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Neuronal migration and axon growth and guidance require precise control of microtubule dynamics and microtubule-based cargo transport. TUBB3 encodes the neuronal-specific β-tubulin isotype III, TUBB3, a component of neuronal microtubules expressed throughout the life of central and peripheral neurons. Human pathogenic TUBB3 missense variants result in altered TUBB3 function and cause errors either in the growth and guidance of cranial and, to a lesser extent, central axons, or in cortical neuronal migration and organization, and rarely in both. Moreover, human pathogenic missense variants in KIF21A, which encodes an anterograde kinesin motor protein that interacts directly with microtubules, alter KIF21A function and cause errors in cranial axon growth and guidance that can phenocopy TUBB3 variants. Here, we review reported TUBB3 and KIF21A variants, resulting phenotypes, and corresponding functional studies of both wildtype and mutant proteins. We summarize the evidence that, in vitro and in mouse models, loss-of-function and missense variants can alter microtubule dynamics and microtubule-kinesin interactions. Lastly, we highlight additional studies that might contribute to our understanding of the relationship between specific tubulin isotypes and specific kinesin motor proteins in health and disease.

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.

BACKGROUND AND AIMS: Induced prismatic effects due to poor fitting spectacle frames is a common problem, seen in most of the spectacle wearers and this improper fitting is often due to optical center demarcation on lenses and this error causes asthenopic symptoms and diplopia. However, these errors are most common in developing countries due to lack of awareness, hence a standardized regulation is required. The current study aimed to estimate the amount of prismatic effect that is induced due to the decentration of an optical center in ophthalmic lens. METHODS: A quantitative cross-sectional study was conducted in single vision spectacle wearers (N = 120) with a mean age of 25 ± 5 years. The pupillometric evaluation was performed to mark the pupil center on the spectacle lens. A lensometry evaluation was done to mark the optic center of the spectacle lens. A comparison was made to note whether the optic center is aligned with pupillary center. Objective assessment was performed through Prentice's rule (P = cF) and subjective symptoms were assessed through a validated visual comfort questionnaire. RESULTS: In this sample, around 57% of the individual with single vision glasses were not looking through the optic center and experiencing induced prismatic effect of -0.7 to 0.6 prism diopter, with mean decentration of 3.5 mm. Forty percent of the individuals with misaligned optic center showed asthenopic symptoms and visual discomfort. CONCLUSION: Optometrist should check quality of dispensing and visual performance before handing over the newly dispensed glasses to the patients.

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.

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.

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.

To treat unilateral limbal stem cell (LSC) deficiency, we developed cultivated autologous limbal epithelial cells (CALEC) using an innovative xenobiotic-free, serum-free, antibiotic-free, two-step manufacturing process for LSC isolation and expansion onto human amniotic membrane with rigorous quality control in a good manufacturing practices facility. Limbal biopsies were used to generate CALEC constructs, and final grafts were evaluated by noninvasive scanning microscopy and tested for viability and sterility. Cultivated cells maintained epithelial cell phenotype with colony-forming and proliferative capacities. Analysis of LSC biomarkers showed preservation of "stemness." After preclinical development, a phase 1 clinical trial enrolled five patients with unilateral LSC deficiency. Four of these patients received CALEC transplants, establishing preliminary feasibility. Clinical case histories are reported, with no primary safety events. On the basis of these results, a second recruitment phase of the trial was opened to provide longer term safety and efficacy data on more patients.

PURPOSE: Retinal artery occlusion (RAO) is an ophthalmic emergency that can lead to poor visual outcomes and is associated with an increased risk of stroke and cardiovascular events. Wide-field swept-source OCT-A (WF SS-OCTA) can provide quick and non-invasive angiographic information with a wide field of view. Here, we looked for associations between OCT-A vascular imaging metrics and vision in RAO patients. METHODS: Patients with diagnoses of central (CRAO) or branched retinal artery occlusion (BRAO) were included. 6mm × 6mm Angio and 15mm × 15mm AngioPlex Montage OCT-A images were obtained for both eyes in each patient using Zeiss Plex Elite 9000 WF SS-OCTA device. Each 6mm × 6mm image was divided into nine Early Treatment Diabetic Retinopathy Study (ETDRS) subfields. Non-perfusion area (NPA) was manually measured using 15mm × 15mm images. A linear regression model was utilized to identify correlation between imaging metrics and vision. P-values less than 0.05 were considered as statistically significant. RESULTS: Twenty-five subjects were included. For RAO eyes, there was a statistically significant inverse correlation between retinal thickness as well as superficial capillary plexus (SCP) vessel density (VD) and vision. An inverse correlation was found between deep capillary plexus (DCP) VD and vision without statistical significance. There was a positive correlation between choroidal thickness as well as choroidal volume and vision without statistical significance. No significant correlation was found between the metrics and vision in contralateral eyes. For NPA and vision, no significant correlation was identified. CONCLUSION: This is the first study to investigate the utility of WF SS-OCTA in RAO and to demonstrate correlations between retinal vascular imaging metrics and visual outcomes. The results of this study provide a basis to understand the structural changes involved in vision in RAO and may guide management of RAO and prevention of cerebral stroke and cardiovascular accidents.

PURPOSE OF REVIEW: This review broadly describes recent neuro-ophthalmic manifestations of varicella-zoster virus (VZV) reported in literature. RECENT FINDINGS: Despite varicella vaccination, the incidence of herpes zoster continues to rise, potentially leading to devastating consequences when ocular complications occur.A small but growing literature documents cases of retinal disease because of varicella reactivation after SARS-CoV-2 vaccination, ischemic optic neuropathy occurring during herpes zoster ophthalmicus, VZV-induced orbital apex syndrome, and immune-mediated ocular complications in patients with prior neuro-ophthalmic manifestations of VZV. SUMMARY: It is important for clinicians to keep abreast of the diverse neuro-ophthalmic manifestations of VZV as early diagnosis and treatment often lead to better visual outcomes.

PURPOSE: To assess the role of static and dynamic ocular biometric parameters measured in the dark and light for predicting progression of primary angle closure suspect (PACS) to primary angle closure (PAC). DESIGN: Retrospective cohort study using prospective randomized controlled trial data from untreated, control eyes. METHODS: Zhongshan Angle Closure Prevention Trial subjects underwent anterior segment optical coherence tomography (AS-OCT) imaging in the dark and light. Static biometric parameters were measured, consisting of angle, iris, lens, and anterior chamber parameters. Dynamic change parameters were calculated by subtracting light measurements from dark measurements. Cox proportional hazards regression models were developed to assess risk factors for PACD progression. RESULTS: A total of 861 eyes of 861 participants were analyzed (36 progressors). On univariable analysis, TISA500 measurements in the light and dark were associated with progression (P < .001), whereas dynamic change parameters were not (P ≥ .08). In the primary multivariable model, older age (hazard ratio [HR] = 1.09 per year), higher intraocular pressure (IOP) (HR = 1.13 per mm Hg), and smaller TISA500 in the light (HR = 1.28 per 0.01 mm2) were significantly associated with greater risk of progression (P ≤ .04). Dark TISA500 had similar significance (HR = 1.28, P = .002) when replacing light TISA500. Risk of progression was more predictive among eyes in the lowest quartile of light TISA500 measurements (HR = 4.56, P < .001) compared to dark measurements (HR = 2.89, P = .003). CONCLUSION: Static parameters measured in the light are as predictive, and possibly more so, of angle closure progression as those measured in the dark. Ocular biometrics measured under light and dark conditions may provide additional information for risk-stratifying patients for angle closure progression.

BACKGROUND: With the SARS-CoV-2 pandemic (COVID-19), data on central and peripheral nervous system involvement, including those causing cranial nerve 6 (CN6) palsy, have been limited to case reports. To extract clinically relevant features of COVID-19-related CN6 palsy, we report on a recurrent pediatric case and analysis of reported cases associated with infection or immunization. METHODS: A PubMed search revealed 18 cases of isolated CN6 palsy in addition to the index case (n = 19). Clinical characteristics, workup, and temporal associations between systemic symptoms onset or vaccination, symptoms onset, and resolution were compiled and analyzed. RESULTS: The median age of CN6 onset was 43 years (interquartile range [IQR]: 28-52). Sixteen cases (84.2%) were associated with COVID-19 illness and 3 (15.8%) were associated with COVID-19 vaccination. Four cases (23.5%) had positive neuroimaging findings. The median latency from first COVID-19 symptoms or vaccination to onset of CN6 palsy was 6 days (IQR: 2.3-16), and the median time from onset to resolution was 30 days (IQR: 14-60). Latency to onset of CN6 palsy was significantly and directly associated with time to resolution (R2 = 0.401, P = 0.010). Patients who had a positive SARS-CoV-2 antibody test had significantly longer days from symptoms to onset (6.0 vs 24.5, P = 0.030), and patients with a positive SARS-CoV-2 polymerase chain reaction test had a significantly shorter time to resolution (17.50 vs 90, P = 0.042). CONCLUSIONS: Isolated CN6 palsy from COVID-19 is rare, can occur in infants as young as 7 months, and can be recurrent. Longer latency from systemic symptoms onset portends greater recovery times, and this relationship may reflect multiple mechanisms by which COVID-19 (and/or an immune response thereto) causes cranial neuropathies with direct clinical relevance.

PURPOSE: To review the literature to determine the efficacy and safety of thermal pulsation technologies in improving signs or symptoms of meibomian gland dysfunction (MGD) and dry eye compared with no therapy or with conventional warm compress therapy or eyelid hygiene. METHODS: A literature search was conducted in the PubMed database in June 2022 and again in March 2023 to identify all studies in the English language on the use of thermal pulsation to treat MGD or dry eye. The search yielded 59 citations, and 11 articles met all of the inclusion criteria. The panel methodologist then assigned a level of evidence rating for each study; 8 studies were rated level I evidence and 3 studies were rated level II evidence. RESULTS: All included studies evaluated a single 12-minute session using the LipiFlow automated thermal pulsation system (TearScience, Inc, or Johnson & Johnson). Improvements were detected in subjective and objective metrics of MGD or dry eye in patients within 1 to 12 months of thermal pulsation treatment compared with nontreatment. Most of the studies (9/11) reported greater efficacy with thermal pulsation than with standard warm compress therapy and eyelid hygiene. Four of these studies showed relevant industry conflicts of interest. Two of the 4 level I studies without direct industry participation concluded that thermal pulsation treatment was not significantly different from conventional hygiene or warm compress therapy control treatments (in symptoms in one of the studies and in objective findings in the second study). No serious adverse events were reported in any of the 11 studies. CONCLUSIONS: According to the current literature, a single thermal pulsation session may improve subjective or objective parameters of MGD and dry eye safely. However, industry support and participation were present in 4 of the 8 level I studies. The durability beyond several months and cost efficacy remain uncertain. Because the inclusion parameters of this assessment captured only the LipiFlow system, the conclusions are limited to that product. High-quality independent studies are needed to assess the long-term benefits of this intervention. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

AIMS: To assess whether associations of cardiopulmonary conditions and markers with glaucoma differ by background genetic risk for primary open angle glaucoma (POAG). METHODS: We constructed a POAG polygenic risk score (PRS) using genome-wide association study summary statistics from a large cross-ancestry meta-analysis. History of glaucoma (including self-report and codes for POAG, 'other glaucoma' or unspecified glaucoma), history of common cardiopulmonary conditions and cardiopulmonary measures were assessed in the UK Biobank. Stratifying by PRS decile 1 (lowest risk) versus decile 10 (highest risk), separate multivariable models were estimated to assess the associations of cardiopulmonary diseases or factors with glaucoma, adjusting for age, sex, smoking and medication use. A Bonferroni correction was used to adjust p values for multiple comparisons. RESULTS: Individuals in POAG PRS decile 1 (417 cases, 44 458 controls; mean age 56.8 years) and decile 10 (2135 cases, 42 413 controls; mean age 56.7 years) were included. Within decile 1, glaucoma cases had significantly higher glycated haemoglobin (38.5 vs 35.9 mmol/mol) and higher prevalence of diabetes (17.5% vs 6.5%), dyslipidaemia (31.2% vs 18.3%) and chronic kidney disease (CKD) (6.7% vs 2.0%) than controls (adjusted p<0.0013 for each). Within decile 10, glaucoma was associated with higher prevalence of dyslipidaemia (27.7% vs 17.3%, p=6.9E-05). The magnitude of association between glaucoma and diabetes, CKD and glycated haemoglobin differed between deciles 1 and 10 (contrast test p value for difference <0.05). CONCLUSION: The relations between systemic conditions and glaucoma vary by underlying genetic predisposition to POAG, with larger associations among those who developed glaucoma despite low genetic risk.

PURPOSE: The purpose of this study was to test the hypothesis that retinopathy of prematurity (ROP) prolongs development of rod-mediated thresholds for detection of stimuli at 10 degrees but not 30 degrees eccentricity. In addition, to evaluate the thresholds at each site for an association with visual acuity (VA) and spherical equivalent (SE). METHODS: We estimated rod-mediated dark-adapted thresholds (DATs) for the detection of 2 degree diameter, 50 ms, blue (λ < 510 nm) flashes at 10 degrees and 30 degrees eccentric in former preterm subjects (n = 111), stratified by ROP severity: None (n = 32), Mild (n = 66), and Severe (n = 13). We also tested Term-born (n = 28) controls. To determine the age at half-maximal sensitivity (Agehalf) for each group and eccentricity, we fit DATs to logistic growth curves. We obtained VA and SE for Preterm subjects and evaluated the course of threshold development at 10 degrees and 30 degrees for significant association with VA and SE predicted at age 10 years. RESULTS: DAT development at 10 degrees was significantly delayed in ROP (Mild and Severe); ROP did not significantly alter DAT development at 30 degrees. At age 10 years, among Preterm subjects, both VA and SE were significantly associated with group (None,Mild, and Severe). SE was predicted by the course of DAT development at 30 degrees. VA was not associated with the course of DAT development at 10 degrees. CONCLUSIONS: At 10 degrees, ROP-whether mild or severe-is associated with significant delays in DAT development, evidence that the late-maturing central retina is vulnerable to ROP. The association of 30 degree threshold and myopia are evidence that more peripheral retina is important to refractive development.

PURPOSE: Neurofilament light chain (NfL) is a neuronal cytoskeletal protein that has been identified as a marker of neurodegeneration in diseases of the central nervous system. In this study, we investigated whether NfL in the aqueous humor (AH) can serve as a marker of neurodegeneration in glaucoma in a racially diverse North American population. DESIGN: Single-center, case-control study. PARTICIPANTS: We enrolled patients with various types and stages of glaucoma undergoing planned ophthalmic surgery as part of their routine care and compared them with patients without glaucoma undergoing phacoemulsification for age-related cataract. METHODS: We collected AH from 39 glaucoma patients and 10 patients without glaucoma. AH NfL was quantified using the Single-Molecule Array (Simoa)® NF-light assay (Quanterix). Demographic information, such as age, body mass index, sex, and self-reported race, as well as clinical information, such as pre-operative intraocular pressure (IOP), maximum IOP, and number of pre-operative glaucoma medications, was obtained by reviewing the medical record. MAIN OUTCOME MEASURES: Levels of AH NfL. RESULTS: In a model controlling for age and body mass index (BMI), NfL was significantly elevated in AH from glaucoma patients (mean: 429 pg/mL; standard deviation [SD]: 1136 pg/mL) compared to AH from patients without glaucoma (mean: 3.1 pg/mL; SD: 1.9 pg/mg): P = 0.002. Higher AH NfL was associated with higher maximum IOP (R = 0.44, P = 0.005), higher pre-operative IOP (R = 0.46, P = 0.003), and more pre-operative glaucoma medications (Rs = 0.61, P < 0.001). There was no association between AH NfL and Humphrey visual field mean deviation (R = -0.20, P = 0.220), retinal nerve fiber layer thickness as measured with optical coherence tomography (R = 0.07, P = 0.694), or glaucoma stage (Rs = 0.015, P = 0.935). CONCLUSION: Our findings suggest that AH NfL may have clinical utility as a marker of glaucomatous neurodegeneration.