髙橋 秀徳

Abstract We herein propose a PraNet-based deep-learning model for estimating the size of non-perfusion area (NPA) in pseudo-color fundus photos from an ultra-wide-field (UWF) image. We trained the model with focal loss and weighted binary cross-entropy loss to deal with the class-imbalanced dataset, and optimized hyperparameters in order to minimize validation loss. As expected, the resultant PraNet-based deep-learning model outperformed previously published methods. For verification, we used UWF fundus images with NPA and used Bland–Altman plots to compare estimated NPA with the ground truth in FA, which demonstrated that bias between the eNPA and ground truth was smaller than 10% of the confidence limits zone and that the number of outliers was less than 10% of observed paired images. The accuracy of the model was also tested on an external dataset from another institution, which confirmed the generalization of the model. For validation, we employed a contingency table for ROC analysis to judge the sensitivity and specificity of the estimated-NPA (eNPA). The results demonstrated that the sensitivity and specificity ranged from 83.3–87.0% and 79.3–85.7%, respectively. In conclusion, we developed an AI model capable of estimating NPA size from only an UWF image without angiography using PraNet-based deep learning. This is a potentially useful tool in monitoring eyes with ischemic retinal diseases.

Abstract The main goal of this study is to identify the association between corneal shape, elevation, and thickness parameters and visual field damage using machine learning. A total of 676 eyes from 568 patients from the Jichi Medical University in Japan were included in this study. Corneal topography, pachymetry, and elevation images were obtained using anterior segment optical coherence tomography (OCT) and visual field tests were collected using standard automated perimetry with 24-2 Swedish Interactive Threshold Algorithm. The association between corneal structural parameters and visual field damage was investigated using machine learning and evaluated through tenfold cross-validation of the area under the receiver operating characteristic curves (AUC). The average mean deviation was − 8.0 dB and the average central corneal thickness (CCT) was 513.1 µm. Using ensemble machine learning bagged trees classifiers, we detected visual field abnormality from corneal parameters with an AUC of 0.83. Using a tree-based machine learning classifier, we detected four visual field severity levels from corneal parameters with an AUC of 0.74. Although CCT and corneal hysteresis have long been accepted as predictors of glaucoma development and future visual field loss, corneal shape and elevation parameters may also predict glaucoma-induced visual functional loss.

PURPOSE: To investigate changes in the interpupillary distance (IPD) after continual instillation of topical prostaglandin analogs (PGAs) in glaucoma patients as an objective indicator of prostaglandin-associated periorbitopathy (PAP). DESIGN: Retrospective, comparative case series. METHODS: A total of 152 institutional patients with glaucoma were enrolled in this study. Inclusion criteria were visual acuities exceeding 10/20 bilaterally and no intraocular surgery during observation. Intervention/observation procedures: First-time bilateral instillation of bimatoprost, travoprost, latanoprost, or tafluprost and IPDs measured by automatic refractometry. IPDs, intraocular pressures (IOPs), and refractive errors were measured before and after continual drug administration (treatment, 2-24 months). MAIN OUTCOME MEASUREMENTS: Post-treatment changes in IPDs. A total of 61 untreated patients served as controls. RESULTS: The IPDs shortened significantly (P < 0.001) after treatment (-0.80 ± 2.1 mm); the IPDs of control subjects remained unchanged (0.05 ± 0.96 mm; P = 0.69). The IPD change after bimatoprost instillation (-2.20 ± 0.97 mm) was significantly (P < 0.001) greater than with other PGAs (-0.65 ± 2.09 mm). The IOPs decreased significantly (P < 0.001) (-3.7 ± 4.3 mm Hg); the refractive errors did not change significantly (P < 0.099) (-0.07 ± 0.69 diopter) post-treatment. The percentages of subjects with 2-mm or greater decreases in IPD after bimatoprost, travoprost, latanoprost, or tafluprost were 85.7%, 20.0%, 18.2%, and 17.2%, respectively, and with 3-mm or greater decreases in IPD 35.7%, 12.0%, 14.5%, and 12.1%, respectively. The specificities were 93.4% and 100% in the control group, respectively, with IPD threshold changes of 2 and 3 mm or more, respectively. CONCLUSIONS: The IPD decreased significantly after topical PGAs within 24 months. The effect was significantly greater with bimatoprost than with other PGAs. The noninvasive, immediate automatic refractometry measurement may be an objective numerical indicator of PAP.

PURPOSE: To determine changes in multiple cytokine concentrations in the anterior chamber during the induction phase of ranibizumab treatment in patients with neovascular age-related macular degeneration (AMD). METHODS: This prospective study included 48 treatment-naïve neovascular AMD eyes of 48 patients who received three consecutive monthly injections of ranibizumab at the Japan Community Health Care Organization Tokyo Shinjuku Medical Center between November 2010 and August 2012. We collected ~0.2 mL aqueous humour before the first and third (2 months later) injections. Controls were 80 eyes with cataracts without retinal disease. The cytokines C-X-C motif chemokine ligand 1 (CXCL1), interferon-γ-induced protein 10 (IP-10), C-X-C motif chemokine ligand 12 (CXCL12), C-X-C motif chemokine ligand 13 (CXCL13), monocyte chemoattractant protein 1 (MCP-1), CCL11, C-C motif chemokine ligand 11 (CCL11), interleukin-6 (IL-6), interleukin-10 (IL-10) and matrix metalloproteinase 9 (MMP-9) were analysed using multiplex cytokine assays. RESULTS: Mean ages of the patients with AMD and controls were 73 and 75 years, respectively, and 31 (65%) and 37 (46%) subjects were men, respectively. Polypoidal choroidal vasculopathy was found in 27 eyes (56%). Mean concentrations of cytokines in aqueous humour in patients with neovascular AMD before the first and third ranibizumab injections were as follows (in pg/mL): CXCL1, 8.4 and 3.3; IP-10, 110 and 55; CXCL12, 480 and 240; CXCL13, 9.2 and 2.6; MCP-1, 620 and 220; CCL11, 7.1 and 2.8; IL-6, 5.9 and 1.6; IL-10, 0.15 and 0.015 (all p<0.0001), and MMP-9, 0.92 and 1.5 (p=0.0216), respectively. Concentrations of all cytokines decreased significantly after two consecutive ranibizumab injections, except for MMP-9, which increased significantly. CONCLUSIONS: After two monthly consecutive antivascular endothelial growth factor injections, inflammatory cytokine levels in the aqueous humour of the eyes with AMD were strongly suppressed, while MMP-9 levels increased.

PURPOSE. Commercially available enzyme-linked immunosorbent assay (ELISA) kits are often used to monitor vascular endothelial growth factor (VEGF) levels in exudative age-related macular degeneration. To test their accuracy, this study performed measurements using the ELISA kits in the presence of anti-VEGF drugs. METHODS. The concentrations of bevacizumab, pegaptanib, or ranibizumab at 28 days and aflibercept at 28 and 56 days after an injection were estimated based on previous pharmacokinetic studies. Vascular endothelial growth factor concentrations were measured with two widely used VEGF ELISA kits in the presence of anti-VEGF drugs or control mouse immunoglobulin G (IgG). The monocyte chemotactic protein-1 (MCP-1) ELISA kit was used as a non-VEGF ELISA control kit. RESULTS. The concentrations of aflibercept, bevacizumab, pegaptanib, and ranibizumab were estimated at 0.14 to 7.2, 4.9, 8.6, and 0.11 to 1.1 mu g/mL, respectively. ELISA underestimated the VEGF concentration 2- to 100-fold lower in the presence of an anti-VEGF drug, except for pegaptanib, at all VEGF concentrations tested (7.8-1500 pg/mL). Vascular endothelial growth factor at 1000 pg/mL was measured as 92, 150, and 170 pg/mL in the presence of aflibercept (7.2 mu g/mL), bevacizumab (4.9 mu g/mL), and ranibizumab (1.1 mu g/mL), respectively (all P &lt; 0.0001), and the measured VEGF concentration decreased proportionately by 90% to 92% with aflibercept, 85% to 94% with bevacizumab, and 83% to 99% with ranibizumab. The control mouse IgG did not interfere with the measurement of VEGF. Ranibizumab did not affect the measurements with MCP-1 ELISA. CONCLUSIONS. Investigators should exercise caution when interpreting measurements of VEGF ELISA in patients being treated with an anti-VEGF drug.

Purpose To investigate the association of posterior vitreous detachment (PVD) with aqueous levels of vascular endothelial growth factor (VEGF) and other inflammatory cytokines. Methods These are prospective comparative studies. Subjects comprised 98 eyes for VEGF concentration and 80 eyes for other cytokines, which are normal except for cataract. PVD was examined by B-mode ultrasonography, and the subjects were divided into complete PVD group (PVD group) or the other group (without PVD group). At the beginning of cataract surgery, aqueous humour was collected and the concentrations of VEGF and other inflammatory cytokines were determined using ELISA and a multiplex cytokine assay, respectively. The concentrations of these cytokines were compared between the two groups. Results Complete PVD was observed in 56 (57%) eyes for VEGF concentration analysis, and 51 (64%) eyes for the other cytokines analysis. The concentrations of VEGF, adjusted for the average age, axial length and gender distribution, was 47 pg/ mL in the PVD group and 72 pg/mL in the without PVD group. The concentrations of IP10, MCP-1, CXCL13 and CCL11 were 53, 450, 3.8 and 6.0 pg/ mL in the PVD group, and 100, 560, 7.0 and 8.4 pg/ mL in the without PVD group, respectively. Multiple regression analysis revealed that the logarithmic concentration of VEGF, IP-10, MCP-1, CXCL13 and CCL11 were significantly lower in the eyes with PVD than in those without PVD independently of age, sex and axial length (p = 0.01, p = 0.002, p = 0.009, 0.006 and 0.03, respectively). Conclusions PVD is related to the change in the multiple intraocular inflammatory cytokines.

Background: In age-related macular degeneration, various factors in clinical practice cause delays to arise between the time exudative change is observed and the time antivascular endothelial growth factor drugs are actually injected. We investigated the influence of injection delay on prognosis. Methods: Subjects were 50 eyes (50 patients from 2 hospitals) that were administered ranibizumab monotherapy for age-related macular degeneration for 1 year since exudative change was first observed. We investigated the mean number of delay days for each injection. Results: Mean injection delay was between 0 and 104 days. Significant prognostic factors for visual acuity were initial best-corrected visual acuity (P , 0.01) and mean injection delay (P = 0.03). We estimated that for an initial best-corrected visual acuity of 0.40 logMAR unit (20/50 Snellen equivalent), the respective best-corrected visual acuity values after 1 year for mean injection delays of 0, 7, 14, 28, and 56 days would be 0.22 (20/33), 0.24 (20/35), 0.26 (20/37), 0.31 (20/40), and 0.39 (20/49). For an initial best-corrected visual acuity of 0.097 (20/25), the respective values would be 0.054 (20/23), 0.075 (20/24), 0.10 (20/25), 0.14 (20/28), and 0.22 (20/33). Conclusion: Long-term visual acuity prognosis worsened when scheduling problems delayed intravitreal injection of anti-vascular endothelial growth factor drugs.

The control of gene transfection in the body is a core issue in gene therapy. Photochemical internalization is a technology that allows light-induced delivery of DNA, drugs or other biological factors directly inside cells. Usually it requires that a photosensitizer be added to the drug-delivery system to photochemically destabilize the endosomal membrane. Here we present a system for in vivo DNA delivery in which these two components are assembled into one structure. This is a ternary complex composed of a core containing DNA packaged with cationic peptides and enveloped in the anionic dendrimer phthalocyanine, which provides the photosensitizing action. The ternary complex showed more than 100-fold photochemical enhancement of transgene expression in vitro with reduced photocytotoxicity. In an animal experiment, subconjuctival injection of the ternary complex followed by laser irradiation resulted in transgene expression only in the laser-irradiated site. This work demonstrates a new biomedical application for dendrimers, and the first success in the photochemical-internalization-mediated gene delivery in vivo.