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Background: Pharmacogenetics/pharmacogenomics (PGx) focuses on the genetic variation that causes the heterogeneity of pharmacokinetics and drug response among individuals and has the potential to predict individual efficacy and/or side effects. This study aims to investigate and understand the implementation of genetic testing for the personalized medication (GTPM) in children's hospitals in Mainland China. Methods: A survey was conducted on 50 children's hospitals from 31 provinces, municipalities, and autonomous regions across Mainland China, and statistical analysis and recommendations were made. Results: Questionnaire response was rate of 76.0% (38/50). Data from 15 hospitals conducting GTPM were included in this study, but only 6 hospitals had offered PGx tests for no less than five drug-related genes, and only 5 hospitals had covered more than ten drugs, which was a small scale overall. 20.0% of the laboratories did not conduct internal quality control, and 33.3% did not participate in inter-laboratory quality assessment. 46.7% of the practitioners did not receive external training. The primary goal for GTPM was to optimize drug dosage in the 15 hospitals, while the main challenge for GTPM was the implementation cost. Conclusion: Although GTPM in pediatrics has made major progress in Mainland China in recent years, there were still various problems in terms of software, hardware configuration, personnel allocation, business scale, quality control, and result interpretation. This requires joint efforts of health administration, medical insurance departments, researchers, and hospitals to promote and improve GTPM. [ABSTRACT FROM AUTHOR]

To update traditional "wet" matrices to dried blood spot (DBS) sampling, based on the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) technique, and develop a method for simultaneous analyzing caffeine and its three primary metabolites (theobromine, paraxanthine, and theophylline), supporting routine therapeutic drug monitoring (TDM) for preterm infants. DBS samples were prepared by a two-step quantitative sampling method, i.e., volumetric sampling of a quantitative 10 μL volume of peripheral blood and an 8 mm diameter whole punch extraction by a methanol/water (80/20, v/v) mixture containing 125 mM formic acid. Four paired stable isotope labeled internal standards and a collision energy defect strategy were applied for the method optimization. The method was fully validated following international guidelines and industrial recommendations on DBS analysis. Cross validation with previously developed plasma method was also proceeded. The validated method was then implemented on the TDM for preterm infants. The two-step quantitative sampling strategy and a high recovery extraction method were developed and optimized. The method validation results were all within the acceptable criteria. Satisfactory parallelism, concordance, and correlation were observed between DBS and plasma concentrations of the four analytes. The method was applied to provide routine TDM services to 20 preterm infants. A versatile LC-MS/MS platform for simultaneous monitoring caffeine and its three primary metabolites was developed, fully validated, and successfully applied into the routine clinical TDM practices. Sampling method switching from "wet" matrices to "dry" DBS will facilitate and support the precision dosing of caffeine for preterm infants. [ABSTRACT FROM AUTHOR]

Purpose: There is marked heterogeneity in treatment response of atomoxetine in patients with attention deficit/hyperactivity disorder (ADHD), especially for the pediatric population. This review aims to evaluate current evidence to characterize the dose-exposure relationship, establish clinically relevant metrics for systemic exposure to atomoxetine, define a therapeutic exposure range, and to provide a dose-adaptation strategy before implementing personalized dosing for atomoxetine in children with ADHD. Methods: A comprehensive search was performed across electronic databases (PubMed and Embase) covering the period of January 1, 1985 to July 10, 2022, to summarize recent advances in the pharmacokinetics, pharmacogenomics/pharmacogenetics (PGx), therapeutic drug monitoring (TDM), physiologically based pharmacokinetics (PBPK), and population pharmacokinetics (PPK) of atomoxetine in children with ADHD. Results: Some factors affecting the pharmacokinetics of atomoxetine were summarized, including food, CYP2D6 and CYP2C19 phenotypes, and drug‒drug interactions (DDIs). The association between treatment response and genetic polymorphisms of genes encoding pharmacological targets, such as norepinephrine transporter (NET/SLC6A2) and dopamine β hydroxylase (DBH), was also discussed. Based on well-developed and validated assays for monitoring plasma concentrations of atomoxetine, the therapeutic reference range in pediatric patients with ADHD proposed by several studies was summarized. However, supporting evidence on the relationship between systemic atomoxetine exposure levels and clinical response was far from sufficient. Conclusion: Personalizing atomoxetine dosage may be even more complex than anticipated thus far, but elucidating the best way to tailor the non-stimulant to a patient's individual need will be achieved by combining two strategies: detailed research in linking the pharmacokinetics and pharmacodynamics in pediatric patients, and better understanding in nature and causes of ADHD, as well as environmental stressors. [ABSTRACT FROM AUTHOR]

Objectives: Sirolimus (SRL), a mammalian target of rapamycin inhibitor, has been widely used to treat patients with vascular anomalies (VAs). The objectives of this study were to summarize the routine blood SRL monitoring data for VAs children, to investigate the factors contributing to the variable blood SRL concentrations and to evaluate the efficacy and safety of SRL therapy. Methods: VAs patients with routine blood SRL monitoring from July 2017 to April 2022 at the Department of Burns and Plastic Surgery, Children's Hospital of Nanjing Medical University were retrospectively collected. Clinical data were obtained from the hospital information system. Results: In total, 67 children (35 females) were enrolled. The therapeutic drug monitoring data showed that the range of measured blood trough concentrations (Ctrough) was 3.6–46.8 ng/mL. At the initial measurements, only 33% of patients were in the target concentration range (10–15 ng/mL). But this proportion became 54% at the last measurements. The whole blood-Ctrough-to-daily dose (Ctrough/Dose) ratio was significantly associated with age and body weight (BW). The patients' laboratory results did not change significantly after SRL treatment. Although the incidence of adverse events was relatively high (44.8%), most of them were mild and tolerable. 70.3% patients had total responses to SRL, whereas 29.7% children exhibited stable disease or progressive disease. No significant differences were found in Ctrough between the total response group and non-response group. Conclusions: This retrospective study revealed a high variability in SRL blood concentrations in Chinese children with VAs. Of note, pediatric patients with older age and a higher BW had a lower Ctrough/Dose ratio. It is a concern whether the range of 10–15 ng/mL is feasible for Chinese children based only on our study. Further studies recruiting more patients are required to redefine the target reference range for children with VAs. [ABSTRACT FROM AUTHOR]

• Successful development and validation the method to monitor the whole blood concentration of cyclosporine A in pediatric patients with minimum time and small-volume plasma consumption. • The analysis method minimized medical costs by optimizing extraction processing and allowed the analysis with a simple one-step protein precipitation method. • 657 cases of CsA concentrations were determined from 197 pediatric patients by a routine EMIT assay and by a validated in-house LC-MS/MS method. • The correlation between the EMIT and LC-MS/MS in different ranges was analyzed, including < 40 ng/mL, > 500 ng/mL, excluding < 40 ng/mL and > 500 ng/mL, 40–––200 ng/mL, and 200–––500 ng/mL, respectively. • This is the first study reporting the comparison of the EMIT and LC-MS/MS for the measurement of whole blood CsA concentration in children. Cyclosporine A (CsA) is a widely used immunosuppressive drug with a narrow therapeutic index and large individual differences. Its therapeutic and toxic effects are closely related to blood drug concentrations, requiring routine therapeutic drug monitoring (TDM). The current main methods for TDM of CsA are enzyme multiplied immunoassay technique (EMIT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). However, few study on the method comparison of the EMIT and LC-MS/MS for the measurement of whole blood CsA concentration in children has been reported. In this study, we developed a simple and sensitive LC-MS/MS assay for the determination of CsA, and 657 cases of CsA concentrations were determined from 197 pediatric patients by a routine EMIT assay and by the validated in-house LC-MS/MS method on the same batch of samples, aimed to address the aforementioned concern. Consistency between the two assays was evaluated using linear regression and Bland-Altman analysis. The linear range of LC-MS/MS was 0.500–2000 ng/mL and that of the EMIT was 40–500 ng/mL, respectively. Overall, the correlation between the two methods was significant (r-value ranging from 0.8842 to 0.9441). Unsatisfactory consistency was observed in the concentrations < 40 ng/mL (r = 0.7325) and 200–500 ng/mL (r = 0.6851). Bland-Altman plot showed a mean bias of −18.0 % (±1.96 SD, −73.8 to 37.8 %) between EMIT and LC-MS/MS. For Passing-Bablok regression between EMIT and LC-MS/MS did not differ significantly (p > 0.05). In conclusion, the two methods were closely correlated, but the CsA concentration by LC-MS/MS assay was slightly higher than that by EMIT method. Switching from the EMIT assay to the LC-MS/MS method was acceptable, and the LC-MS/MS method will receive broader application in clinical settings due to its better analytical capabilities, but the results need to be further verified in different laboratories. [ABSTRACT FROM AUTHOR]

Vibralactone, a hybrid compound derived from phenols and a prenyl group, is a strong pancreatic lipase inhibitor with a rare fused bicyclic β-lactone skeleton. Recently, a researcher reported a vibralactone derivative (compound C1) that caused inhibition of pancreatic lipase with a half-maximal inhibitory concentration of 14 nM determined by structure-based optimization, suggesting a potential candidate as a new antiobesity treatment. In the present study, we sought to identify the main gene encoding prenyltransferase in Stereum vibrans, which is responsible for the prenylation of phenol leading to vibralactone synthesis. Two RNA silencing transformants of the identified gene (vib-PT) were obtained through Agrobacterium tumefaciens-mediated transformation. Compared to wild-type strains, the transformants showed a decrease in vib-PT expression ranging from 11.0 to 56.0% at 5, 10, and 15 days in reverse transcription-quantitative PCR analysis, along with a reduction in primary vibralactone production of 37 to 64% at 15 and 21 days, respectively, as determined using ultra-high-performance liquid chromatography-mass spectrometry analysis. A soluble and enzymatically active fusion Vib-PT protein was obtained by expressing vib-PT in Escherichia coli, and the enzyme's optimal reaction conditions and catalytic efficiency (Km/kcat) were determined. In vitro experiments established that Vib-PT catalyzed the C-prenylation at C-3 of 4-hydroxy-benzaldehyde and the O-prenylation at the 4-hydroxy of 4-hydroxy-benzenemethanol in the presence of dimethylallyl diphosphate. Moreover, Vib-PT shows promiscuity toward aromatic compounds and prenyl donors. IMPORTANCE Vibralactone is a lead compound with a novel skeleton structure that shows strong inhibitory activity against pancreatic lipase. Vibralactone is not encoded by the genome directly but rather is synthesized from phenol, followed by prenylation and other enzyme reactions. Here, we used an RNA silencing approach to identify and characterize a prenyltransferase in a basidiomycete species that is responsible for the synthesis of vibralactone. The identified gene, vib-PT, was expressed in Escherichia coli to obtain a soluble and enzymatically active fusion Vib-PT protein. In vitro characterization of the enzyme demonstrated the catalytic mechanism of prenylation and broad substrate range for different aromatic acceptors and prenyl donors. These characteristics highlight the possibility of Vib-PT to generate prenylated derivatives of aromatics and other compounds as improved bioactive agents or potential prodrugs. [ABSTRACT FROM AUTHOR]

Acanthopanax senticosus extract with excessive standard of Pb, Cd, Hg, and Cu was used as the research object, and the alkyl thiourea functionalised silica was used as a new heavy metal removal scavenger. The heavy metal removal process was optimised by orthogonal experiment with dynamic and static adsorption modes. Meanwhile, the content of Acanthopanax B and Acanthopanax E, the solid content, and the HPLC fingerprint similarity were used as quality monitoring indicators of Acanthopanax senticosus heavy metal removal before and after. Then, the technical adaptability of heavy metal removal by alkyl thiourea functionalised silica was evaluated. Under the optimal dynamic adsorption conditions, the average removal rates of Pb, Cd, Hg, and Cu were 91.64%, 93.04%, 81.77%, and 83.11%, respectively. Under the optimal static adsorption conditions, the average removal rates of Pb, Cd, Hg, and Cu were 82.22%, 89.95%, 81.26%, and 82.97%, respectively. During Acanthopanax senticosus extract heavy metal removal before and after, the change percentage of Acanthopanax B and Acanthopanax E was less than 2.00%, the solid content loss rate was only 0.18%, and the fingerprint similarity was over 99.9%. The method can be used to satisfy the high efficiency of selective removal of harmful elements in Acanthopanax senticosus extract and the effective composition of almost no effect; the method is simple and easy, so it can be recommended for pretreatment of heavy metals in Traditional Chinese Medicine extracts, and this way provides a new thought and research technique to decrease the contents of heavy metals. [ABSTRACT FROM AUTHOR]

Purpose The incidence, risk factors and survival impact of secondary primary malignancies (SPMs) among survivors of nasopharyngeal carcinoma (NPC) treated with definitive intensity-modulated radiation therapy (IMRT) with or without chemotherapy are poorly characterized. Methods and Materials Consecutive patients (n=6,377) from the big-data intelligence platform at Sun Yat-sen University Cancer Center, China (in a high-incidence area) with newly diagnosed non-metastatic pathologically proven non-keratinizing undifferentiated NPC treated with IMRT±chemotherapy between January 2003 and June 2013 were retrospectively analyzed. Cumulative incidence of SPMs was calculated using the Kaplan-Meier method. Cox proportional hazards model was used to identify potential risk factors for SPMs and assess whether SPMs affect overall survival. Results Of the 6,377 patients, 189 (3.0%) suffered SPMs (median follow-up, 62 months). One-, 2-, 3-, 4-, and 5-cumulative risks of SPMs were 0.4%, 0.9%, 1.6%, 2.2%, and 2.6%, respectively. Latency from start of IMRT to SPMs diagnosis was 37 months (range, 6 to 102 months). In patients with SPMs, 14.3% suffered SPMs within 1 year post-IMRT: 1-3 years, 38.1%; 3-5 years, 33.9%; and >5 years, 13.7%. Lung cancer was the most common SPM (50/6,377, 0.78%). Multivariate analysis demonstrated sex (male, 64% increase), age (≥50 years, 68% increase), and smoking history (41% increase) were significant risk factors for SPMs, and SPMs were associated with poorer overall survival. Conclusion This large cohort study confirms SPMs a dreadful complication for long-term survivors of NPC treated with IMRT. SPMs negatively impact overall survival in NPC. Close follow-up is recommended for older male survivors with a smoking history. [ABSTRACT FROM AUTHOR]

Pyrazinamide (PZA)-induced serious liver injury, but the exact mechanism of PZA-induces hepatotoxicity remains controversial. Endoplasmic reticulum (ER) stress-caused cell apoptosis plays a critical role in the development of drug-induced liver injury (DILI). However, the direct connection between PZA toxicity and ER stress is unknown. In this study, we describe the role of ER stress in PZA induced hepatotoxicity in vivo and in vitro . We found that PZA induces apoptosis in HepG2 cells, and causes liver damage in rats, characterized by increased serum ALT, AST and TBA levels. PZA impairs antioxidant defenses, although this effect did not play an important role in resulting liver injury. The ER stress related proteins GRP78, p-PERK, p-eIF2α, ATF4, CHOP and caspase12 were activated after PZA exposure both in vivo and in vitro . Furthermore, as an ER stress inhibitor, sodium 4-phenylbutyrate (4-PBA) could ameliorate PZA toxicity in HepG2 cells and rat liver. These results have potential implications for the pathogenesis of PZA-induced hepatotoxicity in which ER stress especially PERK-eIF2α-ATF4-CHOP pathway participates in hepatocellular injury. [ABSTRACT FROM AUTHOR]

As global energy consumption continues to rise, it is imperative to develop clean and renewable sources of energy as alternatives to the fossil fuel energy sources. Photocatalytic hydrogen generation or photochemical water splitting is a promising carbon-free technology producing H2 and O2 from water. Here, we report an exciting advance in the photocatalytic hydrogen evolution from water under visible light, using newly developed direct Z-scheme heterostructures constructed by oxygen deficient ZnO1-x nanorods and Zn0.2Cd0.8S nanoparticles by calcination. The highest rate for hydrogen production reaches 2518 ümol h-1 over optimal ZnO1-x (10 wt %)/Zn0.2Cd0.8S Z-scheme photocatalyst with a high apparent quantum efficiency (AQY) of 49.5% at 420 nm, which is 20 times higher than bare Zn0.2Cd0.8S and 25 times higher than ZnO1-x sample. From the results of photocurrent response, electrochemical impedance spectroscopy and time-resolved PL spectra, we demonstrate that the high increase in the photocatalytic hydrogen generation arises from the formation of artificial photosynthetic Z-scheme system and oxygen vacancy abundant ZnO1-x in the heterojunction. Direct Z-scheme ZnO1-x/Zn0.2Cd0.8S nanoheterostructures result in an efficient charge carrier separation and strong reduction ability for enhanced H2 production; additionally, the presence of oxygen vacancies in the sample significantly enhances visible light absorption, these synergistic effects lead to highly efficient photocatalytic hydrogen production with an exceptional high quantum efficiency under visible light irradiation. Our findings provide possibilities for creating other high-efficiency photocatalysts mimicking natural photosynthetic Z-scheme system. [ABSTRACT FROM AUTHOR]

Significant pharmacokinetic (PK) differences exist between different forms of valproic acid (VPA), such as syrup and sustained‐release (SR) tablets. This study aimed to develop a population pharmacokinetic (PopPK) model for VPA in children with epilepsy and offer dose adjustment recommendation for switching dosage forms as needed. The study collected 1411 VPA steady‐state trough concentrations (Ctrough) from 617 children with epilepsy. Using NONMEM software, a PopPK model was developed, employing a stepwise approach to identify possible variables such as demographic information and concomitant medications. The final model underwent internal and external evaluation via graphical and statistical methods. Moreover, Monte Carlo simulations were used to generate a dose tailoring strategy for typical patients weighting 20–50 kg. As a result, the PK characteristics of VPA were described using a one‐compartment model with first‐order absorption. The absorption rate constant (ka) was set at 2.64 and 0.46 h−1 for syrup and SR tablets. Body weight and sex were identified as significant factors affecting VPA's pharmacokinetics. The final PopPK model demonstrated acceptable prediction performance and stability during internal and external evaluation. For children taking syrup, a daily dose of 25 mg/kg resulted in the highest probability of achieving the desired target Ctrough, while a dose of 20 mg/kg/day was appropriate for those taking SR tablets. In conclusion, we established a PopPK model for VPA in children with epilepsy to tailor VPA dosage when switching between syrup and SR tablets, aiming to improve plasma VPA concentrations fluctuations. [ABSTRACT FROM AUTHOR]

[Display omitted] Several population pharmacokinetic (PopPK) models of caffeine in preterm infants have been published, but the extrapolation of these models to facilitate model-informed precision dosing (MIPD) in clinical practice is uncertain. This study aimed to comprehensively evaluate their predictive performance using an external , independent dataset. Data used for external evaluation were based on an independent cohort of preterm infants. Currently available PopPK models for caffeine in preterm infants were identified and re-established. Prediction- and simulation-based diagnostics were used to assess model predictability. The influence of prior information was assessed using Bayesian forecasting. 120 plasma samples from 76 preterm infants were included in the evaluation dataset. Twelve PopPK models of caffeine in preterm infants were re-established based on our previously published study. Although two models showed superior predictive performance, none of the 12 PopPK models met all the clinical acceptance criteria of these external evaluation items. Besides, the external predictive performances of most models were unsatisfactory in prediction- and simulation-based diagnostics. Nevertheless, the application of Bayesian forecasting significantly improved the predictive performance, even with only one prior observation. Two models that included the most covariates had the best predictive performance across all external assessments. Inclusion of different covariates, heterogeneity of preterm infant characteristics, and different study designs influenced predictive performance. Thorough evaluation is needed before these PopPK models can be implemented in clinical practice. The implementation of MIPD for caffeine in preterm infants could benefit from the combination of PopPK models and Bayesian forecasting as a helpful tool. [ABSTRACT FROM AUTHOR]

Abstract: The multiferroic (PMN-PT/CFO) n (n =1,2) multilayered thin films have been prepared on SiO2/Si(100) substrate with LNO as buffer layer via a rf magnetron sputtering method. The structure and surface morphology of multilayered thin films were determined by X-ray diffraction (XRD) and atom force microscopy (AFM), respectively. The smooth, dense and crack-free surface shows the excellent crystal quality with root-mean-square (RMS) roughness only 2.9nm, and average grain size of CFO thin films on the surface is about 44nm. The influence of the thin films thickness size, periodicity n and crystallite orientation on their properties including ferroelectric, ferromagnetic properties in the (PMN-PT/CFO) n multilayered thin films were investigated. For multilayered thin films with n =1 and n =2, the remanent polarization Pr are 17.9μC/cm2 and 9.9μC/cm2; the coercivity H c are 1044Oe and 660Oe, respectively. In addition, the relative mechanism are also discussed. [Copyright &y& Elsevier]

Trichoderma spp. play an important role in biotic control, and several are efficacious against nematodes. To study the potential of Trichoderma species in controlling nematodes, fungal filtrates of 329 Trichoderma strains were evaluated for their nematicidal activity against Panagrellus redivivus and Caenorhabditis elegans. Fifteen strains exhibited nematicidal activity against P. redivivus, and 14 strains showed activity against C. elegans. The strain YMF1.02647 showed strong nematicidal activity against both nematodes, and the culture broth could cause more than 90% mortality to the tested nematodes within 48 h. A nematicidal compound was isolated from ethyl acetate extract of Trichoderma YMF1.02647 based on bioassay-guided fractionation. The compound was identified as trichodermin according to the spectroscopic data, which could kill more than 95% both P. redivivus and C. elegans in 72 h at 0.4 g l. [ABSTRACT FROM AUTHOR]

Two new sesquiterpenes, stereumin F (1) and stereumin G (2), together with two known compounds (3β,5α,22E,24R)-5,8-epidioxyergosta-6,22-dien-3-ol (3) and 4-(2-hydroxyethyl)phenol (4), were isolated from the AcOEt extract of the culture broth and the MeOH extract of the mycelium of the fungal strain Stereum sp. CCTCC AF 207024. Their structures were established on the basis of spectral analyses. [ABSTRACT FROM AUTHOR]

Ethyl acetate extract of the branches of Magnolia tripetala exhibited nematicidal activity against Bursaphelenchus xylophilus, Panagrellus redivivus and Caenorhabditis elegans. Two nematicidal phenolic compounds magnolol ( 1) and honokiol ( 2) were isolated from the extract based on bioassay-guided fractionation. The median lethal concentrations (LC50) of compounds 1– 2 were 149.3 and 63.7 mg/l, respectively, against B. xylophilus, 74.5 and 75.9 mg/l, respectively, against P. redivivus, 64.7 and 57.8 mg/l, respectively, against C. elegans at 48 h. [ABSTRACT FROM AUTHOR]

• Children carrying CYP3A5*3 with higher body weight had a higher C 0 /Dose. • Routine CYP3A5 genotyping test played a minor role in <6-year-old pediatric patients. • Exposure levels (C 0 , 2–7 ng/mL) was sufficient to maintain remission status in children with RNS. Tacrolimus, an immunosuppressive drug, was recommended by the 2012 KDIGO guidelines to treat nephrotic syndrome (NS) in children and adults. However, it has high interpatient pharmacokinetic variability and exposure levels should be monitored, although there are no specified target concentrations. This retrospective study aimed to review efficacy and safety after concomitant treatment with tacrolimus and prednisone, and to identify factors that contribute to the variable blood-trough-concentration-to-dose (C 0 /Dose) ratio in children with refractory NS (RNS). A 6-month therapy induced complete or partial remission in 95% of patients. One-year follow-up indicated a high remission rate and low nephrotoxicity. Under maintenance dosages, approximately 95% of the C 0 values were 2–7 ng/mL. Body weight (BW), age, CYP3A5 polymorphisms were the factors affecting the C 0 /Dose ratio. The C 0 /Dose ratio in patients with a BW of <20 kg was 1.5-fold than that in patients with BW of ≥40 kg. Moreover, the C 0 /Dose ratio in patients aged 1–≤6 and 6–≤12 years was significantly lower than that in patients aged 12–≤18 years, by 25% and 48%, respectively. There were no significant association between CYP3A5 genotyping and C 0 /Dose ratio in younger children (1–≤6 years), rather than older children (6–≤18 years). In conclusion, routine CYP3A5 genotyping should be considered in children aged over 6 years and exposure levels (C 0) of 2–7 ng/mL may be feasible when tacrolimus is combined with low-dose prednisone to treat childhood RNS. [ABSTRACT FROM AUTHOR]

Vincristine (VCR), an effective antitumor drug, has been utilized in several polytherapy regimens for acute lymphoblastic leukemia, neuroblastoma and rhabdomyosarcoma. However, clinical evidence shows that the metabolism of VCR varies greatly among patients. The traditional based body surface area (BSA) administration method is prone to insufficient exposure to VCR or severe VCR-induced peripheral neurotoxicity (VIPN). Therefore, reliable strategies are urgently needed to improve efficacy and reduce VIPN. Due to the unpredictable pharmacokinetic changes of VCR, therapeutic drug monitoring (TDM) may help to ensure its efficacy and to manage VIPN. At present, there is a lot of supporting evidence for the suitability of applying TDM to VCR therapy. Based on the consensus guidelines drafted by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), this review aimed to summarize various available data to evaluate the potential utility of VCR TDM for cancer patients. Of note, valuable evidence has accumulated on pharmacokinetics variability, pharmacodynamics, drug exposure–clinical response relationship, biomarkers for VIPN prediction, and assays for VCR monitoring. However, there are still many relevant clinical pharmacological questions that cannot yet be answered merely based on insufficient evidence. Currently, we cannot recommend a therapeutic exposure range and cannot yet provide a dose-adaptation strategy for clinicians and patients. In areas where the evidence is not yet sufficient, more research is needed in the future. The precision medicine of VCR cannot rely on TDM alone and needs to consider the clinical, environmental, genetic background and patient-specific factors as a whole. [ABSTRACT FROM AUTHOR]

Abstract: A theoretical model was established to calculate the magnetoelectric voltage coefficient of piezoelectric (PMN-PT)/piezomagnetic (CFO) laminated composites on Si substrate. Using this model, the transverse and longitudinal magnetoelectric voltage coefficient formula of laminated composites was derived in ideal interface coupling state simply. The magnetoelectric voltage coefficient (α E) is calculated as function of the volume fraction of piezoelectrics and the thickness of Si substrate. It was found that the magnetoelectric voltage coefficient of PMN-PT/CFO laminated composites decreases with increase of Si substrate thickness, which shows strong clamping effect of the substrate. Meanwhile, with increase of substrate thickness, the compressive stress of substrate to PMN-PT enhances, which change the lattice constant of PMN-PT and lead to low optimum PMN-PT volume fraction v. [Copyright &y& Elsevier]

• Vincristine-induced peripheral neuropathy (VIPN) restricts its application. • Latest findings on VIPN were comprehensively reviewed, summarized and discussed. • It's helpful to understand and manage this toxicity for clinicians and patients. Vincristine (VCR), an alkaloid extracted from vinca, is often used in combination with other chemotherapeutic drugs to treat a variety of cancers, such as acute lymphoblastic leukaemia (ALL), malignant lymphoma, and neuroblastoma. However, VCR possesses dose-dependent neurotoxicity, which is the main factor restricting its application. Vincristine-induced peripheral neuropathy (VIPN) not only limits the dose of VCR and leads to the discontinuation of treatment but also triggers serious damage to the physical and mental health of patients. In addition, VIPN brings huge healthcare costs to patients and society. Individuals with VIPN often exhibit mechanical allodynia, sensory/tactile disorders, and numbness in the hands and feet. Unfortunately, VIPN is easily ignored due to its variable symptoms, which gives rise to insufficient research on the aetiology and pathogenesis of this disease, thereby resulting in a lack of appropriate preventive and therapeutic management. We performed a comprehensive review of the latest findings on VIPN in terms of symptoms, risk factors, potential mechanisms, and prevention and treatment measures. The purpose was to help clinicians better understand and accurately diagnose VIPN, select appropriate intervention measures and reduce the damage to cancer patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Automated external defibrillators (AEDs) enable laypeople to provide early defibrillations to patients undergoing cardiac arrest, but scant information is available on the general public's ability to use AEDs. This study assessed the ability of laypeople to operate AEDs, the effect of a 15-minute training, and whether skills differed by age. METHODS: From May 1 to December 31, 2018, a prospective simulation study was conducted with 94 laypeople aged 18-65 years (32 aged 18-24 years, 34 aged 25-54 years, and 28 aged 55-65 years) with no prior AED training. The participants' AED skills were assessed individually pretraining, post-training, and at a three-month follow-up using a simulated cardiac arrest scenario. The critical actions and time intervals were evaluated during the AED operating process. RESULTS: Only 14 (14.9%) participants (eight aged 18-24 years, four aged 25-54 years, and two aged 55-65 years) successfully delivered defibrillations before training. AED operation errors were more likely to occur among the participants aged 55-65 years than among other age groups. After training, the proportion of successful defibrillations increased significantly (18-24 years old: 25.0% vs. 71.9%, P<0.01; 25-54 years old: 11.8% vs. 70.6%, P<0.01; 55-65 years old: 7.1% vs. 67.9%, P<0.01). After three months, 26.1% of the participants aged 55-65 years successfully delivered defibrillations, which was significantly lower than that of participants aged 18-24 years (54.8%) and 25-54 years (64.3%) (P=0.02). There were no differences in time measures among three age groups in each test. CONCLUSIONS: The majority of untrained laypeople cannot effectively operate AEDs. More frequent training and refresher courses are crucial to improve AED skills. [ABSTRACT FROM AUTHOR]

Valproic acid (VPA) is a well-documented contributor to liver injury, which is likely caused by the formation of its toxic metabolites. Monitoring VPA and its metabolites is very meaningful for the pharmacovigilance, but the availability of a powerful assay is a prerequisite. In this study, for the first time, a sensitive and specific LC-MS/MS method was developed and validated to simultaneously quantify the concentrations of VPA and its six pestering isomer metabolites (3-OH-VPA, 4-OH-VPA, 5-OH-VPA, 2-PGA, VPA-G, and 2-ene-VPA) in human plasma, using 5-OH-VPA-d7 and VPA-d6 as the internal standards (ISs). We also figured out another tricky problem that the concentrations of the parent drug and the metabolites vary widely. Of note, after protein precipitation and dilution with acetonitrile (ACN) and 50% ACN successively, the analytes and the ISs were successfully separated on a Kinetex C 18 column. Intriguingly, sacrificing its signal intensity by elevated collision energy of VPA finally achieved the simultaneous determination. As expected, the method showed great linearity (r > 0.998) over the concentration ranges for all analytes. The inter-day and intra-day accuracy and precision were both acceptable. The method was successfully applied in 127 children with epilepsy. This novel assay will support the VPA-associated pharmacovigilance in the future. • Metabolites of valproic acid (VPA) play a causal role in VPA-related liver injury. • Methods for VPA pharmacovigilance by measuring toxic metabolites are still lacking. • Successful separation was achieved for the pestering isomer metabolites of VPA. • Co-analysis of VPA and its metabolites were accomplished in a single injection. • The LC-MS/MS method in this article has not been reported before. [ABSTRACT FROM AUTHOR]

Rankinite (3CaO·2SiO 2 , [C 3 S 2 ]) is valued for its special properties in different environments. Understanding the properties of C 3 S 2 is important for cement design. The lattice parameters, elastic constants and moduli, anisotropy, dynamical and thermal properties of C 3 S 2 under 0–10 GPa was studied by first-principles method. The elastic properties, including bulk, shear and Young's moduli (B , G and E), Poisson's ratio v and hardness H V , thermal conductivity k was calculated from the elastic moduli. The anisotropy of materials can be described by elastic anisotropy index, three-dimensional (3D) surface structure and elastic modulus projection. The results show that C 3 S 2 has anisotropic elasticity, and the degree of anisotropy increases with the increase of pressure. The dynamic properties of C 3 S 2 under different pressures are also calculated and analyzed. At last, the thermodynamic properties of C 3 S 2 at different pressures are predicted and evaluated in detail. • The mechanical properties were all systematically calculated and analyzed. • The elastic anisotropy of C 3 S 2 increased with increasing pressure. • The results reveal that C 3 S 2 can be mechanically and dynamically stable. [ABSTRACT FROM AUTHOR]

We report a novel reversible color switching system based on one-pot hydrogenation/oxygenation reactions over Pd/CeO2−x catalysts and fast interconversion of thionine (TH+) and leuco thionine (LTH). Oxygen vacancies produced by Pd-catalyzed instant hydrogenation of CeO2 and strong metal–support interaction (SMSI) could lead to fast color switching. [ABSTRACT FROM AUTHOR]

Current standard-dose caffeine therapy results in significant intersubject variability. The aims of this study were to develop and evaluate population pharmacokinetic (PPK) models of caffeine in preterm infants through comprehensive screening of covariates and then to propose model-informed precision dosing of caffeine for this population. A total of 129 caffeine concentrations from 96 premature neonates were incorporated into this study. Comprehensive medical record and genotype data of these neonates were collected for analysis. PPK modeling was performed by a nonlinear mixed effects modeling program (NONMEM). Final models based on the current weight (CW) or body surface area (BSA) were evaluated via multiple graphic and statistical methods. The model-informed dosing regimen was performed through Monte Carlo simulations. In addition to CW or BSA, postnatal age, coadministration with erythromycin (ERY), and aryl hydrocarbon receptor coding gene (AHR) variant (rs2158041) were incorporated into the final PPK models. Multiple evaluation results showed satisfactory prediction performance and stability of the CW- and BSA-based models. Monte Carlo simulations demonstrated that trough concentrations of caffeine in preterm infants would be affected by concomitant ERY therapy and rs2158041 under varying dose regimens. For the first time, ERY and rs2158041 were found to be associated with the clearance of caffeine in premature infants. Similar predictive performance and stability were obtained for both CW- and BSA-based PPK models. These findings provide novel insights into caffeine precision therapy for preterm infants. [Display omitted] [ABSTRACT FROM AUTHOR]

Background Major depressive disorder (MDD) is the most prevalent mental disorder in the general population and has been associated with socioeconomic factors. Beijing has undergone significant socioeconomic changes in last decade, however no large-scale community epidemiological surveys of MDD have been conducted in Beijing since 2003. Aims To determine the prevalence of MDD and its socio-demographic correlates in a representative household sample of the general population in Beijing, China. Method Data were collected from the 2010 representative household epidemiological survey of mental disorders in Beijing. The multistage cluster random sampling method was used to select qualified subjects in 18 districts and counties, and then face-to-face interviews were administered using the Chinese version of Structured Clinical Interview for DSM-IV-TR Axis I Disorders-Patient Edition (SCID-I/P) during November 1, 2010 to December 31, 2010. Results 19,874 registered permanent residents were randomly identified and 16,032 (response rate=80.7%) completed face-to-face interviews. The time-point and life-time prevalence rates of MDD were estimated to be 1.10% (95% CI: 0.94–1.26%) and 3.56% (95% CI: 3.27–3.85%) respectively. Significant differences were found in sex, age, location of residence, marital status, education, employment status, personal/family monthly income, perception of family environment and relationship with others, when comparing residents with MDD to those without MDD. Those who were female, aged 45 or above, reported low family income, or reported an “average” or “poor” family environment were associated with a higher risk of MDD. Conclusions The prevalence of MDD reported in this survey is relatively lower than that in other western countries. Female sex, age older than 45, low family income, and poor family environment appear to be independent risk factors for MDD. [ABSTRACT FROM AUTHOR]

Abstract: Objective: This study aimed at determining the mean total sleep time (TST) and the relationship between sleep duration and basic socio-demographic factors and BMI sleep problems in Chinese subjects. Method: A total of 5926 subjects were randomly selected and interviewed using standardized assessment tools. Results: The reported mean TST was 7.76h. Short sleepers were significantly older than medium and long sleepers. There were more urban residents who were short sleepers than medium and long sleepers. Short sleepers reported more sleep problems than medium and long sleepers. Short and long sleepers reported more psychiatric disorders than medium sleepers in both sexes, and short sleepers also had more major medical conditions in women. Short sleepers had a lower BMI than medium and long sleepers after controlling for the effects of age and psychiatric disorders in women. Conclusions: Nationwide epidemiologic surveys in China are needed to further explore the relationship between sleep duration and sleep problems. [Copyright &y& Elsevier]

Abstract: Objective: This study aimed to determine the 12-month and lifetime prevalence of major depressive episode (MDE) and their socio-demographic correlates in both the urban and rural areas of Beijing, China. Methods: A total of 4767 adults were randomly selected and interviewed in Beijing using the Composite International Diagnostic Interview (CIDI 1.0). Basic socio-demographic and clinical data were collected during the interviews. Results: The overall 12-month prevalence of MDE was 3.2%; 2.8% and 3.8% for men and women, respectively. The overall lifetime prevalence of MDE was 5.3%; 4.4% and 6.3% for men and women, respectively. Being older than 25 years of age was independently associated with increased risk of MDE. Sixteen point three percent of the subjects with lifetime MDE attempted suicide while the rate of suicide attempts was only 0.2% in subjects without MDE. The percentage of subjects with MDE who received any type of treatment from medical practitioners was 33.1%; of them, only 5.4% sought help from mental health professionals. Conclusions: National epidemiologic surveys are needed to further explore the prevalence of MDE in China. The low percentage of subjects treated for MDE constitutes a major public health problem that should be urgently addressed. [Copyright &y& Elsevier]

PURPOSE. This study aims to determine the 12-month and lifetime prevalence of generalized anxiety disorder (GAD) and its sociodemographic correlates. DESIGN AND METHODS. A total of 5,926 subjects were randomly selected and interviewed. FINDINGS. The overall 12-month and lifetime prevalence of GAD was 0.8%, and 1.2%, respectively. Being older than 25 years and female, lower education level, unemployed status, and lower (< RMB500/month) or higher (> RMB2000/month) monthly income were associated with increased risk of GAD. PRACTICE IMPLICATIONS. The low percentage of subjects treated for GAD indicates a major public health problem that should be addressed. [ABSTRACT FROM AUTHOR]

Abstract: Background: In China, there is limited information on smoking and its socio-demographic correlates in general, and in psychiatric patients in particular. The aim of this study was to determine the prevalence of lifetime, current mild, and heavy smoking, the socio-demographic correlates of current smoking, and its relationship with psychiatric disorders in the Beijing municipality, China. Methods: A total of 5926 subjects who met the study''s entry criteria were randomly selected from the urban and rural areas of Beijing and interviewed using standardized assessment tools, including the collection of basic socio-demographic and clinical data. All subjects fully cooperated in the interviews and readily disclosed all of the information. Results: The prevalence of lifetime smoking was 35.9%; the rates for current mild and heavy smoking were 21.8% and 10.8%, respectively. An age of 24 years or above, male sex, married, divorced, separated or widowed marital status, relatively low level of education (less than college level), being employed, a relatively high monthly income (more than RMB500), rural abode, and having a psychiatric disorder were risk factors of current smoking. Both current mild and heavy smoking were significantly associated with alcohol dependence, and current heavy smoking was also associated with a history of a major depressive episode. Conclusions: The prevalence of smoking in the rural and urban areas of Beijing is unacceptably high. In addition to certain socio-demographic factors, smoking was associated with common psychiatric disorders. Nationwide surveys are warranted to further explore the prevalence of smoking in China. Effective strategies to reduce the high rate of smoking are also needed. [Copyright &y& Elsevier]

Objective: There has been no large-scale survey of suicide-related behaviours including suicidal ideations, plans and attempts in China involving both rural and urban areas and using standardized assessment tools. The aim of the present study was to determine the lifetime prevalence of suicide-related behaviour and its relationship with sociodemographic factors and psychiatric disorders in the rural and urban regions of Beijing, China. Methods: A total of 5926 subjects were randomly selected in Beijing and interviewed using the Composite International Diagnostic Interview. Basic sociodemographic and clinical data and data on suicide-related behaviour were also collected. Results: The overall lifetime prevalence estimates of suicidal ideation, plans and attempts were 2.3%, 1.4%, and 1.0%, respectively; the corresponding figures were 2.8%, 1.6%, and 1.3% in the rural sample, and 1.8%, 1.3%, and 0.9% in the urban sample. Age (>25years), female sex, unmarried status, lower education level, lower (RMB2000month-1) monthly income and presence of major medical disorders were significantly associated with increased risk of suicide-related behaviour. 36.2% of subjects with suicide-related behavior consulted a medical practitioner and 20.7% consulted a psychiatrist. Conclusions: The prevalence of lifetime suicide-related behaviour in Beijing is lower than in Western countries, but the low percentage of subjects treated for suicide-related behaviour indicates a major public health problem that should be addressed. National surveys are needed to further explore the prevalence of suicide-related behaviour in China. [ABSTRACT FROM AUTHOR]

Abstract: Objective: There has been no large-scale survey of schizophrenia in China involving both rural and urban areas using standardized assessment tools and diagnostic criteria. This study aimed to determine the lifetime prevalence of schizophrenia and its socio-demographic correlates in Beijing, China. Methods: A total of 5926 subjects were randomly selected in Beijing and interviewed using the Composite International Diagnostic Interview (CIDI 1.0). Basic socio-demographic and clinical data were collected during the interviews. Results: The lifetime prevalence of schizophrenia was 0.49%, and 0.44% and 0.55% for men and women, respectively. Unmarried status, lower monthly income, urban abode and positive family history were associated with an increased risk of schizophrenia; 9.7% of the subjects with lifetime schizophrenia reported a history of suicide attempts. The percentage of subjects with schizophrenia who were receiving treatment and their preference to seek treatment from mental health professionals were 58% and 29%, respectively. Conclusions: National surveys are urgently needed to further explore the prevalence of schizophrenia in China. The low percentage of subjects treated for schizophrenia is a serious public health issue that should be addressed in the near future. [Copyright &y& Elsevier]

• Daily TAC dose covariate improved the predictive performance in linear PPK model. • The MM model fit the data better compared with the linear model. • A CYP3A5 genotype-based MM model could achieve the target C 0 of TAC better. • Diltiazem increase the C 0 of TAC, and it is more obvious in CYP3A5*3*3 carriers. • The target C 0 of TAC can be easily achieved by tailoring the dose of diltiazem. The population pharmacokinetics (PPK) of tacrolimus (TAC) in children with refractory nephrotic syndrome (RNS) have not been well-characterized. This study aimed to investigate the significant factors affecting the TAC PPK characteristics of children with RNS and to optimize the dosing regimen. A total of 494 concentrations from 108 children were obtained from routine therapeutic drug monitoring between 2016 and 2018. Information regarding the demographic features, laboratory test results, genetic polymorphisms of CYP3A5 (rs776746) and co-therapy medications were collected. PPK analysis was performed using the nonlinear mixed-effects modelling (NONMEM) software and two modelling strategies (the linear one-compartment model and nonlinear Michaelis–Menten model) were evaluated and compared. CYP3A5 genotype, weight, daily dose of TAC and daily dose of diltiazem were retained in the final linear model. The absorption rate constant (Ka) was set at 4.48 h−1 in the linear model, and the apparent clearance (CL/F) and volume of distribution (V/F) in the final linear model were 14.2 L/h and 172 L, respectively. CYP3A5 genotype, weight and daily dose of diltiazem were the significant factors retained in the final nonlinear model. The maximal dose rate (V max) and the average steady-state concentration at half-Vmax (K m) in the final nonlinear model were 2.15 mg/day and 0.845 ng/ml, respectively. The nonlinear model described the pharmacokinetic data of TAC better than the linear model in children with RNS. A dosing regimen was proposed based on weight, CYP3A5 genotype and daily dose of diltiazem according to the final nonlinear PK model, which may facilitate individualized drug therapy with TAC. [ABSTRACT FROM AUTHOR]