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.

Diabetic retinopathy as the leading cause of blindness and early predictor of cascading complications-risks and mitigation.

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.

Median nerve ultrasonography examination correlates with electrodiagnostic studies for the diagnosis of moderate to severe carpal tunnel syndrome.

OBJECTIVE: The aim of the study was to investigate the associations of cross-sectional area (CSA) of the median nerve measured by ultrasonography, the median to ulnar nerve ratio (MUR), the median to ulnar nerve difference (MUD) and the ratio of CSA of the median nerve to height squared (MHS) in relation to electrodiagnostic classification of moderate and severe carpal tunnel syndrome (CTS) and thus to identify patients suitable for surgical treatment. MATERIALS AND METHODS: A prospective study was conducted in patients aged ≥ 18 years who underwent both median and ulnar nerve ultrasonography and electrodiagnostic studies (EDS). 124 wrists of 62 patients were examined. The patients' characteristics were acquired through a questionnaire. CTS was diagnosed using EDS and classified according to the guidelines of the Czech Republic Association of Electrodiagnostic Medicine. The CSA of the median nerve and of the ulnar nerve were measured at the carpal tunnel inlet. RESULTS: Median nerve CSA at the tunnel inlet ≥ 12 mm2 correlates with electrodiagnostic classification of moderate to severe carpal tunnel syndrome. At this cut-off value, the sensitivity of ultrasonography is 82.4%, its specificity is 87.7%, the positive predictive value is 82.4%, the negative predictive value is 87.7%. MUD, MUR and MHS perform worse than the median nerve CSA, as shown by their lower area under the receiver operating characteristic curve. CONCLUSIONS: Ultrasound could help us indicate surgical treatment for CTS, especially in patients with clinical findings. Our results suggest a cut-off value of CSA at the tunnel inlet of ≥ 12mm2.

Ischemic stroke of unclear aetiology: a case-by-case analysis and call for a multi-professional predictive, preventive and personalised approach.

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.

Oncogenic Fusions in Gliomas: An Institutional Experience.

BACKGROUND/AIM: Gliomas are primary malignancies of the central nervous system (CNS). High-grade gliomas are associated with poor prognosis and modest survival rates despite intensive multimodal treatment strategies. Targeting gene fusions is an emerging therapeutic approach for gliomas that allows application of personalized medicine principles. The aim of this study was to identify detectable fusion oncogenes that could serve as predictors of currently available or newly developed targeted therapeutics in cross-sectional samples from glioma patients using next-generation sequencing (NGS). PATIENTS AND METHODS: A total of 637 patients with glial and glioneuronal tumours of the CNS who underwent tumour resection between 2017 and 2020 were enrolled. Detection of fusion transcripts in FFPE tumour tissue was performed by a TruSight Tumour 170 assay and two FusionPlex kits, Solid Tumour and Comprehensive Thyroid and Lung. RESULTS: Oncogene fusions were identified in 33 patients. The most common fusion was the KIAA1549-BRAF fusion, detected in 13 patients, followed by FGFR fusions (FGFR1-TACC1, FGFR2-CTNNA3, FGFR3-TACC3, FGFR3-CKAP5, FGFR3-AMBRA1), identified in 10 patients. Other oncogene fusions were also infrequently diagnosed, including MET fusions (SRPK2-MET and PTPRZ1-MET) in 2 patients, C11orf95-RELA fusions in 2 patients, EGFR-SEPT14 fusion in 2 patients, and individual cases of SRGAP3-BRAF, RAF1-TRIM2, EWSR1-PALGL1 and TERT-ALK fusions. CONCLUSION: The introduction of NGS techniques provides additional information about tumour molecular alterations that can aid the multimodal management of glioma patients. Patients with gliomas positive for particular targetable gene fusions may benefit from experimental therapeutics, enhancing their quality of life and prolonging survival rates.

DORADA adherence study: full view into RebiSmart subdomains parameters in multiple sclerosis treatment.

PURPOSE: The aim of this article is to provide unique and detailed data on how patients rate the RebiSmart 2.0 in the specific User Study Questionnaire (USQ) domains, and the relationship between their rating and individual level of disability, baseline demographic/socioeconomic factors, and adherence. PATIENTS AND METHODS: Twelve-month, phase IV, observational, multicenter study (no placebo or comparator) to evaluate the ease of use of the RebiSmart autoinjector for self-injection during treatment of CIS/RRMS subjects with Rebif 44 mcg sc three times a week by USQ. A total of 290 subjects participated in the study, with 249 (85.86%) completing the entire study period. RESULTS: The endpoint results demonstrated a very high proportion (>95%) of patients with a positive evaluation of the overall convenience of RebiSmart at each study visit. At the end of the study, all patients would recommend the device to others who need Rebif therapy. The proportion of patients rating the RebiSmart ease of use by individual domains (self-injection steps, changing the cartridge, using the device away from home) as "very easy to use" or "easy to use" and the proportion of patients rating the RebiSmart functions as "helpful" or "very helpful" were more than 80% for each domain at each study visit. CONCLUSION: These findings are in line with the potential benefits of RebiSmart to treatment adherence. They demonstrate an overall, very good perception of the device by patients and its individual functions.

An observational study demonstrating the adherence and ease of use of the injector device, RebiSmart®.

Background: Adherence to Multiple Sclerosis (MS) treatment is considered one of the crucial factors for ensuring optimal clinical outcomes. Research has shown that the use of self-injector devices improves patient compliance with treatment. Therefore, the main purpose of this study is to evaluate the ease of use of RebiSmart® 2.0 in clinically isolated syndrome/relapsing-remitting MS patients during 12 months treatment period.Methods: A total number of 290 subjects entered into data collection; 249 (86%) of them completed the whole 12 months study period. The primary endpoints and the secondary endpoints were assessed by the User Study Questionnaire. Adherence data were retrieved from RebiSmart® 2.0 (Menu - Dose History) on the respective patient's visit. Outcome measures also included Expanded Disability Status Score, Kurtzke Functional Systems, and Modified Social Support Survey, Modified Social Support Survey-5.Results: This study demonstrated a very high proportion (>95%) of patients with a positive rating of the overall ease of use and the overall convenience of RebiSmart®. The proportion of patients with a positive rating of the ease of use by individual domains and the functions of RebiSmart® were also high (>80%).Conclusion: The findings demonstrate a very good perception of the usability of the device by patients overall and in its individual functions.

Comparison of Therapies in MS Patients After the First Demyelinating Event in Real Clinical Practice in the Czech Republic: Data From the National Registry ReMuS.

Background: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system. Well-established drugs used for MS patients after the first demyelinating event in the Czech Republic include glatiramer acetate (GA), interferon beta-1a (IFNß-1a), IFN beta-1b (IFNß-1b), peginterferon beta-1a (peg-IFNß-1a), and teriflunomide. Objective: The objective of this observational study was to compare the effectiveness of the abovementioned drugs in patients with MS who initiated their therapy after the first demyelinating event. Patients were followed for up to 2 years in real clinical practice in the Czech Republic. Methods: A total of 1,654 MS patients treated after the first demyelinating event and followed up for 2 years were enrolled. Evaluation parameters (endpoints) included the annualized relapse rate (ARR), time to next relapse, change in the Expanded Disability Status Scale (EDSS) score, and time of confirmed disease progression (CDP). When patients ended the therapy before the observational period, the reason for ending the therapy among different treatments was compared. Results: No significant difference was found among the groups of patients treated with IFNß-1a/1b, GA, or teriflunomide for the following parameters: time to the first relapse, change in the EDSS score, and the proportion of patients with CDP. Compared to IFNß-1a (44 mcg), a significant increase in the percentage of relapse-free patients was found for GA, but this treatment effect was not confirmed by the validation analysis. Compared to the other drugs, there was a significant difference in the reasons for terminating GA therapy. Conclusion: Small differences were found among GA, IFNß and teriflunomide therapies, with no significant impact on the final outcome after 2 years. Therefore, in clinical practice, we recommend choosing the drug based on individual potential risk from long-term therapy and on patient preferences and clinical characteristics.