DDX58(RIG-I)-related disease is associated with tissue-specific interferon pathway activation.

BACKGROUND: Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic calcifications and skeletal and dental dysplasia. Few families have been described and the genotypic and phenotypic spectrum is poorly defined, with variants in DDX58 (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2. METHODS: Families underwent deep systemic phenotyping and exome sequencing. Functional characterisation with in vitro luciferase assays and in vivo interferon signature using bulk and single cell RNA sequencing was performed. RESULTS: We have identified a novel DDX58 variant c.1529A>T p.(Glu510Val) that segregates with disease in two families with SGMRT2. Patients in these families have widely variable phenotypic features and different ethnic background, with some being severely affected by systemic features and others solely with glaucoma. JOAG was present in all individuals affected with the syndrome. Furthermore, detailed evaluation of skin rash in one patient revealed sparse inflammatory infiltrates in a unique distribution. Functional analysis showed that the DDX58 variant is a dominant gain-of-function activator of interferon pathways in the absence of exogenous RNA ligands. Single cell RNA sequencing of patient lesional skin revealed a cellular activation of interferon-stimulated gene expression in keratinocytes and fibroblasts but not in neighbouring healthy skin. CONCLUSIONS: These results expand the genotypic spectrum of DDX58-associated disease, provide the first detailed description of ocular and dermatological phenotypes, expand our understanding of the molecular pathogenesis of this condition and provide a platform for testing response to therapy.

Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice.

Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development.

Surgical outcomes of Glaucoma associated with Axenfeld-Rieger syndrome.

BACKGROUND: The surgical management of glaucoma associated with Axenfeld-Rieger Syndrome (ARS) is poorly described in the literature. The goal of this study is to compare the effectiveness of various glaucoma surgeries on intraocular pressure (IOP) management in ARS. METHODS: Retrospective cohort study at a university hospital-based practice of patients diagnosed with ARS between 1973 and 2018. Exclusion criterion was follow-up less than 1 year. The number of eyes with glaucoma (IOP ≥ 21 mmHg with corneal edema, Haabs striae, optic nerve cupping or buphthalmos) requiring surgery was determined. The success and survival rates of goniotomy, trabeculotomy±trabeculectomy (no antifibrotics), cycloablation, trabeculectomy with anti-fibrotics, and glaucoma drainage device placement were assessed. Success was defined as IOP of 5-20 mmHg and no additional IOP-lowering surgery or visually devastating complications. Kaplan-Meier survival curves and the Wilcoxon test were used for statistical analysis. RESULTS: In 32 patients identified with ARS (median age at presentation 6.9 years, 0-58.7 years; median follow-up 5.4 years, 1.1-43.7 years), 23 (71.9%) patients were diagnosed with glaucoma at median age 6.3 years (0-57.9 years). In glaucomatous eyes (46 eyes), mean IOP at presentation was 21.8 ± 9.3 mmHg (median 20 mmHg, 4-45 mmHg) on 1.0 ± 1.6 glaucoma medications. Thirty-one eyes of 18 patients required glaucoma surgery with 2.2 ± 1.2 IOP-lowering surgeries per eye. Goniotomy (6 eyes) showed 43% success with 4.3 ± 3.9 years of IOP control. Trabeculotomy±trabeculectomy (6 eyes) had 17% success rate with 14.8 ± 12.7 years of IOP control. Trabeculectomy with anti-fibrotics (14 eyes) showed 57% success with 16.5 ± 13.5 years of IOP control. Ahmed© (FP7 or FP8) valve placement (8 eyes) had 25% success rate with 1.7 ± 1.9 years of IOP control. Baerveldt© (250 or 350) device placement (8 eyes) showed 70% success with 1.9 ± 2.3 years of IOP control. Cycloablation (4 eyes) had 33% success rate with 2.7 ± 3.5 years of IOP control. At final follow-up, mean IOP (12.6 ± 3.8 mmHg, median 11.8 mmHg, 7-19 mmHg) in glaucomatous eyes was significantly decreased (p < 0.0001), but there was no difference in number of glaucoma medications (1.6 ± 1.5, p = 0.1). CONCLUSIONS: In our series, greater than 70% of patients with ARS have secondary glaucoma that often requires multiple surgeries. Trabeculectomy with anti-fibrotics and Baerveldt glaucoma drainage devices showed the greatest success in obtaining IOP control.

Precision medicine to prevent glaucoma-related blindness.

PURPOSE OF REVIEW: Approximately 10% of patients become blind despite using evidence-based guidelines developed from clinical trials and epidemiology studies. Our purpose is to review opportunities to decrease glaucoma-related blindness using the emerging principles of precision medicine. RECENT FINDINGS: The current review focuses on three topics: first, candidate biomarkers for angle-based surgeries, second, head-mounted display (HMD) technology for vision and testing, and third, glaucoma risk alleles discovered by genome-wide association studies. First, in angle-based surgeries, tracers injected into the anterior chamber or Schlemm's canal have allowed visualization of aqueous veins. We describe an innovative use of optical coherence tomography angiography to visualize aqueous veins in a case with 6-year successful outcome following catheter-based trabeculotomy. Second, HMD technology can augment perceived vision and can be used for perimetry testing. Third, developing genetic risk scores that characterize patients who are at highest risk for blindness is a priority. Such biomarker risk scores will integrate genome-wide association study-based risk alleles for glaucoma along with well known demographic and clinical risk factors. SUMMARY: As we gain more knowledge, precision medicine will enable clinicians to decrease glaucoma-related blindness by providing more timely interventions to those patients who are at highest risk for progression to blindness. VIDEO ABSTRACT: http://links.lww.com/COOP/A29.

The future of canine glaucoma therapy.

Canine glaucoma is a group of disorders that are generally associated with increased intraocular pressure (IOP) resulting in a characteristic optic neuropathy. Glaucoma is a leading cause of irreversible vision loss in dogs and may be either primary or secondary. Despite the growing spectrum of medical and surgical therapies, there is no cure, and many affected dogs go blind. Often eyes are enucleated because of painfully high, uncontrollable IOP. While progressive vision loss due to primary glaucoma is considered preventable in some humans, this is mostly not true for dogs. There is an urgent need for more effective, affordable treatment options. Because newly developed glaucoma medications are emerging at a very slow rate and may not be effective in dogs, work toward improving surgical options may be the most rewarding approach in the near term. This Viewpoint Article summarizes the discussions and recommended research strategies of both a Think Tank and a Consortium focused on the development of more effective therapies for canine glaucoma; both were organized and funded by the American College of Veterinary Ophthalmologists Vision for Animals Foundation (ACVO-VAF). The recommendations consist of (a) better understanding of disease mechanisms, (b) early glaucoma diagnosis and disease staging, (c) optimization of IOP-lowering medical treatment, (d) new surgical therapies to control IOP, and (e) novel treatment strategies, such as gene and stem cell therapies, neuroprotection, and neuroregeneration. In order to address these needs, increases in research funding specifically focused on canine glaucoma are necessary.

Primary Open-Angle Glaucoma Preferred Practice Pattern(®) Guidelines.

UNLABELLED: PRIMARY OPEN-ANGLE GLAUCOMA PREFERRED PRACTICE PATTERN® GUIDELINES: Evidence-based update of the Primary Open-Angle Glaucoma Preferred Practice Pattern® (PPP) guidelines, describing the diagnosis and management of patients with primary open-angle glaucoma with an algorithm for patient management and detailed recommendations for evaluation and treatment options.

Primary Angle Closure Preferred Practice Pattern(®) Guidelines.

UNLABELLED: PRIMARY ANGLE CLOSURE PREFERRED PRACTICE PATTERN® GUIDELINES: Evidence-based update of the Primary Angle Closure Preferred Practice Pattern® (PPP) guidelines, describing the diagnosis and management of patients with primary angle closure with detailed recommendations for evaluation and treatment options.

Primary Open-Angle Glaucoma Suspect Preferred Practice Pattern(®) Guidelines.

UNLABELLED: PRIMARY OPEN-ANGLE GLAUCOMA SUSPECT PREFERRED PRACTICE PATTERN® GUIDELINES: Evidence-based update of the Primary Open-Angle Suspect Glaucoma Preferred Practice Pattern® (PPP) guidelines, describing the diagnosis and management of patients with primary open-angle glaucoma suspect with detailed recommendations for evaluation and treatment options.

Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma.

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹8), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹°). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Genome-wide association study and meta-analysis of intraocular pressure.

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma and is influenced by genetic and environmental factors. Recent genome-wide association studies (GWAS) reported associations with IOP at TMCO1 and GAS7, and with primary open-angle glaucoma (POAG) at CDKN2B-AS1, CAV1/CAV2, and SIX1/SIX6. To identify novel genetic variants and replicate the published findings, we performed GWAS and meta-analysis of IOP in >6,000 subjects of European ancestry collected in three datasets: the NEI Glaucoma Human genetics collaBORation, GLAUcoma Genes and ENvironment study, and a subset of the Age-related Macular Degeneration-Michigan, Mayo, AREDS and Pennsylvania study. While no signal achieved genome-wide significance in individual datasets, a meta-analysis identified significant associations with IOP at TMCO1 (rs7518099-G, p = 8.0 × 10(-8)). Focused analyses of five loci previously reported for IOP and/or POAG, i.e., TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2, and SIX1/SIX6, revealed associations with IOP that were largely consistent across our three datasets, and replicated the previously reported associations in both effect size and direction. These results confirm the involvement of common variants in multiple genomic regions in regulating IOP and/or glaucoma risk.

Hypothesis-independent pathway analysis implicates GABA and acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma.

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p < 0.001. In addition, the human leukocyte antigen (HLA) gene family was significantly associated with POAG (p < 0.001). In the POAG subset with normal-pressure glaucoma (NPG), the butanoate metabolism pathway was also significantly associated (p < 0.001) as well as the MAPK and Hedgehog signaling pathways (hsa04010 and hsa04340), glycosaminoglycan biosynthesis-heparan sulfate pathway (hsa00534) and the phenylalanine, tyrosine and tryptophan biosynthesis pathway (hsa0400). The butanoate metabolism pathway overall, and specifically the aspects of the pathway that contribute to GABA and acetyl-CoA metabolism, was the only pathway significantly associated with both POAG and NPG. Collectively these results implicate GABA and acetyl-CoA metabolism in glaucoma pathogenesis, and suggest new potential therapeutic targets.

Association of CAV1/CAV2 genomic variants with primary open-angle glaucoma overall and by gender and pattern of visual field loss.

PURPOSE: The CAV1/CAV2 (caveolin 1 and caveolin 2) genomic region previously was associated with primary open-angle glaucoma (POAG), although replication among independent studies has been variable. The aim of this study was to assess the association between CAV1/CAV2 single nucleotide polymorphisms (SNPs) and POAG in a large case-control dataset and to explore associations by gender and pattern of visual field (VF) loss further. DESIGN: Case-control study. PARTICIPANTS: We analyzed 2 large POAG data sets: the Glaucoma Genes and Environment (GLAUGEN) study (976 cases, 1140 controls) and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium (2132 cases, 2290 controls). METHODS: We studied the association between 70 SNPs located within the CAV1/CAV2 genomic region in the GLAUGEN and NEIGHBOR studies, both genotyped on the Illumina Human 660WQuadv1C BeadChip array and imputed with the Markov Chain Haplotyping algorithm using the HapMap 3 reference panel. We used logistic regression models of POAG in the overall population and separated by gender, as well as by POAG subtypes defined by type of VF defect (peripheral or paracentral). Results from GLAUGEN and NEIGHBOR were meta-analyzed, and a Bonferroni-corrected significance level of 7.7 × 10(-4) was used to account for multiple comparisons. MAIN OUTCOME MEASURES: Overall POAG, overall POAG by gender, and POAG subtypes defined by pattern of early VF loss. RESULTS: We found significant associations between 10 CAV1/CAV2 SNPs and POAG (top SNP, rs4236601; pooled P = 2.61 × 10(-7)). Of these, 9 were significant only in women (top SNP, rs4236601; pooled P = 1.59 × 10(-5)). Five of the 10 CAV1/CAV2 SNPs were associated with POAG with early paracentral VF (top SNP, rs17588172; pooled P = 1.07 × 10(-4)), and none of the 10 were associated with POAG with peripheral VF loss only or POAG among men. CONCLUSIONS: CAV1/CAV2 SNPs were associated significantly with POAG overall, particularly among women. Furthermore, we found an association between CAV1/CAV2 SNPs and POAG with paracentral VF defects. These data support a role for caveolin 1, caveolin 2, or both in POAG and suggest that the caveolins particularly may affect POAG pathogenesis in women and in patients with early paracentral VF defects.

Estrogen pathway polymorphisms in relation to primary open angle glaucoma: an analysis accounting for gender from the United States.

PURPOSE: Circulating estrogen levels are relevant in glaucoma phenotypic traits. We assessed the association between an estrogen metabolism single nucleotide polymorphism (SNP) panel in relation to primary open angle glaucoma (POAG), accounting for gender. METHODS: We included 3,108 POAG cases and 3,430 controls of both genders from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium genotyped on the Illumina 660W-Quad platform. We assessed the relation between the SNP panels representative of estrogen metabolism and POAG using pathway- and gene-based approaches with the Pathway Analysis by Randomization Incorporating Structure (PARIS) software. PARIS executes a permutation algorithm to assess statistical significance relative to the pathways and genes of comparable genetic architecture. These analyses were performed using the meta-analyzed results from the GLAUGEN and NEIGHBOR data sets. We evaluated POAG overall as well as two subtypes of POAG defined as intraocular pressure (IOP) ≥22 mmHg (high-pressure glaucoma [HPG]) or IOP <22 mmHg (normal pressure glaucoma [NPG]) at diagnosis. We conducted these analyses for each gender separately and then jointly in men and women. RESULTS: Among women, the estrogen SNP pathway was associated with POAG overall (permuted p=0.006) and HPG (permuted p<0.001) but not NPG (permuted p=0.09). Interestingly, there was no relation between the estrogen SNP pathway and POAG when men were considered alone (permuted p>0.99). Among women, gene-based analyses revealed that the catechol-O-methyltransferase gene showed strong associations with HTG (permuted gene p≤0.001) and NPG (permuted gene p=0.01). CONCLUSIONS: The estrogen SNP pathway was associated with POAG among women.

3D imaging of aqueous veins and surrounding sclera using a dual-wavelength photoacoustic microscopy.

Understanding aqueous outflow resistance at the level of aqueous veins has been a challenge to the management of glaucoma. This study investigated resolving the anatomies of aqueous veins and the textures of surrounding sclera using photoacoustic microscopy (PAM). A dual wavelength PAM system was established and validated using imaging phantoms, porcine and human globes perfused with an optical contrast agent ex vivo. The system shows lateral resolution of 8.23 µm and 4.70 µm at 1200 nm and 532 nm, respectively, and an axial resolution of 27.6 µm. The system is able to separately distinguish the aqueous veins and the sclera with high contrast in full circumference of the porcine and human globes.

Eye Dynamics and Engineering Network Consortium: Baseline Characteristics of a Randomized Trial in Healthy Adults.

PURPOSE: To improve understanding of intraocular pressure (IOP) and its variance, this project identifies systemic and ocular characteristics of healthy eyes of adult volunteers including IOP variation, ocular biometrics, and aqueous humor dynamics (AHDs). These data serve as baseline controls for further studies from the Eye Dynamics and Engineering Network (EDEN) Consortium. DESIGN: Multicenter open-label clinical trial in healthy adults randomized to 1 week treatment with 2 approved glaucoma drugs in a crossover design. PARTICIPANTS: Among 135 healthy participants, 122 participants (aged 55.2 ± 8.8 years; 92 females, 30 males) completed the protocol. METHODS: Participants from the University of Michigan, Mayo Clinic, and University of Nebraska Medical Center underwent measurements of ocular biometrics, AHD, and IOP using 4 tonometers. Intraocular pressure data during 3 study visits without glaucoma medications were used in the analysis. The PhenX Toolkit survey acquired standardized data on medical history, surgical history, medications, smoking and alcohol exposures, and physical measures. MAIN OUTCOME MEASURES: The variability of IOP measurements within eyes was assessed as visit-to-visit IOP variation, within-visit IOP variation, and within-visit positional IOP variation. The concordance (or correlation) between eyes was also assessed. RESULTS: Average positional change of > 4.7 mmHg was detected with a range of 0.5-11.0 mmHg. Pearson correlation of IOP between eyes within a visit was 0.87 (95% confidence interval [CI], 0.82-0.91) for Goldmann applanation tonometry, 0.91 (95% CI, 0.88-0.94) for Icare rebound tonometry, and 0.91 (95% CI, 0.88-0.94) for pneumatonometry. There was a 4% to 12% asymmetric fluctuation of 3 mmHg or more between eyes between visits using rebound tonometry, 9% with Goldmann applanation tonometry, and 3% to 4% by pneumotonometry. The coefficient of variation between visits for the same eye ranged from 11.2% to 12.9% for pneumatonometry, from 13.6% to 17.4% for rebound tonometry, and 15.8% to 16.2% for Goldmann applanation tonometry. CONCLUSIONS: The current study from the EDEN Consortium describes measurement methods and data analyses with emphasis on IOP variability. Future papers will focus on changes in ocular biometrics and AHD with timolol or latanoprost treatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Characteristics and Outcomes of Glaucoma Associated With Congenital Ectropion Uvea.

PURPOSE: To determine the visual outcomes and effectiveness of glaucoma surgeries in congenital ectropion uvea. DESIGN: Retrospective interventional case series. METHODS: Surgeries and examination findings were collected on 11 eyes of 8 patients with congenital ectropion uvea at 2 academic sites from 2001 to 2021. Visual outcomes, surgical success (intraocular pressure [IOP]: 5-20 mm Hg, no additional IOP-lowering surgery, no visually devastating complications), and survival rates of glaucoma surgeries were assessed. RESULTS: Glaucoma in bilateral congenital ectropion uvea was diagnosed at an earlier age (0.02 ± 0.01 years) than unilateral disease (8.9 ± 5.3 years, P = .002). All eyes required glaucoma surgery with 91% requiring multiple surgeries (3.5 ± 2.1, median 3 surgeries per eye). Trabeculotomy (8 eyes) showed 13% success rate. Although none of the 4 eyes that underwent trabeculectomy with mitomycin C needed repeat trabeculectomy, glaucoma drainage device placement, or cycloablation, 75% required bleb revision surgery. Glaucoma drainage devices (7 eyes) had a 57% success rate with 3 eyes requiring subsequent cycloablation (2) or trabeculectomy (1). At the final follow-up (8.5 ± 6.6 years, median: 7.9 years), all eyes achieved IOP control, and IOP was lower compared with presentation (13.2 ± 2.6 mm Hg vs 32.9 ± 9.9 mm Hg, P = .002). Best-corrected logarithm of the minimum angle of resolution visual acuity at the final follow-up was 0.2 ± 0.2. CONCLUSIONS: Bilateral congenital ectropion uvea presents with glaucoma earlier than unilateral cases. The majority of eyes required multiple glaucoma surgeries. Angle surgery was less effective than trabeculectomy or glaucoma drainage devices. IOP control was obtained in all eyes and affected individuals had good visual outcomes.

Predicting Age-Related Macular Degeneration Progression with Contrastive Attention and Time-Aware LSTM.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries. Identifying patients at high risk of progression to late AMD, the sight-threatening stage, is critical for clinical actions, including medical interventions and timely monitoring. Recently, deep-learning-based models have been developed and achieved superior performance for late AMD prediction. However, most existing methods are limited to the color fundus photography (CFP) from the last ophthalmic visit and do not include the longitudinal CFP history and AMD progression during the previous years' visits. Patients in different AMD subphenotypes might have various speeds of progression in different stages of AMD disease. Capturing the progression information during the previous years' visits might be useful for the prediction of AMD progression. In this work, we propose a Contrastive-Attention-based Time-aware Long Short-Term Memory network (CAT-LSTM) to predict AMD progression. First, we adopt a convolutional neural network (CNN) model with a contrastive attention module (CA) to extract abnormal features from CFPs. Then we utilize a time-aware LSTM (T-LSTM) to model the patients' history and consider the AMD progression information. The combination of disease progression, genotype information, demographics, and CFP features are sent to T-LSTM. Moreover, we leverage an auto-encoder to represent temporal CFP sequences as fixed-size vectors and adopt k-means to cluster them into subphenotypes. We evaluate the proposed model based on real-world datasets, and the results show that the proposed model could achieve 0.925 on area under the receiver operating characteristic (AUROC) for 5-year late-AMD prediction and outperforms the state-of-the-art methods by more than 3%, which demonstrates the effectiveness of the proposed CAT-LSTM. After analyzing patient representation learned by an auto-encoder, we identify 3 novel subphenotypes of AMD patients with different characteristics and progression rates to late AMD, paving the way for improved personalization of AMD management. The code of CAT-LSTM can be found at GitHub.

Hydrodynamic Interaction Between Tear Film and Air Puff From Noncontact Tonometry.

PURPOSE: The purpose of this study was to investigate the mechanism of potential droplet formation in response to air puff deformation with two noncontact tonometers (NCTs). METHODS: Twenty healthy volunteers were examined using two NCTs, Ocular Response Analyzer and Corvis ST, and two contact tonometers, iCare and Tono-Pen. High-speed videos of the tear film response were captured with at spatial resolution of 20 microns/pixel at 2400 fps. Droplet size, droplet velocity, distance between air puff impact location, and the tear meniscus-lid margin were characterized. RESULTS: One subject was excluded due to technical issues. Droplets were detected only in tests with instilled eye drop. Videos showed the tear film rolls away from the apex while remaining adherent to the ocular surface due to the tendency of the fluid to remain attached to a solid surface explained by the Coanda effect. Twelve out of 38 videos with an eye drop administration showed droplet formation. Only one resulted in droplets with predominantly forward motion, which had the shortest distance between air puff impact location and lower meniscus. This distance on average was 5.9 ± 1.1 mm. The average droplet size was 500 ± 200 µm. CONCLUSIONS: Results indicate no droplet formation under typical clinical setting. Hence, standard clinical use of NCT tests is not expected to cause droplets. NCT testing with eye drop administration showed droplet formation at the inferior eyelid boundary, which acts as a barrier and interrupts tear flow. TRANSLATIONAL RELEVANCE: Study of tear film interaction with NCT air puff shows that these tonometers are not expected to cause droplet formation in standard use and that if external drops are required, both eyelids should be held if patients need assistance to maintain open eyes to avoid droplets with predominantly forward motion.

Non-invasive Clinical Measurement of Ocular Rigidity and Comparison to Biomechanical and Morphological Parameters in Glaucomatous and Healthy Subjects.

Purpose: To assess ocular rigidity using dynamic optical coherence tomography (OCT) videos in glaucomatous and healthy subjects, and to evaluate how ocular rigidity correlates with biomechanical and morphological characteristics of the human eye. Methods: Ocular rigidity was calculated using Friedenwald's empirical equation which estimates the change in intraocular pressure (IOP) produced by volumetric changes of the eye due to choroidal pulsations with each heartbeat. High-speed OCT video was utilized to non-invasively measure changes in choroidal volume through time-series analysis. A control-case study design was based on 23 healthy controls and 6 glaucoma cases. Multiple diagnostic modalities were performed during the same visit including Spectralis OCT for nerve head video, Pascal Dynamic Contour Tonometry for IOP and ocular pulse amplitude (OPA) measurement, Corvis ST for measuring dynamic biomechanical response, and Pentacam for morphological characterization. Results: Combining glaucoma and healthy cohorts (n = 29), there were negative correlations between ocular rigidity and axial length (Pearson R = -0.53, p = 0.003), and between ocular rigidity and anterior chamber volume (R = -0.64, p = 0.0002). There was a stronger positive correlation of ocular rigidity and scleral stiffness (i.e., stiffness parameter at the highest concavity [SP-HC]) (R = 0.62, p = 0.0005) compared to ocular rigidity and corneal stiffness (i.e., stiffness parameter at the first applanation [SP-A1]) (R = 0.41, p = 0.033). In addition, there was a positive correlation between ocular rigidity and the static pressure-volume ratio (P/V ratio) (R = 0.72, p < 0.0001). Conclusions: Ocular rigidity was non-invasively assessed using OCT video and OPA in a clinic setting. The significant correlation of ocular rigidity with biomechanical parameters, SP-HC and P/V ratio, demonstrated the validity of the ocular rigidity measurement. Ocular rigidity is driven to a greater extent by scleral stiffness than corneal stiffness. These in vivo methods offer an important approach to investigate the role of ocular biomechanics in glaucoma.

Method for the biomechanical analysis of aqueous veins and perilimbal sclera by three-dimensional photoacoustic imaging and strain field calculation.

A method motivated by the eye's aqueous veins is described for the imaging and strain calculation within soft biological tissues. A challenge to the investigation of the biomechanics of the aqueous vein-perilimbal sclera tissue complex is resolution of tissue deformations as a function of intraocular pressure and the subsequent calculation of strain (a normalized measure of deformation). The method involves perfusion of the eye with a contrast agent during conduction of non-invasive, optical resolution photoacoustic microscopy. This imaging technique permits three-dimensional displacement measurements of tracked points on the inner walls of the veins which are used in a finite element model to determine the corresponding strains. The methods are validated against two standard strain measurement methods. Representative porcine globe perfusion experiments are presented that demonstrate the power of the method to determine complex strain fields in the veins dependent on intraocular pressure as well as vein anatomy. In these cases, veins are observed to move radially outward during increases in intraocular pressure and to possess significant spatial strain variation, possibly influenced by their branching patterns. To the authors' knowledge, these are the only such quantitative, data driven, calculations of the aqueous vein strains available in the open literature.