bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome‐wide association study of anterior uveitis
Authors: Koskimäki Fredrika , Ahokas Oona , Consortium FinnGen , Team Estonian Biobank Research , Elnahas Abdelrahman , Reigo Anu , Reis Kadri , Esko Tõnu , Palta Priit , Leinonen Sanna , Kettunen Johannes , Liinamaa Johanna , Karjalainen Minna , Saarela Ville
Published: January 2025

Aims/Purpose: The purpose of this study was to identify new genetic associations of anterior uveitis through genome‐wide association study (GWAS).

Methods: We conducted a GWAS meta‐analysis combining data from the FinnGen, Estonian Biobank and UK Biobank with a total of 12 205 cases and 917 145 controls. A phenome‐wide association study was performed to investigate associations across phenotypes and traits. Genetic correlations of anterior uveitis were evaluated.

Results: We detected six anterior uveitis associated genomic regions with genome‐wide significance (p < 5 × 10‐8). Three novel loci were identified: INAVA, NLRP3 and NOS2. Three previously reported associations at HLA region, ERAP1 and TNRC18 were detected. All of these loci had biologically relevant genes involved in immunity. We also replicated associations at two loci previously associated with acute anterior uveitis (IL23R and HDAC2‐AS2). Phenome‐wide association study indicated that lead SNPs at three of the anterior uveitis associated loci (ERAP1, INAVA and TNRC18) are associated with other immunity‐related phenotypes, including ankylosing spondylitis and inflammatory bowel disease. A moderate genetic correlation between anterior uveitis and inflammatory bowel disease was found in genetic correlation analysis (rg = 0.39, p = 8 × 10‐5).

Conclusions: We identified six anterior uveitis associated loci including three novel loci with genome‐wide significance. Our findings deepen our understanding of the genetic basis of anterior uveitis and the genetic connections between anterior uveitis and immune related disorders, providing a foundation for further research and potential therapeutic interventions.
Prevalente of color vision anomalies among Brazilian industrial workers and the telemedicine role
Authors: Machado Roberto , Junior Pedro Ribeiro , Filho Mauro Guimarães , Negreiros Ariadne , Negreiros Marco
Published: January 2025

Aims/Purpose: To evaluate the use of a color blindness test (Eyecare Color Vision Test®) applied through of telemedicine to assess the prevalence of color blindness, its subtypes and intensity of presentation in Brazilian industrial workers.

Methods: An observational, cross‐sectional, and retrospective study was carried out. The study sample was a convenience sample, which included all patients from a company with headquarters in all Brazilian regions who underwent consultations for occupational purposes via telemedicine through Eyecare clinic between the months of October 2023 and January 2024. All patients underwent Eyecare Color Vision Test®, a validated virtual test based on the Ishihara Test that consists of 14 images with symbols and numbers. A score above 7 was considered normal for color vision defect.

Results: 2197 workers from 5 regions of Brazil were evaluated through telemedicine. 91.81% were male, the mean age was 37 years, mean visual acuity for right eye was 0.24 (± 0.18) and for left eye was 0.19 (± 0.16). 50 patients, all male, showed changes in the Eyecare Color Vision Test® which resulted in a prevalence of color blindness of 2.28%. From patients with color blindness, 44% had protanomaly or deuteranomaly, 26% had deuteranopia, 18% had protanopia and 12% had an undiagnostic subtype.

Conclusions: Our study was in line with international literature since we found a 2.28% prevalence of CVD in Brazilian industrial workers. Furthermore, we were able to demonstrate that telemedicine can be an important tool for democratizing access to eye health.

References

Parikh D, Armstrong G, Liou V, Husain D. Advances in Telemedicine in Ophthalmology. Semin Ophthalmol. 2020 May 18;35(4):210–5; 30.

Sorkin N, Rosenblatt A, Cohen E, Ohana O, Stolovitch C, Dotan G. Comparison of Ishihara Booklet with Color Vision Smartphone Applications. Optometry and Vision Science. 2016 Jul;93(7):667–72.
Modified Nishida procedure for the treatment of complete cranial nerve palsies: A case series
Authors: Santos Miguel , Ferreira Rui , Fernandes Emanuel , Teixeira Filipa , Gama Rita
Published: January 2025

Aims/Purpose: To describe the clinical characteristics and outcomes of a series of strabismus patients with horizontal recti palsies treated surgically with a Modified Nishida Procedure (MNP).

Methods: A retrospective review of patients who underwent a MNP at Hospital de Santa Maria in Lisbon, Portugal, between November 2023 and February 2024 (n = 5). MNP is a no‐tenotomy, no‐splitting transposition of 1/3 of the muscle body of the vertical recti to the midpoint between itself and the affected horizontal rectus muscle. Inclusion criteria included diplopia due to Grade IV or V palsies of the lateral rectus (LR, n = 4) due to VI nerve palsy or of the medial rectus (MR, n = 1) due to III nerve palsy. A 3‐month post‐operative follow‐up was required. Surgical success was defined as post‐operative horizontal deviation ≤14 prism diopters (PD) and absence of horizontal diplopia in primary gaze.

Results: Mean age was 60±13 years. Two patients had bilateral LR palsy with > 85PD esotropia (ET) and received bilateral MNP combined with 6mm MR recession, with additional MR botulinum toxin (BT) injection two weeks later. Two patients had unilateral LR palsy with 45 PD ET with previous 7mm MR recession: these received unilateral MNP. Surgical success was achieved in 3 of these 4 cases. The unsuccessful case had 40PD residual ET and diplopia at 4 months follow‐up. There were two cases of self‐limiting post‐operative ptosis and one case of a surgical complication where the whole vertical rectus body was transposed due to high muscle friability. The MR paralysis patient had 40PD exotropia and MNP was combined with 7mm LR recession. Surgical success was achieved in this case, and no intra‐ or post‐operative complications occurred. No cases of anterior segment ischemia were detected in this series.

Conclusions: MNP is an effective surgical option as it greatly reduces the horizontal deviations and diplopia associated with severe cranial nerve palsies and has a reduced risk of complications.
Designing and testing anti‐scarring and anti‐inflammatory biomaterials for corneal implants: A promising alternative to human donors.
Authors: Abu‐Dieh Anas , Om Boda , Thathapudi Neethi , Kiyaseh Mozhgan , Roudbaraki Mostafa , Robert Marie‐Claude , Hébert Mélanie , Jabbour Samir , Harissi‐Dagher Mona , Griffith May
Published: January 2025

Purpose: Corneal blindness is mainly treated by cornea transplantation. However, there is a shortage of cornea donors for surgeries in many countries. Even with accessible donors, patients suffering from severe pathologies causing inflammation may not benefit as they are at high risk for graft rejection. The Griffith laboratory is the first to use acellular human collagen implants to regenerate high‐risk corneas in a group of patients. For broader clinical applications, scalable collagen‐like peptide (CLP) synthetic hydrogels are being developed. It is important to identify design patterns to ensure the implants do not cause inflammation.

Methods: The growth of stromal fibroblasts cultured on CLP hydrogels with and without RGD groups are compared, with collagen gels and tissue culture plastic as controls. Cellular growth and viability on the different substrates were compared using the AmarBlue assay. Next, TGF‐β was added to the media to stimulate fibroblast differentiation into myofibroblasts. The latter has been linked to corneal scarring. The proportion of resulting myofibroblasts was determined by immunostaining using anti‐smooth muscle actin (SMA) antibody. Stromal cells seeded onto the hydrogels were also stained against fibronectin to study its implication due to RGD. Furthermore, the CLP‐based hydrogel was tested in vivo on alkali burnt BALB/c mice to investigate their practical biocompatibility and efficacy.

Results: α‐SMA expression was observed in cells grown on CLP‐RGD containing hydrogels but not on tissue culture plastic or CLP‐only control. There was a positive fibronectin expression by cells cultured on CLP‐RGD hydrogels, on 5% collagen hydrogels and on the issue culture control. The CLP‐RGD hydrogel is a smooth and soft gel with desirable water content. The in vivo test showed that there was no sign of inflammation or angiogenesis in the cornea after three months, which can prove the great biocompatibility of the prepared CLP‐based hydrogel.

Conclusions: This project allowed for the testing of cell growth on RGD‐containing CLP hydrogels, which has not been done before. Early results suggest that RGD groups within CLPs induced myofibroblast differentiation and potential pro‐inflammatory responses.
Gene expression profiling of oxidative and anti‐oxidative genes in keratoconus patients
Authors: Sharma Shivam , Singh Lata , Kashyap Seema , Sen Seema , Sharma Namrata
Published: January 2025

Aims/Purpose: Keratoconus (KC) is thinning of corneal stroma & irregular astigmatism, resulting in diminution of vision. Despite its prevalence, the underlying etiology is poorly understood. Emerging evidence suggests a dysregulation of oxidative balance and mitochondrial function in KC corneas. Therefore, our study conducted the gene expression profiling of oxidative stress‐based genes in KC patients.

Methods: This was a prospective study for a period of two years. Fifty KC patients were recruited in this study. Demographic and clinical details were recorded. RNA was isolated from all the corneal samples and their cDNA was synthesized. mRNA expression levels of oxidative stress‐based genes (PRDX6, SCARA3, FOXC1, HMOX1, SOD2, GPX4, NRF2, NOX4) were measured by quantitative real‐time PCR (qRT‐PCR) in corneal tissues of KC patients and healthy controls. The relative gene expression was calculated using the ΔΔCt method.

Results: The study included 50 keratoconus patients (mean age: 25.5 ± 12.34 years; 65% male) and 25 control subjects (mean age: 27.2 ± 11.26 years; 55% male). The severity of keratoconus among patients varied from moderate to advanced stages. In our study, qRT‐PCR analysis revealed significant differential expression of the oxidative and antioxidative genes in keratoconus tissues compared to the control samples. SCARA3, FOXC1, HMOX1, SOD2, GPX4, NRF2 were found downregulated, PRDX6 was upregulated in all the cases. NOX4 showed variable expression patterns with upregulation in 40% cases and downregulation in remaining 60% cases.

Conclusions: The study included 50 keratoconus patients (mean age: 25.5 ± 12.34 years; 65% male) and 25 control subjects (mean age: 27.2 ± 11.26 years; 55% male). The severity of keratoconus among patients varied from moderate to advanced stages. In our study, qRT‐PCR analysis revealed significant differential expression of the oxidative and antioxidative genes in keratoconus tissues compared to the control samples. SCARA3, FOXC1, HMOX1, SOD2, GPX4, NRF2 were found downregulated, PRDX6 was upregulated in all the cases. NOX4 showed variable expression patterns with upregulation in 40% cases and downregulation in remaining 60% cases.

Keywords: Cornea, Keratoconus, Oxidative stress, Real time PCR
Characterizing IPSC‐derived organoid models from the most prevalent retinal dystrophies
Authors: Navinés‐Ferrer Arnau , Gaudó Paula , Méndez‐Vendrell Pilar , Ruiz‐Nogales Sheila , Siles Laura , Pomares Esther
Published: January 2025

Aims/Purpose: To establish novel retina cell models to investigate the mechanisms that lead to cell death in IRD.

Methods: We generated induced pluripotent stems cells (iPSC) from a cohort of patients with some of the most prevalent IRDs: Retinitis Pigmentosa (RP), Stargardt Disease, Best Disease and Achromatopsia. We differentiated them into PR precursors, retinal organoids (RO) or retinal pigment epithelium cells (RPE) and analyzed the functional implications of each gene and pathogenic variant.

Results: All cell models generated from 6 iPSC lines allowed for a better understanding of the molecular mechanisms of IRD. Specifically, in the Best Disease model, we determined using RPE cells that a particular dominant mutation in BEST1 is responsible for a defective closure of the bestrophin pentameric channel. The mutation responsible for RP in RHO shows rhodopsin accumulation and mislocalization, along with an increase of autophagy and ER stress. RO models with mutations in the genes PDE6A and PDE6C, causing respectively RP and Achromatopsia, suggest that expression levels of the pathogenic proteins are diminished. Finally, RPE and RO from two distinct Stargardt Disease patient lines show affectations in bisretinoid disposal, phagocytosis reduction and cell death. Interestingly, those results correlate with the severity of the phenotypes.

Conclusions: We show that a wide range of mutations responsible for IRD can be studied using iPSC‐derived retinal models. This opens the door to a deeper understanding of retinal diseases and are key for the development of successful gene and cell therapies.

References

Inherited retinal dystrophies (IRD) are a group of rare diseases where photoreceptor (PR) cell death leads to partial or total visual impairment. Over 300 genes have been determined to cause these dystrophies, but most of the molecular mechanisms underlying the start and development of the pathology are still waiting to be unraveled.
Progression of diabetic retinopathy during pregnancy: Retrospective study from Birmingham and Solihull
Authors: Khalifa Ahmad
Published: January 2025

Aims/Purpose: To assess the progression of diabetic retinopathy (DR) in pregnant women with pre‐existing diabetes in the Birmingham and Solihull area and to evaluate adherence to recommended screening guidelines.

Methods: A retrospective review was conducted over 12 months (01/09/2022‐31/08/2023) using data from the Diabetic Eye Screening Program (DESP) and hospital records (Medisoft, OCT, and retina images). The study included pregnant women with pre‐existing diabetes who received maternity services at University Hospitals Birmingham (UHB) and were referred to DESP. Patients with gestational diabetes were excluded. Data collected included demographics, DR screening attendance, progression rates, and clinical outcomes.

Results: Out of 149 pregnant women with pre‐existing diabetes, 54 (36.2%) were not referred for initial screening by 12 weeks due to late presentation and delayed diabetes status confirmation. Of the total, 88 (59%) missed the 12‐week screening, 57 (40%) missed the 16‐20 week screening, and 67 (48%) missed the 28‐week screening. At 12 weeks, 27% were R0M0, 9% R1M0, 3% R1M1, and 1% R2M0/R2M1, with 8 referred to HES. At 16‐20 weeks, 43% were R0M0, 16% R1M0, 1% R3SM0, and 1% were unable to assess, with 2 referred to HES. By 28 weeks, 37% were R0M0, 12% R1M0, 1% R3SM1, and 2% were still being graded, with 1 referred to HES. The study highlighted significant cases, including one patient who progressed to severe NPDR and required bilateral PRP and Ozurdex treatment, and another who developed DMO treated with Ozurdex.

Conclusions: Diabetic retinopathy progression during pregnancy remains a significant concern, with many patients missing critical screening appointments, leading to advanced DR stages and severe visual impairment. Despite adherence to screening guidelines, patient non‐compliance and late referrals hinder effective management. Improved patient education and follow‐up strategies are essential to enhance screening attendance and outcomes, thereby preventing severe DR progression during pregnancy. Further research is necessary to develop targeted interventions for better compliance and timely treatment.
Assessing retinal thickness and vascular structures in an Alzheimer's disease mouse model app NL‐F/NL‐F
Authors: Sanchez‐Puebla Lidia , López‐Cuenca Inés , Jiménez María González , Salobrar‐Garcia Elena , Matamoros José A. , Lozano María Pilar Rojas , Fernández‐Albarral José A. , Elvira‐Hurtado Lorena , Ramirez Ana Isabel , Salazar Juan Jose , Nieto‐Vaquero Carmen , Desviat María Isabel Cuartero , Moro María Ángeles , Saito Takashi , Saido Takaomi C. , Ramirez Jose Manuel , de Hoz Rosa
Published: January 2025

Aims/Purpose: In Alzheimer's disease (AD), there are histopathological aspects that cannot be studied in patients, demanding the use of murine models of the disease. The APPNL‐F/NL‐F model reproduces the pathophysiology quite faithfully. The aim of the present study was to analyze the retinal vascular structures and retinal thickness in an AD model at different ages and compares these findings to age‐matched wild type (WT) controls.

Methods: A diachronic study was conducted using spectral‐domain OCT angiography (SD‐OCTA) and AngioTool software to assess retinal vascular structures, alongside OCT for measuring inner and outer retina thickness. We include two study groups: the APPNL‐F/NL‐F AD model and WT controls at 6, 9, 12, 15, 17, and 20 months old. The analysis focused on the three vascular plexus and retinal thickness, using the Early Treatment Diabetic Retinopathy Study (ETDRS) sectors. We considered statistically significant a p‐value < 0.05.

Results: Compared to WT, the APPNL‐F/NL‐F group exhibited both vascular and structural changes starting as early as 6 months, with these changes persisting and evolving at 15, 17, and 20 months. Significant vascular alterations, particularly in the superficial vascular complex (SVC), were noted. There was a marked decrease in vessel area and total vessel length in the SVC, as well as in the intermediate and deep capillary plexus. Additionally, the inner retina predominantly showed a thickness decrease, while the outer retina demonstrated an increased thickness at most time points compared to the control group.

Conclusions: The study identifies early retinal vascular and structural changes in the APPNL‐F/NL‐F model that precede cognitive changes observed at later stages. These findings suggest that the retinal changes in this model more closely resemble those in human AD compared to other transgenic models, highlighting the potential of retinal assessments in early AD diagnosis.
Ultrastructural analysis of retinal pigment epithelial cells in 5XFAD mouse model
Authors: Koskela Ali , Ruuth Johanna , Toropainen Elisa , Kaarniranta Kai
Published: January 2025

Aims/Purpose: The 5xFAD mouse model of Alzheimer's disease overexpresses 42 amino acids long amyloid beta (Aβ42) found also from the drusen of age‐related macular degeneration (AMD) patients. In this model, Aβ42 is produced in all tissues expressing amyloid precursor protein, including retinal pigment epithelial (RPE) cells, making it an interesting candidate model for AMD. Ultrastructural changes in RPE cells of 5XFAD were examined.

Methods: Six‐ and twelve‐months old 5xFAD mice and wild type (WT) littermates (n = 6) were sacrificed and eyes were enucleated. The eyes were sectioned for TEM imaging (JEM‐2100F, Jeol CO, Tokyo, Japan). The TEM images were analyzed for RPE morphology, cell organelle morphology, and autophagic structures.

Results: The 5xFAD RPE showed gradual loss of basal infoldings, accumulation of drusen‐like structures beneath the RPE cells and Bruch's membrane, abnormal RPE cell size, changes in melanosome shape and localization, accumulation of lipofuscin‐like structures, and accumulation of autophagic structures. Closer inspection on autophagic structures revealed change in autophagosome/autolysosome ratio towards higher number of autolysosomes.

Conclusions: The overexpression of Aβ42 was shown to induce changes in the RPE resembling pathology of AMD. Accumulation of lipofuscin‐like structures and autolysosomes suggests dysfunctional autophagic clearance system hampering the cellular homeostasis. Therefore, the RPE cells loose gradually their functioning and polarization which can be seen as a loss of basal infoldings and abnormal size. The change in melanosome shape and localization suggests high oxidative stress resulting malfunction of these organelles. Finally, the appearance of drusen‐like structures beneath the RPE cells can be considered as impaired proteostasis.
Predictive factors of final visual outcome in patients with leber hereditary optic neuropathy treated with lenadogene nolparvovec gene therapy
Authors: Barboni Piero , Newman Nancy , Biousse Valérie , Yu‐Wai‐Man Patrick , Carelli Valerio , Vignal‐Clermont Catherine , Josse Constant , Taiel Magali , Sahel José‐Alain , Sergott Robert
Published: January 2025

Aims/Purpose: To identify the predictive factors of final best‐corrected visual acuity (BCVA) in patients with Leber hereditary optic neuropathy (LHON) due to the m.11778G > A MT‐ND4 mutation who received lenadogene nolparvovec gene therapy in clinical studies.

Methods: The following covariates were studied to identify those that might influence final BCVA: age, gender, timing of treatment, baseline BCVA value and baseline optical coherence tomography (OCT) parameters. Univariate analyses were performed from three phase 3 studies (RESCUE, REVERSE and REFLECT), using BCVA at 1.5 years post‐treatment as the dependent variable. In RESCUE and REVERSE, ND4‐LHON patients received an injection of gene therapy in one eye and a sham injection in the other. In REFLECT, the first‐affected eye received gene therapy, while the other eye was randomly injected with gene therapy or placebo.

Results: In 290 untreated/treated eyes, the covariates statistically significantly associated with an improvement in final BCVA were a longer time from vision loss to treatment (p < 0.05), and thicker optical coherence tomography (OCT) parameters at baseline: ganglion cell layer (GCL) temporal outer segment, GCL superior outer segment, GCL nasal outer segment, and GCL inferior outer segment at ETDRS analysis, and retinal nerve fiber layer (RNFL) inferior quadrant, RNFL nasal quadrant and RNFL superior quadrant (p < 0.05). The greatest effects [95% confidence interval] were observed for the thickness of the inferior and superior outer GCL segments at baseline (‐0.1 [‐0.163; ‐0.037] and ‐0.09 [‐0.146; ‐0.033], respectively; both p = 0.002). A worse baseline BCVA was associated with a worse final BCVA (p < 0.0001).

Conclusions: Timing of treatment administration, baseline BCVA value and baseline thickness of OCT parameters are predictive of the BCVA 1.5 years after treatment in patients with MT‐ND4 LHON who received lenadogene nolparvovec.
Do estrogens receptor agonists have a neuroprotective effect on mouse rgc after optic nerve axotomy?
Authors: Rodríguez‐Ramírez Kristy T. , Galindo‐Romero Caridad , Vidal‐Sanz Manuel , Agudo‐Barriuso Marta
Published: January 2025

Aims/Purpose: Estrogens are known to have neuroprotective effects in the central nervous system1‐2 (CNS) and only this steroid hormone has the capability of rescue neuronal cell death caused by an injury. Estrogen receptors (ERs) are expressed in both sexes and are distributed throughout the CNS, while the ER‐β is the most predominant in the brain.

The aim of this study is:

1. To compare the course of death of RGCs in female and male mice after optic nerve axotomy during the fast (up to 9 days) and slow (from 9 day onwards) phases of RGC loss.

2. To analyse the expression of ER‐α and ER‐β in intact retinas.

3. To study the neuroprotective effect of ER agonism in the two phases of RGC loss.

Methods: Optic nerve crush (ONC) was performed on the left eye of pigmented male and female mice, and the course of retinal ganglion cell3 (RGC) loss analysed up to 21 days after the injury. In intact retinas of both sexes the number of RGCs expressing the estrogen receptors alpha (ER‐α) and beta (ER‐β) was studied. To test the neuroprotective potential of both ERs, ER‐β or ER‐α agonists1‐2 were injected into the vitreous just after ONC and 9 days later, and the retinas analysed at 21 days.

Results: The time course of axotomy‐induced RGC death differs between male and female mice. In males, axotomy‐induced RGC loss is significant after 3 days, whereas in females it is delayed until 5 days. In both sexes, ERs are expressed by more than 70% of RGCs. ER‐β agonism neuroprotects axotomised RGCs at 21 days in both sexes: RGC survival in ER‐β treated animals is 19% higher in males and 17% higher in females than in vehicle treated animals.

Conclusions: The loss of RGCs following axotomy is significant at an earlier in males than in females. RGCs from both sexes express both ERs. Intravitreal administration of ER‐β agonist delays axotomy‐induced RGCs loss during the second, slow phase of death.

References

Chakrabarti M., et al. Estrogen receptor agonists for attenuation of neuroinflammation and neurodegeneration. Brain Res Bull. 2014; 109:22‐31.

Das A., et al. Estrogen receptor agonists and estrogen attenuate TNF‐α‐induced apoptosis in VSC4.1 motoneurons. J Endocrinol. 2011; 208(2):171‐82.

Galindo‐Romero C., et al. Axotomy‐induced retinal ganglion cell death in adult mice: quantitative and topographic time course analyses. Exp Eye Res. 2011; 92(5):377‐87.
Generation of an isogenic control from an induced pluripotent stem cell line of a patient with dominant optic atrophy harbouring the genetic variant C.1024 A > G (P.K342E) in the OPA1 gene
Authors: Jabardo Raquel González , López Marta García , Anda Natalia Robles , Vicente Lydia Jimenez , Monreal Helena Dorado , de Arriba Pablo Rueda , Gallardo Maria Esther
Published: January 2025

Aims/Purpose: Dominant Optic Atrophy (DOA) is an inherited optic neuropathy commonly caused by OPA1 gene mutations, affecting mitochondrial function. The main symptom of patients is vision loss, but the syndromic form of DOA, DOA‐plus, presents with additional manifestations such as deafness and myopathy, among others. The visual impairment occurring in DOA is caused by the degeneration of Retina Ganglion Cells (RGCs), specialized neurons that convey visual information from the retina to the brain. Currently, there is a lack of an effective treatment for DOA patients, which highlights the importance of developing a proper experimental model. Induced Pluripotent Stem Cells (iPSCs) technology could be a promising approach to generate a model of DOA, useful not only for studying mechanisms of disease and therapeutic strategies, but also to confirm if a genetic variant is pathogenic. Our final aim is to determine if a genetic variant in OPA1 gene is pathogenic in a patient with DOA‐plus by the generation of an isogenic human RGC model.

Methods: An iPSC line, OPA1.15, carrying the variant NM_015560.3: c.1024 A > G (p.K342E) in OPA1 gene, obtained from a patient with DOA‐plus was created. Subsequently, a battery of assays was performed to confirm the pluripotency and good quality of the OPA1.15 iPSC line. In this work, as a first step for the creation of the RGC model, the generation of an isogenic control from OPA1.15 with the CRISPR/Cas9 system has been developed.

Results: A bona fide iPSC line from a patient with DOA‐plus has been created. Using this line, an isogenic control was generated with the genome editing tool CRISPR/Cas9.

Conclusions: The iPSC line OPA1.15 and its matched isogenic control will be very useful to generate a RGC model to delve into the pathogenicity of this variant.
Therapeutic potential of targeting BMP/ALK pathway in pathological retinal neovascularization
Authors: AL‐Shabrawey Mohamed , Ghishan Maria , Koneru Nandini , Sharma Sonali , Moustafa Mohamed
Published: January 2025

Aims/Purpose: Pathological retinal neovascularization (PRNV) in ischemic retinopathies presents a significant clinical challenge. This study investigates the role of bone morphogenetic protein (BMP) signaling via ALK receptors in PRNV, with a focus on epigenetic modifications.

Methods: The oxygen‐induced retinopathy (OIR) mouse model was utilized to investigate BMP signaling. Experimental groups included OIR mice treated with Noggin (a BMP inhibitor) or vehicle via ip from postnatal day 12‐16. Additional groups included a combined ALK2 and ALK3 endothelial conditional knockout mice (ALK2/3eKO), subjected to OIR. Capillary degeneration and neovascularization were assessed at postnatal day 17 in flat‐mount retinas using isolectin‐B4 staining. Immunostaining of retinal sections evaluated BMP2, BMP4, and ALK3 localization. In vitro experiments involved human retinal endothelial cells (HRECs) treated with BMP2 (50 ng/ml) or exposed to hypoxia (1% O2) for 48 hours. The impact of BMP2 on vascular endothelial growth factor (VEGF) was assessed through ELISA. MicroRNA (miRNA) expression was analyzed using the GeneChip miRNA 3.0 array. DNA methylation of HRECs was quantified using a colorimetric kit.

Results: Immunostaining revealed an upregulation of BMP2, BMP4, and ALK3 expression in retinal vessels. Noggin‐treated and ALK2/3eKO OIR mice exhibited a significant reduction in capillary dropout and neovascularization (p < 0.01). BMP2 treatment of HRECs elevated VEGF production. MiRNA array analysis indicated significant alterations by BMP2 (4%) and hypoxia (5%), including miRNAs linked to VEGF signaling and angiogenesis. Specifically, BMP2 downregulated miR‐4521, miR‐769‐3p, miR‐23b‐5p, miR‐3195, and miR‐6781‐5p, while upregulating miR‐126‐3p, miR‐921, miR‐7515, miR‐29c, and miR‐20b‐5p. Interestingly, BMP2 and hypoxia induced similar effects on certain miRNAs, such as miR‐769‐3p, miR‐23b, and miR‐20b. The DNA methylation assay demonstrated a statistically significant reduction induced by BMP2.

Conclusions: BMP/ALK signaling plays a potential role in the pathogenesis of PRNV, possibly mediated through epigenetic modifications. Thereby, targeting BMP/ALK signaling holds a promise to mitigate PRNV in ischemic retinopathies
Identification of senescence markers on cultured human corneal endothelial cells
Authors: Sagnial Tomy , He Zhiguo , Gauthier Travers , Aouimeur Inès , Ninotta Sandrine , Philippe Gain , Thuret Jean‐Yves , Thuret Gilles
Published: January 2025

Aims/Purpose: Corneal transplantation is currently the most frequent type of transplantation globally. However, a chronic shortage of donor corneas makes traditional methods unsustainable. Alternatives such as bio‐engineered grafts or direct injection of corneal endothelial cells (CECs) into the patient's eye require the primary culture of CECs. Current CEC culture techniques face a significant challenge: cell senescence. Cells often become senescent during in vitro culture, rendering them unsuitable for clinical use and limiting the yield. Identifying specific markers of senescent CECs is crucial for studying this process. This study aims at identify robust markers of senescence in CEC cultures.

Methods: Primary CEC cultures were obtained from human corneas following published methods. Various senescence markers for general cells and/or CECs were selected from the literature and applied using immunofluorescence (IF) in CEC cultures exhibiting heterogeneous morphology (presence of both very small and large, senescence‐associated cells) at different cell passages. The selected senescence markers were validated using induced senescent CECs by either removing anti‐senescent agents from the culture medium or adding TGF‐β1 or carteolol. β‐Galactosidase activity staining (SPiDER‐β Gal) was also tested.

Results: Two candidate markers appeared suitable for detecting CEC senescence, each with specific attributes. Transgelin marked TGF‐β‐induced senescence, indicating a senescence‐associated secretory phenotype (SASP)‐related senescence, while SPiDER‐β Gal seemed linked to replicative senescence.

Conclusions: Transgelin and SPiDER‐β Galactosidase are promising markers for detecting CEC senescence in vitro. Using both markers may help identify the causes of senescence.
Predicting intraocular pressure using neural networks: Incorporating image data and patient metadata from papila dataset
Authors: Yang Fernando Ly , Roussou Aikaterina , Van Lancker Lauren , Bagchi Akanksha , Panos Chris
Published: January 2025

Aims/Purpose: This study aimed to explore the feasibility of predicting intraocular pressure (IOP) using a neural network model incorporating both image data and patient metadata. The objective was to evaluate the potential of this approach in improving the understanding and prediction of IOP levels in individuals, utilizing data from the PAPILA public database.

Methods: We employed a dataset containing 331 images from the PAPILA database, with 298 images classified as normal and 33 diagnosed with glaucoma. Additionally, patient metadata such as glaucoma diagnosis status, age, sex, refractive defect, pachymetry, and axial length were incorporated. The dataset was divided into 70% for training the neural network model, 15% for validation, and 15% for testing.

Results: The analysis of the neural network model's predictive performance produced the following metrics: Mean Absolute Error (MAE) of 2.515, Root Mean Square Error (RMSE) of 3.131, and Mean Absolute Percentage Error (MAPE) of 16.611%. These results indicate a moderate level of predictive capability for IOP based on the input data.

Conclusions: In conclusion, our study demonstrates promising potential in utilizing artificial intelligence to predict intraocular pressure (IOP) using image data and patient metadata. While our model's predictive performance is moderate, it sets the stage for further advancements. With continued refinement and exploration of additional factors, AI‐driven approaches hold promise for revolutionizing glaucoma management.

References

Kovalyk O, Morales‐Sánchez J, Verdú‐Monedero R, Sellés‐Navarro I, Palazón‐Cabanes A, Sancho‐Gómez JL. PAPILA: Dataset with fundus images and clinical data of both eyes of the same patient for glaucoma assessment. Sci Data. 2022 Jun 9;9(1):291. doi: 10.1038/s41597‐022‐01388‐1. PMID: 35680965; PMCID: PMC9184612.
Exploring image and metadata fusion for glaucoma detection with artificial intelligence
Authors: Yang Fernando Ly , Roussou Aikaterini , Van Lancker Lauren , Bagchi Akanksha , Panos Chris
Published: January 2025

Purpose: This study aimed to evaluate the effectiveness of integrating image data and metadata in glaucoma detection using AI. Early detection is crucial in preventing vision loss, hence the focus on enhancing diagnosis accuracy by combining image features with patient metadata like age, gender, and ocular measurements.

Methods: We used a dataset of 331 images from the PAPILA database, split into normal (298) and glaucoma (33) classes. Initially, the EfficientNetV2B0 model was trained solely on image data. Subsequently, patient metadata such as age, gender, pachymetry, refractive error, and axial length were incorporated. The dataset was split 70% for training, 15% for validation, and 15% for testing.

Results: Training with image data alone yielded a 79% AUC on the test set, indicating moderate performance. Integrating patient metadata improved the AUC to 83%, slightly enhancing diagnostic accuracy. However, statistical analysis using the De Long Test showed no significant difference between the two models, suggesting limited improvement from metadata integration.

Conclusion: This study highlights the potential of integrating patient metadata with image data for glaucoma detection using AI.

References

Kovalyk O, Morales‐Sánchez J, Verdú‐Monedero R, Sellés‐Navarro I, Palazón‐Cabanes A, Sancho‐Gómez JL. PAPILA: Dataset with fundus images and clinical data of both eyes of the same patient for glaucoma assessment. Sci Data. 2022 Jun 9;9(1):291. doi: 10.1038/s41597‐022‐01388‐1. PMID: 35680965; PMCID: PMC9184612.
Maximizing glaucoma detection accuracy through high confidence AI predictions: A RIM One database study
Authors: Yang Fernando Ly , Santos Enrique , Frances Federico Saenz , Escalada Luis Jañez , Roussou Aikaterini , Van Lancker Lauren , Bagchi Akanksha , Panos Chris
Published: January 2025

Purpose: This study aimed to assess an artificial intelligence (AI) model's performance in glaucoma detection using the RIM One public database. Specifically, we examined the impact of considering only high‐confidence predictions from the AI model on overall diagnostic accuracy.

Methods: The RIM One database provided 485 images, including 313 normal and 172 glaucomatous cases. Of these, 248 images were for training the EfficientNetV2B0 model, 63 for validation, and 174 for testing. Initially, the model's performance was evaluated on the entire test set, yielding an AUC of 96%. Subsequently, we investigated the model's performance when limiting predictions to those with a certainty probability over 95%, reducing the test set to 155 images.

Results: The AI model achieved an AUC of 96% when considering all predictions. However, focusing solely on high‐confidence predictions ( > 95% certainty) increased the AUC to 100%. This adjustment reduced the test set size from 174 to 155 images. Statistical analysis using the De Long Test revealed a significant difference between the two AUC values, highlighting the efficacy of high‐confidence predictions.

Conclusion: Our findings demonstrate that by considering only AI predictions with a certainty probability exceeding 95%, we can significantly enhance glaucoma detection's diagnostic accuracy. This approach resulted in a perfect AUC, indicating robust performance in identifying glaucomatous cases. The reduction in test set size suggests that 19 cases may require further evaluation through methods such as visual field testing or optical coherence tomography (OCT) to confirm or exclude the diagnosis of glaucoma. This selective approach not only improves the efficiency of glaucoma diagnosis but also streamlines clinical decision‐making by directing resources to cases with the highest predictive certainty.
Vitreous hemorrhage following istent implantation: A case report
Authors: Haddoum Karim Nassim , Smiri Meryam , Mansouri Abdeljalil , El Sanharawi Mohamed
Published: January 2025

Aims/Purpose: To report a complication of iStent trabecular bypass stent implantation in a patient undergoing combined cataract and microinvasive glaucoma surgery.

Methods: A 72‐year‐old male with a history of glaucoma under fixed combination of bimatoprost‐timolol and oral anticoagulation consulted for decreased vision (visual acuity and visual field). His intra‐ocular pressure (IOP) was 24 mm Hg in right eye (OD) and 23 mm Hg in left eye (OS) with an altered ocular surface.The decision was made to perform combined cataract extraction with iStent implantation left eye then right eye. On postoperative day 1 (OS) patient presented with 15 mm Hg IOP, stage 2 hyphema and grade 3 intravitreal hemorrhage. Hyphema resolved with conservative medical management. The vitreous hemorrhage persisted for two months and required vitrectomy.

Results: Appropriate placement was confirmed by gonioscopy. Six months after vitrectomy the patient has had complete resolution of symptoms without recurrence of hyphema and vitreous hemorrhage. (IOP) was 14 mm Hg in right eye (OD) and 16 mm Hg in left eye (OS). Possible mechanism that we considered was spill‐over hemorrhage from the anterior chamber hyphema. Even if the preoperative examination did not find pseudoexfoliation, this has been associated with zonular instability, which would allow for communication between the anterior and posterior segments. It is generally accepted that intraocular bleeding after phacoemulsification cataract surgery does not justify the withdrawal of anticoagulant agents, there is no clear guidance for combined cataract and MIGS.

Conclusions: This case illustrates a complication of iStent placement. Nothing suggested after the preoperative examination the occurrence of an intravitreal hemorrhage. We describe the evolution of the symptoms, diagnosis and treatment of this patient by putting forward physiopathological hypotheses that may explain the origin of the vitreous hemorrhage.
Influence of age, baseline severity and follow‐up time on visual field progression in primary open angle glaucoma
Authors: Ghinis Achilleas , Van Eijgen Jan , Vens Celine , Molenberghs Geert , Stalmans Ingeborg
Published: January 2025

Aims/Purpose: Challenges in modeling rates of visual field (VF) progression relate to flooring effects and sensitivity to inclusion criteria like follow‐up (FU) duration. We explored the relationship between VF progression and age, disease severity, and FU duration in primary open angle glaucoma (POAG).

Methods: Mean Deviation (MD) of 655 POAG eyes of 424 patients from the UZ Leuven Glaucoma Clinic with at least 5 VFs and 2 years of follow‐up were used. Baseline severity was defined as Above 0 (≥0dB), mild ( < 0 and ≥‐6dB), moderate ( < ‐6 and ≥‐12dB), advanced ( < ‐12 and ≥‐15dB), and severe ( < ‐15dB) disease. Linear mixed models and changepoint detection were used. Sensitivity analysis of modeled progression rates within each severity group was done by varying maximally included duration of FU.

Results: MD progression rates per year were ‐0.34dB (p < 0.001) for Above 0, ‐0.49dB (p < 0.001) for mild, ‐0.49dB (p < 0.001) for moderate, ‐0.26dB (p = 0.009) for advanced, and +0.1dB (p = 0.317) for severe POAG. Random effects correlation between baseline MD and progression rates was 0.36. The fixed effects for age and test related learning effect were non‐significant (p = 0.65) and ‐0.21 (p = 0.004) respectively. The correlation between the implied slope and baseline age was ‐0.26. Changepoint analysis showed that group level progression estimates stabilized when minimum FU times were at least 2.17, 1.99, 2.18, and 4.56 years for mild, moderate, advanced and severe POAG respectively.

Conclusions: Older patients progress faster across severity levels and a significant learning effect is present when excluding patients with severe POAG. Excluding patients with a baseline MD above 0dB, the modeled average MD change is similar between mild and moderate POAG. Less progression is observed in advanced and no progression in severe POAG, consistent with the flooring effect. In mild and moderate POAG patients progression estimates converged after a minimum FU of at least 2 years.
Investigation on the relationship between disc hemorrhage and primary open‐angle glaucoma using genome‐wide association study
Authors: Seo Je Hyun
Published: January 2025

Aims/Purpose: To investigate the genetic loci related of disc hemorrhage (DH) using genome‐wide association studies (GWAS) and the causal association between DH and primary open‐angle glaucoma (POAG) in East Asian population.

Methods: The GWAS was conducted on 8,488 Koreans who underwent ocular examination and fundus photography to determine the presence of DH and POAG. After identifying significant single nucleotide polymorphisms (SNPs) associated with DH, we conducted an analysis to determine the heritability and genetic correlation for DH and POAG. The SNPs discovered in the current research were utilized as instrumental variables (IVs) for the two‐sample Mendelian randomization (MR) analysis. The POAG outcome dataset was validated using Biobank Japan data (n = 179,351), which comprise the East Asian population.

Results: We found that the rs62463744 (TMEM270;ELN), rs11658281 (CCDC42) and rs77127203 (PDE10A;LINC00473) were SNPs associated with DH. The SNP heritability of DH was estimated as 6.7% with showing the absence of the genetic correlation with POAG. The MR analysis using 9 SNPs as IVs, revealed that the causal association of DH on POAG for East Asian population was not present using IVW method [odd ratio (OR) = 1.01, p = 0.69].

Conclusions: The novel loci underlying DH in Korea cohort revealed SNPs in the ELN, CCDC41 and LINC00473 genes. However, the causal effects of DH on the risk of glaucoma were not found. These absence of the causal association with DH on POAG implies that the current understanding of DH is a risk factor for glaucoma, warranting further investigations.
Relationship between persistence with topical antiglaucomatous prescription and patient socioeconomic status at a Tertiary University Hospital in Jerez De La Frontera (Spain)
Authors: Sanchez Javier Benitez‐del‐Castillo , Gonzalez Ignacio Pereira , Jimenez‐Carmona Soledad , Cordoba‐Doña Juan Antonio , de Torres Jimenez Miguel
Published: January 2025

Aims/Purpose: To study the relationship between socioeconomic status and persistence with topical antiglaucomatous medication.

Methods: A retrospective epidemiological observational cohort study was conducted with a sample of 1563 patients. The main dependent variable was persistence (medication possession ratio), the independent variable was socioeconomic status (deprivation index). Additional independent variables were used for multivariate analysis: individual health card index, sex, age, pharmacological group, number of eye drops, preservatives, diagnosis and concurrent medications. Bivariate statistical analysis was obtained using non‐parametric tests. Logistic regression was used for multivariate analysis. The level of statistical significance was set at p < 0.05.

Results: Using Spearman's correlation, we obtained data showing greater persistence in the groups with a higher socioeconomic level (deprivation index 1 and 2, with medication possession ratio values of 79.97 and 75.30, respectively) as opposed to the groups at lower socioeconomic levels (deprivation index 4 and 5, with medication possession ratio values of 73.75 and 69.85, respectively). Logistic regression corroborated this difference, reaching a significant value (no persistence in deprivation index group 5 versus 1) with OR = 1.62; 95%CI: 1.13‐2.31. Additionally, lower persistence was detected in males, under 60 years of age, undergoing treatment with alpha‐agonists, and in patients with ocular hypertension.

Conclusions: Low socioeconomic status of the patient was significantly associated with decreased persistence with topical antiglaucomatous therapy.
Optic nerve deep layer microvasculature according to different optic disc phenotypes in normal‐tension glaucoma
Authors: Lee Yunhan , Song Min Kyung , Shin Joong Won , Lee Jin Yeong , Hong Ji Wook , Kook Michael
Published: January 2025

Aims/Purpose: To determine whether the deep layer microvasculature measured by optical coherence tomography angiography (OCTA) within ẞ‐parapapillary atrophy (ẞ‐PPA) and optic nerve head (ONH) vessel density (VD) differs among various optic disc phenotypes (ODPs) in normal‐tension glaucoma (NTG).

Methods: This cross‐sectional study analyzed 100 NTG subjects with ẞ‐PPA (50 eyes with focal ischemic (FI) ODP and 50 eyes with myopic glaucomatous (MG) ODP matched for age [≤ 10 years] and glaucoma severity [mean deviation ≤ 1 dB]) as well as 50 healthy eyes. Using OCTA, parapapillary choroidal vessel density (pCVD) was measured on en‐face images of choroidal maps within the entire ẞ‐PPA area. The ONH vessel density (ONH‐VD) were evaluated on a 4.5 x 4.5 mm ONH en‐face projection image using the OCTA whole‐signal mode. This deep layer vasculatures were compared among the 3 groups. The relationships between pCVD and ONH‐VD outcomes and various clinical variables were assessed.

Results: pCVD were significantly lower in eyes with MG group than Fl group (71.5% vs. 75.4%, p < 0.001). There is no significant difference in prevalence of choroidal microvasculature dropout (CMvD) between the two glaucomatous ODP types (44% vs. 44%, p = 1.0). Multivariate linear regression analysis in the entire NTG eyes showed that the MG ODP, longer axial length, lower inferior retinal nerve fiber layer thickness, lower inferior capillary density of optic disc, and presence of CMvD were independently associated with lower pCVD (all p < 0.05).

Conclusions: OCTA‐measured pCVD differs between the two ODP types. MG ODP is significantly associated with generalized pCVD loss within the ẞ‐PPA in NTG eyes, while controlling other covariates. Independent effect of MG ODP on pCVD should be kept in mind when interpreting pCVD measurement among NTG eyes with different ODPs.