Mental Health Conditions Associated With Strabismus in a Diverse Cohort of US Adults.

Importance: Greater understanding of the association between strabismus and mental health conditions across sociodemographic backgrounds may inform strategies to improve mental well-being in this population. Objective: To describe the association of strabismus with mental health conditions in a diverse cohort of US adults. Design, Setting, and Participants: This cross-sectional study used data from the National Institutes of Health's All of Us Research Program, an ongoing program launched in 2015. The study included 3646 adults (aged ≥18 years) with strabismus and 3646 propensity score-matched controls. Statistical analysis was conducted from September 12, 2023, to January 29, 2024. Main Outcomes and Measures: Adults with strabismus were propensity score matched on age, gender, race and ethnicity, income, educational level, and insurance status in a 1:1 ratio with adults without strabismus. The prevalences of anxiety, depression, substance use and addiction, bipolar disorder, and schizophrenia spectrum disorder among adults with strabismus were compared with controls. Logistic regression was used to evaluate the association of mental health conditions with sociodemographic factors in each group. Results: This study included 3646 adults with strabismus (median age, 67 years [IQR, 53-76 years]; 2017 women [55%]) and 3646 propensity score-matched controls (median age, 67 years [IQR, 53-76 years]; 2017 women [55%]). Individuals with strabismus had higher prevalences of anxiety (1153 [32%] vs 519 [14%]; difference, 17%; 95% CI, 15%-19%; P < .001), depression (1189 [33%] vs 514 [14%]; difference, 19%; 95% CI, 17%-20%; P < .001), substance use and addiction (116 [3%] vs 51 [1%]; difference, 2%; 95% CI, 1%-3%; P < .001), bipolar disorder (253 [7%] vs 101 [3%]; difference, 4%; 95% CI, 3%-5%; P < .001), and schizophrenia spectrum disorder (103 [3%] vs 36 [1%]; difference, 2%; 95% CI, 1%-3%; P < .001) compared with individuals without strabismus. Among adults with strabismus, higher odds of mental health conditions were associated with younger age (odds ratio [OR], 1.11 per 10-year decrease; 95% CI, 1.06-1.16 per 10-year decrease), female gender (OR, 1.62; 95% CI, 1.41-1.85), Black or African American race and ethnicity (OR, 1.22; 95% CI, 1.01-1.48), low income (OR, 3.06; 95% CI, 2.56-3.67), and high school education or less (OR, 1.58; 95% CI, 1.34-1.85). Conclusions and Relevance: In a diverse and nationwide cohort, adults with strabismus were more likely to have mental health conditions compared with adults without strabismus. Further investigation into the risk factors for poor mental health among adults with strabismus across sociodemographic backgrounds may offer novel opportunities for interventions to improve mental well-being in this population.

Rare protective variants and glaucoma-relevant cell stressors modulate Angiopoietin-like 7 expression.

Rare missense and nonsense variants in the Angiopoietin-like 7 (ANGPTL7) gene confer protection from primary open-angle glaucoma (POAG), though the functional mechanism remains uncharacterized. Interestingly, a larger variant effect size strongly correlates with in silico predictions of increased protein instability (r = -0.98), suggesting that protective variants lower ANGPTL7 protein levels. Here, we show that missense and nonsense variants cause aggregation of mutant ANGPTL7 protein in the endoplasmic reticulum (ER) and decreased levels of secreted protein in human trabecular meshwork (TM) cells; a lower secreted:intracellular protein ratio strongly correlates with variant effects on intraocular pressure (r = 0.81). Importantly, accumulation of mutant protein in the ER does not increase expression of ER stress proteins in TM cells (P > 0.05 for all variants tested). Cyclic mechanical stress, a glaucoma-relevant physiologic stressor, also significantly lowers ANGPTL7 expression in primary cultures of human Schlemm's canal (SC) cells (-2.4-fold-change, P = 0.01). Collectively, these data suggest that the protective effects of ANGPTL7 variants in POAG stem from lower levels of secreted protein, which may modulate responses to physiologic and pathologic ocular cell stressors. Downregulation of ANGPTL7 expression may therefore serve as a viable preventative and therapeutic strategy for this common, blinding disease.

Mitochondrial TXNRD2 and ME3 Genetic Risk Scores Are Associated with Specific Primary Open-Angle Glaucoma Phenotypes.

PURPOSE: Genetic variants in regions that include the mitochondrial genes thioredoxin reductase 2 (TXNRD2) and malic enzyme 3 (ME3) are associated with primary open-angle glaucoma (POAG) in genome-wide association studies (GWASs). To assess their clinical impact, we investigated whether TXNRD2 and ME3 genetic risk scores (GRSs) are associated with specific glaucoma phenotypes. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 2617 patients with POAG and 2634 control participants from the National Eye Institute Glaucoma Human Genetics Collaboration Hereditable Overall Operational Database (NEIGHBORHOOD) consortium. METHODS: All POAG-associated single nucleotide polymorphisms (SNPs) in the TXNRD2 and ME3 loci were identified using GWAS data (P < 0.05). Of these, 20 TXNRD2 and 24 ME3 SNPs were selected after adjusting for linkage disequilibrium. The correlation between SNP effect size and gene expression levels was investigated using the Gene-Tissue Expression database. Genetic risk scores were constructed for each individual using the unweighted sum of TXNRD2, ME3, and TXNRD2 + ME3 combined risk alleles. Age- and sex-adjusted odds ratios (ORs) for POAG diagnosis were calculated per decile for each GRS. Additionally, the clinical features of patients with POAG in the top 1%, 5%, and 10% of each GRS were compared with those in the bottom 1%, 5%, and 10%, respectively. MAIN OUTCOME MEASURES: Primary open-angle glaucoma OR per GRS decile, maximum treated intraocular pressure (IOP), and prevalence of paracentral visual field loss among patients with POAG with high versus low GRSs. RESULTS: A larger SNP effect size strongly correlated with higher TXNRD2 and lower ME3 expression levels (r = 0.95 and r = -0.97, respectively; P < 0.05 for both). Individuals in decile 10 of the TXNRD2 + ME3 GRS had the highest odds of POAG diagnosis (OR, 1.79 compared with decile 1; 95% confidence interval, 1.39-2.30; P < 0.001). Patients with POAG in the top 1% of the TXNRD2 GRS showed higher mean maximum treated IOP compared with the bottom 1% (19.9 mmHg vs. 15.6 mmHg; adjusted P = 0.03). Patients with POAG in the top 1% of the ME3 and TXNRD2 + ME3 GRS showed a higher prevalence of paracentral field loss than the bottom 1% (72.7% vs. 14.3% for ME3 GRS and 88.9% vs. 33.3% for TXNRD2+ME3 GRS; adjusted P = 0.03 for both). CONCLUSIONS: Patients with POAG with higher TXNRD2 and ME3 GRSs showed higher treated IOP and a greater prevalence of paracentral field loss. Functional studies exploring how these variants impact mitochondrial function in patients with glaucoma are warranted. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Role of the anillin-like protein in growth of Cryptococcus neoformans at human host temperature.

Cryptococcus neoformans, a basidiomycete yeast, causes lethal meningitis in immunocompromised individuals. The ability of C. neoformans to proliferate at 37°C is essential for virulence. We identified anillin-like protein, CnBud4, as essential for proliferation of C. neoformans at 37°C and for virulence in a heterologous host Galleria mellonella at 25°C. C. neoformans cells lacking CnBud4 were inviable at 25°C in the absence of active calcineurin and were hypersensitive to membrane stress and an anti-fungal agent fluconazole, phenotypes previously described for C. neoformans mutants lacking septins. CnBud4 localized to the mother-bud neck during cytokinesis in a septin-dependent manner. In the absence of CnBud4, septin complex failed to transition from a collar-like single ring to the double ring during cytokinesis. In an ascomycete yeast, Saccharomyces cerevisiae, the anillin-like homologue ScBud4 participates in the organization of the septin ring at the mother-bud neck and plays an important role in specifying location for new bud emergence, known as axial budding pattern. In contrast to their role in S. cerevisiae, neither septins nor CnBud4 were needed to direct the position of the new bud in C. neoformans, suggesting that this function is not conserved in basidiomycetous yeasts. Our data suggest that the requirement of CnBud4 for growth at 37°C and pathogenicity in C. neoformans is based on its conserved role in septin complex organization.

The genetics of glaucoma: Disease associations, personalised risk assessment and therapeutic opportunities-A review.

Glaucoma refers to a heterogenous group of disorders characterised by progressive loss of retinal ganglion cells and associated visual field loss. Both early-onset and adult-onset forms of the disease have a strong genetic component. Here, we summarise the known genetic associations for various forms of glaucoma and the possible functional roles for these genes in disease pathogenesis. We also discuss efforts to translate genetic knowledge into clinical practice, including gene-based tests for disease diagnosis and risk-stratification as well as gene-based therapies.

Home Monitoring for Glaucoma: Current Applications and Future Directions.

Technological advances provide a number of options for glaucoma monitoring outside the office setting, including home-based tonometry and perimetry. This has the potential to revolutionize management of this chronic disease, improve access to care, and enhance patient engagement. Here, we provide an overview of existing technologies for home-based glaucoma monitoring. We also discuss areas for future research and the potential applications of these technologies to telemedicine, which has been brought to the forefront during the ongoing COVID-19 pandemic.

Treatment of Bilateral Endogenous Aspergillus Endophthalmitis with Multiple Intravitreal Voriconazole Injections with Good Visual Outcome.

Endogenous endophthalmitis caused by Aspergillus species tends to be very aggressive, often leading to devastating visual outcomes. Historically, intravitreal amphotericin injections have played a central role in management, but with variable visual outcomes and a risk of toxicity. Limited reports suggest that use of intravitreal voriconazole is a safe and efficacious alternative, though these cases were treated with only few intravitreal injections. Here, we report a case of bilateral endogenous Aspergillus endophthalmitis treated with 8 intravitreal voriconazole injections in the right eye and 11 in the left eye with good best-corrected final visual outcome (20/50 right eye and 20/40 left eye).

Factors Predicting a Greater Likelihood of Poor Visual Field Reliability in Glaucoma Patients and Suspects.

Purpose: Identify factors predicting worse or better than expected visual field (VF) performance. Methods: A total of 10,262 VFs from 1538 eyes of 909 subjects with manifest or suspected glaucoma were analyzed. Linear mixed-effects models predicted mean deviation (MD) at each timepoint. Differences between observed and predicted MD (ΔMD) were calculated and logistic regression identified factors predicting lower than expected (ΔMD <-1 dB) or higher than expected (ΔMD >1 dB) sensitivity. Results: Both higher and lower than expected sensitivity were more likely in VFs with severe compared with mild damage (relative risk [RR] >1.3, P < 0.05). Higher than expected sensitivity was more likely in VFs with moderate damage (RR = 2.57, P < 0.001). False-positive (FP) errors increased the likelihood of higher than expected sensitivity at all disease stages (RR >2.1 per 10% increase, P < 0.001), whereas false-negative (FN) errors increased the likelihood of lower than expected sensitivity in mild and moderate disease (RR >1.19 per 10% increase, P < 0.05). Fixation loss errors slightly increased the likelihood of higher than expected VF sensitivity in moderate and severe disease (RR >1.1 per 10% increase, P < 0.01). Longer test duration increased likelihood of lower than expected sensitivity at all disease stages (RR >1.36 per minute increase, P < 0.001). Lower than expected sensitivity was more likely in late afternoon tests (RR = 1.27, P < 0.01). A total of 26.6% of VFs had higher or lower than expected sensitivity in the absence of FPs, FNs, or fixation losses. Conclusions: FPs, test duration, and FNs are the primary measures predicting if a VF is likely to be reliable, although tests with normal reliability measures may still be unreliable. Our results help clinicians judge VF reliability and highlight the need to integrate reliability measures with other clinical data when making treatment decisions. Translational Relevance: This likelihood model derived from a large dataset helps clinicians identify VFs that may either falsely suggest disease progression or mask true worsening, thereby improving the utility of VFs in clinical practice.

Expression of mRNAs, miRNAs, and lncRNAs in Human Trabecular Meshwork Cells Upon Mechanical Stretch.

Purpose: Intraocular pressure (IOP), the primary risk factor for primary open-angle glaucoma, is determined by resistance to aqueous outflow through the trabecular meshwork (TM). IOP homeostasis relies on TM responses to mechanical stretch. To model the effects of elevated IOP on the TM, this study sought to identify coding and non-coding RNAs differentially expressed in response to mechanical stretch. Methods: Monolayers of TM cells from non-glaucomatous donors (n = 5) were cultured in the presence or absence of 15% mechanical stretch, 1 cycle/second, for 24 hours using a computer-controlled Flexcell unit. We profiled mRNAs and lncRNAs with stranded total RNA sequencing and microRNA (miRNA) expression with NanoString-based miRNA assays. We used two-tailed paired t-tests for mRNAs and long non-coding RNAs (lncRNAs) and the Bioconductor limma package for miRNAs. Gene ontology and pathway analyses were performed with WebGestalt. miRNA-mRNA interactions were identified using Ingenuity Pathway Analysis Integrative miRNA Target Finder software. Validation of differential expression was conducted using droplet digital PCR. Results: We identified 219 mRNAs, 42 miRNAs, and 387 lncRNAs with differential expression in TM cells upon cyclic mechanical stretch. Pathway analysis indicated significant enrichment of genes involved in steroid biosynthesis, glycerolipid metabolism, and extracellular matrix-receptor interaction. We also identified several miRNA master regulators (miR-125a-5p, miR-30a-5p, and miR-1275) that regulate several mechanoresponsive genes. Conclusions: To our knowledge, this is the first demonstration of the differential expression of coding and non-coding RNAs in a single set of cells subjected to cyclic mechanical stretch. Our results validate previously identified, as well as novel, genes and pathways.

Identification and activity of the functional complex between hnRNPL and the pseudoexfoliation syndrome-associated lncRNA, LOXL1-AS1.

Individuals with pseudoexfoliation (PEX) syndrome exhibit various connective tissue pathologies associated with dysregulated extracellular matrix homeostasis. PEX glaucoma is a common, aggressive form of open-angle glaucoma resulting from the deposition of fibrillary material in the conventional outflow pathway. However, the molecular mechanisms that drive pathogenesis and genetic risk remain poorly understood. PEX glaucoma-associated single-nucleotide polymorphisms are located in and affect activity of the promoter of LOXL1-AS1, a long non-coding RNA (lncRNA). Nuclear and non-nuclear lncRNAs regulate a host of biological processes, and when dysregulated, contribute to disease. Here we report that LOXL1-AS1 localizes to the nucleus where it selectively binds to the mRNA processing protein, heterogeneous nuclear ribonucleoprotein-L (hnRNPL). Both components of this complex are critical for the regulation of global gene expression in ocular cells, making LOXL1-AS1 a prime target for investigation in PEX syndrome and glaucoma.

Differential Expression of Coding and Long Noncoding RNAs in Keratoconus-Affected Corneas.

Purpose: Keratoconus (KC) is the most common corneal ectasia. We aimed to determine the differential expression of coding and long noncoding RNAs (lncRNAs) in human corneas affected with KC. Methods: From the corneas of 10 KC patients and 8 non-KC healthy controls, 200 ng total RNA was used to prepare sequencing libraries with the SMARTer Stranded RNA-Seq kit after ribosomal RNA depletion, followed by paired-end 50-bp sequencing with Illumina Sequencer. Differential analysis was done using TopHat/Cufflinks with a gene file from Ensembl and a lncRNA file from NONCODE. Pathway analysis was performed using WebGestalt. Using the expression level of differentially expressed coding and noncoding RNAs in each sample, we correlated their expression levels in KC and controls separately and identified significantly different correlations in KC against controls followed by visualization using Cytoscape. Results: Using |fold change| ≥ 2 and a false discovery rate ≤ 0.05, we identified 436 coding RNAs and 584 lncRNAs with differential expression in the KC-affected corneas. Pathway analysis indicated the enrichment of genes involved in extracellular matrix, protein binding, glycosaminoglycan binding, and cell migration. Our correlation analysis identified 296 pairs of significant KC-specific correlations containing 117 coding genes enriched in functions related to cell migration/motility, extracellular space, cytokine response, and cell adhesion. Our study highlighted the potential roles of several genes (CTGF, SFRP1, AQP5, lnc-WNT4-2:1, and lnc-ALDH3A2-2:1) and pathways (TGF-ß, WNT signaling, and PI3K/AKT pathways) in KC pathogenesis. Conclusions: Our RNA-Seq-based differential expression and correlation analyses have identified many potential KC contributing coding and noncoding RNAs.

Association of Baseline Anterior Segment Parameters With the Development of Incident Gonioscopic Angle Closure.

IMPORTANCE: Baseline anterior segment imaging parameters associated with incident gonioscopic angle closure, to our knowledge, are unknown. OBJECTIVE: To identify baseline quantitative anterior segment optical coherence tomography parameters associated with the development of incident gonioscopic angle closure after 4 years among participants with gonioscopically open angles at baseline. DESIGN, SETTING, AND PARTICIPANTS: Three hundred forty-two participants aged 50 years or older were recruited to participate in this prospective, community-based observational study. Participants underwent gonioscopy and anterior segment optical coherence tomography imaging at baseline and after 4 years. Custom image analysis software was used to quantify anterior chamber parameters from anterior segment optical coherence tomography images. MAIN OUTCOMES AND MEASURES: Baseline anterior segment optical coherence tomography measurements among participants with gonioscopically open vs closed angles at follow-up. RESULTS: Of the 342 participants, 187 (55%) were women and 297 (87%) were Chinese. The response rate was 62.4%. Forty-nine participants (14.3%) developed gonioscopic angle closure after 4 years. The mean age (SD) at baseline of the 49 participants was 62.9 (8.0) years, 15 (30.6%) were men, and 43 (87.8%) were Chinese. These participants had a smaller baseline angle opening distance at 750 µm (AOD750) (0.15 mm; 95% CI, 0.12-0.18), trabecular iris surface area at 750 µm (0.07 mm2; 95% CI, 0.05-0.08), anterior chamber area (30 mm2; 95% CI, 2.27-3.74), and anterior chamber volume (24.32 mm2; 95% CI, 18.20-30.44) (all P < .001). Baseline iris curvature (-0.08; 95% CI, -0.12 to -0.04) and lens vault (LV) measurements (-0.29 mm; 95% CI, -0.37 to -0.21) were larger among these participants ( all P < .001). A model consisting of the LV and AOD750 measurements explained 38% of the variance in gonioscopic angle closure occurring at 4 years, with LV accounting for 28% of this variance. For every 0.1 mm increase in LV and 0.1 mm decrease in AOD750, the odds of developing gonioscopic angle closure was 1.29 (95% CI, 1.07-1.57) and 3.27 (95% CI, 1.87-5.69), respectively. In terms of per SD change in LV and AOD750, this translates to an odds ratio of 2.14 (95% CI, 2.48-12.34) and 5.53 (95% CI, 1.22-3.77), respectively. A baseline LV cut-off value of >0.56 mm had 64.6% sensitivity and 84.0% specificity for identifying participants who developed angle closure. CONCLUSIONS AND RELEVANCE: These findings suggest that smaller AOD750 and larger LV measurements are associated with the development of incident gonioscopic angle closure after 4 years among participants with gonioscopically open angles at baseline.

Major review: Exfoliation syndrome; advances in disease genetics, molecular biology, and epidemiology.

Exfoliation syndrome (XFS) is a common age-related disorder that leads to deposition of extracellular fibrillar material throughout the body. The most recognized disease manifestation is exfoliation glaucoma (XFG), which is a common cause of blindness worldwide. Recent developments in XFS genetics, cell biology and epidemiology have greatly improved our understanding of the etiology of this complex inherited disease. This review summarizes current knowledge of XFS pathogenesis, identifies gaps in knowledge, and discusses areas for future research.

Nonglaucomatous Cupping: Fundus Photography and Spectral Domain Optical Coherence Tomography Imaging Features.

Nonglaucomatous cupping is commonly encountered in neuro-ophthalmic practice. However, the progression of clinical and imaging findings over time has not been well described. We present serial fundus photographs and spectral domain optical coherence tomography from a pediatric patient with neuromyelitis optic spectrum disorder, which demonstrated progression of both cupping and optic atrophy in the setting of normal intraocular pressure.

Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus.

Exfoliation syndrome (XFS) is a common, age-related, systemic fibrillinopathy. It greatly increases risk of exfoliation glaucoma (XFG), a major worldwide cause of irreversible blindness. Coding variants in the lysyl oxidase-like 1 (LOXL1) gene are strongly associated with XFS in all studied populations, but a functional role for these variants has not been established. To identify additional candidate functional variants, we sequenced the entire LOXL1 genomic locus (∼40 kb) in 50 indigenous, black South African XFS cases and 50 matched controls. The variants with the strongest evidence of association were located in a well-defined 7-kb region bounded by the 3'-end of exon 1 and the adjacent region of intron 1 of LOXL1. We replicated this finding in US Caucasian (91 cases/1031 controls), German (771 cases/1365 controls) and Japanese (1484 cases/1188 controls) populations. The region of peak association lies upstream of LOXL1-AS1, a long non-coding RNA (lncRNA) encoded on the opposite strand of LOXL1. We show that this region contains a promoter and, importantly, that the strongly associated XFS risk alleles in the South African population are functional variants that significantly modulate the activity of this promoter. LOXL1-AS1 expression is also significantly altered in response to oxidative stress in human lens epithelial cells and in response to cyclic mechanical stress in human Schlemm's canal endothelial cells. Taken together, these findings support a functional role for the LOXL1-AS1 lncRNA in cellular stress response and suggest that dysregulation of its expression by genetic risk variants plays a key role in XFS pathogenesis.

Developments in Ocular Genetics: 2013 Annual Review.

PURPOSE: To highlight major advancements in ocular genetics from the year 2013. DESIGN: Literature review. METHODS: A literature search was conducted on PubMed to identify articles pertaining to genetic influences on human eye diseases. This review focuses on manuscripts published in print or online in the English language between January 1, 2013 and December 31, 2013. A total of 120 papers from 2013 were included in this review. RESULTS: Significant progress has been made in our understanding of the genetic basis of a broad group of ocular disorders, including glaucoma, age-related macular degeneration, cataract, diabetic retinopathy, keratoconus, Fuchs' endothelial dystrophy, and refractive error. CONCLUSIONS: The latest next-generation sequencing technologies have become extremely effective tools for identifying gene mutations associated with ocular disease. These technological advancements have also paved the way for utilization of genetic information in clinical practice, including disease diagnosis, prediction of treatment response and molecular interventions guided by gene-based knowledge.