Hollow cubic CuSe@CdS with tunable size for plasmon-induced Vis-NIR driven photocatalytic properties.

The rational design of the dimension and geometry of a plasmonic semiconductor cocatalyst is vitally important for efficient utilization of near-infrared (NIR) light and superior photocatalytic hydrogen generation. Herein, hollow cubic CuSe@CdS composites with different sizes and strong localized surface plasmon resonance (LSPR) were prepared by selenizing size-tunable Cu2O templates and loading CdS nanoparticles. The size of hollow cubic CuSe can affect the surface area and the conduction band potential through the size effect, regulating the carrier behavior of the CuSe@CdS heterojunction. The CuSe@CdS composites show enhanced and wide absorption in the full spectrum due to the LSPR effect of CuSe. Meanwhile, the composites show excellent photocatalytic hydrogen capacity in the full spectrum in a 0.35 M Na2S/0.25 M Na2SO3 sacrificial reagent solution. The best hydrogen production rate of CSCE2 is 1.518 mmol g-1 h-1 (5.54 times higher than that of CdS) under Vis light (780 > λ > 420 nm) irradiation and 0.28 mmol g-1 h-1 under NIR light (λ > 780 nm) illumination. Interestingly, the photocatalytic activity for H2 under Vis-NIR light (λ > 420 nm) is about 3 times (up to 4.45 mmol g-1 h-1) higher than that without NIR light assistance, due to the photothermal effect. Various analyses and DFT calculations demonstrate that the p-n heterojunction formed in the composites consists of p-type CuSe and n-type CdS, which achieves efficient carrier transfer and separation under the synergistic effect of the size effect and the photothermal effect. In addition, the expansion of the photocatalytic performance to the NIR range is mainly due to the "hot-electron" injection mechanism induced by the LSPR effect of CuSe. The reasonable design coupled with the plasmonic materials offers a new path to achieving the highly efficient conversion of solar energy to hydrogen energy.

Covered Stent Treatment for Direct Carotid-Cavernous Fistulas: A Meta-analysis of Efficacy and Safety Outcomes.

BACKGROUND: Direct carotid-cavernous fistulas (dCCFs) involve the abnormal shunting of blood between the internal carotid artery and the cavernous sinus. The use of covered stents (CSs) has been reported for the treatment of complex carotid artery lesions. However, the efficacy and safety of CS treatment for dCCFs remain controversial. Thus, we performed a systematic review and meta-analysis to evaluate these efficacy and safety endpoints. METHODS: A systematic literature review was performed by comprehensively searching the Medline, Embase, and Web of Science databases to identify studies that were related to CS treatment for dCCFs. Then, a meta-analysis was conducted to pool the efficacy and safety outcomes from these studies based on perioperative and follow-up data. RESULTS: Fourteen non-comparative studies enrolling 156 patients with 160 dCCFs met the inclusion criteria. When analyzing perioperative outcomes, the technical success rate was 98.5% [95% confidence interval (CI), 0.948, 1.000], and the immediate complete occlusion rate was 90.9% (95% CI, 0.862, 0.959). Vasospasm and dissection occurred in 32.2% (95% CI, 0.238, 0.463) and 0.1% (95% CI, 0.000, 0.012) of patients, respectively. The in-stent acute thrombus formation rate was 0.1% (95% CI, 0.000; 0.013). Postoperatively, the mortality rate was 0.1% (95% CI, 0.000, 0.013). Based on available follow-up data, the final complete occlusion and parent artery stenosis rates were 99.3% (95% CI, 0.959, 1.000) and 18.6% (95% CI, 0.125, 0.277), respectively. CONCLUSIONS: CS placement can be used to safely and effectively treat dCCFs. These results provide a reference for future clinical trials.

Hydrogen exerts neuroprotective effects after subarachnoid hemorrhage by attenuating neuronal ferroptosis and inhibiting neuroinflammation.

OBJECTIVE: Spontaneous subarachnoid hemorrhage (SAH), the third most common stroke subtype, is associated with high mortality and disability rates. Therefore, finding effective therapies to improve neurological function after SAH is critical. The objective of this study was to investigate the potential neuroprotective effects of hydrogen in the context of SAH, specifically, by examining its role in attenuating neuronal ferroptosis and inhibiting neuroinflammation, which are exacerbated by excess iron ions after SAH. METHODS: Mice were exposed to chambers containing 3% hydrogen, and cells were cultured in incubators containing 60% hydrogen. Neurological function in mice was assessed using behavioral scores. Protein changes were detected using western blotting. Inflammatory factors were detected using enzyme linked immunosorbent assay. Probes, electron microscopy, and related kits were employed to detect oxidative stress and ferroptosis. RESULTS: Hydrogen improved the motor function, sensory function, and cognitive ability of mice after SAH. Additionally, hydrogen facilitated Nuclear factor erythroid 2 -related factor 2 activation, upregulated Glutathione peroxidase 4, and inhibited Toll-like receptor 4, resulting in downregulation of inflammatory responses, attenuation of oxidative stress after SAH, and inhibition of neuronal ferroptosis. CONCLUSION: Hydrogen exerts neuroprotective effects by inhibiting neuronal ferroptosis and attenuating neuroinflammation after SAH.

All-Natural Plant-Derived Polyurethane as a Substitute of a Petroleum-Based Polymer Coating Material.

The development of efficient, biobased polyurethane controlled-release fertilizers from sustainable and eco-friendly biomaterials has received increased research attention, owing to concerns regarding global food security and environmental sustainability. Most previous studies focused on replacing petroleum-based polyols with biopolyols; however, the other main raw material, isocyanate, remained a petrochemical product. Herein, all-natural, plant-derived polyurethane-coated urea was successfully developed using castor oil and biobased isocyanate, and the performance of the coating shell before and after modification was compared. The results showed that the incorporation of a low dose of lauric acid copper into the coating material simultaneously enhanced the hydrophobicity and elasticity of the all-biobased polyurethane membrane, which prolonged the nitrogen release longevity from 3 to 112 days. In addition, the modified membrane showed excellent biodegradability in a soil environment. The novel all-biobased polyurethane coating material and modification technique provide insight for developing sustainable and eco-friendly controlled-release fertilizers.

Integrated multi-omics reveal gut microbiota-mediated bile acid metabolism alteration regulating immunotherapy responses to anti-α4ß7-integrin in Crohn's disease.

Gut microbiota and related metabolites are both crucial factors that significantly influence how individuals with Crohn's disease respond to immunotherapy. However, little is known about the interplay among gut microbiota, metabolites, Crohn's disease, and the response to anti-α4ß7-integrin in current studies. Our research utilized 2,4,6-trinitrobenzene sulfonic acid to induce colitis based on the humanized immune system mouse model and employed a combination of whole-genome shotgun metagenomics and non-targeted metabolomics to investigate immunotherapy responses. Additionally, clinical cases with Crohn's disease initiating anti-α4ß7-integrin therapy were evaluated comprehensively. Particularly, 16S-rDNA gene high-throughput sequencing and targeted bile acid metabolomics were conducted at weeks 0, 14, and 54. We found that anti-α4ß7-integrin therapy has shown significant potential for mitigating disease phenotypes in remission-achieving colitis mice. Microbial profiles demonstrated that not only microbial composition but also microbially encoded metabolic pathways could predict immunotherapy responses. Metabonomic signatures revealed that bile acid metabolism alteration, especially elevated secondary bile acids, was a determinant of immunotherapy responses. Especially, the remission mice significantly enriched the proportion of the beneficial Lactobacillus and Clostridium genera, which were correlated with increased gastrointestinal levels of BAs involving lithocholic acid and deoxycholic acid. Moreover, most of the omics features observed in colitis mice were replicated in clinical cases. Notably, anti-α4ß7 integrin provided sustained therapeutic benefits in clinical remitters during follow-up, and long-lasting remission was linked to persistent changes in the microbial-related bile acids. In conclusion, gut microbiota-mediated bile acid metabolism alteration could play a crucial role in regulating immunotherapy responses to anti-α4ß7-integrin in Crohn's disease. Therefore, the identification of prognostic microbial signals facilitates the advancement of targeted probiotics that activate anti-inflammatory bile acid metabolic pathways, thereby improving immunotherapy responses. The integrated multi-omics established in our research provide valuable insights into potential mechanisms that impact treatment responses in complex diseases.

Menaquinone-4 attenuates ferroptosis by upregulating DHODH through activation of SIRT1 after subarachnoid hemorrhage.

BACKGROUND: Menaquinone-4(MK-4), the isoform of vitamin K2 in the brain, exerts neuroprotective effects against a variety of central nervous system disorders. This study aimed to demonstrate the anti-ferroptosis effects of MK-4 in neurons after SAH. METHODS: A subarachnoid hemorrhage (SAH) model was prepared by endovascular perforation in mice. In vitro hemoglobin stimulation of primary cortical neurons mimicked SAH. MK-4, Brequinar (BQR, DHODH inhibitor), and Selisistat (SEL, SIRT1 inhibitor) were administered, respectively. Subsequently, WB, immunofluorescence was used to determine protein expression and localization, and transmission electron microscopy was used to observe neuronal mitochondrial structure while other indicators of ferroptosis were measured. RESULTS: MK-4 treatment significantly upregulated the protein levels of DHODH; decreased GSH, PTGS2, NOX1, ROS, and restored mitochondrial membrane potential. Meanwhile, MK-4 upregulated the expression of SIRT1 and promoted its entry into the nucleus. BQR or SEL partially abolished the protective effect of MK-4 on, neurologic function, and ferroptosis. CONCLUSIONS: Taken together, our results suggest that MK-4 attenuates ferroptosis after SAH by upregulating DHODH through the activation of SIRT1.

Does the local government multi-objective competition intensify the transfer of polluting industries in the Yangtze River Economic Belt?

Exploring the effect of local government multi-objective competition on the transfer of polluting industries is of great practical significance for promoting the high-quality development in the Yangtze River Economic Belt. This paper adopted the extended shift-share analysis method to measure the scale of inter-provincial transfer of polluting industries in the Yangtze River Economic Belt from 2008 to 2020. Considering local governments' economic, innovation, talent and environmental protection competition, the paper examined the effects of local government multi-objective competition on the transfer of polluting industries in the region, and tested its spatial spillover effects. The results showed that: 1. Different competitions had different effects on the transfer of polluting industries. Economic competition intensified the transfer of polluting industries, while talent, innovation, and environmental protection competition all restrained it, among which environmental protection competition had the strongest restraining effect. 2. Compared with the transfer of polluting industries, the direction of economic competition and environmental protection competition on the transfer of industries did not change, but the degree of influence was reduced, talent competition instead promoted industrial transfer of the research region to some extent. 3. From the basin level, government competition in the upstream region more obviously intensified the transfer of polluting industries; while from the economic scale level, the restraining effect of government competition in the developed region on the transfer of polluting industries was much stronger. 4. Both innovation and environmental protection competition had positive spatial spillover effects. Therefore, it is necessary to optimize the promotion and assessment mechanism of local officials, adopt differentiated competitive constraint mechanisms in accordance with local conditions, guide local governments to transform their development concepts, promote the sharing and common use of technological innovations, and promote the orderly transfer of industries in the Yangtze River Economic Belt.

Adaptive evolution of mitochondrial genomes in Triplophysa cavefishes.

Extreme conditions in caves pose survival challenges for cave dwellers, who gradually develop adaptive survival features. Cavefishes are one of the most successful animals among cave dwellers. Triplophysa cavefishes are an important group of cavefishes, and they show remarkable adaptability to the extreme environments of caves. However, there is a limited understanding of their adaptation mechanisms. In this study, eight complete mitochondrial genomes of Triplophysa cavefishes were newly obtained, and their genomic characteristics, including the base composition, base bias, and codon usage, were analyzed. Phylogenetic analysis was carried out based on 13 mitochondrial protein-coding genes from 44 Nemacheilidae species. This showed that Triplophysa cavefishes and non-cavefishes separate into two reciprocally monophyletic clades, suggesting a single origin of the cave phenotype. Positive selection analysis strongly suggested that the selection pressure in cavefishes is higher than that in non-cavefishes. Furthermore, the ND5 gene in cavefishes showed evidence of positive selection, which suggests that the gene may play an important role in the adaptation of cavefishes to the cave environment. Protein structure analysis of the ND5 subunit implied that the sites of positive selection in cavefishes might allow them to acquire lower ND5 protein stability, compared to that in non-cavefishes, which might help the accumulation of nonsynonymous (mildly deleterious) mutations. Together, our study revealed the genetic signatures of cave adaptation in Triplophysa cavefishes from the perspective of energy metabolism.

Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH.

Subarachnoid hemorrhage (SAH) is a type of stroke with a high disability and mortality rate. Apoptosis caused by massive damage to mitochondria in neuron cells and inflammatory responses caused by high extracellular ATP lead to poor outcomes. USP30 is a deubiquitinating enzyme that inhibits mitophagy, resulting in a failure to remove damaged mitochondria in a timely manner after SAH; nevertheless, the pathway through which USP30 inhibits mitophagy is unknown. This study evaluated the neuroprotective role and possible molecular basis by which inhibiting USP30 to attenuate SAH-induced EBI by promoting neuronal mitophagy. We used an in vitro model of hemoglobin exposure and an in vivo model of intravascular perforation. Increased expression of USP30 was found after SAH in vivo and in vitro, and USP30 inhibition expression in SAH mice treated with MF094 resulted in significant improvement of neurological injury and inflammatory response and mediated good outcomes, suggesting a neuroprotective effect of USP30 inhibition. In cultured neurons, inhibition of USP30 promoted ubiquitination modification of mitochondrial fusion protein 2 (MFN2) by E3 ubiquitin ligase (Parkin), separating damaged mitochondria from the healthy mitochondrial network and prompting mitophagy, causing early clearance of damaged intracellular mitochondria, and reducing the onset of apoptosis. The high extracellular ATP environment was meliorated, reversing the conversion of microglia to a pro-inflammatory phenotype and reducing inflammatory injury. USP30 inhibition had no autophagy-promoting effect on structurally and functionally sound mitochondria and did not inhibit normal intracellular ATP production. The findings suggest that USP30 inhibition has a neuroprotective effect after SAH by promoting early mitophagy after SAH to clear damaged mitochondria.

Transcriptome analysis of the adenoma-carcinoma sequences identifies novel biomarkers associated with development of canine colorectal cancer.

The concept of adenoma-to-cancer transformation in human colorectal cancer (CRC) is widely accepted. However, the relationship between transcriptome features and adenoma to carcinoma transformation in canines is not clear. We collected transcriptome data from 8 normal colon tissues, 4 adenoma tissues, and 15 cancer tissues. Differential analysis was unable to determine the dynamic changes of genes but revealed that PFKFB3 may play a key role in this process. Enrichment analysis explained metabolic dysregulation, immunosuppression, and typical cancer pathways in canine colorectal tumors. MFuzz generated specific dynamic expression patterns of five differentially expressed genes (DEGs). Weighted correlation network analysis showed that DEGs in cluster 3 were associated with malignant tissues, revealing the key role of inflammatory and immune pathways in canine CRC, and the S100A protein family was also found to be involved in the malignant transformation of canine colorectal tumors. By comparing strategies between humans and dogs, we found five novel markers that may be drivers of CRC. Among them, GTBP4 showed excellent diagnostic and prognostic ability. This study was the first systematic exploration of transformation in canine CRC, complemented the molecular characteristics of the development and progression of canine CRC, and provided new potential biomarkers and comparative oncologic evidence for biomarker studies in human colorectal cancer.

Ubiquitin-specific protease 11 structure in complex with an engineered substrate mimetic reveals a molecular feature for deubiquitination selectivity.

Ubiquitin-specific proteases (USPs) are crucial for controlling cellular proteostasis and signaling pathways but how deubiquitination is selective remains poorly understood, in particular between paralogues. Here, we developed a fusion tag method by mining the Protein Data Bank and trapped USP11, a key regulator of DNA double-strand break repair, in complex with a novel engineered substrate mimetic. Together, this enabled structure determination of USP11 as a Michaelis-like complex that revealed key S1 and S1' binding site interactions with a substrate. Combined mutational, enzymatic, and binding experiments identified Met77 in linear diubiquitin as a significant residue that leads to substrate discrimination. We identified an aspartate "gatekeeper" residue in the S1' site of USP11 as a contributing feature for discriminating against linear diubiquitin. When mutated to a glycine, the corresponding residue in paralog USP15, USP11 acquired elevated activity toward linear diubiquitin in-gel shift assays, but not controls. The reverse mutation in USP15 confirmed that this position confers paralog-specific differences impacting diubiquitin cleavage rates. The results advance our understanding of the molecular basis for the higher selectivity of USP11 compared to USP15 and may aid targeted inhibitor development. Moreover, the reported carrier-based crystallization strategy may be applicable to other challenging targets.

Tidal volume challenge-induced hemodynamic changes can predict fluid responsiveness during one-lung ventilation: an observational study.

Background: To evaluate the ability of tidal volume challenge (VTC)-induced hemodynamic changes to predict fluid responsiveness in patients during one-lung ventilation (OLV). Methods: 80 patients scheduled for elective thoracoscopic surgery with OLV were enrolled. The inclusion criteria were: age ≥ 18 years, American Society of Anesthesiologists physical status I-III, normal right ventricular function, normal left ventricular systolic function (ejection fraction ≥55%), and normal or slightly impaired diastolic function. The study protocol was implemented 15 min after starting OLV. Simultaneous recordings were performed for hemodynamic variables of diameter of left ventricular outflow tract, velocity time integral (VTI) of aortic valve, and stroke volume (SV), and ΔSV-VTC, ΔVTI-VTC, and ΔMAP-VTC were calculated at four time points: with VT 5 mL/kg (T1); after VT increased from 5 mL/kg to 8 mL/kg and maintained at this level for 2 min (T2); after VT was adjusted back to 5 mL/kg for 2 min (T3); and after volume expansion (250 mL of 0.9% saline infused over 10-15 min) (T4). Patients were considered as responders to fluid administration if SV increased by ≥10%. Receiver operating characteristic (ROC) curves for percent decrease in SV, VTI, and MAP by VTC were generated to evaluate their ability to discriminate fluid responders from nonresponders. Results: Of the 58 patients analyzed, there were 32 responders (55%) and 26 nonresponders (45%). The basic characteristics were comparable between the two groups (p > 0.05). The area under the curve (AUC) for ΔSV-VTC, ΔVTI-VTC, and ΔMAP-VTC to discriminate responders from nonresponders were 0.81 (95% CI: 0.68-0.90), 0.79 (95% CI: 0.66-0.89), and 0.56 (95% CI: 0.42-0.69). The best threshold for ΔSV-VTC was -16.1% (sensitivity, 78.1%; specificity, 84.6%); the best threshold for ΔVTI-VTC was -14.5% (sensitivity, 78.1%; specificity, 80.8%). Conclusion: Tidal volume challenge-induced relative change of stroke volume and velocity time integral can predict fluid responsiveness in patients during one-lung ventilation.Clinical Trial Registration: Chinese Clinical Trial Registry, No: chictr210051310.

ZDHHC11B is decreased in lung adenocarcinoma and inhibits tumorigenesis via regulating epithelial-mesenchymal transition.

PURPOSE: The role and mechanism of zinc finger DHHC protein 11B (ZDHHC11B) in lung adenocarcinoma (LUAD) remain unclear. We, thus, analyzed the expression pattern, biological function, and potential mechanism of ZDHHC11B in LUAD. METHODS: The expression level and prognostic value of ZDHHC11B were evaluated based on The Cancer Genome Atlas (TCGA) database and further confirmed in LUAD tissues and cells. The effect of ZDHHC11B on the malignant biological progression of LUAD was evaluated in vitro and in vivo. Gene set enrichment analysis (GSEA) and western blot were used to explore the molecular mechanisms of ZDHHC11B. RESULTS: In vitro, ZDHHC11B inhibited the proliferation, migration, and invasion of LUAD cells and induced the apoptosis of LUAD cells. In addition, ZDHHC11B inhibited the growth of tumors in nude mice. GSEA revealed that ZDHHC11B expression is positively correlated with epithelial-mesenchymal transition (EMT). Western blot analysis demonstrated that molecular markers of EMT were inhibited under ZDHHC11B overexpression conditions. CONCLUSIONS: Our findings indicated that ZDHHC11B plays a significant role in inhibiting tumorigenesis via EMT. In addition, ZDHHC11B may be a candidate molecular target for LUAD treatment.

Transcriptomic analysis reveals immune infiltration status and potential biomarkers of canine colorectal cancer.

Colorectal cancer (CRC) in dogs has been shown to have similar molecular characteristics to human colorectal cancer. Although researchers have explored the pathogenesis and immune status of human CRC, the canine CRC has been far less studied. As a result, we analyzed canine colorectal tumors and normal canine intestinal samples by Gene Set Enrichment Analysis (GSEA) and found significant enrichment of immune-related pathways, including the TNF-α signaling pathway and IL6-STAT3 signaling pathway. In addition, the differential infiltration of naive B cells and regulatory T cells suggested that canine CRC was in a state of immunosuppression. Weighted gene co-expression network analysis (WGCNA) revealed the gene modules that contribute to differences in regulatory T cell inetfiltration, Further cross-validation of canine and human CRC differential genes obtained three core genes that are both species-conserved and differentially expressed, CD44, NAT10, and ETV4, of which NAT10 and ETV4 have been little studied in the immune status of colorectal cancer. Our findings may have implications for the pathogenesis and progression of CRC in dogs and could be a new potential therapeutic target for CMT and provide a bioinformatics foundation for later clinical experiment validation.

Hydrogen inhalation therapy regulates lactic acid metabolism following subarachnoid hemorrhage through the HIF-1α pathway.

The neuroprotective effects of hydrogen have been demonstrated, but the mechanism is still poorly understood. In a clinical trial of inhaled hydrogen in patients with subarachnoid hemorrhage (SAH), we found that hydrogen reduced the accumulation of lactic acid in the nervous system. There are no studies demonstrating the regulatory effect of hydrogen on lactate and in this study we hope to further clarify the mechanism by which hydrogen regulates lactate metabolism. In cell experiments, PCR and Western Blot showed that HIF-1α was the target related to lactic acid metabolism that changed the most before and after hydrogen intervention. HIF-1α levels were suppressed by hydrogen intervention treatment. Activation of HIF-1α inhibited the lactic acid-lowering effect of hydrogen. We have also demonstrated the lactic acid-lowering effect of hydrogen in animal studies. Our work clarifies that hydrogen can regulate lactate metabolism via the HIF-1αpathway, providing new insights into the neuroprotective mechanisms of hydrogen.

Rough Nanovaccines Boost Antitumor Immunity Through the Enhancement of Vaccination Cascade and Immunogenic Cell Death Induction.

Nanovaccines have attracted intense interests for efficient antigen delivery and tumor-specific immunity. It is challenging to develop a more efficient and personalized nanovaccine to maximize all steps of the vaccination cascade by exploiting the intrinsic properties of nanoparticles. Here, biodegradable nanohybrids (MP) composed of manganese oxide nanoparticles and cationic polymers are synthesized to load a model antigen ovalbumin to form MPO nanovaccines. More interestingly, MPO could serve as autologous nanovaccines for personalized tumor treatment taking advantage of in situ released tumor-associated antigens induced by immunogenic cell death (ICD). The intrinsic properties of MP nanohybrids including morphology, size, surface charge, chemical, and immunoregulatory functions are fully exploited to enhance of all steps of the cascade and induce ICD. MP nanohybrids are designed to efficiently encapsulate antigens by cationic polymers, drain to lymph nodes by appropriate size, be internalized by dendritic cells (DCs) by rough morphology, induce DC maturation through cGAS-STING pathway, and enhance lysosomal escape and antigen cross-presentation through the "proton sponge effect". The MPO nanovaccines are found to efficiently accumulate in lymph nodes and elicit robust specific T-cell immune responses to inhibit the occurrence of ovalbumin-expressing B16-OVA melanoma. Furthermore, MPO demonstrate great potential to serve as personalized cancer vaccines through the generation of autologous antigen depot through ICD induction, activation of potent antitumor immunity, and reversal of immunosuppression. This work provides a facile strategy for the construction of personalized nanovaccines by exploiting the intrinsic properties of nanohybrids.

Comparative efficacy and safety of combination therapy with infliximab for Crohn's disease: a systematic review and network meta-analysis.

PURPOSE: There is not enough information to position medications for the treatment of Crohn's disease (CD). Therefore, using a network meta-analysis and systematic review, we evaluated the efficacy and safety of combination therapy and infliximab (IFX) monotherapy in CD patients. METHODS: We identified randomized controlled trials (RCTs) in CD patients who were given IFX-containing combination therapy versus IFX monotherapy. Induction and maintenance of clinical remission were the efficacy outcomes, while adverse events were the safety outcomes. The surface under cumulative ranking (SUCRA) probabilities was used to assess ranking in the network meta-analysis. RESULTS: In total, 15 RCTs with 1586 CD patients were included in this study. There was no statistical difference between different combination therapies in induction and maintenance of remission. In terms of inducing clinical remission, IFX + EN (SUCRA: 0.91) ranked highest; in terms of maintaining clinical remission, IFX + AZA (SUCRA: 0.85) ranked highest. There was no treatment that was significantly safer than the others. In terms of any adverse events, serious adverse events, serious infections, and infusion/injection-site reactions, IFX + AZA (SUCRA: 0.36, 0.12, 0.19, and 0.24) was ranked lowest for all risks; while IFX + MTX (SUCRA: 0.34, 0.06, 0.13, 0.08, 0.34, and 0.08) was rated lowest for risk of abdominal pain, arthralgia, headache, nausea, pyrexia, and upper respiratory tract infection. CONCLUSION: Indirect comparisons suggested that efficacy and safety of different combination treatments are comparable in CD patients. For maintenance therapies, IFX + AZA was ranked highest for clinical remission and lowest for adverse events. Further head-to-head trials are required.