Regulatory Toxicology and Pharmacology最新文献

{"title":"Quantifying the effect of human interindividual kinetic differences on the relative potency value for riddelliine N-oxide at low dose levels by a new approach methodology","authors":"F. Widjaja-van den Ende ,&nbsp;M.A.J.S. van Boekel ,&nbsp;C. Davis ,&nbsp;S. Wesseling ,&nbsp;I.M.C.M. Rietjens","doi":"10.1016/j.yrtph.2024.105767","DOIUrl":"10.1016/j.yrtph.2024.105767","url":null,"abstract":"<div><div>Pyrrolizidine alkaloid N-oxides (PA-N-oxides) are predominant in plants and herbal foods, and are converted to pyrrolizidine alkaloids (PAs) upon consumption, leading to toxicity. The effect of interindividual kinetic differences on the relative potency values of PA-N-oxides compared to their PAs (REP_{PANO to PA}) was studied, with riddelliine N-oxide (RIDO) and riddelliine (RID) as model compounds. <em>In vitro</em> kinetic data measured in incubations with 30 fecal and 25 liver S9 donor samples showed high variation across individuals, where the interindividual variability was captured with Bayesian multilevel regression. The distributions of influential PBK model parameters were used as input for physiologically based kinetic (PBK) modeling combined with Monte Carlo (MC) simulations to calculate the probability distribution of REP_{RIDO to RID} values. At low dose levels, interindividual differences were shown to be a factor that influences the REP_{RIDO to RID} value while neither dose nor endpoint used plays a role. The distribution of the REP_{RIDO to RID} value ranged from 0.71 to 0.97 (95th percentile) with a mean value of 0.87. The approach described enables determination of interindividual REP_{PANO to PA} values at low dose levels, which are not accessible in <em>in vivo</em> experiments quantifying the REP_{PANO to PA}value.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105767"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877848","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":"Global regulatory considerations and practices for tumorigenicity evaluation of cell-based therapy","authors":"Dehu Dou ,&nbsp;Jing Lu ,&nbsp;Jinhui Dou ,&nbsp;Yan Huo ,&nbsp;Xinjiang Gong ,&nbsp;Xuefeng Zhang ,&nbsp;Xijing Chen","doi":"10.1016/j.yrtph.2024.105769","DOIUrl":"10.1016/j.yrtph.2024.105769","url":null,"abstract":"<div><div>Cell-based therapy, as a “living drug”, possesses inherent complexity and heterogeneity. Tumorigenicity evaluation is a crucial aspect of safety assessment for cell-based therapies. Stem cell-based therapies such as hESCs and hiPSCs, may contain residual undifferentiated cells in final product, which have a high potential for proliferation and differentiation, posing a risk of tumor formation in vivo. Additionally, the source, phenotype, differentiation status, proliferative capacity, ex vivo culture conditions, ex vivo processing methods, injection site, and route of administration also influence the tumorigenicity risk of the cells. Tumorigenicity evaluation needs to consider the complexity of design and multifactorial influences. Through the analysis and summary of partial existing marketed and under-development products, combined with practical experience, it is found that there are many differences in requirements and practices related to cell tumorigenicity globally. Regulatory requirements also vary, and guidance and support for applicants’ declaration requirements in different regions need to be considered in conjunction with product characteristics and regulatory considerations. This article comprehensively summarizes the requirements of tumorigenicity from main regulatory agencies. Currently, there is no unified global regulatory consensus on technical implementation guide, measures for quantitation or standardization have not been established for evaluation systems. However, based on regulatory requirements and industry practice summaries, through literature research and analysis of tumorigenicity strategy of representative marketed products, the basic focus, and evaluation strategies for tumorigenicity assessment have been preliminarily clarified, providing a reference for the tumorigenicity design of variety of cell-based therapy products.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105769"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915356","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 dual endothelin A and angiotensin II type 1 receptor antagonist sparsentan (FILSPARI®) exhibits a safe nonclinical male fertility toxicity profile","authors":"Patricia W. Bedard ,&nbsp;Francesca Pretto ,&nbsp;Sima Patel ,&nbsp;Celia Jenkinson ,&nbsp;Tacey White ,&nbsp;Donald E. Kohan","doi":"10.1016/j.yrtph.2024.105770","DOIUrl":"10.1016/j.yrtph.2024.105770","url":null,"abstract":"<div><div>Marketed endothelin receptor antagonists (ERAs) have been associated with testicular tubular atrophy and decreases in male animal fertility in chronic toxicity studies in rats and dogs. Consistent with these findings, reduced sperm count has been observed in the clinical setting and is considered a potential class risk with chronic administration of ERAs. In contrast, no such effects on male animal fertility are noted with angiotensin II type 1 receptor blocker (ARB) treatment. Sparsentan (FILSPARI®) is a novel single molecule dual antagonist that antagonizes both the endothelin type A and angiotensin II type 1 receptors. We explored whether the reproductive toxicology profile of this dual endothelin angiotensin antagonist is more like that of marketed ERAs or ARBs. A full package of repeat dose general toxicity, juvenile toxicity, carcinogenicity, and reproductive and developmental toxicity studies was completed with sparsentan. A thorough review of the results from these studies has shown no evidence of effects of sparsentan on spermatogenesis or testicular histopathology. The overall conclusion of this assessment is that sparsentan is not toxic to the testes or the spermatogenic process and is more like ARBs than ERAs in its male fertility toxicity profile.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105770"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915360","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":"Toxicological evaluation of vanadium and derivation of a parenteral tolerable intake value for medical devices","authors":"Charlotte E. Laupheimer ,&nbsp;Yana Kolianchuk ,&nbsp;Rex E. FitzGerald ,&nbsp;Martin F. Wilks ,&nbsp;Arne Jaksch","doi":"10.1016/j.yrtph.2024.105732","DOIUrl":"10.1016/j.yrtph.2024.105732","url":null,"abstract":"<div><div>Vanadium is used in alloys, batteries as well as catalyst and is a known impurity in medical devices and pharmaceuticals. The present work describes the calculation of a parenteral tolerable intake (TI) for vanadium by chronic exposure in implantable medical devices per ISO 10993–17:2023, the applicable standard. The 2023 update of ISO 10993-17 [1] introduces new uncertainty factors (UFs) for calculating a TI. Therefore, we noted differences between the ISO guidance and the ICH Q3D guidance on Permissible Daily Exposure (PDE) for parental elemental pharmaceutical impurities. We derived a TI of 0.20 μg V/kg/day based on the updated ISO guidance, and a PDE of 0.24 μg V/kg/day based on ICH guidance. The latter is considered a more realistic estimate.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105732"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547051","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":"Use of alternatives to animal testing for Environmental Safety Assessment (ESA): Report from the 2023 EPAA partners’ forum","authors":"Jose V. Tarazona ,&nbsp;Ana Fernandez-Agudo ,&nbsp;Ondrej Adamovsky ,&nbsp;Marta Baccaro ,&nbsp;Natalie Burden ,&nbsp;Bruno Campos ,&nbsp;Björn Hidding ,&nbsp;Karen Jenner ,&nbsp;David John ,&nbsp;Katia Lacasse ,&nbsp;Adam Lillicrap ,&nbsp;Delina Lyon ,&nbsp;Samuel K. Maynard ,&nbsp;Amelie Ott ,&nbsp;Veronique Poulsen ,&nbsp;Mike Rasenberg ,&nbsp;Katrin Schutte ,&nbsp;Marta Sobanska ,&nbsp;James R. Wheeler","doi":"10.1016/j.yrtph.2025.105774","DOIUrl":"10.1016/j.yrtph.2025.105774","url":null,"abstract":"<div><div>Environmental Safety Assessments (ESA) are mandatory for several regulatory purposes and are an important component of stewardship/sustainability initiatives. Fish testing is used for assessing chemical toxicity and bioaccumulation potential; amphibians are included in some jurisdictions and their use is increasing to assess endocrine disruption. Alternative methods are becoming more available, covering the principles of the 3Rs (i.e., replacing, reducing and refining animal tests), but their regulatory incorporation is still limited. A cross-sector review by the European Partnership for Alternative Approaches to Animal Testing (EPAA), discussed the status and priorities for accelerating the adoption of non-animal approaches in ESA. The lack of an internationally agreed definition for “animal testing” was recognized as a challenge. For example, testing with vertebrate embryos up to specific developmental stages is a suitable refinement alternative only in some jurisdictions. Invertebrate testing offers refinement alternatives to develop tiered approaches using vertebrate testing as a last resort. Aquatic ESA was identified as a common need by all sectors and regulatory areas, while terrestrial ESA is particularly relevant for agrochemicals. The standardization and validation of some alternative methods as OECD test guidelines (TGs) for fish acute toxicity and fish bioaccumulation have not yet triggered the expected replacement in regulatory settings. Priority actions in these areas are needed to generate confidence in the regulatory use of the available OECD TGs designed as alternatives, including the identification of applicability domains and guidance/decision-trees for integrating different lines of evidence. Case studies under the OECD Integrated Approaches to Testing and Assessment (IATA) program could facilitate further global regulatory uptake. Replacement of fish chronic toxicity testing is more complex and less advanced. A dual approach was suggested, in the short-term, exploring lines of evidence that, alone or in combination, could identify when further fish testing is not needed. The second phase should focus on the application of the 3Rs in those cases where chronic information is needed. Another area of increasing interest is endocrine disruption. It represents a challenge but also an opportunity for implementing mechanistic non-animal methods, in addition to integrate human and ESA. This requires a step-by-step approach with continuous dialogue to ensure that technical developments will address regulatory needs. The review also agreed that the long-term aspiration is a new ESA paradigm, mapping the protection goals and providing connectivity between the chemical legislation and environmental protection policies.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105774"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041489","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":"CDSCO alerts: A retrospective dosage form - Wise analysis of quality control alerts issued to pharmaceutical companies from 2018 to 2023","authors":"Akanksha Dashawant ,&nbsp;Richa Khadke ,&nbsp;Amol Shete ,&nbsp;Vinod Gaikwad","doi":"10.1016/j.yrtph.2025.105775","DOIUrl":"10.1016/j.yrtph.2025.105775","url":null,"abstract":"<div><div>This study comprehensively analyses drug alerts issued by the Central Drugs Standard Control Organization (CDSCO) from 2018 to 2023, focusing on various pharmaceutical dosage forms and related quality control parameters. By categorizing alerts and counting them individually, the research identifies prevalent quality issues and their impact on specific dosage forms. Tablets, parenteral formulations, capsules, and syrups were among the most frequently alerted categories, while expectorants, mouthwashes, and tinctures received fewer alerts. The study underscores the importance of rigorous testing protocols and continuous vigilance in maintaining pharmaceutical quality. Recommendations include adopting global standard quality measures by Indian manufacturers to ensure pharmaceutical safety and efficacy, ultimately benefiting patients and healthcare systems.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105775"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075240","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":"Incorporating Singaporean habits and practices for cosmetics and personal care products into a global consumer aggregate exposure model","authors":"Siti Amelia Juraimi ,&nbsp;Cesar Scrochi ,&nbsp;Jonathan Lok ,&nbsp;Anne Marie Api ,&nbsp;Benjamin P.C. Smith","doi":"10.1016/j.yrtph.2024.105752","DOIUrl":"10.1016/j.yrtph.2024.105752","url":null,"abstract":"<div><div>Understanding consumer habits and practices of cosmetics and personal care products (PCP) is essential to generate realistic product exposure data for the safety assessment of ingredients such as fragrance materials. Product usages can vary across regions due to differences in cultural norms, seasonal and climate conditions, and the availability of different product forms, yet there is limited data published on cosmetics and PCP use outside of North America and Europe. This study reports the habits and practices of cosmetics and PCP (such as frequency and amount of use) in Singapore where participants (<em>n</em> = 494, aged 21–64 years) recorded their product usages and had their products weighed over a two-week period. Overall, similar use patterns were observed across demographic groups within the Singapore population for most of the products surveyed, as were the expected usage amounts. Additionally, the Singaporean dataset was mapped onto the Creme-RIFM aggregate exposure model to assess exposure estimates. Preliminary comparisons with product exposures observed in the United States (US) and Europe suggest that exposures in Singapore are comparable. Findings from this study will contribute to the Creme-RIFM model, expanding its geographic scope and applicability for the global safety assessment of fragrance ingredients and fragranced products.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105752"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755115","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":"Ames mutagenicity of 15 aryl, benzyl, and aliphatic ring N-nitrosamines","authors":"Ayako Furuhama ,&nbsp;Kei-ichi Sugiyama ,&nbsp;Masamitsu Honma","doi":"10.1016/j.yrtph.2024.105763","DOIUrl":"10.1016/j.yrtph.2024.105763","url":null,"abstract":"<div><div>The Ames mutagenicity test is an effective means of screening compounds for their carcinogenic potential. Here, we conducted Ames tests on 15 aryl, benzyl, and aliphatic ring <em>N</em>-nitrosamines. Then, by using two indicators of mutagenicity strength calculated from the Ames test results, namely, maximum specific activity (MSA; number of revertant colonies) and maximum fold increase (MFI; relative ratio of increased colonies), we examined the relationship between Ames mutagenicity strength and Carcinogenic Potency Categorization Approach (CPCA) potency category, which is a structure–activity-relationship–based prediction of the carcinogenic potency of nitrosamines. Eleven of the test compounds were Ames positive and four were negative. Of the 11 positive compounds, three were categorized as strong positive (MSA ≥1000), five as medium positive (100 ≤ MSA &lt;1000), and three as weak positive (MSA &lt;100). The compounds with an aliphatic ring showed a negative relationship between mutagenicity strength (i.e., MSA or MFI) and carcinogenic potential (i.e., CPCA category), whereas, the alpha-methyl aryl <em>N</em>-nitrosamines did not. Overall, <span>MSA</span> and <span>MFI</span> were found to be detailed indicators of the carcinogenic potency of the <em>N</em>-nitrosamines and can potentially be used to support CPCA categorization.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105763"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814067","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":"PBT/PMT assessment of active pharmaceutical ingredients","authors":"Gemma Janer ,&nbsp;Joanne Elmoznino ,&nbsp;Andreas Häner ,&nbsp;Irene Bramke","doi":"10.1016/j.yrtph.2025.105772","DOIUrl":"10.1016/j.yrtph.2025.105772","url":null,"abstract":"<div><div>The EU Commission proposal for a new EU pharmaceutical legislation considers PBT (persistence-bioaccumulation-toxicity) and PMT (persistence-mobility-toxicity) criteria for pharmaceuticals. Under current environmental risk assessment guidance, a PBT assessment is required regardless of the predicted environmental concentrations. However, consumption volumes of pharmaceuticals are contingent on marketing approval by EMA and are therefore predictable and their toxicological potency is established prior to any regulatory approval. Consumption volume and toxicological potency of pharmaceuticals span many orders of magnitude and are strong risk determinants. Routine data generation to evaluate persistence, mobility and bioaccumulation hazards as a means of pinpointing pharmaceuticals of increased environmental concern is therefore of questionable added value.</div><div>We present options to derive action triggers for PBT and/or PMT screening using exposure predictions and toxicological potency data. Our simulations demonstrate that an exposure-based action limit can be established as a trigger for PMT assessment, while a combined trigger based on exposure levels and mammalian toxicity is proposed for PBT assessment. The proposed approach is conservatively designed to ensure that compounds with any potential risks a) of secondary poisoning (main concern for PBT substances) and b) to groundwater/drinking water (main concern for PMT substances) are targeted for full evaluation.</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"156 ","pages":"Article 105772"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010627","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":"Comprehensive extractables and leachables sensitization analysis and practical application of a risk-based approach to sensitization assessment for parenteral drug products","authors":"Patricia Parris ,&nbsp;Geraldine Whelan ,&nbsp;Martyn L. Chilton ,&nbsp;Claire Beaumont ,&nbsp;Anders Burild ,&nbsp;Uma Bruen ,&nbsp;Courtney Callis ,&nbsp;Jessica Graham ,&nbsp;Natalia Kovalova ,&nbsp;Elizabeth A. Martin ,&nbsp;Melisa Masuda-Herrera ,&nbsp;Carsten Worsøe ,&nbsp;Anissa Alami ,&nbsp;Joel Bercu ,&nbsp;Dvir Doron ,&nbsp;Kristen Dusenbury ,&nbsp;Qiang Fu ,&nbsp;Troy Griffin ,&nbsp;Jedd Hillegass ,&nbsp;Esther Johann ,&nbsp;Lee Nagao","doi":"10.1016/j.yrtph.2025.105776","DOIUrl":"10.1016/j.yrtph.2025.105776","url":null,"abstract":"<div><div>The Extractables and Leachables Safety Information Exchange (ELSIE) Consortium added to the sensitization potency analysis of Parris et al. (2023) by including the Product Quality Research Institute (PQRI) extractable and leachable dataset (Johnson et al., 2024; Product Quality Research Institute, 2021). This analysis of the comprehensive E&amp;L dataset showed 5% of chemicals (20/407) had experimental results demonstrating or were predicted to be potent (strong or extreme) sensitizers, supporting the previous conclusion, that potent sensitizers are of low prevalence and are not routinely observed as leachables in pharmaceutical products. By accounting for prevalence of sensitization in the overall E&amp;L dataset, the probability of any potential leachable being more potent than the less than lifetime ICH M7 (10, 20, and 120 μg/day for human exposure of &gt;1–10 years, &gt;1–12 months, and &lt;1 month respectively) and non-mutagenic ELSIE threshold values (35, 110, and 180 μg/day for human exposures of &gt;10 years to lifetime, &gt;1–10 years, and ≤1 year respectively) (Masuda-Herrera et al., 2022) was considered. The M7 and ELSIE thresholds are anticipated to provide ≥95% coverage of induction of sensitization, supporting the use of these thresholds to set the Safety Concern Threshold (SCT).</div></div>","PeriodicalId":20852,"journal":{"name":"Regulatory Toxicology and Pharmacology","volume":"157 ","pages":"Article 105776"},"PeriodicalIF":3.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066288","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}