Postoperative decline in renal function after rectal resection and all-cause mortality: a retrospective cohort study.

AIM: Fluid loss, dehydration and resultant kidney injury are common when a diverting ileostomy is formed during rectal cancer surgery, the consequences of which are unknown. The aim of this retrospective single-site cohort study is to evaluate the impact of sustained postoperative renal dysfunction after rectal resection on long-term renal impairment and survival. METHOD: All patients with rectal adenocarcinoma undergoing resection between January 2003 and March 2017 were included, with follow-up to June 2020. The primary outcome was impact on long-term mortality attributed to a 25% or greater drop in estimated glomerular filtration rate (eGFR) following rectal resection. Secondary outcomes were the long-term effect on renal function resulting from the same drop in eGFR and the effect on long-term mortality and renal function of a 50% drop in eGFR. We also calculated the effect on mortality of a 1% drop in eGFR. RESULTS: A total of 1159 patients were identified. Postoperative reductions in eGFR of 25% and 50% were associated with long-term overall mortality with adjusted hazard ratios of 1.84 (1.22-2.77) (p = 0.004) and 2.88 (1.45-5.71) (p = 0.002). The median survival of these groups was 86.0 (64.0-108.0) months and 53.3 (7.8-98.8) months compared with 144.5 (128.1-160.9) months for controls. Long-term effects on renal function were demonstrated, with those who sustained a >25% drop in renal function having a 38.8% mean decline in eGFR at 10 years compared with 10.2% in controls. CONCLUSION: Persistent postoperative declines in renal function may be linked to long-term mortality. Further research is needed to assess causal relationships and prevention.

Comparative effectiveness of pathological techniques to improve lymph node yield from colorectal cancer specimens: a systematic review and network meta-analysis.

A number of randomised controlled trials (RCT) have compared different techniques to improve lymph node yield (LNY) in colorectal cancer specimens, but data on comparative effectiveness are sparse. Our aim was to compare the relative effectiveness and rank all available techniques. A systematic search of Embase, Cochrane, PubMed and Scopus was performed for randomised trials. Pairwise was meta-analysis performed if more than two homogeneous studies were available for each comparison. Network meta-analysis was used to rank and compare all available techniques. Fifteen studies fulfilled the inclusion criteria. Techniques that were compared included methylene blue (MB), glacial acetic acid, ethanol, distilled water and formaldehyde (GEWF), Carnoy solution (CS), patent blue (PB), formalin, fat clearing (FC) and their combinations. The overall quality of studies was found to be fair. In pairwise meta-analysis MB had a higher lymph node yield weighted mean difference (WMD) = 13.67 (4.83-22.51), P < 0.01, lower number of specimens with fewer than 12 lymph nodes log odds ratio = -1.88 (-2.8, -0.91), P < 0.01 and higher LNY in patients with prior chemoradiotherapy [WMD = 9.11 (3.15, 15.08), P = 0.02] compared to formalin. Evaluation of the network plot revealed a well-connected network. In network meta-analysis MBFC had a higher LNY with [mean difference (MD) 13 and 95% credible interval (CrI) = 2.09-23.91] compared to formalin. MBFC probability of being the best technique for LNY was 91.4%. In network meta-analysis MB did not have a statistically significant difference when compared to formalin. MBFCS seems to be the most effective technique for LNY. Further studies are required to make safe conclusions for outcomes such positive lymph nodes and upstaging.

Physical activity advice in the UK bowel cancer screening setting: qualitative healthcare professional perspectives.

Providing physical activity advice in the bowel cancer screening setting could help to reduce the risk of cancer and cardiometabolic disease in older adults. This study investigated the views of healthcare professionals (HCPs) regarding the provision of physical activity advice as part of the UK Bowel Cancer Screening Programme. A purposive sample of HCPs (aged 22-63 years, with 1-26 years of experience) from four bowel cancer screening disciplines (four endoscopists, four colorectal surgeons, four staff nurses and four specialist screening practitioners) were recruited from a large National Health Service gastroenterology unit. Data collection used individual interviews and focus groups, with topics being guided by an a priori topic guide. All interviews and focus groups were audio-recorded and transcribed verbatim. Three key themes, which contextualize the views and perceptions of HCPs recruited to the study, emerged from the framework analysis: (i) appraisal of the concept; (ii) perceived barriers to implementation; (iii) steps to implementation. While the general concept was viewed positively, there were differences of opinion and a range of perceived barriers were revealed. Ideas for effective implementation were also presented, taking into consideration the need for time efficiencies and importance of optimizing effectiveness. This qualitative study provided important insights into the perceptions of HCPs regarding the provision of physical activity advice in the bowel cancer screening setting, and yielded novel ideas for effective implementation.

Implementing supportive exercise interventions in the colorectal cancer care pathway: a process evaluation of the PREPARE-ABC randomised controlled trial.

BACKGROUND: A colorectal resection is standard treatment for patients with colorectal cancer (CRC). However, the procedure results in significant post-operative mortality and reduced quality of life. Maximising pre-operative cardiopulmonary fitness could improve post-surgical outcomes. PREPARE-ABC is a multi-centre, three-armed, randomised controlled trial investigating the effects of exercise interventions, with motivational support on short and longer-term recovery outcomes in CRC patients undergoing major lower-gastrointestinal surgery. The trial included an internal pilot phase with parallel process evaluation. The aim of the process evaluation was to optimise intervention implementation for the main trial. METHODS: Mixed methods process evaluation conducted in 14 UK hospitals between November 2016 and March 2018. Data included a site profile questionnaire and telephone scoping interview with hospital staff, 34 qualitative observations of standard care and 14 observations of intervention delivery, 13 semi-structured interviews with healthcare professionals (HCPs) and 28 semi-structured interviews with patients. Data analysis focused on describing intervention delivery within each arm, assessing fidelity, acceptability and how variation in delivery was linked to contextual characteristics. RESULTS: Standard care exercise advice was typically limited to maintaining current activity levels, and with lead-in time to surgery affecting whether any exercise advice was provided. Variation in HCP capacity affected the ability of colorectal units to deploy staff to deliver the intervention. Patients' exercise history and motivation prior to surgery influenced HCP perceptions and delivery of the motivational components. Observations indicated a high level of fidelity to delivery of the exercise interventions. All but one of the 28 interviewed patients reported increasing exercise levels as a result of receiving the intervention, with most finding them motivational and greatly valuing the enhanced level of social support (versus standard care) provided by staff. CONCLUSION: Hospital-supervised and home-based exercise interventions were highly acceptable for most patients undergoing surgery for CRC. Delivery of pre- and post-operative exercise within the CRC care pathway is feasible but systematic planning of capacity and resources is required to optimise implementation.

Risk and consequences of dehydration following colorectal cancer resection with diverting ileostomy. A systematic review and meta-analysis.

AIM: This systematic review aims to assess dehydration prevalence and dehydration-related morbidity from diverting ileostomy compared to resections without ileostomy formation in adults undergoing colorectal resection for cancer. METHOD: MEDLINE, Embase, CENTRAL and ClinicalTrials.gov were searched for studies of any design that reported dehydration, renal function and dehydration-related morbidity in adult colorectal cancer patients with diverting ileostomy (last search 12 August 2020). Bias was assessed using the Cochrane Collaboration's tool for assessing risk of bias in randomized trials and the Risk of Bias in Non-randomized Studies of Interventions tool. RESULTS: Of 1927 screened papers, 22 studies were included (21 cohort studies and one randomized trial) with a total of 19 485 patients (12 209 with ileostomy). The prevalence of dehydration was 9.00% (95% CI 5.31-13.45, P < 0.001). The relative risk of dehydration following diverting ileostomy was 3.37 (95% CI 2.30-4.95, P < 0.001). Three studies assessing long-term trends in renal function demonstrated progressive renal impairment persisting beyond the initial insult. Consequences identified included unplanned readmission, delay or non-commencement of adjuvant chemotherapy, and development of chronic kidney disease. DISCUSSION: Significant dehydration is common following diverting ileostomy; it is linked to acute kidney injury and has a long-term impact on renal function. This study suggests that ileostomy confers significant morbidity particularly related to dehydration and renal impairment.

The Role of Self-Determination in Changing Physical Activity Behavior in People Diagnosed With Bowel Polyps: A Pilot Randomized Controlled Trial.

This nonblinded randomized controlled trial investigated the efficacy of a physical activity (PA) intervention underpinned by self-determination theory. Participants (N = 31, mean age 69 years [SD = 4.9]) diagnosed with bowel polyps were randomized to an active lifestyle program (ALP; n = 17) or standard care (n = 14). ALP received supervised exercise and counseling for 6 months. Both groups were followed up at 12 months. Outcomes were change in PA and behavioral regulation. Data were analyzed with intention to treat. At 6 months, differences were observed for behavioral regulation in favor of ALP (p < .05). PA differences were significant for leisure, walking, and vigorous in favor of ALP (p < .05). The self-determination theory can be an effective strategy for promoting PA behavior change in this population, but a larger trial is needed to further explore the utility of the self-determination theory in this context.

Validation of the IPAQ Against Different Accelerometer Cut-Points in Older Cancer Survivors and Adults at Risk of Cancer.

The present study investigated the convergent validity of an interview-administered IPAQ long version (IPAQ-L) in an older population by comparison with objective accelerometry movement data. Data from 52 participants (mean age 67.9 years, 62% male) were included in the analysis. Treadmill derived (TM-ACC: 1,952-5,724 cpm) and free-living physical activity (PA) derived (FL-ACC: 760-5,724 cpm) accelerometer cut-points were used as criterion. IPAQ-L measures (total PA, leisure-time, walking-time, sedentary time) were significantly correlated with accelerometry (P ≤ .05). Differences in sex were observed. Bland-Altman Limits of Agreement analysis showed that the IPAQ-L overestimated PA in relation to accelerometry. Our results show that an interview-administered IPAQ-L shows low to moderate convergent validity with objective PA measures in this population but there may be differences between males and females which should be further investigated.

Assessing the quality of primary care referrals to surgery of patients with diabetes in the East of England: A multi-centre cross-sectional cohort study.

AIM: Peri-operative hyperglycaemia is associated with an increased incidence of adverse outcomes. Communication between primary and secondary care is paramount to minimise these harms. National guidance in the UK recommends that the glycated haemoglobin (HbA1c) should be measured within 3 months prior to surgery and that the concentration should be less that 69 mmol/mol (8.5%). In addition, national guidance outlines the minimum dataset that should be included in any letter at the time of referral to the surgeons. Currently, it is unclear how well this process is being carried out. This study investigated the quality of information being handed over during the referral from primary care to surgical outpatients within the East of England. METHODS: Primary care referrals to nine different NHS hospital Trusts were gathered over a 1-week period. All age groups were included from 11 different surgical specialties. Referral letters were analysed using a standardised data collection tool based on the national guidelines. RESULTS: A total of 1919 referrals were received, of whom 169 (8.8%) had previously diagnosed diabetes mellitus (DM). However, of these, 38 made no mention of DM in the referral letter but were on glucose-lowering agents. Only 13 (7.7%) referrals for patients with DM contained a recent HbA1c, and 20 (11.8%) contained no documentation of glucose-lowering medication. CONCLUSION: This study has shown that the quality of referral letters to surgical specialties for patients with DM in the East of England remain inadequate. There is a clear need for improving the quality of clinical data contained within referral letters from primary care. In addition, we have shown that the rate of referral for surgery for people with diabetes is almost 50% higher than the background population with diabetes.

Canonical Wnt signals combined with suppressed TGFß/BMP pathways promote renewal of the native human colonic epithelium.

BACKGROUND: A defining characteristic of the human intestinal epithelium is that it is the most rapidly renewing tissue in the body. However, the processes underlying tissue renewal and the mechanisms that govern their coordination have proved difficult to study in the human gut. OBJECTIVE: To investigate the regulation of stem cell-driven tissue renewal by canonical Wnt and TGFß/bone morphogenetic protein (BMP) pathways in the native human colonic epithelium. DESIGN: Intact human colonic crypts were isolated from mucosal tissue samples and placed into 3D culture conditions optimised for steady-state tissue renewal. High affinity mRNA in situ hybridisation and immunohistochemistry were complemented by functional genomic and bioimaging techniques. The effects of signalling pathway modulators on the status of intestinal stem cell biology, crypt cell proliferation, migration, differentiation and shedding were determined. RESULTS: Native human colonic crypts exhibited distinct activation profiles for canonical Wnt, TGFß and BMP pathways. A population of intestinal LGR5/OLFM4-positive stem/progenitor cells were interspersed between goblet-like cells within the crypt-base. Exogenous and crypt cell-autonomous canonical Wnt signals supported homeostatic intestinal stem/progenitor cell proliferation and were antagonised by TGFß or BMP pathway activation. Reduced Wnt stimulation impeded crypt cell proliferation, but crypt cell migration and shedding from the crypt surface were unaffected and resulted in diminished crypts. CONCLUSIONS: Steady-state tissue renewal in the native human colonic epithelium is dependent on canonical Wnt signals combined with suppressed TGFß/BMP pathways. Stem/progenitor cell proliferation is uncoupled from crypt cell migration and shedding, and is required to constantly replenish the crypt cell population.

Relationship between the m-FI 11 score and 2-year survival in octogenarians undergoing colorectal cancer resection.

Introduction: The modified Frailty Index (m-FI) offers a simple scoring tool, predicting short-term outcomes in elderly colorectal cancer (CRC) patients. However, links between m-FI scores and 2-year postoperative mortality in octogenarian CRC resection patients remain underexplored. A streamlined frailty index can aid in preoperative assessments to identify elderly patients who are likely to live longer after curative resection surgery to then tailor postoperative care. Our study aims to assess the association between m-FI scores and 2-year postoperative mortality in elderly CRC surgery patients. Methods: A retrospective analysis was conducted on a cohort of consecutive patients aged older than or equal to 80 years who underwent colorectal cancer resection at a tertiary referral centre between 2010 and 2017. The m-FI-11 scores less than or equal to two denoted the non-frail category, whereas m-FI scores equal to or exceeding 3 were categorised as frail. The primary outcome measure was defined as 2-year all-cause mortality. Results: A total of 337 patients were studied. The 2-year overall survival rate was 83% with an overall median survival time of 84 months (95% CI: 74-94 months). Patients with m-FI scores less than or equal to 2 had a 2-year survival rate of 85% and a median survival time of 94 months (95% CI: 84-104 months). Conversely, patients with m-FI scores greater than or equal to 3 had a 2-year survival rate of 72% and a median survival time of 69 months (95% CI: 59-79 months). An m-FI score greater than or equal to 3 showed a hazard ratio of 1.73 (95% CI: 0.92-3.26, P=0.092) for 2-year mortality compared to an m-FI score less than or equal to 2. Conclusion: Higher m-FI scores significantly correlate with an increased 2-year mortality risk among octogenarian CRC resection patients. This highlights the potential of the m-FI as a preoperative tool for identifying patients likely to survive longer post-surgery. Its integration aids in tailored postoperative care strategies, ensuring efficient recovery to functional baselines in this cohort.

Circumferential resection margin positivity due to direct or indirect tumour involvement in rectal cancer - a call for better stratification.

BACKGROUND: A positive circumferential resection margin (CRM) after rectal cancer surgery, which can be the result of direct or indirect tumour involvement, has consistently been associated with increased local recurrence and poorer survival. However, little is known of the differential impact of the mode of tumour involvement on outcomes. METHODS: 1460 consecutive patients undergoing rectal cancer resection between 2003 and 2018 were retrospectively assessed. Histopathology reports for patients with a positive CRM were reviewed to determine cases of direct (R1-tumour) or indirect tumour involvement (R1-other). Disease-free survival (DFS) and overall survival (OS) were assessed by Kaplan-Meier analysis. The role of the mode of CRM positivity was examined by univariate and multivariate Cox proportional hazards models. RESULTS: Eighty-five patients had an R1 resection due to CRM involvement (5.8%). Of those, 69 were due to direct tumour involvement, while 16 were from indirect causes. Kaplan-Meier analysis revealed that R1-other was associated with increased OS (hazard ratio 0.40, log-rank P = 0.006) and DFS (P = 0.043). Multivariate regression confirmed that the mode of CRM positivity was an independent predictor of OS. More interestingly, the patterns of recurrence were different between the two groups, with R1-tumour leading to significantly more local recurrence (P = 0.04). CONCLUSIONS: Our data strongly suggests that direct tumour involvement of the CRM confers worse prognosis after rectal cancer surgery. Importantly, differences in the site and frequency of recurrences make a case for better stratification of patients with a positive CRM to guide treatment decisions.

Perceptions of theatre team members to robotic assisted surgery and the aid of technology in colorectal surgery.

The implementation of robotic assisted surgery (RAS) has brought in a change to the perception and roles of theatre staff, as well as the dynamics of the operative environment and team. This study aims to identify and describe current perceptions of theatre staff in the context of RAS. 12 semi-structured interviews were conducted in a tertiary level university hospital, where RAS is utilised in selected elective settings. Interviews were conducted by an experienced research nurse to staff of the colorectal department operating theatre (nursing, surgical and anaesthetics) with some experience in operating within open, laparoscopic and RAS surgical settings. Thematic analysis on all interviews was performed, with formation of preliminary themes. Respondents all discussed advantages of all modes of operating. All respondents appreciated the benefits of minimally invasive surgery, in the reduced physiological insult to patients. However, interviewees remarked on the current perceived limitations of RAS in terms of logistics. Some voiced apprehension and anxieties about the safety if an operation needs to be converted to open. An overarching theme with participants of all levels and backgrounds was the 'Teamwork' and the concept of the [robotic] team. The physical differences of RAS changes the traditional methods of communication, with the loss of face-to-face contact and the physical 'separation' of the surgeon from the rest of the operating team impacting theatre dynamics. It is vital to understand the staff cultures, concerns and perception to the use of this relatively new technology in colorectal surgery.

Technical and Clinical Outcomes After Colorectal Stenting in Malignant Large Bowel Obstruction: A Single-Center Experience.

PURPOSE: Malignant large bowel obstruction is a surgical emergency that requires urgent decompression. Stents are increasingly being used, though reported outcomes are variable. We describe our multidisciplinary experience in using stents to manage malignant large bowel obstruction. METHODS: All patients undergoing colorectal stent insertion for acute large bowel obstruction in a teaching hospital were included. Outcomes, complications, and length of stay (LOS) were recorded. RESULTS: Over a 7-year period, 73 procedures were performed on 67 patients (37 male, mean age of 76 years). Interventional radiology was involved in all cases. Endoscopic guidance was required in 24 cases (32.9%). In 18 patients (26.9%), treatment intent was to bridge to elective surgery; 16 had successful stent placement; all had subsequent curative resection (laparoscopic resection, 8 of 18; primary anastomosis, 14 of 18). Overall LOS, including both index admission and elective admission, was 16.4 days. Treatment intent was palliative in 49 patients (73.1%). In this group, stents were successfully placed in 41 of 49 (83.7%). Complication rate within 30 days was 20%, including perforation (2 patients), per rectal bleeding (2), stent migration (1), and stent passage (5). Nineteen patients (38.8%) required subsequent stoma formation (6, during same admission; 13, during subsequent admission). Overall LOS was 16.9 days. CONCLUSION: In our experience colorectal stents can be used effectively to manage malignant large bowel obstruction, with only selective endoscopic input. As a bridge to surgery, most patients can avoid emergency surgery and have a primary anastomosis. In the palliative setting, the complication rate is acceptable and two-thirds avoid a permanent stoma.

Single Nucleotide Polymorphisms and Post-operative Complications Following Major Gastrointestinal Surgery: a Systematic Review and Meta-analysis.

BACKGROUND: The human genome is an under-researched area of pre-operative risk stratification. Studies of genetic polymorphisms and their associations with acute post-operative complications in gastrointestinal surgery have reported statistically significant results, but have varied in methodology, genetic variations studied, and conclusions reached. To provide clarity, we conducted a systematic review and meta-analysis of single nucleotide polymorphisms and their association with post-operative complications after major gastrointestinal surgery. METHODS: We performed a literature search using Ovid MEDLINE and Web of Science databases. Studies were included if they investigated genetic polymorphisms and their associations with post-operative complications after major gastrointestinal surgery. We extracted clinical and genetic data from each paper and assessed for quality against the STrengthening the REporting of Genetic Association Studies (STREGA) guidelines. Odds ratios were presented, with 95% confidence intervals, to assess strengths of association. We conducted a meta-analysis on TNF-α-308, which had been assessed in three papers. RESULTS: Our search returned 68 papers, of which 5 were included after screening and full-text review. Twenty-two different single nucleotide polymorphisms (SNPs) were investigated in these studies. We found that all papers were genetic association studies, and had selected SNPs related to inflammation. The outcome investigated was most commonly post-operative infection, but also anastomotic leak and other non-infectious complications. Statistically significant associations were found for TNF-α-308, IL-10-819, PTGS2-765 and IFN-γ-874. There was significant variability in study quality and methodology. We conducted a meta-analysis on associations between the TNF-α-308 polymorphism and post-operative infection and report an OR of 1.18 (CI 0.27-5.21). CONCLUSIONS: We found biologically plausible associations between SNPs involved in inflammation and post-operative infection, but the available data were too limited and of insufficient quality to reach definitive conclusions. Further work is needed, including genome-wide association studies (GWAS).

Method of pedicle division during laparoscopic right hemicolectomy affects lymph node yield and short-term outcomes.

BACKGROUND: Several ways of performing laparoscopic right hemicolectomy (RHC) have evolved. The vascular pedicle can be divided into extracorporeal (RHC-EC) or intracorporeal (RHC-IC). It is not known whether vessel ligation during RHC-EC is as central as during RHC-IC. We compare these approaches in terms of pathological and short-term clinical outcomes. METHODS: Patients undergoing elective laparoscopic RHC in a single centre (July 2013-September 2016) were identified. Data collection included operative details, length of stay, complications, specimen parameters including number and involvement of lymph nodes and recurrence. RESULTS: One hundred and sixty-nine patients were included (94 RHC-IC, 75 RHC-EC). For caecal and ascending colon cancers, mesocolic width was greater after RHC-IC than RHC-EC (7.9 cm versus 6.6 cm, P < 0.05), as was lymph node yield (19.5 versus 17.3, P < 0.05). There was no significant difference in length of colon resected, distal resection margin, number of positive nodes, proportion of node-positive tumours and R1 rate. Operative duration was higher for RHC-IC (163 min versus 91 min, P < 0.001), as was incidence of ileus (35% versus 15%, P < 0.05). Length of stay also tended to be higher (7.4 days versus 6.0 days, P = 0.19). There was no difference in disease recurrence (follow-up 12 months). Body mass index was positively correlated with lymph node yield for RHC-EC, but not for RHC-IC. CONCLUSION: Lymph node yield after laparoscopic RHC is adequate, whether the vascular pedicle is taken intracorporeal or extracorporeal, supporting the use of both approaches. RHC-IC yields more lymph nodes and greater mesocolic width, but involves a longer operation and higher incidence of ileus.

The colon-selective spasmolytic otilonium bromide inhibits muscarinic M(3) receptor-coupled calcium signals in isolated human colonic crypts.

1. Otilonium bromide (OB) is a smooth muscle relaxant used in the treatment of irritable bowel syndrome. Otilonium bromide has been shown to interfere with the mobilization of calcium in intestinal smooth muscle, but the effects on other intestinal tissues have not been investigated. We identified the muscarinic receptor subtype coupled to calcium signals in colonic crypt derived from the human colonic epithelium and evaluated the inhibitory effects of OB. 2. Calcium signals were monitored by fluorescence imaging of isolated human colonic crypts and Chinese hamster ovary cells stably expressing the cloned human muscarinic M(3) receptor subtype (CHO-M(3)). Colonic crypt receptor expression was investigated by pharmacological and immunohistochemical techniques. 3. The secretagogue acetylcholine (ACh) stimulated calcium mobilization from intracellular calcium stores at the base of human colonic crypts with an EC(50) of 14 micro M. The muscarinic receptor antagonists 4-DAMP, AF-DX 384, pirenzepine and methroctamine inhibited the ACh-induced calcium signal with the following respective IC(50) (pK(b)) values: 0.78 nM (9.1), 69 nM (7.2), 128 nM (7.1), and 2510 nM (5.8). 4. Immunohistochemical analyses of muscarinic receptor expression demonstrated the presence of M(3) receptor subtype expression at the crypt-base. 5. Otilonium bromide inhibited the generation of ACh-induced calcium signals in a dose dependent manner (IC(50)=880 nM). 6. In CHO-M(3) cells, OB inhibited calcium signals induced by ACh, but not ATP. In addition, OB did not inhibit histamine-induced colonic crypt calcium signals. 7. The present studies have demonstrated that OB inhibited M(3) receptor-coupled calcium signals in human colonic crypts and CHO-M(3) cells, but not those induced by stimulation of other endogenous receptor types. We propose that the M(3) receptor-coupled calcium signalling pathway is directly targeted by OB at the level of the colonic epithelium, suggestive of an anti-secretory action in IBS patients suffering with diarrhoea.