ObjectiveTo profile aqueous humor (AH)–derived exosomal microRNAs (miRNAs) in primary open-angle glaucoma (POAG) and exfoliation glaucoma (XFG) and investigate their potential as diagnostic biomarkers and modulators of extracellular matrix (ECM) remodeling in glaucoma pathogenesis.DesignProspective, comparative, observational pilot study.Subjects and ControlsAqueous humor was obtained from 21 patients with POAG, 24 patients with XFG, and 14 healthy donors.MethodsExosomes were isolated from pooled AH samples of patients with POAG, XFG, and healthy donors for small RNA sequencing. miR-29a, an ECM-targeting miRNA, was selected for functional validation in transforming growth factor-beta 2 (TGF-β2)– or dexamethasone (Dex)-induced collagen deposition models using human trabecular meshwork cells (HTMCs).Main Outcome MeasuresIdentification of potential glaucoma- and subtype-specific exosomal miRNA biomarkers and evaluation of selected ECM-targeting miRNAs for their roles in modulating collagen expression in vitro.ResultsA total of 130 and 145 miRNAs were differentially expressed in POAG/Healthy and XFG/Healthy comparisons, respectively, with 96 miRNAs commonly dysregulated. Upregulation of ECM-related miRNAs—miR-21-5p, miR-92b-3p, miR-99a-5p, miR-486-3p, miR-486-5p, and miR-1260a—constituted a glaucoma-specific signature, whereas miR-99b-5p and miR-125a-5p showed subtype-specific upregulation in POAG, and miR-26a-5p and miR-451a in XFG. miR-29a-3p, a known antifibrotic miRNA, was significantly downregulated in POAG, XFG, and in HTMCs treated with TGF-β2 or Dex. Functional assays demonstrated that overexpression of miR-29a-3p attenuated TGF-β2- and Dex-induced collagen deposition in HTMCs.ConclusionsThis study provides the first profile of AH-derived exosomal miRNAs in POAG and XFG, identifies potential miRNAs associated with ECM remodeling, and highlights their potential utility as biomarkers and therapeutic targets in glaucoma.Financial Disclosure(s)Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Long-term blood pressure variability (BPV) has emerged as a risk factor for various health problems, including eye diseases, independent of blood pressure (BP) levels. Yet, its role in age-related macular degeneration (AMD) progression remains unknown. This study aimed to assess associations between long-term BPV and the risk of AMD. Prospective analysis of 14-year data from the ALIENOR (Antioxydants, LIpides Essentiels, Nutrition et maladies OculaiRes) study, a French longitudinal population-based cohort study (2006-2020). The ALIENOR study included 963 participants aged ≥73 years from the Three-City (3C) study in Bordeaux, for an ophthalmic follow-up. Systolic BPV (SBPV), diastolic BPV (DBPV), and pulse pressure variability (PPV) were determined as the standard deviation of available BP measurements in 3C visits (1999-2017). Age-related macular degeneration was assessed using retinal color photographs and OCT imaging every 2 years from 2006 to 2020. Shared random effects joint models fitted BPV current values and quantified their effect on AMD onset. The implemented Bayesian approach yielded the mean of adjusted posterior hazard ratios of AMD and their 95% credibility intervals (CrIs). Of the 692 (median age: 79.0 years; 63.5% female) and 475 (median age: 78.5 years; 61.1% female) at-risk participants, 10% and 36% developed advanced and intermediate AMD, respectively. The hazard of advanced AMD was significantly increased by 54% for a 5-mmHg increase in DBPV (adjusted hazard ratio [aHR]: 1.54, 95% CrI: 1.02-2.44), whereas statistical significance was not reached for a 5-mmHg increase in SBPV (aHR: 1.20, 95% CrI: 0.96-1.51) and PPV (aHR: 1.17, 95% CrI: 0.88-1.54). Conversely, BPV was not significantly associated with intermediate AMD (aHR: 0.96, 95% CrI: 0.83-1.11; aHR: 0.96, 95% CrI: 0.71-1.30; and aHR: 0.92, 95% CrI: 0.77-1.09; for a 5-mmHg increase in SBPV, DBPV, and PPV, respectively). This study suggested that long-term variability in BP may be associated with an increased risk of advanced AMD, particularly for DBP. These findings underscore the need for further research to confirm this association, explore the underlying mechanisms, and propose potential interventions that could mitigate this risk. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

PurposeMyopia is associated with increased near-work, time spent indoors, and urban environments. This may in part stem from the spatial frequency (SF) composition of the visual environment in such scenarios compared to nature. We investigated the SF content of natural and man-made environments and how the relative contrast experienced may be affected by viewing distance.DesignExperimental study of environmental contrast.Subjects, Participants, and ControlsDigital images (n = 594) from natural, mixed-urban, urban, and indoor environments across Singapore.MethodsThe fast Fourier transform was computed and radially averaged, and the slope of the amplitude spectra with SF was determined. The total contrast energy within each SF octave (f–2f) was measured to determine exposure deficits between environments and whether environmental contrast was scale invariant (unaffected by changes in viewing distance).Main Outcome MeasuresEnvironment differences in SF gradient, total contrast, and scale invariance.ResultsAs expected, indoor environments displayed the steepest SF gradients at –1.36 ± 0.1, more than urban (–1.22 ± 0.1, P < 0.01), mixed-urban (–1.09 ± 0.1, P < 0.01), and natural (–1.00 ± 0.1, P < 0.01) environments. Specifically, mixed-urban, urban, and indoor environments all lacked contrast at middle and higher SFs compared with natural scenes (P < 0.01 each). Contrast energy/octave was approximately equal for natural environments, signifying the relative SF composition was scale invariant. This was not true for man-made environments. Contrast energy/octave decreased as a function of SF in mixed-urban, urban, and most rapidly in indoor environments (P < 0.001 each), meaning the total contrast experienced in such environments is directly dependent on viewing distance. Consequently, halving viewing distance when indoors would reduce total perceived middle SF contrast by 35%, despite indoor environments already being deficient compared to nature.ConclusionsThe SF content of natural environments is consistent regardless of viewing distance, signifying scale invariance. This does not apply in man-made environments where contrast at all SFs directly depends on viewing distance. This implies that shorter viewing distances in man-made environments further exacerbate inherent deficits in middle and higher SF contrast, and thus these environments may fail to stimulate the eye with sufficient contrast compared to natural environments, possibly explaining why such environments induce myopia.Financial Disclosure(s)The authors have no proprietary or commercial interest in any materials discussed in this article.

ObjectiveSingle nucleotide polymorphisms (SNPs) in IRF4 and HERC2 are associated with risk for disomy or monosomy of chromosome 3 (D3 or M3) uveal melanoma (UM), respectively. The aim of this study was to assess the association between germline genetics and UM outcome and the potential use of a derived prognostic signature for UM.DesignCohort study from Institut Curie, Paris (France) and Erasmus University Medical Center, Rotterdam (The Netherlands).ParticipantsPatients diagnosed with UM at Institut Curie (N = 2059) and Erasmus University Medical Center (N =576).MethodsImpact of IRF4 and HERC2 SNPs on survival was assessed in a cohort of 1339 patients with UM by Kaplan-Meier analysis and Cox proportional hazard regression. Uveal melanoma subtype-specific risk associations with SNPs and iris color were assessed by generalized linear model regression analyses. Classifier of UM subtypes was trained on 560 patients with UM and validated in 2 independent cohorts.Main Outcome MeasuresWe analyzed risk SNPs in the series of patients with UM in relation to tumor and patient characteristics, including eye color, tumor subtype and diameter, and patient outcomes.ResultsIRF4 rs12203592-T and HERC2 rs12913832-G SNPs were associated with improved and worsened progression-free-survival and overall survival, respectively, mainly through their association with chromosome 3 status. Associations between IRF4 and HERC2 risk SNPs and D3 or M3 subtypes, respectively, were largely independent of their role in determining iris pigmentation. A genetic classifier showed significant results in predicting chromosome 3 status and survival but did not outperform established clinical prognostic features.ConclusionsOur study demonstrates that inherited polymorphisms in IRF4 and HERC2 are independently associated with UM subtype and prognosis, although a SNP-based classifier does not yet outperform the established prognostic model.Financial Disclosure(s)Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Measuring ocular rigidity (OR) and the pulsatile choroidal volume change (ΔV) from childhood to adulthood would provide essential insight into the role of the sclera and choroid in axial myopia. A validated measurement method based on Beaton et al (2015) is the only noninvasive, direct, and reliable method available, yet it has never been used in children. This study aims to assess the feasibility and repeatability of noninvasive OR and ΔV measurements in children and young adults using this method. This is a cross-sectional study. Children and young adults aged 6 to 26 years. OCT videos were acquired using enhanced depth imaging mode. A neural network (NN) approach was used to extract the choroid segmentation from OCT videos, which was then used to measure choroidal filling as described by Beaton et al. Ocular rigidity was computed from the ΔV and the ocular pulse amplitude using Friedenwald equation. Intrasession repeatability was assessed for subjects with 2 consecutive measurements of OR. Ocular rigidity, pulsatile choroidal volume change, and the method's yield. Sixty-seven subjects (67 eyes, 27 males) aged 13 ± 6 years were enrolled, and 62 subjects completed the study. ΔV and OR were computed. Out of the 62 videos, 98% (61) of the OCT videos were successfully segmented using the NN approach, with heart rate detectable in 79% (48) of the videos. Average OR and ΔV were 0.027 ± 0.022 μL-1 and 5.7 ± 2.8 μL, respectively (n = 48). The mean submacular choroidal thickness (CT) and pulsatile CT change were 283.6 ± 40.4 μm and 8.36 ± 4.4 μm, respectively. Intrasession repeatability for OR and ΔV was assessed in 31 eyes and was determined to be excellent based on a single measure intraclass correlation coefficient of 0.912, 95% confidence interval (CI) (0.825, 0.956) and 0.941, 95% CI (0.879, 0.972), respectively and a within-subject standard deviation of 0.0037 μL-1 and 1.14 μL, respectively. Measures of OR and ΔV are achievable in children and young adults and have good repeatability. This noninvasive method can be used to establish structural biomechanical changes of the sclera and choroid with myopic axial elongation in childhood and beyond. The author(s) have no proprietary or commercial interest in any materials discussed in this article.