Journal of pharmaceutical and biomedical analysis最新文献

{"title":"LC-MS-based serum metabolomics analysis and potential biomarkers for oxaliplatin induced neurotoxicity in colorectal cancer.","authors":"Yujiao Hua, Juan Lv, Yan Zhang, Yongjuan Ding, Jinghua Chen","doi":"10.1016/j.jpba.2024.116492","DOIUrl":"https://doi.org/10.1016/j.jpba.2024.116492","url":null,"abstract":"<p><p>Oxapliplatin-induced peripheral neuropathy (OIPN) is a significant adverse effect encountered in patients with colorectal cancer undergoing oxaliplatin therapy. However, the pathogenesis of OIPN remains unclear. This study aimed to identify potential diagnostic biomarkers for OIPN and discover the metabolic pathways associated with the disease. Serum samples were collected from 218 subjects, including patients with OIPN and control (CONT). The metabolite profiles were analyzed using nontargeted liquid chromatography-mass spectrometry (LC-MS) serum metabolomics method. Subsequently, differentially altered metabolites were identified and evaluated through multivariate statistical analyses. In this study, patients with OIPN and CONT were distinguished by ten significant metabolites. The levels of racemethionine, O-acetylcarnitine, stearolic acid, aminoadipic acid, iminoarginine, galactaric acid, and all-trans-retinoic acid were increased, whereas the levels of 3-methyl-L-tyrosine, 5-aminopentanoic acid, and erythritol compared were found to be diminished in patients with OIPN when compared to the CONT. Through receiver operating characteristic (ROC) curve analysis, racemethionine, stearolic acid, 5-aminopentanoic acid, erythritol, aminoadipic acid, and all-trans-retinoic acid were pinpointed as promising biomarkers for OIPN. Significantly altered pathways included amino acids (arginine biosynthesis, beta-alanine metabolism, arginine and proline metabolism, alanine, aspartate and glutamate metabolism, lysine degradation, and phenylalanine, tyrosine and tryptophan biosynthesis), lipid (linoleic acid metabolism and the biosynthesis of unsaturated fatty acids), and energy metabolism. This study, by identifying serum biomarkers and dissecting metabolic pathways, offers a groundbreaking perspective on the susceptibility mechanisms underlying OIPN. It stands as an invaluable resource for the adjunctive diagnosis of OIPN, with the potential to diminish the incidence of adverse reactions and to enhance the objectivity and reliability of clinical diagnoses of OIPN.</p>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An LCMS/MS method for the simultaneous determination of ten antimicrobials and its application in critically ill patients.","authors":"Tingting Liu, Xiaomin Chen, Guanxuanzi Zhang, Jing Zhao, Qian Lu, Fang Wang, Hongxia Li, Bing Liu, Ping Zhu","doi":"10.1016/j.jpba.2024.116489","DOIUrl":"https://doi.org/10.1016/j.jpba.2024.116489","url":null,"abstract":"<p><p>Significant pharmacokinetic variation occurs in critically ill patients, leading to underexposure to antibiotics and poor prognosis. In this study, we developed a simple, sensitive, and fast liquid chromatography tandem mass spectrometry (LCMS/MS) platform for the simultaneous quantification of 8 antibacterial and 2 antifungal drugs, which is optimally suited for clinically efficient, real-time therapeutic drug monitoring (TDM). Multiple reaction monitoring (MRM) mass spectrometry was used in this method, and samples were prepared via protein precipitation with methanol. Chromatographic separation was accomplished on a BGIU Column-U02 (2.1ｘ50 mm, 3 µm), with six stable isotopes and one analog as an internal standard. The overall turnaround time of the assay was 5 minutes. All the drugs tested (piperacillin, cefoperazone, meropenem, levofloxacin, moxifloxacin, daptomycin, linezolid, vancomycin, fluconazole and voriconazole) were linear in the test concentration range (r ≥ 0.9900), the accuracy was 95 %-111 %, the precision variation coefficient was greater than or equal to 10 %, the lower limit of quantitation was 0.31-7.51 mg/L, and the coefficient of variation of the matrix factor was less than 10 %. The recovery rates ranged from 85 % to 115 %, and the antibiotics were stable at 4°C and -20°C for 6 days, with an offset of greater than or equal to 15 %. This method was successfully applied to routine TDM in 252 elderly critically ill patients.</p>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of analytical-flow, micro-flow and nano-flow LC-MS/MS for sub-proteome analysis","authors":"","doi":"10.1016/j.jpba.2024.116484","DOIUrl":"10.1016/j.jpba.2024.116484","url":null,"abstract":"<div><div>The accurate and sensitive analysis of sub-proteomic samples, such as host cell proteins (HCPs) in recombinant products and stem cells in medical devices, is crucial for ensuring product safety and efficacy in the biopharmaceutical industry. However, current analytical techniques, such as conventional analytical-flow LC-MS/MS, face limitations in sensitivity due to the low concentrations of target proteins and the complexity of the sample matrix. In this study, a highly sensitive and repeatable micro-flow LC-MS/MS strategy was developed by replacing analytical-flow tubing with micro-flow tubing on an existing analytical-flow LC-MS system for sub-proteomic sample analysis. Method optimization and evaluation were first conducted with monoclonal antibody (mAb) digestion, focusing on enhancing sensitivity and repeatability. Over 8 days, relative standard deviations (RSDs) for retention time and mass area were less than 5 % and 10 %, respectively. Sensitivity improved by 2.91–4.14 times compared to the analytical-flow LC-MS/MS method. After confirming the reliability of the method, the micro-flow LC-MS/MS method was compared to the nano-flow LC-MS/MS method and the analytical-flow LC-MS/MS method in sub-proteomic sample analysis. For HCPs, the micro-flow LC-MS/MS method demonstrated superior qualitative and much better reproducibility than the nano-flow LC-MS/MS method, with more than 98 % of proteins showing intensity RSD values below 20 %. In the analysis of mesenchymal stem cells (MSCs), the micro-flow method demonstrated good reproducibility and better sensitivity than the analytical-flow method. Taking the analysis of the 20^th generation of MSC products as an example, the sample analyzed by micro-flow LC-MS/MS resulted in the identification of 68 % and 8.5 % more peptides and proteins, respectively. Moreover, micro-flow maintained stable system pressure while analyzing umbilical cord stem cells, where nano-flow methods often encounter blockages. This micro-flow LC-MS/MS method is notable for its sensitivity, reproducibility, and straightforward operation, making it highly adaptable for diverse sub-proteomic analyses in biopharmaceutical laboratories.</div></div>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142357971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic variations of plasma and urine metabolic profiles in left anterior descending coronary artery ligation-induced myocardial infarction rats and the regulatory effects of Chinese patent medicine Xin-Ke-Shu","authors":"","doi":"10.1016/j.jpba.2024.116483","DOIUrl":"10.1016/j.jpba.2024.116483","url":null,"abstract":"<div><div>Myocardial infarction (MI) is one of the most severe cardiovascular diseases (CVD). Traditional Chinese medicines have unique advantages in the treatment of CVD, with Xin-Ke-Shu (XKS) being a commonly used Chinese patent medicine for the prevention and treatment of MI patients. This study aimed to investigate the dynamic metabolic profiles of plasma and urine in left anterior descending coronary artery ligation (LAD) -induced MI rats at days 3, 12, and 21 after surgery, and to evaluate the regulatory effects of XKS at these time points using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) metabolomics. The metabolic profiles of plasma and urine in the LAD-induced MI rats showed significant variations at days 3, 12, and 21 after MI. We identified a total of 23 plasma metabolites and 12 urine metabolites as potential pathological markers related to MI progression. These metabolites were mainly involved in pathways such as TCA cycle, arachidonic acid metabolism, glutathione metabolism, glycerophospholipid metabolism, sphingolipid metabolism, and fatty acid metabolism, all of which were associated with imbalance of myocardial energy metabolism, oxidative stress, and calcium overload. Disturbances in the TCA cycle, arachidonic acid metabolism, glutathione metabolism, and purine metabolism in plasma and urine were observed as early as day 3 after MI. By day 12, we noted significant changes in fatty acid metabolism in plasma and urine, along with notable alterations in sphingolipid metabolism in plasma. Disorders in plasma glycerophospholipid metabolism were first evident at day 12 and reached their peak severity by day 21. Treatments with XKS significantly regulated the disturbances in the plasma and urine metabolic profiles of MI rats at days 3, 12, and 21, with medium dose of XKS displaying a particularly strong regulatory effect, especially at day 12. Our study demonstrates that host metabolism undergoes dynamical changes following MI with most metabolic disorders manifesting in the early stage of MI. XKS effectively regulates nearly all of these disturbances and can be administered as soon as possible after MI. These findings provide valuable insights into the metabolic progression of MI and highlight the therapeutic potential of XKS in the treatment of MI.</div></div>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142357972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimized analysis for related substances in spiramycin based on high performance liquid chromatography with hybrid particle column and characterization of its impurities by single heartcut two-dimensional liquid chromatography coupled with quadrupole time-of-flight mass spectrometer","authors":"","doi":"10.1016/j.jpba.2024.116486","DOIUrl":"10.1016/j.jpba.2024.116486","url":null,"abstract":"<div><div>This article described the development and validation of a method for spiramycin related substances based on hybrid particle column. The chromatographic conditions were as follows: water - 0.2 mol/L dipotassium hydrogen phosphate (the pH value adjusted to 9.5 using a 1 mol/L KOH solution) - acetonitrile - methanol (10: 60: 28.5: 1.5, <em>v</em>/<em>v</em>/<em>v</em>/<em>v</em>) as mobile phase A, water - 0.2 mol/L dipotassium hydrogen phosphate (pH 9.5) - acetonitrile - methanol (10: 30: 57: 3, <em>v</em>/<em>v</em>/<em>v</em>/<em>v</em>) as mobile phase B and gradient elution was performed. Compared with previous analytical methods, this method has strong specificity, excellent sensitivity and stability, which could be used for the daily testing of related substances of spiramycin. Furthermore, impurities above 0.1 % were characterized using two-dimensional liquid chromatography coupled with quadrupole time-of-flight mass spectrometer (2D LC-QTOF-MS/MS) and there were 6 impurities reported for the first time.</div></div>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross validation of pharmacokinetic bioanalytical methods: Experimental and statistical design","authors":"","doi":"10.1016/j.jpba.2024.116485","DOIUrl":"10.1016/j.jpba.2024.116485","url":null,"abstract":"<div><div>Pharmacokinetic (PK) analysis is an integral part of drug development. Health agency guidance provides development and validation recommendations for PK bioanalytical methods run in one laboratory. However, as a drug development program progresses, a PK bioanalytical method may need to be run in more than one laboratory. Additionally, a PK bioanalytical method format may change and a new method platform may be validated and implemented during the drug development cycle. Here we describe the cross validation strategy for comparisons of two validated bioanalytical methods used to generate PK data within the same study or across different studies. Current guidance for cross validations is limited and, therefore, Genentech, Inc. has developed a cross validation experimental strategy that utilizes incurred samples along with a comprehensive statistical analysis. One hundred incurred study samples over the applicable range of concentrations are selected based on four quartiles (Q) of in-study concentration levels. The samples are assayed once in the two bioanalytical methods. Bioanalytical method equivalency is assessed for the 100 samples based on pre-specified acceptability criterion: the two methods are considered equivalent if the percent differences in the lower and upper bound limits of the 90 % confidence interval (CI) are both within ±30 %. Quartile by concentration analysis using the same criterion may also need to be performed. A Bland-Altman plot of the percent difference of sample concentrations versus the mean concentration of each sample is also created to help further characterize the data. This strategy is a robust assessment of PK bioanalytical method equivalency and includes subgroup analyses by concentration to assess for biases. This strategy was implemented in two case studies: 1) two different laboratories using the same bioanalytical method and 2) a bioanalytical method platform change from enzyme-linked immunosorbent assay (ELISA) to multiplexing immunoaffinity (IA) liquid chromatography tandem mass spectrometry (IA LC-MS/MS).</div></div>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Derivatization to reduce background interferences for simultaneous quantitation of trimethylamine (TMA) and trimethylamine-N-oxide (TMAO) using liquid chromatography with tandem mass spectrometry","authors":"","doi":"10.1016/j.jpba.2024.116480","DOIUrl":"10.1016/j.jpba.2024.116480","url":null,"abstract":"<div><div>Trimethylamine (TMA) and trimethylamine-<em>N</em>-oxide (TMAO) play a crucial role in many biochemical processes within diverse organisms including animals, plants, fungi and bacteria. Studies have linked these metabolites with cardiovascular and kidney diseases; however, emerging evidence demonstrates their protective properties. Owing to these controversies and co-existence of these metabolites in biological samples, it is crucial to accurately quantify these metabolites to associate their concentrations with various physiological and pathophysiological conditions to elucidate their potential roles. We reported interferences on TMA quantification without derivatizing the analyte. A combined sample preparation method, including sample derivatization with ethyl bromoacetate and use of ion pairing reagent (sodium heptanesulfonate), minimized these interferences and provided improved accuracy and precision for simultaneous quantification of TMA and TMAO. The linearity for TMAO ranged from 0.01 µM to 300 µM and 0.1 µM - 300 µM for TMA. With the application of this method, we reported that the circulating concentrations of TMA was 4 times higher in male mice (33.1 ± 5.9 µmol/L) compared to females (8.3 ± 1.39 µmol/L), whereas TMAO levels were 6 times lower in male (7.2 ± 0.4 µmol/L) than female mice (42.1 ± 4.5 µmol/L). In contrast, concentrations of TMA and TMAO in the colonic tissue did not differ significantly between males and females. The robust analytical method for simultaneously quantifying TMA and TMAO presents a significant value in facilitating investigations on TMA and TMAO biology.</div></div>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142319951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of daurisoline metabolites in rats via the UHPLC-Q-exactive orbitrap mass spectrometer","authors":"","doi":"10.1016/j.jpba.2024.116482","DOIUrl":"10.1016/j.jpba.2024.116482","url":null,"abstract":"<div><div>Daurisoline, a bisbenzylisoquinoline alkaloid extracted from the rhizomes of <em>Menispermum dauricum</em>, exhibits diverse biological activities, encompassing antiplatelet, anti-inflammatory, neuroprotective, and antitumor properties. However, previous investigations have not comprehensively elucidated the metabolic profile and pathways of daurisoline in <em>vivo</em>. Using Ultra-High-Performance Liquid Chromatography with Q-Exactive Orbitrap Mass Spectrometry technology, we comprehensively investigated the metabolites of daurisoline in Sprague-Dawley rats, following intragastric administration. Data collection and analysis were enhanced through Full Scan MS/dd-MS², in conjunction with parallel reaction monitoring, extracted ion chromatography, and diagnostic fragment ions. Sixty-three metabolites were detected and characterized, including sixty-two novel metabolites and coclaurine. This investigation elucidated the <em>cleavage patterns</em> and tissue distribution characteristics of the metabolism of daurisoline. Furthermore, <em>in vivo</em> reactions, including dehydrogenation, hydroxylation, methylation, sulfation and glucuronidation, were thoroughly examined. Investigating the metabolites of daurisoline in rats has deepened our understanding of its metabolism in <em>vivo</em>, aiding in elucidating its metabolic and pharmacological actions. This provides a valuable foundation for further research into its therapeutic efficacy.</div></div>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0731708524005247/pdfft?md5=5f7eed2a611875cc5cdc4129a4d1685c&pid=1-s2.0-S0731708524005247-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142311682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipidomic profiling of amniotic fluid reveals aberrant fetal lung development and fetal growth disrupted by lipid disorders during gestational asthma","authors":"","doi":"10.1016/j.jpba.2024.116475","DOIUrl":"10.1016/j.jpba.2024.116475","url":null,"abstract":"<div><div>This study aimed to investigate how maternal asthma during pregnancy disrupts fetal lung development by altering lipid metabolism in the amniotic fluid, which is crucial for fetal development. A pregnancy-induced asthma model was established in female rats using house dust mite (HDM) as a common allergen. The fetuses were divided into four groups based on whether the mother and fetus were exposed to the allergen: PBS+PBS, PBS+HDM, HDM+PBS, and HDM+HDM. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to analyze changes in the lipid profile of the amniotic fluid and bronchoalveolar lavage fluid (BALF). Principal component analysis (PCA) and ChemRICH methods were used to explore the potential relationship between lipid metabolism abnormalities and impaired fetal lung development. The results indicate that maternal asthma exacerbates asthma-related inflammatory markers in fetuses, leading to pathological changes in the lungs and elevated levels of cytokines IL-5, IL-13, and IgE. Additionally, 18 differential lipids, primarily oxygenated lipids, were identified in the amniotic fluid after modeling, suggesting an enhanced oxidative stress environment for the fetus. This environment causes metabolic disturbances in various lipid groups in fetal lungs, with the HDM+HDM group showing significant abnormalities in lipids critical for lung development, including phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and fatty acids (FA). In conclusion, gestational asthma can reshape the lipid profile in the amniotic fluid and BALF, significantly disrupting fetal growth and lung development. Restoring normal lipid metabolism in the amniotic fluid and fetal lungs may offer a potential therapeutic approach to managing aberrant fetal lung development in asthmatic mothers.</div></div>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “A data-independent acquisition (DIA)-based quantification workflow for proteome analysis of 5000 cells” [J. Pharm. Biomed. Anal. 216 (2022) 114795]","authors":"","doi":"10.1016/j.jpba.2024.116479","DOIUrl":"10.1016/j.jpba.2024.116479","url":null,"abstract":"","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0731708524005211/pdfft?md5=1206f9e913395c769655fffad791d8ff&pid=1-s2.0-S0731708524005211-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142240365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}