Aims: The formation of anti-drug antibodies (ADAs) during anti-tumor necrosis factor (anti-TNF) therapy is reported to lead to reducing serum drug levels, which may bring about a loss of response to treatment. Previous research has suggested an association between specific antibiotic classes and ADA formation during anti-TNF therapy. However, there are few studies specifically examining this association in Chinese inflammatory bowel disease (IBD) patients. Therefore, our study aimed to evaluate the possible effect of antibiotic use on ADA formation to anti-TNF therapy in Chinese patients with IBD. Methods: A total of 166 patients with IBD, including 149 with Crohn's disease (CD) and 17 with ulcerative colitis (UC), were included in this retrospective analysis. These patients were initially treated with anti-TNF therapy (infliximab or adalimumab) after January 2018 and reviewed with available ADA levels before October 2023. After univariable analysis of all the variables, a multivariate Cox proportional hazards model was used to assess the association between antibiotic use and ADA development. Results: Among 166 IBD patients treated with infliximab (108/166, 65.1%) or adalimumab (58/166, 34.9%), 31 patients (18.7%) were measured as positive ADA levels. Cox proportional hazard model demonstrated an increased risk of ADA formation in IBD patients who used ß-lactam-ß-lactamase inhibitor combinations (BL-BLIs) (HR = 5.143, 95%CI 1.136-23.270, p = 0.033), or nitroimidazoles (HR = 4.635, 95%CI 1.641-13.089, p = 0.004) during 12 months before the ADA test. On the contrary, a reduced risk was noted in patients treated with fluoroquinolones (HR = 0.258, 95% CI 0.072-0.924, p = 0.037). Moreover, the median serum infliximab or adalimumab concentration in patients with positive ADA levels was significantly lower than that in patients with negative ADA levels (infliximab: 0.30 vs. 1.85 µg/mL, p < 0.0001; adalimumab: 0.45 vs. 7.55 µg/mL, p = 0.0121). Conclusion: ADA development is associated with various antibiotic classes. BL-BLIs and nitroimidazoles might increase the risk of ADA formation during anti-TNF therapy in Chinese IBD patients, while the treatment with fluoroquinolones could probably reduce such risk. There were certain limitations in the retrospective analysis of the study, therefore, the results are just for reference, and other studies are needed to further confirm our findings.
3D bioprinting techniques have enabled the fabrication of irregular large-sized tissue engineering scaffolds. However, complicated customized designs increase the medical burden. Meanwhile, the integrated printing process hinders the cellular uniform distribution and local angiogenesis. A novel approach is introduced to the construction of sizable tissue engineering grafts by employing hydrogel 3D printing for modular bioadhesion assembly, and a poly (ethylene glycol) diacrylate (PEGDA)-gelatin-dopamine (PGD) hydrogel, photosensitive and adhesive, enabling fine microcage module fabrication via DLP 3D printing is developed. The PGD hydrogel printed micocages are flexible, allowing various shapes and cell/tissue fillings for repairing diverse irregular tissue defects. In vivo experiments demonstrate robust vascularization and superior graft survival in nude mice. This assembly strategy based on scalable 3D printed hydrogel microcage module could simplify the construction of tissue with large volume and complex components, offering promise for diverse large tissue defect repairs.
The human gastrointestinal tract harbors trillions of commensal microorganisms. Emerging evidence points to a possible link between intestinal fungal dysbiosis and antifungal mucosal immunity in inflammatory bowel disease, especially in Crohn's disease (CD). As a protective factor for the gut mucosa, secretory immunoglobulin A (SIgA) prevents bacteria from invading the intestinal epithelium and maintains a healthy microbiota community. In recent years, the roles of antifungal SIgA antibodies in mucosal immunity, including the regulation of intestinal immunity binding to hyphae-associated virulence factors, are becoming increasingly recognized. Here we review the current knowledge on intestinal fungal dysbiosis and antifungal mucosal immunity in healthy individuals and in patients with CD, discuss the factors governing antifungal SIgA responses in the intestinal mucosa in the latter group, and highlight potential antifungal vaccines targeting SIgA to prevent CD.
Crohn Disease , Humans , Crohn Disease/microbiology , Immunoglobulin A, Secretory , Antifungal Agents/therapeutic use , Dysbiosis/microbiology , Fungi
Background: The etiology of inflammatory bowel disease (IBD) remains unclear. However, intestinal metabolism is known to be critical in the pathogenesis of IBD. Bile acid is one of the main intestinal metabolites, and its role in the pathogenesis of IBD is worthy of investigation. This study investigated the role of deoxycholic acid (DCA), a bile acid, in the pathogenesis of IBD. Methods: Peripheral serum metabolomics, fecal metabolomics, and microbiome analyses were performed on patients with IBD and healthy controls. Flow cytometry, real-time quantitative polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, immunohistochemical staining, and immunofluorescence analysis were used to evaluate cytokines in the inflamed colonic mucosa and immune cells and tuft cells in the intestine of mice with dextran sulfate sodium (DSS)-induced colitis. Results: In total, 156 patients with IBD and 58 healthy controls were enrolled. DCA levels in the serum and feces of patients with IBD were significantly decreased compared to the controls. This decrease was associated with a decrease in the abundance of intestinal flora, including Firmicutes, Clostridia, Ruminnococcaceae, and Lachnospiraceae. Additionally, interleukin (IL)-1ß levels in the serum of patients with active Crohn's disease were significantly increased compared with the healthy controls. Moreover, in DCA-treated DSS-induced mice, the expression of IL-1ß and the proportion of CD3+ and CD4+ T cells increased while the number of intestinal tuft cells decreased, compared with the DSS group. Conclusion: In IBD patients, the decreased DCA levels in serum and fecal samples are associated with disturbances in gut microflora diversity and abundance. Possible mechanisms by which DCA affects immunity in DSS-induced murine colitis include increasing IL-1ß secretion, reducing the number of tuft cells in the mucosa, and activating CD4+ and CD3+ T cells to exaggerate immune responses, consequently worsening intestinal inflammation.
Colitis , Inflammatory Bowel Diseases , Animals , Mice , Colitis/chemically induced , Deoxycholic Acid , Dextran Sulfate/toxicity , Inflammation , Interleukin-1beta
Life cycle assessment (LCA) is a widely-used international environmental evaluation and management method. However, the conventional LCA is in a static context without temporal and spatial variations considered, which fails to bring accurate evaluation values and hinders practical applications. Dynamic LCA research has developed vigorously in the past decade and become a hot topic. However, systematical analysis of spatiotemporal dynamic variations and comprehensive operable dynamic models are still lacking. This study follows LCA paradigm and incorporates time- and space-dependent variations to establish a spatiotemporal dynamic LCA model. The dynamic changes are classified into four types: dynamic foreground elementary flows, dynamic background system, dynamic characterization factors, and dynamic weighting factors. Their potential dynamics and possible quantification methods are analyzed. The dynamic LCA model is applied to a residential building, and significant differences can be observed between dynamic and static assessment results from both temporal and spatial perspectives. This study makes a theoretical contribution by establishing a comprehensive dynamic model with both temporal and spatial variations involved. It is expected to provide practical values for LCA practitioners and help with decision-making and environmental management.
Life Cycle Stages , Models, Biological , Animals
The amount of building demolition waste produced in China is large, and waste treatment processes discharge many pollutants. Pre-evaluating waste's environmental damage at the design stage of building projects could provide an opportunity to understand and minimize potential environmental impacts. Tools that can conveniently estimate the amount of demolition waste and quantify its impacts are lacking. This study combines building information modeling (BIM), geographic information system (GIS), and life cycle assessment (LCA) to develop an estimation and evaluation system for building demolition waste. In this system, BIM digitizes the specific characteristics of the evaluated buildings and provides geometric and semantic information for waste estimation. GIS offers geographic information regarding waste treatment plants and landfill site, and is used to design waste transportation routes. LCA provides an environmental impact assessment framework and quantifies ecological damage impacts and resource depletion impacts due to demolition waste. The system includes five modules, which form the basis of an automated calculation tool. The evaluation tool can quickly quantify the amount of waste and assess its impacts, while achieving automated waste estimation and impact evaluation after a building is designed. A building in a middle school is taken as a case study to demonstrate and verify the system. This study provides an operable tool for waste evaluation and management at the design stage. With the increasing application of BIM technology in the construction industry, this tool is expected to gain popularity and promote efficient waste management.
Construction Industry , Waste Management , Construction Materials , Environment , Recycling , Transportation
Background: Previous studies have demonstrated an association between hyperuricemia and cardiovascular disease (CVD). The Framingham study confirmed that patients with high atherosclerotic risks (HARs) had worse prognoses. However, after adjusting for confounding factors, the association between serum uric acid (SUA) and all-cause mortality and cardiovascular mortality remains unclear, especially for HAR patients. Objective: The aim of this study was to reveal the relationship of SUA with all-cause and cardiovascular mortality in HAR patients. Methods: This multicenter cohort study enrolled 3,047 participants, and the follow-up was 68.85 ± 11.37 months. Factors related to cardiovascular and all-cause mortality were tested by multivariate Cox regression analysis. Restricted cubic splines (RCSs) with knots were used to explore the shape of the dose-response relationship with SUA and the hazard ratio (HR) of all-cause and CVD mortality. SUA transformed by RCS was added to the Cox regression model as an independent variable, and all-cause and CVD mortality scores were calculated. Survival receiver operating characteristic curves were produced using a regression model predicting the score. Results: SUA demonstrated a "U-shaped" relationship with all-cause and cardiovascular mortality. SUA predicted all-cause and CVD mortality, with cutoff values of values of >370.5 µmol/L for males and >327.65 µmol/L for females and <180.5 µmol/L for males and <165.7 µmol/L for females, respectively. The survival ROC curve indicated that SUA is able to predict all-cause and CVD mortality, with areas under the curve of 0.702 and 0.711, respectively. The HRs of all-cause mortality (male and female) with hyperuricemia and hypouricemia were 2.08 and 2.01 and 2.04 and 1.98, respectively, and the HRs of CVD mortality (male and female) were 2.09 and 1.79, and 2.02 and 1.89, respectively. Conclusion: Abnormal SUA levels were significant and independent risk factors for all-cause and CVD mortality. Hyperuricemia and hypouricemia increased mortality in both males and females. Routine SUA evaluation and intensive management are needed for HAR patients. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03616769.
PURPOSE: To investigate the therapeutic effect of Tripterygium wilfordii polyglycoside (TWP), a derivative from a Chinese traditional herb, on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, in a model for inflammatory bowel disease (IBD) in rats. METHODS: TWP was administrated to Wistar rats during TNBS-induced colitis to determine its therapeutic effect on active inflammation using the Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR), flow cytometry, and Western blotting. Peripheral blood CD4+ T-cells were isolated from patients with ulcerative colitis (UC) and incubated with TWP to verify its immune regulation mechanism by qRT-PCR and flow cytometry. RESULTS: Intragastric administration of TWP attenuated the severity of intestinal inflammation in TNBS-induced rat colitis, characterized by decreased DAI, histopathological scores, and expression of IL-6, TNFα, IFNγ, and IL-17A in intestinal mucosa. Furthermore, TWP reduced IL-17A+CD4+ T-cells, while enhanced Foxp3+CD25+CD4+ T-cells in peripheral blood, mesenteric lymph nodes (MLN), and spleen in rat colitis. Downstream signaling including ROR-γt, STAT3, and HIF1α expression in intestinal mucosa were suppressed by TWP. In addition, incubation with TWP suppressed IL-17A+CD4+ T-cell differentiation, while it promoted Foxp3+CD25+CD4+ T-cell differentiation in CD4+ T-cells isolated from UC patients. CONCLUSION: TWP successfully ameliorated experimental rat colitis via regulating innate immune responses as well as Th17/Treg balance in intestinal mucosa, peripheral blood, MLN, and spleen. Moreover, the differentiation of peripheral blood CD4+ T-cell isolated from patients with UC was modulated by TWP. TWP may act as an optional complementary and alternative medicine for IBD.
BACKGROUND: Previous studied revealed that psoriasis and Inflammatory bowel disease (IBD) have highly overlapping epidemiological characteristics, genetic susceptibility loci, disease risk factors, immune mechanisms, and comorbidities. More and more biologics have been used to treat psoriasis and IBD. Interleukin (IL)-17 inhibitors played an important role in the treatment of psoriasis, but induced and aggravated inflammatory bowel disease in some patients. IL-23 inhibitors have shown to be effective to both psoriasis and CD. CASE PRESENTATION: Forty-one year old Chinese male patient who came to the hospital for psoriasis, developed severe gastrointestinal symptoms after using an IL-17 inhibitor, and was diagnosed with Crohn's disease (CD). The patient eventually used an IL-23 inhibitor to relieve both psoriasis and CD. CONCLUSION: IBD patients and psoriasis patients have increased probability of suffering from the other disease. The case that patients had suffered from psoriasis and CD before the use of IL-17 inhibitor is quite rare. This case suggests that physicians need to be careful when treating patients with psoriasis and CD with biologics, and it is necessary to evaluate the gastrointestinal tract.
Crohn Disease , Interleukin-17/antagonists & inhibitors , Psoriasis , Adult , Crohn Disease/chemically induced , Humans , Male , Psoriasis/drug therapy
In general, type 2 diabetes (T2D) usually occurs in middle-aged and elderly people. However, the incidence of childhood-onset T2D has increased all across the globe. Therefore, it is very important to determine the molecular and genetic mechanisms of childhood-onset T2D. In this study, the dataset GSE9006 was downloaded from the GEO (Gene Expression Omnibus database); it includes 24 healthy children, 43 children with newly diagnosed Type 1 diabetes (T1D), and 12 children with newly diagnosed T2D. These data were used for differentially expressed genes (DGEs) analysis and weighted co-expression network analysis (WGCNA). We identified 192 up-regulated genes and 329 down-regulated genes by performing DEGs analysis. By performing WGGNA, we found that blue module (539 genes) was highly correlated to cyan module (97 genes). Gene ontology (GO) and pathway enrichment analyses were performed to figure out the functions and related pathways of genes, which were identified in the results of DEGs and WGCNA. Genes with conspicuous logFC and in the high correlated modules were input into GeneMANIA, which is a plugin of Cytoscape application. Thus, we constructed the protein-protein interaction (PPI) network (92 nodes and 254 pairs). Eventually, we analyzed the transcription factors and references related to genes with conspicuous logFC or high-degree genes, which were present in both the modules of WGCNA and PPI network. Current research shows that EGR1 and NAMPT can be used as marker genes for childhood-onset T2D. Gestational diabetes and chronic inflammation are risk factors that lead to the development of childhood-onset T2D.
