Anxiety‐related factors associated with symptom severity in irritable bowel syndrome

Background Gastrointestinal symptom‐specific anxiety and somatization have both been associated with higher symptom severity in patients with irritable bowel syndrome (IBS); however, this relationship has not been explored fully. Moreover, the performance of the visceral sensitivity index (VSI) for measuring gastrointestinal symptom‐specific anxiety has not been examined in a UK population. We conducted a cross‐sectional survey to examine these issues. Methods Gastrointestinal symptom‐specific anxiety was measured using the VSI, and somatization was measured via the patient health questionnaire‐12 (PHQ‐12) in adults from the UK community with Rome IV‐defined IBS. Exploratory factor analysis was performed on the VSI, prior to subsequent analyses, to establish its factor structure. Multiple regression analysis was used to determine the relationship between demographic features, different factors of the VSI, somatization, and IBS symptom severity. Key Results A total of 811 individuals with IBS provided complete data. Factor analysis of the VSI revealed a three‐factor structure, accounting for 47% of the variance. The first of these VSI factors and the PHQ‐12 were both strongly and independently associated with IBS symptom severity, for the group as a whole and for all four IBS subtypes. Most VSI items concerned with overt gastrointestinal symptom‐specific anxiety loaded onto the other two VSI factors that were not associated with symptom severity. Conclusions and Inferences The factor structure of the VSI requires further investigation. Our findings cast doubt on the central role of gastrointestinal symptom‐specific anxiety as a driver for symptom severity in IBS. Awareness of both gastrointestinal and extra‐intestinal symptoms, however, is strongly associated with symptom severity

The cytohesin paralog Sec7 of Dictyostelium discoideum is required for phagocytosis and cell motility

Background: Dictyostelium harbors several paralogous Sec7 genes that encode members of three subfamilies of the Sec7 superfamily of guanine nucleotide exchange factors. One of them is the cytohesin family represented by three members in D. discoideum, SecG, Sec7 and a further protein distinguished by several transmembrane domains. Cytohesins are characterized by a Sec7-PH tandem domain and have roles in cell adhesion and migration. Results: We study here Sec7. In vitro its PH domain bound preferentially to phosphatidylinositol 3,4-bisphosphate (PI(3,4) P-2), phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2) and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P-3). When following the distribution of GFP-Sec7 in vivo we observed the protein in the cytosol and at the plasma membrane. Strikingly, when cells formed pseudopods, macropinosomes or phagosomes, GFP-Sec7 was conspicuously absent from areas of the plasma membrane which were involved in these processes. Mutant cells lacking Sec7 exhibited an impaired phagocytosis and showed significantly reduced speed and less persistence during migration. Cellular properties associated with mammalian cytohesins like cell-cell and cell-substratum adhesion were not altered. Proteins with roles in membrane trafficking and signal transduction have been identified as putative interaction partners consistent with the data obtained from mutant analysis. Conclusions: Sec7 is a cytosolic component and is associated with the plasma membrane in a pattern distinctly different from the accumulation of PI(3,4,5)P-3. Mutant analysis reveals that loss of the protein affects cellular processes that involve membrane flow and the actin cytoskeleton

Habit training versus habit training with direct visual biofeedback in adults with chronic constipation: A randomized controlled trial

Aim: The aim was to determine whether specialist-led habit training using Habit Training with Biofeedback (HTBF) is more effective than specialist-led habit training alone (HT) for chronic constipation and whether outcomes of interventions are improved by stratification to HTBF or HT based on diagnosis (functional defaecation disorder vs. no functional defaecation disorder) by radio-physiological investigations (INVEST). Method: This was a parallel three-arm randomized single-blinded controlled trial, permitting two randomized comparisons: HTBF versus HT alone; INVEST- versus no-INVEST-guided intervention. The inclusion criteria were age 18–70 years; attending specialist hospitals in England; self-reported constipation for >6 months; refractory to basic treatment. The main exclusions were secondary constipation and previous experience of the trial interventions. The primary outcome was the mean change in Patient Assessment of Constipation Quality of Life score at 6 months on intention to treat. The secondary outcomes were validated disease-specific and psychological questionnaires and cost-effectiveness (based on EQ-5D-5L). Results: In all, 182 patients were randomized 3:3:2 (target 384): HT n = 68; HTBF n = 68; INVEST-guided treatment n = 46. All interventions had similar reductions (improvement) in the primary outcome at 6 months (approximately −0.8 points of a 4-point scale) with no statistically significant difference between HT and HTBF (−0.03 points; 95% CI −0.33 to 0.27; P = 0.85) or INVEST versus no-INVEST (0.22; −0.11 to 0.55; P = 0.19). Secondary outcomes showed a benefit for all interventions with no evidence of greater cost-effectiveness of HTBF or INVEST compared with HT. Conclusion: The results of the study at 6 months were inconclusive. However, with the caveat of under-recruitment and further attrition at 6 months, a simple, cheaper approach to intervention may be as clinically effective and more cost-effective than more complex and invasive approaches

UK clinical experience up to 52 weeks with linaclotide for irritable bowel syndrome with constipation

Background: Linaclotide, a guanylate cyclase C agonist, has been shown in clinical trials to improve symptoms of irritable bowel syndrome with constipation (IBS-C). Here we report data from a real-world study of linaclotide in the UK. Methods: This 1-year, multicentre, prospective, observational study in the UK enrolled patients aged 18 years and over initiating linaclotide for IBS-C. The primary assessment was change from baseline in IBS Symptom Severity Scale (IBS-SSS) score at 12 weeks, assessed in patients with paired baseline and 12-week data. Change from baseline in IBS-SSS score at 52 weeks was a secondary assessment. Adverse events were recorded. Results: In total, 202 patients were enrolled: 185 (91.6%) were female, median age was 44.9 years (range 18.1–77.2) and 84 (41.6%) reported baseline laxative use. Mean (standard deviation) baseline IBS-SSS score was 339 (92), with most patients (n = 129; 66.8%) classified as having severe disease (score ⩾300). In patients with paired data, there was a significant mean (95% confidence interval) decrease in IBS-SSS score from baseline to 12 weeks [−77.0 (−96.3, −57.7); p < 0.001; n = 124] and baseline to 52 weeks [−70.7 (−95.0, −46.5); p < 0.001; n = 76]. Overall, 174 adverse events were reported in 77 (38.1%) patients, most commonly diarrhoea (n = 54; 26.7%), abdominal pain (n = 21; 10.4%) and abdominal distension (n = 13; 6.4%). Conclusion: Linaclotide significantly improved IBS-SSS score at 12 and 52 weeks. These results provide insights into outcomes with linaclotide treatment over 1 year in patients with IBS-C in real-world clinical practice

Uk Clinical Experience Up to 52 Weeks With Linaclotide for Irritable Bowel Syndrome With Constipation

BACKGROUND: Linaclotide, a guanylate cyclase C agonist, has been shown in clinical trials to improve symptoms of irritable bowel syndrome with constipation (IBS-C). Here we report data from a real-world study of linaclotide in the UK. METHODS: This 1-year, multicentre, prospective, observational study in the UK enrolled patients aged 18 years and over initiating linaclotide for IBS-C. The primary assessment was change from baseline in IBS Symptom Severity Scale (IBS-SSS) score at 12 weeks, assessed in patients with paired baseline and 12-week data. Change from baseline in IBS-SSS score at 52 weeks was a secondary assessment. Adverse events were recorded. RESULTS: In total, 202 patients were enrolled: 185 (91.6%) were female, median age was 44.9 years (range 18.1-77.2) and 84 (41.6%) reported baseline laxative use. Mean (standard deviation) baseline IBS-SSS score was 339 (92), with most patients (n = 129; 66.8%) classified as having severe disease (score ⩾300). In patients with paired data, there was a significant mean (95% confidence interval) decrease in IBS-SSS score from baseline to 12 weeks [-77.0 (-96.3, -57.7); p < 0.001; n = 124] and baseline to 52 weeks [-70.7 (-95.0, -46.5); p < 0.001; n = 76]. Overall, 174 adverse events were reported in 77 (38.1%) patients, most commonly diarrhoea (n = 54; 26.7%), abdominal pain (n = 21; 10.4%) and abdominal distension (n = 13; 6.4%). CONCLUSION: Linaclotide significantly improved IBS-SSS score at 12 and 52 weeks. These results provide insights into outcomes with linaclotide treatment over 1 year in patients with IBS-C in real-world clinical practice

Treatment of irritable bowel syndrome with diarrhoea using titrated ondansetron (TRITON): study protocol for a randomised controlled trial

Background: Irritable bowel syndrome with diarrhoea (IBS-D) affects up to 4% of the general population. Symptoms include frequent, loose, or watery stools with associated urgency, resulting in marked reduction of quality of life and loss of work productivity. Ondansetron, a 5HT3 receptor antagonist, has had an excellent safety record for over 20 years as an antiemetic, yet is not widely used in the treatment of IBS-D. It has, however, been shown to slow colonic transit and in a small randomised, placebo-controlled, cross-over pilot study, benefited patients with IBS-D. Methods: This trial is a phase III, parallel group, randomised, double-blind, multi-centre, placebo-controlled trial, with embedded mechanistic studies. Participants (n = 400) meeting Rome IV criteria for IBS-D will be recruited from outpatient and primary care clinics and by social media to receive either ondansetron (dose titrated up to 24 mg daily) or placebo for 12 weeks. Throughout the trial, participants will record their worst abdominal pain, worst urgency, stool frequency, and stool consistency on a daily basis. The primary endpoint is the proportion of “responders” in each group, using Food and Drug Administration (FDA) recommendations. Secondary endpoints include pain intensity, stool consistency, frequency, and urgency. Mood and quality of life will also be assessed. Mechanistic assessments will include whole gut transit, faecal tryptase and faecal bile acid concentrations at baseline and between weeks 8 and 11. A subgroup of participants will also undergo assessment of sensitivity (n = 80) using the barostat, and/or high-resolution colonic manometry (n = 40) to assess motor patterns in the left colon and the impact of ondansetron. Discussion: The TRITON trial aims to assess the effect of ondansetron across multiple centres. By defining ondansetron’s mechanisms of action we hope to better identify patients with IBS-D who are likely to respond

Stepped-wedge randomised trial of laparoscopic ventral mesh rectopexy in adults with chronic constipation: Study protocol for a randomized controlled trial

BACKGROUND: Laparoscopic ventral mesh rectopexy (LVMR) is an established treatment for external full-thickness rectal prolapse. However, its clinical efficacy in patients with internal prolapse is uncertain due to the lack of high-quality evidence. METHODS: An individual level, stepped-wedge randomised trial has been designed to allow observer-blinded data comparisons between patients awaiting LVMR with those who have undergone surgery. Adults with symptomatic internal rectal prolapse, unresponsive to prior conservative management, will be eligible to participate. They will be randomised to three arms with different delays before surgery (0, 12 and 24 weeks). Efficacy outcome data will be collected at equally stepped time points (12, 24, 36 and 48 weeks). The primary objective is to determine clinical efficacy of LVMR compared to controls with reduction in the Patient Assessment of Constipation Quality of Life (PAC-QOL) at 24 weeks serving as the primary outcome. Secondary objectives are to determine: (1) the clinical effectiveness of LVMR to 48 weeks to a maximum of 72 weeks; (2) pre-operative determinants of outcome; (3) relevant health economics for LVMR; (4) qualitative evaluation of patient and health professional experience of LVMR and (5) 30-day morbidity and mortality rates. DISCUSSION: An individual-level, stepped-wedge, randomised trial serves the purpose of providing an untreated comparison for the active treatment group, while at the same time allowing the waiting-listed participants an opportunity to obtain the intervention at a later date. In keeping with the basic ethical tenets of this design, the average waiting time for LVMR (12 weeks) will be shorter than that for routine services (24 weeks)

Challenging the Biopsychosocial Model in a Chronic Constipation Clinic

In this article we discuss the results of an ethnographic study of professionals’ and patients’ experiences within a specialist constipation clinic in England. Chronic constipation tends to be poorly understood and inadequately treated. Eleven patients were followed through their illness trajectory during a 5-month fieldwork period, involving 21 home interviews, clinic-based interviews, participant observation, and a focus group. Professionals were likewise observed and interviewed. The clinic could be broadly described as biopsychosocial in its approach. However, professionals expressed uncertainty about how best to provide biopsychosocial care and suggested that some patients were not “open” to psychosocial therapies or to discussing psychosocial aspects of their disease. Patients’ concerns were with being taken seriously, receiving treatment, and narrating intersections of life events, emotional well-being, and the bowels. We situate these findings within the discourse of “functional” disorders and discuss why implementing a biopsychosocial approach is problematic in this case

Surgeons-Don't Forget to Calibrate! Findings from a Sacral Nerve Test Stimulator

Introduction: Sacral nerve stimulation testing (TSNS) for chronic constipation is not accurately predictive of a long-term response1. The decision to implant a permanent device relies on these results. Aims/Background: We recognised that the testing stimulator was an analogue device with potentially inaccurate dial settings. We sought verification of the output waveform. Method: 19 test stimulators were connected to a cross-calibrated oscilloscope. The output Frequency (f), and Pulse Width (pw) of the waveforms generated were measured according to: run 1) the physician's best attempt to set the dials correctly (pw=210 µ Sec, f=14 Hz), and run 2) the closest dial increment to these settings (pw=200 µ Sec, f=10 Hz). Output Voltage (V) was measured in run 3 at dial increments of 0V, 1V, 2V, 5V, and 10V. Results: We assumed an acceptable margin of error of 20% in runs 1 and 2, and 0.5V in run 3. There was a marked range of frequency values; run 1) 10.6 to 29.0 Hz (26% failed), and run 2) 7.9 to 13.0 Hz (11% failed). Findings for pulse width were similarly variable; run 1) 242 to 326 µ Sec (89% failed), and run 2)215 to 274 µ Sec (63% failed). All devices had a residual positive voltage at zero(range:0.29 to 1.00V), and the failure rates at 0,1,2,5 and 10V were 53%, 100%, 100%, 68% and 47% respectively. Conclusion: All fields of clinical practice and research have their instrumentation which requires calibration to provide verifiable readings. Failure to calibrate during TSNS results in patients receiving variable stimulation, potentially reducing the clarity of research findings, and may be a factor in the poor predictive power of testing in chronic constipation