Neeru Amrita Vallabh

Glaucoma is an irreversible blinding disease that affects millions of individuals worldwide. Elevated intraocular pressure (IOP), regulated by the trabecular meshwork (TM) in the anterior eye, is the only modifiable risk factor. Human TM cells can be cultured from donor eyes, providing a precious resource for studying factors that induce or prevent glaucoma. The goal of this study was to produce datasets that define the molecular profile of human non-glaucomatous TM cells. Using 18 human TM cell strains cultured from non-glaucomatous individuals deposited from seven laboratories in the USA and UK, this study used transcriptomic, proteomic, lipidomic, and metabolomic analyses to characterize the molecular content of TM cells. The data herein provides the most comprehensive multiomic analyses of human TM cells to date and will be a useful resource for researchers and clinicians in the TM and glaucoma fields.

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.

Glaucoma is a sight threatening neurodegenerative condition of the optic nerve head associated with ageing and marked by the loss of retinal ganglion cells. Mitochondrial dysfunction plays a crucial role in the pathogenesis of neurodegeneration in the most prevalent type of glaucoma: primary open angle glaucoma (POAG). All previous mitochondrial genome sequencing studies in POAG analyzed mitochondrial DNA (mtDNA) isolated from peripheral blood leukocytes and have not evaluated cells derived from ocular tissue, which better represent the glaucomatous disease context. In this study, we evaluated mitochondrial genome variation and heteroplasmy using massively parallel sequencing of mtDNA in a cohort of patients with POAG, and in a subset assess the role of somatic mitochondrial genome mutations in disease pathogenesis using paired samples of peripheral blood leukocytes and ocular tissue (Tenon’s ocular fibroblasts). An enrichment of potentially pathogenic nonsynonymous mtDNA variants was identified in Tenon’s ocular fibroblasts from participants with POAG. The absence of oxidative DNA damage and predominance of transition variants support the concept that errors in mtDNA replication represent the predominant mutation mechanism in Tenon’s ocular fibroblasts from patients with POAG. Pathogenic somatic mitochondrial genome mutations were observed in people with POAG. This supports the role of somatic mitochondrial genome variants in the etiology of glaucoma.

Background: Selective 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. Methods: Adults 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. Results: 207 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. Conclusion: Outcomes 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.

Background: Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased healthspan. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity, and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand, and meet the healthcare, workforce, wellbeing, and socioeconomic needs of ageing populations, while supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies. Methods: The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19 ^th , 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥70% for approval. Results: The accepted criteria for an ageing-related pathology, disease or syndrome were: Develops and/or progresses with increasing chronological age. Should be associated with, or contribute to, functional decline, or an increased susceptibility to functional decline. Evidenced by studies in humans. Conclusions: Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes.

This literature review evaluates any possible links between primary open-angle glaucoma (POAG) and caloric restriction (CR), body mass index (BMI), and exercise, aiming to map the extent of the literature. Its primary objective is to recognise the nature and breadth of research evidence, identify possible gaps in these topics and develop future studies. The databases searched were MEDLINE (PudMed), Scopus and ScienceDirect, in April 2023 for articles published in English, with no date restriction. A total of 447 search results were retrieved. Of these, 73 were related to CR, 249 to BMI, and 125 to exercise. Records identified included systematic reviews, meta-analyses, randomised controlled trials, cohort studies and animal studies. CR has been shown to halt the degeneration of retinal ganglion cells and protect against various glaucomatous processes in animal models. Low BMI has been shown to be associated with an increased risk of POAG and a faster rate of visual field deterioration in POAG. However, the association between high BMI and POAG is not consistent. Exercise has been shown to cause mechanical, vascular, and neurobiological changes affecting the pathophysiology of POAG. The present review helps identify key characteristics and factors relating to the impacts of CR, BMI, or exercise on POAG.

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.

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.