Nocebo effects and influencing factors in the randomized clinical trials of chronic constipation: A systematic review and meta-analysis.

BACKGROUND: Nocebo effects are unavoidable in randomized clinical trials. We aimed to assess the magnitude of nocebo effects and explore the influencing factors in chronic constipation. METHODS: We searched the PubMed, Embase, and Cochrane Library databases up to July 2022. Randomized, placebo-controlled trials investigating interventions in chronic constipation were included. We conducted a random effects meta-analysis of the proportion of adverse events (AEs) in placebo-treated participants and evaluated the effect of trial characteristics on nocebo effects. KEY RESULTS: We identified 20,204 studies from the databases, of which 61 were included in the final analysis. The pooled placebo AE rate was 30.41%, and AE-related withdrawal rate was 1.53%. The most commonly reported AEs were headache (5.67%), diarrhea (4.45%), abdominal pain (3.98%), nasopharyngitis (3.39%), nausea (3.36%), and flatulence (2.95%). The placebo AE rate was lower in trials conducted in Asia compared to those in Europe, North America, and international trials. It was also lower in trials diagnosed by Rome III compared to clinician's opinion and Rome II. Additionally, the placebo AE rate was lower in single-center trials compared to multicenter trials, lower in 5-8 weeks therapy compared to 9-12 weeks therapy, lower in participants with FC compared to those with IBS-C and CC, lower in trials with 2 arms compared to 3 arms, and higher in trials with prokinetic drugs compared to secretagogues and laxatives. CONCLUSIONS & INFERENCES: The placebo AE rate was 30.41% in patients with chronic constipation. Based on our findings, we recommend that researchers take the nocebo effects into consideration when designing and conducting clinical trials and adopt specific measures to mitigate the negative influence of nocebo effects.

Transcutaneous Electrical Acustimulation Improves Constipation Symptoms and Accelerates Colonic Transit in Patients With Slow Transit Constipation Through Autonomic Mechanism.

OBJECTIVES: Nearly half of patients with slow transit constipation (STC) are not completely satisfied with their traditional remedies. We aimed to evaluate the therapeutic value and possible involved mechanism of transcutaneous electrical acustimulation (TEA) at ST36 in patients with STC. MATERIALS AND METHODS: Seventy patients with STC were randomly divided into TEA (n = 35) and sham-TEA (n = 35) to undergo a two-week treatment with TEA at ST36 or sham point. After the two-week treatment, 18 patients from each group randomly underwent a few physiological tests, including the electrocardiogram (ECG), anorectal manometry, colon transit test, and blood drawing. After a two-week washout period, TEA was performed in both groups for two weeks. RESULTS: Spontaneous bowel movements per week were increased, and scores of constipation symptoms were decreased, after a two-week blind TEA but not sham-TEA, which were sustained after a two-week washout period. Improvement in quality of life and psychologic states also was observed with blind TEA treatment. Mechanistically, the two-week blind TEA accelerated colon transit assessed by barium strip excretion rate (the effect was sustained after a two-week washout period), enhanced vagal nerve activity evaluated by the spectral analysis of heart rate variability derived from the ECG, and decreased circulating vasoactive intestinal peptide. CONCLUSIONS: Noninvasive TEA relieves constipation and improves quality of life and psychologic states in patients with STC, and the effects are sustained for ≥two weeks. The therapeutic effects of TEA may be attributed to the acceleration of colon transit and decrease of vasoactive intestinal peptide mediated through the vagal mechanism.

Electroacupuncture repairs intestinal barrier by upregulating CB1 through gut microbiota in DSS-induced acute colitis.

BACKGROUND: A few studies have reported that electroacupuncture (EA) can repair the intestinal barrier through unknown mechanisms. Cannabinoid receptor 1 (CB1) was shown to play an important role in the protection of the gut barrier in recent studies. Gut microbiota can influence the expression of CB1. In this study, we explored the effect of EA on the gut barrier in acute colitis and its mechanism. METHODS: A dextran sulfate sodium (DSS)-induced acute colitis model, CB1 antagonist model and fecal microbiota transplantation (FMT) model were used in this study. The disease activity index (DAI) score, colon length, histological score, and inflammatory factors were detected to evaluate colonic inflammation. Methods for detecting intestinal barrier functions included the expression of tight junction proteins, intestinal permeability, and the number of goblet cells. Moreover, 16S rRNA sequencing was applied to analyze alterations in the gut microbiota. Western blotting and RT-PCR were performed to assess the levels of CB1 and autophagy-related proteins. Autophagosomes were observed by transmission electron microscopy. RESULTS: EA reduced the DAI score, histological score, levels of inflammatory factors, and restored the colon length. Moreover, EA increased the expression of tight junction proteins and the number of goblet cells, and decreased intestinal permeability. In addition, EA remodeled the community structure of the gut microbiota, increased the expression of CB1, and enhanced the degree of autophagy. However, the therapeutic effects were reversed by CB1 antagonists. In addition, FMT in the EA group exhibited similar effects to EA and upregulated CB1. CONCLUSIONS: We concluded that EA may protect intestinal barrier functions by increasing the expression of CB1 to enhance autophagy through gut microbiota in DSS-induced acute colitis.

A novel fatty acid metabolism-related gene prognostic signature and candidate drugs for patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. Fatty acid metabolism (FAM) is associated with the development and treatment of HCC. This study aimed to build a FAM-related gene model to assess the prognosis of HCC and provide guidance for individual treatment. RNA-sequencing data of patients with HCC from The Cancer Genome Atlas and Gene Expression Omnibus database (GSE14520) were extracted as the training and validation sets, respectively. A FAM-related gene predictive signature was built, and the performance of prognostic model was assessed. The immune infiltration and drug sensitivity were also evaluated. Quantitative real-time polymerase chain reaction and western blot were performed to evaluate the levels of the model genes. A 12-gene FAM-related risk signature was constructed; patients with a higher risk score had poorer prognosis than those with a lower risk score. Risk score was shown as an independent risk factor for overall survival of HCC, and the signature was further confirmed as an effective and accurate model. A nomogram was constructed, and it exhibited the good performance in the prognostic prediction. In addition, the immune cell infiltration and sensitivity to chemotherapy drugs were correlated with different risk levels. Finally, quantitative real-time polymerase chain reaction and western blot proved the changes of above genes. Differential expression of FAM-related genes can be used to predict response to immunotherapy and chemotherapy, and improve the clinical prognosis evaluation of patients with HCC, which provides new clues for further experimental exploration and verification on FAM-related genes in HCC.

Ferroptosis-related long non-coding RNA signature predicts the prognosis of hepatocellular carcinoma.

BACKGROUND: Hepatocellular Carcinoma (HCC) is a highly heterogeneous malignant tumor, and its prognostic prediction is extremely challenging. Ferroptosis is a cell mechanism dependent on iron, which is very significant for HCC development. Long non-coding RNA (lncRNA) is also linked to HCC progression. This work aimed to establish a prognosis risk model for HCC and to discover a possible biomarker and therapeutic target. METHODS: The Cancer Genome Atlas (TCGA) database was used to obtain RNA-seq transcriptome data and clinic information of HCC patients. Firstly, univariate Cox was utilized to identify 66 prognostic ferroptosis-related lncRNAs. Then, the identified lncRNAs were further included in the multivariate Cox analysis to construct the prognostic model. Eventually, we performed quantitative polymerase chain reaction (q-PCR) to validate the risk model. RESULTS: We established a prognostic seventeen-ferroptosis-related lncRNA signature model. The signature could categorize patients into two risk subgroups, with the low-risk subgroup associated with a better prognosis. Additionally, the area under the curve (AUC) of the lncRNAs signature was 0.801, indicating their reliability in forecasting HCC prognosis. Risk score was an independent prognostic factor by regression analyses. Gene set enrichment analysis (GSEA) analyses demonstrated a remarkable enrichment of cancer-related and immune-related pathways in the high-risk group. Besides, the immune status was decreased in the high-risk group. Eventually, three prognostic lncRNAs were validated in human HCCLM3 cell lines. CONCLUSIONS: The risk model based on seventeen-ferroptosis-related lncRNA has significant prognostic value for HCC and may be therapeutic targets associated with ferroptosis in clinical ways.

Efficacy of Endoscopic Ultrasound Elastography in Differential Diagnosis of Gastrointestinal Stromal Tumor Versus Gastrointestinal Leiomyoma.

BACKGROUND The diagnostic efficacy of endoscopic ultrasound (EUS) elastography for alimentary tract diseases remains uncertain. The aim of this study was to evaluate the utility of EUS elastography in differential diagnosis between the 2 most common subepithelium tumors of the digestive tract - gastrointestinal stromal tumors (GISTs) and gastrointestinal leiomyomas (GILs) - which cannot be differentiated by conventional EUS imaging. MATERIAL AND METHODS Electronic records were retrospectively reviewed from Jan 2015 to Jul 2019. Patients accepting EUS elastography with histopathological diagnosis of GISTs or GILs were included. The images of EUS elastography were analyzed by hue histogram in Photoshop. Hue values of RGB, R, G, and B channels of each group were acquired. We used the t test, ROC curve analysis, and binary logistic regression analysis for data post-processing. RESULTS We included 47 patients with GISTs and 14 with GILs. The mean±standard deviations (SD) of hue values were 20.25±0.72, -0.79±0.78, 20.79±1.68, 39.72±1.30 for GISTs and 20.80±0.46, 1.80±1.05, 28.39±2.15, and 31.95±2.60 for GILs of RGB, R, G, and B channels, respectively. The t test showed statistically significant differences in mean hue values between GISTs and GILs in B and G channels, but not in RGB and R channels. The area under the ROC curve combining B and G values was 0.723. Binary logistic regression analysis suggested no statistically significant difference in ability to differentiate between GISTs and GILs with B and G values (P>0.05). CONCLUSIONS There was insufficient evidence to support the application of quantitative EUS elastography for differential diagnosis of GISTs and GILs in this study.