Opthalmology & Visual Sciences publications

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High Polygenic Risk is Associated with Earlier Initiation and Escalation of Treatment in Early Primary Open Angle Glaucoma
(Elsevier, 2023) Marshall, H.N.; Mullany, S.; Han, X.; Qassim, A.; He, W.; Hassall, M.M.; Schmidt, J.; Thomson, D.; Nguyen, T.T.; Berry, E.C.; Knight, L.S.; Hollitt, G.L.; Ridge, B.; Schulz, A.; Mills, R.A.; Healey, P.R.; Agar, A.; Galanopoulos, A.; Landers, J.; Graham, S.L.; et al.
Purpose: To assess the association between a glaucoma polygenic risk score (PRS) and treatment outcomes in primary open-angle glaucoma. Design: Prospective, observational cohort study. Participants: Participants from the Progression Risk of Glaucoma: Relevant SNPs with Significant Association Study were divided into a cohort with suspect glaucoma who were treatment naive at enrollment and one with early manifest and suspect glaucoma receiving treatment at enrollment. Methods: A per-allele weighted glaucoma PRS was calculated for 1107 participants. Multivariable mixedeffects Cox proportional regression analysis assessed the association between PRS and time to commencement of intraocular pressure (IOP)-lowering therapy in 416 patients with suspect glaucoma who were treatment naive at study enrollment. Secondary analysis evaluated the association between PRS and escalation of IOPlowering therapy among 691 patients with suspect and early manifest glaucoma who were receiving IOPlowering therapy at enrollment. Main Outcome Measures: Commencement or escalation of IOP-lowering therapy. Results: A higher PRS was associated with a greater risk of commencing IOP-lowering therapy within 5 years (hazard ratio [HR], 1.45 per 1 standard deviation [/SD]; 95% confidence interval [CI], 1.27e1.62; P < 0.001). Participants in the upper population-based quintile showed a 3.3 times greater risk of commencing therapy by 5 years than those in the lowest quintile (HR, 3.30; 95% CI, 1.63e6,70; P < 0.001) and a 5.4 times greater risk of commencing IOP-lowering therapy by 2 years than the those in the lowest quintile (HR, 5.45; 95% CI, 2.08e14.25; P < 0.001). A higher PRS was associated with a greater risk of treatment escalation among patients receiving treatment at enrollment (HR, 1.19/SD; 95% CI, 1.09e1.31; P < 0.001). In combined analysis of all participants, participants in the top population-based quintile were at 2.3 times greater risk of requiring initiation or escalation of IOP-lowering therapy than those in the lowest quintile (HR, 2.33; 95% CI, 1.75e3.01; P < 0.001). Conclusions: This study demonstrated novel associations between glaucoma polygenic risk and risk of commencement or escalation of IOP-lowering therapy, building on previous work highlighting the potential clinical usefulness of genetic risk stratification in glaucoma.
Open Access
Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse
(Nature Publishing Group, 2023) Hassall, M.M.; Javadiyan, S.; Klebe, S.; Awadalla, M.S.; Sharma, S.; Qassim, A.; White, M.; Thomas, P.Q.; Craig, J.E.; Siggs, O.M.
Nanophthalmos is characterised by shorter posterior and anterior segments of the eye, with a predisposition towards high hyperopia and primary angle-closure glaucoma. Variants in TMEM98 have been associated with autosomal dominant nanophthalmos in multiple kindreds, but definitive evidence for causation has been limited. Here we used CRISPR/Cas9 mutagenesis to recreate the human nanophthalmos-associated TMEM98 p.(Ala193Pro) variant in mice. The p.(Ala193Pro) variant was associated with ocular phenotypes in both mice and humans, with dominant inheritance in humans and recessive inheritance in mice. Unlike their human counterparts, p.(Ala193Pro) homozygous mutant mice had normal axial length, normal intraocular pressure, and structurally normal scleral collagen. However, in both homozygous mice and heterozygous humans, the p.(Ala193Pro) variant was associated with discrete white spots throughout the retinal fundus, with corresponding retinal folds on histology. This direct comparison of a TMEM98 variant in mouse and human suggests that certain nanophthalmos-associated phenotypes are not only a consequence of a smaller eye, but that TMEM98 may itself play a primary role in retinal and scleral structure and integrity.
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Establishing human lacrimal gland cultures from biopsy-sized tissue specimens
(Springer, 2023) Halliday, L.A.; Wood, J.P.M.; Chidlow, G.; Casson, R.J.; Selva, D.; Sun, M.T.
OBJECTIVES: To establish cultures of human lacrimal gland from patient-derived, biopsy-sized, tissue specimens. METHODS: Tissue was obtained after surgical removal from patients without dry eye disease undergoing routine procedures. Samples were subjected to mechanical and enzymatic digestion and resulting cell suspensions were plated onto collagen-coated glass coverslips and grown for up to 21 days. Cultures were analysed by immunocytochemistry and light microscopy, and resultant cellular distributions were compared to those in sections of fixed human lacrimal gland tissue. RESULTS: Dissociation of biopsy-sized pieces of human lacrimal gland and seeding onto coated surfaces allowed development of a mixed population of cells in vitro. Within 7–14 days, cellular aggregation was observed and by 21 days many cells had organised themselves into distinct three-dimensional complexes. Immunohistochemistry revealed a heterogeneous population of cells, including epithelial, myoepithelial, mesenchymal and progenitor cells. Some of the epithelia labelled positively for lysozyme and lactoferrin. CONCLUSIONS: Collection and dissociation of biopsy-sized pieces of human lacrimal gland leads to a cellular preparation that can proliferate in vitro and organise into three-dimensional structures. This is the first report detailing that biopsy-collected specimens of human lacrimal gland can be used to establish cell cultures.
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Association between Body Mass Index and Primary Open-Angle Glaucoma in Three Cohorts
(Elsevier, 2023) Marshall, H.; Berry, E.C.; Torres, S.D.; Mullany, S.; Schmidt, J.; Thomson, D.; Nguyen, T.T.; Knight, L.S.W.; Hollitt, G.; Qassim, A.; Kolovos, A.; Ridge, B.; Schulz, A.; Lake, S.; Mills, R.A.; Agar, A.; Galanopoulos, A.; Landers, J.; Healey, P.R.; Graham, S.L.; et al.
Purpose: To evaluate the relationship between body mass index (BMI) and glaucoma progression. DESIGN: Multicohort observational study Methods: This study combined a retrospective longitudinal analysis of suspect and early manifest primary open-angle glaucoma cases from the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study, with two replication cohorts from the UK Biobank and the Canadian Longitudinal Study of Ageing (CLSA). In the PROGRESSA study, multivariate analysis correlated BMI with longitudinal visual field progression in 471 participants. BMI was then associated with glaucoma diagnosis and cross-sectional VCDR measurements in the UK Biobank, and finally prospectively associated with longitudinal change in VCDR in the CLSA study, and with Results: In the PROGRESSA study, a lower BMI conferred a faster rate of visual field progression (Mean duration of monitoring (5.28±1.80years (10.6±3.59 visits) (beta: 0.04dB/year/SD [0.005, 0.069] P=0.013). In the UK Biobank a 1 standard deviation lower BMI was associated with a worse cross-sectional VCDR (beta: -0.048/SD [-0.056, 0.96] P<0.001), and with a 10% greater likelihood of glaucoma diagnosis, as per specialist grading of retinal fundus imaging (OR: 0.90 [0.84, 0.98] P=0.011). Similarly, a lower BMI was associated with a greater risk of glaucoma diagnosis as per International Classification of Disease data (OR: 0.94/SD 95% CI: [0.91, 0.98] P=0.002). BMI was also positively correlated with IOP (beta: 0.11/SD 95% CI: [0.06, 0.15] P<0.001). Finally, a lower BMI was then associated with greater VCDR change in the CLSA (beta: -0.007/SD 95% CI: [-0.01, -0.001] P=0.023). Conclusions: Body mass index was correlated with longitudinal and cross-sectional glaucomatous outcomes. This supports previous work illustrating a correlation between BMI and glaucoma.
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Association of High Polygenic Risk With Visual Field Worsening Despite Treatment in Early Primary Open-Angle Glaucoma
(American Medical Association, 2023) Siggs, O.M.; Qassim, A.; Han, X.; Marshall, H.N.; Mullany, S.; He, W.; Souzeau, E.; Galanopoulos, A.; Agar, A.; Landers, J.; Casson, R.J.; Hewitt, A.W.; Healey, P.R.; Graham, S.L.; MacGregor, S.; Craig, J.E.
Importance: Irreversible vision loss from primary open-angle glaucoma (POAG) can be prevented through timely diagnosis and treatment, although definitive diagnosis can be difficult in early-stage disease. As a consequence, large numbers of individuals with suspected glaucoma require regular monitoring, even though many of these may never develop disease and other high-risk individuals with suspected glaucoma may have delayed or inadequate treatment. POAG is one of the most heritable common diseases, and this provides an opportunity to use genetic instruments in risk-stratified screening, diagnosis, and treatment of early glaucoma. Objective: To assess the association of glaucoma polygenic risk with glaucoma progression in early-stage disease. Design, Setting, and Participants: This cohort study used clinical and genetic data obtained from a longitudinal cohort study, Progression Risk of Glaucoma: Relevant SNPs With Significant Association (PROGRESSA). Participants of European ancestry with characteristic optic nerve head changes suggestive of glaucoma were included. Data were collected between February 2012 and June 2020. Analysis took place between July 2020 and April 2022. Main Outcomes and Measures: The association of a glaucoma polygenic risk score (PRS) (2673 uncorrelated variants) with rate of peripapillary retinal nerve fiber layer thinning on optical coherence tomography and progression of visual field loss on 24-2 Humphrey visual fields. Results: A total of 1777 eyes from 896 individuals had sufficient data for structural progression analyses and 1563 eyes from 808 individuals for functional progression analyses. The mean (SD) age was 62.1 (9.9) years, 488 (44%) were male, and 1087 of 1103 individuals (98.5%) had European ancestry. An ancestrally matched normative population cohort (n = 17 642) was used for PRS reference. Individuals in the top 5% PRS risk group were at a higher risk of visual field progression compared with the remaining 95% after 5 years (hazard ratio, 1.5; 95% CI, 1.13-1.97; P = .005). Conversely, those in the bottom 20% PRS risk group were at a lower risk of visual field progression compared with an intermediate risk group over 3 years (hazard ratio, 0.52; 95% CI, 0.28-0.96; P = .04). Conclusions and Relevance: In this study, high polygenic risk was associated with more rapid structural and functional progression in early POAG, despite more intensive treatment. A PRS may serve as a valuable adjunct to identify individuals who stand to benefit the most from more frequent surveillance and earlier or more intensive treatment.
Open Access
High polygenic risk is associated with earlier treatment initiation and escalation in glaucoma suspects
(Association for Research in Vision & Ophthalmology, 2022) Marshall, H.; Han, X.; Mullany, S.; Hollitt, G.; Berry, E.C.; Knight, L.; Mills, R.A.; Landers, J.; Healey, P.; Hewitt, A.W.; Graham, S.L.; Casson, R.; MacGregor, S.; Siggs, O.; Craig, J.E.; The Association for Research in Vision & Ophthalmology Annual Meeting (ARVO) (1 May 2022 - 5 May 2022 : Denver, CO, USA & online)
Open Access
The APOE E4 allele is associated with faster rates of mGCIPL thinning in the PROGRESSA cohort
(Association for Research in Vision & Ophthalmology, 2022) Mullany, S.; Marshall, H.; Souzeau, E.; Hassall, M.; Agar, A.; Galanopoulos, A.; Landers, J.; Mitchell, P.; Healey, P.; Graham, S.L.; Hewitt, A.W.; MacGregor, S.; Gharahkhani, P.; Casson, R.; Siggs, O.; Craig, J.E.; The Association for Research in Vision & Ophthalmology Annual Meeting (ARVO) (1 May 2022 - 5 May 2022 : Denver, CO, USA & online)
Open Access
Greater physical activity is associated with neuroretinal thinning in glaucomatous and normative cohorts
(Association for Research in Vision & Ophthalmology, 2022) Berry, E.C.; Marshall, H.; Mullany, S.; Torres, S.D.; Schmidt, J.; Thomson, D.; Hassall, M.; Lake, S.R.; Mills, R.A.; Landers, J.; MacGregor, S.; Casson, R.; Siggs, O.; Craig, J.E.; The Association for Research in Vision & Ophthalmology Annual Meeting (ARVO) (1 May 2022 - 5 May 2022 : Denver, CO, USA & online)
Open Access
A polygenic risk score predicts functional progression in early primary open-angle glaucoma
(Association for Research in Vision & Ophthalmology, 2022) Siggs, O.; Qassim, A.; Han, X.; Marshall, H.; Mullany, S.; Souzeau, E.; Galanopoulos, A.; Agar, A.; Landers, J.; Casson, R.; Hewitt, A.W.; Healey, P.; Graham, S.L.; MacGregor, S.; Craig, J.; The Association for Research in Vision & Ophthalmology Annual Meeting (ARVO) (1 May 2022 - 5 May 2022 : Denver, CO, USA & online)
Open Access
Review of the ophthalmic manifestations of gout and uric acid crystal deposition
(Wiley, 2017) Ao, J.; Goldblatt, F.; Casson, R.J.
Gout is a clinical disorder that is characterized by the deposition of monosodium urate crystals (MSU) in joints and tendons, usually in the presence of prolonged hyperuricaemia. Following an asymptomatic phase of hyperuricaemia, gout usually presents as acute monoarthritis followed by periods of remission and exacerbation. Conjunctival hyperaemia and subconjunctival haemorrhage exacerbated by purine intake are two of the more common manifestations that may go unrecognized. Other ocular and adnexal structures can be affected by urate crystal deposition and associated inflammation, with potentially vision-threatening consequences; however, ocular manifestations of gout are rare and may have been over-reported in the older literature, but our understanding of the clinic-pathological features of ocular urate deposits remains limited.
Open Access
Pressures generated during corneal wound hydration
(Elsevier, 2016) Sun, M.T.; Wood, M.; Chan, W.O.; Casson, R.
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Nationwide trends in vitreoretinal procedures within Australia
(Wiley, 2022) Macri, C.; Singh, G.; Selva, D.; Wong, C.; Sun, M.; Chan, W.O.; 52nd Annual Scientific Congress of the Royal Australian and New Zealand College of Ophthalmologists (25 Feb 2022 - 1 Mar 2022 : Brisbane, QLD, Australia)
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Nationwide trends in vitreoretinal procedures within Australia
(Taylor & Francis, 2023) Macri, C.; Singh, G.; Selva, D.; Wong, C.; Sun, M.; Chan, W.O.
Purpose: To investigate Australian age stratified nationwide trends in vitreoretinal procedures. Methods: Nationwide retrospective analysis of vitreoretinal procedures in Australia over 2001– 2019 using Australian National Hospital Morbidity Database for public and private hospitals. Age and gender-specific trends in selected procedures including pars plana vitrectomy for retinal detachment (PPV for RD), scleral buckle, intravitreal injections, and PPV unrelated to RD were analysed using negative binomial regression. Results: Total included procedures increased from 8102 in 2001 to 136430 in 2019. Between 2001 and 2019, the incidence per 100,000 persons of PPV for RD increased from 7.5 to 20.7, whilst scleral buckling decreased from 10.5 to 4.0. Similarly, the incidence per 100,000 persons of PPV unrelated to RD increased from 18.4 to 67.1, and intravitreal injections increased from 5.6 to 446.0. The rate of scleral buckling decreased by 6% annually (p < .001), most pronounced in those 40 years and above. In contrast, PPV for RD increased by 5% annually (p < .001), also most pronounced in those aged 40 and above. PPV unrelated to RD increased by 7% annually (p < .001), and intravitreal injections increased by 21.0% annually (p < .001). Conclusion: Between 2001 and 2019, the rate of scleral buckling declined compared to an increase in PPV for RD. Our analysis suggests an increasing trend to PPV over scleral buckling for RD repair in Australia over the last two decades. Additionally, rates of PPV unrelated to RD and intravitreal injections increased across all age groups. Overall, these trends mirror those seen internationally and reflect changing practice patterns over time.
Open Access
Normal-tension glaucoma is associated with cognitive impairment
(BMJ Publishing Group, 2022) Mullany, S.; Xiao, L.; Qassim, A.; Marshall, H.; Gharahkhani, P.; Macgregor, S.; Hassall, M.M.; Siggs, O.M.; Souzeau, E.; Craig, J.E.
Background/aims: Recent research suggests an association between normal-tension glaucoma (NTG) and dementia. This study investigated whether cognitive impairment is more strongly associated with NTG than high tension glaucoma (HTG) using cognitive screening within an Australiasian Glaucoma Disease Registry. Methods: The authors completed a case–control cross sectional cognitive screening involving 290 age-matched and sex-matched NTG participants and HTG controls aged ≥65 randomly sampled from the Australian and New Zealand Registry of Advanced Glaucoma. Cognitive screening was performed using the Telephone Version of the Montreal Cognitive Assessment (T-MoCA). The T-MoCA omits points requiring visual interpretation, accounting for confounding factors related to vision loss in visually impaired participants. Cognitive impairment was defined by a T-MoCA score of <11/22. Cognition was compared between NTG and HTG participants using predetermined thresholds and absolute screening scores. Results: A total of 290 participants completed cognitive assessment. There were no differences in NTG (n=144) and HTG (n=146) cohort demographics or ocular parameters at baseline. Cognitive impairment was more prevalent in the NTG cohort than the HTG cohort (OR=2.2; 95% CI 1.1 to 6.7, p=0.030). Though a linear trend was also observed between lower absolute T-MoCA scores in the NTG cohort when compared with the HTG cohort, this association was not statistically significant (p=0.108). Conclusion: This study demonstrated an association between NTG status and poor cognition, supporting the hypothesis that there exists a disease association and shared pathoaetiological features between NTG and dementia.
Open Access
Prevalence of eye conditions, utilization of eye health care services, and ophthalmic medications after entering residential aged care in Australia
(Association for Research in Vision and Ophthalmology, 2021) Khadka, J.; Ratcliffe, J.; Caughey, G.E.; Wesselingh, S.L.; Inacio, M.C.
Purpose This study aims to evaluate the burden and trends of eye diseases, utilisation of eye health care services, and ophthalmic medications among older people living in residential aged care facilities in Australia. Methods A cross-sectional study was conducted using data from the Registry of Senior Australians. Individuals aged ≥65 years who entered permanent residential aged care facilities between 2008 and 2015 were included. The prevalence (95% confidence interval [CI]) of eye diseases by year, eye health care services, and ophthalmic medication use within a year of entry into the service were evaluated. Poisson regression models estimated adjusted rate of change using prevalence ratio (PR) by age, sex, state, and frailty scores. Results Of the 409,186 people studied, 43.6% (N = 178,367) had an eye condition. Of the total cohort, 32.9% (N = 134,566) had chronic eye conditions and 19.7% (N = 80,661) had an acute eye condition. Common chronic eye conditions were glaucoma (13.6%, N = 55,830), cataract (8%, (N = 32,779), blindness (4.5%, N = 18,856), and poor vision (10.3%, N = 42,245). Prevalence of any eye condition (2008: 42.7%, 95% CI = 42.2%-43.2% and 2015: 41.2%, 95% CI = 40.8-41.6%, PR = 0.99, 95% CI = 0.99-0.99, P < 0.001), acute eye conditions (2008: 19.8%, 95% CI = 19.4%-20.2% and 2015: 17.4%, 95% CI = 17.1%-17.6%, PR = 0.97, 95% CI = 0.97-0.98, P < 0.001), and blindness (2008: 5.2%, 95% CI = 5.0%-5.4% and 2015: 3.7%, 95% CI = 3.5%-3.9%, PR = 0.93, 95% CI = 0.93-0.94, p < 0.001). decreased over the study period. The prevalence of glaucoma (2008: 13.5%, 95% CI = 13.2%-13.8% and 2015: 13.8%, 95% CI = 13.5%-13.7%; PR = 1.01, 95% CI = 0.99-1.10, P < 0.001) and cataract (2008: 7.4%, 95% CI = 7.2%-7.7% and 2015: 8.5%, 95% CI = 8.3%-8.7%, PR = 1.00, 95% CI = 1.00-1.01, P < 0.001) remained stable or slightly increased. Overall, 46.4% (N = 82,769) of individuals with eye conditions, accessed at least one eye health service within the first year of entering residential care and 70.5% (N = 125,673) used at least one ophthalmic medication. Optometric services (41.7%, N = 74,358) were the most used eye health care services and anti-infective eye drops (37.2%, N = 66,331) were the most commonly dispensed medications.
Conclusions
The prevalence of blindness among older Australian using residential aged care services decreased over the study period. However, the burden of eye diseases remained high between 2008 and 2015, whereas the use of eye health care services was disproportionately low. This study provides evidence of a significant need for eye health care services for older people with an eye disease in residential aged care facilities. Translational relevance Four in ten long term aged care residents in Australia had at least one eye condition over the study period, indicating potential for a high eye health care needs in aged care settings.
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Orbito-cranial schwannoma - a multicenter experience
(Springer, 2023) Shapira, Y.; Juniat, V.; Dave, T.; Hussain, A.; McNeely, D.; Watanabe, A.; Yoneda, A.; Saeed, P.; Woo, K.I.; Hardy, T.; Selva, D.
OBJECTIVES: To describe the features, management approaches, and outcomes of orbito-cranial schwannomas. METHODS: Retrospective review of ten patients with orbito-cranial schwannomas managed in six orbital services over 22 years. Data collected included demographics, presenting features, neuroimaging characteristics, histology, management approach, complications, and outcomes. RESULTS: Mean age of the patients was 41.4 ± 19.9 years, and 6 (60%) were females. The majority presented with proptosis (90%), limited extraocular motility (80%), eyelid swelling (60%), and optic neuropathy (60%). Most lesions (80%) involved the entire anterior-posterior span of the orbit, with both intra- and extraconal involvement. All tumours involved the orbital apex, the superior orbital fissure, and extended at least to the cavernous sinus. Surgical resection was performed for all. Seven (70%) of the tumours were completely or subtotally resected combining an intracapsular approach by an orbital-neurosurgical collaboration, with no recurrence on postoperative follow-up (6–186 months). Three underwent tumour debulking. Of these, two remained stable on follow-up (6–34 months) and one showed progression of the residual tumour over 9 years (cellular schwannoma on histology) necessitating stereotactic radiotherapy (SRT) for local control. Adjuncts to the orbito-cranial resection included perioperative frozen section (n = 5), endoscopic transorbital approach (n = 2), and image-guided navigation (n = 1). Post-surgical adjuvant SRT was used in three subjects. CONCLUSIONS: These results highlight the possibility of successful surgical control in complex orbito-cranial schwannomas. A combined neurosurgical/orbital approach with consideration of an intracapsular resection is recommended. Recurrence may not occur with subtotal excision and observation may be reasonable. Adjunctive SRT for progression or residual tumour can be considered.
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Establishing human lacrimal gland cultures from biopsy sized samples
(Wiley, 2019) Halliday, L.; Wood, J.; Selva, D.; Sun, M.; 51st Annual Scientific Congress, International Convention Centre (ICC) (8 Nov 2019 - 12 Nov 2019 : Sydney)
Abstract not available
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Secondary and Exploratory Outcomes of the Subthreshold Nanosecond Laser Intervention Randomized Trial in Age-Related Macular Degeneration: A LEAD Study Report
(Elsevier, 2019) Wu, Z.; Luu, C.D.; Hodgson, L.A.B.; Caruso, E.; Brassington, K.H.; Tindill, N.; Aung, K.Z.; Harper, C.A.; Wickremasinghe, S.S.; Sandhu, S.S.; McGuinness, M.B.; Chen, F.K.; Chakravarthy, U.; Arnold, J.J.; Heriot, W.J.; Durkin, S.R.; Wintergerst, M.W.M.; Gorgi Zadeh, S.; Schultz, T.; Finger, R.P.; et al.
Purpose:To evaluate the secondary and exploratory outcomesof the Laser Intervention in Early Stages of Age-Related MacularDegeneration (LEAD) study, a 36-month trial of a subthresholdnanosecond laser (SNL) treatment for slowing the progression tolate age-related macular degeneration (AMD) in its early stages.Design:Multicenter, randomized, sham-controlled trial.Participants:Two-hundred ninety-two patients with bilaterallarge drusen.Methods:Participants were randomly assigned to receive SNLor sham treatment to the study eye at 6-month intervals.Main Outcome Measures:The secondary outcome measure ofthe LEAD study was the time to development of late AMD, definedby multimodal imaging in the nonestudy eye. The exploratoryoutcome measures were the rate of change in best-corrected visualacuity (BCVA), low-luminance visual acuity, microperimetric meansensitivity, drusen volume in the study and nonestudy eyes, andparticipant-reported outcomes based on the Night Vision Question-naire and Impact of Vision Impairment questionnaire.Results:Progression to late AMD in the nonestudy eye wasnot significantly delayed with SNL treatment (hazard ratio, 0.83;95% confidence interval, 0.40e1.71;P¼0.611). There was noevidence of effect modification based on the coexistence of retic-ular pseudodrusen; interactionP¼0.065). There was no signifi-cant difference between study groups in the rate of change of low-luminance visual acuity, microperimetric mean sensitivity, anddrusen volume in the study or nonestudy eyes, and Night VisionQuestionnaire and Impact of Vision Impairment questionnaire2 scores (allP 0.167). The rate of BCVA decline was slightlyhigher for participants in the SNL group compared with the shamtreatment group in the study eye (e0.54 and 0.23 letters/year,respectively;P<0.001) but not the nonestudy eye (e0.48 ande0.56 letters/year, respectively;P¼0.628).Conclusions:Subthreshold nanosecond laser treatment of oneeye did not have an effect on delaying progression to late AMD in thefellow eye and did not, in general, have an impact on the exploratorystructural, functional, and participant-reported outcomes.
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Subthreshold Nanosecond Laser in Age-Related Macular Degeneration: Observational Extension Study of the LEAD Clinical Trial
(Elsevier, 2021) Guymer, R.H.; Chen, F.K.; Hodgson, L.A.B.; Caruso, E.; Harper, C.A.; Wickremashinghe, S.S.; Cohn, A.C.; Sivarajah, P.; Tindill, N.; Luu, C.D.; Wu, Z.; Al-Qureshi, S.; Busija, L.; Louis, D.; Harper, C.; Wickremasinghe, S.; Van Wijngaarden, P.; Lim, L.; Durkin, S.; Runciman, J.; et al.
Purpose To evaluate the long-term effect of subthreshold nanosecond laser (SNL) treatment on progression to late age-related macular degeneration (AMD). Design Observational extension study of a randomized, sham-controlled trial. Participants Two hundred twelve participants with bilateral large drusen. Methods The Laser Intervention in the Early Stages of AMD (LEAD) study was a 36-month trial where participants were randomized to receive SNL or sham treatment in 1 eye at 6-monthly intervals up to 30 months. After the completion of the LEAD study, the 2 largest recruiting sites offered remaining participants an opportunity to enroll in a 24-month observational extension study. This study thus examined all participants from these 2 sites who were enrolled in the LEAD study at baseline, including the additional observational data. Main Outcome Measures Time to develop late AMD, defined on multimodal imaging, between those randomized the SNL or sham treatment. Results Overall, no significant difference was found in the rate of progression over a 60-month period in those randomized to the SNL compared with the sham group (adjusted hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.36–1.09; P = 0.098), similar to the findings at 36 months in the LEAD Study. However, evidence of treatment effect modification continued to emerge based on the coexistence of reticular pseudodrusen (RPD; P = 0.007, adjusted interaction). Namely, progression was slowed significantly with SNL treatment for those without coexistent RPD (adjusted HR, 0.34; 95% CI, 0.16–0.71; P = 0.004), but it was not significantly different for those with RPD (adjusted HR, 1.81; 95% CI, 0.67–4.88; P = 0.239). Conclusions A 24-month observational extension study to the LEAD Study confirmed that SNL treatment did not significantly reduce the overall rate of progression to late AMD in a cohort with intermediate AMD. However, the persistence of a potential beneficial treatment effect in those without coexistent RPD over a longer follow-up duration of an additional 24 months without additional treatment is encouraging. These findings provide further justification for future trials to examine the potential value of SNL treatment for slowing progression in intermediate AMD.
Open Access
Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries
(Springer Nature, 2021) Gharahkhani, P.; Jorgenson, E.; Hysi, P.; Khawaja, A.P.; Pendergrass, S.; Han, X.; Ong, J.S.; Hewitt, A.W.; Segrè, A.V.; Rouhana, J.M.; Hamel, A.R.; Igo, R.P.; Choquet, H.; Qassim, A.; Josyula, N.S.; Cooke Bailey, J.N.; Bonnemaijer, P.W.M.; Iglesias, A.; Siggs, O.M.; Young, T.L.; et al.
Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

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