Ethanol-aqueous environments severely compromise emulsion stability and accelerate the degradation of lipophilic nutraceuticals. In this study, ethanol-tolerant emulsions were engineered through an interfacial-bulk co-design strategy using tea saponin (TS)-reinforced lactoferrin (LF) interfacial layers and fructooligosaccharides (FOS) bulk modulation to improve β-carotene retention. LF-TS association markedly enhanced interfacial activity, reducing interfacial tension from 32.0 to 4.1 mN/m and increasing the emulsifying activity index by 32.8%. Interfacial dilatational rheology confirmed that the ternary LF-TS/FOS system formed the strongest and most elastic interfacial film, while adsorption kinetic analysis revealed a balanced diffusion-penetration-rearrangement pathway that supported efficient interfacial adsorption and film maturation. Meanwhile, FOS-enabled bulk co-structuring generated uniform nano-complexes and improved β-carotene encapsulation efficiency from 64.4% to 90.1%. The optimized emulsions showed enhanced β-carotene retention under multiple environmental stresses, with thermal retention increasing from 43.8% to 77.0% and UV-photodegradation half-life extending from 1.5 to 4.8 h. The co-designed system also maintained good physical stability under high ionic strength and during accelerated storage at 37 °C. Overall, this interfacial-bulk co-modulation strategy provides an effective approach for constructing ethanol-tolerant delivery systems for sensitive lipophilic bioactives.

Frailty is increasingly defined as a multidimensional clinical condition whose prevalence rises with advancing age, extending across multiple medical specialties and exhibiting significant sex- and gender-related differences. Chronic diseases, including neurological conditions such as Parkinson's disease (PD), are key contributors to frailty, possibly through shared mechanisms. Conversely, frailty adversely influences clinical outcomes and disease trajectories, increases mortality risk and alters the risk-benefit profile of therapeutic interventions. This review summarizes current evidence on the aetiologies, clinical and instrumental assessment, emerging fluid biomarkers, and therapeutic implications of frailty in PD. Conventional frailty tools, including the Frailty Index and Fried phenotype, are useful but lack specificity in this specific population, notably because PD-related symptoms overlap with frailty criteria. A multimodal approach integrating gait and balance analysis, cognitive testing, dysautonomia assessment, sarcopenia screening, dysphagia evaluation, and nutritional markers may improve risk stratification. Emerging biomarkers, including inflammatory cytokines, albumin, C-reactive protein/albumin ratio, vitamin D, sarcopenia-related markers, neurofilament light chain, and glial fibrillary acidic protein (GFAP), may further capture biological vulnerability, although validation remains limited. Frailty substantially modulates PD treatment decisions by increasing susceptibility to adverse effects, polypharmacy, falls, cognitive complications, and procedural risk. Frailty should therefore be systematically integrated into pharmacological prescribing, deprescribing, rehabilitation, neuropalliative approaches, and selection (as well as timing) of device-aided therapies. Routine frailty assessment, independent of chronological age, may support more individualized, patient-centred PD care, prioritizing functional independence, safety, quality of life, and minimisation of treatment burden alongside conventional motor management.

Vaccines targeting avian influenza virus A/H7N9 are poorly immunogenic. While the immune responses can be improved with oil-in-water emulsion adjuvants such as Adjuvant System 03 (AS03), the cellular mechanisms underpinning the adjuvant effect are incompletely characterized and poorly understood.

Advanced epithelial ovarian cancer responds poorly to current treatments, creating an urgent need for novel therapeutic strategies. 1,25-dihydroxyvitamin D3 (1,25D3) exerts potent anti-proliferative effects on ovarian cancer cells in vitro, but the concentrations required for growth suppression in cell culture are not readily achievable in vivo, and higher doses induce hypercalcemia, which hinders its clinical translation. Sodium selenite (Na2SeO3) has been identified as a chemopreventive agent that inhibits the growth of multiple cancer types. In this study, we demonstrated that combined treatment with Na2SeO3 and 1,25D3 exerts enhanced anti-proliferative efficacy against ovarian cancer cells both in vitro and in vivo. Specifically, 1,25D3 upregulated the expression of vitamin D receptor (VDR) and Selenoprotein-P1 (SEPP1), and this effect was further enhanced by Na2SeO3 co-treatment. Consistently, Na2SeO3 augmented the suppressive effect of 1,25D3 on ovarian cancer cell proliferation, demonstrating synergistic inhibitory activity. Notably, knockout (KO) of either VDR or SEPP1 abrogated this synergistic effect. Mechanistic investigations confirmed that SEPP1 is a direct target gene of VDR, and functional vitamin D response elements (VDREs) are present within its genomic locus. In vivo, low-dose 1,25D3 (0.3 μg/kg) combined with Na2SeO3 outperformed 1,25D3 monotherapy, with no significant hypercalcemia, ascites formation, or metastasis observed throughout the treatment period. These findings indicate that Na2SeO3 acts in combination with 1,25D3 to induce SEPP1 expression, thereby enhancing the antitumor efficacy of low-dose 1,25D3 against ovarian tumors. This study provides a promising strategy for the safe and effective application of 1,25D3 in ovarian cancer therapy.

Anticoagulants are essential for preventing and treating thromboembolism across a wide range of clinical settings. Yet, they share a narrow therapeutic index that demands a precise understanding of their pharmacodynamic behavior. Thrombin generation provides an integrated measure of anticoagulant effects by capturing the timing, velocity, and total amount of thrombin formed over time. We reviewed the literature to establish a unified theoretical framework, grounded in mechanistic rationale and supported by experimentation, to better define the pharmacodynamics of anticoagulation therapy using thrombin generation as a common language to compare anticoagulant effects across drug classes. Unfractionated and low-molecular-weight heparins and vitamin K antagonists exert broad, multitargeted inhibition that profoundly suppresses peak thrombin and the endogenous thrombin potential. Direct factor Xa inhibitors primarily blunt propagation, direct thrombin inhibitors delay initiation while preserving overall thrombin output, and factor XIa inhibitors act mainly under low tissue factor conditions. Agents that engage multiple components of the coagulation cascade (prothrombinase formation, thrombin feedback activation, or zymogen depletion) produce deeper, cumulative suppression of thrombin generation and maintain efficacy under highly prothrombotic conditions, as seen with mechanical heart valves, antiphospholipid antibody syndrome, and catheter-associated thrombosis. In contrast, selective inhibitors achieve pharmacodynamic predictability but may lose responsiveness in the face of extreme coagulation activation. From a pharmacodynamic perspective, not all anticoagulants are the same. Divergent mechanisms map to unique, reproducible, and informative pharmacodynamic signatures that are characterized using thrombin generation. These signatures help explain why some patients experience breakthrough thrombosis or bleeding despite "on-target" drug levels. Embedding thrombin generation within clinical research allows anticoagulant effects to be interpreted through a mechanistic lens that bridges molecular pharmacology with patient-level variability. This synthesis provides a common language for comparing anticoagulants and lays the foundation for an individualized, pharmacologically informed approach to anticoagulation therapy.

Cardiovascular disease (CVD) and cancer are leading causes of death worldwide, with their comorbidity posing a major public health challenge. In cold regions (latitude ≥ 45° or annual mean temperature ≤ 10 °C), this dual burden is exacerbated by unique environmental exposures and lifestyle factors. This review aims to systematically characterize the epidemiological features of CVD and cancer in cold regions, elucidate the mechanisms by which cold exposure synergistically exacerbates cancer therapy-related cardiovascular toxicity (CTR-CVT), and propose a comprehensive, cold-region-tailored management framework for the prevention, treatment, and rehabilitation of cardio-oncology comorbidity. Cold regions show significantly higher age-standardized incidence and mortality rates for both CVD and cancer compared to temperate regions. Low temperatures, high-sodium diets, and air pollution synergistically increase cardiovascular risk, while lung, colorectal, breast, and prostate cancers substantially exceed global averages. The bidirectional interaction between CVD and cancer involves multiple mechanisms. Cancer therapies induce cardiotoxicity via oxidative stress, mitochondrial dysfunction, ferroptosis, and inflammatory pathways. Conversely, CVD promotes cancer progression through chronic inflammation, neurohormonal activation, cardiac-derived factors, and exosome-mediated communication. Cold stress, acting as a synergistic toxicological factor, exacerbates comorbidity through sympathetic overactivation, amplification of oxidative and inflammatory cascades, and metabolic remodeling that disrupts drug metabolism and myocardial energy supply. In conclusion, CVD-cancer comorbidity in cold regions represents a distinct entity shaped by environmental and lifestyle factors. We propose a full-cycle, cold-region-tailored management system including cold adaptation training, dietary modification, vitamin D supplementation, integrated traditional Chinese and Western medicine, and dynamic monitoring of cardiometabolic and tumor markers. Future research should prioritize large-scale prospective studies, multi-omics approaches for sensitive biomarker identification, and region-specific interventions to reduce this dual disease burden.

Nausea and vomiting of pregnancy (NVP), including its severe form, hyperemesis gravidarum (HG), is a common condition during early pregnancy, with complex and incompletely understood pathophysiological mechanisms. In recent years, attention has increased toward the potential role of vitamin B6 in the management of NVP. This narrative review aims to summarize and integrate current evidence on vitamin B6 metabolism, pregnancy-related physiological changes, potential mechanisms of action, clinical efficacy, safety, and relevant international guideline recommendations in NVP. Current evidence generally supports vitamin B6 as a first-line foundational treatment for mild-to-moderate NVP, particularly when combined with doxylamine, demonstrating favorable clinical utility. Emerging evidence suggests that vitamin B6 may contribute to the development and regulation of NVP through multiple pathways, including neurotransmitter metabolism, neuroendocrine regulation, and mechanisms of the gut-brain axis. However, direct clinical evidence supporting these mechanistic links remains limited. Future studies integrating biomarkers, neuroendocrine pathways, and high-quality clinical investigations are warranted to further clarify the mechanistic role and clinical value of vitamin B6 in NVP.

This case report describes the treatment failure of two direct oral anticoagulants (DOACs) in a patient with multiple thrombophilic conditions, including triple-positive antiphospholipid syndrome (APS) and heterozygous Factor V Leiden mutation. A 69-year-old male with a history of recurrent venous thromboembolism developed a deep vein thrombosis while receiving rivaroxaban, followed by an acute ischemic stroke while on dabigatran. Due to recurrent thrombosis despite therapeutic DOAC therapy, the patient was transitioned to warfarin with low-molecular-weight heparin bridging. After achieving a therapeutic INR, the patient remained stable without further thromboembolic or bleeding events during follow-up in a pharmacist-managed anticoagulation clinic.Current guidelines, including the 2020 ISTH Scientific and Standardization Committee guidance, recommend vitamin K antagonists over DOACs in high-risk APS, particularly in patients with triple-positive antibodies, due to the increased risk of recurrent thrombosis with DOAC therapy. This recommendation is supported by the TRAPS trial, which demonstrated a significantly higher rate of thromboembolic events with rivaroxaban compared to warfarin in triple-positive APS patients.This case supports existing guideline recommendations and highlights the limitations of targeted anticoagulation, including both factor Xa inhibitors and direct thrombin inhibitors, in patients with complex thrombophilia. In patients with high-risk APS or multiple thrombophilic conditions, warfarin has been shown to be more reliable anticoagulation compared with DOACs. The sequential failure of two mechanistically distinct DOACs in this case further underscores the importance of guideline-concordant anticoagulant selection and the role of pharmacists in identifying high-risk patients at the point of prescribing and dispensing.

Label-free identification and real time tracking of biochemical substances became critical for molecular diagnostics and chemical analysis, yet conventional resonant terahertz (THz) metasurface sensing relies on a single resonance, limiting spectral selectivity and dynamic capability. Here, we suggest multiresonant membrane metasurfaces and employ them for simultaneous static characteristic absorption detection and dynamic reaction monitoring within a single pixel. We consider a membrane metasurface supporting multiple quasi-bound states in the continuum designed at target frequencies and enabling the tailoring of the field enhancement and frequency-selective interaction with target analytes. As a proof-of-concept, we achieve label-free detection of the characteristic absorption features of pefloxacin at 0.78 and 0.99 THz, and real time tracking of vitamin C oxidation and denaturation under ambient conditions. The kinetic profiles extracted from the THz amplitude evolution show excellent agreement with nonlinear reaction models (R[2] > 0.92), demonstrating quantitative biochemical tracking capabilities. Our results establish a versatile and scalable THz photonic platform that unifies static molecule identification and dynamic reaction monitoring, paving the way toward integrated on-chip biochemical analytics and multifunctional metasurface sensors.

This cross-sectional study investigated the association between smoking status and serum vitamin B12 concentrations in a Jordanian adult population, using plasma cotinine as a validated biomarker of tobacco exposure. Tobacco use remains a major public health concern in Jordan, where smoking prevalence is among the highest globally. Although previous studies have explored the link between smoking and vitamin B12 status, findings have been inconsistent, and the effects of passive smoke exposure are not well understood. A total of 251 Jordanian adults from Amman and Madaba governorates were categorized as active smokers (n=125), passive smokers (n=63), or non-smokers (n=63). Non-parametric tests (Kruskal-Wallis and Mann-Whitney U) were used to compare group differences, and multiple linear regression was performed on log-transformed vitamin B12 concentrations to identify independent predictors. Vitamin B12 levels differed significantly across groups (p=0.021), with passive smokers showing the highest median concentrations (373.0 pg/mL) compared with active smokers (327.0 pg/mL) and non-smokers (295.0 pg/mL). In the regression model, passive smoking was independently associated with higher vitamin B12 concentrations (B=0.168, p = 0.027), while higher BMI was associated with lower concentrations (B=-0.011, p = 0.039). No significant correlation was observed between cotinine and vitamin B12 levels within any group. These findings suggest a possible compensatory metabolic response in passive smokers. Should these findings be validated, they could have clinical implications for evaluating vitamin B12 status in individuals exposed to tobacco smoke and highlight the urgency of enforcing smoke-free environments. Further investigation is needed to elucidate the mechanisms involved.

Vitamin D deficiency is highly prevalent in children worldwide but has long been regarded only as a risk factor for bone health. Emerging evidence indicates that vitamin D profoundly influences child brain development by regulating neuroimmune responses and synaptic plasticity, forming a "neuroimmune-synaptic plasticity axis." Deficiency is significantly associated with the risk of multiple pediatric neurological disorders, including autism spectrum disorder (ASD), epilepsy, and attention-deficit / hyperactivity disorder (ADHD). This axis exerts irreversible regulatory effects during critical developmental windows from gestation to the preschool period, representing a core causal pathway linking vitamin D deficiency to neurodevelopmental disorders. However, the clinical benefits of vitamin D supplementation are highly heterogeneous, necessitating a move beyond the "one-size-fits-all" paradigm. This review systematically integrates causal mechanisms, molecular pathways, disease-specific associations, and clinical evidence, proposing the "neuroimmune-synaptic plasticity axis" as a central hypothesis. We critically analyze the mechanisms of vitamin D during key neurodevelopmental periods and evaluate sources of heterogeneity in existing clinical trials, including dosage, timing, VDR genotype, and co-nutrients. Finally, we propose a research roadmap for individualized supplementation strategies based on developmental stage, biomarkers, and VDR genotype, aiming to transition vitamin D use from empirical to precision intervention.

Sinefungin is a potent nucleoside antimetabolite of S-adenosylmethionine (SAM). Since its discovery in the 1970s, sinefungin has generated significant scientific interest owing to its role as a bioisostere of SAM and its broad range of biological activities. Despite considerable efforts to uncover the enzymes responsible for sinefungin production in the following years, its biosynthesis remained unclear for decades. Here, we characterize the complete sinefungin biosynthetic gene cluster (sin BGC) from Streptomyces incarnatus NRRL 8089. In vitro and in vivo analyses support a recent finding that the defining carbon-carbon (C-C) bond is formed not by a long-hypothesized PLP-dependent process, but by a vitamin B12-dependent radical SAM enzyme. We provide direct mechanistic evidence, via isotope-labeled products, that the adenosyl group of sinefungin originates from adenosylcobalamin and is atypically consumed via a homolytic SH2 substitution reaction. We also characterize two peptide aminoacyl-tRNA ligases (PEARLs) that append alanines onto the nucleoside scaffold using tRNA-activated amino acids. The PEARLs act directly on small molecules rather than macromolecular substrates, with one PEARL capable of iterative elongation. In addition, we perform in-vitro substrate profiling of several sin BGC-encoded enzymes. We reveal that multiple enzymes show specificity toward phosphorylated intermediates, including the earliest-acting PEARL enzyme. These observations provide an explanation for a cryptic phosphorylation-dephosphorylation strategy observed in the pathway, as they prevent the formation of the highly toxic sinefungin inside the cell. Finally, we leverage these enzymes in a reduced multi-enzyme cascade to biosynthesize sinefungin. Together, these findings expand upon our current knowledge of radical-mediated C-C bond formation and PEARL enzyme catalysis, unlocking biocatalytic possibilities to produce amino acid-nucleoside conjugates.

Objective: To evaluate the relationship between serum micronutrient levels, including calcium, phosphorus, iron, and 25-hydroxyvitamin D, and the incidence of osteoporotic fracture. Methods: A retrospective analysis was performed in 5 984 patients hospitalized in the Department of Osteoporosis, West China Fourth Hospital, Sichuan University, from December 2017 to October 2024. The patients with osteoporotic fracture were divided into case group and those without osteoporotic fracture were divided into control group. Missing data were addressed using multiple imputation. Logistic regression model was used to analyze the association between different micronutrient levels and fracture risk, and mediating effect of bone mineral density was further evaluated. Model discrimination was evaluated using receiver operating characteristic curve and area under the curve (AUC), and differences in AUC were compared by DeLong test. Results: The calcium, phosphorus, and iron levels were significantly lower in patients with osteoporotic fracture than in controls, the difference was significant (all P<0.05). After adjustment for age, sex, BMI, and comorbidity, including diabetes, coronary heart disease, and hypertension, the logistic regression analysis showed that calcium level was significantly inversely associated with osteoporotic fractures, and phosphorus, iron, and 25-hydroxyvitamin D were not significantly associated with osteoporotic fractures. After additional mutual adjustment for phosphorus, iron and 25-hydroxyvitamin D, the association between calcium and fracture remained stable (OR=0.88, 95%CI: 0.82-0.94, P<0.001). This relationship was consistent in different subgroups, with no significant interactions. Bone mineral density had no effect to mediate the association between micronutrients and fracture. Using calcium level in the baseline model significantly increased the AUC, enhancing its discriminative ability (P=0.002). Conclusions: In patients with osteoporosis, the serum calcium levels showed an inverse association with fracture risk, and maintaining adequate calcium may help reduce this risk. The etiological roles of other serum micronutrients, including phosphorus, iron, and 25-hydroxyvitamin D, remain to be further analyzed.