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Designing a deep neural network model that integrates clinical images with other electronic medical records entails various preprocessing operations. Preprocessing of clinical images often requires trimming of parts of the lesions shown in the images, whereas preprocessing of other electronic medical records requires vectorization of these records; for example, patient age is often converted into a categorical vector of 10-year intervals. Although these preprocessing operations are critical to the performance of the classification model, there is no guarantee that the preprocessing step chosen is appropriate for model training. The ability to integrate these preprocessing operations into a deep neural network model and to train the model, including the preprocessing operations, can help design a multi-modal medical classification model. This study proposes integration layers of preprocessing, both for clinical images and electronic medical records, in deep neural network models. Preprocessing of clinical images is realized by a vision transformer layer that selectively adopts the parts of the images requiring attention. The preprocessing of other medical electrical records is performed by adopting full-connection layers and normalizing these layers. These proposed preprocessing-integrated layers were verified using a posttreatment visual acuity prediction task in ophthalmology as a case study. This prediction task requires clinical images as well as patient profile data corresponding to each patient's posttreatment logMAR visual acuity. The performance of a heuristically designed prediction model was compared with the performance of the prediction model that includes the proposed preprocessing integration layers. The mean square errors between predicted and correct results were 0.051 for the heuristic model and 0.054 for the proposed model. Experimental results showed that the proposed model utilizing preprocessing integration layers achieved nearly the same performance as the heuristically designed model.

Purpose To evaluate the association between daily coffee consumption and intraocular pressure (IOP) in healthy persons without glaucoma and the association between daily coffee consumption and history of glaucoma. Design Cross-sectional study. Participants A total of 9850 individuals participated in the first follow-up of the Nagahama Prospective Cohort for Comprehensive Human Bioscience (the Nagahama Study) conducted between 2013 and 2016. Methods All participants underwent a standardized ophthalmic examination. Self-reporting questionnaires were completed by all participants. First, the association between habitual coffee consumption and IOP among nonglaucoma individuals was evaluated by a multivariate linear regression analysis, adjusting for possible confounders. Second, the association between habitual coffee consumption and history of glaucoma also was evaluated using a multivariate logistic regression analysis. Main Outcome Measures The association between habitual coffee consumption and IOP among nonglaucoma individuals. Results Of 9850 participants, 9418 did not have history of glaucoma. Among these participants, the mean ± standard deviation IOP of both eyes was 14.7 ± 2.9 mmHg. The multivariate regression analysis revealed that habitual coffee consumption was associated significantly with IOP (P Conclusions Frequent coffee consumption was associated with a slightly lower IOP in people without glaucoma but was not associated with a decreased risk of glaucoma developing. Additional experimental studies are needed to examine the effects of coffee on IOP and glaucoma risk.

To evaluate the association between central serous chorioretinopathy (CSC) susceptibility genes and choroidal parameters in a large Japanese cohort.Retrospective cohort study.Of the 9850 individuals in the Nagahama study whose second visit was between 2013 and 2016, those with optical coherence tomography (OCT) images with enhanced depth imaging (EDI), axial length, and genome-wide single nucleotide polymorphism (SNP) genotyping data were included. We calculated subfoveal choroidal thickness (SFCT), choroidal vascularity index (CVI), normalized choroidal intensity (NCI), and vertical asymmetry of choroidal thickness. Genome-wide quantitative trait locus (QTL) analyses were performed for each parameter. We screened for four CSC susceptibility SNPs: CFH rs800292, TNFRSF10A rs13278062, GATA5 rs6061548, and VIPR2 rs3793217. Whenever an SNP was not included in the genotyping data after quality control, its proxy SNP was selected.In total, 4586 participants were evaluated. CFH rs800292 was significantly associated with SFCT (P0.001) and CVI (P0.001). VIPR2 rs3793217 was significantly associated with SFCT (P0.001) but not with CVI. Whereas, TNFRSF10A rs13254617 and GATA5 rs6061548 were not significantly associated with SFCT or CVI. None of these SNPs was associated with NCICFH, VIPR2, TNFRSF10A, and GATA5 showed different association patterns with choroidal parameters. Although the mechanism of CSC pathogenesis by choroidal changes is not fully understood, this finding suggests that each gene may be involved in different mechanisms of CSC development. Our genetic study provides a basis for understanding the role of CSC susceptibility genes.

Purpose To describe the distribution of ocular biometry and refraction in Japanese adults. Design Cross-sectional analysis of a prospective cohort study. Participants A total of 9850 individuals participated in the first follow-up of the Nagahama Prospective Cohort for Comprehensive Human Bioscience (the Nagahama Study) conducted between 2013 and 2016. Participants were between 34 and 80 years of age. Methods All participants underwent axial length (AL; in millimeters), anterior chamber depth (ACD; in millimeters), corneal diameter (white to white; in millimeters), and central corneal thickness (CCT; in micrometers) measurement (IOL Master; Carl Zeiss Meditec, Dublin, CA) and refraction (spherical equivalent [SE]; in diopters [D]) and corneal curvature (CC; in millimeters) measurement (ARK-530A; Nidek, Aichi, Japan). Distribution of these ocular biometric parameters and prevalence of myopia, high myopia, and extreme myopia were summarized. Main Outcome Measures Distribution of ocular biometry and refraction. Results After standardization to the national population of 2015, estimates of mean AL and SE were 24.21 mm and –1.44 D, respectively. Estimates of mean CC, corneal diameter, CCT, and ACD were 7.69 mm, 12.01 mm, 543.96 μm, and 3.21 mm, respectively. After standardization of age and gender, the prevalence of myopia (SE, ≤–0.5 D) and high myopia (SE, ≤–6.0 D) were 49.97% and 7.89%, respectively. Approximately 70% of the younger participants (34–59 years of age) showed myopia, whereas high myopia was observed in approximately 10%. Although the number of individuals with myopia or high myopia was higher in the younger age groups, the prevalence of more extreme phenotypes remained stable across all ages, especially in women. Axial length of more than 30 mm was observed only in older women (n = 5 [0.05%]). Conclusions We showed detailed distributions of various ocular biometry and refraction parameters using a large general Japanese cohort. Prevalences of myopia and high myopia from 2013 through 2016 were higher than those in earlier studies, which reflects recent environmental change. However, constant prevalence of extreme myopia across all ages suggests high genetic predisposition of the extreme phenotype.

Purpose To identify novel susceptibility loci for high myopia. Design Genome-wide association study (GWAS) followed by replication and meta-analysis. Participants A total of 14 096 samples from East and Southeast Asian populations (2549 patients with high myopia and 11 547 healthy controls). Methods We performed a GWAS in 3269 Japanese individuals (1668 with high myopia and 1601 control participants), followed by replication analysis in a total of 10 827 additional samples (881 with high myopia and 9946 control participants) from Japan, Singapore, and Taiwan. To confirm the biological role of the identified loci in the pathogenesis of high myopia, we performed functional annotation and Gene Ontology (GO) analyses. Main Outcome Measures We evaluated the association of single nucleotide polymorphisms with high myopia and GO terms enriched among genes identified in the current study. Results We identified 9 loci with genome-wide significance (P Conclusions The current study identified 6 novel loci associated with high myopia and demonstrated an important role of the nervous system in the disease pathogenesis. Our findings give new insight into the genetic factors underlying myopia, including high myopia, by connecting previous findings and allowing for a clarified interpretation of the cause and pathophysiologic features of myopia at the molecular level.

Keratoconus is a common ocular disorder that causes progressive corneal thinning and is the leading indication for corneal transplantation. Central corneal thickness (CCT) is a highly heritable characteristic that is associated with keratoconus. In this two-stage genome-wide association study (GWAS) of CCT, we identified a locus for CCT, namely STON2 rs2371597 (P = 2.32 × 10−13), and confirmed a significant association between STON2 rs2371597 and keratoconus development (P = 0.041). Additionally, strong STON2 expression was observed in mouse corneal epithelial basal cells. We also identified SMAD3 rs12913547 as a susceptibility locus for keratoconus development using predictive analysis with IBM’s Watson question answering computer system (P = 0.001). Further GWAS analyses combined with Watson could effectively reveal detailed pathways underlying keratoconus development., Yoshikatsu Hosoda et al. study the genetic basis for central corneal thickness (CCT) that is associated with keratoconus. They identify two susceptibility loci, STON2 rs2371597 and SMAD3 rs12913547, using two-step genome-wide association study (GWAS) and predictive analysis with IBM’s Watson question answering computer system, respectively.

To identify susceptibility genes for macular neovascularization (MNV) development in central serous chorioretinopathy (CSC).Genome-wide survival analysis using a longitudinal cohort study.We included 402 and 137 patients with CSC but without MNV at their first visit from the Kyoto CSC Cohort and Kobe CSC dataset, respectively. All patients underwent detailed ophthalmic examinations, including multimodal imaging, such as fundus autofluorescence, spectral-domain OCT, and fluorescein angiography/indocyanine green angiography or OCT angiography.We conducted a genome-wide survival analysis using the Kyoto CSC Cohort. We applied the Cox proportional hazard model to adjust for age, sex, and the first principal component. Single nucleotide polymorphisms (SNPs) with P values1.0 × 10The association between SNPs and MNV development in patients with CSC.Rs370974631 near ARMS2 displayed a genome-wide significant association in the meta-analysis of discovery and replication result (hazard ratio [HR]ARMS2, CFH, COL4A3, and B3GALTL were identified as susceptibility genes for MNV development in CSC. These 4 genes are known as susceptibility genes for AMD, whereas COL4A3 and B3GALTL were previously reported to be polypoidal choroidal vasculopathy (PCV)-specific susceptibility genes. Our findings revealed the shared genetic susceptibility between PCV and MNV secondary to CSC.

To investigate the 2-year effectiveness of reduced-fluence photodynamic therapy (rf-PDT) for chronic central serous chorioretinopathy (cCSC).Retrospective cohort study.A total of 223 consecutive patients with newly diagnosed cCSC with active serous retinal detachment (SRD) were included from May 2007 to June 2017 and followed up for at least 2 years. Patients who underwent ocular treatment other than cataract surgery before the beginning of recruitment and those who had macular neovascularization at baseline were excluded.All patients underwent a comprehensive ophthalmic evaluation, including measurements of best-corrected visual acuity (BCVA), slit-lamp examination, dilated fundus examination, color fundus photography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, and spectral-domain OCT. An inverse probability of treatment weighting (IPTW) methodology was applied to balance 18 baseline characteristics between patients who received rf-PDT (rf-PDT group) and those who did not receive treatment (controls). Inverse probability of treatment weighting survival analysis and regression were performed.The proportion of patients whose BCVA at 24 months was the same or improved compared with the baseline visual acuity (VA) (VA maintenance rate).A total of 155 eyes (rf-PDT group: 74; controls: 81) were analyzed. The patients' backgrounds were well balanced after IPTW with standardized differences of0.10. An IPTW regression analysis revealed that the VA maintenance rate was significantly higher in the rf-PDT group than in the controls (93.6% vs. 70.9%,The study suggests the beneficial effect of rf-PDT for cCSC for both VA maintenance and higher proportion of complete SRD remission in the clinical setting.

Purpose To explore novel prognostic factors associated with visual function and number of anti–vascular endothelial growth factor (VEGF) treatments in eyes with active myopic choroidal neovascularization (mCNV) using OCT angiography (OCTA). Design Prospective case series. Participants Twenty-eight treatment-naive eyes with active mCNV from 27 consecutive patients (mean age, 64.4 ± 11.1 years). Methods All eyes received through injection a single loading dose of intravitreal aflibercept (IVA), followed by additional IVA on a pro re nata (PRN) basis during the subsequent 12 months. At baseline, OCTA images of a 3 × 3-mm macular cube were acquired using an OCTA scanner. On binarized and skeletonized OCTA images of the outer retinal layer, OCTA-derived baseline parameters of mCNV—including lesion size, vessel density, vessel length density (VLD), vessel diameter index, and fractal dimension (FD)—were measured and evaluated for correlation with 12-month best-corrected visual acuity (BCVA) and number of additional injections. Main Outcome Measures The primary and secondary outcomes were BCVA 12 months after initial treatment and number of additional injections, respectively. Results There was no significant difference between baseline and 12-month BCVA (0.37 ± 0.30 and 0.30 ± 0.35 logarithm of the minimal angle of resolution, respectively; P = 0.23). The number of additional injections was 0.93 ± 1.02 (mean ± standard deviation). Baseline VLD, FD, and BCVA were correlated with 12-month BCVA (P = 0.02, r = 0.46; P = 0.02, r = 0.46; and P = 0.02, r = 0.45, respectively), and VLD also was correlated with the number of additional injections (P = 0.03, r = 0.42). Conclusions Exuberant mCNV, which is characterized by high VLD and FD derived using OCTA, is a predictor of poor visual outcomes after a single IVA injection followed by a PRN regimen. Only baseline VLD was correlated with the number of additional IVA injections, which indicates that this parameter could help to determine the optimal anti-VEGF treatment regimen for individual eyes with mCNV.

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

Unsupervised machine learning has received increased attention in clinical research because it allows researchers to identify novel and objective viewpoints for diseases with complex clinical characteristics. In this study, we applied a deep phenotyping method to classify Japanese patients with age-related macular degeneration (AMD), the leading cause of blindness in developed countries, showing high phenotypic heterogeneity. By applying unsupervised deep phenotype clustering, patients with AMD were classified into two groups. One of the groups had typical AMD features, whereas the other one showed the pachychoroid-related features that were recently identified as a potentially important factor in AMD pathogenesis. Based on these results, a scoring system for classification was established; a higher score was significantly associated with a rapid improvement in visual acuity after specific treatment. This needs to be validated in other datasets in the future. In conclusion, the current study demonstrates the usefulness of unsupervised classification and provides important knowledge for future AMD studies.

The emergence of pachychoroid disease is changing the concept of age-related macular degeneration (AMD). The concept of pachychoroid diseases was developed through clinical observation of multimodal images of eyes with AMD and central serous chorioretinopathy; however, recent genetic studies have provided a proof of concept for pachychoroid spectrum disease, which should be differentiated from drusen-driven AMD. The genetic confirmation of pachychoroid concept further provides novel viewpoints to decode previously reported findings, which facilitates an understanding of the true nature of pachychoroid diseases and AMD. The purpose of this review was to elucidate the relationship between pachychoroid diseases and AMD by interpreting previous findings on pachychoroid diseases and AMD from the novel viewpoints of genetic associations. We confirmed that previous genetic studies supported the concept of pachychoroid diseases. From a genetic viewpoint, the presence of thick choroid and the presence of choroidal vascular hyperpermeability were important characteristics of pachychoroid spectrum diseases. Previous studies have also suggested the classification of polypoidal choroidal vasculopathy (PCV) into two subtypes, pachychoroid neovasculopathy and drusen-driven PCV. Genetic viewpoints will be beneficial to rearrange subtypes of drusen-driven AMD and pachychoroid spectrum diseases. Further genetic studies are needed to investigate pachyvessels, pachydrusen and the significance of polypoidal lesions in pachychoroid neovasculopathy and drusen-driven AMD/PCV.

To evaluate the association between daily coffee consumption and intraocular pressure (IOP) in healthy persons without glaucoma and the association between daily coffee consumption and history of glaucoma.Cross-sectional study.A total of 9850 individuals participated in the first follow-up of the Nagahama Prospective Cohort for Comprehensive Human Bioscience (the Nagahama Study) conducted between 2013 and 2016.All participants underwent a standardized ophthalmic examination. Self-reporting questionnaires were completed by all participants. First, the association between habitual coffee consumption and IOP among nonglaucoma individuals was evaluated by a multivariate linear regression analysis, adjusting for possible confounders. Second, the association between habitual coffee consumption and history of glaucoma also was evaluated using a multivariate logistic regression analysis.The association between habitual coffee consumption and IOP among nonglaucoma individuals.Of 9850 participants, 9418 did not have history of glaucoma. Among these participants, the mean ± standard deviation IOP of both eyes was 14.7 ± 2.9 mmHg. The multivariate regression analysis revealed that habitual coffee consumption was associated significantly with IOP (P0.001): the higher the consumption of coffee, the lower the IOP of an individual. The IOP of the group who consumed coffee most frequently (3 times daily or more) was 0.4 mmHg lower (95% confidence interval, 0.2-0.5 mmHg lower) than that of the group that consumed coffee least frequently (less than once daily). However, the logistic regression analysis showed that habitual coffee consumption was not associated significantly with history of glaucoma (P = 0.53).Frequent coffee consumption was associated with a slightly lower IOP in people without glaucoma but was not associated with a decreased risk of glaucoma developing. Additional experimental studies are needed to examine the effects of coffee on IOP and glaucoma risk.

To describe the distribution of ocular biometry and refraction in Japanese adults.Cross-sectional analysis of a prospective cohort study.A total of 9850 individuals participated in the first follow-up of the Nagahama Prospective Cohort for Comprehensive Human Bioscience (the Nagahama Study) conducted between 2013 and 2016. Participants were between 34 and 80 years of age.All participants underwent axial length (AL; in millimeters), anterior chamber depth (ACD; in millimeters), corneal diameter (white to white; in millimeters), and central corneal thickness (CCT; in micrometers) measurement (IOL Master; Carl Zeiss Meditec, Dublin, CA) and refraction (spherical equivalent [SE]; in diopters [D]) and corneal curvature (CC; in millimeters) measurement (ARK-530A; Nidek, Aichi, Japan). Distribution of these ocular biometric parameters and prevalence of myopia, high myopia, and extreme myopia were summarized.Distribution of ocular biometry and refraction.After standardization to the national population of 2015, estimates of mean AL and SE were 24.21 mm and -1.44 D, respectively. Estimates of mean CC, corneal diameter, CCT, and ACD were 7.69 mm, 12.01 mm, 543.96 μm, and 3.21 mm, respectively. After standardization of age and gender, the prevalence of myopia (SE, ≤-0.5 D) and high myopia (SE, ≤-6.0 D) were 49.97% and 7.89%, respectively. Approximately 70% of the younger participants (34-59 years of age) showed myopia, whereas high myopia was observed in approximately 10%. Although the number of individuals with myopia or high myopia was higher in the younger age groups, the prevalence of more extreme phenotypes remained stable across all ages, especially in women. Axial length of more than 30 mm was observed only in older women (n = 5 [0.05%]).We showed detailed distributions of various ocular biometry and refraction parameters using a large general Japanese cohort. Prevalences of myopia and high myopia from 2013 through 2016 were higher than those in earlier studies, which reflects recent environmental change. However, constant prevalence of extreme myopia across all ages suggests high genetic predisposition of the extreme phenotype.

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

Genetic studies have investigated the pathogenesis of age-related macular degeneration (AMD). The pachychoroid concept has recently garnered attention as a possible explanation for AMD pathogenesis; the genetic characteristics of pachychoroid diseases have also been elucidated. In this review, we summarize previously reported genetic characteristics of AMD and pachychoroid diseases, and analyze these data to understand the pathogenesis of AMD and pachychoroid diseases. Previous studies show that VIPR2 and the CFH I62V A allele promote development of pachychoroid and central serous chorioretinopathy (CSC), while the CFH I62V G allele promotes development of drusen, pachychoroid neovasculopathy (PCN/PNV), and AMD. ARMS2/HTRA1 also promotes development of drusen, PCN/PNV, and AMD. TNFRSF10A and GATA5 are associated with CSC but not with pachychoroid, and TNFRSF10A is associated with AMD that includes PCN/PNV. These genetic characteristics suggest the following mechanisms of developing AMD and pachychoroid diseases. VIPR2 and the CFH I62V A allele promote pachychoroid development, which can result in CSC development. The CFH I62V G allele promotes a common step during PCN/PNV and AMD development induced by pachychoroid or drusen, such as damage of Bruch's membrane or retinal pigment epithelium (RPE). ARMS2/HTRA1 also promotes damage of Bruch's membrane or RPE, while the association with drusen formation is stronger in ARMS2/HTRA1 than in CFH. TNFRSF10A and GATA5 promote blood-retinal-barrier breakdown to induce CSC, which could lead to PCN/PNV development. Furthermore, recently reported genetic associations with the natural course of CSC suggest the importance of reconsidering the subtype classification of CSC. These associations would enable the development of personalized/precision medicine for CSC and.

Purpose: To evaluate the roles of known myopia-associated genetic variants for development of myopic macular degeneration (MMD) in individuals with high myopia (HM), using case-control studies from the Consortium of Refractive Error and Myopia (CREAM). Methods: A candidate gene approach tested 50 myopia-associated loci for association with HM and MMD, using meta-analyses of case-control studies comprising subjects of European and Asian ancestry aged 30 to 80 years from 10 studies. Fifty loci with the strongest associations with myopia were chosen from a previous published GWAS study. Highly myopic (spherical equivalent [SE] ≤ -5.0 diopters [D]) cases with MMD (N = 348), and two sets of controls were enrolled: (1) the first set included 16, 275 emmetropes (SE ≤ -0.5 D); and (2) second set included 898 highly myopic subjects (SE ≤ -5.0 D) without MMD. MMD was classified based on the International photographic classification for pathologic myopia (META-PM). Results: In the first analysis, comprising highly myopic cases with MMD (N = 348) versus emmetropic controls without MMD (N = 16, 275), two SNPs were significantly associated with high myopia in adults with HM and MMD: (1) rs10824518 (P = 6.20E-07) in KCNMA1, which is highly expressed in human retinal and scleral tissues; and (2) rs524952 (P = 2.32E-16) near GJD2. In the second analysis, comprising highly myopic cases with MMD (N = 348) versus highly myopic controls without MMD (N = 898), none of the SNPs studied reached Bonferroni-corrected significance. Conclusions: Of the 50 myopia-associated loci, we did not find any variant specifically associated with MMD, but the KCNMA1 and GJD2 loci were significantly associated with HM in highly myopic subjects with MMD, compared to emmetropes., Correction--10 Oct 2019: Wong YL, Hysi P, Cheung G, Tedja M, Hoang QV, et al. (2019) Correction: Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium. PLOS ONE 14(10): e0223942. https://doi.org/10.1371/journal.pone.0223942

The recently emerged pachychoroid concept has changed the understanding of age-related macular degeneration (AMD), which is a major cause of blindness; recent studies attributed AMD in part to pachychoroid disease central serous chorioretinopathy (CSC), suggesting the importance of elucidating the CSC pathogenesis. Our large genome-wide association study followed by validation studies in three independent Japanese and European cohorts, consisting of 1546 CSC samples and 13, 029 controls, identified two novel CSC susceptibility loci: TNFRSF10A-LOC389641 and near GATA5 (rs13278062, odds ratio = 1.35, P = 1.26 × 10−13; rs6061548, odds ratio = 1.63, P = 5.36 × 10−15). A T allele at TNFRSF10A-LOC389641 rs13278062, a risk allele for CSC, is known to be a risk allele for AMD. This study not only identified new susceptibility genes for CSC, but also improves the understanding of the pathogenesis of AMD., 特殊な網膜剥離の発症に関わる遺伝子変異を発見 --中心性漿液性脈絡網膜症のゲノムワイド関連解析--. 京都大学プレスリリース. 2019-12-13.

Objective Age-related macular degeneration (ARMD) is a leading cause of visual impairment. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) are the standard treatment for wet ARMD. There is however, variability in patient responses, suggesting patient-specific factors influencing drug efficacy. We tested whether single nucleotide polymorphisms (SNPs) in genes encoding VEGF pathway members contribute to therapy response. Methods and analysis A retrospective cohort of 281 European wet ARMD patients treated with anti-VEGF was genotyped for 138 tagging SNPs in the VEGF pathway. Per patient, we collected best corrected visual acuity at baseline, after three loading injections and at 12 months. We also registered the injection number and changes in retinal morphology after three loading injections (central foveal thickness (CFT), intraretinal cysts and serous neuroepithelium detachment). Changes in CFT after 3 months were our primary outcome measure. Association of SNPs to response was assessed by binomial logistic regression. Replication was attempted by associating visual acuity changes to genotypes in an independent Japanese cohort. Results Association with treatment response was detected for seven SNPs, including in FLT4 (rs55667289: OR=0.746, 95% CI 0.63 to 0.88, p=0.0005) and KDR (rs7691507: OR=1.056, 95% CI 1.02 to 1.10, p=0.005; and rs2305945: OR=0.963, 95% CI 0.93 to 1.00, p=0.0472). Only association with rs55667289 in FLT4 survived multiple testing correction. This SNP was unavailable for testing in the replication cohort. Of six SNPs tested for replication, one was significant although not after multiple testing correction. Conclusion Identifying genetic variants that define treatment response can help to develop individualised therapeutic approaches for wet ARMD patients and may point towards new targets in non-responders., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose To investigate potential genetic prognostic factors associated with spontaneous resolution of serous retinal detachment (SRD) and development of choroidal neovascularization (CNV) in central serous chorioretinopathy (CSC). Design Retrospective analysis of a case series. Participants One hundred ninety-six eyes from 196 patients with active CSC. Methods We retrospectively reviewed medical records and determined the presence or absence of SRD using OCT imaging. The duration until the spontaneous SRD resolution was analyzed using the Kaplan-Meier method, and associations between the duration to spontaneous resolution and Complement factor H (CFH) I62V, Age-Related Maculopathy Susceptibility 2 (ARMS2) A69S, or Vasoactive Intestinal Peptide Receptor 2 (VIPR2) rs3793217 genotypes were evaluated, followed by the assessment of their associations with CNV that developed secondary to CSC. Main Outcome Measures Genetic associations of CFH rs800292, ARMS2 rs10490924, and VIPR2 rs3793217 genotypes with the duration to spontaneous resolution of SRD and development of CNV during follow-up of CSC. Results In 105 of the 196 study participants, we revealed spontaneous SRD resolution in their eyes during follow-up evaluation. Sixty-eight eyes received treatment, and 23 eyes dropped out before spontaneous SRD resolution. Among the 3 genetic polymorphisms assessed herein, only the CFH I62V genotype was predictive of spontaneous SRD resolution among its genotypes (P = 0.017); the average durations for the spontaneous SRD resolution for the individuals with AA, AG, and GG genotype were 126.6±115.5 days, 157.7±243.1 days, and 242.7±198.0 days, respectively, indicating that the G allele was associated with significantly longer persistent SRD (P = 0.035). Among the total number of eyes of all participants, 14 demonstrated CNV during follow-up evaluation. The CFH I62V G and ARMS2 A69S T alleles were associated significantly with CNV development (P = 0.0023 and P = 0.019, respectively), whereas the VIPR2 rs3793217 genotype was not. Conclusions The CFH I62V and ARMS2 A69S genotypes can predict the prognosis of CSC. Knowledge of the genetic status may help physicians determine the need for early treatment and possibly prevent subsequent CNV development. Further prospective studies are needed to confirm the observed genotype–phenotype relationship.

Yoshikatsu Hosoda, Shoji Kuriyama, Yoko Jingami, Hidetsugu Hattori, Hisako Hayashi, Miho Matsumoto Department of Ophthalmology, Otsu Red-Cross Hospital, Otsu, Japan Purpose: The purpose of this study was to compare the level of patient pain during the phacoemulsification and implantation of foldable intraocular lenses while under topical, intracameral, or sub-Tenon lidocaine.Patients and methods: This was a retrospective study. Three hundred and one eyes subjected to cataract surgery were included in this study. All eyes underwent phacoemulsification surgery and intraocular lens implantation using topical, sub-Tenon, or intracameral anesthesia. The topical group received 4% lidocaine drops, and the intracameral group received a 0.1–0.2cc infusion of 1% preservative-free lidocaine into the anterior chamber through the side port combined with topical drops of lidocaine. The sub-Tenon group received 2% lidocaine. Best-corrected visual acuity, corneal endothelial cell loss, and intraoperative pain level were evaluated. Pain level was assessed on a visual analog scale (range 0–2).Results: There were no significant differences in visual outcome and corneal endothelial cell loss between the three groups. The mean pain score in the sub-Tenon group was significantly lower than that in the topical and intracameral groups (P=0.0009 and P=0.0055, respectively). In 250 eyes without high myopia (

To evaluate the visual outcome, primary anatomic success, and cataract progression of phakic eyes of patients aged younger than 50 years treated for rhegmatogenous retinal detachment (RRD) with primary pars plana vitrectomy (PPV). This was a retrospective, observational, cross-sectional study. The data from 53 RRD patients undergoing PPV were analyzed. The time course changes in best-corrected visual acuity (BCVA) and cataract formation were examined. The 53 patients had a mean age of 37.8 years. Forty-eight eyes (90.6 %) achieved anatomic success after the primary surgery. The BCVA improved significantly after surgery (mean ± SD −0.091 ± 0.146) when compared with the baseline (mean ± SD 0.214 ± 0.597; P = 0.0001). No patient aged younger than 40 years (mean 32.5 years; range 17–39) developed significant lens opacity or received cataract surgery within the first 3 years. Of the patients aged older than 40 years (mean 43.8 years; range 40–49), 22 % developed significant lens opacity and received cataract surgery within the first 3 years. A significant difference was found in cataract progression between the two groups within the first 3 years (P = 0.0217), but not over the entire follow-up period (P = 0.1679). We found that lens-sparing PPV for RRD in patients aged younger than 50 years had a reasonable success rate, although cataract progression was evident during the follow-up period in patients aged older than 40 years.

Purpose To investigate whether the photoreceptor layer status of the detached retina, which has the potential to plug the macular hole (MH), can predict postoperative visual acuity (VA). Design Retrospective, consecutive, observational case series. Methods A consecutive series of 48 eyes in 48 patients with surgically closed MHs were recruited into the study. Spectral-domain optical coherence tomography (SD OCT) images were obtained preoperatively and postoperatively. Length gaps between photoreceptor layers and the preoperative diameter of the basal MH in the detached part of the retina was calculated for the photoreceptor outer segment (OS) and the external limiting membrane (ELM). The postoperative photoreceptor layer status at the fovea, including continuity of the ELM line, inner segment ellipsoid line (ISe), and cone outer segment tip (COST) line, was categorized by graders. Results The preoperative OS gap length and ELM gap length correlated significantly with postoperative VA. A larger OS or ELM gap length was associated with a more severe postoperative photoreceptor layer status. Eyes with a moderately reflective lesion had a significantly longer OS gap length and ELM gap length, significantly worse postoperative VA, and more severe photoreceptor layer status than did eyes without such a moderately reflective lesion. Eyes with a better postoperative COST status had significantly better postoperative VA ( P = .0465). Conclusions OS and ELM gap length, which represent the degree of insufficiency of MH plugging, was strongly correlated with postoperative VA; moreover, these preoperative parameters were associated with the postoperative photoreceptor layer status, including glial cell proliferation.

Background/aims To investigate the effectiveness of isolated subtenon triamcinolone acetonide injection (STI) as a primary treatment in eyes with acute Vogt–Koyanagi–Harada (VKH) disease. Design Retrospective, observational, cross-sectional study. Methods The data from 27 eyes in 14 patients with acute VKH treated with STI therapy were analysed retrospectively. The time course change in ocular inflammation, best corrected visual acuity (BCVA) and numbers of recurrences were examined. Results STI led to prompt improvement of BCVA within a week after the primary treatment. After completing therapy, patients with VKH had improved BCVA compared with baseline. In six eyes of three patients (22.2%) treated with STI, ocular inflammation was refractory, or VKH was recurrent despite the treatment. There was significant difference between groups with and without recurrences of inflammation in the frequency of headaches before treatment. In the present study, 21 eyes of 11 patients (77.8%) achieved complete resolution of VKH without recurrence after STI therapy alone. Conclusions This study demonstrated that isolated STI therapy is a useful, minimally invasive, primary treatment option for patients with acute VKH without systemic disorders.

Yoshikatsu Hosoda, Tadamichi Akagi, Nagahisa YoshimuraDepartment of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, JapanAbstract: Malignant glaucoma, which is characterized by a shallow or flat anterior chamber with high intraocular pressure, can usually be resolved by pars plana vitrectomy with anterior hyaloidectomy. We describe two cases in which malignant glaucoma was refractory to conventional treatment and complete vitrectomy. Case one an 88-year-old woman with pseudoexfoliation glaucoma underwent trabeculotomy and subsequently developed malignant glaucoma. Four months after transient recovery by pars plana vitrectomy, the malignant glaucoma recurred. She underwent peripheral iridectomy and local zonulectomy with successful control of her intraocular pressure. In case two, an 85-year-old man had a history of pseudoexfoliation glaucoma. Seven months after phacoemulsification and intraocular lens implantation, he developed malignant glaucoma that was refractory to pars plana vitrectomy. He underwent peripheral iridectomy, goniosynechialysis and trabectome surgery resulting in the successful control of his intraocular pressure. In rare cases of malignant glaucoma refractive to vitrectomy, peripheral iridectomy with or without local zonulectomy is a reasonable and minimally invasive surgical procedure.Keywords: malignant glaucoma, pars plana vitrectomy, peripheral iridectomy

We report on 2 patients with well-documented mixed connective tissue disease (MCTD) accompanied by severe pulmonary hypertension (PH) due to thrombosis or thromboembolism. In a previous report we indicated (1) that patients with MCTD complicated by PH have a significantly worse prognosis than patients with other connective tissue disease (CTD) complicated by PH. Both our patients had anticardiolipin antibody (a-CL) in the initial stages of the disease. We also studied the relationship of a-CL to PH in patients with other CTD. Patients of either MCTD or SLE with high levels of a-CL had significantly higher values of mean pulmonary arterial pressure than patients without a-CL. Several factors were suggested for the pathogenesis of PH such as vasospasm, arteritis, platelet dysfunction, and thrombosis or thromboembolism. The presence of a-CL may be one of important factors in development of PH among patients with MCTD with recurrent pulmonary thrombosis or thromboembolism.

PURPOSE The purpose of this study was to determine whether the outer nuclear layer (ONL) deformation detected by spectral-domain optical coherence tomography (SD-OCT) is correlated with visual acuity before and after surgery in patients with idiopathic epiretinal membrane (ERM). METHODS Forty-four eyes of 44 patients who underwent vitreous surgery for treatment of ERM were included. All patients underwent comprehensive ophthalmologic evaluations including measurement of best corrected visual acuity (BCVA) and SD-OCT before and after surgery. The central foveal thickness (CFT), foveal ONL thickness, juxtafoveal ONL plus outer plexiform layer (OPL) thickness, photoreceptor outer segment thickness, and size of the disrupted interdigitation zone (IZ) line were measured. We defined the "photoreceptor deformation index" (PDI) as the ratio of foveal ONL thickness to the juxtafoveal ONL plus OPL thickness. RESULTS Multiple regression analysis showed that the only significant predictor of preoperative mean logarithm of the minimum angle of resolution (logMAR) BCVA was preoperative CFT (P < 0.0001). Preoperative PDI (P < 0.0001) and disrupted IZ diameter (P = 0.0242) were positively correlated with logMAR at 3 months after surgery. PDI (P < 0.0001) and disrupted IZ diameter (P = 0.0351) were also positively correlated with logMAR BCVA at 6 months after surgery. The only significant predictor of logMAR at 12 months after surgery was preoperative PDI (P < 0.0001). CONCLUSIONS Preoperative PDI was most significantly correlated with postoperative BCVA. These results suggest that PDI is a novel parameter predicting visual outcome after surgery in eyes with ERM.

The effect of interpolation and super-resolution (SR) algorithms on quantitative and qualitative assessments of enlarged optical coherence tomography (OCT) images was investigated in this report. Spectral-domain OCT images from 30 eyes in 30 consecutive patients with diabetic macular edema (DME) and 20 healthy eyes in 20 consecutive volunteers were analyzed. Original image (OR) resolution was reduced by a factor of four. Images were then magnified by a factor of four with and without application of one of the following algorithms: bilinear (BL), bicubic (BC), Lanczos3 (LA), and SR. Differences in peak signal-to-noise ratio (PSNR), retinal nerve fiber layer (RNFL) thickness, photoreceptor layer status, and parallelism (reflects the complexity of photoreceptor layer alterations) were analyzed in each image type. The order of PSNRs from highest to lowest was SR > LA > BC > BL > non-processed enlarged images (NONE). The PSNR was statistically different in all groups. The NONE, BC, and LA images resulted in significantly thicker RNFL measurements than the OR image. In eyes with DME, the photoreceptor layer, which was hardly identifiable in NONE images, became detectable with algorithm application. However, OCT photoreceptor parameters were still assessed as more undetectable than in OR images. Parallelism was not statistically different in OR and NONE images, but other image groups had significantly higher parallelism than OR images. Our results indicated that interpolation and SR algorithms increased OCT image resolution. However, qualitative and quantitative assessments were influenced by algorithm use. Additionally, each algorithm affected the assessments differently.

To investigate the correlation between choroidal and retinal lesions in eyes with acute Vogt-Koyanagi-Harada disease (VKH) using optical coherence tomography (OCT) by using a new parameter, retinal pigment epithelium (RPE) undulation index, which quantitatively describes choroidal deformations.Retrospective, observational, cross-sectional study.Spectral-domain OCT (SD OCT) and swept-source OCT images from a consecutive series of 42 eyes in 22 patients with acute VKH who underwent steroid therapy and 20 healthy eyes in 20 volunteers were analyzed retrospectively. Correlations between best-corrected visual acuity (BCVA), axial length change, and OCT parameters were examined. The RPE undulation index was defined as RPE line length to the total scan length ratio on a foveal-centered scan in the SD OCT image.Eyes with acute VKH showed increased RPE undulation index, choroidal thickness, and retinal thickness compared to normal subjects, which were reduced following steroidal treatment (P.0001, P = .0003, and P.0001, respectively). RPE undulation index was related to choroidal thickness (r = 0.624, P = .0043), retinal thickness (r = 0.483, P = .0028), and BCVA (r = 0.588, P = .0002). Meanwhile, no statistically significant relationship was observed between choroidal thickness and retinal thickness. Axial length changes were significantly correlated with both choroidal thickness (r = 0.842, P.0001) and RPE undulation index (r = 0.600, P = .0139).This study demonstrated that the choroid was diffusely undulated and bulged inward in eyes with acute VKH. Correlations between RPE undulation index and choroid morphology, retinal thickness, and poor BCVA suggest that choroidal folding, quantified by RPE undulation index, is useful in assessing VKH disease severity.

Digital fundus photography, commonly used in the diagnosis and monitoring of many ocular diseases, is an essential part of ophthalmology practice. However, fundus cameras are often costly and rely on separate computers for viewing and transmission of fundus photographs. In addition, adoption of electronic clinical record systems is expected to increase the demand for simple and cost-effective alternatives to the fundus camera that will allow the doctors to capture fundus images themselves during a medical examination. We describe a novel modified technique using slit-lamp biomicroscopy with a noncontact lens, which enables simple and convenient color fundus imaging. We called our new technique slit lampand noncontact lens-assisted photography (SNAP). The technique is basically the same technique as conventional fundus imaging using slit-lamp biomicroscopy with a noncontact lens. However, SNAP images are obtained with a light diffuser on the slit lamp, and the slit lamp oriented at a relatively large angle of approximately 20 to 30 with respect to the optic axis (Fig. 1). SNAP images were captured with a digital single-lens reflex camera (Nikon D300 s, Nikon Imaging Japan Inc., Tokyo, Japan) connected to the slit lamp (RO 5000, Rodenstock, Munich, Germany) and a 90 D lens (Super Field NC lenses, Volk Optical Inc., Mentor, OH, USA). Color fundus photograph-like fundus images of the retina could be captured not only at the posterior pole but also at the peripheral part using the SNAP technique. The imaging fields of SNAP images were wider than those of basic slit-like fundus images and equivalent to those of color fundus photographs obtained with a conventional fundus camera (Fig. 2). Meanwhile, SNAP images displayed unnecessary reflection in the peripheral image.

A 64-year-old Japanese woman with progressive systemic sclerosis (PSS) who developed severe pyloric stenosis is described. The conservative treatments brought only the temporary symptomatic relief, and pyloroplasty became necessary. No ulcerative lesions or tumors were found in the resected stomach or duodenum specimens implicated for stenosis. The histological examinations revealed edema and replacement fibrosis in the pyloric ring. The possible mechanisms of pyloric stenosis are discussed.

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.