Comparative Single Vesicle Analysis of Aqueous Humor Extracellular Vesicles before and after Radiation in Uveal Melanoma Eyes.

Small extracellular vesicles (sEVs) have been shown to promote tumorigenesis, treatment resistance, and metastasis in multiple cancer types; however, sEVs in the aqueous humor (AH) of uveal melanoma (UM) patients have never previously been profiled. In this study, we used single particle analysis to characterize sEV subpopulations in the AH of UM patients by quantifying their size, concentration, and phenotypes based on cell surface markers, specifically the tetraspanin co-expression patterns of CD9, CD63, and CD81. sEVs were analyzed from paired pre- and post-treatment (brachytherapy, a form of radiation) AH samples collected from 19 UM patients. In post-brachytherapy samples, two subpopulations, CD63/81+ and CD9/63/81+ sEVs, were significantly increased. These trends existed even when stratified by tumor location and GEP class 1 and class 2 (albeit not significant for GEP class 2). In this initial report of single vesicle profiling of sEVs in the AH of UM patients, we demonstrated that sEVs can be detected in the AH. We further identified two subpopulations that were increased post-brachytherapy, which may suggest radiation-induced release of these particles, potentially from tumor cells. Further study of the cargo carried by these sEV subpopulations may uncover important biomarkers and insights into tumorigenesis for UM.

Serum total folate, 5-methyltetrahydrofolate and vitamin B12 concentrations on incident risk of lung cancer.

Tobacco smoking is a major known risk factor for lung cancer. While micronutrients, especially those involved in maintaining DNA integrity and regulating gene expression, may be protective, research on this association is limited. This report aimed to investigate associations of total folate, 5-methyltetrahydrofolate (5-mTHF) and vitamin B12 with incident risk of lung cancer, and whether the associations vary by smoking status. A nested case-control study with 490 incident lung cancer cases and 490 controls matched by age (±1 year), sex, residence, and center, drawn from a community-based prospective study in China, was conducted from 2016 to 2019. 5-mTHF accounted for the majority of total folate. Only 4.4% had detectable unmetabolized folic acid. Lung cancer cases had lower levels of 5-mTHF compared to controls. There was an inverse, nonlinear association between 5-mTHF and lung cancer, which persisted after adjustment for covariables (P for trend = .001). Compared to the lowest 5-mTHF quartile, those in higher quartiles had lower risks of lung cancer: second quartile OR = 0.65; 95% CI: 0.45-0.93; third quartile OR = 0.50; 95% CI: 0.34-0.74; fourth quartile OR = 0.56; 95% CI: 0.38-0.83. This inverse association was more pronounced among ever smokers; consistently, the highest risk of lung cancer (OR = 3.21, 95% CI: 1.97-5.24) was observed among ever smokers with low 5-mTHF levels compared to participants who never smoked and had higher 5-mTHF levels. Vitamin B12 was not associated with lung cancer risk. In this sample of Chinese adults without confounding by unmetabolized folic acid, higher levels of 5-mTHF were associated with lower risk of incident lung cancer.

Visual Field Loss Impacts Vision-Specific Quality of Life by Race and Ethnicity: The Multiethnic Ophthalmology Cohorts of California Study.

PURPOSE: To assess the impact of visual field loss (VFL) on vision-specific quality of life (VSQOL) by race, ethnicity, and age. DESIGN: Pooled analysis of cross-sectional data from 3 population-based, prospective cohort studies. PARTICIPANTS: The Multiethnic Ophthalmology Cohorts of California Study (MOCCaS) participants included 6142 Latinos, 4582 Chinese Americans, and 6347 Black Americans from Los Angeles County. METHODS: A total of 17 071 adults aged 40 years and older completed comprehensive interviews and ophthalmic examinations from 2000 to 2018. VFL was measured using the Humphrey Swedish Interactive Threshold Algorithm Standard 24-2 test as decibels (dB) of mean deviation (MD). Multivariable linear regression was used to evaluate the impact of VFL in the better-seeing eye on self-reported VSQOL scores, adjusting for sociodemographic and clinical covariables. Hierarchical modeling was performed to determine the best-fit model after considering main effects and interactions by race, ethnicity, and age. MAIN OUTCOME MEASURES: The VSQOL scores were measured using the 25 Item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). Item response theory was used to model vision-related task and well-being composite scores, and classical test theory was used to calculate 11 vision subscales. RESULTS: The impact of VFL on VSQOL varied by race and ethnicity. Five-point reductions in task and well-being scores were reached after mild-to-moderate VFL for Latinos (6.7 dB and 7.5 dB), mild-to-moderate VFL for Chinese Americans (7.0 dB and 8.7 dB), and moderate-to-severe VFL for Black Americans (10.1 dB and 12.9 dB), respectively. Differences met statistical significance when comparing Latinos and Black Americans (P < 0.001). Visual field loss had the largest effect on driving among all participants. Driving difficulties were the only VSQOL outcome modified by age; participants aged 65 years and older scored 0.487 lower points per MD of VFL (P < 0.001). Subscales most affected by VFL included role function, mental health, and dependency. CONCLUSIONS: Race and ethnicity modified the impact of VFL on VSQOL, even after adjusting for sociodemographic covariates. In MOCCaS, Latinos and Chinese Americans reported a greater change in VSQOL than Black Americans for the same level of VFL. Future work should assess whether findings were due to socioeconomic or cultural differences in perception of visual function.

Ocular Biometric Risk Factors for Progression of Primary Angle Closure Disease: The Zhongshan Angle Closure Prevention Trial.

PURPOSE: To assess baseline ocular biometric risk factors for progression from primary angle closure suspect (PACS) to primary angle closure (PAC) or acute angle closure (AAC). DESIGN: Prospective, observational study. PARTICIPANTS: Six hundred forty-three mainland Chinese with untreated PACS. METHODS: Participants underwent baseline clinical examinations, including gonioscopy, anterior segment OCT (AS-OCT) imaging, and A-scan ultrasound biometry as part of the Zhongshan Angle Closure Prevention (ZAP) Trial. Primary angle closure suspect was defined as an inability to visualize pigmented trabecular meshwork in 2 or more quadrants based on static gonioscopy. Primary angle closure was defined as development of intraocular pressure above 24 mmHg or peripheral anterior synechiae. Progression was defined as development of PAC or an AAC attack. Multivariable logistic regression models were developed to assess biometric risk factors for progression. MAIN OUTCOME MEASURES: Six-year progression from PACS to PAC or AAC. RESULTS: Six hundred forty-three untreated eyes (609 nonprogressors, 34 progressors) of 643 participants were analyzed. In a multivariable model with continuous parameters, narrower horizontal angle opening distance of 500 µm from the scleral spur (AOD500; odds ratio [OR], 1.10 per 0.01-mm decrease; P = 0.03), flatter horizontal iris curvature (IC; OR, 1.96 per 0.1-mm decrease; P = 0.01), and older age (OR, 1.11 per 1-year increase; P = 0.01) at baseline were associated significantly with progression (area under the receiver operating characteristic curve [AUC], 0.73). Smaller cumulative gonioscopy score was not associated with progression (OR, 1.03 per 1-modified Shaffer grade decrease; P = 0.85) when replacing horizontal AOD500 in the multivariable model. In a separate multivariable model with categorical parameters, participants in the lowest quartile of horizontal AOD500 (OR, 3.10; P = 0.002) and IC (OR, 2.48; P = 0.014) measurements and 59 years of age or older (OR, 2.68; P = 0.01) at baseline showed higher odds of progression (AUC, 0.72). CONCLUSIONS: Ocular biometric measurements can help to risk-stratify patients with early angle closure for more severe disease. Anterior segment OCT measurements of biometric parameters describing the angle and iris are predictive of progression from PACS to PAC or AAC, whereas gonioscopy grades are not.

Joint Associations between Plasma 25-Hydroxyvitamin D, Glycemic Status, and First Stroke in General Hypertensive Adults: Results from the China Stroke Primary Prevention Trial (CSPPT).

BACKGROUND: Associations between vitamin D and stroke remain inconsistent. One major risk factor for stroke is high blood glucose, but the role it plays in this association is not well studied. OBJECTIVES: We aimed to evaluate the individual association between plasma 25-hydroxyvitamin D [25(OH)D] and risk of first stroke stratified by fasting blood glucose (FBG), and the joint associations between plasma 25(OH)D, glycemic status, and first stroke in hypertensive adults. METHODS: This study was a nested, case-control design utilizing data from the China Stroke Primary Prevention Trial (CSPPT). This analysis included 591 first stroke cases (of which 475 were ischemic stroke, 114 were hemorrhagic stroke, and 2 were uncertain type) and 591 matched controls. The age range of the study population was 45-75 y. The normal FBG (NFG) group had FBG <5.6 mmol/L,  and the impaired FBG (IFG) group had FBG ≥5.6 mmol/L and <7.0 mmol/L. Diabetes was defined as participants with FBG ≥7 mmol/L or who were receiving treatment with hypoglycemic agents. ORs (95% CIs) were calculated using unconditional logistic regression models. RESULTS: Multivariable adjusted models revealed an inverse association between quartiles of 25(OH)D and risk of first stroke among participants with NFG, but the opposite trend was observed for those with IFG or diabetes. The largest ORs (>2) were observed among patients with diabetes, compared with the reference group of NFG and high 25(OH)D. Those with NFG and low 25(OH)D (OR = 1.73, 95% CI: 1.22 to 2.44) or those with IFG and high 25(OH)D (OR = 1.74, 95% CI: 1.14 to 2.67) both had a higher risk of total stroke. There was a significant interaction between 25(OH)D and a combined group of IFG and diabetes (P = 0.001). Similar results were observed for ischemic stroke. CONCLUSIONS: In a hypertensive population, the relation between plasma 25(OH)D and risk of first stroke was significantly modified by FBG. This trial was registered at https://www.clinicaltrials.gov as NCT00794885.

Anatomic Changes and Predictors of Angle Widening after Laser Peripheral Iridotomy: The Zhongshan Angle Closure Prevention Trial.

PURPOSE: To assess anatomic changes after laser peripheral iridotomy (LPI) and predictors of angle widening based on anterior segment (AS) OCT and angle opening based on gonioscopy. DESIGN: Prospective observational study. PARTICIPANTS: Primary angle-closure suspects (PACSs) 50 to 70 years of age. METHODS: Participants of the Zhongshan Angle Closure Prevention (ZAP) Trial underwent gonioscopy and AS-OCT imaging at baseline and 2 weeks after LPI. Primary angle-closure suspect was defined as the inability to visualize pigmented trabecular meshwork in 2 or more quadrants on static gonioscopy. Laser peripheral iridotomy was performed on 1 eye per patient in superior (between 11 and 1 o'clock) or temporal or nasal locations (at or below 10:30 or 1:30 o'clock). Biometric parameters in horizontal and vertical AS-OCT scans were measured and averaged. Linear and logistic regression modeling were performed to determine predictors of angle widening, defined as change in mean angle opening distance measured at 750 µm from the scleral spur (AOD750); poor angle widening, defined as the lowest quintile of change in mean AOD750; and poor angle opening, defined as residual PACS after LPI based on gonioscopy. MAIN OUTCOME MEASURES: Anatomic changes and predictors of angle widening and opening after LPI. RESULTS: Four hundred fifty-four patients were included in the analysis. Two hundred nineteen underwent superior LPI and 235 underwent temporal or nasal LPI. Significant changes were found among most biometric parameters (P < 0.006) after LPI, including greater AOD750 (P < 0.001). One hundred twenty eyes (26.4%) showed residual PACS after LPI. In multivariate regression analysis, superior LPI location (P = 0.004), smaller AOD750 (P < 0.001), and greater iris curvature (P < 0.001), were predictive of greater angle widening. Temporal or nasal LPI locations (odds ratio [OR], 2.60, P < 0.001) was predictive of poor angle widening. Smaller mean gonioscopy grade (OR, 0.34, 1-grade increment) was predictive of poor angle opening. CONCLUSIONS: Superior LPI location results in significantly greater angle widening compared with temporal or nasal locations in a Chinese population with PACS. This supports consideration of superior LPI locations to optimize anatomic changes after LPI.

Surgical Outcomes of Transposition Surgery for the Correction of Large-Angle Strabismus.

BACKGROUND: Many potential surgical options exist to address large-angle deviations and head turns that result from various forms of paralytic strabismus. Muscle transposition surgeries serve as suitable alternatives to simple resection-recessions. Here, we report outcomes of augmented Hummelsheim and X-type transpositions for the correction of large-angle strabismus and provide insights for surgical planning. METHODS: We performed a retrospective chart review of 40 consecutive patients with strabismus who were treated with an augmented Hummelsheim or X-type transposition surgery at a single academic medical center. Etiologies included cranial nerve palsies (n = 26), monocular elevation palsy (n = 3), Duane syndrome (n = 1), traumatic extraocular muscle damage (n = 8), and chronic progressive external ophthalmoplegia (n = 2). All patients were followed for a minimum of 2 months postsurgery. Logistic regression analyses were performed to assess for predictors of surgical outcome. RESULTS: Forty consecutive patients were enrolled in our series. The median preoperative deviation was 46.5Δ (interquartile range [IQR] 35-70). The median postoperative deviation 2 months after surgery was 0.5Δ (IQR 0-9.5), which represented a significant improvement (P < 0.001). Thirty-three patients (82.5%) experienced an improvement in range and/or centration of binocular single vision (BSV). More patients who underwent an augmented Hummelsheim procedure and had a small overcorrection at postoperative day 3 had a favorable result on postoperative month 2 (79%) compared with those that were initially under-corrected (38%). Multiple logistic regressions found larger preoperative deviation (P < 0.005) and esotropia (P < 0.021) to be predictors of a less favorable surgical outcome (C-statistic = 0.83). Subgroup analysis revealed that less, favorable outcome after X-type transposition occurred most frequently in patients undergoing correction of an esodeviation. CONCLUSION: Augmented Hummelsheim transposition techniques offer effective treatment options for paralytic strabismus with esotropic deviations, whereas X-type transpositions are effective for exotropic deviations and deviations from severe inferior rectus damage. In addition to potentially providing a wider field of BSV, improved centration is often achieved.

PreSMA stimulation changes task-free functional connectivity in the fronto-basal-ganglia that correlates with response inhibition efficiency.

Previous work using transcranial magnetic stimulation (TMS) demonstrated that the right presupplementary motor area (preSMA), a node in the fronto-basal-ganglia network, is critical for response inhibition. However, TMS influences interconnected regions, raising the possibility of a link between the preSMA activity and the functional connectivity within the network. To understand this relationship, we applied single-pulse TMS to the right preSMA during functional magnetic resonance imaging when the subjects were at rest to examine changes in neural activity and functional connectivity within the network in relation to the efficiency of response inhibition evaluated with a stop-signal task. The results showed that preSMA-TMS increased activation in the right inferior-frontal cortex (rIFC) and basal ganglia and modulated their task-free functional connectivity. Both the TMS-induced changes in the basal-ganglia activation and the functional connectivity between rIFC and left striatum, and of the overall network correlated with the efficiency of response inhibition and with the white-matter microstructure along the preSMA-rIFC pathway. These results suggest that the task-free functional and structural connectivity between the rIFCop and basal ganglia are critical to the efficiency of response inhibition. Hum Brain Mapp 37:3236-3249, 2016. © 2016 Wiley Periodicals, Inc.

Age-dependent mesial temporal lobe lateralization in language fMRI.

OBJECTIVE: Functional magnetic resonance imaging (fMRI) activation of the mesial temporal lobe (MTL) may be important for epilepsy surgical planning. We examined MTL activation and lateralization during language fMRI in children and adults with focal epilepsy. METHODS: One hundred forty-two controls and patients with left hemisphere focal epilepsy (pediatric: epilepsy, n = 17, mean age = 9.9 ± 2.0; controls, n = 48; mean age = 9.1 ± 2.6; adult: epilepsy, n = 20, mean age = 26.7 ± 5.8; controls, n = 57, mean age = 26.2 ± 7.5) underwent 3T fMRI using a language task (auditory description decision task). Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8); regions of interest (ROIs) included MTL, Broca's area, and Wernicke's area. We assessed group and individual MTL activation, and examined degree of lateralization. RESULTS: Patients and controls (pediatric and adult) demonstrated group and individual MTL activation during language fMRI. MTL activation was left lateralized for adults, but less so in children (p's < 0.005). Patients did not differ from controls in either age group. Stronger left-lateralized MTL activation was related to older age (p = 0.02). Language lateralization (Broca's and Wernicke's) predicted 19% of the variance in MTL lateralization for adults (p = 0.001), but for not children. SIGNIFICANCE: Language fMRI may be used to elicit group and individual MTL activation. The developmental difference in MTL lateralization and its association with language lateralization suggests a developmental shift in lateralization of MTL function, with increased left lateralization across the age span. This shift may help explain why children have better memory outcomes following resection compared to adults.

Practice Patterns and Sociodemographic Disparities in the Clinical Care of Anatomical Narrow Angles in the United States.

PURPOSE: To assess treatment and visit patterns among patients with newly diagnosed anatomical narrow angle (ANA) and identify sociodemographic factors associated with disparities in care. DESIGN: Retrospective practice pattern evaluation study. METHODS: A total of 263,422 patients diagnosed with ANA between 2007 and 2019 were identified in the Optum Clinformatics Data Mart. Inclusion was limited to newly diagnosed ANA, defined as (1) continuous enrollment during a 2-year lookback period and 1-year study period from first diagnosis; (2) diagnosis by an ophthalmologist or optometrist; and (3) no history of pseudophakia, ANA treatments, or prior primary angle closure glaucoma diagnosis. Outcome measures were treatment with laser peripheral iridotomy (LPI), cataract surgery, or intraocular pressure-lowering medications and number of eye care visits. Logistic and Poisson regression were performed to assess factors associated with treatment and eye care visits, respectively. RESULTS: Among 52,405 eligible cases, 27.7% received LPI, 13.9% received drops, and 15.1% received cataract surgery. Odds of LPI were higher in Asians and Hispanics (odds ratio [OR] ≥ 1.16, P < .001). Non-Whites had higher odds of drops (OR ≥ 1.19, P < .001), but Hispanics had lower odds of cataract surgery (OR = 0.79, P < .001). The mean number of eye care visits was 2.6±2.1 including the day of diagnosis. Older age and treatment were associated with higher rates of eye care visits (rate ratio > 1.15, P < .001). CONCLUSION: More than a quarter of patients with newly diagnosed ANA receive treatment with LPI. Racial minorities are more likely to receive ANA-specific treatments but less likely to receive cataract surgery. These differences may reflect racial differences in disease severity and the need for clearer practice guidelines in ANA care.

Relationship Between Glaucoma and Chronic Stress Quantified by Allostatic Load Score in the All of Us Research Program.

PURPOSE: To assess the relationship between glaucoma and allostatic load (AL), an established framework for quantifying the physiologic effects of chronic stress through measurements of systemic biomarkers. DESIGN: Retrospective case-control study. METHODS: Participants of the National Institutes of Health All of Us (AoU) Research Program with complete AL biomarker data between December 1984 to June 2022 and with (cases) or without (controls) primary glaucoma were identified. AL scores were calculated using the adapted Seeman AL scale consisting of 10 systemic biomarkers: body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, glomerular filtration rate, albumin, C-reactive protein, and homocysteine. AL score was defined as the number of biomarkers with measurements in the highest risk quartiles. Age was calculated as the median age at time of biomarker measurements. Logistic regression analysis was performed to assess the association between the earliest possible AL score and glaucoma adjusted for race/ethnicity. Mediation analysis was performed to estimate the relationship between race/ethnicity and glaucoma mediated by AL score. RESULTS: The study cohort consisted of 349 (16.1%) cases and 1,819 (83.9%) controls with 52.7% females, 2.2% Asians, 10.7% Blacks, 10.0% Hispanics, and 72.5% non-Hispanic Whites. At the earliest timepoint (median [IQR] = 6.4 [1.9-12.2] years prior to diagnosis), cases had higher AL score than controls (3 [1-4] versus 2 [1-3], respectively; p<0.001). On multivariable analysis, higher AL score (OR=1.09 per point), Black race (OR=2.58), and Hispanic ethnicity (OR=2.12) conferred higher risk of glaucoma (p≤0.02). AL score partially mediated higher glaucoma risk among Blacks (7.5%) and Hispanics (5.0%) compared to non-Hispanic Whites. On subgroup analysis, higher AL score was significantly associated with primary open angle glaucoma (POAG; OR=1.11; p=0.01) but not primary angle closure glaucoma (PACG; p=0.87). CONCLUSION: AoU participants with glaucoma had greater AL 6.4 years prior to diagnosis, and AL score partially mediated racial/ethnic differences in glaucoma risk. These findings suggest chronic stress may increase risk for glaucoma and contribute to racial disparities in glaucoma burden.

Patterns and Disparities in Recorded Gonioscopy During Initial Glaucoma Evaluations in the United States.

PURPOSE: To assess patterns in gonioscopy during initial glaucoma evaluations in the United States. DESIGN: Retrospective, case-control study. METHODS: Patients undergoing initial glaucoma evaluation between 2009-2020 were identified in the Optum Clinformatics DataMart. Initial evaluation was defined as follows: (1) glaucoma suspect, anatomical narrow angle (ANA), or primary/secondary glaucoma diagnosed by an ophthalmologist; (2) continuously observable during a 36-month lookback period; (3) no history of glaucoma medications, laser, or surgical procedures; and (4) optical coherence tomography (OCT) or visual field performed within 6 months of initial diagnosis. Logistic regression models were developed to identify factors associated with no record of gonioscopy based on Current Procedural Terminology (CPT) codes. RESULTS: Among 198,995 patients, 20.4% and 29.5% had recorded gonioscopy on the day of diagnosis or within 6 months, respectively. On multivariable analysis, odds of recorded gonioscopy within 6 months of initial evaluation was lower (P < .001) among non-Hispanic Whites (OR=0.84) but similar for Blacks (OR=1.02) and Hispanics (OR=0.96) compared with Asians. Age ≥60 years (OR<0.82), pseudophakia/aphakia (OR=0.58), or residence outside of the Northeast region (OR=0.66-0.84) conferred lower odds of recorded gonioscopy (P < .001). Angle closure glaucoma (OR=0.85), secondary glaucoma (OR=0.31), or open angle glaucoma/suspect (OR=0.12/0.24, respectively) patients were less likely to have recorded gonioscopy compared to ANA patients (P < .01). CONCLUSIONS: More than 70% patients undergoing initial glaucoma evaluation in the United States do not have a record of gonioscopy, especially elderly, non-Hispanic White, and pseudophakic patients in non-Northeast regions. This pattern does not conform to current practice guidelines and could contribute to misdiagnosed disease and suboptimal outcomes.

Prevalence and Risk Factors of Blindness Among Primary Angle Closure Glaucoma Patients in the United States: An IRIS Registry Analysis.

PURPOSE: To assess the prevalence and risk factors of blindness among patients newly diagnosed with primary angle closure glaucoma (PACG) in the United States. DESIGN: Retrospective cross-sectional study. METHODS: Eligible patients from the American Academy of Ophthalmology (AAO) Intelligent Research in Sight (IRIS) Registry had newly diagnosed PACG, defined as: 1) observable during a 24-month lookback period from index date of PACG diagnosis; 2) no history of eye drops, laser, or cataract surgery unless preceded by a diagnosis of anatomical narrow angle (ANA); and 3) no history of glaucoma surgery. Logistic regression models were developed to identify risk factors for any (one or both eyes) or bilateral (both eyes) blindness (visual acuity ≤20/200) at first diagnosis of PACG. RESULTS: Among 43,901 eligible patients, overall prevalence of any and bilateral blindness were 11.5% and 1.8%, respectively. Black and Hispanic patients were at higher risk of any (odds ratios [ORs] 1.42 and 1.21, respectively; P < .001) and bilateral (ORs 2.04 and 1.53, respectively; P < .001) blindness compared with non-Hispanic White patients adjusted for ocular comorbidities. Age <50 or >80 years, male sex, Medicaid or Medicare insurance product, and Southern or Western practice region also conferred a higher risk of blindness (OR > 1.28; P ≤ .01). CONCLUSIONS: Blindness affects 1 of 9 patients with newly diagnosed PACG in the IRIS Registry. Black and Hispanic patients and Medicaid and Medicare recipients are at significantly higher risk. These findings highlight the severe ocular morbidity among patients with PACG and the need for improved disease awareness and detection methods.

Advances and Challenges in Wearable Glaucoma Diagnostics and Therapeutics.

Glaucoma is a leading cause of irreversible blindness, and early detection and treatment are crucial for preventing vision loss. This review aims to provide an overview of current diagnostic and treatment standards, recent medical and technological advances, and current challenges and future outlook for wearable glaucoma diagnostics and therapeutics. Conventional diagnostic techniques, including the rebound tonometer and Goldmann Applanation Tonometer, provide reliable intraocular pressure (IOP) measurement data at single-interval visits. The Sensimed Triggerfish and other emerging contact lenses provide continuous IOP tracking, which can improve diagnostic IOP monitoring for glaucoma. Conventional therapeutic techniques include eye drops and laser therapies, while emerging drug-eluting contact lenses can solve patient noncompliance with eye medications. Theranostic platforms combine diagnostic and therapeutic capabilities into a single device. Advantages of these platforms include real-time monitoring and personalized medication dosing. While there are many challenges to the development of wearable glaucoma diagnostics and therapeutics, wearable technologies hold great potential for enhancing glaucoma management by providing continuous monitoring, improving medication adherence, and reducing the disease burden on patients and healthcare systems. Further research and development of these technologies will be essential to optimizing patient outcomes.

Assessment of angle closure disease in the age of artificial intelligence: A review.

Primary angle closure glaucoma is a visually debilitating disease that is under-detected worldwide. Many of the challenges in managing primary angle closure disease (PACD) are related to the lack of convenient and precise tools for clinic-based disease assessment and monitoring. Artificial intelligence (AI)- assisted tools to detect and assess PACD have proliferated in recent years with encouraging results. Machine learning (ML) algorithms that utilize clinical data have been developed to categorize angle closure eyes by disease mechanism. Other ML algorithms that utilize image data have demonstrated good performance in detecting angle closure. Nonetheless, deep learning (DL) algorithms trained directly on image data generally outperformed traditional ML algorithms in detecting PACD, were able to accurately differentiate between angle status (open, narrow, closed), and automated the measurement of quantitative parameters. However, more work is required to expand the capabilities of these AI algorithms and for deployment into real-world practice settings. This includes the need for real-world evaluation, establishing the use case for different algorithms, and evaluating the feasibility of deployment while considering other clinical, economic, social, and policy-related factors.

Long-Term Risk and Prediction of Progression in Primary Angle Closure Suspect.

Importance: Identifying primary angle closure suspect (PACS) eyes at risk of angle closure is crucial for its management. However, the risk of progression and its prediction are still understudied in long-term longitudinal studies about PACS. Objective: To explore baseline predictors and develop prediction models for the 14-year risk of progression from PACS to primary angle closure (PAC). Design, Setting, and Participants: This cohort study involved participants from the Zhongshan Angle Closure Prevention trial who had untreated eyes with PACS. Baseline examinations included tonometry, ultrasound A-scan biometry, and anterior segment optical coherence tomography (AS-OCT) under both light and dark conditions. Primary angle closure was defined as peripheral anterior synechiae in 1 or more clock hours, intraocular pressure (IOP) greater than 24 mm Hg, or acute angle closure. Based on baseline covariates, logistic regression models were built to predict the risk of progression from PACS to PAC during 14 years of follow-up. Results: The analysis included 377 eyes from 377 patients (mean [SD] patient age at baseline, 58.28 [4.71] years; 317 females [84%]). By the 14-year follow-up visit, 93 eyes (25%) had progressed from PACS to PAC. In multivariable models, higher IOP (odds ratio [OR], 1.14 [95% CI, 1.04-1.25] per 1-mm Hg increase), shallower central anterior chamber depth (ACD; OR, 0.81 [95% CI, 0.67-0.97] per 0.1-mm increase), and shallower limbal ACD (OR, 0.96 [95% CI, 0.93-0.99] per 0.01 increase in peripheral corneal thickness) at baseline were associated with an increased 14-year risk of progression from PACS to PAC. As for AS-OCT measurements, smaller light-room trabecular-iris space area (TISA) at 500 µm from the scleral spur (OR, 0.86 [95% CI, 0.77-0.96] per 0.01-mm2 increase), smaller light-room angle recess area (ARA) at 750 µm from the scleral spur (OR, 0.93 [95% CI, 0.88-0.98] per 0.01-mm2 increase), and smaller dark-room TISA at 500 µm (OR, 0.89 [95% CI, 0.80-0.98] per 0.01-mm2 increase) at baseline were identified as predictors for the 14-year risk of progression. The prediction models based on IOP and central and limbal ACDs showed moderate performance (area under the receiver operating characteristic curve, 0.69; 95% CI, 0.63-0.75) in predicting progression from PACS to PAC, and inclusion of AS-OCT metrics did not improve the model's performance. Conclusions and Relevance: This cohort study suggests that higher IOP, shallower central and limbal ACDs, and smaller TISA at 500 µm and light-room ARA at 750 µm may serve as baseline predictors for progression to PAC in PACS eyes. Evaluating these factors can aid in customizing PACS management.

Federated Learning in Glaucoma: A Comprehensive Review and Future Perspectives.

Current approaches to developing artificial intelligence (AI) models for widespread glaucoma screening have encountered several obstacles. First, glaucoma is a complex condition with a wide range of morphological and clinical presentations. There exists no consensus definition of glaucoma or glaucomatous optic neuropathy. Further, training effective deep learning algorithms poses numerous challenges, including susceptibility to overfitting and lack of generalizability on external data. Therefore, training data should ideally be sourced from large, well-curated, multi-client cohorts to ensure diversity in patient populations, disease presentations, and imaging protocols. However, the construction of centralized repositories for multimodal data faces hurdles such as concerns regarding data sharing, re-identification, storage, regulations, patient privacy, and intellectual property. Federated learning (FL) has emerged as a proposed solution to address some of these concerns by enabling data to remain locally hosted while facilitating distributed model training. This article aims to provide a comprehensive review of the existing literature on FL in the context of its applications for AI tasks related to glaucoma.

Novel hyperparallel optical coherence tomography for angle closure assessment: comparison with swept-source OCT and gonioscopy.

AIM: To evaluate reproducibility and agreement of angle closure assessment by a novel hyperparallel optical coherence tomography (OCT) system (HP-OCT, Cylite Optics, Melbourne, Australia), in comparison with swept-source OCT (SS-OCT, CASIA SS-1000, Tomey Corporation, Nagoya, Japan) and gonioscopy. METHODS: Cross-sectional study. Phakic subjects >40 years, with no relevant ophthalmic history were consecutively recruited from the glaucoma clinic. Subjects underwent same-day evaluation with HP-OCT, SS-OCT and gonioscopy. The primary outcome was the presence of angle closure, defined as iridotrabecular contact in HP-OCT and SS-OCT images at 0°-180° meridional and as non-visibility of the posterior trabecular meshwork (TM) by gonioscopy. Visibility of TM was also assessed (secondary outcome). Intra and interdevice agreement analysis (Gwet AC1) and logistic regression analysis were performed for primary and secondary outcomes, respectively. RESULTS: 154 sectors from horizontal scans of 77 subjects were analysed. The reproducibility of angle closure assessment by HP-OCT was excellent (AC1 of 0.95 for temporal angle and 1.00 for nasal). Agreement for angle closure detection was very good between HP-OCT and SS-OCT (AC1 of 0.88 for temporal and 0.81 for nasal angle) and good between HP-OCT and gonioscopy (AC1 of 0.71 for temporal and 0.78 for nasal angle). TM was identifiable in 64.4% (94/146) of unprocessed HP-OCT images (both open and closed angles), however not visible in any of the SS-OCT unprocessed images. CONCLUSIONS: HP-OCT showed excellent reproducibility for angle closure assessment and good agreement with SS-OCT and gonioscopy. HP-OCT technology also provides a unique capability to visualise regions around TM and Schlemm's canal, opening new avenues for clinical research of distal outflow pathways.

Gap Analysis of Glaucoma Examination Concept Representations within Standard SNOMED Clinical Terms.

PURPOSE: Standardization of eye care data is important for clinical interoperability and research . We aimed to address gaps in the representations of glaucoma examination concepts within Systemized Nomenclature of Medicine - Clinical Terms (SNOMED-CT), the preferred terminology of the American Academy of Ophthalmology. DESIGN: Study of data elements. METHODS: Structured eye exam data fields from two electronic health records (EHR) systems (Epic Systems and Medisoft) were compared against existing SNOMED-CT codes for concepts representing glaucoma examination findings3. Glaucoma specialists from multiple institutions were surveyed to identify high-priority gaps in representation, which were discussed among the SNOMED International Eye Care Clinical Reference Group. Proposals for new codes to address the gaps were formulated and submitted for inclusion in SNOMED-CT. MAIN OUTCOME MEASURES: Gaps in SNOMED-CT glaucoma examination concept representations RESULTS: We identified several gaps in SNOMED-CT regarding glaucoma examination concepts. A survey of glaucoma specialists identified high-priority data elements within the categories of tonometry and gonioscopy. For tonometry, there was consensus that we need to define new codes related to maximum intraocular pressure (IOP) and target IOP, and to delineate all methods of measuring IOP. These new codes were proposed and successfully added to SNOMED-CT for future use. Regarding gonioscopy, the current terminology did not include the ability to denote the gonioscopic grading system used (e.g., Shaffer or Spaeth), degree of angle pigmentation, iris configuration (except for plateau iris), and iris approach. There was also no ability to specify eye laterality or angle quadrant for gonioscopic findings. We proposed a framework for representing gonioscopic findings as observable entities in SNOMED-CT. DISCUSSION: There are existing gaps in the standardized representation of findings related to tonometry and gonioscopy within SNOMED-CT. These are important areas for evaluating clinical outcomes and enabling secondary use of EHR data for glaucoma research. This international, multi-institutional collaborative process enabled identification of gaps, prioritization, and development of data standards to address these gaps. CONCLUSION: Addressing these gaps and augmenting SNOMED-CT coverage of glaucoma examination findings could enhance clinical documentation and future research efforts related to glaucoma.

Expert-Level Detection of Referable Glaucoma from Fundus Photographs in a Safety Net Population: The AI and Teleophthalmology in Los Angeles Initiative.

Purpose: To develop and test a deep learning (DL) algorithm for detecting referable glaucoma in the Los Angeles County (LAC) Department of Health Services (DHS) teleretinal screening program. Methods: Fundus photographs and patient-level labels of referable glaucoma (defined as cup-to-disc ratio [CDR] ≥ 0.6) provided by 21 trained optometrist graders were obtained from the LAC DHS teleretinal screening program. A DL algorithm based on the VGG-19 architecture was trained using patient-level labels generalized to images from both eyes. Area under the receiver operating curve (AUC), sensitivity, and specificity were calculated to assess algorithm performance using an independent test set that was also graded by 13 clinicians with one to 15 years of experience. Algorithm performance was tested using reference labels provided by either LAC DHS optometrists or an expert panel of 3 glaucoma specialists. Results: 12,098 images from 5,616 patients (2,086 referable glaucoma, 3,530 non-glaucoma) were used to train the DL algorithm. In this dataset, mean age was 56.8 ± 10.5 years with 54.8% females and 68.2% Latinos, 8.9% Blacks, 2.7% Caucasians, and 6.0% Asians. 1,000 images from 500 patients (250 referable glaucoma, 250 non-glaucoma) with similar demographics (p ≥ 0.57) were used to test the DL algorithm. Algorithm performance matched or exceeded that of all independent clinician graders in detecting patient-level referable glaucoma based on LAC DHS optometrist (AUC = 0.92) or expert panel (AUC = 0.93) reference labels. Clinician grader sensitivity (range: 0.33-0.99) and specificity (range: 0.68-0.98) ranged widely and did not correlate with years of experience (p ≥ 0.49). Algorithm performance (AUC = 0.93) also matched or exceeded the sensitivity (range: 0.78-1.00) and specificity (range: 0.32-0.87) of 6 LAC DHS optometrists in the subsets of the test dataset they graded based on expert panel reference labels. Conclusions: A DL algorithm for detecting referable glaucoma developed using patient-level data provided by trained LAC DHS optometrists approximates or exceeds performance by ophthalmologists and optometrists, who exhibit variable sensitivity and specificity unrelated to experience level. Implementation of this algorithm in screening workflows could help reallocate eye care resources and provide more reproducible and timely glaucoma care.