Niels Westra, Kai van Hateren, Jos G. W. Kosterink, Marjolijn N. Lub-de Hooge, Thijs H. Oude Munnink, Daan J. Touw
{"title":"Validation of a LC-MS/MS Assay for Rapid and Simultaneous Quantification of Cobicistat and Venetoclax in Human Plasma and Serum","authors":"Niels Westra, Kai van Hateren, Jos G. W. Kosterink, Marjolijn N. Lub-de Hooge, Thijs H. Oude Munnink, Daan J. Touw","doi":"10.1002/bmc.70179","DOIUrl":"10.1002/bmc.70179","url":null,"abstract":"<p>Measuring cobicistat and venetoclax concentrations in human plasma and serum facilitates therapeutic drug monitoring (TDM) and pharmacokinetic (PK) boosting studies. Therefore, the objective of this study was to develop and validate a rapid LC-MS/MS analytical method for the simultaneous determination of cobicistat and venetoclax concentrations in plasma and serum. The method was validated according to EMA and FDA guidelines. Chromatographic separation was performed using a liquid chromatography (LC) system with a C18 column. The elution gradient involved two mobile phases: mobile phase A (ammonium formate) and mobile phase B (acetonitrile). The concentration range was 5–500 μg/L for cobicistat and 50–5000 μg/L for venetoclax. Accuracy and precision were within the required limits, with accuracy ranging from −5.9% to 2.4%, within-day precision from 1.2% to 4.8%, and between-day precision from 0.4% to 4.3%. Cobicistat and venetoclax were stable for at least 8 days under various storage and handling conditions. Clinical TDM samples showed mean concentrations ± standard deviation (SD) of 138.8 ± 123.3 μg/L for cobicistat and 1497.1 ± 1285.9 μg/L for venetoclax. The development and validation of this LC-MS/MS assay provide a reliable and efficient method for the simultaneous quantification of cobicistat and venetoclax in plasma and serum samples.</p>","PeriodicalId":8861,"journal":{"name":"Biomedical Chromatography","volume":"39 9","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bmc.70179","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144716559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Screening for the Breast Cancer-Associated Volatile Organic Compounds by GC–MS With Solid Phase Microextraction","authors":"Yu Zhang, Li-Yang Shao, Yu Li, Jiayi Li, Lingyun Hui, Jing Zhang","doi":"10.1002/bmc.70176","DOIUrl":"10.1002/bmc.70176","url":null,"abstract":"<div>\u0000 \u0000 <p>The use of volatile organic compounds (VOCs) as noninvasive disease biomarkers has been explored as the basis for the diagnosis of human diseases. Although VOCs are of interest clinically, limited studies have been conducted because identifying disease-related VOCs and neglecting irrelevant variance in the data is still a formidable challenge. In our work, the VOCs in the headspace of breast cell medium and human exhaled gas were analyzed by solid-phase microextraction—gas chromatography—mass spectrometry. The common VOCs, which may be the breast cancer (BC)-associated VOCs, were identified by statistical analysis, including 1-butanol, cyclohexanone, nonanal, acetophenone, and benzyl alcohol. Then, after treatment of MCF-7 cells with letrozole, the levels of four VOCs were reduced. Five VOCs in exhaled breath of BC patients with drug therapy were decreased. It further proves that these VOCs are closely BC-associated VOCs. The study screened five BC-associated VOCs from in vitro cell VOCs and human exhaled breath, and provides basic research for VOCs that can be used in the screening of clinical diseases.</p>\u0000 </div>","PeriodicalId":8861,"journal":{"name":"Biomedical Chromatography","volume":"39 9","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Insights Into the Mechanism of Action for Qingzhi Decoction for the Treatment of Non-Alcoholic Fatty Liver Disease via Regulation of the IRS/PI3K/Akt Signaling Pathway and the NRLP3 Inflammasome","authors":"Jiejun Yan, Qian Hou, Jing Liu, Weilan Li","doi":"10.1002/bmc.70156","DOIUrl":"10.1002/bmc.70156","url":null,"abstract":"<div>\u0000 \u0000 <p>The objective of this study is to explore the impacts of Qingzhi Decoction (QZT) in Non-alcoholic fatty liver disease (NAFLD) mice induced by a high-glucose and high-fat diet. UPLC-Orbitrap-Exploris MS characterized 156 bioactive components in QZT. Subsequently, an NAFLD model was established in ICR mice via 8-week feeding with a high-glucose and high-fat diet. The NAFLD mice were randomly divided into four groups. After 8 weeks of drug administration, compared with the control group, the model group showed significant NAFLD-related liver pathological changes, manifested as elevated blood lipid parameters (TC, TG, and LDL) and decreased HDL. Liver injury markers (ALT and AST) and serum inflammatory cytokines (IL-1β, IL-6, and TNF-α) were significantly increased. Molecular analysis indicated that the expression of p-IRs-1, PI3K, and p-Akt was decreased in liver tissue, while the expression of SREBP, NLRP3, caspase1, and GSDMD was increased. QZT treatment alleviated these changes, significantly improving NAFLD pathology, normalizing lipid profiles, and regulating the expression of these molecular markers (<i>p</i> < 0.01). QZT improved insulin resistance, regulated lipid metabolism, and reduced inflammatory response, and its mechanism might be associated with the regulation of IRs-1 and NLRP3 pathways.</p>\u0000 </div>","PeriodicalId":8861,"journal":{"name":"Biomedical Chromatography","volume":"39 9","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144687854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Simultaneous Determination of Four Active Ingredients in Snow Chrysanthemum by HPLC With Determination of Its Antioxidant Activity in Vitro","authors":"Sai Xu, Bin Zhang, Shunyuan Li, Kaiqin Long","doi":"10.1002/bmc.70172","DOIUrl":"10.1002/bmc.70172","url":null,"abstract":"<p>We established a reliable high-performance liquid chromatography coupled with ultraviolet detector (HPLC-UV) method to simultaneously quantify and compare four indicator components in Kunlun Chrysanthemum (<i>Coreopsis tinctoria</i> Nutt.), Jiajin Chrysanthemum (<i>C. tinctoria</i> Nutt.) and Chrysanthemum buds (<i>C. tinctoria</i> Nutt.). We also aimed to evaluate the antioxidant activity of them in vitro. We showed that chlorogenic acid, 3,5-Odicaffeoylquinic acid, and Quercitrin concentrations were highest in Jiajin Chrysanthemum; Luteolin was highest in Chrysanthemum buds, and the four components were at an intermediate level in Kunlun Chrysanthemum. Antioxidant activity demonstrated IC<sub>50</sub> values for DPPH free radical scavenging of Kunlun Chrysanthemum, Jiajin Chrysanthemum, and Snow Chrysanthemum buds of 1.20, 1.33, and 2.41 mg/mL, respectively. The IC<sub>50</sub> values for ABTS radical scavenging were 2.53, 2.43, and 3.38 mg/mL, respectively. It showed differences in the four active ingredients of Snow Chrysanthemums from different origins and harvesting times. This HPLC-UV method accurately and rapidly determined the four active ingredients in Snow Chrysanthemums simultaneously, which may provide a quality control reference for Snow Chrysanthemums. Future studies exploring specific differences in cultivation, climate, harvesting, and drying of Snow Chrysanthemums to optimize its chemical composition would assist in developing its potential as a natural plant resource in health care.</p>","PeriodicalId":8861,"journal":{"name":"Biomedical Chromatography","volume":"39 9","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bmc.70172","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Study on the Mechanism of Lonicerae japonicae Caulis in the Treatment of Rheumatoid Arthritis Based on Transcriptomics and Energy Metabolomics","authors":"Zhenzhen Xu, Jingyi Hou, Jing Li, Shijie Bi, Zewen Wang, Chaoqun Liu, Yanxia Liu, Bin Yu, Jiaye Tian, Yongjiang Yang, Liansheng Qiao, Yanjiang Qiao, Yanling Zhang","doi":"10.1002/bmc.70175","DOIUrl":"10.1002/bmc.70175","url":null,"abstract":"<div>\u0000 \u0000 <p>Rheumatoid arthritis (RA) is an autoimmune disorder characterized by inflammation, with current Western treatments focusing on symptom relief and disease progression control through antiinflammatory, analgesic, and immunosuppressive drugs. However, these therapies have significant side effects and limited long-term efficacy. Therefore, novel treatment options are urgently needed. <i>Lonicerae japonicae</i> Caulis (LJC), a traditional Chinese medicine, has alleviated RA symptoms such as joint pain and swelling. Despite its widespread use, the underlying mechanisms of its therapeutic effects remain poorly understood. This research aimed to uncover the mechanisms by which LJC intervenes in RA, using transcriptomics and energy metabolomics. RA was induced in rats via Type II collagen and incomplete adjuvant. LJC's effects were assessed through joint swelling, TNF-α levels, and histopathology. Mechanisms were analyzed using transcriptomics and metabolomics. The role of chlorogenic acid (CGA) was verified in LPS-induced RAW264.7 cells. LJC reduced joint swelling and TNF-α levels and inhibited synoviocyte proliferation and angiogenesis. Transcriptomics revealed LJC modulated RA pathways and inflammation. Metabolomics identified <i>cis</i>-aconitic acid as a key metabolite in energy metabolism. CGA was confirmed as the primary active component. LJC alleviates RA by inhibiting inflammation and modulating energy metabolism through multiple pathways.</p>\u0000 </div>","PeriodicalId":8861,"journal":{"name":"Biomedical Chromatography","volume":"39 9","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Liupao Tea Ameliorates High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease via Arginine Metabolism: Insights From Metabolomics and Network Pharmacology","authors":"Shuyun Wei, Shuiping Zhang, Jiahui Luo, Wenxin Yu, Xing Zeng, Lunli Lan, Cuiping Yu, Yu Zeng, Yi Feng","doi":"10.1002/bmc.70166","DOIUrl":"10.1002/bmc.70166","url":null,"abstract":"<div>\u0000 \u0000 <p>Non-alcoholic fatty liver disease (NAFLD) has become a prominent public health concern, closely linked to metabolic syndromes. Liupao tea (LT), a traditional Chinese dark tea, has demonstrated hepatoprotective effects by regulating metabolism. This study investigated the protective effects of LT on HFD-induced NAFLD using metabolomics and network pharmacology approaches. We found that LT significantly reduced energy intake in HFD-fed rats, attenuated abnormal visceral fat accumulation, and prevented hyperlipidemia, abnormal liver lipid deposition, and liver steatosis. Serum untargeted metabolomic analysis identified 46 differential metabolites as potential biomarkers associated with 10 metabolic pathways, including arginine and proline metabolism. Network pharmacology suggested that LT exerts its hepatoprotective effects by regulating arginine metabolism and inflammatory factors; key components, such as caffeine and epigallocatechin gallate, showed direct relevance to NAFLD. Following the intervention, targeted metabolomic analysis revealed a significant change in the levels of 18 relevant amino acids, confirming LT's impact on arginine metabolism. Immunohistochemical results demonstrated reduced expression of inflammatory factors (TNF-α, IL-6, IL-1β) in the liver, suggesting improved liver health. Collectively, these findings indicate that LT mitigates HFD-induced NAFLD through regulation of amino acid metabolism and reduction of inflammatory factors, thereby alleviating liver injury.</p>\u0000 </div>","PeriodicalId":8861,"journal":{"name":"Biomedical Chromatography","volume":"39 9","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A Validated Quantitative LC–MS/MS Method for Determination of Deucravacitinib in Rat Plasma and Its Application to a Pharmacokinetic Study","authors":"Pottabattula Mahesh, M. Akiful Haque","doi":"10.1002/bmc.70169","DOIUrl":"10.1002/bmc.70169","url":null,"abstract":"<div>\u0000 \u0000 <p>We developed and validated a novel analytical methodology for the precise quantification of deucravacitinib, an oral TYK2 inhibitor for treating moderate-to-severe plaque psoriasis in adults. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) was employed in this method for sensitive detection of the compound in rat plasma. Analytical separation was performed utilizing an ACE C18 column (4.6 × 100 mm, 5-μm particle size) with a carefully optimized mobile phase composition of methanol and 2-mM ammonium formate (90:10, v/v), maintained at a consistent flow rate of 0.9 mL/min. Detection was executed in positive ionization mode, targeting multiple reaction monitoring (MRM) transitions of m/z 426.8 → 358.4 for the analyte and m/z 394.1 → 363.2 for the internal standard. The validation of the analytical method encompassed an assessment of selectivity, linearity, accuracy, precision, recovery, and stability. This method demonstrated stability, specificity, and no matrix effect at three concentration levels (1.606, 267.600, 507.780 ng/mL). The method's lower limit of quantification (LLOQ) is 0.556 ng/mL. The calibration curve demonstrates linearity from the LLOQ up to 668.132 ng/mL, exhibiting a high correlation coefficient (<i>r</i><sup>2</sup> = 0.9976). The intraday and interday precisions were less than 6.62% and 5.95%, respectively, with accuracies ranging from 90.68% to 103.80%. The recovery of deucravacitinib ranged from 95.34% to 103.80% and remained stable under different conditions. After successful validation, the method was used for pharmacokinetic profiling of deucravacitinib in rats following oral administration.</p>\u0000 </div>","PeriodicalId":8861,"journal":{"name":"Biomedical Chromatography","volume":"39 9","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Response Surface Methodology-Based Extraction of Fumaric Acid From Fumaria officinalis L. and Quantification by RP-HPLC","authors":"Gunay Mammadova, Pelin Koseoglu-Yilmaz","doi":"10.1002/bmc.70173","DOIUrl":"10.1002/bmc.70173","url":null,"abstract":"<div>\u0000 \u0000 <p>In the present study, it was aimed to optimize the extraction of fumaric acid from <i>Fumaria officinalis</i> L. by response surface methodology and its quantification by a newly developed and validated reverse phase high performance liquid chromatography method. Chromatographic separations were performed at 40°C with a C18 column. Aqueous o-phosphoric acid solution and methanol were used as the mobile phase by gradient elution. The flow rate was set at 1.0 mL/min, and the injection volume was 20 μL. Fumaric acid was detected at 215 nm with a UV detector. The method was linear in the range of 10.00–200.00 μg/mL. The limits of detection and quantification were 3.02 μg/mL and 9.15 μg/mL, respectively. The relative mean errors were ≤ 3.77%, whereas the relative standard deviation values were calculated as ≤ 0.48%. The conditions to obtain an extract with high fumaric acid content were optimized by central composite design, a type of response surface methodology. The independent variables were extraction time, solvent volume, and temperature for the maceration procedure, where fumaric acid concentration was the response. The experimental model was evaluated statistically and found to fit well, considering the lack-of-fit <i>p</i> value of 0.211 and coefficient of determination 0.9862 at a confidence level of 95%.</p>\u0000 </div>","PeriodicalId":8861,"journal":{"name":"Biomedical Chromatography","volume":"39 9","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144672716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jan Thomann, Selina Kraus, Livio Erne, Severin B. Vogt, Matthias E. Liechti, Dino Luethi
{"title":"Development and Validation of a Rapid LC–MS/MS Method for Plasma Analysis of Ketamine, Norketamine, Dehydronorketamine, and Hydroxynorketamine","authors":"Jan Thomann, Selina Kraus, Livio Erne, Severin B. Vogt, Matthias E. Liechti, Dino Luethi","doi":"10.1002/bmc.70171","DOIUrl":"10.1002/bmc.70171","url":null,"abstract":"<p>Ketamine, a well-established dissociative anesthetic, has recently gained significant attention for its rapid-acting antidepressant effects, particularly in treatment-resistant depression. In this study, we developed and validated a state-of-the-art liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the bioanalysis of ketamine and its metabolites, norketamine, dehydronorketamine (DHNK), and (2R,6R)-hydroxynorketamine (HNK), in human plasma. The method features a small sample volume, a streamlined protein precipitation protocol, and a rapid sample runtime. The mobile phase gradient is composed of an aqueous ammonium hydrogen carbonate solution and pure acetonitrile. Using positive electrospray ionization, linear quantification ranges of 1–1,000 ng/mL were established for ketamine and norketamine, while ranges of 0.25–100 ng/mL for DHNK and 2.5–1,000 ng/mL for (2R,6R)-HNK were achieved. The method demonstrated high accuracy, precision, selectivity, and sensitivity, along with consistent matrix effects, efficient extraction recovery, and analyte stability. Finally, the method was successfully applied to assess the pharmacokinetics of six clinical trial participants. Overall, this LC–MS/MS method offers a robust and efficient approach for the achiral quantification of ketamine and its metabolites in human plasma. Its minimal sample preparation and reduced analytical runtime make it particularly well-suited for clinical studies, drug monitoring, and forensic investigations.</p>","PeriodicalId":8861,"journal":{"name":"Biomedical Chromatography","volume":"39 9","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bmc.70171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144672771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Predictive Analysis and Activity Validation of Quality Markers in Erchen Pill","authors":"Yingxin Liu, Xintian Lu, Qunfang Mao, Yanming Qiu, Lili Liu, Chuanping Feng","doi":"10.1002/bmc.70163","DOIUrl":"10.1002/bmc.70163","url":null,"abstract":"<div>\u0000 \u0000 <p>The ErChen Pill (ECP), a classical traditional Chinese medicine (TCM), is clinically effective in treating dampness-phlegm-related disorders, including cough, nausea, vomiting, and excessive phlegm production. However, the complexity of the chemical composition of traditional Chinese medicine poses challenges to controlling the quality of ECP. This study aimed to predict and validate the quality markers (Q-markers) of ECP. First, we performed high-performance liquid chromatography (HPLC) to establish fingerprints of 26 batches of ECP and identify common peaks. Subsequently, quality-differentiating components were identified by chemometrics, and potential Q-markers of ECP were further validated through network pharmacology and molecular docking. The five candidate Q-markers—hesperidin, liquiritin apioside, nobiletin, liquiritin, and tangeretin—were selected via multivariate statistical analysis. The results of network pharmacology analysis and molecular docking revealed that the five candidate Q-markers acted on multiple targets and pathways, with high binding ability with core targets. Notably, in vitro experiments validated the anti-tumor effects of liquiritin apioside, which suppressed proliferation and invasion of human prostate cancer PC-3 cells and induced their apoptosis. In this study, we predicted and validated the Q-markers of ECP, providing a scientific basis for the comprehensive evaluation of the quality of ECP.</p>\u0000 </div>","PeriodicalId":8861,"journal":{"name":"Biomedical Chromatography","volume":"39 9","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144672768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}