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Objective: We aimed to determine the piperacillin disposition and optimize the dosing regimens for infants and children with pneumonia., Methods: An opportunistic sampling strategy was used in this pharmacokinetic study. High-performance liquid chromatography was used to measure the concentrations of piperacillin in plasma samples. A population pharmacokinetic model was conducted using NONMEM., Results: The pharmacokinetic data of 90 samples from 64 infants and children with pneumonia (age range: 0.09-1.72 years for infants and 2.12-11.10 years for children) were available. A two-compartment model with first-order elimination was the most suitable model to describe the population pharmacokinetics of piperacillin. A covariate analysis indicated that body weight and age were significant factors affecting clearance. Monte Carlo simulations showed that a 50-mg/kg every 8 h or every 12 h dosing regimen results in underdosing. Results both in infants and children showed that an extended infusion (3 h) of various dosing regimens (80, 100, or 130 mg/kg) three times daily or a 300-mg/kg continuous infusion can reach a therapeutic level based on the chosen target for the probability of target attainment threshold of 70%, 80%, and 90% at minimum inhibitory concentration breakpoints of 8 mg/L and 16 mg/L., Conclusions: A population pharmacokinetic model was obtained to evaluate the disposition of piperacillin, and the optimal dosing regimens were provided for use in infants and children with pneumonia., Competing Interests: Declarations. Funding: This work was supported by the National Key Research and Development Program of China (2023YFC2706100), the National Natural Science Foundation of China (82173897), the Distinguished Young and Middle-aged Scholar of Shandong University, and the Taishan Scholar Program of Shandong Province (tstp20230660). Conflicts of Interest/Competing Interests: Totsapol Jirasomprasert, Li-Yuan Tian, Dian-Ping You, Ya-Kun Wang, Lei Dong, Ya-Hui Zhang, Guo-Xiang Hao, John van den Anker, Yue-E Wu, Bo-Hao Tang, Wei Zhao, and Yi Zheng have no conflicts of interest that are directly relevant to the content of this article. Ethics Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Approval was obtained from the institutional ethics committee. Consent to Participate: Written informed consent was obtained from all parents of the children included in the study. Consent for Publication: Not applicable. Availability of Data and Material: The data that support the findings of this study are available from the corresponding author upon reasonable request. Code Availability: The research code is available from the corresponding author upon reasonable request. Authors’ Contributions: TJ analyzed and interpreted the data for the work, drafted the initial manuscript, and revised the manuscript. L-YT, D-PY, Y-KW, and LD collected the clinical data. G-XH and Y-HZ determined the samples. JvdA and Y-EW provided advice and critically reviewed and revised the manuscript. B-HT, WZ, and YZ contributed equally to the design of the work, supervised the data collection, and critically reviewed and revised the manuscript., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To explore how Qingfei Zhisou oral liquid (, QFZS) adjusts body temperature bias and the interaction of inflammatory factors levels and metabolomic differences., Methods: Dry yeast was subcutaneously injected at 10 mL/kg to establish the pyrexia model. We randomly divided 60 Sprague-Dawley rats into five groups: control, model, positive, low dose of QFZS and high dose of QFZS. Inflammatory proteins were evaluated by Western blotting and immunohistochemistry. For the examination of the endogenous metabolites, enzyme linked immunosorbent assay and ultra-high-performance liquid chromatography high-resolution mass spectrometry were employed., Results: QFZS significantly reduced rats' body temperature within 6 h after dry yeast injection and reduced the secretion of the arginine vasopressin, cyclic adenosine monophosphate, prostaglandin E-2, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β in serum. Meanwhile, we identified 41 metabolites between the model and QFZS groups, including arachidonic acid and lysophospholipids. QFZS restored normal arachidonic acid levels. Based on the differential metabolite enrichment analysis, QFZS's anti-inflammatory and anti-pyrexia effects might be related to the inflammatory pathway regulated by transient receptor potential. Additionally, QFZS treatment reduced transient receptor potential melastatin 2 ion channel expression and affected TNF-α, heat shock protein 70, and cyclooxygenase-2 expression in the hypothalamus., Conclusion: QFZS exerts its regulatory effects on fever by regulating the metabolism of lysophospholipids and arachidonic acid and the regulation of inflammation via transient receptor potential ion channels channels.

Objectives: The optimal dosing regimen of caspofungin in adolescents undergoing allogeneic haematopoietic stem cell transplantation against Candida spp. is unknown. The study aimed to compare body surface area (BSA)-based and fixed dosing regimens through population pharmacokinetic (PPK) analysis and to optimize dosing regimens likely to achieve therapeutic exposures., Methods: Opportunistic sampling was used to collect plasma concentrations through a prospective observational pharmacokinetic study. PPK analysis and Monte Carlo simulations (n = 1000) were performed using NONMEM., Results: A total of 86 samples of 30 adolescents (12-17 years old) were best described by a two-compartment pharmacokinetic model. BSA is the only covariate on clearance and central volume of distribution. For Candida glabrata and Candida albicans, a standard dosing regimen could achieve at least a 90% probability of target attainment for the indicator of AUC0-24/MIC90. Dosing regimen simulations identified a BSA cut-off value of 1.3 m2, where a fixed loading dose (LD) is preferred when BSA ≥ 1.3 m2 and a BSA-based LD is preferred when BSA < 1.3 m2. For maintenance dose (MD), however, the BSA-based dose was proposed, regardless of BSA. The current maximum dosing regimen of LD 70 mg/day and MD 70 mg/day could not result in sufficient antifungal exposure for Candida parapsilosis with MIC90 of 1 mg/L. Furthermore, an LD of 70 mg/day and MD of 60 mg/m2/day rendered 90.4% steady-state trough concentration (Ctrough) over 1 mg/L in the virtual population., Conclusions: Our study proposed optimized dosing regimens of caspofungin based on AUC0-24/MIC90 or Ctrough, which may support further individualized treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The challenges of drug development in pediatric, pregnant and geriatric populations are a worldwide concern shared by regulatory authorities, pharmaceutical companies, and healthcare professionals. Model-informed drug development (MIDD) can integrate and quantify real-world data of physiology, pharmacology, and disease processes by using modeling and simulation techniques to facilitate decision-making in drug development. In this article, we reviewed current MIDD policy updates, reflected on the integrity of physiological data used for MIDD and the effects of physiological changes on the drug PK, as well as summarized current MIDD strategies and applications, so as to present the state of the art of MIDD in pediatric, pregnant and geriatric populations. Some considerations are put forth for the future improvements of MIDD including refining regulatory considerations, improving the integrity of physiological data, applying the emerging technologies, and exploring the application of MIDD in new therapies like gene therapies for special populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Eltrombopag was approved as a first-line treatment for patients older than 2 years old with severe aplastic anemia (SAA). However, data on eltrombopag in children with different types of aplastic anemia (AA), especially non-severe AA (NSAA), are limited. We performed a prospective, single-arm, and observational study to investigate eltrombopag's efficacy, safety, and pharmacokinetics in children with NSAA, SAA, and very severe AA (VSAA). The efficacy and safety were assessed every 3 months. The population pharmacokinetic (PPK) model was used to depict the pharmacokinetic profile of eltrombopag. Twenty-three AA children with an average age of 7.9 (range of 3.0-14.0) years were enrolled. The response (complete and partial response) rate was 12.5%, 50.0%, and 100.0% after 3, 6, and 12 months in patients with NSAA. For patients with SAA and VSAA, these response rates were 46.7%, 61.5%, and 87.5%. Hepatotoxicity occurred in one patient. Fifty-three blood samples were used to build the PPK model. Body weight was the only covariate for apparent clearance (CL/F) and volume of distribution. The allele-T carrier of adenosine triphosphate-binding cassette transporter G2 was found to increase eltrombopag's clearance. However, when normalized by weight, the clearance between the wild-type and variant showed no statistical difference. In patients with response, children with NSAA exhibited lower area under the curve from time zero to infinity, higher CL/F, and higher weight-adjusted CL/F than those with SAA or VSAA. However, the differences were not statistically significant. The results may support further individualized treatment of eltrombopag in children with AA., (© 2024, The American College of Clinical Pharmacology.)

Satisfactory separation of milk-derived extracellular vesicles (MEVs) is important for the downstream analysis of the functions and properties of MEVs. However, the presence of abundant proteins in milk hindered the separation of MEVs. In this study, three pretreatment methods, including sodium citrate (SC), acetic acid (AA), and high-speed centrifugation, were adopted to separate MEVs from goat milk while minimizing the impact of protein. The MEVs were then characterized by nanoparticle tracking, transmission electron microscopy and western blotting experiments. The results indicated that pretreatments with AA and SC greatly decreased the impact of casein, but AA pretreatment damaged the surface structure of MEVs. Additionally, the differential centrifugation process resulted in a slight loss of MEVs. Overall, MEVs with small size and high purity can be obtained under 125 k × g centrifugation combined with SC pretreatment, which suggests a promising method for separation of MEVs from goat milk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Addison's disease and X-linked adrenoleukodystrophy (X-ALD) (Addison's-only) are two diseases that need to be identified. Addison's disease is easy to diagnose clinically when only skin and mucosal pigmentation symptoms are present. However, X-ALD (Addison's-only) caused by ABCD1 gene variation is ignored, thus losing the opportunity for early treatment. This study described two patients with initial clinical diagnosis of Addison's disease. However, they rapidly developed neurological symptoms triggered by infection. After further genetic testing, the two patients were diagnosed with X-ALD., Methods: We retrospectively analyzed X-ALD patients admitted to our hospital. Clinical features, laboratory test results, and imaging data were collected. Whole-exome sequencing was used in molecular genetics., Results: Two patients were included in this study. Both of them had significantly increased adrenocorticotropic hormone level and skin and mucosal pigmentation. They were initially clinically diagnosed with Addison's disease and received hydrocortisone treatment. However, both patients developed progressive neurological symptoms following infectious disease. Further brain magnetic resonance imaging was completed, and the results suggested demyelinating lesions. Molecular genetics suggested variations in the ABCD1 gene, which were c.109&#95;110insGCCA (p.C39Pfs*156), c.1394-2 A > C (NM&#95;000033), respectively. Therefore, the two patients were finally diagnosed with X-ALD, whose classification had progressed from X-ALD (Addison's-only) to childhood cerebral adrenoleukodystrophy (CCALD). Moreover, the infection exacerbates the demyelinating lesions and accelerates the onset of neurological symptoms. Neither the two variation sites in this study had been previously reported, which extends the ABCD1 variation spectrum., Conclusions: Patients with only symptoms of adrenal insufficiency cannot be simply clinically diagnosed with Addison's disease. Being alert to the possibility of ABCD1 variation is necessary, and complete genetic testing is needed as soon as possible to identify X-ALD (Addison's-only) early to achieve regular monitoring of the disease and receive treatment early. In addition, infection, as a hit factor, may aggravate demyelinating lesions of CCALD. Thus, patients should be protected from external environmental factors to delay the progression of cerebral adrenoleukodystrophy., (© 2024. The Author(s).)

Background: Accurate prediction of the optimal dose for β-lactam antibiotics in neonatal sepsis is challenging. We aimed to evaluate whether a reliable clinical decision support system (CDSS) based on machine learning (ML) can assist clinicians in making optimal dose selections., Methods: Five β-lactam antibiotics (amoxicillin, ceftazidime, cefotaxime, meropenem and latamoxef), commonly used to treat neonatal sepsis, were selected. The CDSS was constructed by incorporating the drug, patient, dosage, pharmacodynamic, and microbiological factors. The CatBoost ML algorithm was used to build the CDSS. Real-world studies were used to evaluate the CDSS performance. Virtual trials were used to compare the CDSS-optimized doses with guideline-recommended doses., Findings: For a specific drug, by entering the patient characteristics and pharmacodynamic (PD) target (50%/70%/100% fraction of time that the free drug concentration is above the minimal inhibitory concentration [fT > MIC]), the CDSS can determine whether the planned dosing regimen will achieve the PD target and suggest an optimal dose. The prediction accuracy of all five drugs was >80.0% in the real-world validation. Compared with the PopPK model, the overall accuracy, precision, recall, and F1-Score improved by 10.7%, 22.1%, 64.2%, and 43.1%, respectively. Using the CDSS-optimized doses, the average probability of target concentration attainment increased by 58.2% compared to the guideline-recommended doses., Interpretation: An ML-based CDSS was successfully constructed to assist clinicians in selecting optimal β-lactam antibiotic doses., Funding: This work was supported by the National Natural Science Foundation of China; Distinguished Young and Middle-aged Scholar of Shandong University; National Key Research and Development Program of China., Competing Interests: Declaration of interests All authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Isoniazid is a first-line antituberculosis agent with high variability, which would profit from individualized dosing. Concentrations of isoniazid at 2 h (C 2h ), as an indicator of safety and efficacy, are important for optimizing therapy., Objective: The objective of this study was to establish machine learning (ML) models to predict the C 2h , that can be used for establishing an individualized dosing regimen in clinical practice., Methods: Published population pharmacokinetic (PopPK) models for adults were searched based on PubMed and ultimately four reliable models were selected for simulating individual C 2h datasets under different conditions (demographics, genotype, ethnicity, etc.). Machine learning models were trained on simulated C 2h obtained from the four PopPK models. Five different algorithms were used for ML model building to predict C 2h . Real-world data were used for predictive performance evaluations. Virtual trials were used to compare ML-optimized doses with PopPK model-optimized doses., Results: Categorical boosting (CatBoost) exhibited the highest prediction ability. Target C 2h can be predicted using the ML model combined with the dosing regimen and three covariates (N-acetyltransferase 2 [NAT2] genotypes, weight and race [Asians and Africans]). Real-world data validation results showed that the ML model can achieve an overall prediction accuracy of 93.4%. Using the final ML model, the mean absolute prediction error value decreased by 45.7% relative to the average of PopPK models. Using the ML-optimized dosing regimen, the probability of target attainment increased by 43.7% relative to the PopPK model-optimized dosing regimens., Conclusion: Machine learning models were developed with great predictive performance, which can be used to determine the individualized initial dose of isoniazid in adult patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Bacterial infection is one of the major causes of neonatal morbidity and mortality worldwide. Finding rapid and reliable methods for early recognition and diagnosis of bacterial infections and early individualization of antibacterial drug administration are essential to eradicate these infections and prevent serious complications. However, this is often difficult to perform due to non-specific clinical presentations, low accuracy of current diagnostic methods, and limited knowledge of neonatal pharmacokinetics. Although neonatal medicine has been relatively late to embrace the benefits of machine learning (ML), there have been some initial applications of ML for the early prediction of neonatal sepsis and individualization of antibiotics. This article provides a brief introduction to ML and discusses the current state of the art in diagnosing and treating neonatal bacterial infections, gaps, potential uses of ML, and future directions to address the limitations of current studies. Neonatal bacterial infections involve a combination of physiologic development, disease expression, and treatment response outcomes. To address this complex relationship, future models could consider appropriate ML algorithms to capture time series features while integrating influences from the host, microbes, and drugs to optimize antimicrobial drug use in neonates. All models require prospective clinical trials to validate their clinical utility before clinical use., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In this work, a novel 3D-DNA walker signal amplification strategy was designed to construct a fluorescent aptasensor for the detection of kanamycin (KAN). The aptasensor utilizes split aptamers for the synergistic recognition of KAN. The presence of KAN induces the split aptamers recombination to form the Mg 2+ -DNAzyme structure, which is activated by Mg 2+ to drive the 3D-DNA walker process for cascading signal amplification. Employing gold nanoflowers (AuNFs) as walking substrate material increases the local DNA concentration to enhance the walker efficiency. The prepared fluorescent aptasensor achieved efficient and sensitive detection of KAN with satisfactory results in the concentration range of 1 × 10 -8 - 1 × 10 -3  μg/kg and the detection limit of 5.63 fg/kg. Meanwhile, the designed fluorescent aptasensor exhibited favorable specificity, anti-interference, storage stability and reproducibility, and verified the feasibility of its application in milk samples. The present work provides an effective tool for the regulation of KAN contamination in animal-derived foods with promising prospects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Levofloxacin is a quinolone antibiotic with a broad antibacterial spectrum. It is frequently used in elderly patients with pneumonia. The pharmacokinetic profile of elderly patients changes with age, but data on the pharmacokinetics of levofloxacin in these patients are limited. The aim of this study was to establish a population pharmacokinetic model of levofloxacin in elderly patients with pneumonia and to optimize individualized dosing regimens based on this newly developed model., Methods: This is a prospective, open-label pharmacokinetic study in elderly patients with pneumonia. Blood samples were collected using an opportunistic approach. The plasma concentrations of levofloxacin were determined by high-performance liquid chromatography. A population pharmacokinetic model was established using nonlinear mixed-effect model software. Monte Carlo simulations were used for dose simulation and dose optimization., Results: Data from 51 elderly patients with pneumonia were used for the population pharmacokinetic analysis. A one-compartment model with first-order elimination was most suitable for describing the data, and the estimated glomerular filtration rate was the only covariate that had a significant impact on the model. The final model estimated that the mean clearance of levofloxacin in elderly patients with pneumonia was 5.26 L/h. Monte Carlo simulation results showed that the optimal dosing regimen for levofloxacin was 750 mg once a day in elderly patients with pneumonia, with a minimum inhibitory concentration of 2 mg/L., Conclusions: The population pharmacokinetic model of levofloxacin in elderly patients with pneumonia was established, and the dose optimization of levofloxacin was completed through Monte Carlo simulation., (© 2024 British Pharmacological Society.)

The application of machine learning (ML) has shown promising results in precision medicine due to its exceptional performance in dealing with complex multidimensional data. However, using ML for individualized dosing of medicines is still in its early stage, meriting further exploration. A systematic review of study designs and modeling details of using ML for individualized dosing of different drugs was performed. We have summarized the status of the study populations, predictive targets, and data sources for ML modeling, the selection of ML algorithms and features, and the evaluation and validation of their predictive performance. We also used the Prediction model Risk of Bias Assessment Tool (PROBAST) to assess the risk of bias of included studies. Currently, ML can be used for both a priori and a posteriori dose selection and optimization, and it can also assist the implementation of therapeutic drug monitoring. However, studies are mainly focused on drugs with narrow therapeutic windows, predominantly immunosuppressants (N = 23, 35.9%) and anti-infectives (N = 21, 32.8%), and there is currently only very limited attention for special populations, such as children (N = 22, 34.4%). Most studies showed poor methodological quality and a high risk of bias. The lack of external validation and clinical utility evaluation currently limits the further clinical implementation of ML for dose individualization. We therefore have proposed several ways to improve the clinical relevance of the studies and facilitate the translation of ML models into clinical practice., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Older individuals face an elevated risk of developing bacterial infections. The optimal use of antibacterial agents in this population is challenging because of age-related physiological alterations, changes in pharmacokinetics (PK) and pharmacodynamics (PD), and the presence of multiple underlying diseases. Therefore, population pharmacokinetics (PPK) studies are of great importance for optimizing individual treatments and prompt identification of potential risk factors., Area Covered: Our search involved keywords such as 'elderly,' 'old people,' and 'geriatric,' combined with 'population pharmacokinetics' and 'antibacterial agents.' This comprehensive search yielded 11 categories encompassing 28 antibacterial drugs, including vancomycin, ceftriaxone, meropenem, and linezolid. Out of 127 studies identified, 26 (20.5%) were associated with vancomycin, 14 (11%) with meropenem, and 14 (11%) with piperacillin. Other antibacterial agents were administered less frequently., Expert Opinion: PPK studies are invaluable for elucidating the characteristics and relevant factors affecting the PK of antibacterial agents in the older population. Further research is warranted to develop and validate PPK models for antibacterial agents in this vulnerable population.

Background: Subjective hearing loss (SHL) refers to an individual's self-assessment of their hearing loss. The association and underlying mechanisms between SHL and cognitive impairment still necessitate elucidation., Objectives: To validate potential mechanisms between SHL and cognitive impairment., Design: Cross-section., Setting: Shanghai, China., Participants: A total of 2369 individuals from communities and the cognitive disorder clinic., Measurements: All participants were subjected to a comprehensive neuropsychological assessment, encompassing the Hearing Handicap Inventory for the Elderly-Screening Version (HHIE-S). The participants' brain β-amyloid (Aβ) deposition status, plasma biomarkers associated with Alzheimer's disease (AD), and cardiovascular risk factors were also collected., Results: In individuals with a heightened SHL, elevated HHIE-S score was linked to diminished cognitive and daily functioning as well as heightened levels of depressed mood. This correlation was observed in auditory memory performance but not in visual memory. The influence of SHL on cognitive function was mediated by depressed mood. SHL was associated with diabetes and smoking, whereas cognitive function was associated with hyperlipidemia and alcohol consumption. In individuals with positive brain Aβ deposition, SHL demonstrated associations with cognitive function independent of plasma Aβ42/40 ratio, P-tau181, neurofilament light chain, and APOE allele status., Conclusion: SHL has an independent effect on cognitive impairment. The findings do no provide evidence for the common cause mechanism. Instead, the findings support the presence of a cognitive resource mechanism and an impoverished environment mechanism, along with the potential for a pathological interaction mechanism., Competing Interests: The authors declare that they have no conflict of interest.

Background: Antibacterial therapy plays a crucial role in neonatal infections. The efficacy of antibacterial agents is closely related to the actual dose given to neonates. So we evaluated factors potentially affecting the actual dose of intravenous antibiotics during dispensing process in neonates., Methods: Meropenem, cefoperazone/sulbactam and piperacillin/tazobactam with two strengths were used to evaluate three methods. Method A (M A ) was diluted once and the volumes of 5% glucose for M A were meropenem 4.00 mL, cefoperazone/sulbactam 3.00 mL, piperacillin/tazobactam 9.00 mL. Method B (M B ) differed by doubling the volume of 5% glucose. The difference in method C (M C ) involved diluting with 5% glucose twice. The concentrations were measured by high-performance liquid chromatography. Relative error (RE) was used to evaluate the preparation accuracy., Results: The RE values using M A /M B /M C were: (1) meropenem 0.5 g: 15.1%, 8.0%, 10.4%; 0.25 g: 7.8%, 3.1%, 6.0%; (2) cefoperazone/sulbactam 1.5 g: 13.6%, 4.2%, 3.4%; 0.75 g: 8.8%, 3.5%, 4.0%; (3) piperacillin/tazobactam 4.5 g: 18.2%, 8.7%, 6.3%; 562.5 mg: 8.1%, 2.8%, 6.1%. M B was better than M A in all three drugs. No difference in RE values was found between single and double dilution, except meropenem with 0.25 g. Using M B , meropenem and piperacillin/tazobactam with small drug strength had higher accuracy in preparation., Conclusions: M B was suitable for neonatal drug dispensing because of its high accuracy and simple operation. Drugs with small strength were promoted due to the high accuracy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen., Competing Interests: Declaration of Competing Interest Yang Yang, Shao-Ping Peng, Yu-Mei Yang, Pan Shu, Pei-Jin Li, Shan Li, Hong-Lin Hu and Ren-Hong Tang are employees of Jiangsu Simcere Pharmaceutical Co., Ltd. Yan Xu is employee of Simcere of America. Other authors declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The use of antibiotics to treat diarrhea and other diseases early in life can lead to intestinal disorders in infants, which can cause a range of immune-related diseases. Intestinal microbiota diversity is closely related to dietary intake, with many oligosaccharides impacting intestinal microorganism structures and communities. Thus, oligosaccharide type and quantity are important for intestinal microbiota construction. Galactooligosaccharides (GOS) are functional oligosaccharides that can be supplemented with infant formula. Currently, information on GOS and its impact on intestinal microbiota diversity and disorders is lacking. Similarly, GOS is rarely reported within the context of intestinal barrier function. In this study, 16S rRNA sequencing, gas chromatography, and immunohistochemistry were used to investigate the effects of GOS on the intestinal microbiota and barrier pathways in antibiotic-treated mouse models. The results found that GOS promoted Bifidobacterium and Akkermansia proliferation, increased short-chain fatty acid levels, increased tight junction protein expression (occludin and ZO-1), increased secretory immunoglobulin A (SIgA) and albumin levels, significantly downregulated NF-κB expression, and reduced lipopolysaccharide (LPS), interleukin-IL-1β (IL-1β), and IL-6 levels. Also, a high GOS dose in ampicillin-supplemented animals provided resistance to intestinal damage.

Volatile organic compounds (VOCs) have harmful effects on human health and the environment but detecting low levels of VOCs is challenging due to a lack of reliable biomarkers. However, incorporating gold nanoparticles (Au NPs) into metal-organic frameworks (MOFs) shows promise for VOC detection. In this study, we developed nanoscale Au@UiO-66 that exhibited surface-enhanced Raman scattering (SERS) activity even at very low levels of toluene vapors (down to 1.0 ppm) due to the thickness of the shell and strong π-π interactions between benzenyl-type linkers and toluene. The UiO-66 shell also increased the thermal stability of the Au NPs, preventing aggregation up to 550 °C. This development may be useful for sensitive detection of VOCs for environmental protection purposes.

Background and Objective: High variability in vancomycin exposure in neonates requires advanced individualized dosing regimens. Achieving steady-state trough concentration (C 0 ) and steady-state area-under-curve (AUC 0-24 ) targets is important to optimize treatment. The objective was to evaluate whether machine learning (ML) can be used to predict these treatment targets to calculate optimal individual dosing regimens under intermittent administration conditions., Methods: C 0 were retrieved from a large neonatal vancomycin dataset. Individual estimates of AUC 0-24 were obtained from Bayesian post hoc estimation. Various ML algorithms were used for model building to C 0 and AUC 0-24 . An external dataset was used for predictive performance evaluation., Results: Before starting treatment, C 0 can be predicted a priori using the Catboost-based C 0 -ML model combined with dosing regimen and nine covariates. External validation results showed a 42.5% improvement in prediction accuracy by using the ML model compared with the population pharmacokinetic model. The virtual trial showed that using the ML optimized dose; 80.3% of the virtual neonates achieved the pharmacodynamic target (C 0 in the range of 10-20 mg/L), much higher than the international standard dose (37.7-61.5%). Once therapeutic drug monitoring (TDM) measurements (C 0 ) in patients have been obtained, AUC 0-24 can be further predicted using the Catboost-based AUC-ML model combined with C 0 and nine covariates. External validation results showed that the AUC-ML model can achieve an prediction accuracy of 80.3%., Conclusion: C 0 -based and AUC 0-24 -based ML models were developed accurately and precisely. These can be used for individual dose recommendations of vancomycin in neonates before treatment and dose revision after the first TDM result is obtained, respectively., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Infants and immunocompromised children with cytomegalovirus (CMV) infection have significant morbidity and mortality. Ganciclovir (GCV) and its oral prodrug valganciclovir (VGCV) are the major antiviral options of choice for the prophylaxis and treatment of CMV infection. However, with the currently recommended dosing regimens used in pediatric patients, large intra- and inter-individual variability of pharmacokinetic (PK) parameters and exposure are observed., Areas Covered: This review describes the PK and pharmacodynamic (PD) characteristics of GCV and VGCV in pediatrics. Moreover, the role of therapeutic drug monitoring (TDM) and current clinical practice for GCV and VGCV dosing regimens optimization in pediatrics are discussed., Expert Opinion: GCV/VGCV TDM has shown the potential value to improve the benefit/risk ratio in pediatrics when using the therapeutic ranges derived from adults. However, well-designed studies are required to evaluate the relationship of TDM with clinical outcomes. Furthermore, studies to explore the children-specific dose-response-effect relationships will be helpful to facilitate the TDM practice. In the clinical setting, optimal sampling methods such as limited sampling strategies for pediatrics can be used in TDM and intracellular ganciclovir triphosphate may be used as an alternative TDM marker.

This study aimed to assess the feasibility of utilizing geopolymer for repairing reinforced concrete beams. Three types of beam specimens were fabricated: benchmark specimens without any grooves, rectangular-grooved beams, and square-grooved beams. The repair materials employed included geopolymer material, and epoxy resin mortar, while carbon fiber sheets were used as reinforcement in select cases. The repair materials were applied to the rectangular and square-grooved specimens, with the carbon fiber sheets attached to the tension side of the specimens. To evaluate the flexural strength of the concrete specimens, a third-point loading test was conducted. The test results indicated that the geopolymer exhibited higher compressive strength and shrinkage rate compared to the epoxy resin mortar. Furthermore, the specimens reinforced with carbon fiber sheets demonstrated even greater strength than the benchmark specimens. In terms of flexural strength under cyclic third-point loading tests, the carbon fiber-reinforced specimens exhibited the ability to withstand over 200 cycles of repeated loading at 0.8 times the ultimate load. In contrast, the benchmark specimens could only withstand seven cycles. These findings highlight that the use of carbon fiber sheets not only enhances compressive strength but also improves resistance to cyclic loading.

Ceftriaxone is widely used in children with community-acquired pneumonia. Currently, there are no available data regarding epithelial lining fluid (ELF) concentrations of ceftriaxone in children. Thus, blood and bronchoalveolar lavage fluids samples were collected by using an opportunistic sampling design, then we determined plasma and ELF concentrations in 22 children (0.5-11.7 years), with a total of 36 plasma and 22 ELF samples available for analysis. Ceftriaxone plasma and ELF concentrations ranged from 1.07 to 138.71 mg/L and from 0.61 to 26.69 mg/L, respectively. Ceftriaxone concentration in ELF was 12.18 ± 5.15 (mean ± standard deviation) times higher than that in plasma, ranging from 1.29 to 20.44., (© 2022 The British Pharmacological Society.)

The pharmacokinetic (PK) studies of meropenem in Chinese newborns with late-onset sepsis (LOS) are still lacking. Causative pathogens of LOS and their susceptibility patterns in China differ from the data abroad. We, therefore, conducted a developmental population pharmacokinetic−pharmacodynamic analysis in Chinese newborns with the goal to optimize meropenem dosing regimens for LOS therapy. An opportunistic sampling strategy was used to collect meropenem samples, followed by model building and validation. A Monte Carlo simulation was performed to show the probability of target attainment (PTA) for various dosages. The information from 78 newborns (postmenstrual age: 27.4−46.1 weeks) was compiled and had a good fit to a 1-compartment model that had first order elimination. The median (range) values of estimated weight−normalized volume of distribution (V)and clearance (CL) were 0.60 (0.51−0.69) L/kg and 0.16 (0.04−0.51) L/h/kg, respectively. Covariate analysis revealed that postnatal age (PNA), gestational age (GA) and current weight (CW) were the most important factors in describing meropenem PK. Simulation results showed for LOS with a minimal inhibitory concentration (MIC) of 8 mg/L, the doses of 30 mg/kg 3 times daily (TID) as a 1-h infusion for newborns with GA ≤ 37 weeks and 40 mg/kg TID as a 3-h infusion for those with GA > 37 weeks were optimal, with PTA of 71.71% and 75.08%, respectively. In conclusion, we proposed an evidence-based dosing regimen of meropenem for LOS in Chinese newborns by using the population pharmacokinetic−pharmacodynamic analysis, based on domestic common pathogens and their susceptibility patterns.

Post-synthesis modification is an effective strategy for the preparation of rare earth organic framework materials and the derivation of high-performance functional materials. Here, we report the preparation of a dual emission Ln-MOF material (Eu-Ca-MOF) using Ca-MOF as the parent framework and introducing Eu 3+ ions into its channels through post-synthesis modification. Eu-Ca-MOF has good photoluminescence properties and can be used as a ratiometric fluorescence sensor (I 381 /I 590 ) to detect Hg 2+ ions in water sensitively. The characteristic of Eu-Ca-MOF obtained is that when the material is dispersed in an aqueous solution containing Hg 2+ ions, the characteristic emission of the ligand at 381 nm is enhanced, while the characteristic emission of Eu 3+ at 590 nm is quenched. The peak-to-height ratio of the two emissions can be used to achieve highly sensitive detection of Hg 2+ ions even in the presence of other potentially competing analytes. In addition, Hg 2+ induces Eu-Ca-MOF to produce a significant ratiometric luminescence response, which changes its luminescence color from red to blue, which is beneficial to visual analysis of naked eyes. At the same time, Eu-Ca-MOF has a wider detection range (0.02-200 μM), and a lower limit detection (2.6 nM) for Hg 2+ ions. The lanthanide compounds prepared by post-synthetic modification provide an effective synthesis strategy for photoluminescent materials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Oligosaccharides and N / O -glycans are abundant in human milk and have numerous biological functions (for instance sialylated glycans provide sialic acid for the growth of infant brains), but their variation trends during lactation need further exploration. Qualitative and quantitative analyses of oligosaccharides and N / O -glycans in human milk at different lactation stages (from 7 days to 8 months) were performed using UHPLC-ESI-MS/MS. Thirty-four oligosaccharides, twenty-three N -glycans, and six O -glycans were identified. Oligosaccharides showed the highest abundance in human colostrum and decreased with the progression of lactation, and the abundance of N / O -glycans fluctuated as lactation progressed, while a high abundance of sialylated oligosaccharides and sialylated N / O -glycans was observed in human colostrum. These findings provide evidence for breastfeeding support and contribute to the development of infant formula supplemented with human milk glycans.

Objective: To assess the effect of dl-3-n-butylphthalide (NBP) on angiogenesis and its underlying mechanism in a rat model of chronic myocardial ischemia (CMI)., Methods: Forty Sprague-Dawley rats were randomly divided into four groups: model, low-dose NBP (L-NBP), middle-dose NBP (M-NBP), or high-dose NBP (H-NBP) (n=10/group). All groups received intraperitoneal injections of isoprinosine hydrochloride daily for 14 days. Additionally, the L-NBP, M-NBP, and H-NBP groups received NBP at 3, 6, and 12 mg per kg body weight, respectively, by intraperitoneal injection. An additional 10 rats (control group) received 0.9% sodium chloride via intraperitoneal injection for 14 consecutive days. Echocardiography was used for the measurement of heart function. Immunohistochemical staining for factor VIII-related antigen and microvascular density determination were performed. The protein and mRNA expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in CMI areas were measured by western blot and RT-PCR, respectively., Results: Electrocardiograms showed that NBP improved cardiac function by regulating left ventricular end-diastolic and end-systolic diameters, ejection fraction, and fractional shortening. Compared with the control and model groups, the L-NBP, M-NBP, and H-NBP groups showed increased mRNA and protein expression of VEGFA and HIF-1α in myocardial tissue. The mRNA and protein expression of VEGFA and HIF-α in the H-NBP group were the highest., Conclusion: NBP treatment promotes VEGF and HIF-1α protein expression during myocardial ischemia, which may represent useful biomarkers for coronary collateral establishment and offer potential targets for therapeutic induction of angiogenesis in patients with CMI., Competing Interests: None., (AJTR Copyright © 2022.)

Aims: Meropenem is increasingly used to treat neonatal sepsis. There are several guidelines recommending different dosing regimens of meropenem in neonates. Furthermore, deviations from these guidelines regularly occur in daily clinical practice. Therefore, the current study aimed to evaluate the variations of meropenem dosing guidelines and compare the difference between guideline and clinical practice in terms of the probability of target attainment., Methods: This study is based on a population pharmacokinetic model. After defining the predictive performance of the model, Monte Carlo simulations were used to calculate the probability of target attainment of the currently existing dosing guidelines of meropenem and their use in daily clinical practice., Results: Two guidelines and two labels were included in the Monte Carlo simulations. For 70% fT >MIC (fraction of time when the free meropenem concentration exceeded the minimum inhibitory concentration during the dosing interval), the probability of target attainment of four recommended doses ranged from 59% to 88% (MIC = 2 mg·L -1 ) and from 17% to 47% (MIC = 8 mg·L -1 ). At the clinical practice evaluation, only 20% of patients attained target exposure for the MIC of 8 mg·L -1 with 70% fT >MIC , which was much less than those found in the Food and Drug Administration labels (40%)., Conclusion: This model-based population pharmacokinetics simulation showed that improper guidelines and/or clinical practice deviations will result in low probability of target attainment for patients infected with resistant bacteria and critically ill patients. It is important to develop and adhere to evidence-based and clinically pragmatic guidelines., (© 2022 British Pharmacological Society.)

Background and Objective: Vancomycin is frequently used to treat Gram-positive bacterial infections in neonates. However, there is still no consensus on the optimal initial dosing regimen. This study aimed to assess the performance of pharmacokinetic model-based virtual trials to predict the dose-exposure relationship of vancomycin in neonates., Methods: The PubMed database was searched for clinical trials of vancomycin in neonates that reported the percentage of target attainment. Monte Carlo simulations were performed using nonlinear mixed-effect modeling to predict the dose-exposure relationship, and the differences in outcomes between virtual trials and real-world data in clinical studies were calculated., Results: A total of 11 studies with 14 dosing groups were identified from the literature to evaluate dose-exposure relationships. For the ten dosing groups where the surrogate marker for exposure was the trough concentration, the mean ± standard deviation (SD) for the target attainment between original studies and virtual trials was 3.0 ± 7.3%. Deviations between - 10 and 10% accounted for 80% of the included dosing groups. For the other four dosing groups where the surrogate marker for exposure was concentration during continuous infusion, all deviations were between - 10 and 10%, and the mean ± SD value was 2.9 ± 4.5%., Conclusion: The pharmacokinetic model-based virtual trials of vancomycin exhibited good predictive performance for dose-exposure relationships in neonates. These results might be used to assist the optimization of dosing regimens in neonatal practice, avoiding the need for trial and error., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Aims: Early-onset sepsis (EOS) is a common disease in neonates with a high morbidity and mortality rate. Piperacillin/tazobactam has been used extensively and empirically for EOS treatment without clinically validated dosing regimens, although the population pharmacokinetics (PPK) of piperacillin in neonates has been reported. Therefore, we wanted to study the effectiveness and tolerance of a PPK model-based dosing regimen of piperacillin/tazobactam in EOS patients., Methods: A prospective, single-centre, phase II clinical study of piperacillin/tazobactam in neonates with EOS was conducted. The dosing regimen (90 mg·kg -1 , q8h) was determined based on a previous piperacillin PPK model in young infants using NONMEM v7.4. The pharmacodynamics (PD) target (70%fT > MIC, free drug concentration above MIC during 70% of the dosing interval) attainment was calculated using NONMEM combined with an opportunistic sampling design. The clinical treatment data were collected., Results: A total of 52 neonates were screened and 49 neonates completed their piperacillin/tazobactam treatment course and were included in this analysis. The median (range) values of postmenstrual age were 33.57 (range 26.14-41.29) weeks. Forty-seven (96%) neonates reached their PD target. Eight (16%) neonates experienced treatment failure clinically. The mean (SD, range) duration of treatment and length of hospitalization were 100.1 (62.2, 36.2-305.8) hours and 31 (30, 5-123) days. There were no obvious adverse events and no infection-related deaths occurred in the first month of life., Conclusions: A model-based dosing regimen of piperacillin/tazobactam was evaluated clinically, was tolerated well and was determined to be effective for EOS treatment., (© 2021 British Pharmacological Society.)

Background: Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex problems in the current era of big data., Objective: The aim of this proof-of-concept study was to evaluate whether combining population pharmacokinetic and machine learning approaches could provide a more accurate prediction of the clearance of renally eliminated drugs in individual neonates., Methods: Six drugs that are primarily eliminated by the kidneys were selected (vancomycin, latamoxef, cefepime, azlocillin, ceftazidime, and amoxicillin) as 'proof of concept' compounds. Individual estimates of clearance obtained from population pharmacokinetic models were used as reference clearances, and diverse machine learning methods and nested cross-validation were adopted and evaluated against these reference clearances. The predictive performance of these combined methods was compared with the performance of two other predictive methods: a covariate-based maturation model and a postmenstrual age and body weight scaling model. Relative error was used to evaluate the different methods., Results: The extra tree regressor was selected as the best-fit machine learning method. Using the combined method, more than 95% of predictions for all six drugs had a relative error of < 50% and the mean relative error was reduced by an average of 44.3% and 71.3% compared with the other two predictive methods., Conclusion: A combined population pharmacokinetic and machine learning approach provided improved predictions of individual clearances of renally cleared drugs in neonates. For a new patient treated in clinical practice, individual clearance can be predicted a priori using our model code combined with demographic data., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Human epidermal growth factor receptor 2 (HER2)-directed treatments improve outcomes for patients with HER2-positive metastatic breast cancer (MBC). Current identification of patients with HER2-positive disease relies on tumor tissue testing, which can be inaccurate because of tumor heterogeneity or tumor evolution. Circulating tumor cells (CTCs) are often present in patients with cancer. We hypothesized that HER2 assessment of CTCs in patients with HER2-negative breast cancer could identify a subset of patients with HER2-positive CTCs who could benefit from HER2-directed treatments., Methods: This was a single-arm, two-stage, phase II trial. Patients with HER2-negative progressive MBC with HER2-positive CTC (defined as HER2/CEP17 ratio ≥ 2.0 by fluorescence in situ hybridization), ≥ 1 prior chemotherapy regimen for MBC, and no prior vinorelbine received trastuzumab in combination with vinorelbine on days 1, 8, and 15 of a 21-day cycle. The primary end point was objective response rate., Results: From January 2013 to June 2014, we prospectively screened CTCs from patients with HER2-negative MBC. CTCs were detected in 201 of 311 patients (65%). The median number of CTCs was 10 (interquartile range, 3-57). Sixty-nine of 311 patients (22%) had HER2+ CTCs, with a median of three HER2+ CTCs (range 1-21). Twenty patients with HER2+ CTCs were treated on study. At data cutoff (January 13, 2017), no patients remained on study therapy. The objective response rate was 5% (95% CI, 0.1 to 24.9), with one of 20 patients experiencing a partial response. The clinical benefit rate was 20.0% (1 partial response and 3 stable diseases > 24 weeks, 95% CI, 5.7% to 43.7%). The median progression-free survival was 2.7 months., Conclusion: CTC analysis of patients with HER2-negative MBC identifies a subset with HER2-amplified CTCs. However, clinical activity of an HER2-directed regimen in this population was low. The functional significance of HER2-positive CTCs remains uncertain., Competing Interests: Heather A. ParsonsConsulting or Advisory Role: Foundation MedicineResearch Funding: Puma Biotechnology (paid to institution) William T. BarryEmployment: Rho Gerburg M. WulfStock and Other Ownership Interests: Selecta BiosciencesResearch Funding: Merck, GlaxoSmithKlinePatents, Royalties, Other Intellectual Property: Pin1 as a marker for abnormal cell growth Patent number: 8129131 Steven J. IsakoffConsulting or Advisory Role: AbbVie, OncoPep, Puma Biotechnology, Seattle Genetics, NovartisResearch Funding: Genentech, PharmaMar, AbbVie, OncoPep, Merck, AstraZeneca/MedImmune, Outcomes4Me Ian E. KropEmployment: AMAG Pharmaceuticals, Freeline TherapeuticsLeadership: AMAG Pharmaceuticals, Freeline TherapeuticsStock and Other Ownership Interests: AMAG Pharmaceuticals, Freeline Therapeutics, VertexHonoraria: Genentech/Roche, AstraZeneca, CelltrionConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Daiichi Sankyo, Macrogenics, Taiho Pharmaceutical, Context Therapeutics, Novartis, Merck, Ionis Pharmaceuticals, Bristol Myers Squibb, AstraZenecaResearch Funding: Genentech, Pfizer, MacrogenicsNo other potential conflicts of interest were reported.

Objectives: This study aimed to evaluate the effects and the underlying mechanisms of tertiary butylhydroquinone (TBHQ) on diabetic liver steatosis and cell survival., Materials and Methods: We performed streptozocin injection and used a high-sugar-high-fat diet for mice to develop an animal model of type 2 diabetes mellitus (T2DM). Bodyweight, blood glucose levels, and content of insulin were measured on all of the mice. The liver tissues were observed by hematoxylin-eosin staining. Protein levels of the liver were measured by Western blot analysis in mice. Primary hepatocytes were induced by hypochlorous acid (HClO) and insulin to form insulin resistance (IR). Primary hepatocyte apoptosis was observed by Hoechst staining. The PI3K/AKT signaling pathway and β-arrestin-2 factor were evaluated by Western blot assay., Results: TBHQ reduced the blood glucose level and content of insulin in serum, increased body weight, and effectively alleviated liver steatosis in diabetic mice. TBHQ significantly up-regulated the expression of p-PI3K, p-AKT, GLUT4, GSK3β, and β-arrestin-2 in the liver of diabetic mice. Cell experiments confirmed that TBHQ increased the survival ability of primary hepatocytes, and TBHQ improved the expression of p-PI3K, p-AKT, GLUT4, and GSK3β by activating β-arrestin-2 in primary hepatocytes., Conclusion: TBHQ could alleviate liver steatosis and increase cell survival, and the mechanism is due in part to β-arrestin-2 activation., Competing Interests: The authors have no conflicts of interest to declare.

Purpose: Inflammation has a significant impact on CYP3A activity. We hypothesized that this effect might be age dependent. Our objective was to conduct a population pharmacokinetic study of midazolam in mice at different developmental stages with varying degrees of inflammation to verify our hypothesis., Methods: Different doses (2 and 5 mg/kg) of lipopolysaccharide (LPS) were used to induce different degrees of systemic inflammation in Swiss mice (postnatal age 9-42 days, n = 220). The CYP3A substrate midazolam was selected as the pharmacological probe to study CYP3A activity. Postnatal age, current body weight, serum amyloid A protein 1 (SAA1) levels and LPS doses were collected as covariates to perform a population pharmacokinetic analysis using NONMEM 7.2., Results: A population pharmacokinetic model of midazolam in juvenile and adult mice was established. Postnatal age and current body weight were the most significant and positive covariates for clearance and volume of distribution. LPS dosage was the most significant and negative covariate for clearance. LPS dosage can significantly reduce the clearance of midazolam by 21.8% and 38.7% with 2 mg/kg and 5 mg/kg, respectively. Moreover, the magnitude of the reduction was higher in mice with advancing postnatal age., Conclusion: Both inflammation and ontogeny have an essential role in CYP3A activity in mice. The effect of LPS-induced systemic inflammation on midazolam clearance in mice is dependent on postnatal age., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Zheng et al.)

Objective: The elucidation of CYP2D6 developmental pharmacogenetics in children has improved, however, these findings have been largely limited to studies of Caucasian children. Given the clear differences in CYP2D6 pharmacogenetic profiles in people of different ancestries, there remains an unmet need to better understand the developmental pharmacogenetics in populations of different ancestries. We sought to use loratadine as a substrate drug to evaluate the effects of ontogeny and pharmacogenetics on the developmental pattern of CYP2D6 in Chinese pediatric patients. Methods: Chinese children receiving loratadine treatment were enrolled in the present study. The metabolite-to-parent ratio (M/P ratio), defined as the molar ratio of desloratadine to loratadine of trough concentrations samples at steady-state condition, was used as a surrogate of CYP2D6 activity. Loratadine and desloratadine were determined by LC/MS/MS method. Variants of CYP2D6 were genotyped by polymerase chain reaction for CYP2D6 *4, *10, *41 and long polymerase chain reaction for CYP2D6 *5. Results: A total of 40 patients were available for final analysis. The mean age was 4.50 (range 0.50-9.00) years and the mean weight was 19.64 (range 7.00-42.00) kg. The M/P ratio was significantly lower in intermediate metabolizers (IMs) compared to normal metabolizers (NMs) (10.18 ± 7.97 vs. 18.80 ± 15.83, p = 0.03). Weight was also found to be significantly associated with M/P ratio ( p = 0.03). Conclusion: The developmental pharmacogenetics of CYP2D6 in Chinese children was evaluated using loratadine as a substrate drug. This study emphasizes the importance of evaluating the developmental pharmacogenetics in populations of different ancestries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Wu, Wang, Shi, Zhou, Zheng, Hao, Yang, Su, Wang, Yang and Zhao.)

Purpose: Considering prior investigations on reductions of renal multidrug resistance-associated protein (MRP) 2 and 4 transporters in mice with acute lymphoblastic leukemia (ALL), we sought to characterize the underlying mechanisms responsible for IL-6/STAT3/PXR-mediated changes in the expression of MRP2 and MRP4 in ALL., Subjects and Methods: ALL xenograft models were established and intravenously injected with methotrexate (MTX) of MRPs substrate in NOD/SCID mice. Protein expression of MRPs and associated mechanisms were detected by Western blotting and immunocytochemistry. Plasma concentrations of MTX were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS)., Results: Plasma IL-6 levels in patients with newly diagnosed ALL were increased compared to children with pneumonia. Similarly, plasma IL-6 levels in ALL, ALL-tocilizumab (TCZ, an IL-6 receptor inhibitor) and ALL-S3I-201 (a selective inhibitor of STAT3) mice were increased compared to the control group. The MRP2, MRP4, and PXR expression in HK-2 cells treated with IL-6 were decreased, whereas the p-STAT3 expression was significantly increased compared to the control group results. These results are consistent with clearance of MRPs-mediated MTX in the ALL group. These effects were attenuated by blocking IL-6/STAT3/PXR signaling pathway., Conclusion: Inflammation-mediated changes in pharmacokinetics are thought to be executed through pathways IL-6-activated pathways, which can facilitate a better understanding of the potential for the use of IL-6 to predict the severity of adverse outcomes and the major implications on potential ALL treatments., Competing Interests: Dr Wei Zhao reports grants, non-financial support from National Science and Technology Major Projects (2017ZX09304029-002), grants, non-financial support from National Science Foundation of China (81703603), grants, non-financial support from Young Taishan Scholars Program of Shandong Province, grants, non-financial support from Qilu Young Scholars Program of Shandong University. Dr Yi Zheng reports grants, non-financial support from the Key Technologies R & D Program of Shandong Province (2018GSF118053), outside the submitted work. The authors declare no competing interests., (© 2021 Zhou et al.)

Objectives: Augmented renal clearance (ARC) of primarily renally eliminated antibacterial agents may result in subtherapeutic antibiotic concentrations and, as a consequence, worse clinical outcomes. Cefathiamidine is frequently used as empirical antimicrobial therapy in children with ARC, but pharmacokinetic studies in infants are lacking. This population pharmacokinetic study in infants with ARC was conducted to determine optimal dosing regimens of cefathiamidine. Methods: The population pharmacokinetics was conducted in 20 infants treated with cefathiamidine. Plasma samples of cefathiamidine were collected using opportunistic sampling, and the concentrations were detected by UPLC-MS/MS. Data analysis was performed to determine pharmacokinetic parameters and to characterize pharmacokinetic variability of cefathiamidine using nonlinear mixed effects modelling (NONMEM) software program. Results: The data ( n = 36) from 20 infants (age range, 0.35-1.86 years) with ARC were fitted best with a 1-compartment model. Allometrically scaled weight and age as significant covariates influenced cefathiamidine pharmacokinetics. The median (range) values of estimated clearance and the volume of distribution were 0.22 (0.09-0.29) L/h/kg and 0.34 (0.24-0.41) L/kg, respectively. Monte Carlo simulations showed that the cefathiamidine doses of 100 mg/kg/day q12 h, 50 mg/kg/day q8 h and 75 mg/kg/day q6 h were chosen for bacteria with MIC 0.25, 0.5 and 2 mg/L, respectively. Conclusion: The population pharmacokinetic model of cefathiamidine for infants with ARC was developed. The PTA - based dosing regimens were recommended based on the final model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Du, Zhou, Tang, Wu, Yang, Shi, Yao, Hao, You, van den Anker, Zheng and Zhao.)

Epidermal inclusion cysts (EICs) of the breast develop in the deep breast parenchyma, and they are very rare. Only about 10 cases have been reported in the English-language literature to date. In this report, we present a rare case of a giant EIC with infection arising within the deep breast parenchyma. Unlike a typical EIC of the breast, the EIC in the present case was a cystic and solid lesion containing a large amount of liquid within the cyst and popcorn-like calcification in the wall. In this report, we describe the contrast-enhanced spectral mammography (CESM), ultrasonography, and computed tomography findings and provide a reference for the diagnosis of EICs. To the best of our knowledge, this is the first report of the CESM findings of an EIC. Our case illustrates that CESM has excellent performance similar to that of magnetic resonance imaging and is much more effective than conventional digital mammography. Additionally, our case indicates that precise correlation of CESM with ultrasonography findings contributes to the diagnosis of EICs. This rare case with multiple imaging findings will increase the awareness of EICs in the breast parenchyma.

The pharmacological activity of ceftriaxone depends on the unbound concentration. However, direct measurement of unbound concentrations is obstructive, and high individual variability of the unbound fraction of ceftriaxone was shown in children. We aim to evaluate and validate a method to predict unbound ceftriaxone concentrations in pediatric patients. Ninety-five pairs of concentrations (total and unbound) from 92 patients were measured by the bioanalysis method that we developed. The predictive performance of the three equations (empirical in vivo equation, disease-adapted equation, and multiple linear regression equation) was assessed by the mean absolute prediction error (MAPE), the mean prediction error (MPE), the proportions of the prediction error within ±30% ( P 30 ) and ±50% ( P 50 ), and linear regression of predicted versus actual unbound levels ( R 2 ). The average total and unbound ceftriaxone concentrations were 126.18 ± 81.46 μg/ml and 18.82 ± 21.75 μg/ml, and the unbound fraction varied greatly from 4.75% to 39.97%. The MPE, MAPE, P 30 , P 50 , and R 2 of the empirical in vivo equation, disease equation, and multiple linear equation were 0.17 versus 0.00 versus 0.06, 0.24 versus 0.15 versus 0.27, 63.2% versus 89.5% versus 74.7%, 96.8% versus 97.9% versus 86.3%, and 0.8730 versus 0.9342 versus 0.9315, respectively. The disease-adapted equation showed the best predictive performance. We have developed and validated a bioanalysis method with one-step extraction pretreatment for the determination of total ceftriaxone concentrations, and a prediction equation of the unbound concentration is recommended. The proposed method can facilitate clinical practice and research on unbound ceftriaxone in children. (This study has been registered at ClinicalTrials.gov under identifier NCT03113344.)., (Copyright © 2020 American Society for Microbiology.)

First dose prediction is challenging in neonates. Our objective in this proof-of-concept study was to perform a pharmacokinetic (PK) bridging study from juvenile mice to neonates for drugs metabolized by CYP3A. We selected midazolam and clindamycin as model drugs. We developed juvenile mice population PK models using NONMEM. The PK parameters of these two drugs in juvenile mice were used to bridge PK parameters in neonates using different correction methods. The bridging results were evaluated by the fold-error of 0.5- to 1.5-fold. Simple allometry with and without a correction factor for maximum lifespan potential could be used for a bridging of clearance (CL) and volume of distribution (V d ), respectively, from juvenile mice to neonates. Simulation results demonstrated that for midazolam, 100% of clinical studies for which both the predictive CL and V d were within 0.5- to 1.5-fold of the observed. For clindamycin, 75% and 100% of clinical studies for which the predictive CL and V d were within 0.5- to 1.5-fold of the observed. A PK bridging of drugs metabolized by CYP3A is feasible from juvenile mice to neonates. It could be a complement to the ADE and PBPK models to support the first dose in neonates.

Early life is a crucial period for the development of the intestinal microbiota and is related to the body's immunity. Yet research is lacking regarding the effect of stachyose on infants gut microbiomes at this stage and the mechanism is not clear. Therefore, in this experiment, feces samples collected from infants were transplanted into germ-free mice, to explore the effect of stachyose on the intestinal microbiota and host gut barrier. We found that stachyose promoted the relative abundance of A. muciniphila in human feces; enhanced the symbiotic relationships of A. muciniphila; increased the short-chain fatty acid level, and secretory immunoglobulin A level; reduced the levels of lipopolysaccharide, IL-1, IL-17 and TNF-α through downregulated the expression of NF-κB; increased expression of tight junction proteins (occludin and ZO-1) and goblet cell through A. muciniphila. The intake of stachyose is conducive to promoting the proliferation of beneficial bacteria and enhancing the intestinal barrier in germ-free mice. This research provides a theoretical basis for the use of prebiotics to improve intestinal microbiota and barrier in humans., (Copyright © 2020. Published by Elsevier Ltd.)

Ceftriaxone is a third-generation cephalosporin used to treat infants with community-acquired pneumonia. Currently, there is a large variability in the amount of ceftriaxone used for this purpose in this particular age group, and an evidence-based optimal dose is still unavailable. Therefore, we investigated the population pharmacokinetics of ceftriaxone in infants and performed a developmental pharmacokinetic-pharmacodynamic analysis to determine the optimal dose of ceftriaxone for the treatment of infants with community-acquired pneumonia. A prospective, open-label pharmacokinetic study of ceftriaxone was conducted in infants (between 1 month and 2 years of age), adopting an opportunistic sampling strategy to collect blood samples and applying high-performance liquid chromatography to quantify ceftriaxone concentrations. Developmental population pharmacokinetic-pharmacodynamic analysis was conducted using nonlinear mixed effects modeling (NONMEM) software. Sixty-six infants were included, and 169 samples were available for pharmacokinetic analysis. A one-compartment model with first-order elimination matched the data best. Covariate analysis elucidated that age and weight significantly affected ceftriaxone pharmacokinetics. According to the results of a Monte Carlo simulation, with a pharmacokinetic-pharmacodynamic target of a free drug concentration above the MIC during 70% of the dosing interval (70% fT >MIC ), regimens of 20 mg/kg of body weight twice daily for infants under 1 year of age and 30 mg/kg twice daily for those older than 1 year of age were suggested. The population pharmacokinetics of ceftriaxone were established in infants, and evidence-based dosing regimens for community-acquired pneumonia were suggested based on developmental pharmacokinetics-pharmacodynamics., (Copyright © 2020 American Society for Microbiology.)

Background: Cefotiam, a second-generation cephalosporin, is a broad-spectrum antibiotic with good antibacterial action against both gram-negative and gram-positive bacteria. It is used widely in clinical practice, although bacterial drug resistance makes its clinical use problematic. The authors hypothesized that subtherapeutic concentrations of cefotiam leads to bacterial resistance. The present study was conducted to evaluate whether the standard cefotiam dosing regimen resulted in a subtherapeutic concentrations in children., Method: Data were prospectively collected from pediatric patients with suspected or confirmed community-acquired pneumonia who were receiving cefotiam at the standard dosing regimen (40-80 mg/kg, 2 or 3 times daily). A blood sample was collected after 70%-100% of the dosing interval, and plasma concentrations were determined by high-performance liquid chromatography using an ultraviolet detector., Results: The data from 88 patients (age, 3.0 ± 2.8 years; weight, 15.4 ± 8.3 kg) were used for analysis. The average of cefotiam concentrations was 0.06 mcg/mL (range: <0.05-0.79 mcg/mL). Most patients (n = 72, 81.8%) had concentrations below 0.1 mcg/mL; only 2 patients had concentrations higher than 0.4 mcg/mL., Conclusions: The standard dosing regimen for cefotiam resulted in extremely low plasma concentrations in children; such low concentrations may lead to antimicrobial drug resistance. Thus, an increase in cefotiam dosage in children to 80 mg/kg 4 times daily is recommended (maximum dose on the label).

Purpose: Drug elimination alteration has been well reported in acute lymphoblastic leukemia (ALL). Considering that transporters and glomerular filtration influence, to different extents, the drug disposition, and possible side effects, we evaluated the effects of ALL on major renal transporters and glomerular filtration mediated pharmacokinetic changes, as well as expression of renal drug transporters., Methods: ALL xenograft models were established and intravenously injected with substrates of renal transporters and glomerular filtration separately in NOD/SCID mice. The plasma concentrations of substrates, after single doses, were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS)., Results: With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70-fold, and 1.45-fold, respectively, whereas expression of MRP2 and MRP4 were significantly decreased by 30.98% and 45.28% in the kidney of ALL groups compared with control groups. Clearance of MDR1-mediated digoxin, OAT3-mediated furosemide, and OCT2-mediated metformin increased by 3.04-fold, 1.47-fold, and 1.26-fold, respectively. However, clearance of MRPs-mediated methotrexate was reduced by 39.5%. These results are consistent with mRNA expression. Clearance of vancomycin and amikacin, as markers of glomerular filtration rate, had a 2.14 and 1.64-fold increase in ALL mice, respectively., Conclusions: The specific alteration of renal transporters and glomerular filtration in kidneys provide a rational explanation for changes in pharmacokinetics for ALL.

Aims: Chinese children are more susceptible to the development of thiopurine-induced leukopenia compared with Caucasian populations. The aim of our study was to establish a 6-mercaptopurine (6-MP) dose-concentration-response relationship through exploration of pharmacogenetic factors involved in the thiopurine-induced toxicities in Chinese paediatric patients afflicted by acute lymphoblastic leukaemia (ALL)., Methods: Blood samples were obtained from ALL children treated with 6-MP. We determined the metabolite steady-state concentrations of 6-MP in red blood cells (RBCs) by using high-performance liquid chromatography. Pharmacogenetic analysis was carried out on patients' genomic DNA using the MassArray genotyping platform., Results: Sixty children afflicted by ALL who received 6-MP treatment were enrolled in this study. The median concentration of 6-thioguanine in patients afflicted by leukopenia was 235.83 pmol/8 × 10 8 RBCs, which was significantly higher than for patients unafflicted by leukopenia (178.90 pmol/8 × 10 8 RBCs; P = 0.029). We determined the population special target 6-thioguanine threshold to have equalled 197.50 pmol/8 × 10 8 RBCs to predict leukopenia risk in Chinese paediatric patients afflicted by ALL. Among 36 candidate single nucleotide polymorphisms, our results indicated that NUDT15 (rs116855232) and IMPDH1 (rs2278293) were correlated with a 5.50-fold and 5.80-fold higher risk of leukopenia, respectively. MTHFR rs1801133 variants were found to have had a 4.46-fold significantly higher risk of hepatotoxicity vs wild-type genotype., Conclusion: Our findings support the idea that predetermination of genotypes and monitoring of thiopurine metabolism for Chinese paediatric patients afflicted by ALL is necessary to effectively predict the efficacy of treatments and to minimize the adverse effects of 6-MP maintenance therapy., (© 2020 The British Pharmacological Society.)

Actin-interacting protein 1 (AIP1), also known as WD repeat-containing protein 1 (WDR1), is ubiquitous in eukaryotic organisms, and it plays critical roles in the dynamic reorganization of the actin cytoskeleton. However, the biological function and mechanism of AIP1 in mammalian oocyte maturation is still largely unclear. In this study, we demonstrated that AIP1 boosts ADF/Cofilin activity in mouse oocytes. AIP1 is primarily distributed around the spindle region during oocyte maturation, and its depletion impairs meiotic spindle migration and asymmetric division. The knockdown of AIP1 resulted in the gathering of a large number of actin-positive patches around the spindle region. This effect was reduced by human AIP1 (hAIP1) or Cofilin (S3A) expression. AIP1 knockdown also reduced the phosphorylation of Cofilin near the spindle, indicating that AIP1 interacts with ADF/Cofilin-decorated actin filaments and enhances filament disassembly. Moreover, the deletion of AIP1 disrupts Cofilin localization in metaphase I (MI) and induces cytokinesis defects in metaphase II (MII). Taken together, our results provide evidence that AIP1 promotes actin dynamics and cytokinesis via Cofilin in the gametes of female mice., (© 2020 Federation of American Societies for Experimental Biology.)

Objective: Clinical trials of children's drugs are of great significance to rational drug use in children. However, paediatric drugs trials in China are facing complex challenges. At present, the investigation data on registration status of paediatric drug trials in China are still relatively lacking, and relevant research is urgently needed., Methods: The advanced retrieval function is used to retrieve clinical trials data in the Clinical Trial.gov and Chinese Clinical Trial Registry databases in 22 April 2019. Fifteen key items were analysed to describe trial characteristics, including: registration number, study start date (year), mode of funding, type of disease, medicine type, research stage, research design, sample size, number of experimental groups, placebo group, blind method, implementation centre, child specific, newborn specific and participant age., Results: A total of 1388 clinical trials of paediatric drugs conducted in China were registered. The number of paediatric drug trials grew steadily over time, from less than 20 per year before 2005 to more than 100 per year after 2012. Most clinical trials were postmarketing (n=800, 57.6%), single-centre (n=1045, 75.3%), intervention studies (n=1161, 83.6%) without blinded methods (1169, 84.2%) and funded by non-profit organisations (n=838, 60.4%). The number of clinical trials for antineoplastic agents (n=254, 18.3%), anti-infectives (n=156, 11.2%) and vaccines (n=154, 11.1%) is the largest., Conclusion: Paediatric drug trials in China made a significant progress in recent years. Innovative method and trial design optimisation should be encouraged to accelerate paediatric clinical research. Pharmaceutical companies need to be further stimulated to carry out more high-quality paediatric clinical trials with support of paediatric drug legislation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)