OBJECTIVE: To assess the cost-effectiveness of making treatment decisions for patients with ocular hypertension (OHT) based on a risk prediction (RP) tool in the United Kingdom.
METHODS: A discrete event simulation model was constructed to compare the cost-effectiveness of an alternative care pathway in which the treatment decision was guided by a validated RP tool in secondary care against decision-making based on the standard care (SC). Individual patient sampling was used. Patients diagnosed with OHT and with an intraocular pressure of 24 mm Hg or over entered the model with a set of predefined individual characteristics related to their risk of conversion to glaucoma. These characteristics were retrieved from electronic medical records (n=5740). Different stages of glaucoma were modelled following conversion to glaucoma.
RESULTS: Almost all (99%) patients were treated using the RP strategy, and less than half (47%) of the patients were treated using the SC strategy. The RP strategy produced higher cost but also higher quality-adjusted life years (QALYs) than the SC strategy. The RP strategy was cost-effective compared with the SC strategy in the base-case analysis, with an incremental cost-effectiveness ratio value of £11 522. The RP strategy had a 96% probability of being cost-effective under a £20 000 per QALY threshold.
CONCLUSIONS: The use of an RP tool for the management of patients with OHT is likely to be cost-effective. However, the generalisability of the result might be limited due to the high-risk nature of this cohort and the specific RP threshold used in the study.

A 22-year-old woman with a history of high myopia (-8.00 -3.75 × 011, right eye; -6.75 -3.75 × 174, left eye) presented to our clinic for implantable collamer lens (ICL) evaluation. Medical history was noncontributory. The patient\'s father had a history of glaucoma. Slitlamp and dilated fundus examination were unremarkable with a cup-to-disc ratio of 0.5 in both eyes and a myopic fundus. Intraocular pressures (IOPs) were 20 mm Hg in the right eye and 19 mm Hg in the left eye. Galilei G4 (Ziemer USA, Inc.) measured a white-to-white (WTW) distance of 12.98 mm in the right eye and 13.05 mm in the left eye and central corneal thickness of 512 μm in the right eye and 504 μm in the left eye. Ultrasound biomicroscopy (UBM) (Sonomed Escalon) displayed a sulcus-to-sulcus distance of 12.76 mm in the right eye and 12.75 mm in the left eye and an anterior chamber depth (ACD) of 3.57 mm in the right eye and 3.79 mm in the left eye (Figure 1JOURNAL/jcrs/04.03/02158034-202409000-00014/figure1/v/2024-08-19T175148Z/r/image-tiff). Prednisolone acetate 0.1% ophthalmic suspension eye drops and ofloxacin 0.3% ophthalmic solution eye drops 4 times daily were prescribed prophylactically 2 days preoperatively. A -12.5 and -12 D EVO+ Visian toric ICL -13.2 mm (STAAR Surgical Co.) was implanted along the 180-degree meridian in the right eye and left eye, respectively. Immediate postoperative IOPs were 23 mm Hg in both eyes. The patient was instructed to continue ofloxacin drops for 1 week and taper prednisolone acetate drops over 1 month. On postoperative day (POD) 1, uncorrected distance visual acuity (UDVA) was 20/20 in the right eye and 20/25 in the left eye. The patient\'s IOP was 24 mm Hg in the right eye and 26 mm Hg in the left eye. Anterior chambers (ACs) were unremarkable with minimal edema at the clear temporal corneal incision sites. Anterior segment optical coherence tomography (AS-OCT) vault measurements were 766 μm in the right eye and 697 μm in the left eye. Subsequently, the prednisolone dosage was reduced to 3 times a day, and brimonidine eye drops 3 times a day in both eyes were added to the regimen. On POD 5, the patient returned to the clinic reporting sudden-onset blurred vision with severe retro-orbital pain in the left eye upon awakening. Her UDVA was 20/25 in the right eye and 2/40 in the left eye. IOP was 30 mm Hg in both eyes. The ACs were deep, and there was minimal corneal edema in both eyes. Vaults were 674 μm in the right eye and 623 μm in the left eye (Figure 2JOURNAL/jcrs/04.03/02158034-202409000-00014/figure2/v/2024-08-19T175148Z/r/image-tiff). The patient was instructed to reduce prednisolone to 2 times a day, discontinue brimonidine, and start brimonidine/timolol (Combigan) 2 times a day and latanoprost at bedtime in both eyes. At the routine 1-week postoperative appointment, the patient\'s IOP was 30 mm Hg in the right eye and 29 mm Hg in the left eye. The patient was instructed to reduce prednisolone to once a day, continue brimonidine/timolol 2 times a day and latanoprost at bedtime, and start acetazolamide (Diamox) 250 mg 2 times a day. The patient was told to return to the office in a few days for an IOP check. What are the differential diagnoses concerning this case? What is the most likely mechanism underlying this patient\'s elevated IOP? What additional diagnostic workup would aid you in making the correct diagnosis?

OBJECTIVE: To compare effects of glucagon-like peptide-1 (GLP-1) receptor agonists and metformin on the risk of primary open-angle glaucoma (POAG), ocular hypertension, and the need for first-line glaucoma treatments in patients with type 2 diabetes.
METHODS: A retrospective cohort study was conducted using electronic medical records (EMR) data from the from an international electronic health record network, covering a period from May 2006 to May 2024.
METHODS: Patients diagnosed with type 2 diabetes mellitus (T2DM) who were treated with either GLP-1 receptor agonists or metformin.
METHODS: Data from 120 healthcare organizations across 17 countries were analyzed. Patient outcomes were assessed at 1, 2, and 3 years. Propensity score matching (PSM) was used to balance covariates such as demographics, comorbidities, and medication usage. Risk ratios (RR) with 95% confidence intervals (CI) were calculated.
METHODS: Incidence of POAG, ocular hypertension, and the need for first-line treatments including beta-blockers, prostaglandin analogues, brimonidine, brinzolamide, dorzolamide, netarsudil, and laser trabeculoplasty.
RESULTS: After PSM, both groups included 61,998 patients at the 1-year follow-up, 27,414 at the 2-year follow-up, and 14,100 at the 3-year follow-up. Patients treated with GLP-1 receptor agonists had a significantly decreased risk of developing POAG compared to those on metformin at 1 year (RR 0.59, 95% CI 0.39-0.88), 2 years (RR 0.50, 95% CI 0.32-0.78), and 3 years (RR 0.59, 95% CI 0.37-0.94). Similar protective effects were observed for ocular hypertension with risk reductions of 56% at 1 year (RR 0.44, 95% CI 0.31-0.62), 57% at 2 years (RR 0.43, 95% CI 0.30-0.62), and 49% at 3 years (RR 0.51, 95% CI 0.34-0.75). The risk of first-line therapy initiation was also lower in the GLP-1 receptor agonists group at 1 year (RR 0.63, 95% CI 0.53-0.74), 2 years (RR 0.71, 95% CI 0.59-0.85), and 3 years (RR 0.75, 95% CI 0.62-0.91).
CONCLUSIONS: GLP-1 receptor agonists are associated with a significantly lower incidence of POAG, ocular hypertension, and the need for first-line glaucoma treatments compared to metformin in patients with type 2 diabetes. These findings highlight the potential ocular benefits of GLP-1 receptor agonists and their expanding role in the clinical management of diabetic patients.

Ceramides with varying acyl-chain lengths can have unique biological actions and hence, cellular responses to ceramides may depend not on their overall concentration but on that of individual ceramide species. The purpose of this study was to determine individual ceramide species impacting retinal ganglion cell (RGC) loss under the ocular hypertensive condition. Induced pluripotent stem cell (iPSC)-derived RGCs and primary cultures of human astrocytes were used to determine the effect of individual ceramide species on both RGC viability and astrocyte secretion of inflammatory cytokines in vitro. In in vivo experiments with wild-type (WT) and ceramide synthase 5 (CerS5) knockout mice, intraocular pressure was unilaterally elevated with microbead injection. Retinal function and morphology were evaluated using pattern electroretinography (pERG) and immunofluorescence, respectively. Ceramide levels were determined by LC-MS/MS analysis. Exposure to C16:0-, C18:0-, C18:1-, C20:0- and C24:0-ceramides significantly reduces RGC viability in vitro, with the very long chain C24:0-ceramide being the most neurotoxic; treatment with C18:0-, C18:1- and C24:0-ceramides stimulates an increase of TNF-α secretion by astrocytes. The retinas of CerS5 KO mice have significantly reduced levels of C16:0- and C18:1-ceramides compared to WT; ocular hypertensive eyes of these mice maintain higher pERG amplitudes and RGC numbers compared to WT. Individual ceramides with different chain lengths have different effects on RGCs and astrocytes. Our results demonstrate that suppressing C16:0- and C18:1-ceramide species effectively protects RGCs against ocular hypertensive injury. These results provide a basis for targeting specific ceramide species in the treatment of glaucoma.

This initial methods study presents the initial immunohistochemical and transcriptomic changes in the optic nerve head and retina from three research-consented brain-dead organ donors following prolonged and transient intraocular pressure (IOP) elevation. In this initial study, research-consented brain-dead organ donors were exposed to unilateral elevation of IOP for 7.5 h (Donor 1), 30 h (Donor 2), and 1 h (Donor 3) prior to organ procurement. Optic nerve tissue and retinal tissue was obtained following organ procurement for immunohistological and transcriptomic analysis. Optic nerve sections in Donor 1 exposed to 7.5-hours of unilateral sub-ischemic IOP elevation demonstrated higher levels of protein expression of the astrocytic marker, glial fibrillary acidic protein (GFAP), within the lamina cribrosa with greatest expression inferior temporally in the treated eye compared to control. Spatial transcriptomic analysis performed on optic nerve head tissues from Donor 2 exposed to 30 h of unilateral IOP elevation demonstrated differential transcription of mRNA across laminar and scleral regions. Immunohistochemistry of retinal sections from Donor 2 exhibited higher GFAP and IBA1 expression in the treated eye compared with control, but this was not observed in Donor 3, which was exposed to only 1-hour of IOP elevation. While there were no differences in GFAP protein expression in the retina following the 1-hour IOP elevation in Donor 3, there were higher levels of transcription of GFAP in the inner nuclear layer, and CD44 in the retinal ganglion cell layer, indicative of astrocytic and Müller glial reactivity as well as an early inflammatory response, respectively. We found that transcriptomic differences can be observed across treated and control eyes following unilateral elevation of IOP in brain dead organ donors. The continued development of this model affords the unique opportunity to define the acute mechanotranscriptomic response of the optic nerve head, evaluate the injury and repair mechanisms in the retina in response to IOP elevation, and enable correlation of in vivo imaging and functional testing with ex vivo cellular responses for the first time in the living human eye.

Primary open-angle glaucoma (POAG) is subdivided depending on eye pressure. Patients with normal-tension glaucoma (NTG) have never had high intraocular pressure (IOP) measured while patients with ocular hypertension (OHT) have high eye pressure but no signs of glaucoma. Although IOP is considered to be a risk factor for all glaucoma patients, it is reasonable to assume that other risk factors such as inflammation play a role. We aimed to characterize the proteome and cytokine profile during hypoxia in plasma from patients with NTG (n = 10), OHT (n = 10), and controls (n = 10). Participants were exposed to hypoxia for two hours, followed by 30 min of normoxia. Samples were taken before (\"baseline\"), during (\"hypoxia\"), and after hypoxia (\"recovery\"). Proteomics based on liquid chromatography coupled with mass spectrometry (LC-MS) was performed. Cytokines were measured by Luminex assays. Bioinformatic analyses indicated the involvement of complement and coagulation cascades in NTG and OHT. Regulation of high-density lipoprotein 3 (HDL3) apolipoproteins suggested that changes in cholesterol metabolism are related to OHT. Hypoxia decreased the level of tumor necrosis factor-α (TNF-α) in OHT patients compared to controls. Circulating levels of interleukin-1β (IL-1β) and C-reactive protein (CRP) were decreased in NTG patients compared to controls during hypoxia. After recovery, plasma interleukin-6 (IL-6) was upregulated in patients with NTG and OHT. Current results indicate an enhanced systemic immune response in patients with NTG and OHT, which correlates with pathogenic events in glaucoma. Apolipoproteins may have anti-inflammatory effects, enabling OHT patients to withstand inflammation and development of glaucoma despite high IOP.

OBJECTIVE: Treatment with glucocorticoids following paediatric cataract surgery is crucial to prevent inflammation, but may lead to secondary glaucoma, and hypothalamic-pituitary-adrenal axis suppression. We wish to compare glaucoma outcomes following high-dose and low-dose glucocorticoid treatment after paediatric cataract surgery.
METHODS: This cohort study included Danish children undergoing cataract surgery before 10 years of age, receiving either a low-dose or high-dose postoperative glucocorticoid treatment. Case identification and collection of a standardized dataset were retrospective, from 1 January 2010 to 31 December 2016, and prospective thereafter, until 31 December 2021. High-dose treatment included 0.5-1.0 mg subconjunctival depot dexamethasone or methylprednisolone, followed by 6-8 drops of dexamethasone for 1 week, tapered by one drop weekly. Low-dose treatment included 6 drops for 3 days, followed by 3 drops for 18 days. Sustained (>3 months) ocular hypertension or glaucoma was compared between the two groups.
RESULTS: Overall, 267 children (388 eyes) were included in the study. Ninety-five children (133 eyes) had received high-dose treatment and had a median follow-up time of 89 months (IQR: 57.2-107.4), while 173 children (255 eyes) had received the low-dose treatment and had a median follow-up time of 40.5 months (IQR: 22.9-60.4). Survival curves showed a lower risk of glaucoma in the low-dose group for children with axial lengths ≥18 mm.
CONCLUSIONS: Low-dose glucocorticoid treatment was associated with a lower risk of glaucoma in children with axial lengths ≥18 mm. The same effect was not observed in children with shorter eyes. High-dose glucocorticoid should be limited in children undergoing cataract surgery.

UNASSIGNED: The Rho-associated protein kinase and myosin light chain kinase (ROCK/MYLK) pathway undeniably plays a pivotal role in the pathophysiology of primary open-angle glaucoma (POAG). In our study, we utilized both ocular hypertension (OHT) rabbit models and clinical investigations to gain invaluable insights that propel the development of novel treatments targeting proteins and genes associated with the trabecular meshwork (TM), thereby offering promising avenues for the management of POAG.
UNASSIGNED: Following microbead injections into the anterior chamber of the ocular cavity of rabbits, we observed elevated histiocyte numbers and immune scores for MYLK-4/ pMLC-2, alongside a reduction in the void space within the TM. Notably, treatment was performed with 0.1% ITRI-E-(S)-4046, a compound with dual kinase inhibitor (highly specific inhibitor of ROCK1/2 and MYLK4), significantly reduced intraocular pressure (IOP; P < 0.05) and expanded the void space within the TM (P < 0.0001) compared with OHT rabbits. In clinical investigations, we utilized whole transcriptome sequencing to analyze gene expression specifically related to the TM, obtained from patients (5 early-onset and 5 late-onset) undergoing trabeculectomy.
UNASSIGNED: Our findings revealed 103 differential expression genes (DEGs) out of 265 molecules associated with the Rho family GTPase pathway, exhibiting a P value of 1.25E-10 and a z-score of -2.524. These results underscore significant differences between the early-onset and late-onset POAG and highlight the involvement of the ROCK/MYLK pathway.
UNASSIGNED: These findings underscore the critical involvement of the ROCK/MYLK pathway in both OHT-related and different onsets of POAG, providing valuable insights into the TM-related molecular mechanisms underlying the disease.

Ocular surface disease (OSD) is a complex condition that can cause a range of symptoms (e.g, dryness, irritation, and pain) and can significantly impact the quality of life of affected individuals. Iatrogenic OSD, a common finding in patients with glaucoma who receive chronic therapy with topical ocular antihypertensive drugs containing preservatives such as benzalkonium chloride (BAK), has been linked to damage to the ocular surface barrier, corneal epithelial cells, nerves, conjunctival goblet cells, and trabecular meshwork. Chronic BAK exposure activates inflammatory pathways and worsens symptoms, compromising the success of subsequent filtration surgery in an exposure-dependent manner. In eyes being treated for glaucoma, symptomatic treatment of OSD may provide some relief, but addressing the root cause of the OSD often necessitates reducing or, ideally, eliminating BAK toxicity. Strategies to decrease BAK exposure in patients with glaucoma encompass the use of preservative-free formulations or drugs with alternative and less toxic preservatives such as SofZia®, Polyquad, potassium sorbate, or Purite®. Though the benefits of these alternative preservatives are largely unproven, they might be considered when financial constraints prevent the use of preservative-free versions. For patients receiving multiple topical preserved drugs, the best practice is to switch to nonpreserved equivalents wherever feasible, regardless of OSD severity. Furthermore, nonpharmacological approaches, including laser or incisional procedures, should be considered. This review explores the effects of BAK on the ocular surface and reviews strategies for minimizing or eliminating BAK exposure in patients with glaucoma in order to significantly improve their quality of life and prevent complications associated with chronic exposure to BAK.

UNASSIGNED: Primary open-angle glaucoma (POAG) is a leading cause of blindness, and its primary risk factor is elevated intraocular pressure (IOP) due to pathologic changes in the trabecular meshwork (TM). We previously showed that there is a cross-inhibition between TGFβ and Wnt signaling pathways in the TM. In this study, we determined if activation of the Wnt signaling pathway using small-molecule Wnt activators can inhibit TGFβ2-induced TM changes and ocular hypertension (OHT).
UNASSIGNED: Primary human TM (pHTM) cells and transduced SBE-GTM3 cells were treated with or without Wnt and/or TGFβ signaling activators and used for luciferase assays; for the extraction of whole-cell lysate, conditioned medium, cytosolic proteins, and nuclear proteins for Western immunoblotting (WB); or for immunofluorescent staining. Human donor eyes were perfusion cultured to study the effect of Wnt activators on IOP.
UNASSIGNED: We found that the small-molecule Wnt activators (GSK3β inhibitors) (BIO, SB216763, and CHIR99021) activated canonical Wnt signaling in pHTM cells without toxicity at tested concentrations. This activation inhibited TGFβ signaling as well as TGFβ2-induced extracellular matrix deposition and formation of cross-linked actin networks in pHTM cells or SBE-GTM3 cells. We also observed nuclear translocation of both Smad4 and β-catenin in pHTM cells, which suggested that the cross-inhibition between the TGFβ and Wnt signaling pathways may occur in the nucleus. Using our ex vivo model, we found that CHIR99021 inhibited TGFβ2-induced OHT in perfusion-cultured human eyes.
UNASSIGNED: Our results showed that small-molecule Wnt activators have the potential for treating TGFβ signaling-induced OHT in patients with POAG.