Antiviral research最新文献

{"title":"Combinations of approved oral nucleoside analogues confer potent suppression of alphaviruses in vitro and in vivo","authors":"Sam Verwimp ,&nbsp;Jessica Wagoner ,&nbsp;Elijah Gabriela Arenas ,&nbsp;Lander De Coninck ,&nbsp;Rana Abdelnabi ,&nbsp;Jennifer L. Hyde ,&nbsp;Joshua T. Schiffer ,&nbsp;Judith M. White ,&nbsp;Jelle Matthijnssens ,&nbsp;Johan Neyts ,&nbsp;Stephen J. Polyak ,&nbsp;Leen Delang","doi":"10.1016/j.antiviral.2025.106186","DOIUrl":"10.1016/j.antiviral.2025.106186","url":null,"abstract":"<div><div>Alphaviruses, including chikungunya virus (CHIKV), pose a significant global health threat, yet specific antiviral therapies remain unavailable. We evaluated combinations of three oral directly acting antiviral drugs (sofosbuvir (SOF), molnupiravir (MPV), and favipiravir (FAV)), which are approved for other indications, against CHIKV, Semliki Forest virus (SFV), Sindbis virus (SINV), and Venezuelan Equine Encephalitis virus (VEEV) <em>in vitro</em> and <em>in vivo</em>. We assessed antiviral efficacy in human skin fibroblasts and liver cells, as well as in a mouse model of CHIKV-induced arthritis. In human skin fibroblasts, synergistic antiviral effects were observed for combinations of MPV + SOF and FAV + SOF against CHIKV, and for FAV + SOF against SFV. In human liver cells, FAV + MPV conferred additive to synergistic activity against VEEV and SINV, while SOF synergized with FAV against SINV. In mice, MPV improved CHIKV-induced foot swelling and reduced systemic infectious virus titres. Combination treatment with MPV and SOF significantly reduced swelling and infectious titres compared to monotherapies of each drug. Sequencing of CHIKV RNA from joint tissue revealed that MPV caused dose-dependent increases in mutations in the CHIKV genome. Upon combination therapy of MPV with SOF, the number of mutations was significantly lower compared to monotherapy with several higher doses of MPV. Combining these approved oral nucleoside analogues confers potent suppression of multiple alphaviruses <em>in vitro</em> and <em>in vivo</em> with enhanced control of viral genetic evolution in face of antiviral pressure. These drug combinations may ultimately lead to the development of potent combinations of pan-family alphavirus inhibitors.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"239 ","pages":"Article 106186"},"PeriodicalIF":4.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144072362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic and safety evaluation of lipopeptide-based HIV fusion inhibitor Lipovirtide in rats","authors":"Yuanmei Zhu ,&nbsp;Huihui Chong ,&nbsp;Nian Liu,&nbsp;Yuxian He","doi":"10.1016/j.antiviral.2025.106187","DOIUrl":"10.1016/j.antiviral.2025.106187","url":null,"abstract":"<div><div>Lipovirtide, originally designated as LP-80, is a stearic acid-modified lipopeptide HIV fusion inhibitor with highly potent and long-lasting anti-HIV activity, and it has already progressed to phase II clinical trials. In this report, we investigated the pharmacokinetics and safety profile of LP-80 in Sprague Dawley (SD) rats. LP-80 was absorbed rapidly following subcutaneous injection, exhibiting high absolute bioavailability (F): 92.32 % in male and 84.74 % in female. The time to reach maximum plasma concentration (T_max) ranged from 5.5 to 8 hours (h), and the elimination half-life (T_1/2) was between 6.26 and 7.47 h, indicating a relatively long-lasting presence in the bloodstream. LP-80 was widely distributed across various tissues, with the highest concentration observed in serum, suggesting effective systemic delivery and potential for targeting HIV in different compartments. Only a minimal amount of the parent drug was excreted in feces and urine, which indicates that LP-80 is metabolically stable and not rapidly cleared from the body. Acute, subchronic, and chronic toxicity studies demonstrated that LP-80 was well tolerated in animals, with no significant adverse effects observed. No anti-drug antibodies (ADA) were detected, suggesting low immunogenicity. Furthermore, LP-80 showed no toxic effects on fertility, embryo-fetal development, or offspring development. Collectively, our studies demonstrate that LP-80 is metabolically stable and exhibits a favorable safety profile, supporting its advancement into clinical trials for HIV treatment.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"239 ","pages":"Article 106187"},"PeriodicalIF":4.5,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143949060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing human liver spheroids as a model for antiviral drug evaluation against BSL-3 haemorrhagic fever viruses","authors":"Sarah Chaput ,&nbsp;Jean-Sélim Driouich ,&nbsp;Simon Gruber ,&nbsp;Donna Busler ,&nbsp;Xavier de Lamballerie ,&nbsp;Antoine Nougairède ,&nbsp;Franck Touret","doi":"10.1016/j.antiviral.2025.106188","DOIUrl":"10.1016/j.antiviral.2025.106188","url":null,"abstract":"<div><div>Haemorrhagic fever viruses (HFVs) cause highly lethal syndromes with limited therapeutic options. Increasingly, 3D cell culture models are becoming an important tool in the field of virology. Since the liver is an important target for many HFVs, we evaluated a ready-to-use 96-well liver spheroid model composed of human primary cells for antiviral assessment. We worked with four biosafety level 3 (BSL-3) HFVs in this study: two orthoflaviviruses, Alkhumra haemorrhagic fever virus (AHFV) and yellow fever virus (YFV), and two viruses belonging to <em>Hareavirales</em> order, Pirital virus (PIRV), a surrogate for new-world BSL-4 mammarenaviruses, and Rift Valley fever virus (RVFV). We found that RVFV and PIRV were able to replicate in this model, whereas the orthoflaviviruses were not. A high viral dose was required for robust replication, and infectivity of RVFV in spheroids was low. We successfully demonstrated the antiviral activity of known broad-spectrum antiviral compounds—favipiravir, nitazoxanide, ribavirin, and galidesivir—despite some variability. However, except for ribavirin, higher doses were required in spheroids to detect antiviral effect compared to the 2D cell culture model. Overall, we conclude that human liver spheroids cannot replace traditional models for the selection of antiviral compounds but provide valuable additional complementary information. More broadly, this model could be useful to study viral pathogenicity and host-pathogen interactions.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"239 ","pages":"Article 106188"},"PeriodicalIF":4.5,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploiting Host Kinases to Combat Dengue Virus Infection and Disease.","authors":"Natasha M Bourgeois, Ling Wei, Alexis Kaushansky, John D Aitchison","doi":"10.1016/j.antiviral.2025.106172","DOIUrl":"https://doi.org/10.1016/j.antiviral.2025.106172","url":null,"abstract":"<p><p>The burden of dengue on human health has dramatically increased in recent years, underscoring the urgent need for effective therapeutic interventions. Despite decades of research since the discovery of the dengue virus, no specific antiviral treatments are available and strategies to reliably prevent severe disease remain limited. Direct-acting antivirals against dengue are under active investigation but have shown limited efficacy to date. An underappreciated Achille's heal of the virus is its dependence on host factors for infection and pathogenesis, each of which presents a potential avenue for therapeutic intervention. We and others have demonstrated that dengue virus relies on multiple host kinases, some of which are already targeted by clinically approved inhibitors. These offer drug repurposing opportunities for host-directed dengue treatment. Here, we summarize findings on the role of kinases in dengue infection and disease and highlight potential kinase targets for the development of innovative host-directed therapeutics.</p>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":" ","pages":"106172"},"PeriodicalIF":4.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of the polymerase acidic protein E199K substitution in influenza A viruses on baloxavir susceptibility","authors":"Emi Takashita ,&nbsp;Yoshihiro Yasui ,&nbsp;Asaka Ikegaya ,&nbsp;Kyohei Saka ,&nbsp;Noriyuki Maeshiro ,&nbsp;Hiroko Morita ,&nbsp;Shiho Nagata ,&nbsp;Seiichiro Fujisaki ,&nbsp;Hideka Miura ,&nbsp;Noriko Kishida ,&nbsp;Kazuya Nakamura ,&nbsp;Masayuki Shirakura ,&nbsp;Shinji Watanabe ,&nbsp;Hideki Hasegawa","doi":"10.1016/j.antiviral.2025.106173","DOIUrl":"10.1016/j.antiviral.2025.106173","url":null,"abstract":"<div><div>Baloxavir marboxil, a cap-dependent endonuclease inhibitor, was approved in Japan in 2018 for the treatment and prophylaxis of influenza. Its active form, baloxavir acid, binds to the polymerase acidic (PA) protein endonuclease domain, inhibiting viral RNA cleavage. PA substitutions (e.g., E23K, I38T, E199G) have been associated with reduced susceptibility to baloxavir. During nationwide monitoring in Japan, we identified influenza A(H1N1)pdm09 and A(H3N2) viruses carrying a PA E199K substitution. Database analysis revealed that PA E199K is rare, detected in only 0.01 % of A(H1N1)pdm09 and A(H3N2) viruses. Because its impact on baloxavir susceptibility has not been reported, here, we characterized PA E199K mutant viruses in vitro. Phenotypic analysis showed a 5.0–5.2-fold increase in baloxavir EC₅₀ values in PA E199K mutants, indicating reduced baloxavir susceptibility similar to PA E199G. However, replication efficiency of PA E199K mutants was significantly lower than wild-type viruses, suggesting impaired viral fitness. Unlike PA E199G, PA E199K introduces charge and steric changes that may further reduce replication capacity. While PA E199G mutants have led to a community cluster, PA E199K has only been detected sporadically, likely due to its greater impairment of viral replication. The PA E199K mutants were susceptible to neuraminidase inhibitors. Given the increasing global use of baloxavir, continuous monitoring of resistance-associated substitutions is essential for public health and clinical management.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"239 ","pages":"Article 106173"},"PeriodicalIF":4.5,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influenza A(H1N1)pdm09 virus resistance to baloxavir, oseltamivir and sialic acid mimetics in single and dual therapies: Insights from human airway epithelia and murine models","authors":"Clément Fage ,&nbsp;Sheryline Loison ,&nbsp;Arnaud Charles-Antoine Zwygart ,&nbsp;Romain Poli ,&nbsp;Stéphane Rosset ,&nbsp;Chiara Medaglia ,&nbsp;Mathieu Hubert ,&nbsp;Patricia Suter-Boquete ,&nbsp;Oscar Vadas ,&nbsp;Song Huang ,&nbsp;Samuel Constant ,&nbsp;Paulo Silva ,&nbsp;Francesco Stellacci ,&nbsp;Sophie Clément ,&nbsp;Caroline Tapparel","doi":"10.1016/j.antiviral.2025.106174","DOIUrl":"10.1016/j.antiviral.2025.106174","url":null,"abstract":"<div><div>Influenza viruses pose a significant threat due to annual epidemics and pandemic potential. Resistance to current antivirals underscores the need for new drugs and strategies to prevent its emergence. We previously developed two novel HA-targeting compounds (CD-6′SLN and CD-SA) with demonstrated efficacy against influenza A and B strains. Here, we compared their resistance barrier to that of FDA-approved oseltamivir (OS) and baloxavir marboxil (BXM). We established a resistance testing assay in human airway epithelia (HAE) and in mice. We also evaluated the impact of combination therapies on resistance emergence. In HAE, highly reduced inhibition (HRI) by CD-6′SLN and CD-SA occurred within 2 and 4 weeks respectively without fitness loss, while reduced inhibition (RI) by baloxavir acid (BXA) emerged within 4 weeks. No reduction of susceptibility to OS was observed in the same time frame. Of note, emergence of RI by CD-SA was not delayed in BXA/CD-SA co-treatment, and slightly reduced upon OS/CD-SA co-treatment. In mice, RI by CD-SA was observed after 8 passages in one of three mice treated with OS/CD-SA, but not in mice with single therapies. This study demonstrates that (1) HAE represents a relevant model to detect emergence of resistance and (2) HA-targeting compounds are prone to induce resistance followed by BXA and OS. Importantly, combination of clinically available antivirals and HA-targeting compounds did not prevent the emergence of variants with HA substitutions. Additional research is needed to develop anti-influenza antivirals with high resistance barrier and compounds should be tested in HAE before moving to animal experimentation.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"239 ","pages":"Article 106174"},"PeriodicalIF":4.5,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143918031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptides designed based on 3C substrates exhibit antiviral efficacy in vivo","authors":"Yutong Liu ,&nbsp;Chang Wang ,&nbsp;Huoyan Tong ,&nbsp;Xi Zhou ,&nbsp;Yuan Fang","doi":"10.1016/j.antiviral.2025.106185","DOIUrl":"10.1016/j.antiviral.2025.106185","url":null,"abstract":"<div><div>Enteroviruses are a large group of positive-sense single-stranded RNA viruses including numerous human pathogens such as enterovirus A71 (EV-A71), coxsackieviruses, and echoviruses. The diseases caused by these enteroviruses pose a significant threat to global public health. The 3C protein is a crucial protease in enteroviruses, responsible for cleaving the viral polyprotein into individual active proteins. This process is essential for viral replication and pathogenesis, making 3C an attractive target for the development of anti-enteroviral drugs. In this study, we designed and screened peptides based on the sequences of several substrates of the 3C protease, aiming to impact the function of the 3C protease and thereby exert antiviral effects. Ultimately, we obtained a peptide with good antiviral activity at the cellular level, which we named vp23. This peptide effectively disrupted the protease activity of 3C, provided significant <em>in vivo</em> protection against EV-A71, and possessed strong antiviral effects against multiple enteroviruses such as EV-A71, Coxsackievirus A16 (CV-A16), and Echovirus 11 (Echo 11). Taken together, our results suggest that targeting 3C proteases using rationally designed peptides is an effective antiviral strategy against enteroviruses.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"239 ","pages":"Article 106185"},"PeriodicalIF":4.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143903540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical arsenal for helicase Hunters: Striking the toughest targets in antiviral research","authors":"Holli-Joi Martin ,&nbsp;Mohammad Anwar Hossain ,&nbsp;James Wellnitz ,&nbsp;Enes Kelestemur ,&nbsp;Joshua E. Hochuli ,&nbsp;Sumera Perveen ,&nbsp;Cheryl Arrowsmith ,&nbsp;Timothy M. Willson ,&nbsp;Eugene N. Muratov ,&nbsp;Alexander Tropsha","doi":"10.1016/j.antiviral.2025.106184","DOIUrl":"10.1016/j.antiviral.2025.106184","url":null,"abstract":"<div><div>Helicases have emerged as promising targets in antiviral drug development but remain largely undrugged. To support the focused development of viral helicase inhibitors we identified, collected, and integrated all chemogenomics data for all helicases annotated in the ChEMBL database. After thoroughly curating and enriching the data with accurate annotations we have created a derivative database of helicase inhibitors which we dubbed Heli-SMACC (Helicase-targeting SMAll Molecule Compound Collection). Heli-SMACC contains 13,597 molecules, 29 proteins, and 20,431 bioactivity entries for viral, human, and bacterial helicases. We selected 30 compounds with promising viral helicase activity and tested them in a SARS-CoV-2 NSP13 ATPase assay. Twelve compounds demonstrated ATPase inhibition and a consistent dose-response curve. While Heli-SMACC provides a rich resource for identifying candidate inhibitors, cross-species compound transferability remains a significant challenge. In particular, inhibitory activity observed against viral helicases often does not translate well to human or bacterial homologs and vice versa due to differences in binding site composition, helicase structure, and cofactor dependencies. Despite these limitations, Heli-SMACC offers a valuable starting point for structure-based optimization and target-specific inhibitor design. The Heli-SMACC database may serve as a reference for virologists and medicinal chemists working on the development of novel helicase inhibitors. Heli-SMACC is publicly available at <span><span>https://smacc.mml.unc.edu</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"239 ","pages":"Article 106184"},"PeriodicalIF":4.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ISAR opinion: Product development partnerships to fund pandemic antiviral research","authors":"Luis M. Schang,&nbsp;the International Society for Antiviral Research (ISAR)","doi":"10.1016/j.antiviral.2025.106166","DOIUrl":"10.1016/j.antiviral.2025.106166","url":null,"abstract":"","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"238 ","pages":"Article 106166"},"PeriodicalIF":4.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined doravirine and islatravir cooperate to inhibit NRTI and NNRTI resistant HIV-1 in vitro","authors":"Federica Giammarino ,&nbsp;Chiara Paletti ,&nbsp;Niccolò Bartolini ,&nbsp;Lia Fiaschi ,&nbsp;Camilla Biba ,&nbsp;Ilenia Varasi ,&nbsp;Emanuele Focà ,&nbsp;Roberto Gulminetti ,&nbsp;Micol Ferrara ,&nbsp;Laura Comi ,&nbsp;Ilaria Vicenti ,&nbsp;Antonella Castagna ,&nbsp;Maurizio Zazzi ,&nbsp;Francesco Saladini ,&nbsp;PRESTIGIO Study Group","doi":"10.1016/j.antiviral.2025.106157","DOIUrl":"10.1016/j.antiviral.2025.106157","url":null,"abstract":"<div><div>Doravirine and islatravir have shown promising activity against multidrug resistant HIV-1. In this study we aimed to evaluate the <em>in vitro</em> susceptibility to doravirine and islatravir as well as their combinatorial activity in a panel of 38 recombinant viruses harboring multiple NRTI and NNRTI mutations. One additional recombinant virus had the M184V mutation alone. According to the IC₅₀ fold-change (FC) values calculated with respect to the NL4-3 wild-type strain, full susceptibility to doravirine was detected in 15/39 (38.5 %) samples, while high-level resistance was mainly associated with specific doravirine resistance mutations. Decreased susceptibility to islatravir was associated with the presence of the M184V/I mutation and increasing numbers of TAMs and NRTI resistance mutations. According to ZIP model of the SynergyFinder Plus tool, the combination of doravirine and islatravir showed additive activity in 37/40 (92.5 %) viruses (including the NL4-3 strain), while synergy and antagonism in one and two cases, respectively. The combination sensitivity score calculated by SynergyFinder Plus indicated a cooperative effect between doravirine and islatravir higher than that observed for the reference NL4-3 strain in 22 (56 %) recombinant viruses. The Multi-dimensional Synergy of Combinations (MuSyC) tool predicted synergy and antagonism in 25 (62.5 %, including NL4-3 virus) and 15 (37.5 %) cases, respectively. MuSyC scores showed a negative correlation with doravirine FC values, number of NRTI mutations and presence of M184V/I, but not with islatravir FC values. Doravirine and islatravir may cooperatively inhibit NRTI and NNRTI resistant viruses despite complex mutational profiles, however the accumulation of resistance mutations may reduce the combinatorial activity.</div></div>","PeriodicalId":8259,"journal":{"name":"Antiviral research","volume":"239 ","pages":"Article 106157"},"PeriodicalIF":4.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}