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PURPOSE: To assess the psychometric properties of glaucoma-specific health-related quality of life (HRQoL) item banks (IBs), and explore their efficiency using computerized adaptive testing (CAT) simulations. METHODS: In this cross-sectional, clinical study, 300 Asian glaucoma patients answered 221 items within seven IBs: Ocular Comfort Symptoms (OS); Activity Limitation (AL); Lighting (LT); Mobility (MB); Glaucoma Management (GM); Psychosocial (PSY); and Work (WK). Rasch analysis was conducted to assess each IB's psychometric properties (e.g., item "fit" to the construct; unidimensionality) and a set of analytic performance criteria guiding decision making relating to retaining or dropping domains and items was employed. CAT simulations determined the mean number of items for 'high' and 'moderate' measurement precision (stopping rule: SEM 0.3 and 0.387, respectively). RESULTS: Participants' mean age was 67.2 ± 9.2 years (62% male; 87% Chinese). LT, MB, and GM displayed good psychometric properties overall. To optimize AL's psychometric properties, 16 items were deleted due to poor "fit", high missing data, item bias, low discrimination and/or a low clinical/patient importance rating. To resolve multidimensionality in PSY, we rehomed 16 items into a "Concern (CN)" domain. PSY and CN required further amendment, including collapsing of response categories, and removal of poorly functioning items (N = 7). Due to poor measurement precision, low applicability and high ceiling effect, low test information indices, and low item separation index the WK IB was not considered further. In CAT simulations on the final seven IBs (n = 182 items total), an average of 12.1 and 15.7 items per IB were required for moderate and high precision measurement, respectively. CONCLUSIONS: After reengineering our seven IBs, they displayed robust psychometric properties and good efficiency in CAT simulations. Once finalized, GlauCAT™-Asian may enable comprehensive assessment of the HRQoL impact of glaucoma and associated treatments.

Purpose We hypothesized that the effect of blood lipid–related metabolites on primary open-angle glaucoma (POAG) would differ according to specific lipoprotein particles and lipid sub-fractions. We investigated the associations of blood levels of lipoprotein particles and lipid sub-fractions with POAG. Design Cross-sectional study. Participants Individuals recruited for the baseline visit of the population-based Singapore Epidemiology of Eye Disease study (n = 8503). Methods All participants underwent detailed standardized ocular and systemic examinations. A total of 130 blood lipid–related metabolites were quantified using a nuclear magnetic resonance metabolomics platform. The analyses were conducted in 2 stages. First, we investigated whether and which lipid-related metabolites were directly associated with POAG using regression analyses followed by Bayesian network modeling. Second, we investigated if any causal relationship exists between the identified lipid-related metabolites, if any, and POAG using 2-sample Mendelian randomization (MR) analysis. We performed genome-wide association studies (GWAS) on high-density lipoprotein (HDL) 3 cholesterol (after inverse normal transformation) and used the top variants associated with HLD3 cholesterol as instrumental variables (IVs) in the MR analysis. Main Outcome Measure Primary open-angle glaucoma. Results Of the participants, 175 (2.1%) had POAG. First, a logistic regression model showed that total HDL3 cholesterol (negatively) and phospholipids in very large HDL (positively) were associated with POAG. Further analyses using a Bayesian network analysis showed that only total HDL3 cholesterol was directly associated with POAG (odds ratio [OR], 0.72 per 1 standard deviation increase in HDL3 cholesterol; 95% confidence interval [CI], 0.61–0.84), independently of age, gender, intraocular pressure (IOP), body mass index (BMI), education level, systolic blood pressure, axial length, and statin medication. Using 5 IVs identified from the GWAS and with the inverse variance weighted MR method, we found that higher levels of HDL3 cholesterol were associated with a decreased odds of POAG (OR, 0.91; 95% CI, 0.84–0.99, P = 0.021). Other MR methods, including weighted median, mode-based estimator, and contamination mixture methods, derived consistent OR estimates. None of the routine lipids (blood total, HDL, or low-density lipoprotein [LDL] cholesterol) were associated with POAG. Conclusions Overall, these results suggest that the relationship between HDL3 cholesterol and POAG might be causal and specific, and that dysregulation of cholesterol transport may play a role in the pathogenesis of POAG.

Purpose To examine the efficacy of laser peripheral iridotomy (LPI) in patients who received a diagnosis of primary angle-closure suspect (PACS). Design Prospective, randomized controlled trial. Participants This multicenter, randomized controlled trial ( ClinicalTrials.gov identifier, NCT00347178 ) enrolled 480 patients older than 50 years from glaucoma clinics in Singapore with bilateral asymptomatic PACS (defined as having ≥2 quadrants of appositional angle closure on gonioscopy). Methods Each participant underwent prophylactic LPI in 1 randomly selected eye, whereas the fellow eye served as a control. Patients were followed up yearly for 5 years. Main Outcome Measures The primary outcome measure was development of primary angle closure (PAC; defined as presence of peripheral anterior synechiae, intraocular pressure [IOP] of >21 mmHg, or both or acute angle closure [AAC]) or primary angle-closure glaucoma (PACG) over 5 years. Results Of the 480 randomized participants, most were Chinese (92.7%) and were women (75.8%) with mean age of 62.8 ± 6.9 years. Eyes treated with LPI reached the end point less frequently after 5 years (n = 24 [5.0%]; incidence rate [IR], 11.65 per 1000 eye-years) compared with control eyes (n = 45 [9.4%]; IR, 21.84 per 1000 eye-years; P = 0.001). The adjusted hazard ratio (HR) for progression to PAC was 0.55 (95% confidence interval [CI], 0.37–0.83; P = 0.004) in LPI-treated eyes compared with control eyes. Older participants (per year; HR, 1.06; 95% CI, 1.03–1.10; P Conclusions In patients with bilateral asymptomatic PACS, eyes that underwent prophylactic LPI reached significantly fewer end points compared with control eyes over 5 years. However, the overall incidence of PAC or PACG was low.

AimsTo validate a deep learning (DL) algorithm (DLA) for 360° angle assessment on swept-source optical coherence tomography (SS-OCT) (CASIA SS-1000, Tomey Corporation, Nagoya, Japan).MethodsThis was a reliability analysis from a cross-sectional study. An independent test set of 39 936 SS-OCT scans from 312 phakic subjects (128 SS-OCT meridional scans per eye) was analysed. Participants above 50 years with no previous history of intraocular surgery were consecutively recruited from glaucoma clinics. Indentation gonioscopy and dark room SS-OCT were performed. Gonioscopic angle closure was defined as non-visibility of the posterior trabecular meshwork in ≥180° of the angle. For each subject, all images were analysed by a DL-based network based on the VGG-16 architecture, for gonioscopic angle-closure detection. Area under receiver operating characteristic curves (AUCs) and other diagnostic performance indicators were calculated for the DLA (index test) against gonioscopy (reference standard).ResultsApproximately 80% of the participants were Chinese, and more than half were women (57.4%). The prevalence of gonioscopic angle closure in this hospital-based sample was 20.2%. After analysing a total of 39 936 SS-OCT scans, the AUC of the DLA was 0.85 (95% CI:0.80 to 0.90, with sensitivity of 83% and a specificity of 87%) to classify gonioscopic angle closure with the optimal cut-off value of >35% of circumferential angle closure.ConclusionsThe DLA exhibited good diagnostic performance for detection of gonioscopic angle closure on 360° SS-OCT scans in a glaucoma clinic setting. Such an algorithm, independent of the identification of the scleral spur, may be the foundation for a non-contact, fast and reproducible ‘automated gonioscopy’ in future.

Purpose The aim of the study is to examine the baseline intraocular pressure (IOP) and its changes after performing a water drinking test (WDT) in patients with unilateral hemifacial spasm (HFS). Patients and methods In this prospective observational study, patients aged 21 years and above diagnosed with unilateral HFS were recruited from the Singapore National Eye Centre between January 2015 and August 2016. The unaffected eye of each patient served as a matched control. An interviewer-administered standardized questionnaire on HFS symptoms and ophthalmic examination was performed. Automated perimetry, optical coherence tomography (OCT) of the optic nerve head, color disc stereophotography and water drinking test (WDT) were done. The primary outcome measure was the difference in IOP between eyes affected by HFS and fellow eyes at baseline and at 15, 30 and 45 minutes of the WDT. Results Fifty-four patients with unilateral HFS were included. Mean age was 59.8±9.9 years (range, 37.0-84.0). Of these, 54% were female and 94% were Chinese. Mean baseline IOP was significantly higher in eyes with HFS (13.9±3.1mmHg) compared to fellow eyes (13.3±2.8mmHg) (p=0.008). There was no significant difference in absolute or percentage change in IOP from baseline between the 2 groups at 15, 30 and 45 minutes of the WDT. Mean vertical cup-disc ratio (VCDR) on clinical examination was significantly higher in eyes with HFS (0.5±0.2) compared to fellow eyes (0.4±0.2) (p=0.02). There was no significant difference between the groups for visual field parameters and mean retinal nerve fiber layer thickness on OCT. Conclusion Hemifacial spasm is associated with a small but significant difference in mean baseline IOP and VCDR between affected and fellow eyes. However, when eyes affected by HFS and fellow eyes were challenged with the WDT, both responded in similar ways.

Precis Improvements in post-trabeculectomy visual field outcomes were found to be significantly associated with pre-operative nerve fiber layer thickness parameters extracted from the sectorized structure-function relationship, baseline visual field and severity of glaucoma. Objective To determine whether the pre-operative structure-function relationship helps to predict visual outcomes at one-year post-trabeculectomy. Patients and methods 91 eyes from 87 participants who successfully underwent trabeculectomy were included in our study. All eyes received optical coherence tomography imaging and visual field assessment using 30-2 standard automated perimetry pre-operatively at baseline and post-operatively one year after trabeculectomy. Linear mixed model analysis was used to assess the association of structure and function at baseline, and multivariate analysis to investigate factors associated with post-operative visual field outcomes. Results Results from multivariate and univariate analysis for visual field one year after trabeculectomy showed that a positive pre-operative retinal nerve fiber layer thickness deviation from the structure-function model was found to be significantly associated with improved post-operative visual field outcomes (β=0.06▒dB/μm; 95% CI, 0.03 to 0.09). Other significant factors included baseline visual field mean deviation (β=-0.18; 95% CI -0.23 to -0.13) and the presence of severe glaucoma (β=-1.69; 95% CI, -2.80 to -0.57). Intraocular pressure was positively associated with improved visual field outcomes only in univariate analysis (β=0.06; 95% CI, 0.01 to 0.11). Conclusions and relevance Characteristics derived from the baseline structure-function relationship were found to be strongly associated with post-operative visual field outcomes. These findings suggest that the structure-function relationship could potentially have a role in predicting visual field progression after trabeculectomy.

Corneal diseases, along with glaucoma and cataract, are the leading causes of blindness worldwide. While corneal surgery offers good success rates, early diagnosis and disease prevention is the preferred choice over expensive and complex surgical procedures. Non-contact, high-resolution imaging modalities for imaging the corneal structures are highly desirable for clinical examinations for early diagnosis of corneal diseases. The currently used clinical standard is the in vivo confocal laser scanning microscopy, which is a contact based method. In this context, an in-house developed, non-contact, Gaussian epi-illumination based imaging system was used to image corneal injury in preclinical animal models in vivo. New Zealand white rabbits and Wistar rats were used as the preclinical models for the investigations. The lateral resolution of the developed system is 1.1 μm. The images obtained with the developed system, as well as the dimensional information of the corneal structures, are in good agreement with the data previously reported using standard methods. The proposed system offers a simple, easy operable, real-time, non-contact imaging modality for the evaluation of corneal structures in high-resolution. Agency for Science, Technology and Research (A*STAR) Nanyang Technological University National Medical Research Council (NMRC) The authors acknowledge financial support received through A*STAR-MIG project (BMRC1619077002), SERI-NTU ADVANCED OCULAR ENGINEERING (STANCE) Program Fund, NMRC Singapore Translational Research Investigator Award (NMRC/STaR/0023/2014), NMRC Transition Award (NMRC/TA/0040/2015), and NMRC Transition Award (NMRC/TA/0057/2017) for pursuing parts of the contents presented in this paper, and the research manpower and facilities provided through funding at COLE, NTU.

IMPORTANCE: A glaucoma-specific instrument for estimating utilities across the spectrum of glaucoma severity is currently lacking, hindering the assessment of the cost-effectiveness of glaucoma treatments. OBJECTIVE: To develop and validate the preference-based Glaucoma Utility Instrument (Glau-U) and to ascertain the association between Glau-U utilities and severity of glaucoma and vision impairment. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was conducted in 2 stages at the Singapore National Eye Centre glaucoma clinics. Stage 1 focused on the identification and pretesting of the Glau-U attributes and was carried out between June 2009 and May 2016. Stage 2 involved the development and administration of the discrete choice experiment (DCE) survey and tasks and was conducted between May 7, 2018, and December 11, 2019. Stage 2 participants were English- or Mandarin-speaking Singaporean citizens or permanent residents of Chinese, Malay, or Indian ethnicity who were 40 years or older and had a clinical diagnosis of glaucoma in at least 1 eye. EXPOSURES: Glau-U comprised 6 quality-of-life attributes: activities of daily living, lighting and glare, movement, eye discomfort, other effects of glaucoma, and social and emotional effects. The descriptions or response options for these attributes were no difficulty or never, some difficulty or sometimes, or severe difficulty or often. MAIN OUTCOMES AND MEASURES: Utility weights for Glau-U were developed using a DCE questionnaire, which was interviewer administered to participants. Mixed logit regression determined utility weights for each health state. Glau-U utility weights across better- or worse-eye glaucoma and vision impairment severity were calculated using 1-way analysis of variance. Correlations between Glau-U utilities and better- or worse-eye visual fields and EuroQol 5-Dimension utilities were ascertained to assess convergent and divergent validity. RESULTS: Of the 304 participants (mean [SD] age, 68.3 [8.7] years; 182 men [59.9%]), 281 (92.4%) had no vision impairment in the better eye, 13 (4.3%) had mild impairment, and 10 (3.3%) had moderate to severe vision impairment. Mean (SD) Glau-U utilities decreased as better-eye glaucoma severity increased (none: 0.73 [0.21]; mild: 0.66 [0.21]; moderate: 0.66 [0.20]; severe: 0.60 [0.28]; and advanced or end-stage: 0.22 [0.38]; P

Differentiating the two main forms of primary glaucoma (open-angle and closed-angle glaucoma) depends on the correct assessment of the anterior chamber angle (ACA). This assessment will determine the management plan and prognosis for the disease. The standard method of examining the angle has been, for many years, slit-lamp gonioscopy. This method, although clinically still useful, is less robust for patient follow up and clinical research, given its low reproducibility. Several imaging technologies have been developed in recent years to improve the evaluation of the ACA and overcome the shortcomings of gonioscopy. These recent advances include three-dimensional and 360° analysis by Swept-Source OCT (SS-OCT, CASIA, Tomey, Nagoya, Japan), the introduction of deep learning algorithms for automatic imaging classification and new goniophotographic systems. SS-OCT allows for the first time the assessment of the circumferential extension of angle closure with moderate to good diagnostic performance compared with gonioscopy. Deep learning algorithms are showing promising results for the automation of imaging analysis, and may potentially save physicians’ time in regards of the interpretation of the images. Lastly, goniophotograph systems have the distinct advantage of recordability of gonioscopic findings and are most closely matched to the findings of slit-lamp gonioscopy.

Background/aimsAlthough being a more objective tool for assessment and follow-up of angle closure, reliability studies have reported a moderate diagnostic performance for anterior segment optical coherence tomography (OCT) technologies when comparing with gonioscopy as the reference standard. We aim to determine factors associated with diagnostic disagreement in angle closure when assessed by anterior segment swept source OCT (SS-OCT, CASIA SS-1000; Tomey, Nagoya, Japan) and gonioscopy.MethodsCross-sectional study. A total of 2027 phakic subjects aged ≥50 years, with no relevant previous ophthalmic history, were consecutively recruited from a community polyclinic in Singapore. Gonioscopy and SS-OCT (128 radial scans) for the entire circumference of the angle were performed for each subject. A two-quadrant closed gonioscopic definition was used. On SS-OCT images, angle closure was defined as iridotrabecular contact (ITC) to the extent of ≥35%, ≥50% and ≥75% of the circumferential angle. Diagnostic disagreements between both methods, that is, false positives or overcalls and false negatives or undercalls were defined, respectively, as gonioscopic open/closed angles inversely assessed as closed/open by SS-OCT.ResultsTwo hundred and seventy-two (14.7%) resulted in overcall results (false positives) when ≥50% of the angle circumference was closed using SS-OCT. These eyes had significantly wider (anterior chamber width, 11.7 vs 11.6 mm, pConclusionsWe found that anterior chamber dimensions, determined by ACD and LV, were factors significantly associated with diagnostic disagreement between anterior segment SS-OCT and gonioscopy in angle closure assessment.

PReCIS:: Eyes with glaucoma have tauter optic nerves compared with normal eyes, which may exert more force on the optic nerve head tissues during eye movements. Purpose The purpose of this study was to assess the difference in optic nerve tortuosity during eye movements and globe proptosis between primary open angle glaucoma and normal subjects using orbital magnetic resonance imaging (MRI). Methods Ten Chinese subjects matched for ethnicity and refractive errors were recruited, including 5 normal controls and 5 patients with primary open angle glaucoma. All subjects underwent MRI to assess their optic nerves and globes for 3 eye positions: primary gaze, adduction, and abduction. Optic nerve tortuosity (optic nerve length divided by the distance between 2 ends) and globe proptosis (maximum distance between the cornea and interzygomatic line) were measured from MRI images. Results In adduction, the tortuosity of normal eyes was significantly larger than that of the glaucomatous eyes. Optic nerve tortuosity in adduction in the control and glaucoma groups were 1.004±0.003 (mean±SD) and 1.001±0.001, respectively (P=0.037). Globe proptosis (primary gaze) in glaucoma subjects (19.14±2.11 mm) was significantly higher than that in control subjects (15.32±2.79 mm; P=0.046). Conclusions In this sample, subjects with glaucoma exhibited tauter optic nerves and more protruding eye globes compared with normal eyes. This may impact optic nerve head deformations in anatomically predisposed patients.

Purpose Anterior segment optical coherence tomography (AS-OCT) provides an objective imaging modality for visually identifying anterior segment structures. An automated detection system could assist ophthalmologists in interpreting AS-OCT images for the presence of angle closure. Design Development of an artificial intelligence automated detection system for the presence of angle closure. Methods A deep learning system for automated angle-closure detection in AS-OCT images was developed, and this was compared with another automated angle-closure detection system based on quantitative features. A total of 4135 Visante AS-OCT images from 2113 subjects (8270 anterior chamber angle images with 7375 open-angle and 895 angle-closure) were examined. The deep learning angle-closure detection system for a 2-class classification problem was tested by 5-fold cross-validation. The deep learning system and the automated angle-closure detection system based on quantitative features were evaluated against clinicians' grading of AS-OCT images as the reference standard. Results The area under the receiver operating characteristic curve of the system using quantitative features was 0.90 (95% confidence interval [CI] 0.891–0.914) with a sensitivity of 0.79 ± 0.037 and a specificity of 0.87 ± 0.009, while the area under the receiver operating characteristic curve of the deep learning system was 0.96 (95% CI 0.953–0.968) with a sensitivity of 0.90 ± 0.02 and a specificity of 0.92 ± 0.008, against clinicians' grading of AS-OCT images as the reference standard. Conclusions The results demonstrate the potential of the deep learning system for angle-closure detection in AS-OCT images.

Increased evolution of multidrug resistant pathogens necessitates the development of multifunctional antimicrobials. There is a perceived need for developing new antimicrobials that can interfere with acute inflammation after bacterial infections. Here, we investigated the therapeutic potential of linear polyethylenimine (LPEI) in vitro and in vivo. The minimum inhibitory concentration of LPEI ranged from 8 to 32 μg/mL and elicited rapid bactericidal activity against clinical isolates of meticillin-resistant Staphylococcus aureus (MRSA). The polymer was biocompatible for human cultured ocular and dermal cells. Prophylactic addition of LPEI inhibited the bacterial colonization of human primary dermal fibroblasts (hDFs). In a scratch wound cell migration assay, LPEI attenuated the migration inhibitory effects of bacterial secretions. The polymer neutralized the cytokine release by hDFs exposed to bacterial secretions, possibly by blocking their accessibility to host cell receptors. Topical instillation of LPEI (1 mg/mL) was noncytotoxic and did not affect the re-epithelialization of injured porcine cornea. In a prophylactic in vivo model of S. aureus keratitis, LPEI was superior to gatifloxacin in terms of reducing stimulation of cytokines, corneal edema, and overall severity of the infection. These observations demonstrate therapeutic potential of LPEI for antimicrobial prophylaxis.

Chromatic pupillometry is an emerging modality in the assessment of retinal and optic nerve disorders. Herein, we evaluate the effect of low and moderate refractive errors on pupillary responses to blue- and red-light stimuli in a healthy older population. This study included 139 participants (≥50 years) grouped by refractive error: moderate myopes (>−6.0D and ≤−3.0D, n = 24), low myopes (>−3.0D and 0.5D and R = −0.26, P R = 0.37, P R = 0.43, P P = 0.45), while constriction amplitudes to red light were greater in hyperopes compared to emmetropes (P = 0.04) at moderate to bright light intensities (12.25–14.0 Log photons/cm²/s). Our results demonstrate that low and moderate myopia do not alter pupillary responses to ramping-up blue- and red-light stimuli in healthy older individuals. Conversely, pupillary responses to red light should be interpreted cautiously in hyperopic eyes.

We hypothesized that the effect of blood lipid-related metabolites on primary open-angle glaucoma (POAG) would differ according to specific lipoprotein particles and lipid sub-fractions. We investigated the associations of blood levels of lipoprotein particles and lipid sub-fractions with POAG.Cross-sectional study.Individuals recruited for the baseline visit of the population-based Singapore Epidemiology of Eye Disease study (n = 8503).All participants underwent detailed standardized ocular and systemic examinations. A total of 130 blood lipid-related metabolites were quantified using a nuclear magnetic resonance metabolomics platform. The analyses were conducted in 2 stages. First, we investigated whether and which lipid-related metabolites were directly associated with POAG using regression analyses followed by Bayesian network modeling. Second, we investigated if any causal relationship exists between the identified lipid-related metabolites, if any, and POAG using 2-sample Mendelian randomization (MR) analysis. We performed genome-wide association studies (GWAS) on high-density lipoprotein (HDL) 3 cholesterol (after inverse normal transformation) and used the top variants associated with HLD3 cholesterol as instrumental variables (IVs) in the MR analysis.Primary open-angle glaucoma.Of the participants, 175 (2.1%) had POAG. First, a logistic regression model showed that total HDL3 cholesterol (negatively) and phospholipids in very large HDL (positively) were associated with POAG. Further analyses using a Bayesian network analysis showed that only total HDL3 cholesterol was directly associated with POAG (odds ratio [OR], 0.72 per 1 standard deviation increase in HDL3 cholesterol; 95% confidence interval [CI], 0.61-0.84), independently of age, gender, intraocular pressure (IOP), body mass index (BMI), education level, systolic blood pressure, axial length, and statin medication. Using 5 IVs identified from the GWAS and with the inverse variance weighted MR method, we found that higher levels of HDL3 cholesterol were associated with a decreased odds of POAG (OR, 0.91; 95% CI, 0.84-0.99, P = 0.021). Other MR methods, including weighted median, mode-based estimator, and contamination mixture methods, derived consistent OR estimates. None of the routine lipids (blood total, HDL, or low-density lipoprotein [LDL] cholesterol) were associated with POAG.Overall, these results suggest that the relationship between HDL3 cholesterol and POAG might be causal and specific, and that dysregulation of cholesterol transport may play a role in the pathogenesis of POAG.