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Wang Z, Wiggs J, Aung T, Khawaja A, Khor CC. The genetic basis for adult onset glaucoma: Recent advances and future directions. Prog Retin Eye Res. 2022;90:101066.
Glaucoma, a diverse group of eye disorders that results in the degeneration of retinal ganglion cells, is the world's leading cause of irreversible blindness. Apart from age and ancestry, the major risk factor for glaucoma is increased intraocular pressure (IOP). In primary open-angle glaucoma (POAG), the anterior chamber angle is open but there is resistance to aqueous outflow. In primary angle-closure glaucoma (PACG), crowding of the anterior chamber angle due to anatomical alterations impede aqueous drainage through the angle. In exfoliation syndrome and exfoliation glaucoma, deposition of white flaky material throughout the anterior chamber directly interfere with aqueous outflow. Observational studies have established that there is a strong hereditable component for glaucoma onset and progression. Indeed, a succession of genome wide association studies (GWAS) that were centered upon single nucleotide polymorphisms (SNP) have yielded more than a hundred genetic markers associated with glaucoma risk. However, a shortcoming of GWAS studies is the difficulty in identifying the actual effector genes responsible for disease pathogenesis. Building on the foundation laid by GWAS studies, research groups have recently begun to perform whole exome-sequencing to evaluate the contribution of protein-changing, coding sequence genetic variants to glaucoma risk. The adoption of this technology in both large population-based studies as well as family studies are revealing the presence of novel, protein-changing genetic variants that could enrich our understanding of the pathogenesis of glaucoma. This review will cover recent advances in the genetics of primary open-angle glaucoma, primary angle-closure glaucoma and exfoliation glaucoma, which collectively make up the vast majority of all glaucoma cases in the world today. We will discuss how recent advances in research methodology have uncovered new risk genes, and how follow up biological investigations could be undertaken in order to define how the risk encoded by a genetic sequence variant comes into play in patients. We will also hypothesise how data arising from characterising these genetic variants could be utilized to predict glaucoma risk and the manner in which new therapeutic strategies might be informed.
Eraslan G, Drokhlyansky E, Anand S, Fiskin E, Subramanian A, Slyper M, Wang J, Van Wittenberghe N, Rouhana J, Waldman J, Ashenberg O, Lek M, Dionne D, Win TS, Cuoco M, Kuksenko O, Tsankov A, Branton P, Marshall J, Greka A, Getz G, Segrè A, Aguet F, Rozenblatt-Rosen O, Ardlie K, Regev A. Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function. Science. 2022;376(6594):eabl4290.
Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen tissue types from 16 donors and 25 samples, generating a cross-tissue atlas of 209,126 nuclei profiles, which we integrated across tissues, donors, and laboratory methods with a conditional variational autoencoder. Using the resulting cross-tissue atlas, we highlight shared and tissue-specific features of tissue-resident cell populations; identify cell types that might contribute to neuromuscular, metabolic, and immune components of monogenic diseases and the biological processes involved in their pathology; and determine cell types and gene modules that might underlie disease mechanisms for complex traits analyzed by genome-wide association studies.
Wu M, Yu Z, Matar D, Karvar M, Chen Z, Ng B, Aoki S, Haug V, Orgill D, Panayi A. Human Amniotic Membrane Promotes Angiogenesis in an Oxidative Stress Chronic Diabetic Murine Wound Model. Adv Wound Care (New Rochelle). 2022;
Objective: The development of animal models, which adequately replicate the pathophysiology of chronic wounds, has been challenging. In this study, we utilized an oxidative stress (OS) murine model, which was previously developed by our group, to study the effect of a human amniotic membrane (AM) on chronic wound healing. Approach: Forty-five diabetic (genetically obese leptin receptor-deficient mice [db/db]) mice were separated into three groups. Thirty mice received an OS regimen and a 1 - × 1 cm2 full-thickness excisional dorsal wound. The wounds were either covered with AM and occlusive dressing (db/dbOS-AM) or occlusive dressing only (db/dbOS). Fifteen mice did not receive the OS regimen, and were covered with AM and occlusive dressing (db/db-AM). The wounds were photographed, and tissue was harvested at various time points. Results: Vascular density was higher in the AM-treated groups (db/dbOS-AM: 34 ± 12; db/db-AM: 37 ± 14; vs. db/dbOS: 19 ± 9 cluster of differentiation 31 [CD31+]/high power field [HPF] photograph; p = 0.04 and p = 0.003). Vessel maturity was lowest in the db/dbOS group (21% ± 4%; vs. db/dbOS-AM: 38% ± 10%, p = 0.004; db/db-AM: 40% ± 11%, p = 0.0005). Leukocyte infiltration was higher in the AM groups (db/dbOS-AM: 15 ± 4; db/db-AM: 16 ± 4 vs. db/dbOS: 8 ± 3 lymphocyte common antigen [CD45+]/HPF; p = 0.005 and p = 0.06). AM upregulated various proangiogenic factors, including vascular endothelial growth factor (VEGF), and downregulated genes involved in chronicity, such as osteopontin, as visualized through proteome analysis and western blotting. Cell death was lower in the AM groups (db/dbOS-AM: 28 ± 10, db/db-AM: 7 ± 5 vs. db/dbOS: 17% ± 9% Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling [TUNEL+]; p = 0.03 and p < 0.0001). Innovation: This study offers new insight on the mechanisms of action of human AM in chronic wound healing. Conclusion: AM treatment promoted healing in mice with complex chronic wounds. The AM stimulated angiogenesis through upregulation of proangiogenic factors, improving the wound milieu by increasing leukocyte and growth factor delivery and decreasing cell death.
Tabarestani S, Eslami M, Cabrerizo M, Curiel R, Barreto A, Rishe N, Vaillancourt D, DeKosky S, Loewenstein D, Duara R, Adjouadi M. A Tensorized Multitask Deep Learning Network for Progression Prediction of Alzheimer’s Disease. Front Aging Neurosci. 2022;14:810873.
With the advances in machine learning for the diagnosis of Alzheimer's disease (AD), most studies have focused on either identifying the subject's status through classification algorithms or on predicting their cognitive scores through regression methods, neglecting the potential association between these two tasks. Motivated by the need to enhance the prospects for early diagnosis along with the ability to predict future disease states, this study proposes a deep neural network based on modality fusion, kernelization, and tensorization that perform multiclass classification and longitudinal regression simultaneously within a unified multitask framework. This relationship between multiclass classification and longitudinal regression is found to boost the efficacy of the final model in dealing with both tasks. Different multimodality scenarios are investigated, and complementary aspects of the multimodal features are exploited to simultaneously delineate the subject's label and predict related cognitive scores at future timepoints using baseline data. The main intent in this multitask framework is to consolidate the highest accuracy possible in terms of precision, sensitivity, F1 score, and area under the curve (AUC) in the multiclass classification task while maintaining the highest similarity in the MMSE score as measured through the correlation coefficient and the RMSE for all time points under the prediction task, with both tasks, run simultaneously under the same set of hyperparameters. The overall accuracy for multiclass classification of the proposed KTMnet method is 66.85 ± 3.77. The prediction results show an average RMSE of 2.32 ± 0.52 and a correlation of 0.71 ± 5.98 for predicting MMSE throughout the time points. These results are compared to state-of-the-art techniques reported in the literature. A discovery from the multitasking of this consolidated machine learning framework is that a set of hyperparameters that optimize the prediction results may not necessarily be the same as those that would optimize the multiclass classification. In other words, there is a breakpoint beyond which enhancing further the results of one process could lead to the downgrading in accuracy for the other.
Bloom J, Castillejos A, Jones B, Patel N, Rosenstein B, Stock R. Ocular complications with the use of radium-223: a case series. Radiat Oncol. 2022;17(1):97.
BACKGROUND: Radium-223 is used for the treatment of osseous metastases in castrate-resistant prostate cancer, and has been shown to increase time to the first skeletal-related event, reduce the rate of hospitalization, and improve quality of life. It is well tolerated, with hematologic toxicity as the main adverse event. Thus far, no ocular complication has been reported in the literature after initial administration of radium-223 with a single case reported of ocular complications after a patient's second course of radium-223. CASE PRESENTATIONS: We present three cases of ocular complications after the use of radium-223 in patients with metastatic prostatic adenocarcinoma. Ocular complications presented as blurry vision, and formal diagnosis included uveitis and hyphema. CONCLUSIONS: Documentation of adverse events is exceedingly important due to the high incidence of metastatic prostate cancer and increasing interest for the use of radium-223 in other osteoblastic disease. The authors postulate that these ocular complications may be a result of radiation's potential effect on neovascularization, polypharmacy, or the biomolecular effects of radium-223 on integral signaling proteins, potentially coupled with poor underlying ocular health.
Zhu S, Zidan A, Pang K, Musayeva A, Kang Q, Yin J. Promotion of corneal angiogenesis by sensory neuron-derived calcitonin gene-related peptide. Exp Eye Res. 2022;220:109125.
The normal cornea has no blood vessels but has abundant innervation. There is emerging evidence that sensory nerves, originated from the trigeminal ganglion (TG) neurons, play a key role in corneal angiogenesis. In the current study, we examined the role of TG sensory neuron-derived calcitonin gene-related peptide (CGRP) in promoting corneal neovascularization (CNV). We found that CGRP was expressed in the TG and cultured TG neurons. In the cornea, minimal CGRP mRNA was detected and CGRP immunohistochemical staining was exclusively co-localized with corneal nerves, suggesting corneal nerves are likely the source of CGRP in the cornea. In response to intrastromal suture placement and neovascularization in the cornea, CGRP expression was increased in the TG. In addition, we showed that CGRP was potently pro-angiogenic, leading to vascular endothelial cell (VEC) proliferation, migration, and tube formation in vitro and corneal hemangiogenesis and lymphangiogenesis in vivo. In a co-culture system of TG neurons and VEC, blocking CGRP signaling in the conditioned media of TG neurons led to decreased VEC migration and tube formation. More importantly, subconjunctival injection of a CGRP antagonist CGRP8-37 reduced suture-induced corneal hemangiogenesis and lymphangiogenesis in vivo. Taken together, our data suggest that TG sensory neuron and corneal nerve-derived CGRP promotes corneal angiogenesis.
Gong L, Guan Y, Cho W, Li B, Pan L, Yang Z, Wu M, Yang Z, Chauhan S, Zeng W. A new non-human primate model of desiccating stress-induced dry eye disease. Sci Rep. 2022;12(1):7957.
Dry eye disease (DED), a multifactorial ocular surface disease, is estimated to affect up to 34% of individuals over 50 years old. Although numerous animal models, including rodents and rabbits, have been developed to mimic the pathophysiologic mechanisms involved in dry eye, there is a lack of non-human primate (NHP) models, critical for translational drug studies. Here, we developed a novel desiccating stress-induced dry eye disease model using Rhesus macaque monkeys. The monkeys were housed in a controlled environment room for 21 to 36 days under humidity, temperature, and airflow regulation. Following desiccating stress, NHPs demonstrated clinical symptoms similar to those of humans, as shown by increased corneal fluorescein staining (CFS) and decreased tear-film breakup time (TFBUT). Moreover, corticosteroid treatment significantly reduced CFS scoring, restored TFBUT, and prevented upregulation of tear proinflammatory cytokines as observed in dry eye patients following steroid treatment. The close resemblance of clinical symptoms and treatment responses to those of human DED patients provides great translational value to the NHP model, which could serve as a clinically relevant animal model to study the efficacy of new potential treatments for DED.
Chang DST, Jiang Y, Kim JA, Huang S, Muñoz B, Aung T, He M, Foster P, Friedman D. Cataract progression after Nd:YAG laser iridotomy in primary angle-closure suspect eyes. Br J Ophthalmol. 2022;
BACKGROUND/AIMS: Prophylactic laser peripheral iridotomy (LPI) is performed in primary angle-closure suspect (PACS) eyes to prevent acute angle-closure attacks. However, accelerated cataractogenesis is a potential risk of the procedure that may result in decreased visual acuity. We aimed to assess the long-term impact of LPI on cataract formation in Chinese PACS. METHODS: In the Zhongshan Angle Closure Prevention Trial, eligible bilateral PACS participants received LPI in one randomly selected eye, while the fellow eye remained untreated. Cataract was graded using the Lens Opacity Classification System III, and progression was defined as an increase in grade by at least two units in any category or cataract surgery. RESULTS: In total, 889 participants were randomly assigned to LPI in one eye only (mean age 59±5 years, 83% female). At 72 months, treated eyes had slightly higher average nuclear grades (p<0.001). However, there were no differences between eyes for predefined cataract progression (cumulative probability at 72 months: 21.2% in LPI vs 19.4% in control, p=0.401) or cataract surgery (1% for both). While LPI-treated eyes had a 10% higher risk of progression over 6 years (HR=1.10 (95% CI 0.88 to 1.36)), this was not statistically significant. Visual acuity at 72 months was similar in treated and untreated eyes (p=0.43). CONCLUSION: Although lenses were graded on average as slightly more opaque in laser-treated eyes, prophylactic neodymium:yttrium-aluminum-garnet LPI did not cause significant cataract progression. Our results suggest that LPI treatment of asymptomatic narrow angles does not increase the risk of developing clinically meaningful cataract worsening over time. TRIAL REGISTRATION NUMBER: ISRCTN45213099.
Hynnekleiv L, Magno M, Vernhardsdottir R, Moschowits E, Tønseth KA, Dartt DA, Vehof J, Utheim T. Hyaluronic acid in the treatment of dry eye disease. Acta Ophthalmol. 2022;100(8):844–860.
Dry eye disease (DED) is a highly prevalent and debilitating condition affecting several hundred million people worldwide. Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan commonly used in the treatment of DED. This review aims to critically evaluate the literature on the safety and efficacy of artificial tears containing HA used in DED treatment. Literature searches were conducted in PubMed, including MEDLINE, and in Embase via Ovid with the search term: "(hyaluronic acid OR hyaluronan OR hyaluronate) AND (dry eye OR sicca)". A total of 53 clinical trials are included in this review, including eight placebo-controlled trials. Hyaluronic acid concentrations ranged from 0.1% to 0.4%. Studies lasted up to 3 months. A broad spectrum of DED types and severities was represented in the reviewed literature. No major complications or adverse events were reported. Artificial tears containing 0.1% to 0.4% HA were effective at improving both signs and symptoms of DED. Two major gaps in the literature have been identified: 1. no study investigated the ideal drop frequency for HA-containing eyedrops, and 2. insufficient evidence was presented to recommend any specific HA formulation over another. Future investigations assessing the optimal drop frequency for different concentrations and molecular weights of HA, different drop formulations, including tonicity, and accounting for DED severity and aetiology are essential for an evidence-based, individualized approach to DED treatment.
O’Hare M, Arboleda-Velasquez J. Notch Signaling in Vascular Endothelial and Mural Cell Communications. Cold Spring Harb Perspect Med. 2022;
The Notch signaling pathway is a highly versatile and evolutionarily conserved mechanism with an important role in cell fate determination. Notch signaling plays a vital role in vascular development, regulating several fundamental processes such as angiogenesis, arterial/venous differentiation, and mural cell investment. Aberrant Notch signaling can result in severe vascular phenotypes as observed in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and Alagille syndrome. It is known that vascular endothelial cells and mural cells interact to regulate vessel formation, cell maturation, and stability of the vascular network. Defective endothelial-mural cell interactions are a common phenotype in diseases characterized by impaired vascular integrity. Further refinement of the role of Notch signaling in the vascular junctions will be critical to attempts to modulate Notch in the context of human vascular disease. In this review, we aim to consolidate and summarize our current understanding of Notch signaling in the vascular endothelial and mural cells during development and in the adult vasculature.
Halawa OA, Sekimitsu S, Boland M, Zebardast N. Sex-Based Differences in Medicare Reimbursements among Ophthalmologists Persist across Time. Ophthalmology. 2022;129(9):1056–1063.
PURPOSE: To evaluate differences in Medicare reimbursements between male and female ophthalmologists between 2013 and 2019. DESIGN: Retrospective cohort study. PARTICIPANTS: Ophthalmologists receiving Medicare reimbursements between 2013 and 2019. METHODS: The Centers for Medicare and Medicaid Services Physician and Other Supplier Public Use File was used to determine total reimbursements and number of services submitted by ophthalmologists between 2013 and 2019. Reimbursements were standardized to account for geographic differences in Medicare reimbursement per service. Data from the American Community Survey (ACS) were used to determine socioeconomic characteristics (unemployment, poverty, income, and education) by zip code for the location of each physician's practice. A multivariate linear regression model was used to evaluate differences in annual reimbursements by sex, accounting for calendar year, years of experience, total number of services, ACS zip code data, and proportion of procedural services. MAIN OUTCOME MEASURES: Annual Medicare reimbursement and use of billing codes (e.g., outpatient office visits and eye examinations, diagnostic testing, laser treatment, and surgery). RESULTS: Among 20 281 ophthalmologists who received Medicare reimbursements between 2013 and 2019, 15 451 (76%) were men. The most common billing codes submitted were for outpatient visits and eye examinations (13.8 million charges/year), diagnostic imaging of the retina (5.6 million charges/year), intravitreal injections (2.9 million charges/year), and removal of cataract with insertion of lens (2.4 million charges/year). Compared with men, female ophthalmologists received less in median annual reimbursements (median, $94 734.21 [interquartile range (IQR), $30 944.52-$195 701.70] for women vs. $194 176.90 [IQR, $76 380.76-$355 790.80] for men; P < 0.001) and billed for fewer annual median services (median, 1228 [IQR, 454-2433] vs. 2259 [IQR, 996-4075, respectively]; P < 0.001). After adjustment for covariates, female ophthalmologists billed for 1015 fewer services (95% confidence interval [CI], 1001-1029; P < 0.001) and received $20 209.12 less in reimbursements than men (95% CI, -$21 717.57 to -$18 700.66; P < 0.001). CONCLUSIONS: Female ophthalmologists billed for fewer services and received less in reimbursement from Medicare than men over time and across all categories of billing codes. Disparities persisted after controlling for physician and practice characteristics.
Mei C, Zhang Y, Pan L, Dong B, Chen X, Gao Q, Xu H, Xu W, Fang H, Liu S, McAlinden C, Paschalis E, Wang Q, Yang M, Huang J, Yu AY. A One-Step Electrochemical Aptasensor Based on Signal Amplification of Metallo Nanoenzyme Particles for Vascular Endothelial Growth Factor. Front Bioeng Biotechnol. 2022;10:850412.
In this study, a one-step electrochemical aptasensor was developed to detect the biomarker vascular endothelial growth factor (VEGF), an important protein in the pathogenesis of many retinal diseases, including age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and retinal vein occlusion. The aptamer has a good affinity and can rapidly identify and capture VEGF based on its unique structure. We designed a VEGF aptasensor based on the aptamer recognition and complex metallo nanoenzyme particles as an electron exchange center and bridge between capture DNA and electrode. The aptamers maintained the hairpin structure to avoid nonspecific surface adsorption and expose the capture sequence outwards when the target was inexistent. Conversely, the aptamers opened the hairpin structure to release space to accomplish binding between VEGF and DNA, resulting in increased impedance. The performance of the electrochemical aptasensor is detected by electrochemical impedance spectroscopy (EIS). The limit of detection by EIS was as low as 8.2 pg ml-1, and the linear range was 10 pg ml-1-1 μg ml-1. The electrochemical aptasensor also showed high specificity and reproducibility.
Zabaleta N, Bhatt U, Hérate C, Maisonnasse P, Sanmiguel J, Diop C, Castore S, Estelien R, Li D, Dereuddre-Bosquet N, Cavarelli M, Gallouët AS, Pascal Q, Naninck T, Kahlaoui N, Lemaitre J, Relouzat F, Ronzitti G, Thibaut HJ, Montomoli E, Wilson J, Le Grand R, Vandenberghe L. Durable immunogenicity, adaptation to emerging variants, and low-dose efficacy of an AAV-based COVID-19 vaccine platform in macaques. Mol Ther. 2022;30(9):2952–2967.
The COVID-19 pandemic continues to have devastating consequences on health and economy, even after the approval of safe and effective vaccines. Waning immunity, the emergence of variants of concern, breakthrough infections, and lack of global vaccine access and acceptance perpetuate the epidemic. Here, we demonstrate that a single injection of an adenoassociated virus (AAV)-based COVID-19 vaccine elicits at least 17-month-long neutralizing antibody responses in non-human primates at levels that were previously shown to protect from viral challenge. To improve the scalability of this durable vaccine candidate, we further optimized the vector design for greater potency at a reduced dose in mice and non-human primates. Finally, we show that the platform can be rapidly adapted to other variants of concern to robustly maintain immunogenicity and protect from challenge. In summary, we demonstrate this class of AAV can provide durable immunogenicity, provide protection at dose that is low and scalable, and be adapted readily to novel emerging vaccine antigens thus may provide a potent tool in the ongoing fight against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
Oke I, VanderVeen D, McClatchey T, Lambert S, McClatchey S, Infant Aphakia Treatment Study Group. The accuracy of intraocular lens calculation varies by age in the Infant Aphakia Treatment Study. J AAPOS. 2022;
Refraction predictions from intraocular lens (IOL) calculation formulae are inaccurate in children. We sought to quantify the relationship between age and prediction error using a model derived from the biometry measurements of children enrolled in the Infant Aphakia Treatment Study (IATS) when they were ≤7 months of age. We calculated theoretical predicted refractions in diopters (D) using axial length, average keratometry, and IOL powers at each measurement time point using the Holladay 1 formula. We compared the predicted refraction to the actual refraction and calculated the absolute prediction error (APE). We found that the median APE was 1.60 D (IQR, 0.73-3.11 D) at a mean age (corrected for estimated gestational age) of 0.20 ± 0.14 years and decreased to 1.11 D (IQR, 0.42-2.20 D) at 10.60 ± 0.27 years. We analyzed the association of age with APE using linear mixed-effects models adjusting for axial length, average keratometry, and IOL power and found that as age doubled, APE decreased by 0.25 D (95% CI, 0.09-0.40 D). The accuracy of IOL calculations increases with age, independent of biometry measurements and IOL power.