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Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss from LHON. Mitochondrial variants, including m.14484TC and m.11778GA, have been added to gene arrays, and thus many patients and research participants are tested for LHON mutations. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1,000 people in the general population carry either the m.14484TC or the m.11778GA LHON variant. None of the subset of carriers examined had visual acuity at 20/200 or worse, suggesting a very low penetrance of LHON. Haplogroup analysis of m.14484TC carriers showed a high rate of haplogroup U subclades, previously shown to have low penetrance in pedigrees. Penetrance calculations of the general population are lower than pedigree calculations, most likely because of modifier genetic factors. This Matters Arising Response paper addresses the Watson et al. (2022) Matters Arising paper, published concurrently in The American Journal of Human Genetics.

Many gene therapies are in development for treating people with inherited retinal diseases (IRD). We hypothesized that potential recipients of gene therapy would have knowledge gaps regarding treatment. We aimed to assess knowledge, attitudes, and perceptions of genetic therapies among potential recipients with IRD, using a novel instrument we designed (Attitudes to Gene Therapy-Eye (AGT-Eye)) and their associations with demographic data, self-reported visual status, and tools assessing quality of life and attitudes toward clinical trials using a community-based cross-sectional survey of Australian adults with IRD. AGT-Eye, overall quality of life EQ-5D-5L, National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and Patient Attitudes to Clinical Trials (PACT-22) instruments were administered. Six hundred and eighty-one people completed the study, 51.7% women of mean age 53.5 years (SD ± 15.8). Most participants (91.6%) indicated they would likely accept gene therapy if it was available to them or family members. However, only 28.3% agreed that they had good knowledge of gene therapy. Most obtained information about gene therapy from the internet (49.3%). Respondents with post-graduate degrees scored highest compared to other educational levels on methods (p p = 0.003) and were more likely to see economic value of treatment (p = 0.043). Knowledge gaps were present regarding methods and outcomes of gene therapy. This survey has shown high level of interest in the IRD community for gene therapies, and highlights areas for improved clinician and patient education.

Rationale: Corneal neovascularization (CoNV) is a severe complication of various types of corneal diseases, that leads to permanent visual impairment. Current treatments for CoNV, such as steroids or anti-vascular endothelial growth factor agents, are argued over their therapeutic efficacy and adverse effects. Here, we demonstrate that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) plays an important role in the pathogenesis of CoNV. Methods: Angiogenic activities were assessed in ex vivo and in vitro models subjected to TAK1 inhibition by 5Z-7-oxozeaenol, a selective inhibitor of TAK1. RNA-Seq was used to examine pathways that could be potentially affected by TAK1 inhibition. A gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol was developed as the eyedrop to treat CoNV in a rodent model. Results: We showed that 5Z-7-oxozeaenol reduced angiogenic processes through impeding cell proliferation. Transcriptome analysis suggested 5Z-7-oxozeaenol principally suppresses cell cycle and DNA replication, thereby restraining cell proliferation. In addition, inhibition of TAK1 by 5Z-7-oxozeaenol blocked TNFα-mediated NFκB signalling, and its downstream genes related to angiogenesis and inflammation. 5Z-7-oxozeaenol also ameliorated pro-angiogenic activity, including endothelial migration and tube formation. Furthermore, topical administration of the gelatin-nanoparticles-encapsulated 5Z-7-oxozeaenol led to significantly greater suppression of CoNV in a mouse model compared to the free form of 5Z-7-oxozeaenol, likely due to extended retention of 5Z-7-oxozeaenol in the cornea. Conclusion: Our study shows the potential of TAK1 as a therapeutic target for pathological angiogenesis, and the gelatin nanoparticle coupled with 5Z-7-oxozeaenol as a promising new eyedrop administration model in treatment of CoNV.

In 2018, a consortium of government bodies in China led by the Ministry of Education released theComprehensive Plan to Prevent Nearsightedness among Children and Teenagers(CPPNCT), aiming to reduce the incidence of myopia and control myopic progression in China. Recommendations span from home-based to school-based interventions, including time outdoors, physical activity, light exposure, near-work activity, screen time, Chinese eye exercises, diet and sleep. To date, the levels of evidence for this suite of interventions have not been thoroughly investigated. This review has summarised the evidence of the interventions recommended by the CPPNCT in myopia prevention and control. Thus, the following statements are supposed by the evidence: (1) Increasing time outdoors and reducing near-work time are effective in lowering incident myopia in school-aged children. (2) All interventions have a limited effect on myopia progression. Ongoing research may lead to a better understanding of the underlying mechanisms of myopia development, the interaction of different interventions and recommendations, confounding variables and their true effect on myopia prevention, and the identification of those most likely to respond to specific interventions. This field may also benefit from longer-term studies of the various interventions or strategies covered within this review article, to better understand the persistence of treatment effects over time and explore more novel approaches to myopia control.

Summary We conducted an updated epidemiological study of Leber hereditary optic neuropathy (LHON) in Australia by using registry data to establish the risk of vision loss among different LHON mutations, sex, age at onset, and mitochondrial haplogroup. We identified 96 genetically unrelated LHON pedigrees, including 56 unpublished pedigrees, and updated 40 previously known pedigrees, comprising 620 affected individuals and 4,948 asymptomatic carriers. The minimum prevalence of vision loss due to LHON in Australia in 2020 was one in 68,403 individuals. Although our data confirm some well-established features of LHON, the overall risk of vision loss among those with a LHON mutation was lower than reported previously—17.5% for males and 5.4% for females. Our findings confirm that women, older adults, and younger children are also at risk. Furthermore, we observed a higher incidence of vision loss in children of affected mothers as well as in children of unaffected women with at least one affected brother. Finally, we confirmed our previous report showing a generational fall in prevalence of vision loss among Australian men. Higher reported rates of vision loss in males with a LHON mutation are not supported by our work and other epidemiologic studies. Accurate knowledge of risk is essential for genetic counseling of individuals with LHON mutations. This knowledge could also inform the detection and validation of potential biomarkers and has implications for clinical trials of treatments aimed at preventing vision loss in LHON because an overestimated risk may lead to an underpowered study or a false claim of efficacy.

PURPOSE The Immulite® thyroid stimulating immunoglobulin (TSI) immunoassay is a relatively new commercial assay that has shown good diagnostic accuracy in Graves' hyperthyroidism (GH). However, its clinical utility in thyroid-associated orbitopathy (TAO) is less clear. The purpose of this study was to assess the diagnostic accuracy of the Immulite® TSI immunoassay for TAO and investigate the associations between TSI and other clinical measures. METHODS One hundred and forty patients that had been diagnosed with GH within the previous 12 months were recruited. Identification and grading of TAO were performed at enrolment and serum samples were analysed using the Immulite® TSI immunoassay. RESULTS Of the 140 participants recruited, 75 (53.6%) had TAO. Age, sex and time since GH diagnosis were similar between those with and without TAO (p ≥ 0.300). TSI level tended to decrease with increasing time from GH diagnosis (Spearman's ρ - 0.28, 95% CI - 0.43, - 0.12). TSI levels were higher among those with than those without TAO (median 4.0 vs. 2.7 IU/L, respectively, p = 0.037). There was no correlation between TSI level and inflammatory index score (ρ = 0.14, 95% CI - 0.03, 0.30) or clinical severity (p = 0.527) among those with TAO. TSI level showed poor diagnostic accuracy for TAO (area under the receiver operating characteristic curve 0.60, 95% CI 0.51, 0.70). CONCLUSIONS Although Immulite® TSI level was higher in the presence of TAO, it showed poor diagnostic accuracy and no correlation with clinical markers of TAO severity or activity.

This study investigated the diagnostic performance, feasibility, and end-user experiences of an artificial intelligence (AI)-assisted diabetic retinopathy (DR) screening model in real-world Australian healthcare settings. The study consisted of two components: (1) DR screening of patients using an AI-assisted system and (2) in-depth interviews with health professionals involved in implementing screening. Participants with type 1 or type 2 diabetes mellitus attending two endocrinology outpatient and three Aboriginal Medical Services clinics between March 2018 and May 2019 were invited to a prospective observational study. A single 45-degree (macula centred), non-stereoscopic, colour retinal image was taken of each eye from participants and were instantly screened for referable DR using a custom offline automated AI system. A total of 236 participants, including 174 from endocrinology and 62 from Aboriginal Medical Services clinics, provided informed consent and 203 (86.0%) were included in the analysis. A total of 33 consenting participants (14%) were excluded from the primary analysis due to ungradable or missing images from small pupils (n = 21, 63.6%), cataract (n = 7, 21.2%), poor fixation (n = 2, 6.1%), technical issues (n = 2, 6.1%), and corneal scarring (n = 1, 3%). The area under the curve, sensitivity, and specificity of the AI system for referable DR were 0.92, 96.9% and 87.7%, respectively. There were 51 disagreements between the reference standard and index test diagnoses, including 29 which were manually graded as ungradable, 21 false positives, and one false negative. A total of 28 participants (11.9%) were referred for follow-up based on new ocular findings, among whom, 15 (53.6%) were able to be contacted and 9 (60%) adhered to referral. Of 207 participants who completed a satisfaction questionnaire, 93.7% specified they were either satisfied or extremely satisfied, and 93.2% specified they would be likely or extremely likely to use this service again. Clinical staff involved in screening most frequently noted that the AI system was easy to use, and the real-time diagnostic report was useful. Our study indicates that AI-assisted DR screening model is accurate and well-accepted by patients and clinicians in endocrinology and indigenous healthcare settings. Future deployments of AI-assisted screening models would require consideration of downstream referral pathways.

Many gene therapies are in development for treating people with inherited retinal diseases (IRD). We hypothesized that potential recipients of gene therapy would have knowledge gaps regarding treatment. We aimed to assess knowledge, attitudes, and perceptions of genetic therapies among potential recipients with IRD, using a novel instrument we designed (Attitudes to Gene Therapy-Eye (AGT-Eye)) and their associations with demographic data, self-reported visual status, and tools assessing quality of life and attitudes toward clinical trials using a community-based cross-sectional survey of Australian adults with IRD. AGT-Eye, overall quality of life EQ-5D-5L, National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and Patient Attitudes to Clinical Trials (PACT-22) instruments were administered. Six hundred and eighty-one people completed the study, 51.7% women of mean age 53.5 years (SD ± 15.8). Most participants (91.6%) indicated they would likely accept gene therapy if it was available to them or family members. However, only 28.3% agreed that they had good knowledge of gene therapy. Most obtained information about gene therapy from the internet (49.3%). Respondents with post-graduate degrees scored highest compared to other educational levels on methods (p 0.001) and outcomes (p = 0.003) and were more likely to see economic value of treatment (p = 0.043). Knowledge gaps were present regarding methods and outcomes of gene therapy. This survey has shown high level of interest in the IRD community for gene therapies, and highlights areas for improved clinician and patient education.

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

Importance: Retinal ganglion cells endure significant metabolic stress with ageing and glaucoma-related stressors. Injured cells require increased energy for repair but maintain capacity to recover function despite periods of functional loss. Nicotinamide, a precursor of redox co-factor and metabolite, NAD + , is low in serum of patients with primary open-angle glaucoma and its supplementation provides robust protection of retinal ganglion cells by targeting mitochondrial health in glaucoma models. However, the potential of nicotinamide to improve retinal ganglion cell function in humans with glaucoma is yet unknown. Objective: To determine whether nicotinamide supplementation taken in conjunction with conventional IOP-lowering therapy leads to early improvement in retinal ganglion cell function in people with glaucoma. Design: Crossover, double-masked, randomized clinical trial conducted between October 2017 to January 2019. Setting: Study participants recruited from two tertiary care centers in Melbourne, Australia. Participants: Adults diagnosed and treated for primary glaucoma. Ninety-four participants assessed for study eligibility. Intervention: Participants randomized to first receive oral placebo or nicotinamide and reviewed six-weekly. Accelerated dosing method utilized; participants commenced 6-week course of 1.5 grams/day followed by 6 weeks of 3.0 grams/day. After 12 weeks, participants crossed over to other intervention for 12 weeks without washout. At each visit, visual function measured using full-field flash electroretinography and white-on-white perimetry. Main outcome measures: Primary endpoint was change in inner retinal function determined a-priori as change in photopic negative response (PhNR) parameters: saturated PhNR amplitude (Vmax), ratio of PhNR/b-wave amplitude (Vmax ratio). Results: Fifty-seven participants (65.5±10.0 years, 39% female) enrolled. PhNR Vmax improved beyond 95% coefficient of repeatability (COR) in 23% of participants following 12 weeks of nicotinamide versus 9% on placebo. Conversely, PhNR Vmax deteriorated in 9% on placebo and 7% on nicotinamide. 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 on average by 12.6% [5.0%, 20.2%], (p=0.002) following nicotinamide and 3.6% [-3.4%, 10.5%], (p=0.30) on placebo. A concomitant trend for improved visual field mean deviation was observed with 27% improving ≥1dB on nicotinamide and fewer deteriorating ≥1dB (4%) compared to placebo (p=0.02). Moderate correlation was observed between PhNR and visual field change with treatment. Participants demonstrated excellent treatment adherence rates (>94%) and nicotinamide was well tolerated with minimal side effects. Conclusions and Relevance: Nicotinamide supplementation can improve inner retinal function in patients receiving concurrent IOP-lowering glaucoma therapy. Further studies are underway to elucidate the effects of long-term nicotinamide supplementation on glaucoma progression.

Purpose To investigate quantitatively lipofuscin-associated fundus autofluorescence in patients with macular and cone/cone–rod dystrophies (MD/CCRDs). Design Prospective, single-center, case-control study. Participants Two hundred thirty patients with MD/CCRDs who had undergone genetic testing and 110 control participants without any eye disease. Methods Participants were examined using quantitative fundus autofluorescence (qAF) imaging with a modified confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference (modified Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany). Mean qAF values were obtained by averaging measurements from an 8-segment ring centered on the fovea (qAF8) and compared with controls. Main Outcome Measures The qAF8 levels. Results Elevated qAF8 values were a frequent finding (n = 105 [45%]) and associated with ABCA4 (n = 73 [70%]), PRPH2 (n = 9 [9%]), CERKL (n = 3 [3%]), PROM1 (n = 2 [2%]), CRX (n = 1 [1%]), and CDHR1 (n = 1 [1%]) mutations. Reduced qAF8 values were rare (n = 15 [7%]) and found predominantly among patients with MERTK (n = 3 [20%]) and RDH5 (n = 2 [13%]) mutations. Patients with normal qAF8 values (n = 110 [48%]) showed high genotypic heterogeneity. For various genes including ABCA4, PRPH2, CDHR1, and PROM1, higher qAF8 measures were associated with specific phenotypes and genotypes. For instance, qAF8 values were normal in PRPH2-related central areolar chorioretinal dystrophy but increased in PRPH2-related Stargardt-like retinopathy. Accordingly, high qAF8 levels were associated with specific genetic causes and mutation detection rates in characteristic but genetically heterogenous clinical phenotypes, such as a Stargardt-like flecked fundus, bull’s eye maculopathy, or pattern dystrophy. In genetically unsolved cases (16 with elevated, 35 with normal, 7 with reduced qAF values), qAF8 was used to support or reject ambiguous results of genetic testing, to suggest underlying pathogenic pathways, and to predict disease in otherwise healthy participants. Conclusions Quantitative fundus autofluorescence imaging revealed characteristic qAF levels in association with certain gene mutations and in participants without detected mutations. These findings indicate that qAF may facilitate differential diagnostics of MD/CCRDs and may offer novel pathogenetic insights that may be of particular value for the assessment of future treatment approaches.

IMPORTANCE: This is the largest Gram-negative endophthalmitis specific series and provides important evidence to guide management. BACKGROUND: Endophthalmitis is a sight-threatening emergency. Gram-negative infections are associated with poorer visual outcomes; however, there is limited literature pertaining to this uncommon condition. DESIGN: Prospective case series. PARTICIPANTS: All patients presenting with endophthalmitis to a tertiary institution over a 20-year period. METHODS: Data were collected prospectively and entered into a registry. Patients with microbiological evidence of Gram-negative infection were included in the analysis. MAIN OUTCOMES MEASURES: Final visual acuity (VA), precipitating events, causative organisms, antibiotic sensitivity profiles and risk factors for poor visual outcomes were reported. RESULTS: One hundred Gram-negative organisms were isolated in 97 eyes. Final VA was worse than 6/60 in 65 (67.0%) eyes at follow-up and 29 (29.9%) eyes were eviscerated or enucleated. Microbial keratitis (26.8%, n = 26) and Pseudomonas aeruginosa (34.0%, n = 34) were the most common precipitating event and causative organism, respectively. Eight (8.0%) isolates were third-generation cephalosporin resistant; of which, 7 (88.0%) were sensitive to ciprofloxacin. Preceding microbial keratitis (OR = 13.16, P = .015) or P. aeruginosa infections (OR = 3.40, P = .045) were strongly associated with poorer visual outcomes (worse than 6/60). CONCLUSIONS AND RELEVANCE: Visual outcomes following Gram-negative endophthalmitis are extremely poor, with almost 30% of patients being eviscerated or enucleated. A majority of ceftazidime resistant organisms are sensitive to ciprofloxacin, providing evidence to support the empirical use of quinolones. Clinicians should be mindful that infections secondary to P. aeruginosa or microbial keratitis carry a particularly poor prognosis.

The World Health Organization's Package of Eye Care Interventions (PECI) aims to support incorporation of amblyopia detection and treatment into health service provision. The aim of this study was to systematically review clinical practice guidelines (CPGs) for amblyopia to inform the development of this package.MEDLINE, Embase, CINAHL and Global Index Medicus databases, guideline databases and professional body websites were searched for CPGs published in English between 2010 and 9th March 2020. Guidelines were assessed using the AGREE II tool.Five CPGs from North America published between 2017-2019 were identified. One CPG provided recommendations on amblyopia treatment and four focused on amblyopia detection and assessment. Non-specialist screening for amblyopic risk factors was recommended in children aged 3-5 years. At least one comprehensive eye examination was recommended for infants and children aged 0-5 years. Treatment recommendations consisted of refractive correction followed by occlusion or cycloplegic penalization.Additional evidence is required to compare the benefits and limitations of comprehensive eye examinations for asymptomatic children to those from screening programs. Identified CPGs were produced in high-resource countries and may not be readily applied in lower resource settings where the PECI has the greatest potential to improve service provision.

Although melanocytic choroidal tumours of the choroid are a common eye pathology, no standardised protocol exists for their management in the community.Choroidal naevi are found in approximately 6% of the adult White population, whereas choroidal melanomas are rare, with an annual incidence of 5-10/million/year. Multimodal imaging has advanced the understanding of malignancy imaging biomarkers, but distinguishing between a small melanoma and naevus remains difficult and an algorithm for their management by community practitioners has not been uniformly adopted. One of the authors (BD) devised the MOLES scoring system, which indicates malignancy likelihood according to mushroom shape, orange pigment, large size, enlargement, and subretinal fluid. When applied by ocular oncologists, the system accurately distinguishes choroidal naevi from melanomas. The aim of this study was to evaluate whether community optometrists can appropriately manage patients with melanocytic choroidal tumours using this system.Clinical images of 25 melanocytic choroidal tumours were presented in an online survey, including colour fundus photographs, fundus autofluorescence, optical coherence tomography, and B-scan ultrasound images. Using the MOLES system, 39 optometrists diagnosed tumours as naevus or probable melanoma and decided between community monitoring and ophthalmologist referral. Responses were compared to MOLES grading of the same clinical images by ocular oncologists.Using MOLES, optometrists correctly identified 389/406 probable melanomas (95.8% sensitivity) and 331/516 choroidal naevi (64.1% specificity); correctly referred 773/778 tumours to an ophthalmologist (99.4% sensitivity); and correctly managed 80/144 lesions (55.6% specificity) in the community.Optometrists safely applied the MOLES scoring system in this survey. Further measures are indicated to reduce choroidal naevi over-referral and evaluate MOLES system usage in clinical optometric practice, where some imaging modalities may not be readily available.

To assess the measurement properties of the Attitudes to Gene Therapy for the Eye (AGT-Eye) instrument among Australian adults with inherited retinal diseases (IRDs) and parents/caregivers of people with IRDs. Constructs of interest included sources of information, knowledge of treatment methods, awareness of treatment outcomes, and perceived value of gene therapy for IRDs.A cross-sectional, self-reported, 30-item questionnaire was administered in English from January to June 2021. It was predominantly conducted online with phone and paper alternatives available. Rating scale models were generated separately for each of the four subscales to assess fit, discrimination, and differential item functioning of the items, as well as targeting, reliability, and precision of the subscales. Principal components analysis was used to assess dimensionality.Responses from 681 participants (87.1% online, 12.9% phone/mail) were included (ages 18-93 years; 51.7% female). Removal of two poorly performing items slightly improved subscale properties. Item reliability was high for each of the subscales; however, person reliability was suboptimal, with limited ability to stratify participants according to traits (person separation coefficient1.8 for each subscale). There was no evidence of differential item functioning by gender, online completion, or patient/caregiver status. Evidence of multidimensionality was detected for two subscales.Four subscales of the AGT-Eye will be used to analyze operational knowledge and perceived value of ocular gene therapy in Australia. Measurement properties may be improved with the generation of additional items.Physicians can use the AGT-Eye to assess knowledge and expectations of potential recipients of ocular gene therapy for IRDs.

PURPOSE: To evaluate the secondary and exploratory outcomes of the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study, a 36-month trial of a subthreshold nanosecond laser (SNL) treatment for slowing the progression to late age-related macular degeneration (AMD) in its early stages. DESIGN: Multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two-hundred ninety-two patients with bilateral large drusen. METHODS: Participants were randomly assigned to receive SNL or sham treatment to the study eye at 6-month intervals. MAIN OUTCOME MEASURES: The secondary outcome measure of the LEAD study was the time to development of late AMD, defined by multimodal imaging in the non-study eye. The exploratory outcome measures were the rate of change in best-corrected visual acuity (BCVA), low-luminance visual acuity, microperimetric mean sensitivity, drusen volume in the study and non-study eyes, and participant-reported outcomes based on the Night Vision Questionnaire and Impact of Vision Impairment questionnaire. RESULTS: Progression to late AMD in the non-study eye was not significantly delayed with SNL treatment (hazard ratio, 0.83; 95% confidence interval, 0.40-1.71; P = 0.611). There was no evidence of effect modification based on the coexistence of reticular pseudodrusen; interaction P = 0.065). There was no significant difference between study groups in the rate of change of low-luminance visual acuity, microperimetric mean sensitivity, and drusen volume in the study or non-study eyes, and Night Vision Questionnaire and Impact of Vision Impairment questionnaire scores (all P ≥ 0.167). The rate of BCVA decline was slightly higher for participants in the SNL group compared with the sham treatment group in the study eye (-0.54 and 0.23 letters/year, respectively; P < 0.001) but not the non-study eye (-0.48 and -0.56 letters/year, respectively; P = 0.628). CONCLUSIONS: Subthreshold nanosecond laser treatment of one eye did not have an effect on delaying progression to late AMD in the fellow eye and did not, in general, have an impact on the exploratory structural, functional, and participant-reported outcomes.

Background Dynamic treatment regimens (DTRs) formalise the multi-stage and dynamic decision problems that clinicians often face when treating chronic or progressive medical conditions. Compared to randomised controlled trials, using observational data to optimise DTRs may allow a wider range of treatments to be evaluated at a lower cost. This review aimed to provide an overview of how DTRs are optimised with observational data in practice. Methods Using the PubMed database, a scoping review of studies in which DTRs were optimised using observational data was performed in October 2020. Data extracted from eligible articles included target medical condition, source and type of data, statistical methods, and translational relevance of the included studies. Results From 209 PubMed abstracts, 37 full-text articles were identified, and a further 26 were screened from the reference lists, totalling 63 articles for inclusion in a narrative data synthesis. Observational DTR models are a recent development and their application has been concentrated in a few medical areas, primarily HIV/AIDS (27, 43%), followed by cancer (8, 13%), and diabetes (6, 10%). There was substantial variation in the scope, intent, complexity, and quality between the included studies. Statistical methods that were used included inverse-probability weighting (26, 41%), the parametric G-formula (16, 25%), Q-learning (10, 16%), G-estimation (4, 6%), targeted maximum likelihood/minimum loss-based estimation (4, 6%), regret regression (3, 5%), and other less common approaches (10, 16%). Notably, studies that were primarily intended to address real-world clinical questions (18, 29%) tended to use inverse-probability weighting and the parametric G-formula, relatively well-established methods, along with a large amount of data. Studies focused on methodological developments (45, 71%) tended to be more complicated and included a demonstrative real-world application only. Conclusions As chronic and progressive conditions become more common, the need will grow for personalised treatments and methods to estimate the effects of DTRs. Observational DTR studies will be necessary, but so far their use to inform clinical practice has been limited. Focusing on simple DTRs, collecting large and rich clinical datasets, and fostering tight partnerships between content experts and data analysts may result in more clinically relevant observational DTR studies.

To evaluate the efficacy and safety of interventions for treating eye strain related to computer use relative to placebo or no treatment.Computer use is pervasive and often associated with eye strain, referred to as computer vision syndrome (CVS). Currently, no clinical guidelines exist to help practitioners provide evidence-based advice about CVS treatments, many of which are marketed directly to patients. This systematic review and meta-analysis was designed to help inform best practice for eye care providers.Eligible randomized controlled trials (RCTs) were identified in Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and trial registries, searched from inception through November 23, 2021. Eligible studies were appraised for risk of bias and were synthesized. The certainty of the body of evidence was judged using the Grading of Recommendations, Assessment, Development, and Evaluation system. Standardized mean differences (SMDs) were used when differently scaled measures were combined.Forty-five RCTs, involving 4497 participants, were included. Multifocal lenses did not improve visual fatigue scores compared with single-vision lenses (3 RCTs; SMD, 0.11; 95% confidence interval [CI], -0.14 to 0.37; P = 0.38). Visual fatigue symptoms were not reduced by blue-blocking spectacles (3 RCTs), with evidence judged of low certainty. Relative to placebo, oral berry extract supplementation did not improve visual fatigue (7 RCTs; SMD, -0.27; 95% CI, -0.70 to 0.16; P = 0.22) or dry eye symptoms (4 RCTs; SMD, -0.10; 95% CI, -0.54 to 0.33; P = 0.65). Likewise, berry extract supplementation had no significant effects on critical flicker-fusion frequency (CFF) or accommodative amplitude. Oral omega-3 supplementation for 45 days to 3 months improved dry eye symptoms (2 RCTs; mean difference [MD], -3.36; 95% CI, -3.63 to -3.10 on an 18 unit scale; P0.00001) relative to placebo. Oral carotenoid supplementation improved CFF (2 RCTs; MD, 1.55 Hz; 95% CI, 0.42 to 2.67 Hz; P = 0.007) relative to placebo, although the clinical significance of this finding is unclear.We did not identify high-certainty evidence supporting the use of any of the therapies analyzed. Low-certainty evidence suggested that oral omega-3 supplementation reduces dry eye symptoms in symptomatic computer users.

The electrode to retina (ER) distance is an important contributory factor to the safety and efficacy of a suprachoroidal retinal prosthesis. Measuring ER distance may be performed by different observers during multisite studies. The aim of this study was to assess the interobserver agreement in measuring ER distance.Three independent, trained observers measured ER distance from the center of each suprachoroidal electrode to the inner retinal pigment epithelium in spectral-domain optical coherence tomography (SD-OCT) B-scans. A total of 121 ER distance measurements from 77 B-scans collected over 5 months from one subject implanted with a second-generation 44-channel suprachoroidal retinal prosthesis (NCT03406416) were made by each observer.ER distance ranged from 208 to 509 µm. Pearson's correlation coefficient (ρ) showed agreement of 0.99 (95% confidence interval [CI] = 0.98-0.99) in measuring ER for each pairwise comparison. The mean difference in ER distance between observers ranged from 2.4 to 6.4 µm with pairwise limits of agreement (95% CI) of ±20 µm (5.5% of mean). Intraclass correlation coefficient (ICC) showed agreement of 0.98 (95% CI = 0.97-0.99) between observers.There is high agreement in measuring ER distances for suprachoroidal retinal prostheses using our systematic approach between multiple, trained observers, supporting the use of a single observer for each image.High interobserver agreement outcomes indicate that multiple, trained observers can be used to take ER measurements across different images in suprachoroidal retinal prosthesis studies. This improves multisite study efficiency and gives confidence in interpreting results relating to the safety and efficacy of suprachoroidal retinal prostheses.

Use of the flanged intrascleral haptic fixation technique for insertion of an intraocular lens in the setting of lost capsular support provides predictable refractive outcomes and is a promising alternative to anterior chamber intraocular lenses.

Louis J Stevenson,1 Robin G Abell,1 Myra B McGuinness,2 Rasik B Vajpayee1,3,4 1Royal Victorian Eye and Ear Hospital, Melbourne, Victoria 3002, Australia; 2Centre for Eye Research Australia, Melbourne, Victoria 3002, Australia; 3University of Melbourne, Parkville, Victoria 3010, Australia; 4Vision Eye Institute, Melbourne, Victoria 3004, AustraliaCorrespondence: Rasik B VajpayeeRoyal Victorian Eye and Ear Hospital, University of Melbourne, 32 Gisborne Street, East Melbourne, Victoria 3002, AustraliaEmail rasikv@unimelb.edu.auPurpose: To compare patient demographics, clinical associations and visual outcomes between traumatic and non-traumatic wound dehiscence, following corneal transplantation.Methods: Retrospective review of all patients presenting with post-keratoplasty wound dehiscence to the Royal Victorian Eye and Ear Hospital between January 2005 and December 2017. Patients with wound dehiscence following keratoplasty of any cause were included.Results: Of 71 eyes from 71 patients included, 60 (85%) were penetrating keratoplasty patients. The mean age was 56.4 years (SD=22.7, range 17.6–97) and 62% (n = 44) of patients were male. There were 28 (39%) cases of traumatic dehiscence and 43 (61%) cases of non-traumatic dehiscence. The median time interval from keratoplasty to dehiscence was significantly less in non-traumatic patients than traumatic patients (0.2 years, IQR 0.1–2.0 vs 2.3 years, IQR 0.3–14.8, p=0.01). There was no significant difference in best-corrected visual acuity at 6 months between traumatic and non-traumatic dehiscence (6/60 vs 6/36, p=0.62), suture technique (continuous vs interrupted, p=0.12), or graft type (penetrating keratoplasty vs deep anterior lamellar keratoplasty) after adjusting for keratoconus (p=0.41).Conclusion: Post-keratoplasty wound dehiscence is a serious complication and can cause significant loss of vision. While the risk of dehiscence is lifelong, the first 3 years post-keratoplasty carry the highest risk, with non-traumatic dehiscence tending to occur earlier than traumatic dehiscence.Keywords: graft dehiscence, trauma, keratoplasty, cornea

Purpose There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD. Design The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial. Participants Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy. Methods Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. Main Outcome Measures The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events. Results Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33–1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09–0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80–8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant. Conclusions In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT® laser, but they should not be extrapolated to other short-pulse lasers.

Introduction The aim of this study was to determine the accuracy of orthoptists when examining the optic disc for signs of glaucoma, and to explore the impact of targeted clinical education on accuracy. Methods In this randomized controlled trial, 42 monoscopic color optic disc images were presented to 46 orthoptists who assessed the likelihood of glaucoma as well as optic disc size, shape, tilting, vertical cup-to-disc ratio, cup shape, depth, presence of hemorrhage, peripapillary atrophy, and retinal nerve fiber layer. The level of agreement with specialist ophthalmologists was assessed. Participants were then randomly assigned to an experimental group (targeted postgraduate education on optic disc assessment) or to no intervention. The educational program was designed to increase knowledge of the characteristic features associated with glaucomatous optic neuropathy. All participants re-examined the included optic disc images after a period of 6 to 8 weeks. The primary outcome measure was a change in agreement between attempts. Results The education group showed significant improvements between attempts for identifying hemorrhages (P = .013), retinal nerve fiber layer defects (0.035), disc size (P = .001), peripapillary atrophy (P = .030), and glaucoma likelihood (P = .023). The control group did not show any statistically significant improvement. The intervention group showed significantly more improvement when identifying hemorrhages (P = .013), disc size (P = .001), disc shape (P = .033), and cup shape (P = .020) compared with the control group. Discussion Orthoptists who received additional postgraduate online education based on principles of adult learning were more accurate at assessing the optic disc for glaucoma. These results highlight the value of continuing education to optimize clinical practice in allied health professionals.

To report the long-term observations of the electrode-tissue interface and perceptual stability in humans after chronic stimulation with a 44-channel suprachoroidal retinal implant.Four subjects (S1-4) with end-stage retinitis pigmentosa received the implant unilaterally (NCT03406416). Electrode impedances, electrode-retina distance (measured using optical coherence tomography imaging), and perceptual thresholds were monitored up to 181 weeks after implantation as the subjects used the prosthesis in the laboratory and in daily life. Stimulation charge density was limited to 32 µC/cm2 per phase.Electrode impedances were stable longitudinally. The electrode-retina distances increased after surgery and then stabilized, and were well-described by an asymptotic exponential model. The stabilization of electrode-retina distances was variable between subjects, stabilizing after 45 weeks for S1, 63 weeks for S2, and 24 weeks for S3 (linear regression; Pgradient0.05). For S4, a statistically significant increase in electrode-retina distance persisted (P0.05), but by the study end point the rate of increase was clinically insignificant (exponential model: 0.33 µm/wk). Perceptual electrical thresholds were stable in one subject, decreased over time in two subjects (linear model; P0.05), and increased slightly in one subject but remained within the predefined charge limits (P = 0.02).Chronic stimulation with the suprachoroidal retinal prosthesis over 3 years resulted in stable impedances, small individual changes in perceptual electrical thresholds, and no clinically significant increase in electrode-retina distances after a period of settling after surgery.Chronic stimulation with the 44-channel suprachoroidal retinal implant with a charge density of up to 32 µC/cm2 per phase is suitable for long-term use in humans.

The Immulite® thyroid stimulating immunoglobulin (TSI) immunoassay is a relatively new commercial assay that has shown good diagnostic accuracy in Graves' hyperthyroidism (GH). However, its clinical utility in thyroid-associated orbitopathy (TAO) is less clear. The purpose of this study was to assess the diagnostic accuracy of the Immulite® TSI immunoassay for TAO and investigate the associations between TSI and other clinical measures.One hundred and forty patients that had been diagnosed with GH within the previous 12 months were recruited. Identification and grading of TAO were performed at enrolment and serum samples were analysed using the Immulite® TSI immunoassay.Of the 140 participants recruited, 75 (53.6%) had TAO. Age, sex and time since GH diagnosis were similar between those with and without TAO (p ≥ 0.300). TSI level tended to decrease with increasing time from GH diagnosis (Spearman's ρ - 0.28, 95% CI - 0.43, - 0.12). TSI levels were higher among those with than those without TAO (median 4.0 vs. 2.7 IU/L, respectively, p = 0.037). There was no correlation between TSI level and inflammatory index score (ρ = 0.14, 95% CI - 0.03, 0.30) or clinical severity (p = 0.527) among those with TAO. TSI level showed poor diagnostic accuracy for TAO (area under the receiver operating characteristic curve 0.60, 95% CI 0.51, 0.70).Although Immulite® TSI level was higher in the presence of TAO, it showed poor diagnostic accuracy and no correlation with clinical markers of TAO severity or activity.

Purpose To evaluate anatomical and functional inter-eye symmetry among individuals with Bietti Crystalline Dystrophy (BCD) using clinical and multi-modal imaging methods, with a focus on the number, area, and distribution of the characteristic retinal crystalline deposits. Design Observational case series with prospective and retrospective data. Methods Setting: Multicenter Study population Thirteen Australian and New Zealand participants (26 eyes) with confirmed biallelic CYP4V2 mutations and a characteristic BCD fundus appearance. Procedures and main outcome measures Crystals visible on color fundus photography were manually counted. Crystals were superimposed on aligned multimodal fundus images. Spearman's correlation coefficients (ρ), intraclass correlation coefficients (ICCs), and Bland-Altman plots were used to quantify symmetry between eyes. Main outcome measures Fundus crystal area and count, and absent-autofluorescence (absent-AF) area. Results Median participant age was 48 years, interquartile range 40–60 years. Inter-eye symmetry was high for fundus crystal area (ρ=1.00, 95% CI 1.00–1.00; ICC=0.97, 95% CI 0.88–0.99), fundus crystal count (ρ=0.98, 95% CI 0.92–1.00; ICC=0.97, 95% CI 0.89–0.99), and absent-AF area (ρ=0.88, 95% CI 0.53–0.98; ICC=0.98, 95% CI 0.90–0.99). Average foveal volume, foveal crystal count and area, average and central foveal thickness, best corrected visual acuity, and average macular and central foveal sensitivity were not highly correlated between eyes. Conclusions This study demonstrated strong inter-eye symmetry measured by fundus crystal area, fundus crystal number, and absent-AF area. This may influence the choice of outcome measures for future therapeutic trials for BCD, and provides valuable clinical information for ophthalmologists involved in the care and counselling of BCD patients.

PURPOSE: To investigate differences in quantitative autofluorescence (qAF) imaging measurements between eyes with and without large drusen, and whether qAF measurements change over time in the eyes with large drusen. METHODS: Eighty-five eyes from participants with bilateral large drusen and 51 eyes from healthy participants underwent qAF imaging at least once, and the age-related macular degeneration participants were reviewed 6-monthly. Normalized grey values at 9° to 11° eccentricity from the fovea were averaged to provide a summary measure of qAF values (termed qAF8). RESULTS: In a multivariable model, qAF8 measurements were not significantly different between age-related macular degeneration eyes with large drusen and healthy eyes (P = 0.130), and qAF8 measurements showed a decline over time in the age-related macular degeneration eyes (P = 0.013). CONCLUSION: These findings add to the body of evidence that qAF levels are not increased in eyes with large drusen compared with healthy eyes, and qAF levels show a significant decline over time in the age-related macular degeneration eyes. These findings highlight how the relationship between qAF levels and retinal pigment epithelium health does not seem to be straightforward. Further investigation is required to better understand this relationship, especially if qAF levels are to be used as an outcome measure in intervention trials.

Purpose To investigate the relationship between patient-reported outcome (PRO) questionnaire responses and time to late age-related macular degeneration (AMD; neovascular AMD [nAMD] or multimodal imaging [MMI]-defined atrophy) among individuals with bilateral large drusen, and the prognostic value of baseline PROs for 36-month AMD status. Design Exploratory analyses from a multicenter randomized controlled trial of an AMD intervention (Australian New Zealand Clinical Trials Registry identifier, ACTRN12612000704897). Participants Sham treatment group of the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) Study (n = 141; age, 50–88 years; 77% female). Methods The 28-item Impact of Vision Impairment (IVI-28) and 10-item Night Vision Questionnaire (NVQ-10) were administered at the baseline visit. The PRO scores were derived using rating scale models. Multivariate Cox regression adjusting for demographics and clinical measures of vision (low-luminance visual acuity, low-luminance deficit, and microperimetric sensitivity) from the poorer-performing eye was used to investigate the association between PRO scores and time to late AMD in either eye. Multivariate competing-risk regression was used to estimate cause-specific subhazard ratios for nAMD and atrophy in either eye. Cross-validated logistic lasso models were used to estimate the predicted probability of AMD at 36 months. The area under the receiver operating characteristic curve was assessed to compare prognostic accuracy between models with and without PROs. Main Outcome Measure Time until nAMD or atrophy in either eye. Results The PRO scores were skewed toward higher functional vision. Higher IVI-28 scores were associated with a lower risk of progression to MMI-defined atrophy (20 events: adjusted hazard ratio, 0.65/logit increase; P = 0.002) but not nAMD (10 events; P = 0.562). Insufficient evidence was found of an association between NVQ-10 score and rate of progression to late AMD (P ≥0.149). Baseline IVI-28 scores were found to contribute to the prognosis of atrophy at the 36-month visit (P = 0.010). Conclusions On average, PROs were associated with an increased risk of progression from intermediate AMD to MMI-defined atrophy. Continuing development of instruments to record PROs in the early stages of AMD have the potential to produce inexpensive and efficient tools to assist in the assessment of disease severity and risk of AMD progression.

Purpose To quantify the association between dark adaptation parameters and other clinical measures of visual function among people with and without early and intermediate age-related macular degeneration (AMD). Methods In this cross-sectional study, participants underwent multimodal imaging and visual function testing, including best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), low-luminance deficit (LLD = BCVA - LLVA) and the 10-item Night Vision Questionnaire (NVQ-10). Dynamic and static dark-adapted chromatic perimetry (DACP) was performed. Sensitivity difference was defined as the difference in sensitivity between the 505-nm and 625-nm stimuli. Rod intercept time (RIT) was estimated as the time required to reach a threshold of -3 log candelas/meter2 with the 505-nm stimulus following bleaching. The magnitude of association between the DACP parameters and other clinical tests was estimated via mixed-effects regression. Results A total of 51 participants (aged 51-88 years, 65% female, 39% with AMD) were included. RIT was found to be negatively associated with BCVA (P < 0.001), LLVA (P = 0.005), and NVQ-10 score (P = 0.028) but not LLD (P = 0.763). There was no evidence of an association between sensitivity difference and any of the clinical measures (P ≥ 0.081). Conclusions Reduced rod function, as determined by RIT, was associated with lower NVQ-10 scores (designed to interrogate rod-mediated function) and with worse BCVA and LLVA (measures of cone function). Translational Relevance Decreasing rod function maybe indicative of more generalized photoreceptor dysfunction involving cones. Further development of questionnaires to target function in scotopic conditions may provide an easier to administer test without the need to perform perimetric tests of rod function.

Background Attrition due to death and non-attendance are common sources of bias in studies of age-related diseases. A simulation study is presented to compare two methods for estimating the survivor average causal effect (SACE) of a binary exposure (sex-specific dietary iron intake) on a binary outcome (age-related macular degeneration, AMD) in this setting. Methods A dataset of 10,000 participants was simulated 1200 times under each scenario with outcome data missing dependent on measured and unmeasured covariates and survival. Scenarios differed by the magnitude and direction of effect of an unmeasured confounder on both survival and the outcome, and whether participants who died following a protective exposure would also die if they had not received the exposure (validity of the monotonicity assumption). The performance of a marginal structural model (MSM, weighting for exposure, survival and missing data) was compared to a sensitivity approach for estimating the SACE. As an illustrative example, the SACE of iron intake on AMD was estimated using data from 39,918 participants of the Melbourne Collaborative Cohort Study. Results The MSM approach tended to underestimate the true magnitude of effect when the unmeasured confounder had opposing directions of effect on survival and the outcome. Overestimation was observed when the unmeasured confounder had the same direction of effect on survival and the outcome. Violation of the monotonicity assumption did not increase bias. The estimates were similar between the MSM approach and the sensitivity approach assessed at the sensitivity parameter of 1 (assuming no survival bias). In the illustrative example, high iron intake was found to be protective of AMD (adjusted OR 0.57, 95% CI 0.40–0.82) using complete case analysis via traditional logistic regression. The adjusted SACE odds ratio did not differ substantially from the complete case estimate, ranging from 0.54 to 0.58 for each of the SACE methods. Conclusions On average, MSMs with weighting for exposure, missing data and survival produced biased estimates of the SACE in the presence of an unmeasured survival-outcome confounder. The direction and magnitude of effect of unmeasured survival-outcome confounders should be considered when assessing exposure-outcome associations in the presence of attrition due to death.

Purpose: In a clinical trial (NCT03406416) of a second-generation (44-channel) suprachoroidal retinal prosthesis implanted in subjects with late-stage retinitis pigmentosa (RP), we assessed performance in real-world functional visual tasks and emotional well-being. Methods: The Functional Low-Vision Observer Rated Assessment (FLORA) and Impact of Vision Impairment-Very Low Vision (IVI-VLV) instruments were administered to four subjects before implantation and after device fitting. The FLORA contains 13 self-reported and 35 observer-reported items ranked for ease of conducting task (impossible-easy, central tendency given as mode). The IVI-VLV instrument quantified the impact of low vision on daily activities and emotional well-being. Results: Three subjects completed the FLORA for two years after device fitting; the fourth subject ceased participation in the FLORA after fitting for reasons unrelated to the device. For all subjects at each post-fitting visit, the mode ease of task with device ON was better or equal to device OFF. Ease of task improved over the first six months with device ON, then remained stable. Subjects reported improvements in mobility, functional vision, and quality of life with device ON. The IVI-VLV suggested self-assessed vision-related quality of life was not impacted by device implantation or usage. Conclusions: Subjects demonstrated sustained improved ease of task scores with device ON compared to OFF, indicating the device has a positive impact in the real-world setting. Translational Relevance: Our suprachoroidal retinal prosthesis shows potential utility in everyday life, by enabling an increased environmental awareness and improving access to sensory information for people with end-stage RP.

AimsTo assess associations between features of age-related macular degeneration (AMD) and mortality.MethodsA total of 21 129 participants from the Melbourne Collaborative Cohort Study aged 47-85 years (60% female) were assessed for AMD (2003-2007). Mortality data to December 31, 2012 were obtained through linkage with the National Death Index. Associations were assessed using Cox regression, adjusting for age, sex, smoking, region of birth, education, physical activity, diet and alcohol.ResultsLate AMD was identified in 122 (0.6%) participants, including those with choroidal neovascularisation (n=55, 0.3%), geographic atrophy (n=87, 0.4%) and reticular pseudodrusen (n=87, 0.4%). After a median follow-up period of 8.1 years, 1669 (8%) participants had died, including those from cardiovascular diseases (386), tobacco-related cancers (179), and neurodegenerative disease (157). There was evidence of an increased rate of all-cause mortality for those with choroidal neovascularisation (Hazard Ratio (HR) 1.71 95% CI 1.06-2.76) and geographic atrophy (HR 1.46 95% CI 0.99-2.16). Choroidal neovascularisation was also associated with an increased rate of cardiovascular mortality (HR 3.16 95% CI 1.62-6.15) and geographic atrophy was associated with an increased rate of death from tobacco-related cancer (HR 2.86 95% CI 1.15-7.09). Weak evidence was also present for an association between choroidal neovascularisation and death from neurodegenerative disease (HR 2.49 95% CI 0.79-7.85). Neither reticular pseudodrusen nor the earlier stages of AMD were associated with mortality.ConclusionsLate AMD is associated with an increased rate of all-cause mortality. Choroidal neovascularisation and geographic atrophy were associated with death from cardiovascular disease and tobacco-related cancer, respectively.

Item does not contain fulltext PURPOSE: To better understand the association, in a white population, of physical activity and age-related macular degeneration (AMD)-the main cause of irreversible severe vision loss in developed countries-given the suggestion that a healthy lifestyle may assist in delaying the onset and progression of AMD. DESIGN: Systematic review and meta-analysis. METHODS: Medline, EMBASE, and Google Scholar were systematically searched for studies up to May 2015. Reference lists of published articles were hand searched and study authors were contacted to provide additional data. Those in the lowest category of activity in each study were compared with all other participants to assess the association between physical activity and both early and late AMD using random-effects meta-analysis. RESULTS: Nine studies (subject age range 30-97 years) were included in the meta-analysis. Physical activity was found to have a protective association with both early AMD (8 studies, n = 38 112, odds ratio (OR) 0.92, 95% confidence interval [CI] 0.86-0.98) and late AMD (7 studies, n = 28 854, OR 0.59, 95% CI 0.49-0.72). CONCLUSIONS: Physical activity is associated with lower odds of early and late AMD in white populations. These findings have important implications, reinforcing the public health message of staying active throughout life. However, further longitudinal studies are required to confirm and further characterize a protective effect of physical activity on the onset and/or progression of AMD.

Purpose Nascent geographic atrophy (nGA) describes features on OCT imaging previously observed to precede the development of atrophy. This study sought to prospectively evaluate the predictive ability of nGA for the conventional clinical endpoint of geographic atrophy (GA) as defined on color fundus photography (CFP). Design Prospective, longitudinal, observational study. Participants A total of 284 eyes from 142 participants with bilateral large drusen and without nGA nor late age-related macular degeneration (AMD) at baseline were included. Methods OCT volume scans and CFP images were obtained from all participants at baseline and then at 6-month intervals for up to 36 months. OCT and CFP images were graded independently for the presence of nGA and GA, respectively. Eyes that developed neovascular AMD were censored at the day of its detection. Main Outcome Measures Time to development of GA. Results A total 12 eyes from 10 participants progressed to GA over 36 months of follow-up, and nGA was detected in 10 of these eyes (83%) at a preceding visit (median, 13 months prior; interquartile range, 6–25 months). A total of 40 eyes from 28 participants developed nGA or GA over 36 months of follow-up, and the probability of progression to nGA and GA after 36 months was 20% (95% confidence interval [CI], 14%–28%) and 9% (95% CI, 6%–13%), respectively. After the detection of nGA, the probability of progression to GA was 38% (95% CI, 15%–55%) after 24 months. The development of nGA was associated with a markedly increased risk of progression to GA compared with when it did not develop (adjusted hazard ratio, 78.1; 95% CI, 13.6–448.0; P Conclusions This study prospectively demonstrated that nGA was a strong predictor for the development of GA, providing supportive evidence of the potential value of nGA as a surrogate endpoint in future intervention trials for the early stages of AMD to improve their feasibility substantially.

Importance Bleb-associated endophthalmitis is a potentially vision-threatening complication of trabeculectomy. With improvements in surgical technique and changing patterns of intraoperative antimetabolite use, a re-evaluation of the incidence of bleb-associated endophthalmitis is warranted. Background To investigate changes in the incidence, presentation, management and outcomes of bleb-associated endophthalmitis between 1997 and 2015 in Victoria, Australia. Design A retrospective cohort analysis. Participants Consecutive cases of bleb-associated endophthalmitis managed at the Royal Victorian Eye and Ear Hospital (RVEEH) between 1997 and 2015. Methods Medical record review of consecutive cases of bleb-associated endophthalmitis and statistical analysis were performed. Main outcome measures Visual acuity, including loss of light perception, intraocular pressure, and need for further surgery. Results Sixty-seven eyes with bleb-associated endophthalmitis (BAE) were identified. Of these, 41 had trabeculectomy performed in Victoria during the study period, over which time 11 129 trabeculectomies were performed. The proportion of BAE was stable over time (0.4%). The mean age at presentation was 73.7 ± 12.1 years old and the majority of patients were Caucasian (79.1%). The mean duration between glaucoma filtration surgery and the development of bleb-associated endophthalmitis was 3 years (Interquartile Range = 0.4-6.0 years). The cultures were positive in 71.6% of cases. Approximately 1 in 8 patients required enucleation. The final visual acuity was poor with a Snellen Visual Acuity (VA) of 6/60 or worse in two-thirds of patients. Conclusions and relevance Bleb-associated endophthalmitis is an uncommon complication following glaucoma filtration surgery. The proportion has remained stable over time. Visual outcomes remain poor.

Importance In Australia, nationally representative data of the burden and associations of severe uncorrected refractive error are scarce. Background To report the prevalence and characteristics of severe uncorrected refractive error in Indigenous and non-Indigenous Australians. Design Population-based cross-sectional study. Participants A total of 3098 non-Indigenous Australians aged 50 to 98 and 1738 Indigenous Australians aged 40 to 92 living in 30 randomly selected Australian sites were examined. Methods Severe uncorrected refractive error was defined as an improvement of ≥2 lines on the logMAR chart in one or both eyes in participants with a presenting visual acuity Main outcome measure Severe uncorrected refractive error RESULTS: Prevalence of severe uncorrected refractive error was 11.0% (95% confidence interval 9.3-13.0) in non-Indigenous and 14.5% (12.5-16.7) in Indigenous Australians. Eighty-two percent of non-Indigenous and 77% of Indigenous participants had a spherical equivalent refraction between -2.00D and +2.00D. Indigenous Australians who were older (odds ratio [OR] for 70-79 years vs 40-49 years = 3.59), resided in outer regional areas (OR = 1.78) and did not have an eye examination in the previous 2-years (OR = 1.50) were associated with higher odds of severe uncorrected refractive error. Geographical remoteness (OR = .68 for inner regional), male gender (OR = 1.30), older age (OR for 70-79 years vs 50-59 years = 1.51) and failure to have an eye examination in the previous 2-years (OR = 2.06) were associated with severe uncorrected refractive error among non-Indigenous participants. Conclusions and relevance Increased public awareness of the importance of regular optometric examinations may be required in groups at high risk of severe uncorrected refractive error.

Analysis of time-to-event data, otherwise known as survival analysis, is a common investigative tool in ophthalmic research. For example, time-to-event data is useful when researchers are interested in investigating how long it takes for an ocular condition to worsen or whether treatment can delay the development of a potentially vision-threatening complication. Its implementation requires a different set of statistical tools compared to those required for analyses of other continuous and categorial outcomes. In this installment of the Focus on Data series, we present an overview of selected concepts relating to analysis of time-to-event data in eye research. We introduce censoring, model selection, consideration of model assumptions, and best practice for reporting. We also consider challenges that commonly arise when analyzing time-to-event data in ophthalmic research, including collection of data from two eyes per person and the presence of multiple outcomes of interest. The concepts are illustrated using data from the Laser Intervention in Early Stages of Age-Related Macular Degeneration study and statistical computing code for Stata is provided to demonstrate the application of the statistical methods to illustrative data.

IMPORTANCE: Age-related macular degeneration (AMD), the leading cause of irreversible blindness in older adults, appears to have no effective preventive measures. The common antidiabetic drug metformin has been shown to have protective outcomes in multiple age-associated diseases and may have the potential to protect against the development of AMD. OBJECTIVE: To determine whether metformin use is associated with reduced odds of developing AMD. DESIGN, SETTING, AND PARTICIPANTS: This case-control study of patients from a nationwide health insurance claims database included a population-based sample of patients. Those aged 55 years and older with newly diagnosed AMD from January 2008 to December 2017 were defined as cases and matched with control participants. Data analyses were completed from June 2019 to February 2020. EXPOSURES: Dosage of metformin and exposure to other prescribed medications, as identified from outpatient drug claims. MAIN OUTCOMES AND MEASURES: Risk of developing AMD. RESULTS: A total of 312 404 affected individuals were included (181 817 women [58.2%]). After matching, 312 376 control participants were included (172 459 women [55.2%]; age range, 55 to 107 years). The case group had a slightly higher percentage of participants with diabetes (81 262 participants [26.0%]) compared with the control group (79 497 participants [25.5%]). Metformin use was associated with reduced odds of developing AMD (odds ratio [OR], 0.94 [95% CI, 0.92-0.96]). This association was dose dependent, with low to moderate doses of metformin showing the greatest potential benefit (dosages over 2 years: 1-270 g, OR, 0.91 [95% CI, 0.88-0.94]; 271-600 g, OR, 0.90 [95% CI, 0.87-0.93]; 601-1080 g, OR, 0.95 [95% CI, 0.92-0.98]). Doses of more than 1080 g of metformin over 2 years did not have reduced odds of developing AMD. Both the reduction in odds ratio and the dose-dependent response were preserved in a cohort consisting only of patients with diabetes. Metformin use was associated with a decreased OR of AMD in patients with diabetes without coexisting diabetic retinopathy (OR, 0.93 [95% CI, 0.91-0.95]) but was a risk factor in patients with diabetic retinopathy (OR, 1.07 [95% CI, 1.01-1.15]). CONCLUSION AND RELEVANCE: In this study, metformin use was associated with reduced odds of developing AMD. This association was dose dependent, with the greatest benefit at low to moderate doses. When looking only at patients with diabetes, we saw a preservation of the dose-dependent decrease in the odds of patients developing AMD. Metformin does not appear to be protective in patients with diabetes and coexisting diabetic retinopathy. This study suggests that metformin may be useful as a preventive therapy for AMD and provides the basis for potential prospective clinical trials.

Purpose To determine the prevalence of reticular pseudodrusen (RPD) and its association with age-related macular degeneration (AMD) and AMD risk factors in a large sample. Design Community-based cohort study in Melbourne, Victoria, Australia. Participants A total of 21130 participants 48 to 86 years of age available for ophthalmic assessment at follow-up from 2003 through 2007. Methods Lifestyle, diet, and anthropometric measurements were obtained at baseline and follow-up. At follow-up, digital macular color photographs were graded for early, intermediate, and late AMD as well as the presence of RPD. Data were analyzed using multinomial logistic regression controlling for age, gender, smoking, country of birth, and diet. Main Outcome Measures Detection of RPD based on color fundus photographs. Results Prevalence of RPD was 0.41% (87 of 21130 participants), with 51% having bilateral RPD. Patients with RPD were older compared with patients with large drusen (>125 μm; 76±4 vs. 68±9 years; P 125 μm) were associated with a higher prevalence of RPD. Presence of geographic atrophy (GA) was associated with the highest odds of having RPD (odds ratio [OR], 153; 95% confidence interval [CI], 53–442), followed by choroidal neovascularization (CNV; OR, 90; 95% CI, 26–310), intermediate AMD (OR, 33; 95% CI, 14–77), and early AMD (OR, 12; 95% CI, 5–31) compared with those with no AMD. The ARMS2 single nucleotide polymorphism (SNP) rs10490924, HTRA1 SNPs rs11200638 and rs3793917, and CFH SNPs rs393955, rs1061170, and rs2274700 were associated with increased prevalence of RPD (all P Conclusions Reticular pseudodrusen are highly concurrent with AMD and have similar associations with known AMD risk factors such as age, gender, smoking, and genetic risk factors. Reticular pseudodrusen are associated more strongly with GA than with CNV. Although RPD are not specific to AMD, they are likely to be a strong risk factor for progression to late-stage AMD, similar to focal pigmentary abnormalities and large drusen.

There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD.The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial.Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy.Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RTThe primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events.Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant.In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT

IMPORTANCE: Reticular pseudodrusen (RPD) is strongly associated with late age-related macular degeneration (AMD) but their aetiology remains unknown. RPD have been associated with reduced choroidal thickness (ChT) but most studies are limited by small sample size and varying severity of AMD. BACKGROUND: To investigate the relationship between choroidal thickness and RPD in eyes with intermediate AMD (iAMD), controlling for variables known to influence ChT. DESIGN: Retrospective cohort study. PARTICIPANTS: Participants were recruited from Centre for Eye Research Australia. METHODS: Colour fundus photographs, fundus auto fluorescence, near-infrared and spectral-domain ocular coherence tomography (OCT) were graded for RPD. ChT was measured from enhanced-depth imaging OCT scans at the centre of fovea, 1500 and 3000 μm nasal, temporal, superior and inferior from centre of fovea. MAIN OUTCOME MEASURES: ChT between RPD and non-RPD group. RESULTS: A total of 297 eyes from 152 subjects were included. A total of 84 (28%) had RPD and were older than non-RPD group (75.1 ± 5.4 years and 68.7 ± 6.9 years, respectively; P < 0.001). In unadjusted analysis, the RPD group was significantly associated with thinner choroids across all measured locations (P ≤ 0.022). After adjustment for variables, the presence of RPD was no longer associated with ChT (P ≥ 0.132 for all locations) but age (P < 0.001) and refractive error (P = 0.002) remained significantly associated with ChT. CONCLUSIONS AND RELEVANCE: Age and refractive error, rather than RPD, was significantly associated with reduced ChT in eyes with iAMD. Choroidal insufficiency may be a less important variable in RPD aetiology than previously considered.

Purpose To quantify lipofuscin-associated fundus autofluorescence in patients with pseudoxanthoma elasticum (PXE), a model disease for Bruch's membrane pathology. Methods In this prospective, monocenter, cross-sectional case-control study, 49 patients with PXE (mean age: 46 years, range 18-62) underwent quantitative fundus autofluorescence (qAF) imaging with a modified scanning laser ophthalmoscope containing an internal fluorescent reference for normalization of images. The mean qAF values of a circular ring centered on the fovea (qAF8) were measured and compared to 108 healthy controls (mean age 40 years, range 18-64). Results Overall, patients with PXE showed lower qAF8 values compared to controls (difference from controls -23%, 95% confidence interval [CI] -29% to -16%, P < 0.001). The reduction was most pronounced in patients older than 40 years (-30%, 95% CI -36% to -23%, P < 0.001) and was negatively correlated with the extent of Bruch's membrane calcification (r = -0.49, 95% CI: -0.67 to -0.22). The topographic distribution revealed a greater reduction of qAF values toward the optic disc than temporally compared to controls (P < 0.001). The phenotype of patients with reduced qAF values was characterized by pattern-dystrophy-like changes (71%; 10 of 14), reticular pseudodrusen (71%; 10 of 14) and limited areas of atrophy (29%, 4 of 14). Conclusions Reduced qAF8 values are a characteristic finding in patients with PXE, indicating that Bruch's membrane disease may result in a modification of the accumulation, distribution, or composition (or a combination thereof) of lipofuscin in retinal pigment epithelial cells.

Reticular pseudodrusen (RPD) is strongly associated with late age-related macular degeneration (AMD) but their aetiology remains unknown. RPD have been associated with reduced choroidal thickness (ChT) but most studies are limited by small sample size and varying severity of AMD.To investigate the relationship between choroidal thickness and RPD in eyes with intermediate AMD (iAMD), controlling for variables known to influence ChT.Retrospective cohort study.Participants were recruited from Centre for Eye Research Australia.Colour fundus photographs, fundus auto fluorescence, near-infrared and spectral-domain ocular coherence tomography (OCT) were graded for RPD. ChT was measured from enhanced-depth imaging OCT scans at the centre of fovea, 1500 and 3000 μm nasal, temporal, superior and inferior from centre of fovea.ChT between RPD and non-RPD group.A total of 297 eyes from 152 subjects were included. A total of 84 (28%) had RPD and were older than non-RPD group (75.1 ± 5.4 years and 68.7 ± 6.9 years, respectively; P0.001). In unadjusted analysis, the RPD group was significantly associated with thinner choroids across all measured locations (P ≤ 0.022). After adjustment for variables, the presence of RPD was no longer associated with ChT (P ≥ 0.132 for all locations) but age (P0.001) and refractive error (P = 0.002) remained significantly associated with ChT.Age and refractive error, rather than RPD, was significantly associated with reduced ChT in eyes with iAMD. Choroidal insufficiency may be a less important variable in RPD aetiology than previously considered.