Xenotransplantation最新文献

{"title":"An IgM Cleaving Enzyme for Clearance of Anti-Pig Xenoreactive Antibodies in a Nonhuman Primate Model.","authors":"Alessandro Martinino, Timothy J Smith, Zachary C Elmore, Janghoon Yoon, Joseph Ladowski, Davide Schiliro, Joshua A Hull, Allie Schwalb, Meghan Hu, Ryan Spangler, Kyo Won Lee, Min Jung Kim, Kyha Williams, Annette Jackson, Stuart J Knechtle, Aravind Asokan, Jean Kwun","doi":"10.1111/xen.70023","DOIUrl":"10.1111/xen.70023","url":null,"abstract":"<p><strong>Background: </strong>The removal of preformed antibodies with cleaving enzymes like IdeS (imlifidase) has demonstrated therapeutic potential in organ transplantation for sensitized recipients. However, preformed xenoreactive antibodies (XAbs) against porcine glycans are predominantly IgM and considered detrimental in pig-to-human xenotransplantation.</p><p><strong>Methods: </strong>Recombinant IceM, an endopeptidase cleaving IgM, was generated in Escherichia coli (E. coli). Four maximally MHC-mismatched rhesus macaques underwent two serial skin transplantations to model allosensitized patients awaiting xenotransplantation. IceM was administered IV in allosensitized animals at 28 and 56 days after the first skin transplantation to assess in vivo IgM cleavage. Total IgG and IgM were quantified with western blot, and anti-pig (xenoreactive) IgG/IgM were evaluated using flow crossmatch. B cells and their subpopulations were assessed using flow cytometry.</p><p><strong>Results: </strong>IceM selectively cleaved human IgM, while showing no cleavage activity toward other isotypes, including IgG, IgA, IgD, and IgE. Additionally, IceM cleaves only human and nonhuman primate IgM in vitro, but not in sera from other species. At a dose of 0.5 mg/kg, IceM reduced xenoreactive IgM levels to 13.76% ± 4.98% of baseline (B cell flow crossmatch) at 24 h postadministration, with baseline levels restored approximately 2 weeks after treatment. Additionally, animals showed similar kinetics of xenoreactive IgM degradation with the repeated dose of IceM.</p><p><strong>Conclusion: </strong>In this study, we report a recombinant bacterial enzyme that selectively cleaves IgM in human and nonhuman primate sera. Repeat administration of IceM in macaques enables selective, robust clearance of circulating xenoreactive IgM. This approach will be useful in treating preformed natural and rebound IgM in xenotransplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70023"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442223","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":"Modified CD40L-Activated B-Cell Proliferation Model for Validating the Suppressive Activity of CD40-CD154 Pathway Inhibitors.","authors":"Man Zhang, Hao Feng, Yahui Huang, Tianyi Hu, Jiaxiang Du, Yong Wang, Song Chen, Dengke Pan, Lan Zhu, Gang Chen","doi":"10.1111/xen.70029","DOIUrl":"10.1111/xen.70029","url":null,"abstract":"<p><strong>Background: </strong>CD40-CD154 pathway inhibitors are considered indispensable immunosuppressive drugs in xenotransplantation. At present, novel anti-CD154 and anti-CD40 monoclonal antibodies (mAbs) are continuously being developed. It is important to establish a simple and efficient in vitro method to evaluate the effectiveness of these therapeutic mAbs.</p><p><strong>Methods: </strong>A modified CD40L-activated B-cell proliferation model was established using irradiated NIH/3T3 cells transfected with human CD40 ligand (hCD40L-NIH/3T3) as stimulator cells and human or rhesus monkey peripheral blood mononuclear cells (PBMCs) as responder cells. After 8 days of culture, B-cell proliferation was detected by flow cytometry. Various concentrations of anti-CD40 or anti-CD154 mAbs were added to the co-culture system as an intervention. The inhibitory effects of anti-CD154 and anti-CD40 mAbs on the proliferation of B cells from humans and rhesus monkeys were studied and compared.</p><p><strong>Results: </strong>After 8 days of co-culture, the proliferation rate of B cells in both human and rhesus monkey PBMCs was more than 80%, and the expression of MHC-II and the co-stimulatory molecules CD80, CD86, and CD40 on B cells was significantly up-regulated. All three anti-CD154 mAbs showed a similar strong inhibitory effect on human B-cell proliferation, but the inhibitory effect on the proliferation of rhesus monkey B cells was weaker than that on human B cells, which showed a typical dose-dependent inhibition. The three anti-CD40 mAbs from different sources had different effects. One mAbs potently inhibited both human and monkey B-cell proliferation, whereas the other two mAbs exhibited strong or moderate inhibitory effects on human B-cell proliferation but had little inhibitory effect on monkey B-cell proliferation.</p><p><strong>Conclusion: </strong>We have successfully established a modified CD40L-activated B-cell proliferation model for the in vitro evaluation of CD40-CD154 pathway inhibitors, which may provide important evidence for the selection of appropriate therapeutic antibodies and their dose determination for xenotransplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70029"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492540","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 International Human Xenotransplantation Inventory: Current Data and Future Directions.","authors":"Xiaowei Hu, Wayne J Hawthorne, Leo Buhler","doi":"10.1111/xen.70026","DOIUrl":"10.1111/xen.70026","url":null,"abstract":"<p><strong>Background: </strong>The global demand for organ transplantation outpaces supply, necessitating innovative solutions. Xenotransplantation, using animal organs, cells, and tissues, is a promising solution to address the organ shortage. The World Health Organization and the International Xenotransplantation Association collaboratively established an online inventory in 2006 (www.humanxenotransplant.org) to catalog human xenotransplantation practices. The inventory, managed successively by the Geneva University Hospital and the Sichuan Provincial People's Hospital, aligns with the WHO directives for transparency and best practices in the field of transplantation.</p><p><strong>Methods: </strong>Relevant data have been regularly collected from numerous sources (scientific publications, congresses, press articles, declarations of International Xenotransplantation Association members) by a dedicated team in Switzerland and China ensuring rigorous verification. The initial information is used to create a first entry in the database which is then completed when more details become available.</p><p><strong>Results: </strong>As of May 2024, the inventory contained 54 entries of distinct xenotransplantation procedures undertaken on humans. From these data, various trends can be observed over the last two decades regarding the type of transplantation, their regulation status, and the source animal. Notably, recent high-profile cases of solid organ transplantation involving kidneys and hearts were made feasible through years of progressive xenotransplantation research and ongoing changes to regulations.</p><p><strong>Conclusions: </strong>Recent clinical applications of solid organ xenotransplantation suggests that more clinical procedures may soon follow for patients with end-stage kidney or heart disease, or diabetes. Future perspectives advocate for increased funding and expansion of the current registry or its potential integration into a larger and more broadly internationally recognized registry, such as the Global Observatory on Donation and Transplantation (GODT).</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70026"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493368","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":"How Much Will a Pig Organ Transplant Cost? A Preliminary Estimate of the Cost of Xenotransplantation Versus Allotransplantation in the USA.","authors":"Krish Vasudev, David Kempton Cartwright Cooper","doi":"10.1111/xen.70018","DOIUrl":"10.1111/xen.70018","url":null,"abstract":"<p><p>We reviewed the costs of organ allotransplantation and attempted to estimate the potential costs of xenotransplantation (based on the premise that, when clinically established, the results of pig organ xenotransplantation would be at least equal to those of allotransplantation). The care of patients with end-stage organ failure waiting for an allograft is expensive, particularly if chronic dialysis or mechanical support is required. Xenotransplantation has the potential to eliminate wait times for organ transplants, significantly reduce certain management costs, for example, chronic dialysis, and enable early transplantation before comorbidities develop or increase. The cost of the surgical procurement of a pig organ and its transplantation will be similar to that of allotransplantation, as will the cost of immunosuppressive therapy. The major \"unknown\" is the cost of purchasing a gene-edited pig organ, which is likely to be considerable. We conclude that there will be significant cost savings for the pretransplant care of an individual patient, but these may be offset by the cost of the gene-edited pig organ. However, the ready availability of an unlimited organ supply will greatly increase the number of transplants carried out each year, thus increasing the overall expenditure on transplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70018"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493933","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":"ECG Features in Orthotopic Cardiac Xenotransplantation: Comparisons With Published Literature.","authors":"Chace B Mitchell, Joe Simmons, Sarah J Neal, David C Cleveland, Yaniv Bar-Cohen, John D Cleveland","doi":"10.1111/xen.70005","DOIUrl":"10.1111/xen.70005","url":null,"abstract":"<p><strong>Introduction: </strong>Although there is a plethora of literature on electrocardiographic changes following cardiac allotransplantation, there is little in the field of cardiac xenotransplantation. The only published literature to date is that of the first pig-to-human cardiac xenotransplantation. Here we take a close look at the electrocardiographic parameters in four non-human primate recipients of orthotopic cardiac xenotransplantation to develop baseline metrics for comparison.</p><p><strong>Methods: </strong>Orthotopic cardiac xenotransplantion was carried out in four non-human primate recipients. Electrocardiographic parameters were followed at various intervals using an internal hemodynamic monitoring system (DSI) as well as a standard 12-lead electrocardiogram (ECG). ECG intervals were then compared to published literature on porcine ECG intervals and pig-to-human cardiac xenotransplantation.</p><p><strong>Results: </strong>There were no significant differences observed between timepoints for HR, PR, QRS, QT, or QTc after cardiac xenotransplantation for each animal subject. ECG parameters were statistically similar to those of in situ mini-pig hearts in the literature. ECG parameters from the DSI on average were shorter than those from a traditional ECG, however, DSI parameters were consistent over time.</p><p><strong>Conclusion: </strong>These results demonstrate the possibility of conduction health for genetically engineered porcine donor hearts following cardiac xenotransplantation. Ongoing work to compare the results of an ECG in a porcine donor heart before and after implantation into a NHP is necessary to better characterize variables that may be at play in the function of the conduction system.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"31 6","pages":"e70005"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649085","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":"Xenotransplantation in the Age of Genome Editing: Results From the Expert Report for the Federal Ethics Committee on Nonhuman Biotechnology With a Special Focus on Animal Ethics.","authors":"Samuel Camenzind","doi":"10.1111/xen.70008","DOIUrl":"10.1111/xen.70008","url":null,"abstract":"<p><strong>Background: </strong>The Federal Ethics Committee on Non-Human Biotechnology (ECNH) of Switzerland is an independent expert committee appointed by the Federal Council and mandated to advise the federal authorities from an ethical perspective in the field of nonhuman biotechnology and gene technology. Due to recent developments in the field of xenotransplantation after the introduction of genome editing technologies, the ECNH has commissioned an expert report on the ethical questions of xenotransplantation with a focus on animal ethics. The subject of the inquiry is, in particular, if current developments in the field of xenotransplantation raise new questions regarding ethics in the nonhuman realm or if existing questions have to be re-examined and answered anew.</p><p><strong>Methods: </strong>An interdisciplinary approach was applied to answer this question. Based on the latest empirical results from medicine and biotechnology, xenotransplantation is analyzed and evaluated with reference to the dignity of the creature (Würde der Kreatur)-which is defined in the Swiss Federal Constitution-and the dignity of animals (Tierwürde) that is stipulated in the Swiss Animal Welfare Act and the Federal Act on Non-Human Gene Technology, as well as contemporary positions in the ethics of the human-animal relationship.</p><p><strong>Results: </strong>The report concludes that genome editing for xenotransplantation does not generate any qualitatively new ethical issues concerning ethics in the nonhuman realm. However, contemporary biotechnological developments must be taken as an opportunity to discuss existing ethical issues in an urgent and intensified manner, particularly regarding the significance of animals' moral standing. The lack of consideration of animal-related aspects and the neglect of current developments and the state of the art of animal ethics in the recent discussion about xenotransplantation is a scientific, ethical, and political issue because animals are most negatively affected by xenotransplantation. This is especially relevant because the contemporary state of the art in animal ethics tends to consider and protect animals more strongly than in the past.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"31 6","pages":"e70008"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11648062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830077","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":"Ultrasound Assessment of Pleural Effusions After Orthotopic Pig-to-Baboon Cardiac Xenotransplantation.","authors":"Martin Bender, Julia Radan, Bruno Reichart, Maria Leuschen, Felicia Wall, Maren Mokelke, Elisabeth Neumann, Ines Buttgereit, David Ayares, Eckhard Wolf, Paolo Brenner, Jan-Michael Abicht, Matthias Längin","doi":"10.1111/xen.70006","DOIUrl":"10.1111/xen.70006","url":null,"abstract":"<p><strong>Background: </strong>Pleural effusions develop frequently after cardiac surgery in humans. Lung ultrasound is an essential non-invasive tool in the diagnosis and treatment of these effusions. Pleural effusions also develop regularly after preclinical cardiac xenotransplantation experiments. Unlike in the human setting, modern ultrasound devices lack pre-installed tools for calculating the volume of pleural effusions in baboons. The aim of this study was to analyze ultrasound examinations of pleural effusions after orthotopic pig-to-baboon cardiac xenotransplantation experiments in order to develop a formula for calculating the effusion volume based on ultrasound measurements.</p><p><strong>Methods: </strong>Hearts from seven genetically modified (GGTA1-KO, hCD46/hTBM transgenic) juvenile pigs were orthotopically transplanted into male baboons. Postoperatively, the baboons were tested regularly for the development of pleural effusions using ultrasound. When thoracocentesis was required, the drained effusion volume (EV) was compared to ultrasound-derived calculations using various formulas. These calculations were based on measuring the distance between lung and diaphragm at the effusions' maximum height (H_max). Subsequently, the most promising formula was used to describe the interobserver variability between trained and untrained staff members to predict effusion volumes based on ultrasound measurements.</p><p><strong>Results: </strong>Ultrasound measurement correlated very strongly with the absolute EV (r = 0.9156, p < 0.0001), with EV indexed to total body weight (r = 0.9344, p < 0.0001) and with EV indexed to body surface area (BSA) (r = 0.9394, p < 0.0001). The ratio between H_max and EV increased with total body weight and BSA and also depended on the baboon species. The sonographic measurements taken by an experienced and an inexperienced observer showed only low interobserver variability. A Bland-Altman plot of both observers' measurements showed an overall bias of -2.39%.</p><p><strong>Conclusion: </strong>Ultrasound imaging provides a simple and non-invasive tool for measuring pleural effusion quantity in baboons. This facilitates simple and efficient monitoring even in the hands of untrained personnel and may guide the decision-making to perform thoracocentesis.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"31 6","pages":"e70006"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649087","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":"Distinct Pro-Inflammatory Species-Specific Transcriptional Changes in Human T Cells Following Pig Xenogeneic Stimulation.","authors":"Khodor I Abou-Daya, Mouhamad Al Moussawy, Masahiko Kubo, Lien Lu, Angelica Perez-Gutierrez, Mohamed B Ezzelarab","doi":"10.1111/xen.70007","DOIUrl":"10.1111/xen.70007","url":null,"abstract":"<p><p>Conventional T cell-directed immunosuppression is the mainstay of standard-of-care therapy to prevent graft rejection in clinical organ transplantation. However, it remains ineffective in preventing experimental and clinical organ xenograft rejection. Here, we explored the impact of allogeneic versus xenogeneic antigen stimulation on human T cell responses and gene profile. A comparable proliferative human T cell response was observed in vitro following stimulation with either human or pig cells. Yet, elevated High mobility group box-1 (HMGB1) levels were following xenogeneic but not allogeneic stimulation, suggesting a pro-inflammatory response. Next, human peripheral blood mononuclear cells (PBMC) were cultured with allogeneic human, \"concordant\" xenogeneic monkey, or \"discordant\" xenogeneic pig, intact cells, or cell lysates. Flow-sorted CD3⁺T cells were analyzed for gene expression using NanoString. A distinct pro-inflammatory gene profile was observed in human CD3⁺T cells following co-culture with discordant xenogeneic pig cells, but not concordant xenogeneic monkey cells or allogeneic human cells. Uniquely, stimulation with pig cells induced the expression of the transcription factor NCF4, which promotes inflammasome activation. Pig cell lysate, but not intact pig cells, induced high expression of the DNA-binding cytokine interleukin-26 gene. Collectively, these observations highlight the impact of xenogeneic stimulation of human T cells in pig xenograft recipients and concomitant inflammatory responses, which may contribute to immunosuppression-resistant xenograft rejection. Finally, the impact of genetic engineering of donor pigs on human T cell transcriptomic gene profile is yet to be determined.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"31 6","pages":"e70007"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11648065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830075","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":"Ethical Implications of Social Science Research on Xenotransplantation.","authors":"Johannes Kögel, Paulina Ernst, Jochen Sauermeister, Georg Marckmann","doi":"10.1111/xen.70004","DOIUrl":"10.1111/xen.70004","url":null,"abstract":"<p><p>Social science research has generated extensive knowledge on xenotransplantation, encompassing the perspectives of actual and potential patients, other stakeholders, public opinion and debate, human-animal relationships, animal production and husbandry, bioeconomy, as well as biotechnology governance and regulation. We therefore convened social science researchers to discuss the latest developments in xenotransplantation research and practice in late 2023. Based on a brief workshop report, we aim to highlight the various ethical implications of this debate. After outlining the role of social science research in the ethical evaluation of xenotransplantation, we elaborate three critical points that may become pivotal in the future evolution of xenotransplantation: the framing of xenotransplantation in the clinical setting and in the public, the potential impact of religious beliefs on patients' transplant choices, and the consequences for the allotransplantation system if xenotransplantation becomes clinically established, including the allocation of allo- and xeno-organs.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"31 6","pages":"e70004"},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628876","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":"Xenotransplantation Literature Update December 2023–June 2024","authors":"Shani Kamberi, Raphael P. H. Meier","doi":"10.1111/xen.12883","DOIUrl":"https://doi.org/10.1111/xen.12883","url":null,"abstract":"This updated report highlights significant developments in the field of xenotransplantation since December 2023. Over the past 6 months, there has been a notable increase in discussions regarding the feasibility of clinical trials, with particular emphasis on their progression and associated ethical considerations. This review presents the most pertinent findings from December 2023 to June 2024.","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"2 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260080","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}