Association of retinal image-based, deep learning cardiac BioAge with telomere length and cardiovascular biomarkers.

SIGNIFICANCE: Our retinal image-based deep learning (DL) cardiac biological age (BioAge) model could facilitate fast, accurate, noninvasive screening for cardiovascular disease (CVD) in novel community settings and thus improve outcome with those with limited access to health care services. PURPOSE: This study aimed to determine whether the results issued by our DL cardiac BioAge model are consistent with the known trends of CVD risk and the biomarker leukocyte telomere length (LTL), in a cohort of individuals from the UK Biobank. METHODS: A cross-sectional cohort study was conducted using those individuals in the UK Biobank who had LTL data. These individuals were divided by sex, ranked by LTL, and then grouped into deciles. The retinal images were then presented to the DL model, and individual's cardiac BioAge was determined. Individuals within each LTL decile were then ranked by cardiac BioAge, and the mean of the CVD risk biomarkers in the top and bottom quartiles was compared. The relationship between an individual's cardiac BioAge, the CVD biomarkers, and LTL was determined using traditional correlation statistics. RESULTS: The DL cardiac BioAge model was able to accurately stratify individuals by the traditional CVD risk biomarkers, and for both males and females, those issued with a cardiac BioAge in the top quartile of their chronological peer group had a significantly higher mean systolic blood pressure, hemoglobin A1c, and 10-year Pooled Cohort Equation CVD risk scores compared with those individuals in the bottom quartile (p<0.001). Cardiac BioAge was associated with LTL shortening for both males and females (males: -0.22, r2 = 0.04; females: -0.18, r2 = 0.03). CONCLUSIONS: In this cross-sectional cohort study, increasing CVD risk whether assessed by traditional biomarkers, CVD risk scoring, or our DL cardiac BioAge, CVD risk model, was inversely related to LTL. At a population level, our data support the growing body of evidence that suggests LTL shortening is a surrogate marker for increasing CVD risk and that this risk can be captured by our novel DL cardiac BioAge model.

Hyperbaric oxygen as a model of lens aging in the bovine lens: The effects on lens biochemistry, physiology and optics.

Age related nuclear (ARN) cataracts in humans take years to form and so experimental models have been developed to mimic the process in animals as a means of better understanding the etiology of nuclear cataracts in humans. A major limitation with these animal models is that many of the biochemical and physiological changes are not typical of that seen in human ARN cataract. In this review, we highlight the work of Frank Giblin and colleagues who established an in vivo animal model that replicates many of the changes observed in human ARN cataract. This model involves exposing aged guinea pigs to hyperbaric oxygen (HBO), which by causing the depletion of the antioxidant glutathione (GSH) specifically in the lens nucleus, produces oxidative changes to nuclear proteins, nuclear light scattering and a myopic shift in lens power that mimics the change that often precedes cataract development in humans. However, this model involves multiple HBO treatments per week, with sometimes up to a total of 100 treatments, spanning up to eight months, which is both costly and time consuming. To address these issues, Giblin developed an in vitro model that used rabbit lenses exposed to HBO for several hours which was subsequently shown to replicate many of the changes observed in human ARN cataract. These experiments suggest that HBO treatment of in vitro animal lenses may serve as a more economical and efficient model to study the development of cataract. Inspired by these experiments, we investigated whether exposure of young bovine lenses to HBO for 15 h could also serve as a suitable acute model of ARN cataract. We found that while this model is able to exhibit some of the biochemical and physiological changes associated with ARN cataract, the decrease in lens power we observed was more characteristic of the hyperopic shift in refraction associated with ageing. Future work will investigate whether HBO treatment to age the bovine lens in combination with an oxidative stressor such as UV light will induce refractive changes more closely associated with human ARN cataract. This will be important as developing an animal model that replicates the changes to lens biochemistry, physiology and optics observed in human ARN cataracts is urgently required to facilitate the identification and testing of anti-cataract therapies that are effective in humans.

Relationship between rheological properties and transverse relaxation time (T2) of artificial and porcine vitreous humour.

Vitreous liquefactive processes play an integral role in ocular health. Knowledge of the degree of liquefaction would allow better monitoring of ocular disease progression and enable more informed therapeutic dosing for an individual patient. Presently this process cannot be monitored in a non-invasive manner. Here, we evaluated whether magnetic resonance imaging (MRI) could predict the viscoelasticity and in turn liquefactive state of artificial and biological vitreous humour. Gels comprising identical concentrations of hyaluronic acid and agar ranging from 0.125 to 2.25 mg/ml of each polymer were prepared and their T2 was measured using a turbo-spin echo sequence via 3T clinical MRI. The gels were subsequently subjected to rheological frequency and flow sweeps and trends between T2 and rheological parameters were assessed. The relationship between T2 and vitreous humour rheology was further assessed using ex vivo porcine eyes. An optimised imaging technique improved homogeneity of obtained artificial vitreous humour T2 maps. Strong correlations were observed between T2 and various rheological parameters of the gels. Translation to porcine vitreous humour demonstrated that the T2 of biological tissue was related to its viscoelastic properties. This study shows that T2 can be correlated with various rheological parameters within gels. Future investigations will assess the translatability of these findings to live models.

Repeatability of Arterial Spin Labeling MRI in Measuring Blood Perfusion in the Human Eye.

BACKGROUND: Quantifying blood perfusion in ocular tissues is challenging, partly because the majority of the blood is carried by the choroid, which is difficult to visualize because it is located between the retina and sclera. PURPOSE/HYPOTHESIS: To evaluate the intra- and interday repeatability of MRI measures of chorio-retinal blood perfusion. STUDY TYPE: Prospective, cross-sectional, observational study. POPULATION: Twenty young healthy adults (six male, age: 25 ± 5 years) scanned twice within a single session repeated at the same time of day on 2 days. FIELD STRENGTH/SEQUENCE: Arterial spin labeling (ASL) MRI at 3.0T using pseudocontinuous ASL (PCASL) labeling scheme and a 3D turbo-gradient-spin-echo (TGSE) acquisition, including axial T2 -weighted structural images using a 2D turbo-spin-echo (TSE) sequence. ASSESSMENTS: Region-of-interest analysis for assessment of chorio-retinal blood perfusion. STATISTICAL TESTS: Intra- and interday repeatability of measures analyzed using intraclass correlation coefficients (ICC), Pearson's correlation analysis, paired t-tests, and Bland-Altman plots. RESULTS: The mean chorio-retinal perfusion was 77.86 (standard deviation [SD] = 29.80) ml/100ml/min. Perfusion measurements correlated strongly within a single session (r = 0.95, 95% confidence interval [CI] [0.880-0.980], P < 0.001) and between the two sessions based on a single run (r = 0.80 [0.582-0.913], P < 0.001), and two runs (r = 0.80 [0.479-0.918], P < 0.001). There were mean differences of 2.69 [16.85 to -22.23] ml/100ml/min for intraday measures, -7.44 [27.45 to -42.32] ml/100ml/min for single-run interday measures, and 5.73 [28.71 to -40.17] ml/100ml/min for two-run interday measures, but none were significant (all P > 0.05). DATA CONCLUSION: Quantitative ASL-MRI measurements of chorio-retinal blood perfusion showed high intra- and interday repeatability. The ASL-MRI technique provides reliable measures of chorio-retinal perfusion in vivo. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;49:966-974.

Dynamic functional contribution of the water channel AQP5 to the water permeability of peripheral lens fiber cells.

Although the functionality of the lens water channels aquaporin 1 (AQP1; epithelium) and AQP0 (fiber cells) is well established, less is known about the role of AQP5 in the lens. Since in other tissues AQP5 functions as a regulated water channel with a water permeability (PH2O) some 20 times higher than AQP0, AQP5 could function to modulate PH2O in lens fiber cells. To test this possibility, a fluorescence dye dilution assay was used to calculate the relative PH2O of epithelial cells and fiber membrane vesicles isolated from either the mouse or rat lens, in the absence and presence of HgCl2, an inhibitor of AQP1 and AQP5. Immunolabeling of lens sections and fiber membrane vesicles from mouse and rat lenses revealed differences in the subcellular distributions of AQP5 in the outer cortex between species, with AQP5 being predominantly membranous in the mouse but predominantly cytoplasmic in the rat. In contrast, AQP0 labeling was always membranous in both species. This species-specific heterogeneity in AQP5 membrane localization was mirrored in measurements of PH2O, with only fiber membrane vesicles isolated from the mouse lens, exhibiting a significant Hg2+-sensitive contribution to PH2O. When rat lenses were first organ cultured, immunolabeling revealed an insertion of AQP5 into cortical fiber cells, and a significant increase in Hg2+-sensitive PH2O was detected in membrane vesicles. Our results show that AQP5 forms functional water channels in the rodent lens, and they suggest that dynamic membrane insertion of AQP5 may regulate water fluxes in the lens by modulating PH2O in the outer cortex.

The lens internal microcirculation system delivers solutes to the lens core faster than would be predicted by passive diffusion.

It has been proposed that optical properties of the lens are actively maintained by an internal microcirculation system that utilizes ionic and fluid fluxes to deliver nutrients to deeper regions of the lens tissue via the extracellular space faster than would occur by passive diffusion alone. To test this hypothesis, we utilized a range of commercially available magnetic resonance imaging (MRI) reagents of varying molecular sizes that served as tracers of extracellular solute delivery. The penetration of these tracers into bovine lenses incubated in the absence and presence of solutions that inhibit the microcirculation was monitored in real time over a 4-h period using T1-weighted MRI. We found that only the smaller contrast agents were delivered to the core of the lens and that the rate of solute penetration was significantly faster than that calculated simple diffusion. Next, the lenses were first incubated in either high extracellular K+ to depolarize the lens potential or ouabain to inhibit the Na+ pump. These two perturbations are known to inhibit the circulating ionic and fluid fluxes that are proposed to drive solute delivery into the lens core. Both perturbations inhibited the delivery of the extracellular tracer molecules to the lens core. Our findings suggest that the microcirculation system can potentially be harnessed to deliver exogenous antioxidants to the lens core to afford mature fiber cells protection against oxidative damage that ultimately manifests as age-related nuclear cataract.

Novel roles for the lens in preserving overall ocular health.

Outside the traditional roles of the lens as an important refractive element and a UV filter, it was David Beebe's group that first demonstrated that the lens acts an oxygen sink that protects the tissues of the anterior segment of the eye from oxygen or oxygen metabolites. In this review, we follow on from this work, and present new evidence from our laboratory to demonstrate that the lens serves as a reservoir for the release of the antioxidant glutathione (GSH) into the aqueous humor to provide a source of GSH and/or its precursor amino acids to nearby tissues that interface with the aqueous humor, or to remove toxic metabolites from the eye via the aqueous outflow pathway. In addition to GSH release, our laboratory and others have shown that ATP is released from the lens under hyposmotic conditions to activate purinergic signalling pathways in an autocrine manner to alter lens function. In this review, we raise the idea that ATP and/or its subsequent degradation product adenosine may exert a paracrine function and influence purinergic signalling systems in other tissues to alter aqueous humor outflow. These new secondary roles indicate that the lens is not just a passive optical element, but a highly dynamic and active tissue that interacts with its neighbouring tissues, through modifying the environments in which these tissues function. We believe that the lens actively contributes to the ocular environment and as a consequence, removal of the lens would alter the functionality of neighbouring tissues. We speculate that a long term effect of lens removal may be to inadvertently increase the exposure of anterior tissues of the eye to oxidative stress due to elevated oxygen levels and a reduction in the availability of GSH and purinergic signalling molecules in the aqueous humor. Since cataract surgery is now being performed on younger patients due to our increasing diabetic population, over time, we predict these changes may increase the susceptibility of these tissues to oxidative stress and the incidence of subsequent ocular pathologies. If our view of the lens is correct, the actual loss of the biological lens may have longer term consequences for overall ocular health than currently appreciated.

The effect of flavonoids on visual function in patients with glaucoma or ocular hypertension: a systematic review and meta-analysis.

BACKGROUND: Glaucoma is a leading cause of irreversible blindness worldwide. A major symptom of this pathology is the loss to the visual field in a peripheral to central pattern. Flavonoids are polyphenol compounds sourced from plants, commonly found in green tea, red wine and cocoa, and they have neuroprotective and antioxidant characteristics proposed to be advantageous within the context of glaucoma. Currently, the literature presents conflicting evidence regarding the effect of flavonoids on patients with glaucoma and ocular hypertension; hence a systematic review and meta-analysis was conducted. METHOD: Databases included in our literature search were EMBASE (1980-present), MEDLINE Ovid, Alternative and Complementary Medicine Database (AMED), Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Central Register of Controlled Trials (CENTRAL). Meta-analysis was performed using RevMan 5 (Review Manager) 5 software, version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen). The primary outcomes were visual field mean deviation (MD) and intraocular pressure (IOP). Secondary outcomes were ocular blood flow and blood pressure (BP). CONCLUSION: Meta-analyses showed that flavonoids have a promising role in improving visual function in patients with glaucoma and ocular hypertension (OHT), and appear to play a part in both improving and slowing the progression of visual field loss.

Alterations in Lens Free Water Distribution Are Associated with Shape Deformation in Accommodation.

Objective: To investigate whether a redistribution of water within the crystalline lens is associated with the shape deformation that occurs during accommodation. Design: Observational, cross sectional study. Subjects: Eleven young adults without presbyopia (aged 18-39 years) and 9 middle-aged adults with presbyopia (aged 40-55 years). Methods: Magnetic resonance imaging (MRI) scans of the lens were acquired on a 3 Tesla clinical MRI scanner, without and with the presentation of a 3 Diopter accommodative stimulus. The MRIs were postprocessed using established methods to extract the geometric dimensions and spatial maps of water distribution of the lens. Main Outcome Measures: Accommodative changes in the full 3-dimensional description of lens shape, the lens total-water distribution profile, and the lens free-water distribution profile. Results: Viewing of an accommodative stimulus by young subjects elicited an elastic shape deformation of the lens consistent with accommodation that was associated with an elevated, smoother free-water distribution, primarily in the anterior region of the lens. In contrast, viewing of an accommodative stimulus by presbyopic subjects produced an atypical shape deformation of the lens that was instead associated with a lowered free-water distribution, primarily in the anterior region of the lens. No discernible changes to the lens total-water distribution were observed in response to the accommodative stimulus in either subject cohort. Conclusions: The present study suggests that protein-mediated alterations in the free-water distribution of the anterior region of the lens influence the shape deformation in accommodation, presenting pharmacological modulation of free-water distribution as an attractive novel approach for treating presbyopia. Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.

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

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

A computer model of lens structure and function predicts experimental changes to steady state properties and circulating currents.

BACKGROUND: In a previous study (Vaghefi et al. 2012) we described a 3D computer model that used finite element modeling to capture the structure and function of the ocular lens. This model accurately predicted the steady state properties of the lens including the circulating ionic and fluid fluxes that are believed to underpin the lens internal microcirculation system. In the absence of a blood supply, this system brings nutrients to the core of the lens and removes waste products faster than would be achieved by passive diffusion alone. Here we test the predictive properties of our model by investigating whether it can accurately mimic the experimentally measured changes to lens steady-state properties induced by either depolarising the lens potential or reducing Na+ pump rate. METHODS: To mimic experimental manipulations reported in the literature, the boundary conditions of the model were progressively altered and the model resolved for each new set of conditions. Depolarisation of lens potential was implemented by increasing the extracellular [K+], while inhibition of the Na+ pump was stimulated by utilising the inherent temperature sensitivity of the pump and changing the temperature at which the model was solved. RESULTS: Our model correctly predicted that increasing extracellular [K+] depolarizes the lens potential, reducing and then reversing the magnitude of net current densities around the lens. While lowering the temperature reduced Na+ pump activity and caused a reduction in circulating current, it had a minimal effect on the lens potential, a result consistent with published experimental data. CONCLUSION: We have shown that our model is capable of accurately simulating the effects of two known experimental manipulations on lens steady-state properties. Our results suggest that the model will be a valuable predictive tool to support ongoing studies of lens structure and function.

Automation of Macular Degeneration Classification in the AREDS Dataset, Using a Novel Neural Network Design.

Purpose: To create an ensemble of Convolutional Neural Networks (CNNs), capable of detecting and stratifying the risk of progressive age-related macular degeneration (AMD) from retinal photographs. Design: Retrospective cohort study. Methods: Three individual CNNs are trained to accurately detect 1) advanced AMD, 2) drusen size and 3) the presence or otherwise of pigmentary abnormalities, from macular centered retinal images were developed. The CNNs were then arranged in a "cascading" architecture to calculate the Age-related Eye Disease Study (AREDS) Simplified 5-level risk Severity score (Risk Score 0 - Risk Score 4), for test images. The process was repeated creating a simplified binary "low risk" (Scores 0-2) and "high risk" (Risk Score 3-4) classification. Participants: There were a total of 188,006 images, of which 118,254 images were deemed gradable, representing 4591 patients, from the AREDS1 dataset. The gradable images were split into 50%/25%/25% ratios for training, validation and test purposes. Main Outcome Measures: The ability of the ensemble of CNNs using retinal images to predict an individual's risk of experiencing progression of their AMD based on the AREDS 5-step Simplified Severity Scale. Results: When assessed against the 5-step Simplified Severity Scale, the results generated by the ensemble of CNN's achieved an accuracy of 80.43% (quadratic kappa 0.870). When assessed against a simplified binary (Low Risk/High Risk) classification, an accuracy of 98.08%, sensitivity of ≥85% and specificity of ≥99% was achieved. Conclusion: We have created an ensemble of neural networks, trained on the AREDS 1 dataset, that is able to accurately calculate an individual's score on the AREDS 5-step Simplified Severity Scale for AMD. If the results presented were replicated, then this ensemble of CNNs could be used as a screening tool that has the potential to significantly improve health outcomes by identifying asymptomatic individuals who would benefit from AREDS2 macular supplements.

Examination of alternative eGFR definitions on the performance of deep learning models for detection of chronic kidney disease from fundus photographs.

Deep learning (DL) models have shown promise in detecting chronic kidney disease (CKD) from fundus photographs. However, previous studies have utilized a serum creatinine-only estimated glomerular rate (eGFR) equation to measure kidney function despite the development of more up-to-date methods. In this study, we developed two sets of DL models using fundus images from the UK Biobank to ascertain the effects of using a creatinine and cystatin-C eGFR equation over the baseline creatinine-only eGFR equation on fundus image-based DL CKD predictors. Our results show that a creatinine and cystatin-C eGFR significantly improved classification performance over the baseline creatinine-only eGFR when the models were evaluated conventionally. However, these differences were no longer significant when the models were assessed on clinical labels based on ICD10. Furthermore, we also observed variations in model performance and systemic condition incidence between our study and the ones conducted previously. We hypothesize that limitations in existing eGFR equations and the paucity of retinal features uniquely indicative of CKD may contribute to these inconsistencies. These findings emphasize the need for developing more transparent models to facilitate a better understanding of the mechanisms underpinning the ability of DL models to detect CKD from fundus images.

A multi-centre prospective evaluation of THEIA™ to detect diabetic retinopathy (DR) and diabetic macular oedema (DMO) in the New Zealand screening program.

PURPOSE: To validate the potential application of THEIA™ as clinical decision making assistant in a national screening program. METHODS: A total of 900 patients were recruited from either an urban large eye hospital, or a semi-rural optometrist led screening provider, as they were attending their appointment as part of New Zealand Diabetic Eye Screening Programme. The de-identified images were independently graded by three senior specialists, and final results were aggregated using New Zealand grading scheme, which was then converted to referable/non-referable and Healthy/mild/more than mild/sight threatening categories. RESULTS: THEIA™ managed to grade all images obtained during the study. Comparing the adjudicated images from the specialist grading team, "ground truth", with the grading by the AI platform in detecting "sight threatening" disease, at the patient level THEIA™ achieved 100% imageability, 100% [98.49-100.00%] sensitivity and [97.02-99.16%] specificity, and negative predictive value of 100%. In other words, THEIA™ did not miss any patients with "more than mild" or "sight threatening" disease. The level of agreement between the clinicians and the aggregated results was (k value: 0.9881, 0.9557, and 0.9175), and the level of agreement between THEIA™ and the aggregated labels was (k value: 0.9515). CONCLUSION: This multi-centre prospective trial showed that THEIA™ did not miss referable disease when screening for diabetic retinopathy and maculopathy. It also had a very high level of granularity in reporting the disease level. As THEIA™ has been tested on a variety of cameras, operating in a range of clinics (rural/urban, ophthalmologist-led\optometrist-led), we believe that it will be a suitable addition to a public diabetic screening program.

Magnetic resonance and confocal imaging of solute penetration into the lens reveals a zone of restricted extracellular space diffusion.

It has been proposed that in the absence of blood supply, the ocular lens operates an internal microcirculation system that delivers nutrients to internalized fiber cells faster and more efficiently than would occur by passive diffusion alone. To visualize the extracellular space solute fluxes potentially generated by this system, bovine lenses were organ cultured in artificial aqueous humor (AAH) for 4 h in the presence or absence of two gadolinium-based contrast agents, ionic Gd(3+), or a chelated form of Gd(3+), Gd-diethylenetriamine penta-acetic acid (Gd-DTPA; mol mass = 590 Da). Contrast reagent penetration into the lens core was monitored in real time using inversion recovery-spin echo (IR-SE) magnetic resonance imaging (MRI), while steady-state accumulation of [Gd-DTPA](-2) was also determined by calculating T1 values. After incubation, lenses were fixed and cryosectioned, and sections were labeled with the membrane marker wheat germ agglutinin (WGA). Sections were imaged by confocal microscopy using standard and reflectance imaging modalities to visualize the fluorescent WGA label and gadolinium reagents, respectively. Real-time IR-SE MRI showed rapid penetration of Gd(3+) into the outer cortex of the lens and a subsequent bloom of signal in the core. These two areas of signal were separated by an area in the inner cortex that limited entry of Gd(3+). Similar results were obtained for Gd-DTPA, but the penetration of the larger negatively charged molecule into the core could only be detected by calculating T1 values. The presence of Gd-DTPA in the extracellular space of the outer cortex and core, but its apparent absence from the inner cortex was confirmed using reflectance imaging of equatorial sections. In axial sections, Gd-DTPA was associated with the sutures, suggesting these structures provide a pathway from the surface, across the inner cortex barrier to the lens core. Our studies have revealed inner and outer boundaries of a zone within which a narrowing of the extracellular space restricts solute diffusion and acts to direct fluxes into the lens core via the sutures.

Development of a 3D finite element model of lens microcirculation.

BACKGROUND: It has been proposed that in the absence of a blood supply, the ocular lens operates an internal microcirculation system. This system delivers nutrients, removes waste products and maintains ionic homeostasis in the lens. The microcirculation is generated by spatial differences in membrane transport properties; and previously has been modelled by an equivalent electrical circuit and solved analytically. While effective, this approach did not fully account for all the anatomical and functional complexities of the lens. To encapsulate these complexities we have created a 3D finite element computer model of the lens. METHODS: Initially, we created an anatomically-correct representative mesh of the lens. We then implemented the Stokes and advective Nernst-Plank equations, in order to model the water and ion fluxes respectively. Next we complemented the model with experimentally-measured surface ionic concentrations as boundary conditions and solved it. RESULTS: Our model calculated the standing ionic concentrations and electrical potential gradients in the lens. Furthermore, it generated vector maps of intra- and extracellular space ion and water fluxes that are proposed to circulate throughout the lens. These fields have only been measured on the surface of the lens and our calculations are the first 3D representation of their direction and magnitude in the lens. CONCLUSION: Values for steady state standing fields for concentration and electrical potential plus ionic and fluid fluxes calculated by our model exhibited broad agreement with observed experimental values. Our model of lens function represents a platform to integrate new experimental data as they emerge and assist us to understand how the integrated structure and function of the lens contributes to the maintenance of its transparency.

Inter-day repeatability assessment of human retinal blood flow using clinical laser speckle contrast imaging.

Laser speckle contrast imaging (LSCI) can generate retinal blood flow maps inexpensively and non-invasively. These flow maps can be used to identify various eye disorders associated with reduced blood flow. Despite early success, one of the major obstacles to clinical adoption of LSCI is poor repeatability of the modality. Here, we propose an LSCI registration pipeline that registers contrast maps to correct for rigid movements. Post-registration, intra(same)-day and inter(next)-day repeatability are studied using various quantitative metrics. We have studied LSCI repeatability intra-day by using the coefficient of variation. Using the processing pipelines and custom hardware developed, similar repeatability was observed when compared to previously reported values in the literature. Inter-day repeatability analysis indicates no statistical evidence (p = 0.09) of a difference between flow measurements performed on two independent days. Further improvements to hardware, environmental controls, and participant control must be made to provide higher confidence in the repeatability of blood flow. However, this is the first time that repeatability across two different days (inter-day) using multiple exposure speckle imaging (MESI) has been analyzed and reported.

Patients Perceptions of Artificial Intelligence in Diabetic Eye Screening.

PURPOSE: Artificial intelligence (AI) technology is poised to revolutionize modern delivery of health care services. We set to evaluate the patient perspective of AI use in diabetic retinal screening. DESIGN: Survey. METHODS: Four hundred thirty-eight patients undergoing diabetic retinal screening across New Zealand participated in a survey about their opinion of AI technology in retinal screening. The survey consisted of 13 questions covering topics of awareness, trust, and receptivity toward AI systems. RESULTS: The mean age was 59 years. The majority of participants identified as New Zealand European (50%), followed by Asian (31%), Pacific Islander (10%), and Maori (5%). Whilst 73% of participants were aware of AI, only 58% have heard of it being implemented in health care. Overall, 78% of respondents were comfortable with AI use in their care, with 53% saying they would trust an AI-assisted screening program as much as a health professional. Despite having a higher awareness of AI, younger participants had lower trust in AI systems. A higher proportion of Maori and Pacific participants indicated a preference toward human-led screening. The main perceived benefits of AI included faster diagnostic speeds and greater accuracy. CONCLUSIONS: There is low awareness of clinical AI applications among our participants. Despite this, most are receptive toward the implementation of AI in diabetic eye screening. Overall, there was a strong preference toward continual involvement of clinicians in the screening process. There are key recommendations to enhance the receptivity of the public toward incorporation of AI into retinal screening programs.

Visualizing ocular lens fluid dynamics using MRI: manipulation of steady state water content and water fluxes.

Studies using various MRI techniques have shown that a water-protein concentration gradient exists in the ocular lens. Because this concentration is higher in the core relative to the lens periphery, a gradient in refractive index is established in the lens. To investigate how the water-protein concentration profile is maintained, bovine lenses were incubated in different solutions, and changes in water-protein concentration ratio monitored using proton density weighted (PD-weighted) imaging in the absence and presence of heavy water (D(2)O). Lenses incubated in artificial aqueous humor (AAH) maintained the steady state water-protein concentration gradient, but incubating lenses in high extracellular potassium (KCl-AAH) or low temperature (Low T-AAH) caused a collapse of the gradient due to a rise in water content in the core of the lens. To visualize water fluxes, lenses were incubated in D(2)O, which acts as a contrast agent. Incubation in KCl-AAH and low T-AAH dramatically slowed the movement of D(2)O into the core but did not affect the movement of D(2)O into the outer cortex. D(2)O seemed to preferentially enter the lens cortex at the anterior and posterior poles before moving circumferentially toward the equatorial regions. This directionality of D(2)O influx into the lens cortex was abolished by incubating lenses in high KCl-AAH or low T-AAH, and resulted in homogenous influx of D(2)O into the outer cortex. Taken together, our results show that the water-protein concentration ratio is actively maintained in the core of the lens and that water fluxes preferentially enter the lens at the poles.

Age-Dependent Changes in Total and Free Water Content of In Vivo Human Lenses Measured by Magnetic Resonance Imaging.

Purpose: To use magnetic resonance imaging (MRI) to measure age-dependent changes in total and free water in human lenses in vivo. Methods: Sixty-four healthy adults aged 18 to 86 years were recruited, fitted with a 32-channel head receiver coil, and placed in a 3 Tesla clinical MR scanner. Scans of the crystalline lens were obtained using a volumetric interpolated breath-hold examination sequence with dual flip angles, which were corrected for field inhomogeneity post-acquisition using a B1-map obtained using a turbo-FLASH sequence. The spatial distribution and content of corrected total (ρlens) and free (T1) water along the lens optical axis were extracted using custom-written code. Results: Lens total water distribution and content did not change with age (all P > 0.05). In contrast to total water, a gradient in free water content that was highest in the periphery relative to the center was present in lenses across all ages. However, this initially parabolic free water gradient gradually developed an enhanced central plateau, as indicated by increasing profile shape parameter values (anterior: 0.067/y, P = 0.004; posterior: 0.050/y, P = 0.020) and central free water content (1.932 ms/y, P = 0.022) with age. Conclusions: MRI can obtain repeatable total and free water measurements of in vivo human lenses. The observation that the lens steady-state free, but not total, water gradient is abolished with age raises the possibility that alterations in protein-water interactions are an underlying cause of the degradation in lens optics and overall vision observed with aging.