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Item does not contain fulltext, BACKGROUND: High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. METHODS: The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. FINDINGS: In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17-21%), 2% (1-3%), 8% (7-10%) and 6% (3-9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75-0.81), 0.58 (0.53-0.64), 0.71 (0.69-0.74) and 0.67 (0.62-0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92-1.24). INTERPRETATION: Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for. FUNDING: Supported by the Welsh Government and Fight for Sight (24WG201).

PURPOSE: Toxoplasmic retinochoroiditis is the most common clinical manifestation of an infection with the protozoan parasite, Toxoplasma gondii. Up to 50% of the human population is estimated to be infected with T. gondii; however, the epidemiology of toxoplasmic retinochoroiditis has not been widely reported. We sought to estimate the prevalence of toxoplasmic retinochoroiditis in Australia using data that were collected as part of the Busselton Healthy Ageing Study. DESIGN: Cross-sectional, community-based, prospective cohort study. PARTICIPANTS: 5020 Australian adults (2264 men and 2756 women; age range, 45-69 years, and median age, 58 years). METHODS: Retinal color photographs, centered on the optic disc and macula, were captured using a digital retinal camera after the dilation of the pupils. Three uveitis-subspecialized ophthalmologists assessed each pigmented retinal lesion, and complete concordance of opinion was required to assign a toxoplasmic etiology. Serum T. gondii immunoglobulin (Ig)G levels were measured for those participants with retinal lesions judged to be toxoplasmic retinochoroiditis. MAIN OUTCOME MEASURES: Prevalence of toxoplasmic retinochoroiditis. RESULTS: Eight participants (0.16%) had retinal lesions that were considered to have the characteristic appearance of toxoplasmic retinochoroiditis, plus detectable serum T. gondii IgG, consistent with the diagnosis of toxoplasmic retinochoroiditis. On the assumption that 23.81% of retinal lesions occur at the posterior pole, as reported in a community-based survey conducted in Brazil (Sci Rep. 2021;11:3420), the prevalence of toxoplasmic retinochoroiditis was estimated to be 0.67% or 1 per 149 persons. CONCLUSIONS: Toxoplasmic retinochoroiditis is common in Australian adults. Efforts to quantify and address risk factors for human infection with T. gondii are justified.

Background To generate and validate a method to estimate axial length estimated (ALest) from spherical equivalent (SE) and corneal curvature [keratometry (K)], and to determine if this ALest can replace actual axial length (ALact) for correcting transverse magnification error in optical coherence tomography angiography (OCTA) images using the Littmann-Bennett formula. Methods Data from 1301 participants of the Raine Study Gen2-20 year follow-up were divided into two datasets to generate (n = 650) and validate (n = 651) a relationship between AL, SE, and K. The developed formula was then applied to a separate dataset of 46 participants with AL, SE, and K measurements and OCTA images to estimate and compare the performance of ALest against ALact in correcting transverse magnification error in OCTA images when measuring the foveal avascular zone area (FAZA). Results The formula for ALest yielded the equation: ALest = 2.102K − 0.4125SE + 7.268, R2 = 0.794. There was good agreement between ALest and ALact for both study cohorts. The mean difference [standard deviation (SD)] between FAZA corrected with ALest and ALact was 0.002 (0.015) mm2 with the 95% limits of agreement (LoA) of − 0.027 to 0.031 mm2. In comparison, mean difference (SD) between FAZA uncorrected and corrected with ALact was − 0.005 (0.030) mm2, with 95% LoA of − 0.064 to 0.054 mm2. Conclusions ALact is more accurate than ALest and hence should be used preferentially in magnification error correction in the clinical setting. FAZA corrected with ALest is comparable to FAZA corrected with ALact, while FAZA measurements using images corrected with ALest have a greater accuracy than measurements on uncorrected images. Hence, in the absence of ALact, clinicians should use ALest to correct for magnification error as this provides for more accurate measurements of fundus parameters than uncorrected images.

BACKGROUND: To generate and validate a method to estimate axial length estimated (ALest) from spherical equivalent (SE) and corneal curvature [keratometry (K)], and to determine if this ALest can replace actual axial length (ALact) for correcting transverse magnification error in optical coherence tomography angiography (OCTA) images using the Littmann-Bennett formula. METHODS: Data from 1301 participants of the Raine Study Gen2-20 year follow-up were divided into two datasets to generate (n = 650) and validate (n = 651) a relationship between AL, SE, and K. The developed formula was then applied to a separate dataset of 46 participants with AL, SE, and K measurements and OCTA images to estimate and compare the performance of ALest against ALact in correcting transverse magnification error in OCTA images when measuring the foveal avascular zone area (FAZA). RESULTS: The formula for ALest yielded the equation: ALest = 2.102K - 0.4125SE + 7.268, R2 = 0.794. There was good agreement between ALest and ALact for both study cohorts. The mean difference [standard deviation (SD)] between FAZA corrected with ALest and ALact was 0.002 (0.015) mm2 with the 95% limits of agreement (LoA) of - 0.027 to 0.031 mm2. In comparison, mean difference (SD) between FAZA uncorrected and corrected with ALact was - 0.005 (0.030) mm2, with 95% LoA of - 0.064 to 0.054 mm2. CONCLUSIONS: ALact is more accurate than ALest and hence should be used preferentially in magnification error correction in the clinical setting. FAZA corrected with ALest is comparable to FAZA corrected with ALact, while FAZA measurements using images corrected with ALest have a greater accuracy than measurements on uncorrected images. Hence, in the absence of ALact, clinicians should use ALest to correct for magnification error as this provides for more accurate measurements of fundus parameters than uncorrected images.

Purpose: To report the distribution of peripapillary retinal nerve fiber layer (RNFL) thickness in healthy young adults, investigate factors associated with RNFL thickness, and report the percentage of outside normal limits (ONL) and borderline (BL) RNFL thickness classifications based on the optical coherence tomography (OCT) manufacturer reference database. Methods: Participants of the Raine Study Generation 2 cohort (aged 18–22 years) underwent spectral domain OCT imaging with an RNFL circle scan. Eyes with inadequate scans or optic nerve pathology were excluded. Linear mixed models were used to analyze associations. Results: Data were available for 1288 participants (mean age, 20.0 years). Mean RNFL thicknesses in right and left eyes, respectively, were global = 100.5 µm, 100.3 µm (P = 0.03); temporal = 73.1 µm, 68.9 µm (P < 0.001); superotemporal = 140.6 µm, 136.3 µm (P < 0.001); superonasal = 104.9 µm, 115.1 µm (P < 0.001); nasal = 79.7 µm, 79.1 µm (P = 0.09); inferonasal = 109.8 µm, 111.5 µm (P < 0.001); and inferotemporal = 143.2 µm, 143.6 µm (P = 0.51). Longer axial length was associated with thinner RNFL globally, nasally, inferotemporally, superotemporally, superonasally, and inferonasally, as well as thicker RNFL temporally. The prevalence of ONL and BL classifications was generally higher than the expected rates of 1% and 4%, respectively, in temporal sectors and lower than expected in nasal sectors. The prevalence of global BL classifications was lower than expected (right eye, 2.3%; left eye, 2.6%). Conclusions: Measured RNFL thickness differs with axial length and between right and left eyes. More reference data are needed to better define the normal limits of RNFL variation in different populations. Translational Relevance: This study provides an improved understanding of normal variation in RNFL thickness in young adults.

Contains fulltext : 235428.pdf (Publisher’s version ) (Open Access), Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.

PURPOSE: To report the distribution of peripapillary retinal nerve fiber layer (RNFL) thickness in healthy young adults, investigate factors associated with RNFL thickness, and report the percentage of outside normal limits (ONL) and borderline (BL) RNFL thickness classifications based on the optical coherence tomography (OCT) manufacturer reference database. METHODS: Participants of the Raine Study Generation 2 cohort (aged 18-22 years) underwent spectral domain OCT imaging with an RNFL circle scan. Eyes with inadequate scans or optic nerve pathology were excluded. Linear mixed models were used to analyze associations. RESULTS: Data were available for 1288 participants (mean age, 20.0 years). Mean RNFL thicknesses in right and left eyes, respectively, were global = 100.5 µm, 100.3 µm (P = 0.03); temporal = 73.1 µm, 68.9 µm (P < 0.001); superotemporal = 140.6 µm, 136.3 µm (P < 0.001); superonasal = 104.9 µm, 115.1 µm (P < 0.001); nasal = 79.7 µm, 79.1 µm (P = 0.09); inferonasal = 109.8 µm, 111.5 µm (P < 0.001); and inferotemporal = 143.2 µm, 143.6 µm (P = 0.51). Longer axial length was associated with thinner RNFL globally, nasally, inferotemporally, superotemporally, superonasally, and inferonasally, as well as thicker RNFL temporally. The prevalence of ONL and BL classifications was generally higher than the expected rates of 1% and 4%, respectively, in temporal sectors and lower than expected in nasal sectors. The prevalence of global BL classifications was lower than expected (right eye, 2.3%; left eye, 2.6%). CONCLUSIONS: Measured RNFL thickness differs with axial length and between right and left eyes. More reference data are needed to better define the normal limits of RNFL variation in different populations. TRANSLATIONAL RELEVANCE: This study provides an improved understanding of normal variation in RNFL thickness in young adults.

PURPOSE: To describe the thickness profiles of the full retinal and outer retinal layers (ORL) at the macula in healthy young adults, and associations with best-corrected visual acuity (BCVA). METHODS: In total, 1604 participants (19-30 years) underwent an eye examination that included measurements of their BCVA, axial length, and autorefraction. The retinal thickness at the foveal pit and at the nine Early Treatment of Diabetic Retinopathy Study macular regions (0.5-mm radius around the fovea, and superior, inferior, temporal, and nasal quadrants of the inner and outer rings of the macula) were obtained using spectral-domain optical coherence tomography imaging. A custom program was used to correct for transverse magnification effects because of different axial lengths. RESULTS: The median full retinal and ORL thicknesses at the central macula were 285 µm and 92 µm. The full retina was thinnest centrally and thickest at the inner macula ring, whereas the ORL was thickest centrally and gradually decreased in thickness with increasing eccentricity. There was no association between axial length and the full retinal or ORL thickness. Increased thicknesses of the full retina at the central macula was associated with better BCVA; however, the effect size was small and not clinically significant. CONCLUSIONS: This article mapped the full retinal and ORL thickness profile in a population-based sample of young healthy adults. TRANSLATIONAL RELEVANCE: Thickness values presented in this article could be used as a normative reference for future studies on young adults and in clinical practice.

PURPOSE: Rod-cone dystrophy (RCD) is characterized by centripetal loss of rod followed by cone photoreceptors. In this prospective, observational cohort, we used flood-illumination adaptive optics (AO) imaging to investigate parafoveal cone loss in regions with preserved ellipsoid zone (EZ) in patients with RCD. METHODS: Eight patients with RCD and 10 age-matched healthy controls underwent spectral-domain optical coherence tomography and AO imaging. The RCD cohort underwent a follow-up examination after 6 months. Cone density (CD) and intercone distance (ICD) measurements were performed at 2° temporal from the fovea. Baseline CD and ICD values were compared between the control and patient groups, and longitudinal changes were calculated in the patient group. Residual EZ span in patients was measured in horizontal foveal B-scans. RESULTS: Between the control and patient groups, there was no significant difference in the baseline CD (2094 vs. 1750 cells/deg2, respectively; P = 0.09) and ICD (1.46 vs. 1.62 arcmin, respectively; P = 0.08). Mean CD declined by 198 cells/deg2 (-11.3%; P < 0.01), and mean ICD increased by 0.09 arcmin (+5.6%; P = 0.01) at the 6-month follow-up in the patient group. Mean baseline and follow-up residual EZ spans in the six patients with EZ defect were 3189 µm and 3065 µm, respectively (-3.9%; P = 0.08). CONCLUSIONS: AO imaging detected significant parafoveal cone loss over 6-month follow-up even in regions with preserved EZ. Further studies to refine AO imaging protocol and validate cone metrics as a structural endpoint in early RCD are warranted. TRANSLATIONAL RELEVANCE: CD and ICD may change prior to EZ span shortening in RCD.

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.

[This corrects the article DOI: 10.1371/journal.pgen.1009497.].

Background Mutations in the splicing factor pre-messenger RNA processing factor 31 (PRPF31) gene cause autosomal dominant retinitis pigmentosa 11 (RP11) through a haplo-insufficiency mechanism. We describe the phenotype and progression of microperimetry and autofluorescence endpoints in an Indigenous Australian RP11 family. Patients and Methods Ophthalmic examination, optical coherence tomography, fundus autofluorescence and microperimetry were performed at baseline and every 6–12 months. Baseline and annual change in best-corrected visual acuity (BCVA), microperimetry mean sensitivity (MS) and number of scotoma loci, residual ellipsoid zone (EZ) span and hyperautofluorescent ring (HAR) area were reported. Next-generation and Sanger sequencing were performed in available members. Results 12 affected members from three generations were examined. Mean (SD, range) age at onset of symptoms was 11 (4.5, 4–19) years. MS declined steadily from the third decade and EZ span and HAR area declined rapidly during the second decade. Serial microperimetry showed negligible change in MS over 2–3 years. However, mean EZ span, near-infrared and short-wavelength HAR area reduction was 203 (6.4%) µm/year, 1.8 (8.7%) mm2/year and 1.1 (8.6%) mm2/year, respectively. Genetic testing was performed on 11 affected and 10 asymptomatic members and PRPF31 c.1205 C > A (p.Ser402Ter) mutation was detected in all affected and two asymptomatic members (non-penetrant carriers). Conclusions Our findings suggest that in the studied cohort, the optimal window for therapeutic intervention is the second decade of life and residual EZ span and HAR area can be considered as efficacy outcome measures. Further studies on larger samples with different PRPF31 mutations and longer follow-up duration are recommended.

Background Deletion–insertion (delins) variants in the retina‐specific ATP‐binding cassette transporter gene, subfamily A, member 4 (ABCA4) accounts for <1% in Stargardt disease. The consequences of these delins variants on splicing cannot be predicted with certainty without supporting in vitro data. Methods Candidate ABCA4 variants were revealed by genetic and segregation analysis of a family with pseudodominant Stargardt disease using a commercial panel and Sanger sequencing. RNA extracted from patient‐derived fibroblasts was analyzed by RT‐PCR to evaluate splicing behavior of the ABCA4 variants. Results Affected members carrying the novel c.6031_6044delinsAGTATTTAACCAATATTT variant in exon 44 presented with contrasting phenotypes; from early‐onset cone‐rod dystrophy to late‐onset macular dystrophy. This variant resulted in a 56‐nucleotide deletion in the mutant allele by activation of a cryptic splice acceptor site which disrupts the reading frame and results in a premature termination codon (p.Ile2003LeufsTer41). If translated, the crucial functional domains near the C‐terminus would be truncated from the ABCA4 protein. Conclusion This work demonstrates the intrafamilial phenotypic variability in a pseudodominant Stargardt disease pedigree and the use of patient‐derived fibroblasts to evaluate the effect of a novel ABCA4 delins variant on splicing to complement in silico pathogenicity assessment.

Stargardt disease is one of the most common forms of inherited retinal disease and leads to permanent vision loss. A diagnostic feature of the disease is retinal flecks, which appear hyperautofluorescent in fundus autofluorescence (FAF) imaging. The size and number of these flecks increase with disease progression. Manual segmentation of flecks allows monitoring of disease, but is time-consuming. Herein, we have developed and validated a deep learning approach for segmenting these Stargardt flecks (1750 training and 100 validation FAF patches from 37 eyes with Stargardt disease). Testing was done in 10 separate Stargardt FAF images and we observed a good overall agreement between manual and deep learning in both fleck count and fleck area. Longitudinal data were available in both eyes from 6 patients (average total follow-up time 4.2 years), with both manual and deep learning segmentation performed on all (n = 82) images. Both methods detected a similar upward trend in fleck number and area over time. In conclusion, we demonstrated the feasibility of utilizing deep learning to segment and quantify FAF lesions, laying the foundation for future studies using fleck parameters as a trial endpoint.

PURPOSE: Microperimetry is commonly used to assess retinal function. We perform cross-sectional and longitudinal analysis on microperimetry parameters in USH2A retinopathy and explore end points suitable for future clinical trials. METHODS: Microperimetry was performed using two grids, Grid 1 (18° diameter) and Grid 2 (6° diameter). In Grid 1, four parameters (number of nonscotomatous loci, mean sensitivity [MS], responding point sensitivity [RPS], and edge of scotoma sensitivity [ESS]) were analyzed. In Grid 2, number of nonscotomatous loci and MS were examined. Interocular symmetry was also examined. Longitudinal analysis was conducted in a subset of eyes. RESULTS: Microperimetry could be performed in 16 of 21 patients. In Grid 1 (n = 15; average age, 35.6 years), average number of nonscotomatous loci, MS, RPS, and ESS were 46.6 loci, 10.0 dB, 14.7 and 9.6 dB, respectively. In Grid 2 (n = 13; average age, 37.4 years), 12 eyes had measurable sensitivity across the entire grid. Average MS was 23.8 dB. Interocular analysis revealed large 95% confidence intervals for all parameters. Longitudinally, Grid 1 (n = 12, average follow-up 2.6 years) ESS showed the fastest rate of decline (-1.84 dB/y) compared with MS (-0.34 dB/y) and RPS (-0.90 dB/y). CONCLUSIONS: Our data suggest that ESS may be more useful than MS and RPS in test grids that cover a large extent of the macula. We caution the use of contralateral eye as an internal control. TRANSLATIONAL RELEVANCE: ESS may decrease the duration or sample size of treatment trials in USH2A retinopathy.

PURPOSE: Macular Integrity Assessment (MAIA) microperimetry is used widely in clinical trials and routine practice to assess paracentral scotoma. Current interpretation of MAIA is based on an assumed uniform 25 decibel (dB) cutoff for normal function irrespective of subject age and retinal location. We examined this convention by establishing an age- and loci-specific reference in healthy eyes and comparing this to the <25 dB cutoff. METHODS: Retrospective MAIA results from healthy eyes were analyzed for prevalence of loci with <25 dB. At each locus, a new reference cutoff was derived from quantile regression of sensitivity against age at the 2.5th percentile. Two clinical cases of serial MAIA testing were analyzed using the new approach and compared to the <25 dB cutoff. RESULTS: Fifty-four and 56 age-matched (range: 16-75 years) healthy eyes underwent small (37 loci) and large (68 loci) grid testing, respectively. Retinal sensitivity <25 dB was found in 5% of the small grid (1998 data points) and 10% of the large grid (3808 data points). These were found predominantly in older subjects and at the central point or in the perifoveal region. Quantile regression at each individual locus showed age-related decline with a median gradient of 0.6 dB/decade. CONCLUSIONS: We caution against using <25 dB cutoff in MAIA interpretation and advocate an age- and loci-specific cutoff criterion. TRANSLATIONAL RELEVANCE: Our study suggests that MAIA interpretation is influenced by the criterion used for defining abnormal pointwise measurement.

SIX1/SIX6 polymorphism has been shown to be associated with glaucoma. Studies have also found that, in older adults, retinal nerve fibre layer (RNFL) thickness is significantly thinned with each copy of the risk allele in SIX1/SIX6. However, it is not known whether these genetic variants exert their effects in younger individuals. Comparing a healthy young adult with an older adult cohort (mean age 20 vs 63 years), both of Northern European descent, we found that there was no significant RNFL thinning in each copy of the risk alleles in SIX1/SIX6 in the eyes of younger individuals. The older cohort showed an unexpectedly thicker RNFL in the nasal sector with each copy of the risk allele for both the SIX1 (rs10483727) and SIX6 (rs33912345) variants. In the temporal sector, thinner RNFL was found with each copy of the risk allele in rs33912345 with a decrease trend observed in rs10483727. Our results suggest that SIX1/SIX6 gene variants exert their influence later in adult life.

IMPORTANCE: Atropine eyedrops are a promising treatment for slowing myopia progression in East Asian children. However, its effects on children in Australia, including those of non-Asian background, have not been well-studied. BACKGROUND: The Western Australia Atropine for the Treatment of Myopia (WA-ATOM) study aims to determine the efficacy and long-term effects of low-dose atropine eyedrops in myopia control. This paper describes the study rationale, methodology and participant baseline characteristics. DESIGN: Single-centre, double-masked, randomized controlled trial. PARTICIPANTS: Children (6-16 years) with spherical equivalent ≤-1.50 D in each eye, astigmatism ≤1.50 D and myopia progression by ≥0.50 D/year. METHODS: Enrolled children were randomly assigned 2:1 to receive 0.01% atropine or placebo eyedrops. Participants are examined every 6 months during first 3 years of the study (2-year treatment phase followed by a 1-year washout phase), and then at a 5-year follow-up (2 years after the end of the washout phase). MAIN OUTCOME MEASURES: Annual progression rate of myopia and axial length, tolerability to eyedrops and incidence and severity of unwanted effects. RESULTS: Out of 311 children who were referred, 242 were suitable for study participation, and 153 were subsequently enrolled. The baseline characteristics of enrolled participants are presented. CONCLUSIONS AND RELEVANCE: Outcomes of the WA-ATOM study will inform on the efficacy, tolerability, safety and long-term effects of low-dose atropine eyedrops in myopia control in Australian children. The impact of ocular sun exposure, iris colour and parental myopia on the efficacy of low-dose atropine will also be assessed.

INTRODUCTION: Eye diseases and visual impairment more commonly affect elderly adults, thus, the majority of ophthalmic cohort studies have focused on older adults. Cohort studies on the ocular health of younger adults, on the other hand, have been few. The Raine Study is a longitudinal study that has been following a cohort since their birth in 1989-1991. As part of the 20-year follow-up of the Raine Study, participants underwent a comprehensive eye examination. As part of the 27- and 28-year follow-ups, eye assessments are being conducted and the data collected will be compared with those of the 20-year follow-up. This will provide an estimate of population incidence and updated prevalence of ocular conditions such as myopia and keratoconus, as well as longitudinal change in ocular parameters in young Australian adults. Additionally, the data will allow exploration of the environmental, health and genetic factors underlying inter-subject differential long-term ocular changes. METHODS AND ANALYSIS: Participants are being contacted via telephone, email and/or social media and invited to participate in the eye examination. At the 27-year follow-up, participants completed a follow-up eye screening, which assessed visual acuity, autorefraction, ocular biometry and ocular sun exposure. Currently, at the 28-year follow-up, a comprehensive eye examination is being conducted which, in addition to all the eye tests performed at the 27-year follow-up visit, includes tonometry, optical coherence tomography, funduscopy and anterior segment topography, among others. Outcome measures include the incidence of refractive error and pterygium, an updated prevalence of these conditions, and the 8-year change in ocular parameters. ETHICS AND DISSEMINATION: The Raine Study is registered in the Australian New Zealand Clinical Trials Registry. The Gen2 20-year, 27-year and 28-year follow-ups are approved by the Human Research Ethics Committee of the University of Western Australia. Findin

Introduction Eye diseases and visual impairment more commonly affect elderly adults, thus, the majority of ophthalmic cohort studies have focused on older adults. Cohort studies on the ocular health of younger adults, on the other hand, have been few. The Raine Study is a longitudinal study that has been following a cohort since their birth in 1989-1991. As part of the 20-year follow-up of the Raine Study, participants underwent a comprehensive eye examination. As part of the 27- and 28-year follow-ups, eye assessments are being conducted and the data collected will be compared with those of the 20-year follow-up. This will provide an estimate of population incidence and updated prevalence of ocular conditions such as myopia and keratoconus, as well as longitudinal change in ocular parameters in young Australian adults. Additionally, the data will allow exploration of the environmental, health and genetic factors underlying inter-subject differential long-term ocular changes. Methods and analysis Participants are being contacted via telephone, email and/or social media and invited to participate in the eye examination. At the 27-year follow-up, participants completed a follow-up eye screening, which assessed visual acuity, autorefraction, ocular biometry and ocular sun exposure. Currently, at the 28-year follow-up, a comprehensive eye examination is being conducted which, in addition to all the eye tests performed at the 27-year follow-up visit, includes tonometry, optical coherence tomography, funduscopy and anterior segment topography, among others. Outcome measures include the incidence of refractive error and pterygium, an updated prevalence of these conditions, and the 8-year change in ocular parameters. Ethics and dissemination The Raine Study is registered in the Australian New Zealand Clinical Trials Registry. The Gen2 20-year, 27-year and 28-year follow-ups are approved by the Human Research Ethics Committee of the University of Western Australia. Findings

PURPOSE: To evaluate whether a practical method of imaging lenticular autofluorescence (AF) can provide an individualized measure correlated with age-related lens yellowing in older subjects undergoing tests involving shorter wavelength lights. METHODS: Lenticular AF was imaged with 488-nm excitation using a confocal scanning laser ophthalmoscope (cSLO) routinely used for retinal AF imaging. There were 75 older subjects (ages 47-87) at two sites; a small cohort of younger subjects served as controls. At one site, the cSLO was equipped with an internal reference to allow quantitative AF measurements; at the other site, reduced-illuminance AF imaging (RAFI) was used. In a subset of subjects, lens density index was independently estimated from dark-adapted spectral sensitivities performed psychophysically. RESULTS: Lenticular AF intensity was significantly higher in the older eyes than the younger cohort when measured with the internal reference (59.2 ± 15.4 vs. 134.4 ± 31.7 gray levels; P < 0.05) as well as when recorded with RAFI without the internal reference (10.9 ± 1.5 vs. 26.1 ± 5.7 gray levels; P < 0.05). Lenticular AF was positively correlated with age; however, there could also be large differences between individuals of similar age. Lenticular AF intensity correlated well with lens density indices estimated from psychophysical measures. CONCLUSIONS: Lenticular AF measured with a retinal cSLO can provide a practical and individualized measure of lens yellowing, and may be a good candidate to distinguish between preretinal and retinal deficits involving short-wavelength lights in older eyes.

The full-field electroretinogram (ERG) and visual evoked potential (VEP) are useful tools to assess retinal and visual pathway integrity in both laboratory and clinical settings. Currently, preclinical ERG and VEP measurements are performed with anesthesia to ensure stable electrode placements. However, the very presence of anesthesia has been shown to contaminate normal physiological responses. To overcome these anesthesia confounds, we develop a novel platform to assay ERG and VEP in conscious rats. Electrodes are surgically implanted sub-conjunctivally on the eye to assay the ERG and epidurally over the visual cortex to measure the VEP. A range of amplitude and sensitivity/timing parameters are assayed for both the ERG and VEP at increasing luminous energies. The ERG and VEP signals are shown to be stable and repeatable for at least 4 weeks post surgical implantation. This ability to record ERG and VEP signals without anesthesia confounds in the preclinical setting should provide superior translation to clinical data.

Objective. To examine whether retinal electrophysiology is a useful surrogate marker of drug penetrance into the central nervous system (CNS). Materials and Methods. Brain and retinal electrophysiology were assessed with full-field visually evoked potentials and electroretinograms in conscious and anaesthetised rats following systemic or local administrations of centrally penetrant (muscimol) or nonpenetrant (isoguvacine) compounds. Results. Local injections into the eye/brain bypassed the blood neural barriers and produced changes in retinal/brain responses for both drugs. In conscious animals, systemic administration of muscimol resulted in retinal and brain biopotential changes, whereas systemic delivery of isoguvacine did not. General anaesthesia confounded these outcomes. Conclusions. Retinal electrophysiology, when recorded in conscious animals, shows promise as a viable biomarker of drug penetration into the CNS. In contrast, when conducted under anaesthetised conditions confounds can be induced in both cortical and retinal electrophysiological recordings.

The electroretinogram (ERG, retina) and visual evoked potential (VEP, brain) are widely used in vivo tools assaying the integrity of the visual pathway. Current recordings in preclinical models are conducted under anesthesia, which alters neural physiology and contaminates responses. We describe a conscious wireless ERG and VEP recording platform in rats. Using a novel surgical technique to chronically implant electrodes subconjunctivally on the eye and epidurally over the visual cortex, we are able to record stable and repeatable conscious ERG and VEP signals over at least 1 month. We show that the use of anaesthetics, necessary for conventional ERG and VEP measurements, alters electrophysiology recordings. Conscious visual electrophysiology improves the viability of longitudinal studies by eliminating complications associated with repeated anaesthesia. It will also enable uncontaminated assessment of drug effects, allowing the eye to be used as an effective biomarker of the central nervous system.

PURPOSE: To determine whether there is an age-dependent susceptibility in retinal function in response to repeated anterior chamber cannulation with or without intraocular pressure (IOP) elevation. METHODS: Baseline electroretinograms were measured in 3- and 18-month-old Sprague-Dawley rats (n = 16 each group). Following baseline assessment, eyes were randomly assigned to undergo a 60-min anterior chamber cannulation with IOP either left at baseline (sham, 15 mm Hg) or elevated to 60 mm Hg. This was repeated three additional times, with each episode separated by 1 week. At weeks 1 to 3, dark-adapted retinal function was assessed immediately before cannulation, with final functional assessment at week 4. RESULTS: Both sham and IOP elevated eyes of older rats showed retinal dysfunction, which became more pronounced with the number of repeated insults. This effect was largest for responses arising from the inner retina. Repeated insult in younger eyes did not produce a change in amplitude but an increase in the sensitivity to light of photoreceptoral and bipolar cell components of the electroretinogram. CONCLUSIONS: Repeated trauma, not IOP, produces permanent retinal dysfunction in older eyes. Younger eyes appear to be able to withstand this type of injury by upregulating sensitivity of outer and middle retinal responses to maintain normal inner retinal function.