Differential effects of acetylsalicylic acid and mitomycin C on cytokine-induced Tenon's capsule myofibroblast transdifferentiation and activity: Implications for glaucoma surgery.

Inflammation-driven scarring is a major contributor to surgical failure after subconjunctival bleb forming glaucoma surgery. The current gold standard anti-scarring adjuvant mitomycin C (MMC) has variable effectiveness and is associated with significant risks. Acetylsalicylic acid (ASA), when delivered locally, repurposes the typically pro-inflammatory cyclooxygenase (COX-2) signaling for the resolution of inflammation and mitigating inflammation-mediated fibrosis. The aim of this study is to compare the effects of ASA and MMC in an in vitro model of subconjunctival scarring. Glaucoma patient-derived Tenon's capsule fibroblasts (HTCFs) were treated with TGFß1 (2 ng/mL) plus or minus ASA (1600 µg/ml), or MMC (0.05, 0.1, 0.2 mg/mL). In vitro collagen contraction, MTT, LDH, immunofluorescence, and Western blot assays were performed. To elucidate the mechanistic effects of ASA in TGFß1-induced HTCFs, liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to identify and measure pro-inflammatory and pro-resolving lipid mediator secretion. ASA was at least as effective as MMC in reducing TGFß1-induced HTCF-mediated collagen contraction, metabolic activity, and pro-fibrotic protein expression, with less cytotoxicity. Within cytokine-activated HTCFs, ASA significantly impaired secretion of pro-inflammatory lipid mediators prostaglandin E2 and 6-keto-prostaglandin F1α and significantly increased secretion of the pro-resolving mediators 5-hydroxyeicosatetraenoic acid (HETE), 15-HETE and 18-hydroxyeicosapentaenoic acid (HEPE). ASA reduces cytokine-induced myofibroblast transdifferentiation in HTCFs, being non-inferior to MMC in vitro. ASA's effects are associated with a unique lipid mediator expression profile, suggesting that the ASA-induced resolution of inflammation may be a promising strategy to mitigate inflammation-mediated scarring and could offer a novel alternative as a surgical adjuvant.

Differential effects of dexamethasone and indomethacin on Tenon's capsule fibroblasts: Implications for glaucoma surgery.

Dysregulated wound healing and subsequent fibrosis represents the most common cause of failure in glaucoma filtration surgery. Primary means to prevent this outcome are the anti-metabolite surgical adjuvants, however, topical corticosteroids are commonly used postoperatively to permit further control of wound healing and development of the filtration bleb. Unfortunately, they carry important side effects such as raised intraocular pressure, cataract and increased infection risk. Non-steroidal anti-inflammatory drugs (NSAIDs) show promising results in clinical trials as an alternative wound modulatory drug. NSAIDs exhibit non-inferiority to steroids in terms of post-operative intraocular pressure control and secondary IOP lowering interventions, however there is little known about the differing effects these drugs exert on human Tenon's capsule fibroblast (HTCF) mediated wound healing. The purpose of this study was to assess the individual effects of dexamethasone and indomethacin on the extracellular matrix modifying actions of HTCFs in vitro. To this end, HTCFs were cultured in 3D collagen matrices as well as in 2D monolayers and exposed to clinically relevant concentrations of dexamethasone or indomethacin for up to seven days. HTCF-mediated wound healing functions were assayed through collagen matrix contraction, extracellular matrix morphology, estimation of HCTF proliferation and differentiation into myofibroblasts within the collagen matrices, as well as western blot. Both drugs significantly reduced HTCF-mediated collagen contraction relative to control however there was a significant trend towards greater inhibition with indomethacin exposure compared to dexamethasone. Indomethacin exposure significantly reduced HTCF-mediated collagen remodelling activity compared vehicle control, whereas dexamethasone was unable to reduce remodelling activity at any of the studied exposures. Both drugs reduced myofibroblast differentiation, however indomethacin alone demonstrated an inhibitory effect on final cell number relative to control whereas dexamethasone had no significant effect at any studied exposure. These findings demonstrate that both steroidal and NSAID treatment can mitigate HTCF-mediated collagen contraction and αSMA expression. However, NSAIDs may function to better impede HTCF proliferation and remodelling activity. Taken in the context of previous glaucoma surgical trials, NSAIDs appear to be a viable alternative to steroids for post-operative wound modulation.

Mitomycin C 0.2 mg/ml vs. Mitomycin C 0.4mg/ml during the implantation of an ab externo SIBS microshunt: A mega-analysis.

PURPOSE: To compare the effectiveness and adverse event profile of standalone SIBS microshunt implantation with adjunct MMC 0.2 mg/ml and MMC 0.4 mg/ml. DESIGN: Mega-analysis using individual patient data from international prospective and retrospective clinical studies. STUDY POPULATION: Patients with glaucoma who underwent implantation of a SIBS microshunt with MMC as a standalone procedure. METHODS: A comparison of eyes that received MMC 0.2 mg/ml or 0.4 mg/ml MAIN OUTCOMES MEASURES: Primary outcome was complete success defined as the proportion of eyes at one year with all of the following: (1) no two consecutive IOPs > 17 mmHg; (2) no clinical hypotony (3) ≥20% IOP reduction from baseline and (4) no use of glaucoma medications. Secondary outcomes included IOP thresholds of 12 mmHg,14 mm Hg and 21mmHg, median IOP, number of medications, risk factors for failure, interventions, adverse events, and reoperations. RESULTS: At 1 year, the complete success rate was significantly higher (71.3% vs 50.46%, p<0.001) and the median IOP significantly lower (13.0 vs. 14.2 mmHg, p<0.05) in the MMC 0.4 mg/ml group. MMC 0.2 mg/ml was found to be a significant risk factor for failure (HR 1.75 95%CI 1.14 to 2.67). Needling and surgical revision occurred at a lower rate in the MMC 0.4 mg/ml group (7% vs. 18.8%, p= 0.002 and 4.3% vs.13.7% p= 0.0087, respectively). Adverse events occurred at a similar frequency in both groups (26.6% MMC 0.2 mg/ml vs. 29.6% MMC 0.4 mg/ml, p=0.46), most of which were early and transient. CONCLUSION: SIBS microshunt implantation with MMC 0.4 mg/ml resulted in a higher success rate with greater IOP reduction compared to MMC 0.2 mg/ml. Higher MMC concentration was not associated with increased serious adverse events.

Development and Verification of a Novel Three-Dimensional Aqueous Outflow Model for High-Throughput Drug Screening.

Distal outflow bleb-forming procedures in ophthalmic surgery expose subconjunctival tissue to inflammatory cytokines present in the aqueous humor, resulting in impaired outflow and, consequently, increased intraocular pressure. Clinically, this manifests as an increased risk of surgical failure often necessitating revision. This study (1) introduces a novel high-throughput screening platform for testing potential anti-fibrotic compounds and (2) assesses the clinical viability of modulating the transforming growth factor beta-SMAD2/3 pathway as a key contributor to post-operative outflow reduction, using the signal transduction inhibitor verteporfin. Human Tenon's capsule fibroblasts (HTCFs) were cultured within a 3D collagen matrix in a microfluidic system modelling aqueous humor drainage. The perfusate was augmented with transforming growth factor beta 1 (TGFß1), and afferent pressure to the tissue-mimetic was continuously monitored to detect treatment-related pressure elevations. Co-treatment with verteporfin was employed to evaluate its capacity to counteract TGFß1 induced pressure changes. Immunofluorescent studies were conducted on the tissue-mimetic to corroborate the pressure data with cellular changes. Introduction of TGFß1 induced treatment-related afferent pressure increase in the tissue-mimetic. HTCFs treated with TGFß1 displayed visibly enlarged cytoskeletons and stress fiber formation, consistent with myofibroblast transformation. Importantly, verteporfin effectively mitigated these changes, reducing both afferent pressure increases and cytoskeletal alterations. In summary, this study models the pathological filtration bleb response to TGFß1, while demonstrating verteporfin's effectiveness in ameliorating both functional and cellular changes caused by TGFß1. These demonstrate modulation of the aforementioned pathway as a potential avenue for addressing post-operative changes and reductions in filtration bleb outflow capacity. Furthermore, the establishment of a high-throughput screening platform offers a valuable pre-animal testing tool for investigating potential compounds to facilitate surgical wound healing.

ALK5 Inhibition of Subconjunctival Scarring From Glaucoma Surgery: Effects of SB-431542 Compared to Mitomycin C in Human Tenon's Capsule Fibroblasts.

Purpose: The gold standard for managing postoperative ocular fibrosis in glaucoma surgery is the chemotherapeutic mitomycin C (MMC) despite its association with significant adverse effects. This study compares in vitro the antifibrotic efficacy and cytotoxicity of the small-molecule TGFß1 inhibitor SB-431542 (SB) to MMC. Methods: To measure collagen contraction, human Tenon's capsule fibroblasts (HTCFs) embedded in a three-dimensional collagen lattice were exposed to 0.2 mg/mL MMC or 20 µM SB followed by incubation with 2 ng/mL TGFß1. Total protein extracted from experimentally treated HTCFs underwent immunoblotting for α-smooth muscle actin (α-SMA), matrix metallopeptidase 9 (MMP-9), and EDA splice-variant fibronectin (EDA-FN) expression. Cytotoxicity and cell metabolism were assessed using LIVE/DEAD staining, lactate dehydrogenase (LDH) assay, and methylthiazole tetrazolium (MTT) assay. Results: Collagen lattice contraction in TGFß1-induced HTCFs was significantly lowered by SB and MMC. Pretreatment with SB and MMC significantly lowered protein expression of α-SMA, MMP-9, and EDA-FN in HTCFs relative to TGFß1 alone. HTCF viability in collagen lattices was significantly reduced with MMC pretreatment but not SB pretreatment. MMC-pretreated HTCFs had a significant increase in LDH release after 3 hours and a decrease in MTT activity after 20 minutes, while SB-pretreated HTCFs showed no significant changes via MTT or LDH assay during the same treatment period. Conclusions: SB shows comparable efficacy to MMC in reducing expression of fibrosis-promoting proteins in HTCFs and in vitro scarring activity. SB distinguishes itself from MMC by exhibiting less cytotoxicity in both two-dimensional and three-dimensional in vitro assays. Translational Relevance: This study demonstrates in vitro the potential of SB as a safer alternative ocular antifibrotic agent.

All Consecutive Ab Externo SIBS Microshunt Implantations With Mitomycin C: One-Year Outcomes and Risk Factors for Failure.

PURPOSE: To present the effectiveness, risk factors for surgical failure, and adverse events over 12 months in a consecutive diverse cohort of glaucoma patients who underwent solo or combined ab externo SIBS microshunt with mitomycin C (MMC) with or without previous subconjunctival surgery. DESIGN: Retrospective, consecutive, interventional case series. METHODS: Consecutive glaucomatous eyes on maximally tolerated medical therapy received ab externo SIBS microshunt with MMC implantation as a solo or combined procedure with phacoemulsification from July 2015 to January 2020. The primary outcome was the proportion of eyes at 12-months with the following: (1) no 2 consecutive intraocular pressures (IOPs) >17 mm Hg or clinical hypotony, without (complete success) or with (qualified success) glaucoma medications; and (2) ≥20% reduction from baseline IOP. Secondary outcomes included upper IOP thresholds of 14 and 21 mm Hg with and without a 20% IOP reduction from baseline, median IOP, medications, risk factors for failure, postoperative interventions, complications, and reoperations. RESULTS: A total of 436 eyes underwent surgery; 86 (20%) combined with phacoemulsification, 127 (29%) in eyes with refractory glaucoma, and 234 (51%) stand-alone procedures in non-refractory eyes. Complete success (6-17 mm Hg with no medications) was achieved in 64.0% of combined eyes, 58.1% of refractory eyes, and 74.8% of stand-alone non-refractory eyes; and qualified success rates (6-17 mm Hg with medications) were 90.7%, 84.7%, and 92.4% of eyes, respectively. At 12 months, 67% of eyes were medication free. Significant risk factors for failure included combined procedures in refractory eyes (hazard ratio [HR] = 3.2; 95% CI = 1.4-7.4), receiving <0.4 mg/mL of MMC (HR = 2.2; 95% CI = 1.6-3.1), refractory eyes (HR = 1.7; 95% CI = 1.2-2.5), combined procedures (HR = 1.6; 95% CI = 1.0-2.5), and each additional baseline medication class (HR = 1.3; 95% CI = 1.1-1.5). Postoperative complications occurred in 31% of eyes, and more often in those receiving ≥0.4 mg/mL MMC (odds ratio [OR] = 2.2, 95% CI 1.2-3.8). Needling occurred in 12% of eyes, with significantly higher frequency in refractory eyes (23%) and combined procedures (13%) compared to stand-alone (7%; P < .001). Revisions and reoperations occurred in 4% and 1.4% of eyes, respectively. CONCLUSIONS: The 1-year follow-up data from this large and diverse cohort support promising rates of qualified and complete surgical success with decreased medication burden and few postoperative complications and interventions. Combined phacoemulsification, refractory glaucoma, and receiving <0.4mg/mL MMC were associated with reduced surgical success rates.

Ab Externo SIBS Microshunt with Mitomycin C for Open-Angle Glaucoma: Three-Year Results as a Primary Surgical Intervention.

PURPOSE: To determine the effectiveness, risk factors for surgical failure, and adverse events in a large cohort of patients receiving stand-alone ab externo poly(styrene-block-isobutylene-block-styrene) (SIBS) microshunt implantation with mitomycin C (MMC) over 3 years of follow-up. DESIGN: Retrospective, interventional case series. PARTICIPANTS: Glaucomatous eyes on maximally tolerated medical therapy with no previous subconjunctival glaucoma surgery. METHODS: Records of eyes that underwent ab externo SIBS microshunt with MMC between July 2015 and November 2017 were reviewed. Data from all follow-up visits were utilized and included intraocular pressure (IOP), medication use, postoperative interventions, complications, and reoperations. MAIN OUTCOME MEASURES: The primary outcome was proportion of eyes at 3 years with (1) no 2 consecutive IOPs > 17 mmHg (or < 6 mmHg with > 2 lines of vision loss from baseline); (2) ≥ 20% reduction from baseline IOP; and (3) using no glaucoma medications (complete success). Secondary outcomes included 14 and 21 mmHg upper IOP thresholds with and without ≥ 20% IOP reduction from baseline, qualified success (with glaucoma medications), risk factors for failure, median IOP/medications, postoperative interventions, complications, and reoperations. RESULTS: One hundred fifty-two eyes from 135 patients were included. Complete and qualified success was achieved in 55.6% and 74.8% of eyes, respectively. Time to first glaucoma medication use was a median of 16.9 (interquartile range [IQR], 12.1-34.1) months; however, 59.4% of eyes remained medication free at 3 years. Significant risk factors for failure included receiving < 0.4 mg/ml of MMC (adjusted hazard ratio [HR], 2.42; 95% confidence interval [CI], 1.44-4.05) and baseline IOP < 21 mmHg (adjusted HR, 1.79; 95% CI, 1.03-3.13). The most common complications were choroidal detachment, hyphema, and anterior chamber shallowing, occurring in 7%, 5%, and 5% of eyes, respectively. The needling rate was 15.1%, with significantly higher frequency for baseline IOP > 21 mmHg (HR, 3.21; 95% CI, 1.38-7.48). Revisions occurred in 7% of eyes and reoperations in 2.6%. Eyes receiving < 0.4 mg/ml of MMC underwent more revisions (odds ratio, 4.9; 95% CI, 1.3-18.3). CONCLUSIONS: Three-year follow-up data from this large cohort continues to support promising rates of qualified and complete success, with decreased medication burden postoperatively and few postoperative complications and interventions. Comparisons to other filtering surgeries will further facilitate integration of the SIBS microshunt into the surgical treatment paradigm. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A Comparison of Diagnostic Accuracy of Imaging Modalities to Detect Optic Disc Drusen: The Age of Enhanced Depth Imaging Optical Coherence Tomography.

PURPOSE: To identify the most accurate diagnostic imaging modality to detect optic disc drusen (ODD) between B-scan ultrasonography (US), fundus photography, fundus autofluorescence (FAF), and enhanced depth imaging optical coherence tomography (EDI-OCT). DESIGN: Comparative diagnostic analysis. METHODS: Two hundred five eyes of 105 patients referred to 2 tertiary care neuro-ophthalmology clinics for suspected ODD were recruited: 108 eyes had ODD and 97 did not have ODD. All eyes received a full in-person ophthalmic exam with 3D view of the optic nerve and all 4 imaging modalities. Images were independently reviewed by 3 masked neuro-ophthalmologists to determine the presence or absence of ODD. Final interpretation was made through consensus. The reference standard was defined as the attending ophthalmologist's clinical judgement based on open chart review, with access to all image modalities and clinical information, including disease course. Main outcome measures were sensitivity, specificity, accuracy, and precision for each imaging modality. Examiner confidence was quantified as the proportion of eyes in which the reviewers were certain of their decision. RESULTS: The EDI-OCT had the highest sensitivity and accuracy (95%, 97%) to detect ODD, compared with FAF (84%, 92%), US (74%, 86%), and fundus photography (38%, 66%), respectively. All image modalities had high specificity (> 97%) and precision (> 93%). The EDI-OCT also had highest examiner confidence (96%) compared with all others (88%). CONCLUSIONS: Among all modalities, EDI-OCT was the imaging modality with the highest diagnostic utility for the detection of ODD and should be considered as the preferred initial diagnostic modality.

Understanding Inflammation-associated Ophthalmic Pathologies: A Novel 3D Co-culture Model of Monocyte-myofibroblast Immunomodulation.

PURPOSE: Inflammation is associated with, and may be causal of, a variety of ophthalmic pathologies. These pathologies are currently difficult to model in vitro because they involve complex interactions between the innate immune system, stromal cells, and other cells that normally maintain ocular tissue homeostasis. Using transscleral drainage channel fibrosis after glaucoma surgery as an example of inflammation-associated ocular fibrosis, we have assessed a simple but novel 3D cell culture system designed to reveal the immunomodulatory impacts of ocular connective tissue cells on monocytes, a major cellular component of the circulating immune system. METHODS: Primary human Tenon's capsule fibroblasts derived from five unrelated patients were activated into myofibroblasts in 3D collagen matrices under isometric tension, with and without exposure to an inflammatory cytokine-enhanced milieu, and co-cultured with an immortalized human monocyte cell line (THP-1 cells). Quantitative PCR analyses were performed on 8 candidate genes to assess the impacts of inflammatory cytokines on the myofibroblasts and the monocytes in mono-cultures and compared to cells in co-culture to clearly distinguish any co-culture-induced impacts on gene expression. RESULTS: Our data indicate that both Tenon's capsule myofibroblasts in 3D mono-culture and THP-1 monocytes in suspension mono-culture were responsive to inflammatory cytokine stimuli. Co-culture with Tenon's capsule myofibroblasts significantly modulated the gene expression responses of THP-1 monocytes to inflammatory cytokine stimulation, indicative of an immunomodulatory "feedback" system between these cell types. CONCLUSION: Our findings provide proof of principle for the use of simple 3D co-culture systems as a means to enhance our understanding of ocular stromal cell interactions with cells of the innate immune system and to provide more informative in vitro models of inflammation-associated ophthalmic pathologies.

Impact of Inhaled and Intranasal Corticosteroids Exposure on the Risk of Ocular Hypertension and Glaucoma: A Systematic Review and Meta-Analysis.

Purpose: Starting in 2019, the Global Initiative for Asthma recommended the use of inhaled corticosteroids (ICS) as part of reliever combination therapy in patients 12 years of age and older, thus dramatically increasing the population exposure to ICS. ICS and intranasal corticosteroids (INS) are commonly used for a variety of respiratory diseases. Chronic steroid use is a well-known risk factor for elevated intraocular pressure (IOP) and glaucoma regardless of route of administration. This study aimed to determine the reported risk of glaucoma, ocular hypertension (OHT) and IOP elevation associated with ICS and INS use. Materials and Methods: Systematic literature search in MEDLINE, EMBASE, Cochrane, CINAHL, BIOSIS, and Web of Science databases from the date of inception identified studies that assess ocular outcomes related to glaucoma in ICS and INS users. Study selection, risk of bias assessment and data extraction were done independently in duplicate. Meta-analysis assessed glaucoma incidence, OHT incidence and IOP changes in patients using ICS and INS. Study adhered to PRISMA guidelines. Study protocol was registered with PROSPERO: CRD42020190241. Results: Qualitative and quantitative analyses included 65 and 41 studies, respectively. Incidence of glaucoma was not significantly different in either ICS or INS users compared to control over 45,457 person-years of follow-up. Similarly, no significant difference in OHT incidence over 4431 person-years was detected. In studies reporting IOP, a significantly higher IOP was observed (0.69 mmHg) in 857 ICS or INS users compared to 615 controls. However, no significant increase in IOP was observed within ICS or INS users when compared to pre-treatment baseline. Conclusion: Overall, use of ICS or INS does not significantly increase the incidence of glaucoma or OHT. However, ICS and INS patients had significantly higher IOPs compared to untreated patients. Awareness of these findings is significant in care of patients with additional risk factors for glaucoma.

Successes and shortfalls of community Plusoptix photoscreening: results from the iSee study in Southwestern Ontario.

OBJECTIVE: The purpose of this work is to provide the final results from a community-wide photoscreening program in Southwestern Ontario for children aged 18 to 72 months, and to estimate the prevalence of amblyogenic risk factors in this population. STUDY DESIGN: Prospective, multisite photoscreening program. PARTICIPANTS: 5959 children aged 18-72 months were recruited and screened in Southwestern Ontario at 210 locations over a period of 3 years and 4 months. METHODS: Ophthalmic screening examinations were performed with the Plusoptix S12 photoscreener. The threshold for the referral criteria used was the manufacturer's criteria on receiver operating characteristics 4. RESULTS: The screening was negative in 5386 children (90.4%), positive in 403 (6.8%), and unreadable in 170 (2.9%); 42% of all screened children were ≤36 months old. The estimated amblyogenic risk factor prevalence of anisometropia was 4.0%, astigmatism was 3.1%, hyperopia was 1.1%, myopia was 0.4%, and strabismus was 0.4%. Of the 403 referred children, 99 (24.5%) completed a formal eye examination based on the responses returned to the study site. CONCLUSIONS: This is the first Canadian study that provides data on amblyogenic risk factors based on a volunteer-led photoscreening program. Photoscreening is an effective screening tool, particularly for pre-school-aged children; however, the lack of mandatory follow-up to ensure that children receive proper treatment based on cycloplegic refraction reduces the efficacy of screening.

Rapid visual field progression in a patient with glaucoma as the presenting manifestation of sarcoidosis.

PURPOSE: To report a case of accelerated visual field progression secondary to a new orbital apex lesion in a patient with a longstanding history of fatigue and cough. OBSERVATIONS: A 73-year-old myopic female with known open angle glaucoma presented with accelerated unilateral visual field progression. Maximally tolerated medical therapy was instituted over a period of 1-2 years with imminent discussions of surgical intervention. Around this time the patient reported worsening cough and fatigue, which were initially attributed to glaucoma medication side effects. Consideration of the patient's remote history of melanoma and the current asymmetry of the visual field progression triggered a computerized tomography (CT) scan of the orbits as part of the management. An orbital apex lesion was discovered, raising suspicion for metastatic melanoma, and restaging CT imaging uncovered renal, hepatic, and mediastinal masses. Unexpectedly, biopsies revealed non-necrotizing granulomatous inflammatory processes consistent with a diagnosis of sarcoidosis. It is perhaps noteworthy that the patient had received interferon therapy for management of her melanoma; previous reports have associated interferon exposure with subsequent sarcoid disease, regardless of duration of therapy or elapsed time since exposure. CONCLUSIONS AND IMPORTANCE: Although rare, sarcoidosis can occur virtually anywhere in the body, including the orbital apex. Its common early symptoms, fatigue and cough, are insidious and seen frequently in this patient's age group and medication side effect profile. It is important to maintain an appropriate index of suspicion when monitoring atypical visual field progression in a patient with glaucoma. In this case, imaging, subsequent biopsy, and a multi-specialty team were integral to this patient's diagnosis and management.

Trends in Glaucoma Filtration Procedures: A Retrospective Administrative Health Records Analysis Over a 13-Year Period in Canada.

BACKGROUND: Glaucoma surgical management has evolved significantly with the introduction of minimally invasive glaucoma surgery. Our aim was to evaluate trends in Canadian glaucoma surgery billing code usage as a surrogate index of the current impact of this new technology in Canada's publicly funded health-care system. METHODS: Retrospective administrative health records analysis of all patients who underwent a publicly funded glaucoma filtration procedure from January 2003 to December 2016 in the 6 largest Canadian provinces. The frequency of glaucoma-related procedures was adjusted against primary open-angle glaucoma prevalence data. Frequency of all glaucoma filtration procedures with and without implantation of a drainage device in each province per year is reported. RESULTS: Nationwide, glaucoma filtration procedures per 1000 primary open-angle glaucoma patients per year remained constant, with increased drainage device implantation over time (P<0.0001). Ontario and Nova Scotia mirrored the overall population. British Columbia and Saskatchewan showed increased rates of glaucoma filtration surgery, with increased drainage device implantations. In Quebec, overall filtration surgery decreased, while the rate of device implantation increased (p<0.0001). Alberta showed a decline in filtration surgery and device implantations from 2003 to 2008, and then increased thereafter. CONCLUSION: Over the study period, there was a distinct trend towards billing code usage for implanted devices. Challenges encountered during this investigation highlight the need for identifiers in provincial health databases to accommodate the introduction of novel technologies. The absence of specific billing codes for newer technologies prevents accurate analyses of impact, utilization, efficacy and cost implications in contemporary patient management.

The Pro-Fibrotic Behavior of Human Tenon's Capsule Fibroblasts in Medically Treated Glaucoma Patients.

PURPOSE: The aim of this study was to compare human Tenon's capsule fibroblasts (HTCFs) obtained from patients who received medical therapy for glaucoma (glaucomatous patients) and patients not treated for glaucoma (non-glaucomatous patients) in terms of wound healing and fibrosis. PATIENTS AND METHODS: Bioartificial tissues (BATs) were generated using primary HTCF-populated collagen lattices. Pro-fibrotic gene expression within HTCFs was compared between glaucomatous patients and non-glaucomatous patients after BAT culture. The BATs were also assessed regarding fibroblast-myofibroblast transition, collagen remodeling and collagen contraction using alpha-smooth muscle actin immunohistochemistry, picrosirius red staining and collagen contraction assays, respectively. RESULTS: Pro-fibrotic gene expression in BAT-cultured HTCFs derived from glaucomatous patients was significantly increased compared to non-glaucomatous patients. BATs imbued with HTCFs collected from glaucomatous patients exhibited a greater proportion of myofibroblasts as well as increased collagen contraction/remodeling compared to HTCFs isolated from non-glaucomatous patients. CONCLUSION: HTCFs from glaucomatous and non-glaucomatous patients differ in the expression of genes involved in fibrosis, proportion of fibroblasts undergoing transdifferentiation into myofibroblasts, contractile properties and collagen remodeling. These results suggest that for any number of reasons, at a cellular level, patients who received medical therapy for glaucoma have eyes primed for fibrosis.

Secondary surgical intervention after primary glaucoma filtration surgery: an Ontario population-based study.

OBJECTIVE: To identify factors associated with secondary surgical intervention after glaucoma filtration surgery. DESIGN: Population-based retrospective cohort. METHODS: Patient records with billing claims for a primary glaucoma filtration surgery occurring between April 2003 and March 2015 were identified. Each identified record was examined for instances of secondary glaucoma surgeries within the patient's first postoperative year. Baseline characteristics of patients who required secondary surgical intervention were compared with those who did not. A multivariable Cox proportional hazards model was used to calculate hazard ratios. RESULTS: Within a cohort of 10,097 patients, 349 (3.46%) underwent a secondary surgical intervention within the first postoperative year. Interventions were less frequent after surgeries that included an indwelling drainage device (HR=0.58 95% CI, 0.37-0.89), phacoemulsification (HR=0.33, 0.21-0.52), or both (HR=0.09, 0.03-0.31). Patients with preoperative aminoglycoside and mydriatic exposure had significantly increased risk of secondary surgical intervention (HR=3.19, 1.89-5.36) and (HR=2.32, 1.49-3.61). Patients who underwent surgery on their contralateral eye experienced secondary surgical interventions more frequently: 7.44 per 10,000 person-days (versus 1.18 per 10,000 person-days, p < 0.0001). No significant differences in the rates of secondary surgical intervention were observed for patients taking different classes of glaucoma medications or those exposed to higher amounts of benzalkonium chloride. CONCLUSIONS: In Ontario, the overall rates of secondary surgical interventions in the first postoperative year are low but significantly higher in certain patient populations. Further work is required to address the higher rate of secondary surgical intervention in patients with a history of certain perioperative eye drop medications and those who require sequential-bilateral procedures.

Optical coherence tomography for glaucoma diagnosis: An evidence based meta-analysis.

PURPOSE: Early detection, monitoring and understanding of changes in the retina are central to the diagnosis of glaucomatous optic neuropathy, and vital to reduce visual loss from this progressive condition. The main objective of this investigation was to compare glaucoma diagnostic accuracy of commercially available optical coherence tomography (OCT) devices (Zeiss Stratus, Zeiss Cirrus, Heidelberg Spectralis and Optovue RTVue, and Topcon 3D-OCT). PATIENTS: 16,104 glaucomatous and 11,543 normal eyes reported in 150 studies. METHODS: Between Jan. 2017 and Feb 2017, MEDLINE®, EMBASE®, CINAHL®, Cochrane Library®, Web of Science®, and BIOSIS® were searched for studies assessing glaucoma diagnostic accuracy of the aforementioned OCT devices. Meta-analysis was performed pooling area under the receiver operating characteristic curve (AUROC) estimates for all devices, stratified by OCT type (RNFL, macula), and area imaged. RESULTS: 150 studies with 16,104 glaucomatous and 11,543 normal control eyes were included. Key findings: AUROC of glaucoma diagnosis for RNFL average for all glaucoma patients was 0.897 (0.887-0.906, n = 16,782 patient eyes), for macula ganglion cell complex (GCC) was 0.885 (0.869-0.901, n = 4841 eyes), for macula ganglion cell inner plexiform layer (GCIPL) was 0.858 (0.835-0.880, n = 4211 eyes), and for total macular thickness was 0.795 (0.754-0.834, n = 1063 eyes). CONCLUSION: The classification capability was similar across all 5 OCT devices. More diagnostically favorable AUROCs were demonstrated in patients with increased glaucoma severity. Diagnostic accuracy of RNFL and segmented macular regions (GCIPL, GCC) scans were similar and higher than total macular thickness. This study provides a synthesis of contemporary evidence with features of robust inclusion criteria and large sample size. These findings may provide guidance to clinicians when navigating this rapidly evolving diagnostic area characterized by numerous options.

Assessing the Methodological Quality of Glaucoma Clinical Practice Guidelines and Their Recommendations on Microinvasive Glaucoma Surgery: A Systematic Review.

INTRODUCTION: Clinical practice guidelines (CPG) are regarded by many as critical communications providing guidance within specific medical fields. Over a decade ago, the first microinvasive glaucoma surgical (MIGS) procedures were introduced. Since then, a number of these novel intraocular pressure controlling surgical options have been approved worldwide. Governing bodies and health care administration often utilize CPGs when considering funding for newer technologies. This highlights the importance of well-written, accurate, and up-to-date CPGs in the rapidly evolving field of MIGS. If CPGs are unable to fill this role, their use in treatment decision-making is doing a disservice to patients, who will be denied currently available and potentially superior care. To determine the overall value of a CPG, the methodological quality with which it was developed, in addition to the current relevance and appropriateness of its recommendations, should be evaluated. The objective of the present study was to assess the methodological quality of currently available international glaucoma CPGs, as well as their coverage of MIGS as a surrogate marker of relevance and appropriateness to policy-makers and ophthalmologists alike. MATERIALS AND METHODS: To identify potentially relevant CPGs, a predefined search strategy was used to search the following databases: Medline, EMBASE, BIOSIS, and Web of Science. All CPGs related to adult glaucoma and published in English were included. CPG methodological quality was assessed by 3 individuals using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. Studies were then assessed for coverage of MIGS devices and procedures. RESULTS: Search strategy and subsequent screening identified 11 CPGs for analysis. Eight were of high quality according to the AGREE II criteria. Three included basic information on MIGS, but none provided specific recommendations regarding their indications or which patient populations would benefit most. CONCLUSIONS: Many international glaucoma CPGs are of high methodological quality. However, coverage of MIGS is sparse, nonspecific and in many instances, absent. This causes CPGs to be a suboptimal source in guiding physicians and health policy-makers in areas characterized by novel and/or rapidly evolving technologies. Mechanisms to incorporate updated evidence in CPGs would have to be considered before they can be used as a source of contemporary clinical decision-making.

The value of corneoscleral rim cultures in keratoplasty: a systematic review and cost-effectiveness analysis.

PURPOSE: This study evaluated the performance of donor corneoscleral rim cultures for predicting infection after corneal transplantation, and determines if there is a correlation between positive corneoscleral rim cultures and postkeratoplasty infection. DESIGN AND DATA SOURCES: This was a systematic review, prognostic accuracy analysis, and cost-effectiveness analysis. Databases searched were: Medline (Ovid), Embase (Ovid), CINAHL, Cochrane Library, Web of Science, and BioSis Previews. Grey literature was also explored. MATERIALS AND METHODS: A systematic review was conducted to locate published and unpublished studies. All studies examining corneal button contamination and its association with endophthalmitis and keratitis posttransplantation were included. Extracted data were used to calculate sensitivity, specificity, positive predictive value, and negative predictive value. Cost data from the London Laboratory Services Group in London, ON were used to calculate the cost-effectiveness of culturing donor rim cultures. RESULTS: Of 7,870 grafts, 954 had a positive rim culture (12.1%), with 12 patients going on to develop keratitis or endophthalmitis (1.3%). The prevalence of keratitis and endophthalmitis in this study was 0.15%, and the positive predictive value 1.5%. Of the 12 infections, nine were fungal and three bacterial. The estimated cost of a positive and negative test result was CAD$45.99 and $14.15, respectively. The cost to run all 7,870 tests was estimated to be $141,735.86, with an incremental cost-effectiveness ratio of $40,215.70. CONCLUSION: There was a significant divergence between bacterial and fungal rim-culture results. Bacterial cultures predicted clinical infection poorly, did not change management, and were expensive. Fungal cultures predicted clinical infection in over 10% of patients, had the potential to change management, and were 40% less expensive than full rim culturing (bacterial and fungal tests). Fungal rim cultures may be considered in areas where fungal infection rates are high.

The Effects of Phacoemulsification on Intraocular Pressure and Topical Medication Use in Patients With Glaucoma: A Systematic Review and Meta-analysis of 3-Year Data.

PURPOSE: For patients with comorbid cataract and primary open-angle glaucoma (POAG), guidance is lacking as to whether cataract extraction and traditional filtering surgery should be performed as a staged or combined procedure. Achieving this guidance requires an evidence-based understanding of the effects of phacoemulsification alone on intraocular pressure (IOP) in patients with POAG. For this reason, a systematic review and meta-analysis was undertaken to synthesize evidence quantifying the effect of phacoemulsification on IOP and the required number of topical glaucoma medications in patients with cataract and POAG. MATERIALS AND METHODS: Database searches were last run on August 15, 2016 to identify potentially relevant studies. Identified articles were screened for relevance and meta-analysis was used to compute postoperative mean and percentage reduction in IOP (IOPR%) as well as mean difference in topical glaucoma medications. RESULTS: The search strategy identified 1613 records. Thirty-two studies (1826 subjects) were included in quantitative synthesis. A 12%, 14%, 15%, and 9% reduction in IOP from baseline occurred 6, 12, 24, and 36 months after phacoemulsification. A mean reduction of 0.57, 0.47, 0.38, and 0.16 medications per patient of glaucoma medication occurred 6, 12, 24, and 36 months after phacoemulsification. CONCLUSIONS: Phacoemulsification as a solo procedure does lower IOP in patients with POAG, and reduces dependency on topical glaucoma medications. These effects appear to last at least 36 months with gradual loss of the initial effect noted after 2 years. Certain populations appear to experience much greater reductions in IOP than others and future work to identify these high responding patients is needed.