Inflammatory Bowel Diseases最新文献

{"title":"Higher-Dose Infliximab Induction Achieves Better Maintenance Trough Levels in a National Pediatric IBD Cohort-A Retrospective Study.","authors":"Emily Stenke, Dahlal Alhassan, Molly Moclair, Sarah Cooper, Anna Dominika, Ciara Lang, Shoana Quinn, Annemarie Broderick, Emer Fitzpatrick, Billy Bourke, Lorraine Stallard, Séamus Hussey","doi":"10.1093/ibd/izaf031","DOIUrl":"https://doi.org/10.1093/ibd/izaf031","url":null,"abstract":"<p><strong>Background: </strong>Proactive drug monitoring in our national cohort of children with inflammatory bowel disease suggested that 5 mg/kg dosing of infliximab (IFX) was associated with inadequate trough levels (TLs), thus we commenced empiric 10 mg/kg dosing in 2019.</p><p><strong>Methods: </strong>This was a retrospective study of patients commenced on 5 or 10 mg/kg IFX between 2018 and 2020. The primary outcome was pre-fourth TL ≥5 µg/mL. Data source verification and analysis were undertaken retrospectively.</p><p><strong>Results: </strong>During the study period, 122 patients were commenced on IFX and eligible for inclusion. Of these, 72% were male, 76% had Crohn's disease (CD), 23% had ulcerative colitis; mean (standard deviation [SD]) age at diagnosis was 11.8 (2.7) years; 60 commenced 5 mg/kg. Baseline parameters were comparable between groups. Fewer patients in the 5 mg/kg than 10 mg/kg group had pre-fourth TLs ≥5 µg/mL (6/48 [12.5%] vs 28/50 [56%], P < .001; mean [SD] TL 3.5 [6.3] vs 10.0 [9.9], P < .001). The 5 mg/kg group was less likely to have target pre-third TLs (6% vs 80%, P < .001); more likely to have treatment escalation (78% vs 45%, P < .001), and less likely to de-escalate (10% vs 29% P = .008). Proactive therapeutic dose monitoring (TDM) was practiced throughout the study period and mean (SD) IFX exposure per kg/week was similar in both groups by 1 year (1.4 [0.43] vs 1.56 [0.56] mg/kg/week, P = .137), as were infliximab durability and clinical outcomes.</p><p><strong>Conclusions: </strong>Our real-world data show that 5 mg/kg infliximab induction does not achieve target TLs in most children with CD. Higher-dose regimens should be considered, especially if proactive therapeutic drug monitoring is not available.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556657","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":"Erythrocyte Methotrexate-Polyglutamate Concentrations in Pediatric Inflammatory Bowel Disease.","authors":"Eva Vermeer, Eduard A Struys, Marry Lin, Johan E van Limbergen, Nanne K H de Boer, Maja Bulatović-Ćalasan, Tim G J de Meij, Robert de Jonge","doi":"10.1093/ibd/izaf035","DOIUrl":"https://doi.org/10.1093/ibd/izaf035","url":null,"abstract":"<p><strong>Background and aims: </strong>Therapeutic drug monitoring (TDM) of methotrexate (MTX) is challenging due to its pharmacokinetics and short plasma half-life. Intracellular MTX-polyglutamates (PG1-5), which accumulate over time, have not been assessed in pediatric inflammatory bowel disease (IBD). This study aimed to evaluate erythrocyte MTX-PG as a potential TDM tool in pediatric IBD.</p><p><strong>Methods: </strong>In this cross-sectional study, MTX-PG concentrations were measured in erythrocytes of children with IBD on stable low-dose MTX for at least 12 weeks using stable-isotope dilution liquid chromatography-tandem mass spectrometry. The influence of administration route, MTX dosage, and anthropometrics on MTX-PG concentrations was examined.</p><p><strong>Results: </strong>Seventy-eight patients were included, showing MTX-PG3 as the predominant subspecies (median 27.0 nmol/L) with a median MTX-PGtotal of 74.8 nmol/L. A higher MTX dose correlated significantly with elevated levels of MTX-PG3, MTX-PG4, MTX-PG5, and MTX-PGtotal (P < .01). Adjusted for body surface area, MTX dose remained significantly associated with higher MTX-PG concentrations (P < .01). However, comparison by administration route was limited due to a few patients on subcutaneous MTX (n = 4).</p><p><strong>Conclusions: </strong>We observed high interindividual variability in the reached erythrocyte MTX-PG concentrations. Body surface adjusted or unadjusted MTX dosage showed a positive linear correlation with erythrocyte MTX-PG concentrations in children with IBD. This is a prerequisite for TDM and provides a strong basis for further research into the relation between TDM of MTX, efficacy, and toxicity.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467965","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":"Placental Transfer of Upadacitinib Among Pregnant Women with Inflammatory Bowel Disease.","authors":"Samantha Ehrlich, Millie Long, Sunanda Kane, Uma Mahadevan","doi":"10.1093/ibd/izaf027","DOIUrl":"https://doi.org/10.1093/ibd/izaf027","url":null,"abstract":"","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472480","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-Cell Transcriptomic Profile of Innate Cell Populations in Mesenteric Lymph Nodes of Inflammatory Bowel Disease Patients.","authors":"Pauline Wils, Mohammad Reza Habibi Kavashkohie, Fabiana Sélos Guerra, Séverine Landais, Manuel Rubio, Heena Mehta, Marika Sarfati, Laurence Chapuy","doi":"10.1093/ibd/izaf017","DOIUrl":"https://doi.org/10.1093/ibd/izaf017","url":null,"abstract":"<p><strong>Background and aims: </strong>Innate immune cells, including dendritic cells (DCs), monocytes (Mono), macrophages (Mac), natural killer (NK), and innate lymphoid cells (ILC), contribute to chronic inflammation in lymphoid tissues. Here, we characterized the innate immune cell landscape in inflamed mesenteric lymph nodes (MLNs) of patients with inflammatory bowel diseases (IBD) at the single-cell level.</p><p><strong>Methods: </strong>Surgically resected colonic MLNs were obtained from patients with Crohn's disease (CD; n = 3), ulcerative colitis (UC; n = 3), non-inflamed UC (n = 1), and non-IBD (n = 2). CD45+CD3-CD19- non-T/non-B cells were FACS-sorted to capture rare innate immune cells. Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) was performed on the BD Rhapsody platform alongside multiparameter flow cytometry staining.</p><p><strong>Results: </strong>CITE-seq analysis unveiled the molecular signature of 11 Mono/Mac/DC (MMDC) and 7 NK/ILC enriched clusters in human MLNs. DC clusters included 3 newly characterized DC clusters such as CD1c/CD163/VCAN/CD64-expressing DC3; AXL-expressing DCs; and a CD103+ DC subset, expressing LTB, S100B, and IL22RA2 (encoding IL22BP). Mono/Mac clusters comprised inflammatory monocytes, which accumulated in IBD compared to non-IBD MLNs. Among NK/ILC clusters, we identified a cytotoxic ILC subset (IL7R, KLRD1, GNLY), previously not reported in MLNs, reminiscent of cytotoxic ILC1-like cells found in inflamed gut mucosa.</p><p><strong>Conclusion: </strong>CITE-seq and flow-cytometry analyses of colonic MLNs from patients with active IBD reveal the molecular signature and cell distribution of previously uncharacterized DC and ILC subpopulations in human MLNs. These findings expand our understanding of immune responses during chronic inflammation in IBD.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467970","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":"Novel Transcriptomic Signatures in Fibrostenotic Crohn's Disease: Dysregulated Pathways, Promising Biomarkers, and Putative Therapeutic Targets.","authors":"Animesh Acharjee, Uday Shivaji, Giovanni Santacroce, Sarah Akiror, Louisa Jeffery, Csilla Varnai, Gary Reynolds, Davide Zardo, Snehali Majumder, Asma Amamou, Georgios V Gkoutos, Marietta Iacucci, Subrata Ghosh","doi":"10.1093/ibd/izaf021","DOIUrl":"https://doi.org/10.1093/ibd/izaf021","url":null,"abstract":"<p><strong>Background: </strong>Fibrosis is a common complication in Crohn's disease (CD), often leading to intestinal strictures. This study aims to explore the transcriptomic signature of fibrostenotic ileal CD for a comprehensive characterization of biological and cellular mechanisms underlying intestinal fibrosis.</p><p><strong>Methods: </strong>Nine CD patients undergoing surgery for fibrotic ileal strictures were prospectively recruited. RNA was extracted from fresh resected samples for bulk transcriptomics. Differentially expressed genes (DEGs) were identified (adj. P value < .05), and machine learning analyses were employed to compare gene expression patterns between strictures and non-strictured margins. Pathway enrichment analysis pinpointed relevant pathways. Furthermore, a random forest model was constructed to evaluate the significance of targeted genes. Relevant genes were subsequently validated through qPCR and further analyzed using a publicly available bulk RNA-seq dataset (GSE192786). Single-cell RNA sequencing (scRNA-seq) analysis was performed using the 10× Chromium Controller platform.</p><p><strong>Results: </strong>Bulk transcriptomics revealed unique transcriptomes with 81 DEGs, 64 significantly up-regulated, and 17 down-regulated in strictures compared to non-strictured margins. Up-regulated genes were mainly associated with inflammation, matrix and tissue remodeling, adipogenesis and cellular stress, while down-regulated genes were linked to epithelial barrier integrity. LY96, AKAP11, SRM, GREM1, EHD2, SERPINE1, HDAC1, and FGF2 showed high specificity for strictures. scRNA-seq linked up-regulated GREM1 exclusively to fibroblasts, while EHD2 and FGF2 showed upregulation in both fibroblasts and endothelial cells. LY96 and SRM were expressed by immune cells, whereas HDAC1, AKAP11, and SERPINE1 showed low expression across all cellular subsets.</p><p><strong>Conclusions: </strong>This study comprehensively characterizes resected CD ileal strictures, elucidating main dysregulated pathways and identifying promising biomarkers and putative therapeutic targets.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467969","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 Psychosocial and Neurodevelopmental Disorders on Pediatric Ulcerative Colitis: A Single-Center, Retrospective, Observational Study.","authors":"Akio Nakamura, Keisuke Jimbo, Mitsuyoshi Suzuki, Musashi Hibio, Masumi Nagata, Nobuyasu Arai, Eri Miyata, Takahiro Kudo, Eri Hoshino, Hiromichi Shoji","doi":"10.1093/ibd/izaf034","DOIUrl":"https://doi.org/10.1093/ibd/izaf034","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to evaluate the effects of psychosocial and neurodevelopmental disorders on pediatric ulcerative colitis management. Specifically, the relationships between these disorders and disease severity, as well as treatment strategies, were assessed through a single-center, retrospective, observational study.</p><p><strong>Methods: </strong>The study included pediatric patients with ulcerative colitis (UC) under 15 years of age diagnosed by colonoscopy and histological evaluation between January 2022 and May 2024. Data on comorbid functional gastrointestinal disorders and neurodevelopmental disorders were obtained from patients' electronic medical records, and their effects on disease severity and treatment choices were analyzed.</p><p><strong>Results: </strong>Of the 166 patients with UC, 21.4% had neurodevelopmental disorders, and 17.5% had functional gastrointestinal disorders. Patients with these comorbidities had significantly lower Pediatric Ulcerative Colitis Activity Index scores, with notable differences in parameters such as abdominal pain and stool consistency. In addition, these patients had more extensive disease and higher rates of immunomodulator (66.1%) and biologic use (46.4%) than those without these complications. The prevalence of functional gastrointestinal disorders was higher in patients with autism spectrum disorder, and specialized care at a developmental outpatient clinic was required in 23.2% of cases.</p><p><strong>Conclusions: </strong>Psychosocial and neurodevelopmental disorders are prevalent in children with UC and significantly affect both disease severity and therapeutic approaches. The findings suggest that comprehensive management involving psychosocial interventions and multidisciplinary support is crucial for effectively treating these patients.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467967","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":"Addressing the Challenges of Inflammatory Bowel Disease-Primary Sclerosing Cholangitis Treatment: Prognosis Optimization Strategies in the Era of Precision Medicine.","authors":"Kaili Lin, Wenjuan Feng, Sheng Li","doi":"10.1093/ibd/izaf007","DOIUrl":"10.1093/ibd/izaf007","url":null,"abstract":"","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467963","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":"S1P Lyase Inhibition Increased Intestinal S1P, Disrupted the Intestinal Barrier and Aggravated DSS-Induced Colitis.","authors":"Prabhdeep Kaur, Thangaraj Karuppuchamy, Amruth Chilukuri, Margaret Kim, Josef Urrete, Zining Shen, Leo Saxon, Luke R Lundborg, Zbigniew Mikulski, Paul Jedlicka, Jesús Rivera-Nieves","doi":"10.1093/ibd/izaf030","DOIUrl":"10.1093/ibd/izaf030","url":null,"abstract":"<p><strong>Background: </strong>Sphingosine-1-phospate (S1P) receptor agonists (eg, ozanimod) desensitize migrating lymphocytes by irreversibly binding to S1P receptors (S1PR) and triggering their proteasomal degradation. Desensitized lymphocytes cannot sense S1P, therefore, halting lymphocyte recirculation. The S1P lyase (SPL) irreversibly degrades S1P and its inhibition disrupts the S1P gradient. We previously found that systemic SPL inhibitors induce central immunosuppression. Here, we examined whether SPL inhibition may attenuate colitis without systemic immunotoxicity.</p><p><strong>Methods: </strong>We first analyzed SPL expression and localization in mice using qRT-PCR and immunohistochemistry. SPL inhibitors 4-deoxypyridoxine hydrochloride (DOP) and 2-acetyl-4-(tetrahydroxybutyl) imidazole (THI) were used to inhibit SPL systemically, whereas a conditional intestinal epithelial cell (IEC)-specific SPL-deficient mouse was used to evaluate the effects of IEC-specific SPL inhibition on survival, disease activity, histological severity of dextran sulfate sodium-induced colitis, S1P levels, and intestinal permeability.</p><p><strong>Results: </strong>Sgpl1 mRNA transcripts and protein were ubiquitously expressed in gastrointestinal (GI) tract leukocytes and IEC. Systemic SPL inhibitors did not induce colitis by themselves but depleted CD4+ and CD8+ T cells from blood. However, contrary to its therapeutic effects on ileitis, systemic inhibition reduced survival, accelerated weight loss, worsened histopathological inflammation indices, and tissue damage. We then examined the effects of IEC-specific inhibition on peripheral cell counts and severity of colitis. We found that while it spared peripheral immunity, it similarly hastened colitis. Finally, we examined whether colitis acceleration was due to epithelial barrier compromise after disruption of the S1P gradient. We found that not only systemic but also IEC-specific SPL inhibition increased local S1P levels and led to IEC barrier compromise.</p><p><strong>Conclusion: </strong>Homeostatic intestinal S1P levels are critical for the regulation of IEC barrier function. Further studies using adaptive immunity-based inflammatory bowel diseases (IBD) models are required to assess the translational value of IEC-specific SPL inhibition as a therapeutic target for human IBD.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440688","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":"NHE3 Controls Proliferation and Migration of Colonic Epithelial Cells.","authors":"Claudio Bernardazzi, Tultul Saha, Michael A Gurney, Daniel Laubitz, Pujarini Dutta Dey, Tarek Masannat, Irshad Ali Sheikh, Monica T Midura-Kiela, Fayez K Ghishan, Pawel R Kiela","doi":"10.1093/ibd/izaf024","DOIUrl":"https://doi.org/10.1093/ibd/izaf024","url":null,"abstract":"<p><strong>Background: </strong>In the gut, Na+/H+ exchanger 3 (NHE3; SLC9A3) plays important roles in pH regulation, absorption of Na+, and indirectly of other nutrients. NHE3-deficient mice develop inflammatory bowel disease (IBD)-like dysbiosis and spontaneous colitis, and rare mutations in the SLC9A3 gene may confer a risk factor for very early-onset IBD. However, the roles of NHE3 in the epithelial cell functions beyond the canonical ion transport, especially in the face of injury, remain poorly understood. Thus, we aimed to investigate the role of NHE3 in colonic epithelial cell proliferation and migration during wound healing.</p><p><strong>Methods: </strong>Colonic organoids from NHE3+/+ and NHE3-/- mice and SK-CO-15 cells with shRNA-mediated NHE3 knockdown (NHE3KD) were used to assess the intrinsic role of NHE3 in cellular proliferation, migration, wound healing, adhesion to the extracellular matrix (ECM), activation status of focal adhesion kinase (pFAKY397), and in gene transcription.</p><p><strong>Results: </strong>NHE3-/- colonoids showed increased cell proliferation and reduced ECM adhesion. NHE3-/- colonoids and NHE3KD cells showed increased spontaneous motility, enhanced migration in serum gradient, and in 2 models of wound healing. This was associated with FAK and Src activation and modulation of genes associated with cell-cell interactions, cell-ECM interactions, and the formation of focal adhesions. Inhibition of FAK autophosphorylation eliminated the effect of NHE3 deficiency on cell migration.</p><p><strong>Conclusions: </strong>Inhibition of NHE3, unconfounded by chronic inflammatory or microbial pressure, may represent a permissible mechanism beneficial to the host by modulating cellular plasticity and promoting epithelial wound healing. These unexpected results provide a novel insight into the pleiotropic roles of NHE3 in mucosal homeostasis.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440674","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":"Upadacitinib in Autoimmune Enteropathy-A Case Report.","authors":"Simone Chin, Julie Lokan, Darren Wong, Peter De Cruz, Matthew Choy","doi":"10.1093/ibd/izaf002","DOIUrl":"https://doi.org/10.1093/ibd/izaf002","url":null,"abstract":"","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414089","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}