bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.