bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results of implementation of new genomics in spanish national health system
Authors: Ayuso Carmen 
Published: January 2025

In Spain, Inherited Retinal Dystrophies (IRD) gene diagnosis has been implemented from several decades ago (from 90's of last century), throughout the collaborative and multidisciplinary work of six teams located around the country (EsRetNet https://www.esretnet.org/, and others).Along this time, we have developed guidelines to extend and improve gene testing for IRD in Spain (Ministry of Health, 2019 (https://portal.guiasalud.es/gpc/distrofias-hereditarias-retina/), and different molecular approaches have been implemented to increase the rate of molecular characterization of the patients, rising next generation sequencing (NGS) for routine, in 2013.In January 2024, the pipeline for Gene testing in Spanish National Health System (NHS) was released, including ophthalmological genetic disorders (https://cgen.sanidad.gob.es/#/). This pipeline defines the conditions to be studied, using ICD 10 and ORPHA codification, the reasons to refer, and the molecular procedures to apply, among others.Moreover, during the last 4 years the Spanish Program: Impact genomics has provided WGS for more than 2,000 Rare Diseases patients, including some with IRD, to explore the feasibility to implement WGS in NHS.In the Department of Clinical Genetics of Fundacion Jimenez Diaz, Madrid, we have integrated in these national programs, as well as have introduced through research projects, the use of long reads WGS for IRD characterization.As a result, we show the results of the cases studied in our centre. By March 2024, 6,025 unrelated affected IRD families had been recorded, 5,123 of them could be genetically studied, comprising around 8,000 cases. The families were distributed into 3 categories: Non syndromic Retinitis Pigmentosa (RP) (2,597 families; 60% characterized), Syndromic RP (651 families; 69% characterized), and NonRP (Macular Dystrophies, Cone Dystrophies, Cone Rod Dystrophies, etc) (1,875 families; 63% characterized)In our cohort, the largest in the world from one single centre, 192 different genes were found as responsible for IRD, and about of 2,000 different causative variants were identified, half of them present in only one family. Despite this huge genetic heterogeneity, one fourth of the characterised families showed involvement of only seven genes (ABCA4, USH2A, RPGR, CRB1, RS1, PRPH2, and BEST1). RPE65 gene biallelic pathogenic variants were present in 30 families (around 50 affected cases).This approach has allowed to implement not only the molecular characterization, but also to offer authorized treatment (Luxturna) for more than 30 Spanish cases in 6 centres and access to reproductive counselling and techniques, as PGT for severe IRD conditions.
MR‐imaging biomarkers for eye tumors
Authors: Beenakker Jan‐Willem 
Published: January 2025

In the clinical care for eye tumor patients, more and more applications of magnetic resonance imaging (MRI) have emerged in the last years. In retinoblastoma, for example, it is routinely used to screen for tumor invasion in the optic nerve. In uveal melanoma, the most frequently occurring primary intraocular malignancy in adults, MRI's three‐dimensional visualization of the tumor and surrounding structures give it an increasingly prominent place in radiotherapy planning. As a result of these clinical applications, functional MRI‐parameters, which are often obtained in the same scan session, gain in relevance. These functional sequences non‐invasively obtain tumor biomarkers that can be used for differential diagnosis, prognosis and response assessment. In this lecture we will cover the most important MR‐biomarkers, explain the underlying biology they probe, and highlight their clinical and scientific applications.We will start with perfusion‐weighted MRI (PWI), a technique that obtains information on the tumor perfusion by administering an intravenous contrast agent while continuously imaging the eye. In addition to explaining the various pharmacokinetic models to quantitatively assess these data, we will show how, the clinically more feasible, semi‐quantitative assessment can already be used for differential diagnosis and early assessment of treatment response. Subsequently, we will discuss diffusion weighted imaging (DWI), a biomarker of the lesion's cellularity. Although it is a powerful biomarker to discriminate between benign and malignant lesions, its clinical value for prognosis and treatment response are still debated. We will end with a few clinical cases that demonstrate how these and other MR‐biomarkers complement the conventional ophthalmic imaging.
Vision research in community optical practices (e.g., product testing and development, including bsc and MSC theses; opportunities for big data studies)
Authors: Mihelčič Matjaž 
Published: January 2025

In the optometrists’ offices, we usually do not expect to find research setups or laboratory instruments. There is however an increasing practice to host students who work on their Bachelor‐ and Master theses, gathering data for their studies. This combination is beneficial for the staff, as they refresh the knowledge in research; it is beneficial for patients, because many times, new / innovative equipment can be utilised during a standard exam. And it is beneficial for the students, since they have access to consenting patients, a non‐recruited group of subjects, which comprises a much more valid sample for observational studies then making recruitment at eye clinics or hospitals.Ethical approval for the studies is usually obtained via university, but in some countries, it is possible to get it via practice, provided the supervisor fulfils the requirements.In some instances, testing of new instruments can be done in optometric practices, providing the clinicians with insights of research and development, enabling them to give valuable input to industry.Beside regular occupational vision tests, also assessment of visual function in special groups, like certain professions can be made (ex. Policemen, Firemen, Aircraft pilots, Astronauts). This way, the data about speciality needs can be collected and used for academic research.Recent developments of AI‐assisted diagnostics and telemedicine have also addressed optometric practices – for example, the recently approved I‐screen programme, which is funded by European Commission via Horizon 22, employs pilot optometric practices throughout Europe as primary sites of patient acquisition. During regular eye‐exams, patients are screened with OCTs for early forms of dry age‐related macular degeneration. This group of retinal diseases is increasing in prevalence and treatment options are slowly becoming available. However, if patients with relevant clinical signs are not discovered timely, the outcome of the treatment is not as good, or treatment is not applicable at all. Again, an advantage of such studies is that they can provide information on the prevalences of ocular conditions in a community sample that better reflects the population than patients visiting clinics or hospitals.
Panretinal photocoagulation of retina today
Authors: Schwartz Stephen G. 
Published: January 2025

Panretinal photocoagulation (PRP) remains an important clinical tool in the care of many retinal vascular diseases, especially proliferative diabetic retinopathy (PDR) and neovascular glaucoma (NVG) due to ischemic central retinal vein occlusion (CRVO) and other causes.As compared to anti‐vascular endothelial growth factor (anti‐VEGF) therapy, PRP offers the advantages of (1) much lower costs; (2) reduced or eliminated risks of endophthalmitis; and (3) greater duration of treatment effect, especially if the patient becomes lost to follow‐up. Also as compared with anti‐VEGF therapy, PRP offers the disadvantages of (1) greater risk of visual field loss; (2) possibly worse visual acuity (VA) outcomes; and (3) greater risk of diabetic macular edema (DME) in patients with PDR.In the author's opinion, as anti‐VEGF utilization increases worldwide, PRP is probably underutilized today in the care of patients with PDR, CRVO, and NVG. There is a concern that anti‐VEGF masks signs of neovascularization. For example, patients with CME due to CRVO or DME associated with nonproliferative diabetic retinopathy (NPDR) are started on anti‐VEGF therapy. Over time, the CME/DME generally improves and the physician may then use a “treat and extend” protocol. At this stage of the treatment, there is a risk that, as the intervals extend beyond a certain timeframe, the patients become at risk for vitreous hemorrhage, NVG, and other vision‐threatening complications. In other words, the anti‐VEGF masks early signs of neovascularization of the disc (NVD), neovascularization elsewhere (NVE), and/or neovascularization of the iris (NVI).The author recommends that patients with NPDR or nonischemic CRVO who are treated with long‐ term anti‐VEGF injections should be monitored for signs of progression to PDR or ischemic CRVO, respectively, especially when anti‐VEGF treatment intervals are extended beyond 2‐3 months. Certain patients may be considered for “prophylactic” treatment with PRP in this situation, especially those with sclerotic peripheral retinal vessels noted on ultra‐wide field fundus imaging.
Why and how does simulation‐based education work?
Authors: Filipe Helena Prior 
Published: January 2025

Simulation‐Based Education (SBE) should be rooted in educational philosophies, and not simply defined by technology. SBE should underline ethical considerations like professionalism while mirroring and amplifying real‐world scenarios to optimize learning. Crafting vibrant SBE environments relies on mastering the nuances of how we learn best. Drawing from empirical evidence and learning theories is crucial in designing effective simulation‐based learning experiences.We propose a journey illuminated by how SBE programs and their outcomes can be comprehensively enhanced, including patient safety and healthcare quality, through education science implementation. We will also delve into the rewards and hurdles of a comprehensive approach to SBE that weaves these educational experiences seamlessly into well‐structured SBE Centers.
Meta‐analysis of treatment outcomes for patients with m.117 | 8G>A MT‐ND4 leber hereditary optic neuropathy
Authors: Newman Nancy , Biousse Valérie , Yu‐Wai‐Man Patrick , Carelli Valerio , Vignal‐Clermont Catherine , Montestruc François , Taiel Magali , Sahel José‐Alain 
Published: January 2025

Aims/Purpose: To assess the visual outcomes of patients with Leber hereditary optic neuropathy (LHON) harboring the m.11778G>A MT‐ND4 mutation treated with no treatment (natural history), idebenone or lenadogene nolparvovec gene therapy.Methods: Efficacy outcomes were clinically relevant recovery (CRR) from nadir and final best‐corrected visual acuity (BCVA). For the natural history and idebenone groups, a systematic review of the literature and available clinical/regulatory reports was performed. A total of 5 and 13 natural history studies were selected for the meta‐analyses of CRR from nadir and final BCVA, while 7 and 3 idebenone studies were selected, respectively. For the lenadogene nolparvovec group, all phase 3 studies were included (RESCUE, REVERSE, RESTORE and REFLECT). The overall effect and its 95% confidence interval (CI) were estimated using a random effects model.Results: For each meta‐analysis, patients had a mean age of approximately 30 years at the time of vision loss and were mostly (≥78%) men. The CRR from nadir [95% CI] at eye level was estimated at 17% [7%; 30%] (n = 316 eyes), 31% [24%; 40%] (n = 313) and 59% [54%; 64%] (n = 348) in untreated, idebenone‐treated and lenadogene nolparvovec‐treated eyes, respectively. This gradient of efficacy was also observed with CRR at the patient level and final BCVA.Conclusions: There was a gradient of efficacy in all assessed visual outcomes, more marked for CRR than for final BCVA, with lenadogene nolparvovec gene therapy superior to idebenone treatment, and both superior to the natural history of the disease.
Changes in visual acuity categories in a historical population of patients with leber hereditary optic neuropathy from case record survey‐2 (CRS‐2)
Authors: Klopstock Thomas , Leroy Bart , Yu‐Wai‐Man Patrick , van Everdingen Judith , Krawczynski Maciej , Lamperti Costanza , Carelli Valerio , Llòria Xavier 
Published: January 2025

Aims/Purpose: The Case Record Survey‐2 (CRS‐2; NCT02796274) aimed to establish the natural history of Leber hereditary optic neuropathy (LHON) in idebenone‐naïve patients. Here, we present change in visual acuity (VA) categories in subacute/dynamic eyes.Methods: Retrospective clinical data were extracted from case records of LHON patients. Eligibility: aged ≥12 y, m.11778G>A, m.3460G>A, or m.14484T>C mitochondrial DNA mutation, symptom onset after 1999 and ≥2 VA assessments within 5 years of symptom onset. VA categories (logMAR): <1.00, 1.00–1.68, >1.68. Baseline was the first VA assessment after symptom onset; subacute/dynamic eyes were those with baseline ≤1 year after symptom onset.Results: A total of 385 subacute/dynamic eyes had available data. Median (interquartile range; IQR) time from symptom onset to baseline was 1.3 (0.6–3.3) months; median (IQR) time from symptom onset to last visit was 8.8 (4.0–39.9) months. At baseline, 41% (157/385) of eyes were <1.00 logMAR. Of these, 30% (47/157) remained <1.00 logMAR at last visit; 41% (64/157) and 29% (46/157) worsened to 1.00–1.68 and >1.68 logMAR, respectively. At baseline, 36% (138/385) of eyes were 1.00–1.68 logMAR. Of these, 49% (67/138) remained 1.00–1.68 logMAR at last visit, 31% (43/138) worsened to >1.68 logMAR and 20% (28/138) improved to <1.00 logMAR. At baseline, 23% (90/385) of eyes were >1.68 logMAR. Of these, 68% (61/90) remained >1.68 logMAR at last visit; 27% (24/90) and 6% (5/90) improved to 1.00–1.68 and <1.00 logMAR, respectively.Conclusions: The CRS‐2 study offers important insights into changes in VA category, based on baseline VA, in idebenone‐naïve eyes. However, given the variability in follow‐up time in retrospective natural history studies, caution must be taken in interpreting these results.
Systems pharmacology demonstrates broad‐spectrum efficacy in animal models of retinopathies
Authors: Leinonen Henri , Vainionpää Katri , Montaser Ahmed , Seemab Umair , Zhang Jianye , Occelli Laurence , Kolesnikov Alexander , Kefalov Vladimir , Kiser Philip , Tabaka Marcin , Petersen‐Jones Simon , Palczewski Krzysztof 
Published: January 2025

Aims/Purpose: Excessive levels of the intracellular second messengers Ca2+ and cAMP have been linked with photoreceptor cell death during retinal degeneration (RD). We investigated if a combination (TMB) of common clinical drugs; tamsulosin and metoprolol (alpha‐ and beta‐adrenergic antagonists, Gq‐ and Gs‐coupled, respectively), and bromocriptine (a D2‐like dopamine‐receptor agonist, Gi‐coupled), that inhibit intracellular Ca2+ and cAMP signaling could be repurposed to mitigate RD.Methods: Drug efficacy was tested in four distinct RD models: rd10, P23H, and Rpe65−/− mice; and PDE6A−/− dogs. The duration of the drug trials ranged from 1‐wk to 7‐months. Drug serum levels were measured by liquid chromatography‐mass spectrometry (LC‐MS). We used primarily photopic and scotopic electroretinography (ERG) and optical coherence tomography (OCT) to assess drug efficacy. Molecular biology methods such as immunohistochemistry, immunoblotting, and RNA‐sequencing (bulk and single cell) were used to document therapeutic mechanisms, as well as to confirm therapeutic effects.Results: Dietary TMB improved cone function and slowed cone degeneration in P23H mice. In rd10 mice, both rod and cone function were significantly improved by TMB; and cone degeneration was significantly slowed. In dark‐reared rd10 mice, the drug efficacy was associated with decreased lipid peroxidation preceding the onset of cone degeneration. Dietary TMB improved retinal function and optomotor responses in Rpe65−/− mice but did not halt rod or cone degeneration. Seven‐month‐long subcutaneous sustained infusion of TMB into PDE6A−/− dogs led to higher cone counts at the end of the trial. TMB mitigated forskolin‐induced cAMP activity in an ex vivo retina preparation.Conclusions: Our results suggest that simultaneous inhibition of Gs‐ and Gq‐coupled receptors and activation of Gi‐coupled receptors by a combination of existing drugs is a viable therapeutic strategy for RD.
Conditioned media from dental pulp stem cells to counteract the age‐related macular degeneration
Authors: Zerti Darin , Carozza Giulia , Pulcini Fanny , Lancia Loreto , Mattei Vincenzo , Monache Simona Delle , Maccarone Rita 
Published: January 2025

Aims/Purpose: Age‐related macular degeneration (AMD) is the leading cause of blindness in the elderly. To date, there are no effective therapies to counteract the AMD towards the most severe stages characterized by a progressive loss of photoreceptors triggered by retinal pigmented epithelium dysfunction. Given their easily source and their high proliferative potential, Dental Pulp Stem Cells (DPSCs) showed promise for regenerative medicine. The main advantage of DPSCs is related to their immunosuppressive and immunoregulatory abilities, including the capability to promote regeneration of damaged tissues. It is well known the therapeutic potential of DPSCs secretome (conditioned media, CM), including trophic factors and cytokines, as a treatment of neurogenerative diseases. We evaluated the capability of DPSCs‐CM cultured in hypoxia and normoxic conditions to counteract retinal degeneration in an animal model of AMD.Methods: DPSCs‐CM were intravitreally injected the day before the exposure of albino rats to high intensity light (LD). We evaluated the retinal function, and we performed morphological and molecular analysis a week after the LD, in accordance with the well‐established protocol of our light damage model.Results: DPSCs‐CM obtained from hypoxia or normoxia, were able to preserve the retinal function, to reduce microglial activation and their migration toward outer nuclear layer (ONL). Furthermore, we demonstrated that the treatment with normoxic DPSCs‐CM limited the hot spot extension and preserved the ONL thickness better than the hypoxic DPSCs‐CM. The different concentrations of growth factors and cytokines detected in both CM played a key role in the understanding of the greatest protective effect of the normoxic‐CM compared to hypoxic‐CM.Conclusions: Taken together, our study demonstrated that normoxic DPSCs‐CM represents an eligible candidate to counteract retinal degeneration and, therefore, a promising therapeutic agent for AMD.
Development of a bioreactor to examine the response of corneal cells to fluid shear stress
Authors: Bonizzi Matthia 
Published: January 2025

Aims/Purpose: Mechanical stimulation plays an important role in regulating cell behavior. While several studies have examined how corneal epithelial cells respond to mechanical stimuli such as fluidic shear stress, little is known about how keratocytes respond. The purpose of this study was to design a bioreactor system to determine the effect of shear stress on the behavior of corneal epithelial cells and keratocytes in an in‐vitro 3D corneal hydrogel model.Methods: A bioreactor chamber was made of PDMS containing 4 wells. 10 μl cell seeded hydrogels, consisting of 3.5 mg/ml collagen type I and 10 mM PEG (polyethylene‐glycol) containing 5 x 104 keratocytes, were added to each well to replicate the stroma. A 20 μm PCL (polycaprolactone) electrospun membrane was placed on top of each hydrogel and seeded with 1.6 x 103 corneal epithelial cells. The chamber was connected to a pump system to allow fluid to pass over the hydrogels at specified flow rates. Several tests were performed to validate the bioreactor and examine the cell response to fluid shear stress.Results: The bioreactor was successfully tested for hydraulic sealing and sterility maintenance. The shear stress was calculated using a simple mechanical model and validated using computational fluid dynamics software. Preliminary studies using collagen hydrogels showed a high degree of contraction so PEG was introduced to the hydrogels to assist in stabilization. The response of corneal epithelial cells to different rates of shear stress was examined by analyzing the expression of YAP (Yes‐Associated‐Protein) and ZO‐1 (Zonula‐occludens‐1), both of which are known to be mechano‐sensitive.Conclusions: The bioreactor has been developed and validated to apply shear stress to corneal hydrogel models. Further studies will further evaluate the response of epithelial cells and keratocytes to fluid flow at different shear rates.
Endothelial cell heterogeneity in arteriolar annuli: Implications in retinal blood flow regulation
Authors: González David Ramos , López‐Luppo Mariana , Jaramillo Patricia , Carretero Ana , Nacher Victor , Navarro Marc , Ruberte Jesús 
Published: January 2025

Aims/Purpose: To investigate the endothelial cell heterogeneity in retinal arterioles with special focus in arteriolar annuli.Methods: We compared structural and molecular characteristics between endothelial cells located in arteriolar annuli and endothelial cells located in other regions of retinal arterioles. Immunohistochemical, histochemical, and electron transmission microscopy assays were performed.Results: Molecular analysis showed that arteriolar annuli endothelial cells showed a decreased expression of PECAM‐1 together with an increased expression of NADPH‐diaphorase in comparison with other regions of retinal arterioles. PECAM‐1 is involved cell‐cell adhesion. Therefore, this result suggests a decrease in cellular adhesion at the arteriolar annuli. NADPH diaphorase reflects nitric oxide synthase activity. Thus, its increase indicates NO synthesis suggesting localized vasodilation and decrease of platelet aggregation at arteriolar annuli. An increased expression of von Willebrand factor in concomitance with a higher presence of Weibel‐Palade bodies was also observed in endothelial cells at the arteriolar annuli, suggesting that von Willebrand factor is stored and released in a regulated manner. Furthermore, transmission electron microscopy showed the presence of two endothelial cell subtypes in arteriolar annuli: activated endothelial cells, and shear stress‐adapted endothelial cells. Activated endothelial cells exhibited enlarged nuclei with chromatin condensed in the periphery, swollen perinuclear space, and an increased number of vesicles and caveolae. By contrast, shear stress‐adapted endothelial cells were thicker than the rest of endothelial cells and showed bilobulated nuclei, a well‐developed endoplasmic reticulum, as well as large increase in the number of mitochondria.Conclusions: All our results suggest that endothelium at arteriolar annuli, a structure suggested to regulate retinal blood flow by exerting a sphincter‐like activity, is formed by a subset of endothelial cells endowed with distinctive structural and molecular features which allow them to play a key role in the maintenance of blood flow through two mechanisms: the establishment of an antithrombotic milieu, and the vasodilation of arteriolar annuli.