Publications by authors named "Georgia Kaidonis"

25 Publications

  • Page 1 of 1

somatic mosaicism in a patient with bilateral optic nerve sheath meningiomas: illustrative case.

J Neurosurg Case Lessons 2022 Jun 6;3(23):CASE2247. Epub 2022 Jun 6.

Departments of Ophthalmology.

Background: In the past decade, next-generation sequencing has spurred significant progress in the understanding of cytogenetic alterations that occur in meningiomas. Eighty percent of adult meningiomas harbor pathogenic somatic variants involving , , , , , or Somatic variants in associated with meningiomas usually localize to the gene's WD40 domains but are mutually exclusive to germline mutations, which cause a distinctive autosomal dominant syndrome.

Observations: This case involved a 15-year-old girl with bilateral optic nerve sheath meningiomas, diffuse meningiomatosis, and syndromic features, including craniosynostosis, brain anomalies, syndactyly, brachydactyly, epicanthus, and patent ductus arteriosus. Genetic testing of the meningioma specimen 7 years after biopsy showed a pathogenic p.R641C variant within the WD40 domain of the gene. Additional testing of unaffected tissues identified the same variant at lower allele frequencies, consistent with postzygotic somatic mosaicism.

Lessons: The authors report postzygotic somatic mosaicism for a p.R641C variant in the gene in a patient with bilateral optic nerve sheath meningiomas, diffuse meningiomatosis and a constellation of systemic findings previously recognized in patients with germline mutations of this gene. This is the first report of optic nerve sheath meningioma in a patient with mutation in the gene.
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http://dx.doi.org/10.3171/CASE2247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204931PMC
June 2022

Identifying Genetic Biomarkers Predicting Response to Anti-Vascular Endothelial Growth Factor Injections in Diabetic Macular Edema.

Int J Mol Sci 2022 Apr 6;23(7). Epub 2022 Apr 6.

Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.

Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME); however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance ( < 5 × 10) for association with increased CMT: a single SNP on chromosome 6 near (rs78466540, = 1.16 × 10) and a locus on chromosome 12 near (top SNP rs11614480, = 2.69 × 10). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of (top SNP rs148980760, = 5.30 × 10) and intronic in (top SNP rs57801753, = 1.71 × 10); one near on chromosome 5 (rs187876551, = 1.52 × 10); and one near on chromosome 6 (rs118074968, = 4.94 × 10). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches.
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http://dx.doi.org/10.3390/ijms23074042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8999697PMC
April 2022

The effect of insulin on response to intravitreal anti-VEGF injection in diabetic macular edema in type 2 diabetes mellitus.

BMC Ophthalmol 2022 Feb 28;22(1):94. Epub 2022 Feb 28.

Menzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street (Private Bag 23), Hobart, Tas, 7000, Australia.

Objectives: To assess whether insulin therapy impacts the effectiveness of anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of diabetic macular edema (DME) in type 2 diabetes mellitus.

Methods: This was a retrospective multi-center analysis. The best-corrected visual acuity (BCVA) at 12 months, BCVA change, central macular thickness (CMT), CMT change, and cumulative injection number were compared between the insulin and the oral hypoglycemic agent (OHA) groups.

Results: The mean final BCVA and CMT improved in both the insulin (N = 137; p < 0.001; p < 0.001, respectively) and the OHA group (N = 61; p = 0.199; p < 0.001, respectively). The two treatment groups were comparable for final BCVA (p = 0.263), BCVA change (p = 0.184), final CMT (p = 0.741), CMT change (p = 0.458), and the cumulative injections received (p = 0.594). The results were comparable between the two groups when stratified by baseline vision (p > 0.05) and baseline HbA1c (p > 0.05).

Conclusion: Insulin therapy does not alter treatment outcomes for anti-VEGF therapy in DME.
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http://dx.doi.org/10.1186/s12886-022-02325-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883612PMC
February 2022

Case Report: Crying Blood.

Optom Vis Sci 2021 03;98(3):217-221

Division of Dermatopathology, Columbia University Medical Center, New York, New York.

Significance: Hemolacria (bloody tears) is a rare clinical presentation with varied underlying etiologies. Thorough clinical evaluation is essential to diagnosis and management.

Purpose: This study aimed to report unilateral hemolacria in a known contact lens wearer with an occult, palpebral, conjunctival pyogenic granuloma and review the literature.

Case Report: A 21-year-old female contact lens wearer presented to the clinic after three episodes of sudden painless bloody tears from the right eye. She was referred to the oculoplastic clinic for evaluation. On everting her right upper lid, a fleshy, nontender, ovoid, pedunculated mass was found attached to the palpebral conjunctiva of the right, nasal, upper tarsus. Surgical excision was performed in the office, and pathological examination of the lesion was consistent with pyogenic granuloma.

Conclusions: Unilateral hemolacria should raise clinical suspicion for a hidden conjunctival lesion such as pyogenic granuloma, although other more sinister causes of hemolacria must also be considered. Thorough evaluation including eyelid eversion is critical in identifying and managing occult conjunctival lesions.
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http://dx.doi.org/10.1097/OPX.0000000000001653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005461PMC
March 2021

MicroRNA-Related Genetic Variants Are Associated With Diabetic Retinopathy in Type 1 Diabetes Mellitus.

Invest Ophthalmol Vis Sci 2019 09;60(12):3937-3942

Department of Ophthalmology, Flinders University, College of Medicine and Public Health, Flinders Medical Centre, Adelaide, South Australia, Australia.

Purpose: Few studies have explored the association of genetic variants in microRNA genes and binding sites with diabetic retinopathy (DR) in type 1 diabetes. We conducted a genome-wide scan for single nucleotide polymorphisms (SNPs) in these genes by using data from a genome-wide association study (GWAS).

Methods: All known SNPs were imputed from our GWAS data (n = 325) of DR cases and diabetic controls (no DR). Relevant SNPS were extracted using miRNASNP and PolymiRTS (version 2) databases. χ2 tests and logistic regression (adjusting for age, sex, duration of diabetes, HbA1c, and hypertension) were used to test the association between the imputed SNPs and DR phenotypes (any DR, nonproliferative DR [NPDR], proliferative DR [PDR], diabetic macular edema [DME], and sight-threatening DR defined as PDR, severe NPDR, or clinically significant macula edema [CSME]) compared with diabetic controls. Top-ranking SNPs were genotyped in a larger cohort (N = 560) to confirm their association with DR.

Results: Three SNPs (rs10061133, rs1049835, rs9501255) were selected and genotyped in the final cohort. Rs10061133 in MIR449b was protective of sight-threatening DR (odds ratio [OR] = 0.32, P = 3.68 × 10-4) and PDR (OR = 0.30, P = 8.12 × 10-4), and the associations became more significant as the cohort increased in size.

Conclusions: Rs10061133 in MIR449b is significantly associated with a decreased risk of PDR and sight-threatening DR in Caucasian patients with type 1 diabetes. This can guide future studies on genetic risk profiling and on developing microRNA-related therapies for sight-threatening DR.
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http://dx.doi.org/10.1167/iovs.18-25570DOI Listing
September 2019

The intravitreal injection pain study: a randomized control study comparing subjective pain with injection technique.

Acta Ophthalmol 2019 Dec 11;97(8):e1153-e1154. Epub 2019 Jun 11.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.

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http://dx.doi.org/10.1111/aos.14142DOI Listing
December 2019

Hippocampal sub-regional differences in the microRNA response to forebrain ischemia.

Mol Cell Neurosci 2019 07 23;98:164-178. Epub 2019 May 23.

Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address:

Transient forebrain ischemia, as occurs with cardiac arrest and resuscitation, results in impaired cognitive function secondary to delayed neuronal cell death in hippocampal cornu ammonis-1 (CA1). Comparatively, hippocampal neurons in the adjacent dentate gyrus (DG) survive, suggesting that elucidating the molecular mechanisms underpinning hippocampal sub-regional differences in ischemic tolerance could be central in the development of novel interventions to improve outcome in survivors of forebrain ischemia. MicroRNAs (miRNAs) are non-coding RNAs that modulate the translation of target genes and have been established as an effective therapeutic target for other models of injury. The objective of the present study was to assess and compare post-injury miRNA profiles between CA1 and DG using a rat model of forebrain ischemia. CA1 and DG sub-regions were dissected from rat hippocampi following 10 min of forebrain ischemia at three time points (3 h, 24 h, and 72 h) and at baseline. Pronounced differences between CA1 and DG were observed for several select miRNAs, including miR-181a-5p, a known regulator of cerebral ischemic injury. We complexed fluorescent in situ hybridization with immunohistochemistry to observe cell-type specific and temporal differences in mir-181a-5p expression between CA1 and DG in response to injury. Using established miRNA-mRNA prediction algorithms, we extended our observations in CA1 miRNA dysregulation to identify key functional pathways as potential modulators of CA1 ischemic vulnerability. In summary, our observations support a central role for miRNAs in selective CA1 ischemic vulnerability and suggest that cell-specific miRNA targeting could be a viable clinical approach to preserve CA1 neurons and improve cognitive outcomes for survivors of transient forebrain ischemia.
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http://dx.doi.org/10.1016/j.mcn.2019.05.003DOI Listing
July 2019

Long-term survival rates of patients undergoing vitrectomy for diabetic retinopathy in an Australian population: A population-based audit-Response.

Clin Exp Ophthalmol 2019 08 21;47(6):817-818. Epub 2019 May 21.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.

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http://dx.doi.org/10.1111/ceo.13531DOI Listing
August 2019

Mitochondrial haplogroups are not associated with diabetic retinopathy in a large Australian and British Caucasian sample.

Sci Rep 2019 01 24;9(1):612. Epub 2019 Jan 24.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.

Mitochondrial haplogroups H1, H2 and UK have previously been reported to be associated with proliferative diabetic retinopathy (PDR) in Caucasian patients with diabetes. We aimed to replicate this finding with a larger sample and expand the analysis to include different severities of DR, and diabetic macular edema (DME). Caucasian participants (n = 2935) with either type 1 or type 2 diabetes from the Australian Registry of Advanced Diabetic Retinopathy were enrolled in this study. Twenty-two mitochondrial single nucleotide polymorphisms were genotyped by MassArray and haplogroups reconstructed using Haplogrep. Chi square tests and logistic regressions were used to test associations between haplogroup and DR phenotypes including any DR, non-proliferative DR (NPDR), proliferative DR (PDR) and DME. After stratifying the samples in type 1 and type 2 diabetes groups, and adjusting for sex, age, diabetes duration, concurrent HbA1c and hypertension, neither haplogroups H1, H2, UK, K or JT were associated with any DR, NPDR, PDR or DME.
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http://dx.doi.org/10.1038/s41598-018-37388-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345891PMC
January 2019

Long-term survival rates of patients undergoing vitrectomy for diabetic retinopathy in an Australian population: a population-based audit.

Clin Exp Ophthalmol 2019 07 20;47(5):598-604. Epub 2019 Feb 20.

Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia, Australia.

Importance: Five-year survival rates in patients undergoing vitrectomy for diabetic retinopathy (DR) vary from 68% to 95%. No study has been conducted in an Australian population.

Background: We aimed to determine the survival rates of patients undergoing diabetic vitrectomy in an Australian population.

Design: Retrospective audit, tertiary centre hospitals and private practices.

Participants: All individuals in South Australia and the Northern Territory who underwent their first vitrectomy for diabetic complications between January 1, 2007 and December 31, 2011.

Methods: An audit of all eligible participants has been completed previously. Survival status as of July 6, 2018 and cause of death were obtained using SA/NT DataLink. Kaplan-Meier survival curves and multivariate cox-regressions were used to analyse survival rates and identify risk factors for mortality.

Main Outcome Measures: Five-, seven- and nine-year survival rates.

Results: The 5-, 7- and 9-year survival rates were 84.4%, 77.9% and 74.7%, respectively. The most common cause of death was cardiovascular disease. Associated with increased mortality independent of age were Indigenous ethnicity (HR = 2.04, 95% confidence interval [CI]: 1.17-3.57, P = 0.012), chronic renal failure (HR = 1.76, 95% CI: 1.07-2.89, P = 0.026) and renal failure requiring dialysis (HR = 2.32, 95% CI: 1.25-4.32, P = 0.008).

Conclusions And Relevance: Long-term survival rates after diabetic vitrectomy in Australia are similar to rates reported in other populations. Indigenous ethnicity and chronic renal failure were the most significant factors associated with long-term mortality. This information can guide allocation of future resources to improve the prognosis of these high risk groups.
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http://dx.doi.org/10.1111/ceo.13466DOI Listing
July 2019

A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes.

Acta Ophthalmol 2018 Nov 4;96(7):e811-e819. Epub 2018 Sep 4.

Singapore Eye Research Institute, Singapore National Eye Centre, Yong Loo Lin School of Medicine, National University of Singapore, Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore.

Purpose: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.

Methods: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts.

Results: Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10 . Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10 and 1.23 × 10 , respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429).

Conclusion: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.
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http://dx.doi.org/10.1111/aos.13769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263819PMC
November 2018

Elucidating sex differences in response to cerebral ischemia: immunoregulatory mechanisms and the role of microRNAs.

Prog Neurobiol 2019 05 16;176:73-85. Epub 2018 Aug 16.

Stanford University School of Medicine, Department of Anesthesiology, Perioperative & Pain Medicine, United States. Electronic address:

Cerebral ischemia remains a major cause of death and disability worldwide, yet therapeutic options remain limited. Differences in sex and age play an important role in the final outcome in response to cerebral ischemia in both experimental and clinical studies: males have a higher risk and worse outcome than females at younger ages and this trend reverses in older ages. Although the molecular mechanisms underlying sex dimorphism are complex and are still not well understood, studies suggest steroid hormones, sex chromosomes, differential cell death and immune pathways, and sex-specific microRNAs may contribute to the outcome following cerebral ischemia. This review focuses on differential effects between males and females on cell death and immunological pathways in response to cerebral ischemia, the central role of innate sex differences in steroid hormone signaling, and upstreamregulation of sexually dimorphic gene expression by microRNAs.
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http://dx.doi.org/10.1016/j.pneurobio.2018.08.001DOI Listing
May 2019

Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy.

BMC Med Genet 2018 05 8;19(1):71. Epub 2018 May 8.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

Background: Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) are sight-threatening complications of diabetes mellitus and leading causes of adult-onset blindness worldwide. Genetic risk factors for diabetic retinopathy (DR) have been described previously, but have been difficult to replicate between studies, which have often used composite phenotypes and been conducted in different populations. This study aims to identify genetic risk factors for DME and PDR as separate complications in Australians of European descent with type 2 diabetes.

Methods: Caucasian Australians with type 2 diabetes were evaluated in a genome-wide association study (GWAS) to compare 270 DME cases and 176 PDR cases with 435 non-retinopathy controls. All participants were genotyped by SNP array and after data cleaning, cases were compared to controls using logistic regression adjusting for relevant covariates.

Results: The top ranked SNP for DME was rs1990145 (p = 4.10 × 10, OR = 2.02 95%CI [1.50, 2.72]) on chromosome 2. The top-ranked SNP for PDR was rs918519 (p = 3.87 × 10, OR = 0.35 95%CI [0.22, 0.54]) on chromosome 5. A trend towards association was also detected at two SNPs reported in the only other reported GWAS of DR in Caucasians; rs12267418 near MALRD1 (p = 0.008) in the DME cohort and rs16999051 in the diabetes gene PCSK2 (p = 0.007) in the PDR cohort.

Conclusion: This study has identified loci of interest for DME and PDR, two common ocular complications of diabetes. These findings require replication in other Caucasian cohorts with type 2 diabetes and larger cohorts will be required to identify genetic loci with statistical confidence. There is considerable overlap in the patient cohorts with each retinopathy subtype, complicating the search for genes that contribute to PDR and DME biology.
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http://dx.doi.org/10.1186/s12881-018-0587-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941644PMC
May 2018

Visual outcomes following vitrectomy for diabetic retinopathy amongst Indigenous and non-Indigenous Australians in South Australia and the Northern Territory.

Clin Exp Ophthalmol 2018 05 16;46(4):417-423. Epub 2017 Nov 16.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.

Importance: Visual outcomes following diabetic vitrectomy have not previously been studied in an Australian population.

Background: This analysis aimed to determine the rate of, and factors associated with visual success following diabetic vitrectomy performed for Indigenous and non-Indigenous Australians, and investigate factors predisposing to early progression to diabetic retinopathy (DR) requiring vitrectomy.

Design: Retrospective, population-based audit.

Participants: All patients undergoing vitrectomy for the complications of DR in South Australia (SA) and the Northern Territory (NT) between 2007 and 2011.

Methods: Medical records were audited and data collected, including demographics, diabetic history, past treatment for DR, indication for vitrectomy and visual acuity pre and postoperatively.

Main Outcome Measures: Visual success (gain of ≥15 ETDRS letters) at 6 and 12 months, postoperatively.

Results: A total of 495 diabetic vitrectomies, for 404 eyes of 335 patients were performed in SA and NT between 2007 and 2011. 77 (23%) patients requiring diabetic vitrectomy were Indigenous Australians. 87% of patients undergoing diabetic vitrectomy had stable or improved vision at 1 year, postoperatively. There was no significant difference between indigenous and non-indigenous eyes achieving visual success (P = 0.929). Timely preoperative laser treatment (P = 0.03) and preoperative visual acuity (P = 0.01) were the predominant factors associated with visual success.

Conclusions And Relevance: Indigenous patients are just as likely to have improved vision following diabetic vitrectomy as non-Indigenous Australians. However, the small subset of indigenous patients with blind eyes prior to vitrectomy are significantly less likely to improve from surgery. The underlying factors associated with poor outcomes in this group requires further exploration.
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http://dx.doi.org/10.1111/ceo.13083DOI Listing
May 2018

Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

Diabetes 2017 12 26;66(12):3130-3141. Epub 2017 Sep 26.

Institute for Translational Genomics and Population Sciences, LA BioMed, and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA.

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR ( = 2,969 case and 4,096 control subjects) and severe DR ( = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.
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http://dx.doi.org/10.2337/db17-0398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697951PMC
December 2017

En Face Optical Coherence Tomography Angiography Imaging Versus Fundus Photography in the Measurement of Choroidal Nevi.

Ophthalmic Surg Lasers Imaging Retina 2017 09;48(9):741-747

Background And Objectives: Choroidal nevi are common benign intraocular tumors with a small risk of malignant transformation. This retrospective study investigates the use of en face spectral-domain optical coherence tomography angiography (SD-OCTA) in determining the clinical features and measurement of choroidal nevi.

Patients And Methods: Patients with choroidal nevi were imaged with both OCTA and a fundus photography device. Greatest longitudinal dimension (GLD), perpendicular dimension (PD), and the GLD/PD ratio were assessed on each device. Inter-device variation and intra- and inter-rater reliability analyses were performed.

Results: Fourteen patients with choroidal nevi were included. No significant difference between the GLD/PD ratio as measured by all three devices was found (Chi-square = 2.8, 2 df, P = .247). Intraclass correlation coefficients were greater than 0.7 for repeated measures on all devices, suggesting good repeatability and reproducibility.

Conclusion: This study demonstrated inter-device consistency and high intra- and inter-rater reliability when measuring choroidal nevi. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:741-747.].
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http://dx.doi.org/10.3928/23258160-20170829-09DOI Listing
September 2017

Association of disease-specific causes of visual impairment and 10-year mortality amongst Indigenous Australians: the Central Australian Ocular Health Study.

Clin Exp Ophthalmol 2018 01 20;46(1):18-24. Epub 2017 Jul 20.

Department of Ophthalmology, Flinders Medical Centre, Adelaide, South Australia, Australia.

Importance: Visual impairment significantly impairs the length and quality of life, but little is known of its impact in Indigenous Australians.

Background: To investigate the association of disease-specific causes of visual impairment with all-cause mortality.

Design: A retrospective cohort analysis.

Participants: A total of 1347 Indigenous Australians aged over 40 years.

Methods: Participants visiting remote medical clinics underwent clinical examinations including visual acuity, subjective refraction and slit-lamp examination of the anterior and posterior segments. The major ocular cause of visual impairment was determined. Patients were assessed periodically in these remote clinics for the succeeding 10 years after recruitment. Mortality rates were obtained from relevant departments.

Main Outcome Measures: All-cause 10-year mortality and its association with disease-specific causes of visual impairment.

Results: The all-cause mortality rate for the entire cohort was 29.3% at the 10-year completion of follow-up. Of those with visual impairment, the overall mortality rate was 44.9%. The mortality rates differed for those with visual impairment due to cataract (59.8%), diabetic retinopathy (48.4%), trachoma (46.6%), 'other' (36.2%) and refractive error (33.4%) (P < 0.0001). Only those with visual impairment from diabetic retinopathy were any more likely to die during the 10 years of follow-up when compared with those without visual impairment (HR 1.70; 95% CI, 1.00-2.87; P = 0.049).

Conclusions And Relevance: Visual impairment was associated with all-cause mortality in a cohort of Indigenous Australians. However, diabetic retinopathy was the only ocular disease that significantly increased the risk of mortality. Visual impairment secondary to diabetic retinopathy may be an important predictor of mortality.
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http://dx.doi.org/10.1111/ceo.13009DOI Listing
January 2018

Spectral Domain Optical Coherence Tomography Angiography in Stargardt's Macular Dystrophy.

Ophthalmol Retina 2017 Sep - Oct;1(5):452-454. Epub 2017 Feb 7.

Byers Eye Institute at Stanford, Stanford University School of Medicine, Palo Alto, California. Electronic address:

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http://dx.doi.org/10.1016/j.oret.2016.12.008DOI Listing
February 2017

The superficial and deep retinal capillary plexus in cases of fovea plana imaged by spectral-domain optical coherence tomography angiography.

Am J Ophthalmol Case Rep 2017 Jun 25;6:41-44. Epub 2016 Oct 25.

Byers Eye Institute at Stanford, Stanford University School of Medicine, Palo Alto, CA, United States.

Purpose: To describe the appearance of the superficial and deep retinal capillary plexi in three patients with fovea plana of differing severity using spectral-domain optical coherence tomography angiography (OCTA).

Observations: In the first case of grade 1 fovea plana (a patient with 20/25 vision), OCTA showed an orderly branching pattern of vessels from the superficial and deep retinal plexi extending to the center of the fovea. The second case of grade 3 fovea plana (20/30 vision) showed some disruption of the orderly vascular pattern with small caliber vessels from both superficial and deep layers densely covering the fovea center. Case 3 represented a patient with grade 4 fovea plana associated with PAX6 mutation and poor visual acuity. OCTA revealed a disorganized pattern of large and small caliber vessels from the superficial capillary network extending into the center of the fovea.

Conclusions And Importance: Previously available imaging modalities were unable to specifically target different layers of the retinal vasculature. Using OCTA we have been able to show progressive changes in the vascular pattern in the deep and superficial retinal layers of patients with different grades of fovea plana. This novel imaging technique may play a role in the classification and assessment of patients with fovea plana.
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http://dx.doi.org/10.1016/j.ajoc.2016.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722189PMC
June 2017

A single-nucleotide polymorphism in the MicroRNA-146a gene is associated with diabetic nephropathy and sight-threatening diabetic retinopathy in Caucasian patients.

Acta Diabetol 2016 Aug 21;53(4):643-50. Epub 2016 Mar 21.

Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.

Aims: This study aimed to investigate whether the single-nucleotide polymorphism (SNP) rs2910164 residing within microRNA-146a (miR-146a) is associated with diabetic microvascular complications diabetic nephropathy (DN), proliferative diabetic retinopathy (PDR) or diabetic macular oedema (DME) in either Caucasian patients with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus.

Methods: Caucasian patients with T1DM (n = 733) or T2DM (n = 2215) were recruited from ophthalmology, renal and endocrine clinics in Australia and the UK. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be on treatment with oral hypoglycaemic drugs or insulin. In total, 890 participants had DN (168 with T1DM and 722 with T2DM), 731 had PDR (251 with T1DM and 480 with T2DM) and 1026 had DME (170 with T1DM and 856 with T2DM). Participants were genotyped for SNP rs2910164 in miR-146a. Analyses investigating association were adjusted for relevant clinical covariates including age, sex, DM duration, HbA1c and hypertension.

Results: A significant association was found between the C allele of rs2910164 and DN in the T1DM group (OR 1.93; CI 1.23-3.03; P = 0.004), but no association found in the T2DM group (OR 1.05; CI 0.83-1.32; P = 0.691). In the subset of T2DM patients, the C allele was specifically associated with DME (OR 1.25; CI 1.03-1.53; P = 0.025). No association with DME was found in the T1DM group (OR 0.87; CI 0.54-1.42); P = 0.583), or with PDR for either type of DM.

Conclusions: Rs2910164 is significantly associated with microvascular complications DN in patients with T1DM and DME in patients with T2DM.
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http://dx.doi.org/10.1007/s00592-016-0850-4DOI Listing
August 2016

Promoter polymorphism at the tumour necrosis factor/lymphotoxin-alpha locus is associated with type of diabetes but not with susceptibility to sight-threatening diabetic retinopathy.

Diab Vasc Dis Res 2016 Mar 28;13(2):164-7. Epub 2016 Jan 28.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, SA, Australia Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS, Australia.

Aim: To investigate, in a large cohort of 2494 individuals with diabetes mellitus, whether functional single nucleotide polymorphisms in the promoter region of tumour necrosis factor (TNF) and lymphotoxin-alpha (LTA) genes are associated with type of diabetes or presence of diabetic retinopathy.

Methods: A total of 334 type 1 diabetes and 999 type 2 diabetes participants with sight-threatening diabetic retinopathy, and 260 type 1 diabetes and 901 type 2 diabetes participants with no diabetic retinopathy or minimal non-proliferative diabetic retinopathy, were genotyped for two single nucleotide polymorphisms (rs1800629 and rs361525).

Results: The A allele of rs1800629 was associated with type 1 diabetes (p < 0.001; odds ratio = 0.62). After adjustment for age, sex, diabetes duration, HbA1c, hypertension and nephropathy, no significant association was found between rs1800629 or rs361525 and sight-threatening diabetic retinopathy.

Conclusion: An association between the A allele of rs1800629 and type of diabetes was found. No association was found between two promoter variants of TNF and LTA, and diabetic retinopathy in a large cohort of Caucasian patients with type 1 diabetes and type 2 diabetes.
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http://dx.doi.org/10.1177/1479164115616902DOI Listing
March 2016

Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene.

Diabetologia 2015 Oct 19;58(10):2288-97. Epub 2015 Jul 19.

Department of Ophthalmology, Flinders Medical Centre, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.

Aims/hypothesis: Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study.

Methods: Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot.

Results: The top ranked variant was rs3805931 with p = 2.66 × 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10(-5)) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10(-8)). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina.

Conclusions/interpretation: Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.
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http://dx.doi.org/10.1007/s00125-015-3697-2DOI Listing
October 2015

Common Sequence Variation in the VEGFC Gene Is Associated with Diabetic Retinopathy and Diabetic Macular Edema.

Ophthalmology 2015 Sep 11;122(9):1828-36. Epub 2015 Jun 11.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.

Purpose: To investigate associations between single nucleotide polymorphisms (SNPs) in the VEGFC gene and the development of diabetic retinopathy (DR) in white patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM).

Design: Cross-sectional, case control study.

Participants: White patients with T1DM or T2DM (n = 2899) were recruited from ophthalmology and endocrine clinics in Australia and the United Kingdom. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be receiving oral hypoglycemic treatment or insulin.

Methods: Participants were categorized according to their worst-ever DR grading, as having "no DR" (no history of nonproliferative DR [NPDR], proliferative DR [PDR], or diabetic macular edema [DME]) or "any DR" (further subclassified as NPDR or PDR, without or with DME). Clinical characteristics, glycemic control (hemoglobin A1c [HbA1c]), and presence of diabetic complications were determined at recruitment. Genotyping was performed for 13 VEGFC tag SNPs.

Main Outcome Measures: Odds ratios (ORs) were determined for associations with DR of VEGFC tag SNPs, individually and within haplotypes. Logistic regression was used to adjust for clinical covariates, including DM type, age, sex, DM duration, hypertension, nephropathy, HbA1c, and smoking.

Results: Participants with DM but "no DR" (n = 980) were compared with 1919 participants with DM and "any DR." Three VEGFC SNPs were associated with DR after logistic regression: rs17697419 (P = 0.001; OR, 0.67; confidence interval [CI], 0.52-0.85), rs17697515 (P = 0.001; OR, 0.62; CI, 0.47-0.81), and rs2333526 (P = 0.005; OR, 0.69; CI, 0.54-0.90). rs17697515 Was also specifically associated with DME in those with T2DM (P = 0.004; OR, 0.53; CI, 0.35-0.82). Haplotype analysis revealed 2 significantly associated haplotypes, both protective against DR development.

Conclusions: Significant associations were found between VEGFC tag SNPs (individually and within haplotypes) and the presence of any DR or DME in white participants with T1DM and T2DM.
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http://dx.doi.org/10.1016/j.ophtha.2015.05.004DOI Listing
September 2015

Review of the prevalence of diabetic retinopathy in Indigenous Australians.

Clin Exp Ophthalmol 2014 Dec 5;42(9):875-82. Epub 2014 May 5.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.

The purpose of this review is to compare the prevalence of diabetic retinopathy (DR) between Indigenous and non-Indigenous Australians with Diabetes Mellitus (DM). Australian DR prevalence data from 6 Indigenous studies (n = 2865) and 5 non-Indigenous studies (n = 9801) conducted between 1985 and 2013 were included for analysis. Estimated prevalence of any DR among Indigenous Australians with DM was 23.4% compared with 28.9% for non-Indigenous Australians (χ(2)  = 26.9, P < 0.001). In studies performed after 1990, a significantly higher rate of diabetic macular edema was found in Indigenous compared with non-Indigenous Australians with DM (7.6% versus 4.9%, χ(2)  = 6.67, P = 0.01). Although there are limitations in comparing these studies, one explanation for the observed data could be a model in which Indigenous Australians are relatively resistant to early stage DR, but with a subset progressing to sight threatening DR due to individual genetic and environmental susceptibility factors coupled with poor glycemic control.
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http://dx.doi.org/10.1111/ceo.12338DOI Listing
December 2014

Genetic study of diabetic retinopathy: recruitment methodology and analysis of baseline characteristics.

Clin Exp Ophthalmol 2014 Jul 28;42(5):486-93. Epub 2013 Oct 28.

Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.

Background: Diabetic retinopathy (DR) is a blinding disease of increasing prevalence that is caused by a complex interplay of genetic and environmental factors. Here we describe the patient recruitment methodology, case and control definitions, and clinical characteristics of a study sample to be used for genome-wide association analysis to detect genetic risk variants of DR.

Methods: One thousand six hundred sixty-nine participants with either type 1 (T1) or type 2 (T2) diabetes mellitus (DM) aged 18 to 95 years were recruited in Australian hospital clinics. Individuals with T2DM had disease duration of at least 5 years and were taking oral hypoglycaemic medication, and/or insulin therapy. Participants underwent ophthalmic examination. Medical history and biochemistry results were collected. Venous blood was obtained for genetic analysis.

Results: Six hundred eighty-three diabetic cases (178 T1DM and 505 T2DM participants) with sight-threatening DR, defined as severe non-proliferative DR, proliferative DR or diabetic macular oedema were included in this analysis. Eight hundred twelve individuals with DM but no DR or minimal non-proliferative DR were recruited as controls (191 with T1DM and 621 with T2DM). The presence of sight-threatening DR was significantly correlated with DM duration, hypertension, nephropathy, neuropathy, HbA1C and body mass index. Diabetic macular oedema was associated with T2DM (P < 0.001), whereas proliferative DR was associated with T1DM (P < 0.001).

Conclusions: Adoption of a case-control study design involving extremes of the DR phenotype makes this a suitable cohort, for a well-powered genome-wide association study to detect genetic risk variants for DR.
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http://dx.doi.org/10.1111/ceo.12239DOI Listing
July 2014
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