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.

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.

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.

Choroid Segmentation of Retinal OCT Images Based on CNN Classifier and l 2-l q Fitter.

Optical coherence tomography (OCT) is a noninvasive cross-sectional imaging technology used to examine the retinal structure and pathology of the eye. Evaluating the thickness of the choroid using OCT images is of great interests for clinicians and researchers to monitor the choroidal thickness in many ocular diseases for diagnosis and management. However, manual segmentation and thickness profiling of choroid are time-consuming which lead to low efficiency in analyzing a large quantity of OCT images for swift treatment of patients. In this paper, an automatic segmentation approach based on convolutional neural network (CNN) classifier and l 2-l q (0 < q < 1) fitter is presented to identify boundaries of the choroid and to generate thickness profile of the choroid from retinal OCT images. The method of detecting inner choroidal surface is motivated by its biological characteristics after light reflection, while the outer chorioscleral interface segmentation is transferred into a classification and fitting problem. The proposed method is tested in a data set of clinically obtained retinal OCT images with ground-truth marked by clinicians. Our numerical results demonstrate the effectiveness of the proposed approach to achieve stable and clinically accurate autosegmentation of the choroid.

Alteration of retinal metabolism and oxidative stress may implicate myopic eye growth: Evidence from discovery and targeted proteomics in an animal model.

Myopia, the most common cause of impaired vision, may induce sight- threatening diseases or ocular complications due to axial elongation. The exact mechanisms underlying myopia development have received much attention and understanding of these is necessary for clinical prevention or therapeutics. In this study, quantitative proteomics using Isotope Coded Protein Label (ICPL) was applied to identify differentially regulated proteins in the retinas of myopic chicks and, from their presence, infer the possible pathogenesis of excessive ocular elongation. Newly hatched white leghorn chicks (n = 15) wore -10D and + 10D lenses bilaterally for 3 and 7 days, respectively, to develop progressive lens-induced myopia (LIM) and hyperopia (LIH). Retinal proteins were quantified with nano-liquid chromatography electrospray ionization coupled with tandem mass spectrometry (nanoLC-ESI-MS/MS). Bioinformatics analysis of differentially regulated proteins revealed that the majority originated from the cytoplasmic region and were related to various metabolic, glycolytic, or oxidative processes. The fold changes of four proteins of interest (vimentin, apolipoprotein A1, interphotoreceptor retinoid binding protein, and glutathione S-transferase) were further confirmed by a novel high-resolution multiple reaction monitoring mass spectrometry (MRM-HR) using a label-free approach. SIGNIFICANCE: Discovery of effective protein biomarkers of myopia has been extensively studied to inhibit myopia progression. This study first applied lens-induced hyperopia and myopia in the same chick to maximize the inter-ocular differences, aiming to discover more protein biomarker candidates. The findings provided new evidence that myopia was metabolism related, accompanied by altered energy generation and oxidative stress at retinal protein levels. The results in the retina were also compared to our previous study in vitreous using ICPL quantitative technology. We have now presented the protein changes in these two adjacent tissues, which may provide extra information of protein changes during ocular growth in myopia.

Defocus Incorporated Multiple Segments (DIMS) spectacle lenses slow myopia progression: a 2-year randomised clinical trial.

AIM: To determine if 'Defocus Incorporated Multiple Segments' (DIMS) spectacle lenses slow childhood myopia progression. METHODS: A 2-year double-masked randomised controlled trial was carried out in 183 Chinese children aged 8-13 years, with myopia between -1.00 and -5.00 D and astigmatism ≤1.50 D. Children were randomly assigned to wear DIMS (n=93) or single vision (SV) spectacle lenses (n=90). DIMS lens incorporated multiple segments with myopic defocus of +3.50 D. Refractive error (cycloplegic autorefraction) and axial length were measured at 6month intervals. RESULTS: 160 children completed the study, n=79 in the DIMS group and n=81 in the SV group. Average (SE) myopic progressions over 2 years were -0.41±0.06 D in the DIMS group and -0.85±0.08 D in the SV group. Mean (SE) axial elongation was 0.21±0.02 mm and 0.55±0.02 mm in the DIMS and SV groups, respectively. Myopia progressed 52% more slowly for children in the DIMS group compared with those in the SV group (mean difference -0.44±0.09 D, 95% CI -0.73 to -0.37, p<0.0001). Likewise, children in the DIMS group had less axial elongation by 62% than those in the SV group (mean difference 0.34±0.04 mm, 95% CI 0.22 to 0.37, p<0.0001). 21.5% children who wore DIMS lenses had no myopia progression over 2 years, but only 7.4% for those who wore SV lenses. CONCLUSIONS: Daily wear of the DIMS lens significantly retarded myopia progression and axial elongation in myopic children. Our results demonstrated simultaneous clear vision with constant myopic defocus can slow myopia progression. TRIAL REGISTRATION NUMBER: NCT02206217.

Statistical framework for validation without ground truth of choroidal thickness changes detection.

Monitoring subtle choroidal thickness changes in the human eye delivers insight into the pathogenesis of various ocular diseases such as myopia and helps planning their treatment. However, a thorough evaluation of detection-performance is challenging as a ground truth for comparison is not available. Alternatively, an artificial ground truth can be generated by averaging the manual expert segmentations. This makes the ground truth very sensitive to ambiguities due to different interpretations by the experts. In order to circumvent this limitation, we present a novel validation approach that operates independently from a ground truth and is uniquely based on the common agreement between algorithm and experts. Utilizing an appropriate index, we compare the joint agreement of several raters with the algorithm and validate it against manual expert segmentation. To illustrate this, we conduct an observational study and evaluate the results obtained using our previously published registration-based method. In addition, we present an adapted state-of-the-art evaluation method, where a paired t-test is carried out after leaving out the results of one expert at the time. Automated and manual detection were performed on a dataset of 90 OCT 3D-volume stack pairs of healthy subjects between 8 and 18 years of age from Asian urban regions with a high prevalence of myopia.

Data on differentially expressed proteins in retinal emmetropization process in guinea pig using integrated SWATH-based and targeted-based proteomics.

Myopia is generally regarded as a failure of normal emmetropization process, however, its underlying molecular mechanisms are unclear. Retinal protein profile changes using integrated SWATH and MRM-HR MS were studied in guinea pigs at 3- and 21-days of age, where the axial elongation was significantly detected. Differential proteins expressions were identified, and related to pathways which are important in postnatal development in retina, proliferation, breakdown of glycogen-energy and visual phototransduction. These results are significant as key retinal protein players and pathways that underlying emmetropization can be discovered. All raw data generated from IDA and SWATH acquisitions were accepted and published in the Peptide Atlas public repository (http://www.peptideatlas.org/) for general release (Data ID PASS00746). A more comprehensive analysis of this data can be obtained in the article "Integrated SWATH-based and targeted-based proteomics provide insights into the retinal emmetropization process in guinea pig" in Journal of Proteomics (Shan et al., 2018) [1].

Proteomic analysis of chick retina during early recovery from lens­induced myopia.

Myopia development has been extensively studied from different perspectives. Myopia recovery is also considered important for understanding the development of myopia. However, despite several previous studies, retinal proteomics during recovery from myopia is still relatively unknown. Therefore, the aim of the present study was to investigate the changes in protein profiles of chicken retinas during early recovery from lens­induced myopia to evaluate the signals involved in the adjustment of this refractive disorder. Three­day old chickens wore glasses for 7 days (­10D lens over the right eye and a plano lens as control over the left eye), followed by 24 h without lenses. Protein expression in the retina was measured by two­dimensional fluorescence difference gel electrophoresis (2D­DIGE). Pro­Q Diamond phosphoprotein staining 2D gel electrophoresis was used to analyze phosphoprotein profiles. Protein spots with significant differences (P<0.05) were analyzed by mass spectrometry. The minus lens­treated eye became myopic, however following 24 h recovery, less myopia was observed. 2D­DIGE proteomic analysis demonstrated that three identified protein spots were upregulated at least 1.2­fold in myopic recovery retinas compared with those of the controls, Ras related protein Rab­11B, S­antigen retina and pineal gland and 26S proteasome non­ATPase regulatory subunit 14. Pro­Q Diamond images further revealed three protein spots with significant changes (at least 1.8­fold): ß­tubulin was downregulated, while peroxiredoxin 4 and ubiquitin carboxyl­terminal hydrolase­L1 were upregulated in the recovery retinas compared with the control eye retinas. The present study detected previously unreported protein changes in recovering eyes, therefore revealing their potential involvement in retinal remodeling during eye ball reforge.

Integrated SWATH-based and targeted-based proteomics provide insights into the retinal emmetropization process in guinea pig.

Myopia is generally regarded as a failure of normal emmetropization process, however, its underlying molecular mechanisms are unclear. To investigate the retinal protein profile changes during emmetropization, we studied differential protein expressions of ocular growth in young guinea pigs at 3 and 21 days old respectively, when significant axial elongation was detected (P < 0.001, n = 10). Independent pooled retinal samples of both eyes were subjected to SWATH mass spectrometry (MS) followed by bioinformatics analysis using cloud-based platforms. A comprehensive retina SWATH ion-library consisting of 3138 (22,871) unique proteins (peptides) at 1% FDR was constructed. 40 proteins were found to be significantly up-regulated and 8 proteins down-regulated during emmetropization (≥log2 of 0.43 with ≥2 peptides matched per protein; P < 0.05). Using pathway analysis, the most significant pathway identifiable was 'phototransduction' (P = 1.412e-4). Expression patterns of 7 proteins identified in this pathway were further validated and confirmed (P < 0.05) with high-resolution Multiple Reaction Monitoring (MRM-HR) MS. Combining discovery and targeted proteomics approaches, this study for the first time comprehensively profiled protein changes in the guinea pig retina during normal emmetropization-associated eye growth. The findings of this study are also relevant to the myopia development, which is the result of failed emmetropization. SIGNIFICANCE: Myopia is considered as a failure of emmetropization. However, the underlying biochemical mechanism of emmetropization, a visually guided process in which eye grows towards the optimal optical state of clear vision during early development, is not well understood. Retina is known as the key tissue to regulate this active eye growth. we studied eye growth of young guinea pigs and harvested their retinal tissues. A comprehensive SWATH ion library with identification of a total 3138 unique proteins were established, in which 48 proteins exhibited significant differential expressions between 3 and 21 days old. After MRM-HR confirmation, 'phototransduction' were found as the most active pathway during emmetropic eye growth. This study is the first in discovering key retinal protein players and pathways which are presumably orchestrated by biological mechanism(s) underlying emmetropization.

Early quantitative profiling of differential retinal protein expression in lens-induced myopia in guinea pig using fluorescence difference two-dimensional gel electrophoresis.

The current study aimed to investigate the differential protein expression in guinea pig retinas in response to lens-induced myopia (LIM) before fully compensated eye growth. Four days old guinea pigs (n=5) were subjected to ­4D LIM for 8 days. Refractive errors were measured before and at the end of the lens wear period. Ocular dimensions were also recorded using high­frequency A­scan ultrasonography. After the LIM treatment, retinas of both eyes were harvested and soluble proteins were extracted. Paired retinal protein expressions in each animal were profiled and compared using a sensitive fluorescence difference two­dimensional gel electrophoresis. The quantitative retinal proteomes of myopic and control eye were analysed using computerised DeCyder software. Those proteins that were consistently changed with at least 1.2­fold difference (P<0.05) in the same direction in all five animals were extracted, trypsin digested and identified by tandem mass spectrometry. Significant myopia was induced in guinea pigs after 8 days of lens wear. The vitreous chamber depth in lens­treated eyes was found to be significantly elongated. Typically, more than 1,000 protein spots could be detected from each retina. Thirty­two of them showed differential expression between myopic and untreated retina. Among these proteins, 21 spots were upregulated and 11 were downregulated. Eight protein spots could be successfully identified which included ß­actin, enolase 1, cytosolic malate dehydrogenase, Ras­related protein Rab­11B, protein­L­isoaspartate (D­aspartate) O­methyltransferase, PKM2 protein, X­linked eukaryotic translation initiation factor 1A and ACP1 protein. The present study serves as the first report to uncover the retinal 2D proteome expressions in mammalian guinea pig myopia model using a top­down fluorescent dyes labelling gel approach. The results showed a downregulation in glycolytic enzymes that may suggest a significant alteration of glycolysis during myopia development. Other protein candidates also suggested multiple pathways which could provide new insights for further study of the myopic eye growth.

Isotope-coded protein label based quantitative proteomic analysis reveals significant up-regulation of apolipoprotein A1 and ovotransferrin in the myopic chick vitreous.

This study used isotope-coded protein label (ICPL) quantitative proteomics and bioinformatics analysis to examine changes in vitreous protein content and associated pathways during lens-induced eye growth. First, the vitreous protein profile of normal 7-day old chicks was characterized by nano-liquid chromatography electrospray ionization tandem mass spectrometry. A total of 341 unique proteins were identified. Next, myopia and hyperopia were induced in the same chick by attaching -10D lenses to the right eye and +10D lenses to the left eye, for 3 and 7 days. Protein expression in lens-induced ametropic eyes was analyzed using the ICPL approach coupled to LCMS. Four proteins (cystatin, apolipoprotein A1, ovotransferrin, and purpurin) were significantly up-regulated in the vitreous after 3 days of wearing -10D lenses relative to +10D lens contralateral eyes. The differences in protein expression were less pronounced after 7 days when the eyes approached full compensation. In a different group of chicks, western blot confirmed the up-regulation of apolipoprotein A1 and ovotransferrin in the myopic vitreous relative to both contralateral lens-free eyes and hyperopic eyes in separate animals wearing +10D lenses. Bioinformatics analysis suggested oxidative stress and lipid metabolism as pathways involved in compensated ocular elongation.

Optical Defocus Rapidly Changes Choroidal Thickness in Schoolchildren.

The current study aimed to examine the short-term choroidal response to optical defocus in schoolchildren. Myopic schoolchildren aged 8-16 were randomly allocated to control group (CG), myopic defocus group (MDG) and hyperopic defocus group (HDG) (n = 17 per group). Children in MDG and HDG received additional +3D and -3D lenses, respectively, to their full corrections on the right eyes. Full correction was given to their left eyes, and on both eyes in the CG. Axial length (AXL) and subfoveal choroidal thickness (SFChT) were then measured by spectral domain optical coherence tomography. Children wore their group-specific correction for 2 hours after which any existing optical defocus was removed, and subjects wore full corrections for another 2 hours. Both the AXL and SFChT were recorded hourly for 4 hours. The mean refraction of all subjects was -3.41 ± 0.37D (± SEM). SFChT thinned when exposed to hyperopic defocus for 2 hours but less thinning was observed in response to myopic defocus compared to the control group (p < 0.05, two-way ANOVA). Removal of optical defocus significantly decreased SFChT in the MDG and significantly increased SFChT in the HDG after 1 and 2 hours (mean percentage change at 2-hour; control vs. hyperopic defocus vs. myopic defocus; -0.33 ± 0.59% vs. 3.04 ± 0.60% vs. -1.34 ± 0.74%, p < 0.01). Our results showed short-term exposure to myopic defocus induced relative choroidal thickening while hyperopic defocus led to choroidal thinning in children. This rapid and reversible choroidal response may be an important clinical parameter in gauging retinal response to optical defocus in human myopia.

Cyclic Adenosine Monophosphate Activates Retinal Apolipoprotein A1 Expression and Inhibits Myopic Eye Growth.

PURPOSE: Apolipoprotein A1 (ApoA1) has been shown to inhibit myopia development in chicks, but the underlying biological mechanism remains unknown. Because ApoA1 interacts with cyclic adenosine monophosphate (cAMP) in many cellular systems, we examined whether this interaction is important in myopia development. METHODS: The nonmetabolizable cAMP analogue 8-Bromo-cAMP (8-Br-cAMP) was administered intravitreally to the right eyes of 8-day old chicks for 4 consecutive days. Control eyes received vehicle. Chicks in group 1 received 8-Br-cAMP (0.1 mM or 1 mM) and were fitted with -10 diopter (D) lenses on both eyes, whereas chicks in group 2 (0.1 mM 8-Br-cAMP) wore plano lenses over both eyes. The levels of retinal cAMP and ApoA1 were examined in another two groups of chicks wearing -10 D (group 3) and +10 D lenses (group 4) over their right eyes for 3 days, respectively (plano over left eyes). RESULTS: The 8-Br-cAMP significantly inhibited development of lens-induced myopia (group 1: 0.1 mM versus vehicle: +1.71 ± 1.22 D versus -8.00 ± 2.19 D; 1 mM versus vehicle: +1.38 ± 1.34 D versus -9.96 ± 1.14 D, mean ± SEM, P < 0.01 for both); 1 mM, but not 0.1 mM 8-Br-cAMP increased expression of retinal ApoA1 levels in right eyes (P < 0.01). The 8-Br-cAMP had minimal effect on normal eye growth. Both retinal cAMP and ApoA1 levels were significantly increased only in hyperopic eyes (group 4). CONCLUSIONS: The 8-Br-cAMP robustly inhibited development of lens-induced myopia. The increase in retinal ApoA1 observed in cAMP-treated and hyperopic eyes suggested a possible interplay between ApoA1 and cAMP in regulating eye growth.