Journal of Mass Spectrometry and Advances in the Clinical Lab最新文献

{"title":"Ocrelizumab quantitation by liquid chromatography-tandem mass spectrometry","authors":"Erik I. Hallin ,&nbsp;Trond Trætteberg Serkland ,&nbsp;Kjell-Morten Myhr ,&nbsp;Øivind Torkildsen ,&nbsp;Silje Skrede","doi":"10.1016/j.jmsacl.2022.07.004","DOIUrl":"10.1016/j.jmsacl.2022.07.004","url":null,"abstract":"<div><h3>Introduction</h3><p>Ocrelizumab is a monoclonal anti-CD20 antibody approved for the treatment of multiple sclerosis (MS). The clinical value of therapeutic drug monitoring (TDM) for this antibody in treatment of MS is unknown, and an adequately specific and precise quantitation method for ocrelizumab in patient serum could facilitate investigation. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based quantitation methods have been shown to have higher analytic specificity and precision than enzyme-linked immunosorbent assays.</p></div><div><h3>Objectives</h3><p>To establish and validate an LC-MS/MS-based quantitation method for ocrelizumab.</p></div><div><h3>Methods</h3><p>We present an LC-MS/MS-based quantitation method using immunocapture purification followed by trypsinization and analysis by a triple quadrupole mass analyzer obtaining results within the same day.</p></div><div><h3>Results</h3><p>We found that the ocrelizumab peptide GLEWVGAIYPGNGDTSYNQK (Q1/Q3 Quantifier ion: 723.68³⁺/590.77 y11²⁺ Qualifier ion: 723.68³⁺/672.30 y12²⁺) can be used for quantitation and thereby developed a method for quantifying ocrelizumab in human serum with a quantitation range of 1.56 to 200 µg/mL. The method was validated in accordance with EMA requirements in terms of selectivity, carry-over, lower limit of quantitation, calibration curve, accuracy, precision and matrix effect. Ocrelizumab serum concentrations were measured in three MS patients treated with ocrelizumab, immediately before and after ocrelizumab infusion, with additional sampling after 2, 4, 8 and 12 weeks. Measured serum concentrations of ocrelizumab showed expected values for both Cmax and drug half-life over the sampled time period.</p></div><div><h3>Conclusion</h3><p>We have established a reliable quantitation method for serum ocrelizumab that can be applied in clinical studies, facilitating the evaluation of ocrelizumab TDM in MS.</p></div>","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6c/74/main.PMC9334332.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40589849","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":"Clinical validation of a liquid chromatography-tandem mass spectrometry method for the quantification of calcineurin and mTOR inhibitors in dried matrix on paper discs","authors":"Ignacio Guillermo Bressán ,&nbsp;María Isabel Giménez ,&nbsp;Susana Francisca Llesuy","doi":"10.1016/j.jmsacl.2022.06.002","DOIUrl":"10.1016/j.jmsacl.2022.06.002","url":null,"abstract":"<div><h3>Introduction</h3><p>Advances in liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) have enabled the quantification of immunosuppressants using microsampling techniques. In this context, dried matrix on paper discs (DMPD) could be a useful alternative to conventional venipuncture. Although analytical validation is necessary to establish the suitability of method performance, it is not sufficient to proceed with its implementation into routine clinical practice. Also necessary is that equivalence between sampling methods be demonstrated in a clinical validation study.</p></div><div><h3>Objetives</h3><p>To clinically validate a LC-MS/MS method for the quantification of tacrolimus, sirolimus, everolimus and cyclosporin A using DMPD.</p></div><div><h3>Methods</h3><p>According to the recommendations of international guidelines, at least 40 whole blood (WB) and DMPD paired samples for each analyte were collected by skilled technicians and analyzed using LC-MS/MS. Results were evaluated in terms of statistical agreement and bias values at medical decision points.</p></div><div><h3>Results</h3><p>For all analytes, Passing-Bablok regression analysis revealed that confidence intervals (CIs) for slopes and intercepts included 1 and 0, respectively. It also showed that biases at medical decision points were not clinically relevant. No statistically significant differences between DMPD and WB were found using difference plots and agreement analysis. In this regard, CIs for bias estimators included 0, and more than 95% of the results fell within the limits of agreement.</p></div><div><h3>Conclusion</h3><p>The feasibility of the clinical application of simultaneous quantification of tacrolimus, sirolimus, everolimus and cyclosporin A in DMPD was demonstrated. Results showed that this microsampling technique is interchangeable with conventional WB sampling when specimens are collected by trained personnel.</p></div>","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667145X22000177/pdfft?md5=1bfb6b7c19afa801057c5b82bc6a4d1e&pid=1-s2.0-S2667145X22000177-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73369821","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":"Development and validation of a paper spray mass spectrometry method for the rapid quantitation of remdesivir and its active metabolite, GS-441524, in human plasma","authors":"Christine Skaggs ,&nbsp;Hannah Zimmerman ,&nbsp;Nicholas Manicke ,&nbsp;Lindsey Kirkpatrick","doi":"10.1016/j.jmsacl.2022.06.001","DOIUrl":"10.1016/j.jmsacl.2022.06.001","url":null,"abstract":"<div><h3>Introduction</h3><p>Remdesivir (GS-5734) is a nucleoside analog prodrug with antiviral activity against several single-stranded RNA viruses, including the novel severe respiratory distress syndrome virus 2 (SARS-CoV-2). It is currently the only FDA-approved antiviral agent for the treatment of individuals with COVID-19 caused by SARS-CoV-2. However, remdesivir pharmacokinetics/pharmacodynamics (PK/PD) and toxicity data in humans are extremely limited. It is imperative that precise analytical methods for the quantification of remdesivir and its active metabolite, GS-441524, are developed for use in further studies. We report, herein, the first validated anti-viral paper spray-mass spectrometry (PS-MS/MS) assay for the quantification of remdesivir and GS-441524 in human plasma. We seek to highlight the utility of PS-MS/MS technology and automation advancements for its potential future use in clinical research and the clinical laboratory setting.</p></div><div><h3>Methods</h3><p>Calibration curves for remdesivir and GS-441524 were created utilizing seven plasma-based calibrants of varying concentrations and two isotopic internal standards of set concentrations. Four plasma-based quality controls were prepared in a similar fashion to the calibrants and utilized for validation. No sample preparation was needed. Briefly, plasma samples were spotted on a paper substrate contained within pre-manufactured plastic cassette plates, and the spots were dried for 1 h. The samples were then analyzed directly for 1.2 min utilizing PS-MS/MS. All experiments were performed on a Thermo Scientific Altis triple quadrupole mass spectrometer utilizing automated technology.</p></div><div><h3>Results</h3><p>The calibration ranges were 20 – 5000 and 100 – 25000 ng/mL for remdesivir and GS-441524, respectively. The calibration curves for the two antiviral agents showed excellent linearity (average R² = 0.99–1.00). The inter- and intra-day precision (%CV) across validation runs at four QC levels for both analytes was less than 11.2% and accuracy (%bias) was within ± 15%. Plasma calibrant stability was assessed and degradation for the 4 °C and room temperature samples were seen beginning at Day 7. The plasma calibrants were stable at −20 °C. No interference, matrix effects, or carryover was discovered during the validation process.</p></div><div><h3>Conclusions</h3><p>PS-MS/MS represents a useful methodology for rapidly quantifying remdesivir and GS-441524, which may be useful for clinical PK/PD, therapeutic drug monitoring (TDM), and toxicity assessment, particularly during the current COVID-19 pandemic and future viral outbreaks.</p></div>","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/93/b8/main.PMC9188284.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9835437","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":"Simple, high-throughput measurement of gut-derived short-chain fatty acids in clinically relevant biofluids using gas chromatography-mass spectrometry","authors":"Joshua T Bain ,&nbsp;Maarten W Taal ,&nbsp;Nicholas M Selby ,&nbsp;James C Reynolds ,&nbsp;Liam M Heaney","doi":"10.1016/j.jmsacl.2022.07.002","DOIUrl":"10.1016/j.jmsacl.2022.07.002","url":null,"abstract":"<div><h3>Introduction</h3><p>The quantitative measurement of circulating gut bacteria-derived metabolites has increased in recent years due to their associations with health and disease. While much of the previous attention has been placed on metabolites considered as deleterious to health, a shift to the investigation of short-chain fatty acids (SCFAs) as potential health promotors has been observed.</p></div><div><h3>Objectives</h3><p>To develop a simple, high-throughput and quantitative assay to measure gut-derived SCFAs in clinically relevant biofluids using gas chromatography-mass spectrometry (GC–MS).</p></div><div><h3>Methods</h3><p>A short (7.5 min) GC–MS assay was optimized for measurement of seven straight- and branched-chain SCFAs and their deuterated isotopes using a wax-based column for analysis without prior derivatization. The assay was validated using routine criteria to assess precision, accuracy, matrix effects, recovery, and extraction reproducibility. Assay applicability was tested in cohorts of healthy individuals and kidney disease patients.</p></div><div><h3>Results</h3><p>The assay was demonstrated to be precise, accurate and reproducible with acceptable levels of matrix effect and analyte recovery. Lower limits of detection and quantitation were in the low ng/mL range. An investigation into different blood collection tube chemistries demonstrated that lithium heparin plasma and serum clotting activator tubes are recommended for use in future cross-study comparisons. Kidney disease patient analyses demonstrated variable differences across SCFAs when comparing hemodialysis to earlier stages of chronic kidney disease, demonstrating the suitability of the assay for translation to clinical analyses.</p></div><div><h3>Conclusion</h3><p>The assay has been validated and identified as reliable for use in larger-scale studies for the analysis of SCFAs in human plasma and serum.</p></div>","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40620965","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":"Mitigating analyte to stable isotope labelled internal standard cross-signal contribution in quantitative liquid chromatography-tandem mass spectrometry.","authors":"Mirjana Radovanovic, Graham Jones, Richard O Day, Peter Galettis, Ross L G Norris","doi":"10.1016/j.jmsacl.2022.04.002","DOIUrl":"10.1016/j.jmsacl.2022.04.002","url":null,"abstract":"<p><strong>Background: </strong>Utilising stable isotope labelled internal standards (SIL-IS) in quantitative LC-MS/MS drug analysis is the most widely used approach to normalise for variability during sample quantification processes. However, compounds containing atoms such as Sulphur, Chlorine or Bromine, could potentially cause cross-signal contribution to the SIL-IS from the naturally occurring isotopes, resulting in non-linear calibration curves. A simple, novel method of mitigating the effect is presented here. It entails monitoring of a less abundant SIL-IS isotope, as the precursor ion, of a mass that has no/minimal isotopic contribution from the analyte isotopes.</p><p><strong>Methods: </strong>Experiments were conducted on two LC-MS/MS analysers: Waters Xevo TQ-S and Shimadzu 8050. Flucloxacillin (FLX) was used as an example. Two transitions were selected for FLX (<i>m</i>/<i>z</i> 454 → 160 → 295) and one for each of the SIL-IS isotopes (<i>m</i>/<i>z</i> 458 → 160 for the isotope 457 g/mol and <i>m</i>/<i>z</i> 460 → 160 for the isotope 459 g/mol). Assay biases were assessed at three SIL-IS concentrations: 0.7, 7 and 14 mg/L for each isotope.</p><p><strong>Results: </strong>When using the SIL-IS isotope <i>m</i>/<i>z</i> 458 → 160 at a concentration of 0.7 mg/L, biases were up to 36.9 % on both instruments. Increasing the SIL-IS concentration to 14 mg/L, reduced the bias to 5.8 %. Using the less abundant isotope, <i>m</i>/<i>z</i> 460 → 160, resulted in biases of 13.9 % at an SIL-IS concentration of 0.7 mg/L.</p><p><strong>Conclusions: </strong>Applying this method will mitigate cross-signal contribution from the analyte isotopes to the corresponding SIL-IS, minimise the use of SIL-IS, and, thereby, reduce overall cost.</p>","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2022-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87027125","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":"Indirect reference intervals using an R pipeline","authors":"Dustin R. Bunch","doi":"10.1016/j.jmsacl.2022.02.004","DOIUrl":"https://doi.org/10.1016/j.jmsacl.2022.02.004","url":null,"abstract":"<div><h3>Background</h3><p>Indirect reference intervals require robust statistical approaches to separate the pathological and healthy values. This can be achieved with a data pipeline created in R, a freely available statistical programming language.</p></div><div><h3>Methods</h3><p>A data pipeline was created to ingest, partition, normalize, remove outliers, and identify reference intervals for testosterone (Testo; n  = 7,207) and aspartate aminotransferase (AST; n  = 5,882) using data sets from NHANES.</p></div><div><h3>Results</h3><p>The estimates for AST and Testo determined by this pipeline approximated current RIs. Care should be taken when using this pipeline as there are limitations that depend on the pathology of the analyte and the data set being used for RI estimation.</p></div><div><h3>Conclusions</h3><p>R can be used to create a robust statistical reference interval pipeline.</p></div>","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667145X22000050/pdfft?md5=8b513f5edfb6148b1e837e73de9d6aba&pid=1-s2.0-S2667145X22000050-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91720359","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":"Clinical lipidomics – A community-driven roadmap to translate research into clinical applications","authors":"Olga Vvedenskaya ,&nbsp;Michal Holčapek ,&nbsp;Michael Vogeser ,&nbsp;Kim Ekroos ,&nbsp;Peter J. Meikle ,&nbsp;Anne K. Bendt","doi":"10.1016/j.jmsacl.2022.02.002","DOIUrl":"10.1016/j.jmsacl.2022.02.002","url":null,"abstract":"<div><p>Lipid metabolites, beyond triglycerides and cholesterol, have been shown to have vast potential for applications in clinical applications, with substantial societal and economical value. To successfully evolve from the current research-grade methods to assays suitable for routine clinical applications, a harmonization – if not standardization – of these mass spectrometry-based workflows is necessary. Input on clinical needs and technological capabilities must be obtained from all relevant stakeholders, including wet lab scientists, informaticians and data scientists, manufacturers, and medical professionals. In order to build bridges between this diverse group of professionals, the International Lipidomics Society and its Clinical Lipidomics Interest Group were created. This opinion article is intended to provide an overview of international efforts to tackle the issues of workflow harmonization, and to serve as an open invitation for others to join this growing community.</p></div>","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/de/1a/main.PMC8844780.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39659814","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":"Simultaneous determination of vitamin D metabolites 25(OH)D3 and 1α,25(OH)2D3 in human plasma using liquid chromatography tandem mass spectrometry","authors":"Shan Xu ,&nbsp;Rui Ni ,&nbsp;Lihong Lv ,&nbsp;Rui Chen ,&nbsp;Yao Chen ,&nbsp;Fengjiao Huang ,&nbsp;Zhiru Xu","doi":"10.1016/j.jmsacl.2022.04.001","DOIUrl":"10.1016/j.jmsacl.2022.04.001","url":null,"abstract":"<div><h3>Background</h3><p>Although measurement of 25(OH)D₃ is a routine analytical method to determine plasma vitamin D status, 1α,25(OH)₂D₃ is the biologically active form. Hence, simultaneous measurement of 25(OH)D₃ and 1α,25(OH)₂D₃ could provide better insight into vitamin D status and pharmacokinetics. However, 1α,25(OH)₂D₃ has a low plasma concentration, making its quantification challenging for most analytical techniques. Here, we demonstrate use of liquid chromatography tandem mass spectrometry (LC-MSMS) for the development of a simple and rapid method for the simultaneous quantification of 25(OH)D₃ and 1α,25(OH)₂D₃.</p></div><div><h3>Methods</h3><p>Samples were purified from 250 µL human plasma. Chromatography was performed on an analytical column, under gradient conditions using a mobile phase consisting of methanol-lithium acetate. The mass detector was operated in positive multiple reaction monitoring mode. The established method was validated according to the guidance issued by ICH and FDA. Furthermore, a clinical study was performed using this method to detect the plasma concentrations of 1α,25(OH)₂D₃ after oral administration of calcitriol.</p></div><div><h3>Results and conclusion</h3><p>The method was acceptably linear over the concentration ranges of 20–1200 pg/mL for 1α,25(OH)₂D₃ and 1–60 ng/mL for 25(OH)D₃, respectively, with correlation coefficients of r² &gt; 0.993. Both the inter-assay and intra-assay precision was &lt; 15%, and the analytical recoveries were within 100% ± 10%, with no significant matrix effect or carryover. Thereby, we, provide a facile method for the simultaneous detection of vitamin D metabolites in plasma.</p></div>","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667145X22000098/pdfft?md5=e82a51347f1111076a94713c2ace54ea&pid=1-s2.0-S2667145X22000098-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87630428","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":"The triple quadrupole: Innovation, serendipity and persistence","authors":"Richard A. Yost","doi":"10.1016/j.jmsacl.2022.05.001","DOIUrl":"https://doi.org/10.1016/j.jmsacl.2022.05.001","url":null,"abstract":"","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90627249","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":"The triple quadrupole: Innovation, serendipity and persistence","authors":"Richard A. Yost","doi":"10.1016/j.jmsacl.2022.05.001","DOIUrl":"https://doi.org/10.1016/j.jmsacl.2022.05.001","url":null,"abstract":"","PeriodicalId":52406,"journal":{"name":"Journal of Mass Spectrometry and Advances in the Clinical Lab","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667145X22000141/pdfft?md5=aa5ab93ac305b116f3313c2e30a45553&pid=1-s2.0-S2667145X22000141-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91720406","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}