OBJECTIVE:Pigment dispersion syndrome (PDS) is a known risk factor for glaucoma, with at least 1 in 10 patients with PDS developing glaucoma. There are no standardized clinical tools to stratify the risk of glaucoma onset or progression in the context of PDS. This study investigated whether multitrait polygenic risk scores (PRSs) built from variants collectively associated with open-angle glaucoma, intraocular pressure (IOP), and vertical cup:disc ratio (VCDR) could stratify individuals with PDS for their risk of glaucoma development. DESIGN:Cross-sectional study of 2 independent PDS cohorts: the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG, n = 264), and the Glaucoma Services at the University of Iowa Carver College of Medicine (n = 203). PARTICIPANTS:Participants of European ancestry with PDS were classified as PDS-Glaucoma (n = 288), PDS-Glaucoma Suspect (n = 110), or PDS-No Glaucoma (n = 69). METHODS:Previously published and validated PRS for open-angle glaucoma, IOP, and VCDR were expressed as a percentile or quintile of an ancestrally matched normal population. Multivariable logistic and linear regressions and survival analyses were performed. MAIN OUTCOME MEASURES:Odds of pigmentary glaucoma and odds of clinically relevant outcomes. RESULTS:Participants from ANZRAG with PDS in the top quintile of an open-angle glaucoma-PRS had greater odds of glaucoma diagnosis compared with the bottom quintile (adjusted odds ratio [OR], 5.29; 95% confidence interval [CI], 1.57-21.28; P = 0.011). This observation was replicated among participants with PDS from the University of Iowa (adjusted OR, 4.07; 95% CI, 1.24-13.85; P = 0.021). Among those with PDS-Glaucoma across both cohorts combined, participants in the top quintile of glaucoma-PRS compared with the bottom quintile were diagnosed 8 years earlier (95% CI, 5.17-10.41; P < 0.001), recorded a maximum IOP 8 mmHg higher (95% CI, 2.89-11.95; P = 0.001), were at greater risk of escalation to incisional surgery (adjusted OR, 1.37; 95% CI, 1.03-1.87; P = 0.038), and were at greater risk of additional incisional surgeries to the same eye (adjusted OR, 1.27; 95% CI, 1.08-1.52; P = 0.006). A PRS for IOP also differentiated pigmentary glaucoma status; a PRS for VCDR did not. CONCLUSIONS:A multitrait PRS for open-angle glaucoma stratifies risk of glaucoma onset and disease severity among individuals with PDS. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

PURPOSE: To develop an automated deep learning system for detecting the presence and location of disc hemorrhages in optic disc photographs.DESIGN: Development and testing of a deep learning algorithm.METHODS: Optic disc photos (597 images with at least 1 disc hemorrhage and 1075 images without any disc hemorrhage from 1562 eyes) from 5 institutions were classified by expert graders based on the presence or absence of disc hemorrhage. The images were split into training (n = 1340), validation (n = 167), and test (n = 165) datasets. Two state-of-the-art deep learning algorithms based on either object-level detection or image level classification were trained on the dataset. These models were compared to one another and against 2 independent glaucoma specialists. We evaluated model performance by the area under the receiver operating characteristic curve (AUC). AUCs were compared with the Hanley-McNeil method.RESULTS: The object detection model achieved an AUC of 0.936 (95% CI = 0.857-0.964) across all held-out images (n = 165 photographs), which was significantly superior to the image classification model (AUC = 0.845, 95% CI = 0.740-0.912; P = .006). At an operating point selected for high specificity, the model achieved a specificity of 94.3% and a sensitivity of 70.0%, which was statistically indistinguishable from an expert clinician ( P = .7). At an operating point selected for high sensi tivity, the model achieves a sensitivity of 96.7% and a specificity of 73.3%.CONCLUSIONS: An autonomous object detection model is superior to an image classification model for detecting disc hemorrhages, and performed comparably to 2 clinicians. (Am J Ophthalmol 2023;255: 161169.& COPY; 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC ND license ( http://creativecommons.org/licenses/by-ncnd/4.0/ ))

Purpose To test an online training course for non-ophthalmic diabetic retinopathy (DR) graders for recognition of glaucomatous optic nerves in Vietnam. Methods This was an uncontrolled, experimental, before-and-after study in which 43 non-ophthalmic DR graders underwent baseline testing on a standard image set, completed a self-paced, online training course and were retested using the same photographs presented randomly. Twenty-nine local ophthalmologists completed the same test without the training course. DR graders then underwent additional one–to-one training by a glaucoma specialist and were retested. Test performance (% correct, compared with consensus grades from four fellowship-trained glaucoma experts), sensitivity, specificity, positive and negative predictive value, and area under the receiver operating (AUC) curve, were computed. Results Mean age of DR graders (32.6±5.5 years) did not differ from ophthalmologists (32.3±7.3 years, p=0.13). Online training required a mean of 297.9 (SD 144.6) minutes. Graders’ mean baseline score (33.3%±14.3%) improved significantly after training (55.8%±12.6%, p<0.001), and post-training score did not differ from ophthalmologists (58.7±15.4%, p=0.384). Although grader sensitivity reduced before [85.5% (95% CI 83.5% to 87.3%)] versus after [80.4% (78.3% to 82.4%)] training, specificity improved significantly [47.8 (44.9 to 50.7) vs 79.8 (77.3 to 82.0), p<0.001]. Grader AUC also improved after training [66.6 (64.9 to 68.3)] to [80.1 (78.5 to 81.6), p<0.001]. Additional one-to-one grader training by a glaucoma specialist did not further improve grader scores. Conclusion Non-ophthalmic DR graders can be trained to recognise glaucoma using a short online course in this setting, with no additional benefit from more expensive one–to-one training. After 5-hour online training in recognising glaucomatous optic nerve head, scores of non-ophthalmic DR graders doubled, and did not differ from local ophthalmologists. Intensive one-to-one training did not further improve performance

Purpose: To determine the prevalence of fast global and central visual field (VF) progression in individuals with glaucoma under routine care. Design: Observational study. Participants: Six hundred ninety-three eyes of 461 individuals with glaucoma followed up over a median of 4.5 years. Methods: This study included (1) patients at a private ophthalmology clinic in Melbourne, Australia, and (2) individuals in 2 prospective longitudinal observational studies across 3 sites in the United States. All individuals had a diagnosis of glaucoma and were under routine care, and had performed 5 or more reliable 24-2 VF tests over a 1- to 5-year period. Ordinary least squares regression analyses were used to calculate the rate of global mean deviation (MD) change over time and the rate of the mean total deviation values of the 12 test locations within the central 10 degrees region (MTD10) for each eye. Main Outcome Measures: Prevalence of progression based on the rate of MD and the MTD10 change across various fixed cutoffs and cutoffs based on the estimated normal distribution (from the positive slopes). Results: Based on the MD and the MTD10, 12.5% and 11.7% of the eyes, respectively, exhibited a rate of change that was less than -1.0 dB/year (being a rate that typically is defined as "fast progression" for MD values), and 29.0% of the eyes showed a change of less than -0.5 dB/year on MTD10. Furthermore, 12.7% and 9.1% of the eyes exhibited a rate of change that exceeded the 1% cutoff of the estimated normal distribution MD and the MTD10 values, respectively. Conclusions: This study found that approximately 1 in 8 eyes with glaucoma receiving routine care showed fast progression based on global MD values (< -1.0 dB/year) and that nearly 1 in 3 eyes showed a < -0.5 dB/ year decline centrally. These findings highlight the clinical importance of assessing progressive central VF loss and reinforce the need for new therapies to prevent functional disability in a notable proportion of individuals who continue to exhibit fast progression. (c) 2023 by the American Academy of Ophthalmology

Nanophthalmos and posterior microphthalmos are ocular abnormalities in which both eyes are abnormally small, and typically associated with extreme hyperopia. We recruited 40 individuals from 13 kindreds with nanophthalmos or posterior microphthalmos, with 12 probands subjected to exome sequencing. Nine probands (69.2%) were assigned a genetic diagnosis, with variants in MYRF, TMEM98, MFRP, and PRSS56. Two of four PRSS56 families harbored the previously described c.1066dupC variant implicated in over half of all reported PRSS56 kindreds, with different surrounding haplotypes in each family suggesting a mutational hotspot. Individuals with a genetic diagnosis had shorter mean axial lengths and higher hyperopia than those without, with recessive forms associated with the most extreme phenotypes. These findings detail the genetic architecture of nanophthalmos and posterior microphthalmos in a cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.

Importance Retinal ganglion cells endure significant metabolic stress in glaucoma but maintain capacity to recover function. Nicotinamide, a precursor of NAD + , is low in serum of glaucoma patients and its supplementation provides robust protection of retinal ganglion cells in preclinical models. However, the potential of nicotinamide in human glaucoma is unknown. Background To determine whether nicotinamide supplementation alongside conventional IOP-lowering therapy improves retinal ganglion cell function in glaucoma. Design Crossover, double-masked, randomised clinical trial. Participants recruited from two tertiary care centres. Participants Fifty-seven participants, diagnosed and treated for primary glaucoma, enrolled. Methods Participants received oral placebo or nicotinamide and reviewed six-weekly. Participants commenced 6-weeks of 1.5 grams/day then 6 weeks of 3.0 grams/day followed by crossover without washout. Visual function measured using electroretinography and perimetry. Main outcome measures Change in inner retinal function, determined by photopic negative response (PhNR) parameters: saturated PhNR amplitude (Vmax), ratio of PhNR/b-wave amplitude (Vmax ratio). Results PhNR Vmax improved beyond 95% coefficient of repeatability (COR) in 23% of participants following nicotinamide versus 9% on placebo. Overall, Vmax improved by 14.8% [95% CI: 2.8%, 26.9%], (p=0.02) on nicotinamide and 5.2% [−4.2%, 14.6%], (p=0.27) on placebo. Vmax ratio improved by 12.6% [5.0%, 20.2%], (p=0.002) following nicotinamide, 3.6% [−3.4%, 10.5%], (p=0.30) on placebo. A trend for improved visual field mean deviation was observed with 27% improving ≥1dB on nicotinamide and fewer deteriorating (4%) compared to placebo (p=0.02). Conclusions Nicotinamide supplementation can improve inner retinal function in glaucoma. Further studies underway to elucidate the effects of long-term nicotinamide supplementation. Trial Registration ANZCTR trial ID: ACTRN12617000809336 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373001

Clinical & Experimental OphthalmologyVolume 48, Issue 4 p. 525-528 LETTER TO THE EDITOR Comparison between surgical outcomes of glaucoma drainage implant surgery performed with and without intraluminal stent Lingwei W. Tao MBBS MMed(OphthSci), Corresponding Author lingwei.tao@eyeandear.org.au orcid.org/0000-0002-3160-6238 Centre for Eye Research Australia, Melbourne, Victoria, Australia Correspondence Dr Lingwei W. Tao, Royal Victorian Eye and Ear Hospital, 32 Gisborne Street, East Melbourne, VIC 3012, Australia. Email: lingwei.tao@eyeandear.org.auSearch for more papers by this authorAlp Atik FRANZCO, orcid.org/0000-0001-6754-6380 Centre for Eye Research Australia, Melbourne, Victoria, Australia Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorHye J. Kwon, orcid.org/0000-0002-1352-4757 Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorCatherine Green FRANZCO, Centre for Eye Research Australia, Melbourne, Victoria, Australia Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorMichael Coote FRANZCO, Centre for Eye Research Australia, Melbourne, Victoria, Australia Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorYu X. G. Kong PhD FRANZCO, Centre for Eye Research Australia, Melbourne, Victoria, Australia Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorJonathan B. Ruddle FRANZCO, Centre for Eye Research Australia, Melbourne, Victoria, Australia Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia Royal Victorian Children’s Hospital, Parkville, Victoria, AustraliaSearch for more papers by this author Lingwei W. Tao MBBS MMed(OphthSci), Corresponding Author lingwei.tao@eyeandear.org.au orcid.org/0000-0002-3160-6238 Centre for Eye Research Australia, Melbourne, Victoria, Australia Correspondence Dr Lingwei W. Tao, Royal Victorian Eye and Ear Hospital, 32 Gisborne Street, East Melbourne, VIC 3012, Australia. Email: lingwei.tao@eyeandear.org.auSearch for more papers by this authorAlp Atik FRANZCO, orcid.org/0000-0001-6754-6380 Centre for Eye Research Australia, Melbourne, Victoria, Australia Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorHye J. Kwon, orcid.org/0000-0002-1352-4757 Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorCatherine Green FRANZCO, Centre for Eye Research Australia, Melbourne, Victoria, Australia Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorMichael Coote FRANZCO, Centre for Eye Research Australia, Melbourne, Victoria, Australia Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorYu X. G. Kong PhD FRANZCO, Centre for Eye Research Australia, Melbourne, Victoria, Australia Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, AustraliaSearch for more papers by this authorJonathan B. Ruddle FRANZCO, Centre for Eye Research Australia, Melbourne, Victoria, Australia Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia Royal Victorian Children’s Hospital, Parkville, Victoria, AustraliaSearch for more papers by this author First published: 23 January 2020 https://doi.org/10.1111/ceo.13714Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Volume48, Issue4May/June 2020Pages 525-528 RelatedInformation

PURPOSE. To evaluate the short-term changes in inner retinal function using the photopic negative response (PhNR) after intraocular pressure (IOP) reduction in glaucoma. METHODS. Forty-seven participants with glaucoma who were commencing a new or additional IOP-lowering therapy (treatment group) and 39 participants with stable glaucoma (control group) were recruited. IOP, visual field, retinal nerve fiber layer thickness, and electroretinograms (ERGs) were recorded at baseline and at a follow-up visit (3 +/- 2 months). An optimized protocol developed for a portable ERG device was used to record the PhNR. The PhNR saturated amplitude (V-max), V-max ratio, semi-saturation constant (K), and slope of the Naka-Rushton function were analyzed. RESULTS. A significant percentage reduction in IOP was observed in the treatment group (28 +/- 3%) compared to the control group (2 +/- 3%; P < 0.0001). For PhNR V-max, there was no significant interaction (F-1,F-83 = 2.099, P = 0.15), but there was a significant difference between the two time points (F-1,F-83 = 5.689, P = 0.019). Post hoc analysis showed a significant difference between baseline and 3 months in the treatment group (mean difference, 1.23 mu V; 95% confidence interval [CI], 0.24-2.22) but not in the control group (0.30 mu V; 95% CI, 0.78-1.38). K and slope were not significantly different in either group. Improvement beyond test-retest variability was seen in 17% of participants in the treatment group compared to 3% in the control group (P = 0.007, chi(2) test). CONCLUSIONS. The optimized protocol for measuring the PhNR detected short-term improvements in a proportion of participants following IOP reduction, although the majority showed no change.

BackgroundTo assess the clinical and patient-centred effectiveness of a novel residential ocular care (ROC) model in Australian individuals residing in residential care.MethodsIn this prospective, multicentred, randomised controlled trial conducted in 38 Australian aged-care facilities (2015–2017), 178 visually impaired individuals living in residential care facilities (mean age ±SD: 83.9±8.6 years; 65.7% women) were cluster randomised to ROC (n=95) or usual care (n=83) pathways. The ROC arm comprised a tailored and comprehensive within-site eye examination and care rehabilitation pathway, while usual care participants were given a referral to an external eyecare provider. Outcomes included presenting distance and near visual acuity (PNVA); Rasch-transformed Reading, Emotional and Mobility scores from the Impact of Vision Impairment questionnaire; quality of vision (QoV comprising Rasch-transformed Frequency, Severity and Bother domains) scores; Euroqol-5-Dimensions (raw scores); Cornell Scale for Depression (raw scores) and 6-month falls frequency, assessed at baseline and 6 months post intervention. Within-group and between-group comparisons were conducted using linear mixed models, adjusted for baseline differences in characteristics between the two arms.ResultsAt 6 months, intention-to-treat analyses showed significant between-group improvements in ROC residents compared with usual care for PNVA, Emotional and QoV scores (all p<0.05) These significant findings were retained in per-protocol analyses. No other between-group changes were observed.ConclusionOur ROC model was effective in improving near vision, emotional well-being and perceived burden of vision-related symptoms in residential care dwellers in Australia with vision impairment. Future studies to evaluate the cost effectiveness and implementation of ROC in Australia are warranted.

Purpose: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10- and 15-mg bimatoprost implant in subjects with open-angle glaucoma (OAG) and ocular hypertension (OHT) after initial and repeated administrations. Design: Randomized, 20-month, multicenter, subject- and efficacy evaluator-masked, parallel-group, phase 3 clinical study. Participants: Adults with OAG or OHT in each eye, open iridocorneal angle inferiorly in the study eye, and study eye baseline IOP (hour 0; 8 AM) of 22-32 mmHg after washout. Methods: Study eyes received bimatoprost implant 10 mg (n = 198) or 15 mg (n = 198) on day 1 with readministration at weeks 16 and 32, or twice-daily topical timolol maleate 0.5% (n = 198). Intraocular pressure was measured at hours 0 and 2 at each visit. Main Outcome Measures: Primary end points were IOP and change from baseline IOP through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). Results: Both dose strengths of bimatoprost implant were noninferior to timolol in IOP lowering after each administration. Mean diurnal IOP was 24.0, 24.2, and 23.9 mmHg at baseline and from 16.5-17.2, 16.5-17.0, and 17.1-17.5 mmHg through week 12 in the 10-mg implant, 15-mg implant, and timolol groups, respectively. The incidence of corneal and inflammatory TEAEs of interest (e.g., corneal endothelial cell loss, iritis) was higher with bimatoprost implant than timolol and highest with the 15-mg dose strength. Incidence of corneal TEAEs increased after repeated treatment; with 3 administrations at fixed 16-week intervals, incidence of >= 20% CECD loss was 10.2% (10-mg implant) and 21.8% (15-mg implant). Mean best-corrected visual acuity (BCVA) was stable; 3 implant-treated subjects with corneal TEAEs had >2-line BCVA loss at their last visit. Conclusions: Both dose strengths of bimatoprost implant met the primary end point of noninferiority to timolol through week 12. One year after 3 administrations, IOP was controlled in most subjects without additional treatment. The risk-benefit assessment favored the 10-mg implant over the 15-mg implant. Ongoing studies are evaluating other administration regimens to reduce the potential for CECD loss. The bimatoprost implant has potential to improve adherence and reduce treatment burden in glaucoma. (C) 2020 by the American Academy of Ophthalmology.

AIMS:To report 15 cases of intraocular lens (IOL) calcification following intraocular surgery and to identify common risk factors.METHODS:A retrospective case review of patients with IOL calcification reported from the Royal Victorian Eye and Ear Hospital, Melbourne, Australia, and six surgeons in private practice in the Australian states of Victoria, New South Wales and Queensland.RESULTS:15 cases of IOL calcification were identified. Eight cases were in hydrophilic acrylic IOLs and seven in hydrophilic acrylic IOLs with hydrophobic surface properties. Five cases occurred following intraocular injection of gas during endothelial keratoplasties. Two cases occurred following pars plana vitrectomy where gas was used. The remaining eight cases did not involve the injection of any intraocular gas; six cases were following trabeculectomy surgery, and two cases were after insertion of a 'piggyback' sulcus IOL. In each case, the calcification had a characteristic pattern, being centrally placed in the pupillary zone, mainly affecting the anterior lens surface.CONCLUSION:The aetiology of IOL calcification is not fully understood, although there are known risk factors such as using hydrophilic acrylic materials and the use of intraocular gas. Surgical consideration of a patient's ocular comorbidities before IOL implantation is an important tool to mitigate some of this risk.

AbstractPurposeRefractive error is caused by a disparity between the axial length and focusing power of the eye. Nanophthalmos is a rare ocular abnormality in which both eyes are abnormally small, typically causing extreme hyperopic refractive error, and associated with an increased risk of angle-closure glaucoma.MethodsA cohort of 40 individuals from 13 unrelated nanophthalmos kindreds were recruited, with 11 probands subjected to exome sequencing.ResultsNine probands (69.2%) were assigned a genetic diagnosis, with variants in PRSS56 (4), MFRP (3), and previously reported variants in TMEM98 (1) and MYRF (1). Two of the four PRSS56 probands harboured the previously described c.1066dupC frameshift variant implicated in over half of all reported PRSS56 kindreds, with surrounding haplotypes distinct from each other, and from a previously reported Tunisian c.1066dupC haplotype. Individuals with a genetic diagnosis had shorter mean axial lengths (P=7.22×10−9) and more extreme hyperopia (P=0.0005) than those without a genetic diagnosis, with recessive forms associated with the shortest axial lengths and highest hyperopia. All individuals with an axial length below 18 mm in their smaller eye (17/17) were assigned a genetic diagnosis.ConclusionsThese findings detail the genetic architecture of nanophthalmos in an Australian cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.