Attitudes Toward Glaucoma Genetic Risk Assessment in Unaffected Individuals.

Purpose: Integrating polygenic risk scores (PRS) into healthcare has the potential to stratify an individual's risk of glaucoma across a broad population. Glaucoma is the most common cause of irreversible blindness worldwide, therefore effective screening for glaucoma endorsed by the population is highly important. This study assessed the attitude of unaffected individuals toward PRS testing for glaucoma, and sought to identify factors associated with interest in testing. Methods: We surveyed 418 unaffected individuals including 193 with a first-degree relative with glaucoma, 117 who had a recent eye examination, and 108 general members of the community. Results: Overall, 71.3% of the individuals indicated an interest in taking a polygenic risk test for glaucoma. Interest was more likely in those who believed glaucoma to be a severe medical condition (odds ratio [OR] = 14.58, 95% confidence interval [CI] = 1.15-185.50, P = 0.039), those concerned about developing glaucoma (OR = 4.37, 95% CI = 2.32-8.25, P < 0.001), those with an intention to take appropriate measures regarding eye health (OR = 2.39, 95% CI = 1.16-4.95, P = 0.019), and those preferring to know if considered to be at-risk or not (OR = 4.52, 95% CI = 2.32-8.83, P < 0.001). Conclusions: Our results show strong interest in genetic risk assessment for glaucoma among unaffected individuals in Australia. Translational Relevance: These findings represent a valuable assessment of interest in glaucoma polygenic risk testing among potential target populations, which will be integral to the implementation and uptake of novel PRS-based tests into clinical practice.

Outcomes of corneal transplantation in Australia, in an era of lamellar keratoplasty.

Widespread adoption of modern lamellar procedures has altered the pattern of practice of corneal transplantation. Herein, we describe recent findings from the Australian Corneal Graft Registry and place these data into an international context. The total number of grafts reported to the Registry has doubled over the past decade. Deep anterior lamellar keratoplasty is increasingly used for keratoconus, while endokeratoplasty has displaced penetrating keratoplasty for Fuchs endothelial dystrophy. Graft survival and visual outcomes for modern lamellar procedures have shown improvement over time. First deep anterior lamellar and penetrating grafts for keratoconus show comparable survival and long-term best-corrected visual acuity is equivalent. Penetrating grafts for Fuchs endothelial dystrophy exhibit significantly better survival than do endokeratoplasties, largely because the latter undergo more early graft failures. However, visual rehabilitation is swifter in surviving endokeratoplasties. Significantly fewer recipients of a deep anterior lamellar graft or endokeratoplasty require spectacle or contact lens correction, compared with penetrating keratoplasty.

Attitudes Towards Polygenic Risk Testing in Individuals with Glaucoma.

PURPOSE: Glaucoma is the leading cause of irreversible blindness worldwide; however, vision loss resulting from glaucoma generally can be prevented through early identification and timely implementation of treatment. Recently, polygenic risk scores (PRSs) have shown promise in stratifying individual risk and prognostication for primary open-angle glaucoma (POAG) to reduce disease burden. Integrating PRS testing into clinical practice is becoming increasingly realistic; however, little is known about the attitudes of patients toward such testing. DESIGN: Cross-sectional, questionnaire-based study. PARTICIPANTS: Among the participants in the Australian and New Zealand Registry of Advanced Glaucoma, 2369 were invited to participate who fit the inclusion criteria of adults with a diagnosis of POAG who had not received genetic results that explain their condition, were not known to be deceased, resided in Australia, and had agreed to receive correspondence. METHODS: One thousand one hundred sixty-nine individuals (response rate, 49%) with POAG completed the survey evaluating their attitudes towards polygenic risk testing for glaucoma. MAIN OUTCOME MEASURES: Sociodemographic, health, perception, and emotional factors were examined to assess associations with interest in PRS testing. Interest in PRS testing was evaluated through assessing likelihood to take the test to predict personal risk of disease and disease severity, and whether the individual would recommend the test to family members or others. RESULTS: Our results show strong interest in the test, with 69.4% of individuals (798 of 1150) indicating a keenness in testing before diagnosis, had it been available. In particular, interest was seen in those from an urban area (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.15-2.49; P = 0.007), those who perceived their risk of developing glaucoma as higher (OR, 2.05; 95% CI, 1.28-3.29; P = 0.003), and those who were worried about developing glaucoma (OR, 2.07; 95% CI, 1.27-3.37; P = 0.004). People who were interested in testing were more likely to change their eye health-seeking intentions and to recommend testing to family members and others, as well as to undergo testing for prognostication. CONCLUSIONS: These findings will help to facilitate the clinical implementation of PRS testing for glaucoma to reduce irreversible vision loss.

Women's Authorship of Reviews in Ophthalmic Journals Over Time.

PURPOSE: To investigate prevalence and trends in women's authorship of articles in ophthalmic review journals over 2 decades. DESIGN: Literature survey. METHODS: Total number of authors, and number and gender of first and senior (last-named) authors, were identified in all full reviews published in Prog Retin Eye Res, Surv Ophthalmol, and Curr Opin Ophthalmol for the calendar years 1999, 2009, and 2019. The gender of authors was assigned manually by multiple methods. The subspecialty area of each review was captured by keyword and text search. Country of origin was determined from attributions of first and senior authors. RESULTS: The gender of 841 first and senior authors was assigned unequivocally for 471 articles (96%). The frequency of women's authorship rose significantly over time (1999, 2009, 2019) for both first authors (19%, 32%, 44%; P < 0.001) and senior authors (16%, 19%, 29%; P = 0.018). The number of single-author reviews decreased significantly over time (P < 0.001), as did the proportion of reviews with neither a first nor a senior woman author (P < 0.001). Women's first authorship increased over time for reviews on glaucoma (P < 0.001), while women's senior authorship increased for anterior segment/cataract (P = 0.036). The proportion of reviews with a woman first or senior author did not differ by country of origin (P = 0.887 and P = 0.520, respectively). CONCLUSIONS: Women's authorship of articles in ophthalmic review journals increased significantly over the 20-year period, but a gender disparity remained: in 2019, more than 55% of first authors, and more than 70% of senior authors, were men.

DNA methylation at the 9p21 glaucoma susceptibility locus is associated with normal-tension glaucoma.

PURPOSE: Recent genome-wide association studies reported strong association of genetic variation at the CDKN2B/CDKN2B-AS1 locus on 9p21 with normal-tension glaucoma (NTG) in multiple populations. The mechanism by which this locus causes disease remains to be elucidated. We investigated the association of DNA methylation of CpG islands at this locus with NTG. METHODS: We conducted a retrospective case-control study of 178 NTG cases and 202 unaffected controls from Australia. CDKN2B and CDKN2B-AS1 promoter methylation was measured quantitatively using the MassCleave assay, and assessed for association with the disease, and the genotype of the associated risk variants using IBM SPSS statistics 22.0 CpG sites at which methylation status was associated with NTG were validated using pyrosequencing. RESULTS: We identified one CpG site (F1:13-14) in the CDKN2B promoter which showed significant association with NTG (p = 0.001). The association was highly significant in female cases (p = 0.006) but not in male cases (p = 0.054). The association was validated using an independent method confirming the likely association of DNA methylation with NTG in females (p = 0.015), but not in males (p = 0.497). In addition, methylation at CpG sites in CDKN2B was also associated with genotype at rs1063192, which is known to confer risk for NTG. CONCLUSION: This study reveals an association of methylation status in the CDKN2B promoter with NTG, particularly in females. This suggests that the observed genetic association with the disease at this locus could be in part due to epigenetic mechanisms, and is likely to be independent of the association of nonsynonymous coding variation within the gene.

Is there evidence for a surgeon learning curve for endothelial keratoplasty in Australia?

IMPORTANCE: Expected outcomes from endokeratoplasty may vary with surgeon experience. BACKGROUND: It was explored whether a surgeon learning curve exists for Descemet stripping endothelial keratoplasties (manual or automated) performed in Australia. DESIGN: This is a prospective cohort study, with various clinical settings. PARTICIPANTS: There were 2139 recipients of 2615 endothelial grafts, registered by 85 surgeons between January 2006 and December 2013. METHODS: Kaplan-Meier survival analyses and Cox proportional hazards regression were used to examine longitudinal graft survival. Manual and automated Descemet stripping endothelial keratoplasties were analysed together. Pearson chi-squared analyses were performed to examine differences amongst groups. Continuity correction was used for 2 × 2 tests, and statistical significance was set at P < 0.05 (two-sided). MAIN OUTCOME MEASURE: The main parameter measured was endothelial graft survival. RESULTS: Survival of the first 56 registered grafts was significantly poorer than survival of subsequent grafts (χ2  = 8.83, df = 1, P = 0.003), when data were combined for all surgeons. Surgeon workload influenced graft survival significantly (P < 0.001). This variable was retained in multivariate analysis designed to investigate independent factors influencing graft survival. Primary non-functioning grafts were significantly less likely to be reported for endokeratoplasties performed by surgeons with more than 56 registered grafts, compared with those registering 56 or fewer grafts (4.3% vs. 8.5%; χ2  = 18.38, df = 1, P < 0.001). CONCLUSIONS AND RELEVANCE: Our findings suggest that for less experienced or low-volume surgeons, longitudinal graft survival improved once 56 or more endokeratoplasties had been performed, indicative of a learning curve. The learning curve was less apparent for surgeons with 57 or more Descemet stripping endothelial keratoplasties and/or Descemet stripping automated endothelial keratoplasties registered during the 8-year study period. Different learning curves may be anticipated for these two groups of surgeons.

A comparison of endothelial and penetrating keratoplasty outcomes following failed penetrating keratoplasty: a registry study.

PURPOSE: To compare graft survival and visual outcomes for endothelial keratoplasty (EK) after a first penetrating keratoplasty (PK), with outcomes of repeat PK after a first PK. METHODS: 400 eyes with a second graft (65 EKs, 335 PKs) performed after failure of a primary PK were identified through the Australian Corneal Graft Registry, a national prospectively followed cohort. Grafts were performed after January 2008 (follow-up of the second graft extending to 6.75 years maximum). Kaplan-Meier graft survival plots were constructed and Cox proportional hazards regression was used to identify independent risk factors for graft failure. Best-corrected Snellen visual acuity (BCVA) at last follow-up was compared with pregraft acuity. RESULTS: Poor Kaplan-Meier graft survival was observed for PK-EK compared with PK-PK (log-rank=29.66, p<0.001). Variables retained in multivariate analysis as significantly influencing survival of the second graft included graft type (PK-EK or PK-PK, p<0.001), length of survival of the previous PK (global p=0.011), graft era (global p=0.018), occurrence of rejection in the second graft (p=0.005) and a history of raised intraocular pressure at any time (p=0.048), but not indication for the first graft. BCVA improved in the majority of surviving grafts and attainment of 6/12 vision was similar for both PK-EK and PK-PK groups. CONCLUSIONS: Our registry findings suggest that repeat PK may deliver a better outcome in terms of graft survival than EK after a failed PK that was performed initially for keratoconus or pseudophakic bullous keratopathy. For surviving grafts, visual outcomes appeared equivalent across groups.

Adequacy of published screening criteria for retinopathy of prematurity.

BACKGROUND: Criteria for screening preterm infants for retinopathy of prematurity vary around the world. We aimed to analyse the efficacy of alternative screening criteria. DESIGN: We collected retrospective data at a tertiary level neonatal nursery. PARTICIPANTS: Our participants were 1007 babies, born between 1997 and 2011, at <32 weeks gestational age or <1500 g birth weight (as recommended by the National Health and Medical Research Council in 1996), who had completed follow-up to full retinal vascularization, with defined presence or absence of retinopathy of prematurity. METHODS: We determined whether disease would be detected using an alternative Australian screening model (gestational age <30 weeks or birth weight <1250 g) or screening criteria utilized in developed countries with similar standards of neonatal care. MAIN OUTCOME MEASURES: Detection of retinopathy of prematurity is our main outcome. RESULTS: Using several of the alternative criteria, two neonates with clinically significant retinopathy of prematurity, one of whom required laser treatment to preserve sight, would not have been screened, and their disease may have gone undetected. Use of <30 weeks gestational age or <1500 g birth weight as the criteria would still have screened these infants but would have reduced the number of infants screened by 24.9%. CONCLUSIONS: Some commonly utilized international screening criteria for retinopathy of prematurity may risk clinically significant cases being missed and others may screen babies unnecessarily. Alternative criteria should be considered and '<30 weeks gestational age and/or <1500 g birth weight' appears a viable option.

A comparison of lamellar and penetrating keratoplasty outcomes: a registry study.

OBJECTIVES: To investigate changing patterns of practice of keratoplasty in Australia, graft survival, visual outcomes, the influence of experience, and the surgeon learning curve for endothelial keratoplasty. DESIGN: Observational, prospective cohort study. PARTICIPANTS: From a long-standing national corneal transplantation register, 13 920 penetrating keratoplasties, 858 deep anterior lamellar keratoplasties (DALKs), and 2287 endokeratoplasties performed between January 1996 and February 2013 were identified. METHODS: Kaplan-Meier functions were used to assess graft survival and surgeon experience, the Pearson chi-square test was used to compare visual acuities, and linear regression was used to examine learning curves. MAIN OUTCOME MEASURES: Graft survival. RESULTS: The total number of corneal grafts performed annually is increasing steadily. More DALKs but fewer penetrating grafts are being performed for keratoconus, and more endokeratoplasties but fewer penetrating grafts are being performed for Fuchs' dystrophy and pseudophakic bullous keratopathy. In 2012, 1482 grafts were performed, compared with 955 in 2002, translating to a requirement for 264 extra corneal donors across the country in 2012. Comparing penetrating grafts and DALKs performed for keratoconus over the same era, both graft survival (P <0.001) and visual outcomes (P <0.001) were significantly better for penetrating grafts. Survival of endokeratoplasties performed for Fuchs' dystrophy or pseudophakic bullous keratopathy was poorer than survival of penetrating grafts for the same indications over the same era (P <0.001). Visual outcomes were significantly better for penetrating grafts than for endokeratoplasties performed for Fuchs' dystrophy (P <0.001), but endokeratoplasties achieved better visual outcomes than penetrating grafts for pseudophakic bullous keratopathy (P <0.001). Experienced surgeons (>100 registered keratoplasties) achieved significantly better survival of endokeratoplasties (P <0.001) than surgeons who had performed fewer grafts (<100 registered keratoplasties). In the hands of experienced, high-volume surgeons, endokeratoplasty failures occurred even after 100 grafts had been performed. CONCLUSIONS: More corneal transplants, especially DALKs and endokeratoplasties, are being performed in Australia than ever before. Survival of DALKs and endokeratoplasties is worse than the survival of penetrating grafts performed for the same indications over the same timeframe. Many endokeratoplasties fail early, but the evidence for a surgeon learning curve is unconvincing.

Co-expression of a scFv antibody fragment and a reporter protein using lentiviral shuttle plasmid containing a self-processing furin-2A sequence.

It is often desirable to co-express a reporter protein with a potential therapeutic protein, to verify correct targeting of an expression strategy. Vectors containing a viral self-processing 2A sequence have been reported to drive equimolar expression of two or more transgenes from a single promoter. Here, we report on the co-expression of a secreted antibody fragment and an intracellular reporter protein, enhanced yellow fluorescent protein from lentiviral shuttle plasmids by inserting a furin-2A (F2A) sequence between the two cDNAs, in two different orientations, in the expression cassette. We show that the order of these two transgenes relative to the F2A sequence affects expression levels. Reduced expression of each transgene positioned downstream of F2A, compared with upstream of F2A, was observed (p<0.05). Moreover, protein expression from double-cDNA plasmids was significantly lower than from their corresponding single transgene counterparts (p<0.05).

The influence of Australian eye banking practices on corneal graft survival.

OBJECTIVE: To identify eye banking practices that influence corneal graft survival. DESIGN, SETTING AND PARTICIPANTS: Prospective cohort study of records of 19,254 followed corneal grafts in 15160 patients, submitted to the Australian Corneal Graft Registry between May 1985 and July 2012. MAIN OUTCOME MEASURES: Influence of corneal preservation method (organ culture, moist pot, Optisol, other); death-to-enucleation, death-to-preservation and enucleation-to-graft times; transportation by air; graft era; and indication for graft on probability of graft survival at most recent follow-up. RESULTS: In multivariate analysis, 919 penetrating grafts performed using corneas transported interstate by air exhibited worse survival than 14,684 grafts performed using corneas retrieved and used locally (hazard ratio [HR], 1.44; 95% CI, 1.21-1.73; P = 0.001). This was also the case for traditional lamellar grafts (64 corneas transported by air and 813 used locally; HR, 1.69; 95% CI, 1.03-2.78; P = 0.038). Indication for graft influenced survival of penetrating grafts (4611 keratoconus, 727 emergency or high-risk, 10,265 other indication; global P < 0.001) and traditional lamellar grafts (65 keratoconus, 212 emergency or high-risk, 600 other indication; global P < 0.001). The preservation medium in which corneas used for traditional lamellar grafts were stored exerted a marginal influence on graft survival (global P = 0.047). CONCLUSIONS: Donor corneas transported interstate exhibited poorer survival after transplantation than those retrieved and grafted locally. Higher proportions of emergency procedures involving transported corneas did not account for this difference. Where possible, efforts to avoid transportation of corneal tissue by air freight within Australia may be warranted.

e-Mental health in South Australia: impact of age, gender and region of residence.

Respondents to the 2008 South Australian Health Omnibus survey (n=2996) indicated whether, in the previous 12 months, they had searched for information on the Internet relating to emotional issues such as depression, anxiety or relationship problems. Logistic regression was used to examine the penetration of e-mental health in rural and metropolitan areas (region of residence), and determine if other demographic variables (age group, gender) also impacted on the likelihood of an individual reporting that they had used the Internet to obtain such information. Overall, 9% of respondents reported that they had used the Internet for this purpose. The multivariate model was significant, F(11, 2985)=4.82, P<0.0001, with middle-aged rural females most likely to report doing so (18.1%), whereas older rural males were least likely to report doing so (2.2.%). These findings have important implications for the design of e-mental health promotional programs that provide information and interventions to improve mental health.

Evaluating the effectiveness of multidisciplinary low-vision rehabilitation.

PURPOSE: To objectively evaluate the changes in vision-specific quality of life (QoL) after multidisciplinary low-vision rehabilitation at the Royal Society for the Blind Low-Vision Clinic. METHODS: The standard care model at the Royal Society for the Blind Low-Vision Clinic is optical management at the initial assessment, with subsequent referral to multidisciplinary services as required. Participants completed the Impact of Vision Impairment Questionnaire (IVI) and Veterans Affairs Low-Vision Visual Functioning Questionnaire (VA LV VFQ-48) before initial assessment, at 30 days (to assess the outcome of optical management) and at 3 months follow-up (to assess the outcome of multidisciplinary services). RESULTS: Seventy-one participants completed the study. Using the VA LV VFQ-48, an improvement (p < 0.05) was seen at 30 days follow-up in overall visual ability, and the reading, visual information, and visual motor subscores. However, at 3 months follow-up, all subscores were not significantly different from pre-rehabilitation levels. In contrast, for the IVI, there was no improvement in both the overall score and the mobility subscale at 30 days follow-up, but a significant improvement at 3 months follow-up. Greater improvements in visual function were seen for those with low vision (<20/60-20/200) compared with those with blindness, those aged >85 years compared with those aged 80 to 85 and <80 years, and those without glaucoma (visual motor subscore). CONCLUSIONS: The VA LV VFQ-48 and IVI demonstrated improvements in QoL after low-vision rehabilitation. The timing of the observed changes varied between the two questionnaires, reflecting the different content of these instruments and the timing of delivery of multidisciplinary services, but also suggests that continued rehabilitation may be warranted to maintain a patient's QoL.

The outcome of corneal transplantation in infants, children, and adolescents.

OBJECTIVE: To examine factors affecting penetrating corneal graft survival and visual outcomes in patients aged less than 20 years. DESIGN: Large prospective, cohort study. PARTICIPANTS: Records of 14 865 followed penetrating corneal grafts in 11 929 patients were searched to identify 765 grafts in 640 patients aged younger than 20 years of age at the time of graft. METHODS: Records submitted to the Australian Corneal Graft Registry by 381 ophthalmic surgeons and 253 follow-up practitioners from May 1985 to June 2009 were analyzed using Kaplan-Meier survival plots and Cox proportional hazards regression analysis. MAIN OUTCOMES MEASURES: Probability of corneal graft survival and Snellen acuity at the time of most recent follow-up and at defined intervals post-graft. RESULTS: Infants (<5 years) exhibited poorer graft survival than children aged 5 to 12 years. Adolescents (13-19 years) exhibited better corneal graft survival than other age groups; 86% of grafts in adolescents were for keratoconus. Factors significantly affecting corneal graft survival in pediatric patients included indication for graft, graft inflammation, history of intraocular surgery, vascularization, rejection episodes, post-graft operative procedures, and refractive surgery. Fourteen percent of pediatric grafts failed, of which 65% failed within 2 years post-graft. Forty-four percent of failures were due to unknown causes (18) or irreversible rejection (30). CONCLUSIONS: Corneal grafts for keratoconus in adolescents show excellent survival. Infants exhibit poor graft survival and visual outcomes, especially those undergoing transplantation for Peters' anomaly. Corneal graft survival and visual outcomes vary more by indication for graft than recipient age. The major reason for graft failure is irreversible rejection. Corneal transplantation improves overall bilateral vision in pediatric patients.

Multiple sclerosis: patients' information sources and needs on disease symptoms and management.

OBJECTIVE: To investigate the current information sources of patients with multiple sclerosis (MS) in the early stages of their disease and to identify patients' preferred source of information. The relative amounts of information from the different sources were also compared. METHODS: Participants at a newly diagnosed information session organized by the Multiple Sclerosis Society of South Australia were invited to complete a questionnaire. Participants were asked to rate on a visual analog scale how much information they had received about MS and optic neuritis from different information sources and how much information they would like to receive from each of the sources. RESULTS: A close to ideal amount of information is being provided by the MS society and MS specialist nurses. There is a clear deficit between what information patients are currently receiving and the amount of information they actually want from various sources. Patients wish to receive significantly more information from treating general practitioners, eye specialists, neurologists, and education sessions. Patients have identified less than adequate information received on optic neuritis from all sources. CONCLUSION: This study noted a clear information deficit regarding MS from all sources. This information deficit is more pronounced in relation to optic neuritis and needs to be addressed in the future. PRACTICE IMPLICATIONS: More patient information and counselling needs to be provided to MS patients even at early stages of their disease, especially in relation to management of disease relapse.