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Tawfik A, Pistilli M, Maguire MG, Chen Y, Yu Y, Greiner JV, Asbell PA, Ying G-S, and Group DEAM (DREAM) SR. Association of Dry Eye Symptoms and Signs in Patients with Dry Eye Disease. Ophthalmic Epidemiol 2023;:1-9.Abstract
PURPOSE: To determine the correlations among symptoms and signs of dry eye disease (DED) in the Dry Eye Assessment and Management (DREAM) study. METHODS: A total of 535 patients with moderate-to-severe DED were assessed for symptoms using the Ocular Surface Disease Index (OSDI) and four DED signs in both eyes (conjunctival lissamine green staining, corneal fluorescein staining, Schirmer's testing, and tear break-up time (TBUT)) following standardized protocols at baseline and follow-up visits (months 3, 6, and 12). Spearman correlation coefficients (rho) were calculated for correlations among symptoms and signs of DED at baseline and among changes in symptoms and signs from baseline at 12 months. The confidence intervals and p-values for correlation coefficients were calculated using a cluster bootstrapping to account for inter-eye correlation. RESULTS: At baseline, OSDI total score was not correlated with signs; however, OSDI subscale score of ocular symptoms was weakly correlated with corneal staining score (rho = 0.14, p = .002) and Schirmer test score (rho = 0.11, p = .01). There were statistically significant correlations among the four signs (p < .001), with absolute correlation coefficient ranging from 0.14 (conjunctival staining score vs. TBUT) to 0.33 (conjunctival staining score vs. cornea staining score). The correlations among changes in symptoms and signs were weaker, with the highest correlation between change in conjunctival staining and corneal staining (rho = 0.21, p < .001). CONCLUSIONS: Consistent with previous studies, among DREAM participants with moderate-to-severe DED at baseline, correlations of DED symptoms with signs were low and correlations among four objective signs were low to moderate. The correlations among changes in symptoms and signs were even weaker.
Morrison DG, Heidary G, Chang MY, Binenbaum G, Cavuoto KM, Galvin J, Trivedi R, Kim SJ, Pineles SL. Levodopa/Carbidopa to Augment the Treatment of Amblyopia: A Report by the American Academy of Ophthalmology. Ophthalmology 2023;130(11):1221-1227.Abstract
PURPOSE: To review the published literature on the use of levodopa/carbidopa to augment the treatment of amblyopia. METHODS: Literature searches for English language studies were last conducted in October 2022 in the PubMed database with no date restrictions. The combined searches yielded 55 articles, of which 23 were reviewed in full text. Twelve of these were considered appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. Nine studies were rated level I, and 3 studies were rated level II; there were no level III studies. RESULTS: The duration of treatment was limited to 3 to 16 weeks because of concern about long-term adverse effects such as tardive dyskinesia. This complication was not reported in any of the study participants. The dose of levodopa ranged from 1.5 to 8.3 mg/kg/day, generally divided into 3 daily doses. The carbidopa dose was approximately 25% of the levodopa dose in all treatments. Evidence from these studies indicates that augmenting traditional patch occlusion therapy with the oral administration of levodopa/carbidopa can improve the vision of amblyopic children, but the effect was small (0.17-0.3 logarithm of the minimum angle of resolution [logMAR] units) and only statistically significant when compared with patching alone in 2 of the 12 studies cited. Regression of vision was reported in the majority of studies (9 of 12 reported; range, 0-0.17 logMAR unit regression) after discontinuation of therapy. Short-term side effects of the medications were not consistently reported but were most frequently mild and included headache and nausea. CONCLUSIONS: The best available evidence is currently insufficient to show that augmenting amblyopia therapy using up to 16 weeks of levodopa/carbidopa will result in meaningful improvement in visual acuity. Given the potential for significant side effects such as tardive dyskinesia with long-term therapy, levodopa/carbidopa does not appear to be a viable option for amblyopia therapy FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Monavarfeshani A, Yan W, Pappas C, Odenigbo KA, He Z, Segrè AV, van Zyl T, Hageman GS, Sanes JR. Transcriptomic analysis of the ocular posterior segment completes a cell atlas of the human eye. Proc Natl Acad Sci U S A 2023;120(34):e2306153120.Abstract
Although the visual system extends through the brain, most vision loss originates from defects in the eye. Its central element is the neural retina, which senses light, processes visual signals, and transmits them to the rest of the brain through the optic nerve (ON). Surrounding the retina are numerous other structures, conventionally divided into anterior and posterior segments. Here, we used high-throughput single-nucleus RNA sequencing (snRNA-seq) to classify and characterize cells in six extraretinal components of the posterior segment: ON, optic nerve head (ONH), peripheral sclera, peripapillary sclera (PPS), choroid, and retinal pigment epithelium (RPE). Defects in each of these tissues are associated with blinding diseases-for example, glaucoma (ONH and PPS), optic neuritis (ON), retinitis pigmentosa (RPE), and age-related macular degeneration (RPE and choroid). From ~151,000 single nuclei, we identified 37 transcriptomically distinct cell types, including multiple types of astrocytes, oligodendrocytes, fibroblasts, and vascular endothelial cells. Our analyses revealed a differential distribution of many cell types among distinct structures. Together with our previous analyses of the anterior segment and retina, the data presented here complete a "Version 1" cell atlas of the human eye. We used this atlas to map the expression of >180 genes associated with the risk of developing glaucoma, which is known to involve ocular tissues in both anterior and posterior segments as well as the neural retina. Similar methods can be used to investigate numerous additional ocular diseases, many of which are currently untreatable.
Ashok A, Tai WL, Lennikov A, Chang K, Chen J, Li B, Cho K-S, Utheim TP, Chen DF. Electrical stimulation alters DNA methylation and promotes neurite outgrowth. J Cell Biochem 2023;124(10):1530-1545.Abstract
Electrical stimulation (ES) influences neural regeneration and functionality. We here investigate whether ES regulates DNA demethylation, a critical epigenetic event known to influence nerve regeneration. Retinal ganglion cells (RGCs) have long served as a standard model for central nervous system neurons, whose growth and disease development are reportedly affected by DNA methylation. The current study focuses on the ability of ES to rescue RGCs and preserve vision by modulating DNA demethylation. To evaluate DNA demethylation pattern during development, RGCs from mice at different stages of development, were analyzed using qPCR for ten-eleven translocation (TETs) and immunostained for 5 hydroxymethylcytosine (5hmc) and 5 methylcytosine (5mc). To understand the effect of ES on neurite outgrowth and DNA demethylation, cells were subjected to ES at 75 µAmp biphasic ramp for 20 min and cultured for 5 days. ES increased TETs mediated neurite outgrowth, DNA demethylation, TET1 and growth associated protein 43 levels significantly. Immunostaining of PC12 cells following ES for histone 3 lysine 9 trimethylation showed cells attained an antiheterochromatin configuration. Cultured mouse and human retinal explants stained with β-III tubulin exhibited increased neurite growth following ES. Finally, mice subjected to optic nerve crush injury followed by ES exhibited improved RGCs function and phenotype as validated using electroretinogram and immunohistochemistry. Our results point to a possible therapeutic regulation of DNA demethylation by ES in neurons.
Oke I, Hunter DG, Mantagos IS, Heidary G. The impact of the COVID-19 pandemic on the surgical volume of pediatric ophthalmology and strabismus fellows. J AAPOS 2023;27(5):305-307.Abstract
This study used data from the annual fellowship survey over 7 academic years (2014-15 to 2020-21) to describe the trends in surgical experience for pediatric ophthalmology and strabismus fellows and to quantify the impact of the COVID-19 pandemic on trainee surgical volume. The overall number of procedures performed by fellows in the primary surgeon role declined during the first academic year impacted by the pandemic but recovered in the second year. There was an increase in the number of intraocular cases performed per year during the 7-year study interval.
Zhao L, Wen Q, Nasrazadani D, Cheung NL, Weinert MC, Freedman SF, Silver J, Priestley YM, Congdon N, Prakalapakorn GS. Refractive Accuracy and Visual Outcome by Self-Refraction Using Adjustable-Focus Spectacles in Young Children: A Randomized Clinical Trial. JAMA Ophthalmol 2023;Abstract
IMPORTANCE: Uncorrected refractive error is the most common cause of vision impairment in children. Most children 12 years or older can achieve visual acuity (VA) of 20/25 or better by self-refraction using adjustable-focus spectacles, but data on younger children are lacking. OBJECTIVE: To assess refractive accuracy, corrected VA, and factors associated with not achieving VA of 20/25 or better among children aged 5 to 11 years performing self-refraction with Adspecs adjustable-focus spectacles (Adaptive Eyecare), compared with noncycloplegic autorefraction and cycloplegic refraction. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional noninferiority trial conducted from September 2, 2015, to December 14, 2017. The study setting was an academic pediatric eye clinic. Children aged 5 to 11 years with uncorrected VA of 20/40 or worse in 1 or both eyes and without systemic or ocular conditions preventing best-corrected VA of 20/25 or better were enrolled. Children who had best-corrected VA worse than 20/25 were excluded. Study data were analyzed from September 2017 to June 2023. EXPOSURES: Children were taught to self-refract with adjustable-focus spectacles. MAIN OUTCOMES AND MEASURES: Spherical equivalent refractive error (using self-refraction, noncycloplegic autorefraction, and cycloplegic refraction) and VA (uncorrected and using self-refraction, noncycloplegic autorefraction, and cycloplegic refraction) for study eyes were evaluated. Potential predictors of failure to achieve VA of 20/25 or better with self-refraction were assessed using logistic regression. RESULTS: A total of 127 consecutive children were enrolled. After exclusions, 112 children (median [IQR] age, 9.0 [8.0-10.3] years; 52 boys [46.4%]) were included in the study. Mean (SD) spherical equivalent refractive power was -2.00 (1.52) diopters (D) for self-refraction, -2.32 (1.43) D for noncycloplegic autorefraction, and -1.67 (1.49) D for cycloplegic refraction. Mean (SD) difference in refractive power between self-refraction and noncycloplegic autorefraction was 0.32 (1.11) D (97.5% 1-sided CI, 0.11 to ∞ D; P < .001) and between self-refraction and cycloplegic refraction was -0.33 (1.15) D (97.5% 1-sided CI, -0.54 to ∞ D; P = .77). The proportion of children with corrected VA of 20/25 or better was 79.5% (89 of 112) with self-refraction, 85.7% (96 of 112) with noncycloplegic autorefraction, and 79.5% (89 of 112) with cycloplegic refraction (self-refraction vs noncycloplegic autorefraction: McNemar P value = .27; self-refraction vs cycloplegic refraction: McNemar P value > .99). Those failing to achieve best-corrected VA of 20/25 or better with self-refraction had higher astigmatism (odds ratio [OR], 10.6; 95% CI, 3.1-36.4; P < .001) and younger age (OR, 1.5; 95% CI, 1.1-2.2; P = .02). CONCLUSIONS AND RELEVANCE: Self-refraction among children aged 5 to 11 years may result in more myopic power than cycloplegic refraction but not necessarily to a clinically relevant degree. Although the proportion of children achieving VA of 20/25 or better with self-refraction using adjustable-focus spectacles did not differ from cycloplegic refraction, it was less likely among younger children and those with higher astigmatism.
Ferreira Neto LC, Alves MS, Prichula J, Agnes G, de Oliveira TF, Trentin D, Merib J. An affordable and semiautomated approach as a novel strategy for the extraction of DNA using magnetic ionic liquids followed by real time-polymerase chain reaction. Anal Methods 2023;15(30):3752-3757.Abstract
This technical note describes a novel and straightforward experimental strategy for the extraction/capture of DNA using magnetic ionic liquid (MIL) followed by real time-polymerase chain reaction (qPCR) analysis. An affordable and low-cost magneto-based multiwell platform was first examined for capturing DNA allowing for simultaneous extractions that increased the analysis throughput of the experimental workflow. This configuration was composed of a series of neodymium rod magnets attached to a multiwell device in which a magneto-active extraction phase (MIL) was suspended for a single drop microextraction (SDME) approach. In this configuration, up to 32 extractions were able to be performed simultaneously, and DNA was successfully extracted from aqueous samples. Furthermore, as a proof-of-concept, this affordable and simple experimental strategy proved to be efficient for the extraction/capture of DNA from challenging samples such as whole blood without any pretreatment. This fact also consists of important feature compared to previous methodologies that required additional steps of sample preparation.
Xie L, Yin Y, Jayakar S, Kawaguchi R, Wang Q, Peterson S, Shi C, Turnes BL, Zhang Z, Oses-Prieto J, Li J, Burlingame A, Woolf CJ, Geschwind D, Rasband M, Benowitz LI. The oncomodulin receptor ArmC10 enables axon regeneration in mice after nerve injury and neurite outgrowth in human iPSC-derived sensory neurons. Sci Transl Med 2023;15(708):eadg6241.Abstract
Oncomodulin (Ocm) is a myeloid cell-derived growth factor that enables axon regeneration in mice and rats after optic nerve injury or peripheral nerve injury, yet the mechanisms underlying its activity are unknown. Using proximity biotinylation, coimmunoprecipitation, surface plasmon resonance, and ectopic expression, we have identified armadillo-repeat protein C10 (ArmC10) as a high-affinity receptor for Ocm. ArmC10 deletion suppressed inflammation-induced axon regeneration in the injured optic nerves of mice. ArmC10 deletion also suppressed the ability of lesioned sensory neurons to regenerate peripheral axons rapidly after a second injury and to regenerate their central axons after spinal cord injury in mice (the conditioning lesion effect). Conversely, Ocm acted through ArmC10 to accelerate optic nerve and peripheral nerve regeneration and to enable spinal cord axon regeneration in these mouse nerve injury models. We showed that ArmC10 is highly expressed in human-induced pluripotent stem cell-derived sensory neurons and that exposure to Ocm altered gene expression and enhanced neurite outgrowth. ArmC10 was also expressed in human monocytes, and Ocm increased the expression of immune modulatory genes in these cells. These findings suggest that Ocm acting through its receptor ArmC10 may be a useful therapeutic target for nerve repair and immune modulation.
Kurukuti NM, Nadeau M, Paschalis EI, Houston KE. An Adjustable Magnetic Levator Prosthesis for Customizable Eyelid Re-Animation in Severe Blepharoptosis: Design and Proof-of-Concept. Transl Vis Sci Technol 2023;12(8):11.Abstract
PURPOSE: Blepharoptosis is a common oculoplastic condition causing incomplete opening of the upper eyelid. Surgical approaches, the mainstay for correction, often fail to improve blink function. The purpose of this study was to develop a nonsurgical treatment option for severe ptosis that allows blink re-animation. METHODS: Magnetic force required to perform blink re-animation was characterized by evaluation of eye-opening and closing using inter-palpebral fissure (IPF) outcomes with various combinations of eyelid array and box magnets. Optimal size of the spectacle magnet that achieved forces required for optimal blink dynamics was selected using simulation. The adjustable magnetic levator prosthesis (aMLP) included an eyelid array magnet and an adjustable rotating spectacle magnet that allowed change in the magnetic direction, thus changing the net magnetic interactive force between the magnets. The clinical feasibility of aMLP in improving eye opening without limiting eye closing was evaluated in patients with ptosis through a proof-of-concept study using IPF and comfort outcomes. RESULTS: Optimal eye opening and closing was achieved by a magnet-array combination providing 45 grams of surface force (gF) in the tested ptosis population. The aMLP was able to modulate eye opening and closing with change in rotation of the spectacle magnet in two patients with ptotis. The best fitting of an aMLP improved IPF opening without limiting eye closing and with good comfort reported. CONCLUSIONS: Preliminary results suggest that the an aMLP can correct ptosis without adversely affecting blink function. Further evaluation in a larger patient population is warranted. TRANSLATIONAL RELEVANCE: A nonsurgical, proof of concept, adjustable magnetic treatment option for blink re-animation in patients with severe ptosis is presented.
Oke I, Gaier ED, Repka MX. Factors associated with visual acuity improvement with a binocular digital therapeutic for amblyopia. J AAPOS 2023;27(5):300-303.Abstract
We combined data from 121 amblyopic children enrolled in two prospective open-label pilot studies and a randomized trial of a binocular digital therapeutic to identify factors associated with positive response to amblyopia treatment. Visual acuity improved ≥1 line in 81% of participants after 12 weeks of therapy. Treatment response was not found to be associated with age, severity of amblyopia, or prior treatment status. Although these findings may suggest broad efficacy for this treatment approach, further investigation in larger cohorts is needed to identify factors associated with treatment response.
Azad AD, Reshef ER, Lee NG. Hyperglobus and Pseudoptosis in Type 1 Lipogenic Thyroid Eye Disease. Am J Ophthalmol Case Rep 2023;32:101890.Abstract
PURPOSE: We present a case of Type 1 (lipogenic) Thyroid Eye Disease (TED) and our aim is to describe an atypical presentation of a rare orbital process. OBSERVATIONS: A man in his 50s presented with left-sided eyelid drooping. His exam showed no evidence of active inflammation but did show left hyperglobus and ipsilateral upper eyelid pseudoptosis. He had no prior history or symptoms of Graves' Disease and imaging did not show evidence of extraocular muscle enlargement, bony asymmetries, or masses in the orbit. Subsequent lab work showed a low TSH (thyroid-stimulating hormone), elevated free T4 (thyroxine) and T3 (triiodothyronine), and elevated TSI (thyroid-stimulating immunoglobulin) index. CONCLUSIONS AND IMPORTANCE: This is a unique and atypical presentation of a patient diagnosed with Type 1 (lipogenic) TED causing hyperglobus and pseudoptosis secondary to fat expansion in the absence of other classic TED findings such as contralateral eyelid retraction or extraocular muscle enlargement. Thyroid eye disease can have a heterogenous disease presentation, as evidenced by this case, and should always be considered in the differential diagnosis of pseudoptosis.
Peli E, Goldstein R, Jung J-H. The Invisibility of Scotomas I: The Carving Hypothesis. Optom Vis Sci 2023;Abstract
SIGNIFICANCE: Veridical depictions of scene appearance with scotomas allow better understanding of the impact of field loss and may improve the development and implementation of rehabilitation. Explanation and depiction of the invisibility of scotoma may lead to patients' understanding and thus better compliance with related treatments. PURPOSE: Simulations of perception with scotomas guide training, patient education, and rehabilitation research. Most simulations incorrectly depict scotomas as black patches, though the scotomas and the missing contents are usually invisible to patients. We present a novel approach to capture the reported appearance of scenes with scotomas. METHODS: We applied a content-aware image resizing algorithm to carve out the content elided under the scotoma. With video sequences we show how and why eye movements fail to increase the visibility of the carved scotomas. RESULTS: Numerous effects, reported by patients, emerge naturally from the scotoma carving. Carving-eliminated scotomas over natural images are barely visible, despite causing substantial distortions. Low resolution and contrast sensitivity at farther eccentricities and saccadic blur reduce the visibility of the distortions. In a walking scenario, static objects moving smoothly to the periphery disappear into, and then reemerge out of peripheral scotomas invisibly. CONCLUSIONS: Scotoma carving provides a viable hypothetical simulation of vision with scotomas, due to loss of neurons at the retinal ganglion cell level and higher. As a hypothesis, it generates predictions that lend themselves to future clinical testing. The different effects of scotomas due to loss of photoreceptors are left for follow-up work.
Elhusseiny AM, Khodeiry MM, Lee RK, Shaarawy T, Waqar S, Sayed MS. Early Experience with the Paul Glaucoma Implant in Childhood Glaucoma: A Case Series. Clin Ophthalmol 2023;17:1939-1944.Abstract
PURPOSE: The Paul glaucoma implant (PGI, Advanced Ophthalmic Innovations, Singapore, Republic of Singapore) is a recently developed novel non-valved glaucoma drainage device (GDD) designed to effectively reduce the intraocular pressure (IOP) in glaucoma patients with a theoretically reduced risk of postoperative complications such as hypotony, endothelial cell loss, strabismus, and diplopia. Limited literature has evaluated its use in adult glaucoma; however, its use in pediatric glaucoma has not been reported to date. We present our early experience with PGI in refractory childhood glaucoma. PATIENTS AND METHODS: This study was retrospective single-surgeon case series in a single tertiary center. RESULTS: Three eyes of 3 patients with childhood glaucoma were enrolled in the study. During nine months of follow-up, postoperative IOP and number of glaucoma medications were significantly lower than preoperative values in all the enrolled patients. None of the patients developed postoperative complications including postoperative hypotony, choroidal detachment, endophthalmitis, or corneal decompensation. CONCLUSION: PGI is an efficient and relatively safe surgical treatment option in patients with refractory childhood glaucoma. Further studies with larger number of participants and longer follow-up period are required to confirm our encouraging results.
Pan L, Cho K-S, Wei X, Xu F, Lennikov A, Hu G, Tang J, Guo S, Chen J, Kriukov E, Kyle R, Elzaridi F, Jiang S, Dromel PA, Young M, Baranov P, Do C-W, Williams RW, Chen J, Lu L, Chen DF. IGFBPL1 is a master driver of microglia homeostasis and resolution of neuroinflammation in glaucoma and brain tauopathy. Cell Rep 2023;42(8):112889.Abstract
Microglia shift toward an inflammatory phenotype during aging that is thought to exacerbate age-related neurodegeneration. The molecular and cellular signals that resolve neuroinflammation post-injury are largely undefined. Here, we exploit systems genetics methods based on the extended BXD murine reference family and identify IGFBPL1 as an upstream cis-regulator of microglia-specific genes to switch off inflammation. IGFBPL1 is expressed by mouse and human microglia, and higher levels of its expression resolve lipopolysaccharide-induced neuroinflammation by resetting the transcriptome signature back to a homeostatic state via IGF1R signaling. Conversely, IGFBPL1 deficiency or selective deletion of IGF1R in microglia shifts these cells to an inflammatory landscape and induces early manifestation of brain tauopathy and retinal neurodegeneration. Therapeutic administration of IGFBPL1 drives pro-homeostatic microglia and prevents glaucomatous neurodegeneration and vision loss in mice. These results identify IGFBPL1 as a master driver of the counter-inflammatory microglial modulator that presents an endogenous resolution of neuroinflammation to prevent neurodegeneration in eye and brain.

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