Defocus incorporated multiple segments (DIMS) spectacle lenses increase the choroidal thickness: a two-year randomized clinical trial.

BACKGROUND: Myopia control interventions, such as defocus incorporated multiple segments (DIMS) spectacle lenses, have been adopted in school-aged children to reduce the prevalence of myopia and its complications. This study aimed to investigate the effect of DIMS spectacle lenses on subfoveal choroidal thickness (SfChT) over a period of two years, as the choroidal response to myopic control is a crucial factor in exploring its potential effect on predicting myopia progression. METHODS: This study involved a secondary analysis of our previous randomized clinical trial. Myopic school-aged children aged 8-13 years were recruited in a two-year study investigating the effect of DIMS spectacle lenses on myopia progression. The treated group received DIMS spectacle lenses (n = 78), while the control group was treated with a pair of single vision (SV) spectacle lenses (n = 80). SfChT was monitored at 1 week, 1, 3, 6, 12, 18 and 24 months post lens wear using spectral-domain optical coherence tomography and a custom made auto-segmentation algorithm utilizing convolutional neural networks. RESULTS: SfChT increased significantly after one week of DIMS spectacle lens wear compared to those wearing SV spectacle lenses (adjusted mean change relative to baseline ± SEM at one week; DIMS vs. SV, 6.75 ± 1.52 µm vs. - 3.17 ± 1.48 µm; P < 0.0001, general linear model). The thickness of choroid increased to 13.64 ± 2.62 µm after 12 months of DIMS lens wear while the choroid thinned in SV group (- 9.46 ± 2.55 µm). Choroidal changes demonstrated a significant negative association with axial elongation over two years in both the DIMS and SV groups. Choroidal change at three months significantly predicted the changes in AL at 12 months after controlling the effect of age and gender. CONCLUSIONS: Our study demonstrated a significant choroidal thickening in response to myopic defocus incorporated in a spectacle lens after one week of lens wear, sustained over the two-year study period. The results suggested that choroidal changes at three months may help predict changes in axial length after one year. Trial registration ClinicalTrials.gov. Myopia control with the multi-segment lens. NCT02206217. Registered 29 July 2014, https://clinicaltrials.gov/ct2/show/study/NCT02206217.

Differential Responses of Retinal Neurons and Glia Revealed via Proteomic Analysis on Primary and Secondary Retinal Ganglion Cell Degeneration.

To explore the temporal profile of retinal proteomes specific to primary and secondary retinal ganglion cell (RGC) loss. Unilateral partial optic nerve transection (pONT) was performed on the temporal side of the rat optic nerve. Temporal and nasal retinal samples were collected at 1, 4 and 8 weeks after pONT (n = 4 each) for non-biased profiling with a high-resolution hybrid quadrupole time-of-flight mass spectrometry running on label-free SWATHTM acquisition (SCIEX). An information-dependent acquisition ion library was generated using ProteinPilot 5.0 and OneOmics cloud bioinformatics. Combined proteome analysis detected 2531 proteins with a false discovery rate of <1%. Compared to the nasal retina, 10, 25 and 61 significantly regulated proteins were found in the temporal retina at 1, 4, and 8 weeks, respectively (p < 0.05, FC ≥ 1.4 or ≤0.7). Eight proteins (ALDH1A1, TRY10, GFAP, HBB-B1, ALB, CDC42, SNCG, NEFL) were differentially expressed for at least two time points. The expressions of ALDH1A1 and SNCG at nerve fibers were decreased along with axonal loss. Increased ALDH1A1 localization in the inner nuclear layer suggested stress response. Increased GFAP expression demonstrated regional reactivity of astrocytes and Muller cells. Meta-analysis of gene ontology showed a pronounced difference in endopeptidase and peptidase inhibitor activity. Temporal proteomic profiling demonstrates established and novel protein targets associated with RGC damage.

Thinning of the Lamina Cribrosa and Deep Layer Microvascular Dropout in Patients With Open Angle Glaucoma and High Myopia.

PRCIS: Lamina cribrosa (LC) thinning (thickness of ≤128.00 µm) helps to distinguish open angle glaucoma from high myopia, which was associated with the presence of microvasculature dropout and elevated intraocular pressure. PURPOSE: The purpose of this study was to analyze the factors associated with LC thickness in highly myopic eyes with and without open angle glaucoma. METHODS: In total, 240 highly myopic eyes with γ-zones (194 eyes without and 46 eyes with open angle glaucoma) were examined, and the LC center, externally oblique border, an abrupt change of scleral curvature (scleral step), deep layer microvasculature dropout and global retinal nerve fiber layer thickness were investigated on optical coherence tomography and optical coherence tomography angiography. RESULTS: LC were thinner in highly myopic open angle glaucoma compared with high myopia alone (107.76±9.86 vs. 137.07±18.51 µm, P <0.001), which was associated with deep layer microvasculature dropout and elevated intraocular pressure. The areas under the receiver operating characteristic curve for detecting open angle glaucoma from the LC thickness was 0.964, which was statistically higher ( P <0.05) than from the global retinal nerve fiber layer thickness (0.921) and vertical cup-to-disc ratio (0.902). A LC thickness cutoff value of 128 µm provided 100% sensitivity for detecting open angle glaucoma with 84% specificity. CONCLUSIONS: Highly myopic eyes with open angle glaucoma appear to have a thinner LC, which was associated with elevated intraocular pressure and deep layer microvasculature dropout. LC thinning (≤128.00 µm) helps distinguish open angle glaucoma from high myopia with an abnormal retinal nerve fiber layer thickness distribution and unclear shallow disc cupping.

Long-term myopia control effect and safety in children wearing DIMS spectacle lenses for 6 years.

This study evaluated the long-term myopia control effect and safety in children wearing Defocus Incorporated Multiple Segments (DIMS) spectacle lenses. Participants who completed the 2-year RCT were followed for a total of 6 years; their cycloplegic refractions and axial length were measured. Group 1 (n = 36) wore DIMS spectacles for 6 years; Group 2 (n = 14) wore DIMS lens for the first 3.5 years and SV spectacles afterwards; Group 3 (n = 22) wore SV spectacles in the first 2 years and switched to DIMS; Group 4 (n = 18) wore SV spectacles in the first 2 years, switched to DIMS for 1.5 years and then SV spectacles again. Group 1 showed no significant differences in myopia progression (- 0.52 ± 0.66 vs. - 0.40 ± 0.72D) and axial elongation (0.32 ± 0.26 vs. 0.28 ± 0.28 mm, both p > 0.05) between the first and the later 3 years. In the last 2.5 years, DIMS lens groups (Groups 1 and 3) had less myopia progression and axial elongation than the single vision groups (Groups 2 and 4). There was no evidence of rebound after stopping the treatment. Post-wear visual functions in all groups were within norms. The results supported that DIMS lenses provided sustained myopia control without adverse effects over the 6-year study period.Trial registration: clinicaltrials.gov; NCT02206217.

Additive effects of narrowband light and optical defocus on chick eye growth and refraction.

BACKGROUND: In the past decade and during the COVID pandemic, the prevalence of myopia has reached epidemic proportions. To address this issue and reduce the prevalence of myopia and its complications, it is necessary to develop more effective interventions for controlling myopia. In this study, we investigated the combined effects of narrowband lights and competing defocus on eye growth and refraction in chicks, an important step in understanding the potential for these interventions to control myopia. This is the first time these effects have been characterized. METHODS: Three groups of five-day-old chicks (n = 8 per group) were raised in three different lighting conditions: white, red, and blue for 13 days in a 12/12-h light/dark diurnal cycle. One eye was randomly selected for applications of a dual-power optical lens (- 10 D/ + 10 D, 50∶50), while another eye was left untreated as control. Vitreous chamber depth (VCD), axial length (AL), choroidal thickness (CT) and refractive errors were measured at pre-exposure (D0) and following 3 (D3), 7 (D7), 10 (D10), and 13 days (D13) of light exposure. RESULTS: Under white light, the dual-power lens induced a hyperopic shift [at D13, mean spherical equivalent refraction (SER), treated vs. control: 4.81 ± 0.43 D vs. 1.77 ± 0.21 D, P < 0.001] and significantly reduced the progression of axial elongation (at D13, change in AL, treated vs. control: 1.25 ± 0.04 mm vs. 1.45 ± 0.05 mm, P < 0.01). Compared to white light alone, blue light alone induced a hyperopic shift (at D13, mean SER, blue vs. white: 2.75 ± 0.21 D vs. 1.77 ± 0.21 D, P < 0.01) and significantly reduced axial elongation (at D13, change in AL, blue vs. white: 1.17 ± 0.06 mm vs. 1.45 ± 0.05 mm, P < 0.01) in control eyes. When comparing all conditions, eyes exposed to blue light plus dual-power lens had the least axial elongation (at D13, change in AL, 0.99 ± 0.05 mm) and were the most hyperopic (at D13, mean SER, 6.36 ± 0.39 D). CONCLUSIONS: Both narrowband blue light and dual-power lens interventions were effective in inducing a hyperopic shift in chicks, and provided protection against myopia development. The combination of these interventions had additive effects, making them potentially even more effective. These findings support the use of optical defocus interventions in combination with wavelength filters in clinical studies testing their effectiveness in treating myopia in children.

Regulation of Aqueous Humor Secretion by Melatonin in Porcine Ciliary Epithelium.

Secretion of melatonin, a natural hormone whose receptors are present in the ciliary epithelium, displays diurnal variation in the aqueous humor (AH), potentially contributing to the regulation of intraocular pressure. This study aimed to determine the effects of melatonin on AH secretion in porcine ciliary epithelium. The addition of 100 µM melatonin to both sides of the epithelium significantly increased the short-circuit current (Isc) by ~40%. Stromal administration alone had no effect on the Isc, but aqueous application triggered a 40% increase in Isc, similar to that of bilateral application without additive effect. Pre-treatment with niflumic acid abolished melatonin-induced Isc stimulation. More importantly, melatonin stimulated the fluid secretion across the intact ciliary epithelium by ~80% and elicited a sustained increase (~50-60%) in gap junctional permeability between pigmented ciliary epithelial (PE) cells and non-pigmented ciliary epithelial (NPE) cells. The expression of MT3 receptor was found to be >10-fold higher than that of MT1 and MT2 in porcine ciliary epithelium. Aqueous pre-treatment with MT1/MT2 antagonist luzindole failed to inhibit the melatonin-induced Isc response, while MT3 antagonist prazosin pre-treatment abolished the Isc stimulation. We conclude that melatonin facilitates Cl- and fluid movement from PE to NPE cells, thereby stimulating AH secretion via NPE-cell MT3 receptors.

Changes in relative peripheral refraction in children who switched from single-vision lenses to Defocus Incorporated Multiple Segments lenses.

PURPOSE: To investigate changes in relative peripheral refraction (RPR) associated with myopia progression in children who wore single-vision (SV) lenses for 2 years and switched to Defocus Incorporated Multiple Segments (DIMS) lenses in the third year versus children who wore DIMS lenses for 3 years. METHODS: In the first 2 years, children were allocated randomly to wear either DIMS or SV lenses. In the third year, children in the DIMS group continued to wear these lenses, while those in the SV group were switched to DIMS lenses (Control-to-DIMS group). Central and peripheral refraction and axial length were monitored every 6 months. RESULTS: Over 3 years, the DIMS group (n = 65) showed good myopia control and maintained a relatively constant and symmetrical RPR profile without significant changes. In the first 2 years, children who wore SV lenses (n = 55) showed asymmetrical RPR changes, with significant increases in hyperopic RPR at 20° nasal (N) (mean difference: 0.88 ± 1.06 D, p < 0.0001) and 30N (mean difference: 1.07 ± 1.09 D, p < 0.0001). The Control-to-DIMS group showed significant myopia retardation after wearing DIMS lenses in the third year. When compared with the RPR changes in the first 2 years, significant reductions in hyperopic RPR were observed at 20N (mean difference: -1.14 ± 1.93 D, p < 0.0001) and 30N (mean difference: -1.07 ± 1.17 D, p < 0.0001) in the third year. However, no significant difference between the RPR changes found in the nasal retina and temporal retina (p > 0.05) was noted in the third year. CONCLUSION: Symmetrical changes in RPR were found in children switching from SV to DIMS lenses, and a symmetrical pattern of RPR was noted in children who wore DIMS for 3 years. Myopia control using myopic defocus in the mid-periphery influenced the RPR changes and retarded myopia progression by altering the eye's growth pattern.

Mechanistic Effects of Baicalein on Aqueous Humor Drainage and Intraocular Pressure.

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma that results from impeded fluid drainage. The increase in outflow resistance is caused by trabecular meshwork (TM) cell dysfunction and excessive extracellular matrix (ECM) deposition. Baicalein (Ba) is a natural flavonoid and has been shown to regulate cell contraction, fluid secretion, and ECM remodeling in various cell types, suggesting the potential significance of regulating outflow resistance and IOP. We demonstrated that Ba significantly lowered the IOP by about 5 mmHg in living mice. Consistent with that, Ba increased the outflow facility by up to 90% in enucleated mouse eyes. The effects of Ba on cell volume regulation and contractility were examined in primary human TM (hTM) cells. We found that Ba (1-100 µM) had no effect on cell volume under iso-osmotic conditions but inhibited the regulatory volume decrease (RVD) by up to 70% under hypotonic challenge. In addition, Ba relaxed hTM cells via reduced myosin light chain (MLC) phosphorylation. Using iTRAQ-based quantitative proteomics, 47 proteins were significantly regulated in hTM cells after a 3-h Ba treatment. Ba significantly increased the expression of cathepsin B by 1.51-fold and downregulated the expression of D-dopachrome decarboxylase and pre-B-cell leukemia transcription factor-interacting protein 1 with a fold-change of 0.58 and 0.40, respectively. We suggest that a Ba-mediated increase in outflow facility is triggered by cell relaxation via MLC phosphorylation along with inhibiting RVD in hTM cells. The Ba-mediated changes in protein expression support the notion of altered ECM homeostasis, potentially contributing to a reduction of outflow resistance and thereby IOP.

Retinal Proteomic Analysis in a Mouse Model of Endotoxin-Induced Uveitis Using Data-Independent Acquisition-Based Mass Spectrometry.

Uveitis is a group of sight-threatening ocular inflammatory diseases, potentially leading to permanent vision loss in patients. However, it remains largely unknown how uveitis causes retinal malfunction and vision loss. Endotoxin-induced uveitis (EIU) in rodents is a good animal model to study uveitis and associated acute retinal inflammation. To understand the pathogenic mechanism of uveitis and screen potential targets for treatment, we analyzed the retinal proteomic profile of the EIU mouse model using a data-independent acquisition-based mass spectrometry (SWATH-MS). After systemic LPS administration, we observed activation of microglial cells accompanied with the elevation of pro-inflammatory mediators and visual function declines. In total, we observed 79 upregulated and 90 downregulated differentially expressed proteins (DEPs). Among the DEPs, we found that histone family members (histone H1, H2A, H2B) and blood proteins including haptoglobin (HP), hemopexin (HPX), and fibrinogen gamma chain (FGG) were dramatically increased in EIU groups relative to those in control groups. We identified phototransduction and synaptic vesicle cycle as the top two significant KEGG pathways. Moreover, canonical pathway analysis on DEPs using Ingenuity Pathway Analysis revealed top three most significant enriched pathways related to acute phase response signaling, synaptogenesis signaling, and eif2 signaling. We further confirmed upregulation of several DEPs associated with the acute phase response signaling including HP, HPX, and FGG in LPS-treated retinas by qPCR and Western blot. In summary, this study serves as the first report to detect retinal proteome changes in the EIU model. The study provides several potential candidates for exploring the mechanism and novel therapeutic targets for uveitis and other retinal inflammatory diseases.

Myopia Control Effect Is Influenced by Baseline Relative Peripheral Refraction in Children Wearing Defocus Incorporated Multiple Segments (DIMS) Spectacle Lenses.

The aim of this study is to investigate if baseline relative peripheral refraction (RPR) influences the myopia control effects in Chinese myopic children wearing Defocus Incorporated Multiple Segments (DIMS) lenses. Peripheral refraction at 10°, 20°, and 30° nasal (10 N, 20 N, 30 N) and temporal (10 T, 20 T, 30 T) retina were measured at six-month intervals for children who participated in a 2-year randomized controlled trial. The relationship between the baseline peripheral refractions and myopia progression and axial length changes were analysed. A total of 79 children and 81 children in the DIMS and single vision (SV) group were investigated, respectively. In the DIMS group, more baseline myopic RPR spherical equivalent (SE) was associated with more myopic progression (10 N: r = 0.36, p = 0.001; 20 N: r = 0.35, p = 0.001) and greater axial elongation (10 N: r = −0.34, p = 0.001; 20 N: r = −0.29, p = 0.006) after adjusting for co-factors. In the SV group, baseline RPR had association with only myopia progression (10 N: r = 0.37, p = 0.001; 20 N: r = 0.36, p = 0.001; 30 N: r = 0.35, p = 0.002) but not with axial elongation after Bonferroni correction (p > 0.008). No statistically significant relationship was found between temporal retina and myopia progression or axial elongation in both groups. Children with baseline myopic RPR had statistically significant more myopia progression (mean difference around −0.40 D) and more axial elongation (mean difference 0.15 mm) when compared with the children having baseline hyperopic RPR in the DIMS group but not in the SV group. In conclusion, the baseline RPR profile may not influence future myopia progression or axial elongation for the SV lens wearers. However, DIMS lenses slowed down myopia progression and was better in myopia control for the children with baseline hyperopic RPR than the children with myopic RPR. This may partially explain why myopia control effects vary among myopic children. Customised myopic defocus for individuals may optimise myopia control effects, and further research to determine the optimal dosage, with consideration of peripheral retinal profile, is warranted.

Development pattern of ocular biometric parameters and refractive error in young Chinese adults: a longitudinal study of first-year university students.

BACKGROUND: The increase in the prevalence of myopia has become a matter of serious public health concern, and few studies to date have examined the ocular biometric parameters of myopia in young Chinese adults. This study aimed to investigate the longitudinal ocular biometric and refractive development of first-year university students and the influence of near work. METHODS: This study included 526 first-year university students from Tianjin Medical University (mean age, 18.34 years; 313 females and 213 males). From 2016 to 2018, participants underwent ocular biometry measurements and subjective refraction annually. Near-work activities such as the use of electronic devices, online games, reading, and writing as well as demographic data were recorded by questionnaires. RESULTS: The prevalence of myopia in this population from 2016 to 2018 was 92.40%, 92.59%, and 92.97%, respectively. Importantly, the prevalence of high myopia increased significantly from 20.91% to 28.33% (P < .001). The spherical equivalent refraction was significantly more myopic by approximately - 0.38 D (from - 4.18 ± 2.44 to - 4.56 ± 2.57 D; P < .001) during the period. The axial length, central corneal thickness, and lens thickness became significantly different (all P < .05), and the axial length significantly increased by 0.12 mm during 2 years (P < .001). Using binary logistic regression analysis, the data indicated that spending more time on online games (odds ratio, 2.09; 95% confidence interval, 1.33-3.29) could speed up the progression of myopia (P < .05). CONCLUSIONS: This study showed that the prevalence of high myopia continued to increase in undergraduate students over 2 years. Baseline myopia correlated with myopic shift, the time spent on online games, and parental myopia were significantly associated with an increase in myopia in these young adult populations.

Transcriptional profiling of the chick retina identifies down-regulation of VIP and UTS2B genes during early lens-induced myopia.

Gene expression of the chick retina was examined during the early development of lens-induced myopia (LIM) using whole transcriptome sequencing. Monocular treatment of the right eyes with -10 diopter (D) lenses was performed on newly born chicks for one day (LIM-24) or two days (LIM-48), while the contralateral eyes without lenses served as controls. Myopia development was confirmed by demonstrating significant elongation of the optical axis in lens-treated eyes compared to untreated control eyes. RNA was extracted and RNA-seq was performed using the Illumina HiSeqTM 2000 platform. Data analysis was carried out on a Partek® Flow platform. Using screening criteria of ≥1.30-fold change and a false discovery rate <1%, 11 (five down-regulated and six up-regulated) and 35 differentially expressed genes (six down-regulated and twenty-nine up-regulated) were identified at 24 hours and 48 hours, respectively. Using another cohort for validation, Quantitative PCR confirmed significant changes in the expression of VIP and UTS2B mRNA (P <0.05) after only 24 hours of LIM treatment and numerical changes in the expression for PCGF5 and FOXG1, which were consistent with transcriptome sequencing but did not reach statistical significance. These data suggest that concerted changes of retinal gene expression may be instrumental in the initiation of axial elongation and myopia development.

Baicalein-A Potent Pro-Homeostatic Regulator of Microglia in Retinal Ischemic Injury.

Retinal ischemia is a common cause of many retinal diseases, leading to irreversible vision impairment and blindness. Excessive neuroinflammation, including microglial activation and T-cell responses, has been identified as a critical factor associated with neurodegeneration in retinal ischemia. Baicalein is a natural flavonoid reported to have broad anti-inflammatory and neuroprotective bioactivities. Herein, the effects of baicalein on microglia activation in vitro and in vivo were investigated. We found that baicalein exhibited robust anti-inflammatory effect on cultured human and mouse microglia, as demonstrated by decreased induction of pro-inflammatory cytokines and the phosphorylation of phosphoinositide 3-kinase (PI3K) and nuclear factor kappa B (NFκB). Proteomic analysis further unraveled baicalein's effect on modulating IL-17 signaling pathways and its upstream regulator IL-1ß. Intravitreal administration of baicalein in the mouse model of retinal ischemia/reperfusion (I/R) injury attenuated microglial activation and retinal T-cell infiltration, particularly the T helper 17 cells. Additionally, baicalein was shown to exert neuroprotective effects by significantly reducing the retinal ganglion cell (RGC) loss after I/R injury, leading to an improved retinal function and spatial vision. These results suggest that baicalein, a natural flavonoid, acts as a negative regulator of activated microglia and immune responses both in vitro and in vivo, effectively alleviating neurodegeneration in retinal I/R injury. This finding indicates that baicalein could be a potential therapeutic agent against currently incurable degenerative retinal diseases.

Alteration of EIF2 Signaling, Glycolysis, and Dopamine Secretion in Form-Deprived Myopia in Response to 1% Atropine Treatment: Evidence From Interactive iTRAQ-MS and SWATH-MS Proteomics Using a Guinea Pig Model.

Purpose: Atropine, a non-selective muscarinic antagonist, effectively slows down myopia progression in human adolescents and several animal models. However, the underlying molecular mechanism is unclear. The current study investigated retinal protein changes of form-deprived myopic (FDM) guinea pigs in response to topical administration of 1% atropine gel (10 g/L). Methods: At the first stage, the differentially expressed proteins were screened using fractionated isobaric tags for a relative and absolute quantification (iTRAQ) approach, coupled with nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) (n = 24, 48 eyes) using a sample pooling technique. At the second stage, retinal tissues from another cohort with the same treatment (n = 12, 24 eyes) with significant ocular changes were subjected to label-free sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics for orthogonal protein target confirmation. The localization of Alpha-synuclein was verified using immunohistochemistry and confocal imaging. Results: A total of 1,695 proteins (8,875 peptides) were identified with 479 regulated proteins (FC ≥ 1.5 or ≤0.67) found from FDM eyes and atropine-treated eyes receiving 4-weeks drug treatment using iTRAQ-MS proteomics. Combining the iTRAQ-MS and SWATH-MS datasets, a total of 29 confident proteins at 1% FDR were consistently quantified and matched, comprising 12 up-regulated and 17 down-regulated proteins which differed between FDM eyes and atropine treated eyes (iTRAQ: FC ≥ 1.5 or ≤0.67, SWATH: FC ≥ 1.4 or ≤0.71, p-value of ≤0.05). Bioinformatics analysis using IPA and STRING databases of these commonly regulated proteins revealed the involvement of the three commonly significant pathways: EIF2 signaling; glycolysis; and dopamine secretion. Additionally, the most significantly regulated proteins were closely connected to Alpha-synuclein (SNCA). Using immunostaining (n = 3), SNCA was further confirmed in the inner margin of the inner nuclear layer (INL) and spread throughout the inner plexiform layer (IPL) of the retina of guinea pigs. Conclusion: The molecular evidence using next-generation proteomics (NGP) revealed that retinal EIF2 signaling, glycolysis, and dopamine secretion through SNCA are implicated in atropine treatment of myopia in the FDM-induced guinea pig model.

Evaluation of an Optical Defocus Treatment for Myopia Progression Among Schoolchildren During the COVID-19 Pandemic.

Importance: Myopia progression has been found to be worsening during the COVID-19 pandemic. It is important to control the rapid myopia progression in this period. Objective: To analyze the association of COVID-19-related lockdown measures with myopia progression in schoolchildren and to compare the performance of defocus incorporated multiple segments (DIMS) lens with that of single vision lens (SVL) treatment in reducing myopia progression. Design, Setting, and Participants: This cohort study involved an exploratory, prespecified, comparison of 2 independent longitudinal studies performed at the same institute beginning in 2019. Data from Hong Kong schoolchildren (aged 7-13 years) were gathered and analyzed. Data analysis was performed from June to July 2021. Exposure: Schoolchildren in study 1 wore a DIMS lens for 18 months, and those in study 2 wore a SVL for 24 months. Main Outcomes and Measures: Cycloplegic spherical equivalent refraction and axial length were measured. Studies 1 and 2 started before the start of lockdown measures and continued throughout the lockdown. In both studies, periods of fewer and more COVID-19-related lockdown measures were identified. Because COVID-19 lockdown caused deviations from the visit schedule, myopia progression was normalized to 12-month change, which were compared between DIMS and SVL groups, also during the periods with less and more lockdown time. Results: There were 115 participants (58 girls [50.4%]; mean [SD] age, 10.3 [1.5] years) in the DIMS group; their mean (SD) baseline refraction was -4.02 (1.46) D. There were 56 participants (29 girls [51.8%]; mean [SD] age, 10.8 [1.5] years) in the SVL group; their mean (SD) baseline refraction was -2.99 (1.06) D. After controlling for the covariates, DIMS treatment was significantly associated with 34% less axial elongation (0.19 mm [95% CI, 0.16 to 0.22 mm] vs 0.30 mm [95% CI, 0.25 to 0.35 mm]; P < .001) and 46% less myopic progression after 12 months (-0.31 D [95% CI, -0.39 to -0.23 D] vs -0.57 D [95% CI, -0.69 to -0.45 D]; P = .001) compared with SVL treatment. In both the DIMS and SVL groups, more lockdown time was associated with significantly more spherical equivalent refraction (-0.54 D [95% CI, -0.64 to 0.44 D] vs -0.34 D [95% CI, -0.44 to -0.25 D]; P = .01) and axial length (0.29 mm [95% CI, 0.25 to 0.32 mm] vs 0.20 mm [95% CI, 0.16 to 0.24 mm]; P = .001) compared with less lockdown time. No significant interaction between treatment type and lockdown time was observed. Conclusions and Relevance: In this exploratory analysis, myopia progressed more rapidly in schoolchildren during the period when there were more COVID-19-related lockdown measures. However, optical treatment with DIMS was significantly associated with slower myopia progression compared with SVL treatment during the lockdown period.

Myopia control effect of defocus incorporated multiple segments (DIMS) spectacle lens in Chinese children: results of a 3-year follow-up study.

AIMS: To determine myopia progression in children who continued to wear the defocus incorporated multiple segments (DIMS) lenses or switched from single vision (SV) to DIMS lenses for a 1-year period following a 2-year myopia control trial. METHODS: 128 children participated in this study. The children who had worn DIMS lenses continued to wear DIMS lenses (DIMS group), and children who had worn SV lenses switched to wear DIMS lenses (Control-to-DIMS group). Cycloplegic spherical equivalent refraction (SER) and axial length (AL) were measured at 6-month interval. Historical controls were age matched to the DIMS group at 24 months and used for comparing the third-year changes. RESULTS: Over 3 years, SER and AL changes in the DIMS group (n=65) were -0.52±0.69D and 0.31±0.26 mm; these changes were not statistically significant over time (repeated measures analysis of variance, p>0.05).SER (-0.04±0. 38D) and AL (0.08±0.12 mm) changes in the Control-to-DIMS group (n=55) in the third year were less compared with the first (mean difference=0.45 ± 0.30D, 0.21±0.11 mm, p<0.001) and second (0.34±0.30D, 0.12±0.10 mm, p<0.001) years.Changes in SER and AL in both groups over that period were significantly less than in the historical control group (DIMS vs historical control: mean difference=-0.18±0.42D, p=0.012; 0.08±0.15 mm, p=0.001; Control-to-DIMS versus historical control: adjusted mean differences=-0.30±0.42D, p<0.001; 0.12±0.16 mm, p<0.001). CONCLUSIONS: Myopia control effect was sustained in the third year in children who had used the DIMS spectacles in the previous 2 years and was also shown in the children switching from SV to DIMS lenses.

Targeting Lysosomes to Reverse Hydroquinone-Induced Autophagy Defects and Oxidative Damage in Human Retinal Pigment Epithelial Cells.

In age-related macular degeneration (AMD), hydroquinone (HQ)-induced oxidative damage in retinal pigment epithelium (RPE) is believed to be an early event contributing to dysregulation of inflammatory cytokines and vascular endothelial growth factor (VEGF) homeostasis. However, the roles of antioxidant mechanisms, such as autophagy and the ubiquitin-proteasome system, in modulating HQ-induced oxidative damage in RPE is not well-understood. This study utilized an in-vitro AMD model involving the incubation of human RPE cells (ARPE-19) with HQ. In comparison to hydrogen peroxide (H2O2), HQ induced fewer reactive oxygen species (ROS) but more oxidative damage as characterized by protein carbonyl levels, mitochondrial dysfunction, and the loss of cell viability. HQ blocked the autophagy flux and increased proteasome activity, whereas H2O2 did the opposite. Moreover, the lysosomal membrane-stabilizing protein LAMP2 and cathepsin D levels declined with HQ exposure, suggesting loss of lysosomal membrane integrity and function. Accordingly, HQ induced lysosomal alkalization, thereby compromising the acidic pH needed for optimal lysosomal degradation. Pretreatment with MG132, a proteasome inhibitor and lysosomal stabilizer, upregulated LAMP2 and autophagy and prevented HQ-induced oxidative damage in wildtype RPE cells but not cells transfected with shRNA against ATG5. This study demonstrated that lysosomal dysfunction underlies autophagy defects and oxidative damage induced by HQ in human RPE cells and supports lysosomal stabilization with the proteasome inhibitor MG132 as a potential remedy for oxidative damage in RPE and AMD.

Baicalein, Baicalin, and Wogonin: Protective Effects against Ischemia-Induced Neurodegeneration in the Brain and Retina.

Ischemia is a common pathological condition present in many neurodegenerative diseases, including ischemic stroke, retinal vascular occlusion, diabetic retinopathy, and glaucoma, threatening the sight and lives of millions of people globally. Ischemia can trigger excessive oxidative stress, inflammation, and vascular dysfunction, leading to the disruption of tissue homeostasis and, ultimately, cell death. Current therapies are very limited and have a narrow time window for effective treatment. Thus, there is an urgent need to develop more effective therapeutic options for ischemia-induced neural injuries. With emerging reports on the pharmacological properties of natural flavonoids, these compounds present potent antioxidative, anti-inflammatory, and antiapoptotic agents for the treatment of ischemic insults. Three major active flavonoids, baicalein, baicalin, and wogonin, have been extracted from Scutellaria baicalensis Georgi (S. baicalensis); all of which are reported to have low cytotoxicity. They have been demonstrated to exert promising pharmacological capabilities in preventing cell and tissue damage. This review focuses on the therapeutic potentials of these flavonoids against ischemia-induced neurotoxicity and damage in the brain and retina. The bioactivity and bioavailability of baicalein, baicalin, and wogonin are also discussed. It is with hope that the therapeutic potential of these flavonoids can be utilized and developed as natural treatments for ischemia-induced injuries of the central nervous system (CNS).

Thrombospondin-1 mediates Rho-kinase inhibitor-induced increase in outflow-facility.

Rho-kinase (ROCK) inhibitors, a novel class of anti-glaucoma agents, act by increasing the aqueous humor outflow through the conventional trabecular meshwork pathway. However, the downstream signaling consequences of the ROCK inhibitor are not completely understood. Our data show that Y39983, a selective ROCK inhibitor, could induce filamentous actin remodeling, reduced cell motility (as measured by cell migration), and transepithelial resistance in primary human TM (hTM) cells. After 2 days Y39983 treatment of hTM cells, a proteomic study identified 20 proteins whose expression was significantly altered. Pathway analysis of those proteins revealed the involvement of the p53 pathway, integrin signaling pathway, and cytoskeletal pathway regulation by Rho GTPase. Thrombospondin-1 (TSP1), a matricellular protein that is increased in glaucoma patients, was downregulated fivefold following Y39983 treatment. More importantly, both TSP1 antagonist leucine-serine-lysine-leucine (LSKL) and small interfering RNA (siRNA) reduced TSP1 gene and protein expressions as well as hTM cell migration. In the presence of Y39983, no further inhibition of cell migration resulted after LSKL and TSP1 siRNA knockdown. Likewise, LSKL triggered a dose-dependent increase in outflow facility in ex vivo mouse eyes, to a similar extent as Y39983 (83.8% increase by Y39983 vs. 71.2% increase by LSKL at 50 µM). There were no additive effects with simultaneous treatment with LSKL and Y39983, supporting the notion that the effects of ROCK inhibition were mediated by TSP1.

SWATH Based Quantitative Proteomics Reveals Significant Lipid Metabolism in Early Myopic Guinea Pig Retina.

Most of the previous myopic animal studies employed a single-candidate approach and lower resolution proteomics approaches that were difficult to detect minor changes, and generated limited systems-wide biological information. Hence, a complete picture of molecular events in the retina involving myopic development is lacking. Here, to investigate comprehensive retinal protein alternations and underlying molecular events in the early myopic stage, we performed a data-independent Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH) based proteomic analysis coupled with different bioinformatics tools in pigmented guinea pigs after 4-day lens-induced myopia (LIM). Myopic eyes compared to untreated contralateral control eyes caused significant changes in refractive error and choroid thickness (p < 0.05, n = 5). Relative elongation of axial length and the vitreous chamber depth were also observed. Using pooled samples from all individuals (n = 10) to build a species-specific retinal ion library for SWATH analysis, 3202 non-redundant proteins (with 24,616 peptides) were identified at 1% global FDR. For quantitative analysis, the 10 individual retinal samples (5 pairs) were analyzed using a high resolution Triple-TOF 6600 mass spectrometry (MS) with technical replicates. In total, 37 up-regulated and 21 down-regulated proteins were found significantly changed after LIM treatment (log2 ratio (T/C) > 0.26 or < -0.26; p ≤ 0.05). Data are accepted via ProteomeXchange with identifier PXD025003. Through Ingenuity Pathways Analysis (IPA), "lipid metabolism" was found as the top function associated with the differentially expressed proteins. Based on the protein abundance and peptide sequences, expression patterns of two regulated proteins (SLC6A6 and PTGES2) identified in this pathway were further successfully validated with high confidence (p < 0.05) using a novel Multiple Reaction Monitoring (MRM) assay on a QTRAP 6500+ MS. In summary, through an integrated discovery and targeted proteomic approach, this study serves as the first report to detect and confirm novel retinal protein changes and significant biological functions in the early LIM mammalian guinea pigs. The study provides new workflow and insights for further research to myopia control.