Ophthalmology (Eye & Ear Hospital) - Research Publications
Now showing items 1-12 of 750
Knowledge, beliefs, mental health, substance use, and behaviors related to the COVID-19 pandemic among US adults: a national online survey
(SPRINGER HEIDELBERG, 2021-05-12)
Aim: Given the need for data to inform public health messaging to mitigate the COVID-19 pandemic, this national survey sought to assess the state of COVID-19-related knowledge, beliefs, mental health, substance use changes, and behaviors among a sample of U.S. adults. Subject and methods: In the period March 20-30, 2020, we collected data on COVID-19-related knowledge, awareness and adoption of preventive practices, depression and anxiety (Patient Health Questionnaire-4), stress (Impact of Event Scale-6), pessimism, and tobacco and alcohol use. Differences between age groups (18-39 years, 40-59 years and ≥ 60 years) were tested using Pearson's chi-squared tests or ANOVAs; associations between drinking and smoking and depression, anxiety, and stress were tested using adjusted logistic regression models. Results: Approximately half of the sample (N Total = 6391) were 50-69 years old and 58% were female. COVID-19 knowledge (mean = 12.0; SD = 1.2) and protective practice awareness (mean = 9.1; SD = 0.8) were high. Among respondents, 44% had a score consistent with depression and anxiety (PHQ-4 score ≥ 6), and 52% reported high stress scores (≥ median of 1.33). COVID-19-related anxiety and depression were associated with increased drinking (AOR = 1.79; 95% CI = 1.49, 2.15) and smoking (AOR = 2.17; 95% CI = 1.64, 2.88). High stress scores were also associated with increased drinking (AOR = 1.80; 95% CI = 1.49, 2.17, p < 0.001) and smoking (AOR = 1.75; 95% CI = 1.31, 2.33). Conclusions: In spite of high knowledge levels, important gaps were identified. High prevalence of poor mental health outcomes and associated increases in drinking and smoking warrant ongoing risk communications tailoring to effectively disseminate information and expanding psychosocial services, particularly via telehealth, to mitigate the negative mental health impact of COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1007/s10389-021-01564-4.
Regional and socioeconomic predictors of perceived ability to access coronavirus testing in the United States: results from a nationwide online COVID-19 survey
(ELSEVIER SCIENCE INC, 2021-06-01)
PURPOSE: Access to COVID-19 testing remained a salient issue during the early months of the pandemic, therefore this study aimed to identify 1) regional and 2) socioeconomic predictors of perceived ability to access Coronavirus testing. METHODS: An online survey using social media-based advertising was conducted among U.S. adults in April 2020. Participants were asked whether they thought they could acquire a COVID-19 test, along with basic demographic, socioeconomic and geographic information. RESULTS: A total of 6,378 participants provided data on perceived access to COVID-19 testing. In adjusted analyses, we found higher income and possession of health insurance to be associated with perceived ability to access Coronavirus testing. Geographically, perceived access was highest (68%) in East South Central division and lowest (39%) in West North Central. Disparities in health insurance coverage did not directly correspond to disparities in perceived access to COVID-19 testing. CONCLUSIONS: Sex, geographic location, income, and insurance status were associated with perceived access to COVID-19 testing; interventions aimed at improving either access or awareness of measures taken to improve access are warranted. These findings from the pandemic's early months shed light on the importance of disaggregating perceived and true access to screening during such crises.
Classifying Retinal Degeneration in Histological Sections Using Deep Learning
(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2021-06-01)
Purpose: Artificial intelligence (AI) techniques are increasingly being used to classify retinal diseases. In this study we investigated the ability of a convolutional neural network (CNN) in categorizing histological images into different classes of retinal degeneration. Methods: Images were obtained from a chemically induced feline model of monocular retinal dystrophy and split into training and testing sets. The training set was graded for the level of retinal degeneration and used to train various CNN architectures. The testing set was evaluated through the best architecture and graded by six observers. Comparisons between model and observer classifications, and interobserver variability were measured. Finally, the effects of using less training images or images containing half the presentable context were investigated. Results: The best model gave weighted-F1 scores in the range 85% to 90%. Cohen kappa scores reached up to 0.86, indicating high agreement between the model and observers. Interobserver variability was consistent with the model-observer variability in the model's ability to match predictions with the observers. Image context restriction resulted in model performance reduction by up to 6% and at least one training set size resulted in a model performance reduction of 10% compared to the original size. Conclusions: Detecting the presence and severity of up to three classes of retinal degeneration in histological data can be reliably achieved with a deep learning classifier. Translational Relevance: This work lays the foundations for future AI models which could aid in the evaluation of more intricate changes occurring in retinal degeneration, particularly in other types of clinically derived image data.
Model Structure Uncertainty in the Characterization and Growth of Geographic Atrophy
(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2021-05-01)
Purpose: To identify the most suitable model for assessing the rate of growth of total geographic atrophy (GA) by analysis of model structure uncertainty. Methods: Model structure uncertainty refers to unexplained variability arising from the choice of mathematical model and represents an example of epistemic uncertainty. In this study, we quantified this uncertainty to help identify a model most representative of GA progression. Fundus autofluorescence (FAF) images and GA progression data (i.e., total GA area estimation at each presentation) were acquired using Spectralis HRA+OCT instrumentation and RegionFinder software. Six regression models were evaluated. Models were compared using various statistical tests, [i.e., coefficient of determination (r2), uncertainty metric (U), and test of significance for the correlation coefficient, r], as well as adherence to expected physical and clinical assumptions of GA growth. Results: Analysis was carried out for 81 GA-affected eyes, 531 FAF images (range: 3-17 images per eye), over median of 57 months (IQR: 42, 74), with a mean baseline lesion size of 2.62 ± 4.49 mm2 (range: 0.11-20.69 mm2). The linear model proved to be the most representative of total GA growth, with lowest average uncertainty (original scale: U = 0.025, square root scale: U = 0.014), high average r2 (original scale: 0.92, square root scale: 0.93), and applicability of the model was supported by a high correlation coefficient, r, with statistical significance (P = 0.01). Conclusions: Statistical analysis of uncertainty suggests that the linear model provides an effective and practical representation of the rate and progression of total GA growth based on data from patient presentations in clinical settings. Translational Relevance: Identification of correct model structure to characterize rate of growth of total GA in the retina using FAF images provides an objective metric for comparing interventions and charting GA progression in clinical presentations.
Focus on Survival Analysis for Eye Research.
(Association for Research in Vision and Ophthalmology (ARVO), 2021-05-03)
Analysis of time-to-event data, otherwise known as survival analysis, is a common investigative tool in ophthalmic research. For example, time-to-event data is useful when researchers are interested in investigating how long it takes for an ocular condition to worsen or whether treatment can delay the development of a potentially vision-threatening complication. Its implementation requires a different set of statistical tools compared to those required for analyses of other continuous and categorial outcomes. In this installment of the Focus on Data series, we present an overview of selected concepts relating to analysis of time-to-event data in eye research. We introduce censoring, model selection, consideration of model assumptions, and best practice for reporting. We also consider challenges that commonly arise when analyzing time-to-event data in ophthalmic research, including collection of data from two eyes per person and the presence of multiple outcomes of interest. The concepts are illustrated using data from the Laser Intervention in Early Stages of Age-Related Macular Degeneration study and statistical computing code for Stata is provided to demonstrate the application of the statistical methods to illustrative data.
Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction
Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. We assess the effects of nicotinamide (a precursor to NAD) on retinal ganglion cells (the affected neuron in glaucoma) in normal physiological conditions and across a range of glaucoma relevant insults including mitochondrial stress and axon degenerative insults. We demonstrate retinal ganglion cell somal, axonal, and dendritic neuroprotection by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We performed metabolomics enriched for small molecular weight metabolites for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption, including consistent changes to α-ketoglutaric acid, creatine/creatinine, homocysteine, and glycerophosphocholine. This metabolic disruption is prevented by nicotinamide. Nicotinamide provides further neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term nicotinamide treatment as a neuroprotective therapy for human glaucoma.
IMI Prevention of Myopia and Its Progression.
(Association for Research in Vision and Ophthalmology (ARVO), 2021-04-28)
The prevalence of myopia has markedly increased in East and Southeast Asia, and pathologic consequences of myopia, including myopic maculopathy and high myopia-associated optic neuropathy, are now some of the most common causes of irreversible blindness. Hence, strategies are warranted to reduce the prevalence of myopia and the progression to high myopia because this is the main modifiable risk factor for pathologic myopia. On the basis of published population-based and interventional studies, an important strategy to reduce the development of myopia is encouraging schoolchildren to spend more time outdoors. As compared with other measures, spending more time outdoors is the safest strategy and aligns with other existing health initiatives, such as obesity prevention, by promoting a healthier lifestyle for children and adolescents. Useful clinical measures to reduce or slow the progression of myopia include the daily application of low-dose atropine eye drops, in concentrations ranging between 0.01% and 0.05%, despite the side effects of a slightly reduced amplitude of accommodation, slight mydriasis, and risk of an allergic reaction; multifocal spectacle design; contact lenses that have power profiles that produce peripheral myopic defocus; and orthokeratology using corneal gas-permeable contact lenses that are designed to flatten the central cornea, leading to midperipheral steeping and peripheral myopic defocus, during overnight wear to eliminate daytime myopia. The risk-to-benefit ratio needs to be weighed up for the individual on the basis of their age, health, and lifestyle. The measures listed above are not mutually exclusive and are beginning to be examined in combination.
Human Mitoribosome Biogenesis and Its Emerging Links to Disease
Mammalian mitochondrial ribosomes (mitoribosomes) synthesize a small subset of proteins, which are essential components of the oxidative phosphorylation machinery. Therefore, their function is of fundamental importance to cellular metabolism. The assembly of mitoribosomes is a complex process that progresses through numerous maturation and protein-binding events coordinated by the actions of several assembly factors. Dysregulation of mitoribosome production is increasingly recognized as a contributor to metabolic and neurodegenerative diseases. In recent years, mutations in multiple components of the mitoribosome assembly machinery have been associated with a range of human pathologies, highlighting their importance to cell function and health. Here, we provide a review of our current understanding of mitoribosome biogenesis, highlighting the key factors involved in this process and the growing number of mutations in genes encoding mitoribosomal RNAs, proteins, and assembly factors that lead to human disease.
Binding of Gtf2i-β/δ transcription factors to the ARMS2 gene leads to increased circulating HTRA1 in AMD patients and in vitro.
(Elsevier BV, 2021-01)
The disease-initiating molecular events for age-related macular degeneration (AMD), a multifactorial retinal disease affecting many millions of elderly individuals worldwide, are still unknown. Of the over 30 risk and protective loci so far associated with AMD through whole genome-wide association studies (GWAS), the Age-Related Maculopathy Susceptibility 2 (ARMS2) gene locus represents one of the most highly associated risk regions for AMD. A unique insertion/deletion (in/del) sequence located immediately upstream of the High Temperature Requirement A1 (HTRA1) gene in this region confers high risk for AMD. Using electrophoretic mobility shift assay (EMSA), we identified that two Gtf2i-β/δ transcription factor isoforms bind to the cis-element 5'- ATTAATAACC-3' contained in this in/del sequence. The binding of these transcription factors leads to enhanced upregulation of transcription of the secretory serine protease HTRA1 in transfected cells and AMD patient-derived induced pluripotent stem cells (iPSCs). Overexpression of Htra1 in mice using a CAG-promoter demonstrated increased blood concentration of Htra1 protein, caused upregulation of vascular endothelial growth factor (VEGF), and produced a choroidal neovascularization (CNV)-like phenotype. Finally, a comparison of 478 AMD patients to 481 healthy, age-matched controls from Japan, India, Australia, and the USA showed a statistically increased level of secreted HTRA1 blood concentration in AMD patients compared with age-matched controls. Taken together, these results suggest a common mechanism across ethnicities whereby increased systemic blood circulation of secreted serine protease HTRA1 leads to subsequent degradation of Bruch's membrane and eventual CNV in AMD.
Receptor-ligand supplementation via a self-cleaving 2A peptide-based gene therapy promotes CNS axonal transport with functional recovery
(AMER ASSOC ADVANCEMENT SCIENCE, 2021-03-01)
Gene replacement approaches are leading to a revolution in the treatment of previously debilitating monogenic neurological conditions. However, the application of gene therapy to complex polygenic conditions has been limited. Down-regulation or dysfunction of receptor expression in the disease state or in the presence of excess ligand has been shown to compromise therapeutic efficacy. Here, we offer evidence that combined overexpression of both brain-derived neurotrophic factor and its receptor, tropomyosin receptor kinase B, is more effective in stimulating axonal transport than either receptor administration or ligand administration alone. We also show efficacy in experimental glaucoma and humanized tauopathy models. Simultaneous administration of a ligand and its receptor by a single gene therapy vector overcomes several problems relating to ligand deficiency and receptor down-regulation that may be relevant to multiple neurodegenerative diseases. This approach shows promise as a strategy to target intrinsic mechanisms to improve neuronal function and facilitate repair.
Deficits in Monocyte Function in Age Related Macular Degeneration: A Novel Systemic Change Associated With the Disease
(FRONTIERS MEDIA SA, 2021-03-17)
Age-related macular degeneration (AMD) is characterized by the accumulation of debris in the posterior eye. In this study we evaluated peripheral blood monocyte phagocytic function at various stages of AMD and in aged matched control participants. Real-time tri-color flow cytometry was used to quantify phagocytic function of peripheral blood monocyte subsets (non-classic, intermediate and classic) isolated from subjects with intermediate or late AMD and compared with age matched healthy controls. Assessment of phagocytic function of monocytes isolated from those with and without reticular pseudodrusen was also made, and the effect of glatiramer acetate on phagocytic function assessed. Phagocytic function was reduced in all subjects with AMD, irrespective of stage of disease. However, there was no correlation between phagocytic function and drusen load, nor any difference between the level of phagocytosis in those with or without reticular pseudodrusen. Treatment with glatiramer acetate increased phagocytosis of classical and non-classical monocytes, normalizing the reduction in phagocytosis observed in those with AMD. These findings suggest that defective systemic phagocytosis is associated with both intermediate and late stages of AMD, highlighting a potential role in the accumulation of debris that occurs early in the disease process. Assessing peripheral monocyte phagocytic function provides further insights into the etiology of this disease and offer a novel therapeutic target.
Glial Cells in Glaucoma: Friends, Foes, and Potential Therapeutic Targets
(FRONTIERS MEDIA SA, 2021-03-16)
Glaucoma is the second leading cause of blindness worldwide, affecting ~80 million people by 2020 (1, 2). The condition is characterized by a progressive loss of retinal ganglion cells (RGCs) and their axons accompanied by visual field loss. The underlying pathophysiology of glaucoma remains elusive. Glaucoma is recognized as a multifactorial disease, and lowering intraocular pressure (IOP) is the only treatment that has been shown to slow the progression of the condition. However, a significant number of glaucoma patients continue to go blind despite intraocular pressure-lowering treatment (2). Thus, the need for alternative treatment strategies is indisputable. Accumulating evidence suggests that glial cells play a significant role in supporting RGC function and that glial dysfunction may contribute to optic nerve disease. Here, we review recent advances in understanding the role of glial cells in the pathophysiology of glaucoma. A particular focus is on the dynamic and essential interactions between glial cells and RGCs and potential therapeutic approaches to glaucoma by targeting glial cells.