3D printed biopolymer/black phosphorus nanoscaffolds for bone implants: A review.

Bone implantation is one of the recognized and effective means of treating bone defects, but osteoporosis and bone tumor-related bone abnormalities have a series of problems such as susceptibility to infection, difficulty in healing, and poor therapeutic effect, which poses a great challenge to clinical medicine. Three-dimensional things may be printed using 3D printing. Researchers can feed materials through the printer layer by layer to create the desired shape for a 3D structure. It is widely employed in the healing of bone defects, and it is an improved form of additive manufacturing technology with prospective future applications. This review's objective is to provide an overview of the findings reports pertaining to 3D printing biopolymers in recent years, provide an overview of biopolymer materials and their composites with black phosphorus for 3D printing bone implants, and the characterization methods of composite materials are also summarized. In addition, summarizes 3D printing methods based on ink printing and laser printing, pointing out their special features and advantages, and provide a combination strategy of photothermal therapy and bone regeneration materials for black phosphorus-based materials. Finally, the associations between bone implant materials and immune cells, the bio-environment, as well as the 3D printing bone implants prospects are outlined.

Ruthenium Clusters Modification Carbon Layer-Encapsulated NiCoP Nanoneedles as Advanced Electrocatalyst for Efficient Seawater Splitting Application.

Developing efficient and durable electrocatalyst for seawater splitting is crucial in hydrogen production. Herein, a multi-scale design strategy was employed to fabricate ruthenium clusters modification carbon layer-encapsulated nickel-cobalt-phosphorus (Ru/C/NiCoP) nanoneedles electrocatalyst supported on nickel foam (NF). We demonstrated that Ru/C/NiCoP/NF exhibited exceptional oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) performances, with low overpotential, Tafel slope and superior stability. Furthermore, the electrocatalytic mechanism of Ru/C/NiCoP was elucidated through the combination of ex-situ and in-situ characterizations, along with comprehensive electrochemical tests. Strikingly, Ru clusters and the carbon layer engendered robust electronic interaction reaction, accelerated the charge transfer rate, provided more active sites, and enhanced intrinsic catalytic activity, thus substantially promoting the OER kinetics and HER reaction steps as well as stability. In addition, the two-electrode system constructed with Ru/C/NiCoP/NF achieved current density of 10 mA cm-2 in both pure water and seawater at ultra-low potential of 1.46/1.47 V, with Faraday efficiency close to 100%. Even at higher current density of 100 mA cm-2, the required driving voltage remained low at 1.75/1.77 V, maintaining stable operation for 150 h, outperforming most reported non-noble catalysts. This innovative strategy provides facile and versatile approach for developing advanced electrocatalysts in seawater electrolysis application.

Pedestrian behavior among Chinese seniors: Insights from factor analysis and structural equation modeling.

Pedestrians contribute significantly to the total number of road fatalities and injuries, with their behavior playing a pivotal role in traffic mishaps. Despite this, a limited body of research has delved into the walking behaviors of Chinese seniors. Given this gap, our study rigorously examines the patterns of seniors' walking behaviors and their influencing factors. We employed exploratory factor analysis to decipher the intrinsic component structures of seniors' walking patterns in China. Subsequently, structural equation modeling was utilized to analyze the impact of demographic attributes and personality characteristics on these behaviors. The findings revealed a four-dimensional structure for senior walking behaviors: transgression, inattention, aggression, and positive behaviors. Introducing personality traits as variables notably enhanced the explanatory power of our model. Specifically, anger, altruism, and normlessness significantly influenced certain dimensions of walking behaviors, while sensation-seeking did not exhibit any notable effect. This study not only highlights the complexity and diversity of elderly walking behaviors but also underscores the importance of tailored interventions to improve walking safety and quality of life for seniors.

Copper metabolism-related signature for prognosis prediction and MMP13 served as malignant factor for breast cancer.

Objectives: To comprehensively analyze the copper metabolism in Breast cancer, we established a prognostic signature for breast cancer (BC) related to copper metabolism. Methods: Copper metabolism-related genes were sourced from previous literatures and were selected by the Univariate Cox regression. Cu-enrichment scores were calculated via ssGSEA. Differentially expressed genes were identified with limma between high and low Cu-enrichment scores group, then we used the Random Survival Forest and LASSO to build the CuScore for BC. Kaplan-Meier analysis, ROC curves, and Cox regression were used to evaluate CuScore. Genomic mutations were analyzed with GISTIC. Immune cells were examined using ESTIMATE, ssGSEA and TIMER. Enrichment analysis used clusterProfiler and GSVA. The GDSC database and oncoPredict package analyzed chemotherapeutic sensitivity. MMP13 was selected for in vitro assays. Results: Four copper metabolism-related genes (UBE2D2, SLC31A1, ATP7A, and MAPK1) with prognostic value were identified. Higher expression levels of these genes were associated with higher Cu-enrichment scores, a factor of malignancy in breast cancer. Among 115 differentially expressed genes, 19 prognostic genes were identified, with three (CEACAM5, MMP13, and CRISP3) highlighted by Random Survival Forest and LASSO. Higher CuScores correlated with worse prognoses and were effective in predicting breast cancer outcomes. CuScore and metastasis were independent prognostic factors. Tumor-infiltrating immune cells were associated with lower CuScores. GO-GSEA analysis indicated six immune-related pathways might be regulated by CuScore. Patients with higher CuScores had lower TMB and were more sensitive to Sapitinib and LCL161, while those with lower CuScores might respond better to anti-PD1 therapy. High MMP13 expression in breast cancer was linked to malignancy, affecting cell proliferation and migration. Conclusion: The identified copper metabolism-related gene signature has the potential to predict prognosis and guide clinical treatment for BC. Among these genes, MMP13 may act as a malignant factor in BC.

Physiologically based pharmacokinetic model of brivaracetam to predict the exposure and dose exploration in hepatic impairment and elderly populations.

Brivaracetam (BRV) is a new third-generation antiseizure medication for the treatment of focal epileptic seizures. Its use has been increasing among epileptic populations in recent years, but pharmacokinetic (PK) behavior may change in hepatic impairment and the elderly populations. Due to ethical constraints, clinical trials are difficult to conduct and data are limited. This study used PK-Sim® to develop a physiologically based pharmacokinetic (PBPK) model for adults and extrapolate it to hepatic impairment and the elderly populations. The model was evaluated with clinical PK data, and dosage explorations were conducted. For the adult population with mild hepatic impairment, the dose is recommended to be adjusted to 70 % of the recommended dose, and to 60 % for moderate and severe hepatic impairment. For the elderly population with mild hepatic impairment under 80 years old, it is recommended that the dose be adjusted to 60 % of the recommended dose and to 50 % for moderate and severe conditions. The elderly population with hepatic impairment over 80 years old is adjusted to 50 % of the recommended dose for all stages. Healthy elderly do not need to adjust. The BRV PBPK model was successfully developed, studying exposure in hepatic impairment and elderly populations and optimizing dosing regimens.

Microalgae-bacterial consortiums for enhanced degradation of nonylphenol: Biodegradability and kinetic analysis.

The widespread use of non-ionic surfactant nonylphenol (NP) has led to significant water pollution, posing a threat to both ecological stability and human health. However, the efficient biodegradation method and system of NP-biodegradation remain complex scientific challenges. In this study, we isolated and characterized three Pseudomonas sp. strains SW-1 (Scenedesmus quadricauda-associated), ZL-2 (Ankistrodesmus acicularis-associated), XQ-3 (Chlorella vulgaris-associated), and one NP-degrading Cupriavidus sp. strain EB-4, which exhibited the ability to utilize NP as the sole carbon source. Furthermore, four consortiums of microalgae-bacterial, S. quadricauda and SW-1 (S-SW), A. acicularis and ZL-2 (A-ZL), C. vulgaris and XQ-3 (C-XQ), S. quadricauda and EB-4 (S-EB), were constructed to investigate their biodegradability and kinetic characteristics of NP degradation from water. The consortiums showed higher degradation efficiency compared to individual microalgae or bacteria. The C-XQ consortium exhibited the highest degradation rate, removing over 94% of NP within just seven days. The first-order model with the following order of degradation rate by consortiums was C-XQ (0.3960 d-1) > S-SW (0.3506 d-1) > A-ZL (0.1968 d-1) > S-EB (0.1776 d-1). Compared with the results of our previous study, the interaction between microalgae and bacteria is not a simple additive relationship. Our findings highlight the potential of an algal-bacterial consortium for the remediation of NP-contaminated environments.

Development of a sequential release nanomaterial for co-delivery of hypoxia-induced tirapazamine and HIF-1α siRNA in cancer therapy.

Unlike traditional drug carriers, sequential drug delivery systems can release different drugs in order, with the first released drug providing a prerequisite for the later released drug to maximize its function, thereby achieving stronger anti-tumor effects. Herein we constructed a temporal sequential system designated TPZ@MSN/HIF-1α siRNA@PDA@GOx (MTRPG) in which mesoporous silica nanoparticles were used as cores to load hypoxia induced chemotherapy drug tirapazamine (TPZ) and gene targeted nucleic acid drug HIF-1α siRNA, polydopamine (PDA) as acid -responsive coating as well as to realize photothermal therapy, and glucose oxidase (GOx) as the outermost layer to achieve starvation therapy and construct a deepened hypoxia to activate TPZ. Through in vitro and in vivo experiments, we demonstrated that the first released glucose oxidase catalyzed the oxidation of glucose, achieving starvation treatment while reducing the acidic environment and further exacerbating hypoxia in tumor cells. The reduced acidic conditions enabled the degradation of PDA, resulting in the release of loaded HIF-1α siRNA and TPZ. At the same time, PDA could also exert photothermal therapy under 808 nm near-infrared (808 nm NIR) laser irradiation. The later released hypoxia induced chemotherapy drug TPZ amplifies its anti-tumor activity under intensified hypoxia conditions. Meanwhile, the released HIF-1α siRNA interfered with the up-regulated HIF-1α induced by the deepened hypoxia condition, which caused hypoxia tolerance in tumors, reduced its expression activity, and achieved synergistic killing of tumor cells with chemotherapy. This work provides an effective multimodal synergistic therapy strategy to promote tumor therapeutic index, which may possess a promising future in clinical application.

Changes in lipids and medium- and long-chain fatty acids during the spontaneous fermentation of ripened pu-erh tea.

During the fermentation of ripened pu-erh tea (RPT), the composition of lipids and other compounds changes significantly. In this study, we conducted industrial fermentation of RPT and observed that the levels of water extract, tea polyphenols, free amino acids, catechins, caffeine, rutin, theophylline, luteolin, and myricetin decreased, while the level of soluble sugar increased. Additionally, the levels of gallic acid, quercetin, ellagic acid, and kaempferol first increased and then decreased during fermentation. We identified a total of 731 lipids, which were classified into seven categories using a lipomics method. Among these lipids, 85 with relatively high contents decreased, while 201 lipids with low contents increased after fermentation. This led to an overall decrease in the sum contents of lipids and dominant lipids, including glycerophospholipids and saccharolipids. We also detected 33 medium- and long-chain fatty acids, with α-linolenic acid (881.202 ± 12.13-1322.263 ± 19.78 µg/g), palmitic acid (797.275 ± 19.56-955.180 ± 30.49 µg/g), and linoleic acid (539.634 ± 15.551-706.869 ± 12.14 µg/g) being the predominant ones. Coenzymes Q9 (62.76-63.57 µg/g) and Q10 (50.82-59.33 µg/g) were also identified in the fermentation process. Our findings shed light on the changes in lipids during the fermentation of RPT and highlight the potential bio-active compounds, such as α-linolenic acid, linoleic acid, Coenzymes Q9, and Q10, in ripened pu-erh tea. This contributes to a better understanding of the fermentation mechanism for RPT.

Oilseed flax cultivation: optimizing phosphorus use for enhanced growth and soil health.

Introduction: Oilseed flax (Linum usitatissimum L.) yields are phosphate (P) fertilizer-limited, especially in the temperate semiarid dryland regions of North China. However, there are limited studies on the effects of P-fertilizer inputs on plant growth and soil microorganisms in flax planting systems. Methods: To address this gap, a field experiment was conducted with four treatments: no P addition and application of 40, 80, and 120 kg P ha-¹, respectively. The aim was to investigate the influence of various P fertilizer inputs on yield, plant dry matter, P use efficiency, as well as the population of soil arbuscular mycorrhizal fungi (AMF) and bacteria in dryland oilseed flax. Results: Our results show that the P addition increased the dry matter, and the yield of oilseed increased by ~200% at 120 kg P ha-1 addition with inhibition on the growth of AMF hyphae. The moderate P supply (80 kg ha-1) was adequate for promoting P translocation, P use efficiency, and P recovery efficiency. Soil pH, available P, and available K significantly (p< 0.05) promoted the abundance of the dominant taxa (Acidobacteria_GP6, Sphingobacteria and Bacteroidetes). In addition, it is imperative to comprehend the mechanism of interaction between phosphorus-fertilizer inputs and microbiota in oilseed flax soil. Discussion: This necessitates further research to quantify and optimize the moderate phosphorus supply, regulate soil microbes to ensure high phosphorus utilization, and ultimately establish a sustainable system for oilseed flax cultivation in the local area.

Association Between Antibodies That Bind Epstein-Barr Virus (EBV) gp350 and gH/gL and Shedding of EBV in Saliva From Nasopharyngeal Carcinoma Multiplex Family Members in Taiwan.

Elevated levels of Epstein-Barr virus (EBV) gp350 and gH/gL antibodies have been associated with a lower risk of developing nasopharyngeal carcinoma (NPC), although the evidence remains inconclusive and unexplained. We conducted a longitudinal study within a high-risk Taiwanese cohort, analyzing total immunoglobulin against EBV-gp350 and -gH/gL in blood and EBV DNA shedding in saliva. Contrary to our hypothesis-that elevated levels of antibodies previously shown to be associated with a lower NPC risk should result in a decrease in EBV shedding in saliva-higher anti-gp350 antibodies at baseline were significantly associated with detectable EBV DNA in saliva at follow-up (odds ratio [OR], 1.99 [95% confidence interval {CI}, 1.03-3.97]; P = .04). Higher anti-EBV-gH/gL antibodies at baseline were not significantly associated with risk of detectable EBV DNA at follow-up (OR, 0.69 [95% CI, .35-1.32]; P = .26). These findings underscore the complexity of virus-host interactions and emphasize the need for further investigations into their role in EBV-associated diseases.

Association of Pain Intensity and Sensitivity with Suicidal Ideation in Adolescents with Depressive Disorder.

Purpose: The purpose of this study was to further explore the association of pain intensity and sensitivity with suicidal ideation in adolescents with depressive disorder by comparing the differences in pain intensity and sensitivity between adolescent patients with depressive disorders and healthy controls. Patients and Methods: A consecutive enrollment method was used to select 158 adolescent patients with depressive disorders from three hospitals in Anhui Province as the MDD group, and 47 healthy adolescents were recruited as the Control group. The subjects' suicidal ideation was assessed using the Positive and Negative Suicide Ideation scale (PANSI), and the intensity of somatic pain was assessed using the Numerical Rating Scale-11 (NRS-11). Subjects were assessed for forearm and tibial pain sensitivity using a hand-held pressure pain instrument, and experimental pain sensitivity measures included pressure pain threshold (PPT) and pressure pain tolerance (PTO). Differences in pain intensity and sensitivity between the MDD group and the Control group were compared, and the association of pain intensity and sensitivity with suicidal ideation was analyzed. Results: The incidence of physical pain in adolescent depressive disorder was higher at 88.6%, which was significantly higher than the Control group (P<0.001), and the pain intensity in the MDD group (3.77±2.48) was significantly higher than the Control group (0.617±0.99) (P <0.001).The Pain tolerance was significantly higher in the MDD group (forearm 105.37 ± 41.46; tibia 121.29 ± 41.60) than in the Control group (forearm 91.92 ± 37.62; tibia 105.47 ± 35.52) (P < 0.05).Linear regression analysis showed that the greater the pain intensity and pain tolerance, the higher the total PANSI score.Binary logistic regression showed that pain intensity was an influencing factor for suicidal ideation. Conclusion: Adolescents with depressive disorders have higher pain intensity and lower pain sensitivity than healthy adolescents. Increased pain intensity and pain tolerance were positively correlated with suicidal ideation.

Efficient Deep-Blue Organic Light-Emitting Diodes Employing Doublet Sensitization.

Fast and efficient exciton utilization is a crucial solution and highly desirable for achieving high-performance blue organic light-emitting diodes (OLEDs). However, the rate and efficiency of exciton utilization in traditional OLEDs, which employ fully closed-shell materials as emitters, are inevitably limited by spin statistical limitations and transition prohibition. Herein, a new sensitization strategy, namely doublet-sensitized fluorescence (DSF), is proposed to realize high-performance deep-blue electroluminescence. In the DSF-OLED, a doublet-emitting cerium(III) complex, Ce-2, is utilized as sensitizer for multi-resonance thermally activated delayed fluorescence emitter ν-DABNA. Experimental results reveal that holes and electrons predominantly recombine on Ce-2 to form doublet excitons, which subsequently transfer energy to the singlet state of ν-DABNA via exceptionally fast (over 108 s-1) and efficient (≈100%) Förster resonance energy transfer for deep-blue emission. Due to the circumvention of spin-flip in the DSF mechanism, near-unit exciton utilization efficiency and remarkably short exciton residence time of 1.36 µs are achieved in the proof-of-concept deep-blue DSF-OLED, which achieves a Commission Internationale de l'Eclairage coordinate of (0.13, 0.14), a high external quantum efficiency of 30.0%, and small efficiency roll-off of 14.7% at a luminance of 1000 cd m-2. The DSF device exhibits significantly improved operational stability compared with unsensitized reference device.

From expansion to efficiency: Machine learning-based forecasting of Japan's building material stocks under demographic declines.

Japan's unique demographic trajectory, marked by population decline and aging, coupled with continued urbanization, presents distinct challenges for aligning built environment capacity with resource efficiency. This study aims to investigate the historical evolution and project future scenarios of building material stock (MS) and their spatial distribution across Japan's three major metropolitan areas. Through a comprehensive material flow and stock analysis, the historical accumulation of building materials from 2009 to 2020 was quantified, revealing a dominance of concrete and an increasing overall stock. The contributions of various driving factors to changes in construction areas were explored, identifying population dynamics as the predominant influence. Leveraging shared socioeconomic pathway scenarios (SSPs), this research forecasted building floor area and MS until 2050 under five distinct SSPs. The results indicated an overall reduction across all scenarios, yet with a continued concentration in high-density urban cores. The substantial gap between the highest and lowest projected MS scenarios highlighted opportunities for material conservation and emission reductions through sustainable practices. Sustainable urban development in densely populated regions necessitates a balance between infrastructure provision and environmental conservation, while in sparsely populated areas, the focus shifts to the efficient management and utilization of vacant properties and materials to cope with the impacts of significant population declines. By offering insights into the building floor area and MS implications of Japan's demographic changes, this study underscores the necessity of sustainable urban planning and resource management strategies to navigate the challenges posed by demographic shifts, ultimately contributing to sustainable development and environmental conservation goals.

Solid-state nanochannels based on electro-optical dual signals for detection of analytes.

The sensitive detection of analytes of different sizes is crucial significance for environmental protection, food safety and medical diagnostics. The confined space of nanochannels provides a location closest to the molecular reaction behaviors in real systems, thereby opening new opportunities for the precise detection of analytes. However, due to the susceptibility to external interference on the confined space of nanochannels, the high sensitivity nature of the current signals through the nanochannels is more troubling for the detection reliability. Combining highly sensitive optical signals with the sensitive current signals of solid-state nanochannels establishes a nanochannel detection platform based on electro-optical dual signals, potentially offering more sensitive, specific, and accuracy detection of analytes. This review summarizes the last five years of applications of solid-state nanochannels based on electro-optical dual signals in analytes detection. Firstly, the detection principles of solid-state nanochannels and the construction strategies of nanochannel electro-optical sensing platforms are discussed. Subsequently, the review comprehensively outlines the applications involving nanochannels with electrical signals combined with fluorescence signals, electrical signals combined with surface-enhanced Raman spectroscopy signals, and electrical signals combined with other optical signals in analyte detection. Additionally, the perspectives and difficulties of nanochannels are investigated on the basis of electro-optical dual signals.

A Review on Recent Advancements of Biomedical Radar for Clinical Applications.

The field of biomedical radar has witnessed significant advancements in recent years, paving the way for innovative and transformative applications in clinical settings. Most medical instruments invented to measure human activities rely on contact electrodes, causing discomfort. Thanks to its non-invasive nature, biomedical radar is particularly valuable for clinical applications. A significant portion of the review discusses improvements in radar hardware, with a focus on miniaturization, increased resolution, and enhanced sensitivity. Then, this paper also delves into the signal processing and machine learning techniques tailored for radar data. This review will explore the recent breakthroughs and applications of biomedical radar technology, shedding light on its transformative potential in shaping the future of clinical diagnostics, patient and elderly care, and healthcare innovation.

Cell-Specific Effects of Insulin in a Murine Model of Restenosis Under Insulin-Sensitive and Insulin-Resistant Conditions.

Restenosis following percutaneous revascularization is a major challenge in patients with insulin resistance and diabetes. Currently, the vascular effects of insulin are not fully understood. In vitro, insulin's effects on endothelial cells (ECs) are beneficial, whereas on vascular smooth muscle cells (SMCs), they are mitogenic. We previously demonstrated a suppressive effect of insulin on neointimal growth under insulin-sensitive conditions that was abolished in insulin-resistant conditions. Here, we aimed to determine the cell-specific effects of insulin on neointimal growth in a model of restenosis under insulin-sensitive and insulin-resistant conditions. Vascular cell-specific insulin receptor (IR)-deficient mice were fed a low-fat diet (LFD) or a high-fat, high-sucrose diet (HFSD) and implanted with an insulin pellet or vehicle prior to femoral artery wire injury. In insulin-sensitive conditions, insulin decreased neointimal growth only in controls. However, under insulin-resistant conditions, insulin had no effect in either control, EC-specific or SMC-specific IR-deficient mice. These data demonstrate that EC and SMC IRs are required for the anti-restenotic effect of insulin in insulin-sensitive conditions and that, in insulin resistance, insulin has no adverse effect on vascular SMCs in vivo.

Enhanced Energy Storage Properties and DFT Investigation of a Zn-Co-Mo Heterojunction Rich in Oxygen Vacancies with Dual Electron Transport Pathways.

Petal-like heterojunction materials ZnCo2O4/CoMoO4 with abundant oxygen vacancies are prepared on nickel foam (NF) using modified ionic hybrid thermal calcination technology. Nanoscale ion intermixing between Zn and Mo ions induces oxygen vacancies in the annealing process, thus creating additional electrochemical active sites and enhancing the electrical conductivity. The ZnCo2O4/CoMoO4 conductive network skeleton forms the primary transport pathway for electrons, while the internal electric field of the heterojunction serves as the secondary pathway. ZnCo2O4/CoMoO4 exhibits excellent rate performance and high capacity attributable to its unique double electron transport mode and the effect of oxygen vacancies. The initial discharge capacity at a current of 0.1 A g-1 is approximately 1774 mAh g-1, and the reversible capacity remains at 1100 mAh g-1 after 200 cycles. After a high current of 1 A g-1, the reversible capacity is observed to remain at approximately 1240 mAh g-1. The electronic structure, crystal structure, and work function of the heterojunction interface model are then analyzed by density functional theory (DFT). The analysis results indicate that the charge at the ZnCo2O4/CoMoO4 interface is unevenly distributed, which leads to an enhanced degree of electrochemical reaction. The presence of an internal electric field improves the transport efficiency of the carriers. Experimental and theoretical calculations demonstrate that the ZnCo2O4/CoMoO4 anode material designed in this work provides a reference for fabricating transition metal oxide-based lithium-ion batteries.

Physiologically based pharmacokinetic models for predicting lamotrigine exposure and dose optimization in pediatric patients receiving combination therapy with carbamazepine or valproic acid.

INTRODUCTION: Lamotrigine (LTG) is an antiepileptic drug that has been used in pediatric epilepsy as a combination therapy or monotherapy after stabilization in recent years. However, there are significant drug-drug interactions (DDI) between LTG and combined drugs such as carbamazepine (CBZ) and valproic acid (VPA). It is particularly important to consider the risk of DDI in combination therapy for intractable epilepsy in pediatric patients. Therefore, it is necessary to adjust the dosage of LTG accordingly. The aim of this study was to establish and validate a pediatric physiologically based pharmacokinetic (PBPK) model for predicting LTG exposure. The model is designed to explore the potential for quantifying pharmacokinetic (PK) DDI of LTG when administered concurrently with CBZ or VPA in pediatric patients. METHOD: Adult and pediatric PBPK models for LTG and VPA were developed using PK-Sim® software in combination with physiological information and drug-specific parameters, and a DDI model was developed in combination with the published CBZ model. The models were validated against available PK data. RESULTS: Predictive and observational results in adults, children, and the DDI model were in good agreement. The recommended doses of LTG for preschool children (2-6 years) and school-aged children (6-12 years) in the absence of drug interactions were 1.47 and 1.2 times higher than those for adults, respectively; 3.1 and 2.6 times higher than those for adults in combination with CBZ; and 0.67 and 0.57 times lower than those for adults in combination with VPA. In addition, plasma exposures in adolescents (12-18 years) were similar to those in adults at the same doses. CONCLUSION: We have successfully developed PBPK models and DDI models for LTG in adults and children, which provide a reference for rational drug use in the pediatric population.

Differential EBV protein-specific antibody response between responders and non-responders to EBVSTs immunotherapy.

Epstein-Barr virus (EBV) is associated with a diverse range of lymphomas. EBV-specific T-cell (EBVST) immunotherapies have shown promise in safety and clinical effectiveness in treating EBV-associated lymphomas, but not all patients respond to treatment. To identify the set of EBV-directed antibody responses associated with clinical response in patients with EBV-associated lymphomas, we comprehensively characterized the immune response to the complete EBV proteome using a custom protein microarray in 56 EBV-associated lymphoma patients who were treated with EBVST infusions enrolled in Phase I clinical trials. Significant differences in antibody profiles between responders and non-responders emerged at 3 months post-EBVST infusion. Twenty-five IgG antibodies were present at significantly higher levels in non-responders compared to responders at 3 months post-EBVST infusion, and 10 of these IgG antibody associations remained after adjustment for sex, age, and cancer diagnosis type. Random forest prediction analysis further confirmed that these 10 antibodies were important for predicting clinical response. Differential IgG antibody responses were directed against LMP2A (four fragments), BGRF1/BDRF1 (two fragments), LMP1, BKRF2, BKRF4, and BALF5. Paired analyses using blood samples collected at both pre-infusion and 3 months post-EBVST infusion indicated an increase in the mean antibody level for six other anti-EBV antibodies (IgG: BGLF2, LF1, BGLF3; IgA: BGLF3, BALF2, BBLF2/3) in non-responders. Overall, our results indicate that EBV-directed antibodies can be biomarkers for predicting the clinical response of individuals with EBV-associated lymphomas treated with EBVST infusions.