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Purpose: To assess intra- (repeatability) and inter-observer (reproducibility) variability of laser speckle flowgraphy (LSFG) for retinal blood flow (RBF) measurement in 20 eyes of wild type (C57BL/6J) mice and effect of intravitreal Aflibercept on RBF in optic nerve head (ONH) region of 10 eyes of Ins2 (Akita) diabetic mice., Methods: 'Mean blur rate (MBR)' was measured for all quadrants of tissue area (MT), vessel (MV) and total area (MA) of ONH region. Changes in MT were analysed at each timepoint. Repeatability was evaluated by measuring MBR variability without changing mouse head position, and reproducibility after resetting mouse head position by another operator. Coefficient of repeatability (CR) through Bland-Altman plot method coefficient of variation (COV) and Intraclass correlation coefficient (ICC) was calculated. Intravitreal Aflibercept (1 μg) was administered to Akita eyes and intraocular pressure (IOP) was measured using a tonometer at baseline, day 7, 14, 21 and 28 post-injection. Hurvich and Tsai's criterion was used., Results: Coefficient of repeatability values of repeatability and reproducibility for all quadrants were within limits of agreement. Reliability was excellent (ICC 0.98-0.99) and reproducibility was moderate to excellent (ICC 0.64-0.96). There was a non-significant IOP increase in all Akita eyes at Day 28 (p > 0.05), and significant increase in MT in all quadrants at Day 21 and superior, inferior and temporal quadrants at Day 28 (p < 0.05)., Conclusion: Laser speckle flowgraphy demonstrates excellent repeatability and moderate to excellent reproducibility in measuring RBF. Intravitreal Aflibercept injection results in a significant increase in MT up to 28 days post-injection without significant increase in IOP., (© 2024 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Optical coherence tomography angiography (OCTA) has transformed ocular vascular imaging, revealing microvascular changes linked to various systemic diseases. This review explores its applications in diabetes, hypertension, cardiovascular diseases, and neurodegenerative diseases. While OCTA provides a valuable window into the body's microvasculature, interpreting the findings can be complex. Additionally, challenges exist due to the relative non-specificity of its findings where changes observed in OCTA might not be unique to a specific disease, variations between OCTA machines, the lack of a standardized normative database for comparison, and potential image artifacts. Despite these limitations, OCTA holds immense potential for the future. The review highlights promising advancements like quantitative analysis of OCTA images, integration of artificial intelligence for faster and more accurate interpretation, and multi-modal imaging combining OCTA with other techniques for a more comprehensive characterization of the ocular vasculature. Furthermore, OCTA's potential future role in personalized medicine, enabling tailored treatment plans based on individual OCTA findings, community screening programs for early disease detection, and longitudinal studies tracking disease progression over time is also discussed. In conclusion, OCTA presents a significant opportunity to improve our understanding and management of systemic diseases. Addressing current limitations and pursuing these exciting future directions can solidify OCTA as an indispensable tool for diagnosis, monitoring disease progression, and potentially guiding treatment decisions across various systemic health conditions., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: To evaluate reproducibility and agreement of angle closure assessment by a novel hyperparallel optical coherence tomography (OCT) system (HP-OCT, Cylite Optics, Melbourne, Australia), in comparison with swept-source OCT (SS-OCT, CASIA SS-1000, Tomey Corporation, Nagoya, Japan) and gonioscopy., Methods: Cross-sectional study. Phakic subjects >40 years, with no relevant ophthalmic history were consecutively recruited from the glaucoma clinic. Subjects underwent same-day evaluation with HP-OCT, SS-OCT and gonioscopy. The primary outcome was the presence of angle closure, defined as iridotrabecular contact in HP-OCT and SS-OCT images at 0°-180° meridional and as non-visibility of the posterior trabecular meshwork (TM) by gonioscopy. Visibility of TM was also assessed (secondary outcome). Intra and interdevice agreement analysis (Gwet AC1) and logistic regression analysis were performed for primary and secondary outcomes, respectively., Results: 154 sectors from horizontal scans of 77 subjects were analysed. The reproducibility of angle closure assessment by HP-OCT was excellent (AC1 of 0.95 for temporal angle and 1.00 for nasal). Agreement for angle closure detection was very good between HP-OCT and SS-OCT (AC1 of 0.88 for temporal and 0.81 for nasal angle) and good between HP-OCT and gonioscopy (AC1 of 0.71 for temporal and 0.78 for nasal angle). TM was identifiable in 64.4% (94/146) of unprocessed HP-OCT images (both open and closed angles), however not visible in any of the SS-OCT unprocessed images., Conclusions: HP-OCT showed excellent reproducibility for angle closure assessment and good agreement with SS-OCT and gonioscopy. HP-OCT technology also provides a unique capability to visualise regions around TM and Schlemm's canal, opening new avenues for clinical research of distal outflow pathways., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The study aimed to evaluate the impact of compensating retinal nerve fiber layer (RNFL) thickness for demographic and anatomical factors on glaucoma detection in Chinese and Indian adults. A population-based study included 1995 healthy participants (1076 Chinese and 919 Indians) to construct a multivariable linear regression compensation model. This model was applied to 357 Chinese glaucoma patients, 357 healthy Chinese, and 357 healthy Indians using Cirrus spectral-domain optical coherence tomography (OCT). The compensated RNFL thickness considered age, refractive error, optic disc parameters, and retinal vessel density. Results showed that although the average RNFL thickness was significantly higher in Chinese participants compared to Indians, the compensation model reduced this difference to nonsignificance. Moreover, the compensation model significantly improved the area under the receiver operating characteristic curve (0.90 vs. 0.78; p<0.001), sensitivity (75% vs. 51%), and specificity (67% vs. 32%) in distinguishing Chinese glaucoma patients from healthy Indian individuals. The compensation model significantly enhanced the diagnostic accuracy of RNFL thickness in distinguishing glaucoma in the Chinese ethnic group compared to the OCT instrument's default values. These results suggest that modifying RNFL measurements based on individual characteristics can yield substantial benefits for glaucoma detection across ethnicities., (© 2024 The Author(s). Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

Background: The goal of the present study was to identify differences in retinal microvasculature between healthy Caucasians and healthy Asians in order to provide a better understanding of the variability between different ethnic groups., Methods: In this cross-sectional study, 191 healthy Chinese and Caucasian participants were enrolled. They underwent optical coherence tomography angiography (OCTA) scans with Zeiss Cirrus HD-5000 Spectral-Domain with AngioPlex. Linear regression models were used to investigate the association of OCTA metrics with potential risk factors., Results: Whereas participants in both groups are comparable in age and sex, Chinese participants had a longer axial length, higher spherical equivalent, higher intraocular pressure ( p < 0.001), and a significantly higher perfusion density of large vessels in the superficial capillary plexus ( p < 0.001). Regarding the foveolar avascular area (FAZ), Chinese participants had a larger superficial FAZ, a wider superficial FAZ perimeter, and a more circular deep FAZ shape ( p < 0.001)., Conclusions: There are significant differences in the retinal vasculature between Caucasian and Asian eyes as measured using OCTA. This needs to be considered when developing normative databases. Whether such findings relate to inter-racial differences in the incidence of retinal vascular disease remains to be shown.

Background: In vivo confocal microscopy (IVCM) is a vital tool in studying dry eye disease (DED), providing insights into morphological changes at ocular surface unit levels. This review presents the main differences in corneal structure between aqueous-deficient dry eye disease (AD-DED) and normal eyes., Methods: A comprehensive search of PubMed, Web of Science, Embase, and MEDLINE databases from January 2000 to December 2023 was conducted. The study selection process, as well as data selection and examination, were independently performed by two members of the review team., Results: The review reveals a consistent decrease in corneal surface epithelial cell density in AD-DED cases compared to a control group, but conflicting data on basal epithelial cell density. Notably, the abnormal hyperreflectivity of keratocytes in patients with Sjogren's syndrome was recorded, and there was a significant keratocyte density in AD-DED subjects compared to evaporative DED and control groups. Studies also found a decrease in sub-basal nerve density, increased tortuosity, and the fragmentation of nerve fibers. Dendritic cell density and dendritic cell dendrites increase in AD-DED patients compared to healthy subjects., Conclusions: IVCM is a powerful tool for enhancing our understanding of the pathophysiological mechanisms underlying DED. However, the review underscores the urgent need to standardize the terminology, analysis, and units used for accurate interpretation, a crucial step in advancing our knowledge of DED.

The choroid, which is a highly vascularized layer between the retina and sclera, is essential for supplying oxygen and nutrients to the outer retina. Choroidal vascular dysfunction has been implicated in numerous ocular diseases, including age-related macular degeneration, central serous chorioretinopathy, polypoidal choroidal vasculopathy, and myopia. Traditionally, the in vivo assessment of choroidal blood flow relies on techniques such as laser Doppler flowmetry, laser speckle flowgraphy, pneumotonometry, laser interferometry, and ultrasonic color Doppler imaging. While the aforementioned methods have provided valuable insights into choroidal blood flow regulation, their clinical applications have been limited. Recent advancements in optical coherence tomography and optical coherence tomography angiography have expanded our understanding of the choroid, allowing detailed visualization of the larger choroidal vessels and choriocapillaris, respectively. This review provides an overview of the available techniques that can investigate the choroid and its blood flow in vivo. Future research should combine these techniques to comprehensively image the entire choroidal microcirculation and develop robust methods to quantify choroidal blood flow. The potential findings will provide a better picture of choroidal hemodynamics and its effect on ocular health and disease., Competing Interests: Declaration of competing interest All authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Phototransduction involves changes in concentration of ions and other solutes within photoreceptors and in subretinal space, which affect osmotic pressure and the associated water flow. Corresponding expansion and contraction of cellular layers can be imaged using optoretinography (ORG), based on phase-resolved optical coherence tomography (OCT). Until now, ORG could reliably detect only photoisomerization and phototransduction in photoreceptors, primarily in cones under bright stimuli. Here, by employing a phase-restoring subpixel motion correction algorithm, which enables imaging of the nanometer-scale tissue dynamics during minute-long recordings, and unsupervised learning of spatiotemporal patterns, we discover optical signatures of the other retinal structures' response to visual stimuli. These include inner and outer segments of rod photoreceptors, retinal pigment epithelium, and subretinal space in general. The high sensitivity of our technique enables detection of the retinal responses to dim stimuli: down to 0.01% bleach level, corresponding to natural levels of scotopic illumination. We also demonstrate that with a single flash, the optoretinogram can map retinal responses across a 12° field of view, potentially replacing multifocal electroretinography. This technique expands the diagnostic capabilities and practical applicability of optoretinography, providing an alternative to electroretinography, while combining structural and functional retinal imaging in the same OCT machine., (© 2024. The Author(s).)

Purpose: Neurovascular coupling impairment and inner retinal layer thinning are early detectable retinal changes in diabetes, and both worsen during progression of diabetic retinopathy (DR). However, direct interactions between these features have not been investigated so far. Therefore, we aimed to analyze associations between the retinal functional hyperemic response to light stimulation and the thickness of individual neuroretinal layers in eyes with early non-proliferative DR., Methods: Thirty patients with type 1 diabetes featuring mild (n = 15) or moderate (n = 15) non-proliferative DR and 14 healthy subjects were included in this cross-sectional study. Retinal vessel diameters were measured before and during illumination with flickering light using a dynamic vessel analyzer. Individual layer thickness in the macula was analyzed from spectral domain optical coherence tomography., Results: Flicker light-induced vessel dilation was significantly reduced in patients compared to healthy controls (veins: 3.0% vs. 6.1%, p < 0.001; arteries: 1.3% vs. 5.1%, p = 0.005). Univariately, the response in retinal veins of diabetes patients correlated significantly with ganglion cell layer (GCL) thickness (r = 0.46, p = 0.010), and negatively with hemoglobin A1c (HbA1c) levels (r=-0.41, p = 0.023) and age (r=-0.38, p = 0.037), but not with baseline diameters, glucose levels, or diabetes duration. In a multiple regression model only GCL thickness (p = 0.017, β = 0.42) and HbA1c (p = 0.045, β=-0.35) remained significantly associated with the vascular flicker light response., Conclusion: The results indicate that thinner GCL and worse glycemic control both contribute to reduced retinal neurovascular coupling in patients with clinical signs of DR. Progression of neurovascular dysfunction in DR might be related to structural degeneration of the neurovascular complex in the inner retina., (© 2024. The Author(s).)

Background: Myopia affects 1.4 billion individuals worldwide. Notably, there is increasing evidence that choroidal thickness plays an important role in myopia and risk of developing myopia-related conditions. With the advancements in artificial intelligence (AI), choroidal thickness segmentation can now be automated, offering inherent advantages such as better repeatability, reduced grader variability, and less reliance for manpower. Hence, we aimed to evaluate the agreement between AI-automated and manual segmented measurements of subfoveal choroidal thickness (SFCT) using two swept-source optical coherence tomography (OCT) systems., Methods: Subjects aged ≥ 16 years, with myopia of ≥ 0.50 diopters in both eyes, were recruited from the Prospective Myopia Cohort Study in Singapore (PROMYSE). OCT scans were acquired using Triton DRI-OCT and PLEX Elite 9000. OCT images were segmented both automatically with an established SA-Net architecture and manually using a standard technique with adjudication by two independent graders. SFCT was subsequently determined based on the segmentation. The Bland-Altman plot and intraclass correlation coefficient (ICC) were used to evaluate the agreement., Results: A total of 229 subjects (456 eyes) with mean [± standard deviation (SD)] age of 34.1 (10.4) years were included. The overall SFCT (mean ± SD) based on manual segmentation was 216.9 ± 82.7 µm with Triton DRI-OCT and 239.3 ± 84.3 µm with PLEX Elite 9000. ICC values demonstrated excellent agreement between AI-automated and manual segmented SFCT measurements (PLEX Elite 9000: ICC = 0.937, 95% CI: 0.922 to 0.949, P < 0.001; Triton DRI-OCT: ICC = 0.887, 95% CI: 0.608 to 0.950, P < 0.001). For PLEX Elite 9000, manual segmented measurements were generally thicker when compared to AI-automated segmented measurements, with a fixed bias of 6.3 µm (95% CI: 3.8 to 8.9, P < 0.001) and proportional bias of 0.120 (P < 0.001). On the other hand, manual segmented measurements were comparatively thinner than AI-automated segmented measurements for Triton DRI-OCT, with a fixed bias of - 26.7 µm (95% CI: - 29.7 to - 23.7, P < 0.001) and proportional bias of - 0.090 (P < 0.001)., Conclusion: We observed an excellent agreement in choroidal segmentation measurements when comparing manual with AI-automated techniques, using images from two SS-OCT systems. Given its edge over manual segmentation, automated segmentation may potentially emerge as the primary method of choroidal thickness measurement in the future., (© 2024. The Author(s).)

Introduction: Myopia and its vision-threatening complications present a significant public health problem. This review aims to provide an updated overview of the multitude of known and emerging interventions to control myopia, including their potential effect, safety, and costs., Methods: A systematic literature search of three databases was conducted. Interventions were grouped into four categories: environmental/behavioral (outdoor time, near work), pharmacological (e.g., atropine), optical interventions (spectacles and contact lenses), and novel approaches such as red-light (RLRL) therapies. Review articles and original articles on randomized controlled trials (RCT) were selected., Results: From the initial 3224 retrieved records, 18 reviews and 41 original articles reporting results from RCTs were included. While there is more evidence supporting the efficacy of low-dose atropine and certain myopia-controlling contact lenses in slowing myopia progression, the evidence about the efficacy of the newer interventions, such as spectacle lenses (e.g., defocus incorporated multiple segments and highly aspheric lenslets) is more limited. Behavioral interventions, i.e., increased outdoor time, seem effective for preventing the onset of myopia if implemented successfully in schools and homes. While environmental interventions and spectacles are regarded as generally safe, pharmacological interventions, contact lenses, and RLRL may be associated with adverse effects. All interventions, except for behavioral change, are tied to moderate to high expenditures., Conclusion: Our review suggests that myopia control interventions are recommended and prescribed on the basis of accessibility and clinical practice patterns, which vary widely around the world. Clinical trials indicate short- to medium-term efficacy in reducing myopia progression for various interventions, but none have demonstrated long-term effectiveness in preventing high myopia and potential complications in adulthood. There is an unmet need for a unified consensus for strategies that balance risk and effectiveness for these methods for personalized myopia management., (© 2024. The Author(s).)

Background/aims: To investigate whether compensating retinal nerve fibre layer (RNFL) thickness measurements for demographic and anatomical ocular factors can strengthen the structure-function relationship in patients with glaucoma., Methods: 600 eyes from 412 patients with glaucoma (mean deviation of the visual field (MD VF) -6.53±5.55 dB) were included in this cross-sectional study. Participants underwent standard automated perimetry and spectral-domain optical coherence tomography imaging (Cirrus; Carl Zeiss Meditec). Compensated RNFL thickness was computed considering age, refractive error, optic disc parameters and retinal vessel density. The relationship between MD VF and RNFL thickness measurements, with or without demographic and anatomical compensation, was evaluated sectorally and focally., Results: The superior arcuate sector exhibited the highest correlation between measured RNFL and MD VF, with a correlation of 0.49 (95% CI 0.37 to 0.59). Applying the compensated RNFL data increased the correlation substantially to 0.62 (95% CI 0.52 to 0.70; p<0.001). Only 61% of the VF locations showed a significant relationship (Spearman's correlation of at least 0.30) between structural and functional aspects using measured RNFL data, and this increased to 78% with compensated RNFL measurements. In the 10°-20° VF region, the slope below the breakpoint for compensated RNFL thickness demonstrated a more robust correlation (slope=1.66±0.18 µm/dB; p<0.001) than measured RNFL (slope=0.27±0.67 µm/dB; p=0.688)., Conclusion: Compensated RNFL data improve the correlation between RNFL measurements and VF parameters. This indicates that creating structure-to-function maps that consider anatomical variances may aid in identifying localised structural and functional loss in glaucoma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Spectral-domain optical coherence tomography (SDOCT) is the gold standard of imaging the eye in clinics. Penetration depth with such devices is, however, limited and visualization of the choroid, which is essential for diagnosing chorioretinal disease, remains limited. Whereas swept-source OCT (SSOCT) devices allow for visualization of the choroid these instruments are expensive and availability in praxis is limited. We present an artificial intelligence (AI)-based solution to enhance the visualization of the choroid in OCT scans and allow for quantitative measurements of choroidal metrics using generative deep learning (DL). Synthetically enhanced SDOCT B-scans with improved choroidal visibility were generated, leveraging matching images to learn deep anatomical features during the training. Using a single-center tertiary eye care institution cohort comprising a total of 362 SDOCT-SSOCT paired subjects, we trained our model with 150,784 images from 410 healthy, 192 glaucoma, and 133 diabetic retinopathy eyes. An independent external test dataset of 37,376 images from 146 eyes was deployed to assess the authenticity and quality of the synthetically enhanced SDOCT images. Experts' ability to differentiate real versus synthetic images was poor (47.5% accuracy). Measurements of choroidal thickness, area, volume, and vascularity index, from the reference SSOCT and synthetically enhanced SDOCT, showed high Pearson's correlations of 0.97 [95% CI: 0.96-0.98], 0.97 [0.95-0.98], 0.95 [0.92-0.98], and 0.87 [0.83-0.91], with intra-class correlation values of 0.99 [0.98-0.99], 0.98 [0.98-0.99], and 0.95 [0.96-0.98], 0.93 [0.91-0.95], respectively. Thus, our DL generative model successfully generated realistic enhanced SDOCT data that is indistinguishable from SSOCT images providing improved visualization of the choroid. This technology enabled accurate measurements of choroidal metrics previously limited by the imaging depth constraints of SDOCT. The findings open new possibilities for utilizing affordable SDOCT devices in studying the choroid in both healthy and pathological conditions., (© 2024. The Author(s).)

Purpose: To assess the diagnostic performance and structure-function association of retinal retardance (RR), a customized metric measured by a prototype polarization-sensitive optical coherence tomography (PS-OCT), across various stages of glaucoma., Methods: This cross-sectional pilot study analyzed 170 eyes from 49 healthy individuals and 68 patients with glaucoma. The patients underwent PS-OCT imaging and conventional spectral-domain optical coherence tomography (SD-OCT), as well as visual field (VF) tests. Parameters including RR and retinal nerve fiber layer thickness (RNFLT) were extracted from identical circumpapillary regions of the fundus. Glaucomatous eyes were categorized into early, moderate, or severe stages based on VF mean deviation (MD). The diagnostic performance of RR and RNFLT in discriminating glaucoma from controls was assessed using receiver operating characteristic (ROC) curves. Correlations among VF-MD, RR, and RNFLT were evaluated and compared within different groups of disease severity., Results: The diagnostic performance of both RR and RNFLT was comparable for glaucoma detection (RR AUC = 0.98, RNFLT AUC = 0.97; P = 0.553). RR showed better structure-function association with VF-MD than RNFLT (RR VF-MD = 0.68, RNFLT VF-MD = 0.58; z = 1.99; P = 0.047) in glaucoma cases, especially in severe glaucoma, where the correlation between VF-MD and RR (r = 0.73) was significantly stronger than with RNFLT (r = 0.43, z = 1.96, P = 0.050). In eyes with early and moderate glaucoma, the structure-function association was similar when using RNFLT and RR., Conclusions: RR and RNFLT have similar performance in glaucoma diagnosis. However, in patients with glaucoma especially severe glaucoma, RR showed a stronger correlation with VF test results. Further research is needed to validate RR as an indicator for severe glaucoma evaluation and to explore the benefits of using PS-OCT in clinical practice., Translational Relevance: We demonstrated that PS-OCT has the potential to evaluate the status of RNFL structural damage in eyes with severe glaucoma, which is currently challenging in clinics.

The objective of this study is to define structure-function relationships of pathological lesions related to age-related macular degeneration (AMD) using microperimetry and multimodal retinal imaging. We conducted a cross-sectional study of 87 patients with AMD (30 eyes with early and intermediate AMD and 110 eyes with advanced AMD), compared to 33 normal controls (66 eyes) recruited from a single tertiary center. All participants had enface and cross-sectional optical coherence tomography (Heidelberg HRA-2), OCT angiography, color and infra-red (IR) fundus and microperimetry (MP) (Nidek MP-3) performed. Multimodal images were graded for specific AMD pathological lesions. A custom marking tool was used to demarcate lesion boundaries on corresponding enface IR images, and subsequently superimposed onto MP color fundus photographs with retinal sensitivity points (RSP). The resulting overlay was used to correlate pathological structural changes to zonal functional changes. Mean age of patients with early/intermediate AMD, advanced AMD and controls were 73(SD = 8.2), 70.8(SD = 8), and 65.4(SD = 7.7) years respectively. Mean retinal sensitivity (MRS) of both early/intermediate (23.1 dB; SD = 5.5) and advanced AMD (18.1 dB; SD = 7.8) eyes were significantly worse than controls (27.8 dB, SD = 4.3) (p < 0.01). Advanced AMD eyes had significantly more unstable fixation (70%; SD = 63.6), larger mean fixation area (3.9 mm 2 ; SD = 3.0), and focal fixation point further away from the fovea (0.7 mm; SD = 0.8), than controls (29%; SD = 43.9; 2.6 mm 2 ; SD = 1.9; 0.4 mm; SD = 0.3) (p ≤ 0.01). Notably, 22 fellow eyes of AMD eyes (25.7 dB; SD = 3.0), with no AMD lesions, still had lower MRS than controls (p = 0.04). For specific AMD-related lesions, end-stage changes such as fibrosis (5.5 dB, SD = 5.4 dB) and atrophy (6.2 dB, SD = 7.0 dB) had the lowest MRS; while drusen and pigment epithelial detachment (17.7 dB, SD = 8.0 dB) had the highest MRS. Peri-lesional areas (20.2 dB, SD = 7.6 dB) and surrounding structurally normal areas (22.2 dB, SD = 6.9 dB) of the retina with no AMD lesions still had lower MRS compared to controls (27.8 dB, SD = 4.3 dB) (p < 0.01). Our detailed topographic structure-function correlation identified specific AMD pathological changes associated with a poorer visual function. This can provide an added value to the assessment of visual function to optimize treatment outcomes to existing and potentially future novel therapies., (© 2024. The Author(s).)

The aim of the present study was to investigate retinal microcirculatory and functional metabolic changes in patients after they had recovered from a moderate to severe acute COVID-19 infection. Retinal perfusion was quantified using laser speckle flowgraphy. Oxygen saturation and retinal calibers were assessed with a dynamic vessel analyzer. Arterio-venous ratio (AVR) was calculated based on retinal vessel diameter data. Blood plasma samples underwent mass spectrometry-based multi-omics profiling, including proteomics, metabolomics and eicosadomics. A total of 40 subjects were included in the present study, of which 29 had recovered from moderate to severe COVID-19 within 2 to 23 weeks before inclusion and 11 had never had COVID-19, as confirmed by antibody testing. Perfusion in retinal vessels was significantly lower in patients (60.6 ± 16.0 a.u.) than in control subjects (76.2 ± 12.1 a.u., p = 0.006). Arterio-venous (AV) difference in oxygen saturation and AVR was significantly lower in patients compared to healthy controls (p = 0.021 for AVR and p = 0.023 for AV difference in oxygen saturation). Molecular profiles demonstrated down-regulation of cell adhesion molecules, NOTCH3 and fatty acids, and suggested a bisphasic dysregulation of nitric oxide synthesis after COVID-19 infection. The results of this study imply that retinal perfusion and oxygen metabolism is still significantly altered in patients well beyond the acute phase of COVID-19. This is also reflected in the molecular profiling analysis of blood plasma, indicating a down-regulation of nitric oxide-related endothelial and immunological cell functions.Trial Registration: ClinicalTrials.gov ( https://clinicaltrials.gov ) NCT05650905., (© 2024. The Author(s).)

With the increasing incidences of orbital wall injuries, effective reconstruction materials and techniques are imperative for optimal clinical outcomes. In this literature review, we delve into the efficacy and potential advantages of using titanium implants coated with nanostructured hydroxyapatite for the reconstruction of the orbital wall. Titanium implants, recognized for their durability and mechanical strength, when combined with the osteoconductive properties of hydroxyapatite, present a potentially synergistic solution. The purpose of this review was to critically analyze the recent literature and present the state of the art in orbital wall reconstruction using titanium implants coated with nanostructured hydroxyapatite. This review offers clinicians detailed insight into the benefits and potential drawbacks of using titanium implants coated with nanostructured hydroxyapatite for orbital wall reconstruction. The highlighted results advocate for its benefits in terms of osseointegration and provide a novel strategy for orbital reconstruction, though further studies are essential to establish long-term efficacy and address concerns.

Purpose: The purpose of this study was to investigate rod photopigment bleaching-driven intrinsic optical signals (IOS) in the human outer retina and its measurement repeatability based on a commercial optical coherence tomography (OCT) platform., Methods: The optical path length of the rod photoreceptor subretinal space (SRS), that is, the distance between signal bands of rod outer segment tips and retinal pigment epithelium, was measured in 15 healthy subjects in ambient light and during a long-duration bleaching white-light exposure., Results: On 2 identical study days (day 1 and day 2 [D1 and D2]), light stimulation resulted in a significant decrease in rod SRS by 21.3 ± 7.6% and 19.8 ± 8.5% (both P < 0.001), respectively. The test-retest reliability of the SRS maximum change of an individual subject was moderate for single measures (intraclass correlation coefficient [ICC] = 0.730, 95% confidence interval [CI] = 0.376, 0.900, P < 0.001) and good for average measures (ICC = 0.844, 95% CI = 0.546, 0.947, P < 0.001). The mean area under the stimulus response curve with values of 14.8 ± 9.4 and 15.5 ± 7.5 µm × minutes (P = 0.782) showed excellent agreement between the stimulus response on D1 and D2. Intermittent dark adaptation of the retina led to an initial increase of the SRS by 6.1% (P = 0.018) and thereafter showed a decrease toward baseline, despite continued dark adaptation., Conclusions: The data indicate the potential of commercial OCT in measuring slow IOS in the outer retina suggesting that the rod SRS could serve as a biomarker for photoreceptor function. The presented approach could provide an easily implementable clinical tool for the early detection of diseases affecting photoreceptor health.

Purpose: We wanted to develop a deep-learning algorithm to automatically segment optic nerve head (ONH) and macula structures in three-dimensional (3D) wide-field optical coherence tomography (OCT) scans and to assess whether 3D ONH or macula structures (or a combination of both) provide the best diagnostic power for glaucoma., Methods: A cross-sectional comparative study was performed using 319 OCT scans of glaucoma eyes and 298 scans of nonglaucoma eyes. Scans were compensated to improve deep-tissue visibility. We developed a deep-learning algorithm to automatically label major tissue structures, trained with 270 manually annotated B-scans. The performance was assessed using the Dice coefficient (DC). A glaucoma classification algorithm (3D-CNN) was then designed using 500 OCT volumes and corresponding automatically segmented labels. This algorithm was trained and tested on three datasets: cropped scans of macular tissues, those of ONH tissues, and wide-field scans. The classification performance for each dataset was reported using the area under the curve (AUC)., Results: Our segmentation algorithm achieved a DC of 0.94 ± 0.003. The classification algorithm was best able to diagnose glaucoma using wide-field scans, followed by ONH scans, and finally macula scans, with AUCs of 0.99 ± 0.01, 0.93 ± 0.06 and 0.91 ± 0.11, respectively., Conclusions: This study showed that wide-field OCT may allow for significantly improved glaucoma diagnosis over typical OCTs of the ONH or macula., Translational Relevance: This could lead to mainstream clinical adoption of 3D wide-field OCT scan technology.

Introduction: Diabetic retinopathy (DR) is a leading cause of preventable blindness among working-age adults, primarily driven by ocular microvascular complications from chronic hyperglycemia. Comprehending the complex relationship between microvascular changes in the eye and disease progression poses challenges, traditional methods assuming linear or logistical relationships may not adequately capture the intricate interactions between these changes and disease advances. Hence, the aim of this study was to evaluate the microvascular involvement of diabetes mellitus (DM) and non-proliferative DR with the implementation of non-parametric machine learning methods., Research Design and Methods: We conducted a retrospective cohort study that included optical coherence tomography angiography (OCTA) images collected from a healthy group (196 eyes), a DM no DR group (120 eyes), a mild DR group (71 eyes), and a moderate DR group (66 eyes). We implemented a non-parametric machine learning method for four classification tasks that used parameters extracted from the OCTA images as predictors: DM no DR versus healthy, mild DR versus DM no DR, moderate DR versus mild DR, and any DR versus no DR. SHapley Additive exPlanations values were used to determine the importance of these parameters in the classification., Results: We found large choriocapillaris flow deficits were the most important for healthy versus DM no DR, and became less important in eyes with mild or moderate DR. The superficial microvasculature was important for the healthy versus DM no DR and mild DR versus moderate DR tasks, but not for the DM no DR versus mild DR task-the stage when deep microvasculature plays an important role. Foveal avascular zone metric was in general less affected, but its involvement increased with worsening DR., Conclusions: The findings from this study provide valuable insights into the microvascular involvement of DM and DR, facilitating the development of early detection methods and intervention strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aimed to examine the impact of diabetes and hypertension on retinal nerve fiber layer (RNFL) thickness components. Optical coherence tomography (OCT) measurements do not consider blood vessel contribution, which this study addressed. We hypothesized that diabetes and/or hypertension would lead to thinner RNFL versus controls due to the vascular component. OCT angiography was used to measure the RNFL in 121 controls, 50 diabetes patients, 371 hypertension patients, and 177 diabetes patients with hypertension. A novel technique separated the RNFL thickness into original (vascular component) and corrected (no vascular component) measurements. Diabetes-only (98 ± 1.7 µm; p = 0.002) and diabetes with hypertension (99 ± 0.8 µm; p = 0.001) patients had thinner original RNFL versus controls (102 ± 0.8 µm). No difference was seen between hypertension-only patients (101 ± 0.5 µm; p = 0.083) and controls. After removing the blood vessel component, diabetes/hypertension groups had thinner corrected RNFL versus controls (p = 0.024). Discrepancies in diabetes/hypertension patients were due to thicker retinal blood vessels within the RNFL thickness (p = 0.002). Our findings suggest that diabetes and/or hypertension independently contribute to neurodegenerative thinning of the RNFL, even in the absence of retinopathy. The differentiation of neuronal and vascular components in RNFL thickness measurements provided by the novel technique highlights the importance of considering vascular changes in individuals with these conditions., (© 2023 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

Importance: Clinical trial results of topical atropine eye drops for childhood myopia control have shown inconsistent outcomes across short-term studies, with little long-term safety or other outcomes reported., Objective: To report the long-term safety and outcomes of topical atropine for childhood myopia control., Design, Setting, and Participants: This prospective, double-masked observational study of the Atropine for the Treatment of Myopia (ATOM) 1 and ATOM2 randomized clinical trials took place at 2 single centers and included adults reviewed in 2021 through 2022 from the ATOM1 study (atropine 1% vs placebo; 1999 through 2003) and the ATOM2 study (atropine 0.01% vs 0.1% vs 0.5%; 2006 through 2012)., Main Outcome Measures: Change in cycloplegic spherical equivalent (SE) with axial length (AL); incidence of ocular complications., Results: Among the original 400 participants in each original cohort, the study team evaluated 71 of 400 ATOM1 adult participants (17.8% of original cohort; study age, mean [SD] 30.5 [1.2] years; 40.6% female) and 158 of 400 ATOM2 adult participants (39.5% of original cohort; study age, mean [SD], 24.5 [1.5] years; 42.9% female) whose baseline characteristics (SE and AL) were representative of the original cohort. In this study, evaluating ATOM1 participants, the mean (SD) SE and AL were -5.20 (2.46) diopters (D), 25.87 (1.23) mm and -6.00 (1.63) D, 25.90 (1.21) mm in the 1% atropine-treated and placebo groups, respectively (difference of SE, 0.80 D; 95% CI, -0.25 to 1.85 D; P = .13; difference of AL, -0.03 mm; 95% CI, -0.65 to 0.58 mm; P = .92). In ATOM2 participants, the mean (SD) SE and AL was -6.40 (2.21) D; 26.25 (1.34) mm; -6.81 (1.92) D, 26.28 (0.99) mm; and -7.19 (2.87) D, 26.31 (1.31) mm in the 0.01%, 0.1%, and 0.5% atropine groups, respectively. There was no difference in the 20-year incidence of cataract/lens opacities, myopic macular degeneration, or parapapillary atrophy (β/γ zone) comparing the 1% atropine-treated group vs the placebo group., Conclusions and Relevance: Among approximately one-quarter of the original participants, use of short-term topical atropine eye drops ranging from 0.01% to 1.0% for a duration of 2 to 4 years during childhood was not associated with differences in final refractive errors 10 to 20 years after treatment. There was no increased incidence of treatment or myopia-related ocular complications in the 1% atropine-treated group vs the placebo group. These findings may affect the design of future clinical trials, as further studies are required to investigate the duration and concentration of atropine for childhood myopia control.

Glaucoma is a slowly progressing optic neuropathy that may eventually lead to blindness. To help patients receive customized treatment, predicting how quickly the disease will progress is important. Structural assessment using optical coherence tomography (OCT) can be used to visualize glaucomatous optic nerve and retinal damage, while functional visual field (VF) tests can be used to measure the extent of vision loss. However, VF testing is patient-dependent and highly inconsistent, making it difficult to track glaucoma progression. In this work, we developed a multimodal deep learning model comprising a convolutional neural network (CNN) and a long short-term memory (LSTM) network, for glaucoma progression prediction. We used OCT images, VF values, demographic and clinical data of 86 glaucoma patients with five visits over 12 months. The proposed method was used to predict VF changes 12 months after the first visit by combining past multimodal inputs with synthesized future images generated using generative adversarial network (GAN). The patients were classified into two classes based on their VF mean deviation (MD) decline: slow progressors (< 3 dB) and fast progressors (> 3 dB). We showed that our generative model-based novel approach can achieve the best AUC of 0.83 for predicting the progression 6 months earlier. Further, the use of synthetic future images enabled the model to accurately predict the vision loss even earlier (9 months earlier) with an AUC of 0.81, compared to using only structural (AUC = 0.68) or only functional measures (AUC = 0.72). This study provides valuable insights into the potential of using synthetic follow-up OCT images for early detection of glaucoma progression., (© 2023. The Author(s).)

Data on how retinal structural and vascular parameters jointly influence the diagnostic performance of detection of multiple sclerosis (MS) patients without optic neuritis (MSNON) are lacking. To investigate the diagnostic performance of structural and vascular changes to detect MSNON from controls, we performed a cross-sectional study of 76 eyes from 51 MS participants and 117 eyes from 71 healthy controls. Retinal macular ganglion cell complex (GCC), retinal nerve fiber layer (RNFL) thicknesses, and capillary densities from the superficial (SCP) and deep capillary plexuses (DCP) were obtained from the Cirrus AngioPlex. The best structural parameter for detecting MS was compensated RNFL from the optic nerve head (AUC = 0.85), followed by GCC from the macula (AUC = 0.79), while the best vascular parameter was the SCP (AUC = 0.66). Combining structural and vascular parameters improved the diagnostic performance for MS detection (AUC = 0.90; p<0.001). Including both structure and vasculature in the joint model considerably improved the discrimination between MSNON and normal controls compared to each parameter separately (p = 0.027). Combining optical coherence tomography (OCT)-derived structural metrics and vascular measurements from optical coherence tomography angiography (OCTA) improved the detection of MSNON. Further studies may be warranted to evaluate the clinical utility of OCT and OCTA parameters in the prediction of disease progression., (© 2023 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

With the identification of novel targets, the number of interventional clinical trials in ophthalmology has increased. Visual acuity has for a long time been considered the gold standard endpoint for clinical trials, but in the recent years it became evident that other endpoints are required for many indications including geographic atrophy and inherited retinal disease. In glaucoma the currently available drugs were approved based on their IOP lowering capacity. Some recent findings do, however, indicate that at the same level of IOP reduction, not all drugs have the same effect on visual field progression. For neuroprotection trials in glaucoma, novel surrogate endpoints are required, which may either include functional or structural parameters or a combination of both. A number of potential surrogate endpoints for ophthalmology clinical trials have been identified, but their validation is complicated and requires solid scientific evidence. In this article we summarize candidates for clinical endpoints in ophthalmology with a focus on retinal disease and glaucoma. Functional and structural biomarkers, as well as quality of life measures are discussed, and their potential to serve as endpoints in pivotal trials is critically evaluated., (Copyright © 2022. Published by Elsevier Ltd.)

The imaging data of one eye from 154 healthy and 143 glaucoma participants were acquired to evaluate the contributions of the neuronal and vascular components within the retinal nerve fiber layer (RNFL) for detecting glaucoma and modeling visual field loss through the use of optical coherence tomography (OCT) and OCT angiography. The neuronal and vascular components within the circumpapillary RNFL were independently evaluated. In healthy eyes, the neuronal component showed a stronger association with age (r = -0.52, p < 0.001) compared to measured RNFL thickness (r = -0.46, p < 0.001). Using the neuronal component alone improved detection of glaucoma (AUC: 0.890 ± 0.020) compared to measured RNFL thickness (AUC: 0.877 ± 0.021; χ 2 = 5.54, p = 0.019). Inclusion of the capillary components with the sectoral neuronal component resulted in a significant improvement in glaucoma detection (AUC: 0.927 ± 0.015; χ 2 = 15.34, p < 0.001). After adjusting for potential confounders, AUC increased to 0.952 ± 0.011. Results from modeling visual field loss in glaucoma eyes suggest that visual field losses associated with neuronal thinning were moderated in eyes with a larger capillary component. These findings suggest that segregation of the neurovascular components could help improve understanding of disease pathophysiology and affect disease management in glaucoma., (© 2023 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.)

Background/aims: Neurofilament light chain (NfL) levels in cerebrospinal fluid and serum are reliable indicators for neuroaxonal damage in a broad spectrum of neurodegenerative diseases. Herein, we investigate NfL levels in serum and anterior chamber fluid of patients with glaucoma., Methods: Patients scheduled for routine glaucoma or cataract surgery were recruited for this study. Retinal nerve fibre layer thickness was measured by optical coherence tomography (OCT, Heidelberg Spectralis). NfL levels in serum and in anterior chamber fluid were analysed with Simoa SR-X Analyzer (Quanterix; NFLIGHT, Lexington, Massachusetts, USA). T-test was used for parametric data and Mann-Whitney-U test for nonparametric data. Spearman's rank-order correlation was used to investigate correlations. P values<0.05 were considered as statistically significant., Results: Sixty patients with glaucoma and 58 controls were enrolled. Serum NfL concentration of patients with glaucoma was similar to serum NfL concentration in controls (median (IQR); 22.7 (18.9) pg/mL vs 22.5 (24.0) pg/mL; p=0.763). A positive correlation of serum NfL with age was observed in both patients with glaucoma (r=0.77; p<0.001) and in the control group (r=0.82, p<0.001). In the anterior chamber fluid, the NfL concentration was substantially increased in patients with glaucoma compared with controls (20.7 (101.3) pg/mL vs 3.1 (2.9) pg/mL; p<0.001). Furthermore, we found a positive correlation of anterior chamber fluid NfL with preoperative intraocular pressure (r=0.39, p=0.003) and with retinal nerve fibre layer thickness (r=0.58, p<0.001)., Conclusion: NfL levels in anterior chamber fluid are elevated in patients with glaucoma and correlate with intraocular pressure and retinal nerve fibre layer thickness. The presented data strongly support anterior chamber fluid NfL as a new marker for glaucoma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: For OCT retinal thickness measurements to be used as a prodromal age-related macular degeneration (AMD) risk marker, the 3-dimensional (3D) topographic variation of the relationship between genetic susceptibility to AMD and retinal thickness needs to be assessed. We aimed to evaluate individual retinal layer thickness changes and topography at the macula that are associated with AMD genetic susceptibility., Design: Genetic association study., Participants: A total of 1579 healthy participants (782 Chinese, 353 Malays, and 444 Indians) from the multiethnic Singapore Epidemiology of Eye Diseases study were included., Methods: Spectral-domain OCT and automatic segmentation of individual retinal layers were performed to produce 10 retinal layer thickness measurements at each ETDRS subfield, producing 3D topographic information. Age-related macular degeneration genetic susceptibility was represented via single nucleotide polymorphisms (SNPs) and aggregated via whole genome (overall) and pathway-specific age-related macular degeneration polygenic risk score (PRS AMD )., Main Outcome Measures: Associations of individual SNPs, overall PRS AMD , and pathway-specific PRS AMD with retinal thickness were analyzed by individual retinal layer and ETDRS subfield., Results: CFH rs10922109, ARMS2-HTRA1 rs3750846, and LIPC rs2043085 were the top AMD susceptibility SNPs associated with retinal thickness of individual layers ( P  < 1.67 × 10 -3 ), all at the central subfield. The overall PRS AMD was most associated with thinner L9 (outer segment photoreceptor/retinal pigment epithelium complex) thickness at the central subfield (β = -0.63 μm; P  = 5.45 × 10 - 9 ). Pathway-specific PRS AMD for the complement cascade (β = -0.53 μm; P  = 9.42 × 10 - 7 ) and lipoprotein metabolism (β = -0.05 μm; P  = 0.0061) were associated with thinner photoreceptor layers (L9 and L7 [photoreceptor inner/outer segments], respectively) at the central subfield. The mean PRS AMD score was larger among Indians compared with that of the Chinese and had the thinnest thickness at the L9 central subfield (β = -1.00 μm; P  = 2.91 × 10 - 7 ; R 2  = 5.5%). Associations at other retinal layers and ETDRS regions were more heterogeneous., Conclusions: Overall genetic susceptibility to AMD and the aggregate effects of the complement cascade and lipoprotein metabolism pathway are associated most significantly with L7 and L9 photoreceptor thinning at the central macula in healthy individuals. Photoreceptor thinning has potential to be a prodromal AMD risk marker, and topographic variation should be considered., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2023 by the American Academy of Ophthalmology.)

Importance: The 3-dimensional (3-D) structural phenotype of glaucoma as a function of severity was thoroughly described and analyzed, enhancing understanding of its intricate pathology beyond current clinical knowledge., Objective: To describe the 3-D structural differences in both connective and neural tissues of the optic nerve head (ONH) between different glaucoma stages using traditional and artificial intelligence-driven approaches., Design, Setting, and Participants: This cross-sectional, clinic-based study recruited 541 Chinese individuals receiving standard clinical care at Singapore National Eye Centre, Singapore, and 112 White participants of a prospective observational study at Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania. The study was conducted from May 2022 to January 2023. All participants had their ONH imaged using spectral-domain optical coherence tomography and had their visual field assessed by standard automated perimetry., Main Outcomes and Measures: (1) Clinician-defined 3-D structural parameters of the ONH and (2) 3-D structural landmarks identified by geometric deep learning that differentiated ONHs among 4 groups: no glaucoma, mild glaucoma (mean deviation [MD], ≥-6.00 dB), moderate glaucoma (MD, -6.01 to -12.00 dB), and advanced glaucoma (MD, <-12.00 dB)., Results: Study participants included 213 individuals without glaucoma (mean age, 63.4 years; 95% CI, 62.5-64.3 years; 126 females [59.2%]; 213 Chinese [100%] and 0 White individuals), 204 with mild glaucoma (mean age, 66.9 years; 95% CI, 66.0-67.8 years; 91 females [44.6%]; 178 Chinese [87.3%] and 26 White [12.7%] individuals), 118 with moderate glaucoma (mean age, 68.1 years; 95% CI, 66.8-69.4 years; 49 females [41.5%]; 97 Chinese [82.2%] and 21 White [17.8%] individuals), and 118 with advanced glaucoma (mean age, 68.5 years; 95% CI, 67.1-69.9 years; 43 females [36.4%]; 53 Chinese [44.9%] and 65 White [55.1%] individuals). The majority of ONH structural differences occurred in the early glaucoma stage, followed by a plateau effect in the later stages. Using a deep neural network, 3-D ONH structural differences were found to be present in both neural and connective tissues. Specifically, a mean of 57.4% (95% CI, 54.9%-59.9%, for no to mild glaucoma), 38.7% (95% CI, 36.9%-40.5%, for mild to moderate glaucoma), and 53.1 (95% CI, 50.8%-55.4%, for moderate to advanced glaucoma) of ONH landmarks that showed major structural differences were located in neural tissues with the remaining located in connective tissues., Conclusions and Relevance: This study uncovered complex 3-D structural differences of the ONH in both neural and connective tissues as a function of glaucoma severity. Future longitudinal studies should seek to establish a connection between specific 3-D ONH structural changes and fast visual field deterioration and aim to improve the early detection of patients with rapid visual field loss in routine clinical care.

Glaucoma is a leading cause of irreversible blindness worldwide. To date, intraocular pressure (IOP) is the only modifiable risk factor in glaucoma treatment, but even in treated patients, the disease can progress. Cannabinoids, which have been known to lower IOP since the 1970s, have been shown to have beneficial effects in glaucoma patients beyond their IOP-lowering properties. In addition to the classical cannabinoid receptors CB 1 and CB 2 , knowledge of non-classical cannabinoid receptors and the endocannabinoid system has increased in recent years. In particular, the CB 2 receptor has been shown to mediate anti-inflammatory, anti-apoptotic, and neuroprotective properties, which may represent a promising therapeutic target for neuroprotection in glaucoma patients. Due to their vasodilatory effects, cannabinoids improve blood flow to the optic nerve head, which may suggest a vasoprotective potential and counteract the altered blood flow observed in glaucoma patients. The aim of this review was to assess the available evidence on the effects and therapeutic potential of cannabinoids in glaucoma patients. The pharmacological mechanisms underlying the effects of cannabinoids on IOP, neuroprotection, and ocular hemodynamics have been discussed.

In myopic eyes, pathological remodelling of collagen in the posterior sclera has mostly been observed ex vivo. Here we report the development of triple-input polarization-sensitive optical coherence tomography (OCT) for measuring posterior scleral birefringence. In guinea pigs and humans, the technique offers superior imaging sensitivities and accuracies than dual-input polarization-sensitive OCT. In 8-week-long studies with young guinea pigs, scleral birefringence was positively correlated with spherical equivalent refractive errors and predicted the onset of myopia. In a cross-sectional study involving adult individuals, scleral birefringence was associated with myopia status and negatively correlated with refractive errors. Triple-input polarization-sensitive OCT may help establish posterior scleral birefringence as a non-invasive biomarker for assessing the progression of myopia., (© 2023. The Author(s).)

Purpose: This prospective, randomized, observer-masked, parallel-group study aimed to compare the effect of topical azithromycin and oral doxycycline on tear film thickness (TFT) and signs and symptoms of ocular surface disease (OSD) in patients with meibomian gland dysfunction (MGD). Methods: Patients were randomized to either receive topical azithromycin or oral doxycycline. After a baseline visit, three follow-up visits at intervals of 2 weeks were scheduled. Main outcome of the study was change in TFT as measured with ultrahigh resolution optical coherence tomography. Results: Twenty patients were included in the analysis. TFT significantly increased in both groups ( P  = 0.028 vs. baseline) with no difference between the groups ( P  = 0.096). As secondary outcomes, ocular surface disease index (OSDI) score and composite signs of OSD significantly decreased in both groups ( P  = 0.023 for OSDI and P  = 0.016 for OSD signs vs. baseline). While eye-related adverse events (AEs) occurred more frequently in the azithromycin group, systemic AEs were more common in the doxycycline group. Conclusions: Both treatments improved signs and symptoms of OSD in patients with MGD with no difference between the groups. Due to the higher frequency of systemic side effects of doxycycline, azithromycin eye drops seem to be an alternative with comparable efficacy. Clinical Trial Registration number: NCT03162497.

Purpose: To use optical coherence tomography angiography (OCTA) parameters from both the retinal and choroidal microvasculature to detect the presence and severity of diabetic retinopathy (DR)., Method: This is a cross-sectional case-control study. OCTA parameters from retinal vasculature, fovea avascular zone (FAZ) and choriocapillaris were evaluated from 3×3 mm 2 fovea-centred scans. Areas under the receiver operating characteristic (ROC) curve were used to compare the discriminative power on the presence of diabetes mellitus (DM), the presence of DR and need for referral: group 1 (no DM vs DM no DR), group 2 (no DR vs any DR) and group 3 (non-proliferative DR (NPDR) vs proliferative DR (PDR))., Results: 35 eyes from 27 participants with no DM and 132 eyes from 75 with DM were included. DR severity was classified into three groups: no DR group (62 eyes), NPDR (51 eyes), PDR (19 eyes). All retinal vascular parameters, FAZ parameters and choriocapillaris parameters were strongly altered with DR stages (p<0.01), except for the deep plexus FAZ area (p=0.619). Choriocapillaris parameters allowed to better discriminate between no DM versus DM no DR group compared with retinal parameters (areas under the ROC curve=0.954 vs 0.821, p=0.006). A classification model including retinal and choroidal microvasculature significantly improved the discrimination between DR and no DR compared with each parameter separately (p=0.029)., Conclusions: Evaluating OCTA parameters from both the retinal and choroidal microvasculature in 3×3 mm scans improves the discrimination of DM and early DR., Competing Interests: Competing interests: GT reported receiving travel support from Carl Zeiss Pte Ltd; receiving personal fees and consultancy fees from Novartis; receiving grants from Bayer AG and Santen Pharmaceutical Company, Ltd; and receiving travel support from Alcon outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Pathologic myopia is a severe form of myopia that can lead to permanent visual impairment. The recent global increase in the prevalence of myopia has been projected to lead to a higher incidence of pathologic myopia in the future. Thus, imaging myopic eyes to detect early pathological changes, or predict myopia progression to allow for early intervention, has become a key priority. Recent advances in optical coherence tomography (OCT) have contributed to the new grading system for myopic maculopathy and myopic traction maculopathy, which may improve phenotyping and thus, clinical management. Widefield fundus and OCT imaging has improved the detection of posterior staphyloma. Non-invasive OCT angiography has enabled depth-resolved imaging for myopic choroidal neovascularisation. Artificial intelligence (AI) has shown great performance in detecting pathologic myopia and the identification of myopia-associated complications. These advances in imaging with adjunctive AI analysis may lead to improvements in monitoring disease progression or guiding treatments. In this review, we provide an update on the classification of pathologic myopia, how imaging has improved clinical evaluation and management of myopia-associated complications, and the recent development of AI algorithms to aid the detection and classification of pathologic myopia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The purpose of this study was to investigate the correlation between the pattern of optical coherence tomography (OCT) en face maps of the tear film lipid layer (TFLL) and lipid layer thickness (LLT), fluorescein breakup time (FBUT), and Schirmer I test values in healthy subjects., Methods: Measurements from four clinical data sets were retrospectively analyzed, and TFLL patterns were classified into 3 categories: homogeneous (HOM), wavy (WAV), or dotted (DOT) appearance. Linear mixed model analyses were performed. Intraclass correlation coefficients and index of qualitative variation were computed to investigate interrater and intrasubject variabilities., Results: For the LLT, a significant difference between HOM and DOT ( P < 0.001, β HOMvsDOT = -6.42 nm) and WAV and DOT ( P = 0.002, β WAVvsDOT = -4.04 nm) was found. Furthermore, the difference between WAV and DOT regarding FBUT ( P < 0.001, β WAVvsDOT = -3.065 seconds) was significant, while no significant differences between any of the classes with respect to the Schirmer I test values were found. An intraclass correlation coefficient of 89.0% reveals a good interrater reliability, and an index of qualitative variation of 60.0% shows, on average, a considerable variability in TFLL pattern class for repeated measurements over 1 hour., Conclusions: A new classification method for OCT en face maps of the TFLL is presented. Significant differences between patterns were found with respect to LLT and FBUT. A dotted pattern on dark background appears to be the most stable type of TFLL. The analysis of OCT en face maps of the TFLL provides complimentary information to conventional imaging methods and might give new insights into the characteristics of the TFLL., Competing Interests: Conflicts of interest statement: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To compare imaging modalities for the choroid of the eye, and evaluate various choroidal changes in uveitides entities., Methods: A comprehensive systematic literature review was conducted looking at current imaging modalities available to assess choroid architecture and commonly used parameters available to qualify and quantify choroidal changes, before looking at specific uveitides entities with choroidal involvement which have been broadly separated into non-infectious and infectious in etiology., Results: We describe the various modalities currently available to evaluate the choroid of the eye such as Ultrasound B Scan, ICGA, and OCT. Choroidal changes in various ocular and systemic diseases such as Behcet's Disease, Sarcoidosis, Syphillis, Tuberculosis, and many more have been reported and published., Conclusion: Multiple choroidal tomographic and angiotomographic findings have been demonstrated for evaluation in uveitis. These findings can manifest in multiple ocular and systemic diseases, and can be illustrated using the various imaging modalities at present. Future advancements in choroidal imaging would help to adapt these findings into parameters for clinical practice to properly evaluate these ocular and systemic diseases.

Introduction: Detection of neurological conditions is of high importance in the current context of increasingly ageing populations. Imaging of the retina and the optic nerve head represents a unique opportunity to detect brain diseases, but requires specific human expertise. We review the current outcomes of artificial intelligence (AI) methods applied to retinal imaging for the detection of neurological and neuro-ophthalmic conditions., Method: Current and emerging concepts related to the detection of neurological conditions, using AI-based investigations of the retina in patients with brain disease were examined and summarised., Results: Papilloedema due to intracranial hypertension can be accurately identified with deep learning on standard retinal imaging at a human expert level. Emerging studies suggest that patients with Alzheimer's disease can be discriminated from cognitively normal individuals, using AI applied to retinal images., Conclusion: Recent AI-based systems dedicated to scalable retinal imaging have opened new perspectives for the detection of brain conditions directly or indirectly affecting retinal structures. However, further validation and implementation studies are required to better understand their potential value in clinical practice.

A novel decorrelation-based approach for measuring localized transverse flow velocity using line-scan (LS) optical coherence tomography (OCT) is proposed. The new approach allows for separation of the flow velocity component along the line-illumination direction of the imaging beam from other orthogonal velocity components, from particle diffusion motion, and from noise-induced distortion in the OCT signal's temporal autocorrelation. The new method was verified by imaging flow in a glass capillary and a microfluidic device and mapping the spatial distribution of the flow velocity within the beam's illumination plane. This method can be extended in the future to map the three-dimensional flow velocity fields for both ex -vivo and in-vivo applications., Competing Interests: The authors declare no conflicts of interest related to this article., (© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Our study aims to identify children at risk of developing high myopia for timely assessment and intervention, preventing myopia progression and complications in adulthood through the development of a deep learning system (DLS). Using a school-based cohort in Singapore comprising of 998 children (aged 6-12 years old), we train and perform primary validation of the DLS using 7456 baseline fundus images of 1878 eyes; with external validation using an independent test dataset of 821 baseline fundus images of 189 eyes together with clinical data (age, gender, race, parental myopia, and baseline spherical equivalent (SE)). We derive three distinct algorithms - image, clinical and mix (image + clinical) models to predict high myopia development (SE ≤ -6.00 diopter) during teenage years (5 years later, age 11-17). Model performance is evaluated using area under the receiver operating curve (AUC). Our image models (Primary dataset AUC 0.93-0.95; Test dataset 0.91-0.93), clinical models (Primary dataset AUC 0.90-0.97; Test dataset 0.93-0.94) and mixed (image + clinical) models (Primary dataset AUC 0.97; Test dataset 0.97-0.98) achieve clinically acceptable performance. The addition of 1 year SE progression variable has minimal impact on the DLS performance (clinical model AUC 0.98 versus 0.97 in primary dataset, 0.97 versus 0.94 in test dataset; mixed model AUC 0.99 versus 0.97 in primary dataset, 0.95 versus 0.98 in test dataset). Thus, our DLS allows prediction of the development of high myopia by teenage years amongst school-going children. This has potential utility as a clinical-decision support tool to identify "at-risk" children for early intervention., (© 2023. The Author(s).)

Studies using machine learning (ML) approaches have reported high diagnostic accuracies for glaucoma detection. However, none assessed model performance across ethnicities. The aim of the study is to externally validate ML models for glaucoma detection from optical coherence tomography (OCT) data. We performed a prospective, cross-sectional study, where 514 Asians (257 glaucoma/257 controls) were enrolled to construct ML models for glaucoma detection, which was then tested on 356 Asians (183 glaucoma/173 controls) and 138 Caucasians (57 glaucoma/81 controls). We used the retinal nerve fibre layer (RNFL) thickness values produced by the compensation model, which is a multiple regression model fitted on healthy subjects that corrects the RNFL profile for anatomical factors and the original OCT data (measured) to build two classifiers, respectively. Both the ML models (area under the receiver operating [AUC] = 0.96 and accuracy = 92%) outperformed the measured data (AUC = 0.93; P < 0.001) for glaucoma detection in the Asian dataset. However, in the Caucasian dataset, the ML model trained with compensated data (AUC = 0.93 and accuracy = 84%) outperformed the ML model trained with original data (AUC = 0.83 and accuracy = 79%; P < 0.001) and measured data (AUC = 0.82; P < 0.001) for glaucoma detection. The performance with the ML model trained on measured data showed poor reproducibility across different datasets, whereas the performance of the compensated data was maintained. Care must be taken when ML models are applied to patient cohorts of different ethnicities., (© 2023. The Author(s).)

Introduction: The aim of this study was to describe the design and the participants' baseline characteristics of a prospective natural history study of geographic atrophy (GA) secondary to age-related macular degeneration., Methods: The optical coherence tomography (OCT) and microperimetry biomarker evaluation in patients with GA (OMEGA) study was conducted at a tertiary referral center (ClinicalTrials.gov identifier: NCT05963646). Participants were followed for 12 months during 4 visits (baseline and follow-up exams at weeks 12, 24, and 48) with best-corrected Early Treatment of Diabetic Retinopathy Study visual acuity, low-luminance visual acuity (LLVA), and quick contrast sensitivity function testing. Further, participants underwent spectral-domain OCT, OCT angiography, fundus autofluorescence imaging, and mesopic microperimetry testing., Results: Thirty participants (median [IQR] age of 79 [77, 84] years) and 37 study eyes were included with a (median [IQR]) GA area of 1.40 mm2 (0.49, 5.24) at baseline. Out of 37 study eyes, six developed macular neovascularizations (16%). The study-eye best-corrected visual acuity was (median [IQR]) 0.18 logarithm of the minimum angle of resolution (logMAR) (0.06, 0.26), LLVA 0.66 logMAR (0.36, 0.88), and the microperimetry mean sensitivity 18.4 dB (9.21, 20.9). The highest correlation between square root GA area and a visual function test was evident for LLVA (R2 of 0.578), followed by area under the log contrast sensitivity function curve (0.519) and microperimetral retinal sensitivity (0.487)., Conclusion: This report lays out the design and baseline characteristics of the OMEGA study, which aims to contribute to the understanding of the natural history of GA. The OMEGA study will provide estimates of the ability to detect change and retest reliability for a panel of structure and functional assessments., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Quantitative changes in retinal vessels and thinning of optic nerves have been associated with subclinical (atherosclerosis, inflammation) and clinical age-related brain pathologies (stroke and neurodegeneration). However, data on the association between both retinal vascular and neuronal parameters with cortical cerebral microinfarcts (CMIs) and how these factors jointly influence cognition are lacking., Aim: We investigated the association of retinal vascular and neuronal changes with CMIs on 3 T MRI and explored their interaction with cognitive impairment in a memory-clinic population., Methods: A total of 538 participants were included. Retinal vascular parameters (caliber, tortuosity, and fractal dimension) were measured from retinal fundus photographs using a semi-automated computer-assisted program. Retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thicknesses were obtained from optical coherence tomography. Cortical CMIs were defined as hypointense on T1-weighted MRI, <5 mm in diameter and restricted to the cortex. Cognition was assessed using Clinical Dementia Rating Sum-of-Boxes (CDR-SoB) score and detailed neuropsychological test. Multivariable regression analysis was conducted adjusting for age, sex, hypertension, hyperlipidemia, diabetes mellitus, smoking, diagnosis, white matter hyperintensities volume, lacunes, and cerebral microbleeds., Results: Larger venular caliber (Rate ratios (RR): 1.15, 95% CI: 1.01-1.38, p = 0.014), increased venular fractal dimension (RR: 1.58, 95% CI: 1.31-1.91, p ⩽ 0.001), increased venular tortuosity (RR: 1.54, 95% CI: 1.35-1.75, p ⩽ 0.001), and thinner GC-IPL (RR: 1.24, 95% CI: 1.13-1.36, p ⩽ 0.001) were associated with CMI counts. Among individuals in highest tertile of retinal parameters, a significant interaction was observed between venular tortuosity (RR: 1.12, 95% CI: 1.02-1.22, p-interaction = 0.014) and GC-IPL (RR: 1.05, 95% CI: 1.01-1.11, p-interaction < 0.001) with CMIs on CDR-SoB., Conclusion: Retinal vascular and neuronal parameters are associated with cortical CMIs, and persons with both pathologies are likely to have cognitive impairment. Further studies may be warranted to evaluate the clinical utility of retinal parameters and CMI in risk prediction for cognitive dysfunction.

The aim of this cross-sectional study was to assess retinal oxygen metabolism in patients with type 2 diabetes and different stages of nonproliferative diabetic retinopathy (DR) (n = 67) compared with healthy control subjects (n = 20). Thirty-four patients had no DR, 15 had mild DR, and 18 had moderate to severe DR. Retinal oxygen saturation in arteries and veins was measured using the oxygen module of a retinal vessel analyzer. Total retinal blood flow (TRBF) was measured using a custom-built Doppler optical coherence tomography system. Retinal oxygen extraction was calculated from retinal oxygen saturation and TRBF. Arteriovenous difference in oxygen saturation was highest in healthy subjects (34.9 ± 7.5%), followed by patients with no DR (32.5 ± 6.3%) and moderate to severe DR (30.3 ± 6.5%). The lowest values were found in patients with mild DR (27.3 ± 8.0%, P = 0.010 vs. healthy subjects). TRBF tended to be higher in patients with no DR (40.1 ± 9.2 μL/min) and mild DR (41.8 ± 15.0 μL/min) than in healthy subjects (37.2 ± 5.7 μL/min) and patients with moderate to severe DR (34.6 ± 10.4 μL/min). Retinal oxygen extraction was the highest in healthy subjects (2.24 ± 0.57 μL O2/min), followed by patients with no DR (2.14 ± 0.6 μL O2/min), mild DR (1.90 ± 0.77 μL O2/min), and moderate to severe DR (1.78 ± 0.57 μL O2/min, P = 0.040 vs. healthy subjects). These results indicate that retinal oxygen metabolism is altered in patients with type 2 diabetes. Furthermore, retinal oxygen extraction decreases with increasing severity of DR., (© 2022 by the American Diabetes Association.)

Aims/hypothesis: There is evidence that diabetes is accompanied by a break-down of functional hyperemia, an intrinsic mechanism of neural tissues to adapt blood flow to changing metabolic demands. However, to what extent functional hyperemia is altered in different stages of diabetic retinopathy (DR) in patients with type II diabetes is largely unknown. The current study set out to investigate flicker-induced retinal blood flow changes in patients with type II diabetes at different stages of DR., Materials and Methods: A total of 76 subjects were included in the present parallel-group study, of which 56 had diabetes with either no DR or different stages of non-proliferative DR ( n = 29 no DR, 12 mild DR, 15 moderate to severe DR). In addition, 20 healthy subjects were included as controls. Retinal blood flow was assessed before and during visual stimulation using a combined measurement of retinal vessel calibers and blood velocity by the means of Doppler optical coherence tomography (OCT). To measure systemic autonomic nervous system function, heart rate variability (HRV) was assessed using a short-term orthostatic challenge test., Results: In healthy controls, retinal blood flow increased by 40.4 ± 27.2% during flicker stimulation. Flicker responses in patients with DR were significantly decreased depending on the stage of the disease (no DR 37.7 ± 26.0%, mild DR 26.2 ± 28.2%, moderate to severe DR 22.3 ± 13.9%; p = 0.035, ANOVA). When assessing systemic autonomous neural function using HRV, normalized low frequency (LF) spectral power showed a significantly different response to the orthostatic maneuver in diabetic patients compared to healthy controls ( p < 0.001)., Conclusion/interpretation: Our study indicates that flicker induced hyperemia is reduced in patients with DR compared to healthy subjects. Further, this impairment is more pronounced with increasing severity of DR. Further studies are needed to elucidate mechanisms behind the reduced hyperemic response in patients with type II diabetes., Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [NCT03 552562]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hommer, Kallab, Schlatter, Janku, Werkmeister, Howorka, Schmidl, Schmetterer and Garhöfer.)

Objective: To describe the normative quantitative parameters of the macular retinal vasculature, as well as their systemic and ocular associations using OCT angiography (OCTA)., Design: Population-based, cross-sectional study., Subjects: Adults aged > 50 years were recruited from the third examination of the population-based Singapore Malay Eye Study., Methods: All participants underwent a standardized comprehensive examination and spectral-domain OCTA (Optovue) of the macula. OCT angiography scans that revealed pre-existing retinal disease, revealed macular pathology, and had poor quality were excluded., Main Outcome Measures: The normative quantitative vessel densities of the superficial layer, deep layer, and foveal avascular zone (FAZ) were evaluated. Ocular and systemic associations with macular retinal vasculature parameters were also evaluated in a multivariable analysis using linear regression models with generalized estimating equation models., Results: We included 1184 scans (1184 eyes) of 749 participants. The mean macular superficial vessel density (SVD) and deep vessel density (DVD) were 45.1 ± 4.2% (95% confidence interval [CI], 37.8%-51.4%) and 44.4 ± 5.2% (95% CI, 36.9%-53.2%), respectively. The mean SVD and DVD were highest in the superior quadrant (48.7 ± 5.9%) and nasal quadrant (52.7 ± 4.6%), respectively. The mean FAZ area and perimeter were 0.32 ± 0.11 mm 2 (95% CI, 0.17-0.51 mm) and 2.14 ± 0.38 mm (95% CI, 1.54-2.75 mm), respectively. In the multivariable regression analysis, female sex was associated with higher SVD (β = 1.25, P ≤ 0.001) and DVD (β = 0.75, P = 0.021). Older age (β = -0.67, P < 0.001) was associated with lower SVD, whereas longer axial length (β = -0.42, P = 0.003) was associated with lower DVD. Female sex, shorter axial length, and worse best-corrected distance visual acuity were associated with a larger FAZ area. No association of a range of systemic parameters with vessel density was found., Conclusions: This study provided normative macular vasculature parameters in an adult Asian population, which may serve as reference values for quantitative interpretation of OCTA data in normal and disease states., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: There is no simple model to screen for Alzheimer's disease, partly because the diagnosis of Alzheimer's disease itself is complex-typically involving expensive and sometimes invasive tests not commonly available outside highly specialised clinical settings. We aimed to develop a deep learning algorithm that could use retinal photographs alone, which is the most common method of non-invasive imaging the retina to detect Alzheimer's disease-dementia., Methods: In this retrospective, multicentre case-control study, we trained, validated, and tested a deep learning algorithm to detect Alzheimer's disease-dementia from retinal photographs using retrospectively collected data from 11 studies that recruited patients with Alzheimer's disease-dementia and people without disease from different countries. Our main aim was to develop a bilateral model to detect Alzheimer's disease-dementia from retinal photographs alone. We designed and internally validated the bilateral deep learning model using retinal photographs from six studies. We used the EfficientNet-b2 network as the backbone of the model to extract features from the images. Integrated features from four retinal photographs (optic nerve head-centred and macula-centred fields from both eyes) for each individual were used to develop supervised deep learning models and equip the network with unsupervised domain adaptation technique, to address dataset discrepancy between the different studies. We tested the trained model using five other studies, three of which used PET as a biomarker of significant amyloid β burden (testing the deep learning model between amyloid β positive vs amyloid β negative)., Findings: 12 949 retinal photographs from 648 patients with Alzheimer's disease and 3240 people without the disease were used to train, validate, and test the deep learning model. In the internal validation dataset, the deep learning model had 83·6% (SD 2·5) accuracy, 93·2% (SD 2·2) sensitivity, 82·0% (SD 3·1) specificity, and an area under the receiver operating characteristic curve (AUROC) of 0·93 (0·01) for detecting Alzheimer's disease-dementia. In the testing datasets, the bilateral deep learning model had accuracies ranging from 79·6% (SD 15·5) to 92·1% (11·4) and AUROCs ranging from 0·73 (SD 0·24) to 0·91 (0·10). In the datasets with data on PET, the model was able to differentiate between participants who were amyloid β positive and those who were amyloid β negative: accuracies ranged from 80·6 (SD 13·4%) to 89·3 (13·7%) and AUROC ranged from 0·68 (SD 0·24) to 0·86 (0·16). In subgroup analyses, the discriminative performance of the model was improved in patients with eye disease (accuracy 89·6% [SD 12·5%]) versus those without eye disease (71·7% [11·6%]) and patients with diabetes (81·9% [SD 20·3%]) versus those without the disease (72·4% [11·7%])., Interpretation: A retinal photograph-based deep learning algorithm can detect Alzheimer's disease with good accuracy, showing its potential for screening Alzheimer's disease in a community setting., Funding: BrightFocus Foundation., Competing Interests: Declaration of interests CYC, ARR, SW, CCT, P-AH, and VCTM are filing a patent for the deep learning model in this study. All authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Many artificial intelligence (AI) studies have focused on development of AI models, novel techniques, and reporting guidelines. However, little is understood about clinicians' perspectives of AI applications in medical fields including ophthalmology, particularly in light of recent regulatory guidelines. The aim for this study was to evaluate the perspectives of ophthalmologists regarding AI in 4 major eye conditions: diabetic retinopathy (DR), glaucoma, age-related macular degeneration (AMD) and cataract., Methods: This was a multi-national survey of ophthalmologists between March 1st, 2020 to February 29th, 2021 disseminated via the major global ophthalmology societies. The survey was designed based on microsystem, mesosystem and macrosystem questions, and the software as a medical device (SaMD) regulatory framework chaired by the Food and Drug Administration (FDA). Factors associated with AI adoption for ophthalmology analyzed with multivariable logistic regression random forest machine learning., Results: One thousand one hundred seventy-six ophthalmologists from 70 countries participated with a response rate ranging from 78.8 to 85.8% per question. Ophthalmologists were more willing to use AI as clinical assistive tools (88.1%, n = 890/1,010) especially those with over 20 years' experience (OR 3.70, 95% CI: 1.10-12.5, p = 0.035), as compared to clinical decision support tools (78.8%, n = 796/1,010) or diagnostic tools (64.5%, n = 651). A majority of Ophthalmologists felt that AI is most relevant to DR (78.2%), followed by glaucoma (70.7%), AMD (66.8%), and cataract (51.4%) detection. Many participants were confident their roles will not be replaced (68.2%, n = 632/927), and felt COVID-19 catalyzed willingness to adopt AI (80.9%, n = 750/927). Common barriers to implementation include medical liability from errors (72.5%, n = 672/927) whereas enablers include improving access (94.5%, n = 876/927). Machine learning modeling predicted acceptance from participant demographics with moderate to high accuracy, and area under the receiver operating curves of 0.63-0.83., Conclusion: Ophthalmologists are receptive to adopting AI as assistive tools for DR, glaucoma, and AMD. Furthermore, ML is a useful method that can be applied to evaluate predictive factors on clinical qualitative questionnaires. This study outlines actionable insights for future research and facilitation interventions to drive adoption and operationalization of AI tools for Ophthalmology., Competing Interests: DG reports appointment as Physician Leader (Telemedicine) for Raffles Medical Group (SGX:$BSL.SI) and investments in digital health start-ups AskDr, Doctorbell (acquired by MaNaDr), Shyfts, and VISRE. JC reports appointment as a consultant to Boston AI labs. AYL reports grants from Santen, personal fees from Genentech, US FDA, Johnson and Johnson, grants from Carl Zeiss Meditec, personal fees from Topcon, Gyroscope, non-financial support from Microsoft, grants from Regeneron, outside the submitted work; This article does not reflect the views of the US FDA. PK reports having acted as a consultant for DeepMind, Roche, Novartis, Apellis, and BitFount and is an equity owner in Big Picture Medical. He has received speaker fees from Heidelberg Engineering, Topcon, Allergan, and Bayer. AF reports honoraria, advisory board and grant funding from Alcon, Bayer, Novartis, Allergan, Roche, and Syneos Health. AL reports grants from Roche and Novartis, and appointment as a consultant to NotalVision, Allergan, Bayer, WebMD, and Beyeonics. AG reports appointment to provide lectures for Pfizer, Thea, and Polpharma. TS reports appointment as a consultant & advisory board for Bayer Yakuhin, Boehringer-Ingelheim, Novartis, Chugai, Senju, and Santen. DM reports funding support from the Singapore National Medical Research Council (NMRC-CIRG18Nov-0013), and the Duke-NUS Medical School, Singapore (ACP 05/FY2019/P2/06-A60). DM also reports appointment as consultant and Advisory Board Member of Optomed, Finland. TW reports appointment as the deputy group chief executive officer (research and education) of Singapore Health Services, a consultant & advisory board for Allergan, Bayer, Boehringer-Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics), Roche, and co-founder of Plano. DT reports funding from the following grants for research about AI in healthcare: National Medical Research Council, Singapore (NMRC/HSRG/0087/2018; MOH-000655-00), National Health Innovation Center, Singapore (NHIC-COV19-2005017), SingHealth Fund Limited Foundation (SHF/HSR113/2017), Duke-NUS Medical School, Singapore (Duke-NUS/RSF/2021/0018; 05/FY2020/EX/15-A58), and Agency for Science, Technology and Research (ASTAR), Singapore (A20H4g2141 and A20H4g2141). DT, GL, and TW also report being the co-inventors of a deep learning system for retinal diseases and co-founders of related start-up Eyris; potential conflicts of interests are managed according to institutional policies of the Singapore Health System (SingHealth) and the National University of Singapore (NUS). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gunasekeran, Zheng, Lim, Chong, Zhang, Ng, Keel, Xiang, Park, Park, Chandra, Wu, Campbel, Lee, Keane, Denniston, Lam, Fung, Chan, Sadda, Loewenstein, Grzybowski, Fong, Wu, Bachmann, Zhang, Yam, Cheung, Pongsachareonnont, Ruamviboonsuk, Raman, Sakamoto, Habash, Girard, Milea, Ang, Tan, Schmetterer, Cheng, Lamoureux, Lin, van Wijngaarden, Wong and Ting.)

Purpose: To identify choroidal characteristics associated with susceptibility to development of naturally occurring and experimentally induced myopia., Methods: We compared choroidal properties between pigmented and albino guinea pig (GP) strains. Biometry, cycloplegic refractive error (RE), and eye wall sublayer thickness were measured from 171 GPs at postnatal day (P)6, 14, and 28. Forty-three P14 GPs underwent two-week monocular form-deprivation myopia (FDM). En face images of choroidal vasculature were obtained with a customized swept-source optical coherence tomography. Multivariate regression analyses were performed, with P28 RE as the outcome and P14 choroidal thickness (ChT) as the main predictor variable. Proteomic analysis was performed on choroidal tissue from P14 albino and pigmented GPs., Results: At P14, RE was correlated with thickness of the choroid (β = 0.06), sclera (β = 0.12), and retina (β = 0.27; all P < 0.001). P14 ChT was correlated with P28 RE both with (β = 0.06, P = 0.0007) and without FDM (β = 0.05, P = 0.008). Multivariate regression analysis, taking into account FDM (versus physiological growth) and strain, revealed that for every 10-µm greater ChT at P14, P28 RE was 0.50D more positive (P = 0.005, n = 70). En face images of choroidal sublayers showed that albino choroids were relatively underdeveloped, with frequent avascular regions. Consistent with this finding, proteomic analysis suggested abnormalities of the nitric oxide system in the albino GP choroid., Conclusions: Current results are consistent with the notion that greater ChT could protect from or delay the onset of myopia, while lower ChT is associated with greater susceptibility to myopia development. The underlying mechanism could be related to dysfunction of the choroidal vascular system.