Search Results (32,968)

Background/Objectives: Low back pain (LBP) is a leading cause of disability worldwide, and exercise-based rehabilitation is recognized as an effective management strategy. However, adherence to exercise remains challenging. Fully immersive virtual reality (VR) exercise interventions may enhance engagement and clinical outcomes. This study aimed to examine the effect of a fully immersive VR exercise game on pain, fear-avoidance beliefs, and disability in individuals with chronic non-specific LBP. Methods: A single-blinded randomized controlled trial was conducted, involving 28 participants aged 18–60 years with chronic non-specific LBP. Participants were randomly allocated to either a VR exercise group with standard education (n = 14) or a conventional home exercise group with standard education (n = 14). Both groups performed their assigned intervention once per day for two weeks. Outcomes included the Fear-Avoidance Beliefs Questionnaire (FABQ), Numeric Pain Rating Scale (NPRS), Oswestry Disability Index (ODI), Back Beliefs Questionnaire (BBQ), and functional performance tests (six-minute walk test, repeated sit-to-stand, and trunk flexion). Measures were assessed at baseline and after a 2-week intervention period. Exercise adherence was recorded using a self-reported log. Results: No significant within- or between-group differences were observed for FABQ scores. However, a significant between-group difference was reported for pain reduction in the VR group (p = 0.044). No significant differences were reported for disability or belief-related outcomes, or for physical performance outcomes, including the 6 min walk test, repeated sit-to-stand test, and trunk flexion test. Conclusions: A fully immersive VR exercise intervention resulted in greater short-term pain reduction compared to conventional exercise in individuals with chronic non-specific LBP. However, it had little impact on fear-avoidance beliefs or disability, highlighting the need for multimodal approaches that address broader biopsychosocial factors. Full article

Background: In patients with atrial fibrillation receiving long-term anticoagulation therapy with dabigatran etexilate (DABE), moxifloxacin (MFLX) is frequently coadministered to treat concurrent infections; however, the potential drug–drug interaction (DDI) between these agents remains unclear. Herein, we examined the underlying mechanism by which MFLX attenuates DABE pharmacokinetics in rats; subsequently, we elucidated the DDI in humans by establishing a physiologically based pharmacokinetic (PBPK) model based on these animal data. Methods: The 3- and 14-day effects of 40 mg/kg MFLX once daily and secondary bile acid (SBA)-containing dietary intervention on the pharmacokinetic profile of DABE and its active form, dabigatran (DAB), were examined in a rat model. Ileum tissues were harvested to measure the expression of P-glycoprotein (P-gp), pregnane X receptor (PXR), and peroxisome proliferator-activated receptor alpha (PPARα). In addition, we examined the effects of secondary bile acids (SBAs) on P-gp expression and quantified P-gp-mediated DABE efflux transport activity in Caco-2 cells. A PBPK model was used to predict the risk of DAB exposure under this DDI scenario and under combined high-risk conditions, including renal impairment and advanced age. Results: Treatment with MFLX for 3 and 14 days inhibited SBA-producing gut microbiota, thereby suppressing the conversion of primary bile acids to SBAs. Concurrently, a marked reduction in intestinal P-gp expression was observed, along with a significant enhancement of the oral bioavailability of DABE. These effects were reversed by SBA-containing diets. In vitro experiments using Caco-2 cells revealed that physiologically relevant concentrations of SBA significantly upregulated P-gp expression and function, whereas MFLX incubation alone showed no direct modulatory effect on these transporters or regulators. PBPK simulation results showed that in vivo exposure of DAB would increase by 41.7%, 104%, 251%, and 115% when coadministered with MFLX alone, with coexisting mild renal impairment, moderate renal impairment, and aging, respectively. Conclusions: MFLX increases DAB exposure by reducing SBA-regulated intestinal P-gp function. PBPK simulations suggest a low risk of DDI from MFLX coadministration alone; however, caution is warranted in patients with aging or renal impairment. Full article

Background/Objectives: Colonoscopy is the standard examination for many symptomatic patients referred for lower-gastrointestinal investigation, but it is resource-intensive and may be a burdensome experience. Colon capsule endoscopy (CCE) offers a minimally invasive, sedation-free first-line examination, although clinically important findings, inadequate cleansing or incomplete transit can generate downstream colonoscopy. DanCap aims to compare the costs and clinical consequences of a CCE-first pathway with routine conventional colonoscopy (CC). Methods: DanCap is a single-centre, cluster-allocated crossover trial at Odense University Hospital, Denmark. General practice clinics follow CCE or CC according to the parity of their pre-existing provider number, with pathways crossing after 200 consecutive CCE participants; no trial-generated random allocation sequence is used. Eight hundred symptomatic adults aged >18 years referred for expedited lower-gastrointestinal investigation are planned. CCE participants with suspected cancer, any polyp ≥6 mm, inadequate cleansing or an incomplete examination are referred for colonoscopy. The primary outcome is pathway cost. Registered secondary outcomes and prespecified process measures include polyp and colorectalcancer detection, examination quality, reinvestigation and patient-reported consequences. FIT and microbiome are registered secondary outcomes; participation in the substudy is optional and the analyses are exploratory within the CCEpathway. Primary analyses will follow the assigned pathway and account for GP clinic clustering, period and allocation sequence. Expected Results: The trial will quantify the resource use and clinical consequences of implementing CCE in routine symptomatic practice. Conclusions: DanCap is intended to inform decisions about CCE pathway implementation rather than to establish unbiased whole-cohort test sensitivity or specificity. Trial registration: ClinicalTrials.gov NCT06475560; first submitted 20 June 2024 and first posted 26 June 2024. Recruitment began on 27 November 2024; the registry listed the study as recruiting when last updated on 19 March 2026. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are transforming obesity management, yet landmark trials often incompletely measure and report a central mediator of response: dietary intake. Because GLP-1RAs promote weight loss primarily by suppressing appetite and reducing energy consumption, capturing changes in dietary intake is essential to interpreting efficacy, safety, and translation into clinical care. This perspective argues that failure to measure and report comprehensive dietary intake raises concerns under four core bioethical principles. It undermines autonomy by limiting evidence for shared decision-making across the treatment continuum. It challenges non-maleficence because inadequate energy, protein, and micronutrient intake may contribute to lean mass loss and nutrient deficiencies, particularly in vulnerable populations. It weakens beneficence because failing to report a measurable mediator diminishes the scientific value of research requiring substantial investment and participant burden. It raises justice concerns because the equitable distribution of assessment burden and access to resulting nutritional care cannot be evaluated without transparent reporting. To meet the ethical and scientific obligations of clinical research, future trials should preregister dietary intake as a key secondary or safety endpoint. Investigators should report total energy, macronutrient, and micronutrient distribution at baseline and serial follow-up alongside dietary assessment methods, food composition databases, and assessor training. Journal editors, funders, and regulatory bodies should support development of consensus-based, nutrition-specific reporting recommendations aligned with CONSORT principles and encourage preregistration of dietary trial endpoints. Registered dietitian nutritionists should be prospectively integrated into GLP-1RA trial teams from design through data interpretation. Advancing the standard of obesity care requires that the research community look beyond the scale and ground clinical translation in the nutritional context in which pharmacotherapy operates. Full article

Differentiated thyroid carcinoma is a morphologic diagnosis, not a direct measure of preserved thyroid function. Although most papillary, follicular, and oncocytic thyroid carcinomas retain architectural or cytologic features of follicular-cell derivation, a clinically important subset loses the molecular machinery required for effective iodine transport, organification, and radioiodine therapy. This functional divergence is central to the biology of radioiodine-indifferent and radioiodine-refractory thyroid cancer. This review examines the role of oncogenic MAPK/ERK signaling as a principal regulator of thyroid lineage suppression and therapeutic failure. Aberrant activation of the RAF–MEK–ERK axis, most prominently through BRAF^V600E, RAS alterations, and receptor tyrosine kinase fusions, does more than promote proliferation. It reshapes follicular-cell identity by repressing thyroid-lineage transcriptional programs and silencing iodine-handling genes, including SLC5A5/NIS, TPO, TG, TSHR, SLC26A4, and related components of the iodine metabolic transcriptome. This repression is mediated through coordinated transcriptional, epigenetic, and post-transcriptional mechanisms involving lineage transcription factors such as PAX8, NKX2-1, and FOXE1; chromatin-modifying programs including histone deacetylation and PRC2/EZH2-associated repression; DNA methylation; and non-coding RNA networks. Importantly, ERK-driven functional dedifferentiation is not always a fixed terminal state. Preclinical models and early clinical trials demonstrate that pharmacologic inhibition of the MAPK pathway can restore iodine avidity in selected radioiodine-refractory tumors, creating the theranostic basis for redifferentiation therapy. Iodine-124 PET/CT and lesion-level dosimetry have shown that restored iodine uptake can be measured diagnostically and then exploited therapeutically with iodine-131. However, clinical translation remains limited by inter- and intratumoral heterogeneity, incomplete durability of response, adaptive pathway reactivation, persistent epigenetic repression, tumor microenvironmental influences, and the absence of standardized dosimetric thresholds. We propose that advanced follicular-cell-derived thyroid cancers should be understood along a functional differentiation continuum rather than through morphology alone. Within this framework, radioiodine refractoriness reflects not merely treatment failure, but a therapeutically interrogable state of lineage suppression. Refinement of redifferentiation therapy will require genotype-informed patient selection, functional imaging, standardized dosimetry, rational combination strategies, and prospective trials capable of distinguishing true restoration of radioiodine therapeutic efficacy from the antiproliferative effects of kinase inhibition alone. Full article

The liver is an immunologically distinctive organ. Portal blood continuously delivers gut-derived antigens and microbial products, requiring hepatic immunity to balance surveillance with restraint. In hepatocellular carcinoma (HCC), this physiology is commonly overlaid by chronic injury, inflammation, and fibrosis, so the background liver forms part of the disease context in which the tumor microenvironment (TME) develops. This review synthesizes how cellular architecture, tumor-intrinsic programs, and structural, metabolic, and microbial conditions interact to shape immune evasion and heterogeneity. HCC provides the principal evidence base, with intrahepatic cholangiocarcinoma (iCCA) used as a structured, biologically distinct comparator. We organize therapies by the microenvironmental barriers they are intended to modify and distinguish established clinical efficacy from evidence that the proposed mechanisms mediate treatment benefit. Single-cell and spatial studies have resolved cellular states and spatial arrangements, including onco-fetal endothelial–myeloid neighborhoods and a macrophage–fibroblast boundary band separating lymphocyte-rich stroma from malignant tissue. These patterns operate within fibrotic and metabolically altered tissue and vary by etiology, spatial context, and tumor type. Vascular endothelial growth factor blockade with immune checkpoint inhibition and dual checkpoint blockade are established first-line options in advanced HCC. Chemo-immunotherapy is established in biliary tract cancer, and IDH1 inhibition has established efficacy in IDH1-mutant cholangiocarcinoma. Myeloid- and stroma-directed strategies, natural-product approaches, and engineered-cell therapies remain preclinical or early clinical. None of the pivotal trials tested whether the proposed microenvironmental mechanism mediated treatment benefit. The liver TME informs treatment selection without yet determining it. Full article

Static pedobarometry is widely used to assess plantar pressure distribution and postural control; however, its clinical interpretation depends on measurement repeatability and reliability. The aim of our article is to evaluate the repeatability of plantar pressure parameters and the spatial localization of the center of pressure (CoP) and peak pressure (PP) during static bipedal standing. Five healthy adults underwent 30 repeated static measurements using the Sidas Press-Cam platform under standardized laboratory conditions. Analyzed parameters included contact area, mean pressure, peak pressure, and the center of pressure coordinates. Repeatability was assessed using intraclass correlation coefficients (ICC), standard error of measurement (SEM), and Bland–Altman analysis. Contact area showed high single-measure repeatability (ICC (2, 1) = 0.90). Peak pressure and mean pressure demonstrated moderate repeatability for single trials but excellent repeatability when averaged (ICC (2, k) = 0.97–0.996). The center of pressure exhibited greater mediolateral than anteroposterior variability. Peak pressure localization remained stable within 3 SD and predominantly on the dominant limb. Averaging multiple trials enhances measurement repeatability, suggesting that repeated static pedobarometric assessments may provide more consistent estimates of plantar pressure parameters. However, these findings should be interpreted as preliminary evidence from an intra-session repeatability study due to the limited sample size. Full article

Ischemic heart disease is currently diagnosed mainly through cardiac computed tomography (CT) angiography and functional testing, both of which detect only advanced arterial macrocalcification, at a stage when treatment can merely slow disease progression rather than reverse it. Yet, macrocalcification represents the end product of a much earlier molecular process, which is microcalcification. This process is driven by smooth muscle cell and macrophage apoptosis, matrix vesicle release, and osteogenic phenotypic transitions within the arterial intima, occurring years to decades before mineral deposits become visible on CT. [¹⁸F]Sodium fluoride (NaF) positron emission tomography (PET) exploits fluoride binding at accessible hydroxyapatite surfaces to detect increased tracer uptake associated with active mineral deposition, including mineralization occurring at a microscopic scale below the direct spatial resolution of clinical PET. Studies demonstrate that anti-atherosclerotic interventions, including statins, and tissue-nonspecific alkaline phosphatase inhibition can suppress NaF uptake even when CT-based calcium scores remain unchanged or continue to rise, a dissociation now also observed in human trials of statins and PCSK9 inhibitors. This review traces the cellular and histological basis of arterial calcification, outlines the principles and limitations of NaF-PET imaging, and evaluates its emerging role—supported by artificial intelligence-based quantification—as a tool for monitoring targeted anti-atherosclerotic treatment. Full article

Background: Hantavirus pulmonary syndrome (HPS), also designated hantavirus cardiopulmonary syndrome, is caused by New World hantaviruses, principally Sin Nombre virus in North America and Andes virus in South America. The syndrome is characterized by rapidly progressive noncardiogenic pulmonary edema and myocardial depression, with case fatality rates of 25% to 40%. A 2026 outbreak aboard an expedition cruise ship in the South Atlantic, comprising 13 cases and three deaths, confirmed that Andes virus can be transmitted between humans in a confined setting remote from the rodent reservoir. Methods: Virological, pathophysiological, clinical, and therapeutic aspects of HPS were reviewed, with particular emphasis on cardiopulmonary mechanisms. Sources were identified through PubMed, Scopus, and Google Scholar, with priority given to original research articles, clinical series, and controlled trials published through 2025. Literature published in English and Spanish was included. Results: Pathogenic hantaviruses enter endothelial cells and platelets via αvβ3 integrins, disrupting the VEGF-VEGFR2 signaling axis and rendering endothelial cells hypersensitive to physiological VEGF concentrations. Expansion of CD8+ T cells and activated macrophages releases TNF-alpha, IFN-gamma, and nitric oxide, amplifying microvascular permeability and contributing to myocardial depression. Autopsy studies demonstrate direct hantaviral myocarditis with viral antigen in cardiac endothelium and interstitial macrophages. Transpulmonary thermodilution confirms simultaneous hypovolemia, reduced global ejection fraction, and elevated extravascular lung water. Because the incubation period is long and the cardiopulmonary phase is substantially immune-mediated, seroconversion precedes rather than follows clinical deterioration, which preserves the diagnostic utility of IgM serology in a disease that can kill within 48 h. VA-ECMO initiated at the first signs of cardiopulmonary decompensation has reported survival rates approaching 80% in selected experienced centers. No antiviral has demonstrated efficacy in controlled trials during the cardiopulmonary phase, and no licensed vaccine exists. Conclusions: HPS produces a mixed shock state through increased microvascular permeability, T cell-mediated immunopathology, and direct myocarditis. Management follows a stepwise algorithm: suspected HPS triggers immediate complete blood count with peripheral blood smear and concurrent hantavirus IgM serology and RT-PCR, followed by ICU admission, conservative fluid resuscitation guided by transpulmonary thermodilution, and early contact with an ECMO-capable center at the first sign of rising lactate, falling cardiac index, refractory shock, arrhythmia, or rapid oxygenation failure. Full article

Depression is defined by clinical symptoms, but its biology varies considerably among patients. In this review, dietary tryptophan allocation describes the routes taken by tryptophan after intestinal absorption. Some is incorporated into proteins. Some enters serotonin and melatonin synthesis or the kynurenine pathway, while gut bacteria convert another fraction into indole compounds. Brain availability also depends on the circulating free pool and competition with other large neutral amino acids. This term does not imply a new biochemical pathway. It allows these known processes to be considered in relation to inflammation, metabolism, the gut microbiota, medication use, and current disease state. Recent meta-analyses indicate that peripheral tryptophan is lower in depression. They do not show a consistent increase in the kynurenine-to-tryptophan ratio, and findings from cerebrospinal fluid vary between studies. Human multiomics studies have associated microbial and metabolite profiles with cognition and response to treatment, although the evidence remains largely correlational. Changes in kynurenine, 3-hydroxykynurenine, and quinolinic acid are more apparent in inflammatory subgroups than in unselected samples. Modern evidence for L-tryptophan monotherapy is sparse. Trials of 5-hydroxytryptophan and interventions directed at the gut microbiota have also produced mixed results. Studies should characterize participants and sampling conditions more carefully. Diet and competition among amino acids need to be recorded. Albumin concentration, medication exposure, and disease state also affect interpretation. Considering these variables together may improve biomarker analyses and support trials in more biologically homogeneous groups. Dietary tryptophan allocation is proposed for these research purposes, not for clinical diagnosis or routine supplementation. Full article

Background/Objectives: Brain-derived neurotrophic factor (BDNF) and antioxidant networks mediated by Selenoprotein P (SEPP1) are core drivers of structural neuroplasticity and blood–brain barrier integrity, yet their co-regulatory behavior during subacute stroke neurorehabilitation remains poorly understood. This pilot study quantified concurrent changes in serum BDNF and SEPP1 during rehabilitation. Methods: Sixteen subacute post-stroke patients with mild stroke severity were assigned to an intensive multi-modal neurorehabilitation protocol incorporating high-intensity interval training (Treated, n = 7) or standard care (Control, n = 9); the biomarker sampling window averaged 73.4 days. Fasting venous blood was collected at baseline and post-intervention and analyzed by ELISA. Results: BDNF changes (ΔBDNF) differed significantly between arms (U = 57.0, p = 0.0081): the Treated cohort showed a uniform decrease (mean Δ: −0.240 ± 0.103 ng/mL), while Controls showed stabilization or a slight increase (mean Δ: +0.118 ± 0.339 ng/mL). ΔBDNF and ΔSEPP1 were significantly, positively correlated across the cohort (ρ = 0.596, p = 0.015). Conclusions: The BDNF decline in the Treated group is consistent with the “central sink” hypothesis, but may more plausibly reflect stress/cortisol-mediated suppression induced by the high training intensity, contrasting with increases typically reported after moderate-intensity subacute-phase exercise. The collinear coupling with SEPP1 suggests a link between neurotrophic synthesis and antioxidant buffering during post-stroke tissue remodeling, though this correlational finding does not by itself establish a single, coordinated mechanism. Full article

Stroke remains one of the leading causes of death and long-term neurological disability worldwide, while currently available therapeutic strategies are limited by narrow treatment windows and incomplete neuroprotection. In this context, plant-derived polyphenols have attracted increasing attention as potential adjunctive agents because of their multimodal biological activity. This review focuses on resveratrol and curcumin, two of the most extensively investigated polyphenols, and evaluates their potential role in the prevention and treatment of ischaemic and haemorrhagic stroke. Evidence from in vitro studies, animal models, and early clinical trials indicates that both compounds may attenuate key mechanisms involved in stroke-related brain injury, including oxidative stress, neuroinflammation, mitochondrial dysfunction, apoptosis, autophagy dysregulation, blood–brain barrier disruption, and microglial activation. Emerging evidence further suggests that interactions with the gut microbiota and modulation of the gut–brain axis may contribute to their biological effects by influencing intestinal barrier integrity, microbial metabolite production, systemic inflammation, and vascular risk. Preclinical studies show that resveratrol and curcumin can reduce infarct volume, limit cerebral oedema, preserve neuronal viability, promote angiogenesis and neurogenesis, and improve neurological and cognitive outcomes. Their beneficial effects have been reported both when administered before stroke onset and after cerebral injury, suggesting potential relevance for both prevention and post-stroke therapy. However, interpretation of these findings requires consideration of the translational limitations of experimental stroke models, which do not fully reproduce the heterogeneity, comorbidities, age profile, and variable reperfusion patterns characteristic of human stroke. Although commonly used models such as middle cerebral artery occlusion provide important mechanistic and therapeutic insights, preclinical efficacy should therefore not be regarded as a direct predictor of clinical benefit. Resveratrol and curcumin may also complement established and emerging treatment strategies, including thrombolysis, endovascular interventions, antihypertensive therapy, and stem cell-based approaches. Nevertheless, their clinical translation remains limited by poor solubility, low bioavailability, rapid metabolism, and insufficient clinical evidence. Novel formulations, including nanoparticles, exosome-based delivery systems, and structurally modified analogues, may help overcome these barriers by improving brain targeting and therapeutic efficacy. Overall, resveratrol and curcumin represent promising but still investigational candidates for adjunctive stroke therapy, requiring further well-designed clinical trials to define their optimal dosing, timing, safety, and clinical value. Full article

Background: Hypertensive disorders of pregnancy (HDP), particularly gestational hypertension and preeclampsia, are major causes of maternal and perinatal morbidity. Metabolic disorders such as gestational diabetes mellitus (GDM), type 2 diabetes mellitus (T2DM), obesity, and polycystic ovary syndrome (PCOS) share mechanisms with HDP, including insulin resistance, inflammation, oxidative stress, endothelial dysfunction, and placental maladaptation. Metformin may influence these pathways, but its clinical effect on hypertensive outcomes remains uncertain. Methods: A focused narrative review was conducted using structured, targeted searches of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar for literature published primarily from January 2015 through March 2026, supplemented by landmark studies, clinical guidelines, randomized trials, large observational cohorts, systematic reviews, meta-analyses, and mechanistic and placental studies. Evidence was selected for its relevance to the predefined phenotype-based framework and synthesized qualitatively across mechanistic, clinical, and translational domains. Results: Metformin improves insulin sensitivity and may reduce gestational weight gain, metabolic stress, inflammatory signaling, and oxidative stress. Some randomized trials and meta-analyses in GDM, obesity, and PCOS suggest lower rates of pregnancy-induced hypertension or preeclampsia, whereas recent randomized and population-based studies report neutral effects. Findings are limited by heterogeneous populations, late treatment initiation, variable comparators, supplemental insulin use, inconsistent HDP definitions, and insufficient statistical power. Conclusions: Metformin may act as a metabolic and vascular modifier in selected pregnancies, but current evidence does not support its routine use specifically for HDP prevention. Its public health value lies primarily in accessible metabolic treatment and integration into comprehensive antenatal and postpartum risk reduction pathways, rather than replacement of aspirin, blood pressure surveillance, or maternal–fetal monitoring. Full article

Pelvic floor dysfunctions are highly prevalent and can substantially impair quality of life. Physiotherapy is considered a first-line conservative treatment, and the integration of technologies such as ultrasound may enhance outcomes through visual biofeedback. Objectives: To evaluate the effectiveness of ultrasound as a biofeedback tool in physiotherapeutic interventions for pelvic floor dysfunctions across different populations. Methods: A systematic review was conducted following PRISMA guidelines and registered in PROSPERO (CRD420261278982). The literature search was conducted between February and March 2025 in PubMed, Web of Science, Scopus, Medline, and PEDro. Randomized controlled trials using ultrasound as biofeedback in physiotherapy interventions were included. Methodological quality was assessed using the PEDro scale, and risk of bias was evaluated with the RoB 2 tool. Results: Two randomized controlled trials involving 75 women were included. One study investigated older women with urinary incontinence, whereas the other included postpartum women with pregnancy-related pelvic girdle pain. In Galea et al., transabdominal ultrasound biofeedback was not superior to conventional feedback based on vaginal palpation for urinary leakage, incontinence frequency, or quality of life, although the ultrasound group showed a significant within-group reduction in leakage episodes. In Kuo et al., ultrasound-guided biofeedback combined with pelvic floor and stabilization exercises reduced pain and disability compared with education alone and improved walking performance, but it was not consistently superior to exercise without biofeedback and did not significantly improve pelvic floor muscle contractility. The small number of studies, heterogeneity of populations and interventions, and low to very low certainty of the evidence limited the strength of the findings. Conclusions: Ultrasound-based biofeedback may be a useful adjunct to pelvic floor physiotherapy, particularly for facilitating correct muscle contraction and supporting motor learning. However, the available evidence does not demonstrate a consistent additional clinical benefit over conventional feedback or exercise alone. These findings should therefore be interpreted cautiously. Further high-quality randomized controlled trials with larger samples, standardized protocols, and longer follow-up are required. Full article

Background: Population aging is driving a convergent rise in three disorders historically managed in isolation: cardiovascular disease, neurocognitive decline, and osteoporotic bone loss. Mechanistic data indicate that these systems are coupled through shared regulators of calcium trafficking, inflammation resolution, vascular integrity, and inflammaging. On this basis, a “Heart–Brain–Bone” axis has been proposed; it should be understood as an integrative conceptual framework that organizes evidence drawn from three separate studies, not as a validated physiological entity with agreed diagnostic criteria or demonstrated modifiability. Three lipid-soluble nutrients—long-chain omega-3 polyunsaturated fatty acids (EPA/DHA), vitamin D3 (cholecalciferol), and vitamin K2 (menaquinone-7 [MK-7])—act on overlapping nodes of this network. Methods: We performed a structured narrative review. PubMed/MEDLINE, Embase, the Cochrane Library, and Web of Science were searched from database inception to 25 June 2026 using predefined term blocks for each nutrient, each organ domain, and each candidate mechanism, and the search was updated on 7 August 2026. Records were screened against prespecified inclusion and exclusion criteria by two authors independently, with disagreements resolved by a third. The strength of evidence for each nutrient–organ relationship was graded with an explicitly defined four-level scheme ((−) to (+++)) applied separately to preclinical, observational, randomized and meta-analytic evidence. Results: Vitamin K2-dependent gamma-carboxylation of matrix Gla protein (MGP) and osteocalcin has been proposed to influence whether calcium is incorporated into the bone matrix or deposited in the arterial wall, offering a candidate mechanistic account of the “calcium paradox” associated with isolated vitamin D3 supplementation; EPA/DHA-derived specialized pro-resolving mediators may support resolution of endothelial and neuronal inflammation; and bone-, vascular- and brain-derived signals (osteocalcin, FGF23, the neurovascular unit) interconnect the three organs. These mechanisms are biologically plausible but remain insufficiently confirmed in humans. The clinical evidence is heterogeneous, formulation- and population-dependent, and comprises positive, neutral and null results: cardiovascular omega-3 trials are discordant (REDUCE-IT, which used icosapent ethyl [an EPA ethyl ester], positive; VITAL/STRENGTH/ASCEND null, predominantly in lower-risk or replete cohorts); cognitive trials are largely null or subgroup-dependent (MAPT, DO-HEALTH, VITAL); and MK-7 improves surrogate bone and calcification biomarkers and slowed coronary artery calcification in one recent randomized imaging trial (VitaK-CAC), whereas combined MK-7 plus vitamin D3 did not slow aortic valve or coronary calcification in AVADEC and MK-7 did not reduce bone loss in early menopausal women. Recognized safety signals include a dose-dependent increase in atrial fibrillation with high-dose omega-3, adverse skeletal effects of high-dose or bolus vitamin D, and clinically relevant interference of even low-dose MK-7 with vitamin K antagonist therapy. Conclusions: No adequately powered randomized trial has demonstrated that the combination of long-chain omega-3, vitamin D3 and MK-7 is superior to its individual components or to placebo for any clinical endpoint. The combined regimen is therefore mechanistically rational and hypothesis-generating rather than clinically established; benefit appears most plausible in individuals with elevated risk or demonstrable nutritional insufficiency, and least in replete, low-risk populations. Findings should be interpreted within a broader healthy-aging context that includes lifestyle and psychosocial factors. Adequately powered factorial randomized controlled trials stratified by baseline Omega-3 index, 25(OH)D and vitamin K status, with prespecified mechanistic biomarkers and hard endpoints, are required. Full article