Special Commentary: Reporting Clinical Endpoints in Studies of Minimally Invasive Glaucoma Surgery.

Minimally invasive glaucoma surgery (MIGS) refers to a group of procedures generally characterized by an ab interno approach, minimal trauma to ocular tissue, moderate efficacy, an excellent safety profile, and rapid recovery. The number of MIGS procedures continues to increase, and their use has become widespread among glaucoma and cataract specialists. Standardization of the methodology and reporting of clinical endpoints in MIGS investigations enhances interpretation and comparison across different studies. The assessment of surgical interventions not only should consider statistical significance, but also whether the outcome is meaningful to patients. Minimal clinically important difference (MCID) is defined as the smallest change in a treatment outcome that is considered beneficial for an individual patient and prompts a change in their clinical management. Expert consensus is an accepted approach to determine the MCID. The American Academy of Ophthalmology's Glaucoma Preferred Practice Pattern® Committee is an expert panel that develops guidelines identifying characteristics and components of quality eye care. The Committee recommends that the cumulative probability of surgical success at 2 years with Kaplan-Meier survival analysis be used as the primary efficacy endpoint in MIGS studies. The Committee suggests that surgical success for standalone MIGS be defined as intraocular pressure (IOP) of 21 mmHg or less and reduced by 20% or more from baseline without an increase in glaucoma medications, additional laser or incisional glaucoma surgery, loss of light perception vision, or hypotony. The proposed MCID for the cumulative probability of success of standalone MIGS at 2 years is 50%. The panel recommends that surgical success for MIGS combined with cataract extraction with intraocular lens implantation (CE-IOL) be defined as a decrease in glaucoma medical therapy of 1 medication or more from baseline without an increase in IOP or IOP of 21 mmHg or less and reduced by 20% or more from baseline without an increase in glaucoma medications, additional laser or incisional glaucoma surgery, loss of light perception vision, or hypotony. The suggested MCID for the cumulative probability of success for MIGS combined with CE-IOL at 2 years is 65%. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Aqueous and Plasma Levels of Phosphorylated Tau 181 in Individuals with Normal Cognition.

Background: Plasma and cerebrospinal fluid (CSF) levels of p-tau181 have been associated with Alzheimer's disease (AD). The retina and vitreous have shown measurable quantities of phosphorylated tau 181 (p-tau181). The aqueous humor, which can be collected during cataract surgery, may have measurable concentrations of p-tau181. Objective: To determine whether p-tau181 is detectable in the aqueous humor and if so, whether it is associated with other measures that might be consistent with AD such as higher plasma p-tau181 concentration and lower Montreal Cognitive Assessment (MoCA-BLIND version 7.1) score. Methods: Aqueous humor samples, blood samples, and MoCA-BLIND scores were collected from patients who did not carry a clinical diagnosis of cognitive impairment at the time of cataract surgery. Aqueous p-tau181 concentrations and plasma p-tau181 concentrations were then measured using ultra-sensitive single-molecule assay ELISA technology. A rank-transformed mixed-effects multivariate regression model was used to determine associations between aqueous concentrations, plasma concentrations, and MoCA-BLIND scores. Results: 16 eyes of 16 participants were enrolled with an average age of 71.6. Average MoCA-BLIND score was 20.6/22, average aqueous p-tau181 concentration was 6.4 pg/mL, and average plasma p-tau181 concentration was 3.1 pg/mL. Higher plasma p-tau181 was significantly associated with higher aqueous p-tau181 (p = 0.02). Aqueous p-tau181 and plasma p-tau181 were negatively associated with MoCA-BLIND scores (p = 0.005 and p = 0.001 respectively) in these patients. Conclusions: Aqueous p-tau181 is positively correlated with plasma p-tau181 and is negatively correlated with MoCA-BLIND scores. Further study in individuals with mild cognitive impairment or AD characterized by cerebrospinal fluid and volumetric MRI metrics may yield further insights.

Influence of Growth Differentiation Factor 15 on Intraocular Pressure in Mice.

Growth differentiation factor 15 (GDF15), a stress-sensitive cytokine, and a distant member of the transforming growth factor ß superfamily, has been shown to exhibit increased levels with aging, and in various age-related pathologies. Although GDF15 levels are elevated in the aqueous humor (AH) of glaucoma (optic nerve atrophy) patients, the possible role of this cytokine in the modulation of intraocular pressure (IOP) or AH outflow is unknown. The current study addresses this question using transgenic mice expressing human GDF15 and GDF15 null mice, and by perfusing enucleated mouse eyes with recombinant human GDF15 (rhGDF15). Treatment of primary cultures of human trabecular meshwork cells with a telomerase inhibitor, an endoplasmic reticulum stress-inducing agent, hydrogen peroxide, or an autophagy inhibitor resulted in significant elevation in GDF15 levels relative to the respective control cells. rhGDF15 stimulated modest but significant increases in the expression of genes encoding the extracellular matrix, cell adhesion proteins, and chemokine receptors (C-C chemokine receptor type 2) in human trabecular meshwork cells compared with controls, as deduced from the differential transcriptional profiles using RNA-sequencing analysis. There was a significant increase in IOP in transgenic mice expressing human GDF15, but not in GDF15 null mice, compared with the respective wild-type control mice. The AH outflow facility was decreased in enucleated wild-type mouse eyes perfused with rhGDF15. Light microcopy-based histologic examination of the conventional AH outflow pathway tissues did not reveal identifiable differences between the GDF15-targeted and control mice. Taken together, these results reveal the modest elevation of IOP in mice expressing human GDF15 possibly stemming from decreased AH outflow through the trabecular pathway.

Resident involvement in cataract surgery at the Veterans Health Administration: complications, case complexity, and the role of experience.

PURPOSE: To characterize intraoperative complications, case complexity, and changes in complication rates with surgical experience for cataract surgeries involving residents at the Veterans Health Administration (VHA). SETTING: All VHA facilities where cataract surgery was performed. DESIGN: Multicenter, retrospective cohort study. METHODS: A retrospective review of all cataract surgeries within the VHA between July 2010 and June 2021 was conducted. Several parameters, including resident involvement, intraoperative complications, and case complexity as determined by Current Procedural Terminology codes, and use of pupil expansion or capsular support devices, were collected. Complication rates were compared between residents and attendings. RESULTS: Of 392 428 cataract surgeries completed across 108 VHA facilities, 90 504 were performed by attendings alone, while 301 924 involved a resident. Of these, 10 244 (11.3%) of attending cases were complex compared with 32 446 (10.7%) of resident cases. Pupil expansion devices were required in 8191 of attending cases (9.05%) and 31 659 (10.5%) of cases involving residents ( P < .001). Similarly, cases involving residents were more likely than attending-only cases to require a capsular support device (0.835% vs 0.586%, P < .001). Cases involving residents were more likely to have posterior capsular rupture (4.75% vs 2.58%, P < .001) and dropped nucleus (0.338% vs 0.198%, P < .001). Higher resident case volumes were associated with significantly lower complication rates for posterior capsular rupture, dropped nucleus, zonular loss, and suprachoroidal hemorrhage. CONCLUSIONS: Although residents had higher intraoperative complication rates than attendings, these rates were reduced with surgical experience. Residents were involved in a similar number of complex surgical cases as attendings.

Role of vasorin, an anti-apoptotic, anti-TGF-ß and hypoxia-induced glycoprotein in the trabecular meshwork cells and glaucoma.

Glaucoma, one of the leading causes of irreversible blindness, is commonly associated with elevated intraocular pressure due to impaired aqueous humour (AH) drainage through the trabecular meshwork. The aetiological mechanisms contributing to impaired AH outflow, however, are poorly understood. Here, we identified the secreted form of vasorin, a transmembrane glycoprotein, as a common constituent of human AH by mass spectrometry and immunoblotting analysis. ELISA assay revealed a significant but marginal decrease in vasorin levels in the AH of primary open-angle glaucoma patients compared to non-glaucoma cataract patients. Human trabecular meshwork (HTM) cells were confirmed to express vasorin, which has been shown to possess anti-apoptotic and anti-TGF-ß activities. Treatment of HTM cells with vasorin induced actin stress fibres and focal adhesions and suppressed TGF-ß2-induced SMAD2/3 activation in HTM cells. Additionally, cobalt chloride-induced hypoxia stimulated a robust elevation in vasorin expression, and vasorin suppressed TNF-α-induced cell death in HTM cells. Taken together, these findings reveal the importance of vasorin in maintenance of cell survival, inhibition of TGF-ß induced biological responses in TM cells, and the decreasing trend in vasorin levels in the AH of glaucoma patients suggests a plausible role for vasorin in the pathobiology of ocular hypertension and glaucoma.

Elevated Levels of Growth/Differentiation Factor-15 in the Aqueous Humor and Serum of Glaucoma Patients.

Dysregulated levels of growth/differentiation factor-15 (GDF15), a divergent member of the transforming growth factor-beta super family, have been found to be associated with the pathology of various diseases. In this study, we evaluated the levels of GDF15 in aqueous humor (AH) and serum samples derived from primary open-angle glaucoma (POAG) and age- and gender-matched non-glaucoma (cataract) patients to assess the plausible association between GDF15 and POAG. GDF15 levels were determined using an enzyme-linked immunosorbent assay, and data analysis was performed using the Wilcoxon rank sum test, or the Kruskal-Wallis test and linear regression. GDF15 levels in the AH (n = 105) of POAG patients were significantly elevated (by 7.4-fold) compared to cataract patients (n = 117). Serum samples obtained from a subgroup of POAG patients (n = 41) also showed a significant increase in GDF15 levels (by 50%) compared to cataract patients. GDF15 levels were elevated in male, female, African American, and Caucasian POAG patients. This study reveals a significant and marked elevation of GDF15 levels in the AH of POAG patients compared to non-glaucoma cataract control patients. Although serum GDF15 levels were also elevated in POAG patients, the magnitude of difference was much smaller relative to that found in the AH.

Transition to a Night Float System in Ophthalmology Residency: Perceptions of Resident Wellness and Performance.

Purpose The purpose of this study is to characterize the influence of a new night float rotation on resident wellness and performance in the Duke University Eye Center Ophthalmology Residency Program. Methods We analyzed three classes of ophthalmology residents: one class ( n = 4) utilized the new night float rotation with no daytime clinical duties, while two senior classes ( n = 12) utilized the traditional call system wherein they had daytime and nighttime responsibilities. Residents completed a questionnaire regarding their perceptions of the night float rotation. Supervising attendings ( n = 15) were also surveyed about their perceptions of the new rotation. Results Zero of the four residents on the night float rotation reported burnout compared with 6 of 11 residents in the traditional call system. Most residents supported the adoption of the night float rotation, but this trend was less apparent among fellows and attendings. Most respondents believed the new night float rotation reduced burnout, fatigue, and work hours while increasing time for nonclinical activities. Perceived skills gained while on call were felt to be similar between the two call systems. Fellows and attendings believed residents in the night float system performed similarly or better than residents in the traditional system in indicators such as knowledge and enthusiasm. There was no significant difference in the average number of patient encounters (290.8 ± 30.5 vs. 310.7 ± 25.4, p = 0.163), phone encounters (430.8 ± 20.2 vs. 357.1 ± 90.0, p = 0.068), or average hours worked per week (57.3 ± 4.6 vs. 58.0 ± 5.7 p = 0.797) per resident between night float residents and traditional call residents. Conclusions This study shows resident support for a night float rotation in ophthalmology residency at Duke, with reductions in burnout and more time for nonclinical activities without affecting perceived clinical performance. We hope this study serves as an impetus for other ophthalmology programs considering a transition to a night float system.

Learning From the 2021 Ophthalmology Match: Virtual Residency Matching During the COVID-19 Pandemic.

Background: The effect of virtual interviews on residency match outcomes during the COVID-19 pandemic is unknown. Examining the ophthalmology match may help inform all specialties undergoing virtual interviews. Objective: To determine the impact of allopathic applicant match characteristics in the first year of the virtual residency Match process. Methods: Using the Association of University Professors of Ophthalmology match database, a retrospective review was conducted of all allopathic applicants to ophthalmology residency programs in the United States from the 2016 through the 2021 match cycles. Demographic information, interview numbers, and match outcomes were compared between the 2016-2020 (in-person) and 2021 (virtual) cycles. Results: A total of 3343 allopathic applicants were analyzed. Applicants in the 2021 Match applied to significantly more programs than 2016-2020 applicants did (78.7±23.6 vs 73.1±22.7, P<.001). Among matched and unmatched applicants, there was no significant difference in the number of interviews granted or completed. There was a significant reduction in the match rate between the 2016-2020 and 2021 Match cycles (81.3% vs 76.6%, P=.0009). A subanalysis of applicants who went to medical schools with ophthalmology residency programs (N=2308) found that the home institution match rate was significantly higher for the 2021 Match compared to the aggregate 2016-2020 Matches (26.1% vs 20.6%, respectively, P=.015). Conclusions: Significantly more applicants to ophthalmology residency programs matched at their home institutions in the 2021 virtual match cycle compared to the previous 5 years without influencing the interview numbers granted and attended.

Infections and glaucoma.

Glaucoma is an intraocular pressure-related ophthalmic disease with multiple causes that results in an optic neuropathy and vision loss. Intraocular pressure elevation is among its strongest risk factors. While glaucoma is mostly primary in etiology, secondary glaucoma is not infrequent. Recognizing its cause is imperative, since treatment is often different depending on the pathophysiologic mechanism. Numerous clinically relevant ophthalmic infections can result in robust inflammatory responses that may result in pressure elevation or intraocular anatomic configurations that predispose to pressure elevation. Knowing the mechanisms by which these infections can lead to glaucoma is critical in treating, and we consolidate what is currently known in regards to how infectious diseases lead to glaucoma.

Long-Term Decrease of Intraocular Pressure in Rats by Viral Delivery of miR-146a.

Purpose: To evaluate the effects of miR-146a in trabecular meshwork (TM) cells and on intraocular pressure (IOP) in vivo via viral delivery of miR-146a to the anterior chamber of rat eyes. Methods: Human TM cells were transfected with miR-146 mimic or inhibitor. Some cells from each group were then subjected to cyclic mechanical stress (CMS). Other cells from each group had no force applied. Gene expression was then analyzed by quantitative polymerase chain reaction (qPCR). Replication-deficient adenovirus and lentivirus expressing miR-146a were inoculated into the anterior segment of Brown Norway rat eyes. IOP was monitored by rebound tonometry, visual acuity was evaluated by optokinetic tracking (OKT), and inflammation markers in the anterior segment were examined by slit-lamp, qPCR, and semi-thin sections. Results: miR-146 affected the expression of genes potentially involved in outflow homeostasis at basal levels and under CMS. Both lentiviral and adenoviral vectors expressing miR-146a resulted in sustained decreases in IOP ranging from 2.6 to 4.4 mmHg. Long term follow-up of rats injected with lentiviral vectors showed a sustained effect on IOP of 4.4 ± 2.9 mmHg that lasted until rats were sacrificed more than 8 months later. Eyes showed no signs of inflammation, loss of visual acuity, or other visible abnormalities. Conclusions: Intracameral delivery of miR-146a can provide a long-term decrease of IOP in rats without signs of inflammation or other visible adverse effects. Transitional Relevance: The IOP-lowering effects of miR-146 observed in rats provides a necessary step toward the development of an effective gene therapy for glaucoma in humans.

Anti-fibrotic activity of a rho-kinase inhibitor restores outflow function and intraocular pressure homeostasis.

Glucocorticoids are widely used as an ophthalmic medication. A common, sight-threatening adverse event of glucocorticoid usage is ocular hypertension, caused by dysfunction of the conventional outflow pathway. We report that netarsudil, a rho-kinase inhibitor, decreased glucocorticoid-induced ocular hypertension in patients whose intraocular pressures were poorly controlled by standard medications. Mechanistic studies in our established mouse model of glucocorticoid-induced ocular hypertension show that netarsudil both prevented and reduced intraocular pressure elevation. Further, netarsudil attenuated characteristic steroid-induced pathologies as assessed by quantification of outflow function and tissue stiffness, and morphological and immunohistochemical indicators of tissue fibrosis. Thus, rho-kinase inhibitors act directly on conventional outflow cells to prevent or attenuate fibrotic disease processes in glucocorticoid-induced ocular hypertension in an immune-privileged environment. Moreover, these data motivate the need for a randomized prospective clinical study to determine whether netarsudil is indeed superior to first-line anti-glaucoma drugs in lowering steroid-induced ocular hypertension.

Netarsudil Improves Trabecular Outflow Facility in Patients with Primary Open Angle Glaucoma or Ocular Hypertension: A Phase 2 Study.

PURPOSE: Intraocular pressure (IOP) reduction is key to controlling primary open angle glaucoma (POAG). Pharmacotherapies for POAG or ocular hypertension (OHT) commonly lower IOP by increasing uveoscleral outflow or decreasing aqueous humor production. Netarsudil (Rhopressa), a Rho kinase inhibitor, reduces IOP by improving trabecular outflow facility, which is reduced in POAG. We investigated the effects of netarsudil on aqueous humor dynamics in patients with POAG or OHT. DESIGN: Double-masked, randomized, vehicle-controlled, Phase 2 trial. METHODS: Netarsudil 0.02% was instilled in 1 eye and vehicle into the contralateral eye of 20 patients once daily in the morning for 7 days. The primary endpoint was change in mean diurnal outflow facility on day 8 versus that on day 1 (baseline). Outflow facility was measured by using Schiøtz tonography, IOP by pneumotonometry, and episcleral venous pressure (EVP) by automated venomanometry. RESULTS: Eighteen patients (90%) completed the study. Mean diurnal outflow facility increased 0.039 versus 0.007 µL/min/mm Hg from baseline in the netarsudil- and the vehicle-treated groups, respectively (P < .001 vs. baseline for netarsudil), a treatment difference of 0.03 µL/min/mm Hg (P ≤ .001). Mean diurnal IOP change from baseline at day 8 was -4.52 mm Hg for netarsudil versus -0.98 mm Hg for vehicle, a treatment difference of -3.54 mm Hg (P < .0001). Mean diurnal EVP change from baseline was -0.79 mm Hg in the netarsudil-treated group versus 0.10 mm Hg for vehicle, a treatment difference of -0.89 mm Hg (P < .001). All patients reporting an adverse event reported conjunctival hyperemia of mild or moderate severity. CONCLUSIONS: Netarsudil acts on the conventional outflow pathway, both proximal and distal, to significantly reduce IOP in POAG and OHT by improving trabecular outflow facility and decreasing EVP.

Infectious and Sterile Endophthalmitis in Eyes with Glaucoma Drainage Device from Two Large Ophthalmic Institutions.

PURPOSE: To describe the predisposing factors, presentation, management, and outcome of glaucoma drainage implant (GDI)-associated endophthalmitis. DESIGN: Retrospective chart review. PARTICIPANTS: Eyes that developed GDI-associated endophthalmitis between December 1, 2011, and December 23, 2019, at the Duke Eye Center and Cole Eye Institute. METHODS: Patient data search was performed on the basis of diagnostic codes for GDI and endophthalmitis. Endophthalmitis was defined clinically according to each physician's discretion. Eyes with infection source other than GDI were excluded. Worse vision was defined as a decrease of more than 2 Snellen lines. Data were collected on baseline demographics, systemic and ocular comorbidities, ocular surgical history, best-corrected visual acuity (BCVA), intraocular pressure (IOP), clinical presentation, eye culture results, and treatments performed. Statistical analysis included the paired t test and odds radio calculations. MAIN OUTCOME MEASURES: Visual acuity and IOP at final follow-up. RESULTS: Thirty cases (0.7%) of GDI endophthalmitis were identified among 4073 GDIs performed at the 2 institutions with active follow-up. Device exposure was identified in 20 eyes (67%) on presentation. The average follow-up after presentation was 22.4 ± 25 months. The most frequently identified organism on culture was Streptococcus pneumoniae. Same-day injection of intravitreal antibiotics was the universal first-line therapy. From baseline to final follow-up, the mean BCVA decreased from -0.84 ± 0.77 to -1.30 ± 0.93 (logarithm of the minimum angle of resolution, P = 0.02). Mean IOP did not change from baseline to final visit in the overall cohort (16.2 ± 8.2 mmHg to 14.6 ± 9.4 mmHg, P = 0.30) and in the subgroup that underwent tube explant (15.9 ± 5.5 mmHg to 15.2 ± 10.4 mmHg, P = 0.97). Eighteen of 20 tube exposure cases (90%) underwent tube explant, 1 underwent tube revision, and 1 re-epithelialized. CONCLUSIONS: Glaucoma drainage implant-associated endophthalmitis was correlated with poor visual outcome. Immediate intravitreal antibiotic delivery was a universal first-line therapy. Tube exposure was a necessary risk factor for late-onset endophthalmitis and required surgical removal or repair.

Recurrent Tube Erosions with Anti-Vascular Endothelial Growth Factor Therapy in Patients with Age-Related Macular Degeneration.

PURPOSE: To determine the rates of primary and recurrent glaucoma tube shunt erosions in patients with age-related macular degeneration (AMD) receiving anti-vascular endothelial growth factor (VEGF) intravitreal injections. DESIGN: Retrospective case series. PARTICIPANTS: Patients with AMD who underwent tube revision for erosion at the Duke Eye Center from January 1, 1999, to January 1, 2019, were identified. Patients with and without anti-VEGF injections were compared. METHODS: Patient demographics, ocular diagnoses, glaucoma tube shunt types and locations, and dates of glaucoma surgeries and anti-VEGF injections were collected. Statistical analyses were performed with P < 0.05 as significant. MAIN OUTCOME MEASURES: Outcome measures included the number of tube erosions, time from anti-VEGF injection to tube erosion, and secondary complications after tube revisions. RESULTS: A total of 150 patients with AMD with anti-VEGF (309 tubes) and 262 patients with AMD without anti-VEGF (459 tubes) were identified. There was no statistically significant difference in the number of tube erosions in patients with anti-VEGF (15 tubes, 4.8%) versus without anti-VEGF (12 tubes, 2.6%) (P = 0.10). However, patients receiving anti-VEGF had on average a greater number of tube erosion events (2.1±0.7 events) compared with patients without anti-VEGF (1.3±0.7, P < 0.01). Ten patients (91%) received concurrent anti-VEGF injections at the time of tube erosion, and the average duration of prior anti-VEGF therapy was approximately 2 years. Tube erosion was noted 46.5±60.7 days from the preceding anti-VEGF injection. Secondary complications after tube revision in the anti-VEGF group included 5 explanted tubes for recurrent erosions. CONCLUSIONS: Our results suggest intravitreal anti-VEGF injections are linked to higher rates of recurrent glaucoma tube erosions in patients with AMD. The majority of patients received chronic and serial anti-VEGF injections. Thus, additional consideration should be given to glaucoma surgical planning in patients receiving anti-VEGF injections, especially in those with a primary tube erosion.

Factors Impacting Outcomes and the Time to Recovery From Malignant Glaucoma.

PURPOSE: To identify factors associated with the successful treatment of malignant glaucoma (MG). DESIGN: Retrospective case series. METHODS: Setting: single institution; study population: 64 eyes (55 subjects) with MG; observation procedure(s): chart review; main outcome measures: anatomy, intraocular pressure (IOP), best visual acuity (BVA). RESULTS: 87.5% (n=56/64) of eyes with MG required surgical intervention. Vitrectomy was more likely to be successful in eyes with a history of <3 incisional surgeries, <3 glaucoma drops, or IOP ≤30 mm Hg (P < .05). If vitrectomy was performed within 30 days, recovery of anatomy, BVA, and IOP occurred sooner (P < .05). IOP reduction was greater in subjects treated with oral carbonic anhydrase inhibitors (P = .016) or Nd:YAG laser hyaloidotomy (P = .007), and without a history of MG (P = .007). Time to maximal improvement was significantly longer for IOP and BVA than anatomy (P < .001). Treatment of MG with an oral carbonic anhydrase inhibitor hastened anatomic recovery (P = .01). Time to improvement in BVA was significantly faster in men and African Americans (P < .05). Time to maximal reduction in IOP occurred sooner in eyes that underwent anterior chamber reformation in clinic (P < .002). Trabeculectomy surgery prior to MG was associated with prolonged recovery of anatomy, BVA, and IOP (P < .05). CONCLUSIONS: Earlier vitrectomy may shorten recovery times for MG. Nd:YAG laser hyaloidotomy and oral carbonic anhydrase inhibitors may lead to greater IOP reduction. The time to maximal improvement in IOP and BVA may be longer than the time to anatomic resolution. Although trabeculectomy may impede time to recovery from MG, oral carbonic anhydrase inhibitors may shorten the time to anatomic recovery and anterior chamber reformation may hasten IOP recovery.

Role of the autotaxin-lysophosphatidic acid axis in glaucoma, aqueous humor drainage and fibrogenic activity.

Ocular hypertension due to impaired aqueous humor (AH) drainage through the trabecular meshwork (TM) is a major risk factor for glaucoma, a leading cause of irreversible blindness. However, the etiology of ocular hypertension remains unclear. Although autotaxin, a secreted lysophospholipase D and its catalytic product lysophosphatidic acid (LPA) have been shown to modulate AH drainage through TM, we do not have a complete understanding of their role and regulation in glaucoma patients, TM and AH outflow. This study reports a significant increase in the levels of autotaxin, lysophosphatidylcholine (LPC), LPA and connective tissue growth factor (CTGF) in the AH of Caucasian and African American open angle glaucoma patients relative to age-matched non-glaucoma patients. Treatment of human TM cells with dexamethasone, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) increased the levels of autotaxin protein, a response that was mitigated by inhibitors of glucocorticoid receptor, NF-kB and SMAD3. Dexamethasone, TNF-α, IL-1ß and LPC treatment of TM cells also led to an increase in the levels of CTGF, fibronectin and collagen type 1 in an autotaxin dependent manner. Additionally, in perfused enucleated mouse eyes, autotaxin and LPC were noted to decrease, while inhibition of autotaxin was increased aqueous outflow through the TM. Taken together, these results provide additional evidence for dysregulation of the autotaxin-LPA axis in the AH of glaucoma patients, reveal molecular insights into the regulation of autotaxin expression in TM cells and the consequences of autotaxin inhibitors in suppressing the fibrogenic response and resistance to AH outflow through the TM.

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures: Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-ß A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.