Non-Invasive Retinal Vessel Analysis as a Predictor for Cardiovascular Disease.

Cardiovascular disease (CVD) is the most frequent cause of death worldwide. The alterations in the microcirculation may predict the cardiovascular mortality. The retinal vasculature can be used as a model to study vascular alterations associated with cardiovascular disease. In order to quantify microvascular changes in a non-invasive way, fundus images can be taken and analysed. The central retinal arteriolar (CRAE), the venular (CRVE) diameter and the arteriolar-to-venular diameter ratio (AVR) can be used as biomarkers to predict the cardiovascular mortality. A narrower CRAE, wider CRVE and a lower AVR have been associated with increased cardiovascular events. Dynamic retinal vessel analysis (DRVA) allows the quantification of retinal changes using digital image sequences in response to visual stimulation with flicker light. This article is not just a review of the current literature, it also aims to discuss the methodological benefits and to identify research gaps. It highlights the potential use of microvascular biomarkers for screening and treatment monitoring of cardiovascular disease. Artificial intelligence (AI), such as Quantitative Analysis of Retinal vessel Topology and size (QUARTZ), and SIVA-deep learning system (SIVA-DLS), seems efficient in extracting information from fundus photographs and has the advantage of increasing diagnosis accuracy and improving patient care by complementing the role of physicians. Retinal vascular imaging using AI may help identify the cardiovascular risk, and is an important tool in primary cardiovascular disease prevention. Further research should explore the potential clinical application of retinal microvascular biomarkers, in order to assess systemic vascular health status, and to predict cardiovascular events.

Current trends in targeting the oxidative stress in glaucoma (Review).

Glaucoma is a progressive optic neuropathy characterised by retinal ganglion cell degeneration and visual field loss. Glaucoma is considered to be the leading cause of blindness in the industrialised countries. Oxidative damage is an important pathogenic factor in glaucoma, which triggers trabecular meshwork (TM) degeneration, which then leads to intraocular hypertension. Neurodegenerative insults during glaucomatous neurodegeneration initiate an immune response to restore tissue homeostasis. However, the oxidative stress (OS) that develops during the pathogenic processes of glaucoma, along with the agerelated OS, plays a critical role in shifting the physiological equilibrium. In the TM from glaucoma donors, proinflammatory markers were found, which were induced by the activation of a stress response. Chronic changes in the composition of antioxidants found in aqueous humour may induce alterations in TM as well as in the optic nerve head cells. Highlighting the pathogenic role of reactive oxygen species (ROS) in glaucoma has implications in preventing this disease. Various clinical trials are available to test the efficacy of antioxidant drugs in glaucoma management. In this review, we discuss the OS as a therapeutic target, suggesting that the modulation of a pro-oxidant/antioxidant status might be a relevant target for glaucoma prevention and therapy.

New Treatment Horizons in Uveal and Cutaneous Melanoma.

Melanoma is a complex and heterogeneous malignant tumor with distinct genetic characteristics and therapeutic challenges in both cutaneous melanoma (CM) and uveal melanoma (UM). This review explores the underlying molecular features and genetic alterations in these melanoma subtypes, highlighting the importance of employing specific model systems tailored to their unique profiles for the development of targeted therapies. Over the past decade, significant progress has been made in unraveling the molecular and genetic characteristics of CM and UM, leading to notable advancements in treatment options. Genetic mutations in the mitogen-activated protein kinase (MAPK) pathway drive CM, while UM is characterized by mutations in genes like GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. Chromosomal aberrations, including monosomy 3 in UM and monosomy 10 in CM, play significant roles in tumorigenesis. Immune cell infiltration differs between CM and UM, impacting prognosis. Therapeutic advancements targeting these genetic alterations, including oncolytic viruses and immunotherapies, have shown promise in preclinical and clinical studies. Oncolytic viruses selectively infect malignant cells, inducing oncolysis and activating antitumor immune responses. Talimogene laherparepvec (T-VEC) is an FDA-approved oncolytic virus for CM treatment, and other oncolytic viruses, such as coxsackieviruses and HF-10, are being investigated. Furthermore, combining oncolytic viruses with immunotherapies, such as CAR-T cell therapy, holds great potential. Understanding the intrinsic molecular features of melanoma and their role in shaping novel therapeutic approaches provides insights into targeted interventions and paves the way for more effective treatments for CM and UM.

Social Infrastructure and the Alleviation of Loneliness in Europe.

In Europe, individualist societies, in which people more highly value independence, have fewer people who are lonely. Yet these societies also have more people who live alone, a strong determinant of loneliness. Evidence suggests that some unrecognized societal-level resources or characteristics can explain this. We uncover multiple pathways toward a lower degree of loneliness among European societies using an ideal method for this purpose, fuzzy-set qualitative comparative analysis. Using data from the 2014 wave of the European Social Survey and other sources, we analyzed loneliness outcomes among 26 European societies. Our findings suggest two necessary conditions for a low degree of loneliness: high internet access and high association participation. Further, three pathways are sufficient for achieving less loneliness at the societal level. Most societies that have less loneliness follow both the welfare support and cultural support pathways. The third path, commercial provision, is mutually exclusive with welfare support because the former requires a weak welfare state. The surest policy for building societies that have lower rates of loneliness includes the expansion of internet accessibility, the fostering of civil society through association participation and volunteering, and a welfare state that protects potentially vulnerable populations while funding opportunities for social interaction. This article further contributes methodologically by demonstrating "configurational robustness testing," a more comprehensive means to implement current best practices for fuzzy-set qualitative comparative analysis robustness testing.

Differences and Similarities in Epidemiology and Risk Factors for Cutaneous and Uveal Melanoma.

Both cutaneous melanoma (CM) and uveal melanoma (UM) represent important causes of morbidity and mortality. In this review, we evaluate the available knowledge on the differences and similarities between cutaneous melanoma and uveal melanoma, focusing on the epidemiological aspects and risk factors. Uveal melanoma is a rare condition but is the most prevalent primary intra-ocular malignant tumor in adults. Cutaneous melanoma, on the other hand, is significantly more common. While the frequency of cutaneous melanoma has increased in the last decades worldwide, the incidence of uveal melanoma has remained stable. Although both tumors arise from melanocytes, they are very distinct entities biologically, with complex and varied etiologies. Both conditions are encountered more frequently by individuals with a fair phenotype. ultraviolet-radiation is an important, well-documented risk factor for the development of CM, but has shown not to be of specific risk in UM. Although cutaneous and ocular melanomas seem to be inherited independently, there are reported cases of concomitant primary tumors in the same patient.

Drug-Loaded Polymeric Particulated Systems for Ophthalmic Drugs Release.

Drug delivery to the anterior or posterior segments of the eye is a major challenge due to the protection barriers and removal mechanisms associated with the unique anatomical and physiological nature of the ocular system. The paper presents the preparation and characterization of drug-loaded polymeric particulated systems based on pre-emulsion coated with biodegradable polymers. Low molecular weight biopolymers (chitosan, sodium hyaluronate and heparin sodium) were selected due to their ability to attach polymer chains to the surface of the growing system. The particulated systems with dimensions of 190-270 nm and a zeta potential varying from -37 mV to +24 mV depending on the biopolymer charges have been obtained. Current studies show that particles release drugs (dexamethasone/pilocarpine/bevacizumab) in a safe and effective manner, maintaining therapeutic concentration for a longer period of time. An extensive modeling study was performed in order to evaluate the drug release profile from the prepared systems. In a multifractal paradigm of motion, nonlinear behaviors of a drug delivery system are analyzed in the fractal theory of motion, in order to correlate the drug structure with polymer. Then, the functionality of a SL(2R) type "hidden symmetry" implies, through a Riccati type gauge, different "synchronization modes" (period doubling, damped oscillations, quasi-periodicity and intermittency) during the drug release process. Among these, a special mode of Kink type, better reflects the empirical data. The fractal study indicated more complex interactions between the angiogenesis inhibitor Bevacizumab and polymeric structure.

Diagnostic methods for the etiological assessment of infectious corneal pathology (Review).

Infectious keratitis is a leading cause of visual morbidity, including blindness, all across the globe, especially in developing countries. Prompt and adequate treatment is mandatory to maintain corneal integrity and to recover the best possible final visual acuity. Although in most of the cases practitioners chose to employ empirical broad-spectrum antimicrobial medication that is usually effective, in some instances, they face the need to identify the causative agent to establish the appropriate therapy. An extensive search was conducted on published literature before December 2020 concerning the main laboratory investigations used to identify the microbial agents found in infectious keratitis, their indications, advantages, and disadvantages, as well as the results reported by other studies concerning different diagnostic tools. At present, the gold standard for diagnosis is still considered to be the isolation of microorganisms in cultures, along with the examination of smears, but other newer techniques, such as polymerase chain reaction (PCR), next-generation sequencing (NGS), and in vivo confocal microscopy (IVCM) have gained popularity in the last decades. Currently, these newer methods have proved to be valuable adjuvants in making the diagnosis, but technological advances hold promise that, in the future, these methods will have increased performance and availability, and may become the new gold standard, replacing the classic cultures and smears.

Current trends in gene therapy for retinal diseases (Review).

The eye is considered an effective target for genetic therapy, as it has a privileged immune status, it is easily accessed for medication delivery and it is affected by a number of inherited disorders. In particular, the retina is considered for gene therapy due to the fact that it can be visualized with ease, it does not have lymphatic vessels, nor a direct blood network for the outer layers and its cells do not divide after birth, and thus transgene expression is not affected. As gene therapy is currently on a continuously progressive development trend, this emerging field of gene manipulation techniques has yielded promising results. This involves the development of treatments for a number of debilitating and blinding diseases, which were to date considered intractable. However, numerous unanswered questions remain as regards the long-term efficacy and safety profile of these treatments. The present review article discusses the current research status regarding genetic manipulation techniques aimed at addressing visual impairment related to retinal disorders, both inherited and degenerative.

The Learning Curve of Surgery of Diabetic Tractional Retinal Detachment-A Retrospective, Comparative Study.

Background and Objectives: There are few data in the literature concerning the learning curve of tractional retinal detachment (TRD) surgery. We have analyzed the experience gained by a vitreoretinal surgeon over 10 years. Materials and Methods: A retrospective, comparative study of 34 TRD cases operated using 20G instruments between 2008 and 2011 (group A) and 94 cases operated using 23G instruments between 2015 and 2019 (group B). The preoperative characteristics, the type of endotamponade, and the anatomical and functional success were reviewed. Results: The group A patients had a significantly higher rate of concomitant vitreous hemorrhage (VH) at presentation (64.7% vs. 37.2%) and of non-macular retinal detachments (52.9% vs. 39.3%). The rate of silicone oil endotamponade was high in both groups (76.4% vs. 68.1%), but in group B 25.5% were left without a tamponade (vs. none in group A). A postoperative anatomical success was obtained in 76.5% of eyes in group A and 84.04% of eyes in group B (where it was improved to 89.3% by reinterventions). The presenting visual acuity (VA) was very low in both groups (0.01 and 0.05, respectively). The proportion of eyes with improved or stabilized VA was 85.3% in group A and 79.8% in group B (statistically non-significant difference). Conclusions: The anatomical success rate improves quite slowly with increasing surgeon experience and can be further improved by reinterventions. Visual improvement does not match the rate of anatomical improvement. With increasing experience and self-confidence, the surgeon will approach more difficult cases, a fact that may slow down the increase in surgical success rates.

Uveal melanoma diagnosis and current treatment options (Review).

Uveal melanoma is a rare condition accounting for only 5% of all primary melanoma cases. Still, it is the most frequently diagnosed primary intraocular malignant tumor in adults. Almost 90% of the tumors involve the choroid and only a small percentage affects the ciliary body or the iris. There is a consistent difference in incidence between different regions with individuals of northern European descent having a significantly higher risk as compared to Hispanics, Asians, and Blacks. Among the many risk factors, mutations in the G protein subunit alpha Q (GNAQ) or G protein subunit alpha 11 (GNA11) genes and different receptors are highly suggestive. While iris melanoma can easily be noticed by the patient itself or diagnosed at a routine slit-lamp evaluation, a consistent percentage of posterior uveal tumors are incidentally diagnosed at funduscopic evaluation as they can evolve silently for years, especially if located in the periphery. Uveal melanoma classifications rely on the tumor size (thickness and basal diameter) and also on intraocular and extraocular extension. The differential diagnosis with pseudomelanomas is carried out according to the tumor aspect and position. Iris melanoma has a better prognosis and a lower mortality rate as compared to choroidal melanoma that has a much higher rate of metastasis (50% of the patients) and a subsequent limited life expectancy from 6 to 12 months. While conservative therapeutic options for the primary tumor, relying on different surgical excision techniques and/or irradiation therapies, offer good local tumor control, the treatment options for metastatic disease, although numerous, are still inadequate in preventing a fatal outcome.

Intraocular pressure changes during and after silicone oil endotamponade (Review).

Silicone oil (SIO) has rapidly become an indispensable adjunct in vitreoretinal surgery. Constant improvements in purity and also in viscosity have not totally prevented specific complications that may occur during endotamponade. Results of in vitro studies that suggested that higher viscosity silicone oil might be superior in terms of stability and safety are confirmed in real life only if endotamponade lasts for more than 6 months. Intraocular pressure changes induced by the silicone oil endotamponade or oil extraction are documented from its very first use and are potentially threatening vision. The purpose of this review is to update current knowledge on the incidence, risk factors, pathogenesis, and management of secondary silicone oil glaucoma. Also, in a retrospective evaluation on cases with complex retinal detachments that underwent 23G vitrectomy and high viscosity SIO endotamponade, we have noticed that a considerable number of cases developed significant intraocular pressure changes during SIO endotamponade and after SIO removal, especially in early postoperative period.

Influence of unilateral intravitreal bevacizumab injection on the incidence of symptomatic choroidal neovascularization in the fellow eye in patients with neovascular age-related macular degeneration (Review).

Neovascular age-related macular degeneration (neovascular ARMD) represents only 10% of ARMD cases but is responsible, if untreated, for quick and severe central vision loss due to major macular changes. The presence of choroidal neovascularization (CNV) in one eye is associated with an approximately 10% risk of CNV development in the fellow eye each year. Intravitreal anti-VEGF therapy has quickly evolved as the standard treatment in neovascular ARMD in the last decade due to significant anatomical and functional improvements, especially in the early stages. In many reports an improvement in the untreated fellow eye was mentioned and systemic exposure was soon confirmed for all anti-VEGF agents after unilateral intravitreal injection. In particular, bevacizumab intravitreal injection is followed by a consistent reduction of serum VEGF levels and the drug was shown to have the longest serum half-life raising important debates about its safety. Once bevacizumab was detected in the fellow eye of an animal model after unilateral injection, the possible influence on fellow eye conversion rate into neovascular ARMD was questioned. Although comparative studies have not found statistically significant differences between drugs regarding the incidence of symptomatic CNV in the fellow eye during treatment, we observed, on a retrospective 36-month evaluation, a reduced incidence of symptomatic CNV in the fellow eye that might be explained by the consistent systemic exposure of bevacizumab.

Outcomes of simultaneous vs. sequential pars plana vitrectomy and cataract surgery.

The coexistence of cataract and vitreoretinal diseases is common in clinical practice. The technological achievements of the last decade in both types of surgeries, allow simultaneous interventions on lens and retina. This retrospective study assessed the morphofunctional results obtained after performing simultaneous surgeries in a series of 87 patients presenting with both pathologies. The cases were retrospectively reviewed from their clinical records from 2017 to 2019. The patients were divided into two groups: group 1 comprising 41 cases underwent the combined procedure and group 2 comprising 46 patients underwent vitrectomy, followed by cataract surgery after 3-10 months. The functional and anatomical outcomes and the complications were assessed pre- and post-operatively. The statistical analysis was carried out by MaxStat software. The final best corrected visual acuity (BCVA), in group 1 was <0.1 in 4.88% of the cases, 0.1 to 0.3 in 17.07%, 0.3 to 0.5 in 51.22% and >0.5 in 26.83% eyes. In group 2, the final BCVA, after both surgeries were completed was <0.1 in 8.7% cases, 0.1 to 0.3 in 30.43%, 41.3% were 0.3 to 0.5 and 19.57% were >0.5. During the cataract surgery, the most common intraoperative complication was miosis, followed by posterior capsule rupture. Postoperative, 12.2% cases from group 1 developed an immediate inflammatory reaction in the anterior chamber, and 17.07% presented with posterior capsular opacification (PCO). Simultaneous surgery is safe and effective in obtaining a good morphological and functional result and offers the advantage of a clear eye media that allows a safer vitrectomy and thus a quicker rehabilitation of the patient. The analysis of the risks and benefits of each procedure should be taken into account and the cases selected individually for either simultaneous or sequential surgery in order to obtain the best outcomes.

Current diagnosis and management strategies in pachychoroid spectrum of diseases (Review).

This review presents a systematic analysis of the literature regarding the pachychoroid disease spectrum nomenclature, diagnosis criteria and therapeutic options. Pachychoroid related diseases are a new concept, introduced into the ophthalmological nomenclature in 2013 and evolving both as concept and as classification since then. The six disorders included in this phenotype have some common characteristics (thick choroid, pachyvessels, attenuation of the choriocapillaris), but also show individual features. The classification of the pachychoroid spectrum was revised many times, with the recent addition of the focal choroidal excavation (FCE) and peripapillary pachychoroid syndrome (PPS). As the terminology is developing, so is the number of case reports and case series from the initial report in 2013 to 57 reports in 2019. This review takes into account both the current literature and the clinical experience of the authors, emphasizing the understanding of the pathogenesis and aiming to update the therapeutic options available.

Artificial intelligence and deep learning in ophthalmology - present and future (Review).

Since its introduction in 1959, artificial intelligence technology has evolved rapidly and helped benefit research, industries and medicine. Deep learning, as a process of artificial intelligence (AI) is used in ophthalmology for data analysis, segmentation, automated diagnosis and possible outcome predictions. The association of deep learning and optical coherence tomography (OCT) technologies has proven reliable for the detection of retinal diseases and improving the diagnostic performance of the eye's posterior segment diseases. This review explored the possibility of implementing and using AI in establishing the diagnosis of retinal disorders. The benefits and limitations of AI in the field of retinal disease medical management were investigated by analyzing the most recent literature data. Furthermore, the future trends of AI involvement in ophthalmology were analyzed, as AI will be part of the decision-making regarding the scientific investigation, diagnosis and therapeutic management.

Ocular cicatricial pemphigoid (Review).

Ocular cicatricial pemphigoid is a particular form of mucous membrane pemphigoid and it is characterized by a chronic bilateral conjunctivitis with relapsing-remitting periods. Without therapy 75% of the cases develop visual loss due to major ocular complications (e.g. severe dry-eye syndrome, corneal erosions, corneal keratinization, entropion, symblepharon). Pathogenesis remains uncertain and probably linked to an autoimmune type II hypersensitivity response in patients with a genetic predisposition and exposure to different environmental triggers. With a worldwide distribution, no racial predilection and an estimated incidence that largely varies from 1/10,000-1/60,000, ocular cicatricial pemphigoid predominantly affects women aged ~60 years. Conjunctival biopsy with direct immunofluorescence is the gold standard in diagnosis confirmation, but up to 40% of the patients have a negative biopsy result that does not rule out the diagnosis. The skin and many other mucous membranes (e.g. oral, trachea, esophagus, pharynx, larynx, urethra, vagina and anus) may be involved. The disease grading relies on Foster staging system (based on clinical signs) and Mondino and Brown system (based on the inferior fornix depth loss). The differential diagnosis includes atopy, allergies, trauma, chemical burns, radiation, neoplasia, infectious, inflammatory and autoimmune etiologies. The main goals of the treatment are to stop disease progression, to relieve symptoms and to prevent complications. With long-term systemic therapy 90% of the cases can be efficiently controlled. While Dapsone is the first-line treatment in mild to moderate disease in patients without G6PD deficiency, more severe cases require immunosuppressant therapy with azathioprine, mycophenolate mofetil, methotrexate or cyclosporine. Cyclophosphamide, biologics (etanercept or rituximab) and intravenous immunoglobulin therapy are usually reserved for recalcitrant disease and unsatisfactory results to conventional therapy. Dry eye syndrome requires constant lubricating medication and topical steroids, cyclosporine-A and tacrolimus. Surgery should be planed only in quiescent phase as minor conjunctival trauma can significantly worsen the disease.

The role of Optical Coherence Tomography in optic neuropathies.

Optical neuropathies are neuro-ophthalmologic disorders, the main symptoms of which are the decrease of visual acuity and the alteration of the color vision. Optical coherence tomography has been one of the most important innovations in ophthalmology, which offered the possibility to analyze specific structures of the retina. Optical coherence tomography performs in vivo, real-time, noncontact scanning and provides cross-sectional and volumetric images with a resolution approaching that of histology. Optical coherence tomography offers the opportunity to study neurological diseases in an objective and non-invasive manner. The measurements of retinal nerve fiber layer can be an objective measurement of nerve swelling or nerve atrophy. By analyzing the ganglion cell complex, optical coherence tomography can help detect early axonal damage and may predict the visual outcome. It can be useful for diagnosis and follow-up of optic nerve and chiasmal compressive diseases. Furthermore, optical coherence tomography is useful in patients with multiple sclerosis in distinguishing macular disease from optic neuritis and in monitoring the treatment. Multiple studies and clinical observations support the importance of optical coherence tomography in the diagnosis, treatment, and follow-up of optic neuropathies. ABBREVIATIONS: OCT = optical coherence tomography, VA = visual acuity, RNFL = retinal nerve fiber layer, GCL = ganglion cells layer, MS = multiple sclerosis, ON = optic neuropathy, NAION = non-arteritic ischemic anterior optic neuropathy, LHON = Leber hereditary optic neuropathy, RE = right eye, LE = left eye.

Multiple sclerosis with ophthalmologic onset - case report.

Ophthalmological and neurological signs and symptoms were assessed in a patient diagnosed with retrobulbar optic neuritis associated with multiple sclerosis (MS). The patient presented with progressive decrease of visual acuity, intermittent diplopia, paresthesia of the left arm and equilibrium disturbances. The complete ophthalmologic examination (clinical examination, visual field, optical coherence tomography) along with an MRI exam supported the diagnosis of MS with active lesions associated with retrobulbar optic neuritis. The corticosteroid therapy, followed by betaferon led to the remission of both ophthalmological and neurological signs. The multidisciplinary approach of the case played an important role in the early establishment of the diagnosis as well as the functional recovery of this patient.

Anatomical results and complications after silicone oil removal.

The aim of the report was to evaluate anatomical results and intra and postoperative complications after silicone oil (SIO) removal. METHODS: Retrospective, interventional study evaluating consecutive cases with ambulatory SIO removal after vitrectomy for complex retinal detachments. The anatomical result was the main followed parameter. Intra and postoperative complications and also intraocular pressure changes were evaluated. Cases were followed-up for at least 12 months. RESULTS: A total of 98 consecutive cases were reviewed. The main duration of oil endotamponade was 5.46 months (3-16 months). In 15 cases (15.30%) signs of SIO emulsification were noted at the time of removal. A stable anatomical result after SIO removal was obtained in 94 out of 98 cases (95.91%). Retinal detachment recurrence appeared in first month postoperatively (1 case) and between the 3rd and 4th month postoperatively (3 cases). Main indications for 5000cs SIO endotamponade during ambulatory 23G vitrectomy were represented by proliferative vitreoretinopathy (PVR) (78 cases - 79.59%), proliferative diabetic retinopathy (17 cases - 17.34%) and giant retinal tears (3 cases - 3.06%). 29 eyes (29.59%) were pseudophakic at primary surgery. However, most phakic eyes showed cataract appearance and progression during SIO endotamponade and also after SIO removal. Intraocular pressure significantly decreased after SIO removal with the occurrence of various choroidal detachments in 8 cases (8.16%), resolving spontaneously within the first week postoperatively. CONCLUSIONS: In our experience, the retinal detachment recurrence rate after SIO removal was 4.08%. This promising anatomical result confirms the need for an accurate primary surgery and also for a safe moment of SIO removal according to the severity of primary pathology.

Terson's Syndrome - case report.

Terson's Syndrome is represented by a vitreous, retrohyaloid, retinal, or subretinal hemorrhage occurring consequent to an acute intracranial hemorrhage or elevated intracranial pressure. The outcome may include a complete clearing of the blood and the restoration of VA or persistent hemorrhage. This report presents the case of a 43-year-old woman who underwent bilateral surgery for a persistent vitreous hemorrhage and a hematoma underneath the internal limiting membrane in the left eye. The event followed shortly after a subarachnoid hemorrhage due to the rupture of a posterior communicating artery aneurism. Vitrectomy was performed in both eyes, together with the peeling of the internal limiting membrane in the left eye, followed by a bilateral good outcome.