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Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. With an ageing population, it is anticipated that the number of AMD cases will increase dramatically, making a solution to this debilitating disease an urgent requirement for the socioeconomic future of the European Union and worldwide. The present paper reviews the limitations of the current therapies as well as the socioeconomic impact of the AMD. There is currently no cure available for AMD, and even palliative treatments are rare. Treatment options show several side effects, are of high cost, and only treat the consequence, not the cause of the pathology. For that reason, many options involving cell therapy mainly based on retinal and iris pigment epithelium cells as well as stem cells are being tested. Moreover, tissue engineering strategies to design and manufacture scaffolds to mimic Bruch’s membrane are very diverse and under investigation. Both alternative therapies are aimed to prevent and/or cure AMD and are reviewed herein.

Ophthalmology is notable for significant technological innovations (e.g laser, microscopy…) that allow for diagnostic and therapeutic advances every year. This article presents the main significant therapeutic progress and highlights the growing use of artificial intelligence in diagnosis of eye disease. We include a focus on emergent virus-mediated ocular conditions that have garnered attention lately, as the number of patients with viral infections is increasing worldwide., Competing Interests: les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Laser assisted in situ keratomileusis (LASIK) surgery is the leading and most performed refractive surgery nowadays. A possible complication of LASIK surgery is infectious keratitis which can lead to disastrous corneal damage and result in permanent loss of vision. LASIK procedures have become increasingly accessible, and the demand for refractive surgery has risen among patients, challenging the medical field to improve the prevention of post-operative infections. Nevertheless, a wide range of pathogens have been described as responsible for post-LASIK keratitis. However, non-tuberculous mycobacterial keratitis remains an infrequent occurrence and is poorly described in the literature. To the best of our knowledge, this is the first ever reported case of post-LASIK keratitis caused by Mycobacterium wolinskyi. We describe the clinical and microbial characteristics, leading to its challenging treatment choice., (© 2024. The Author(s).)

Background : Techniques for the preparation of grafts for Descemet membrane endothelial keratoplasty (DMEK) can be classified into those that involve the manual dissection of the Descemet membrane (DM) and those that use an injection of a liquid or a gas to achieve a separation of the DM from the posterior corneal stroma. The purpose of this study was to evaluate the efficiency of the liquid bubble technique. Methods : The success rate of the technique was calculated retrospectively using the operating reports. Video files for each graft preparation were retrieved and the time, number of injections, and number of injections sites required for the hydrodissection were measured. The number of cases in which a manual dissection of the Descemet membrane was necessary was recorded. Information on donor age and graft preservation time were retrieved from the eye bank file. Results : In 58 cases, the success rate was 98.3%. In the 28 procedures where a video was available, the median time for hydrodissection was 4.4 min. The median number of injection sites was 2, with a median number of injections of 3.5. Manual dissection as a rescue technique was performed in 25% of cases, with one case resulting in graft tears. The mean graft diameter was 7.6 mm. The mean donor age was 66 years, and the mean graft storage time was 22 days. Conclusions : The liquid bubble technique can be a fast and valuable choice for DMEK graft preparation, especially in centers where the tissue is prepared in the operating theater.

Introduction: Conjunctival cysts are usually asymptomatic but they can cause foreign body sensation and contribute to dry eye disease. The purpose of this case report is to describe the presentation and treatment of an infected inclusion cyst of a conjunctival nevus in a healthy 36-year-old patient., Case Presentation: A healthy 36-year-old man presented to the emergency department for redness and pain in his left eye for 1 day. Slit-lamp examination revealed a conjunctival hyperemia and a conjunctival nevus with 4 inclusion cysts, one of which was filled with purulent material. Fluorescein staining of the conjunctival epithelium was negative. Α mini-incision of the white cyst was performed using a 30 G needle, followed by bimanual drainage and topical treatment with tobramycin and moxifloxacin drops every 3 h for a week. A swab of the purulent drainage was positive for gram-positive flora. One week after the drainage of the cyst, the patient was asymptomatic and on slit-lamp examination, the 4 inclusion cysts were filled with a transparent liquid, there was not any vessel dilation and fluorescein staining was negative., Conclusion: Conjunctival inclusion cysts, although considered benign, can become infected and form a conjunctival abscess. A mini-incision on the slit lamp combined with bimanual drainage and followed by topical antibiotic drops seems to be a safe and effective treatment., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background and Objectives : The purpose of this study was to compare two commercially available specular microscopes (Tomey EM-4000 and Nidek CEM-530) in a real-life clinical setting in terms of intra- and interdevice variability. The study was conducted on all patients seen in a clinical practice specializing in anterior segment pathologies, regardless of the purpose of their visit. Materials and Methods : In total, 112 eyes of 56 patients (age 23-85 years old) were included in the study. Each eye was measured three times with each device (for a total of six measurements), and results for central corneal thickness (CCT) and corneal endothelial cell density (ECD) were recorded. The results were then evaluated with the D'Agostino-Pearson normality test and compared with a Wilcoxon signed-rank test, t -test, ANOVA or Mann-Whitney test for intra- and interdevice variability. Results : Both specular microscopes produced very reliable reproducible intradevice results: The Tomey EM-4000 measured an ECD of 2390 ± 49.57 cells/mm 2 (mean ± standard error of mean); the range was 799-3010 cells/mm 2 . The determined CCT was 546 ± 5.104 µm (mean ± standard error of mean [SEM]); the range was 425-615 µm. The measurements with the Nidek CEM-530 revealed an ECD of 2417 ± 0.09 cells/mm 2 (mean ± SEM); the range was 505-3461 cells/mm 2 (mean ± SEM). The mean CCT detected was 546.3 ± 4.937 µm (mean ± SEM); the range was 431-621 µm. The interdevice differences were statistically significant for both parameters, ECD ( p = 0.0175) and CCT ( p = 0.0125) ( p < 0.05). Conclusions : The Nidek CEM-530 and the Tomey EM-4000 both produced reliable and reproducible results in terms of ECD and CCT. The absolute measurements were statistically significantly different for CCT and ECD for both devices; the Nidek produces slightly higher values.

Competing Interests: The authors declare that they have no conflict of interest.

Worldwide stroke is the second leading cause of death and the third leading cause of death and disability combined. The estimated global economic burden by stroke is over US$891 billion per year. Within three decades (1990-2019), the incidence increased by 70%, deaths by 43%, prevalence by 102%, and DALYs by 143%. Of over 100 million people affected by stroke, about 76% are ischemic stroke (IS) patients recorded worldwide. Contextually, ischemic stroke moves into particular focus of multi-professional groups including researchers, healthcare industry, economists, and policy-makers. Risk factors of ischemic stroke demonstrate sufficient space for cost-effective prevention interventions in primary (suboptimal health) and secondary (clinically manifested collateral disorders contributing to stroke risks) care. These risks are interrelated. For example, sedentary lifestyle and toxic environment both cause mitochondrial stress, systemic low-grade inflammation and accelerated ageing; inflammageing is a low-grade inflammation associated with accelerated ageing and poor stroke outcomes. Stress overload, decreased mitochondrial bioenergetics and hypomagnesaemia are associated with systemic vasospasm and ischemic lesions in heart and brain of all age groups including teenagers. Imbalanced dietary patterns poor in folate but rich in red and processed meat, refined grains, and sugary beverages are associated with hyperhomocysteinaemia, systemic inflammation, small vessel disease, and increased IS risks. Ongoing 3PM research towards vulnerable groups in the population promoted by the European Association for Predictive, Preventive and Personalised Medicine (EPMA) demonstrates promising results for the holistic patient-friendly non-invasive approach utilising tear fluid-based health risk assessment, mitochondria as a vital biosensor and AI-based multi-professional data interpretation as reported here by the EPMA expert group. Collected data demonstrate that IS-relevant risks and corresponding molecular pathways are interrelated. For examples, there is an evident overlap between molecular patterns involved in IS and diabetic retinopathy as an early indicator of IS risk in diabetic patients. Just to exemplify some of them such as the 5-aminolevulinic acid/pathway, which are also characteristic for an altered mitophagy patterns, insomnia, stress regulation and modulation of microbiota-gut-brain crosstalk. Further, ceramides are considered mediators of oxidative stress and inflammation in cardiometabolic disease, negatively affecting mitochondrial respiratory chain function and fission/fusion activity, altered sleep-wake behaviour, vascular stiffness and remodelling. Xanthine/pathway regulation is involved in mitochondrial homeostasis and stress-driven anxiety-like behaviour as well as molecular mechanisms of arterial stiffness. In order to assess individual health risks, an application of machine learning (AI tool) is essential for an accurate data interpretation performed by the multiparametric analysis. Aspects presented in the paper include the needs of young populations and elderly, personalised risk assessment in primary and secondary care, cost-efficacy, application of innovative technologies and screening programmes, advanced education measures for professionals and general population-all are essential pillars for the paradigm change from reactive medical services to 3PM in the overall IS management promoted by the EPMA., Competing Interests: Conflicts of InterestThe authors declare no conflict of interest. Prof. Dr. Olga Golubnitschaja is an editor of the EPMA J., and recused herself from all decisions about the paper. She is a shareholder of 3PMedicon. Dr. Jiri Polivka Jr. is a shareholder of 3PMedicon., (© The Author(s) 2024.)

Background and Objectives: The aim of the research was to investigate the differences in the concentrations of IL-12, IL-4, IL-10, and IFN-γ in tears after LASIK and PRK procedures., Materials and Methods: The study included 68 myopic eyes up to -3.0 D refractive spherical equivalent, divided into two groups: Group 1 LASIK ( n = 31) and Group 2 PRK ( n = 37). Three tear samples were taken from each eye: immediately before the procedure (t 0 ), 1 h after the procedure (t 1 ), and 24 h after the procedure (t 2 ). The concentrations of IL-12p70, IL-4, IL-10, and IFN-γ in the tear samples were determined by flow cytometry. Participants were not taking anti-inflammatory therapy 24 h after the procedure., Results: IL-4 levels 1 h after treatment did not differ between LASIK and PRK ( p = 0.990), while 24 h after PRK there was a significant decrease in IL-4 levels ( p < 0.05), but not after LASIK ( p = 0.476). In both the LASIK ( p < 0.05) and PRK ( p < 0.05) groups, there is an increase in IL-10 concentrations 1 h after treatment, which persists 24 h after LASIK ( p < 0.05) but not after PRK ( p = 0.081). There is an increase in IL-12p70 concentration 1 h after treatment in both the LASIK ( p < 0.001) and PRK groups ( p < 0.001). There is also an increase in IL-12p70 concentration 24 h after PRK ( p < 0.005), but not after LASIK ( p = 0.775)., Conclusions: IL-4 concentration shows a significantly higher value in the LASIK group than in the PRK group after 24 h. IL-10 and IL-12p70 levels increase one hour after surgery in both groups. After 24 h, the IL-10 levels remain elevated in the LASIK group, and the IL-12p70 levels remain elevated in the PRK group. Thus, LASIK and PRK procedures show different inflammatory dynamics.

Oxidative stress (OS) is involved in the pathogenesis of retinal neurodegenerative diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) and an important target of therapeutic treatments. New therapeutics are tested in vivo despite limits in terms of transferability and ethical concerns. Retina cultures using human tissue can deliver critical information and significantly reduce the number of animal experiments along with increased transferability. We cultured up to 32 retina samples derived from one eye, analyzed the model's quality, induced OS, and tested the efficiency of antioxidative therapeutics. Bovine, porcine, rat, and human retinae were cultured in different experimental settings for 3-14 d. OS was induced by a high amount of glucose or hydrogen peroxide (H 2 O 2 ) and treated with scutellarin, pigment epithelium-derived factor (PEDF), and/or granulocyte macrophage colony-stimulating factor (GM-CSF). The tissue morphology, cell viability, inflammation, and glutathione level were determined. The retina samples showed only moderate necrosis (23.83 ± 5.05 increased to 27.00 ± 1.66 AU PI-staining over 14 d) after 14 days in culture. OS was successfully induced (reduced ATP content of 288.3 ± 59.9 vs. 435.7 ± 166.8 nM ATP in the controls) and the antioxidants reduced OS-induced apoptosis (from 124.20 ± 51.09 to 60.80 ± 319.66 cells/image after the scutellarin treatment). Enhanced mammalian animal and human retina cultures enable reliable, highly transferable research on OS-triggered age-related diseases and pre-clinical testing during drug development.

Background: Amblyopia is the most common developmental vision disorder in children. The initial treatment consists of refractive correction. When insufficient, occlusion therapy may further improve visual acuity. However, the challenges and compliance issues associated with occlusion therapy may result in treatment failure and residual amblyopia. Virtual reality (VR) games developed to improve visual function have shown positive preliminary results. The aim of this study is to determine the efficacy of these games to improve vision, attention, and motor skills in patients with residual amblyopia and identify brain-related changes. We hypothesize that a VR-based training with the suggested ingredients (3D cues and rich feedback), combined with increasing the difficulty level and the use of various games in a home-based environment is crucial for treatment efficacy of vision recovery, and may be particularly effective in children., Methods: The AMBER study is a randomized, cross-over, controlled trial designed to assess the effect of binocular stimulation (VR-based stereoptic serious games) in individuals with residual amblyopia (n = 30, 6-35 years of age), compared to refractive correction on vision, selective attention and motor control skills. Additionally, they will be compared to a control group of age-matched healthy individuals (n = 30) to account for the unique benefit of VR-based serious games. All participants will play serious games 30 min per day, 5 days per week, for 8 weeks. The games are delivered with the Vivid Vision Home software. The amblyopic cohort will receive both treatments in a randomized order according to the type of amblyopia, while the control group will only receive the VR-based stereoscopic serious games. The primary outcome is visual acuity in the amblyopic eye. Secondary outcomes include stereoacuity, functional vision, cortical visual responses, selective attention, and motor control. The outcomes will be measured before and after each treatment with 8-week follow-up., Discussion: The VR-based games used in this study have been conceived to deliver binocular visual stimulation tailored to the individual visual needs of the patient, which will potentially result in improved basic and functional vision skills as well as visual attention and motor control skills., Trial Registration: This protocol is registered on ClinicalTrials.gov (identifier: NCT05114252) and in the Swiss National Clinical Trials Portal (identifier: SNCTP000005024)., (© 2023. The Author(s).)

Planning astigmatic correction is a complex task. Biomechanical simulation models are useful for predicting the effects of the physical procedure on the cornea. Algorithms based on these models allow preoperative planning and simulate the outcome of patient-specific treatment. The objective of this study was to develop a customised optimisation algorithm and determine the predictability of astigmatism correction by femtosecond laser arcuate incisions. In this study, biomechanical models and Gaussian approximation curve calculations were used for surgical planning. Thirty-four eyes with mild astigmatism were included, and corneal topographies were evaluated before and after femtosecond laser-assisted cataract surgery with arcuate incisions. The follow-up time was up to 6 weeks. Retrospective data showed a significant reduction in postoperative astigmatism. A total of 79.4% showed a postoperative astigmatic value less than 1 D. Clinical refraction was significantly reduced from -1.39 ± 0.79 D preoperatively to -0.86 ± 0.67 D postoperatively ( p 0.02). A positive reduction in topographic astigmatism was also observed ( p < 0.00). The best-corrected visual acuity increased postoperatively ( p < 0.001). We can conclude that customised simulations based on corneal biomechanics are a valuable tool for correcting mild astigmatism with corneal incisions in cataract surgery to improve postoperative visual outcomes.

Neovascular age-related macular degeneration (nvAMD) is characterized by choroidal neovascularization (CNV), which leads to retinal pigment epithelial (RPE) cell and photoreceptor degeneration and blindness if untreated. Since blood vessel growth is mediated by endothelial cell growth factors, including vascular endothelial growth factor (VEGF), treatment consists of repeated, often monthly, intravitreal injections of anti-angiogenic biopharmaceuticals. Frequent injections are costly and present logistic difficulties; therefore, our laboratories are developing a cell-based gene therapy based on autologous RPE cells transfected ex vivo with the pigment epithelium derived factor (PEDF), which is the most potent natural antagonist of VEGF. Gene delivery and long-term expression of the transgene are enabled by the use of the non-viral Sleeping Beauty (SB100X) transposon system that is introduced into the cells by electroporation. The transposase may have a cytotoxic effect and a low risk of remobilization of the transposon if supplied in the form of DNA. Here, we investigated the use of the SB100X transposase delivered as mRNA and showed that ARPE-19 cells as well as primary human RPE cells were successfully transfected with the Venus or the PEDF gene, followed by stable transgene expression. In human RPE cells, secretion of recombinant PEDF could be detected in cell culture up to one year. Non-viral ex vivo transfection using SB100X-mRNA in combination with electroporation increases the biosafety of our gene therapeutic approach to treat nvAMD while ensuring high transfection efficiency and long-term transgene expression in RPE cells.

Purpose: To report the prevalence of late postoperative opacification of a hydrophilic and hydrophobic acrylic intraocular lens (IOL) and to assess the risk factors in a subset of 212 eyes of patients referred to the University Eye Department in Basel, Switzerland., Design: Retrospective case series., Methods: A survey was performed at all large ophthalmological clinics in Switzerland regarding exchanged Lentis LS-502-1 lenses, and the number of affected eyes was counted. Moreover, consecutive patients who were referred to a tertiary clinic between September 2015 and November 2016 with Lentis LS-502-1 opacification were investigated. Peri- and postoperative charts, medical history, and topical and systemic medications were assessed., Results: A total of 674 opacified Lentis LS-502-1 lenses have been reported in Switzerland, and 212 consecutive eyes of 182 patients were included in the study. All IOLs had a similar pattern of opacification with a yellowish, diffuse appearance, and most of them showed a small, paracentral, roundish area that was less affected or not at all. Arterial hypertension (73%), hypercholesterolemia (34%), and diabetes (21%) were the main associated systemic diseases, and statins (34%) and betablockers (34%) were the main treatments used., Conclusions: The prevalence of IOL opacification was 9.9%. No associated systemic eye disease or medications could be detected, which was implicated in the opacification process. The reason for opacification remains unclear, but it seems to be unrelated to the patient's state; therefore, it is attributed to primary calcification., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background : The aim of the study was to compare macular thickness behavior and clinical outcomes after femtosecond laser-assisted cataract surgery (FLACS) versus phacoemulsification conventional surgery (PCS). Methods : Macular Optical Coherence Tomography OCT was analyzed in 42 patients preoperatively, 1 day, 12 days, 4 weeks and 6 weeks postoperatively according to the 9-field Early Treatment Diabetic Retinopathy Study (ETDRS) grid. Clinical findings were collected in both the FLACS group and the PCS group. Results : There was no significant difference in macular thickness between the FLACS and PCS groups ( p > 0.05). However, from postoperative day 12 onwards, there was a significant increase in macular thickness observed in both groups ( p < 0.001). In the FLACS group, a significant increase in visual acuity was observed on the first postoperative day, as compared to the PCS group ( p = 0.006). Conclusions : The use of a low-energy high-frequency femtosecond laser has potentially no effect on postoperative macular thickness. In the FLACS group, visual rehabilitation was significantly faster as compared to the PCS group. No complications occurred intraoperatively in either group.

(1) Background: Mid-stromal isolated Bowman layer transplantation aims to reduce and stabilize corneal ectasia in patients with advanced, progressive keratoconus. The purpose of this review is to evaluate the effectiveness and safety of this new surgical technique. (2) Methods: Following the PRISMA statement and checklist, we searched Medline, the Cochrane Controlled Trials Register, and Embase and used a broad systematic search strategy according to the Cochrane Collaboration. (3) Results: Eight studies with a total number of 120 eyes of 106 patients met our inclusion criteria. One month after Bowman layer transplantation, patients with keratoconus showed a significant decrease in the measured simulated keratometry (-4.74 D [95% CI -6.79 to -2.69]) and the maximum keratometry (-7.41 D [95% CI -9.64 to -5.19]), which remained significant one year postoperatively (-2.91 D [95% CI -5.29 to -0.53] and -5.80 D [-8.49 to -3.12]). Intra- and postoperative complications were observed in 3% and 9% of the patients, respectively. An estimated success rate of 75% to 85% was achieved by experienced surgeons at 5 to 8 years postoperatively. (4) Conclusions: Bowman layer transplantation may be an effective and safe treatment option in patients with advanced, progressive keratoconus. Additional multicenter prospective interventional studies are needed to confirm these preliminary findings.

Type 2 diabetes (T2DM) defined as the adult-onset type that is primarily not insulin-dependent, comprises over 95% of all diabetes mellitus (DM) cases. According to global records, 537 million adults aged 20-79 years are affected by DM that means at least 1 out of 15 persons. This number is projected to grow by 51% by the year 2045. One of the most common complications of T2DM is diabetic retinopathy (DR) with an overall prevalence over 30%. The total number of the DR-related visual impairments is on the rise, due to the growing T2DM population. Proliferative diabetic retinopathy (PDR) is the progressing DR and leading cause of preventable blindness in working-age adults. Moreover, PDR with characteristic systemic attributes including mitochondrial impairment, increased cell death and chronic inflammation, is an independent predictor of the cascading DM-complications such as ischemic stroke. Therefore, early DR is a reliable predictor appearing upstream of this "domino effect". Global screening, leading to timely identification of DM-related complications, is insufficiently implemented by currently applied reactive medicine. A personalised predictive approach and cost-effective targeted prevention shortly - predictive, preventive and personalised medicine (PPPM / 3PM) could make a good use of the accumulated knowledge, preventing blindness and other severe DM complications. In order to reach this goal, reliable stage- and disease-specific biomarker panels are needed characterised by an easy way of the sample collection, high sensitivity and specificity of analyses. In the current study, we tested the hypothesis that non-invasively collected tear fluid is a robust source for the analysis of ocular and systemic (DM-related complications) biomarker patterns suitable for differential diagnosis of stable DR versus PDR. Here, we report the first results of the comprehensive ongoing study, in which we correlate individualised patient profiles (healthy controls versus patients with stable D as well as patients with PDR with and without co-morbidities) with their metabolic profiles in the tear fluid. Comparative mass spectrometric analysis performed has identified following metabolic clusters which are differentially expressed in the groups of comparison: acylcarnitines, amino acid & related compounds, bile acids, ceramides, lysophosphatidyl-choline, nucleobases & related compounds, phosphatidyl-cholines, triglycerides, cholesterol esters, and fatty acids. Our preliminary data strongly support potential clinical utility of metabolic patterns in the tear fluid indicating a unique metabolic signature characteristic for the DR stages and PDR progression. This pilot study creates a platform for validating the tear fluid biomarker patterns to stratify T2DM-patients predisposed to the PDR. Moreover, since PDR is an independent predictor of severe T2DM-related complications such as ischemic stroke, our international project aims to create an analytical prototype for the "diagnostic tree" (yes/no) applicable to healthrisk assessment in diabetes care., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2023.)

Proliferative diabetic retinopathy (PDR) the sequel of diabetic retinopathy (DR), a frequent complication of diabetes mellitus (DM), is the leading cause of blindness in the working-age population. The current screening process for the DR risk is not sufficiently effective such that often the disease is undetected until irreversible damage occurs. Diabetes-associated small vessel disease and neuroretinal changes create a vicious cycle resulting in the conversion of DR into PDR with characteristic ocular attributes including excessive mitochondrial and retinal cell damage, chronic inflammation, neovascularisation, and reduced visual field. PDR is considered an independent predictor of other severe diabetic complications such as ischemic stroke. A "domino effect" is highly characteristic for the cascading DM complications in which DR is an early indicator of impaired molecular and visual signaling. Mitochondrial health control is clinically relevant in DR management, and multi-omic tear fluid analysis can be instrumental for DR prognosis and PDR prediction. Altered metabolic pathways and bioenergetics, microvascular deficits and small vessel disease, chronic inflammation, and excessive tissue remodelling are in focus of this article as evidence-based targets for a predictive approach to develop diagnosis and treatment algorithms tailored to the individual for a cost-effective early prevention by implementing the paradigm shift from reactive medicine to predictive, preventive, and personalized medicine (PPPM) in primary and secondary DR care management., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© The Author(s) 2023.)

Due to the reactive medical approach applied to disease management, stroke has reached an epidemic scale worldwide. In 2019, the global stroke prevalence was 101.5 million people, wherefrom 77.2 million (about 76%) suffered from ischemic stroke; 20.7 and 8.4 million suffered from intracerebral and subarachnoid haemorrhage, respectively. Globally in the year 2019 - 3.3, 2.9 and 0.4 million individuals died of ischemic stroke, intracerebral and subarachnoid haemorrhage, respectively. During the last three decades, the absolute number of cases increased substantially. The current prevalence of stroke is 110 million patients worldwide with more than 60% below the age of 70 years. Prognoses by the World Stroke Organisation are pessimistic: globally, it is predicted that 1 in 4 adults over the age of 25 will suffer stroke in their lifetime. Although age is the best known contributing factor, over 16% of all strokes occur in teenagers and young adults aged 15-49 years and the incidence trend in this population is increasing. The corresponding socio-economic burden of stroke, which is the leading cause of disability, is enormous. Global costs of stroke are estimated at 721 billion US dollars, which is 0.66% of the global GDP. Clinically manifested strokes are only the "tip of the iceberg": it is estimated that the total number of stroke patients is about 14 times greater than the currently applied reactive medical approach is capable to identify and manage. Specifically, lacunar stroke (LS), which is characteristic for silent brain infarction, represents up to 30% of all ischemic strokes. Silent LS, which is diagnosed mainly by routine health check-up and autopsy in individuals without stroke history, has a reported prevalence of silent brain infarction up to 55% in the investigated populations. To this end, silent brain infarction is an independent predictor of ischemic stroke. Further , small vessel disease and silent lacunar brain infarction are considered strong contributors to cognitive impairments, dementia, depression and suicide, amongst others in the general population. In sub-populations such as diabetes mellitus type 2, proliferative diabetic retinopathy is an independent predictor of ischemic stroke. According to various statistical sources, cryptogenic strokes account for 15 to 40% of the entire stroke incidence. The question to consider here is, whether a cryptogenic stroke is fully referable to unidentifiable aetiology or rather to underestimated risks. Considering the latter, translational research might be of great clinical utility to realise innovative predictive and preventive approaches, potentially benefiting high risk individuals and society at large. In this position paper, the consortium has combined multi-professional expertise to provide clear statements towards the paradigm change from reactive to predictive, preventive and personalised medicine in stroke management, the crucial elements of which are:Consolidation of multi-disciplinary expertise including family medicine, predictive and in-depth diagnostics followed by the targeted primary and secondary (e.g. treated cancer) prevention of silent brain infarctionApplication of the health risk assessment focused on sub-optimal health conditions to effectively prevent health-to-disease transitionApplication of AI in medicine, machine learning and treatment algorithms tailored to robust biomarker patternsApplication of innovative screening programmes which adequately consider the needs of young populations., Competing Interests: Conflict of interestThe authors declare no conflict of interest. OG is the Editor-in-Chief of the journal, but had no involvement in, influence over, or access to the details of the peer review process of this work., (© The Author(s) 2022.)

The introduction of new therapeutics requires validation of Good Manufacturing Practice (GMP)-grade manufacturing including suitable quality controls. This is challenging for Advanced Therapy Medicinal Products (ATMP) with personalized batches. We have developed a person-alized, cell-based gene therapy to treat age-related macular degeneration and established a vali-dation strategy of the GMP-grade manufacture for the ATMP; manufacturing and quality control were challenging due to a low cell number, batch-to-batch variability and short production duration. Instead of patient iris pigment epithelial cells, human donor tissue was used to produce the transfected cell product ("tIPE"). We implemented an extended validation of 104 tIPE productions. Procedure, operators and devices have been validated and qualified by determining cell number, viability, extracellular DNA, sterility, duration, temperature and volume. Transfected autologous cells were transplanted to rabbits verifying feasibility of the treatment. A container has been engineered to ensure a safe transport from the production to the surgery site. Criteria for successful validation and qualification were based on tIPE's Critical Quality Attributes and Process Parameters, its manufacture and release criteria. The validated process and qualified operators are essential to bring the ATMP into clinic and offer a general strategy for the transfer to other manufacture centers and personalized ATMPs.

More and more patients suffer from multifactorial neurodegenerative diseases, such as age-related macular degeneration (AMD). However, their pathological mechanisms are still poorly understood, which complicates the development of effective therapies. To improve treatment of multifactorial diseases, cell-based gene therapy can be used to increase the expression of therapeutic factors. To date, there is no approved therapy for dry AMD, including late-stage geographic atrophy. We present a treatment option for dry AMD that transfers the brain-derived neurotrophic factor ( BDNF ) gene into retinal pigment epithelial (RPE) cells by electroporation using the plasmid-based Sleeping Beauty ( SB ) transposon system. ARPE-19 cells and primary human RPE cells were co-transfected with two plasmids encoding the SB100X transposase and the transposon carrying a BDNF transcription cassette. We demonstrated efficient expression and secretion of BDNF in both RPE cell types, which were further increased in ARPE-19 cell cultures exposed to hydrogen peroxide. BDNF-transfected cells exhibited lower apoptosis rates and stimulated neurite outgrowth in human SH-SY5Y cells. This study is an important step in the development of a cell-based BDNF gene therapy that could be applied as an advanced therapy medicinal product to treat dry AMD or other degenerative retinal diseases., Competing Interests: Zsuzsanna Izsv&aacute;k and Zolt&aacute;n Ivics are co-inventors on several Sleeping Beauty-related patents.

Background: Non-viral transposon-mediated gene delivery can overcome viral vectors' limitations. Transposon gene delivery offers the safe and life-long expression of genes such as Pigment Epithelium-Derived Factor (PEDF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) to counteract retinal degeneration by reducing oxidative stress damage., Objective: The study aimed at using Sleeping Beauty transposon to transfect human Retinal Pigment Epithelial (RPE) cells with the neuroprotective factors PEDF and GM-CSF to investigate the effect of these factors on oxidative stress damage., Methods: Human RPE cells were transfected with PEDF and GM-CSF by electroporation, using the hyperactive Sleeping Beauty transposon gene delivery system (SB100X). Gene expression was determined by RT-qPCR, and protein level by Western Blot as well as ELISA. The cellular stress level and the neuroprotective effect of the proteins were determined by measuring the concentrations of the antioxidant glutathione in human RPE cells, and conducting immunohistochemical examination of retinal integrity, inflammation, and apoptosis of rat Retina-Organotypic Cultures (ROC) exposed to H 2 O 2 ., Results: Human RPE cells were efficiently transfected showing a significantly augmented gene expression and protein secretion. Human RPE cells overexpressing PEDF and/or GM-CSF or pretreated with recombinant proteins presented significantly increased glutathione levels post- H 2 O 2 incubation than non-transfected/untreated controls. rPEDF and/or rGM-CSF-treated ROC exhibited decreased inflammatory reactions and cell degeneration., Conclusion: GM-CSF and/or PEDF could be delivered successfully to RPE cells with combined use of SB100X and electroporation. PEDF and/or GM-CSF reduced H 2 O 2 -mediated oxidative stress damage in RPE cells and ROC offering an encouraging technique to re-establish a cell protective environment to halt age-related retinal degeneration., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: To evaluate the outcomes and safety of a minimally invasive technique for sutured IOL scleral fixation in case of compromised capsular and iris support., Materials and Methods: In this retrospective study, we explain our mini-invasive technique and assess the outcomes in terms of visual acuity, pre- or postoperative complications, and IOL position (Sensar AR40e, AMO) in a case series of three patients., Results: The expected best corrected visual acuity could be achieved after one month. Surgeries were uneventful with a stable eye. No postoperative complications occurred except for one patient who had a conjunctival disinsertion. Neither postoperative hypotony nor raised IOP was found. Additionally, no patient experienced corneal edema at one week control, IOL dislocation, vitreous hemorrhage, or new pupil's irregularity., Conclusions: In conclusion, each scleral technique has its own advantages and its inherent postoperative complications. To date, there is no evidence of superiority of any single technique. By improving our scleral sutured lens techniques, we could improve peroperative ocular stability, potentially decrease postoperative complication rate, and offer a rapid recovery with a stable visual acuity within a month., Competing Interests: The authors have no conflicts of interest., (Copyright © 2021 Mateusz Kecik et al.)

Background and Objectives: Evaporative dry eye disease is frequently associated with meibomian gland dysfunction. Patients are often unhappy because of daily drops, care burden, and suboptimal conventional treatments. In this study, we assessed the efficacy of a novel device, the Eye-light ® , a combination of intense pulsed light therapy and low-level light therapy, as a novel treatment for meibomian gland dysfunction and dry eye disease. Materials and Methods: This was a retrospective, single-center study carried out over a 6-week period, in which 22 eyes from 11 patients were included. Each patient received four combined light therapy treatment sessions, once weekly over 4 weeks. Patients underwent a clinical examination and filled out a standardized questionnaire to evaluate symptoms one week prior to treatment, and one week after the fourth session. Results: Combined light therapy improved several ocular surface outcome measures in our patients. This study demonstrates that this adjunctive treatment significantly improves the ocular surface and quality of life of patients with dry eye disease and meibomian gland dysfunction. Conclusions: Combined light therapy may be included in meibomian gland dysfunction treatment protocols as an adjunctive rescue treatment.