Toxicological Sciences最新文献

{"title":"A twin transition in regulatory toxicology: moving toward Chemicals 2.0 and phasing out animal testing.","authors":"Andrew P Worth, Elisabet Berggren","doi":"10.1093/toxsci/kfae130","DOIUrl":"10.1093/toxsci/kfae130","url":null,"abstract":"<p><p>The European regulatory framework on chemicals is at a crossroads. There are calls for the framework to be more effective, by better protecting people and the environment. There is also room for it to be more efficient and cost-effective, by harmonizing assessment practices across sectors and avoiding the need for unnecessary testing. At the same time, there is a political commitment to phase out animal testing in chemical safety assessments. In this commentary, we argue that these needs are not at odds with each other. On the contrary, the European Commission's roadmap to phase out animal testing could also be the transition pathway to a more efficient, effective, and sustainable regulatory ecosystem. Central to our proposal is a framework based on biological reasoning in which biological questions can be answered by a choice of methods, with non-animal methods progressively becoming the only choice. Within this framework, a tiered approach to testing and assessment allows for greater efficiency and effectiveness, while also introducing considerations of proportionality and cost-effectiveness. Testing strategies, and their component methods, should be developed in tandem and judged in terms of their outcomes, and the protection levels they inform, rather than their ability to predict the outputs of animal tests.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"160-165"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a physiologically based pharmacokinetic model for flunixin in cattle and swine following dermal exposure.","authors":"Xue Wu, Qiran Chen, Wei-Chun Chou, Fiona P Maunsell, Lisa A Tell, Ronald E Baynes, Jennifer L Davis, Majid Jaberi-Douraki, Jim E Riviere, Zhoumeng Lin","doi":"10.1093/toxsci/kfae139","DOIUrl":"10.1093/toxsci/kfae139","url":null,"abstract":"<p><p>Flunixin meglumine is a nonsteroidal anti-inflammatory drug (NSAID). Banamine Transdermal is a pour-on formulation of flunixin approved for pain control in beef and dairy cattle, but not for calves and some classes of dairy cattle or swine. Violative flunixin residues in edible tissues in cattle and swine have been reported and are usually attributed to non-compliant drug use or failure to observe an appropriate withdrawal time. This project aimed to develop a physiologically based pharmacokinetic (PBPK) model for flunixin in cattle and swine to predict withdrawal intervals (WDI) after exposures to different therapeutic regimens of Banamine Transdermal. Due to the lack of comprehensive skin physiological data in cattle, the model was initially developed for swine and then adapted for cattle. Monte Carlo simulation was employed for population variability analysis. The model predicted WDIs were rounded to 1 and 2 d for liver and muscle in cattle, respectively, under FDA tolerance levels, while under EU maximum residue limits, the WDIs were rounded to 1, 3, 2, and 2 d for liver, kidney, muscle, and fat, respectively, following a labeled single transdermal 3.3 mg/kg dose in cattle. The model was converted into a user-friendly interactive PBPK (iPBPK) interface. This study reports the first transdermal absorption model for drugs in cattle. This iPBPK model provides a scientifically based tool for the prediction of WDIs in cattle and swine administered with flunixin in an extra-label manner, especially by the transdermal route.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"181-194"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547644","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":"Impact of artificial sunlight aging on the respiratory effects of polyethylene terephthalate microplastics through degradation-mediated terephthalic acid release in male mice.","authors":"Yasuhiro Ishihara, Mizuo Kajino, Yoko Iwamoto, Tatsuto Nakane, Yu Nabetani, Tomoaki Okuda, Maori Kono, Hiroshi Okochi","doi":"10.1093/toxsci/kfae135","DOIUrl":"10.1093/toxsci/kfae135","url":null,"abstract":"<p><p>Microplastics are ubiquitous in the atmosphere, leading to human exposure through inhalation. Airborne microplastics undergo degradation due to sunlight irradiation, yet the respiratory risks associated with degraded microplastics remain poorly understood. In this study, we investigated the respiratory effects of polyethylene terephthalate (PET) degraded by artificial sunlight and created a transport and degradation model of PET for risk assessment. PET fibers were cut and subjected to artificial sunlight irradiation. Mice exposed to aged PET showed increased airway resistance induced by methacholine (MCh) inhalation, along with lung inflammation and neutrophil infiltration. Terephthalic acid (TPA) was continuously released from PET aged by artificial sunlight. Exposure to TPA also caused lung inflammation and enhanced airway resistance induced by MCh in mice. These findings indicate that aged PET can cause respiratory impairment via TPA release. A simple transport and degradation model was developed to quantitatively relate the abundance of aged PET produced in this study (i.e. 4,000 × 96 W m-2 h) and aged fractions of PET that can be generated in the atmosphere. Our results suggested 10% to 60% of PET was degraded as that produced in this study over sunny regions in summer, whereas only lower than 1% in high-latitude cities in Europe in winter. This study demonstrates the importance of considering the abundance of aged PET and further development of a transport and degradation model of PET to assess the risk of degraded PET in the atmosphere.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"242-252"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830004","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":"Using transcriptomic signatures to elucidate individual and mixture effects of inorganic arsenic and manganese in human placental trophoblast HTR-8/SVneo cells.","authors":"Anastasia N Freedman, Hadley Hartwell, Rebecca Fry","doi":"10.1093/toxsci/kfae147","DOIUrl":"10.1093/toxsci/kfae147","url":null,"abstract":"<p><p>Prenatal exposure to the toxic metal inorganic arsenic (iAs) is associated with adverse pregnancy and fetal growth outcomes. These adverse outcomes are tied to physiological disruptions in the placenta. Although iAs co-occurs in the environment with other metals such as manganese (Mn), there is a gap in the knowledge of the effects of metal mixtures on the placenta. To address this, we exposed human placental trophoblast cells to iAs, Mn, and an iAs-Mn mixture at 3 concentrations and evaluated transcriptome-wide gene expression and placental migration. We hypothesized that co-exposure to iAs-Mn in a mixture would result in a synergistic/enhanced transcriptomic effect compared to either metal alone. We also anticipated that genes involved in inflammatory or immune-related pathways would be differentially expressed in relation to the mixture compared to single-metals. The results highlight that iAs exposure alone had a stronger genomic response than Mn exposure, with 2-fold the number of differentially expressed genes (DEGs). When analyzing DEGs present across all concentrations of study, the iAs-Mn mixture resulted in the greatest number of DEGs. The results highlight that iAs exposure alone influences the expression of toll-like receptor-initiated response pathways including Triggering Receptor Expressed on Myeloid Cells-1. Exposure to Mn alone influenced the expression of Nicotinamide adenine dinucleotide biosynthesis pathways. In contrast, exposure to the iAs-Mn mixtures resulted in altered expression of inflammatory and immune response-related pathways, including the Nuclear factor erythroid 2-related factor 2 (NRF2)-mediated oxidative stress response pathway. Migration was unaffected by iAs, Mn, or the iAs-Mn mixture. These findings provide novel toxicogenomic insights into iAs- and Mn-induced placental transcriptomic dysregulations at environmentally relevant concentrations, with implications that in utero exposure to metal mixtures can influence inflammatory and immune pathways within the placenta.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"216-226"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioinformatic workflows for deriving transcriptomic points of departure: current status, data gaps, and research priorities.","authors":"Jason O'Brien, Constance Mitchell, Scott Auerbach, Liam Doonan, Jessica Ewald, Logan Everett, Adam Faranda, Kamin Johnson, Anthony Reardon, John Rooney, Kan Shao, Robert Stainforth, Matthew Wheeler, Deidre Dalmas Wilk, Andrew Williams, Carole Yauk, Eduardo Costa","doi":"10.1093/toxsci/kfae145","DOIUrl":"10.1093/toxsci/kfae145","url":null,"abstract":"<p><p>There is a pressing need to increase the efficiency and reliability of toxicological safety assessment for protecting human health and the environment. Although conventional toxicology tests rely on measuring apical changes in vertebrate models, there is increasing interest in the use of molecular information from animal and in vitro studies to inform safety assessment. One promising and pragmatic application of molecular information involves the derivation of transcriptomic points of departure (tPODs). Transcriptomic analyses provide a snapshot of global molecular changes that reflect cellular responses to stressors and progression toward disease. A tPOD identifies the dose level below which a concerted change in gene expression is not expected in a biological system in response to a chemical. A common approach to derive such a tPOD consists of modeling the dose-response behavior for each gene independently and then aggregating the gene-level data into a single tPOD. Although different implementations of this approach are possible, as discussed in this manuscript, research strongly supports the overall idea that reference doses produced using tPODs are health protective. An advantage of this approach is that tPODs can be generated in shorter term studies (e.g. days) compared with apical endpoints from conventional tests (e.g. 90-d subchronic rodent tests). Moreover, research strongly supports the idea that reference doses produced using tPODs are health protective. Given the potential application of tPODs in regulatory toxicology testing, rigorous and reproducible wet and dry laboratory methodologies for their derivation are required. This review summarizes the current state of the science regarding the study design and bioinformatics workflows for tPOD derivation. We identify standards of practice and sources of variability in tPOD generation, data gaps, and areas of uncertainty. We provide recommendations for research to address barriers and promote adoption in regulatory decision making.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"147-159"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142584276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum glutamate dehydrogenase activity enables sensitive and specific diagnosis of hepatocellular injury in humans.","authors":"Jiri Aubrecht, David Potter, John Michael Sauer, Roscoe Warner, Kent J Johnson, Mitchell R McGill, Katrina Peron, Nicholas M P King","doi":"10.1093/toxsci/kfae143","DOIUrl":"10.1093/toxsci/kfae143","url":null,"abstract":"<p><p>Serum activities of alanine- and aspartate aminotransferases (ALT and AST) are considered the \"gold standard\" biomarkers of hepatocyte injury in clinical practice and drug development. However, due to the expression of ALT and AST in myocytes, the diagnosis of hepatocellular injury in patients with underlying muscle diseases, including drug-induced muscle injury, is severely limited. Thus, we proposed glutamate dehydrogenase (GLDH) as a liver-specific alternative to serum ALT and AST. In fact, our exploratory studies showed that GLDH has comparable performance to ALT for detecting hepatocyte injury without interference from concomitant muscle injury. Here, we report the results of studies confirming the reference intervals in a healthy human population and the sensitivity and specificity of GLDH for the detection of hepatocyte injury in human subjects. In human subjects, we could not perform liver biopsies due to ethical reasons; we also confirmed the relationship of GLDH and histopathologic lesions using 32 model toxicants in rats. Furthermore, we have shown that injury to tissues that are known to express appreciable levels of GLDH does not affect serum GLDH measurements, indicating excellent liver specificity of serum GLDH. Finally, we observed faster elimination of GLDH than ALT in humans, indicating that decreasing GLDH values could be considered an early sign of recovery. This study provides comprehensive evidence of excellent sensitivity and liver specificity of GLDH for diagnosis of hepatocellular injury, including evaluation of reference intervals, which is essential for the interpretation of serum GLDH in human subjects.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"171-180"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health risk assessment of toxic metals and DNA damage in somatic and germ cells by soil and groundwater of a major cement factory in Nigeria.","authors":"Okunola A Alabi, Funmilayo E Ayeni, Tomiwa A Afolabi","doi":"10.1093/toxsci/kfae140","DOIUrl":"10.1093/toxsci/kfae140","url":null,"abstract":"<p><p>The waste generated from cement manufacturing is an important source of heavy metal contamination of groundwater and soil. This study investigated the concentration of toxic metals in the soil of a major cement factory and nearby groundwater. Ecological and carcinogenic risks of the metals were calculated. Potential reproductive toxicity and genotoxic effects of the samples were assessed in the sex and somatic cells of male mice using sperm abnormalities and bone marrow micronucleus (MN) assays, respectively. Also, the serum ALP, ALT, AST, total testosterone (TT), luteinizing hormone (LH), and follicle-stimulating hormone (FSH); and liver SOD and CAT activities were measured in the treated mice. Cr, Cu, Ni, Zn, Mn, Cd, and Pb levels in the soil and groundwater exceeded the allowable maximum standard. Ingestion and dermal contact were the most probable routes of human exposure with children having about 3 times higher probability of exposure to the metals than adults. Ni, Pb, and Cr presented carcinogenic risks in children and adults. In the MN result, nuclear abnormalities in the studied mice especially micronucleated polychromatic erythrocytes increased significantly (P < 0.05). Compared to the negative control, the ratio of PCE/NCE showed the cytotoxicity of the 2 samples. Data further showed a significant increase in the serum ALP, AST, and ALT while the liver CAT and SOD activities concomitantly decreased in the exposed mice. Sperm morphology results showed that the samples contained constituents capable of inducing reproductive toxicity in exposed organisms, with alterations to the concentrations of TT, LH, and FSH. Toxic metal constituents of the samples were believed to induce these reported reproductive toxicity and genotoxic effects. These results showed the environmental pollution caused by cement factories and the potential effects the pollutants might have on exposed eukaryotic organisms.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"227-241"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547645","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":"Peripubertal exposure to oxyfluorfen, a diphenyl herbicide, delays pubertal development in the male rat by antagonizing androgen receptor activity.","authors":"Ashley S Murr, Angela R Buckalew, Grace Devane, Jarod R Bailey, Jermaine L Ford, Leon Earl Gray, Tammy E Stoker","doi":"10.1093/toxsci/kfae144","DOIUrl":"10.1093/toxsci/kfae144","url":null,"abstract":"<p><p>We recently identified the herbicide oxyfluorfen as an inhibitor of iodide uptake by the sodium iodide symporter, a key step in thyroid hormone synthesis, using in vitro assays. We also observed a suppression of serum T4 and T3 in juvenile rats exposed orally to oxyfluorfen for 4 to 8-d. The purpose of the present study was to further evaluate the effects of an extended 31-d oral exposure using a male pubertal rat study (15 to 500 mg/kg). Oxyfluorfen delayed puberty at all doses (1.3 to 3.5-d) suppressing ventral prostate at 62.5 mg/kg and above and seminal vesicle weights at 31.25 mg/kg and above with no effect on testosterone or luteinizing hormone. Serum T4 and T3 were suppressed by all doses up to 80%, with a linear increase in serum TSH. Based on delayed puberty without changes in testosterone, we hypothesized that oxyfluorfen interferes with androgen receptor (AR) function. Results from our Hershberger study, with oxyfluorfen (62.5 and 125 mg/kg) co-treated with testosterone propionate (TP, 1 mg/kg) for 10-d showed 3 of 5 of the androgenic tissue weights were suppressed compared with TP alone indicating AR antagonism. We next confirmed this effect in an in vitro AR transcriptional activation reporter assay (0 to 20 μM) with 125 pM 5αDH-11-ketotestosterone and found concentration-dependent inhibition of AR luminescence activity (EC50 1.75 µM) without cytotoxicity. Thus, this study confirms the endocrine-disrupting mechanism of oxyfluorfen using in vitro and in vivo evaluations of the thyroid hormone and AR pathways. This abstract does not necessarily reflect U.S. EPA policy.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"206-215"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568513","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":"Increasing the utility of epidemiologic studies as key evidence in chemical risk assessment.","authors":"Heather R Schaefer, Melissa J Vincent, Carol J Burns, Sabine S Lange","doi":"10.1093/toxsci/kfae134","DOIUrl":"10.1093/toxsci/kfae134","url":null,"abstract":"<p><p>The Society of Toxicology 2024 meeting assembled risk assessors, epidemiologists, and toxicologists to discuss the utility of integrating epidemiologic data into the derivation of reference values. Advantages of the use of epidemiologic evidence include (i) human relevance; (ii) increased likelihood that exposure levels are relevant to risk assessment; and (iii) incorporation of uncertainties attributed to co-exposures or other population-based considerations. The workshop panelists discussed the challenges of incorporating epidemiologic evidence due to uncertain exposure measurements, confounding, heterogeneity, and inherent study design limitations. Capturing uncertainty is a critical step. In summary, epidemiologic evidence can be a valuable tool for risk analysis. This workshop brief captures constructive considerations from practitioners in the field that can increase the utility of epidemiologic studies in chemical risk assessment and harmonize the approach for use in dose-response assessment that will ultimately reduce uncertainty related to chemical exposures.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"166-170"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lead exposure at the feto-maternal interface: a cause for concern for fetal membrane trophoblasts.","authors":"Pilar Flores-Espinosa, Ramkumar Menon, Ananth Kammala, Lauren S Richardson","doi":"10.1093/toxsci/kfae149","DOIUrl":"10.1093/toxsci/kfae149","url":null,"abstract":"<p><p>The integrity of fetal membranes enables biological functions that protect the fetus and maintain the pregnancy. Any compromise in fetal membrane function can predispose a pregnant woman to prelabor rupture of the membranes (pPROMs) and subsequently to preterm birth (PTB). Epidemiologic data suggest that lead exposure during pregnancy is one of several risk factors associated with PTB and pPROM. This heavy metal can cross placental and fetal membrane barriers, disrupting homeostasis in these tissues. Autophagy contributes to the maintenance of fetal membrane homeostasis during gestation, and dysfunctional autophagy is associated with pPROM. In this study, we determined the mechanistic impact of lead-induced cellular changes, autophagy, senescence, and inflammation in chorion trophoblast cells (CTCs) and amnion epithelial cells (AECs) of the fetal membranes. Lead exposure in CTCs induced autophagy dysfunction (increase in LC3B-II), augmented senescence (increased SA-β-galactosidase activity), and increased the release of inflammation. In AECs, lead exposure did effect autophagy, senescence, nor inflammation. The differential changes observed in CTCs and AECs after exposure to high lead concentrations may promote the weakening of fetal membranes and contribute to preterm rupture.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"195-205"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}