Search Results (71)

Background/Objectives: Busulfan is a cornerstone conditioning agent for pediatric hematopoietic stem cell transplantation (HSCT), yet its narrow therapeutic index and substantial pharmacokinetic (PK) variability complicate dosing. This review synthesizes current evidence on pediatric busulfan PK, exposure-guided dosing, and the transition from conventional therapeutic drug monitoring (TDM) to model-informed precision dosing (MIPD). Methods: We conducted a focused narrative search of PubMed, Web of Science, and ScienceDirect from database inception to August 2026 and synthesized relevant literature on pediatric busulfan PK, exposure–response relationships, TDM, population PK modeling, Bayesian methods, and emerging quantitative approaches. Results: Body size is the primary determinant of busulfan clearance in children, while maturation, underlying disease, concomitant medications, and pharmacogenetic variation may contribute additional variability, although their effects are inconsistent across populations. Busulfan exposure is associated with HSCT outcomes and toxicity; however, reported targets differ by dosing regimen, conditioning intensity, disease category, and exposure metric. Reliable exposure estimation requires accurate sampling records and validated bioanalysis, while limited sampling strategies may improve clinical feasibility. Integrating population PK models with Bayesian estimation enables individualized dose adjustment, although routine implementation requires external validation and compatibility with local workflows. Emerging approaches, including physiologically based PK, PK/PD, and machine learning models, show promise but lack sufficient clinical validation for routine use. Conclusions: TDM remains the foundation of pediatric busulfan precision dosing, while MIPD provides a framework for integrating patient characteristics, measured concentrations, and validated models. Standardized workflows, population-appropriate exposure targets, prospective validation, and evidence of improved clinical outcomes are essential for broader implementation. Full article

Background/Objectives: Microplastics (MPs) and nanoplastics (NPs) have emerged as ubiquitous environmental contaminants resulting from the extensive production, use, and degradation of plastic materials. Human exposure occurs primarily through contaminated food and drinking water, with inhalation representing an additional important route. Growing concern has focused on the ability of these particles, particularly NPs, to cross biological barriers, enter the systemic circulation, and reach human tissues. The aim of this review was to summarize current evidence on dietary exposure to MPs and NPs, their gastrointestinal bioavailability and toxicokinetics, and their potential systemic health effects, with particular emphasis on organ-specific responses, underlying biological mechanisms, and the strength and limitations of the available evidence. Methods: A comprehensive narrative review of the scientific literature published between 2000 and 2026 was conducted using PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar. Original research articles and review papers addressing dietary exposure, occurrence in food and drinking water, migration from food-contact materials, gastrointestinal absorption, translocation, biodistribution, bioaccumulation, elimination, molecular mechanisms, and potential organ-specific or systemic health effects were included. Publications without full-text availability, conference proceedings, editorials, commentaries, duplicate publications, and studies without relevance to human exposure or health were excluded. Results: Food, drinking water, beverages, and food-contact materials represent important sources of human exposure to MPs and NPs. Following ingestion, most larger particles are eliminated through the gastrointestinal tract, whereas smaller MPs and particularly NPs may cross biological barriers and potentially reach the systemic circulation and distant tissues. Experimental studies consistently identify interconnected biological responses involving oxidative stress, inflammation, mitochondrial dysfunction, barrier impairment, immune dysregulation, genotoxicity, apoptosis, and endocrine disruption. These mechanisms have been associated with alterations in the gastrointestinal, respiratory, cardiovascular, nervous, urinary, reproductive, endocrine, and skeletal systems and with biological processes relevant to carcinogenesis. However, most mechanistic evidence derives from in vitro and animal models, whereas human evidence remains limited and predominantly observational. Consequently, the extent to which these experimental findings translate into clinically significant effects in humans remains uncertain. Conclusions: Current evidence supports the biological plausibility of systemic effects associated with MNP exposure but is insufficient to establish causal relationships between chronic dietary exposure and specific human diseases. The detection of MNPs in human tissues and reported associations with pathological conditions should therefore be interpreted cautiously. Standardized analytical methods, improved characterization of realistic human exposure, and well-designed longitudinal epidemiological studies integrating quantitative exposure assessment with validated clinical outcomes are required to clarify dose–response relationships, long-term health effects, and the clinical significance of MNP exposure. Full article

Background: Substantial inter-individual variability in imatinib systemic exposure may influence both efficacy and toxicity. Based on recommendations of the International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), the IRCCS-CRO of Aviano started in 2018 offering physicians the opportunity to monitor plasma concentrations of imatinib and its active metabolite, norimatinib, as part of a diagnostic service for patients with Gastrointestinal Stromal Tumor (GIST). This study aims to evaluate the potential clinical utility of imatinib Therapeutic Drug Monitoring (TDM) in predicting response and toxicity in a real-world cohort of 63 patients with GIST. Methods: Imatinib and its active metabolite norimatinib trough concentrations (C_min) were quantified using a validated LC–MS/MS method. Associations between drug exposure and clinical–demographic characteristics, treatment-related toxicity, and progression-free survival (PFS) were evaluated. Results: A total of 437 plasma samples from 63 patients were collected. Marked inter- and intra-patient variability in imatinib exposure was observed (43% and 31% respectively); 67% of patients receiving 400 mg/day had a C_min below the recommended target concentration (1100 ng/mL). Female sex was significantly associated with higher imatinib exposure (median C_min 1114 vs. 786 ng/mL in males; p = 0.0018). Combined age–sex analysis showed a significant difference between women and men < 60 years (1041 vs. 668 ng/mL; p = 0.0068, Bonferroni-adjusted). A strong exposure–toxicity relationship emerged, with higher imatinib levels in samples collected at toxicity occurrence vs. the others (1728 vs. 927 ng/mL; p < 0.0001), without a direct association between sex and toxicity. No significant association between C_min and PFS was observed; however, disease progression was more frequent in patients with C_min < 500 ng/mL and absent in those with C_min >1500 ng/mL (60% vs. 0%, respectively). Conclusions: TDM was found to be a potentially useful tool for predicting clinically relevant toxicity and outcome. Sex and age significantly influence exposure, supporting tailored dosing strategies. Full article

Endocrine-disrupting pesticides (EDPs) are environmental toxicants capable of perturbing hormonal homeostasis through multiple molecular and cellular mechanisms. Growing evidence indicates that these compounds contribute to a broad spectrum of adverse health outcomes extending beyond classical endocrine dysfunction. This review critically synthesizes current knowledge on the toxicological mechanisms of EDPs and evaluates epidemiological evidence linking exposure to human disease. Mechanistically, EDPs act through modulation of nuclear hormone receptors, disruption of membrane-associated signaling pathways, interference with hormone synthesis, metabolism, and transport, induction of oxidative stress and mitochondrial dysfunction, and epigenetic reprogramming. These molecular events converge on shared biological pathways that affect multiple organ systems and life stages. Human and experimental evidence associates EDP exposure with reproductive dysfunction, endocrine-related cancers, metabolic disorders, thyroid abnormalities, and neurodevelopmental impairments. Particular concern surrounds exposure during critical windows of susceptibility, especially prenatal development and early childhood, when endocrine systems are highly vulnerable to disruption and developmental programming. Across disease endpoints, recurring mechanisms, including endocrine receptor perturbation, oxidative stress, inflammation, and epigenetic alterations, support a unifying toxicological framework linking diverse adverse outcomes. Despite substantial progress, important uncertainties remain regarding chronic low-dose exposure, non-monotonic dose–response relationships, cumulative effects of pesticide mixtures, and the translation of mechanistic findings into human risk assessment. Future research should integrate repeated biomonitoring, advanced mixture modeling, mechanistic biomarkers, and multi-omics approaches within longitudinal life-course studies. Improved integration of toxicological and epidemiological evidence will strengthen causal inference, refine hazard characterization, and support more protective regulatory strategies for reducing the human health burden associated with endocrine-disrupting pesticides worldwide. Full article

Messenger RNA (mRNA) entered clinical medicine through vaccines, where the innate immune reactivity that complicates protein therapeutics acts as a built-in adjuvant. The success of the coronavirus disease 2019 (COVID-19) mRNA vaccines inspired an expansive vision of an mRNA 2.0 era extending the modality to rare and common diseases, with delivery framed as the principal challenge. This review accepts much of that vision but argues it rests on an unstated assumption: that all protein therapeutics form a single pharmacological class. They do not. We propose a taxonomy, the Dose–Response Architecture Classification, separating two classes. Exposure-controlled therapeutics require a specific quantity of active protein on a defined regimen, as outcomes depend on reproducible exposure; examples include insulin, erythropoietin, growth hormone, coagulation factors, and narrow-therapeutic-index biologics. Threshold-response therapeutics depend on surpassing a functional threshold rather than maintaining a precise concentration; these include vaccines, many enzyme-replacement therapies, genome editing, receptor-saturating antibodies, and immune-cell reprogramming. Because an mRNA drug is dosed as an instruction, and a single message is translated into a variable number of proteins through a multiplicative, stochastic intracellular chain, the dose-to-effect relationship is inherently variable. Our central, deliberately falsifiable proposition is that mRNA is suitable for threshold-response therapeutics but unsuitable for exposure-controlled therapeutics unless a construct or delivery system demonstrates validated post-delivery output control within predefined pharmacokinetic and pharmacodynamic limits. This is a pharmacological boundary, not a delivery obstacle. We conclude that the greatest advances in mRNA 2.0 will come not from delivery alone but from disciplined indication triage by class. Full article

Background: Metronomic chemo-endocrine therapy combining fulvestrant with metronomic VEC (vinorelbine, cyclophosphamide, and capecitabine)—the FulVEC regimen—demonstrated promising activity in an initial cohort of 38 patients with advanced ER+/HER2− breast cancer (JCM 2023). Here, we present an extended analysis of 72 consecutive patients, with a focus on a novel hypothesis: that treatment-emergent adverse events (AEs) requiring dose modification serve as a surrogate for sufficient pharmacological exposure in metronomic combination chemotherapy. Methods: Retrospective analysis of 72 consecutive patients with metastatic ER+/HER2− breast cancer treated with FulVEC at Jagiellonian University Hospital between 2018 and 2024. Efficacy endpoints included progression-free survival (PFS), overall survival (OS), and biochemical response, as assessed by CA15-3 dynamics. Patients were stratified by AE severity requiring intervention (grade 0: no modification; grade 1: dose reduction; and grade 2: treatment delay). The association between AE grade and efficacy outcomes was assessed using Spearman’s correlation, the log-rank test, and the chi-square test. Results: The median PFS was 8.5 months, and the median OS was 18.0 months. The biochemical benefit rate (any CA15-3 decline) was 81.6%. No statistically significant differences in efficacy were observed according to prior exposure to CDK4/6 inhibitors, fulvestrant, or cytotoxic components of the FulVEC regimen. A monotonic dose–response relationship was observed across AE grade categories: non-progression rates increased from 73.2% (grade 0) to 84.2% (grade 1) and 91.7% (grade 2); biochemical benefit rates from 68.4% to 90.9% and 100.0%; and median CA15-3 reduction deepened from −34% to −44% and −52%, respectively (Spearman r = 0.258 and p = 0.043 for AE grade vs. treatment duration). Formal log-rank comparisons of PFS and OS across the three AE-grade categories did not reach statistical significance (p = 0.583 and p = 0.743, respectively), reflecting the limited size of the treatment-delay subgroup (n = 12); the dose–response signal should, therefore, be regarded as exploratory. No patient required permanent treatment discontinuation due to toxicity. Conclusions: The extended FulVEC cohort confirms durable activity and a reproducible, manageable safety profile in a heavily pretreated population, including CDK4/6i-refractory patients. The exploratory, hypothesis-generating observation of a dose–response gradient between AE severity and clinical outcomes raises the possibility that treatment-emergent AEs may, in some patients, reflect adequate pharmacological exposure to the metronomic regimen. Given confounding by treatment duration and survivor bias, and the absence of pharmacokinetic data, this hypothesis requires prospective validation and does not, at this stage, support any change to current treatment practice. Full article

Objective: This cross-sectional study aimed to examine the association between recreational volleyball participation and knee osteoarthritis (KOA) risk in a community-based population, focusing on participation frequency, cumulative exposure periods, and clinical outcomes. Methods: Utilizing data from the Osteoarthritis Initiative (OAI) cohort (n = 2539; ages 45–79), volleyball engagement was assessed via the Historical Physical Activity Survey Instrument across four age periods (12–18, 19–34, 35–49, ≥50). Participants were stratified into non-volleyball, low-frequency, and high-frequency groups. Outcomes included knee pain (WOMAC score ≥ 1), radiographic OA (ROA), and symptomatic OA (SOA). Logistic regression models adjusted for age, sex, BMI, and race were employed to evaluate the associations. Results: Volleyball participation reported across all four age periods was associated with higher odds of ROA (adjusted OR = 2.394, 95%CI: 1.247–4.596, p = 0.009). High-frequency participation alone, however, was not associated with knee pain, ROA, or SOA (all p > 0.05). No significant associations were observed between cumulative participation and knee pain or SOA, and no dose–response relationship was found for participation frequency. Conclusions: Recreational volleyball participation was not associated with higher prevalence of knee pain or symptomatic radiographic KOA, outcomes that may be more clinically relevant than radiographic findings alone. Although participation across all four life periods was associated with higher odds of ROA, this structural finding should not be overinterpreted because it was based on a small subgroup and a non-monotonic pattern in a cross-sectional analysis. Full article

Background: Heat exposure is a leading climate-related health threat, yet whether the heat–disease burden relationship is moderated by national adaptive capacity remains poorly quantified at the global level. We examined associations between heat exposure and cause-specific disability-adjusted life year (DALY) burden across climate vulnerability strata and projected future burden to 2050 under IPCC AR6 warming scenarios. Methods: We constructed a country–year panel spanning 187 countries and 34 years (1990–2023) by merging ERA5 reanalysis temperature data; GBD 2023 DALY rates for cardiovascular diseases (CVD), chronic kidney disease (CKD), and chronic respiratory diseases (CRD); ND-GAIN adaptive-capacity scores; and WHO GHO health system indicators. Countries were stratified into adaptive-capacity tertiles (Low: n = 63; Medium: n = 62; High: n = 62). We used two-way fixed-effects panel regression with country-clustered standard errors, a formal Chow test of slope equality, lagged exposure models, and a benefit-of-adaptation counterfactual. Future DALY burden was projected to 2030, 2045, and 2050 using country-specific ERA5 warming trends scaled to IPCC AR6 SSP scenario multipliers. Findings: The heat–CVD dose–response was 26 times larger in Low versus High adaptive-capacity countries (β = −346.2 vs. −13.1 DALY years per 100,000 per °C). The Chow test confirmed statistically significant slope heterogeneity across tertiles for all three outcomes (CVD: F = 22.0, p < 0.0001; CKD: F = 14.9, p < 0.0001; CRD: F = 9.4, p < 0.0001). CKD burden rose 47·8% globally between 1990 and 2023, with the strongest within-country heat–CKD association in Medium adaptive-capacity countries (β = −61.5, p < 0.0001). These findings were robust to lagged exposure specifications. Under SSP5-8.5 by 2050, Low adaptive-capacity countries face a projected CVD DALY rate change 23 times larger than High adaptive-capacity countries (−16.2% vs. −0.7%). Upgrading Low adaptive-capacity countries to High tertile standards would avert 15.6% of projected CVD DALY burden under SSP5-8.5 by 2050. Conclusions: Adaptive capacity substantially moderates the health consequences of heat exposure. The quantified benefit of adaptation investment—expressed as averted DALY burden—provides a direct metric for health-system strengthening and climate adaptation financing, particularly in low-income settings facing the steepest projected burden increases. These results position adaptive capacity as a critical social determinant of planetary health, linking Earth-system boundary transgression to inequitably distributed human disease burden across the global community. Full article

Micro- and nanoplastics (MPs/NPs) are ubiquitous environmental contaminants increasingly detected in air, food, drinking water, and human tissues, raising concerns about their potential long-term health effects. Accumulating evidence indicates that these particles can enter the human body, cross biological barriers, and elicit cellular and molecular responses relevant to disease development. This review synthesizes current mechanistic evidence linking MP/NP exposure to cardiovascular disease (CVD) and cancer, two leading global causes of morbidity and mortality that share interconnected pathogenic pathways. Key mechanisms include chronic inflammation, oxidative stress, gut microbiota dysbiosis, genotoxicity, and epigenetic alterations, all of which are widely implicated in both conditions. However, the available evidence is still largely derived from in vitro and animal studies, with limited human epidemiological data. Important uncertainties remain regarding real-world exposure characterization, dose–response relationships, and long-term clinical outcomes, underscoring the need for standardized analytical approaches, validated exposure and effect biomarkers, and large-scale longitudinal studies to clarify causal associations for both cancer and CVD. Taken together, current evidence suggests that MPs/NPs may represent emerging environmental contributors to shared pathogenic pathways linking CVD and cancer; however, establishing causality in humans will require well-designed longitudinal studies that integrate exposure assessment and clinical outcomes. Full article

Polycyclic aromatic hydrocarbons (PAHs) represent a major class of ubiquitous environmental pollutants, posing significant risks to ecosystems and human health due to their persistence, toxicity, and potential for bioaccumulation. This review provides a comprehensive synthesis of current scientific knowledge on PAHs, integrating insights from chemical kinetics, environmental fate, and toxicological mechanisms. The fundamental structural chemistry of PAHs and its direct influence on their physicochemical properties and environmental properties are discussed. The major anthropogenic and natural sources of PAHs are detailed, alongside the chemical kinetics behind their formation during incomplete combustion and their transformation in environmental media. Unlike previous reviews that address PAH sources, remediation, or health effects as separate topics, this review uniquely traces the mechanistic continuum from molecular formation kinetics through physicochemical partitioning and environmental transport to toxicological endpoints, providing a causally linked framework for understanding how structural properties ultimately determine biological outcomes. A central focus is placed on the environmental fate and transport of PAHs across atmospheric, aquatic, and terrestrial compartments, highlighting processes such as gas–particle partitioning, sediment accumulation, and long-range transport. The review further elucidates the complex toxicological pathways of PAHs, including metabolic activation to reactive intermediates, DNA adduct formation, oxidative stress, and their roles in carcinogenesis and other systemic health effects. The analysis reveals strong scientific consensus on the carcinogenic mechanism of parent PAHs via CYP450-mediated metabolic activation to diol-epoxide intermediates while identifying critical areas of uncertainty: the current regulatory framework based on 16 priority PAHs underestimates total carcinogenic risk by a factor of 2–5, mixture toxicology remains poorly characterized, and dose–response relationships for non-cancer endpoints (cardiovascular, neurodevelopmental, immunotoxic) lack the quantitative data needed for robust risk assessment. Finally, human exposure pathways and health risk characterization approaches are discussed, highlighting the need for cumulative, mixture-based assessment frameworks. Full article

Radiation-induced biological responses emerge through complex interactions across multiple biological scales, ranging from molecular damage to tissue remodeling and organism-level outcomes. Although traditional radiobiology has primarily focused on DNA damage and linear dose–response relationships, increasing evidence suggests that radiation responses are highly context-dependent and cannot be fully explained by genomic alterations alone. In particular, low-dose and chronic radiation exposures often induce biological effects that involve dynamic regulatory processes beyond direct mutational burden. The narrative review proposes a conceptual multiscale framework for predictive radiobiology that integrates genomic damage, post-transcriptional regulation, network rewiring, and tissue microenvironmental interactions. Within this framework, “predictive radiobiology” refers to the integrative prediction of radiation-induced outcomes, including radiosensitivity, tissue remodeling, fibrosis progression, therapeutic response, and long-term carcinogenic risk. We discuss how radiation-induced signaling extends beyond DNA double-strand breaks to include RNA-binding protein-mediated regulation, adaptive network responses, and extracellular matrix-dependent cellular plasticity. Recent advances in multi-omics, single-cell analysis, spatial biology, and three-dimensional organotypic models have revealed that radiation responses are governed by interconnected molecular and tissue-level processes. Furthermore, artificial intelligence and systems-level computational approaches provide new opportunities for modeling non-linear and context-dependent radiation effects across biological scales. We further discuss current limitations, including data integration challenges, reproducibility issues, and the translational gap between experimental models and clinical applications. Collectively, this conceptual framework highlights the need for integrative and multiscale approaches to improve mechanistic understanding and predictive modeling in modern radiobiology. Full article

Ischemic heart disease (IHD) is a chronic and progressive condition characterized by reduced blood flow, mainly due to atherosclerosis. It is currently the leading cause of mortality among cardiovascular diseases. In recent years, per- and polyfluoroalkyl substances (PFAS), a group of ubiquitous and highly persistent environmental contaminants, have emerged as potential risk factors for IHD. PFAS are well-established endocrine disruptors and have been associated with hypercholesterolemia, hypertriglyceridemia, and insulin resistance. Despite the limited number of epidemiological studies and inconsistent findings from occupational settings, accumulating evidence suggests that elevated exposure to certain PFAS compounds may increase the risk of IHD and vascular dysfunction, including processes related to atherosclerosis development, sometimes with dose–response relationships and sex-specific patterns. Mechanistic evidence supports this link, indicating that PFAS exposure induces molecular and cellular alterations relevant to cardiovascular pathophysiology, including increased oxidative stress and vascular inflammation, and disruption of lipid metabolism. In addition, PFAS may affect epigenetic regulation, telomere length, and mitochondrial DNA copy number, which are emerging biomarkers associated with atherosclerosis and IHD and may indicate early cardiovascular vulnerability. Future research integrating innovative approaches and advanced analytical techniques may help address current knowledge gaps and clarify the mechanistic pathways linking PFAS exposure to clinical cardiovascular outcomes. Full article

Background: This study aimed to evaluate the association between comorbidity and hospital admission, hospital length of stay (LOS), and in-hospital mortality among adult trauma patients across the injury severity spectrum in South Korea, and to assess whether these associations vary according to injury severity. Methods: We conducted a retrospective cohort study using the national Community-Based Severe Trauma Survey (2019–2023). Adult patients (≥18 years) with trauma were included after excluding records with missing key exposure or outcome variables. Comorbidity was defined using the ICD-10–based Elixhauser comorbidity framework. In addition to a binary classification (any vs. none), comorbidity burden was categorized into 0, 1, 2, and ≥3 conditions to evaluate dose–response relationships. The primary outcomes were hospital admission, LOS, and in-hospital mortality. Multivariable logistic regression models were used for admission and mortality, and regression models were applied for LOS, adjusting for demographic characteristics, injury mechanism, physiologic status, and system-level factors. Effect modification by injury severity was assessed using interaction terms and ISS-stratified analyses. Results: Among 49,259 patients, 32,999 (67.0%) had at least one comorbidity. Patients with comorbidities were older, had higher injury severity, and showed higher admission rates, longer LOS, and higher in-hospital mortality compared with those without comorbidities. After adjustment, comorbidity remained independently associated with increased odds of admission, prolonged LOS, and in-hospital mortality. A dose–response relationship was observed, with increasing comorbidity burden associated with progressively worse outcomes (p for trend < 0.001). In addition, substantial heterogeneity was identified across individual comorbidities, with conditions such as metastatic cancer, liver disease, coagulopathy, renal disease, and fluid and electrolyte disorders showing stronger associations with adverse outcomes. The magnitude of these associations varied across ISS strata, indicating injury severity-dependent effects. Conclusions: In this nationwide cohort, comorbidity burden and type were important determinants of acute-care utilization and in-hospital mortality among trauma patients. Incorporating comorbidity information into early risk stratification may improve prognostic accuracy and support more efficient resource allocation and clinical decision-making across the trauma care continuum. Full article

Quantifying the mixture effects on humans exposed remains challenging because mixture components are correlated and may act bidirectionally by exhibiting nonlinear dose-response relationships, which may contribute to subclinical organ dysfunction. The liver is a vital organ in the body with broad functions, making it vulnerable to injury as it is the first organ exposed to circulating toxicants, which can precipitate hepatic damage. Our study’s objective was to evaluate the combined and component-specific associations of a multi-chemical exposure mixture of heavy metals, polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (dioxins), and polychlorinated dibenzofurans (furans), with liver biomarkers, and to compare concentration-based results with the toxic equivalent (TEQ) potency of the weighted results for dioxin-like compounds. In an unweighted analytic sample of U.S. adults from NHANES 2003–2004 with 947 complete cases, we examined heavy metals (cadmium, lead, and mercury), PCBs (12 congeners), dioxins (7 congeners), and furans (10 congeners) in relation to eight liver biomarkers (albumin, ALP, ALT, AST, GGT, LDH, total bilirubin, and total protein). We applied multi-exposure linear regression, weighted quantile sum (WQS) regression, quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR), with parallel TEQ-based models using WHO 2005 TEFs for dioxin-like PCBs, dioxins, and furans. Across mixture methods, the mixture structure was chemically sparse, with a limited set of recurring contributors. Total bilirubin showed the most consistent positive mixture association across qgcomp and BKMR and persisted under TEQ weighting, with prominent PCB- and dioxin-like contributions (notably PCB81/PCB TEQs and dioxin-related components). Albumin demonstrated inverse mixture patterns in BKMR and TEQ-BKMR, with dioxin-like components (notably Dioxin3 and Dioxin3_TEQ) repeatedly emerging as key drivers. For ALT, ALP, AST, GGT, LDH, and total protein, overall mixture effects were frequently attenuated or null in qgcomp despite structured component weights, indicating bidirectional sub-mixtures and internal counterbalancing. BKMR PIPs similarly concentrated on a small number of dominant predictors (e.g., lead for ALP, mercury for ALT, PCB28 for AST, and cadmium and PCB189 for LDH), while interaction summaries provided limited evidence of stable non-additivity. Using multiple complementary mixture methods, we identified outcome-specific mixture patterns suggesting hepatobiliary vulnerability. TEQ concordance supports toxicological relevance of the dioxin-like axis, while metals and non–dioxin-like mechanisms likely contribute additional pathways. Full article

The relationship between blood glucose levels and blood pressure is well established in clinical literature, yet its precise quantitative characterization, including nonlinear effects, threshold phenomena, and demographic modifiers, remains incompletely understood. In this study, we conducted a comprehensive cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) spanning 11 survey cycles (1999–2023), comprising 54,881 adult participants with at least one glycemic marker and standardized blood pressure measurements. Of these, 26,981 had valid fasting plasma glucose (FPG) measurements, and 49,327 had valid glycated hemoglobin (HbA1c) measurements. We employed restricted cubic splines (RCS), generalized additive models (GAMs), and segmented regression to characterize the dose–response relationship between glycemic markers and both systolic (SBP) and diastolic blood pressure (DBP). A 10 mg/dL increase in FPG was associated with a 0.32 mmHg increase in SBP (95% CI: 0.26–0.38, p < 0.001) after adjusting for age, sex, and body mass index (BMI). Nonlinearity was statistically significant for all exposure–outcome combinations (p < 10⁻⁷ for Wald tests). Segmented regression identified a FPG breakpoint at 122.1 mg/dL (95% CI: 119.5–125.6), below which SBP increased at 0.39 mmHg per mg/dL and above which the association was essentially flat. Stratified analyses revealed that the glucose–BP association was strongest in females (β = 0.048 per mg/dL) compared with males (β = 0.021), and in prediabetic individuals (β = 0.065) compared with those with established diabetes (β = 0.014). In the statistical mediation decomposition, body mass index accounted for 23.5% of the total FPG–SBP association. A significant FPG × BMI interaction (p < 0.001) indicated that the glucose–BP relationship is modulated by adiposity. These findings provide a large-scale population-level analysis of the glucose–blood pressure dose–response relationship and identify potential thresholds warranting further investigation for integrated cardiometabolic risk management (95% bootstrap CI: 19.3–28.9%; 1000 resamples); given the cross-sectional design and BMI’s plausible role as a shared upstream determinant of glucose and blood pressure, this proportion is reported as a confounding decomposition rather than as evidence of causal mediation. Insulin resistance (HOMA-IR) and C-reactive protein did not contribute significantly as additional decomposition pathways. Full article