AAPS Journal最新文献

{"title":"Immunogenicity in Approved Adeno-Associated Virus-Based Gene Therapies: A Framework for a Tailored Assessment Strategy.","authors":"Ching-Ha Lai, Susan C Irvin, Laura I Salazar-Fontana, Christine Grimaldi, Boris Gorovits, Yuanxin Xu, Michael A Partridge","doi":"10.1208/s12248-026-01303-1","DOIUrl":"10.1208/s12248-026-01303-1","url":null,"abstract":"<p><p>Adeno-associated virus (AAV)-based gene therapy has emerged as a promising approach for treating a variety of genetic disorders by delivering therapeutic genes to target tissues. There have been numerous publications reporting nonclinical assessments of immune responses to various AAV-based gene therapy products (GTPs). However, the immune response data from approved GTPs in humans have not been systematically reviewed, and the utility of the data generated in these clinical studies has not been evaluated. This manuscript is intended as a comprehensive review of the nonclinical and clinical immunogenicity data, with focus on adaptive immunity, from nine AAV-based GTPs approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) between 2017 and early 2026. It also offers science-based recommendations to inform the future development of GTPs. The accumulated experience from these approved GTPs support a tailored, risk-based approach to immunogenicity monitoring: pre-existing anti-vector antibodies show limited association to clinical response and cellular immune response measurement via ELISpot have practical limitations in clinical studies. These findings advocate for simplified analytical strategies - tailored to the drug development stage and informed by nonclinical data - that incorporate clinical safety markers such as liver function tests, cardiac damage markers, and transgene protein expression as indicators of clinically meaningful immune responses.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148921730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring a Persistent Terbinafine - CYP2D6 Interaction Using Physiologically - Based Pharmacokinetic Modeling.","authors":"Devendra Pade, Jan Wahlstrom","doi":"10.1208/s12248-026-01288-x","DOIUrl":"10.1208/s12248-026-01288-x","url":null,"abstract":"<p><p>Terbinafine (TBNF), a lipophilic anti-fungal agent prescribed for onychomycosis distributes extensively into adipose, skin and peripheral tissues. TBNF and metabolite desmethyl terbinafine (DMT) are potent inhibitors of CYP2D6. A combination of prolonged half-life and CYP2D6 inhibition causes clinically significant interactions with drugs involving CYP2D6 metabolism that may persist for weeks after dosing cessation. A physiologically based pharmacokinetic (PBPK) model for TBNF and DMT incorporating in vitro and clinical information was developed and verified to predict their steady state pharmacokinetics. Experimentally determined Ki_u,CYP2D6 for TBNF and DMT enabled to predict the interaction with CYP2D6 substrates Desipramine, Amitriptyline and Nortriptyline. The PBPK model predicted steady-state plasma concentration-time profiles of TBNF and DMT after daily administration of 250 mg and 125 mg TBNF were in agreement with the observed data, including sustained plasma concentrations after dosing cessation. This enabled prediction of drug interactions with the CYP2D6 substrates during and after termination of TBNF dosing. The distribution of TBNF into adipose and skin acts as a depot leading to its slow re-distribution back into plasma, followed by sequential metabolism to DMT and CYP2D6 inhibition. The model was validated against data from three independent drug interaction reports. This PBPK framework can be applied in different clinical pharmacology settings for drugs characterized by extensive distribution, formation rate limited metabolism and enzyme inhibition. The framework provides applicability in informing the rational design of clinical trials where sustained plasma drug levels warrant patient monitoring long after termination of dosing.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148921693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vitro Release Testing for Long Acting Injectables - a Workshop Summary Report.","authors":"Talia Flanagan, Diane Burgess, Marieta Duvnjak, Nikoletta Fotaki, Kate Harris, Krutika Meena Harish Jain, Dawen Kou, Adam McCartan, Heather Mead, Johanna Milsmann, Randy Mrsny, Vasiliki Paraskevopoulou, Sharadvi Thati, Marta Venczel, David Curran","doi":"10.1208/s12248-026-01278-z","DOIUrl":"10.1208/s12248-026-01278-z","url":null,"abstract":"<p><p>A three-session webinar series was held by the IQ Consortium in early May 2023 on the topic of in vitro release testing of long acting injectable and parenteral (non-oral) drug products. Attendance was excellent, indicating the high level of interest in this topic. This paper provides a high-level overview of the talks that were given during the webinar and the open discussion session.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-step Sintered 3D-printed Fixed-dose Combined Bilayer Tablets for Compartmentalized Delivery of First-line Anti-tubercular Drugs.","authors":"Tukaram Ram Karanwad, Saurabh Bodake, Sachin B Jorvekar, Santa Mandal, Roshan M Borkar, Subham Banerjee","doi":"10.1208/s12248-026-01286-z","DOIUrl":"10.1208/s12248-026-01286-z","url":null,"abstract":"<p><p>The bioavailability of Rifampicin (RIF) in fixed-dose combination (FDC) with Isoniazid (INH) poses a significant challenge in tuberculosis therapy due to RIF's rapid degradation under gastric conditions when co-administered with INH, resulting in subtherapeutic plasma levels and compromised therapeutic efficacy. To overcome this issue, we developed a novel Selective Laser Sintering (SLS)-mediated 3D printing approach using SmartEx QD 100 and Eudragit L 100-55 polymers. This advanced technique enabled the fabrication of compartmentalized FDC 3D printed bilayer tablets, designed to release INH in the stomach and RIF in the intestine, thereby preserving RIF stability while maintaining synergistic drug action. The bilayer tablets met pharmacopeial standards for dimensional accuracy, weight variation, friability, and hardness, with adequate tensile and shear strength for ease of handling. Micro-CT and SEM-EDX analysis confirmed uniform pore formation, drug distribution, and successful interlayer fusion. In vitro dissolution demonstrated complete release of INH within 45 min in the gastric region, while RIF exhibited minimal release in the gastric environment and sustained release in the intestinal region. Pharmacokinetic studies in New Zealand white rabbits indicated INH and RIF achieved respective C_max values of 432.00 ± 109.16 ng/mL and 84.57 ± 43.79 ng/mL, with distinct T_max profiles supporting compartmentalized release. This study concludes with the transformative potential of SLS-mediated 3D printing in developing personalized, stable, and effective anti-tuberculosis therapies. By ensuring precise compartmentalized drug delivery, this innovation enhances treatment outcomes, improves patient compliance, and offers a promising platform for future advancements in complex drug delivery systems.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148914292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melittin-modified Paclitaxel Liposomes as a Synergistic Strategy for Anti-keloid Therapy.","authors":"Haozhong Luo, Wenxiu Pan, Wenxue Liu, Yuchen Zhang, Meijuan Zou, Hongyu Piao","doi":"10.1208/s12248-026-01282-3","DOIUrl":"10.1208/s12248-026-01282-3","url":null,"abstract":"<p><p>To address the challenges associated with keloid pharmacotherapy, we developed a melittin (MEL)-modified paclitaxel (PTX) liposomal delivery system as a reconstitutable lyophilized formulation intended for subcutaneous injection. MEL, an amphipathic membrane-active peptide, was incorporated as a functional component to enhance liposome-cell interactions and facilitate intracellular delivery of PTX. This design aimed to improve the in vitro anti-keloid activity of PTX liposomes while providing a lyophilized injectable formulation suitable for reconstitution before use. After MEL modification, the zeta potential shifted upward with increasing MEL content, supporting MEL surface modification of PTX liposomes through electrostatic interactions. Moreover, freeze-dried MEL-modified PTX liposomes showed comparable particle size, zeta potential, and release behavior to the original liposomes. Although the encapsulation efficiency (EE%) of PTX and the modification efficiency (ME%) of MEL were slightly reduced after lyophilization, the formulation maintained good storage stability at 4 ± 2°C for 6 months. Confocal microscopy and flow cytometry analyses using coumarin 6 (C6) instead of PTX showed enhanced cellular uptake in human keloid fibroblasts (HKF). The CCK-8 assay indicated that although MEL-Liposome (600:1) alone did not obviously inhibit HKF proliferation under the tested conditions, MEL-PTX-Liposome (600:1) showed significantly stronger antiproliferative activity than PTX-Liposome. Specifically, MEL-PTX-Liposome (600:1) reduced HKF cell migration to 16.8% (control, 92.6%; PTX-Liposome, 36.9%), representing a significant improvement over PTX-Liposome. These findings support MEL-modified PTX liposomes as a promising reconstitutable lyophilized injectable formulation for subcutaneous anti-keloid therapy and provide a formulation basis for further translational development.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148914280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding Nonlinearities in AAV-Based Gene Therapy Using PBPK Modelling.","authors":"Aneesh Rajwade, Shufang Liu, Mokshada Kumar, Dhaval K Shah","doi":"10.1208/s12248-026-01285-0","DOIUrl":"10.1208/s12248-026-01285-0","url":null,"abstract":"<p><p>The objective of this research was to develop a physiologically based pharmacokinetic (PBPK) model for AAV-based gene therapy, which can capture the nonlinearity observed in both viral vector and transgene product pharmacokinetics (PK) across a wide range of doses, while accounting for the effect of immunogenicity. To develop the PBPK model, previously published PK data generated in mice using AAV8 vector containing the transgene for a non-binding monoclonal antibody was used. Immunocompetent mice were administered with AAV at a wide range of doses (1E8, 1E9, 5E9, 1E10, 2E10, 1E11, 2E11, 1E12, and 1E13vg per mouse), and the PK of transgene and transgene product (i.e., antibody) in plasma and/or tissue was collected. The nonlinearity in transgene product concentrations was characterized using a saturable production process and a concentration-dependent antibody elimination rate was used to characterize the effect of anti-drug antibody (ADA) on transgene product. The model successfully described the PK of both the vector and the transgene product across all dose levels and accurately captured the sigmoidal dose-exposure-response relationship for AAV. Notably, the model described a dose-dependent ADA response, with the high dose group exhibiting an earlier onset and faster rate of transgene product elimination. Lower dose group showed delayed onset and minimal ADA-mediated elimination of transgene product. Overall, the PBPK model presented here effectively characterizes vector and transgene product kinetics in mice and demonstrates utility in preclinical-to-clinical translation and dose optimization of AAV-based gene therapies.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148914244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting Cannabidiol Pharmacokinetics in Older Adults Via Physiologically Based Pharmacokinetic Modeling.","authors":"Lixuan Qian, Aiden-Hung P Nguyen, Mary F Paine, Zhu Zhou","doi":"10.1208/s12248-026-01281-4","DOIUrl":"10.1208/s12248-026-01281-4","url":null,"abstract":"<p><p>Cannabidiol (CBD) use continues to increase, particularly among older adults. However, knowledge of CBD disposition in this ever-growing and understudied population, along with the relative contributions of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes to CBD metabolism, remain limited. Inclusion of UGT activators (e.g., alamethicin, MgCl₂) may alter in vitro estimates of enzyme contributions. CBD has also been reported to produce time-dependent inhibition (TDI) of certain CYPs, potentially affecting its own disposition. We combined in vitro data with physiologically based pharmacokinetic (PBPK) modeling to further characterize TDI and reversible CYP inhibition by CBD, quantify the contributions of CYPs and UGTs to CBD metabolism, and determine in vitro assay conditions that best reflect in vivo CBD metabolism. PBPK modeling was next used to extrapolate CBD exposure from young (18-64 years) to older (65-98 years) adults. CBD exhibited TDI only toward CYP1A2, which had a negligible effect on CBD metabolism. Inclusion of alamethicin + MgCl₂ increased the apparent contribution by UGTs to CBD metabolism, leading to an overestimate of UGT-mediated metabolism. PBPK model validation using drug-drug interaction studies supported contributions of 86% and 14% for CYPs and UGTs, respectively, as best capturing observed CBD exposure. Simulations in older adults generally showed increased CBD exposure relative to young adults, with the magnitude depending on age and administration route. Overall, these results improve our understanding of CBD pharmacokinetics, support more informed risk assessment in older adults, and provide a more robust foundation for future studies.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148914265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Neutralizing-antibody Assay for Detection of β-NGF Binding Domain-specific Antibodies Against a β-NGF/TNFR2 Bispecific Therapeutic Antibody.","authors":"Nellie Moshkovich, Anish Bhandari, Enowmpey Enowtambong, Surekha R Krishnan, Lin Yang, Weiping Shao","doi":"10.1208/s12248-026-01298-9","DOIUrl":"10.1208/s12248-026-01298-9","url":null,"abstract":"<p><p>Immunogenicity assessment for therapeutic bispecific antibodies often requires domain-specific characterization, including evaluation of neutralizing antibody (NAb) responses to individual domains. For our beta Nerve Growth Factor (β-NGF)-Tumor Necrosis Factor Receptor 2 (TNFR2) bispecific antibody, anti-drug antibody (ADA) mapping revealed a predominant immune response to the β-NGF binding domain, leading us to explore the correlation of β-NGF domain-specific NAbs with clinical impact. Because drug or target in the sample can interfere with NAb detection, the development of a NAb assay format with sufficient drug and target tolerance is required. To that end, we developed a domain-specific NAb assay, integrating a modified biotin-drug extraction and acid dissociation (BEAD) procedure that includes target blocking to eliminate false-positives. We termed this assay format the \"BEAD with target blocking\" (BEAD-TB) method. The workflow features sequential acid dissociation to liberate drug-bound NAbs, followed by selective enrichment of β-NGF domain-specific Nabs. We conducted a comprehensive assessment to ensure adequate sensitivity, selectivity, drug tolerance (up to 10 μg/mL), target tolerance (up to 10 ng/mL) and robustness for the assay to accurately detect β-NGF binding domian-specific NAbs in ADA-positive patients. Our domain specific NAb assay demonstrated a robust, innovative solution for detecting neutralizing responses in the context of complex bispecific biologics, leading to reliable immunogenicity evaluation in drug development.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148914222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosome-Based Drug Delivery Systems in Colorectal Cancer: Current Evidence and Future Perspectives.","authors":"Lucas Henrique Domingos da Silva, Juliana Ferreira Floriano, Marlus Chorilli","doi":"10.1208/s12248-026-01301-3","DOIUrl":"10.1208/s12248-026-01301-3","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is one of the most common malignant neoplasms worldwide, being the third most frequently diagnosed cancer and the second leading cause of death. Due to the high incidence of CRC cases, its biological complexity, and high morbidity and mortality, the development of more effective and less aggressive therapeutic approaches is an urgent need. Extracellular vesicles (EVs), especially EXs, are a very viable alternative as a nanocarrier for anticancer molecules for the treatment of CRC, as EXs are biologically relevant EVs with considerable therapeutic potential. EXs are nanoscale vesicles approximately 30-200 nm in diameter, identical in composition to the membrane of their parent cells, and carry a bioactive cargo of proteins, lipids, nucleic acids, and glycoconjugates. Beyond their physiological functions, EXs are gaining prominence as next-generation drug delivery platforms. Their ability to improve the efficacy of antitumor therapies, potentially reducing adverse effects associated with conventional chemotherapy and radiotherapy, makes them very promising. Furthermore, functionalizing the surface with targeting ligands, such as MUC1 aptamers, AS1411, or iRGD peptides, can further increase its specificity for CRC cells. Advances in drug delivery techniques, including passive incubation, electroporation, and chemical modification, have enabled the incorporation of conventional chemotherapeutic agents such as doxorubicin, 5-fluorouracil, and SN-38, as well as nucleic acid-based therapies, including microRNA and siRNA. Due to the limitations and invasive nature of current treatments for CRC, new studies to obtain innovative and targeted therapeutic strategies are essential to reduce harmful effects. Therefore, exosome-based drug delivery systems represent a promising and clinically relevant avenue for future cancer therapy.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148914276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Impact of Food Induced Fluid Viscosity on Disintegration and Dissolution of Immediate Release Midodrine HCl Tablet.","authors":"Fathima T Doole, Ranganath Wahalathantrige Don, Ishwor Poudel, Timothy Lex, Yi-Hsien Cheng, Fang Wu, Wei-Jhe Sun, Lei Zhang, Peter Langguth, Wenlei Jiang, Zongming Gao","doi":"10.1208/s12248-026-01291-2","DOIUrl":"10.1208/s12248-026-01291-2","url":null,"abstract":"<p><p>The prediction of bioavailability (BA) and bioequivalence (BE) for immediate-release (IR) solid oral dosage forms is critical during development and post-approval phases of drug products. ICH M13A provides the option of using in vitro tests, such as disintegration and dissolution in biorelevant media, pilot studies, and modeling to justify not conducting in vivo fed BE studies. The gastrointestinal (GI) tract environment changes significantly after food intake, including variations in pH, enzyme activity, and fluid viscosity that influence drug dissolution and absorption. Existing biorelevant dissolution media (FeSSIF, FeSSGF etc.) simulate human GI fluid composition but do not account for food-induced viscosity changes. This study explored impacts of food-induced fluid viscosity (pH 1.2 buffer containing hydroxypropyl methylcellulose (HPMC)) on disintegration and dissolution profiles of midodrine HCl tablets. Using USP Apparatus II and disintegration testing, we evaluated dissolution and disintegration of five approved generic midodrine HCl tablets with demonstrated BE. High-viscosity media significantly delayed tablet disintegration and drug dissolution compared to low-viscosity fasting conditions. We modified dissolution methods to closely simulate fed state GI conditions by varying agitation speed, prolonging dissolution time, adding medium stagewise to simulate dilution of gastric fluid, and adding water to mimic co-administered drinks. Results showed increased dissolution with higher agitation speeds and continued dissolution in viscous media over extended time. Stagewise dissolution in medium with reduced viscosity to mimic gastric secretion did not accelerate drug release compared to viscous media. In contrast, co-administered water enabled tablet swelling and disintegration, leading to complete drug release within 15 min, which is more consistent with the in vivo PK data under fed conditions. These findings may help refine in vitro dissolution conditions to better mimic fed-state.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148914296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}