Intraocular cetuximab: Safety and effect on axial elongation in young Guinea pigs with lens-induced myopization.

This study aimed to examine the intraocular tolerability of the epidermal growth factor receptor antibody cetuximab, when applied intravitreally, and its effect on axial elongation. Guinea pigs aged 2-3 weeks were subjected to bilateral plano glasses and bilateral lens-induced myopization (LIM) as a single procedure for group I (n = 8) and group II (n = 8), respectively. In the animals of group III (n = 8), group IV (n = 8), and group V (n = 8), the right eyes of the animals, in addition to LIM, received four weekly intravitreal injections of cetuximab (Erbitux®) in doses of 6.25 µg, 12.5 µg, and 25 µg, respectively. As controls, the left eyes, in addition to LIM, received corresponding intraocular injections of phosphate-buffered saline. The animals underwent regular ophthalmoscopic examinations and biometry for axial length measurements. With increasing doses of cetuximab, the inter-eye difference in axial elongation (at study end, left eyes minus right eyes) were significantly the smallest in group I (0.00 ± 0.02 mm) and group II (-0.01 ± 0.02 mm), they were larger in group III (0.04 ± 0.04 mm) and group IV (0.10 ± 0.03 mm), and they were the largest in group V (0.11 ± 0.01 mm). The inter-eye difference in axial elongation enlarged (P < 0.001) with the number of injections applied. Retinal thickness at the posterior pole (right eyes) was significantly thicker in group V than in group II (P < 0.01). The density of apoptotic cells (visualized by TUNEL-staining) did not vary significantly between any of the groups (all P > 0.05). The results suggest that intravitreal injections of cetuximab in young guinea pigs with LIM resulted in a reduction in axial elongation in a dose-dependent and number of treatment-dependent manner. Intraocular toxic effects, such as intraocular inflammation, retinal thinning, or an increased density of apoptotic cells in the retina, were not observed in association with the intravitreally applied cetuximab.

Reduction of experimental ocular axial elongation by neuregulin-1 antibody.

Background: Since the mechanisms underlying myopic axial elongation have remained unclear, we examined the effect of neuregulin-1 (NRG-1), an epidermal growth factor family member, on myopic axial elongation. Methods: The guinea pigs aged two to three weeks were subjected to bilateral negative lens-induced axial elongation and received weekly intravitreal injections into their right eyes of NRG-1 antibody (doses: 5 µg, n = 8; 10 µg, n = 8, 20 µg, n = 9) or of NRG-1 (doses: 0.05 µg, n = 8; 0.01 µg, n = 9; 0.2 µg, n = 8), underwent only bilateral negative lens-induced axial elongation (myopia control group, n = 10), or underwent no intervention (control group, n = 10). The contralateral eyes received corresponding intravitreal phosphate-buffered solution injections. One week after the last injection, the guinea pigs were sacrificed, the eyeballs were removed, the thicknesses of the retina and sclera were histologically examined, the expression of NRG-1 and downstream signal transduction pathway members (ERK1/2 and PI3K/AKT) and the mRNA expression of NRG-1 in the retina was assessed. Results: The inter-eye difference in axial length at study end increased (p < 0.001) from the normal control group (-0.02 ± 0.09 mm) and the myopia control group (-0.01 ± 0.09 mm) to the low-dose NRG-1 antibody group (-0.11 ± 0.05 mm), medium-dose NRG-1 antibody group (-0.17 ± 0.07 mm), and high-dose NRG-1 antibody group (-0.28 ± 0.06 mm). The relative expression of NRG-1, ERK1/2, and PI3K/AKT in the retina decreased in a dose-dependent manner from the myopia control group to the NRG-1 antibody groups and the normal control group. The relative NRG-1 mRNA expression in the retina was higher (p < 0.01) in the myopic control group than in the NRG-1 antibody groups and normal control group. Scleral and retinal thickness decreased from the normal control group to the NRG-1 antibody groups to the myopic control group. After intraocular injection of NRG-1 protein, there was a slight dose-dependent increase in the difference in axial length between the right and left eye, however not statistically significantly, from the normal control group (-0.02 ± 0.09 mm) to the high-dose NRG-1 protein group (0.03 ± 0.03 mm; p = 0.12). Conclusion: Intravitreal NRG-1 antibody application was dose-dependently and time-dependently associated with a reduction in negative lens-induced axial elongation in young guinea pigs.

Intravitreal Short-Hairpin RNA Attenuated Adeno-Associated Virus-Induced Knockdown of Amphiregulin and Axial Elongation in Experimental Myopia.

Background: Epidermal growth factor (EGF) and its family members have been reported to be involved in myopic axial elongation. We examined whether short hairpin RNA attenuated adeno-associated virus (shRNA-AAV)-induced knockdown of amphiregulin, an EGF family member, has an influence on axial elongation. Methods: Three-week-old pigmented guinea pigs underwent lens-induced myopization (LIM) without additional intervention (LIM group; n = 10 animals) or additionally received into their right eyes at baseline an intravitreal injection of scramble shRNA-AAV (5 × 1010 vector genome [vg]) (LIM + Scr-shRNA group; n = 10) or of amphiregulin (AR)-shRNA-AAV (5 × 1010 vg/5 µL) (LIM + AR-shRNA-AAV group; n = 10), or they received an injection of AR-shRNA-AAV at baseline and three weekly amphiregulin injections (20 ng/5 µL) (LIM + AR-shRNA-AAV + AR group; n = 10). The left eyes received equivalent intravitreal injections of phosphate-buffered saline. Four weeks after baseline, the animals were sacrificed. Results: At study end, interocular axial length difference was higher (P < 0.001), choroid and retina were thicker (P < 0.05), and relative expression of amphiregulin and p-PI3K, p-p70S6K, and p-ERK1/2 was lower (P < 0.05) in the LIM + AR-shRNA-AAV group than in any other group. The other groups did not differ significantly when compared with each other. In the LIM + AR-shRNA-AAV group, the interocular axial length difference increased with longer study duration. TUNEL assay did not reveal significant differences among all groups in retinal apoptotic cell density. In vitro retinal pigment epithelium cell proliferation and migration were the lowest (P < 0.05) in the LIM + AR-shRNA-AAV group, followed by the LIM + AR-shRNA-AAV + AR group. Conclusions: shRNA-AAV-induced knockdown of amphiregulin expression, in association with suppression of epidermal growth factor receptor signaling, attenuated axial elongation in guinea pigs with LIM. The finding supports the notion of EGF playing a role in axial elongation.

Association between vitamin D and myopia in adolescents and young adults: Evidence of national cross-sectional study.

PURPOSE: Studies have indicated that the observed association between vitamin D and myopia was confounded by time spent outdoors. This study aimed to elucidate this association using a national cross-sectional dataset. METHODS: Participants with 12 to 25 years who participated in non-cycloplegic vision exam from National Health and Nutrition Examination Survey (NHANES) 2001 to 2008 were included in the present study. Myopia was defined as spherical equivalent of any eyes ≤ -0.5 diopters (D). RESULTS: 7,657 participants were included. The weighted proportion of emmetropes, mild myopia, moderate myopia, and high myopia were 45.5%, 39.1%, 11.6%, and 3.8%, respectively. After adjusting for age, gender, ethnicity, TV/computer usage, and stratified by education attainment, every 10 nmol/L increment of serum 25(OH)D concentration was associated with a reduced risk of myopia (odds ratio [OR] = 0.96, 95% confidence interval [95%CI] 0.93-0.99 for any myopia; OR = 0.96, 95%CI 0.93-1.00 for mild myopia; OR = 0.99, 95%CI 0.97-1.01 for moderate myopia; OR = 0.89, 95%CI 0.84-0.95 for high myopia). Serum 25(OH)D level was closely correlated with time spent outdoors. After categorizing time spent outdoors into quarters (low, low-medium, medium-high, and high), every 1 quarter increment of time spent outdoors was associated with 2.49 nmol/L higher serum 25(OH)D concentration. After adjusting for time spent outdoors, serum 25(OH)D level did not show significant association with myopia (OR = 1.01, 95%CI 0.94-1.06 for 10 nmol/L increment). CONCLUSIONS: The association between high serum vitamin D and reduced risk of myopia is confounded by longer time spent outdoors. Evidence from the present study does not support that there is a direct association between serum vitamin D level with myopia.

Development and validation of medical record-based logistic regression and machine learning models to diagnose diabetic retinopathy.

PURPOSES: Many factors were reported to be associated with diabetic retinopathy (DR); however, their contributions remained unclear. We aimed to evaluate the prognostic and diagnostic accuracy of logistic regression and three machine learning models based on various medical records. METHODS: This was a cross-sectional study. We investigated the prevalence and associations of DR among 757 participants aged 40 years or older in the 2005-2006 National Health and Nutrition Examination Survey (NHANES). We trained the models to predict if the participants had DR with 15 predictor variables. Area under the receiver operating characteristic (AUROC) and mean squared error (MSE) of each algorithm were compared in the external validation dataset using a replicate cohort from NHANES 2007-2008. RESULTS: Among the 757 participants, 53 (7.00%) subjects had DR, the mean (standard deviation, SD) age was 57.7 (13.04), and 78.0% were male (n = 42). Logistic regression revealed that female gender (OR = 4.130, 95% CI: 1.820-9.380; P < 0.05), HbA1c (OR = 1.665, 95% CI: 1.197-2.317; P < 0.05), serum creatine level (OR = 2.952, 95% CI: 1.274-6.851; P < 0.05), and eGFR level (OR = 1.009, 95% CI: 1.000-1.014, P < 0.05) increased the risk of DR. The average performance obtained from internal validation was similar in all models (AUROC ≥ 0.945), and k-nearest neighbors (KNN) had the highest value with an AUROC of 0.984. In external validation, they remained robust or with modest reductions in discrimination with AUROC still ≥ 0.902, and KNN also performed the best with an AUROC of 0.982. Both logistic regression and machine learning models had good performance in the clinical diagnosis of DR. CONCLUSIONS: This study highlights the utility of comparing traditional logistic regression to machine learning models. We found that logistic regression performed as well as optimized machine learning methods when classifying DR patients.

Thickness of retinal pigment epithelium-Bruch's membrane complex in adult Chinese using optical coherence tomography.

PURPOSE: To study thickness of RPE-BM complex in adult Chinese subjects and its correlation with systemic and ocular biometric parameters. DESIGN: Population-based longitudinal study. Cross-sectional study. PARTICIPANTS: The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6 ± 9.8 years (range: 50-93 years). METHODS: A detailed ophthalmic examination was performed including spectral-domain optical coherence tomography (SD OCT) for measurement of the thickness of RPE-BM complex. Use Heidelberg software "Heidelberg Eye Explorer" for segmentation and measurements. MAIN OUTCOME MEASURE: Thickness of RPE-BM complex. RESULTS: In total, 3276 people (6530 eyes) were included in the study. In total, 1844 (56.3%) subjects were female. The mean age was 64.3 ± 9.6 years (range: 50-93 years). The mean refractive error (spherical equivalent) was -0.18 ± 2.04 diopters (range: -22.0 to +7.50 diopters). Mean thickness of the RPE-BM complex at the foveal center was 25.09 ± 3.98 µm (range: 17-37 µm). In multiple regression analysis, subfoveal thickness of the RPE-BM complex was associated with age (p = 0.039; beta: 0.22; B: 0.10 (95% CI: 0.01, 0.20)) and hypertension history (p = 0.038; beta: 0.23; B: 1.96 (95% CI: 0.12, 3.81)). CONCLUSION: Mean subfoveal thickness of the RPE-BM complex was 25.09 ± 3.98 µm in elderly subjects with a mean age of 64.3 years increased with age and hypertension history. The increase in the thickness of RPE-BM complex may play a role in the pathophysiologic features of various age-related ocular conditions.

Visual impairment and major eye diseases in stroke: a national cross-sectional study.

OBJECTIVES: Major ocular diseases share common risk factors and pathogeneses with stroke. This study aimed to evaluate the relation between stroke and ocular diseases including visual impairment (VI). METHODS: The cross-sectional study investigated the prevalence and associations of VI and major eye diseases with stroke among 4570 participants in the 2005-2008 National Health and Nutrition Examination Survey (NHANES). The association of VI and major ocular diseases with stroke were estimated using univariate and multivariate logistic regression crude models and models adjusted for demographics and clinical factors. We also conducted stratified analyses by diabetes and hypertension status. RESULTS: VI was associated with stroke, and the odds ratios (ORs) for mild and moderate and severe visual impairment (MSVI) were 6.79 (95% confidence interval (CI): 2.44-18.88) and 9.46 (95% CI: 2.19-40.94) after adjusting for age and gender (all P < 0.05). Ocular disease was associated with stroke with OR reaching 5.54 (95% CI: 1.83-16.74), and the OR was 9.61 (95% CI: 3.05-30.23) for stroke patients suffering DR after adjusting for age and gender (all P < 0.05). After multivariable adjustment, the associations were limited to mild VI (OR = 10.00, 95% CI: 3.16-30.58), MSVI (OR = 8.57, 95% CI: 1.58-43.36), and any ocular disease (OR = 5.18, 95% CI: 1.46-18.42) (all P < 0.05). Significant associations between stroke and any ocular disease and DR were observed among diabetic participants, and significant relation between stroke and MSVI was found among hypertension patients. CONCLUSIONS: The sample of the US population demonstrates significant associations between VI and major ocular disease with stroke.

Circulating MicroRNAs as Quantitative Biomarkers for Diagnosis and Prognosis of Uveal Melanoma.

For uveal melanoma (UM) patients, it is significant to establish diagnosis and prognosis evaluation systems through imaging techniques. However, imaging examinations are short of quantitative biomarkers and it is difficult to finish early diagnosis of UM. In order to discover new molecular biomarkers for the diagnosis and prognostic evaluation of UM, six circulating miRNAs (mir-132-3p, mir-21-5p, mir-34a-5p, mir-126-3p, mir-199a-3p, mir-214-3p) were chosen as candidates for independent validation. Validation of these miRNAs was performed in a cohort of 20 patients, including 10 spindle-shaped melanoma and 10 epithelioid cell melanoma, and 10 healthy donors. Then 5 patients with metastatic UM were included to validate the performance of miRNAs in advanced UM. Serum levels of miRNAs were determined using quantitative real-time PCR. We confirmed significantly higher levels of three miRNAs in serum of UM patients in comparison to healthy controls, and miR-199a-3p had the best performance (p < 0.0001; AUC = 0.985). MiR-214-3p and miR-21-5p were significantly upregulated in serum of epithelioid cell melanoma patients compared to spindle-shaped melanoma patients and miR-132-3p and, conversely, were significantly downregulated in serum of epithelioid cell melanoma patients. MiR-21-5p shows their best performance (p < 0.0001; AUC = 0.980). Both miR-199a-3p and miR-21-5p showed great performance in advanced UM. Significantly higher levels of miR-21-5p (p < 0.001) were found in serum of metastatic UM patients compared to patients with localized spindle-shaped melanoma, and significantly higher levels of miR-199a-3p (p < 0.001) were detected in serum of metastatic UM patients compared to healthy controls. Our preliminary data indicate promising diagnostic utility of circulating miR-199a-3p and promising prognostic utility of circulating miR-21-5p in both early and advanced UM patients.

Prevalence, Years Lived With Disability, and Time Trends for 16 Causes of Blindness and Vision Impairment: Findings Highlight Retinopathy of Prematurity.

Background: Cause-specific prevalence data of vision loss and blindness is fundamental for making public health policies and is essential for prioritizing scientific advances and industry research. Methods: Cause-specific vision loss data from the Global Health Data Exchange was used. The burden of vision loss was measured by prevalence and years lived with disability (YLDs). Findings: In 2019, uncorrected refractory error and cataract were the most common causes for vision loss and blindness globally. Women have higher rates of cataract, age-related macular degeneration (AMD), and diabetic retinopathy (DR) than men. In the past 30 years, the prevalence of moderate/severe vision loss and blindness due to neonatal disorders has increased by 13.73 and 33.53%, respectively. Retinopathy of prematurity (ROP) is the major cause of neonatal disorders related vision loss. In 2019, ROP caused 101.6 thousand [95% uncertainty intervals (UI) 77.5-128.2] cases of vision impairment, including 49.1 thousand (95% UI 28.1-75.1) moderate vision loss, 27.5 thousand (95% UI 19.3-36.60) severe vision loss and, 25.0 thousand (95% UI 14.6-35.8) blindness. The prevalence of new-onset ROP in Africa and East Asia was significantly higher than other regions. Variation of preterm birth prevalence can explain 49.8% geometry variation of ROP-related vision loss burden among 204 countries and territories. After adjusting for preterm prevalence, government health spending per total health spending (%), rather than total health spending per person, was associated with a reduced burden of ROP-related vision loss in 2019 (-0.19 YLDs for 10% increment). By 2050, prevalence of moderate, severe vision loss and blindness due to ROP is expected to reach 43.6 (95% UI 35.1-52.0), 23.2 (95% UI 19.4-27.1), 31.9 (95% UI 29.7-34.1) per 100,000 population. Conclusion: The global burden of vision loss and blindness highlights the prevalent of ROP, a major and avoidable cause for childhood vision loss. Advanced screening techniques and treatments have shown to be effective in preventing ROP-related vision loss and are urgently needed in regions with high ROP-related blindness rates, including Africa and East Asia.

Prediction of the Fundus Tessellation Severity With Machine Learning Methods.

Purpose: To predict the fundus tessellation (FT) severity with machine learning methods. Methods: A population-based cross-sectional study with 3,468 individuals (mean age of 64.6 ± 9.8 years) based on Beijing Eye Study 2011. Participants underwent detailed ophthalmic examinations including fundus images. Five machine learning methods including ordinal logistic regression, ordinal probit regression, ordinal log-gamma regression, ordinal forest and neural network were used. Main Outcome Measure: FT precision, recall, F1-score, weighted-average F1-score and AUC value. Results: Observed from the in-sample fitting performance, the optimal model was ordinal forest, which had correct classification rate (precision) of 81.28%, while 34.75, 93.73, 70.03, and 24.82% in each classified group by FT severity. The AUC value was 0.7249. And the F1-score was 65.05%, weighted-average F1-score was 79.64% on the whole dataset. For out-of-sample prediction performance, the optimal model was ordinal logistic regression, which had precision of 77.12% on the validation dataset, while 19.57, 92.68, 64.74, and 6.76% in each classified group by FT severity. The AUC value was 0.7187. The classification accuracy of light FT group was the highest, while that of severe FT group was the lowest. And the F1-score was 54.46%, weighted-average F1-score was 74.19% on the whole dataset. Conclusions: The ordinal forest and ordinal logistic regression model had the strong prediction in-sample and out-sample performance, respectively. The threshold ranges of the ordinal forest model for no FT and light, moderate, severe FT were [0, 0.3078], [0.3078, 0.3347], [0.3347, 0.4048], [0.4048, 1], respectively. Likewise, the threshold ranges of ordinal logistic regression model were ≤ 3.7389, [3.7389, 10.5053], [10.5053, 13.9323], > 13.9323. These results can be applied to guide clinical fundus disease screening and FT severity assessment.

Epiregulin, epigen and betacellulin antibodies and axial elongation in young guinea pigs with lens-induced myopization.

BACKGROUND: To examine an effect of intravitreally applied antibodies against epidermal growth factor family members, namely epiregulin, epigen and betacellulin, on ocular axial elongation. METHODS: The experimental study included 30 guinea pigs (age:3-4 weeks) which underwent bilateral lens-induced myopization and received three intraocular injections of 20 µg of epiregulin antibody, epigen antibody and betacellulin antibody in weekly intervals into their right eyes, and of phosphate-buffered saline into their left eyes. Seven days after the last injection, the animals were sacrificed. Axial length was measured by sonographic biometry. RESULTS: At baseline, right eyes and left eyes did not differ (all P > 0.10) in axial length in neither group, nor did the interocular difference in axial length vary between the groups (P = 0.19). During the study period, right and left eyes elongated (P < 0.001) from 8.08 ± 0.07 mm to 8.59 ± 0.06 mm and from 8.08 ± 0.07 mm to 8.66 ± 0.07 mm, respectively. The interocular difference (left eye minus right eye) in axial elongation increased significantly in all three groups (epiregulin-antibody:from 0.03 ± 0.06 mm at one week after baseline to 0.16 ± 0.08 mm at three weeks after baseline;P = 0.001); epigen-antibody group:from -0.01 ± 0.06 mm to 0.06 ± 0.08 mm;P = 0.02; betacellulin antibody group:from -0.05 ± 0.05 mm to 0.02 ± 0.04 mm;P = 0.004). Correspondingly, interocular difference in axial length increased from -0.02 ± 0.04 mm to 0.13 ± 0.06 mm in the epiregulin-antibody group (P < 0.001), and from 0.01 ± 0.05 mm to 0.07 ± 0.05 mm in the epigen-antibody group (P = 0.045). In the betacellulin-antibody group the increase (0.01 ± 0.04 mm to 0.03 ± 0.03 mm) was not significant (P = 0.24). CONCLUSIONS: The EGF family members epiregulin, epigen and betacellulin may be associated with axial elongation in young guinea pigs, with the effect decreasing from epiregulin to epigen and to betacellulin.

Prevalence and Associations of Vitreomacular Traction: The Beijing Eye Study.

PURPOSE: To explore the prevalence and associations of vitreous macular traction (VMT) in Chinese population. METHODS: A population-based cross-sectional study with 3468 individuals (mean age of 64.6 ± 9.8 years) based on Beijing Eye Study 2011. Participants underwent detailed ophthalmic examinations, including spectral domain optical coherence tomography (SD-OCT). VMT was defined as abnormal posterior vitreous detachment with anatomical deformation of the fovea, which may include pseudocyst, macular schisis, cystoid macular edema, and subretinal fluid. MAIN OUTCOME MEASURE: Prevalence of VMT. RESULTS: A VMT was detected in 151 (2.3%) eyes (prevalence rate (mean ± SE): 2.3± 0.2%; 95% CI: 1.9%, 2.7%) of 80 (2.4%) subjects (prevalence rate: 2.4± 0.3%; 95% CI: 1.9%, 2.9%). Mean age of all subjects with VMT was 70.1± 8.7 years (median, 70.0 years; range, 50-90 years), mean refractive error was -0.22 ± 2.38D (median, 0.25 D; range, -15.00 to 5.25D). In multivariate analysis, prevalence of VMT was associated with elder age (P=0.001, OR 1.06), female gender (P = 0.036, OR 1.77), subfoveal retinal thickness (P = 0.005, OR 1.01), and subfoveal choroidal thickness (P = 0.026, OR 0.10). CONCLUSION: In adult Chinese in Greater Beijing, the prevalence of VMT was 2.3% for eyes or 2.4% for subjects. While it was associated with elder age, female gender, thicker subfoveal retinal thickness and thinner subfoveal choroidal thickness.

Global, regional, and national prevalence, disability adjusted life years, and time trends for refraction disorders, 1990-2019: findings from the global burden of disease study 2019.

BACKGROUND: To evaluate global burden of refraction disorders by year, age, region, gender, socioeconomic status and other national characteristics in terms of disability adjusted life years (DALYs) and prevalence from Global Burden of Disease (GBD) study 2019 and World Bank Open Data 2019. METHODS: Global, regional, and national DALY numbers, crude DALY rates, age-standardized DALY and prevalence rates of refraction disorders were acquired from the GBD study 2019. Mobile cellular subscriptions, urban population, GDP per capita, access to electricity and total fertility rate were obtained from the World Bank to explore the factors that influenced the health burden of refraction disorders. Kruskal-Wallis test, linear regression and multiple linear regression were performed to evaluate the associations between the health burden with socioeconomic levels and other national characteristics. Wilcoxon Signed-Rank Test was used to investigate the gender disparity. RESULTS: Globally, age-standardized DALY rates of refraction disorders decreased from 88.9 (95% UI: 60.5-120.3) in 1990 to 81.5 (95% UI: 55.0-114.8) in 2019, and might fall to 73.16 (95% UI: 67.81-78.51) by 2050. Age-standardized prevalence rates would also reduce to 1830 (95% UI: 1700-1960) by 2050, from 2080 (95% UI: 1870-2310) in 1990 to 1960 (95% UI: 1750-2180) in 2019. In low SDI region, age-standardized DALY rates (equation: Y = 114.05*X + 27.88) and prevalence rates (equation: Y = 3171.1*X + 403.2) were positively correlated with SDI in linear regression respectively. East Asia had the highest blindness rate caused by refraction disorders in terms of age-standardized DALY rates (11.20, 95% UI: 7.38-16.36). Gender inequality was found among different age groups and SDI regions. CONCLUSION: Health burden of refraction disorders decreased in recent years, and may continue to alleviate in the next three decades. Older ages, females and lower socioeconomic status were associated with higher refraction disorders health burden.