Pharmeuropa bio & scientific notes最新文献

{"title":"Joint WHO/EDQM Collaborative study for the establishment of WHO 3^rd International Standard and Ph. Eur. Biological Reference Preparation for Prekallikrein activator in albumin batch 7.","authors":"B Fox, E Regourd, P Rigsby, C Longstaff, E Terao","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>An international collaborative study was jointly organised by the World Health Organization (WHO) and the European Directorate for the Quality of Medicines & HealthCare (EDQM) to establish the WHO 3^rd International Standard (IS) for Prekallikrein activator (PKA) and European Pharmacopoeia (Ph. Eur.) PKA in albumin Biological Reference Preparation (BRP) batch 7. Twenty-six laboratories took part in the study to calibrate these replacement batches, as well as an additional reserve batch for the WHO IS, against the current WHO 2^nd IS for PKA (02/168). Ph. Eur. PKA in albumin BRP batch 6 was also included to evaluate the continuity of the consecutive batches of BRP. The centrally calculated overall Huber's means based on the results from laboratories with at least two valid assays were 29.6 and 29.6 IU/ampoule for the candidate WHO 3^rd IS (Sample A) and reserve batch (Sample B), and were 38.4 and 37.0 IU/vial for the current BRP batch 6 (Sample C) and the candidate BRP batch 7 (Sample D). The intra-laboratory variation expressed as coefficient of variation (CV) ranged between 1.4 and 16.6 %. The inter-laboratory variation expressed as CV based on Huber's means ranged between 4.4 and 5.4 %. The Huber's mean activity of Sample D against Sample C was 36.6 IU/vial with a CV of 1.7 %. These results confirm the good continuity of the consecutive batches of BRP. Based on the results of this study, it is recommended to establish Sample A as the WHO 3^rd IS for PKA with an assigned potency of 30 IU/ampoule and Sample D as the Ph. Eur. PKA in albumin BRP batch 7 with an assigned potency of 37 IU/vial. Sample B is intended to be kept as a future reserve replacement WHO IS.</p>","PeriodicalId":39192,"journal":{"name":"Pharmeuropa bio & scientific notes","volume":"2024 ","pages":"106-126"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishment of Erythropoietin for physicochemical tests CRS batch 2.","authors":"B Cowper, D Le Tallec, A Costanzo","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Here we report the outcome of a collaborative study aimed at demonstrating the suitability of the candidate Chemical Reference Substance (CRS) as a replacement reference (batch 2) for the physicochemical methods in European Pharmacopoeia monograph <i>1316 Erythropoietin concentrated solution</i>. Results from the study demonstrated that for the physicochemical methods described in the monograph - capillary zone electrophoresis, polyacrylamide gel electrophoresis and immunoblotting, peptide mapping and glycan mapping - the candidate CRS is essentially identical to CRS batch 1 and is suitable to be established as Erythropoietin for physicochemical tests CRS batch 2. CRS batch 2 is a freeze-dried preparation presented in vials. It was adopted at the 177th session of the European Pharmacopoeia Commission in November 2023 and is available from the European Directorate for the Quality of Medicines & HealthCare (EDQM) under product code Y0001725.</p>","PeriodicalId":39192,"journal":{"name":"Pharmeuropa bio & scientific notes","volume":"2024 ","pages":"251-274"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Collaborative study for the establishment of Ph. Eur. Biological Reference Preparation for Human tetanus immunoglobulin batch 2.","authors":"P Stickings, R Tierney, J Hockley, P Rigsby, E Terao","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>This publication describes the outcome of a project to develop a replacement European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) for Human tetanus immunoglobulin (TIg) as well as for the World Health Organization (WHO) International Standard (IS) for Tetanus Immunoglobulin, Human. Bulk TIg was kindly provided by a European manufacturer and was used to prepare the candidate standard. The candidate standard was freeze-dried and calibrated in an international collaborative study jointly co-ordinated by the Medicines & Healthcare products Regulatory Agency (MHRA) and the European Directorate for the Quality of Medicines & HealthCare (EDQM, Council of Europe). The results of this study show that there was good agreement between laboratories for the potency estimates obtained for the candidate standard relative to the current WHO IS/Ph. Eur. BRP. The study also demonstrated that the candidate standard is suitable for use in Ph. Eur. assays for potency testing of TIg products and there was good agreement in the potency estimates obtained using the different assay methods included in the study. Accelerated degradation studies performed at the MHRA over a period of 4 years suggest that the freeze-dried candidate standard will be very stable. The candidate standard was established as Ph. Eur. BRP for Human tetanus immunoglobulin, batch 2 with an assigned potency of 45 IU/ampoule. The same preparation was also adopted by the WHO Expert Committee on Biological Standardization (ECBS) to serve as the WHO 2^nd IS for Tetanus Immunoglobulin, Human (13/240).</p>","PeriodicalId":39192,"journal":{"name":"Pharmeuropa bio & scientific notes","volume":"2024 ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140294864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Collaborative study for the establishment of Ph. Eur. Biological Reference Preparation for Human tetanus immunoglobulin batch 2.","authors":"P Stickings, R Tierney, J Hockley, P Rigsby, E Terao","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>This publication describes the outcome of a project to develop a replacement European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) for Human tetanus immunoglobulin (TIg) as well as for the World Health Organization (WHO) International Standard (IS) for Tetanus Immunoglobulin, Human. Bulk TIg was kindly provided by a European manufacturer and was used to prepare the candidate standard. The candidate standard was freeze-dried and calibrated in an international collaborative study jointly co-ordinated by the Medicines & Healthcare products Regulatory Agency (MHRA) and the European Directorate for the Quality of Medicines & HealthCare (EDQM, Council of Europe). The results of this study show that there was good agreement between laboratories for the potency estimates obtained for the candidate standard relative to the current WHO IS/Ph. Eur. BRP. The study also demonstrated that the candidate standard is suitable for use in Ph. Eur. assays for potency testing of TIg products and there was good agreement in the potency estimates obtained using the different assay methods included in the study. Accelerated degradation studies performed at the MHRA over a period of 4 years suggest that the freeze-dried candidate standard will be very stable. The candidate standard was established as Ph. Eur. BRP for Human tetanus immunoglobulin, batch 2 with an assigned potency of 45 IU/ampoule. The same preparation was also adopted by the WHO Expert Committee on Biological Standardization (ECBS) to serve as the WHO 2nd IS for Tetanus Immunoglobulin, Human (13/240).</p>","PeriodicalId":39192,"journal":{"name":"Pharmeuropa bio & scientific notes","volume":"2023 ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139522002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Collaborative study for the establishment of Golimumab Biological Reference Preparation Batch 1.","authors":"M Wadhwa, P Rigsby, M-E Behr-Gross","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A candidate preparation of the fully human anti-tumour necrosis factor (TNF) monoclonal antibody golimumab was formulated and lyophilised at the Medicines and Healthcare products Regulatory Agency (MHRA) prior to evaluation in a collaborative study for its suitability to serve as a World Health Organization (WHO) International Standard (IS)/European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) for the potency assay of golimumab. Fifteen laboratories tested the preparations using different cell-based TNF-α neutralisation assays. Among them, seven laboratories also performed binding assays and one additional laboratory assessed antibody-dependent cellular cytotoxicity. The results of this study and the stability data generated by the MHRA indicated that the candidate preparation, coded 22/116, was suitable to serve as an IS for golimumab based on the data obtained for biological activity. This candidate standard was established in 2024 as the first IS for golimumab with an assigned potency of 500 IU per ampoule for TNF neutralising activity. In the same study, the suitability of this preparation of golimumab to serve as the Ph. Eur. BRP for the golimumab potency assay, as described in the Ph. Eur. monographs on <i>Golimumab injection (3187)</i> and <i>Golimumab concentrated solution (3103)</i>, was also evaluated. The corresponding analysis, based on the measurement of the inhibitory action of golimumab on the cytotoxic activity of TNF-α, was performed using data from a subset of six laboratories - whose experts were members of the P4 Biologicals Working Party (responsible for the elaboration of the golimumab monographs) - using the TNF-α-sensitive mouse fibrosarcoma cell lines WEHI-164 or WEHI-164 clone 13 variant (WEHI-13VAR, ATCC CRL-2148) in example bioassay procedure(s) described in Ph. Eur. monographs <i>3103</i> and <i>3187</i>, or running the same cell-based assays using in-house procedures. The results obtained were compared with those obtained from different cell-based neutralisation assays that were used by other laboratories in the context of establishing the 1st WHO IS for golimumab. Based on the analyses, preparation 22/116 was adopted by the Ph. Eur. Commission in June 2024 as <i>Golimumab BRP batch 1</i> with an assigned potency of 500 IU of TNF neutralising activity per ampoule.</p>","PeriodicalId":39192,"journal":{"name":"Pharmeuropa bio & scientific notes","volume":"2024 ","pages":"234-239"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142773133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Collaborative study for the establishment of replacement batches of Ph. Eur. Heparin Low-Molecular-Mass for Calibration CRS.","authors":"S Caruncho Garcia-Moreno, B Mulloy, I Rodrigo-Castro, W Denault, D Le Tallec, E Terao","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>An international collaborative study was run within the framework of the Biological Standardisation Programme (BSP) of the Council of Europe and the Commission of the European Union to establish replacement batches for European Pharmacopoeia (Ph. Eur.) Heparin Low-Molecular-Mass (LMM) for calibration Chemical Reference Substance batch 3 (CRS3) used for the characterisation of LMM heparins by high performance size-exclusion chromatography. Two candidate batches (A, cCRS4 and B, cCRS5) were filled using the same material as the existing official calibrants, adopted with either an assigned number-average molecular mass (Mna) or a broad standard table (BST). Fifteen laboratories evaluated the suitability of these candidate batches for use as calibrants with the pharmacopoeial dual refractive index/ultraviolet (RI/UV) detector calibration method, as well as with a modified mobile phase and the BST calibration method. Seven preparations of LMM heparin were tested. The results confirmed that the proposed batches are suitable for use with the same characteristic Mna as CRS3 and with the BST established for the World Health Organization (WHO) 2^nd International Standard (IS). The BST calibration method gave comparable results to the RI/UV method, while showing better reproducibility, being easier to perform and requiring no calibrant with UV absorbance. The modified mobile phase had no impact on the calculated values while improving separation between the calibrant and salt peaks. The two candidate batches were adopted as Ph. Eur. Heparin LMM for calibration CRS batches 4 and 5, respectively, with the assigned Mna value of 3800 and a BST. In anticipation of the depletion of the calibrant required for use with the RI/UV method, and taking into account the unlikely procurement of a new lot of suitable starting material, it was recommended to include the BST method in Ph. Eur. monograph <i>0828, Heparins, low-molecular-mass</i>. In order to improve peak separation, it was also recommended to include the use of ammonium acetate solution as mobile phase in the monograph, both for the Ph. Eur. RI/UV and the proposed BST calibration methods. Further to this study, Ph. Eur. monograph <i>0828</i> was revised to replace the RI/UV method by the BST method. This contributed to the harmonisation of methods across regions, thereby facilitating a concerted global action for the development and establishment of the next batches of calibrants for the quality control of LMM heparins.</p>","PeriodicalId":39192,"journal":{"name":"Pharmeuropa bio & scientific notes","volume":"2023 ","pages":"81-111"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138463209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assay discrepancies using human coagulation factor VIII chromogenic kits: Results from a plasma-derived factor VIII collaborative study (BSP112).","authors":"S Raut,&nbsp;A Daas,&nbsp;P Rigsby,&nbsp;A Costanzo","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Chromogenic assay discrepancies were reported at General European Official Medicines Control Laboratories Network (GEON) meetings by laboratories testing FVIII-products. The objectives of the present investigation were to carry out a controlled collaborative study to examine these reports and to delineate the reasons for these discrepancies by assessing affected and unaffected FVIII products. The laboratories followed a strict study protocol, which included assessing their own individual observed factor X (FX) activation times, i.e. the time to reach 50% of maximal FX activation (T_1/2), for each chromogenic kit. This measurement was used, in parallel with the kit manufacturers' prescribed FX activation times, to assess the performance of the chromogenic potency assays on FVIII test products. This study confirmed a significant discrepancy between Coatest® and Coamatic® kits and between Siemens and Coamatic® kits when the kit manufacturers' prescribed T_1/2 incubation times were followed. Coamatic® kits tended to produce higher potencies than the Coatest® or Siemens kits. Furthermore, FX activation assays revealed marked differences between individual laboratories for all three chromogenic kits in the observed T_1/2 incubation times, which also did not correspond to the prescribed T_1/2 incubation times. The resulting differences in potency between kits, in some cases, were significantly reduced when using the actual observed T_1/2 incubation times instead of the prescribed T_1/2 incubation times. The study showed that FVIII potency discrepancies can occur between chromogenic kits. To compensate for this, laboratories should ideally perform FX activation curves for each new chromogenic kit in order to determine the correct observed T_1/2 incubation times, which can then be used to determine FVIII potencies in therapeutic concentrates.</p>","PeriodicalId":39192,"journal":{"name":"Pharmeuropa bio & scientific notes","volume":"2023 ","pages":"1-14"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9569743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of a qPCR method for determination of viral genome titres of AAV2-based vector preparations.","authors":"V Ridoux,&nbsp;S Laurens,&nbsp;S Venturini,&nbsp;D Le Tallec,&nbsp;A Costanzo","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The viral genome titre is universally used for the dosing of adeno-associated virus (AAV)-based vectors used for gene therapy. To standardise this determination, the development of a common method would be valuable to facilitate comparison of viral doses used in the clinic and in the subsequent quality control of the products. A collaborative study was initiated by the Gene Therapy Working Group of the General European Official Medicines Control Laboratories Network in order to validate a qPCR-based method targeting the ITR2 sequence common to a broad variety of AAV vectors, independently from the serotype of the capsid or from the specific transgene. Five preparations of AAV vectors from various serotypes, including the AAV2/2 (RSS2) and AAV2/8 (RSS8) Reference Standard Stocks (American Type Culture Collection, USA) were used in the study. A plasmid carrying the ITR2 sequence was used to prepare standard curves. Its digestion outside the ITR regions facilitated melting of the hairpin ITR sequence during PCR, allowing better accessibility to the DNA polymerase. The results show that this qPCR method is satisfactory in terms of accuracy and precision. The reproducibility is also acceptable when compared with other similar studies, as it was shown previously that titres obtained by qPCR generally show higher inter-laboratory variability. The use of RSS2 or RSS8 as normalisation control in each assay demonstrated a promising help to identify potential sources of variation in a given laboratory or to smooth out inter-laboratory variations, thus improving reproducibility.</p>","PeriodicalId":39192,"journal":{"name":"Pharmeuropa bio & scientific notes","volume":"2023 ","pages":"42-59"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9974372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Informal investigation on the added value of a potential certification system for the qualification of raw materials for the production of ATMPs.","authors":"S Le Maux,&nbsp;V Closson-Carella,&nbsp;O Kolaj-Robin,&nbsp;H Bruguera,&nbsp;E Charton","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The manufacture of advanced therapy medicinal products (ATMPs) is critically impacted by the quality of the raw materials (RMs) used. Following the need expressed by stakeholders to establish a certification scheme for biological RMs used in the manufacture of ATMPs, the European Pharmacopoeia (Ph. Eur.) Cell Therapy Products Working Party (CTP WP) conducted an informal investigation with the aim of issuing a technical opinion on the feasibility of such a certification scheme. Seven RM Drug Master Files were reviewed for compliance of the RM with Ph. Eur. general chapter <i>5.2.12. Raw materials of biological origin for the production of cell-based and gene therapy medicinal products</i> by members of the CTP WP who were representatives of competent authorities and experienced in the evaluation of RMs for ATMPs. This article presents the results of these case studies, including the potential benefits and concerns identified by the experts. It was concluded that it would be technically feasible, albeit challenging, to set up a certification system for RMs of biological origin against chapter <i>5.2.12</i>. Although the establishment of such a scheme is currently perceived by some CTP WP members as premature, it could potentially be beneficial for all stakeholders (RM manufacturers, ATMP manufacturers and assessors).</p>","PeriodicalId":39192,"journal":{"name":"Pharmeuropa bio & scientific notes","volume":"2023 ","pages":"60-68"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10287238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation and application of a SEC-HPLC method for the determination of total protein in therapeutic immunoglobulins as an alternative to the European Pharmacopoeia methods.","authors":"V Esposito, A Carocci, F Luciani, A Battistone, A Gaggioli, F Esposito","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Several analytical procedures are described in the European Pharmacopoeia (Ph. Eur.) to determine total protein content. However, the method for the determination of protein content in therapeutic immunoglobulins prescribed in the Ph. Eur. monographs is the Kjeldahl method. The Kjeldahl method is time-consuming and requires the use of large amounts of hazardous reagents, which also results in the production of a large amount of hazardous chemical waste. The purpose of this work was to validate an alternative chromatographic method that requires no hazardous reagents and saves time, using the same instrumental conditions specified in the Ph. Eur. for the human immunoglobulin size-exclusion high-performance liquid chromatography (SEC-HPLC) molecular-size distribution assay. The chromatographic separation was achieved with a TSKgel G3000SW (600 × 7.5 mm, 10 µm) column, using an isocratic elution, with detection at 280 nm wavelength. The mobile phase consisted of an aqueous solution of 0.03 M disodium hydrogen phosphate dehydrate, 0.01 M sodium dihydrogen phosphate monohydrate, 0.2 M sodium chloride and 1 mM sodium azide. The protein content of the test samples was determined referring to a standard with a known protein concentration (i.e. Human immunoglobulin (molecular size) Biological Reference Preparation). The method was validated evaluating the characteristics precision and trueness according to the ICH Q2 guideline, and the goodness of linear fit for the signal response was assessed (given for information only). In addition, the equivalence of methods was evaluated with two one-sided t-tests (TOST) analysis with the Kjeldahl method mentioned in Ph. Eur. monographs on therapeutic immunoglobulins, and with Bland-Altman analysis of SEC-HPLC and manufacturers' data (Kjeldahl and biuret methods). The uncertainty of measurement was also calculated in order to evaluate the accuracy and quality of the results, thus facilitating a reliable compliance/non-compliance decision. Based on the outcome, the method is proposed as a suitable and convenient alternative for the determination of protein content in human immunoglobulins.</p>","PeriodicalId":39192,"journal":{"name":"Pharmeuropa bio & scientific notes","volume":"2023 ","pages":"69-81"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92156910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}