Jennifer C. Fan Gaskin

Purpose The direct effect of iStent inject on intraocular pressure (IOP) in patients with glaucoma is difficult to quantify in pragmatic trials where rates of post-surgical IOP-lowering therapy differ between intervention groups. We aimed to quantify the causal effect of iStent inject on unmedicated IOP at 12- and 24-months post-surgery. Methods Adults with mild-to-moderate glaucoma were 1:1 randomised to receive cataract surgery with iStent inject or cataract surgery alone at an Australian hospital (2017-2020, NCT03106181 ). IOP-lowering medications were prescribed as per clinician discretion. An exploratory analysis was used to estimate the controlled direct effect of iStent inject on IOP, analogous to the effect expected if all participants had undergone medication washout prior to assessment. Results Ninety-five eyes from 80 people were included (67.4% male, mean age 73.0 years, mean baseline IOP 17.1 mmHg). IOP-lowering medication was required for 53% of eyes in each group at 12 months (n=76); at 24 months (n=86) it was required for 43% and 64% in the active and control groups, respectively. Mean IOP was similar between intervention groups at each outcome visit. The controlled direct effect favoured the iStent inject group at 12 months (-2.1-mmHg difference, 95% CI -4.0,-0.3) but was attenuated at 24 months (-0.5 mmHg-difference, 95% CI -2.6,1.6). Conclusion Although the iStent inject was estimated to have an effect on lowering unmedicated IOP at 12 months, this effect had largely disappeared by 24 months. Medication washout is recommended when safe and practical in future trials to estimate these direct effects with more certainty.

Background: Glaucoma filtration surgery (GFS) is performed to slow down disease progression in glaucoma, a leading cause of irreversible blindness worldwide. Following surgery, pathological wound healing may lead to conjunctival fibrosis and filtering failure. Myofibroblast transition of human Tenon’s fibroblast (HTF) is responsible for postoperative conjunctival scarring, with TGFβ signalling playing a key role in this process. However, the detailed molecular mechanism underlying myofibroblast transition in HTF remain understudied. Methods: In this study, we performed transcriptomic analysis to delineate the TGFβ1-induced changes in the transcriptome of HTF. HTF was isolated from three patients following GFS and treated with TGFβ1 for 5 days, followed by RNA-seq for transcriptomic profiling. Results: Our results identified 3362 differentially expressed genes (DEGs) in HTF following TGFβ1 treatment, of which 1532 were upregulated and 1820 were downregulated. Using gene ontology analysis, we identified signalling pathways associated with the pathogenesis of conjunctival fibrosis, including pathways involved in myofibroblast differentiation, TGFβ-signalling, collagen and extracellular matrix organisation, epithelial to mesenchymal transition, and cell cycle regulation. This study provided detailed characterisation of the transition from HTF to myofibroblast, and highlighted key genes that are upregulated (LDLRAD4, CDKN2B, FZD8, MYOZ1) and downregulated (SOD3, LTBP4 and RCAN2) in this myofibroblast transition process. Conclusions: Overall, this study provided insights into the transcriptional landscape of HTFs and myofibroblast differentiation, which has important implication to understanding the pathophysiology of conjunctival scarring and development of new therapeutic agents.

Background: Traditional reactive ‘wait and see’ approaches in glaucoma management often result in unacceptable rates of permanent vision loss. This consensus defines a proactive ‘interventional glaucoma’ framework tailored for the Australian and New Zealand healthcare context. Methods: A modified Delphi consensus process was utilised, consisting of a lead panel of 12 experts (10 Australian, 1 New Zealand, and 1 Singaporean) and a validation cohort of 55 glaucoma specialists and ophthalmologists. Consensus was established via live panel presentations and real‐time electronic polling. Participants evaluated statements using a three‐tier scale: agree, stand aside, or object, with a pre‐defined consensus threshold of an objection rate < 20%. Results: Twelve consensus statements were ratified. Key points include the formalised classification of glaucoma as a progressive optic neuropathy and the staging of disease to personalise target intraocular pressures to minimise progression. Selective laser trabeculoplasty and Minimally Invasive Glaucoma Surgery were recognised for their role in reducing the daily medication burden for mild‐to‐moderate disease. Traditional incisional surgeries remain the gold standard for advanced or refractory cases. The emerging role of Polygenic Risk Scores in adult‐onset glaucoma was also acknowledged. Conclusions: This Australian and New Zealand Glaucoma Society consensus on interventional glaucoma advocates for a shift towards an interventional paradigm. By utilising advanced diagnostics and timely procedural interventions, clinicians can better preserve visual function and optimise long‐term patient quality of life.

(1) Background: Proliferative vitreoretinopathy (PVR) is the most common cause of failure in retinal detachment surgery and often leads to blindness. Oxidative stress is known to contribute to scar formation; therefore, reducing oxidative stress may protect against PVR development. This study investigated the therapeutic effects of the antioxidant 3′,4′-dihydroxyflavonol (DiOHF) in two preclinical models of PVR. (2) Methods: A retinal pigment epithelial cell line (ARPE-19) was used to investigate the anti-fibrotic effects of DiOHF. PVR was induced in one eye of each animal using dispase. Animals then received either vehicle or DiOHF eye drops in both eyes for 28 days. Eyes were harvested for mass spectrometry to perform proteomic analysis or to quantify tissue accumulation of DiOHF. Proteomic analysis was also performed in ARPE to validate these findings. (3) Results: In DiOHF-treated eyes with induced PVR, proteomic profiles showed reduced fibrosis, inflammation, cell migration, and oxidative stress compared with vehicle-treated PVR eyes. The in vitro studies confirmed that DiOHF inhibited wound healing responses, cell contraction, proliferation, and the generation of reactive oxygen species in ARPE-19 cells. Proteomic analysis in ARPE-19 also showed a similar trend. (4) Conclusions: This study provides compelling evidence that DiOHF eye drops offer protective effects against PVR in preclinical models.

Background: The success of minimally invasive bleb surgery (MIBS) such as the PreserFlo MicroShunt (PFMS) is limited by post‐operative bleb fibrosis. Current clinical practice prescribes the use of off‐label cytotoxic antimetabolites such as Mitomycin C (MMC) as antifibrotic therapy. This study investigates the anti‐scarring properties of a novel compound, 3′,4′‐Dihydroxyflavonol (DiOHF) in a rabbit model of PFMS filtration surgery. Methods: Fifteen New Zealand white rabbits underwent unilateral MIBS with PFMS. Treatment was randomised to the following groups: (1) vehicle ( n = 5), (2) DiOHF ( n = 5), both applied three times daily for 2 weeks or (3) a single dose of MMC administered intraoperatively ( n = 5). Blebs were photographed post‐operatively on Days 0, 7 and 14 for clinical examination. Eyes were harvested on Day 14 and processed for immunohistochemical tissue staining to assess collagen deposition, expression of αSMA, oxidative stress, fibroblast activity, angiogenesis and inflammation in the conjunctiva/Tenon's layer. Results: At 2‐weeks post‐surgery, MMC blebs were larger and more ischaemic than other treatments (Bleb size: MMC vs. DiOHF, p = 0.0098; MMC vs. vehicle, p = 0.0001. Ischaemia: p = 0.0004 for both). Compared to vehicle control, DiOHF blebs expressed decreased vimentin ( p = 0.0099), αSMA ( p = 0.0231) and 3‐nitrotyrosine ( p = 0.0410) after 2 weeks. DiOHF blebs expressed less CD45 than other treatments (DiOHF vs. Vehicle, p = 0.0013; DiOHF vs. MMC, p = 0.0232) and less collagen accumulation (DiOHF vs. vehicle, p = 0.0512). There was no difference in CD31 expression between treatment groups. Conclusions: DiOHF inhibited scarring following implantation of PFMS in rabbit eyes by reducing local oxidative stress, inflammation and fibroblastic activity. DiOHF may be a safer and more effective wound modulating agent than the conventional use of MMC.

The advent of minimally invasive glaucoma surgery (MIGS) has expanded the treatment options available for glaucoma by providing options for reducing intraocular pressure without the serious complication profile associated with incisional glaucoma surgery. MIGS devices aim to enhance aqueous outflow through the trabecular pathway or to bypass this pathway with drainage of fluid into the suprachoroidal or subconjunctival spaces. Having a wide range of glaucoma treatment options available helps tailor treatment to patients' individual intraocular pressure targets and aetiologies of glaucoma. This review will describe the categories and mechanisms of MIGS, comment on their relative efficacies, safety data, advantages and limitations and explore potential future changes in the glaucoma treatment paradigm in relation to MIGS.

Cornea vascularisation is a significant cause of ocular morbidity. Disease or injury often triggers the development of new blood vessels in the cornea, compromising its clarity and impairing vision. Common causes of corneal neovascularisation include infections, chemical burns, and local and systemic inflammatory disorders. Topical corticosteroid eye drops remain the standard therapy; however, extended use of corticosteroids has been known to cause side-effects including cataracts and raised intraocular pressure. As such, an alternative therapy has been actively sought. Vascular endothelial growth factor (VEGF) is a major angiogenic factor implicated in neovascularisation. The success of anti-VEGF agents in managing leaking blood vessels in neovascular age-related macular degeneration provides an opportunity to explore its use in the treatment of corneal neovascularisation. The therapeutic potential of anti-VEGF agents has been evaluated in experimental models of corneal neovascularisation and clinical trials with variable results. Here, we review the study results and discuss the development of new strategies that may improve treatment outcomes for corneal neovascularisation.

Background/Objectives: Glaucoma is the leading cause of irreversible blindness, with a significant proportion of cases remaining undiagnosed globally. The interpretation of optic disc and retinal nerve fibre layer images poses challenges for optometrists and ophthalmologists, often leading to misdiagnosis. AI has the potential to improve diagnosis. This study aims to validate an AI system (a convolutional neural network based on the Inception-v3 architecture) for detecting glaucomatous optic neuropathy (GON) using colour fundus photographs from a UK population and to compare its performance against Australian optometrists. Methods: A retrospective external validation study was conducted, comparing AI’s performance with that of 11 AHPRA-registered optometrists in Australia on colour retinal photographs, evaluated against a reference (gold) standard established by a panel of glaucoma specialists. Statistical analyses were performed using sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). Results: For referable GON, the sensitivity of the AI (33.3% [95%CI: 32.4–34.3) was significantly lower than that of optometrists (65.1% [95%CI: 64.1–66.0]), p < 0.0001, although with significantly higher specificity (AI: 97.4% [95%CI: 97.0–97.7]; optometrists: 85.5% [95%CI: 84.8–86.2], p < 0.0001). The optometrists demonstrated significantly higher AUROC (0.753 [95%CI: 0.744–0.762]) compared to AI (0.654 [95%CI: 0.645–0.662], p < 0.0001). Conclusion: The AI system exhibited lower performance than optometrists in detecting referable glaucoma. Our findings suggest that while AI can serve as a screening tool, both AI and optometrists have suboptimal performance for the nuanced diagnosis of glaucoma using fundus photographs alone. Enhanced training with diverse populations for AI is essential for improving GON detection and addressing the significant challenge of undiagnosed cases.

Post-operative fibrosis of the filtering bleb limits the success of glaucoma filtration surgery (GFS). To minimise subconjunctival scarring following GFS, treatment with antimetabolites such as Mitomycin C (MMC) has become standard practice; however, their use is associated with considerable side effects. This study aimed to investigate the anti-scarring properties of 3′,4′-dihydroxyflavonol (DiOHF). GFS was performed in New Zealand white rabbits who received eye drops of DiOHF three times daily and vehicle eye drops after surgery (n = 5) or a single intraoperative treatment of MMC (n = 5). Blebs were imaged immediately following surgery and on days 7, 15, 21, and 28 for clinical examination. On day 28, eyes were harvested to assess collagen deposition, expression of α-SMA, oxidative stress, angiogenesis, fibroblast activity, and inflammation in the conjunctiva/Tenon’s layer. At 7 and 28 days post-GFS, MMC-treated blebs were more ischaemic than DiOHF- or vehicle-treated blebs. On day 28, DiOHF treatment significantly suppressed collagen accumulation, CD31 expression, Vimentin expression, and CD45 expression compared to the vehicle control. No difference was observed in 3-Nitrotyrosine or αSMA expression between treatment groups. Treatment with DiOHF reduced conjunctival scarring and angiogenesis in rabbits with GFS, which was comparable to MMC. DiOHF may be a safer and more effective wound-modulating agent than conventional antifibrotic therapy in GFS.