Topiramate, acupuncture, and BoNT-A for chronic migraine: a network meta-analysis.

BACKGROUND: Botulinum neurotoxin A (BoNT-A) was the primary choice for preventive treatment of chronic migraine. Topiramate and acupuncture showed promising effect for chronic migraine, but their effectiveness relative to BoNT-A was rarely studied. We aimed to perform a network meta-analysis to compare the effectiveness and acceptability between topiramate, acupuncture, and BoNT-A. METHODS: We searched OVID Medline, Embase, the Cochrane register of controlled trials (CENTRAL), the Chinese Clinical Trial Register, and clinicaltrials.gov for randomized controlled trials (RCTs) that compared topiramate, acupuncture, and BoNT-A with any of them or placebo in the preventive treatment of chronic migraine. A network meta-analysis was performed by using a frequentist approach and a random-effects model. The primary outcomes were reduction in monthly headache days and monthly migraine days at week 12. Acceptability was defined as the number of dropouts owing to adverse events. RESULTS: We included 15 RCTs (n = 2545). Eleven RCTs were at low risk of bias. The network meta-analyses (n = 2061) showed that acupuncture (2061 participants; standardized mean difference [SMD] -1.61, 95% CI: -2.35 to -0.87) and topiramate (582 participants; SMD -0.4, 95% CI: -0.75 to -0.04) ranked the most effective in the reduction of monthly headache days and migraine days, respectively; but they were not significantly superior over BoNT-A. Topiramate caused the most treatment-related adverse events and the highest rate of dropouts owing to adverse events. CONCLUSIONS: Topiramate and acupuncture were not superior over BoNT-A; BoNT-A was still the primary preventive treatment of chronic migraine. Large-scale RCTs with direct comparison of these three treatments are warranted to verified the findings.

Statin use and fall risk in adults: a cross-sectional survey and mendelian randomization analysis.

Background and Objective: The issue of falls poses a significant threat to the health of the elderly population. Although statins can cause myopathy, which implies that they may cause balance problems and increase the risk of falling, this has not been tested. Our objective was to assess whether the use of statins is linked to a higher risk of falls. Methods: A cross-sectional survey study and Mendelian randomization (MR) study were conducted to examine whether the use of statins was associated with an increased risk of falling and balance problems. The cross-sectional study included 2,656 participants from the US population (NHANES) who reported information on balance and falling problems in the past year and their use of statins. Univariate and multivariate logistic regression models were used to investigate the association between statin use and the likelihood of falling or experiencing balance problems. The MR study identified five Single Nucleotide Polymorphisms (SNPs) that predict statin use across five ancestry groups: Admixed African or African, East Asian, European, Hispanic, and South Asian. Additionally, SNPs predicting the risk of falls were acquired from the UK Biobank population. A two-sample MR analysis was performed to examine whether genetically predicted statin use increased the risk of falls. Results: The use of statins was found to be associated with an increased likelihood of balance and falling problems (balance problem, OR 1.25, 95%CI 1.02 to 1.55; falling problem, OR 1.27, 95%CI 1.03-1.27). Subgroup analysis revealed that patients under the age of 65 were more susceptible to these issues when taking statins (balance problem, OR 3.42, 95%CI 1.40 to 9.30; falling problem, OR 5.58, 95%CI 2.04-15.40). The MR analysis indicated that the use of statins, as genetically proxied, resulted in an increased risk of falling problems (OR 1.21, 95% CI 1.1-1.33). Conclusion: Our study found an association between the use of statins and an increased risk of balance problems and falls in adults over 40 years old, and the MR study result suggested statin use increased risk of falls. The risk was higher in participants under 65 years old compared to those over 65 years old.

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Acupuncture treatment for functional constipation (FC) is characterized by precise efficacy, rapid onset of action in the early stages, long-term stable effects, and overall regulation. This paper reviews recent literatures on acupuncture treatment for FC, indicating that acupuncture acts from multiple perspectives and pathways, including promoting intestinal motility, regulating intestinal microbiota, modulating the brain-gut axis, alleviating intestinal inflammation, and improving rectal hyposensitivity. Future research could delve into the mechanical sensation conduction mechanisms of acupuncture in improving rectal hyposensitivity, identify key intestinal microbiota genera and metabolic characteristics regulated by acupuncture, explore the network relationships among different mechanisms, and clarify the differential mechanisms of various acupuncture treatment protocols to optimize clinical therapy and enhance the clinical efficacy of acupuncture for FC.

Effects of acupuncture on gut microbiota and short-chain fatty acids in patients with functional constipation: a randomized placebo-controlled trial.

Objective: To comprehensively evaluate the effect of acupuncture on gut microbiota, identify specific microbes closely related to the clinical efficacy of acupuncture, and explored the role of short-chain fatty acids (SCFAs). Methods: A randomized placebo-controlled trial was conducted with 80 FC patients and 28 healthy controls (HCs). FC patients randomly received 16 acupuncture (n = 40) or sham acupuncture (n = 40) sessions over 4 weeks; HCs received no treatment. The change in the proportion of patients with mean weekly complete spontaneous bowel movements (CSBMs) was considered as the primary outcome measure. Moreover, the composition and the predictive metabolic function of the gut microbiota from feceal samples were analyzed by 16S rRNA gene sequencing, while feceal SCFAs were identified via gas chromatography-mass spectrometry (GC-MS). Results: Compared to sham acupuncture, acupuncture significantly increased the proportion of CSBM responders, and improved spontaneous bowel movements (SBMs), straining, stool consistency, and quality of life. Moreover, Sequencing of 16S rRNA genes revealed that acupuncture improved ß-diversity and restored the composition of gut microbiota. Specifically, the abundance of beneficial bacteria such as g_Lactobacillus increased while that of pathogenic bacteria such as g_Pseudomonas decreased after acupuncture, which were significantly correlated with alleviated symptoms. Moreover, ten microbes including g_Coprobacter, g_Lactobacillus, and g_Eubacterium_coprostanoligenes_group might be considered acupuncture-specific microbes, and formed a stable interaction network. Additionally, GC-MS analysis indicated that acupuncture increased the content of butyrate acid in the gut, which was positively correlated with an increase in defecation frequency and a decrease in acupuncture-related pathogens. Finally, acupuncture specific-microbes including g_Coprobacter, g_Lactobacillus, g_Pseudomonas, g_Eubacterium_coprostanoligenes_group, g_Erysipelotrichaceae_UCG.003, g_Prevotellaceae_UCG.001, and g_Rolstonia could accurately predict the clinical efficacy of acupuncture (AUC = 0.918). Conclusion: Acupuncture could effectively improve clinical symptoms in FC patients, and was associated with gut microbiota reshaping and increased butyrate acid levels. Moreover, key microbial genera such as g_Coprobacter and g_Lactobacillus was predictive of acupuncture efficacy in treating FC. Future studies are required to validate the causal relationship between key microbial genera and acupuncture clinical efficacy, and should explore further metabolic pathways for designing personalized treatment strategies. Clinical Trial Registration: http://www.chictr.org.cn, Identifier: ChiCTR2100048831.

Gut microbiota and major depressive disorder: A bidirectional Mendelian randomization.

BACKGROUND: Observational studies showed an association between gut microbiota and depression, but the causality relationship between them is unclear. We aimed to determine whether there is a bidirectional causal relationship between the composition of gut microbiota and major depressive disorders (MDD) and explore the role of gut microbiota in decreasing the risk of MDD. METHODS: Our two-sample Mendelian randomization (MR) study acquired top SNPs associated with the composition of gut microbiota (n = 18,340) and with MDDs (n = 480,359) from publicly available genome-wide association studies (GWAS). The SNPs estimates were pooled using inverse-variance weighted meta-analysis, with sensitivity analyses-weighted median, MR Egger, and MR Pleiotropy Residual Sum and Outlier (PRESSO). RESULTS: The Actinobacteria class had protective causal effects on MDD (OR 0.88, 95%CI 0.87 to 0.9). The Bifidobacterium (OR 0.89, 95%CI 0.88 to 0.91) were further found to have similar effects as the Actinobacteria class. The genus Ruminococcus1 had a protective effect on MDD (OR 0.88, 95%CI 0.76 to 0.99) while the Streptococcaceae family and its genus had an anti-protective effect on MDD (OR 1.07, 95%CI 1.01 to 1.13), but these findings were not supported by the MR-Egger analysis. Bidirectional MR showed no effect of MDD on gut microbiota composition. LIMITATIONS: The use of summary-level data, the risk of sample overlap and low statistical power are the major limiting factors. CONCLUSIONS: Our MR analysis showed a protective effect of Actinobacteria, Bifidobacterium, and Ruminococcus and a potentially anti-protective effect of Streptococcaceae on MDD pathogenesis. Further studies are needed to transform the findings into practice.

Global trends in research on irritable bowel syndrome and the brain-gut axis: Bibliometrics and visualization analysis.

Irritable bowel syndrome (IBS) is a gastrointestinal disorder with no structural damage, and its pathogenesis remains unclear. Studies have shown that the brain-gut axis is closely related to the occurrence of IBS. However, studies of IBS related to the brain-gut axis have not been systematically analyzed by bibliometrics and visual analysis. This study is based on 631 publications in the Web of Science Core Collection (WoSCC) to analyze hot spots and trends in this field. The collaborations between different authors, institutions, countries, and keywords were bibliometrically analyzed by CiteSpace software. Meanwhile, VOSviewer analyzed the references. The results show that since 2012, the number of publications has been growing rapidly. According to the collaborative network analysis, the United States, the National University of Ireland, Cork, and J.F. Cryan are the countries, institutions, and authors contributing the most, respectively. Through keywords and literature analysis, mechanisms and therapy associated with IBS and the brain-gut axis have still been a research focus in recent years. Furthermore, the physiological and pathological mechanisms of the brain-gut axis influencing IBS (related to gastrointestinal dysfunction, vagus nerve, visceral pain, intestinal flora, serotonin, tryptophan metabolism, stress, brain-derived neurotrophic factor (BDNF), and malonyldialdehyde) are the future research trends, especially the mechanisms related to intestinal flora. This is the first bibliometric and visualization analysis of IBS and brain-gut axis-related literature to explore research hotspots and trends.

Genetically proxied inhibition of tumor necrosis factor and the risk of colorectal cancer: A drug-target mendelian randomization study.

Background: Previous studies suggested that anti-TNF drugs might be repurposed as a preventive treatment for colorectal cancer. We aimed to examine whether genetically proxied inhibition of tumor necrosis factor receptor 1 (TNFR1) reduces the absolute risk of colorectal cancer through mendelian randomization (MR) analysis. Methods: We obtained 28 single nucleotide polymorphisms (SNPs) that were located within a ±15 kilobase window of the TNFRSF1A-the gene that encodes the TNFR1 protein, and we used genetic data from three GWAS studies of circulating levels of TNFR1, C-reactive protein (CRP), and white blood counts (WBC) to screen SNPs that proxied the inhibition of TNFR1. Positive control analyses were then performed by using another three GWAS data from the ulcerative colitis cohort (n = 45,975), Crohn's disease cohort (n = 40,266), and multiple sclerosis cohort (n = 115,803) to confirm the effect of the included SNPs. A two-sample mendelian randomization analysis was performed to examine the association between TNFR1 inhibition and the absolute risk reduction (ARR) of colorectal cancer. Results: We finally included seven SNPs to proxy the anti-TNF effect, and these SNPs caused lower levels of TNFR1, CRP, and white blood counts. In positive control analyses, the included SNPs caused lower odds ratio of ulcerative colitis and Crohn's disease but a higher odds ratio of multiple sclerosis, consistent with drug mechanistic actions and previous trial evidence. By using the inverse-variance weighted analyses to combine the effects of the seven SNPs, we found that the anti-TNF effect was associated with a 0.988 (95%CI 0.985-0.991) mg/L decrease in CRP levels and a reduction in the risk of colorectal cancer (absolute risk reduction -2.1%, 95%CI -3.8% to -0.4%, p = 0.01). Conclusion: Our study confirmed that anti-TNF drugs were associated with a risk reduction in colorectal cancer. Physicians could consider using anti-TNF drugs for the prevention of colorectal cancer, especially in patients with high risks of developing cancer.

Differential Sleep Traits Have No Causal Effect on Inflammatory Bowel Diseases: A Mendelian Randomization Study.

Background: Previous studies suggested an association of sleep disorders with inflammatory bowel disease (IBD) and indicated that using pharmacological treatments for the modulation of circadian rhythms might prevent IBD pathogenesis or aggravation, but whether the effect of sleep traits on IBD was causal is inconclusive and, therefore, prevents drug repurposing based on the previous studies. We aimed to examine the causal effect of different sleep traits on the pathogenesis of IBD. Methods: Genetic instruments for sleep traits were selected from the largest GWAS studies available in the UK Biobank (n = 449,734) and the 23andMe Research (n = 541,333). A two-sample Mendelian randomization (MR) study was conducted to examine the association of the genetic instruments with IBD (12,882 cases and 21,770 controls), ulcerative colitis (6,968 cases, 20,464 controls), and Crohn's disease (5,956 cases and 14,927 controls). We applied the inverse-variance weighted (IVW) method to estimate causal effects, and we used the weighted median and MR-Egger method for sensitivity analyses. Results: We found that sleep duration (OR, 1.00, 95% CI 1.00-1.01), short sleep duration (OR, 1.07, 95% CI 0.41-2.83), morningness (OR, 1.05, 95% CI 0.87-1.27), daytime napping (OR, 1.64, 95% CI 0.62-4.4), frequent insomnia (OR, 1.17, 95% CI 0.8-1.72), any insomnia (OR, 1.17, 95% CI 0.69-1.97), and snoring (OR, 0.31, 95% CI 0.06-1.54) had no causal effect on IBD, and these sleep traits had no causal effect on ulcerative colitis and Crohn's disease either. Most of the sensitivity analyses showed consistent results with those of the IVW method. Conclusion: Our MR study did not support the causal effect of sleep traits on IBD. Pharmacological modulation of circadian rhythms for the prevention of IBD pathogenesis was unwarranted.

Chinese herbal medicine versus antispasmodics in the treatment of irritable bowel syndrome: A network meta-analysis.

BACKGROUND: Chinese herbal medicine (CHM) is gaining popularity in treating irritable bowel syndrome (IBS). Although its efficacy was shown in recent randomized controlled trials (RCTs), it is rarely compared with antispasmodics to confirm its effectiveness. We aimed to resolve this uncertainty through a network meta-analysis. METHODS: We searched for RCTs that compared CHM or antispasmodics with placebo or one of them in the treatment of IBS. The primary outcomes were adequate relief of global IBS symptoms and abdominal pain. The data were pooled using a random-effects model. The effect size measure was pooled relative risk (RR), and treatments were ranked according to their P-scores. KEY RESULTS: We included 57 RCTs (n = 8869). After completion of treatment, drotaverine, individual CHM, otilonium, cimetropium, standard CHM, and pinaverium were efficacious in adequate relief of global IBS symptoms, and drotaverine ranked the first (RR, 2.33 [95% CI, 1.31-4.14], P-score =0.91); no difference was found between these treatments. After completion of treatment, drotaverine, standard CHM, pinaverium, and individual CHM were efficacious in abdominal pain, and drotaverine ranked the first (RR, 2.71 [95% CI, 1.69-4.36], P-score =0.91); no difference was found between these treatments. Standard CHM had significantly more adverse events than placebo (RR, 1.82 [95% CI, 1.12-2.94]) and other treatments. CONCLUSIONS: CHM and antispasmodics were efficacious for improvement of global IBS symptoms and abdominal pain. The adverse events of CHM were higher than antispasmodics; however, the heterogeneity of CHM formulas and the very low quality of the evidence warrants further investigation.

Searching for a Definition of Refractory Irritable Bowel Syndrome: a Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: The pathological mechanism of irritable bowel syndrome (IBS) is unclarified, which commonly leads to unresponsiveness to conventional treatments. The diagnostic criteria for refractory IBS are not clearly defined. We performed a systematic review to summarize the key points of the definition of refractory IBS in different studies. We also conducted a meta-analysis to explore whether the diverse definitions for refractory IBS affect the therapeutic effect of gut-directed hypnotherapy (GDH). METHODS: We searched OVID Medline, Embase and Cochrane (until September 2020) for randomized controlled trials (RCTs) recruiting patients with refractory IBS. We evaluated the definition of refractory IBS through the following aspects: duration of symptoms, unresponsive to dietary intervention, lifestyle modification, pharmacology, psychology, severity assessment and adequate explanation. The effect of the different definitions for refractory IBS on the therapeutic effect of gut-directed hypnotherapy (GDH) was checked by a meta-analysis. RESULTS: Twenty-one RCTs were finally included. Six (28.6%) out of 21 RCTs recruited patients with symptoms lasting for over 12 months; 8 (38.1%) RCTs reported a prior use of dietary intervention; 1 (4.8%) RCT reported the use of lifestyle modification; 11 (52.4%) RCTs recruited patients who were unresponsive to pharmacology; 2 (9.5%) RCTs recruited patients with no response to psychological therapy ; 5 (23.8%) RCTs had symptoms severity assessment; and 8 (38.1%) RCTs recruited patients who were informed adequately. Despite being tested in trials with heterogeneous definition of refractory IBS, GDH had similar effectiveness when compared with supportive treatment [standardized mean difference (SMD)=-0.69, 95%CI: -0.93 to -0.44)] or waiting-list control (SMD=-0.54, 95%CI: -0.98 to -0.10). CONCLUSIONS: Varied definitions in refractory IBS were common phenomena in clinical studies. Resistance to symptom severity assessment and psychological treatments should be more explicitly defined. Gut-directed hypnotherapy was efficacious for refractory IBS and was not affected by the diversity in the definition of refractory IBS among RCTs.

Efficacy of acupuncture for migraine prophylaxis: a trial sequential meta-analysis.

BACKGROUND: Acupuncture is commonly used for migraine prophylaxis; however, evidence of its efficacy was equivocal. AIM: We aimed to evaluated the efficacy of acupuncture in migraine prophylaxis and calculated the required information size (RIS) to determine whether further clinical studies are required. METHODS: We searched Cochrane library, EMBASE and PubMed from inception to April 23th, 2020. Randomized trials that compared acupuncture with conventional drug therapy or sham acupuncture were included. The primary outcome was migraine episodes. Secondary outcomes were responder rate and adverse event. RESULTS: Twenty studies (n = 3380) met the inclusion criteria. When it comes to migraine episodes, Acupuncture was superior over sham acupuncture [SMD = - 0.29, 95% CI (- 0.47 to - 0.11), P = 0.002] after treatment, while the difference between acupuncture and prophylactic drugs was not significant [SMD = - 0.21, 95% CI (- 0.42 to 0.00), P = 0.06].Both TSA graphs indicated that more RCTs are needed. As for responder rate, the results after treatment showed that acupuncture was statistically significantly better than sham acupuncture [RR 1.30, 95% CI (1.09-1.55), P = 0.003] as well as conventional drugs [RR 1.24, 95% CI (1.04-1.48), P = 0.01]. Both of their cumulative Z-curves intersected with the trial sequential monitoring boundaries favoring acupuncture. Compared to prophylactic medication, acupuncture can cause less adverse events [RR 0.34, 95% CI (0.14-0.81), P = 0.01]. CONCLUSION: Acupuncture can reduce migraine episodes compared to sham one and can be an alternative and safe prophylactic treatment for conventional drugs therapy, but it should be further verified through more RCTs. Available studies suggested acupuncture was superior to sham acupuncture and conventional drugs in terms of responder rate as verified by TSA.

Calcitonin Gene-Related Peptide Monoclonal Antibodies Versus Botulinum Neurotoxin a in the Preventive Treatment of Chronic Migraine: An Adjusted Indirect Treatment Comparison Meta-Analysis.

Purpose: Calcitonin gene-related peptide monoclonal antibodies (CGRPmAbs) are new agents approved by the US Food and Drug Administration for preventive treatment of chronic migraine. Comparison between CGRPmAbs and previously approved Botulinum neurotoxin A (BoNT-A) will inform optimal preventive treatment of chronic migraine, but head-to-head trials are lacking. We therefore aimed to perform adjusted indirect comparison between CGRPmAbs and BoNT-A through a meta-analysis. Methods: OVID MEDLINE, EMBASE and the Cochrane central register of controlled trials, clinical registries, and government websites were searched from inception to September 2019. Randomized controlled trials comparing CGRPmAbs or BoNT-A with placebo in the preventive treatment of chronic migraine were included. The primary outcomes were headache days and migraine days measured at week 12. Data were synthesized by using a frequentist approach; and the treatments were ranked by P-score. Results: We included 10 trials (n = 4,678) after screening 1049 candidates. Six trials were with low risk of bias. Fremanezumab had an effect similar to BoNT-A in the reduction of headache days at week 12 (standard mean difference [SMD] 0.08, 95%CI -0.55 to -0.7). Galcanezumab reduced more migraine days than BoNT-A at week 12 (SMD, -0.94, 95%CI -1.24 to -0.63); fremanezumab showed similar findings (SMD, -0.55, 95%CI -0.85 to -0.24). Galcanezumab and fremanezumab had better effect in mitigating headache impact at week 12. CGRPmAbs and BoNT-A had similar adverse event rate. Conclusion: CGRPmAbs and BoNT-A had similar effect in the preventive treatment of chronic migraine. BoNT-A might be preferentially selected owing to its cost-effectiveness profiles. Further studies with direct comparison of the two treatments are warranted.

Chinese Herbal Medicine for Irritable Bowel Syndrome: A Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials.

Purpose: Chinese herbal medicine (CHM) is an important complementary and alternative therapy for the management of irritable bowel syndrome (IBS). Previous meta-analyses suggested that CHM is effective for IBS; nonetheless, its effectiveness is inconclusive owing to repeated significance testing. We aimed to examine the efficacy and safety of CHM for IBS through a meta-analysis and trial sequential analysis (TSA). Methods: We searched OVID Medline, Embase, Cochrane Central Register of Controlled Trials, and Web of Science from January 1, 1980, to September 20, 2020. The primary outcome was adequate relief of global IBS symptoms. The secondary outcomes included relief of abdominal pain and treatment-related adverse events. The relative ratio (RR) and required information size (RIS) were calculated for each outcome. Results: Ten trials recruiting 2,501 participants were included. Seven (70%) trials were at low risk of bias (RoB). Compared with placebo, CHM was associated with a significantly higher proportion of adequate relief of global IBS symptoms [RR 1.76 (95% confidence interval (95%CI), 1.33-2.33); I 2 = 81.1%; p < 0.001]. The RIS was 1,083 for the primary outcome, and the accrued information size was 1,716. The analysis of the relief of abdominal pain (three trials with 916 participants) showed similar results compared with placebo [RR 1.85 (95%CI, 1.59-2.14); I 2 = 0%; p < 0.001; RIS = 197 participants]. CHM was associated with a higher proportion of adverse events compared with placebo [RR 1.51 (95%CI, 1.14-2); I 2 = 0%; p = 0.004]. Conclusion: CHM was effective in relieving IBS symptoms but caused a higher adverse event rate than placebo. TSA analysis confirmed the findings with sufficient information size.

Pharmacologic Treatments for Irritable Bowel Syndrome: an Umbrella Systematic Review.

BACKGROUND AND AIMS: Multiple pharmacologic treatments are available for the management of irritable bowel syndrome (IBS), and a large body of evidence has been presented. However, the strength and credibility of the evidence have not been comprehensively evaluated. We aimed to review the systematic reviews and meta- analyses of pharmacologic treatments for IBS and evaluate the credibility of the findings. METHODS: We searched MEDLINE, Embase, and Cochrane library from inception to September 2019 for systematic reviews evaluating the effectiveness of pharmacologic treatments for IBS. We summarized relative ratios (RR), evaluated the credibility of the evidence and classified the evidence into convincing, highly suggestive, suggestive, and weak. RESULTS: We included 11 systematic reviews with 40 meta-analyses (330 randomized controlled trials and 86,459 participants) assessing 10 treatment categories and 2 drugs. Most of the pharmacologic treatments were significantly superior over placebo as reported by the included meta-analyses. The evidence for 5-hydroxytryptamine (5-HT)3 antagonists (RR=1.56, 95%CI: 1.43-1.71), antispasmodics (RR=1.19, 95%CI: 1.02-1.39), and alosetron (RR=1.46, 95%CI: 1.26-1.71) were highly suggestive for relieving global IBS symptoms. 5-HT4 agonists (RR= 1.26, 95%CI: 1.19-1.34) and guanylate cyclase-C (GCC) agonists (RR=1.73, 95%CI: 1.54-1.95) were found to give convincing evidence for the improvement of the responder rate. 5-HT3 antagonists (RR=1.32, 95%CI: 1.26-1.38) offered convincing evidence for relieving abdominal pain. CONCLUSIONS: Evidence for 5-HT3 antagonists, 5-HT4 agonists and GCC agonists, antispasmodics, and alosetron were suggestive for the treatment of IBS. However, owing to the risk of bias in randomization methods, the results for GCC should be interpreted with caution.

Management of haemorrhoids: protocol of an umbrella review of systematic reviews and meta-analyses.

INTRODUCTION: The prevalence of haemorrhoidal diseases was high in general population, and many treatments are proposed for the management of haemorrhoids. The treatments include conservative and surgical interventions; the credibility and strength of current evidence of their effectiveness are not comprehensively evaluated. We aim to evaluate the credibility of systematic reviews and meta-analyses that assess the effectiveness of the treatments for haemorrhoidal diseases through an umbrella review. METHODS AND ANALYSIS: We will search Ovid Medline, Embase, Cochrane library and Web of Science from inception to March 2020 without any language restriction. We will include meta-analyses that examine the effectiveness of treatments in the management of haemorrhoids. Two reviewers will independently screen the titles and abstracts of retrieved articles, and they will extract data from the included meta-analyses. For each meta-analysis, we will estimate the effect size of a treatment through the random-effect model and the fixed-effect model, and we will evaluate between-study heterogeneity (Cochrane's Q and I2 statistics) and small-study effect (Egger's test); we will also estimate the evidence of excess significance bias. Evidence of each treatment will be graded according to prespecified criteria. Methodological quality of each meta-analysis will be evaluated by using Assessment of Multiple Systematic Reviews 2. The corrected cover area method will be used to assess the impact of overlap in reviews on the findings of the umbrella review. ETHICS AND DISSEMINATION: We will present the results of the umbrella review at conferences and publish the final report in a peer-reviewed journal. The umbrella review does not require ethical approval. PROSPERO REGISTRATION NUMBER: CRD42019140702.

Somatosensory stimulation treatments for postoperative analgesia of mixed hemorrhoids: Protocol for a systematic review and network meta-analysis.

BACKGROUND: Pain after hemorrhoidal surgery bothers both clinicians and patients. Somatosensory stimulation treatments have shown promising effect on the pain after hemorrhoidal surgery, but the comparative effectiveness between them has not been studied. We aim to determine the relative effectiveness among these treatments on pain relief after hemorrhoidal surgery by using network meta-analysis. METHOD: We will search the following electronic databases: MEDLINE, EMBASE, the Cochrane library, Chinese Biomedicine database (CBM), China National Knowledge Infrastructure (CNKI). We will include randomized controlled trials (RCTs) that examine the effect of somatosensory stimulation treatments on pain after hemorrhoidal surgery. The primary outcome will be the responder rate after treatment. The secondary outcomes will include the assessments with pain intensity scales (visual analog scale, numeric rating scale, or other scales) on day 1 to 7 after surgery. Two independent reviewers will extract needed information from eligible trials using standardized electronic forms. Network meta-analysis will be performed using a frequentist framework based on electrical network theory. The relative effectiveness of the treatments will be ranked by using P score, which is the mean probability of a treatment ranking the best in all treatments. Meta-regression will be performed to assess the impact of surgery type, anesthesia methods, and funding source on the treatment ranking. The quality of the eligible RCTs will be evaluated by the Cochrane risk of bias tool. ETHICS AND DISSEMINATION: The result of this network meta-analysis will clarify which is the relatively best somatosensory-stimulation treatment in relieving postoperative pain caused by hemorrhoidal surgery, and the review will, therefore, guide the management of postoperative pain after hemorrhoidal surgery for clinicians and patients. This review does not require ethical approval and will be reported in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: PROSPERO CRD42018115558.

Pharmacological treatments for patients with irritable bowel syndrome: An umbrella review of systematic reviews and meta-analyses.

INTRODUCTION: Several pharmacological treatments are beneficial for patients with irritable bowel syndrome (IBS), and there are numbers of systematic reviews evaluating the effectiveness of these treatments. However, the overall quality of the evidence has not been quantitatively assessed. The aim of this study is to evaluate the possible biases in the published systematic reviews and determine the treatments with reliable evidence. METHODS AND ANALYSIS: We will perform an umbrella review to identify eligible systematic reviews. A comprehensive literature search will be conducted in MEDLINE, EMBASE, and the Cochrane library for systematic reviews. We will describe the general information such as participants, interventions, outcome measurements, and conclusion. Additionally, the heterogeneity and inconsistency between trials will be assessed by the I statistical test and Cochrane Q test. We will assess risk of bias, and summarize the strength evidence. CONCLUSION: The umbrella reviews will assess the reliability of the evidence so that doctors and patients can make better medical choices. PROSPERO REGISTRATION NUMBER: CRD42018109597.

Comparative effectiveness of pharmacological treatments for patients with diarrhea-predominant irritable bowel syndrome: Protocol of a systematic review and network meta-analysis.

BACKGROUND: Several pharmacological treatments are recommended by guidelines with moderate to high evidence for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), but the comparative effectiveness and safety among these treatments are unknown. The review is to assess the comparative effectiveness and safety of pharmacological treatments for IBS-D using network meta-analysis. METHODS: We will search Ovid Medline, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) for relevant randomized controlled trials (RCTs) that compare guideline-recommended pharmacological treatments with placebo or one of the treatments. We will include RCTs that recruit patients with IBS-D, RCTs that assess the improvement in IBS-D global symptoms, abdominal pain, stool frequency, or stool consistency, and RCTs that assess the responder rate and adverse event rate. We will use standardized mean difference to synthesize continuous variables and use odds ratio to synthesize categorical variables. Traditional meta-analysis will be performed to assess the comparative effectiveness of the pharmacological treatments in direct evidence, and network meta-analysis will be performed to combine both direct and indirect evidence. Transitivity of the evidence in the network will be assessed by using a generalized Cochrane Q statistic and net-heat plot. CONCLUSIONS: The result of the review will inform clinical decisions for clinicians, patients, and police makers in the treatment of IBS-D. RESULTS: Ethical approval and informed consent are not required for this systematic review. We will disseminate the result through a peer-reviewed journal and conference abstracts. PROSPERO REGISTRATION NUMBER: PROSPERO CDR42018099294.