Multi-faceted CRISPR/Cas technological innovation aspects in the framework of 3P medicine.

Since 2009, the European Association for Predictive, Preventive and Personalised Medicine (EPMA, Brussels) promotes the paradigm change from reactive approach to predictive, preventive, and personalized medicine (PPPM/3PM) to protect individuals in sub-optimal health conditions from the health-to-disease transition, to increase life-quality of the affected patient cohorts improving, therefore, ethical standards and cost-efficacy of healthcare to great benefits of the society at large. The gene-editing technology utilizing CRISPR/Cas gene-editing approach has demonstrated its enormous value as a powerful tool in a broad spectrum of bio/medical research areas. Further, CRISPR/Cas gene-editing system is considered applicable to primary and secondary healthcare, in order to prevent disease spread and to treat clinically manifested disorders, involving diagnostics of SARS-Cov-2 infection and experimental treatment of COVID-19. Although the principle of the proposed gene editing is simple and elegant, there are a lot of technological challenges and ethical considerations to be solved prior to its broadly scaled clinical implementation. This article highlights technological innovation beyond the state of the art, exemplifies current achievements, discusses unsolved technological and ethical problems, and provides clinically relevant outlook in the framework of 3PM.

Antithrombotic and antiplatelet effects of plant-derived compounds: a great utility potential for primary, secondary, and tertiary care in the framework of 3P medicine

Thromboembolism is the third leading vascular disease, with a high annual incidence of 1 to 2 cases per 1000 individuals within the general population. The broader term venous thromboembolism generally refers to deep vein thrombosis, pulmonary embolism, and/or a combination of both. Therefore, thromboembolism can affect both – the central and peripheral veins. Arterial thromboembolism causes systemic ischemia by disturbing blood flow and oxygen supply to organs, tissues, and cells causing, therefore, apoptosis and/or necrosis in the affected tissues. Currently applied antithrombotic drugs used, e.g. to protect affected individuals against ischemic stroke, demonstrate significant limitations. For example, platelet inhibitors possess only moderate efficacy. On the other hand, thrombolytics and anticoagulants significantly increase hemorrhage. Contextually, new approaches are extensively under consideration to develop next-generation antithrombotics with improved efficacy and more personalized and targeted application. To this end, phytochemicals show potent antithrombotic efficacy demonstrated in numerous in vitro, ex vivo, and in vivo models as well as in clinical evaluations conducted on healthy individuals and persons at high risk of thrombotic events, such as pregnant women (primary care), cancer, and COVID-19-affected patients (secondary and tertiary care). Here, we hypothesized that specific antithrombotic and antiplatelet effects of plant-derived compounds might be of great clinical utility in primary, secondary, and tertiary care. To increase the efficacy, precise patient stratification based on predictive diagnostics is essential for targeted protection and treatments tailored to the person in the framework of 3P medicine. Contextually, this paper aims at critical review toward the involvement of specific classes of phytochemicals in antiplatelet and anticoagulation adapted to clinical needs. The paper exemplifies selected plant-derived drugs, plant extracts, and whole plant foods/herbs demonstrating their specific antithrombotic, antiplatelet, and fibrinolytic activities relevant for primary, secondary, and tertiary care. One of the examples considered is antithrombotic and antiplatelet protection specifically relevant for COVID-19-affected patient groups.

Mitochondrial health quality control: measurements and interpretation in the framework of predictive, preventive, and personalized medicine.

Mitochondria are the "gatekeeper" in a wide range of cellular functions, signaling events, cell homeostasis, proliferation, and apoptosis. Consequently, mitochondrial injury is linked to systemic effects compromising multi-organ functionality. Although mitochondrial stress is common for many pathomechanisms, individual outcomes differ significantly comprising a spectrum of associated pathologies and their severity grade. Consequently, a highly ambitious task in the paradigm shift from reactive to predictive, preventive, and personalized medicine (PPPM/3PM) is to distinguish between individual disease predisposition and progression under circumstances, resulting in compromised mitochondrial health followed by mitigating measures tailored to the individualized patient profile. For the successful implementation of PPPM concepts, robust parameters are essential to quantify mitochondrial health sustainability. The current article analyses added value of Mitochondrial Health Index (MHI) and Bioenergetic Health Index (BHI) as potential systems to quantify mitochondrial health relevant for the disease development and its severity grade. Based on the pathomechanisms related to the compromised mitochondrial health and in the context of primary, secondary, and tertiary care, a broad spectrum of conditions can significantly benefit from robust quantification systems using MHI/BHI as a prototype to be further improved. Following health conditions can benefit from that: planned pregnancies (improved outcomes for mother and offspring health), suboptimal health conditions with reversible health damage, suboptimal life-style patterns and metabolic syndrome(s) predisposition, multi-factorial stress conditions, genotoxic environment, ischemic stroke of unclear aetiology, phenotypic predisposition to aggressive cancer subtypes, pathologies associated with premature aging and neuro/degeneration, acute infectious diseases such as COVID-19 pandemics, among others.

Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine.

Endothelin-1 (ET-1) is involved in the regulation of a myriad of processes highly relevant for physical and mental well-being; female and male health; in the modulation of senses, pain, stress reactions and drug sensitivity as well as healing processes, amongst others. Shifted ET-1 homeostasis may influence and predict the development and progression of suboptimal health conditions, metabolic impairments with cascading complications, ageing and related pathologies, cardiovascular diseases, neurodegenerative pathologies, aggressive malignancies, modulating, therefore, individual outcomes of both non-communicable and infectious diseases such as COVID-19. This article provides an in-depth analysis of the involvement of ET-1 and related regulatory pathways in physiological and pathophysiological processes and estimates its capacity as a predictor of ageing and related pathologies,a sensor of lifestyle quality and progression of suboptimal health conditions to diseases for their targeted preventionand as a potent target for cost-effective treatments tailored to the person.

Mitochondrial health quality control: measurements and interpretation in the framework of predictive, preventive, and personalized medicine

Mitochondria are the “gatekeeper” in a wide range of cellular functions, signaling events, cell homeostasis, proliferation, and apoptosis. Consequently, mitochondrial injury is linked to systemic effects compromising multi-organ functionality. Although mitochondrial stress is common for many pathomechanisms, individual outcomes differ significantly comprising a spectrum of associated pathologies and their severity grade. Consequently, a highly ambitious task in the paradigm shift from reactive to predictive, preventive, and personalized medicine (PPPM/3PM) is to distinguish between individual disease predisposition and progression under circumstances, resulting in compromised mitochondrial health followed by mitigating measures tailored to the individualized patient profile. For the successful implementation of PPPM concepts, robust parameters are essential to quantify mitochondrial health sustainability. The current article analyses added value of Mitochondrial Health Index (MHI) and Bioenergetic Health Index (BHI) as potential systems to quantify mitochondrial health relevant for the disease development and its severity grade. Based on the pathomechanisms related to the compromised mitochondrial health and in the context of primary, secondary, and tertiary care, a broad spectrum of conditions can significantly benefit from robust quantification systems using MHI/BHI as a prototype to be further improved. Following health conditions can benefit from that: planned pregnancies (improved outcomes for mother and offspring health), suboptimal health conditions with reversible health damage, suboptimal life-style patterns and metabolic syndrome(s) predisposition, multi-factorial stress conditions, genotoxic environment, ischemic stroke of unclear aetiology, phenotypic predisposition to aggressive cancer subtypes, pathologies associated with premature aging and neuro/degeneration, acute infectious diseases such as COVID-19 pandemics, among others.

Anti-breast cancer effects of phytochemicals: primary, secondary, and tertiary care.

Breast cancer incidence is actually the highest one among all cancers. Overall breast cancer management is associated with challenges considering risk assessment and predictive diagnostics, targeted prevention of metastatic disease, appropriate treatment options, and cost-effectiveness of approaches applied. Accumulated research evidence indicates promising anti-cancer effects of phytochemicals protecting cells against malignant transformation, inhibiting carcinogenesis and metastatic spread, supporting immune system and increasing effectiveness of conventional anti-cancer therapies, among others. Molecular and sub-/cellular mechanisms are highly complex affecting several pathways considered potent targets for advanced diagnostics and cost-effective treatments. Demonstrated anti-cancer affects, therefore, are clinically relevant for improving individual outcomes and might be applicable to the primary (protection against initial cancer development), secondary (protection against potential metastatic disease development), and tertiary (towards cascading complications) care. However, a detailed data analysis is essential to adapt treatment algorithms to individuals' and patients' needs. Consequently, advanced concepts of patient stratification, predictive diagnostics, targeted prevention, and treatments tailored to the individualized patient profile are instrumental for the cost-effective application of natural anti-cancer substances to improve overall breast cancer management benefiting affected individuals and the society at large.

Caution, "normal" BMI: health risks associated with potentially masked individual underweight-EPMA Position Paper 2021.

An increasing interest in a healthy lifestyle raises questions about optimal body weight. Evidently, it should be clearly discriminated between the standardised "normal" body weight and individually optimal weight. To this end, the basic principle of personalised medicine "one size does not fit all" has to be applied. Contextually, "normal" but e.g. borderline body mass index might be optimal for one person but apparently suboptimal for another one strongly depending on the individual genetic predisposition, geographic origin, cultural and nutritional habits and relevant lifestyle parameters-all included into comprehensive individual patient profile. Even if only slightly deviant, both overweight and underweight are acknowledged risk factors for a shifted metabolism which, if being not optimised, may strongly contribute to the development and progression of severe pathologies. Development of innovative screening programmes is essential to promote population health by application of health risks assessment, individualised patient profiling and multi-parametric analysis, further used for cost-effective targeted prevention and treatments tailored to the person. The following healthcare areas are considered to be potentially strongly benefiting from the above proposed measures: suboptimal health conditions, sports medicine, stress overload and associated complications, planned pregnancies, periodontal health and dentistry, sleep medicine, eye health and disorders, inflammatory disorders, healing and pain management, metabolic disorders, cardiovascular disease, cancers, psychiatric and neurologic disorders, stroke of known and unknown aetiology, improved individual and population outcomes under pandemic conditions such as COVID-19. In a long-term way, a significantly improved healthcare economy is one of benefits of the proposed paradigm shift from reactive to Predictive, Preventive and Personalised Medicine (PPPM/3PM). A tight collaboration between all stakeholders including scientific community, healthcare givers, patient organisations, policy-makers and educators is essential for the smooth implementation of 3PM concepts in daily practice.

Homocysteine metabolism as the target for predictive medical approach, disease prevention, prognosis, and treatments tailored to the person.

Homocysteine (Hcy) metabolism is crucial for regulating methionine availability, protein homeostasis, and DNA-methylation presenting, therefore, key pathways in post-genomic and epigenetic regulation mechanisms. Consequently, impaired Hcy metabolism leading to elevated concentrations of Hcy in the blood plasma (hyperhomocysteinemia) is linked to the overproduction of free radicals, induced oxidative stress, mitochondrial impairments, systemic inflammation and increased risks of eye disorders, coronary artery diseases, atherosclerosis, myocardial infarction, ischemic stroke, thrombotic events, cancer development and progression, osteoporosis, neurodegenerative disorders, pregnancy complications, delayed healing processes, and poor COVID-19 outcomes, among others. This review focuses on the homocysteine metabolism impairments relevant for various pathological conditions. Innovative strategies in the framework of 3P medicine consider Hcy metabolic pathways as the specific target for in vitro diagnostics, predictive medical approaches, cost-effective preventive measures, and optimized treatments tailored to the individualized patient profiles in primary, secondary, and tertiary care.

Targeting phytoprotection in the COVID-19-induced lung damage and associated systemic effects-the evidence-based 3PM proposition to mitigate individual risks.

The risks related to the COVID-19 are multi-faceted including but by far not restricted to the following: direct health risks by poorly understood effects of COVID-19 infection, overloaded capacities of healthcare units, restricted and slowed down care of patients with non-communicable disorders such as cancer, neurologic and cardiovascular pathologies, among others; social risks-restricted and broken social contacts, isolation, professional disruption, explosion of aggression in the society, violence in the familial environment; mental risks-loneliness, helplessness, defenceless, depressions; and economic risks-slowed down industrial productivity, broken delivery chains, unemployment, bankrupted SMEs, inflation, decreased capacity of the state to perform socially important programs and to support socio-economically weak subgroups in the population. Directly or indirectly, the above listed risks will get reflected in a healthcare occupation and workload which is a tremendous long-term challenge for the healthcare capacity and robustness. The article does not pretend to provide solutions for all kind of health risks. However, it aims to present the scientific evidence of great clinical utility for primary, secondary, and tertiary care to protect affected individuals in a cost-effective manner. To this end, due to pronounced antimicrobial, antioxidant, anti-inflammatory, and antiviral properties, naturally occurring plant substances are capable to protect affected individuals against COVID-19-associated life-threatening complications such as lung damage. Furthermore, they can be highly effective, if being applied to secondary and tertiary care of noncommunicable diseases under pandemic condition. Thus, the stratification of patients evaluating specific health conditions such as sleep quality, periodontitis, smoking, chronic inflammation and diseases, metabolic disorders and obesity, vascular dysfunction, and cancers would enable effective managemenet of COVID-19-associated complications in primary, secondary, and tertiary care in the context of predictive, preventive, and personalized medicine (3PM).

Mass spectrometry analysis of human tear fluid biomarkers specific for ocular and systemic diseases in the context of 3P medicine.

Over the last two decades, a large number of non-communicable/chronic disorders reached an epidemic level on a global scale such as diabetes mellitus type 2, cardio-vascular disease, several types of malignancies, neurological and eye pathologies-all exerted system's enormous socio-economic burden to primary, secondary, and tertiary healthcare. The paradigm change from reactive to predictive, preventive, and personalized medicine (3PM/PPPM) has been declared as an essential transformation of the overall healthcare approach to benefit the patient and society at large. To this end, specific biomarker panels are instrumental for a cost-effective predictive approach of individualized prevention and treatments tailored to the person. The source of biomarkers is crucial for specificity and reliability of diagnostic tests and treatment targets. Furthermore, any diagnostic approach preferentially should be noninvasive to increase availability of the biomaterial, and to decrease risks of potential complications as well as concomitant costs. These requirements are clearly fulfilled by tear fluid, which represents a precious source of biomarker panels. The well-justified principle of a "sick eye in a sick body" makes comprehensive tear fluid biomarker profiling highly relevant not only for diagnostics of eye pathologies but also for prediction, prognosis, and treatment monitoring of systemic diseases. One prominent example is the Sicca syndrome linked to a cascade of severe complications that include dry eye, neurologic, and oncologic diseases. In this review, protein profiles in tear fluid are highlighted and corresponding biomarkers are exemplified for several relevant pathologies, including dry eye disease, diabetic retinopathy, cancers, and neurological disorders. Corresponding analytical approaches such as sample pre-processing, differential proteomics, electrophoretic techniques, high-performance liquid chromatography (HPLC), enzyme-linked immuno-sorbent assay (ELISA), microarrays, and mass spectrometry (MS) methodology are detailed. Consequently, we proposed the overall strategies based on the tear fluid biomarkers application for 3P medicine practice. In the context of 3P medicine, tear fluid analytical pathways are considered to predict disease development, to target preventive measures, and to create treatment algorithms tailored to individual patient profiles.

All around suboptimal health - a joint position paper of the Suboptimal Health Study Consortium and European Association for Predictive, Preventive and Personalised Medicine.

First two decades of the twenty-first century are characterised by epidemics of non-communicable diseases such as many hundreds of millions of patients diagnosed with cardiovascular diseases and the type 2 diabetes mellitus, breast, lung, liver and prostate malignancies, neurological, sleep, mood and eye disorders, amongst others. Consequent socio-economic burden is tremendous. Unprecedented decrease in age of maladaptive individuals has been reported. The absolute majority of expanding non-communicable disorders carry a chronic character, over a couple of years progressing from reversible suboptimal health conditions to irreversible severe pathologies and cascading collateral complications. The time-frame between onset of SHS and clinical manifestation of associated disorders is the operational area for an application of reliable risk assessment tools and predictive diagnostics followed by the cost-effective targeted prevention and treatments tailored to the person. This article demonstrates advanced strategies in bio/medical sciences and healthcare focused on suboptimal health conditions in the frame-work of Predictive, Preventive and Personalised Medicine (3PM/PPPM). Potential benefits in healthcare systems and for society at large include but are not restricted to an improved life-quality of major populations and socio-economical groups, advanced professionalism of healthcare-givers and sustainable healthcare economy. Amongst others, following medical areas are proposed to strongly benefit from PPPM strategies applied to the identification and treatment of suboptimal health conditions:Stress overload associated pathologiesMale and female healthPlanned pregnanciesPeriodontal healthEye disordersInflammatory disorders, wound healing and pain management with associated complicationsMetabolic disorders and suboptimal body weightCardiovascular pathologiesCancersStroke, particularly of unknown aetiology and in young individualsSleep medicineSports medicineImproved individual outcomes under pandemic conditions such as COVID-19.

Flavonoids as an effective sensitizer for anti-cancer therapy: insights into multi-faceted mechanisms and applicability towards individualized patient profiles.

Cost-efficacy of currently applied treatments is an issue in overall cancer management challenging healthcare and causing tremendous economic burden to societies around the world. Consequently, complex treatment models presenting concepts of predictive diagnostics followed by targeted prevention and treatments tailored to the personal patient profiles earn global appreciation as benefiting the patient, healthcare economy, and the society at large. In this context, application of flavonoids as a spectrum of compounds and their nano-technologically created derivatives is extensively under consideration, due to their multi-faceted anti-cancer effects applicable to the overall cost-effective cancer management, primary, secondary, and even tertiary prevention. This article analyzes most recently updated data focused on the potent capacity of flavonoids to promote anti-cancer therapeutic effects and interprets all the collected research achievements in the frame-work of predictive, preventive, and personalized (3P) medicine. Main pillars considered are: - Predictable anti-neoplastic, immune-modulating, drug-sensitizing effects; - Targeted molecular pathways to improve therapeutic outcomes by increasing sensitivity of cancer cells and reversing their resistance towards currently applied therapeutic modalities.

Sleep quality and COVID-19 outcomes: the evidence-based lessons in the framework of predictive, preventive and personalised (3P) medicine.

Sleep quality and duration play a pivotal role in maintaining physical and mental health. In turn, sleep shortage, deprivation and disorders are per evidence the risk factors and facilitators of a broad spectrum of disorders, amongst others including depression, stroke, chronic inflammation, cancers, immune defence insufficiency and individual predisposition to infection diseases with poor outcomes, for example, related to the COVID-19 pandemic. Keeping in mind that COVID-19-related global infection distribution is neither the first nor the last pandemic severely affecting societies around the globe to the costs of human lives accompanied with enormous economic burden, lessons by predictive, preventive and personalised (3P) medical approach are essential to learn and to follow being better prepared to defend against global pandemics. To this end, under extreme conditions such as the current COVID-19 pandemic, the reciprocal interrelationship between the sleep quality and individual outcomes becomes evident, namely, at the levels of disease predisposition, severe versus mild disease progression, development of disease complications, poor outcomes and related mortality for both - population and healthcare givers. The latter is the prominent example clearly demonstrating the causality of severe outcomes, when the long-lasting work overload and shift work rhythm evidently lead to the sleep shortage and/or deprivation that in turn causes immune response insufficiency and strong predisposition to the acute infection with complications. This article highlights and provides an in-depth analysis of the concerted risk factors related to the sleep disturbances under the COVID-19 pandemic followed by the evidence-based recommendations in the framework of predictive, preventive and personalised medical approach.

Challenging management of severe chronic disorders in acute pandemic situation: Chronic liver disease under COVID-19 pandemic as the proof-of-principle model to orchestrate the measures in 3PM context.

Chronic liver disease management is a comprehensive approach requiring multi-professional expertise and well-orchestrated healthcare measures thoroughly organized by responsible medical units. Contextually, the corresponding multi-faceted chain of healthcare events is likely to be severely disturbed or even temporarily broken under the force majeure conditions such as global pandemics. Consequently, the chronic liver disease is highly representative for the management of any severe chronic disorder under lasting pandemics with unprecedented numbers of acutely diseased persons who, together with the chronically sick patient cohorts, have to be treated using the given capacity of healthcare systems with their limited resources. Current study aimed at exploring potentially negative impacts of the SARS CoV-2 outbreak on the quality of the advanced chronic liver disease (ACLD) management considering two well-classified parameters, namely, (1) the continuity of the patient registrations and (2) the level of mortality rates, comparing pre-COVID-19 statistics with these under the current pandemic in Slovak Republic. Altogether 1091 registrations to cirrhosis registry (with 60.8% versus 39.2% males to females ratio) were included with a median age of 57 years for patients under consideration. Already within the very first 3 months of the pandemic outbreak in Slovakia (lockdown declared from March 16, 2020, until May 20, 2020), the continuity of the patient registrations has been broken followed by significantly increased ACLD-related death rates. During this period of time, the total number of new registrations decreased by about 60% (15 registrations in 2020 versus 38 in 2018 and 38 in 2019). Corresponding mortality increased by about 52% (23 deaths in 2020 versus 10 in 2018 and 12 in 2019). Based on these results and in line with the framework of 3PM guidelines, the pandemic priority pathways (PPP) are strongly recommended for maintaining tertiary care uninterrupted. For the evidence-based implementation of PPP, creation of predictive algorithms and individualized care strategy tailored to the patient is essential. Resulting classification of measures is summarized as follows:The Green PPP Line is reserved for prioritized (urgent and comprehensive) treatment of patients at highest risk to die from ACLD (tertiary care) as compared to the risk from possible COVID-19 infection.The Orange PPP Line considers patients at middle risk of adverse outcomes from ACLD with re-addressing them to the secondary care. As further deterioration of ACLD is still probable, pro-active management is ascertained with tertiary center serving as the 24/7 telemedicine consultation hub for a secondary facility (on a physician-physician level).The Red PPP Line is related to the patients at low risk to die from ACLD, re-addressing them to the primary care. Since patients with stable chronic liver diseases without advanced fibrosis are at trivial inherent risk, they should be kept out of the healthcare setting as far as possible by the telemedical (patient-nurse or patient- physician) measurements. The assigned priority has to be monitored and re-evaluated individually-in intervals based on the baseline prognostic score such as MELD. The approach is conform with principles of predictive, preventive and personalized medicine (PPPM / 3PM) and demonstrates a potential of great clinical utility for an optimal management of any severe chronic disorder (cardiovascular, neurological and cancer) under lasting pandemics.

Flavonoids against the Warburg phenotype-concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism.

The Warburg effect is characterised by increased glucose uptake and lactate secretion in cancer cells resulting from metabolic transformation in tumour tissue. The corresponding molecular pathways switch from oxidative phosphorylation to aerobic glycolysis, due to changes in glucose degradation mechanisms known as the 'Warburg reprogramming' of cancer cells. Key glycolytic enzymes, glucose transporters and transcription factors involved in the Warburg transformation are frequently dysregulated during carcinogenesis considered as promising diagnostic and prognostic markers as well as treatment targets. Flavonoids are molecules with pleiotropic activities. The metabolism-regulating anticancer effects of flavonoids are broadly demonstrated in preclinical studies. Flavonoids modulate key pathways involved in the Warburg phenotype including but not limited to PKM2, HK2, GLUT1 and HIF-1. The corresponding molecular mechanisms and clinical relevance of 'anti-Warburg' effects of flavonoids are discussed in this review article. The most prominent examples are provided for the potential application of targeted 'anti-Warburg' measures in cancer management. Individualised profiling and patient stratification are presented as powerful tools for implementing targeted 'anti-Warburg' measures in the context of predictive, preventive and personalised medicine.

Mitochondriopathies as a Clue to Systemic Disorders-Analytical Tools and Mitigating Measures in Context of Predictive, Preventive, and Personalized (3P) Medicine.

The mitochondrial respiratory chain is the main site of reactive oxygen species (ROS) production in the cell. Although mitochondria possess a powerful antioxidant system, an excess of ROS cannot be completely neutralized and cumulative oxidative damage may lead to decreasing mitochondrial efficiency in energy production, as well as an increasing ROS excess, which is known to cause a critical imbalance in antioxidant/oxidant mechanisms and a "vicious circle" in mitochondrial injury. Due to insufficient energy production, chronic exposure to ROS overproduction consequently leads to the oxidative damage of life-important biomolecules, including nucleic acids, proteins, lipids, and amino acids, among others. Different forms of mitochondrial dysfunction (mitochondriopathies) may affect the brain, heart, peripheral nervous and endocrine systems, eyes, ears, gut, and kidney, among other organs. Consequently, mitochondriopathies have been proposed as an attractive diagnostic target to be investigated in any patient with unexplained progressive multisystem disorder. This review article highlights the pathomechanisms of mitochondriopathies, details advanced analytical tools, and suggests predictive approaches, targeted prevention and personalization of medical services as instrumental for the overall management of mitochondriopathy-related cascading pathologies.

Genoprotective activities of plant natural substances in cancer and chemopreventive strategies in the context of 3P medicine.

Severe durable changes may occur to the DNA structure caused by exogenous and endogenous risk factors initiating the process of carcinogenesis. By evidence, a large portion of malignancies have been demonstrated as being preventable. Moreover, the targeted prevention of cancer onset is possible, due to unique properties of plant bioactive compounds. Although genoprotective effects of phytochemicals have been well documented, there is an evident lack of articles which would systematically present the spectrum of anticancer effects by phytochemicals, plant extracts, and plant-derived diet applicable to stratified patient groups at the level of targeted primary (cancer development) and secondary (cancer progression and metastatic disease) prevention. Consequently, clinical implementation of knowledge accumulated in the area is still highly restricted. To stimulate coherent co-development of the dedicated plant bioactive compound investigation on one hand and comprehensive cancer preventive strategies on the other hand, the current paper highlights and deeply analyses relevant evidence available in the area. Key molecular mechanisms are presented to detail genoprotective and anticancer activities of plants and phytochemicals. Clinical implementation is discussed. Based on the presented evidence, advanced chemopreventive strategies in the context of 3P medicine are considered.

Covid-19 pandemic by the "real-time" monitoring: the Tunisian case and lessons for global epidemics in the context of 3PM strategies.

Covid-19 is neither the first nor the last viral epidemic which societies around the world are, were and will be affected by. Which lessons should be taken from the current pandemic situation? The Covid-19 disease is still not well characterised, and many research teams all over the world are working on prediction of the epidemic scenario, protective measures to populations and sub-populations, therapeutic and vaccination issues, amongst others. Contextually, countries with currently low numbers of Covid-19-infected individuals such as Tunisia are intended to take lessons from those countries which already reached the exponential phase of the infection distribution as well as from those which have the exponential phase behind them and record a minor number of new cases such as China. To this end, in Tunisia, the pandemic wave has started with a significant delay compared with Europe, the main economic partner of the country. In this paper, we do analyse the current pandemic situation in this country by studying the infection evolution and considering potential protective strategies to prevent a pandemic scenario. The model is predictive based on a large number of undetected Covid-19 cases that is particularly true for some country regions such as Sfax. Infection distribution and mortality rate analysis demonstrate a highly heterogeneous picture over the country. Qualitative and quantitative comparative analysis leads to a conclusion that the reliable "real-time" monitoring based on the randomised laboratory tests is the optimal predictive strategy to create the most effective evidence-based preventive measures. In contrast, lack of tests may lead to incorrect political decisions causing either unnecessary over-protection of the population that is risky for a long-term economic recession, or under-protection of the population leading to a post-containment pandemic rebound. Recommendations are provided in the context of advanced predictive, preventive and personalised (3P) medical approach.

Voice perturbations under the stress overload in young individuals: phenotyping and suboptimal health as predictors for cascading pathologies.

Verbal communication is one of the most sophisticated human motor skills reflecting both-the mental and physical health of an individual. Voice parameters and quality changes are usually secondary towards functional and/or structural laryngological alterations under specific systemic processes, syndrome and pathologies. These include but are not restricted to dry mouth and Sicca syndromes, body dehydration, hormonal alterations linked to pubertal, menopausal, and andropausal status, respiratory disorders, gastrointestinal reflux, autoimmune diseases, endocrinologic disorders, underweight versus overweight and obesity, and diabetes mellitus. On the other hand, it is well-established that stress overload is a significant risk factor of cascading pathologies, including but not restricted to neurodegenerative and psychiatric disorders, diabetes mellitus, cardiovascular disease, stroke, and cancers. Our current study revealed voice perturbations under the stress overload as a potentially useful biomarker to identify individuals in suboptimal health conditions who might be strongly predisposed to associated pathologies. Contextually, extended surveys applied in the population might be useful to identify, for example, persons at high risk for respiratory complications under pandemic conditions such as COVID-19. Symptoms of dry mouth syndrome, disturbed microcirculation, altered sense regulation, shifted circadian rhythm, and low BMI were positively associated with voice perturbations under the stress overload. Their functional interrelationships and relevance for cascading associated pathologies are presented in the article. Automated analysis of voice recordings via artificial intelligence (AI) has a potential to derive digital biomarkers. Further, predictive machine learning models should be developed that allows for detecting a suboptimal health condition based on voice recordings, ideally in an automated manner using derived digital biomarkers. Follow-up stratification and monitoring of individuals in suboptimal health conditions are recommended using disease-specific cell-free nucleic acids (ccfDNA, ctDNA, mtDNA, miRNA) combined with metabolic patterns detected in body fluids. Application of the cost-effective targeted prevention within the phase of reversible health damage is recommended based on the individualised patient profiling.

Cell-free nucleic acid patterns in disease prediction and monitoring-hype or hope?

Interest in the use of cell-free nucleic acids (CFNAs) as clinical non-invasive biomarker panels for prediction and prevention of multiple diseases has greatly increased over the last decade. Indeed, circulating CFNAs are attributable to many physiological and pathological processes such as imbalanced stress conditions, physical activities, extensive apoptosis of different origin, systemic hypoxic-ischemic events and tumour progression, amongst others. This article highlights the involvement of circulating CFNAs in local and systemic processes dealing with the question, whether specific patterns of CFNAs in blood, their detection, quantity and quality (such as their methylation status) might be instrumental to predict a disease development/progression and could be further utilised for accompanying diagnostics, targeted prevention, creation of individualised therapy algorithms, therapy monitoring and prognosis. Presented considerations conform with principles of 3P medicine and serve for improving individual outcomes and cost efficacy of medical services provided to the population.