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.

Vitamin D and myopia: a review.

Myopia is a worldwide public health problem of vision disorder caused by multiple factors, which has posed a huge socioeconomic burden, raising concerns about sight-threatening ocular complications. Vitamin D, as a kind of fat-soluble vitamin, related to time-spent-outdoors, has been considered by extensive studies to have potential relationship with myopia. We reviewed studies published in a decade which estimated the association of blood vitamin D status with myopia and summarized the universality and individuality of all research articles. Several research articles suggested the known environmental risk factors of myopia, including age, gender, ethnicity, education level, parental and school conditions, time-spent-outdoors, and sunlight exposure, and recent epidemiological studies demonstrate that increased vitamin D levels, by virtue of the extended outdoor time, may be an important modifiable factor and a protective effect that delay the progression of myopia in children and adolescents rather than in adults. The genetic studies have been conducted to get access to the evidence of gene polymorphism for explaining the association of serum vitamin D status and myopia, but the precise genetic interpretation of vitamin D and myopia remains unclear so far; on the other hand, the possible mechanisms are various like copolymerization mechanism, calcium homeostasis and imbalance of ciliary muscle function regulation, but nearly all of the investigators are inclined to remain skeptical. This article reviews the age-related epidemiological proofs, existent genetics correlations, possible underlying biological mechanisms and further values for the protective association between vitamin D and myopia, providing the possibility of prevention or postponement for 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.

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.

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.