Glaucoma: now and beyond.

The glaucomas are a group of conditions leading to irreversible sight loss and characterised by progressive loss of retinal ganglion cells. Although not always elevated, intraocular pressure is the only modifiable risk factor demonstrated by large clinical trials. It remains the leading cause of irreversible blindness, but timely treatment to lower intraocular pressure is effective at slowing the rate of vision loss from glaucoma. Methods for lowering intraocular pressure include laser treatments, topical medications, and surgery. Although modern surgical innovations aim to be less invasive, many have been introduced with little supporting evidence from randomised controlled trials. Many cases remain undiagnosed until the advanced stages of disease due to the limitations of screening and poor access to opportunistic case finding. Future research aims to generate evidence for intraocular pressure-independent neuroprotective treatments, personalised treatment through genetic risk profiling, and exploration of potential advanced cellular and gene therapies.

Adjunctive modulation of wound healing during cataract surgery to promote survival of a previous trabeculectomy.

BACKGROUND: Trabeculectomy is a surgical treatment for glaucoma to lower intraocular pressure with high success rates; however, it is often associated with an increased rate of cataract formation. Cataract can cause symptoms such as glare in bright conditions, foggy vision, and difficulty in driving at night. Cataract extraction surgery is highly successful in improving vision, but it comes at a cost of trabeculectomy failure, with a reported risk of 30% to 40%. An additional intervention to promote trabeculectomy survival after cataract extraction is needed. This review encompassed all adjunctive therapies used at the time of cataract surgery to increase trabeculectomy survival rate. OBJECTIVES: To investigate the effect of the adjunctive modulation of wound healing during cataract surgery on the survival of a previously functioning trabeculectomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2021, Issue 4); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov; and the WHO ICTRP. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 14 April 2021. SELECTION CRITERIA: We planned to include all randomised controlled trials (RCTs) of participants who had a functioning trabeculectomy and were undergoing cataract surgery that compared any adjunctive therapy intended to modulate wound healing (such as 5-fluorouracil, mitomycin C, or anti-vascular endothelial growth factor (VEGF) therapy) with no adjuvant therapy.  DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. Our primary outcome was trabeculectomy failure at 6 months and 12 months after cataract surgery. Secondary outcomes were mean intraocular pressure difference from pre-cataract surgery baseline to 6 to 18 months post-cataract surgery; number of medications required to control eye pressure compared to before cataract surgery; bleb appearance as measured by a summation score of the Moorfields bleb grading system or other equivalent numerical grading systems; visual field progression measured by difference in mean deviation from baseline; and any complications. MAIN RESULTS: We did not identify any RCTs of adjunctive modulation of wound healing during cataract surgery to promote survival of a previous trabeculectomy. AUTHORS' CONCLUSIONS: There is a need for an RCT to investigate the role of adjuvant wound modulating therapy at the time of cataract surgery to promote survival of a functioning trabeculectomy.

Ab interno supraciliary microstent surgery for open-angle glaucoma.

BACKGROUND: Glaucoma is the leading cause of global irreversible blindness, often associated with raised intraocular pressure (IOP). Where medical or laser treatment has failed or is not tolerated, surgery is often required. Minimally-invasive surgical approaches have been developed in recent years to reduce IOP with lower surgical risks. Supraciliary microstent surgery for the treatment of open-angle glaucoma (OAG) is one such approach. OBJECTIVES: To evaluate the efficacy and safety of supraciliary microstent surgery for the treatment of OAG, and to compare with standard medical, laser or surgical treatments. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2020, Issue 8); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 27 August 2020. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of supraciliary microstent surgery, alone or with cataract surgery, compared to other surgical treatments (cataract surgery alone, other minimally invasive glaucoma device techniques, trabeculectomy), laser treatment or medical treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts from the database search to identify studies that met the selection criteria. Data extraction, analysis, and evaluation of risk of bias from selected studies was performed independently and according to standard Cochrane methodology. MAIN RESULTS: One study met the inclusion criteria of this review, evaluating the efficacy and safety of the Cypass supraciliary microstent surgery for the treatment of OAG, comparing phacoemulsification + supraciliary microstent surgery with phacoemulsification alone over 24 months. This study comprised 505 eyes of 505 participants with both OAG and cataract, 374 randomised to the phacoemulsification + microstent group.  In this study, the perceived risk of bias from random sequence generation, allocation concealment and selective reporting was low. However, we considered the study to be at high risk of performance bias as surgeons/investigators were unmasked. Attrition bias was unclear, with 448/505 participants contributing to per protocol analysis. Insertion of a Cypass supraciliary microstent combined with phacoemulsification probably increases the proportion of participants who are medication-free (not using eye-drops) at 24 months compared with phacoemulsification alone (85% versus 59%, risk ratio (RR) 1.27, 95% confidence interval (CI) 1.09 to 1.49, moderate-certainty evidence). There is high-certainty evidence that a greater improvement in mean IOP occurs in the phacoemulsification + microstent group - mean (SD) change in IOP from baseline of -5.4 (3.9) mmHg in the phacoemulsification group, compared to -7.4 (4.4) mmHg in the phacoemulsification + microstent group at 24 months (mean difference -2.0 mmHg, 95% CI -2.85 to -1.15). There is moderate-certainty evidence that insertion of a microstent is probably associated with a greater reduction in use of IOP-lowering drops (mean reduction of 0.7 medications in the phacoemulsification group, compared to a mean reduction of 1.2 medications in the phacoemulsification + microstent group). Insertion of a microstent during phacoemulsification may reduce the requirement for further glaucoma intervention to control IOP at a later stage compared to phacoemulsification alone (RR 0.26, 95% CI 0.07 to 1.04, low-certainty evidence). There is no evidence relating to the rate of visual field progression, or proportion of participants whose visual field loss progressed in this study. There is moderate-certainty evidence showing little or no difference in the proportion of participants experiencing postoperative complications over 24 months between participants in the microstent group compared to those who received phacoemulsification alone (RR 1.1, 95% CI 0.8 to 1.4). Five year post-approval data regarding the safety of the Cypass supraciliary microstent showed increased endothelial cell loss, associated with the position of the microstent in the anterior chamber. There were no reported health-related quality of life (HRQoL) outcomes in the included study. AUTHORS' CONCLUSIONS: Data from this single RCT show superiority of supraciliary microstent surgery when combined with phacoemulsification compared to phacoemulsification alone in achieving medication-free control of OAG. However, there are long-term safety concerns with the device used in this trial, relating to the observed significant loss of corneal endothelial cells at five years following device implantation. At the time of this review, this device has been withdrawn from the market. This review has found that few high-quality studies exist comparing supraciliary microstent surgery to standard medical, laser or surgical glaucoma treatments. This should be addressed by further appropriately designed RCTs with sufficient long-term follow-up to ensure robust safety data are obtained. Consideration of health-related quality of life outcomes should also feature in trial design.

Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition.

Covalent modification of histones is a fundamental mechanism of regulated gene expression in eukaryotes, and interpretation of histone modifications is an essential feature of epigenetic control. Bromodomains are specialized binding modules that interact with acetylated histones, linking chromatin recognition to gene transcription. Because of their ability to function in a domain-specific fashion, selective disruption of bromodomain:acetylated histone interactions with chemical probes serves as a powerful means for understanding biological processes regulated by these chromatin adaptors. Here we describe the discovery and characterization of potent and selective small molecule inhibitors for the bromodomains of CREBBP/EP300 that engage their target in cellular assays. We use these tools to demonstrate a critical role for CREBBP/EP300 bromodomains in regulatory T cell biology. Because regulatory T cell recruitment to tumors is a major mechanism of immune evasion by cancer cells, our data highlight the importance of CREBBP/EP300 bromodomain inhibition as a novel, small molecule-based approach for cancer immunotherapy.

Long-Term Outcomes of Trabeculectomy Augmented with Mitomycin C Undertaken within the First 2 Years of Life.

PURPOSE: To evaluate the long-term effectiveness and safety of mitomycin C (MMC)-augmented trabeculectomy undertaken within the first 2 years of life for the surgical management of glaucoma. DESIGN: Retrospective, consecutive, noncomparative case series. PARTICIPANTS: All children who underwent MMC-augmented trabeculectomy within 2 years of birth between May 2002 and November 2012. METHODS: The medical records of 40 consecutive eyes of 26 children who underwent surgery by a single surgeon were reviewed. Data collected during routine clinical care were analyzed. MAIN OUTCOME MEASURES: Assessment of clinical outcomes included intraocular pressure (IOP), final visual acuity, bleb morphology, surgical complications (early and late), postoperative interventions, and further glaucoma surgery performed. Surgical success was defined as final IOP of 5 mmHg or more and of 21 mmHg or less, with anti-glaucoma medications (qualified success) and without (complete success), stable ocular dimensions and optic disc cupping, and no further glaucoma surgery (including needling) or loss of light perception. Surgical outcomes were evaluated using Kaplan-Meier life table analysis. RESULTS: Forty eyes of 26 children were studied over a mean follow-up period of 62.8 months. Most cases (80%) were of primary congenital glaucoma after failed goniotomy surgery. Cumulative probabilities of survival at 1, 5, and 7 years were 78%, 67%, and 60%, respectively. Of eyes regarded as successful, 96% (25/26 eyes) had controlled IOP without topical medication and 44% achieved visual acuity of 20/40 or better. In only 1 of the 40 eyes did a cystic avascular bleb develop, with all the other eyes being non-cystic in nature (diffuse and elevated or flat) at final follow-up. Sixty-four percent (9/14 eyes) of cases regarded as failures ultimately underwent glaucoma drainage device implantation. CONCLUSIONS: A contemporary pediatric trabeculectomy technique augmented with MMC is an effective procedure in the management of glaucoma within the first 2 years of life, as shown by the successful long-term outcomes and low incidence of sight-threatening complications. Trabeculectomy after failed goniotomy surgery or as a primary surgical intervention may offer a phakic infant with glaucoma an excellent opportunity to achieve long-term control of IOP without medications and may be associated with optimal visual outcomes.

Evaluation of the effect of elevated intraocular pressure and reduced ocular perfusion pressure on retinal capillary bed filling and total retinal blood flow in rats by OMAG/OCT.

PURPOSE: To determine if retinal capillary filling is preserved in the face of acutely elevated intraocular pressure (IOP) in anesthetized rats, despite a reduction in total retinal blood flow (RBF), using optical microangiography/optical coherence tomography (OMAG/OCT). METHODS: OMAG provided the capability of depth-resolved imaging of the retinal microvasculature down to the capillary level. Doppler OCT was applied to measure the total RBF using an enface integration approach. The microvascular pattern, capillary density, and total RBF were monitored in vivo as the IOP was increased from 10 to 100mmHg in 10mmHg intervals and returned back to 10mmHg. RESULTS: In animals with mean arterial pressure (MAP) of 102±4mmHg (n=10), when IOP was increased from 0 to 100mmHg, the capillary density remained at or above 80% of baseline for the IOP up to 60mmHg [or ocular perfusion pressure (OPP) at 40mmHg]. This was then decreased, achieving 60% of baseline at IOP 70mmHg and OPP of 30mmHg. Total RBF was unaffected by moderate increases in IOP up to 30mmHg, beyond which total RBF decreased linearly, reaching 50% of baseline at IOP 60mmHg and OPP 40mmHg. Both capillary density and total RBF were totally extinguished at 100mmHg, but fully recovered when IOP returned to baseline. By comparison, a separate group of animals with lower MAP (mean=75±6mmHg, n=7) demonstrated comparable decreases in both capillary filling and total RBF at IOPs that were 20mmHg lower than in the initial group. Both were totally extinguished at 80mmHg, but fully recovered when IOP returned to baseline. Relationships of both parameters to OPP were unchanged. CONCLUSION: Retinal capillary filling and total RBF responses to IOP elevation can be monitored non-invasively by OMAG/OCT and both are influenced by OPP. Retinal capillary filling was relatively preserved down to a perfusion pressure of 40mmHg, despite a linear reduction in total RBF.

Optimized feline vitrectomy technique for therapeutic stem cell delivery to the inner retina.

OBJECTIVE: To describe an optimized surgical technique for feline vitrectomy which reduces bleeding and aids posterior gel clearance in order to facilitate stem cell delivery to the inner retina using cellular scaffolds. PROCEDURES: Three-port pars plana vitrectomies were performed in six-specific pathogen-free domestic cats using an optimized surgical technique to improve access and minimize severe intraoperative bleeding. RESULTS: The surgical procedure was successfully completed in all six animals. Lens sparing vitrectomy resulted in peripheral lens touch in one of three animals but without cataract formation. Transient bleeding from sclerotomies, which was readily controlled, was seen in two of the six animals. No cases of vitreous hemorrhage, severe postoperative inflammation, retinal detachment, or endophthalmitis were observed during postoperative follow-up. CONCLUSIONS: Three-port pars plana vitrectomy can be performed successfully in the cat in a safe and controlled manner when the appropriate precautions are taken to minimize the risk of developing intraoperative hemorrhage. This technique may facilitate the use of feline models of inner retinal degeneration for the development of stem cell transplantation techniques using cellular scaffolds.

Optometrist-delivered selective laser trabeculoplasty in the HES - a training protocol and early service evaluation.

Over the last decade, the delivery of glaucoma care in the UK has changed dramatically, with more non-medical ophthalmic practitioners involved in the care of glaucoma patients. Optometrists and other non-medical professionals are now involved in the delivery of laser treatments in the Hospital Eye Service (HES), but there is currently no standardised national training framework for non-medical clinicians. Moorfields Eye Hospital and UCL's Institute of Ophthalmology have developed and delivered an education and training programme for the delivery of lasers, including Selective Laser Trabeculoplasty (SLT) by non-medical ophthalmic practitioners. The training programme is based on medical education principles, is informed by previous qualitative research into the role of ophthalmic practitioners in the delivery of laser treatments and is expected to have multidisciplinary benefits for ophthalmic healthcare. Clinical audit data indicate that optometrists can deliver safe SLT treatments, adhering to local protocols.

Acquisition of RGC phenotype in human Müller glia with stem cell characteristics is accompanied by upregulation of functional nicotinic acetylcholine receptors.

PURPOSE: Human Müller glia with stem cell characteristics (hMGSCs) can be induced to express genes and proteins of retinal ganglion cells (RGCs) upon in vitro inhibition of Notch-1 activity. However, it is not known whether expression of these markers is accompanied by acquisition of RGC function. This study investigated whether hMGSCs that express RGC markers also display neural functionality, as measured by their intracellular calcium concentration ([Ca(2+)]i) responsiveness following neurotransmitter stimulation in vitro. METHODS: Changes in mRNA expression of RGC markers and neurotransmitter receptors were assessed either by conventional or quantitative reverse transcription PCR (RT-PCR), while changes in protein levels were confirmed by immunocytochemistry. The [Ca(2+)]i levels were estimated by fluorescence microscopy. RESULTS: We showed that while undifferentiated hMGSCs displayed a profound elevation of [Ca(2+)]i after stimulation with N-methyl-D-aspartate (NMDA), this was lost following Notch-1 inhibition. Conversely, untreated hMGSCs did not respond to muscarinic receptor stimulation, whereas [Ca(2+)]i was increased in differentiated hMGSCs that expressed RGC precursor markers. Differentiated hMGSC-derived RGCs, but not undifferentiated hMGSCs, responded to stimulation by nicotine with a substantial rise in [Ca(2+)]i, which was inhibited by the α4ß2 and α6ß2 nicotinic receptor antagonist methyllycaconitine. Notch-1 attenuation not only caused a decrease in the gene expression of the Notch effector HES1 and increased expression of RGC markers, but also an increase in the gene and protein expression of α4 and α6 nicotinic receptor subunits. CONCLUSIONS: These observations suggest that in response to Notch-1 inhibition, hMGSCs differentiate into a population of RGCs that exhibit some of the functionality observed in differentiated RGCs.

Validation of the RCOphth and UKEGS glaucoma risk stratification tool 'GLAUC-STRAT-fast'.

BACKGROUND/AIMS: The aim of this study was to validate the Glaucoma Risk Stratification Tool (GLAUC-STRAT-fast) currently recommended by the Royal College of Ophthalmologists for the risk stratification of patients with glaucoma in the UK National Health Service Hospital Eye Service. METHODS: GLAUC-STRAT fast was applied to the LiGHT trial participants by risk-stratifying the worse eye of each patient at baseline and after 3 years of treatment. Metrics of disease severity or treatment intensity used for the validation were: increased number of monitoring visits or treatment escalations; needing a trabeculectomy; a reduction of >2 dB in visual field mean deviation (VF MD) during the monitoring period; identification of rapid VF loss on total (TD) and/or pattern deviation (PD). The proportion of eyes within each baseline stratum for each of the above markers was compared against the other strata, using a χ2 test for proportions. RESULTS: There was an association between the baseline stratification and the number of treatment escalations needed to maintain the eye-specific target intraocular pressure (p=0.001), the number of visits needed throughout the 3-year follow-up period (p=0.001), the need for trabeculectomy (p<0.001) and absolute loss of MD over the course of the monitoring period (p<0.001). The rate of VF progression was not associated with baseline risk stratification for TD or PD progression (p≥0.007, with Bonferroni correction). CONCLUSION: The GLAUC-STRAT fast tool is a useful tool for risk stratifying eyes with ocular hypertension or open angle glaucoma. Further research is needed to confirm and validate its applicability to more advanced glaucomas and generalisability to clinical use. TRIAL REGISTRATION NUMBER: The LiGHT trial is registered at controlled-trials.com (ISRCTN32038223).

Preserflo microshunt implant for the treatment of refractory uveitic glaucoma: 36-month outcomes.

OBJECTIVES: To determine 36-month efficacy and safety outcomes of the PRESERFLO Microshunt implant in the treatment of refractory uveitic glaucoma. METHODS: Consecutive patients with uncontrolled uveitic glaucoma despite maximum medical treatment received PRESERFLO Microshunt implant with mitomycin C (MMC) in a tertiary referral glaucoma practice. Efficacy and safety outcomes data were collected at month 6, 12, 24, and 36, postoperatively. The primary outcome was surgical success, defined as intraocular pressure (IOP) between 5 and 21 mmHg or > 20% reduction from baseline, and absence of criteria for surgical failure. Secondary outcomes were IOP, visual acuity (VA), use of glaucoma medical therapy, surgical complications, rate of reoperation for glaucoma. RESULTS: 21 eyes of 21 patients were included. The mean rate of success was 0.74 (95%CI 0.48-0.88), 0.68 (0.43-0.84), 0.47 (0.25-0.67), and 0.47 (0.25-0.67, at 6, 12, 24, and 36 months postoperatively, respectively. The mean IOP decreased by 30.7% (95% CI 13.7-47.7), 26.5% (95% CI 3.2-49.8), 33.5% (95% CI 21.8-45.3), and 30.1% (95% CI 7.2-52.9) from baseline at postoperative month 6, 12, 24, and 36, respectively (p < 0.001). The mean ± SD number of glaucoma medications decreased from 4.1 ± 0.9 to 0.9 ± 1.2 at the final follow up (p = 0.0005). No sight-threatening complications were reported by 36 months. CONCLUSIONS: Three-year results of the PRESERFLO Microshunt implant demonstrated favourable efficacy and safety profile in the treatment of refractory uveitic glaucoma.

Clinical risk stratification in glaucoma.

Glaucoma is the leading cause of preventable sight loss in the United Kingdom and the provision of timely glaucoma care has been highlighted as a significant challenge in recent years. Following a recent high-profile investigation, The Healthcare Safety Investigation Branch recommended the validation of risk stratification models to safeguard the vision-related quality of life of glaucoma patients. There continues to be no nationally agreed evidence-based risk stratification model for glaucoma care across the United Kingdom. Some models have used simple measures of disease staging such as visual field mean deviation as surrogates for risk, but more refined, individualised risk stratification models should include factors related to both visual impairment and visual disability. Candidate tools should also incorporate both ocular and systemic co-morbidities, rate of disease progression, visual needs and driving status and undergo clinical refinement and validation to justify implementation. The disruption to routine glaucoma care caused by the COVID-19 pandemic has only highlighted the importance of such risk stratification models and has accelerated their development, application and evaluation. This review aims to critically appraise the available evidence underpinning current approaches for glaucoma risk stratification and to discuss how these may be applied to contemporary glaucoma care within the United Kingdom. Further research will be essential to justify and validate the utility of glaucoma risk stratification models in everyday clinical practice.

Cell-Based Therapies for Glaucoma.

Glaucomatous optic neuropathy (GON) is the major cause of irreversible visual loss worldwide and can result from a range of disease etiologies. The defining features of GON are retinal ganglion cell (RGC) degeneration and characteristic cupping of the optic nerve head (ONH) due to tissue remodeling, while intraocular pressure remains the only modifiable GON risk factor currently targeted by approved clinical treatment strategies. Efforts to understand the mechanisms that allow species such as the zebrafish to regenerate their retinal cells have greatly increased our understanding of regenerative signaling pathways. However, proper integration within the retina and projection to the brain by the newly regenerated neuronal cells remain major hurdles. Meanwhile, a range of methods for in vitro differentiation have been developed to derive retinal cells from a variety of cell sources, including embryonic and induced pluripotent stem cells. More recently, there has been growing interest in the implantation of glial cells as well as cell-derived products, including neurotrophins, microRNA, and extracellular vesicles, to provide functional support to vulnerable structures such as RGC axons and the ONH. These approaches offer the advantage of not relying upon the replacement of degenerated cells and potentially targeting earlier stages of disease pathogenesis. In order to translate these techniques into clinical practice, appropriate cell sourcing, robust differentiation protocols, and accurate implantation methods are crucial to the success of cell-based therapy in glaucoma. Translational Relevance: Cell-based therapies for glaucoma currently under active development include the induction of endogenous regeneration, implantation of exogenously derived retinal cells, and utilization of cell-derived products to provide functional support.

Expansion of patient eligibility for virtual glaucoma clinics: a long-term strategy to increase the capacity of high-quality glaucoma care.

AIMS: The virtual glaucoma clinic (VGC) is a well-established diagnostic pathway for delivery of glaucoma care. Current UK national guidance recommends VGCs for patients with ocular hypertension, glaucoma suspects or early glaucoma. This study evaluates whether expanded eligibility criteria, including other glaucoma phenotypes and disease stages, can deliver safe and effective care with a positive patient experience. METHODS: Records of over 8000 patients were reviewed in order to determine suitability for VGC attendance using expanded eligibility criteria. Patients with three prior consecutive visits within the glaucoma service were included. Follow-up interval, clinic type, visual acuity (VA), intraocular pressure (IOP) and visual field performance were recorded. Patient satisfaction was recorded for a sample of 118 patients. RESULTS: 2017 patients over 31 months were included. Two-thirds of eyes had ocular comorbidities, a fifth of eyes had undergone prior cataract surgery and 10% of eyes had undergone a prior laser treatment for glaucoma. After three visits, 32% of patients remained in the VGC, 42% were seen in face-to-face clinics and 25% were discharged. There were no clinically significant changes in VA, IOP and visual field performance during follow-up. 72% of patients expressed a preference to continue their care within VGCs. CONCLUSIONS: This study demonstrates that VGCs with expanded patient eligibility criteria can deliver high-quality glaucoma care that is safe, effective and with high levels of patient satisfaction. This approach provides a long-term solution to adapt delivery of glaucoma care to our expanding and ageing population.

Effect of trabeculectomy on the rate of progression of visual field damage.

OBJECTIVES: This study quantifies the effect of trabeculectomy on the rate of progression (RoP) of visual field (VF) damage utilising pre- and post-operative visual function as the outcome instead of surrogate outcomes of success. METHODS: Clinical and VF data from 199 sequential patients who underwent trabeculectomy between 2015 and 2016 were extracted from the network of sites of Moorfields Eye Hospital NHS Foundation Trust. Of these, we analysed 80 eyes of 74 patients who met our inclusion criteria of at least three reliable VFs before and after surgery (false positive rate <15%). The change in mean RoP (dB/year) was tested using point-wise sensitivity values through a mixed effect model with random effects on both intercepts and slopes. A broken-stick regression of sensitivity over time, with a breakpoint at the day of surgery, modelled the individual change in RoP. RESULTS: We analysed 10 [9,12] VFs per subject (Median [Interquartile Range]). At surgery, the age was 67 [57, 72] years, mean deviation was -10.84 [-14.7, -5.6] dB and the IOP was 18 [15, 20] mmHg. One year after surgery, the IOP was 10 [8,13] mmHg (p = 0.002). Mean RoP before surgery was -0.94 [-1.20, -0.69] dB/year (Mean [95% credible intervals]) and it was slowed down by 0.62 [0.26, 0.97] dB/year (p < 0.001) after surgery. CONCLUSIONS: Trabeculectomy leads to a significant reduction in the RoP of VF loss postoperatively.

Design and Conduct of Randomized Clinical Trials Evaluating Surgical Innovations in Ophthalmology: A Systematic Review.

PURPOSE: Surgical innovations are necessary to improve patient care. After an initial exploratory phase, novel surgical technique should be compared with alternative options or standard care in randomized controlled trials (RCTs). However, surgical RCTs have unique methodological challenges. Our study sought to investigate key aspects of the design, conduct, and reporting of RCTs of novel surgeries. DESIGN: Systematic review. METHODS: The protocol was prospectively registered in PROSPERO (CRD42021253297). RCTs evaluating novel surgeries for cataract, vitreoretinal, glaucoma, and corneal diseases were included. Medline, EMBASE, Cochrane Library, and Clinicaltrials.gov were searched. The search period was January 1, 2016, to June 16, 2021. RESULTS: A total of 52 ophthalmic surgery RCTs were identified in the fields of glaucoma (n = 12), vitreoretinal surgery (n = 5), cataract (n = 19), and cornea (n = 16). A description defining the surgeon's experience or level of expertise was reported in 30 RCTs (57%) and was presented in both control and intervention groups in 11 (21%). Specification of the number of cases performed in the particular surgical innovation being assessed prior to the trial was reported in 10 RCTs (19%) and an evaluation of quality of the surgical intervention in 7 (13%). Prospective trial registration was recorded in 12 RCTs (23%) and retrospective registration in 13 (25%); and there was no registration record in the remaining 28 (53%) studies. CONCLUSIONS: Important aspects of the study design such as the surgical learning curve, surgeon's previous experience, quality assurance, and trial registration details were often missing in novel ophthalmic surgical procedures. The Idea, Development, Exploration, Assessment, Long-term follow-up (IDEAL) framework aims to improve the quality of study design.

Optic Nerve Head Gene Transcription Sequelae to a Single Elevated IOP Exposure Provides Insights Into Known Responses to Chronically Elevated IOP.

Purpose: To clarify the optic nerve head (ONH) gene expression responses associated with a single, axon-damaging exposure to elevated IOP in relation to the composite cellular events previously identified in models of chronically elevated IOP. Methods: Anesthetized rats were exposed unilaterally to an 8-hour pulse-train controlled elevation of IOP (PT-CEI) at 60 mm Hg, while others received normotensive CEI at 20 mm Hg. ONH RNA was harvested at 0 hours and 1, 2, 3, 7, and 10 days after either CEI and from naïve animals. RNA sequencing was performed to analyze ONH gene expression. DAVID Bioinformatics tools were used to identify significant functional annotation clusters. Gene function was compared between PT-CEI and two models of chronic ocular hypertension from the literature. Results: The number of significantly changed genes peaked immediately (n = 1354) after PT-CEI (0 hours). This was followed by a lull (<4 genes per time point) at 1 and 2 days after PT-CEI. Gene activity increased again at 3 days (136 genes) and persisted at 7 (78 genes) and 10 (339 genes) days. Significant gene functional categories included an immediate upregulation of Defense Response at 0 hours, followed by upregulation in Cell Cycle, a reduction in Axonal-related genes at 3 to 10 days, and upregulation of Immune Response-related genes at 10 days following PT-CEI. The most commonly upregulated gene expression across our PT-CEI study and two chronic models of ocular hypertension were cell cycle related. Conclusions: The PT-CEI model places in sequence ONH gene expression responses previously reported in models with chronically elevated IOP and may provide insights into their role in optic nerve damage.

Comparing the Effectiveness of Phacoemulsification + Endoscopic Cyclophotocoagulation Laser versus Phacoemulsification Alone for the Treatment of Primary Open Angle Glaucoma in Patients with Cataract (CONCEPT): Study Methodology.

OBJECTIVE: To describe the methodology of the Comparing the Effectiveness of Phacoemulsification + Endoscopic Cyclophotocoagulation Laser and Phacoemulsification Alone for the Treatment of Primary Open Angle Glaucoma in Patients with Cataract (CONCEPT) study, a randomized controlled trial. DESIGN: Double-masked, randomized controlled trial. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Participants will be recruited from 5 United Kingdom-based centers. One hundred and sixty eyes with a diagnosis of primary open-angle glaucoma and visually significant cataract will be included. Eighty eyes will be randomized to undergo cataract surgery alone and eighty to undergo cataract surgery with endoscopic cyclophotocoagulation (ECP). METHODS: The baseline diurnal washout intraocular pressure (IOP) will be measured. The participants will be randomized to undergo cataract surgery alone or cataract surgery with ECP upon completion of uncomplicated cataract surgery. At the 1- and 2-year post surgery follow-up visits, the measurements of washout diurnal IOP will be repeated. MAIN OUTCOME MEASURES: Diurnal washout IOP, use of glaucoma medications, and adverse events. CONCLUSIONS: We described the methodology of the first randomized controlled trial comparing cataract surgery alone with cataract surgery combined with ECP in the context of patients with primary open-angle glaucoma and symptomatic cataract. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Glaucoma Drainage Device Surgery Outcomes in Children With Uveitic Glaucoma.

PURPOSE: To evaluate outcomes of glaucoma drainage device (GDD) implantation children with uveitic glaucoma. DESIGN: Retrospective interventional case series. METHODS: Success was defined as intraocular pressure (IOP) ≥5 and ≤21 mm Hg. Failure was defined at final follow-up when the IOP was outside the success criterion, and visual function was no perception of light or if further glaucoma surgery (excluding removal of intraluminal stent suture or needling) was required. RESULTS: Fifty eyes of 36 children with uveitic glaucoma underwent GDD implantation. Mean age at surgery was 10.1±3.1 years (range 5-17) with a mean follow-up of 113±61 months (range 8-228). Mean cumulative probabilities of success (95% CI) were 0.98 (0.86-1.00) at 1 year, 0.87 (0.73-0.94) at 5 years, and 0.59 (0.32-0.78) at 15 years. Fourteen tubes were classified as failed, with 12 due to uncontrolled IOP (11 eyes required a second GDD); 1 eye, removal of the tube due to plate exposure; and 1 eye, lost light perception. Postoperative complications occurred in 36% of patients and included hypotony (22%), tube exposure (6%), tube obstruction (4%), corneal decompensation (2%), and cystoid macular edema (2%). Visual acuity remained stable (preoperation 0.35±0.42 vs postoperation 0.45±0.67, P = .49). IOP was significantly reduced from 31.4±7.5 mm Hg to 14.4±5.1 mm Hg (P < .0001) as were the number of glaucoma medications 3.5±1.0 vs 1.1±1.3 (P < .0001). CONCLUSIONS: Refractory pediatric uveitic glaucoma can be treated successfully by GDD implantation. Further interventions to manage consequences of glaucoma or the underlying disease are common, and visual function is maintained in the majority of cases.