Ivica Smokovski

Objective: Thyroid disorders are among the most common endocrine conditions worldwide. However, in the Republic of North Macedonia, national level data on their prevalence and demographic distribution are lacking. This study aimed to determine the prevalence and demographic patterns of nonmalignant thyroid disorders using data from the National eHealth System. Methods: This retrospective, population-based , cross-sectional study analyzed 269,690 anonymized records of patients diagnosed with nonmalignant thyroid disorders, derived from the National eHealth System as of 31 October 2024. Diagnoses were identified using the International Classification of Diseases, 10th Revision codes E00–E07. Results: The overall national prevalence of nonmalignant thyroid disorders was 14.68%. Prevalence was higher in women (24.36%) than in men (4.85%) and increased with age, with the highest prevalence of 21.9% among those aged 60–79 years. Women had significantly higher odds of thyroid disorders than men (odds ratio: 6.32; 95% confidence interval: 6.25–6.38; p < 0.0001). Prevalence was higher in urban than in rural areas (17.1% vs. 10.9%). Hypothyroidism (E03) was the most common disorder, affecting 9.7% of the population. Conclusion: This is the first national level study to examine the epidemiology of nonmalignant thyroid disorders in the Republic of North Macedonia. The findings reveal marked variations in prevalence by sex, age, and place of residence, underscoring the need for targeted public health strategies and further investigation.

Chronic sympathoexcitation (sympathetic overdrive syndrome) is defined as the sustained dominance of sympathetic over parasympathetic tone, measurable at the organ, vascular, and neural levels, and differs fundamentally from brief, adaptive “fight-or-flight” responses. Persistent vasoconstrictor drive perturbs cellular metabolism and reshapes host–tumor interfaces. Although this state is well characterized in cardiometabolic medicine, its oncologic implications remain comparatively underexplored, despite converging evidence that adrenergic inputs modulate tumor and stromal behavior. One of the main reasons for presenting this conceptual innovation study is that the sympathetic overdrive phenotype (SOP) carriers, by far, are not rare in the population. Robust statistics towards SOP incidence and prevalence are still missing, despite the urgency of plausible healthcare solutions. Currently, the best described SOP-relevant subpopulation are the Flammer Syndrome phenotype (FSP) carriers who, for instance, are highly prevalent in the academic career-making professional groups. Certain genetic predispositions play a role, however, the key pathways involved into the health-to-disease transition are epigenetically regulated and, to a large extent, represent systemic modifiable phenotype-associated risk factors which are, therefore, a promising target for holistic proactive medical approaches with a high potential to save lives and financial resources. Graphical Abstract The alternative text for this image may have been generated using AI.

Acute ischemic stroke (AIS) remains a leading cause of mortality and long-term disability globally, with survivors at high risk of recurrent stroke, cardiovascular events, and post-stroke dementia. Statins, while widely used for their lipid-lowering effects, also possess pleiotropic properties, including anti-inflammatory, endothelial-stabilizing, and neuroprotective actions, which may offer added benefit in AIS management. This article synthesizes emerging evidence on statins’ dual mechanisms of action and evaluates their role in reducing recurrence, improving survival, and mitigating cognitive decline. Key challenges limiting the full therapeutic potential of statins include interindividual variability in response and pharmacogenomic and biomarker-related resistance, inconsistencies across clinical guidelines, and limited central nervous system bioavailability. Innovations such as pharmacogenomic-guided therapy, pleiotropy-linked biomarkers, and advanced drug delivery systems (e.g., nanoparticle and intranasal formulations) may help overcome these barriers. Combination strategies with agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors or sodium–glucose cotransporter 2 (SGLT2) inhibitors, and targeted interventions against neuroinflammatory resistance, show promise in enhancing treatment efficacy. In doing so, we propose a shift from conventional statin use to a precision medicine paradigm that can better serve AIS survivors, especially those at risk of post-stroke dementia or those living in resource-constrained settings. While such innovations, for example, genetic testing and novel delivery methods, may not yet be feasible in all contexts, particularly low-resource environments, they represent long-term goals for equity-driven innovation. Equity in access to high-intensity statins and novel therapies remains a global priority, particularly in low- and middle-income countries. Future research should prioritize personalized, biomarker-driven approaches and inclusive clinical trials to optimize statin use across diverse AIS populations. By advancing these strategies, statins can evolve from cardiovascular agents into integral components of precision neurovascular medicine, improving long-term outcomes and quality of life for stroke survivors.

Cancer drug resistance poses a significant challenge in oncology, primarily driven by cancer cell plasticity, which promotes tumor initiation, progression, metastasis, and therapeutic evasion in many different cancers. Breast cancers (BCs) are a prominent example of that, with an estimated 2.3 million new cases and 670,000 BC-related deaths registered worldwide annually. Triple-negative BC is especially challenging for treatments demonstrating particularly aggressive disease course, an early manifestation of metastatic disease, frequent drug-resistant cancer types, and poor individual outcomes. Although chemosensitizing agents have been developed, their clinical utility in oncology remains unproven. The mitogen-activated protein kinase (MAPK) pathway is considered a critical regulator of intracellular and extracellular signaling highly relevant for both — genetic and epigenetic modifications. Dysregulation of the MAPK signaling pathways plays a significant role in conferring chemoresistance in BC. Contextually, targeting the MAPK pathway represents a promising strategy for overcoming drug resistance and enhancing the therapeutic efficacy of anticancer agents in BC treatment. On the other hand, flavonoids, a prominent class of phytochemicals, are key modulators of MAPK signaling. Flavonoids interact with the ERK, JNK, p38, and ERK5 pathways of the MAPK signaling cascade and present a promising avenue for developing novel anti-cancer therapies and re-sensitizing agents for the treatment of BC. Compounds such as quercetin, kaempferol, genistein, luteolin, myricetin, EGCG, baicalein, baicalin, nobiletin, morin, delphinidin, acacetin, isorhamnetin, apigenin, silymarin, among others, have been identified as specific modulators of MAPK signaling, exerting complex downstream effects in BC cells increasing therewith drug efficacy and suppressing tumor growth and aggressivity. These properties reflect mechanisms of great clinical relevance to overcome therapeutic resistance in overall BC management. This article highlights corresponding mechanisms and provides clinically relevant illustrations in the framework of 3P medicine for primary (protection of individuals at high risk against health-to-disease transition) and secondary care (protection against metastatic BC progression). 3PM novelty makes good use of patient phenotyping and stratification, predictive multi-level diagnostics, and application of Artificial Intelligence (AI) tools to the individualized interpretation of big data — all proposed for cost-effective treatments tailored to individualized patient profiles with clear benefits to patients and advanced BC management.

Background Chronic kidney disease (CKD) significantly increases stroke risk and severity, posing challenges in both acute management and long-term outcomes. CKD contributes to cerebrovascular pathology through systemic inflammation, oxidative stress, endothelial dysfunction, vascular calcification, impaired cerebral autoregulation, and a prothrombotic state, all of which exacerbate stroke risk and outcomes. Methods This review synthesizes evidence from peer-reviewed literature to elucidate the pathophysiological mechanisms linking CKD and stroke. It evaluates the efficacy and safety of acute reperfusion therapies—intravenous thrombolysis and endovascular thrombectomy—in CKD patients with acute ischemic stroke. Considerations, such as renal function, drug dosage adjustments, and the risk of contrast-induced nephropathy, are critically analyzed. Evidence-based recommendations and research priorities are drawn from an analysis of current practices and existing knowledge gaps. Results CKD influences stroke outcomes through systemic and local pathophysiological changes, necessitating tailored therapeutic approaches. Reperfusion therapies are effective in CKD patients but require careful monitoring of renal function to mitigate risks, such as contrast-induced nephropathy and thrombolytic complications. The bidirectional relationship between stroke and CKD highlights the need for integrated management strategies to address both conditions. Early detection and optimized management of CKD significantly reduce stroke-related morbidity and mortality. Conclusion Optimizing stroke care in CKD patients requires a comprehensive understanding of their pathophysiology and clinical management challenges. This article provides evidence-based recommendations, emphasizing individualized treatment decisions and coordinated care. It underscores the importance of integrating renal considerations into stroke treatment protocols and highlights the need for future research to refine therapeutic strategies, address knowledge gaps, and consider tailored interventions to improve outcomes and quality of life for this high-risk population. Graphical Abstract

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.