Does Bevacizumab Improve Outcomes After Ahmed Glaucoma Valve Implantation for Refractory Glaucoma?: A Meta-Analysis.

PRCIS: Mean intraocular pressure (IOP), complete and overall success, mean IOP-lowering medications, incidence of hypertensive phase, and complications were found to be comparable between patients undergoing Ahmed glaucoma valve implantation (AGVI) with adjunctive bevacizumab versus AGVI alone. OBJECTIVE: This meta-analysis aims to assess how adjunctive bevacizumab impacts the surgical outcomes of AGVI compared with AGVI alone in all subtypes of refractory glaucoma. METHODS: A systematic search of databases for relevant randomized controlled trials (RCTs) was performed in March 2023. Primary outcomes included mean IOP and success rates. Secondary outcomes were mean IOP-lowering medications, incidence of hypertensive phase, and complications. Qualitative assessment, meta-analysis, subgroup analyses, and sensitivity analysis were performed. RESULTS: Five RCTs comprising 203 eyes were included in the quantitative analysis. Initial meta-analysis showed a strong yet nonsignificant trend (all P > 0.05) favoring adjunctive bevacizumab in all outcomes of interest. Significant heterogeneity was observed for mean IOP and success outcomes at all time points (all I2 > 50%). Subgroup analysis of the administration route revealed a reduced incidence of hyphaema in the intravitreal bevacizumab subgroup (odds ratio: 0.10; 95% CI: 0.02 to 0.59; P = 0.01) with significant heterogeneity persisting in the intravitreal bevacizumab subgroup for all measures (all I2 > 50%). Post hoc sensitivity analysis of studies without concurrent pan-retinal photocoagulation for mean IOP and success outcomes demonstrated more conservative effect sizes with a corresponding decrease in heterogeneity for all measures (all I2 < 30%). CONCLUSION: Published studies investigating the role of adjunctive bevacizumab show a strong trend to improve outcomes but contain a relatively small number of participants. This analysis underpins the need for an adequately powered RCT to explore the role of anti-vascular endothelial growth factor agents in AGVI surgery.

A new model of axon degeneration in the mouse optic nerve using repeat intraocular pressure challenge.

We characterize a new experimental model for inducing retinal ganglion cell (RGC) dysfunction and degeneration in mice. C57BL/6J mice were subjected to two acute periods of intraocular pressure (IOP) elevation (50 mmHg for 30 min) by cannulation of the anterior chamber. We used full-field electroretinography and visual evoked potentials (VEPs) to measure subsequent changes in retina and optic nerve function, and histochemical techniques to assess RGC survival and optic nerve structure. In 12 month old mice, a single IOP challenge caused loss and subsequent recovery of RGC function over the following 28 days with minimal cell death and no observed axonal damage. A second identical IOP challenge resulted in persistent RGC dysfunction and significant (36%) loss of RGC somas. This was accompanied by a 16.7% delay in the latency and a 27.6% decrease in the amplitude of the VEP. Severe axonal damage was seen histologically with enlargement of axons, myelin disruption, reduced axon density, and the presence of glial scarring. In contrast, younger 3 month old mice when exposed to a single or repeat IOP challenge showed quicker RGC functional recovery after a single challenge and full functional recovery after a repeat challenge with no detectable optic nerve dysfunction. These data demonstrate a highly reproducible and minimally invasive method for inducing RGC degeneration and axonal damage in mice. Resilience of the optic nerve to damage is highly dependent on animal age. The time-defined nature of functional versus structural loss seen in this model stands to facilitate investigation of neuroglial responses in the retina after IOP injury and the associated evaluation of neuroprotective treatment strategies. Further, the model may be used to investigate the impact of aging and the cellular switch between neurorecovery and neurodegeneration.

Photoreceptor laminin drives differentiation of human pluripotent stem cells to photoreceptor progenitors that partially restore retina function.

Blindness caused by advanced stages of inherited retinal diseases and age-related macular degeneration are characterized by photoreceptor loss. Cell therapy involving replacement with functional photoreceptor-like cells generated from human pluripotent stem cells holds great promise. Here, we generated a human recombinant retina-specific laminin isoform, LN523, and demonstrated the role in promoting the differentiation of human embryonic stem cells into photoreceptor progenitors. This chemically defined and xenogen-free method enables reproducible production of photoreceptor progenitors within 32 days. We observed that the transplantation into rd10 mice were able to protect the host photoreceptor outer nuclear layer (ONL) up to 2 weeks post transplantation as measured by full-field electroretinogram. At 4 weeks post transplantation, the engrafted cells were found to survive, mature, and associate with the host's rod bipolar cells. Visual behavioral assessment using the water maze swimming test demonstrated visual improvement in the cell-transplanted rodents. At 20 weeks post transplantation, the maturing engrafted cells were able to replace the loss of host ONL by extensive association with host bipolar cells and synapses. Post-transplanted rabbit model also provided congruent evidence for synaptic connectivity with the degenerated host retina. The results may pave the way for the development of stem cell-based therapeutics for retina degeneration.

Time-Frequency Analysis of ERG With Discrete Wavelet Transform and Matching Pursuits for Glaucoma.

Purpose: To examine the performance of two time-frequency feature extraction techniques applied to electroretinograms (ERGs) for the prediction of glaucoma severity. Methods: ERGs targeting the photopic negative response were obtained in 103 eyes of 55 patients with glaucoma. Features from the ERG recordings were extracted using two time-frequency extraction techniques based on the discrete wavelet transform (DWT) and the matching pursuit (MP) decomposition. Amplitude markers of the time-domain signal were also extracted. Linear and multivariate adaptive regression spline (MARS) models were fitted using combinations of these features to predict estimated retinal ganglion cell counts, a measure of glaucoma disease severity derived from standard automated perimetry and optical coherence tomography imaging. Results: Predictive models using features from the time-frequency analyses-using both DWT and MP-combined with amplitude markers outperformed predictive models using the markers alone with linear (P = 0.001) and MARS (P ≤ 0.011) models. For example, the proportions of variance (R2) explained by the MARS model using the DWT and MP features with amplitude markers were 0.53 and 0.63, respectively, compared to 0.34 for the model using the markers alone (P = 0.011 and P = 0.001, respectively). Conclusions: Novel time-frequency features extracted from the photopic ERG substantially added to the prediction of glaucoma severity compared to using the time-domain amplitude markers alone. Translational Relevance: Substantial information about retinal ganglion cell dysfunction exists in the time-frequency domain of ERGs that could be useful in the management of glaucoma.

Evaluation of Generative Adversarial Networks for High-Resolution Synthetic Image Generation of Circumpapillary Optical Coherence Tomography Images for Glaucoma.

Importance: Deep learning (DL) networks require large data sets for training, which can be challenging to collect clinically. Generative models could be used to generate large numbers of synthetic optical coherence tomography (OCT) images to train such DL networks for glaucoma detection. Objective: To assess whether generative models can synthesize circumpapillary optic nerve head OCT images of normal and glaucomatous eyes and determine the usability of synthetic images for training DL models for glaucoma detection. Design, Setting, and Participants: Progressively growing generative adversarial network models were trained to generate circumpapillary OCT scans. Image gradeability and authenticity were evaluated on a clinical set of 100 real and 100 synthetic images by 2 clinical experts. DL networks for glaucoma detection were trained with real or synthetic images and evaluated on independent internal and external test data sets of 140 and 300 real images, respectively. Main Outcomes and Measures: Evaluations of the clinical set between the experts were compared. Glaucoma detection performance of the DL networks was assessed using area under the curve (AUC) analysis. Class activation maps provided visualizations of the regions contributing to the respective classifications. Results: A total of 990 normal and 862 glaucomatous eyes were analyzed. Evaluations of the clinical set were similar for gradeability (expert 1: 92.0%; expert 2: 93.0%) and authenticity (expert 1: 51.8%; expert 2: 51.3%). The best-performing DL network trained on synthetic images had AUC scores of 0.97 (95% CI, 0.95-0.99) on the internal test data set and 0.90 (95% CI, 0.87-0.93) on the external test data set, compared with AUCs of 0.96 (95% CI, 0.94-0.99) on the internal test data set and 0.84 (95% CI, 0.80-0.87) on the external test data set for the network trained with real images. An increase in the AUC for the synthetic DL network was observed with the use of larger synthetic data set sizes. Class activation maps showed that the regions of the synthetic images contributing to glaucoma detection were generally similar to that of real images. Conclusions and Relevance: DL networks trained with synthetic OCT images for glaucoma detection were comparable with networks trained with real images. These results suggest potential use of generative models in the training of DL networks and as a means of data sharing across institutions without patient information confidentiality issues.

The Effect of Aging on Retinal Function and Retinal Ganglion Cell Morphology Following Intraocular Pressure Elevation.

Aging and elevated intraocular pressure (IOP) are two major risk factors for glaucomatous optic neuropathy; a condition characterized by the selective, progressive injury, and subsequent loss of retinal ganglion cells (RGCs). We examined how age modified the capacity for RGCs to functionally recover following a reproducible IOP elevation (50 mmHg for 30 min). We found that RGC functional recovery (measured using electroretinography) was complete by 7 days in 3-month-old mice but was delayed in 12-month-old mice until 14 days. At the 7-day recovery endpoint when RGC function had recovered in young but not older eyes, we examined RGC structural responses to IOP-related stress by analyzing RGC dendritic morphology. ON-RGC cell volume was attenuated following IOP elevation in both young and older mice. We also found that following IOP elevation OFF-RGC dendritic morphology became less complex per cell volume in young mice, an effect that was not observed in older eyes. Our data suggest that adaptations in OFF-RGCs in young eyes were associated with better functional recovery 7 days after IOP elevation. Loss of RGC cellular adaptations may account for delayed functional recovery in older eyes.

High-Density Lipoprotein 3 Cholesterol and Primary Open-Angle Glaucoma: Metabolomics and Mendelian Randomization Analyses.

PURPOSE: We hypothesized that the effect of blood lipid-related metabolites on primary open-angle glaucoma (POAG) would differ according to specific lipoprotein particles and lipid sub-fractions. We investigated the associations of blood levels of lipoprotein particles and lipid sub-fractions with POAG. DESIGN: Cross-sectional study. PARTICIPANTS: Individuals recruited for the baseline visit of the population-based Singapore Epidemiology of Eye Disease study (n = 8503). METHODS: All participants underwent detailed standardized ocular and systemic examinations. A total of 130 blood lipid-related metabolites were quantified using a nuclear magnetic resonance metabolomics platform. The analyses were conducted in 2 stages. First, we investigated whether and which lipid-related metabolites were directly associated with POAG using regression analyses followed by Bayesian network modeling. Second, we investigated if any causal relationship exists between the identified lipid-related metabolites, if any, and POAG using 2-sample Mendelian randomization (MR) analysis. We performed genome-wide association studies (GWAS) on high-density lipoprotein (HDL) 3 cholesterol (after inverse normal transformation) and used the top variants associated with HLD3 cholesterol as instrumental variables (IVs) in the MR analysis. MAIN OUTCOME MEASURE: Primary open-angle glaucoma. RESULTS: Of the participants, 175 (2.1%) had POAG. First, a logistic regression model showed that total HDL3 cholesterol (negatively) and phospholipids in very large HDL (positively) were associated with POAG. Further analyses using a Bayesian network analysis showed that only total HDL3 cholesterol was directly associated with POAG (odds ratio [OR], 0.72 per 1 standard deviation increase in HDL3 cholesterol; 95% confidence interval [CI], 0.61-0.84), independently of age, gender, intraocular pressure (IOP), body mass index (BMI), education level, systolic blood pressure, axial length, and statin medication. Using 5 IVs identified from the GWAS and with the inverse variance weighted MR method, we found that higher levels of HDL3 cholesterol were associated with a decreased odds of POAG (OR, 0.91; 95% CI, 0.84-0.99, P = 0.021). Other MR methods, including weighted median, mode-based estimator, and contamination mixture methods, derived consistent OR estimates. None of the routine lipids (blood total, HDL, or low-density lipoprotein [LDL] cholesterol) were associated with POAG. CONCLUSIONS: Overall, these results suggest that the relationship between HDL3 cholesterol and POAG might be causal and specific, and that dysregulation of cholesterol transport may play a role in the pathogenesis of POAG.

Multivariate Normative Comparison, a Novel Method for Improved Use of Retinal Nerve Fiber Layer Thickness to Detect Early Glaucoma.

PURPOSE: Detection of early glaucoma remains limited with the conventional analysis of the retinal nerve fiber layer (RNFL). This study assessed whether compensating the RNFL thickness for multiple demographic and anatomic factors improves the detection of glaucoma. DESIGN: Cross-sectional study. PARTICIPANTS: Three hundred eighty-seven patients with glaucoma and 2699 healthy participants. METHODS: Two thousand six hundred ninety-nine healthy participants were enrolled to construct and test a multivariate compensation model, which then was applied in 387 healthy participants and 387 patients with glaucoma (early glaucoma, n = 219; moderate glaucoma, n = 97; and advanced glaucoma, n = 71). Participants underwent Cirrus spectral-domain OCT (Carl Zeiss Meditec) imaging of the optic disc and macular cubes. Compensated RNFL thickness was generated based on ethnicity, age, refractive error, optic disc (ratio, orientation, and area), fovea (distance and angle), and retinal vessel density. The RNFL thickness measurements and their corresponding areas under the receiver operating characteristic curve (AUCs) were obtained. MAIN OUTCOME AND MEASURES: Measured and compensated RNFL thickness measurements. RESULTS: After applying the Asian-specific compensation model, the standard deviation of RNFL thickness reduced, where the effect was greatest for Chinese participants (16.9%), followed by Malay participants (13.9%), and Indian participants (12.1%). Multivariate normative comparison outperformed measured RNFL for discrimination of early glaucoma (AUC, 0.90 vs. 0.85; P < 0.001), moderate glaucoma (AUC, 0.94 vs. 0.91; P < 0.001), and advanced glaucoma (AUC, 0.98 vs. 0.96; P < 0.001). CONCLUSIONS: The multivariate normative database of RNFL showed better glaucoma discrimination capability than conventional age-matched comparisons, suggesting that accounting for demographic and anatomic variance in RNFL thickness may have usefulness in improving glaucoma detection.

Prediction of glaucoma severity using parameters from the electroretinogram.

Glaucoma is an optic neuropathy that results in the progressive loss of retinal ganglion cells (RGCs), which are known to exhibit functional changes prior to cell loss. The electroretinogram (ERG) is a method that enables an objective assessment of retinal function, and the photopic negative response (PhNR) has conventionally been used to provide a measure of RGC function. This study sought to examine if additional parameters from the ERG (amplitudes of the a-, b-, i-wave, as well the trough between the b- and i-wave), a multivariate adaptive regression splines (MARS; a non-linear) model and achromatic stimuli could better predict glaucoma severity in 103 eyes of 55 individuals with glaucoma. Glaucoma severity was determined using standard automated perimetry and optical coherence tomography imaging. ERGs targeting the PhNR were recorded with a chromatic (red-on-blue) and achromatic (white-on-white) stimulus with the same luminance. Linear and MARS models were fitted to predict glaucoma severity using the PhNR only or all ERG markers, derived from chromatic and achromatic stimuli. Use of all ERG markers predicted glaucoma severity significantly better than the PhNR alone (P ≤ 0.02), and the MARS performed better than linear models when using all markers (P = 0.01), but there was no significant difference between the achromatic and chromatic stimulus models. This study shows that there is more information present in the photopic ERG beyond the conventional PhNR measure in characterizing RGC function.

Association between digital smart device use and myopia: a systematic review and meta-analysis.

BACKGROUND: Excessive use of digital smart devices, including smartphones and tablet computers, could be a risk factor for myopia. We aimed to review the literature on the association between digital smart device use and myopia. METHODS: In this systematic review and meta-analysis we searched MEDLINE and Embase, and manually searched reference lists for primary research articles investigating smart device (ie, smartphones and tablets) exposure and myopia in children and young adults (aged 3 months to 33 years) from database inception to June 2 (MEDLINE) and June 3 (Embase), 2020. We included studies that investigated myopia-related outcomes of prevalent or incident myopia, myopia progression rate, axial length, or spherical equivalent. Studies were excluded if they were reviews or case reports, did not investigate myopia-related outcomes, or did not investigate risk factors for myopia. Bias was assessed with the Joanna Briggs Institute Critical Appraisal Checklists for analytical cross-sectional and cohort studies. We categorised studies as follows: category one studies investigated smart device use independently; category two studies investigated smart device use in combination with computer use; and category three studies investigated smart device use with other near-vision tasks that were not screen-based. We extracted unadjusted and adjusted odds ratios (ORs), ß coefficients, prevalence ratios, Spearman's correlation coefficients, and p values for associations between screen time and incident or prevalent myopia. We did a meta-analysis of the association between screen time and prevalent or incident myopia for category one articles alone and for category one and two articles combined. Random-effects models were used when study heterogeneity was high (I2>50%) and fixed-effects models were used when heterogeneity was low (I2≤50%). FINDINGS: 3325 articles were identified, of which 33 were included in the systematic review and 11 were included in the meta-analysis. Four (40%) of ten category one articles, eight (80%) of ten category two articles, and all 13 category three articles used objective measures to identify myopia (refraction), whereas the remaining studies used questionnaires to identify myopia. Screen exposure was measured by use of questionnaires in all studies, with one also measuring device-recorded network data consumption. Associations between screen exposure and prevalent or incident myopia, an increased myopic spherical equivalent, and longer axial length were reported in five (50%) category one and six (60%) category two articles. Smart device screen time alone (OR 1·26 [95% CI 1·00-1·60]; I2=77%) or in combination with computer use (1·77 [1·28-2·45]; I2=87%) was significantly associated with myopia. The most common sources of risk of bias were that all 33 studies did not include reliable measures of screen time, seven (21%) did not objectively measure myopia, and nine (27%) did not identify or adjust for confounders in the analysis. The high heterogeneity between studies included in the meta-analysis resulted from variability in sample size (range 155-19 934 participants), the mean age of participants (3-16 years), the standard error of the estimated odds of prevalent or incident myopia (0·02-2·21), and the use of continuous (six [55%] of 11) versus categorical (five [46%]) screen time variables INTERPRETATION: Smart device exposure might be associated with an increased risk of myopia. Research with objective measures of screen time and myopia-related outcomes that investigates smart device exposure as an independent risk factor is required. FUNDING: None.

Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction.

Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. We assess the effects of nicotinamide (a precursor to NAD) on retinal ganglion cells (the affected neuron in glaucoma) in normal physiological conditions and across a range of glaucoma relevant insults including mitochondrial stress and axon degenerative insults. We demonstrate retinal ganglion cell somal, axonal, and dendritic neuroprotection by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We performed metabolomics enriched for small molecular weight metabolites for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption, including consistent changes to α-ketoglutaric acid, creatine/creatinine, homocysteine, and glycerophosphocholine. This metabolic disruption is prevented by nicotinamide. Nicotinamide provides further neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term nicotinamide treatment as a neuroprotective therapy for human glaucoma.

Targeting Diet and Exercise for Neuroprotection and Neurorecovery in Glaucoma.

Glaucoma is a leading cause of blindness worldwide. In glaucoma, a progressive dysfunction and death of retinal ganglion cells occurs, eliminating transfer of visual information to the brain. Currently, the only available therapies target the lowering of intraocular pressure, but many patients continue to lose vision. Emerging pre-clinical and clinical evidence suggests that metabolic deficiencies and defects may play an important role in glaucoma pathophysiology. While pre-clinical studies in animal models have begun to mechanistically uncover these metabolic changes, some existing clinical evidence already points to potential benefits in maintaining metabolic fitness. Modifying diet and exercise can be implemented by patients as an adjunct to intraocular pressure lowering, which may be of therapeutic benefit to retinal ganglion cells in glaucoma.

Retinal energy metabolism in health and glaucoma.

Energy metabolism refers to the processes by which life transfers energy to do cellular work. The retina's relatively large energy demands make it vulnerable to energy insufficiency. In addition, evolutionary pressures to optimize human vision have been traded against retinal ganglion cell bioenergetic fragility. Details of the metabolic profiles of the different retinal cells remain poorly understood and are challenging to resolve. Detailed immunohistochemical mapping of the energy pathway enzymes and substrate transporters has provided some insights and highlighted interspecies differences. The different spatial metabolic patterns between the vascular and avascular retinas can account for some inconsistent data in the literature. There is a consilience of evidence that at least some individuals with glaucoma have impaired RGC energy metabolism, either due to impaired nutrient supply or intrinsic metabolic perturbations. Bioenergetic-based therapy for glaucoma has a compelling pathophysiological foundation and is supported by recent successes in animal models. Recent demonstrations of visual and electrophysiological neurorecovery in humans with glaucoma is highly encouraging and motivates longer duration trials investigating bioenergetic neuroprotection.

Experimental models of glaucoma filtration surgery.

Glaucoma filtration surgery plays an important role in achieving intraocular pressure (IOP) reduction in patients who have high IOP despite maximum medical therapy. Preclinical experimental models of glaucoma filtration surgery contribute a great deal to our knowledge of the wound healing processes that predispose to scarring and may lead to poor outcomes. However, this research needs to be interpreted in the light of the specific study design, animal model and methods used. We review the existing literature addressing various models of experimental glaucoma filtration surgery, discuss the considerations in assessing these models and describe future steps in evaluating potential therapeutics and bleb characteristics that could impact translational research in this field.

Highlights from the 2019 International Myopia Summit on 'controversies in myopia'.

Myopia is an emerging public health issue with potentially significant economic and social impact, especially in East Asia. However, many uncertainties about myopia and its clinical management remain. The International Myopia Summit workgroup was convened by the Singapore Eye Research Institute, the WHO Regional Office for the Western Pacific and the International Agency for the Prevention of Blindness in 2019. The aim of this workgroup was to summarise available evidence, identify gaps or unmet needs and provide consensus on future directions for clinical research in myopia. In this review, among the many 'controversies in myopia' discussed, we highlight three main areas of consensus. First, development of interventions for the prevention of axial elongation and pathologic myopia is needed, which may require a multifaceted approach targeting the Bruch's membrane, choroid and/or sclera. Second, clinical myopia management requires co-operation between optometrists and ophthalmologists to provide patients with holistic care and a tailored approach that balances risks and benefits of treatment by using optical and pharmacological interventions. Third, current diagnostic technologies to detect myopic complications may be improved through collaboration between clinicians, researchers and industry. There is an unmet need to develop new imaging modalities for both structural and functional analyses and to establish normative databases for myopic eyes. In conclusion, the workgroup's call to action advocated for a paradigm shift towards a collaborative approach in the holistic clinical management of myopia.

Nox4 Facilitates TGFß1-Induced Fibrotic Response in Human Tenon's Fibroblasts and Promotes Wound Collagen Accumulation in Murine Model of Glaucoma Filtration Surgery.

Collagen accumulation in sub-conjunctival tissue at the surgical wound is one of the major complications associated with glaucoma filtration surgery (GFS). This process often leads to unwanted fibrotic scar formation at the lesion site and dysfunction of tissues. Previously, we demonstrated that NADPH oxidase 4 (Nox4) is implicated in transforming growth factor-beta (TGFß)-induced collagen production in ocular fibroblasts and scarring responses in a mouse model of corneal injury. Here, we propose that Nox4 is an important facilitator of TGFß-induced responses. We tested this hypothesis in human Tenon's fibroblasts (HTF) and also assessed a role of Nox4 in an experimental mouse model of GFS. TGFß1 induced Nox4 mRNA expression but downregulated Nox5 in HTF. Targeting Nox4 gene expression with an adenovirus carrying a Nox4 small interfering RNA (siRNA) (Ad-Nox4i) or removal of hydrogen peroxide (H2O2) with EUK-134 (25 µM) in HTFs significantly reduced TGFß1-induced Nox4 expression, H2O2 production, and collagen synthesis (p < 0.05, n = 3-6). SIS3 (5 µM) that prevents Smad3 phosphorylation is found to suppress TGFß1-induced collagen production in HTFs. Furthermore, Ad-Nox4i and EUK-134 both abolished TGFß1-stimulated proliferation of HTFs. We also compared collagen deposition at the wound arising from GFS between wildtype (WT) and Nox4 knockout (KO) mice. Both collagen deposition and fibrovascularization at the wound were significantly decreased in Nox4 KO mice at 14 days after GFS. Our results provide comprehensive evidence that Nox4 is an important mediator for TGFß1-induced responses in HTFs and collagen deposition in surgical wound following GFS in mice. As such, pharmacological inhibition of Nox4 would be a viable therapeutic strategy for the control of scarring after glaucoma surgery.

Prevalence and associations of non-retinopathy ocular conditions among older Australians with self-reported diabetes: The National Eye Health Survey.

AIM: To determine the prevalence and associations of non-retinopathy ocular conditions among older Australian adults with diabetes. METHODS: Multistage random-cluster sampling was used to select 3098 non-indigenous Australians aged 50y or older (46.4% male) and 1738 indigenous Australians aged 40y or older (41.1% male) from all levels of geographic remoteness in Australia. Participants underwent a standardised questionnaire to ascertain diabetes history, and a clinical examination to identify eye disease. We determined the prevalence of uncorrected refractive error, visually significant cataract, cataract surgery, age-related macular degeneration, glaucoma, ocular hypertension, retinal vein occlusion and epiretinal membrane among those with and without self-reported diabetes. RESULTS: Participants with self-reported diabetes had a higher prevalence of cataract surgery than those without diabetes (28.8% vs 16.9%, OR 1.78, 95%CI: 1.35-2.34 among non-indigenous Australians, and 11.3% vs 5.2%, OR 1.62, 95%CI: 1.22-2.14 among indigenous Australians). Diabetic retinopathy (DR) increased the odds of cataract surgery among self-reported diabetic indigenous and non-indigenous Australians (OR 1.89, P=0.004 and OR 2.33, P<0.001 respectively). Having diabetes for ≥20y and having vision-threatening DR increased the odds of cataract surgery among indigenous Australians with diabetes (OR 3.73, P=0.001 and 7.58, P<0.001, respectively). CONCLUSION: Most non-retinopathy ocular conditions are not associated with self-reported diabetes. However, to account for Australia's worsening diabetes epidemic, interventions to reduce the impact of diabetes-related blindness should include increased cataract surgery services.

Nuclear response to divergent mitochondrial DNA genotypes modulates the interferon immune response.

Mitochondrial OXPHOS generates most of the energy required for cellular function. OXPHOS biogenesis requires the coordinated expression of the nuclear and mitochondrial genomes. This represents a unique challenge that highlights the importance of nuclear-mitochondrial genetic communication to cellular function. Here we investigated the transcriptomic and functional consequences of nuclear-mitochondrial genetic divergence in vitro and in vivo. We utilized xenomitochondrial cybrid cell lines containing nuclear DNA from the common laboratory mouse Mus musculus domesticus and mitochondrial DNA (mtDNA) from Mus musculus domesticus, or exogenous mtDNA from progressively divergent mouse species Mus spretus, Mus terricolor, Mus caroli and Mus pahari. These cybrids model a wide range of nuclear-mitochondrial genetic divergence that cannot be achieved with other research models. Furthermore, we used a xenomitochondrial mouse model generated in our laboratory that harbors wild-type, C57BL/6J Mus musculus domesticus nuclear DNA and homoplasmic mtDNA from Mus terricolor. RNA sequencing analysis of xenomitochondrial cybrids revealed an activation of interferon signaling pathways even in the absence of OXPHOS dysfunction or immune challenge. In contrast, xenomitochondrial mice displayed lower baseline interferon gene expression and an impairment in the interferon-dependent innate immune response upon immune challenge with herpes simplex virus, which resulted in decreased viral control. Our work demonstrates that nuclear-mitochondrial genetic divergence caused by the introduction of exogenous mtDNA can modulate the interferon immune response both in vitro and in vivo, even when OXPHOS function is not compromised. This work may lead to future insights into the role of mitochondrial genetic variation and the immune function in humans, as patients affected by mitochondrial disease are known to be more susceptible to immune challenges.

Artificial Intelligence Algorithms to Diagnose Glaucoma and Detect Glaucoma Progression: Translation to Clinical Practice.

Purpose: This concise review aims to explore the potential for the clinical implementation of artificial intelligence (AI) strategies for detecting glaucoma and monitoring glaucoma progression. Methods: Nonsystematic literature review using the search combinations "Artificial Intelligence," "Deep Learning," "Machine Learning," "Neural Networks," "Bayesian Networks," "Glaucoma Diagnosis," and "Glaucoma Progression." Information on sensitivity and specificity regarding glaucoma diagnosis and progression analysis as well as methodological details were extracted. Results: Numerous AI strategies provide promising levels of specificity and sensitivity for structural (e.g. optical coherence tomography [OCT] imaging, fundus photography) and functional (visual field [VF] testing) test modalities used for the detection of glaucoma. Area under receiver operating curve (AROC) values of > 0.90 were achieved with every modality. Combining structural and functional inputs has been shown to even more improve the diagnostic ability. Regarding glaucoma progression, AI strategies can detect progression earlier than conventional methods or potentially from one single VF test. Conclusions: AI algorithms applied to fundus photographs for screening purposes may provide good results using a simple and widely accessible test. However, for patients who are likely to have glaucoma more sophisticated methods should be used including data from OCT and perimetry. Outputs may serve as an adjunct to assist clinical decision making, whereas also enhancing the efficiency, productivity, and quality of the delivery of glaucoma care. Patients with diagnosed glaucoma may benefit from future algorithms to evaluate their risk of progression. Challenges are yet to be overcome, including the external validity of AI strategies, a move from a "black box" toward "explainable AI," and likely regulatory hurdles. However, it is clear that AI can enhance the role of specialist clinicians and will inevitably shape the future of the delivery of glaucoma care to the next generation. Translational Relevance: The promising levels of diagnostic accuracy reported by AI strategies across the modalities used in clinical practice for glaucoma detection can pave the way for the development of reliable models appropriate for their translation into clinical practice. Future incorporation of AI into healthcare models may help address the current limitations of access and timely management of patients with glaucoma across the world.