Digital biomarkers: 3PM approach revolutionizing chronic disease management - EPMA 2024 position.

Non-communicable chronic diseases (NCDs) have become a major global health concern. They constitute the leading cause of disabilities, increased morbidity, mortality, and socio-economic disasters worldwide. Medical condition-specific digital biomarker (DB) panels have emerged as valuable tools to manage NCDs. DBs refer to the measurable and quantifiable physiological, behavioral, and environmental parameters collected for an individual through innovative digital health technologies, including wearables, smart devices, and medical sensors. By leveraging digital technologies, healthcare providers can gather real-time data and insights, enabling them to deliver more proactive and tailored interventions to individuals at risk and patients diagnosed with NCDs. Continuous monitoring of relevant health parameters through wearable devices or smartphone applications allows patients and clinicians to track the progression of NCDs in real time. With the introduction of digital biomarker monitoring (DBM), a new quality of primary and secondary healthcare is being offered with promising opportunities for health risk assessment and protection against health-to-disease transitions in vulnerable sub-populations. DBM enables healthcare providers to take the most cost-effective targeted preventive measures, to detect disease developments early, and to introduce personalized interventions. Consequently, they benefit the quality of life (QoL) of affected individuals, healthcare economy, and society at large. DBM is instrumental for the paradigm shift from reactive medical services to 3PM approach promoted by the European Association for Predictive, Preventive, and Personalized Medicine (EPMA) involving 3PM experts from 55 countries worldwide. This position manuscript consolidates multi-professional expertise in the area, demonstrating clinically relevant examples and providing the roadmap for implementing 3PM concepts facilitated through DBs.

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.

Impact of diabetes on clinical and safety outcomes in acute ischemic stroke patients receiving reperfusion therapy: A meta-analysis.

BACKGROUND: Patients with diabetes are known to have worse outcomes after an acute ischemic stroke (AIS) relative to those without diabetes. However, the impact of diabetes on the outcomes after the reperfusion therapy is poorly understood. OBJECTIVES: This study investigated prognostic accuracy of diabetes and its association with clinical and safety outcomes in AIS patients receiving intravenous thrombolysis (IVT), endovascular thrombectomy (EVT), or both. MATERIAL AND METHODS: Studies were identified from PubMed, Embase and Cochrane databases, using the following inclusion criteria: (a) AIS patients receiving reperfusion therapy, (b) age ≥ 18 years, (c) hemispheric stroke, and (d) the availability of comparative data between diabetic and nondiabetic groups and relevant poststroke outcomes. Random effects modelling was used to study the association of diabetes with functional outcome at discharge and at 90 days, mortality at 90 days, recanalization status, and postreperfusion safety outcomes, including rates of symptomatic intracerebral hemorrhage (sICH) and hemorrhagic transformation (HT). Forest plots of odds ratios (ORs) were generated. RESULTS: Of a total cohort of 82,764 patients who received reperfusion therapy, 16,877 had diabetes. Diabetes significantly increased the odds of poor functional outcome at discharge (OR 1.310; 95% confidence interval (95% CI): [1.091; 1.574]; p = 0.0037) and at 90 days (OR 1.487; 95% CI: [1.335; 1.656]; p < 0.00010), mortality at 90 days (OR 1.709; 95% CI: [1.633; 1.788]; p < 0.0001), sICH (OR 1.595; 95% CI: [1.301; 1.956]; p < 0.0001), and HT (OR 1.276; 95% CI: [1.055; 1.543]; p = 0.0118). CONCLUSION: Our meta-analysis demonstrates that diabetes is significantly associated with poor functional outcome, increased mortality and poor postprocedural safety outcomes, including sICH and HT.

Prevalence and impact of diabetes in hospitalized COVID-19 patients: A systematic review and meta-analysis.

BACKGROUND: Diabetes is a cardiometabolic comorbidity that may predispose COVID-19 patients to worse clinical outcomes. This study sought to determine the prevalence of diabetes in hospitalized COVID-19 patients and investigate the association of diabetes severe COVID-19, rate of acute respiratory distress syndrome (ARDS), mortality, and need for mechanical ventilation by performing a systematic review and meta-analysis. METHODS: Individual studies were selected using a defined search strategy, including results up until July 2021 from PubMed, Embase, and Cochrane Central Register of Controlled Trials. A random-effects meta-analysis was performed to estimate the proportions and level of association of diabetes with clinical outcomes in hospitalized COVID-19 patients. Forest plots were generated to retrieve the odds ratios (OR), and the quality and risk assessment was performed for all studies included in the meta-analysis. RESULTS: The total number of patients included in this study was 10 648, of whom 3112 had diabetes (29.23%). The overall pooled estimate of prevalence of diabetes in the meta-analysis cohort was 31% (95% CI, 0.25-0.38; z = 16.09, P < .0001). Diabetes significantly increased the odds of severe COVID-19 (OR 3.39; 95% CI, 2.14-5.37; P < .0001), ARDS (OR 2.55; 95% CI, 1.74-3.75; P = <.0001), in-hospital mortality (OR 2.44; 95% CI, 1.93-3.09; P < .0001), and mechanical ventilation (OR 3.03; 95% CI, 2.17-4.22; P < .0001). CONCLUSIONS: Our meta-analysis demonstrates that diabetes is significantly associated with increased odds of severe COVID-19, increased ARDS rate, mortality, and need for mechanical ventilation in hospitalized patients. We also estimated an overall pooled prevalence of diabetes of 31% in hospitalized COVID-19 patients.

First stratified diabetes prevalence data for Republic of Macedonia derived from the National eHealth System.

AIMS: To find diabetes prevalence of diagnosed cases, stratified by gender, age, and urban/rural municipalities in the Republic of Macedonia, based on data derived from the National eHealth System. METHODS: The National eHealth System was searched for all patients with ICD-10 diagnoses E10-E14 in their electronic healthcare records. Data records from the National eHealth System contained patient's gender, date of birth, place of living, and ICD-10 code. RESULTS: Total number of diagnosed diabetes cases was 84,568: 36,119 males (42.7%) and 48,449 females (57.3%). Diabetes prevalence of diagnosed cases in population 20-79 years was 5.0% (n = 78,233; N = 1,562,203), prevalence was higher in females than in males (4.6% vs 3.4%); in rural than in urban municipalities (5.6% vs 3.6%), and was highest in the age group 60-79 years (14.6%). CONCLUSION: These were the first findings on diabetes prevalence of diagnosed cases in the Republic of Macedonia derived from the National eHealth System, stratified by age, gender, and urban/rural municipalities. These data could enable more precise estimations of the total diabetes prevalence in the country, including both diagnosed and undiagnosed cases, and further analysis of the risk factors leading to higher diabetes prevalence in females and rural municipalities in the Republic of Macedonia.

Multi-System Complications after Intravenous Cocaine Abuse.

BACKGROUND: Use and abuse of cocaine are associated with numerous adverse effects, independent of the route of administration. More severe conditions of poisoning, however, are observed after cocaine intravenous administration. AIM: We present a case of severe poisoning after violent intravenous injection of cocaine, but with a good outcome. CASE PRESENTATION: Cocaine was intravenously (i.v.) administered in 16-years old female patient as a homicide attempt. Shortly after that, patient experienced series of generalised tonic-clonic seizures, was highly febrile (40°C), somnolent, agitated, presenting with tachycardia, tachypnea and with increased blood pressure 150/90 mmHg. Neurologic status, lumbar puncture and computerised tomography (CT) of the brain were without remarks. Electroencephalogram (EEG) was characterised with signs of diffuse encephalopathy, and acid-base analyses resulted in metabolic acidosis. Urine screening revealed the presence of cocaine and benzodiazepines. The patient presented with signs of the hepatic lesion, acute renal insufficiency (ARI), and increased D-dimers resulting from activated fibrinolysis. The patient was discharged in stable general condition after being hospitalised for 23 days. CONCLUSION: Intravenous abuse of cocaine results in overdose and serous multi-system complications requiring multidisciplinary diagnostic and intensive therapeutic approach.

Postmenopausal breast cancer: European challenge and innovative concepts.

Breast cancer (BC) epidemic is recognised now worldwide as the reality of the early twenty-first century. Increasing trends in the postmenopausal BC prevalence, even for the European countries earlier demonstrating relatively stable incidence rates of the disease, are highly alarming for the healthcare givers. This new actuality requires a substantial revision of the paradigm currently applied to the BC management and creation of highly innovative concepts. Current multi-centred study highlights new complex mechanisms of the development and progression of the postmenopausal BC. Innovative concepts are presented which argue for more effective predictive and preventive approaches well justified in view of the clusters of the symptoms analysed here and demonstrated as highly prevalent in the postmenopausal breast cancer versus BC-free individuals. Another conceptual novelty presented here is a new interpretation of the "Seed and Soil" theory of metastasis in BC. According to the new concept, the "pre-metastatic niches" ("Soil") are created by a systemic hypoxia a long time before the breast malignancy is clinically manifested.

NUTRITIONAL THERAPY IN THE TREATMENT OF ACUTE CORROSIVE INTOXICATION IN ADULTS.

INTRODUCTION: Acute intoxications with corrosive substances can cause severe chemical injuries of the upper gastrointestinal tract, most often located in the mouth, pharynx, esophagus, stomach and duodenum. If a patient survives the acute phase of intoxication, regenerative response may result in esophageal and/or gastric stenosis, and increased risk of esophageal and gastric cancer. Such intoxication may be fatal due to perforation or tracheal necrosis. Enteral nutrition is a nutritional method when nutritional substances are administered through specially designed tubing placed through the nose or percutaneously, directly into the GIT. AIM: The aim of this study is to describe the methods of artificial nutrition in patients with acute corrosive intoxications and the importance of nutritional support in the treatment of these intoxications. DISCUSSION: Nutrition in the treatment of acute corrosive intoxications is one of the most important therapeutic processes that largely contribute to faster recovery of the post-corrosive injuries of upper GIT, stabilization of biologic, immunologic and metabolic parameters, and reduction of length of stay in hospital Aim of the treatment of acute corrosive intoxications is to prevent perforation and progressive fibrosis, and esophageal and gastric stenosis. There are different and often conflicting positions, on the conservative treatment of acute corrosive intoxications in adults. Such treatment mainly consists of anti-secretory treatment, antibiotics and intensive hyper-alimentation, aiming to prevent late post-corrosive intoxications. CONCLUSION: It is considered that nutritional support plays a major role in maintenance of metabolic processes and prevention of severe metabolic complications that could additionally aggravate the condition and impair the treatment.

Diabetes Care in Republic of Macedonia: Challenges and Opportunities.

BACKGROUND: The Republic of Macedonia (RoM) has experienced a rapid rise in the prevalence of type 2 diabetes (T2D) over the past 2 decades, a period characterized by significant social, political, and economic change. RoM now has one of the highest rates of diabetes in Europe. OBJECTIVES: To explore the modifiable conditions that may underlie and exacerbate the T2D epidemic; describe the state of diabetes care; and consider improved mechanisms for prevention and treatment, including research priorities, in RoM. METHODS: Methods included data mining from reliable sources and collaboration of authors to consider and describe applications of research from outside RoM and to identify evidence-based strategies to reduce the burden of T2D in RoM. FINDINGS: In 2014, the national prevalence of diabetes was 11.44% of the population (20-79 years) of RoM. Per capita caloric intake has increased significantly over the past 2 decades, with the majority of these calories coming from sugar, pork, chicken, beef, and sunflower oil. Excess calories, in the form of nutrient-deficient foods, animal products, and added oils promote insulin resistance and T2D. Tobacco use and lack of physical activity also contribute to the diabetes epidemic. Insulin, especially insulin analogues, are widely available and used to manage diabetes, often over other interventions that are more appropriate for patients with T2D, and more frequently than in other more developed countries, resulting in higher and unsustainable related costs. CONCLUSIONS: A new National eHealth System allows for better identification and monitoring of citizens with diabetes. However, the rapidly growing expense of insulin in the past has been unsustainable. The potential exists for a stronger role for lifestyle interventions in prevention and treatment of T2D. Significant changes in dietary patterns parallel the rise in diabetes prevalence and are likely a leading cause of diabetes and its complications. Research in RoM is needed to determine the impact and acceptability of dietary interventions for prevention and treatment of T2D, as a first step toward reduction of diabetes prevalence and its complications and controlling spiraling health care costs.

Influence of age on the survival and mortality rate in acute caustic poisonings.

OBJECTIVE: Acute poisonings with caustic substances can cause severe chemical injuries to the upper gastrointestinal tract, which can be localized from the mouth to the small intestines. They are seen very often among young people in their most productive years. The aim of this study is to examine the influence of patient's age on the mortality rate and survival of patients with acute caustic poisonings, and also to analyze their correlation. MATERIAL AND METHODS: We studied medical records from 415 patients, aged between 14 and 90 years, who were hospitalized and treated at the University Clinic for toxicology and urgent internal medicine, Skopje, Republic of Macedonia, in the period between 2007 and 2011. RESULTS: In the survey we included 415 patients with acute corrosive poisonings, from which 295 (71.08%) were females and 120 (28. 92%) were males. 388 (93.49%) from the total number of patients ingested the corrosive agent with suicidal attempt and 27 (6.5%) ingested it accidentally. CONCLUSION: Unregulated production, import, packing and labeling of various caustic agents, due to inappropriate legislative, made them one of the most often abused substances in everyday life, especially in developing countries where the number of caustic poisonings rises.

Respiratory complications from acute corrosive poisonings in adults.

INTRODUCTION: Acute corrosive poisonings are caused by ingestion of corrosive chemicals which are most commonly used as household agents. Intoxications with these kind of agents produce numerous and severe post-corrosive complications of the upper gastrointestinal tract. On the other hand, our experience showed that corrosive agents may also cause injuries of the respiratory system, which makes the treatment very hard and additionally complicates the severe clinical condition of the patient. OBJECTIVE: The aim of the study is to show the incidence of respiratory complications in acute corrosive poisonings, the need of various clinical investigations and also the treatment and final outcome of these kind of poisoning. METHODS: We retrospectively analyzed clinical records of 415 patients hospitalized and treated at the University clinic for toxicology and urgent internal medicine, in Skopje, Republic of Macedonia, in the period between 2007 and 2011. The protocol consisted of methods for analyzing the systemic complications, with an accent on the post-corrosive respiratory complications. RESULTS: From the total number of patients even 98 (23.61%) exhibited systemic complications, from which 51 (52.04%) are respiratory complications. The majority of patients are female (n=40, 78.43%) and the most common complication is pneumonia (n=47). The youngest patient in this study was 14 and the oldest was 87 years old. CONCLUSION: Besides the gastrointestinal complications in the acute corrosive poisonings respiratory complications are also very often. They complicate the clinical state of patient and very often lead to fatal endings.