Rodent genetically modified models of glaucoma.

Glaucoma, one of the leading causes of irreversible blindness worldwide, is a complex and heterogenous disease. While environmental factors are important, it is well-recognized that the disease has a strong heritable component. With the advent of large-cohort genome wide association studies, a myriad of genetic risk loci has been linked to different forms of glaucoma. Animal models have been an indispensable tool in characterizing these loci, especially if they lie within coding regions in the genome. Not only do these models connect genotype to phenotype, advancing our understanding of glaucoma pathogenesis in the process, they also have valuable utility as a platform for the pre-clinical testing of potential therapies. In this review, we will outline genetic models used for studying the major forms of glaucoma, including primary open angle glaucoma, normal tension glaucoma, primary angle closure glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma, and early onset glaucoma, including congenital and developmental glaucoma, and how studying these models have helped shed light on human glaucoma.

The Structural Layers of the Porcine Iris Exhibit Inherently Different Biomechanical Properties.

Purpose: The purpose of this study was to isolate the structural components of the ex vivo porcine iris tissue and to determine their biomechanical properties. Methods: The porcine stroma and dilator tissues were separated, and their dimensions were assessed using optical coherence tomography (OCT). The stroma underwent flow test (n = 32) to evaluate for permeability using Darcy's Law (ΔP = 2000 Pa, A = 0.0391 mm2), and both tissues underwent stress relaxation experiments (ε = 0.5 with initial ramp of δε = 0.1) to evaluate for their viscoelastic behaviours (n = 28). Viscoelasticity was characterized by the parameters ß (half width of the Gaussian distribution), τm (mean relaxation time constant), E0 (instantaneous modulus), and E∞ (equilibrium modulus). Results: For the stroma, the hydraulic permeability was 9.49 ± 3.05 × 10-6 mm2/Pa · s, and the viscoelastic parameters were ß = 2.50 ± 1.40, and τm = 7.43 ± 4.96 s, with the 2 moduli calculated to be E0 = 14.14 ± 6.44 kPa and E∞ = 6.08 ± 2.74 kPa. For the dilator tissue, the viscoelastic parameters were ß = 2.06 ± 1.33 and τm = 1.28 ± 1.27 seconds, with the 2 moduli calculated to be E0 = 9.16 ± 3.03 kPa and E∞ = 5.54 ± 1.98 kPa. Conclusions: We have established a new protocol to evaluate the biomechanical properties of the structural layers of the iris. Overall, the stroma was permeable and exhibited smaller moduli than those of the dilator muscle. An improved characterization of iris biomechanics may form the basis to further our understanding of angle closure glaucoma.

Intravitreal Neuroglobin Mitigates Primate Experimental Glaucomatous Structural Damage in Association with Reduced Optic Nerve Microglial and Complement 3-Astrocyte Activation.

Current management of glaucomatous optic neuropathy is limited to intraocular pressure control. Neuroglobin (Ngb) is an endogenous neuroprotectant expressed in neurons and astrocytes. We recently showed that exogenous intravitreal Ngb reduced inflammatory cytokines and microglial activation in a rodent model of hypoxia. We thus hypothesised that IVT-Ngb may also be neuroprotective in experimental glaucoma (EG) by mitigating optic nerve (ON) astrogliosis and microgliosis as well as structural damage. In this study using a microbead-induced model of EG in six Cynomolgus primates, optical coherence imaging showed that Ngb-treated EG eyes had significantly less thinning of the peripapillary minimum rim width, retinal nerve fibre layer thickness, and ON head cupping than untreated EG eyes. Immunohistochemistry confirmed that ON astrocytes overexpressed Ngb following Ngb treatment. A reduction in complement 3 and cleaved-caspase 3 activated microglia and astrocytes was also noted. Our findings in higher-order primates recapitulate the effects of neuroprotection by Ngb treatment in rodent EG studies and suggest that Ngb may be a potential candidate for glaucoma neuroprotection in humans.

Propranolol Ameliorates the Antifungal Activity of Azoles in Invasive Candidiasis.

The effectiveness of current antifungal therapies is hampered by the emergence of drug resistance strains, highlighting an urgent need for new alternatives such as adjuvant antifungal treatments. This study aims to examine the synergism between propranolol and antifungal drugs, based on the premise that propranolol is known to inhibit fungal hyphae. In vitro studies demonstrate that propranolol potentiates the antifungal activity of azoles and that the effect is more pronounced for propranolol-itraconazole combination. Using an in vivo murine systemic candidemia model, we show that propranolol-itraconazole combination treatment resulted in a lower rate of body weight loss, decreased kidney fungal bioburden and renal inflammation when compared to propranolol and azole treatment alone or untreated control. Altogether, our findings suggest that propranolol increases the efficacy of azoles against C. albicans, offering a new therapeutic strategy against invasive fungal infections.

Hong Kong's new wave of migration: socio-political factors of individuals' intention to emigrate.

With a recent surge in the outward movement of the population, a new wave of emigration has been suggested to have started in Hong Kong. It is speculated that recent socio-political changes in Hong Kong may have contributed to this phenomenon. Therefore, five socio-political variables-mobility, sense of place, trust and confidence in the law and the legal system, global citizenship, and perception of inequality-are employed in this study as proposed determinants to investigate the intention of Hong Kong residents to migrate to mainland China and to other international destinations. A random telephone questionnaire survey representative of the local population was conducted, with a total of 801 valid samples collected. Stepwise multiple regression analysis was carried out. The results showed that all five proposed socio-political variables successfully predicted people's migration intention to mainland China and to foreign countries, with important variations between the two choices. Our results carry strong implications for understanding people's concerns behind their intention to emigrate. Further, our findings present a challenge for Hong Kong; society may gradually be failing to accommodate individuals with diverse perceptions and values, particularly in terms of trust and confidence in the law and the legal system, and individuals' sense of global citizenship.

Incidence of COVID-19 Vaccination-Related Uveitis and Effects of Booster Dose in a Tertiary Uveitis Referral Center.

Background: We report vaccine and booster-related uveitis in Singapore, a country with high vaccination and booster rates to highlight the differences and potential role of prophylactic treatment for sight-threatening infectious uveitis. Methods: Clinical data extracted from the de-identified uveitis database in Singapore National Eye Center. Six patients (eight eyes) developed uveitis within 14 days after undergoing COVID-19 vaccination (primary and/or booster). Results: All patients received two doses of COVID-19 vaccination, and 1.39% (6/431) developed COVID-19 vaccine-related uveitis. Fifty-percent% (3/6) with non-infectious anterior uveitis (NIAU) presented with a non-granulomatous anterior uveitis (AU). The remaining (3/6) presenting with a granulomatous AU were diagnosed with reactivation of cytomegalovirus, varicella-zoster virus and toxoplasma chorioretinitis, respectively. All the patients responded to definitive treatment specific to their diagnosis. The mean visual acuity at presentation was 0.36 ± 0.20 logMAR and improved to 0.75 ± 0.09 (p = 0.009). Mean time from vaccination to uveitis was 9.7 (range: 3-14) days. All patients developed uveitis after second vaccination dose. 16.67% (1/6) patients had a recurrence after the third booster dose. None of the three patients with infectious uveitis developed recurrence but had received maintenance therapy up to or during the booster. Conclusion: Uveitis after COVID-19 vaccination is uncommon. In our series, a higher rate of reactivations of latent infections was seen. With definitive treatment, all cases were self-limited without systemic sequelae. Prophylactic treatment during booster vaccine may prevent reactivation of sight-threatening infections and reduce morbidity although risk-benefits should be considered for individual patients given the low rate of occurrence.

Case Report: Peripheral Ulcerative Keratitis in Systemic Solid Tumour Malignancies.

Purpose: To describe a case series of peripheral ulcerative keratitis (PUK) as a paraneoplastic condition in three patients with known underlying systemic solid tumor malignancies. Observations: Three patients with different systemic malignancies (1 recurrent breast cancer, 1 metastatic thyroid cancer, and 1 metastatic gastric adenocarcinoma) were identified to have PUK with significant corneal stromal melt. Autoimmune and infective work up for other etiologies were all negative. They all responded well to topical steroids and intravenous methylprednisolone. One patient had recurrences of her PUK and required repeated amniotic grafts and tectonic keratoplasties before her corneal condition stabilized. Conclusions and Importance: PUK can be a rare manifestation of systemic solid tumor malignancies. Although PUK may not be an indicator of progression of the underlying malignancy, it can be sight-threatening. This case series highlights the necessity for clinicians to refer patients with systemic malignancies presenting with inflamed eyes for an early ophthalmological review. This facilitates the detection of this blinding disease, allowing for early therapeutic interventions and potentially better visual outcomes for these patients.

Cicatricial Conjunctivitis and Concurrent Clinical Features: A Case Study.

Purpose: We report a case of cicatricial conjunctivitis to illustrate the clinical approach for management of such a case. This is a 52-year-old Chinese man who presented with bilateral red eyes associated with itching for a year. He had a history of chronic itchy rash in the chest and the arms. Otherwise there was no history of autoimmune disease, asthma, sinusitis, or drug allergy. On examination, he had diffuse hyperemia over both conjunctivae, with symblepharon involving the inferior bulbar and palpebral conjunctivae, associated with cicatrization of the caruncles, and obliteration of inferior lacrimal puncta. There were mild subtarsal papillary reaction with Meibomian gland dysfunction and presence of inferior mis-directed eyelashes. The corneas showed multiple foci of superficial epitheliopathy. A clinical diagnosis of chronic cicatricial conjunctivitis was made, with differential diagnosis of chronic atopic allergic conjunctivitis. Conjunctival biopsy was performed from the inferior conjunctival adhesions and it showed patchy chronic stromal inflammation with focal lymphoplasmacytic sub-epithelial infiltrates and loss of goblet cells. The stroma shows marked fibrosis, with no evidence of mast cells or eosinophils. In particular, there were no deposits of IgA, IgM, C3, and fibrinogen in the basement membrane. The patient was treated with topical loteprednol, glucocorticoids and artificial tears, and his symptoms improved after treatment. Conclusion: We present a man with cicatricial conjunctivitis with chronic subconjunctival inflammation and fibrosis but no immune deposits in the conjunctival basement membrane on histology, to illustrate the clinical approach and diagnostic challenges in managing such a case.

Profiling mentally ill offenders in Hong Kong: A 10-year retrospective review study.

INTRODUCTION: This study aimed to analyze the estimated prevalence of mental disorders among offenders and compare the estimated crime rate between mentally ill patients and the total population in Hong Kong. METHODS: Service data of offenders referred to psychiatrists at the Siu Lam Psychiatric Centre from January 2011 to December 2020 were analyzed. Demographic data of gender, age on admission, educational level, principal psychiatric diagnosis, index offense, and assessment outcome were collected. RESULTS: Data of 7535 offenders (74.8% males) aged 14 to 97 (mean: 41.3 ± 13.7) years were analyzed. More than 60% (66.2%) had a diagnosable mental disorder. The most prevalent principal psychiatric diagnosis was schizophrenia and related disorder (22.8%), followed by mental and behavioral disorders due to psychoactive substance use (18.6%), and mood disorders (8.8%). The commonest index offenses were theft and related offenses (20.5%), followed by acts intended to cause injury (19.7%), and illicit drug offenses (11.6%). The estimated prevalence of mental illness among prison population was 7.1% (male: 8.2%, female: 5.0%). The estimated crime rate for mentally ill patients was found to be 43.3 to 263.2 per 100 000 population. DISCUSSION: The estimated prevalence of mental disorders among offenders and the estimated crime rate for mentally ill patients are relatively low in Hong Kong. The result was an important effort to document the changing characteristics of mentally ill offenders and provide an estimation of the prevalence and crime rate for mentally ill patients in Hong Kong.

The Management of Ocular Surface Squamous Neoplasia (OSSN).

The rise of primary topical monotherapy with chemotherapeutic drugs and immunomodulatory agents represents an increasing recognition of the medical management of ocular surface squamous neoplasia (OSSN), which may replace surgery as the standard of care in the future. Currently, there is no consensus regarding the best way to manage OSSN with no existing guidelines to date. This paper seeks to evaluate evidence surrounding available treatment modalities and proposes an approach to management. The approach will guide ophthalmologists in selecting the most appropriate treatment regime based on patient and disease factors to minimize treatment related morbidity and improve OSSN control. Further work can be done to validate this algorithm and to develop formal guidelines to direct the management of OSSN.

Managing Psoriatic Arthritis With Inflammatory Bowel Disease and/or Uveitis.

Psoriatic arthritis (PsA) is a chronic inflammatory disease that presents with psoriasis (PsO), peripheral and axial arthropathy. The heterogeneity of disease presentation leads to the term "psoriatic disease (PsD)" which is thought to better encompass the range of clinical manifestations. PsA is associated with several comorbidities such as cardiovascular diseases, metabolic syndrome and other extra-articular manifestations including uveitis, and inflammatory bowel disease (IBD). While novel therapeutics are being developed following advances in our understanding of the pathogenesis of the disease, the diverse combinations of PsA with its various comorbidities still pose a clinical challenge in managing patients with PsA. This article reviews our current understanding of the pathogenesis of PsA and how various pathways in the pathogenesis lead to the two comorbid extra-articular manifestations - uveitis and IBD. We also review current evidence of treatment strategies in managing patients with PsA with comorbidities of uveitis and/or IBD.

The Role of Autophagy in Chemical Proteasome Inhibition Model of Retinal Degeneration.

We recently demonstrated that chemical proteasome inhibition induced inner retinal degeneration, supporting the pivotal roles of the ubiquitin-proteasome system in retinal structural integrity maintenance. In this study, using beclin1-heterozygous (Becn1-Het) mice with autophagic dysfunction, we tested our hypothesis that autophagy could be a compensatory retinal protective mechanism for proteasomal impairment. Despite the reduced number of autophagosome, the ocular tissue morphology and intraocular pressure were normal. Surprisingly, Becn1-Het mice experienced the same extent of retinal degeneration as was observed in wild-type mice, following an intravitreal injection of a chemical proteasome inhibitor. Similarly, these mice equally responded to other chemical insults, including endoplasmic reticulum stress inducer, N-methyl-D-aspartate, and lipopolysaccharide. Interestingly, in cultured neuroblastoma cells, we found that the mammalian target of rapamycin-independent autophagy activators, lithium chloride and rilmenidine, rescued these cells against proteasome inhibition-induced death. These results suggest that Becn1-mediated autophagy is not an effective intrinsic protective mechanism for retinal damage induced by insults, including impaired proteasomal activity; furthermore, autophagic activation beyond normal levels is required to alleviate the cytotoxic effect of proteasomal inhibition. Further studies are underway to delineate the precise roles of different forms of autophagy, and investigate the effects of their activation in rescuing retinal neurons under various pathological conditions.

Ethnic variation in medial orbital wall anatomy and its implications for decompression surgery.

BACKGROUND: To describe the inter-ethnic variation in medial orbital wall anatomy between Chinese, Malay, Indian and Caucasian subjects. METHODS: Single-centre, retrospective, Computed Tomography (CT)-based observational study. 20 subjects of each ethnicity, were matched for gender and laterality. We excluded subjects younger than 16 years and those with orbital pathology. OsiriX version 8.5.1 (Pixmeo., Switzerland) and DICOM image viewing software CARESTREAM Vue PACS (Carestream Health Inc., USA) were used to measure the ethmoidal sinus length, width and volume, medial orbital wall and floor angle and the relative position of the posterior ethmoid sinus to the posterior maxillary wall. Statistical analyses were performed using Statistical Package for Social Sciences version 25.0 (IBM, USA). RESULTS: There were 12 males (60 %) in each group, with no significant difference in age (p = 0.334-0.994). The mean ethmoid sinus length in Chinese, Malay, Indian and Caucasian subjects, using the Chinese as reference, were 37.2, 36.9, 38.0 and 37.4mm, the mean width was 11.6, 10.5, 11.4 and 10.0mm (p = 0.020) and the mean ethmoid sinus volume were 3362, 3652, 3349 and 3898mm3 respectively. The mean medial orbital wall and floor angle was 135.0, 131.4, 131.0 and 136.8 degrees and the mean relative position of posterior ethmoid sinus to posterior maxillary wall were - 2.0, -0.2, -1.5 and 1.6mm (p = 0.003) respectively. CONCLUSIONS: No inter-ethnic variation was found in decompressible ethmoid sinus volume. Caucasians had their posterior maxillary sinus wall anterior to their posterior ethmoidal walls unlike the Chinese, Malay and Indians. Awareness of ethnic variation is essential for safe orbital decompression.

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. Design, Setting, and Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. Main Outcomes and Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses. Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. Conclusions and Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.

Safety profiles of terahertz scanning in ophthalmology.

Terahertz (THz) technology has emerged recently as a potential novel imaging modality in biomedical fields, including ophthalmology. However, the ocular biological responses after THz electromagnetic exposure have not been investigated. We conducted a rabbit study to evaluate the safety profiles of THz scanning on eyes, at a tissue, cellular, structural and functional level. Eight animals (16 eyes) were analysed after excessive THz exposure (control, 1 h, 4 h, and 1 week after continuous 4-h exposure; THz frequency = 0.3 THz with continuous pulse generated at 40 µW). We found that at all the time points, the corneas and lens remained clear with no corneal haze or lens opacity formation clinically and histopathologically. No thermal effect, assessed by thermographer, was observed. The rod and cone cell-mediated electroretinography responses were not significantly altered, and the corneal keratocytes activity as well as endothelial viability, assessed by in-vivo confocal microscopy, was not affected. Post-exposed corneas, lens and retinas exhibited no significant changes in the mRNA expression of heat shock protein (HSP)90AB1), DNA damage inducible transcript 3 (DDIT3), and early growth response (EGR)1. These tissues were also negative for the inflammatory (CD11b), fibrotic (fibronectin and α-smooth muscle actin), stress (HSP-47) and apoptotic (TUNEL assay) responses on the immunohistochemical analyses. The optical transmittance of corneas did not change significantly, and the inter-fibrillar distances of the corneal stroma evaluated with transmission electron microscopy were not significantly altered after THz exposure. These results provide the basis for future research work on the development of THz imaging system for its application in ophthalmology.

PreservCyt Is an Optimal Fixative that Permits Cytologic and Molecular Analyses of Vitreoretinal Lymphoma Biopsies.

Purpose: Vitreoretinal lymphoma (VRL) is a potentially fatal intraocular malignancy. Diagnosis is hampered by poor preservation of morphology and DNA/RNA integrity, which precludes adjunctive molecular analysis. We aimed to determine the optimum fixative protocol for VRL biopsies that permits cytology, IHC/flow cytometry and molecular analyses.Methods: Six fixatives were compared on cultured Pfeiffer cells used as a cellular model. Cells were fixed and evaluated on cellular morphology, antibody staining, DNA/RNA amount and integrity. VRL clinical cases were used as validation and proof-of-concept.Results: PreservCyt was the best fixative for preserving cellular morphology and high-quality RNA/DNA from vitreous fluid biopsies. Cells from clinical VRL cases fixed with PreservCyt showed adequate cellular morphology and IHC positivity. Sufficient DNA was obtained for IgH clonality and MYD88 mutation detection using remnant cytological fluid.Conclusions: PreservCyt maintains good morphology and RNA/DNA integrity suggesting that it is a suitable fixative for VRL diagnosis and molecular analysis.

Single B-Cell Genomic Analyses Differentiate Vitreoretinal Lymphoma from Chronic Inflammation.

PURPOSE: To test whether analyzing DEPArray (Menarini Silicon Biosystems) isolated single B cells from the vitreous fluid can reveal crucial genomic and clinicopathological features to distinguish patients with vitreoretinal lymphoma (VRL) from those with chronic inflammation using immunoglobulin heavy chain (IGH), disease biomarker myeloid differentiation primary response 88 (MYD88)L265P mutation, and copy number profiling. DESIGN: A single-center, retrospective study. PARTICIPANTS: Remnant vitreous biopsies from 7 patients with VRL and 4 patients with chronic inflammation were acquired for molecular analysis. METHODS: Vitreous fluid samples were prefixed in PreservCyt (Hologic) and underwent cytologic analysis and immunohistochemistry examination. Single cells were isolated using the DEPArray NxT system, followed by downstream genomic analysis. MAIN OUTCOME MEASURES: The frequencies of the dominant IGH and MYD88L265P mutation and the genome-wide copy number aberration (CNA) profiles of individual vitreous-isolated B cells were characterized. RESULTS: An average of 10 to 13 vitreous B cells were used in the single-cell IGH and MYD88 analyses. Higher frequencies of dominant IGH (88.8% ± 13.2%) and MYD88L265P mutations (35.0% ± 31.3%) were detected in patients with VRL than in patients with chronic inflammation (65.9% ± 13.4% and 1.5% ± 2.6% for IGH and MYD88L265P, respectively). In a cytology-proven VRL case, all 15 vitreous isolated B cells were derived from the same clone with 100% paired IGH: immunoglobulin light chain (IGK) sequences. Genome-wide copy number profiling revealed a high degree of similarity between B cells from the same patient with VRL, with extensive gains and losses at the same areas across the whole genome. In addition, 14 of 15 B cells showed a BCL2/JH t(14;18) translocation, confirming cellular malignancy with a clonal origin. Clustering analysis of the copy number profiles revealed that malignant B cells derived from different patients with VRL had no common genome-wide signatures. CONCLUSIONS: Single B-cell genomic characterization of the IGH, MYD88L265P mutation, and copy number profile enables VRL diagnosis. Because our study involved only a small cohort, these meaningful proof-of-concept data now warrant further investigation in a larger patient cohort.

Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract.

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10-16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10-19), TMPRSS5 (rs4936279, P = 2.5 × 10-10), LINC01412 (rs16823886, P = 1.3 × 10-9), GLTSCR1 (rs1005911, P = 9.8 × 10-9), and COMMD1 (rs62149908, P = 1.2 × 10-8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye.

Clinical features and survival outcomes of ocular melanoma in a multi-ethnic Asian cohort.

Ocular melanomas are uncommon cancers in Southeast Asia unlike in the West. We conducted a retrospective review of patients (n = 44) with histologically-proven ocular melanoma within a multi-ethnic Asian cohort from Singapore. Clinicopathological features and relapse patterns were examined, and survival outcomes of interest included recurrence-free survival (RFS) and overall survival (OS). Survival analysis was performed using the Kaplan-Meier method and multivariable Cox proportional regression. The study cohort included 18 male and 26 female patients, with a median age of 52 years (range 8-78). Median follow-up was 154 months. For uveal melanomas (n = 29), the 5-year RFS and OS was 56.8% and 76.6%, respectively; whilst for conjunctival melanomas (n = 15), the 5-year RFS and OS was 30.1% and 68.8%, respectively. Fifteen patients (38.5%) eventually developed metastasis, following which the median survival was only 17 months. Multivariate analysis demonstrated that higher T stage was a significant independent predictor for both OS (HR 8.69, 95% CI 1.03 to 73.09, p = 0.047) and RFS (HR 11.62, 95% CI 2.45 to 55.00, p = 0.002). Smoking history was independently predictive of better RFS (HR 0.08, 95% CI 0.01 to 0.78, p = 0.030). In conclusion, our study demonstrates the poor ocular melanoma outcomes in Southeast Asians, highlighting the necessity for urgent research in this area of unmet clinical need.