Enantioselective Nickel-Electrocatalyzed Reductive Propargylic Carboxylation with CO2.

The exploitation of carbon dioxide (CO2) as a sustainable, plentiful, and harmless C1 source for the catalytic synthesis of enantioenriched carboxylic acids has long been acknowledged as a pivotal task in synthetic chemistry. Herein, we present a current-driven nickel-catalyzed reductive carboxylation reaction with CO2 fixation, facilitating the formation of C(sp3)-C(sp2) bonds by circumventing the handling of moisture-sensitive organometallic reagents. This electroreductive protocol serves as a practical platform, paving the way for the synthesis of enantioenriched propargylic carboxylic acids (up to 98% enantiomeric excess) from racemic propargylic carbonates and CO2. The efficacy of this transformation is exemplified by its successful utilization in the asymmetric total synthesis of (S)-arundic acid, (R)-PIA, (S)-chizhine D, (S)-cochlearin G, and (S,S)-alexidine, thereby underscoring the potential of asymmetric electrosynthesis to achieve complex molecular architectures sustainably.

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors.

VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidine-based VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a KD value of 0.49 ± 0.20 µM. In vitro, A4 significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.

Prognostic characteristics of a six-gene signature based on ssGSEA in sarcoma.

BACKGROUND: Sarcoma is a rare malignant tumor originating of the interstitial or connective tissue with a poor prognosis. Next-generation sequencing technology offers new opportunities for accurate diagnosis and treatment of sarcomas. There is an urgent need for new gene signature to predict prognosis and evaluate treatment outcomes. METHODS: We used transcriptome data from the Cancer Genome Atlas (TCGA) database and single sample gene set enrichment analysis (ssGSEA) to explore the cancer hallmarks most associated with prognosis in sarcoma patients. Then, weighted gene coexpression network analysis, univariate COX regression analysis and random forest algorithm were used to construct prognostic gene characteristics. Finally, the prognostic value of gene markers was validated in the TCGA and Integrated Gene Expression (GEO) (GSE17118) datasets, respectively. RESULTS: MYC targets V1 and V2 are the main cancer hallmarks affecting the overall survival (OS) of sarcoma patients. A six-gene signature including VEGFA, HMGB3, FASN, RCC1, NETO2 and BIRC5 were constructed. Kaplan-Meier analysis suggested that higher risk scores based on the six-gene signature associated with poorer OS (P < 0.001). The receiver Operating characteristic curve showed that the risk score based on the six-gene signature was a good predictor of sarcoma, with an area under the curve (AUC) greater than 0.73. In addition, the prognostic value of the six-gene signature was validated in GSE17118 with an AUC greater than 0.72. CONCLUSION: This six-gene signature is an independent prognostic factor in patients with sarcoma and is expected to be a potential therapeutic target for sarcoma.

Bispecific antibodies in cancer therapy: Target selection and regulatory requirements.

In recent years, the development of bispecific antibodies (bsAbs) has been rapid, with many new structures and target combinations being created. The boom in bsAbs has led to the successive issuance of industry guidance for their development in the US and China. However, there is a high degree of similarity in target selection, which could affect the development of diversity in bsAbs. This review presents a classification of various bsAbs for cancer therapy based on structure and target selection and examines the advantages of bsAbs over monoclonal antibodies (mAbs). Through database research, we have identified the preferences of available bsAbs combinations, suggesting rational target selection options and warning of potential wastage of medical resources. We have also compared the US and Chinese guidelines for bsAbs in order to provide a reference for their development.

Extracellular matrix bioink boosts stemness and facilitates transplantation of intestinal organoids as a biosafe Matrigel alternative.

Organoids hold inestimable therapeutic potential in regenerative medicine and are increasingly serving as an in vitro research platform. Still, their expanding applications are critically restricted by the canonical culture matrix and system. Synthesis of a suitable bioink of bioactivity, biosecurity, tunable stiffness, and printability to replace conventional matrices and fabricate customized culture systems remains challenging. Here, we envisaged a novel bioink formulation based on decellularized extracellular matrix (dECM) from porcine small intestinal submucosa for organoids bioprinting, which provides intestinal stem cells (ISCs) with niche-specific ECM content and biomimetic microstructure. Intestinal organoids cultured in the fabricated bioink exhibited robust generation as well as a distinct differentiation pattern and transcriptomic signature. This bioink established a new co-culture system able to study interaction between epithelial homeostasis and submucosal cells and promote organoids maturation after transplantation into the mesentery of immune-deficient NODSCID-gamma (NSG) mice. In summary, the development of such photo-responsive bioink has the potential to replace tumor-derived Matrigel and facilitate the application of organoids in translational medicine and disease modeling.

Novel Small-Molecule PD-L1 Inhibitor Induces PD-L1 Internalization and Optimizes the Immune Microenvironment.

Blocking the PD-1/PD-L1 interaction has become an important strategy for tumor therapy, which has shown outstanding therapeutic effects in clinical settings. However, unsatisfactory response rates and immune-related adverse effects limit the use of anti-PD1/PD-L1 antibodies. Here, we report the discovery and identification of S4-1, an innovative small-molecule inhibitor of PD-L1. In vitro, S4-1 effectively altered the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, improved its localization to endoplasmic reticulum, and thus enhanced the cytotoxicity of peripheral blood mononuclear cells toward tumor cells. In vivo, S4-1 significantly inhibited tumor growth in both lung and colorectal cancer models, particularly in colorectal cancer, where it led to complete clearance of a portion of the tumor cells. Furthermore, S4-1 induced T-cell activation and inversed the inhibitory tumor microenvironment, consistent with the PD-L1/PD-1 pathway blockade. These data support the continued evaluation of S4-1 as an alternative ICB therapeutic strategy.

Novel phthalimides regulating PD-1/PD-L1 interaction as potential immunotherapy agents.

Programmed cell death 1(PD-1)/programmed cell death ligand 1(PD-L1) have emerged as one of the most promising immune checkpoint targets for cancer immunotherapy. Despite the inherent advantages of small-molecule inhibitors over antibodies, the discovery of small-molecule inhibitors has fallen behind that of antibody drugs. Based on docking studies between small molecule inhibitor and PD-L1 protein, changing the chemical linker of inhibitor from a flexible chain to an aromatic ring may improve its binding capacity to PD-L1 protein, which was not reported before. A series of novel phthalimide derivatives from structure-based rational design was synthesized. P39 was identified as the best inhibitor with promising activity, which not only inhibited PD-1/PD-L1 interaction (IC50 = 8.9 nmol/L), but also enhanced killing efficacy of immune cells on cancer cells. Co-crystal data demonstrated that P39 induced the dimerization of PD-L1 proteins, thereby blocking the binding of PD-1/PD-L1. Moreover, P39 exhibited a favorable safety profile with a LD50 > 5000 mg/kg and showed significant in vivo antitumor activity through promoting CD8+ T cell activation. All these data suggest that P39 acts as a promising small chemical inhibitor against the PD-1/PD-L1 axis and has the potential to improve the immunotherapy efficacy of T-cells.

Multifunctional hydrogel based on dopamine-modified hyaluronic acid, gelatin and silver nanoparticles for promoting abdominal wall defect repair.

Abdominal wall defects are often accompanied by severe infections and complications, creating a significant challenge for clinicians. There is an urgent need to develop a novel wound dressing that can effectively prevent intra-abdominal infection and promote the healing of defective abdominal walls. Based on a hydrogel dressing containing hyaluronic acid (HA) and gelatin (GT), herein we integrated dopamine with a catechol structure to enhance its antioxidant and adherent properties. HA is oxidized to form an aldehyde group, and subsequently grafted with dopamine. The dopamine-modified HA undergoes amidation reaction with GT at different concentrations. In addition, silver nanoparticles (AgNPs) were introduced to the hydrogel to enhance the antibacterial properties. The in vitro studies on GT/DA-HA demonstrated excellent physical and chemical properties, biodegradability, and biocompatibility. In a rat full-thickness skin defect model and a full-thickness abdominal wall defect model, the GT/DA-HA hydrogel could accelerate the healing process by improving wet adhesion, reducing wound inflammation, and promoting angiogenesis and formation of granulation tissues. The multifunctional hydrogel developed in this study shows great potential for treating full-thickness abdominal wall defects.

Human circulating bacteria and dysbiosis in non-infectious diseases.

Blood microorganisms were once thought to indicate infection. Blood in healthy people appears to be devoid of growing bacteria; nonetheless, intracellular dormant forms of bacteria have been reported previously. With breakthroughs in sequencing and bioinformatics, the presence of bacterial DNA in healthy human blood initiated the controversy of human blood microbiota (HBM). Recently, bacteria-specific DNA and culturable bacteria were found in healthy human blood. Researchers wanted to study the phenomena of a "healthy blood microbiota" by providing a thorough description of bacterially produced nucleic acids using many complementing molecular and traditional microbiological approaches. Because blood is a relatively limited and particular environment, culturability and plate count issues can be overcome using enhanced cultured procedures. However, more evidence is required to confirm that healthy human blood contains normal microbiota. Cavities, mouth and intestinal microbiota, trauma, surgery, and animal/insect bites can introduce bacteria into human blood. All these factors strengthen the concept of transient blood bacteria too. The presence of blood bacteria may be caused by temporary immunological clearance and absorption by dendritic or M cells. This review provides an extensive and comprehensive analysis that suggests that healthy blood bacteria may not be typical microbiota but transient circulatory microorganisms. In this study, we look at how contaminants (Escherichia, Shigella, Pseudomonads, etc.) from the skin, laboratory environments, and reagents can affect the interpretation of blood-derived microbial information and the relationship between the circulating bacteria and non-communicable diseases. Circulating transient bacteria may play a role in the pathogenesis of non-infectious diseases such as diabetes and CVD. Contamination-free hematological studies can aid in understanding the disease mechanisms, therapy, and biomarkers.

Trocar Puncture With a Sump Drain for Crohn's Disease With Intra-Abdominal Abscess: A 10-Year Retrospective Cohort Study.

Background: Traditional percutaneous catheter drainage (PCD) and surgical intervention could not always achieve satisfactory results for patients with Crohn's disease (CD) who have complications with intra-abdominal abscess. We proposed a trocar puncture with sump drainage for the treatment of CD with intra-abdominal abscess and compared it with the conventional PCD and surgical intervention. Methods: Crohn's disease patients with intra-abdominal abscess and admitted to our hospital from 2011 to 2020 were identified by reviewing the electronic medical records. We divided them into Trocar, PCD, and fecal diverting (FD) groups, according to the ways of treating an abscess. Outcomes, risk factors for abscess recurrence, and postoperative complications were compared among the three groups. Results: A total of 69 patients were included and they were divided into Trocar (n = 18), PCD (n = 29), and FD (n = 22) groups. Four patients in the PCD group were transferred to receive the FD surgery due to the failure of initial treatment. The incidence of abscess recurrence was significantly higher in the PCD (48%) and FD (50%) groups compared to the patients using the trocar puncture with the sump drain (Trocar group) (16.7%). There were 8 patients in Trocar, 22 in PCD, and 20 s in the FD group who received enterectomy. None of the patients in the Trocar had an ultimate stoma and the incidence of postoperative complications was statistically lower [0% (Trocar) vs. 31.8% (PCD) vs. 45% (FD), P < 0.05]. The way of initial treating of the abscess was significantly correlated with the abscess recurrence and postoperative complications. Conclusions: Trocar puncture with a sump drain had a lower incidence of abscess recurrence, abdominal adhesions, postdrainage, and postoperative complications compared to the conventional PCD or surgical intervention.

Efficacy and safety of over-the-scope clips (OTSC®) for closure of gastrointestinal fistulas less than 2 cm.

BACKGROUND AND AIM: Gastrointestinal (GI) fistula is a complication of surgery associated with potential morbidity and mortality. The aim of this study was to evaluate the efficacy and safety of over-the-scope clips (OTSC®) for closing GI fistulas. METHODS: Patients with GI fistula who underwent endoscopic closure using OTSC® were enrolled. The clinical date, duration, location and diameter of the fistula, technical success of the OTSC®, complications, follow-up periods and clinical success were recorded. RESULTS: A total of 98 patients with GI fistula underwent OTSC® closure. Their median age was 50 years (range 16-88 years), and the median duration of the fistula was 185.5 days (range 12-3129 days). The mean diameter of fistula was 4.64 ± 1.16 mm. Technical success was achieved in 100% of the patients, and clinical success was achieved in 55.10% (54/98) of the patients after a median follow-up of 168.5 days (range 36-424 days). Based on the location of the fistula, the clinical success rate of treating a fistula in the esophagus and small intestine was 100%, followed by the rectum (70%, 7/10), anastomotic stoma (61.90%, 13/21), duodenum (53.33%, 8/15), colon (47.06%, 8/17), stomach (43.47%, 10/23) and appendix stump (33.33%, 2/6). The duration of the fistula (HR 3.609, 95% CI 1.387-9.387, P = 0.009) was a risk factor for clinical success by multivariate analysis. CONCLUSION: OTSC® is a safe and efficient treatment for GI fistula and is a potential alternative to the surgical approach. Before OTSC® placement, the duration of the fistula should be assessed since it is related to the successful closures with OTSC®.

STING-mediated Syk Signaling Attenuates Tumorigenesis of Colitis­associated Colorectal Cancer Through Enhancing Intestinal Epithelium Pyroptosis.

BACKGROUND: Stimulator of interferon genes (STING) has essential functions in the immune responses and can induce cancer cell apoptosis. However, it is not completely clear how STING plays a role in colitis-associated colorectal cancer (CAC) and whether it can trigger pyroptosis during the tumorigenesis of CAC. METHODS: To investigate the role of STING-modulated pyroptosis in the development of CAC, STING knockout and Wild type mice were challenged with azoxymethane (AOM) and dextran sodium sulfate (DSS) to establish a murine CAC model. STING pharmacological agonist was used to further study the functions of STING signaling in the tumorigenesis. Moreover, STING endogenous ligand was employed to verify the effects of STING in human colon cancer cells. RESULTS: STING deficiency mice were more susceptible to CAC by reducing pyroptosis of tumor cells, whereas overactivation of STING with the agonist suppressed tumorigenesis of CAC. STING also managed CAC development by modulating tumor cells proliferation, adhesion, and invasion, as well as inflammatory response. The ex vivo studies indicated that STING could induce pyroptosis via spleen tyrosine kinase (Syk), and Syk knockdown weakened such pyroptotic tumor cells death. In addition, the visible physical interaction between STING and Syk was observed in colorectal tumor samples of CAC patients. CONCLUSIONS: STING-mediated Syk signaling may regulate the tumorigenesis of CAC by modulating pyroptosis of tumor cells, and modulation of STING/Syk serves as a novel therapeutic strategy for CAC therapy.

Anti-influenza A Virus Effects and Mechanisms of Emodin and Its Analogs via Regulating PPARα/γ-AMPK-SIRT1 Pathway and Fatty Acid Metabolism.

The peroxisome proliferator-activated receptor (PPAR) α/γ-adenosine 5'-monophosphate- (AMP-) activated protein kinase- (AMPK-) sirtuin-1 (SIRT1) pathway and fatty acid metabolism are reported to be involved in influenza A virus (IAV) replication and IAV-pneumonia. Through a cell-based peroxisome proliferator responsive element- (PPRE-) driven luciferase bioassay, we have investigated 145 examples of traditional Chinese medicines (TCMs). Several TCMs, such as Polygonum cuspidatum, Rheum officinale Baillon, and Aloe vera var. Chinensis (Haw.) Berg., were found to possess high activity. We have further detected the anti-IAV activities of emodin (EMO) and its analogs, a group of common important compounds of these TCMs. The results showed that emodin and its several analogs possess excellent anti-IAV activities. The pharmacological tests showed that emodin significantly activated PPARα/γ and AMPK, decreased fatty acid biosynthesis, and increased intracellular ATP levels. Pharmaceutical inhibitors, siRNAs for PPARα/γ and AMPKα1, and exogenous palmitate impaired the inhibition of emodin. The in vivo test also showed that emodin significantly protected mice from IAV infection and pneumonia. Pharmacological inhibitors for PPARα/γ and AMPK signal and exogenous palmitate could partially counteract the effects of emodin in vivo. In conclusion, emodin and its analogs are a group of promising anti-IAV drug precursors, and the pharmacological mechanism of emodin is linked to its ability to regulate the PPARα/γ-AMPK pathway and fatty acid metabolism.

Cardiac surgery under cardiopulmonary bypass in pregnancy: report of four cases.

BACKGROUND: Open heart surgery during pregnancy is relatively rare at home and abroad, and there is a higher risk and probability of maternal and infant death. How to carry out heart valve replacement under cardiopulmonary bypass (CPB) under the premise of ensuring the safety of mother and child is the focus of attention at home and abroad. CASE INTRODUCTION: We reported four cases of cardiac surgeries under CPB during pregnancy performed in our hospital from March 2020 to March 2021. Two of the patients continued their pregnancy after cardiac surgery under CPB. Three patients had infective endocarditis and the other one had an ascending aortic aneurysm. Three patients underwent heart valve placement with the mechanical mitral valve when the other one underwent Bentall surgery. The operations of four cases were all successful, and further follow-up evaluation of the pregnant women and fetuses showed no abnormalities. The patients' detailed information is shown in the following table. CONCLUSION: Heart disease during pregnancy should be treated actively and proactively when the patient has obvious symptoms. Heart valve replacement under CPB will be the first choice, and this may become the primary surgical treatment for symptomatic heart disease during pregnancy.

Could Jinfukang alleviate the chemotherapy-related adverse effects in non-small cell lung cancer patients?: A protocol for a double-blind, randomized controlled trial.

BACKGROUND: Lung cancer is the main cause of cancer-related death in the world, and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Cisplatin and its derivatives are the first-line chemotherapeutic drugs for patients with advanced lung cancer, but the chemotherapy-related adverse reactions greatly impact the quality of life (QOL) of patients and limit their use. Jinfukang is a commonly used traditional Chinese medicine preparation with anti-tumor effect in China, which has been approved by China Food and Drug Administration against NSCLC. At present, there is a lack of strict randomized controlled trials to study whether Jinfukang could alleviate the chemotherapy-related adverse effects in the treatment of advanced NSCLC. Therefore, we intend to perform a double-blind, placebo controlled, randomized trial to evaluate the effect of Jinfukang in alleviating the chemotherapy-related adverse effects of patients with advanced NSCLC. METHODS: This is a prospective, double-blind, randomized, placebo controlled trial. According to the randomized control principle, 168 patients will be divided into treatment group and control group at 1:1 ratio. The patients in the two groups will be treated continuously for 3 cycles and followed up for 3 years. Outcome indicators include: the incidence of chemotherapy-related adverse effects, the progression-free survival (PFS), total effective rate, and QOL evaluation. We will use SPSS19.0 to analyze the results. CONCLUSIONS: This study will help to evaluate the effect of Jinfukang alleviating chemotherapy-related adverse effects in the treatment of advanced NSCLC. TRIAL REGISTRATION: DOI 10.17605/OSF.IO/YWBSC.

Intestinal mucosa-derived DNA methylation signatures in the penetrating intestinal mucosal lesions of Crohn's disease.

The purpose of this study was to evaluate genome-wide DNA methylation changes in intestinal mucosa tissue of adult patients with Crohn's disease comprehensively. DNA methylation chip was used to analyze abnormal methylation sites among penetrating and non-penetrating intestinal mucosa tissue of Crohn's disease and normal intestinal mucosa tissue of healthy controls. Methylation abnormalities of different locus were verified by pyrosequencing and quantitative polymerase chain reaction. Differential DNA methylation sites were participated in the positive regulation of apoptosis and the positive regulation of IL-8 production and were enriched in signaling pathways related to inflammatory bowel disease and extracellular matrix receptor interaction signaling pathways. Correlation analysis showed that the methylation abnormalities of HLA-DRB1 (r = - 0.62, P < 0.001), MUC1 (r = - 0.45, P = 0.01), YPEL5 (r = - 0.55, P = 0.001) and CBLB (r = - 0.62, P < 0.001) were significantly negatively correlated with their relative expression levels. The degree of methylation abnormality of MUC1 was negatively correlated with the disease activity score of Crohn's disease (r = - 0.50, P = 0.01). Apoptosis, interleukin-8 production and abnormal extracellular matrix might be involved in the mechanism of penetrating intestinal mucosal lesions in Crohn's disease. The degree of abnormal methylation of MUC1 was negatively correlated with the disease activity of Crohn's disease.

Macropore design of tissue engineering scaffolds regulates mesenchymal stem cell differentiation fate.

Craniosynostosis is a debilitating birth defect characterized by the premature fusion of cranial bones resulting from premature loss of stem cells located in suture tissue between growing bones. Mesenchymal stromal cells in long bone and the cranial suture are known to be multipotent cell sources in the appendicular skeleton and cranium, respectively. We are developing biomaterial constructs to maintain stemness of the cranial suture cell population towards an ultimate goal of diminishing craniosynostosis patient morbidity. Recent evidence suggests that physical features of synthetic tissue engineering scaffolds modulate cell and tissue fate. In this study, macroporous tissue engineering scaffolds with well-controlled spherical pores were fabricated by a sugar porogen template method. Cell-scaffold constructs were implanted subcutaneously in mice for up to eight weeks then assayed for mineralization, vascularization, extracellular matrix composition, and gene expression. Pore size differentially regulates cell fate, where sufficiently large pores provide an osteogenic niche adequate for bone formation, while sufficiently small pores (<125 µm in diameter) maintain stemness and prevent differentiation. Cell-scaffold constructs cultured in vitro followed the same pore size-controlled differentiation fate. We therefore attribute the differential cell and tissue fate to scaffold pore geometry. Scaffold pore size regulates mesenchymal cell fate, providing a novel design motif to control tissue regenerative processes and develop mesenchymal stem cell niches in vivo and in vitro through biophysical features.

JINLING (Judicious INdex of Luminal INflammation Grade) score, an effective indicator to assess inflammation severity in Crohn's disease.

BACKGROUND: With the increasing demand for individualized treatment in Crohn's disease, a score for accurate evaluation of inflammation grade will be of great significance. We have developed the JINLING score to assess inflammation severity for Crohn's disease, which incorporates an endoscopic score (SES-CD) and a 2-item patient-reported outcome (PRO2). The aim of this study was to examine the performance of JINLING score in evaluating inflammation grade and the correlation with the clinical outcomes. METHODS: The correlation between JINLING score and Global Histologic Disease Activity Score (GHAS), fecal calprotectin (FCP), and C-reactive protein (CRP) level was performed in an exploration phase with a retrospective data set. The data on clinical outcomes including medication effects, Crohn's disease-related surgery and biochemical results were collected from a single-center prospective validation cohort. RESULTS: JINLING score correlated significantly with FCP, CRP, and hemoglobin in the exploration cohort (all P < 0.05). The receiver operating characteristic (ROC) curves based on a threshold Crohn's disease activity index value of 150, GHAS of 4, and FCP of 60 µg/g to identify disease activity, all showed a higher area under the curve with JINLING score than SES-CD or PRO2 alone. In the validation cohort, patients with high inflammation grade (JINLING ≥4) had higher GHAS, CRP, and FCP than low inflammation grade patients. High JINLING score was associated with an increased risk of treatment failure (hazard ratio 2.93; 95% confidence interval 1.13-7.61, P = 0.021). CONCLUSION: This newly developed index served well for quantifying inflammation grade and predicting clinical outcomes. JINLING score has the potential to facilitate clinical decision-making and personalized therapy for Crohn's disease patients.

Early Enteral Nutrition Preserves Intestinal Barrier Function through Reducing the Formation of Neutrophil Extracellular Traps (NETs) in Critically Ill Surgical Patients.

BACKGROUND: The gut was suggested as the driver of critical illness and organ injury. Recently, excessive formation of neutrophil extracellular traps (NETs) was associated with mucosal inflammation. Direct investigation of intestinal mucosa is essential to illuminate the potential mechanism of gut barrier in critically ill patients. We hypothesized that early enteral nutrition (EN) could decrease intestinal NETs and maintain the gut barrier. METHODS: Intestinal biopsies were obtained using biopsy forceps from critically ill surgical patients complicated with enterocutaneous fistula. Expressions of tight junction (TJ) proteins, mucosal inflammation, and apoptosis were evaluated. Moreover, NET-associated proteins were evaluated in intestinal specimens of patients by Western blot and immunofluorescence analysis. RESULTS: The intestinal barrier was significantly impaired in critically ill patients receiving early total parenteral nutrition (TPN), evidenced by intestinal villi atrophy, inflammatory infiltration, increased enterocyte apoptosis, and abnormal TJ expressions. Early EN significantly alleviated these intestinal injuries. In addition, we observed increased formation of the NET structure and elevated expressions of NET-associated proteins in intestines of critically ill surgical patients. Early EN was associated with the diminished presence of NETs and reduced expression of NET-associated proteins. Mechanically, analysis of the TLR4 pathway showed a significant increase in TLR4, NFκB, and MAPK signaling in patients receiving TPN when compared to those receiving early EN. CONCLUSION: The intestinal barrier is disrupted in the human gut during critical illness. Our data suggests that an increased NET structure was showed in the gut of critically ill surgical patients, and early EN treatment was associated with the reduction of NET formation and the preservation of mucosal immunity.

Incidence and risk factors of surgical site infection following colorectal surgery in China: a national cross-sectional study.

PURPOSES: Surgical site infection (SSI) after colorectal surgery is a frequent complication associated with the increase in morbidity, medical expenses, and mortality. To date, there is no nationwide large-scale database of SSI after colorectal surgery in China. The aim of this study was to determine the incidence of SSI after colorectal surgery in China and to further evaluate the related risk factors. METHODS: Two multicenter, prospective, cross-sectional studies covering 55 hospitals in China and enrolling adult patients undergoing colorectal surgery were conducted from May 1 to June 30 of 2018 and the same time of 2019. The demographic and perioperative characteristics were collected, and the main outcome was SSI within postoperative 30 days. Multivariable logistic regressions were conducted to predict risk factors of SSI after colorectal surgery. RESULTS: In total, 1046 patients were enrolled and SSI occurred in 74 patients (7.1%). In the multivariate analysis with adjustments, significant factors associated with SSI were the prior diagnosis of hypertension (OR, 1.903; 95% confidence interval [CI], 1.088-3.327, P = 0.025), national nosocomial infection surveillance risk index score of 2 or 3 (OR, 3.840; 95% CI, 1.926-7.658, P < 0.001), laparoscopic or robotic surgery (OR, 0.363; 95% CI, 0.200-0.659, P < 0.001), and adhesive incise drapes (OR, 0.400; 95% CI, 0.187-0.855, P = 0.018). In addition, SSI group had remarkably increased length of postoperative stays (median, 15.0 d versus 9.0d, P < 0.001), medical expenses (median, 74,620 yuan versus 57,827 yuan, P < 0.001), and the mortality (4.1% versus 0.3%, P = 0.006), compared with those of non-SSI group. CONCLUSION: This study provides the newest data of SSI after colorectal surgery in China and finds some predictors of SSI. The data presented in our study can be a tool to develop optimal preventive measures and improve surgical quality in China.