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AimsTo compare the biomechanically corrected intraocular pressure (IOP) estimate (bIOP) provided by the Corvis-ST with Goldmann applanation tonometry (GAT-IOP) in patients with high-tension and normal-tension primary open-angle glaucoma (POAG; HTG and NTG), ocular hypertension (OHT) and controls. Moreover, we compared dynamic corneal response parameters (DCRs) of the Corvis-ST in POAG, OHT and controls, evaluated the correlation between global visual field parameters mean deviation and pattern SD (MD and PSD) and DCRs in the POAG group.Methods156 eyes of 156 patients were included in this prospective, single-centre, observational study, namely 41 HTG and 33 NTG, 45 OHT cases and 37 controls. Central corneal thickness (CCT), GAT-IOP and bIOP were measured, GAT-IOP was also adjusted for CCT (GATAdj). DCRs provided by Corvis-ST were evaluated, MD and PSD were recorded by 24–2 full-threshold visual field. To evaluate the difference in DCRs between OHT, HTG and NTG, a general linear model was used with sex, medications and group as fixed factors and bIOP and age as covariates.ResultsThere was a significant difference between GAT-IOP, GATAdj and bIOP in NTG and HTG, OHT and controls. NTG corneas were significantly softer and more deformable compared with controls, OHT and HTG as demonstrated by significantly lower values of stiffness parameters A1 and highest concavity and higher values of inverse concave radius (all p<0.05). There was a significant correlation (p<0.05) between MD, PSD and many DCRs with POAG patients with softer or more compliant corneas more likely to show visual field defects.ConclusionsCorneal biomechanics might be a significant confounding factor for IOP measurement that should be considered in clinical decision-making. The abnormality of corneal biomechanics in NTG and the significant correlation with visual field parameters might suggest a new risk factor for the development or progression of NTG.

Primary open angle glaucoma is a leading cause of visual impairment and blindness which is commonly treated with drugs or laser but may require surgery. Tenon’s ocular fibroblasts are involved in wound-healing after glaucoma filtration surgery and may compromise a favourable outcome of glaucoma surgery by contributing to fibrosis. To investigate changes in gene expression and key pathways contributing to the glaucomatous state we performed genome-wide RNA sequencing. Human Tenon’s ocular fibroblasts were cultured from normal and glaucomatous human donors undergoing eye surgery (n = 12). mRNA was extracted and RNA-Seq performed on the Illumina platform. Differentially expressed genes were identified using a bioinformatics pipeline consisting of FastQC, STAR, FeatureCounts and edgeR. Changes in biological functions and pathways were determined using Enrichr and clustered using Cytoscape. A total of 5817 genes were differentially expressed between Tenon’s ocular fibroblasts from normal versus glaucomatous eyes. Enrichment analysis showed 787 significantly different biological functions and pathways which were clustered into 176 clusters. Tenon’s ocular fibroblasts from glaucomatous eyes showed signs of fibrosis with fibroblast to myofibroblast transdifferentiation and associated changes in mitochondrial fission, remodeling of the extracellular matrix, proliferation, unfolded protein response, inflammation and apoptosis which may relate to the pathogenesis of glaucoma or the detrimental effects of topical glaucoma therapies. Altered gene expression in glaucomatous Tenon’s ocular fibroblasts may contribute to an unfavourable outcome of glaucoma filtration surgery. This work presents a genome-wide transcriptome of glaucomatous versus normal Tenon’s ocular fibroblasts which may identify genes or pathways of therapeutic value to improve surgical outcomes.

Background The post-operative evaluation of trabeculectomy blebs has traditionally relied on subjective clinical grading systems performed at the slit-lamp. This study explores the use of swept source anterior-segment optical coherence tomography (AS-OCT) to objectively measure bleb internal reflectivity and morphology, and to distinguish blebs with surgical success vs. failure. Methods Cross-sectional study of patients with glaucoma who had undergone trabeculectomy at least one year prior. Swept source AS-OCT was used to capture filtering blebs in the sagittal plane. Standardised regions of interests on the sagittal plane were segmented, and pixel intensity values and bleb height were measured. Receiver operating characteristic curves were used to examine the discriminatory ability of pixel intensity values and bleb morphology to classify blebs with surgical success or failure. Results 100 eyes of 65 patients were included, with a median post-operative follow up of 7.0 years (IQR 3.2–16 years). The proportion of complete success, qualified success and failure was 45%, 33%, and 22% respectively. The maximum bleb height was significantly greater in the blebs with complete success (1.74 vs. 1.25 vs. 1.23 mm in CS vs. QS vs. F, one-way ANOVA, p  < 0.0001). Mean pixel intensity was significantly lower in blebs with complete success (150.8 vs. 157.4 vs. 167.4 in CS vs. QS vs. F, p  = 0.0001). Bleb intensity standard deviation (AUC 0.81), maximal bleb height (AUC 0.76), mean pixel intensity (AUC 0.75) and minimum pixel intensity (AUC 0.75) offered the best discrimination between surgical success and failure. Conclusions Swept-source AS-OCT can be used to quantify bleb internal reflectivity and morphology, which can be used to distinguish between well vs. poorly functioning blebs. These parameters may assist surgeons in the objective evaluation of post-operative bleb outcomes.

A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (P interaction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratio highest vs. lowest total resilience metabolite quartile =0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1b V265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.

The corneal endothelium has a crucial role in maintaining a clear and healthy cornea. Corneal endothelial cell loss occurs naturally with age; however, a diagnosis of glaucoma and surgical intervention for glaucoma can exacerbate a decline in cell number and impairment in morphology. In glaucoma, the mechanisms for this are not well understood and this accelerated cell loss can result in corneal decompensation. Given the high prevalence of glaucoma worldwide, this review aims to explore the abnormalities observed in the corneal endothelium in differing glaucoma phenotypes and glaucoma therapies (medical or surgical including with new generation microinvasive glaucoma surgeries). Descemet membrane endothelial keratoplasty (DMEK) is increasingly being used to manage corneal endothelial failure for glaucoma patients and we aim to review the recent literature evaluating the use of this technique in this clinical scenario.

This paper describes a technique for using swept-source anterior segment optical coherence tomography (AS-OCT) to visualize internal bleb microstructure and objectively quantify dimensions of the scleral flap and trabeculo-Descemet window (TDW) in non-penetrating glaucoma filtration surgery (GFS). This was a cross-sectional study of 107 filtering blebs of 67 patients who had undergone deep sclerectomy surgery at least 12 months prior. The mean post-operative follow-up duration was 6.5 years +/− 4.1 [standard deviation (SD)]. The maximal bleb height was significantly greater in the complete success (CS) blebs compared to the qualified success (QS) and failed (F) blebs (1.48 vs. 1.17 vs. 1.10 mm in CS vs. QS vs. F, one-way ANOVA, p < 0.0001). In a subcohort of deep sclerectomy blebs augmented by intraoperative Mitomycin-C, the trabeculo-Descemet window was significantly longer in the complete success compared to the qualified success group (613.7 vs. 378.1 vs. 450.8 µm in CS vs. QS vs. F, p = 0.004). The scleral flap length, thickness, and width were otherwise similar across the three outcome groups. The quantification of surgical parameters that influence aqueous outflow in non-penetrating GFS can help surgeons better understand the influence of these structures on aqueous outflow and improve surgical outcomes.

BackgroundSelective laser trabeculoplasty (SLT), a National Institute for Care and Health Excellence recommended first-line treatment for open-angle glaucoma and ocular hypertension, is increasingly delivered by optometrists. This retrospective multicentre observational study evaluates real-world outcomes of SLT comparing optometrist-treated to ophthalmologist-treated eyes.MethodsAdults aged ≥40 years receiving first SLT treatment at three UK hospital eye units (Aintree, Manchester, Macclesfield) between 1 August 2018 and 1 August 2021 were analysed using anonymised local audit data. Outcomes included intraocular pressure (IOP), visual acuity (VA), drop burden, complications including post-SLT IOP spikes, and composite treatment failures including repeat laser or glaucoma surgery, evaluated at 6-monthly intervals up to 24 months. Groups were compared with parametric and non-parametric tests, accounting for intereye correlation, and Kaplan-Meier survival analysis using composite treatment failure endpoints was conducted.Results207 eyes (131 patients) were analysed, 84 (56 patients) optometrist-treated eyes compared with 123 ophthalmologist-treated eyes (75 patients). No statistically significant differences (p>0.05) were found in change in VA, IOP or glaucoma drops from pre-SLT baseline between optometrist and ophthalmologist-treated eyes, at all time points. More cataracts were detected in optometrist-treated eyes, however, this did not affect differences in VA or cataract surgery frequency. More optometrist-treated eyes underwent glaucoma surgery, however, ophthalmologist-treated eyes had higher drop burden and chance of composite treatment failure up to month 18.ConclusionOutcomes of SLT treatment by optometrists and ophthalmologists are comparable up to 24 months post-treatment. Ophthalmologist-treated eyes may have had more aggressive eye-drop treatment, preventing the need for surgery.

Late-onset retinal degeneration (L-ORD) is a rare autosomal dominant retinal dystrophy, characterised by extensive sub-retinal pigment epithelium (RPE) deposits, RPE atrophy, choroidal neovascularisation and photoreceptor cell death associated with severe visual loss. L-ORD shows striking phenotypic similarities to age-related macular degeneration (AMD), a common and genetically complex disorder, which can lead to misdiagnosis in the early stages. To date, a single missense mutation (S163R) in the C1QTNF5 gene, encoding C1q And Tumor Necrosis Factor Related Protein 5 (C1QTNF5) has been shown to cause L-ORD in a subset of affected families. Here, we describe the identification and characterisation of three novel pathogenic mutations in C1QTNF5 in order to elucidate disease mechanisms . In silico and in vitro characterisation show that these mutations perturb protein folding, assembly or polarity of secretion of C1QTNF5 and, importantly, all appear to destabilise the wildtype protein in co-transfection experiments in a human RPE cell line. This suggests that the heterozygous mutations in L-ORD show a dominant negative, rather than a haploinsufficient, disease mechanism. The function of C1QTNF5 remains unclear but this new insight into the pathogenetic basis of L-ORD has implications for future therapeutic strategies such as gene augmentation therapy.

Purpose: The purpose of this study was to genotype two previously identified SNPs (rs1048661:R141L, and rs3825942:G153D) in the lysyl oxidase-like 1 (LOXL1) gene and determine their association with pseudoexfoliation glaucoma (XFG) in patients from Pune, India. Methods: All subjects underwent detailed phenotyping, and DNA extraction was performed on blood samples by using standardized techniques. Exon 1 of the LOXL1 gene containing the SNPs (rs3825942:G153D; rs1048661:R141L) were Sanger sequenced, and the results were analyzed using sequence analysis software SeqScape 2.1.1. Results: Data were analyzed from 71 patients with XFG and 81 disease-negative, age-matched controls. There was a strong association between the G allele of rs3825942 and XFG with an odds ratio of 10.2 (CI: 3.92-26.6; P < 0.001). The G allele of rs1048661 also showed an increase in risk relative to the T allele (OR = 1.49; CI: 0.88-2.51; P = 0.13), but this was not significant. Haplotype combination frequencies were estimated for rs1048661 and rs3825942; the GG haplotype was associated with a significant increase in risk (OR = 3.91; CI: 2.27-6.73; P < 0.001). Both the GA and TG haplotypes were associated with decreased XFG risk, although the latter was not significant (GA: OR = 0.08; CI: 0.03-0.21; P < 0.001; TG: OR = 0.67; CI: 0.40-1.13; P = 0.13). Conclusion: The risk G allele in rs3852942 (G153D) is strongly associated with the development of XFG in the Western Indian population. Genetic screening strategies to identify LOXL1 risk alleles in the population can assist in case definition and early diagnosis, targeting precious resources to high-risk patients.

A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve=0.579), they offered marginal prediction improvement in PRS-only-based models (P=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites-lactate (P=8.8E-12), pyruvate (P=1.9E-10), and citrate (P=0.02)-linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (P =0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratio =0.71, 95% Confidence Interval=0.64-0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (P=0.002) and optic nerve damage (P<0.0003) in mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.