Small molecules for inflammatory bowel disease and the risk of infection and malignancy: A systematic review and meta-Analysis.

OBJECTIVES: This meta-analysis aimed to ascertain whether small molecule drugs increase the risk of infection or malignancy in adult IBD patients. METHODS: A comprehensive search of eight databases was conducted from their inception to November 2023. The risk of infections or malignancies in adult IBD patients treated with JAK inhibitors and S1P receptor modulators was compared. Fixed-effects or random-effects models were performed, and relative risk (RR) and 95 % confidence interval (CI) were calculated. RESULTS: 27 RCTs from 14 studies were included (n = 10,623). The evidence indicates that small molecule drugs increase the risk of any infections (RR: 1.23, 95 %CI: 1.05-1.44) and herpes zoster (RR: 2.23, 95 %CI: 1.39-3.57). Specifically, UC patients on Filgotinib and Tofacitinib, and CD patients on Upadacitinib, showed elevated risks of any infections (RR: 1.27, 95 % CI: 1.04-1.56; RR: 1.42, 95 % CI: 1.16-1.75; RR: 1.57, 95 % CI: 1.11-2.22). CD patients on Upadacitinib also had a significantly higher risk of herpes zoster (RR: 2.64, 95 %CI: 1.16-5.99). No infections were associated with S1P receptor modulators, and similarly, no malignancies were linked to small molecule drugs. CONCLUSIONS: JAK inhibitors increase the risk of any infections and herpes zoster Over a one-year follow-up period in IBD patients. Continuous monitoring of their long-term safety is necessary.

Discovery and Validation of Ferroptosis-Associated Genes of Ulcerative Colitis.

Background: Ulcerative colitis (UC) is a long-lasting idiopathic condition, but its precise mechanisms remain unclear. Meanwhile, evidence has demonstrated that ferroptosis seems to interlock with the progress of UC. This research sought to identify hub genes of UC related to ferroptosis. Methods: First, the relevant profiles for this article were obtained from GEO database. From the FerrDb, 479 genes linked to ferroptosis were retrieved. Using analysis of the difference and WGCNA on colonic samples from GSE73661, the remaining six hub genes linked to ferroptosis and UC were discovered. Through logistic regression analyses, the diagnostic model was constructed and was then evaluated by external validation using dataset GSE92415. Afterwards, the correlation between immune cell filtration in UC and hub genes was examined. Finally, a mice model of colitis was established, and the results were verified using qRT-PCR. Results: We acquired six hub genes linked to ferroptosis and UC. In order to create a diagnostic model for UC, we used logistic regression analysis to screen three of the six ferroptosis related genes (HIF1A, SLC7A11, and LPIN1). The ROC curve showed that the three hub genes had outstanding potential for disease diagnosis (AUC = 0.976), which was subsequently validated in samples from GSE92415 (AUC = 0.962) and blood samples from GSE3365 (AUC = 0.847) and GSE94648 (AUC = 0.769). These genes might be crucial for UC immunity based upon the results on the immune system. Furthermore, mouse samples examined using qRT-PCR also verified our findings. Conclusion: In conclusion, the findings have important implications for ferroptosis and UC, and these hub genes may also offer fresh perspectives on the aetiology and therapeutic approaches of UC.

Indomethacin Does Not Reduce Post-ERCP Pancreatitis in High-Risk Patients Receiving Pancreatic Stenting.

BACKGROUND: Rectal indomethacin reduces pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP). However, there is insufficient evidence regarding its added benefits in patients already receiving prophylactic pancreatic stenting. Our goal was to evaluate the impact of indomethacin in high-risk patients undergoing pancreatic stenting. METHODS: A cohort study was conducted on all patients who underwent the rescue cannulation technique for challenging bile duct cannulation (selected high-risk patients). Patients were split into two groups based on the prophylaxis method for post-ERCP pancreatitis (PEP): one receiving a combination of indomethacin and pancreatic stenting, while the other received pancreatic stenting alone. Comparative analyses were carried out on PEP, hyperamylasemia, gastrointestinal bleeding, and postoperative hospital stay among post-ERCP pancreatitis patients. RESULTS: Between November 2017 and May 2023, a total of 607 patients with native papillae were enrolled, with 140 grouped into the indomethacin plus stent group and 467 into the stent alone group. The overall PEP rate was 4.4% in the entire cohort, with no statistical differences observed between the groups in terms of PEP rates (P = 0.407), mild PEP (P = 0.340), moderate to severe PEP (P = 1.000), hyperamylasemia (P = 0.543), gastrointestinal bleeding (P = 0.392), and postoperative hospital stay (P = 0.521). Furthermore, sensitivity analysis using multivariable analysis also validated these findings. CONCLUSIONS: Indomethacin did not reduce the incidence or severity of PEP in high-risk patients who routinely received prophylactic pancreatic stent placement. Therefore, the additional administration of rectal indomethacin to further mitigate PEP appears to be not necessary.

Clinical characteristics and the risk factors for the exacerbation of symptoms in patients with inflammatory bowel disease during the COVID-19 pandemic.

Background: In 2023, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant caused a large-scale outbreak of coronavirus disease 2019 (COVID-19) in China. It is not clear the risk factors that lead to the exacerbation of symptoms in patients with inflammatory bowel disease (IBD) after COVID-19 infection. Our study aims to find out the risk factors for the exacerbation of IBD-related symptoms in IBD patients with COVID-19 infection and to provide guidance for the clinical management of IBD. Methods: This is a retrospective, observational study. The online questionnaire was distributed to conduct a survey to collect demographic, clinical, and IBD related characteristics in IBD patients. Univariate and multivariate regression analyses were conducted to assess the independent effects. Results: In total, 534 cases of IBD patients were analyzed in our study. Among them, 466 (87.3%) cases diagnosed with COVID-19, 160 (34.3%) cases experienced exacerbation of IBD symptoms, and 84 (18.0%) patients opted for medication discontinuation. Male sex (OR 2.04, 95% CI 1.34-3.49, p = 0.001), and the decrease in body mass index (BMI) (OR 0.93, 95% CI 0.87-1.00, p = 0.035) were positively correlated with the exacerbation of IBD symptoms. Furthermore, the medication discontinuation (OR 2.60, 95% CI 1.58-4.30, p < 0.001) was strongly positively correlated with the exacerbation of IBD symptoms. No significant association was seen between age, comorbidities, smoking, disease activity, vaccination, therapy for COVID-19 and the worsening of IBD symptoms. Conclusion: This study confirms that the infection rate of COVID-19 in China IBD patients was comparable to the general population. Male sex, the decrease in BMI and medication discontinuation are significant risk factors for the exacerbation of IBD-related symptoms in IBD patients with COVID-19 infection.

Transpancreatic Sphincterotomy After Double Guidewire Technique Was Noninferior to Primary Transpancreatic Sphincterotomy in Difficult Biliary Cannulation.

BACKGROUND: When unintentional pancreatic duct access occurs during difficult biliary cannulation, the double guidewire (DGW) or transpancreatic sphincterotomy (TPS) may be utilized. DGW can be easily switched to TPS due to the existing guidewire in the pancreatic duct. However, the efficacy of TPS after DGW, named sequential DGW-TPS technique, versus primary TPS has not been assessed. AIMS: Our aim was to compare the benefits and adverse events of sequential DGW-TPS technique and primary TPS. METHODS: We performed a comparative retrospective cohort study that enrolled a total of 117 patients with native papillae. The patients were divided into one of 2 groups according to the primary bile duct access technique (sequential DGW-TPS or primary TPS), both with pancreatic stenting. RESULTS: Between November 2017 and May 2023, a total of 84 patients were grouped into sequential DGW-TPS and 33 into primary TPS. The overall post-ERCP pancreatitis (PEP) rate was 4.3% in the entire cohort, with no statistical differences were observed between the groups in terms of PEP rates (P = 0.927), PEP severity (P = 1.000), first biliary cannulation success (P = 0.621), overall cannulation success (P = 1.000), hyperamylasemia incidence (P = 0.241), elevated amylase levels (P = 0.881), and postoperative hospital stay (P = 0.185). Furthermore, these results remained consistent in multivariable regression analysis. CONCLUSIONS: The sequential DGW-TPS technique showed a comparable safety and biliary cannulation success rate to primary TPS in difficult biliary cannulation. Given the potential long-term complications associated with TPS, DGW should be first if inadvertent pancreatic access occurs, with TPS serving as second only if DGW fails.

DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells.

Epithelial barrier dysfunction and crypt destruction are hallmarks of inflammatory bowel disease (IBD). Intestinal stem cells (ISCs) residing in the crypts play a crucial role in the continuous self-renewal and rapid recovery of intestinal epithelial cells (IECs). However, how ISCs are dysregulated in IBD remains poorly understood. Here, we observe reduced DHX9 protein levels in IBD patients, and mice with conditional DHX9 depletion in the intestinal epithelium (Dhx9ΔIEC) exhibit an increased susceptibility to experimental colitis. Notably, Dhx9ΔIEC mice display a significant reduction in the numbers of ISCs and Paneth cells. Further investigation using ISC-specific or Paneth cell-specific Dhx9-deficient mice demonstrates the involvement of ISC-expressed DHX9 in maintaining epithelial homeostasis. Mechanistically, DHX9 deficiency leads to abnormal R-loop accumulation, resulting in genomic instability and the cGAS-STING-mediated inflammatory response, which together impair ISC function and contribute to the pathogenesis of IBD. Collectively, our findings highlight R-loop-mediated genomic instability in ISCs as a risk factor in IBD.

Sporadic gastrinoma with refractory benign esophageal stricture: A case report.

BACKGROUND: Gastrinoma is characterized by an excessive release of gastrin, leading to hypersecretion of gastric acid, subsequently resulting in recurrent peptic ulcers, chronic diarrhea, and even esophageal strictures. This case report aims to improve awareness and facilitate early diagnosis and treatment of gastrinoma by presenting a rare case of gastrinoma with refractory benign esophageal stricture (RBES). Additionally, it highlights the persistent challenges that gastroenterologists encounter in managing RBES. CASE SUMMARY: This case demonstrates a patient with gastrinoma who developed RBES and complete esophageal obstruction despite management with maximal acid suppressive therapy, multiple endoscopic bougie dilations and endoscopic incisional therapy (EIT). CONCLUSION: It is essential to diagnose gastrinoma as early as possible, as inadequately controlled acid secretion over an extended period increases the risk of developing severe esophageal strictures. In patients with esophageal strictures causing complete luminal obstruction, blind reopening EIT presents challenges and carries a high risk of perforation.

Microbiome and its relevance to indigenous inflammatory bowel diseases in China.

BACKGROUND: Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract with an unknown etiology. Although dysbiosis is implicated in its pathogenesis, deep sequencing and oral microbiota study in Chinese IBD patients is absent. AIM: To explore the role of oral / intestinal microbiota in patients with IBD and the potential associations therein. METHODS: Clinical data, fecal and saliva samples were harvested from 80 patients with IBD (Crohn's disease, CD, n = 69; Ulcerative colitis, UC, n = 11) and 24 normal controls. Microbiomics (16S rRNA sequencing and 16S rRNA full-length sequencing) were used to detect and analyze the difference between IBD patients and normal control. RESULTS: Compared with normal controls, a higher abundance of the intestinal Shigella spp. (Shigella flexneri and Shigella sonnei, which were positively relate to the severity of IBD), lower abundance of intestinal probiotics (Prevotella, Faecalibacterium and Roseburia), and higher abundance of oral Neisseria were present in IBD patients with microbiome. The higher inflammation-related markers, impaired hepatic and renal function, and dyslipidaemia were present in patients with IBD. A higher intake of red meat and increased abundance of Clostridium in the gut were found in CD patients, while the elevated abundance of Ruminococcus in the gut was showed in UC ones. The bacterial composition of saliva and fecal samples was completely different, yet there was some correlation in the distribution of dominant probiotics. CONCLUSION: Enteric dysbacteriosis and the infections of pathogenic bacteria (Shigella) may associate with the occurrence or development of IBD.

Use of double-balloon endoscopy and an endoscopic scoring system to assess endoscopic remission in isolated small bowel Crohn's disease after treatment with infliximab.

Background: It is unclear how clinical and endoscopic factors affect the attainment of endoscopic remission (ER) in patients with small bowel Crohn's disease (SB-CD) who are infliximab-naïve. Objectives: We aimed to identify the effect of different factors on attaining ER using double-balloon endoscopy (DBE) evaluation. Design: A single-center retrospective observational study was conducted from 1 January 2018 to 30 November 2022. Among 262 patients who were screened for isolated SB-CD by baseline DBE, 108 patients were assessed for effectiveness during maintenance infliximab therapy by a second DBE evaluation. Methods: DBE findings before and after infliximab therapy were compared. ER was defined as a simple endoscopic score for CD (SES-CD) below 3, and segmental ER as SES-CD activity of 0. Multivariate regression with calculations of odds ratios (OR) was used to determine the impact of different factors on attaining ER. Results: In all, 41 patients (38.0%) achieved ER. An elevated C-reactive protein at week 6 was independently associated with a decreased probability of ER [OR: 0.86, 95% confidence interval (CI) = 0.75-0.98, p = 0.03]. Segmental ER of the terminal ileum, rather than the proximal ileum, was associated with a higher rate of ER (60.9% versus 38.2%, p = 0.01). High baseline SES-CD (⩾16) was unrelated to overall ER. For patients with disease in the terminal ileum, those with moderate/severe disease were less likely to attain segmental ER than those with mild disease [adjusted odds ratios (aOR): 0.27, 95% CI: 0.09-0.83, p = 0.02]. A large ulcer in the terminal ileum was associated with a lower rate of segmental ER (aOR: 0.18, 95% CI: 0.06-0.56, p = 0.01). Conclusion: For infliximab-naïve patients with SB-CD, the overall severity of the endoscopic score was unrelated to attainment of ER. Patients were less likely to attain segmental ER if they had greater endoscopic inflammation or larger ulcers in the terminal ileum.

Deep learning-based lesion detection and severity grading of small-bowel Crohn's disease ulcers on double-balloon endoscopy images.

BACKGROUND AND AIMS: Double-balloon endoscopy (DBE) is widely used in diagnosing small-bowel Crohn's disease (CD). However, CD misdiagnosis frequently occurs if inexperienced endoscopists cannot accurately detect the lesions. The CD evaluation may also be inaccurate owing to the subjectivity of endoscopists. This study aimed to use artificial intelligence (AI) to accurately detect and objectively assess small-bowel CD for more refined disease management. METHODS: We collected 28,155 small-bowel DBE images from 628 patients from January 2018 to December 2022. Four expert gastroenterologists labeled the images, and at least 2 endoscopists made the final decision with agreement. A state-of-the-art deep learning model, EfficientNet-b5, was trained to detect CD lesions and evaluate CD ulcers. The detection included lesions of ulcer, noninflammatory stenosis, and inflammatory stenosis. Ulcer grading included ulcerated surface, ulcer size, and ulcer depth. A comparison of AI model performance with endoscopists was performed. RESULTS: The EfficientNet-b5 achieved high accuracies of 96.3% (95% confidence interval [CI], 95.7%-96.7%), 95.7% (95% CI, 95.1%-96.2%), and 96.7% (95% CI, 96.2%-97.2%) for the detection of ulcers, noninflammatory stenosis, and inflammatory stenosis, respectively. In ulcer grading, the EfficientNet-b5 exhibited average accuracies of 87.3% (95% CI, 84.6%-89.6%) for grading the ulcerated surface, 87.8% (95% CI, 85.0%-90.2%) for grading the size of ulcers, and 85.2% (95% CI, 83.2%-87.0%) for ulcer depth assessment. CONCLUSIONS: The EfficientNet-b5 achieved high accuracy in detecting CD lesions and grading CD ulcers. The AI model can provide expert-level accuracy and objective evaluation of small-bowel CD to optimize the clinical treatment plans.

Natural Course of Common Bile Duct Microlithiasis.

BACKGROUND: Common bile duct microlithiasis (CBDM) with a diameter of ≤ 3 mm can pass spontaneously without causing any symptoms, but in some cases, it can also cause severe cholangitis and pancreatitis. The optimal strategy for managing CBDM is yet to be determined. METHODS: Data of 154 patients with CBDM were collected and divided into two groups: with endoscopic retrograde cholangiopancreatography (with ERCP, n = 82) and without ERCP (n = 72). Clinical outcomes, including the incidence of unfavorable outcomes (UOs), such as cholangitis and pancreatitis, were observed and compared between the two groups. RESULTS: The incidence of UOs was significantly lower in the ERCP group than in the without ERCP group (3.7% vs. 23.6%, respectively, p < 0.001). Moreover, the total number of readmissions was also lower in the ERCP group than in the without ERCP group (p < 0.001). A multivariate analysis adjusted for age, sex, and the American Society of Anesthesiologists (ASA) class revealed that endoscopic sphincterotomy (EST) and cholecystectomy were associated with a lower risk of UOs. CONCLUSION: The high rate of UOs in CBDM patients without ERCP suggests that its natural clinical course may not be as favorable as previously suggested. This finding implies that efforts should be made to clear the bile ducts.

Evaluation of symptomatic small bowel stricture in Crohn's disease by double-balloon endoscopy.

PURPOSE: To assess the efficacy of double-balloon endoscopy (DBE) for the detection of small-bowel strictures in Crohn's disease (CD). METHODS: This tertiary-referral hospital cohort study was conducted between January 2018 and May 2022. CD patients with symptoms of small-bowel stricture were enrolled sequentially. All of the patients were subjected to both computed tomography enterography (CTE) and DBE, and their symptoms of stricture were assessed using the Crohn's Disease Obstructive Score (CDOS). The diagnostic yield of DBE was compared to that of CTE, and the relationship between the DBE findings and CDOS was investigated. The factors influencing the DBE diagnosis were examined using Cox regression analysis. RESULTS: This study included 165 CD patients. The CDOS scores were higher in 95 patients and lower in 70 patients. DBE detected 92.7% (153/165) and CTE detected 85.5% (141/165) of the strictures. The DBE diagnostic yields were 94.7% (90/95) in the high CDOS patients and 91.4% (64/70) in the low CDOS patients (P = 0.13). Patients with a history of abdominal surgery and abscess had a lower diagnosis rate in the multivariate analysis. CONCLUSION: DBE has been demonstrated to be an efficient diagnostic method for detecting small bowel strictures in CD patients. Additionally, there was no difference in the diagnostic yields between patients with low and high obstructive scores.

Melatonin attenuates monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats via activation of Sirtuin-3.

Melatonin possesses potent hepatoprotective properties, but it remains to be elucidated whether melatonin has a therapeutic effect on monocrotaline (MCT)-induced hepatic sinusoidal obstruction syndrome (HSOS). In this study, male Sprague Dawley rats were intraperitoneally injected with melatonin or the same volume of vehicle at 0 and 24 h after MCT intragastric administration. Next, hematoxylin-eosin staining and electron microscopy were performed to evaluate the hepatic sinusoidal injury of rats. Endothelial cell marker RECA-1 was observed by immunohistochemistry. Hepatic oxidative stress was analyzed by detecting malondialdehyde, glutathione S-transferase, and reactive oxygen species. Assessment of liver function was carried out by analysis of serum aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin levels. Real-time polymerase chain reaction and Western blot analysis were used to identify liver Sirtuin-3 (SIRT3) and active matrix metallopeptidase 9 (MMP-9) expression. Besides, liver sinusoidal endothelial cells (LSECs) were used for the in vitro functional verification experiment. Specifically, liver histology of the melatonin-treated groups showed that the pathological damages caused by MCT were significantly attenuated, total HSOS scores were decreased, and the elevation of serum hyaluronic acid observed in the model group was also reduced. Moreover, melatonin treatment also improved the survival of rats after partial hepatectomy. Administration of melatonin ameliorated MCT-induced LSECs injury, hepatic oxidative stress, and hepatic dysfunction. Furthermore, melatonin treatment increased SIRT3 expression while attenuating MMP-9 activity in liver tissues. Cell experiment also demonstrated that SIRT3 might mediate the protective effect of melatonin on LSECs. Collectively, our study provided the potential rationale for the application of melatonin for the prevention of MCT-induced HSOS.

Interobserver Agreement among Cytopathologists in False-Negative Cases by Cytological Diagnosis with Endoscopic Ultrasound-Guided Fine Needle Aspiration in Solid Pancreatic Lesions.

INTRODUCTION: Early detection and accurate pathological assessment are critical to improving prognosis of pancreatic cancer. EUS has been widely used in diagnosing pancreatic lesions and can obtain histological diagnosis by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). However, comprehensive assessment of the interobserver agreement (IOA) among cytopathologists evaluating EUS-FNA specimens is still limited. Therefore, this study evaluated IOA among cytopathologists for EUS-FNA specimens of solid pancreatic lesions, especially in false-negative cases of cytological diagnosis and analyzed the factors that influence cytological diagnosis of EUS-FNA so as to improve the diagnostic efficiency of EUS-FNA. METHODS: We retrieved EUS-FNA samples of pancreatic solid lesions from 2017 to 2021 and collected their clinical/cytological data. Two cytopathologists independently reviewed these cases using a quoted, novel standardized cytology scoring tool. Ultimately, we calculated IOA among cytopathologists and performed a binary logistic regression analysis to evaluate factors influencing the cytological diagnosis of EUS-FNA. RESULTS: 161 patients were included, and 60 cases with a clinical diagnosis of pancreatic cancer but a cytological diagnosis of benign and atypical constituted the false-negative group. IOAs for cytological diagnosis of overall patients and the false-negative group were in perfect/moderate agreement with Kendall's W values of 0.896 and 0.462, respectively. The number of diagnostic cells in the scoring tool had the highest level of agreement (κ = 0.721) for overall patients. There was at best moderate agreement on other quantity and quality parameters for both all cases and false-negative group. Logistic regression analysis showed the number of diagnostic cells (OR = 6.110, p < 0.05) and amount of blood (OR = 0.320, p < 0.05) could influence cytological diagnosis. CONCLUSIONS: The false-negative rate of our study as high as 37.26% (60/161) is mainly related to strict standards of cytopathologists, and their ability to standardize pancreatic cytology is still improving. Suboptimal agreement among cytopathologists for cytological diagnosis and the number of diagnostic cells may be associated with the occurrence of false-negative diagnosis. Further regression analysis confirmed that the number of diagnostic cells and obscuring blood were important factors in cytological diagnosis. Therefore, refinement of cytological diagnostic criteria, standardization of specimen quality evaluation, and training of cytopathologists may improve the agreement of cytopathologists, thus improving the repeatability of cytological diagnosis and reducing the occurrence of false-negative events.

Efficacy and safety of esophageal submucosal tumors treated with internal traction method-assisted submucosal tunneling endoscopic resection: a single-center, single-blind, randomized controlled study.

BACKGROUND AND OBJECTIVES: Submucosal tunnel endoscopic resection (STER) is an effective technique for treating esophageal submucosal tumors, but the efficacy and safety of treating esophageal submucosal tumors with internal traction method-assisted STER have not been determined. The objectives of this study were to assess the feasibility, safety, and efficacy of internal traction method-assisted STER for the removal of esophageal submucosal tumors. PATIENTS AND METHODS: Eighty patients who underwent STER for esophageal submucosal tumors were included in the study. They were randomized and assigned to the two groups. The dual-knife method was used for STER. Forty patients underwent conventional STER (control group) and 40 underwent internal traction method-assisted STER in which self-made rubber band traction with clips was used (study group). In the study group, one end of the self-made rubber band was fixed on the surface of esophageal submucosal tumors with a clip, and the other end of the self-made rubber band was set on the anal side of the contralateral esophageal wall with a clip. RESULTS: STER was successful in all cases. Lesion features and demographics were similar between the two groups. In addition, broad exposure of the submucosal tissue was obtained by applying tension to the self-made rubber band traction with clips. The en bloc resection rate and complete resection rate were both 100% in the study group. However, the en bloc resection rate and complete resection rate were 85.0% and 100%, respectively, in the control group. Complications, such as perforation and pneumomediastinum, were significantly reduced in the study group, and there was a significant difference in the number of occurrences of bleeding, operation duration, fasting time, and patient length of stay between the study group and control group (P < 0.05). During the mean 13.7 month follow-up, there were no patients with esophageal fistula, recurrence, or distant metastasis in either group. CONCLUSIONS: This original study showed that esophageal submucosal tumors could be effectively and safely treated with internal traction method-assisted STER, and this technique might be superior to conventional STER due to its fewer complications, shorter operation duration, and shorter inpatient length of stay.

The Mechanosensitive Ion Channel PIEZO1 in Intestinal Epithelial Cells Mediates Inflammation through the NOD-Like Receptor 3 Pathway in Crohn's Disease.

BACKGROUND: Crohn's disease (CD) is an incurable chronic intestinal inflammatory disease with no recognized cause. It has been reported that the mechanosensitive ion channel PIEZO1 initiates proinflammatory responses. However, little is known about the role of PIEZO1 in CD. METHODS: Ileum biopsies were obtained from 30 patients with CD and 15 healthy volunteers. Clinical data were collected to determine the relationship between CD and PIEZO1. First, HT29 cells were incubated with Yoda1 and GsMTx4 (Grammostola spatulata mechanotoxin 4) to activate and inhibit PIEZO1, respectively. Second, PIEZO1 knockdown was performed using small interfering RNA. Third, calcium imaging, flow cytometry, and immunofluorescence were used to detect intracellular calcium and mitochondrial function. Last, real-time quantitative polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assay were used to quantify PIEZO1, proinflammatory cytokines, and NLRP3 (NOD-like receptor 3)-related compounds. RESULTS: PIEZO1 was highly expressed in the ileum of patients with CD and correlated positively with the Crohn's Disease Activity Index, platelet count, and hematocrit and fecal calprotectin levels. In HT29 cells, Yoda1 triggered calcium influx, which was inhibited by GsMTx4 treatment and small interfering RNA-mediated PIEZO1 knockdown. Increased calcium concentrations resulted in increased reactive oxygen species accumulation and decreased mitochondrial membrane potential, whereas decreased calcium concentrations caused by GsMTx4 and PIEZO1 knockdown had the opposite effect. Mechanistically, molecules in the NLRP3 pathway were activated in patients with CD and HT29 cells were stimulated by lipopolysaccharide; these effects were reversed by the knockdown of PIEZO1. Finally, PIEZO1 and NLRP3 knockdown decreased proinflammatory cytokine levels in HT29 cells. CONCLUSIONS: PIEZO1 in intestinal epithelial cells caused calcium influx, which resulted in mitochondrial dysfunction and activated the NLRP3 inflammasome, mediating intestinal inflammation.

PIEZO1 was highly expressed in patients with active Crohn's disease. Its expression was significantly increased in the ileum and was associated with intestinal inflammation. In intestinal epithelial cells, PIEZO1 triggered calcium influx, resulting in mitochondrial dysfunction, and activated the NLRP3 inflammasome, thereby mediating intestinal inflammation.

Association between triglyceride-glucose index and atrial fibrillation: A retrospective observational study.

Background: Insulin resistance is associated with atrial remodeling as well as atrial fibrillation (AF). However, there was limited evidence on the relationship of triglyceride-glucose index (TyG) index, a simple, valuable marker of insulin resistance, with AF. Thus, we aimed to investigate the association between TyG index and AF among hospitalized patients. Methods: A retrospective observational study was conducted in Daping Hospital, which included 356 hospitalized patients from the Department of Cardiology. Clinical and biochemical parameters were collected from electronic medical records and AF was diagnosed from electrocardiogram (ECG) findings. Results: We found that the TyG index was significantly higher in the AF group than in the group without AF. Multivariate logistic regression revealed that hypertension (OR = 1.756, 95%CI 1.135-2.717, P = 0.011) and TyG index (OR = 2.092, 95%CI 1.412-3.100, P<0.001) were positively associated with AF. The analysis of the area under the ROC curve was performed and revealed that area under curve (AUC) of TyG index was 0.600 (95%CI, 0.542-0.659, P = 0.001), the optimal critical value was 8.35, the sensitivity was 65.4%, and the specificity was 52.0%. Additional subgroup analyses of diabetic and non-diabetic subjects were also performed and found the TyG index was increased in non-diabetic subjects with AF. Furthermore, a logistic regression analysis showed TyG index was associated with AF (OR = 3.065, 95% CI, 1.819-5.166, P<0.001) in non-diabetic subjects. However, TyG index was not associated with AF in diabetic subjects. Conclusion: Elevated TyG index is an independent risk factor for AF among non-diabetic hospitalized patients.

Vitamin B5 rewires Th17 cell metabolism via impeding PKM2 nuclear translocation.

Metabolic rewiring is essential for Th17 cells' functional identity to sense and interpret environmental cues. However, the environmental metabolic checkpoints with specific regulation of Th17 cells, manifesting potential therapeutic opportunities to autoimmune diseases, remain largely unknown. Here, by screening more than one hundred compounds derived from intestinal microbes or diet, we found that vitamin B5 (VB5) restrains Th17 cell differentiation as well as related autoimmune diseases such as experimental autoimmune encephalomyelitis and colitis. Mechanistically, VB5 is catabolized into coenzyme A (CoA) in a pantothenate kinase (PANK)-dependent manner, and in turn, CoA binds to pyruvate kinase isoform 2 (PKM2) to impede its phosphorylation and nuclear translocation, thus inhibiting glycolysis and STAT3 phosphorylation. In humans, reduced serum VB5 levels are found in both IBD and MS patients. Collectively, our study demonstrates a role of VB5 in Th17 cell metabolic reprograming, thus providing a potential therapeutic intervention for Th17 cell-associated autoimmune diseases.