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Aim: The coronavirus pandemic has led to significant challenges for healthcare delivery across the globe. Non-emergency endoscopic activity in the UK has been postponed, raising concerns of increased delays in the diagnosis of colorectal cancer and a surge in demand once services resume. Measures to mitigate this risk must be considered., Method: This paper reviews various investigative modalities for colorectal disease which could be deployed during cessation of colonoscopy services. We focus on colon capsule endoscopy (CCE) due to its relevance during the COVID-19 pandemic and its ability to triage patients effectively to further endoscopic investigations., Results: CT of the abdomen and pelvis has been suggested as a triage tool while access to colonoscopy is limited. However, CT may lead to the spread of COVID-19 as patients attend the hospital, and it exposes them to the risks of radiation. Faecal immunochemistry tests have been demonstrated as a good predictor of colonic pathology and could be safely used to risk stratify patients when prioritizing colonoscopy. CCE is a safe and innovative technology for investigating the colon. Procedures can be carried out in the community and can be conducted safely during the coronavirus pandemic. It has been shown to be an accurate detector of colonic neoplasia and can reduce demand for colonoscopy., Conclusion: As colonoscopy services resume, they will probably experience high demand leading to further delays for patients. CCE could be used to reduce the number of patients requiring colonoscopy and triage those requiring further endoscopic investigations appropriately., (Colorectal Disease © 2020 The Association of Coloproctology of Great Britain and Ireland.)

Aim: The goal of this European Society of ColoProctology project was to establish a multidisciplinary, international guideline for haemorrhoidal disease (HD) and to provide guidance on the most effective (surgical) treatment for patients with HD., Methods: The development process consisted of six phases. In phase one we defined the scope of the guideline. The patient population included patients with all stages of haemorrhoids. The target group for the guideline was all practitioners treating patients with haemorrhoids and, in addition, healthcare workers and patients who desired information regarding the treatment management of HD. The guideline needed to address both the diagnosis of and the therapeutic modalities for HD. Phase two consisted of the compilation of the guideline development group (GDG). All clinical members needed to have affinity with the diagnosis and treatment of haemorrhoids. Further, attention was paid to the geographical distribution of the clinicians. Each GDG member identified at least one patient in their country who could read English to comment on the draft guideline. In phase three review questions were formulated, using a reversed process, starting with possible recommendations based on the GDG's knowledge. In phase four a literature search was performed in MEDLINE (Ovid), PubMed, Embase (Ovid) and the Cochrane Database of Systematic Reviews. The search was focused on existing systematic reviews addressing each review question, supplemented by other studies published after the time frame covered by the systematic reviews. In phase five data of the included papers were extracted by the surgical resident (RT) and checked by the methodologist (JK) and the GDG. If needed, meta-analysis of the systematic reviews was updated by the surgical resident and the methodologist using Review Manager. During phase six the GDG members decided what recommendations could be made based on the evidence found in the literature using GRADE., Results: There were six sections: (i) symptoms, diagnosis and classification; (ii) basic treatment; (iii) outpatient procedures; (iv) surgical interventions; (v) special situations; (vi) other surgical techniques. Thirty-four recommendations were formulated., Conclusion: This international, multidisciplinary guideline provides an up to date and evidence based summary of the current knowledge of the management of HD and may serve as a useful guide for patients and clinicians., (Colorectal Disease © 2020 The Association of Coloproctology of Great Britain and Ireland.)

The early life gut microbiota plays a crucial role in regulating and maintaining the intestinal barrier, with disturbances in these communities linked to dysregulated renewal and replenishment of intestinal epithelial cells. Here we sought to determine pathological cell shedding outcomes throughout the postnatal developmental period, and which host and microbial factors mediate these responses. Surprisingly, neonatal mice (Day 14 and 21) were highly refractory to induction of cell shedding after intraperitoneal administration of liposaccharide (LPS), with Day 29 mice showing strong pathological responses, more similar to those observed in adult mice. These differential responses were not linked to defects in the cellular mechanisms and pathways known to regulate cell shedding responses. When we profiled microbiota and metabolites, we observed significant alterations. Neonatal mice had high relative abundances of Streptococcus, Escherichia, and Enterococcus and increased primary bile acids. In contrast, older mice were dominated by Candidatus Arthromitus, Alistipes, and Lachnoclostridium, and had increased concentrations of SCFAs and methyamines. Antibiotic treatment of neonates restored LPS-induced small intestinal cell shedding, whereas adult fecal microbiota transplant alone had no effect. Our findings further support the importance of the early life window for microbiota-epithelial interactions in the presence of inflammatory stimuli and highlights areas for further investigation., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies forExperimental Biology.)

Background: Scottish Surgical Boot Camps are the induction course for new start Core Surgical Trainees (Residents) in Scotland. The aim is to capitalise on trainees' receptiveness at a time of transition, and to give them a safe and "flying start." At their inception, these were the first such courses in the UK to integrate technical and non-technical skills training. As well as knowledge and skills, trainees have learned norms and expectations of a community of professional practice., Methods: Over 9 consecutive years of delivery and quality improvement, faculty have learned much about the safe use of simulation, as an adjuvant training modality for a range of competences required in the operating room, the clinic/office, the wards and other clinical domains., Conclusion: In this paper we describe the development and content of the course, discuss the importance of the whole "activity system," and present some evaluation data. We give tips for success, such as using simulations of escalating complexity, and the power of seemingly incidental Learning Outcomes., Competing Interests: Declaration The authors have no disclosures or conflicts of interest to declare. Scottish Surgical Boot Camps are funded by NHS Education for Scotland., (Copyright © 2019 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Background: We hypothesise that a physical activity (PA) intervention will improve the quality of life (QoL) of people with a stoma. A feasibility study of the intervention and trial parameters is necessary to inform a future main trial., Methods: Participants received a weekly PA consultation by telephone, video conferencing, or face-to-face for 12 weeks with a PA instructor who prescribed physical activities and supported participants by addressing stoma-related concerns and using behaviour change techniques. A feasibility study of the intervention and trial parameters was conducted in three UK sites using mixed methods., Results: The number of eligible patients consenting to the study was 30 out of 174 (17%). Most participants were female (73%); 73% had an ileostomy and 27% a colostomy; mean time since diagnosis was 6 months. A total of 18 (64%) participants completed pre- (baseline) and post-intervention (follow-up) measures. Results show an improvement on all scales measuring QoL and disease-specific fatigue. The median PA consultation rate per participant was eight sessions. Participants reported completing 75% or more of the prescribed PA each week. Eight stoma-related themes were identified from qualitative interviews: fear of hernia, bending down, fatigue, pain, prolapse, surgical wounds, stoma appliance, and stigma. The intervention appeared to address these issues., Conclusion: This feasibility study demonstrated that a novel manualised PA intervention for people with a stoma is safe, feasible, and acceptable, and shows promise for improving outcomes. However, difficulties with recruitment will need to be carefully considered to ensure the success of future studies in this area., Trial Registration: ISCTN, ISRCTN58613962; Registered 14/9/2017., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2020.)

Objective: To study the role of α4β7 integrin for gut homing of monocytes and to explore the biological consequences of therapeutic α4β7 inhibition with regard to intestinal wound healing., Design: We studied the expression of homing markers on monocyte subsets in the peripheral blood and on macrophage subsets in the gut of patients with IBD and controls with flow cytometry and immunohistochemistry. Integrin function was addressed with dynamic adhesion assays and in vivo gut homing assays. In vivo wound healing was studied in mice deficient for or depleted of α4β7 integrin., Results: Classical and non-classical monocytes were clearly dichotomous regarding homing marker expression including relevant expression of α4β7 integrin on human and mouse non-classical monocytes but not on classical monocytes. Monocyte-expressed α4β7 integrin was functionally important for dynamic adhesion to mucosal vascular addressin cell adhesion molecule 1 and in vivo gut homing. Impaired α4β7-dependent gut homing was associated with reduced (effect size about 20%) and delayed wound healing and suppressed perilesional presence of wound healing macrophages. Non-classical monocytes in the peripheral blood were increased in patients with IBD under clinical treatment with vedolizumab., Conclusion: In addition to reported effects on lymphocytes, anti-α4β7 therapy in IBD also targets non-classical monocytes. Impaired gut homing of such monocytes might lead to a reduction of wound healing macrophages and could potentially explain increased rates of postoperative complications in vedolizumab-treated patients, which have been observed in some studies., Competing Interests: Competing interests: MFN has served as an advisor for Pentax, Giuliani, MSD, AbbVie, Janssen, Takeda and Boehringer. MFN and SZ received research support from Takeda, Roche and Shire., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Microbiome dysbiosis predisposes to colorectal cancer (CRC), but a population-based study of oral antibiotic exposure and risk patterns is lacking., Objective: To assess the association between oral antibiotic use and CRC risk., Design: A matched case-control study (incident CRC cases and up to five matched controls) was performed using the Clinical Practice Research Datalink from 1989 to 2012., Results: 28 980 CRC cases and 137 077 controls were identified. Oral antibiotic use was associated with CRC risk, but effects differed by anatomical location. Antibiotic use increased the risk of colon cancer in a dose-dependent fashion (p trend <0.001). The risk was observed after minimal use, and was greatest in the proximal colon and with antibiotics with anti-anaerobic activity. In contrast, an inverse association was detected between antibiotic use and rectal cancers (p trend =0.003), particularly with length of antibiotic exposure >60 days (adjusted OR (aOR), 0.85, 95% CI 0.79 to 0.93) as compared with no antibiotic exposure. Penicillins, particularly ampicillin/amoxicillin increased the risk of colon cancer (aOR=1.09 (1.05 to 1.13)), whereas tetracyclines reduced the risk of rectal cancer (aOR=0.90 (0.84 to 0.97)). Significant interactions were detected between antibiotic use and tumour location (colon vs rectum, p interaction <0.001; proximal colon versus distal colon, p interaction =0.019). The antibiotic-cancer association was found for antibiotic exposure occurring >10 years before diagnosis (aOR=1.17 (1.06 to 1.31))., Conclusion: Oral antibiotic use is associated with an increased risk of colon cancer but a reduced risk of rectal cancer. This effect heterogeneity may suggest differences in gut microbiota and carcinogenesis mechanisms along the lower intestinal tract., Competing Interests: Competing interests: DP reports grant and patent royalties through institution from Bristol Myers Squibb, grant from Compugen, stock from Trieza Therapeutics and Dracen Pharmaceuticals, and founder equity from Potenza; being consultant for Aduro Biotech, Amgen, Astra Zeneca (Medimmune/Amplimmune), Bayer, DNAtrix, Dynavax Technologies Corporation, Ervaxx, FLX Bio, Rock Springs Capital, Janssen, Merck, Tizona, and Immunomic-Therapeutics; being on the scientific advisory board of Five Prime Therapeutics, Camden Nexus II, WindMil; being on the board of director for Dracen Pharmaceuticals outside the submitted work. SC reports being consultant for Novartis and Theravance outside the submitted work. CS reports a grant from Bristol Myers Squibb for microbiome research outside the submitted work., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Vedolizumab is an anti-a4b7 monoclonal antibody that is licensed for the treatment of moderate to severe Crohn's disease and ulcerative colitis. The aims of this study were to establish the real-world effectiveness and safety of vedolizumab for the treatment of inflammatory bowel disease., Methods: This was a retrospective study involving seven NHS health boards in Scotland between June 2015 and November 2017. Inclusion criteria included: a diagnosis of ulcerative colitis or Crohn's disease with objective evidence of active inflammation at baseline (Harvey-Bradshaw Index[HBI] ≥5/Partial Mayo ≥2 plus C-reactive protein [CRP] >5 mg/L or faecal calprotectin ≥250 µg/g or inflammation on endoscopy/magnetic resonance imaging [MRI]); completion of induction; and at least one clinical follow-up by 12 months. Kaplan-Meier survival analysis was used to establish 12-month cumulative rates of clinical remission, mucosal healing, and deep remission [clinical remission plus mucosal healing]. Rates of serious adverse events were described quantitatively., Results: Our cohort consisted of 180 patients with ulcerative colitis and 260 with Crohn's disease. Combined median follow-up was 52 weeks (interquartile range [IQR] 26-52 weeks). In ulcerative colitis, 12-month cumulative rates of clinical remission, mucosal healing, and deep remission were 57.4%, 47.3%, and 38.5%, respectively. In Crohn's disease, 12-month cumulative rates of clinical remission, mucosal healing, and deep remission were 58.4%, 38.9%, and 28.3% respectively. The serious adverse event rate was 15.6 per 100 patient-years of follow-up., Conclusions: Vedolizumab is a safe and effective treatment for achieving both clinical remission and mucosal healing in ulcerative colitis and Crohn's disease., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Physical activity (PA) is positively associated with quality of life. People with a stoma are less likely to engage in PA than those without a stoma., Methods: In this feasibility intervention study, we will perform the following: (1) Develop a PA intervention for people with a stoma. An Expert Working Group of behavioural scientists, exercise scientists, clinicians and a Patient Advisory Group of people with a bowel stoma will meet with the research team to inform the development of a PA intervention for people with a stoma. A manual of the intervention will be the main output. (2) Explore PA instructors' experiences of delivering the PA intervention. PA instructors will record on paper the number of PA consultations with each patient and a researcher will interview the PA instructors about their experiences of delivering the intervention. (3) Assess the level of patient (bowel cancer or inflammatory bowel disease (IBD) patients with a stoma between 6 weeks and 24 months post-surgery) engagement with the PA intervention and their views on intervention acceptability and usefulness. Patients will keep a PA diary to record daily pedometer recorded step count and type and duration of activities. A researcher will interview patients about their experiences of the PA intervention. (4) Assess screening, eligibility, consent, data completion, loss to follow up, and missing data rates, representativeness of participants and potential treatment effects. A researcher will record on paper all study procedure parameters. Quality of life (stoma-quality of life; Functional Assessment of Cancer Therapy, Short IBD questionnaire), fatigue (FACIT fatigue scale) and PA (accelerometer) will be measured pre- and post-intervention in patients. For IBD patients only, blood will be taken to measure systemic inflammation., Discussion: We hypothesise that a PA intervention will be an effective means of improving the quality of life of people with a stoma. Before embarking on a full randomised controlled trial to test this hypothesis, a PA intervention needs to be developed and a feasibility study of the proposed PA intervention conducted., Trial Registration: ISRCTN58613962, Protocol version: 0.1. 14 September 2017., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Paneth cells are key epithelial cells that provide an antimicrobial barrier and maintain integrity of the small-intestinal stem cell niche. Paneth cell abnormalities are unfortunately detrimental to gut health and are often associated with digestive pathologies such as Crohn's disease or infections. Similar alterations are observed in individuals with impaired autophagy, a process that recycles cellular components. The direct effect of autophagy impairment on Paneth cells has not been analysed. To investigate this, we generated a mouse model lacking Atg16l1 specifically in intestinal epithelial cells, making these cells impaired in autophagy. Using three-dimensional intestinal organoids enriched for Paneth cells, we compared the proteomic profiles of wild-type and autophagy-impaired organoids. We used an integrated computational approach combining protein-protein interaction networks, autophagy-targeted proteins and functional information to identify the mechanistic link between autophagy impairment and disrupted pathways. Of the 284 altered proteins, 198 (70%) were more abundant in autophagy-impaired organoids, suggesting reduced protein degradation. Interestingly, these differentially abundant proteins comprised 116 proteins (41%) that are predicted targets of the selective autophagy proteins p62, LC3 and ATG16L1. Our integrative analysis revealed autophagy-mediated mechanisms that degrade key proteins in Paneth cell functions, such as exocytosis, apoptosis and DNA damage repair. Transcriptomic profiling of additional organoids confirmed that 90% of the observed changes upon autophagy alteration have effects at the protein level, not on gene expression. We performed further validation experiments showing differential lysozyme secretion, confirming our computationally inferred downregulation of exocytosis. Our observations could explain how protein-level alterations affect Paneth cell homeostatic functions upon autophagy impairment.This article has an associated First Person interview with the joint first authors of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

The intestinal epithelial monolayer, at the boundary between microbes and the host immune system, plays an important role in the development of inflammatory bowel disease (IBD), particularly as a target and producer of pro-inflammatory TNF. Chronic overexpression of TNF leads to IBD-like pathology over time, but the mechanisms driving early pathogenesis events are not clear. We studied the epithelial response to inflammation by combining mathematical models with in vivo experimental models resembling acute and chronic TNF-mediated injury. We found significant villus atrophy with increased epithelial cell death along the crypt-villus axis, most dramatically at the villus tips, in both acute and chronic inflammation. In the acute model, we observed overexpression of TNF receptor I in the villus tip rapidly after TNF injection and concurrent with elevated levels of intracellular TNF and rapid shedding at the tip. In the chronic model, sustained villus atrophy was accompanied by a reduction in absolute epithelial cell turnover. Mathematical modelling demonstrated that increased cell apoptosis on the villus body explains the reduction in epithelial cell turnover along the crypt-villus axis observed in chronic inflammation. Cell destruction in the villus was not accompanied by changes in proliferative cell number or division rate within the crypt. Epithelial morphology and immunological changes in the chronic setting suggest a repair response to cell damage although the villus length is not recovered. A better understanding of how this state is further destabilised and results in clinical pathology resembling IBD will help identify suitable pathways for therapeutic intervention.

Background: There is a lack of standardised outcomes for haemorrhoidal disease making comparison between trials difficult. A need for a very well validated severity score is essential to facilitate meta-analysis of comparative studies, enabling evidence-based clinical practice., Methods: The Hubble trial provides a large cohort of patients with haemorrhoidal disease randomised to rubber band ligation (RBL) or haemorrhoidal artery ligation. The haemorrhoid severity score (HSS) was collected on each patient at baseline, 6 weeks and 1 year after intervention. This allows for the responsiveness of the HSS instrument to be examined and compared with a more specific instrument, the Vaizey incontinence score (also collected). Responsiveness was tested using four methods (effect size, standardised response means (SRM), significance of change, and responsiveness statistic)., Results: The four tests of responsiveness demonstrated that the HSS was more responsive to changes in the patient's health status following both of the interventions compared to the Vaizey questionnaire. For example, between baseline and 6 weeks, the RBL intervention effect size scores and SRM calculations indicated a non-significant small amount of change (0.20 and 0.16 respectively). However, using the HSS, the effect size and SRM demonstrated a large magnitude of change (1.12 and 1.01, respectively) which was significant. Similar results were observed at 1 year. Significance of change scores and the index of responsiveness were also higher for the HSS questionnaire than the Vaizey across both treatment modalities., Conclusions: The HSS is a highly responsive tool for the detection of changes in haemorrhoid symptoms. It should form an essential patient-reported outcome tool for future studies on haemorrhoidal disease.

Objective: Our objective was to compare the cost effectiveness of stapled haemorrhoidopexy (SH) and traditional haemorrhoidectomy (TH) in the treatment of grade II-IV haemorrhoidal disease from the perspective of the UK national health service., Methods: An economic evaluation was conducted alongside an open, two-arm, parallel-group, pragmatic, multicentre, randomised controlled trial conducted in several hospitals in the UK. Patients were randomised into either SH or TH surgery between January 2011 and August 2014 and were followed up for 24 months. Intervention and subsequent resource use data were collected using case review forms and questionnaires. Benefits were collected using the EQ-5D-3L (EuroQoL-five dimensions-three levels) instrument. The primary economic outcome was incremental cost measured in pounds (£), year 2016 values, relative to the incremental benefit, which was estimated using quality-adjusted life-years (QALYs). Cost and benefits accrued in the second year were discounted at 3.5%. The base-case analysis was based on imputed data. Uncertainty was explored using univariate sensitivity analyses., Results: Participants (n = 777) were randomised to SH (n = 389) or TH (n = 388). The mean cost of SH was £337 (95% confidence interval [CI] 251-423) higher than that of TH and the mean QALYs were -0.070 (95% CI -0.127 to -0.011) lower than for TH. The base-case cost-utility analysis indicated that SH has zero probability of being cost effective at both the £20,000 and the £30,000 threshold. Results from the sensitivity analyses were similar to those from the base-case analysis., Conclusions: The evidence suggests that, on average, the total mean costs over the 24-month follow-up period were significantly higher for the SH arm than for the TH arm. The QALYs were also, on average, significantly lower for the SH arm. These results were supported by the sensitivity analyses. Therefore, in terms of cost effectiveness, TH is a superior surgical treatment for the management of grade II-IV haemorrhoids when compared with SH.

The intestinal epithelium is a single layer of cells which provides the first line of defence of the intestinal mucosa to bacterial infection. Cohesion of this physical barrier is supported by renewal of epithelial stem cells, residing in invaginations called crypts, and by crypt cell migration onto protrusions called villi; dysregulation of such mechanisms may render the gut susceptible to chronic inflammation. The impact that excessive or misplaced epithelial cell death may have on villus cell migration is currently unknown. We integrated cell-tracking methods with computational models to determine how epithelial homeostasis is affected by acute and chronic TNFα-driven epithelial cell death. Parameter inference reveals that acute inflammatory cell death has a transient effect on epithelial cell dynamics, whereas cell death caused by chronic elevated TNFα causes a delay in the accumulation of labelled cells onto the villus compared to the control. Such a delay may be reproduced by using a cell-based model to simulate the dynamics of each cell in a crypt-villus geometry, showing that a prolonged increase in cell death slows the migration of cells from the crypt to the villus. This investigation highlights which injuries (acute or chronic) may be regenerated and which cause disruption of healthy epithelial homeostasis., (© 2018 The Author(s).)

Aim: Haemorrhoids are a common condition, with nearly 30,000 procedures carried out in England in 2014/15, and result in a significant quality-of-life burden to patients and a financial burden to the healthcare system. This study examined the cost effectiveness of haemorrhoidal artery ligation (HAL) compared with rubber band ligation (RBL) in the treatment of grade II-III haemorrhoids., Method: This analyses used data from the HubBLe study, a multicentre, open-label, parallel group, randomised controlled trial conducted in 17 acute UK hospitals between September 2012 and August 2015. A full economic evaluation, including long-term cost effectiveness, was conducted from the UK National Health Service (NHS) perspective. Main outcomes included healthcare costs, quality-adjusted life-years (QALYs) and recurrence. Cost-effectiveness results were presented in terms of incremental cost per QALY gained and cost per recurrence avoided. Extrapolation analysis for 3 years beyond the trial follow-up, two subgroup analyses (by grade of haemorrhoids and recurrence following RBL at baseline), and various sensitivity analyses were undertaken., Results: In the primary base-case within-trial analysis, the incremental total mean cost per patient for HAL compared with RBL was £1027 (95% confidence interval [CI] £782-£1272, p < 0.001). The incremental QALYs were 0.01 QALYs (95% CI -0.02 to 0.04, p = 0.49). This generated an incremental cost-effectiveness ratio (ICER) of £104,427 per QALY. In the extrapolation analysis, the estimated probabilistic ICER was £21,798 per QALY. Results from all subgroup and sensitivity analyses did not materially change the base-case result., Conclusions: Under all assessed scenarios, the HAL procedure was not cost effective compared with RBL for the treatment of grade II-III haemorrhoids at a cost-effectiveness threshold of £20,000 per QALY; therefore, economically, its use in the NHS should be questioned.

Our work addresses two key challenges, one biological and one methodological. First, we aim to understand how proliferation and cell migration rates in the intestinal epithelium are related under healthy, damaged (Ara-C treated) and recovering conditions, and how these relations can be used to identify mechanisms of repair and regeneration. We analyse new data, presented in more detail in a companion paper, in which BrdU/IdU cell-labelling experiments were performed under these respective conditions. Second, in considering how to more rigorously process these data and interpret them using mathematical models, we use a probabilistic, hierarchical approach. This provides a best-practice approach for systematically modelling and understanding the uncertainties that can otherwise undermine the generation of reliable conclusions-uncertainties in experimental measurement and treatment, difficult-to-compare mathematical models of underlying mechanisms, and unknown or unobserved parameters. Both spatially discrete and continuous mechanistic models are considered and related via hierarchical conditional probability assumptions. We perform model checks on both in-sample and out-of-sample datasets and use them to show how to test possible model improvements and assess the robustness of our conclusions. We conclude, for the present set of experiments, that a primarily proliferation-driven model suffices to predict labelled cell dynamics over most time-scales.

Intestinal epithelial cells play a fundamental role in maintaining homeostasis. Shedding of intestinal cells in a controlled manner is critical to maintenance of barrier function. Barrier function is maintained during this shedding process by a redistribution of tight junctional proteins to facilitate closure of the gap left by the shedding cell. However, despite the obvious importance of epithelial cell shedding to gut health, a central question is how the extrusion of epithelial cells is achieved, enabling barrier integrity to be maintained in the healthy gut and restored during inflammation remains largely unanswered. Recent studies have provided evidence that excessive epithelial cell shedding and loss of epithelial barrier integrity is triggered by exposure to lipopolysaccharide or tumor necrosis factor alpha. Subsequent studies have provided evidence of the involvement of specific cellular components and signaling mechanisms as well as the functionality of microbiota that can be either detrimental or beneficial for intestinal barrier integrity. This review will focus on the evidence and decipher how the signaling systems through which the mucosal immune system and microbiota can regulate epithelial cell shedding and how these mechanisms interact to preserve the viability of the epithelium.

Background: Optimum surgical intervention for low-grade haemorrhoids is unknown. Haemorrhoidal artery ligation (HAL) has been proposed as an efficacious, safe therapy while rubber band ligation (RBL) is a commonly used outpatient treatment. We compared recurrence after HAL versus RBL in patients with grade II-III haemorrhoids., Methods: This multicentre, open-label, parallel group, randomised controlled trial included patients from 17 acute UK NHS trusts. We screened patients aged 18 years or older presenting with grade II-III haemorrhoids. We excluded patients who had previously received any haemorrhoid surgery, more than one injection treatment for haemorrhoids, or more than one RBL procedure within 3 years before recruitment. Eligible patients were randomly assigned (in a 1:1 ratio) to either RBL or HAL with Doppler. Randomisation was computer-generated and stratified by centre with blocks of random sizes. Allocation concealment was achieved using a web-based system. The study was open-label with no masking of participants, clinicians, or research staff. The primary outcome was recurrence at 1 year, derived from the patient's self-reported assessment in combination with resource use from their general practitioner and hospital records. Recurrence was analysed in patients who had undergone one of the interventions and been followed up for at least 1 year. This study is registered with the ISRCTN registry, ISRCTN41394716., Findings: From Sept 9, 2012, to May 6, 2014, of 969 patients screened, 185 were randomly assigned to the HAL group and 187 to the RBL group. Of these participants, 337 had primary outcome data (176 in the RBL group and 161 in the HAL group). At 1 year post-procedure, 87 (49%) of 176 patients in the RBL group and 48 (30%) of 161 patients in the HAL group had haemorrhoid recurrence (adjusted odds ratio [aOR] 2·23, 95% CI 1·42-3·51; p=0·0005). The main reason for this difference was the number of extra procedures required to achieve improvement (57 [32%] participants in the RBL group and 23 [14%] participants in the HAL group had a subsequent procedure for haemorrhoids). The mean pain 1 day after procedure was 3·4 (SD 2·8) in the RBL group and 4·6 (2·8) in the HAL group (difference -1·2, 95% CI -1·8 to -0·5; p=0·0002); at day 7 the scores were 1·6 (2·3) in the RBL group and 3·1 (2·4) in the HAL group (difference -1·5, -2·0 to -1·0; p<0·0001). Pain scores did not differ between groups at 21 days and 6 weeks. 15 individuals reported serious adverse events requiring hospital admission. One patient in the RBL group had a pre-existing rectal tumour. Of the remaining 14 serious adverse events, 12 (7%) were among participants treated with HAL and two (1%) were in those treated with RBL. Six patients had pain (one treated with RBL, five treated with HAL), three had bleeding not requiring transfusion (one treated with RBL, two treated with HAL), two in the HAL group had urinary retention, two in the HAL group had vasovagal upset, and one in the HAL group had possible sepsis (treated with antibiotics)., Interpretation: Although recurrence after HAL was lower than a single RBL, HAL was more painful than RBL. The difference in recurrence was due to the need for repeat bandings in the RBL group. Patients (and health commissioners) might prefer such a course of RBL to the more invasive HAL., Funding: NIHR Health Technology Assessment programme., (Copyright © 2016 Brown et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)