Individualized treatment with voriconazole in the Chinese population: Inflammation level as a novel marker for dose optimization.

AIMS: The aim of this study was to explore the influence and possible mechanisms of pharmacokinetics-related gene polymorphisms, especially CYP2C19 polymorphisms, and non-genetic factors combined with the inflammatory status on the voriconazole (VRC) metabolism of the Chinese population. METHODS: Clinical studies were performed by collecting more than one VRC trough concentration and C-reactive protein (CRP) level. A total of 265 blood samples were collected from 120 patients. RESULTS: Results of multiple regression analyses demonstrated that CYP2C19 genotypes and albumin (Alb) level remained predictors of Cmin ss/D in patients with no to mild inflammation (R2 = 0.12, P < .001). In addition, in patients with moderate to severe inflammation, it resulted in a significant model containing factors of CRP and total bilirubin (T-Bil) levels (R2 = 0.19, P < .001). In non-clinical studies, 32 rats were divided into control and inflammatory groups, and it was found that the mean residence time (MRT(0-t) ) of VRC in the inflammatory group was significantly longer than that in the control group (P < .001), which may be due to down-regulation of mRNA and protein expression of CYP2C19 (CYP2C6 in rats) through interleukin (IL)-6/signal transducer and activator of transcription (STAT) 3 pathway. CONCLUSIONS: Therefore, the effect of CYP2C19 polymorphisms on VRC metabolism may be masked by inflammatory status, which should be of more concern than CYP2C19 polymorphisms in patients with moderate to severe inflammation. Additionally, the impact of Alb and T-Bil on VRC metabolism should not be disregarded.

Determination of trace chelating carboxylic acids in rice by green extraction combined with liquid chromatography-mass spectrometry analysis and its application in the evaluation of old and new rice.

RATIONALE: Accurate identification of old rice samples from new ones benefits their market circulation and consumers. However, the current detection methods are still not satisfactory because of their insufficient accuracy or (and) time-consuming process. METHODS: Chelating carboxylic acids (CCAs) were selectively extracted from rice, by stirring with chelating resin and a dilute Na2CO3 solution. The green analytical chemistry guidelines for sample preparation were investigated by using the green chemistry calculator AGREE prep. The extractant was determined by liquid chromatography-mass spectrometry (LC/MS), and statistical analysis of the analytical data was carried out to evaluate the significance of the difference by ChiPlot. RESULTS: The limit of quantitation for the CCAs is in the range of 1 to 50 ng/mL, with a reasonable reproducibility. The CCAs in 23 rice samples were determined within a wide concentration range from 0.03 to 1174 µg/g. Intriguingly, the content of citric acid, malonic acid, α-ketoglutaric acid and cis-aconite acid in new rice was each found to be distinctively higher than that in old rice by several times. Even mixtures of old and new rice were found to show much difference in the concentration of citric acid and malic acid. CONCLUSION: A green analytical method has been developed for the simultaneous determination of CCAs by LC/MS analysis, and the identification of old rice samples from new ones was easily carried out according to their CCA content for the first time. The results indicated that the described method has powerful potential for the accurate identification of old rice samples from new ones.

Effects of Wuzhi Capsule on Whole-Blood Tacrolimus Concentration Levels: A Systematic Review and Meta-Analysis.

BACKGROUND: Wuzhi Capsule (WZC) is a traditional Chinese medicinal herb widely used to treat drug-induced hepatitis or liver dysfunction and is usually prescribed in China to increase tacrolimus concentration. Several studies with small sample sizes have shown that WZC can increase tacrolimus concentration levels in clinical practice. This study aimed to evaluate the effect of WZC on whole-blood tacrolimus concentration levels and safety. METHODS: We searched 7 databases for randomized clinical trials (RCTs) and observational studies (OSs) comparing whole-blood tacrolimus concentration levels between WZC and non-WZC treatments. Data analysis was performed using Review Manager version 5.3. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. RESULTS: Eleven studies involving 6 RCTs and 5 OSs were included. The meta-analysis indicated that whole-blood tacrolimus concentration levels in the WZC group was significantly higher than that of the non-WZC group [weighted mean difference = 1.38, 95% CI (confidence interval), 1.21-1.56, P < 0.001], and similar results were shown in all the subgroups of follow-up time, different primary disease, and different WZC doses. In the self-control OSs, the whole-blood tacrolimus concentration levels in the WZC group was significantly higher than the non-WZC group (weighted mean difference = 1.17, 95% CI, 0.71-1.64, P < 0.001). WZC was generally well tolerated and there was no significant difference in the incidence of adverse reactions between the 2 groups. CONCLUSIONS: WZC can increase whole-blood tacrolimus concentration levels. This may be an economical and practical treatment choice for patients, especially those with poor oral tacrolimus absorption capabilities. Nevertheless, RCTs and OSs with large sample sizes and high quality are needed in the future to confirm these positive results.

Uptake, translocation, and metabolism of organophosphate esters (OPEs) in plants and health perspective for human: A review.

Plant uptake, accumulation, and transformation of organophosphate esters (OPEs) play vital roles in their geochemical cycles and exposure risks. Here we reviewed the recent research advances in OPEs in plants. The mean OPE concentrations based on dry/wet/lipid weight varied in 4.80-3,620/0.287-26.8/12,000-315,000 ng g-1 in field plants, and generally showed positive correlations with those in plant habitats. OPEs with short-chain substituents and high hydrophilicity, particularly the commonly used chlorinated OPEs, showed dominance in most plant samples, whereas some tree barks, fruits, seeds, and roots demonstrated dominance of hydrophobic OPEs. Both hydrophilic and hydrophobic OPEs can enter plants via root and foliar uptake, and the former pathway is mainly passively mediated by various membrane proteins. After entry, different OPEs undergo diverse subcellular distributions and acropetal/basipetal/intergenerational translocations, depending on their physicochemical properties. Hydrophilic OPEs mainly exist in cell sap and show strong transferability, hydrophobic OPEs demonstrate dominant distributions in cell wall and limited migrations owing to the interception of Casparian strips and cell wall. Additionally, plant species, transpiration capacity, growth stages, commensal microorganisms, and habitats also affect OPE uptake and transfer in plants. OPE metabolites derived from various Phase I transformations and Phase II conjugations are increasingly identified in plants, and hydrolysis and hydroxylation are the most common metabolic processes. The metabolisms and products of OPEs are closely associated with their structures and degradation resistance and plant species. In contrast, plant-derived food consumption contributes considerably to the total dietary intakes of OPEs by human, particularly the cereals, and merits specifical attention. Based on the current research limitations, we proposed the research perspectives regarding OPEs in plants, with the emphases on their behavior and fate in field plants, interactions with plant-related microorganisms, multiple uptake pathways and mechanisms, and comprehensive screening analysis and risk evaluation.

Bioinformatics-Based Identification of CircRNA-MicroRNA-mRNA Network for Calcific Aortic Valve Disease.

Background: Calcific aortic valve disease (CAVD) is the most common native valve disease. Valvular interstitial cell (VIC) osteogenic differentiation and valvular endothelial cell (VEC) dysfunction are key steps in CAVD progression. Circular RNA (circRNAs) is involved in regulating osteogenic differentiation with mesenchymal cells and is associated with multiple disease progression, but the function of circRNAs in CAVD remains unknown. Here, we aimed to investigate the effect and potential significance of circRNA-miRNA-mRNA networks in CAVD. Methods: Two mRNA datasets, one miRNA dataset, and one circRNA dataset of CAVD downloaded from GEO were used to identify DE-circRNAs, DE-miRNAs, and DE-mRNAs. Based on the online website prediction function, the common mRNAs (FmRNAs) for constructing circRNA-miRNA-mRNA networks were identified. GO and KEGG enrichment analyses were performed on FmRNAs. In addition, hub genes were identified by PPI networks. Based on the expression of each data set, the circRNA-miRNA-hub gene network was constructed by Cytoscape (version 3.6.1). Results: 32 DE-circRNAs, 206 DE-miRNAs, and 2170 DE-mRNAs were identified. Fifty-nine FmRNAs were obtained by intersection. The KEGG pathway analysis of FmRNAs was enriched in pathways in cancer, JAK-STAT signaling pathway, cell cycle, and MAPK signaling pathway. Meanwhile, transcription, nucleolus, and protein homodimerization activity were significantly enriched in GO analysis. Eight hub genes were identified based on the PPI network. Three possible regulatory networks in CAVD disease were obtained based on the biological functions of circRNAs including: hsa_circ_0026817-hsa-miR-211-5p-CACNA1C, hsa_circ_0007215-hsa-miR-1252-5p-MECP2, and hsa_circ_0007215-hsa-miR-1343-3p- RBL1. Conclusion: The present bionformatics analysis suggests the functional effect for the circRNA-miRNA-mRNA network in CAVD pathogenesis and provides new targets for therapeutics.

Development of UHPLC-MS/MS method for simultaneous determination of tacrolimus and sirolimus in human whole blood and comparisons with two immunoassays.

Tacrolimus (TAC) and sirolimus (SIR) antirejection medications are widely used in organ transplantation. We aimed to develop an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) assay for quantifying TAC and SIR simultaneously and evaluating agreement with chemiluminescence microparticle immunoassay (CMIA) and electrochemiluminescence immunoassay (ECLIA). Whole blood samples collected from 209 TAC and 208 SIR patients were assessed by UHPLC-MS/MS, CMIA and ECLIA. The agreement of the three techniques was assessed using the Bland-Altman plot. The UHPLC-MS/MS assay had a calibration range of 1-100 ng/ml for TAC and SIR. The accuracy and precision were -2.73-4.32% and <4.71% for TAC, respectively, and 0.07-4.84% and <6.5% for SIR, respectively. The three methods had good correlation. In comparison with UHPLC-MS/MS, two immunoassays showed a slight deviation in proportion. An UHPLC-MS/MS method for simultaneously detecting TAC and SIR in human whole blood was developed, validated and comparatively analyzed with CMIA and ECLIA. For determining TAC and SIR, immunoassays displayed acceptable analytical performances in terms of precision and correlation compared with UHPLC-MS/MS. However, further investigation is warranted to examine the novel method.

Stenocarpella chrysopogonis, a New Species Causing Leaf Streak Disease of Chrysopogon zizanioides in Southern China.

Vetiver grass (Chrysopogon zizanioides) has been widely used in recent years for ecological environment management, restoration of degraded ecosystems, and essential oil extraction. In 2019, a leaf streak disease of C. zizanioides was observed in Zhanjiang, Guangdong Province, China. The disease appeared as large streak lesions on the leaves, on which conidiomata were formed. A pathogenicity test with the fungus isolated from these lesions confirmed Koch's postulates and thus the fungus as the causal agent of this disease. A morphological resemblance of the pathogen to Stenocarpella was noted upon microscopic examination. Phylogenetic trees inferred from both individual and combined ITS, LSU, and tef1 sequences confirmed the pathogen as a species of the Diaporthaceae and revealed it to be closely related to Phaeocytostroma and Stenocarpella species. As morphological characters clearly placed the pathogen in the genus Stenocarpella, it was described as S. chrysopogonis.

Integrated microarray for identifying the hub mRNAs and constructed miRNA-mRNA network in coronary in-stent restenosis.

As a major complication after percutaneous coronary intervention (PCI) in patients who suffer from coronary artery disease, in-stent restenosis (ISR) poses a significant challenge for clinical management. A miRNA-mRNA regulatory network of ISR can be constructed to better reveal the occurrence of ISR. The relevant data set from the Gene Expression Omnibus (GEO) database was downloaded, and 284 differentially expressed miRNAs (DE-miRNAs) and 849 differentially expressed mRNAs (DE-mRNAs) were identified. As predicted by online tools, 65 final functional genes (FmRNAs) were overlapping DE-mRNAs and DE-miRNAs target genes. In the biological process (BP) terms of gene ontology (GO) functional analysis, the FmRNAs were mainly enriched in the cellular response to peptide, epithelial cell proliferation, and response to peptide hormone. In the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the FmRNAs were mainly enriched in breast cancer, endocrine resistance, and Cushing syndrome. Jun proto-oncogene, activator protein-1 (AP-1) transcription factor subunit (JUN), insulin-like growth factor 1 receptor (IGF1R), member RAS oncogene family (RAB14), specificity protein 1 (SP1), protein tyrosine phosphatase nonreceptor type 1 (PTPN1), DDB1 and CUL4 associated factor 10 (DCAF10), retinoblastoma-binding protein 5 (RBBP5), and eukaryotic initiation factor 4A-I (EIF4A1) were hub genes in the protein-protein interaction network (PPI network). The miRNA-mRNA network containing DE-miRNAs and hub genes was built. Hsa-miR-139-5p-JUN, hsa-miR-324-5p-SP1 axis pairs were found in the miRNA-mRNA network, which could promote ISR development. The aforementioned results indicate that the miRNA-mRNA network constructed in ISR has a regulatory role in the development of ISR and may provide new approaches for clinical treatment and experimental development.

Impact of cytochrome P450 2C19 polymorphisms on the clinical efficacy and safety of voriconazole: an update systematic review and meta-analysis.

OBJECTIVE: To assess the impact of cytochrome P450 (CYP) 2C19 polymorphisms on the clinical efficacy and safety of voriconazole. METHODS: We systematically searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and three Chinese databases from their inception to 18 March 2021 using a predefined search algorithm to identify relevant studies. Studies that reported voriconazole-treated patients and information on CYP2C19 polymorphisms were included. The efficacy outcome was success rate. The safety outcomes included overall adverse events, hepatotoxicity, and neurotoxicity. RESULTS: A total of 20 studies were included. Intermediate metabolizers (IMs) and poor metabolizers (PMs) were associated with increased success rates compared with normal metabolizers (NMs) [risk ratio (RR), 1.18; 95% confidence interval (CI), 1.03-1.34; I2 = 0%; P = 0.02; RR, 1.28; 95% CI, 1.06-1.54; I2 = 0%; P = 0.01]. PMs were at increased risk of overall adverse events in comparison with NMs and IMs (RR, 2.18; 95% CI, 1.35-3.53; I2 = 0%; P = 0.001; RR, 1.80; 95% CI, 1.23-2.64; I2 = 0%; P = 0.003). PMs demonstrated a trend towards an increased incidence of hepatotoxicity when compared with NMs (RR, 1.60; 95% CI, 0.94-2.74; I2 = 27%; P = 0.08), although there was no statistically significant difference. In addition, there was no significant association between CYP2C19 polymorphisms and neurotoxicity. CONCLUSION: IMs and PMs were at a significant higher success rate in comparison with NMs. PMs were significantly associated with an increased incidence of all adverse events compared with NMs and IMs. Researches are expected to further confirm these findings. Additionally, the relationship between hepatotoxicity and CYP2C19 polymorphisms deserves clinical attention.

Impact of DNA methylation on ADME gene expression, drug disposition, and efficacy.

Interindividual differences in drug response have always existed in clinical treatment. Genes involved in drug absorption, distribution, metabolism, and excretion (ADME) play an important role in the process of pharmacokinetics. The effects of genetic polymorphism and nuclear receptors on the expression of drug metabolism enzymes and transporters can only explain some individual differences in clinical treatment. Several key ADME genes have been demonstrated to be regulated by epigenetic mechanisms that can potentially affect inter-individual variability in medical treatment. Emerging studies have focused on the importance of DNA methylation for ADME gene expression and for drug response. Among them, the most studied are anti-tumor drugs, followed by anti-tuberculous and anti-platelet drugs. Therefore, we provide an epigenetics perspective on variability in drug response. The review summarizes the correlation between ADME gene expression and DNA methylation, including the exact methylation locations, and focuses on the corresponding drug disposition and effects to illuminate interindividual differences in clinical medication.

Development of Neuronal Excitability of the Bushy Cells in Anteroventral Cochlear Nucleus of Rats.

The ultrafast and precise single-onset action potential (AP) of the bushy cells (BCs) in the anteroventral cochlear nucleus (AVCN) plays an important role in precise processing of temporal auditory information for localizing sound sources and communication cues. The specialized properties of high conductance of the low-voltage-activated potassium (K+LVA) channel contribute to generate ultrafast and precise single-onset APs in BCs. However, the developmental changes of K+LVA distribution and their contributions to shape neuronal excitability of BCs remain unclear. Therefore, we investigated the developmental changes in neuronal excitability of BCs and K+LVA distribution at different developmental periods. Using electrophysiological recording, we first characterized the firing pattern of BCs in response to a sequence of current injections at different developmental periods. The expression of the K+LVA subunit Kv1.1 in AVCN was examined with Western blot. The results indicated that BCs showed single-onset AP firing patterns and paused multiple APs firing patterns at the postnatal time of day 7 (P7) and were then refined into single-onset firing patterns at P14 and P21. With development, the active membrane properties, including latency and half-width of AP, and passive membrane properties, including capacitance, input resistance, and time constant, were significantly decreased. Furthermore, the refinement of firing patterns in BCs was correlated with the upregulation of the Kv1.1 channel in AVCN. In summary, the present study indicated that BCs optimize precise and single-onset firing with development, possibly driven by the changes in membrane properties and upregulation of Kv1.1 in AVCN.

Cr/C lamellar multilayer grating in conical diffraction mounting for beam splitter used in X-ray free-electron lasers.

A lamellar multilayer grating in a conical diffraction mounting was proposed as a beam splitter for X-ray free-electron lasers. Theoretical calculations demonstrated that the distribution of diffraction efficiency can be adjusted by optimizing the groove depth or d-spacing. A Cr/C multilayer lamellar grating with a line density of approximately 2500 L/mm was fabricated. The performance of the element was measured in the Optics Beamline PM-1 (BESSY-II) at an energy of 1500 eV. A five-order diffraction pattern was recognized, and the diffraction efficiencies of the -/+first-order were approximately 12.6 and 4.4%, respectively. The asymmetric distribution of diffraction efficiency can be caused by the different sidewall angles of the grating groove.

N-methyl-N-nitrosourea induces zebrafish anomalous angiogenesis through Wnt/ß-catenin pathway.

N-methyl-N-nitrosourea (MNU) is a prevalent environmental carcinogen, which leads to tumors in various organs in animal models, while the mechanisms involved were still not fully understood. It is well known that anomalous angiogenesis is a key step in tumorigenesis and progression. In this study, we found that MNU induced abnormal angiogenesis which was accompanied by upregulation of rspo1, p53 and vegfaa in zebrafish embryos. Moreover, it revealed that MNU-induced ectopic sprouting of blood vessels was significantly reduced in rspo1-knockdown but not p53-knockdown embryos, indicating that rspo1 was necessary for MNU-induced abnormal angiogenesis. Additionally, pharmaceutical activation or inhibition of Wnt/ß-catenin signaling pathway using (2'Z,3'E)- 6-bromoindirubin-3'-oxime or CCT036477 significantly increased or inhibited the pro-angiogenic effect of MNU on developing zebrafish embryos, which was confirmed by the effect of proliferation and migration in MNU-treated bEnd.3 cells. These data together indicated that rspo1/Wnt/ß-catenin/vegfaa axis is involved in the modulation of MNU-induced anomalous angiogenesis.

Repetitive Transcranial Magnetic Stimulation for Neuropathic Pain and Neuropsychiatric Symptoms in Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Neuropathic pain and neuropsychiatric symptoms are common complications reported by the traumatic brain injury (TBI) population. Although a growing body of research has indicated the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for the management of neurological and psychiatric disorders, little evidence has been presented to support the effects of rTMS on neuropathic pain and neuropsychiatric symptoms in patients with TBI in all age groups. In addition, a better understanding of the potential factors that might influence the therapeutic effect of rTMS is necessary. The objective of this preregistered systematic review and meta-analysis was to quantify the effects of rTMS on physical and psychological symptoms in individuals with TBI. We systematically searched six databases for randomized controlled trials (RCTs) of rTMS in TBI patients reporting pain and neuropsychiatric outcomes published until March 20, 2022. The mean difference (MD) with 95% confidence intervals (CIs) was estimated separately for outcomes to understand the mean effect size. Twelve RCTs with 276 TBI patients were ultimately selected from 1605 records for systematic review, and 11 of the studies were included in the meta-analysis. Overall, five of the included studies showed a low risk of bias. The effects of rTMS on neuropathic pain were statistically significant (MD = -1.00, 95% CI -1.76 to -0.25, P = 0.009), with high heterogeneity (I 2 = 76%). A significant advantage of 1 Hz rTMS over the right dorsolateral prefrontal cortex (DLPFC) in improving depression (MD = -6.52, 95% CI -11.58 to -1.46, P = 0.01) was shown, and a significant improvement was noted in the Rivermead Post-Concussion Symptoms Questionnaire-13 (RPQ-13) scores of mild TBI patients after rTMS (MD = -5.87, 95% CI -10.63 to -1.11, P = 0.02). However, no significance was found in cognition measurement. No major adverse events related to rTMS were reported. Moderate evidence suggests that rTMS can effectively and safely improve neuropathic pain, while its effectiveness on depression, postconcussion symptoms, and cognition is limited. More trials with a larger number of participants are needed to draw firm conclusions. This trial is registered with PROSPERO (PROSPERO registration number: CRD42021242364.

NMR Assignments of Six Asymmetrical N-Nitrosamine Isomers Determined in an Active Pharmaceutical Ingredient by DFT Calculations.

N-nitrosamines, which are well-known pro-mutagens, are found in drugs, pickled food and tobacco. Therefore, controlling their concentrations is very important. When an HPLC, GC or NMR analysis is conducted to investigate certain asymmetrical N-nitrosamines, two sets of signals attributed to the asymmetric N-nitrosamine isomers are usually observed. However, few reports on the NMR assignment of asymmetrical N-nitrosamine isomers have been published. In this study, we investigated the NMR assignments of the Z/E isomers of six asymmetrical N-nitrosamines by means of density functional theory (DFT) calculations. The configuration of the major isomer of asymmetrical N-nitrosamine 3 was the Z-configuration. The configuration of the major isomers of asymmetrical N-nitrosamines 4-7 was the E-configuration. Then, we determined the Z/E ratios of these asymmetrical N-nitrosamines by means of variable temperature (VT) and room temperature (RT) 1H-NMR experiments. The ratios of the Z/E isomer 3 quickly increased beyond 100% in the VT 1H NMR experiments. The ratios of Z/E isomers 4-7 were increased in the range of 10-60% in the VT 1H NMR experiments. The results of this study indicate that identifying the isomers of asymmetrical N-nitrosamine is necessary to control the quality of N-nitrosamines for active pharmaceutical ingredients (APIs).

Mo/Si lamellar multilayer gratings with high efficiency and enhanced resolution for the x-ray region of 1000-1700eV.

The d-spacing of the multilayer lamellar grating was theoretically optimized to improve the energy resolution and maintain a high efficiency. Based on the study of the growth behavior of Mo/Si multilayer on the lamellar grating under different sputtering pressures, Ar gas pressure of 1 mTorr was selected, which can fabricate the multilayer with lower roughness and a good replication of the groove shape. An absolute diffraction efficiency of 25.6% and a Cff factor of 1.79 were achieved for the -1st order of the Mo/Si lamellar multilayer grating at an energy of 1700 eV.

The influence of CYP2C19 polymorphisms on voriconazole trough concentrations: Systematic review and meta-analysis.

BACKGROUND: Voriconazole primary metabolism is catalysed by CYP2C19. A large variability of trough concentrations in patients with invasive fungal infection treated with voriconazole has been observed in clinical practice. It remains controversial whether the CYP2C19 polymorphisms are responsible for voriconazole metabolism in the individual variation. OBJECTIVES: The primary aim of this study was to assess the effect of CYP2C19 polymorphisms on voriconazole trough concentrations. METHODS: Following a systematic literature review, we performed a meta-analysis for mean differences (MD) of voriconazole trough concentrations (Cmin ), voriconazole dosage adjusted trough concentrations (Cmin /D) and for risk ratio (RR) of the proportion of patients in the target therapeutic range between pairwise comparisons of CYP2C19 phenotypes. RESULTS: Compared with normal metabolisers (NMs), intermediate metabolisers (IMs) (MD: 0.82, 95% CI: 0.57 to 1.07, I2  = 44%, p < .00001) or poor metabolisers (PMs) (MD: 1.59, 95% CI: 1.14 to 2.05, I2  = 46%, p < .00001) had significantly higher voriconazole Cmin (µg·ml-1 ), while rapid metabolisers (RMs) had significantly lower voriconazole Cmin (MD: -0,87, 95% CI: -1.35 to -0.38, I2  = 0%, p = .0004). In addition, IMs had significantly lower Cmin than PMs (MD: -0.59, 95% CI: -0.97 to -0.20, I2  = 22%, p = .003). Similarly, the Cmin /D (µg·kg·ml-1 ·mg-1 ) was significantly higher in IMs (MD: 0.13, 95% CI: 0.05 to 0.22, I2  = 0%, p = .002) and PMs (MD: 0.20, 95% CI: 0.07 to 0.34, I2  = 0%, p = .003) than that in NMs, and also, IMs had significantly lower Cmin /D than PMs (MD: -0.11, 95% CI: -0.14 to -0.08, I2  = 0%, p < .00001). Furthermore, PMs had a significantly higher proportion of the target therapeutic range than NMs (RR: 1.34, 95% CI: 1.09 to 1.64, I2  = 50%, p = .005). CONCLUSIONS: Compared to NMs, IMs and PMs had higher voriconazole trough concentrations, especially in Asians, while RMs had lower voriconazole trough concentrations. In addition, PMs had a higher proportion of the target therapeutic range than NMs, especially in Asians. CYP2C19 genotyping is expected to be used to preemptively guide the individualisation of voriconazole in clinical practice.

Thermal and temporal stability of the nitridated Ru/B4C multilayer for high-flux monochromator application.

A nitridated Ru/B4C multilayer with period of 3.0 nm and 80 bilayers were fabricated to study thermal and temporal stability. The multilayer was annealed from room temperature to 490°C, and the in situ X-ray measurements showed that the reflectivity remains mostly unchanged up to 300°C. An essential drop of the reflectivity occurred at 490°C with significantly increased interface roughness. A new layered structure with larger thickness than the original multilayer started to appear at 400°C. The nitridated Ru/B4C multilayer remains intact after two years of storage in air, which demonstrated a very good temporal stability.

Screening anaphylactoid components of Shuang Huang Lian Injection by analyzing spectrum-effect relationships coupled with UPLC-TOF-MS.

Shuang Huang Lian Injection (SHLI) has been used in China for over 30 years as an effective and widely used Chinese herbal prescription to treat acute respiratory infectious. SHLI has, however, caused many severe anaphylactoid reactions. It is important to identify the potential anaphylactoid components of SHLI. Spectrum-effect relationships were used to explore potentially anaphylactoid components. Based on the original herbal formula, honeysuckle, Fructus Forsythiae and Radix Scutellariae extracts were prepared and combined in appropriate proportions. The preparations were then injected into the caudal vein of rats to obtain in vivo serum samples for pharmacological evaluation and fingerprint analysis. The release rate of ß-hexosaminidase from RBL-2H3 cells and plasma histamine level was used as the pharmacological index. Chromatographic fingerprint analysis identified 22 common peaks. Regression analysis and correlation analysis were used to calculate the relationships between the peaks and the pharmacological effects and identified peaks 5, 6, 11, 12 and 17 as likely anaphylactoid agents. The correlated peaks were identified by comparing the fingerprints with in vitro samples and reference standard samples and the structure was identified by UPLC-TOF-MS. This study established a prospective method to clarify the anaphylactoid components in SHLI, which would provide guidances for screening anaphylactoid components in other traditional Chinese medicine injections.

Nitridated Ru/B4C multilayer mirrors with improved interface structure, zero stress, and enhanced hard X-ray reflectance.

Ru/B4C multilayer mirrors are used for hard X-ray monochromators with moderate spectral resolution and high integral flux. To overcome the problem of large compressive stress inherent in Ru/B4C multilayers, a reactive sputtering technique using a mixture working gas of argon and nitrogen with different partial pressures was tested, and the fabricated multilayers had a period of 3 nm. The intrinsic stress was essentially reduced after nitridation and relaxed to zero value at approximately 15% partial pressure of nitrogen in the working gas. Interface roughness was slightly increased which can be caused by the polycrystalline structure inside the nitridated samples. More importantly, the nitridated multilayers showed an enhanced reflectance (67% at 8.04 keV photon energy) as compared with the one fabricated with pure Ar (54%). The structure analysis with transmission electron microscopy and X-ray photoelectron spectroscopy demonstrated that nitrogen incorporated into a multilayer structure was mostly located in the B4C layers forming BN compounds, which suppressed the diffusion of boron, stabilized the interfaces and enhanced the reflectance.