Therefore, it is meaningful for ophthalmologists to have a comprehensive understand of these two diseases, and provide early diagnosis and proper intervention including genetic consultation.

Agreement, repeatability, and reproducibility of quantitative retinal layer assessment using swept-source and spectral-domain optical coherence tomography in eyes with retinal diseases.

Purpose: To evaluate the agreement and precision of retinal thickness measurements obtained using swept-source optical coherence tomography (SS-OCT) and spectral-domain OCT (SD-OCT) in healthy eyes and eyes with retinopathy. Methods: This cross-sectional prospective study involved three DRI-OCT Triton (SS-OCT) and three 3D-OCT-1 Maestro (SD-OCT) devices. One of each device (Maestro and Triton) was paired with a single operator. Healthy subjects and patients with retinal diseases were recruited, with study eye and testing order randomized. At least 3 scans per eye were captured for wide scan (12 mm × 9 mm-Triton and Maestro) and macular cube scan (7 mm × 7 mm-Triton, 6 mm × 6 mm-Maestro). Thickness of the full retina, ganglion cell layer + inner plexiform layer (GCL+), and ganglion cell complex (GCL++) were obtained from wide scan and cube scans. Agreement of the measurements between the Triton and Maestro was evaluated by Bland-Altman analysis and Deming regression for each group. Repeatability and reproducibility were assessed using a two-way random effect analysis of variance (ANOVA) model for each parameter by group. Results: Twenty-five healthy subjects (25 eyes) and 26 patients with retinal diseases (26 eyes), including, but not limited to, age-related macular degeneration, macular hole, and diabetic retinopathy were recruited. Overall, the measurement differences between Triton and Maestro were <6 µm (mean differences of full retina, GCL++, and GCL+ thickness were ≤5.5 µm, 1.3 µm, and 2.8 µm, respectively) and not statistically significant across the parameters. The repeatability and reproducibility estimates indicate high precision in both devices and groups. Across all the parameters, the repeatability limit was ≤7.6 µm for Triton and ≤12.7 µm for Maestro; reproducibility limit was ≤9.2 µm for Triton and ≤14.4 µm for Maestro. In eyes with retinal pathology, the repeatability coefficient of variation (CV)% was ≤2.6% for Triton and ≤3.4% for Maestro; reproducibility CV% was ≤3.3% for Triton and ≤3.5% for Maestro. Conclusion: Both Triton SS-OCT and Maestro SD-OCT provide reliable measurements of retinal thickness in healthy eyes and eyes with retinal diseases. Excellent agreement between the two devices indicates interoperability when testing healthy eyes or eyes with retinal pathology. These findings support the use of thickness measurements from Triton SS-OCT and Maestro SD-OCT in clinical practice.

Agreement and precision of wide and cube scan measurements between swept-source and spectral-domain OCT in normal and glaucoma eyes.

This study aimed to evaluate agreement of Wide scan measurements from swept-source optical coherence tomography (SS-OCT) Triton and spectral-domain OCT (SD-OCT) Maestro in normal/glaucoma eyes, and to assess the precision of measurements from Wide and Cube scans of both devices. Three Triton and three Maestro operator/device configurations were created by pairing three operators, with study eye and testing order randomized. Three scans were captured for Wide (12 mm × 9 mm), Macular Cube (7 mm × 7 mm-Triton; 6 mm × 6 mm-Maestro), and Optic Disc Cube (6 mm × 6 mm) scans for 25 normal eyes and 25 glaucoma eyes. Parameter measurements included circumpapillary retinal nerve fiber layer(cpRNFL), ganglion cell layer + inner plexiform layer (GCL+), and ganglion cell complex (GCL++). A two-way random effect analysis of variance model was used to estimate the repeatability and reproducibility; agreement was evaluated by Bland-Altman analysis and Deming regression. The precision estimates were low, indicating high precision, for all thickness measurements with the majority of the limits < 5 µm for the macula and < 10 µm for the optic disc. Precision of the Wide and Cube scans were comparable. Excellent agreement between the two devices was found for Wide scans, with the mean difference < 3 µm across all measurements (cpRNFL < 3 µm, GCL+ < 2 µm, GCL ++ < 1 µm), indicating interoperability. A single Wide scan covering the peripapillary and macular regions may be useful for glaucoma diagnosis and management.

Agreement and Precision of Wide and Cube Scan Measurements between Swept-source and Spectral-domain OCT in Normal and Glaucoma Eyes.

This study aimed to evaluate agreement of Wide scan measurements from swept-source optical coherence tomography(SS-OCT) Triton and spectral-domain OCT(SD-OCT) Maestro in normal/glaucoma eyes, and to assess the precision of measurements from Wide and Cube scans of both devices. Three Triton and three Maestro operator/device configurations were created by pairing three operators, with study eye and testing order randomized. Three scans were captured for Wide (12mm×9mm), Macular Cube (7mmx7mm-Triton; 6mmx6mm-Maestro), and Optic Disc Cube (6mmx6mm) scans for 25 normal eyes and 25 glaucoma eyes. Thickness of circumpapillary retinal nerve fiber layer(cpRNFL), ganglion cell layer+inner plexiform layer(GCL+), and ganglion cell complex(GCL++) was obtained from each scan. A two-way random effect analysis of variance model was used to estimate the repeatability and reproducibility; agreement was evaluated by Bland-Altman analysis and Deming regression. Precision limit estimates were low: <5µm for macular and <10µm for optic disc parameters. Precision for Wide and Cube scans of both devices were comparablein both groups. Excellent agreement between the two devices was found for Wide scans, with the mean difference<3µm across all measurements (cpRNFL<3µm, GCL+<2µm, GCL++<1µm), indicating interoperability. A single Wide scan covering the peripapillary and macular regions may be useful for glaucoma management.