Sismanogleio General Hospital

Vitamin D is a pleiotropic hormone with an established role in skeletal integrity and broader actions in immune regulation, inflammation, cellular proliferation, and energy homeostasis. Despite decades of research, its extra-skeletal effects remain controversial, largely due to discordant findings across observational studies, Mendelian randomization studies (MRS), and randomized controlled trials (RCTs). Unlike many prior reviews, this state-of-the-art review synthesizes triangulated evidence across these study designs to clarify outcome-specific causal relationships and ongoing controversies. Triangulated evidence provides strong and consistent support for a causal role of vitamin D in skeletal health, particularly in the prevention and treatment of rickets and osteomalacia, and in fracture risk reduction among vitamin D–deficient and older populations. For selected extra-skeletal outcomes, modest and threshold-dependent benefits are observed, including reductions in cancer mortality, protection against autoimmune disorders, most convincingly multiple sclerosis, and decreased risk of acute respiratory infections, including COVID-19, primarily in individuals with low baseline 25(OH)D concentrations. In contrast, associations with cardiovascular disease, metabolic disorders, obesity, and most neuropsychiatric outcomes are not consistently supported by genetic or interventional evidence, suggesting limited or non-causal effects. Across outcomes, evidence indicates a non-linear relationship between vitamin D status and health, with increased risk concentrated at low 25-hydroxyvitamin D concentrations and limited benefit beyond sufficiency. All-cause mortality shows a modest, threshold-dependent association, with supplementation benefits largely confined to deficient or older populations. Key challenges include assay variability, non-linear dose–response relationships, and RCT designs that frequently enroll vitamin D–replete populations, resulting in substantial methodological heterogeneity and limiting causal inference. Overall, the presented triangulated model may reconcile longstanding inconsistencies by reframing vitamin D as a context-dependent determinant of health. These findings argue against indiscriminate population-wide supplementation and support targeted strategies focused on the identification and correction of deficiency. Vitamin D should be regarded neither as a universal panacea nor as a trivial supplement, but as a context-dependent hormone whose clinical value lies in outcome-specific correction of deficiency. Created in BioRender by Dimitra Petropoulou (January 20, 2026) BioRender.com/rd3udxs.

Background: Statins are established therapies for reducing cardiovascular and cerebrovascular risk. Beyond their lipid-lowering effects, they exert pleiotropic actions, including anti-inflammatory, immunomodulatory, antioxidant, anti-apoptotic, and vascular effects. Methods: This narrative review explores the effects of statins in a range of characteristic neurological disorders beyond stroke prevention, encompassing migraine, neurodegenerative and neuroinflammatory diseases, myasthenia gravis (MG), traumatic brain injury (TBI), brain tumors, epilepsy, and peripheral neuropathy (PN). A literature search was conducted in PubMed, Embase, and Scopus, focusing on proposed mechanisms of action, clinical outcomes, and potential neurological adverse effects. Results: Research suggests potential benefits of statins in migraine, TBI and its complications, brain tumors, and epilepsy. Favorable findings have also been reported in neurodegenerative and neuroinflammatory conditions, including Parkinson’s disease, Huntington’s disease, and multiple sclerosis. Despite earlier concerns regarding a possible association between statin use and an increased risk of dementia, subsequent studies have challenged this association, with some suggesting even a protective effect. Potential neurological adverse effects also warrant attention, particularly the reported association between statin exposure and new-onset or worsening MG. In contrast, data linking statin use to amyotrophic lateral sclerosis and PN are controversial and do not support causality. Interpretation of the available findings is complicated by heterogeneity in statin type and lipophilicity, dosage, treatment duration, disease stage, and study design. Clinical evidence is derived predominantly from observational studies, which are susceptible to confounding and other methodological limitations. Randomized controlled trials remain relatively few, with some further limited by small sample sizes. Conclusions: The pleiotropic properties of statins provide a rationale for investigating their potential therapeutic role across a broad spectrum of neurological disorders. Nevertheless, the available evidence remains heterogeneous and, in several conditions, conflicting. Further adequately powered randomized controlled trials are needed to establish whether statins translate their proposed pleiotropic effects into clinically meaningful benefits in specific neurological disorders and to better characterize their potential neurological risks.

Cancer remains a major global health challenge, with persistent limitations in early diagnosis, metastatic disease control, and the achievement of durable therapeutic responses with acceptable toxicity. These challenges highlight the need for more precise biomarkers and more effective therapeutic strategies. Increasing evidence implicates dysregulated lipid metabolism as a central contributor to tumor development and progression. In recent years, proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3 (ANGPTL3), and cholesteryl ester transfer protein (CETP) have gained particular attention due to their roles in cholesterol homeostasis, oncogenic signaling, and immune modulation within the tumor microenvironment (TME). This narrative review evaluates the potential of these lipid-regulatory mediators as diagnostic biomarkers and therapeutic targets in oncology. The majority of available evidence derives from preclinical and epidemiological studies, with PCSK9 representing the most extensively investigated target. Findings are sometimes contradictory and strongly influenced by tumor type, disease stage, and biological context, which currently precludes the clinical applicability of these molecules as reliable biomarkers. Similar limitations apply to their translational potential as actionable therapeutic targets. Nevertheless, emerging preclinical evidence suggests that modulation of these glycoproteins may enhance the efficacy of chemotherapy, targeted therapies, and immunotherapy, including nanomedicine-based approaches. Of note, clinical research investigating the role of PCSK9 inhibition in oncology is currently ongoing, whereas comparable studies focusing on ANGPTL3 and CETP remain scarce. Overall, further mechanistic, translational, and prospective clinical investigations are warranted to elucidate the involvement of these lipid-regulatory proteins in cancer biology and to define their potential integration into future oncologic diagnostic and therapeutic strategies.

INTRODUCTION:Carbapenem-resistant Gram-negative bacteria represent a major global health threat driven by diverse β-lactamase enzymes, particularly KPC, metallo-β-lactamases, and OXA-type carbapenemases, leading to limited treatment options and high mortality. The development of novel β-lactam/β-lactamase inhibitor (BLBLI) combinations has significantly improved outcomes in resistant infections by restoring β-lactam activity against key resistance mechanisms, primarily among Enterobacterales. AREAS COVERED:This expert review summarizes the pharmacology, clinical efficacy, and safety of approved and emerging BLBLIs, including ceftolozane-tazobactam, cefepime-enmetazobactam, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, aztreonam-avibactam, and sulbactam-durlobactam. Emphasis is placed on activity against carbapenem-resistant Enterobacterales, difficult-to-treat Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii. Evidence derives from clinical trials, real-world studies, and pharmacokinetic/pharmacodynamic (PK/PD) analyses from major databases (PubMed, Scopus, Web of Science) from inception through January 2026, focusing on dosing optimization and outcomes. EXPERT OPINION:BLBLIs have transformed the management of KPC-producing infections, markedly reducing mortality compared with legacy therapies. However, their impact is threatened by the rising prevalence of metallo-β-lactamases and the persistent therapeutic gap in carbapenem-resistant A. baumannii. Future success will depend on next-generation inhibitors with broader enzyme coverage, optimized dosing strategies guided by PK/PD principles, and robust antimicrobial stewardship to preserve long-term efficacy.

Dengue virus infection is a febrile illness caused by the Orthoflavivirus Dengue, which is transmitted by the mosquitoes Aedes aegypti or Aedes albopictus. Despite the fact that Dengue virus (DENV) is present in tropical and subtropical areas, climate change with global warming has been associated with the spread of Aedes aegypti and Aedes albopictus mosquitoes in several other regions worldwide. Notably, as the presence of Aedes albopictus has been confirmed in Southern Europe, already locally transmitted cases of Dengue virus infection have been reported in Europe. Apart from Europe, Australia has reported DENV cases in the 21st century that have been associated with the transmission of Aedes aegypti in the neighboring islands. Climate change, namely increasing temperatures, higher humidity and rainfalls, together with the development of urban heat islands, uncontrollable deforestation and urbanization, travelling and trade, has contributed significantly to the spread of DENV infection. Modern diagnosis based upon the advent of “multi-omics” techniques and machinery learning programs will be of the utmost importance for the early and accurate diagnosis of DENV infection. Finally, preventive measures for controlling Dengue virus infection, such as the use of repellents, educational programs, and improvement in water storage and waste management at the community levels would be very useful. Regarding climate change, the One Health Approach by integrating collaboration of various sectors and raising public awareness seems to be of the utmost importance in this context. Further investigations regarding the development of antiviral agents and vaccines will be an important asset in our armamentarium against DENV infection.