Stereoptic serious games as a visual rehabilitation tool for individuals with a residual amblyopia (AMBER trial): a protocol for a crossover randomized controlled trial.

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).

674 Cases of Late Postoperative Intraocular Lens Opacification of a Hydrophilic-Hydrophobic Acryl Intraocular Lens in Switzerland and Retrospective Opacification Risk Factor Assessment of 212 Cases.

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.

Comparison of Conventional and Femtosecond Laser-Assisted Cataract Surgery Regarding Macula Behavior and Thickness.

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.

Molecular and Functional Characterization of BDNF-Overexpressing Human Retinal Pigment Epithelial Cells Established by Sleeping Beauty Transposon-Mediated Gene Transfer.

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.

Comparison of Femtosecond Laser-Assisted and Ultrasound-Assisted Cataract Surgery with Focus on Endothelial Analysis.

Femtosecond laser-assisted cataract surgery has the potential to make critical steps of cataract surgery easier and safer, and reduce endothelial cell loss, thus, improving postoperative outcomes. This study compared FLACS with the conventional method in terms of endothelial cells behavior, clinical outcomes, and capsulotomy precision. METHODS: In a single-center, randomized controlled study, 130 patients with cataracta senilis received FLACS or conventional cataract surgery. RESULTS: A significant endothelial cell loss was observed postoperatively, compared to the preoperative values in both groups. The endothelial cell counts was significantly better in the FLACS group in cataract grade 2 (p = 0.048) patients, compared to conventionally at 4 weeks. The effective phaco time was notably shorter in grade 2 of the FLACS group (p = 0.007) compared to the conventional. However, no statistically significant differences were found for the whole sample, including all cataract grades, due to the overall cataract density in the FLACS group being significantly higher (2.60 ± 0.58, p < 0.001) as compared to conventional methods (2.23 ± 0.42). CONCLUSIONS: Low energy FLACS provides a better result compared to endothelial cell loss, size, and shape variations, as well as in effective phaco time within certain cataract grade subgroups. A complete comparison between two groups was not possible because of the higher cataract grade in the FLACS. FLACS displayed a positive effect on endothelial cell preservation and was proven to be much more precise.

Meibomian Gland Dysfunction: Intense Pulsed Light Therapy in Combination with Low-Level Light Therapy as Rescue Treatment.

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.

Going non-viral: the Sleeping Beauty transposon system breaks on through to the clinical side.

Molecular medicine has entered a high-tech age that provides curative treatments of complex genetic diseases through genetically engineered cellular medicinal products. Their clinical implementation requires the ability to stably integrate genetic information through gene transfer vectors in a safe, effective and economically viable manner. The latest generation of Sleeping Beauty (SB) transposon vectors fulfills these requirements, and may overcome limitations associated with viral gene transfer vectors and transient non-viral gene delivery approaches that are prevalent in ongoing pre-clinical and translational research. The SB system enables high-level stable gene transfer and sustained transgene expression in multiple primary human somatic cell types, thereby representing a highly attractive gene transfer strategy for clinical use. Here we review several recent refinements of the system, including the development of optimized transposons and hyperactive SB variants, the vectorization of transposase and transposon as mRNA and DNA minicircles (MCs) to enhance performance and facilitate vector production, as well as a detailed understanding of SB's genomic integration and biosafety features. This review also provides a perspective on the regulatory framework for clinical trials of gene delivery with SB, and illustrates the path to successful clinical implementation by using, as examples, gene therapy for age-related macular degeneration (AMD) and the engineering of chimeric antigen receptor (CAR)-modified T cells in cancer immunotherapy.

Combined Topical Anti-inflammatory and Oral Acetazolamide in the Treatment of Central Serous Chorioretinopathy.

SIGNIFICANCE: Central serous chorioretinopathy (CSCR) is still a therapeutic challenge with no criterion standard treatment. However, anatomic changes at the level of the retinal pigment epithelium could prove of predictive value in the course of the disease for selective treatment in cases of increased risk of chronicity. PURPOSE: This pilot study analyzes the efficacy for treating acute CSCR with combined systemic acetazolamide 250 mg twice a day and nepafenac 0.1% eye drops three times a day in comparison with an untreated control group. It also evaluates the presence a pigment epithelial detachment (PED) as a risk factor for chronic CSCR. METHODS: Nineteen consecutive patients (group 1) with new or new onset of recurrent CSCR were treated with oral acetazolamide and nepafenac eye drops for at least 2 months. A control group of 14 patients (group 2) with new or new onset of recurrent CSCR were untreated while under regular observation for 4 months. Primary end points were central macular thickness and best-corrected visual acuity after 4 months. Secondary end points were complete regression of subretinal fluid at 3 months and association of PED at baseline with recurrent or chronic CSCR imaged by optical coherence tomography. RESULTS: Group 1 showed significantly faster resolution of subretinal fluid with a mean central macular thickness at 4 months of 271 ± 85 µm compared with 322 ± 79 µm for group 2 (P < .05), but with no functional benefit with a best-corrected visual acuity at 4 months of 0.8 ± 0.2 for group 1 compared with 0.9 ± 0.1 for the control group (P < .05). Patients with a small flat PED were at a higher risk of developing chronic CSCR compared with patients with a dome-shaped or no PED (P < .05). CONCLUSIONS: Central serous chorioretinopathy remains a therapeutic challenge. This pilot study shows faster resolution of subretinal fluid with treatment but without functional benefit compared with observation. The presence of small, flat PED was associated with development of chronic CSCR.

[Changes in Retinal Vascular Caliber after Intravitreal Aflibercept Treatment for Diabetic Macular Oedema]. / Der Einfluss von intravitrealem Aflibercept auf das retinale Gefäßkaliber bei Patienten mit diabetischem Makulaödem.

PURPOSE: Diabetic retinopathy is characterised by impaired retinal vascular autoregulation with signs of early retinal hyperperfusion and subsequent capillary drop out and peripheral ischemia. Initial retinal vascular dilation indicates disease progression and subsequent constriction signals a proliferative state. In this pilot study, we examined the effect of intravitreal aflibercept on retinal vessel diameter in patients with diabetic macular oedema. METHODS: Twelve eyes of nine treatment-naive patients with diabetic macular oedema were examined during the first three months of treatment with aflibercept. The calibers of retinal arteries and veins and the central retinal arterial and vein equivalent were registered over the course of treatment. The evolution of the diabetic macular oedema was also registered and correlated to the retinal vascular caliber. RESULTS: During treatment, there was a significant reduction in the diameter of retinal arteries as well as in the central retinal arterial equivalent. The calibers of the retinal veins were also reduced, but not significantly. Macular oedema was significantly reduced, which however did not correlate with the vascular caliber changes. CONCLUSIONS: This pilot study demonstrates for the first time a possible significant reduction in retinal arterial caliber under aflibercept treatment for diabetic macular oedema. Further studies are needed to verify whether this response to intravitreal anti-VEGF treatment also signifies an improvement in retinal vascular homeostasis.

Avoiding Complications From Patient Positioning for Intraocular Surgery.

Collaboration of the surgical and anesthesia teams for patient positioning is essential to assure patient comfort and safety, preventing systemic and ophthalmic complications. The goals and rationales of positioning for intraocular surgery are discussed including placing the head above the heart, elevating the chin, using a head rest that is sufficiently firm, maximizing anesthesia care team access and minimizing fire risk, and taping the patient's head to the operating table to reduce unexpected movement with intraocular injury.

Case Report: Masquerading Large-vessel Giant Cell Arteritis.

SIGNIFICANCE: Large-vessel giant cell arteritis (GCA) can be a diagnostic dilemma for the eye care provider because it may not involve the typical cranial arteries. When any of its potential ocular complications are diagnosed, it is important to consider this unusual form of GCA. PURPOSE: To report an unusual ophthalmic presentation of large-vessel GCA with sequential bilateral anterior ischemic optic neuropathy and branch retinal artery occlusion. METHODS: A 65-year-old previously healthy woman experienced sequential bilateral anterior ischemic optic neuropathy with branch retinal artery occlusion in the absence of other signs and symptoms suggestive of cranial GCA. RESULTS: Extensive workup, including temporal artery biopsy, failed to demonstrate vascular inflammation suggestive of GCA or vascular abnormalities, such as atheromatous plaques, but coincidentally revealed a breast tumor, which was excised. Positron emission tomography scan was performed revealing distinct hypermetabolism of the thoracic and abdominal aorta consistent with large-vessel GCA, and corticosteroid therapy was initiated. CONCLUSIONS: Large-vessel GCA is an underdiagnosed and undertreated type of GCA that does not typically affect the cranial arteries but rather larger proximal aortic branches. When associated with ocular complications, it can be a puzzling diagnostic dilemma for the eye care provider.

Performance of real-world functional vision tasks by blind subjects improves after implantation with the Argus® II retinal prosthesis system.

BACKGROUND: The main objective of this study was to test Argus II subjects on three real-world functional vision tasks. DESIGN: The study was designed to be randomized and prospective. Testing was conducted in a hospital/research laboratory setting at the various participating centres. PARTICIPANTS: Twenty eight Argus II subjects, all profoundly blind, participated in this study. METHODS: Subjects were tested on the three real-world functional vision tasks: Sock Sorting, Sidewalk Tracking and Walking Direction Discrimination task MAIN OUTCOME MEASURES: For the Sock Sorting task, percentage correct was computed based on how accurately subjects sorted the piles on a cloth-covered table and on a bare table. In the Sidewalk Tracking task, an 'out of bounds' count was recorded, signifying how often the subject veered away from the test course. During the Walking Direction Discrimination task, subjects were tested on the number of times they correctly identified the direction of testers walking across their field of view. RESULTS: The mean percentage correct OFF versus ON for the Sock Sorting task was found to be significantly different for both testing conditions (t-test, P < 0.01). On the Sidewalk Tracking task, subjects performed significantly better with the system ON than they did with the system OFF (t-test, P < 0.05). Eighteen (18) of 27 subjects (67%) performed above chance with the system ON, and 6 (22%) did so with system OFF on the Walking Direction Discrimination task. CONCLUSIONS: Argus II subjects performed better on all three tasks with their systems ON than they did with their systems OFF.

Aqueous humor polymerase chain reaction in uveitis - utility and safety.

BACKGROUND: To study the value and safety of aqueous humor polymerase chain reaction (PCR) analysis for Herpes simplex, varicella zoster, cytomegalovirus, Epstein-Barr virus and Toxoplasma gondii in patients with uveitis. METHODS: Records of 45 consecutive patients with anterior and posterior uveitis who underwent AC paracentesis with PCR were reviewed. The main outcome measure was frequency of PCR positivity. Secondary outcomes were alteration of treatment, safety of paracentesis, and correlation of keratitic precipitates with PCR positivity, RESULTS: The overall PCR positivity was 48.9 % (22/45). Therapy was changed because of the PCR results in 14/45 patients (37.7 %). One patient experienced a paracentesis related complication (1/45, 2.2 %) without long-term sequelae. CONCLUSION: Aqueous PCR altered the diagnosis and treatment in over a third of our patients and was relatively safe. Aqueous PCR should be considered for uveitis of atypical clinical appearance, recurrent severe uveitis of uncertain etiology, and therapy refractory cases.

Transplantation of PEDF-transfected pigment epithelial cells inhibits corneal neovascularization in a rabbit model.

BACKGROUND: The purpose of this study was to investigate the effect of recombinant pigment epithelium-derived factor (rPEDF), secreted by ARPE-19 cells transfected with the human PEDF gene and transplanted subconjunctivally in normal and in rabbits in which corneal neovascularization was elicited by a chemical burn. METHODS: Twenty grey Chinchilla Bastard rabbits were randomly assigned to four groups; neovascularization was induced in groups A, B, and C by alkali cauterization. Seven days later, group A received no cell implantation, non-transfected ARPE-19 cells were implanted subconjunctivally in group B, and PEDF-transfected ARPE-19 cells were implanted subconjunctivally in groups C and D (non-cauterized). In-vivo rPEDF secretion was analyzed by immunoblotting, and ELISA of extracts of conjunctival tissue samples taken at different time points. Digital photographs acquired on days 7, 14, and 21 after cauterization were evaluated for lead vessel length, vascular invasion area, and overall neovascularization rate. RESULTS: At days 14 and 21 after cauterization, significant differences were observed between groups A, B, and C in lead vessel length (day 21: 5.91 ± 0.45, 5.11 ± 1.22, 3.79 ± 0.59 mm, repectively), vascular invasion area (day 21: 35.5 ± 8.65, 34.86 ± 4.92, 19.2 ± 5.03 mm(2) respectively), and rate of corneal neovascularization. Compared to controls, neovascularization was reduced by 37.5 % on day 14 and 47 % on day 21. Analysis of conjunctival tissue extracts showed that rPEDF was secreted by the transplanted PEDF-transfected cells. CONCLUSION: Subconjunctivally transplanted, PEDF-transfected ARPE-19 cells secrete rPEDF, which inhibits the corneal neovascularization elicited by alkali cauterization.

Diagnostic Dilemma in Sequential Branch Retinal Vein and Artery Occlusion.

PURPOSE: To report on an unusual case of a branch retinal vein occlusion followed by occlusion of the respective branch retinal artery of the same eye 7 years later, in a young, otherwise healthy man with marginal elevation of antiphospholipid antibodies. CASE REPORT: On first presentation, a 30-year-old male patient was diagnosed as having a branch retinal vein occlusion with the sole risk factor of slightly increased diastolic pressure. On second presentation, 7 years later, a transient occlusion of the respective branch retinal artery was diagnosed on the same patient. Extensive ophthalmologic and general medical evaluations were performed including cardiovascular, coagulation, and immunology testing. Coagulopathy screening revealed slightly elevated titers of anticardiolipin IgM and anti-beta 2 glycoprotein-I IgM antibodies, and aspirin prophylaxis was initiated. CONCLUSIONS: Retinal vascular occlusions are typically associated with well-defined, classical risk factors in older people. In younger, otherwise healthy patients, further autoimmune hypercoagulable disorders are often causal. Our case suggests the contribution of slightly elevated antiphospholipid IgM antibodies, although this remains to be proven.

[Drug-induced toxicity and ophthalmology]. / Toxicité médicamenteuse et ophtalmologie.

Affecting primarily the anterior part of the eye, all the structures of ophthalmological body may however be reached in case of drug- induced toxicity: eyelids and the conjunctiva for example in the syndromes of Lyell and Steven-Johnson, cornea with cornea verticillata related to amiodarone, ciliary muscle (accommodation) or pupil related to antidepressants, lens with glucocorticoid-induced cataract, retinal toxicity of anti malarial synthesis or optical neuropathy with ethambutol. Unfortunately often underrated because of their usual benignity, drug side effects affecting the eye yet can be severe. Simple, conscientious and planned monitoring however allowes for a large majority of our patients to minimize the risk of visual function impairment, thus preserving optimal visual function over time.

[The management of diabetic retinopathy and diabetic macular edema; joint forces fight for sight]. / Prise en charge de la rétinopathie diabétique: un combat pour la vue.

Despite the considerable progress in prevention and treatement options since the first big epidemiologic studies in the 80's, diabetic retinopathy still represents the primary cause of blindness in the working age population. The intensified prevention efforts that took place recentyears did show hopeful results as the incidence of diabetic retinopathy seems to decline. However a still considerable number of patients does not meet metabolic or treatment recommandations. In the aftermath of an ongoing globalisation and growing urbanisation of the society, there is an even bigger need of understanding the disease as well as improving prevention and treatment guidelines.

Development of very large electrode arrays for epiretinal stimulation (VLARS).

BACKGROUND: Retinal implants have been developed to treat blindness causing retinal degenerations such as Retinitis pigmentosa (RP). The retinal stimulators are covering only a small portion of the retina usually in its center. To restore not only central vision but also a useful visual field retinal stimulators need to cover a larger area of the retina. However, large area retinal stimulators are much more difficult to implant into an eye. Some basic questions concerning this challenge should be answered in a series of experiments. METHODS: Large area retinal stimulators were fabricated as flexible multielectrode arrays (MEAs) using silicon technology with polyimide as the basic material for the substrate. Electrodes were made of gold covered with reactively sputtered iridium oxide. Several prototype designs were considered and implanted into enucleated porcine eyes. The prototype MEAs were also used as recording devices. RESULTS: Large area retinal stimulator MEAs were fabricated with a diameter of 12 mm covering a visual angle of 37.6° in a normal sighted human eye. The structures were flexible enough to be implanted in a folded state through an insertion nozzle. The implants could be positioned onto the retinal surface and fixated here using a retinal tack. Recording of spontaneous activity of retinal neurons was possible in vitro using these devices. CONCLUSIONS: Large flexible MEAs covering a wider area of the retina as current devices could be fabricated using silicon technology with polyimide as a base material. Principal surgical techniques were established to insert such large devices into an eye and the devices could also be used for recording of retinal neural activity.

The paradigm change from reactive medical services to 3PM in ischemic stroke: a holistic approach utilising tear fluid multi-omics, mitochondria as a vital biosensor and AI-based multi-professional data interpretation.

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.