Environmental and Molecular Mutagenesis最新文献

{"title":"Consensus findings of an International Workshops on Genotoxicity Testing workshop on using transcriptomic biomarkers to predict genotoxicity.","authors":"Roland Froetschl, J Christopher Corton, Henghong Li, Jiri Aubrecht, Scott S Auerbach, Florian Caiment, Tatyana Y Doktorova, Yurika Fujita, Danyel Jennen, Naoki Koyama, Matthew J Meier, Roman Mezencev, Leslie Recio, Takayoshi Suzuki, Carole L Yauk","doi":"10.1002/em.22645","DOIUrl":"https://doi.org/10.1002/em.22645","url":null,"abstract":"<p><p>Gene expression biomarkers have the potential to identify genotoxic and non-genotoxic carcinogens, providing opportunities for integrated testing and reducing animal use. In August 2022, an International Workshops on Genotoxicity Testing (IWGT) workshop was held to critically review current methods to identify genotoxicants using transcriptomic profiling. Here, we summarize the findings of the workgroup on the state of the science regarding the use of transcriptomic biomarkers to identify genotoxic chemicals in vitro and in vivo. A total of 1341 papers were examined to identify the biomarkers that show the most promise for identifying genotoxicants. This analysis revealed two independently derived in vivo biomarkers and three in vitro biomarkers that, when used in conjunction with standard computational techniques, can identify genotoxic chemicals in vivo (rat or mouse liver) or in human cells in culture using different gene expression profiling platforms, with predictive accuracies of ≥92%. These biomarkers have been validated to differing degrees but typically show high reproducibility across transcriptomic platforms and model systems. They offer several advantages for applications in different contexts of use in genotoxicity testing including: early signal detection, moderate-to-high-throughput screening capacity, adaptability to different cell types and tissues, and insights on mechanistic information on DNA-damage response. Workshop participants agreed on consensus statements to advance the regulatory adoption of transcriptomic biomarkers for genotoxicity. The participants agreed that transcriptomic biomarkers have the potential to be used in conjunction with other biomarkers in integrated test strategies in vitro and using short-term rodent exposures to identify genotoxic and non-genotoxic chemicals that may cause cancer and heritable genetic effects. Following are the consensus statements from the workgroup. Transcriptomic biomarkers for genotoxicity can be used in Weight of Evidence (WoE) evaluation to: determine potential genotoxic mechanisms and hazards; identify misleading positives from in vitro genotoxicity assays; serve as new approach methodologies (NAMs) integrated into the standard battery of genotoxicity tests. Several transcriptomic biomarkers have been developed from sufficiently robust training data sets, validated with external test sets, and have demonstrated performance in multiple laboratories. These transcriptomic biomarkers can be used following established study designs and models designated through existing validation exercises in WoE evaluation. Bridging studies using a selection of training and test chemicals are needed to deviate from the established protocols to confirm performance when a transcriptomic biomarker is being applied in other: tissues, cell models, or gene expression platforms. Top dose selection and time of gene expression analysis are critical and should be established during transcriptomic bi","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931001","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":"Machine learning enhances genotoxicity assessment using MultiFlow® DNA damage assay.","authors":"Panuwat Trairatphisan, Lena Dorsheimer, Peter Monecke, Jan Wenzel, Rubin James, Andreas Czich, Yasmin Dietz-Baum, Friedemann Schmidt","doi":"10.1002/em.22648","DOIUrl":"https://doi.org/10.1002/em.22648","url":null,"abstract":"<p><p>Genotoxicity is a critical determinant for assessing the safety of pharmaceutical drugs, their metabolites, and impurities. Among genotoxicity tests, mechanistic assays such as the MultiFlow® DNA damage assay (MFA) allows the investigations on mode of action (MoA) of DNA damage through four mechanistic markers recorded at two time points. Previous studies have shown that machine learning (ML) can enhance precision on classifying the MoA of genotoxicants. Nevertheless, these approaches need to be tailored to specific chemical spaces and lab conditions for accurate risk assessment. In this study, we applied various state-of-the-art ML algorithms available in an open-source R package (caret) to build MFA-ML models using data from Bryce et al. (2016). The best model achieved 95% accuracy on the training dataset and correctly predicted genotoxicity in 16 out of 17 cases in the test dataset. Incorporating molecular descriptors properties from established in silico models demonstrated further improved performance of the approach to cover challenging examples of pharmaceuticals exhibiting a pharmacological mode of action that could interfere with the biomarker response. Further model validation on an external test set with 49 non-overlapped compounds showed a high model accuracy at 92%. Additionally, a tailored graphical user interface was developed using a freely available R package (shiny) to support visual analysis of MFA data including MoA predictions, facilitating broad usage by laboratory scientists. Lastly, a perspective on the integration of MoA predictions as additional evidence into a genotoxicity assessment workflow is proposed.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909408","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":"Genetic instability of a single exposure to sevoflurane at different concentrations in monitored mice.","authors":"Maria Vitória Destro, Mariane A P Silva, Tony F Grassi, Lídia R de Carvalho, Daisy M F Salvadori, Leandro G Braz, Mariana G Braz","doi":"10.1002/em.22647","DOIUrl":"https://doi.org/10.1002/em.22647","url":null,"abstract":"<p><p>Sevoflurane is an inhalation anesthetic widely used for general anesthesia, but its genotoxic potential is controversial in clinical studies. It is unknown whether the effects are due to surgery or the anesthetic. Thus, for the first time, the present study investigated genotoxicity in peripheral blood cells and in target organs (liver, lung, and kidney) and micronucleus (MN) in the bone marrow of a single exposure to sevoflurane at three different concentrations in monitored mice. Ninety Swiss mice were distributed into the following groups: exposure to sevoflurane at 3.3% (low), 4.5% (intermediate), and 6.0% (high) in 40% oxygen (O₂) for 2 h; negative control (no exposure); negative control with O₂; and positive control. The exposed animals were heated, monitored for vital signs (temperature, O₂ saturation, heart rate/pulse, and respiratory rate), and anesthetized via a modern low-flow digital system. Mice were euthanized 2 and 24 h after exposure for evaluation by the comet assay and MN test, respectively. No DNA damage occurred in the 3.3% group for any of the organs evaluated, and no genotoxic or mutagenic effects were observed at any sevoflurane concentration in the peripheral blood or liver cells. However, a significant increase in DNA damage was observed at higher concentrations in kidney (4.5%) and lung cells (6.0%) and in the MN frequency (groups 4.5% and 6.0%). No cytotoxicity or histological alterations were observed. In conclusion, high concentrations of sevoflurane induce DNA damage, but concentrations equivalent to those used in clinical practice do not demonstrate genotoxic or mutagenic effects.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893059","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":"Outcome of IWGT workshop on transcriptomic biomarkers for genotoxicity: Key considerations for bioinformatics.","authors":"Matthew J Meier, Florian Caiment, J Christopher Corton, Roland Frötschl, Yurika Fujita, Danyel Jennen, Roman Mezencev, Carole Yauk","doi":"10.1002/em.22644","DOIUrl":"https://doi.org/10.1002/em.22644","url":null,"abstract":"<p><p>As a part of the International Workshop on Genotoxicity Testing (IWGT) in 2022, a workgroup was formed to evaluate the level of validation and regulatory acceptance of transcriptomic biomarkers that identify genotoxic substances. Several such biomarkers have been developed using various molecular techniques and computational approaches. Within the IWGT workgroup on transcriptomic biomarkers, bioinformatics was a central topic of discussion, focusing on the current approaches used to process the underlying molecular data to distill a reliable predictive signal; that is, a gene set that is indicative of genotoxicity and can then be used in later studies to predict potential DNA damaging properties for uncharacterized chemicals. While early studies used microarray data, a technological shift occurred in the past decade to incorporate modern transcriptome measuring techniques such as high-throughput transcriptomics, which in turn is based on high-throughput sequencing. Herein, we present the workgroup's review of the current bioinformatic approaches to identify genes comprising transcriptomic biomarkers. Within the context of regulatory toxicology, the reproducibility of a given analysis is critical. Therefore, the workgroup provides consensus recommendations on how to facilitate sufficient reporting of experimental parameters for the analytical procedures used in a transcriptomic biomarker study, including the recommendation to develop a biomarker-specific reporting module within the OECD Omics Reporting Framework.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827734","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":"Evaluation of the standard battery of in vitro genotoxicity tests to predict in vivo genotoxicity through mathematical modeling: A report from the 8th International Workshop on Genotoxicity Testing.","authors":"Mirjam Luijten, Jan van Benthem, Takeshi Morita, Raffaella Corvi, Patricia A Escobar, Yurika Fujita, Jennifer Hemmerich, Naveed Honarvar, David Kirkland, Naoki Koyama, David P Lovell, Miriam Mathea, Andrew Williams, Stephen Dertinger, Stefan Pfuhler, Jeroen L A Pennings","doi":"10.1002/em.22640","DOIUrl":"https://doi.org/10.1002/em.22640","url":null,"abstract":"<p><p>In human health risk assessment of chemicals and pharmaceuticals, identification of genotoxicity hazard usually starts with a standard battery of in vitro genotoxicity tests, which is needed to cover all genotoxicity endpoints. The individual tests included in the battery are not designed to pick up all endpoints. This explains why resulting data can appear contradictory, thereby complicating accurate interpretation of the findings. Such interpretation could be improved through application of mathematical modeling. One of the advantages of mathematical modeling is that the strengths and weaknesses of each test are taken into account. Furthermore, the generated predictions are objective and convey the associated uncertainties. This approach was explored by the working group \"Predictivity of In Vitro Genotoxicity Testing,\" convened in the context of the 8th International Workshop on Genotoxicity Testing (IWGT). Specifically, we applied mathematical modeling to a database with publicly available in vitro and in vivo data for genotoxicity. The results indicate that a mammalian in vitro clastogenicity test and a mammalian cell gene mutation test together provide strong predictive weight-of-evidence for evaluating genotoxic hazard of a substance, although they are better in predicting absence of genotoxic potential than in predicting presence of genotoxic potential. Remarkably, the bacterial reverse mutation (Ames) test did not significantly change these predictions when used in combination with in vitro mutagenicity and clastogenicity tests using cells of mammalian origin. However, in case only data from a bacterial reverse mutation test are available for the assessment of genotoxic potential, these do bear weight of evidence and thus can be used. Genotoxicity assays are generally executed in tiers, in which the bacterial reverse mutation test often is the starting point. Thus, it is reasonable to suspect that early in development test results from the bacterial reverse mutation test have influenced the composition of the database studied here. We performed several tests on the robustness of the database used for the analyses presented here, and the forthcoming results do not indicate a strong bias. Further research comparing in vitro genotoxicity data with in vivo data for additional compounds will provide more insights whether it is indeed time to reconsider the composition of the standard in vitro genotoxicity battery.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767318","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":"Hollaender award 2023: Adventures in applied genetic toxicology","authors":"Rosalie K. Elespuru","doi":"10.1002/em.22642","DOIUrl":"10.1002/em.22642","url":null,"abstract":"<p>This work describes career “adventures” into applied research in environmental mutagenesis. Surprising and interesting results, as well as publications in <i>Nature and Science</i>, may counter an assumption that applied research is not as exciting or impactful as basic research. The narrative is described in terms of “mentors,” whose advice had a lasting impact and resonated in many ways. Adventures included forays into nitrosamine mutagenicity, nanomaterial assessment, photoactivated DNA damaging agents, p53 gene mutagenicity, germ cell mutagenic risk, bacterial mutagenicity assays, genotoxicity of cell phone radiation, Covid diagnostic PCR assays, personalized cancer prevention, and &gt;25 years in regulatory safety assessment at FDA. FDA work included review of genotoxicity data, experiments in the lab, international standards generation, and collaboration with others to foster better analyses of DNA damaging agents, generally in relation to cancer risk. As demonstrated by accidental adventures that led to scientific as well as life-altering personal realizations, many of the most critical happenings in science and in life turn out to be “random,” unexpected, events. Finally, with this work and that of my lifelong tripmate William Lijinsky as models, it is suggested that a “non-hypothesis driven,” open-ended approach to research can be path-breaking and forefront.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 9","pages":"301-314"},"PeriodicalIF":2.3,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142727278","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":"Transcriptomic and epigenomic signatures distinguish high- and low-risk endotypes for liver tumor development","authors":"Sandra L. Grimm,&nbsp;Tia Talley,&nbsp;Rahul K. Jangid,&nbsp;Amrit Koirala,&nbsp;Micah B. Castillo,&nbsp;Preethi H. Gunaratne,&nbsp;Cristian Coarfa,&nbsp;Cheryl L. Walker","doi":"10.1002/em.22639","DOIUrl":"10.1002/em.22639","url":null,"abstract":"<p>The epigenome is a target for environmental exposures and a potential determinant of inter-individual differences in response. In genetically identical C57Bl/6 mice exposed from gestation to weaning to the endocrine-disrupting chemical (EDC) tributyltin (TBT), hepatic tumor development later in life varied across multiple cohorts over time and depending on sex and diet. In one cohort where approximately half of TBT-exposed male mice developed liver tumors at 10 months (Katz et al. Hepatic tumor formation in adult mice developmentally exposed to organotin, <i>Environmental Health Perspectives</i>, <b>128</b> (1), 17010, 2020), transcriptomic (RNA-seq) and epigenomic (ChIP-seq) profiling was performed on blood and liver tissue from mice that developed tumors (i.e., “high-risk”) and equivalently exposed mice did not (i.e., “low-risk”). Blood transcriptomic signatures separated TBT-exposed from vehicle controls but did not discriminate between animals that developed tumors versus those that did not. However, uninvolved liver tissue of mice with tumors exhibited transcriptomic and epigenomic signatures distinct from liver tissue of mice without tumors and had many features in common with tumors. These high-risk transcriptomic and epigenomic features were also found in 10/26 TBT-exposed mice at 5 months, indicating that this risk signature preceded tumor development. Thus, while early life exposure to TBT exhibits variable penetrance for hepatic tumor development, indicating TBT exposure is not sufficient for liver tumorigenesis, increased risk for hepatic tumor development is linked to epigenomic and transcriptomic reprogramming of the liver induced by this EDC.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 9","pages":"351-359"},"PeriodicalIF":2.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715689","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":"Bruce Nathan Ames, 1928–2024: A meaningful scientific life","authors":"Errol Zeiger","doi":"10.1002/em.22641","DOIUrl":"10.1002/em.22641","url":null,"abstract":"","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 9","pages":"298-300"},"PeriodicalIF":2.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22641","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680415","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":"Investigation of mutagenicity of styrene in tumor target and non-target tissues of transgenic Big Blue® mice.","authors":"B Bhaskar Gollapudi, Karen Philp, Jeffrey T Weinberg","doi":"10.1002/em.22638","DOIUrl":"10.1002/em.22638","url":null,"abstract":"<p><p>Styrene has been shown to induce lung tumors in mice, but not in rats. The current study investigated the potential role of genotoxicity as an initial key event in the mode of action for styrene-induced lung tumors in mice. Transgenic male B6C3F1 Big Blue® mice were treated by oral gavage for 28 consecutive days with 0 (corn oil), 75, 150, or 300 mg/kg/day of styrene. The 300 mg/kg/day represented the tumorigenic dose in the oral gavage carcinogenicity study conducted in B6C3F1 mice. Following a 28-day expression period, mutant frequencies were assessed at the cII locus of the transgene in the tumor target (lung) and non-target tissues (liver, glandular stomach, and duodenum). Mice treated with N-ethyl-N-nitrosourea (40 mg/kg/day) by oral gavage on Days 1, 2, and 3 of the study and sacrificed on Day 56 served as the positive control group. Genomic DNA was extracted from the selected tissues, processed for the recovery of the transgene into infectious phage, plated onto Escherichia coli strain G1250, and incubated at 37°C for titer determination or at 24°C for the selection of mutant plaques. There were no treatment-related increases in mutant frequency in any of the tissues. The positive control group had a significant increase in the frequency of cII mutants assuring the adequacy of the experimental conditions to detect induced mutations. To conclude, mutagenicity is not considered a plausible initial key event in the mode of action for styrene-induced mouse lung tumors as these data support that styrene is not an in vivo mutagen.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615498","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":"AOP report: Development of an adverse outcome pathway for deposition of energy leading to abnormal vascular remodeling","authors":"Tatiana Kozbenko,&nbsp;Nadine Adam,&nbsp;Veronica S. Grybas,&nbsp;Benjamin J. Smith,&nbsp;Dalya Alomar,&nbsp;Robyn Hocking,&nbsp;Janna Abdelaziz,&nbsp;Amanda Pace,&nbsp;Marjan Boerma,&nbsp;Omid Azimzadeh,&nbsp;Steve Blattnig,&nbsp;Nobuyuki Hamada,&nbsp;Carole Yauk,&nbsp;Ruth Wilkins,&nbsp;Vinita Chauhan","doi":"10.1002/em.22636","DOIUrl":"10.1002/em.22636","url":null,"abstract":"<p>Cardiovascular diseases (CVDs) are complex, encompassing many types of heart pathophysiologies and associated etiologies. Radiotherapy studies have shown that fractionated radiation exposure at high doses (3–17 Gy) to the heart increases the incidence of CVD. However, the effects of low doses of radiation on the cardiovascular system or the effects from space travel, where radiation and microgravity are important contributors to damage, are not clearly understood. Herein, the adverse outcome pathway (AOP) framework was applied to develop an AOP to abnormal vascular remodeling from the deposition of energy. Following the creation of a preliminary pathway with the guidance of field experts and authoritative reviews, a scoping review was conducted that informed final key event (KE) selection and evaluation of the Bradford Hill criteria for the KE relationships (KERs). The AOP begins with a molecular initiating event of deposition of energy; ionization events increase oxidative stress, which when persistent concurrently causes the release of pro-inflammatory mediators, suppresses anti-inflammatory mechanisms and alters stress response signaling pathways. These KEs alter nitric oxide levels leading to endothelial dysfunction, and subsequent abnormal vascular remodeling (the adverse outcome). The work identifies evidence needed to strengthen understanding of the causal associations for the KERs, emphasizing where there are knowledge gaps and uncertainties in both qualitative and quantitative understanding. The AOP is anticipated to direct future research to better understand the effects of space on the human body and potentially develop countermeasures to better protect future space travelers.</p>","PeriodicalId":11791,"journal":{"name":"Environmental and Molecular Mutagenesis","volume":"65 S3","pages":"4-30"},"PeriodicalIF":2.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/em.22636","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497353","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}