Medication-overuse headache (MOH) associated with migraine is a biologically driven disorder involving central sensitization, maladaptive neuroplasticity, and enhanced calcitonin gene-related peptide (CGRP) signaling. While structured deprescribing addresses medication-related drivers, withdrawal alone often provides limited and unsustained benefit. Anti-CGRP preventive therapies offer targeted modulation of migraine pathways without reinforcing medication overuse. This study integrates pathophysiological insights with real-world evidence from a single-center study of 47 patients treated with combined deprescribing and anti-CGRP therapy. Clinically meaningful reductions in monthly migraine days were observed, with 85.1% achieving ≥50% reduction at 6 months and 78.7% achieving >75% reduction at 12 months. Our clinical experience also suggests that long-standing combination analgesic overuse may be associated with a slower treatment response. The present findings support a mechanism-based treatment approach and suggest that combining preventive therapy with deprescribing may optimize long-term outcomes in patients with migraine-associated MOH.

Circadian rhythms regulate key biological processes central to cancer biology, including cell cycle control, DNA repair, metabolism, immune function, and drug pharmacokinetics. Experimental models consistently demonstrate marked time-of-day differences in the efficacy and toxicity of chemotherapy, targeted agents, and immunotherapies. Clinical studies of chronomodulated chemotherapy—particularly with fluoropyrimidines, platinum compounds, and anthracyclines—show reproducible reductions in treatment-related toxicity, while effects on survival outcomes remain variable and often sex dependent. Emerging clinical evidence also suggests that timing of immune checkpoint inhibitor administration may influence progression-free and overall survival across several tumor types. However, translation into routine oncology practice has been limited by interindividual variability in circadian phase, tumor-specific disruption of clock function, lack of validated biomarkers, and logistical constraints of time-specific drug delivery. Advances in circadian phenotyping, wearable monitoring, and adaptive dosing technologies now offer feasible pathways toward individualized, biology-driven treatment timing. This narrative review critically evaluates mechanistic, preclinical, and clinical evidence for chronotherapy across oncological treatment modalities and examines challenges and opportunities for its integration into precision cancer care.

Introduction Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed the management of type 2 diabetes and obesity by improving glycemic control, promoting weight loss, and reducing cardiovascular risk. This study aimed to evaluate national trends in GLP-1 RA utilization and expenditure in Croatia between 2010 and 2024. Methods We conducted a nationwide, retrospective analysis using the International Medical Statistics and IQVIA pharmaceutical databases. Utilization was measured in defined daily doses per 1000 inhabitants per day, and financial expenditure was expressed in euros. Trends were contextualized within evolving clinical evidence, guideline recommendations, and healthcare reimbursement policies. Results Total noninsulin antidiabetic drug consumption more than doubled between 2010 and 2024, with the use of GLP-1 RAs rising from negligible at the time of market entry to that worth 15.99 defined daily doses per 1000 inhabitants per day in 2024, representing 16.1% of total prescriptions. Expenditure on GLP-1 RAs reached 42.07 million euros in 2024, accounting for 42.7% of total noninsulin antidiabetic spending. Semaglutide emerged as the dominant agent according to both utilization and cost, followed by dulaglutide and liraglutide. Obesity-specific indications were underutilized, largely due to lack of reimbursement. Conclusions GLP-1 RA prescribing has increased substantially in Croatia over the past decade, reflecting their growing therapeutic importance. However, economic constraints, restrictive reimbursement, and sociocultural barriers continue to limit access, particularly in obesity care. Our findings highlight the need to align reimbursement frameworks and clinical practice with emerging evidence to maximize the cardiometabolic and public health benefits of GLP-1 RAs.

Hematological malignancies remain one of the leading causes of morbidity and mortality despite advances in targeted therapies, immunotherapy, and stem cell transplantation. Emerging evidence indicates that treatment efficacy and toxicity depend not only on the choice of therapy but also on its timing relative to the patient's internal circadian rhythm. The circadian clock orchestrates fundamental processes in hematopoiesis and immunity, such as stem‐cell proliferation, leukocyte trafficking, DNA repair, and drug metabolism, while its disruption promotes malignant transformation, therapeutic resistance, and systemic toxicity. This narrative review synthesizes current understanding of circadian regulation in hematopoietic and immune systems, the mechanistic and preclinical foundations of chronotherapy in blood cancers, and the limited but growing body of clinical evidence linking treatment timing with outcome in leukemia, lymphoma, and transplantation. The review also examines practical challenges, including inter‐individual variability, disease‐induced circadian disruption, and hospital workflow constraints, while highlighting emerging technologies, such as transcriptomic clocks, wearable biosensors, and AI‐driven scheduling algorithms, that are poised to enable personalized, time‐aware therapy. By integrating temporal precision into existing therapeutic frameworks, chronotherapy may represent a promising investigational dimension of precision medicine in hematological oncology. However, its clinical value remains to be defined through prospective studies that incorporate validated circadian biomarkers, predefined timing windows, and clinically meaningful efficacy and toxicity endpoints.

Metabolic syndrome (MetS) is a complex and heterogeneous condition characterized by the coexistence of obesity, type 2 diabetes mellitus (T2DM), hypertension, chronic low-grade inflammation, and metabolic dysfunction. Increasing evidence suggests that the gut microbiota plays a central role in the development and progression of MetS by influencing host metabolism, intestinal barrier integrity, immune activation, endocrine signaling, and vascular homeostasis. This narrative review summarizes current evidence regarding gut microbiota alterations across major obesity-related metabolic phenotypes, including obesity alone, obesity complicated by T2DM, and obesity associated with hypertension. Obesity is generally characterized by reduced microbial diversity, depletion of beneficial taxa such as Faecalibacterium prausnitzii and Akkermansia muciniphila, impaired short-chain fatty acid (SCFA) signaling, increased intestinal permeability, and metabolic endotoxemia. The coexistence of T2DM is associated with a more pronounced depletion of butyrate-producing bacteria, altered bile acid metabolism, impaired incretin signaling, and enhanced inflammatory activation that may contribute to insulin resistance and hyperglycemia. In hypertensive obesity, gut dysbiosis appears to preferentially involve disturbances within the gut–vascular axis, including reduced SCFA-producing taxa, increased trimethylamine N-oxide production, endothelial dysfunction, oxidative stress, and vascular inflammation. Although microbial signatures partially overlap among metabolic phenotypes, functional alterations in microbial metabolites and host–microbiota interactions may better explain disease heterogeneity than isolated taxonomic changes. Current evidence supports the potential role of microbiota-targeted interventions and integrated multi-omics approaches in future precision medicine strategies for cardiometabolic disease prevention and management.

Chronic kidney disease is increasingly recognised as a systemic disorder with important neurological consequences, including cognitive impairment. However, the field remains challenging because CKD-related cognitive decline involves diverse uremic toxins, overlapping vascular, inflammatory, metabolic, endothelial, and neurodegenerative pathways, inconsistent cognitive screening practices, and no unified treatment strategy. Within this context, the kidney–brain axis provides a useful framework for integrating renal dysfunction, toxin retention, systemic inflammation, blood–brain barrier disruption, and cognitive vulnerability. Of these mechanisms, uremic neurotoxicity offers a biologically credible connection between compromised renal clearance and cerebral dysfunction. Retained solutes such as indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid, trimethylamine-N-oxide, urea, guanidino compounds, lanthionine, quinolinic acid, and homocysteine may induce endothelial injury, oxidative stress, neuroinflammation, mitochondrial dysfunction, excitotoxicity, and glial activation. Although these pathways are supported by experimental and translational studies, direct causal evidence in humans remains limited, and most clinical data should currently be interpreted as associative rather than definitive proof of causality. These processes converge on neuronal and synaptic vulnerability and may elucidate the distinctive cognitive profile associated with chronic kidney disease, particularly deficits in attention, processing speed, and executive function. This review summarizes the most recent evidence on the epidemiology and clinical phenotype of cognitive impairment in chronic kidney disease. It also discusses the molecular and cellular mechanisms of uremic neurotoxicity and examines new biomarkers of the kidney–brain axis, including neurofilament light chain, glial fibrillary acidic protein, brain-derived neurotrophic factor, tight junction proteins, and uremic toxins. However, these biomarkers remain insufficiently validated for routine clinical use, as their interpretation is complicated by reduced renal clearance, systemic inflammation, comorbid vascular disease, methodological heterogeneity, and the lack of longitudinal studies linking biomarker changes to cognitive outcomes. Therapeutic strategies targeting uremic toxins remain compelling from a mechanistic standpoint, but they are not yet fully developed in clinical practice. Subsequent research ought to amalgamate toxin profiling, cognitive phenotyping, neuroimaging, endothelial and inflammatory biomarkers, alongside patient-centered outcomes. Integrating cognitive assessment into nephrology care may enhance risk stratification, collaborative decision-making, and personalised management for patients with chronic kidney disease.

Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus and the leading cause of end‐stage renal disease. Oxidative stress and inflammation are central drivers of DN progression, yet no effective therapies exist to prevent or delay renal injury. This study investigated the renoprotective effects of glycine (GLY), N‐acetylcysteine (NAC), and their combination administered at early versus late stages of streptozotocin induced diabetes. Forty‐eight male Wistar rats (n = 48) were allocated into five groups: healthy controls (Group 1, n = 6), untreated diabetic rats (Group 2, n = 6), and three treatment groups (Groups 3–5, each n = 12). Diabetes was induced by a single intraperitoneal streptozotocin injection (55 mg/kg). Group 3 received NAC (100 mg/kg), Group 4 received GLY (250 mg/kg), and Group 5 received NAC + GLY. Each treatment group was subdivided into early (6 week, n = 6) and late (12 week, n = 6) intervention subgroups. Treatments were administered orally. Renal tissue was evaluated using classic histology, geometric morphometric analysis, and biochemical assays of superoxide dismutase (SOD) and myeloperoxidase (MPO). Statistical analyzes were performed using ANOVA with appropriate post hoc tests (p < 0.05). Untreated diabetic rats (Group 2) showed significantly decreased SOD activity, increased MPO levels, marked mesangial matrix expansion, glomerular hypercellularity, tubular epithelial degeneration, and interstitial inflammation with fibrosis. NAC (Group 3) and GLY (Group 4) each improved oxidative stress markers and partially restored glomerular and tubular morphology, with early treatment subgroups exhibiting more substantial benefit than late subgroups. The combined NAC + GLY therapy (Group 5) demonstrated the strongest renoprotective effect, preserving renal structure and biochemical parameters closest to healthy controls. To conclude, early combined administration of glycine and N‐acetylcysteine yields superior protection against diabetes‐induced renal injury compared with individual treatments. These findings support the therapeutic potential of antioxidant‐amino acid combinations in preventing or delaying diabetic nephropathy.

This translational synthesis highlights the potential role of obesity-induced low-grade chronic inflammation in modulating clinical outcomes among patients with spondyloarthritis (SpA). Obesity transforms adipose tissue into a pro-inflammatory endocrine organ, where hypertrophic adipocytes release adipokines such as leptin alongside cytokines including TNF-α and IL-6, potentially contributing to macrophage polarization toward an M1 phenotype and activating NF-κB signaling pathways. This systemic immunometabolic priming may lower activation thresholds at the enthesis—the primary pathological site in SpA—potentially amplifying IL-23/IL-17 axis activity via Th17 bias, innate-like lymphocyte responses, and stromal–immune crosstalk under mechanical stress. Clinically, patients with SpA and obesity have been reported to demonstrate heightened disease activity (BASDAI, ASDAS), impaired function (BASFI), accelerated radiographic progression (syndesmophytes, enthesophytes), and diminished biologic response rates, potentially attributable to pharmacokinetic alterations (e.g., subtherapeutic TNF inhibitor levels) and pharmacodynamic resistance. Multisystem comorbidities, including non-alcoholic fatty liver disease, cardiovascular events, metabolic syndrome, sleep disturbances, and depression, further exacerbate morbidity and diminish quality of life. Therapeutic implications emphasize obesity as a modifiable disease modifier. Weight loss interventions, including hypocaloric diets, anti-inflammatory regimens (e.g., Mediterranean diet), multicomponent exercise, GLP-1 receptor agonists, and bariatric surgery, have been associated with reductions in inflammatory biomarkers, improved remission rates (MDA, DAPSA), and prolonged drug survival by restoring adipokine balance and disrupting mechano-inflammatory loops. Future randomized controlled trials should prioritize long-term evaluations of integrated multidisciplinary strategies that combine metabolic optimization with immunomodulatory therapies, addressing adherence challenges through psychological support and patient-tailored protocols, while elucidating dose–response relationships for GLP-1RAs and exercise in diverse SpA subtypes to establish precision management paradigms that mitigate cardiometabolic burden and improve holistic outcomes.

Spinal muscular atrophy (SMA) therapies that restore SMN expression improve survival and motor function but often fail to fully stabilize distal motor units or sustain endurance. We propose a hypothesis-driven adjunctive approach, intended to complement SMN-restoring therapies, in which localized nanotube-enabled interfaces acting at or near the distal motor unit and neuromuscular junction enhance neuromuscular transmission reliability in surviving, remodeled motor units. The model predicts a temporal cascade: improved junctional reliability and reduced activity-dependent failure, followed by consistent motor unit output across repeated activation, and ultimately, enhanced endurance and functional reserve. Phenotype-specific responsiveness identifies patients most likely to benefit, specifically those with preserved-but-limited residual motor unit substrate accompanied by measurable neuromuscular junction instability. Drawing on shared mechanisms from ALS, spinal cord injury, and other neuromuscular disorders, we discuss mechanistic, translational, safety, regulatory, and ethical considerations. This framework links objective physiological constructs to functional outcomes, offering a mechanistically grounded path for adjunctive therapy development in SMA and related conditions.

Chronic inflammatory diseases and autoimmune diseases are overlapping but distinct immune-mediated disorders that represent a growing worldwide health concern, characterised by persistent inflammation, tissue damage, and progressive organ dysfunction. In the United States alone, more than $180 billion is spent annually on managing these conditions, yet fewer than 10% of patients achieve long-term remission. These figures highlight the limitations of conventional therapies, which often control symptoms rather than adequately modify the underlying disease process. This review provides a focused and comparative overview of emerging therapeutic strategies across representative immune-mediated disorders, with particular emphasis on mesenchymal stem cells, Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors, chimeric antigen receptor T-cell therapies, therapeutic vaccines, microbiome-modulating interventions, and nanotechnology-based drug delivery systems. In parallel, artificial intelligence (AI) is increasingly contributing to biomarker discovery, drug repurposing, and treatment stratification, thereby supporting the development of predictive and personalised medicine. Overall, these advances support a shift toward mechanism-based, multimodal, and more durable treatment strategies, although further clinical validation remains necessary.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by debilitating pain and progressive joint destruction. Tumor necrosis factor-alpha (TNF-α), a key pro-inflammatory cytokine, has been implicated in modulating both peripheral and central pain pathways. TNF-α inhibitors, initially developed to halt structural damage in RA, have demonstrated substantial efficacy in pain relief, independent of their anti-inflammatory properties. This narrative review explores the mechanistic pathways through which TNF-α contributes to pain sensitization and highlights the role of TNF-α inhibitors in disrupting these pathways. Evidence suggests that these biologics not only reduce synovial inflammation but also modulate neuroinflammatory circuits, altering pain perception at the spinal and supraspinal levels. Despite their clinical success, variability in patient response and concerns regarding long-term safety necessitate further research into personalized therapeutic strategies. Identifying biomarkers predictive of pain relief could enhance treatment precision. Ultimately, the integration of TNF-α inhibitors into multidisciplinary pain management approaches holds promise for improving clinical outcomes and quality of life in RA.

Obesity and hypertension are interrelated global health challenges sharing common pathophysiological mechanisms, including insulin resistance, chronic inflammation and neurohormonal dysregulation. Emerging evidence highlights the gut microbiome as a crucial mediator in this interplay, influencing intestinal barrier integrity, systemic inflammation and metabolic homeostasis.