Investigative ophthalmology & visual science最新文献

{"title":"Trabecular Meshwork Abnormalities in a Model of Congenital Glaucoma Due to LTBP2 Mutation.","authors":"Odalys Torné, Kazuya Oikawa, Leandro B C Teixeira, Julie A Kiland, Gillian J McLellan","doi":"10.1167/iovs.65.12.28","DOIUrl":"10.1167/iovs.65.12.28","url":null,"abstract":"<p><strong>Purpose: </strong>To characterize early trabecular meshwork (TM) morphologic abnormalities in a feline model of human primary congenital glaucoma (PCG) caused by mutation in LTBP2.</p><p><strong>Methods: </strong>Eyes from 41 cats, including 19 normal and 22 homozygous for LTBP2 mutation, across various postnatal stages (birth, 2 weeks, 5 weeks, and 12 weeks) were paraformaldehyde fixed, anterior segments dissected, post-fixed in glutaraldehyde, osmicated, and processed and sectioned for transmission electron microscopy. Cell morphology, nuclear shape, and intertrabecular space (ITS) were quantitatively assessed, and the structure of the fibrillar extracellular matrix in the TM was systematically evaluated.</p><p><strong>Results: </strong>The earliest differences in TM morphology between PCG and normal cats were identified at 2 weeks postnatally. Elastic fibers in the TM were discontinuous and disorganized (P = 0.0122), and by 5 weeks of age PCG cats presented significantly less ITS (P = 0.0076) and morphologically rounder TM cells than normal cats (P = 0.0293). By 12 weeks of age, the ITS was further collapsed (P < 0.0001), and the TM cells were morphologically elongated and attenuated in PCG compared to controls (P = 0.0028).</p><p><strong>Conclusions: </strong>In this feline model of PCG due to LTBP2 mutation, development of ultrastructural TM extracellular matrix abnormalities are first observed by 2 weeks and cellular abnormalities by 5 weeks of age. By 12 weeks of age, when intraocular pressure becomes significantly elevated, the TM morphologic abnormalities are already well established. These findings suggest that the postnatal period between 0 and 5 weeks of age is critical for TM and PCG development and progression in cats.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11500042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fetuin-B Interacts With Insulin Receptor-β and Promotes Insulin Resistance in Retina Cells.","authors":"Wenyi Zhang, Xin Wang, Shuwei Tian, Jianming Wang, Aiyi Zhou","doi":"10.1167/iovs.65.12.16","DOIUrl":"10.1167/iovs.65.12.16","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to investigate the correlation between insulin and Fetuin-B (FETUB) and the influence of FETUB on insulin signaling pathway in diabetic retinopathy (DR).</p><p><strong>Methods: </strong>Enzyme-linked immunosorbent assay (ELISA) was used to analyze FETUB and insulin levels in the serum and aqueous fluid of patients with DR and healthy controls. Quantitative PCR (q-PCR), Western blotting, and ELISA were used to examine FETUB expression in ARPE-19, BV2, and Müller cells under insulin stimulation. Co-immunoprecipitation was used to investigate the interaction of FETUB with insulin receptor-β (IRβ). Insulin resistance (IR)-BV2 and IR-Müller cells were treated with FETUB recombinant protein or FETUB short hairpin RNA (shRNA) to explore the influence of FETUB on insulin signaling pathway in DR. LY294002 (a PI3K pathway inhibitor) was used to determine whether FETUB affects glucose metabolism via the PI3K/Akt pathway.</p><p><strong>Results: </strong>In aqueous fluid, FETUB concentrations were positively correlated with insulin levels. FETUB expression increased in Müller and BV2 cells under insulin regulation, and FETUB interacted with IRβ in retinal cells and mice retina. The interaction between IRβ and FETUB increased in BV2 and Müller cells under high-glucose than in controls. Insulin signaling pathway activation was suppressed in FETUB recombinant protein-treated BV2 and Müller cells but increased in FETUB shRNA-transfected cells. FETUB shRNA could not reverse LY294002-mediated inhibition of glucose transporter-4 expression.</p><p><strong>Conclusions: </strong>Retinal cells are the source of insulin-regulated FETUB. The FETUB interacts with IRβ and affects insulin signaling pathway in BV2 and Müller cells. FETUB may aggravate IR in BV2 and Müller cells via the PI3K/Akt pathway.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11469143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Impact of Spliceosome Inhibition in SF3B1-Mutated Uveal Melanoma.","authors":"Josephine Q N Nguyen, Wojtek Drabarek, Aïsha M C H J Leeflang, Tom Brands, Thierry P P van den Bosch, Robert M Verdijk, Harmen J G van de Werken, Job van Riet, Dion Paridaens, Annelies de Klein, Erwin Brosens, Emine Kiliç","doi":"10.1167/iovs.65.12.11","DOIUrl":"10.1167/iovs.65.12.11","url":null,"abstract":"<p><strong>Purpose: </strong>Unfortunately, treatment of patients with uveal melanoma (UM) with metastatic disease is limited. Twenty percent of patients with UM harbor a mutation in the splicing factor gene SF3B1, suggesting that aberrant spliceosome function plays a vital role in tumorigenesis. Splicing inhibitors exploit the preferential sensitivity of spliceosome-compromised leukemic cells to these compounds.</p><p><strong>Methods: </strong>We studied the effect of the splicing inhibitor E7107 using two UM cell lines and ex vivo cultured SF3B1- and BAP1-mutated primary UM tumor slices. These UM cell lines and ex vivo tumor slices were exposed for 24 hours to different concentrations of E7107. Tumor slices were stained with hematoxylin and eosin (H&E) and incubated with BAP1, MelanA, MIB-1, and caspase-3 antisera.</p><p><strong>Results: </strong>The E7107-exposed UM cell lines exhibited decreased cell viability and increased apoptosis, with the greatest effect on SF3B1-mutated UM cells. A similar effect on UM tumor slices was observed upon exposure to E7107. Additionally, RNA was isolated for differential isoform expression analysis. No significant difference in isoform usage was found genome-wide. However, specific genes were differentially expressed after E7107 treatment in the SF3B1-mutated samples. Moreover, E7107 had the greatest effect on intron retention.</p><p><strong>Conclusions: </strong>This study indicates/suggests that mutated SF3B1 UM cells are more sensitive to the splicing inhibitor E7107 than wild-type SF3B1 UM cells.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statistical Model of Ocular Wavefronts With Accommodation.","authors":"María Mechó-García, María Arcas-Carbonell, Elvira Orduna-Hospital, Ana Sánchez-Cano, Norberto López-Gil, Rute J Macedo-de-Araújo, Miguel Faria-Ribeiro, Paulo Fernandes, José Manuel González-Méijome, Jos Rozema","doi":"10.1167/iovs.65.12.12","DOIUrl":"10.1167/iovs.65.12.12","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to determine the minimum number of orthonormal basis functions, applying Principal Component Analysis (PCA), to represent the most wavefront aberrations at different accommodation stages. The study also aims to generate synthetic wavefront data using these functions.</p><p><strong>Methods: </strong>Monocular wavefront data from 191 subjects (26.15 ± 5.56 years old) were measured with a Hartmann-Shack aberrometer, simulating accommodation from 0 diopters (D) to 5 D in 1 D steps. The wavefronts for each accommodative demand were rescaled for different pupil sizes: 4.66, 4.76, 4.40, 4.09, 4.07, and 3.68 mm. PCA was applied to 150 wavefront parameters (25 Zernike coefficients × 6 accommodation levels) to obtain eigenvectors for dimensional reduction. A total of 49 eigenvectors were modeled as a sum of 2 multivariate Gaussians, from which 1000 synthetic data sets were generated.</p><p><strong>Results: </strong>The first 49 eigenvectors preserved 99.97% of the original data variability. No significant differences were observed between the mean values and standard deviation of the generated and original 49 eigenvectors (two one-sided test [TOST], P > 0.05/49) and (F-test, P > 0.05/49), both with Bonferroni correction. The mean values of the generated parameters (1000) were statistically equal to those of the original data (TOST, P > 0.05/150). The variability of the generated data was similar to the original data for the most important Zernike coefficients (F-test, P > 0.05/150).</p><p><strong>Conclusions: </strong>PCA significantly reduces the dimensionality of wavefront aberration data across 6 accommodative demands, reducing the variable space by over 66%. The synthetic data generated by the proposed wavefront model for accommodation closely resemble the original clinical data.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Severity Stratification of Coronary Artery Disease Using Novel Inner Ellipse-Based Foveal Avascular Zone Biomarkers.","authors":"Natasa Jeremic, Maximilian Pawloff, Dmitrii Lachinov, Stephanie Rokitansky, Matthias Hasun, Franz Weidinger, Andreas Pollreisz, Hrvoje Bogunovic, Ursula Schmidt-Erfurth","doi":"10.1167/iovs.65.12.15","DOIUrl":"10.1167/iovs.65.12.15","url":null,"abstract":"<p><strong>Purpose: </strong>Given the similarities between the retinal and coronary microvasculature, the retina holds promising potential to serve as a non-invasive screening tool for coronary artery disease (CAD). We aimed to develop novel inner ellipse-based metrics and discern whether foveal avascular zone (FAZ) alterations can serve as indicators for CAD presence and severity.</p><p><strong>Methods: </strong>Patients admitted to the Department of Cardiology who underwent coronary angiography were included. This resulted in an inclusion of 212 patients, of which 73 had no CAD. During the same visit, 6 × 6-mm (nominal size) fovea-centered optical coherence tomography angiography images of both eyes were acquired. The Gensini score (GS) was utilized to quantify CAD severity. Six known FAZ shape metrics were assessed and three novel biomarkers based on the inner ellipse were defined: absolute inner ellipse difference, Hausdorff distance, and Chamfer distance.</p><p><strong>Results: </strong>Eight out of nine metrics showed significant associations with the GS in the left eye. However, significant differences across three CAD severity groups were only demonstrated by the novel metrics. Utilizing the Chamfer distance, age, and sex, patients with and without CAD could be distinguished with an average area under the curve (AUC) of 0.89 (95% confidence interval [CI], 0.84-0.95). Moreover, three CAD severity groups could be discerned with a macro average AUC of 0.77 (95% CI, 0.72-0.84).</p><p><strong>Conclusions: </strong>A comprehensive assessment of FAZ shape descriptors was performed, and a strong association with CAD was found. The inner ellipse-based biomarkers especially demonstrated high predictive abilities for CAD presence and severity.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11469242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinal Organoid Microenvironment Enhanced Bioactivities of Microglia-Like Cells Derived From HiPSCs.","authors":"Mei-Ling Gao, Tong-Yu Wang, Xin Lin, Chun Tang, Mengyao Li, Zhan-Pei Bai, Zhi-Cong Liu, Li-Jun Chen, Qing-Ran Kong, Shao-Hui Pan, Shan-Shan Zeng, Ya Guo, Jian-Qi Cai, Xiu-Feng Huang, Jun Zhang","doi":"10.1167/iovs.65.12.19","DOIUrl":"10.1167/iovs.65.12.19","url":null,"abstract":"<p><strong>Purpose: </strong>Microglia-like cells derived from stem cells (iMG) provide a plentiful cell source for studying the functions of microglia in both normal and pathological conditions. Our goal is to establish a simplified and effective method for generating iMG in a precisely defined system. Additionally, we aim to achieve functional maturation of iMG through coculture with retinal organoids.</p><p><strong>Methods: </strong>In this study, iMG were produced under precisely defined conditions. They were subjected to LPS and poly IC stimulation. Additionally, we examined distinct phenotypic and functional variances between iMG and HMC3, a commonly used human microglia cell line. To investigate how the retinal cell interaction enhances microglial properties, iMG were cocultured with retinal organoids, producing CC-iMG. We performed RNA sequencing, electrophysiological analysis, and transmission electron microscope (TEM) to examine the maturation of CC-iMG compared to iMG.</p><p><strong>Results: </strong>Our results demonstrated that iMG performed immune-responsive profiles closely resembling those of primary human microglia. Compared to HMC3, iMG expressed a higher level of typical microglial markers and exhibited enhanced phagocytic activity. The transcriptomic analysis uncovered notable alterations in the ion channel profile of CC-iMG compared to iMG. Electrophysiological examination demonstrated a heightened intensity of inward- and outward-rectifying K+ currents in CC-iMG. Furthermore, CC-iMG displayed elevated numbers of lysosomes and mitochondria, coupled with increased phagocytic activity.</p><p><strong>Conclusions: </strong>These findings contribute to advancing our understanding of human microglial biology, specifically in characterizing and elucidating the functions of CC-iMG, thereby offering an in vitro microglial model for future scientific research and potential clinical applications in cell therapy.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NMNAT1 Is Essential for Human iPS Cell Differentiation to the Retinal Lineage.","authors":"Hiroshi Kuribayashi, Toshiro Iwagawa, Akira Murakami, Takeshi Kawamura, Yutaka Suzuki, Sumiko Watanabe","doi":"10.1167/iovs.65.12.37","DOIUrl":"https://doi.org/10.1167/iovs.65.12.37","url":null,"abstract":"<p><strong>Purpose: </strong>The gene encoding nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), a nicotinamide adenine dinucleotide synthetase localized in the cell nucleus, is a causative factor in Leber's congenital amaurosis, which is the earliest onset type of inherited retinal degeneration. We sought to investigate the roles of NMNAT1 in early retinal development.</p><p><strong>Methods: </strong>We used human induced pluripotent stem cells (hiPSCs) and established NMNAT1-knockout (KO) hiPSCs using CRISPR/cas9 technology to reveal the roles of NMNAT1 in human retinal development.</p><p><strong>Results: </strong>NMNAT1 was not essential for the survival and proliferation of immature hiPSCs; therefore, we subjected NMNAT1-KO hiPSCs to retinal organoid (RO) differentiation culture. The expression levels of immature hiPSC-specific genes decreased in a similar manner after organoid culture initiation up to 2 weeks in the control and NMNAT1-KO. Neuroectoderm-specific genes were induced in the control and NMNAT1-KO organoids within a few days after starting the organoid culture; PAX6 and TUBB3 were higher in NMNAT1-KO organoids up to 7 days than in the control organoids. However, the induction of genes involving retinal early development, such as RAX, which was induced at around day 10 in this culture, was considerably reduced in NMNAT1-KO organoids. Morphological examination also showed failure of retinal primordial structure formation, which became visible at around 2 weeks of the control culture, in the NMNAT1-KO organoids. Decreased intracellular NAD levels and poly(ADP-ribosyl)ation were observed in NMNAT1-KO organoids at 7 to 10 days of the culture. Mass spectrometry analysis of inhibited proteins in the poly(ADP-ribosyl)ation pathway identified poly(ADP-ribosyl)ation of poly(ADP-ribose) polymerase 1 (PARP1) as a major protein.</p><p><strong>Conclusions: </strong>These results indicate that NMNAT1 was dispensable for neural lineage differentiation but essential for the commitment of retinal fate differentiation in hiPSCs. The NMNAT1-NAD-PARP1 axis may play a critical role in the appropriate development of human retinal lineage differentiation.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Short- and Long-Term Perceptual Learning of Clinical Dynamic Visual Acuity Test.","authors":"Xiaobing Wang, Mingxin Yan, Jingmin Li, Yuexin Wang","doi":"10.1167/iovs.65.12.43","DOIUrl":"https://doi.org/10.1167/iovs.65.12.43","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to investigate the short- and long-term learning effect of dynamic visual acuity (DVA) tests.</p><p><strong>Methods: </strong>Participants between 18 and 30 years with corrected to normal visual acuity were enrolled in this study. Three repeated sessions were performed, with 15 minutes and 15 days' intervals between sessions. Each session included 9 DVA tests of horizontal, vertical, and diagonal motions of E optotypes at 20, 40, and 80 degrees per second (dps). The short- and long-term learning effects were analyzed from repeated DVA tests.</p><p><strong>Results: </strong>Of the 58 enrolled participants, the mean age was 23.1 ± 2.1 years. DVA significantly varied among motion types and velocities (P < 0.05, respectively). There was a significant short-term learning effect for 20 (P = 0.004), 40 (P < 0.001), and 80 (P = 0.014) dps DVA test of horizontal motion, 40 dps DVA test of vertical (P = 0.003), and diagonal motion (P = 0.036). The long-term learning effect was detected in the 40 dps diagonal motion DVA test (P = 0.015). The short- and long-term learning effects were positively associated with initial DVA in most combinations of motion type and velocity tests (P < 0.05, respectively). The short- (P = 0.031) and long-term (P = 0.024) learning effect of 80 dps horizontal motion DVA test was greater in male than female participants.</p><p><strong>Conclusions: </strong>There is a significant short-term learning effect in the DVA test of various motion types, but the long-term learning effect was rarely observed, and it is greater in participants with worse initial DVA.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive Evaluation of the Genetic Basis of Keratoconus: New Perspectives for Clinical Translation.","authors":"Miriam Cerván-Martín, Inmaculada Higueras-Serrano, Sara González-Muñoz, Andrea Guzmán-Jiménez, Blas Chaves-Urbano, Rogelio J Palomino-Morales, Arancha Poo-López, Luis Fernández-Vega-Cueto, Jesús Merayo-Lloves, Ignacio Alcalde, Lara Bossini-Castillo, F David Carmona","doi":"10.1167/iovs.65.12.32","DOIUrl":"10.1167/iovs.65.12.32","url":null,"abstract":"<p><strong>Purpose: </strong>Keratoconus (KC) is a corneal disorder with complex etiology, apparently involving both genetic and environmental factors, characterized by progressive thinning and protrusion of the cornea. We aimed to identify novel genetic regions associated with KC susceptibility, elucidate relevant genes for disease development, and explore the translational implications for therapeutic intervention and risk assessment.</p><p><strong>Methods: </strong>We conducted a genome-wide association study (GWAS) that integrated previously published data with newly generated genotyping data from an independent European cohort. To evaluate the clinical translation of our results, we performed functional annotation, gene prioritization, polygenic risk score (PRS), and drug repositioning analyses.</p><p><strong>Results: </strong>We identified two novel genetic loci associated with KC, with rs2806689 and rs807037 emerging as lead variants (P = 1.71E-08, odds ratio [OR] = 0.88; P = 1.93E-08, OR = 1.16, respectively). Most importantly, we identified 315 candidate genes influenced by confirmed KC-associated variants. Among these, MINK1 was found to play a pivotal role in KC pathogenesis through the WNT signaling pathway. Moreover, we developed a PRS model that successfully differentiated KC patients from controls (P = 7.61E-16; area under the curve = 0.713). This model has the potential to identify individuals at high risk for developing KC, which could be instrumental in early diagnosis and management. Additionally, our drug repositioning analysis identified acetylcysteine as a potential treatment option for KC, opening up new avenues for therapeutic intervention.</p><p><strong>Conclusions: </strong>Our study provides valuable insights into the genetic and molecular basis of KC, offering new targets for therapy and highlighting the clinical utility of PRS models in predicting disease risk.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11500050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic Performance for Detection of Glaucomatous Structural Damage Using Pixelwise Analysis of Retinal Thickness Measurements.","authors":"Hongli Yang, Juan Reynaud, Glen P Sharpe, Dawn Jennings, Cindy Albert, Trinity Holthausen, Xiue Jiang, Shaban Demirel, Steven L Mansberger, Marcelo T Nicolela, Stuart K Gardiner, Balwantray C Chauhan, Claude F Burgoyne, Brad Fortune","doi":"10.1167/iovs.65.12.17","DOIUrl":"10.1167/iovs.65.12.17","url":null,"abstract":"<p><strong>Purpose: </strong>To compare the diagnostic accuracy of thickness measurements of individual and combined macular retinal layers to discriminate 188 glaucomatous and 148 glaucoma suspect eyes from 362 healthy control (HC) eyes on a pixel-by-pixel basis.</p><p><strong>Methods: </strong>For this retrospective study, we manually corrected the segmentations of posterior pole optical coherence tomography (OCT) scans to determine the thickness of the nerve fiber layer (NFL), ganglion cell layer (GCL), inner plexiform layer (IPL), the ganglion cell complex (GCC), and the total neural retina (TR). For each eye, the total number of pixels with thickness values less than the fifth percentile of the HC distribution was used to create a receiver operating characteristic (ROC) curve for each layer and for layer combinations.</p><p><strong>Results: </strong>Using total abnormal pixel count criteria to discriminate glaucoma from HC eyes, the individual layers with the highest area under the ROC curve (AUC) were the NFL and GCL; IPL performance was significantly lower (P < 0.05). GCC had a significant higher AUC (94.3%) than individual the AUC of the NFL (92.3%) (P = 0.0231) but not higher than AUC of the GCL (93.4%) (P = 0.3487). The highest AUC (95.4%) and sensitivity (85.1%) at 95% specificity was found for the Boolean combination of NFL or GCL. The highest AUC is not significantly higher (P = 0.0882) than the AUC of the GCC but the highest sensitivity is significantly higher than the sensitivity of the GCC. This pattern was similar for discriminating between suspect and HC eyes (P = 0.0356).</p><p><strong>Conclusions: </strong>Using pixel-based methods, the diagnostic accuracy of NFL and GCL exceeded that of IPL and TR. GCC had equivalent performance as NFL and GCL. The specific spatial locations within the posterior pole that exhibit best performance vary depending on which layer is being assessed. Recognizing this dependency highlights the importance of considering multiple layers independently, as they offer complementary information for effective and comprehensive diagnosis.</p>","PeriodicalId":14620,"journal":{"name":"Investigative ophthalmology & visual science","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11469280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}