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1. Clinical effectiveness of subsensory sacral neuromodulation in adults with faecal incontinence: the SUBSoNIC crossover RCT and mechanistic study

Author: Paul F Vollebregt, Yan Li Goh, Claire L Chan, Thomas Dudding, Paul Furlong, Shaheen Hamdy, Joanne Haviland, Richard Hooper, James Jones, Eleanor McAlees, Christine Norton, P Ronan O’Connell, S Mark Scott, Natasha Stevens, Kerry Tubby, Sian Worthen, Yuk Lam Wong, and Charles H Knowles
Subjects: humans, adult, faecal incontinence, magnetoencephalography, follow-up studies, cross-over studies, arm, healthy volunteers, sample size, covid-19, brain, electric stimulation therapy, randomised controlled trial, mechanistic study, Medicine
Abstract: Trial design Randomised, multicentre, double-blind crossover trial (with 2 × 16-week periods) of active neurostimulation versus sham stimulation with subsequent open-label follow-up to 58 weeks. Embedded mechanistic sub-study using magnetoencephalography to study bidirectional functional connectivity between brain and anorectum. Methods Participants: adults aged 18–80 years, with chronic symptoms of faecal incontinence refractory to first-line treatments (and meeting national criteria for sacral neuromodulation). Interventions: active: chronic, subsensory (low amplitude) stimulation of a mixed sacral nerve (usually S3) using a commercially available surgically implanted pulse generator; sham: identical implant but turned off (or to 0.05 V). Patient-chosen sub- or supra-sensory open-label stimulation from week 32 to week 58. Primary objectives: (1) to determine whether sub-sensory sacral neuromodulation led to a reduction in total faecal incontinence episodes per week compared to sham stimulation; (2) to identify whether clinical responses to sub-sensory sacral neuromodulation were biologically related to changes in evoked and induced activity between the brain and anorectum. Primary outcome: total faecal incontinence episodes per week based on paper bowel diary performed in the final 4 weeks of each crossover period (allowing 12-week washout). Randomised allocation (1 : 1) to arm 1 (sacral neuromodulation/sham) or arm 2 (sham/sacral neuromodulation) at time of surgery was stratified by sex and centre. Blinding: participants, surgeons and assessors; tamper-proof tape masked stimulation settings. Statistical methods: Poisson regression models failed to converge for the count outcomes, hence paired t-tests were used, and treatment effects summarised by mean differences [with 95% confidence intervals (CIs)]. Sample size: a total of 90 patients (45 per group) were required to detect a 30% reduction in episodes, allowing for 10% loss to follow-up (alpha = 0.05; power 90%). Results Recruitment: a total of 39 patients of 220 screened and 65 pre-enrolled (arm 1: N = 17; arm 2: N = 22) were recruited to the crossover trial at nine sites from the United Kingdom and one site from Ireland between February 2018 and July 2022, of whom only 16 (arm 1: N = 9; arm 2: N = 7) had complete primary outcome data. Nineteen completed follow-up to 58 weeks. Trial delivery was severely affected and terminated early due to COVID-19. Main barriers were the inability to continue face-to-face patient visits, redeployment of research staff to COVID-19 facing clinical roles and cancelling of sacral neuromodulation procedures due to lack of priority for non-urgent surgery. A total of 25 patients underwent magnetoencephalography studies compared to 20 healthy volunteers. Primary outcome (N = 16): sacral neuromodulation conferred a non-significant reduction in mean faecal incontinence episodes per week compared to sham (−0.7, 95% CI −1.5 to 0.0; p = 0.06). Secondary outcomes: in participants who also used the e-event recorder to record the number of faecal incontinence episodes in both periods (n = 7), estimate of effect size was greater but less precise (−1.5, −3.5 to +0.5; p = 0.12). Data suggested successful allocation concealment. Improvements were observed in faecal incontinence symptoms in the follow-up cohort (at 58 weeks) compared to baseline (approx. 3 fewer faecal incontinence episodes per week). A small number of expected adverse events all resolved. Magnetoencephalography studies demonstrated bidirectional afferent evoked cortical and efferent induced anal activity that did not vary greatly from control subjects (n = 20) and appeared unchanged by sacral neuromodulation. Conclusions Due to under-recruitment it is important to interpret the findings on the experimental efficacy of sacral neuromodulation as exploratory. Effects on symptoms observed during double-blinded crossover point to some efficacy over sham, though not large in comparison with placebo responses. The magnitude of effect was highly dependent on method and interpretation of event recording. Study registration Current Controlled Trials ISRCTN98760715. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 14/144/08) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 19. See the NIHR Funding and Awards website for further award information. Plain language summary A treatment called sacral neuromodulation is commonly offered to adults experiencing bowel (faecal) incontinence. A battery powered unit is implanted into the lower back in the region of the sacrum (tailbone). This is connected to a specially developed lead with electrodes that rest on the nerves of the lower spine. This stimulator then continuously sends electrical impulses to the nerves and muscles that control the lower bowel (rectum and anus). The aim is to improve bowel control. Previous studies have reported a great benefit of sacral neuromodulation in some patients, but others have little or no response. The SUBsensory Sacral Neuromodulation for InContinence trial recruited 39 patients (of 90 intended) who met the current national criteria for sacral neuromodulation. It compared the effect on numbers of weekly faecal incontinence episodes with the device either on (active) or off (sham) using a special study design called a randomised crossover trial. All participants had the device on and off for 16 weeks in random order (crossing over in the middle). Using stimulation below the level that can be felt (subsensory), both the patients and the research team were unaware of whether the stimulator was on or off (called double blinding). Due to COVID-19, only 16 patients had complete data for analysis, which was much less than the intended number of 90. The results showed that patients experienced reductions in faecal incontinence episodes during both on and off periods (i.e. there was a strong placebo effect). However, slightly greater effects were seen during the on period suggesting a possible genuine biological effect of sacral neuromodulation. The study also showed that the way we record symptoms during research trials for example with paper bowel diaries needs improvement, as the bowel diaries were not fully completed by some participants. Although this is the first double-blind trial of its kind for sacral neuromodulation, all conclusions must bear in mind the poor recruitment and retention of patients. Scientific summary Background Faecal incontinence (FI), defined as the recurrent involuntary loss of faecal material leading to a social or hygienic problem, is a common and debilitating condition with profound effects on quality-of-life and high societal costs. Initial treatments including pharmacological and behavioural therapies (e.g. biofeedback) have variable outcomes and are poorly evidenced. Traditional surgical approaches focusing on anal sphincter reconstruction or augmentation are invasive, irreversible, and risk significant morbidity. A stoma is the final option. Chronic low-amplitude stimulation of the mixed sacral spinal nerves using an implanted electrode and pulse generator – sacral neuromodulation (SNM) is a less invasive alternative, now considered the first-line surgical treatment option for adults with FI in whom non-operative therapies have failed to alleviate symptoms. Current evidence for SNM is based on extensive observational data and few randomised trials that are heterogeneous in design and outcomes. Despite having widespread regulatory approval, SNM remains an expensive intervention with need for greater confidence in efficacy. A further concern regarding SNM therapy is the lack of evidence and understanding of the mechanism of any effect. Objectives Our primary aim was to determine the clinical efficacy of sub-sensory chronic low voltage electrical SNM using a commercially-available implantable device in adults with FI in whom conservative treatment has failed. We sought to determine whether SNM, compared to sham, led to a clinically important reduction in weekly FI episodes. The study also included mechanistic studies to examine whether clinical responses to sub-sensory SNM were biologically related to changes in the central pathway between the brain and anorectum. Methods Trial design SUBsensory Sacral Neuromodulation for InContinence (SUBSoNIC) was a multicentre, randomised double-blind crossover trial at nine UK sites and one site in Ireland in which SNM was compared to sham stimulation. We aimed to randomise 90 eligible participants (adults aged 18–80 years, where non-surgical approaches to National Institute for Health and Care Excellence (NICE) standard have failed and meeting minimum FI severity criterion) to two study arms after SNM implantation. Both arms had two intervention periods (ON-OFF or OFF-ON) of 16-week duration (T0–T16 and T16–T32). Efficacy outcomes were derived from assessments in the final 4 weeks of each cross-over period (T12–T16 and T28–T32) thus allowing for almost 3 months intervention before outcome assessments (and adequate washout for participants in the ON–OFF sequence). Mechanistic studies were performed in the final 2 weeks of the 4-week assessment periods in a subgroup of consecutively consenting participants from both arms until data saturation. After completing the crossover phase of the study, participants were followed up for a further 26 weeks. During this time, participants had either sub- or supra-sensory ‘open label’ stimulation based on preference as would have been normal for routine clinical practice. Further efficacy outcomes were recorded at T54–T58 to provide an indication of the short-term effectiveness of SNM within the rigor of a clinical trial unit (CTU)-monitored prospective study. Interventions Chronic low voltage stimulation of the third or fourth sacral root was achieved by surgical implantation of a commercially available Conformité Européenne-marked active implantable (class III) medical device [Medtronic InterStimTM (Medtronic, Minneapolis, MN, USA)] used in accord with the manufacturer’s instructions and local practice. For the active intervention (ON), the clinical team programmed the device using standard settings of a 14-Hz frequency and 210-µs pulse width. Optimal electrode configuration was determined by cumulatively increasing the amplitude of stimulation by 0.1 V from zero for each electrode until the sensory threshold was reached. The amplitude and site of stimulation were recorded for each electrode with the electrode configuration that achieved sensation in the anus or perineum at lowest amplitude being chosen for chronic stimulation. Sub-sensory chronic stimulation was initiated by reducing the amplitude to a level just below the habituated sensory threshold (for blinding). For the sham intervention (OFF), sensory thresholds were recorded identically; however, the level was then adjusted to zero volts or 0.05 V (the latter was required in some participants due to the new device handset limitations). Mechanistic studies were undertaken at the Institute of Health and Neurodevelopment (IHN) at Aston University in a subgroup of patients identified in the Midlands region (compared to 20 healthy volunteers without FI). A protocol including spatial registration (magnetic resonance imaging head) and a series of magnetoencephalographic (MEG) acquisitions measured induced and evoked cortical activity relevant to determining functional connectivity between the anus and brain (using anal electrical stimulation) and brain and anorectum (using volitional anal squeeze). Control paradigms (tibial nerve stimulation and fist clench) were used respectively. Outcomes The primary clinical outcome was reduction in FI events per week (recorded on paper bowel diaries over a 4-week period) in SNM versus sham phase of crossover (16 and 32 weeks). Secondary clinical outcomes including other bowel diary measures, e-event recording and a panel of summative questionnaires were recorded at 16, 32 and 58 weeks. Mechanistic outcomes included spatial localisation, relative cortical source signal strength and latencies of evoked and induced responses. Allocation and blinding Randomised allocation (1 : 1) to group 1 (SNM/sham) or group 2 (sham/SNM) was performed at the time of surgery using an online randomisation system managed by the Pragmatic Clinical Trials Unit at QMUL, with a randomisation list generated by an independent statistician to ensure allocation concealment. Randomisation was stratified by sex and centre with block sizes of four. Members of the research team, statisticians, surgeons who performed the surgical procedure, and participants were blinded to intervention status (SNM or sham). Participants were informed of the allocation ratio of 1 : 1 and that blinding prevented them from knowing in which group they were participating. Tamper-proof tape was used to mask stimulation settings. Sample size and statistics The study was designed to detect a mean 30% reduction between SNM and sham stimulation in FI event rate (ratio 0.7). At 90% power and 5% significance level with a cross-over design this required 90 participants (45 per group), allowing for 10% loss to follow-up. The pre-specified analysis for the primary outcome involved a mixed Poisson regression applied to the counts of FI events, with fixed effects of cross-over period and stratification factors, a random effect of individual, and a random effect of period within individual (the latter to allow for an over-dispersed Poisson distribution). When it came to the analysis, owing in part to the small numbers, the Poisson regression models did not converge for the count outcomes. Instead we applied a paired t-test to the FI rates in order to estimate the difference between SNM and sham with a 95% confidence interval and p-value. Results Clinical results The COVID-19 pandemic had a major effect on trial recruitment and patient retention. The trial was terminated on 24 July 2022 with just 39 patients randomised. Trial delivery was severely affected and terminated early due to COVID-19. Main barriers were the inability to continue face-to-face patient visits, redeployment of research staff to COVID-19 facing clinical roles and cancelling of SNM procedures due to lack of priority for non-urgent surgery. In total, 220 patients were screened for eligibility at nine sites from the UK and one site from Ireland between February 2018 and July 2022. Of these, 155 patients declined study participation or were ineligible due to study specific exclusion criteria. A total of 65 patients were pre-enrolled and consented to the study, of whom 26 did not meet the baseline minimum frequency criteria of FI episodes per week or did not receive an implant. The remaining 39 patients were randomised (arm 1: N = 17; arm 2: N = 22); however, only 16 completed the primary outcome during both cross-over periods (arm 1: N = 9; arm 2: N = 7). The remaining 23 participants withdrew from the study (N = 12), were excluded on the basis of problems of eligibility (N = 5) or did not complete the primary outcome data (N = 6: still included in the cohort follow-up phase). A total of 22 participants started the cohort follow-up phase, although 3 of these participants did not complete the final follow-up visit, leaving 19 participants for the 1-year effectiveness assessment. There were no major differences at baseline between allocated groups. As predicted, about 90% participants were female with mean age about 57 years. Almost all participants reported symptoms of urgency, combined with varying combinations of passive and urge FI. All participants reported previous conservative management for their FI symptoms (as per NICE guidance). Numbers of FI events at baseline were concordant with design assumptions (based on approx. seven events in a 1-week period). Median St Mark’s incontinence score was 19 in both groups, indicating severe symptoms (max score 24). E-event recordings were only undertaken by a minority (14/39) of participants. Test stimulation was performed using a tined lead in 68.6% participants. General anaesthesia was used in 70.6% of procedures and median operating time was 36 minutes (range 30–55 minutes). The lead was positioned in foramina S3 in most participants (91.4%) with some variations in fidelity of siting based on individual electrode responses (only 50% lead placements achieved the ideal published standard of motor or sensory responses for three electrodes
Published: 2024
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2. Local Myoelectric Sensing During Human Colonic Tissue Perfusion

Author: Matan Ben-David, Raj Makwana, Tal Yered, Gareth J. Sanger, Charles H. Knowles, Nir Wasserberg, and Erez Shor
Subjects: anastomotic leakage, human colon, Medicine (General), R5-920
Abstract: Objectives: Anastomotic leakage (AL) is one of the most devastating complications after colorectal surgery. The verification of the adequate perfusion of the anastomosis is essential to ensuring anastomosis integrity following colonic resections. This study aimed to evaluate the efficacy of measuring the electrical activity of the colonic muscularis externa at an anastomosis site for perfusion analysis following colorectal surgery. Methods: Strips of human isolated colon were maintained in a horizontal tissue bath to record spontaneous contractions and myoelectric activity and spike potentials (using a bipolar electrode array for the wireless transmission of myoelectric data—the xBar system) from the circular muscle. Intraoperative myoelectric signal assessment was performed by placing the electrode array on the colon prior to and following mesenteric artery ligation, just prior to colonic resection. Results: In human isolated colon, the amplitude, duration, and frequency of contractions were inhibited during hypoxia by >80% for each measurement, compared to control values and time-matched oxygenated muscle. Intraoperative (N = 5; mean age, 64.8 years; range, 54–74 years; 60% females) myoelectric signal assessment revealed a decline in spike rate following arterial ligation, with a mean reduction of 112.64 to 51.13 spikes/min (p < 0.0008). No adverse events were observed during the study, and the device did not substantially alter the surgical procedure. Conclusions: The electrical and contraction force of the human colon was reduced by ischemia, both in vitro and in vivo. These preliminary findings also suggest the potential of the xBar system to measure such changes during intraoperative and possibly postoperative periods to predict the risk of anastomotic viability as a surrogate of evolving dehiscence.
Published: 2024
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3. Implementation of a batched stepped wedge trial evaluating a quality improvement intervention for surgical teams to reduce anastomotic leak after right colectomy

Author: Mary L. Venn, Charles H. Knowles, Elizabeth Li, James Glasbey, Dion G. Morton, Richard Hooper, and ESCP EAGLE Safe Anastomosis Collaborative
Subjects: Stepped wedge trial, Batched stepped wedge, Incomplete trial design, Cluster randomised trial, Group randomised trial, Colorectal surgery, Medicine (General), R5-920
Abstract: Abstract Background Large-scale quality improvement interventions demand robust trial designs with flexibility for delivery in different contexts, particularly during a pandemic. We describe innovative features of a batched stepped wedge trial, ESCP sAfe Anastomosis proGramme in CoLorectal SurgEry (EAGLE), intended to reduce anastomotic leak following right colectomy, and reflect on lessons learned about the implementation of quality improvement programmes on an international scale. Methods Surgical units were recruited and randomised in batches to receive a hospital-level education intervention designed to reduce anastomotic leak, either before, during, or following data collection. All consecutive patients undergoing right colectomy were included. Online learning, patient risk stratification and an in-theatre checklist constituted the intervention. The study was powered to detect an absolute risk reduction of anastomotic leak from 8.1 to 5.6%. Statistical efficiency was optimised using an incomplete stepped wedge trial design and study batches analysed separately then meta-analysed to calculate the intervention effect. An established collaborative group helped nurture strong working relationships between units/countries and a prospectively designed process evaluation will enable evaluation of both the intervention and its implementation. Results The batched trial design allowed sequential entry of clusters, targeted research training and proved to be robust to pandemic interruptions. Staggered start times in the incomplete stepped wedge design with long lead-in times can reduce motivation and engagement and require careful administration. Conclusion EAGLE’s robust but flexible study design allowed completion of the study across globally distributed geographical locations in spite of the pandemic. The primary outcome analysed in conjunction with the process evaluation will ensure a rich understanding of the intervention and the effects of the study design. Trial registration National Institute of Health Research Clinical Research Network portfolio IRAS ID: 272,250. Health Research Authority approval 18 October 2019. ClinicalTrials.gov, identifier NCT04270721, protocol ID RG_19196.
Published: 2023
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4. Systematic review of preoperative and intraoperative colorectal Anastomotic Leak Prediction Scores (ALPS)

Author: Charles H Knowles, Richard L Hooper, Dmitri Nepogodiev, Tom Pampiglione, Mary L Venn, and Dion G Morton
Subjects: Medicine
Abstract: Objective To systematically review preoperative and intraoperative Anastomotic Leak Prediction Scores (ALPS) and validation studies to evaluate performance and utility in surgical decision-making. Anastomotic leak (AL) is the most feared complication of colorectal surgery. Individualised leak risk could guide anastomosis and/or diverting stoma.Methods Systematic search of Ovid MEDLINE and Embase databases, 30 October 2020, identified existing ALPS and validation studies. All records including >1 risk factor, used to develop new, or to validate existing models for preoperative or intraoperative use to predict colorectal AL, were selected. Data extraction followed CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies guidelines. Models were assessed for applicability for surgical decision-making and risk of bias using Prediction model Risk Of Bias ASsessment Tool.Results 34 studies were identified containing 31 individual ALPS (12 colonic/colorectal, 19 rectal) and 6 papers with validation studies only. Development dataset patient populations were heterogeneous in terms of numbers, indication for surgery, urgency and stoma inclusion. Heterogeneity precluded meta-analysis. Definitions and timeframe for AL were available in only 22 and 11 ALPS, respectively. 26/31 studies used some form of multivariable logistic regression in their modelling. Models included 3–33 individual predictors. 27/31 studies reported model discrimination performance but just 18/31 reported calibration. 15/31 ALPS were reported with external validation, 9/31 with internal validation alone and 4 published without any validation. 27/31 ALPS and every validation study were scored high risk of bias in model analysis.Conclusions Poor reporting practices and methodological shortcomings limit wider adoption of published ALPS. Several models appear to perform well in discriminating patients at highest AL risk but all raise concerns over risk of bias, and nearly all over wider applicability. Large-scale, precisely reported external validation studies are required.PROSPERO registration number CRD42020164804.
Published: 2023
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5. Cell shape characteristics of human skeletal muscle cells as a predictor of myogenic competency: A new paradigm towards precision cell therapy

Author: Charlotte Desprez, Davide Danovi, Charles H Knowles, and Richard M Day
Subjects: Biochemistry, QD415-436
Abstract: Skeletal muscle-derived cells (SMDC) hold tremendous potential for replenishing dysfunctional muscle lost due to disease or trauma. Current therapeutic usage of SMDC relies on harvesting autologous cells from muscle biopsies that are subsequently expanded in vitro before re-implantation into the patient. Heterogeneity can arise from multiple factors including quality of the starting biopsy, age and comorbidity affecting the processed SMDC. Quality attributes intended for clinical use often focus on minimum levels of myogenic cell marker expression. Such approaches do not evaluate the likelihood of SMDC to differentiate and form myofibres when implanted in vivo, which ultimately determines the likelihood of muscle regeneration. Predicting the therapeutic potency of SMDC in vitro prior to implantation is key to developing successful therapeutics in regenerative medicine and reducing implementation costs. Here, we report on the development of a novel SMDC profiling tool to examine populations of cells in vitro derived from different donors. We developed an image-based pipeline to quantify morphological features and extracted cell shape descriptors. We investigated whether these could predict heterogeneity in the formation of myotubes and correlate with the myogenic fusion index. Several of the early cell shape characteristics were found to negatively correlate with the fusion index. These included total area occupied by cells, area shape, bounding box area, compactness, equivalent diameter, minimum ferret diameter, minor axis length and perimeter of SMDC at 24 h after initiating culture. The information extracted with our approach indicates live cell imaging can detect a range of cell phenotypes based on cell-shape alone and preserving cell integrity could be used to predict propensity to form myotubes in vitro and functional tissue in vivo.
Published: 2023
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6. Pathway Of Low Anterior Resection syndrome relief after Surgery (POLARiS) feasibility trial protocol: a multicentre, feasibility cohort study with embedded randomised control trial to compare sacral neuromodulation and transanal irrigation to optimised conservative management in the management of major low anterior resection syndrome following rectal cancer treatment

Author: Deborah D Stocken, Charles H Knowles, Roel Hompes, Neil Corrigan, Julie Cornish, Julie Croft, Alexandra Harriet Coxon-Meggy, Irene Vogel, Judith White, Alun Meggy, Deborah Keller, and Aaron Quyn
Subjects: Medicine
Abstract: Introduction Rectal cancer is common with a 60% 5-year survival rate. Treatment usually involves surgery with or without neoadjuvant chemoradiotherapy or adjuvant chemotherapy. Sphincter saving curative treatment can result in debilitating changes to bowel function known as low anterior resection syndrome (LARS). There are currently no clear guidelines on the management of LARS with only limited evidence for different treatment modalities.Methods and analysis Patients who have undergone an anterior resection for rectal cancer in the last 10 years will be approached for the study. The feasibility trial will take place in four centres with a 9-month recruitment window and 12 months follow-up period. The primary objective is to assess the feasibility of recruitment to the POLARiS trial which will be achieved through assessment of recruitment, retainment and follow-up rates as well as the prevalence of major LARS.Feasibility outcomes will be analysed descriptively through the estimation of proportions with confidence intervals. Longitudinal patient reported outcome measures will be analysed according to scoring manuals and presented descriptively with reporting graphically over time.Ethics and dissemination Ethical approval has been granted by Wales REC1; Reference 22/WA/0025. The feasibility study is in the process of set up. The results of the feasibility trial will feed into the design of an expanded, international trial.Trial registration number CT05319054.
Published: 2023
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7. Total collagen content and distribution is increased in human colon during advancing age

Author: Nicholas Baidoo, Ellie Crawley, Charles H. Knowles, Gareth J. Sanger, and Abi Belai
Subjects: Medicine, Science
Abstract: Background The effect of ageing on total collagen content of human colon has been poorly investigated. The aim of this study was to determine if ageing altered total collagen content and distribution in the human colon. Methods Macroscopically normal ascending colon was obtained at surgery from cancer patients (n = 31) without diagnosis of diverticular disease or inflammatory bowel disease. Masson’s trichrome and Picrosirius red stains were employed to identify the total collagen content and distribution within the sublayers of the colonic wall for adult (22–60 years; 6 males, 6 females) and elderly (70 – 91years; 6 males, 4 female) patients. A hydroxyproline assay evaluated the total collagen concentration for adult (30–64 years; 9 male, 6 female) and elderly (66–91 years; 8 male, 8 female) patients. Key results Histological studies showed that the percentage mean intensity of total collagen staining in the mucosa, submucosa and muscularis externa was, respectively, 14(1.9) %, 74(3.2) % and 12(1.5) % in the adult ascending colon. Compared with the adults, the total collagen fibres content was increased in the submucosa (mean intensity; 163.1 ± 11.1 vs. 124.5 ± 7.8; P < 0.05) and muscularis externa (42.5 ± 8.0 vs. 20.6 ± 2.8; P < 0.01) of the elderly patients. There was no change in collagen content of the mucosa. The total collagen concentration was increased in the elderly by 16%. Sex-related differences were not found, and data were combined for analysis. Conclusions Greater total collagen content was found in the submucosa and muscularis externa of the elderly human male and female colon. These changes may contribute to a possible loss of function with ageing.
Published: 2022

8. Non-drug therapies for the management of chronic constipation in adults: the CapaCiTY research programme including three RCTs

Author: Charles H Knowles, Lesley Booth, Steve R Brown, Samantha Cross, Sandra Eldridge, Christopher Emmett, Ugo Grossi, Mary Jordan, Jon Lacy-Colson, James Mason, John McLaughlin, Rona Moss-Morris, Christine Norton, S Mark Scott, Natasha Stevens, Shiva Taheri, and Yan Yiannakou
Subjects: anorectal physiology, biofeedback, chronic constipation, defaecatory disorder, trans-anal irrigation, ventral mesh rectopexy, Public aspects of medicine, RA1-1270
Abstract: Background: Chronic constipation affects 1–2% of adults and significantly affects quality of life. Beyond the use of laxatives and other basic measures, there is uncertainty about management, including the value of specialist investigations, equipment-intensive therapies using biofeedback, transanal irrigation and surgery. Objectives: (1) To determine whether or not standardised specialist-led habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback is more clinically effective than standardised specialist-led habit training alone, and whether or not outcomes of such specialist-led interventions are improved by stratification to habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback or habit training alone based on prior knowledge of anorectal and colonic pathophysiology using standardised radiophysiological investigations; (2) to compare the impact of transanal irrigation initiated with low-volume and high-volume systems on patient disease-specific quality of life; and (3) to determine the clinical efficacy of laparoscopic ventral mesh rectopexy compared with controls at short-term follow-up. Design: The Chronic Constipation Treatment Pathway (CapaCiTY) research programme was a programme of national recruitment with a standardised methodological framework (i.e. eligibility, baseline phenotyping and standardised outcomes) for three randomised trials: a parallel three-group trial, permitting two randomised comparisons (CapaCiTY trial 1), a parallel two-group trial (CapaCiTY trial 2) and a stepped-wedge (individual-level) three-group trial (CapaCiTY trial 3). Setting: Specialist hospital centres across England, with a mix of urban and rural referral bases. Participants: The main inclusion criteria were as follows: age 18–70 years, participant self-reported problematic constipation, symptom onset > 6 months before recruitment, symptoms meeting the American College of Gastroenterology’s constipation definition and constipation that failed treatment to a minimum basic standard. The main exclusion criteria were secondary constipation and previous experience of study interventions. Interventions: CapaCiTY trial 1: group 1 – standardised specialist-led habit training alone (n = 68); group 2 – standardised specialist-led habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback (n = 68); and group 3 – standardised radiophysiological investigations-guided treatment (n = 46) (allocation ratio 3 : 3 : 2, respectively). CapaCiTY trial 2: transanal irrigation initiated with low-volume (group 1, n = 30) or high-volume (group 2, n = 35) systems (allocation ratio 1 : 1). CapaCiTY trial 3: laparoscopic ventral mesh rectopexy performed immediately (n = 9) and after 12 weeks’ (n = 10) and after 24 weeks’ (n = 9) waiting time (allocation ratio 1 : 1 : 1, respectively). Main outcome measures: The main outcome measures were standardised outcomes for all three trials. The primary clinical outcome was mean change in Patient Assessment of Constipation Quality of Life score at the 6-month, 3-month or 24-week follow-up. The secondary clinical outcomes were a range of validated disease-specific and psychological scoring instrument scores. For cost-effectiveness, quality-adjusted life-year estimates were determined from individual participant-level cost data and EuroQol-5 Dimensions, five-level version, data. Participant experience was investigated through interviews and qualitative analysis. Results: A total of 275 participants were recruited. Baseline phenotyping demonstrated high levels of symptom burden and psychological morbidity. CapaCiTY trial 1: all interventions (standardised specialist-led habit training alone, standardised specialist-led habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback and standardised radiophysiological investigations-guided habit training alone or habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback) led to similar reductions in the Patient Assessment of Constipation Quality of Life score (approximately –0.8 points), with no statistically significant difference between habit training alone and habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback (–0.03 points, 95% confidence interval –0.33 to 0.27 points; p = 0.8445) or between standardised radiophysiological investigations and no standardised radiophysiological investigations (0.22 points, 95% confidence interval –0.11 to 0.55 points; p = 0.1871). Secondary outcomes reflected similar levels of benefit for all interventions. There was no evidence of greater cost-effectiveness of habit training plus pelvic floor retraining using computer-assisted direct visual biofeedback or stratification by standardised radiophysiological investigations compared with habit training alone (with the probability that habit training alone is cost-effective at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year gain; p = 0.83). Participants reported mixed experiences and similar satisfaction in all groups in the qualitative interviews. CapaCiTY trial 2: at 3 months, there was a modest reduction in the Patient Assessment of Constipation Quality of Life score, from a mean of 2.4 to 2.2 points (i.e. a reduction of 0.2 points), in the low-volume transanal irrigation group compared with a larger mean reduction of 0.6 points in the high-volume transanal irrigation group (difference –0.37 points, 95% confidence interval –0.89 to 0.15 points). The majority of participants preferred high-volume transanal irrigation, with substantial crossover to high-volume transanal irrigation during follow-up. Compared with low-volume transanal irrigation, high-volume transanal irrigation had similar costs (median difference –£8, 95% confidence interval –£240 to £221) and resulted in significantly higher quality of life (0.093 quality-adjusted life-years, 95% confidence interval 0.016 to 0.175 quality-adjusted life-years). CapaCiTY trial 3: laparoscopic ventral mesh rectopexy resulted in a substantial short-term mean reduction in the Patient Assessment of Constipation Quality of Life score (–1.09 points, 95% confidence interval –1.76 to –0.41 points) and beneficial changes in all other outcomes; however, significant increases in cost (£5012, 95% confidence interval £4446 to £5322) resulted in only modest increases in quality of life (0.043 quality-adjusted life-years, 95% confidence interval –0.005 to 0.093 quality-adjusted life-years), with an incremental cost-effectiveness ratio of £115,512 per quality-adjusted life-year. Conclusions: Excluding poor recruitment and underpowering of clinical effectiveness analyses, several themes emerge: (1) all interventions studied have beneficial effects on symptoms and disease-specific quality of life in the short term; (2) a simpler, cheaper approach to nurse-led behavioural interventions appears to be at least as clinically effective as and more cost-effective than more complex and invasive approaches (including prior investigation); (3) high-volume transanal irrigation is preferred by participants and has better clinical effectiveness than low-volume transanal irrigation systems; and (4) laparoscopic ventral mesh rectopexy in highly selected participants confers a very significant short-term reduction in symptoms, with low levels of harm but little effect on general quality of life. Limitations: All three trials significantly under-recruited [CapaCiTY trial 1, n = 182 (target 394); CapaCiTY trial 2, n = 65 (target 300); and CapaCiTY trial 3, n = 28 (target 114)]. The numbers analysed were further limited by loss before primary outcome. Trial registration: Current Controlled Trials ISRCTN11791740, ISRCTN11093872 and ISRCTN11747152. Funding: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 14. See the NIHR Journals Library website for further project information.
Published: 2021
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9. Electrophysiological Responses in the Human S3 Nerve During Sacral Neuromodulation for Fecal Incontinence

Author: Gerrit E. Gmel, Paul F. Vollebregt, Marjolein E. G. Thijssen, Rosana Santos Escapa, Eleanor McAlees, Dave Mugan, John L. Parker, and Charles H. Knowles
Subjects: sacral neuromodulation, fecal incontinence (FI), electrophysiology, evoked compound action potential (ECAP), myoelectric activity, sacral nerve, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Intra-operative electrode placement for sacral neuromodulation (SNM) relies on visual observation of motor contractions alone, lacking complete information on neural activation from stimulation. This study aimed to determine whether electrophysiological responses can be recorded directly from the S3 sacral nerve during therapeutic SNM in patients with fecal incontinence, and to characterize such responses in order to better understand the mechanism of action (MOA) and whether stimulation is subject to changes in posture. Eleven patients undergoing SNM were prospectively recruited. A bespoke stimulating and recording system was connected (both intraoperatively and postoperatively) to externalized SNM leads, and electrophysiological responses to monopolar current sweeps on each electrode were recorded and analyzed. The nature and thresholds of muscle contractions (intraoperatively) and patient-reported stimulation perception were recorded. We identified both neural responses (evoked compound action potentials) as well as myoelectric responses (far-field potentials from muscle activation). We identified large myelinated fibers (conduction velocity: 36–60 m/s) in 5/11 patients, correlating with patient-reported stimulation perception, and smaller myelinated fibers (conduction velocity
Published: 2021
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10. Expression of p16 Within Myenteric Neurons of the Aged Colon: A Potential Marker of Declining Function

Author: Alexandra Palmer, Sarah Epton, Ellie Crawley, Marilisa Straface, Luke Gammon, Meghan M. Edgar, Yichen Xu, Shezan Elahi, Joanne Chin-Aleong, Joanne E. Martin, Cleo L. Bishop, Charles H. Knowles, and Gareth J. Sanger
Subjects: senescence, p16, aging, human, colon, myenteric neuron, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Human colonic neuromuscular functions decline among the elderly. The aim was to explore the involvement of senescence. A preliminary PCR study looked for age-dependent differences in expression of CDKN1A (encoding the senescence-related p21 protein) and CDKN2A (encoding p16 and p14) in human ascending and descending colon (without mucosa) from 39 (approximately 50: 50 male: female) adult (aged 27–60 years) and elderly donors (70–89 years). Other genes from different aging pathways (e.g., inflammation, oxidative stress, autophagy) and cell-types (e.g., neurons, neuron axonal transport) were also examined. Unlike CDKN1A, CDKN2A (using primers for p16 and p14 but not when using p14-specific primers) was upregulated in both regions of colon. Compared with the number of genes appearing to upregulate in association with temporal age, more genes positively associated with increased CDKN2A expression (respectively, 16 and five of 44 genes studied for ascending and descending colon). Confirmation of increased expression of CDKN2A was sought by immunostaining for p16 in the myenteric plexus of colon from 52 patients, using a semi-automated software protocol. The results showed increased staining not within the glial cells (S100 stained), but in the cytoplasm of myenteric nerve cell bodies (MAP2 stained, with identified nucleus) of ascending, but not descending colon of the elderly, and not in the cell nucleus of either region or age group (5,710 neurons analyzed: n = 12–14 for each group). It was concluded that increased p16 staining within the cytoplasm of myenteric nerve cell bodies of elderly ascending (but not descending) colon, suggests a region-dependent, post-mitotic cellular senescence-like activity, perhaps involved with aging of enteric neurons within the colon.
Published: 2021
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11. Supported Intervention Versus Intervention Alone for Management of Fecal Incontinence in Patients With Inflammatory Bowel Disease

Author: Lesley Dibley, Ailsa Hart, Julie Duncan, Charles H. Knowles, Sally Kerry, Doris Lanz, Vladislav Berdunov, Vichithranie W. Madurasinghe, Tiffany Wade, Helen Terry, Azmina Verjee, Mandy Fader, and Christine Norton
Subjects: Advanced and Specialized Nursing, Medical–Surgical Nursing
Published: 2023
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12. Coexistent faecal incontinence and constipation: A cross-sectional study of 4027 adults undergoing specialist assessment

Author: Paul F. Vollebregt, Lukasz Wiklendt, Phil G Dinning, Charles H. Knowles, and S.Mark Scott
Subjects: Anorectal physiology, Constipation, Faecal incontinence, Pelvic floor dysfunction, Medicine (General), R5-920
Abstract: Background: In contrast to paediatric and geriatric populations, faecal incontinence and constipation in adults are generally considered separate entities. This may be incorrect. Methods: Cross-sectional study of consecutive patients (18–80 years) referred to a tertiary unit (2004–2016) for investigation of refractory faecal incontinence and/or constipation and meeting Rome IV core criteria (applied post-hoc) for self-reported symptoms. We sought to determine how frequently both diagnoses coexisted, how frequently coexistent diagnoses were recognised by the referring clinician and to evaluate differences in clinical characteristics between patients with single or both diagnoses. Findings: Study sample consisted of 4,027 patients (3,370 females [83·7%]). According to Rome IV criteria, 807 (20·0%) patients self-reported faecal incontinence in isolation, 1,569 (39·0%) patients had functional constipation in isolation, and 1,651 (41·0%) met criteria for both diagnoses (coexistent symptoms). In contrast, only 331 (8·2%) patients were referred for coexistent symptoms. Of the 1,651 patients with self-reported coexistent symptoms, only 225 (13·6%) were recognised by the referrer i.e. 86·4% were missed. Coexistent symptoms were most often missed in patients referred for faecal incontinence in isolation. In this group of 1,640 patients, 765 (46·7%) had concomitant symptoms of functional constipation. Opioid usage, comorbidities, childhood bowel problems, mixed incontinence symptoms, prolapse symptoms and structural abnormalities on defaecography were associated with reclassification. Interpretation: Over 40% of adults referred for anorectal physiological investigation had coexistent diagnoses of faecal incontinence and functional constipation, based on validated criteria. This overlap is overlooked by referrers, poorly documented in current literature, and may impact management.
Published: 2020
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13. Efficacy and mechanism of sub-sensory sacral (optimised) neuromodulation in adults with faecal incontinence: study protocol for a randomised controlled trial

Author: Eleanor McAlees, Paul F. Vollebregt, Natasha Stevens, Tom C. Dudding, Anton V. Emmanuel, Paul L. Furlong, Shaheen Hamdy, Richard L. Hooper, James F. X. Jones, Christine Norton, P. Ronan O’Connell, S. Mark Scott, and Charles H. Knowles
Subjects: Faecal incontinence, Sacral neuromodulation, Sacral nerve stimulation, Randomised controlled trial, Magneticoencepholograpy, Evoked potential, Medicine (General), R5-920
Abstract: Abstract Background Faecal incontinence (FI) is a substantial health problem with a prevalence of approximately 8% in community-dwelling populations. Sacral neuromodulation (SNM) is considered the first-line surgical treatment option in adults with FI in whom conservative therapies have failed. The clinical efficacy of SNM has never been rigorously determined in a trial setting and the underlying mechanism of action remains unclear. Methods/design The design encompasses a multicentre, randomised, double-blind crossover trial and cohort follow-up study. Ninety participants will be randomised to one of two groups (SNM/SHAM or SHAM/SNM) in an allocation ratio of 1:1. The main inclusion criteria will be adults aged 18–75 years meeting Rome III and ICI definitions of FI, who have failed non-surgical treatments to the UK standard, who have a minimum of eight FI episodes in a 4-week screening period, and who are clinically suitable for SNM. The primary objective is to estimate the clinical efficacy of sub-sensory SNM vs. SHAM at 32 weeks based on the primary outcome of frequency of FI episodes using a 4-week paper diary, using mixed Poisson regression analysis on the intention-to-treat principle. The study is powered (0.9) to detect a 30% reduction in frequency of FI episodes between sub-sensory SNM and SHAM stimulation over a 32-week crossover period. Secondary objectives include: measurement of established and new clinical outcomes after 1 year of therapy using new (2017 published) optimised therapy (with standardised SNM-lead placement); validation of new electronic outcome measures (events) and a device to record them, and identification of potential biological effects of SNM on underlying anorectal afferent neuronal pathophysiology (hypothesis: SNM leads to increased frequency of perceived transient anal sphincter relaxations; improved conscious sensation of defaecatory urge and cortical/subcortical changes in afferent responses to anorectal electrical stimulation (main techniques: high-resolution anorectal manometry and magnetoencephalography). Discussion This trial will determine clinical effect size for sub-sensory chronic electrical stimulation of the sacral innervation. It will provide experimental evidence of modifiable afferent neurophysiology that may aid future patient selection as well as a basic understanding of the pathophysiology of FI. Trial registration International Standard Randomised Controlled Trial Number: ISRCTN98760715. Registered on 15 September 2017.
Published: 2018
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14. Stepped-wedge randomised trial of laparoscopic ventral mesh rectopexy in adults with chronic constipation: study protocol for a randomized controlled trial

Author: Ugo Grossi, Natasha Stevens, Eleanor McAlees, Jon Lacy-Colson, Steven Brown, Anthony Dixon, Gian Luca Di Tanna, S. Mark Scott, Christine Norton, Nadine Marlin, James Mason, Charles H. Knowles, and On behalf of the NIHR CapaCiTY working group
Subjects: CapaCiTY, CapaCiTY study 3, Chronic constipation, Laparoscopic ventral mesh rectopexy (LVMR), Rectopexy, Internal rectal prolapse, Medicine (General), R5-920
Abstract: Abstract 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). Trial registration ISRCTN registry, ISRCTN11747152. Registered on 30 September 2015. The trial was prospectively registered (first patient enrolled on 21 March 2016).
Published: 2018
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15. Double-blinded randomised placebo controlled trial of enterosgel (polymethylsiloxane polyhydrate) for the treatment of IBS with diarrhoea (IBS-D)

Author: Carol Angela Howell, Anu Kemppinen, Victoria Allgar, Matthew Dodd, Charles H Knowles, John McLaughlin, Preeti Pandya, Peter Whorwell, Elena Markaryan, and Yan Yiannakou
Subjects: Irritable Bowel Syndrome, Diarrhea, Treatment Outcome, Double-Blind Method, Quality of Life, Gastroenterology, Humans, Abdominal Pain
Abstract: ObjectiveIrritable bowel syndrome with diarrhoea (IBS-D) is a common and challenging condition that significantly reduces quality of life. Enterosgel (polymethylsiloxane polyhydrate) is an intestinal adsorbent which sequesters harmful molecules and is safe and effective in acute infective diarrhoea. This randomised controlled multicentre trial aimed to investigate its safety and efficacy in patients with IBS-D.DesignAfter a 2-week screening phase, participants were randomised into an 8-week double-blind phase, followed by an 8-week open-label and follow-up phase. Participants recorded stool consistency, pain and global symptoms in e-diaries and questionnaires. The primary outcome was the percentage of responders on a composite abdominal pain (≥30% decrease in the weekly score) and stool consistency (50% reduction in days per week with at least one stool of BSFS type 6 or 7) score during at least 4 weeks of the treatment period.Results440 patients with IBS-D were randomised to the double-blind phase with 393 continuing to the open-label phase. The Primary outcome responder rate by intention-to-treat for enterosgel versus placebo was 37.4% vs 24.3% (OR 1.95, NNT 8, p=0.002). Enterosgel also improved stool consistency (48.5% vs 32.5%, pConclusionEnterosgel is safe and effective in IBS-D, providing an alternative to the limited current treatment options.Trial registration numberISRCTN17149988.
Published: 2022
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16. Systematic Characterization of Defecographic Abnormalities in a Consecutive Series of 827 Patients With Chronic Constipation

Author: Ugo Grossi, S. Mark Scott, Paul F. Vollebregt, Stuart A. Taylor, Charles H. Knowles, Henriette Heinrich, and Gian Luca Di Tanna
Subjects: Adult, Male, medicine.medical_specialty, Constipation, Adolescent, Young Adult, medicine, Humans, Defecography, In patient, Cleveland Clinic constipation score, Defecation, Aged, Aged, 80 and over, Gynecology, Chronic constipation, medicine.diagnostic_test, business.industry, Megarectum, Gastroenterology, General Medicine, Middle Aged, medicine.disease, University hospital, Cross-Sectional Studies, Rectal Diseases, Chronic Disease, Female, medicine.symptom, business, Intestinal Obstruction, Symptom score
Abstract: Barium defecography can assess structural and functional abnormalities in patients with chronic constipation.The purpose of this study was to determine the prevalence of individual and overlapping defecographic findings in this setting.This was a cross-sectional study.The study was conducted at a university hospital tertiary GI physiology department.Consecutive examinations of 827 consecutive patients presenting over a 30-month period with well-defined symptom severity (≥12 points on the Cleveland Clinic Constipation score) were included. Systematic evaluation of images with results stratified by sex is described.Six individual functional or anatomic (intussusception, rectocele, enterocele, megarectum, excessive dynamic perineal descent) defecographic observations were defined a priori, thus permitting 26 possible combinations of findings (ie, 63 abnormal types + 1 normal).Patients with constipation (mean symptom score = 19) were predominantly female (88%), with median age of 49 years (range, 17-98 y) . All 6 individual radiologic findings were identified with a total of 43 combinations found in the cohort; the 14 most prevalent of these accounted for85% of patients. Only 136 patients (16.4%) had a normal defecography (34.3% males vs 13.9% females; p0.0001). Overall, 612 patients (74.0%) had structural (n = 508 (61.4%)) or functional (n=104 (12.6%)) abnormalities in isolation, with 79 (9.6%) others exhibiting combinations of both. Functional abnormalities in isolation were more common in males compared with females (22.5% vs11.2%; p = 0.025) as opposed to structural abnormalities (57.8% vs 85.7%; p0.0001). Expulsion time was longer in females compared with males (110 s (60-120 s) vs 90 s (60-120 s); p = 0.049).The study was limited by its lack of multiorgan opacification.These results provide a contemporary atlas of defecographic findings in constipation. Several individual structural and functional features have been systematically classified, with overlap greater than previously acknowledged and profound differences among sexes that carry implications for tailoring management. See Video Abstract at http://links.lww.com/DCR/B552.ANTECEDENTES:La defecografía con bario puede evaluar anomalías estructurales y funcionales en pacientes con estreñimiento crónico.OBJETIVO:Determinar la prevalencia de hallazgos defecográficos individuales y superpuestos en este entorno.DISEÑO:Transversal.ENTORNO CLINICO:Hospital Universitario de tercer nivel, departamento de fisiología gastrointestinal.PACIENTES:Exploraciones consecutivas de 827 pacientes consecutivos que se presentaron durante un período de 30 meses con una gravedad de los síntomas bien definida (≥12 puntos en la escala de estreñimiento de la Cleveland Clinic): evaluación sistemática de imágenes con resultados estratificados por sexo.PRINCIPALES MEDIDAS DE VALORACION:Se definieron a priori seis observaciones defecográficas individuales, funcionales o anatómicas (intususcepción, rectocele, enterocele, megarecto, descenso perineal dinámico excesivo), lo que permitió 26 combinaciones posibles de hallazgos (es decir, 63 tipos anormales + 1 normal).RESULTADOS:Los pacientes con estreñimiento (puntuación media de síntomas, 19) eran predominantemente mujeres (88%) con una edad mediana de 49 (17-98) años. Se identificaron 6 hallazgos radiológicos individuales con un total de 43 combinaciones encontradas en la cohorte; los 14 más predominantes de éstos representaron85% de los pacientes.Solo 136 (16,4%) pacientes tuvieron una defecografía normal (34,3% hombres vs. 13,9% mujeres; P0,0001). En general, 612 (74,0%) pacientes tenían anomalías estructurales (n = 508 [61,4%]) o funcionales (n = 104 [12,6%]) de forma aislada, y otros 79 (9,6%) presentaban combinaciones de ambas. Las anomalías funcionales aisladas fueron más comunes en los hombres en comparación con las mujeres (22,5% vs. 11,2%, P = 0,025) en comparación con las anomalías estructurales (57,8 vs. 85,7%, P0,0001). El tiempo de expulsión fue mayor en las mujeres en comparación con los hombres (110 [60-120] vs. 90 [60-120] segundos; P = 0,049).LIMITACIONES:Falta de opacificación multiorgánica.CONCLUSIONES:Estos resultados proporcionan un atlas contemporáneo de hallazgos defecográficos en estreñimiento. Varias características individuales, estructurales y funcionales; se han clasificado sistemáticamente, con una superposición mayor que la reconocida anteriormente y con grandes diferencias entre los sexos que tienen implicaciones para adaptar su tratamiento. Consulte Video Resumen en http://links.lww.com/DCR/B552.
Published: 2021
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17. Understanding the physiology of human defaecation and disorders of continence and evacuation

Author: Charles H. Knowles, Paul T. Heitmann, Phil G. Dinning, P. J. Lunniss, S. Mark Scott, and Paul F. Vollebregt
Subjects: Pelvic floor, Constipation, Hepatology, Demographics, business.industry, Dietary intake, Gastroenterology, Physiology, medicine.disease, medicine.anatomical_structure, medicine, Anorectal function, Stool frequency, medicine.symptom, business, Irritable bowel syndrome
Abstract: The act of defaecation, although a ubiquitous human experience, requires the coordinated actions of the anorectum and colon, pelvic floor musculature, and the enteric, peripheral and central nervous systems. Defaecation is best appreciated through the description of four phases, which are, temporally and physiologically, reasonably discrete. However, given the complexity of this process, it is unsurprising that disorders of defaecation are both common and problematic; almost everyone will experience constipation at some time in their life and many will develop faecal incontinence. A detailed understanding of the normal physiology of defaecation and continence is critical to inform management of disorders of defaecation. During the past decade, there have been major advances in the investigative tools used to assess colonic and anorectal function. This Review details the current understanding of defaecation and continence. This includes an overview of the relevant anatomy and physiology, a description of the four phases of defaecation, and factors influencing defaecation (demographics, stool frequency/consistency, psychobehavioural factors, posture, circadian rhythm, dietary intake and medications). A summary of the known pathophysiology of defaecation disorders including constipation, faecal incontinence and irritable bowel syndrome is also included, as well as considerations for further research in this field.
Published: 2021
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18. Rectocele: Incidental or important? Observe or operate? Contemporary diagnosis and management in the multidisciplinary era

Author: Adil E. Bharucha and Charles H. Knowles
Subjects: Endocrine and Autonomic Systems, Physiology, Rectocele, Gastroenterology, Humans, Female, Prospective Studies, Colorectal Neoplasms, Constipation, Aged, Defecography, Retrospective Studies
Abstract: More common in older women than younger women, rectoceles may be secondary to pelvic floor weakness and/or pelvic floor dysfunction with impaired rectal evacuation. Rectoceles may be small (lt;2 cm), medium (2-4 cm), or large (gt;4 cm). Arguably, large rectoceles are more likely to be associated with symptoms (e.g., difficult defecation). It can be challenging to ascertain the extent to which a rectocele is secondary to pelvic floor dysfunction and/or whether a rectocele, rather than associated pelvic floor dysfunction, is responsible for symptoms. Surgical repair should be considered when initial treatment measures (e.g., bowel modifying agents and pelvic floor biofeedback therapy) are unsuccessful.We summarize the clinical features, diagnosis, and management of rectoceles, with an emphasis on outcomes after surgical repair. This review accompanies a retrospective analysis of outcomes after multidisciplinary, transvaginal rectocele repair procedures undertaken by three colorectal surgeons in 215 patients at a large teaching hospital in the UK. A majority of patients had a large rectocele. Some patients also underwent an anterior levatorplasty and/or an enterocele repair. All patients were jointly assessed, and some patients underwent surgery by colorectal and urogynecologic surgeons. In this cohort, the perioperative data, efficacy, and harms outcomes are comparable with historical data predominantly derived from retrospective series in which patients had a good outcome (67%-78%), symptoms of difficult defecation improved (30%-50%), and patients had a recurrent rectocele 2 years after surgery (17%). Building on these data, prospective studies that rigorously evaluate outcomes after surgical repair are necessary.
Published: 2022
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19. Faecal incontinence in adults

Author: Adil E. Bharucha, Charles H. Knowles, Isabelle Mack, Allison Malcolm, Nicholas Oblizajek, Satish Rao, S. Mark Scott, Andrea Shin, and Paul Enck
Subjects: Adult, Diarrhea, Quality of Life, Anal Canal, Humans, Female, Pelvic Floor, General Medicine, Constipation, Fecal Incontinence
Abstract: Faecal incontinence, which is defined by the unintentional loss of solid or liquid stool, has a worldwide prevalence of ≤7% in community-dwelling adults and can markedly impair quality of life. Nonetheless, many patients might not volunteer the symptom owing to embarrassment. Bowel disturbances, particularly diarrhoea, anal sphincter trauma (obstetrical injury or previous surgery), rectal urgency and burden of chronic illness are the main risk factors for faecal incontinence; others include neurological disorders, inflammatory bowel disease and pelvic floor anatomical disturbances. Faecal incontinence is classified by its type (urge, passive or combined), aetiology (anorectal disturbance, bowel symptoms or both) and severity, which is derived from the frequency, volume, consistency and nature (urge or passive) of stool leakage. Guided by the clinical features, diagnostic tests and therapies are implemented stepwise. When simple measures (for example, bowel modifiers such as fibre supplements, laxatives and anti-diarrhoeal agents) fail, anorectal manometry and other tests (endoanal imaging, defecography, rectal compliance and sensation, and anal neurophysiological tests) are performed as necessary. Non-surgical options (diet and lifestyle modification, behavioural measures, including biofeedback therapy, pharmacotherapy for constipation or diarrhoea, and anal or vaginal barrier devices) are often effective, especially in patients with mild faecal incontinence. Thereafter, perianal bulking agents, sacral neuromodulation and other surgeries may be considered when necessary.
Published: 2022
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20. Redundancy in the International Anorectal Physiology Working Group Manometry Protocol: A Diagnostic Accuracy Study in Fecal Incontinence

Author: Emma V. Carrington, Daphne Ang, S. Mark Scott, Paul F. Vollebregt, and Charles H. Knowles
Subjects: Protocol (science), Physiology, business.industry, Anorectal manometry, Gastroenterology, Diagnostic accuracy, 03 medical and health sciences, Rest period, 0302 clinical medicine, 030220 oncology & carcinogenesis, Anesthesia, medicine, Fecal incontinence, Hypertonia, Anorectal physiology, 030211 gastroenterology & hepatology, In patient, medicine.symptom, business
Abstract: Anorectal manometry (ARM) is essential for identifying sphincteric dysfunction. The International Anorectal Physiology Working Group (IAPWG) protocol and London Classification provide a standardized format for performing and interpreting ARM. However, there is scant evidence to support timing and number of constituent maneuvers. To assess the impact of protocol modification on diagnostic accuracy in patients with fecal incontinence. Retrospective analysis of high-resolution ARM recordings from consecutive patients based on the current IAPWG protocol and modifications thereof: (1) baseline rest period (60 vs. 30 vs. 10 s); (2) number of abnormal short squeezes (SS) out of 3 (SS1/SS2/SS3) based on maximal incremental squeeze pressures over 5 s; (3) resting anal pressures (reflecting recovery) at 25–30 versus 15–20 s after SS1. One hundred patients (86 F, median age 55 [IQR: 39–65]; median St. Mark’s incontinence score 14 [10–17]) were studied. 26% and 8% had anal hypotonia and hypertonia, respectively. Compared with 60-s resting pressure, measurements had perfect correlation (κ = 1.0) over 30 s, and substantial correlation (κ = 0.85) over 10 s. After SS1, SS2, and SS3, 43%, 49%, and 46% had anal hypocontractility, respectively. Correlation was substantial between SS1 and SS2 (κ = 0.799) and almost perfect between SS2 and SS3 (κ = 0.9). Compared to resting pressure of 5 s before SS1, pressure recordings at 25–30 and 15–20 s after SS1 were significantly correlated. A 30-s resting anal pressure, analysis of 2 short-squeezes with a 20-s between-maneuver recovery optimizes study duration without compromising diagnostic accuracy. These findings indicate the IAPWG protocol has redundancy.
Published: 2021
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21. Altered anal slow‐wave pressure activity in low anterior resection syndrome: short case series in two independent specialist centres provide new mechanistic insights

Author: Lukasz Wiklendt, Daphne Ang, Phil G. Dinning, Mira Mekhael, Charles H. Knowles, Paul F Vollebregt, S Mark Scott, Peter Christensen, and Mary L Venn
Subjects: Male, Manometry, faecal incontinence, Anal Canal, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, Pelvic floor dysfunction, Wave pressure, medicine, Humans, pelvic floor dysfunction, obstructed defaecation, pathophysiology, Low Anterior Resection, Rectal Neoplasms, business.industry, Anorectal manometry, Gastroenterology, Anterior resection syndrome, Syndrome, Anal canal, medicine.disease, University hospital, medicine.anatomical_structure, high-resolution anorectal manometry, 030220 oncology & carcinogenesis, Anesthesia, Healthy individuals, 030211 gastroenterology & hepatology, business, Anal sphincter, Fecal Incontinence
Abstract: Aim: Conventional parameters (anal resting and squeeze pressures) measured with anorectal manometry (ARM) fail to identify anal sphincter dysfunction in many patients with low anterior resection syndrome (LARS). We aimed to assess whether there are differences in anal canal slow-wave pressure activity in LARS patients and healthy individuals. Method: High-resolution ARM (HR-ARM) traces of 21 consecutive male LARS patients referred to the Royal London Hospital, UK (n = 12) and Aarhus University Hospital, Denmark (n = 9) were compared with HR-ARM data from 37 healthy men. Results: Qualitatively (by visual inspection of HR-ARM recordings), the frequency of slow-wave pressure activity was strikingly different in 11/21 (52.4%) LARS patients from that observed in all the healthy individuals. Quantitative analysis showed that peaks of the mean spectrum in these 11 LARS patients occurred at approximately 6–7 cycles per minute (cpm), without activity at higher frequencies. An equivalent pattern was found in only 2/37 (5.4%) healthy individuals (P
Published: 2021
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22. Clinical Impact of Rectal Hyposensitivity: A Cross-Sectional Study of 2,876 Patients With Refractory Functional Constipation

Author: Paul F. Vollebregt, Rebecca E. Burgell, Charles H. Knowles, Richard Hooper, and S. Mark Scott
Subjects: Adult, Male, medicine.medical_specialty, Constipation, Adolescent, Manometry, medicine.medical_treatment, Gastroenterology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Sensory threshold, Pressure, medicine, Humans, Defecography, Defecation, Aged, Aged, 80 and over, Hepatology, medicine.diagnostic_test, business.industry, Megarectum, Rectum, Odds ratio, Enema, Middle Aged, medicine.disease, Cross-Sectional Studies, Sensory Thresholds, 030220 oncology & carcinogenesis, Functional constipation, Female, 030211 gastroenterology & hepatology, medicine.symptom, business
Abstract: INTRODUCTION Normal bowel function requires intact sensory pathways. Diminished rectal sensation (rectal hyposensitivity [RH]) is associated with constipation, although its clinical importance remains unclear. METHODS Consecutive patients (aged 18-80) attending a tertiary center (2004-2016) for investigation of refractory functional constipation (Rome IV core criteria defined, applied post hoc) were included. Patients completed a clinical symptom questionnaire and underwent anorectal physiologic investigations, including rectal sensory testing (balloon distension) to determine 3 well-established sensory thresholds. Multivariate regression analyses were performed to evaluate associations between RH, symptomology, and allied physiologic investigations. RESULTS Of 2,876 patients meeting inclusion criteria, 722 (25%) had RH based on ≥1 elevated sensory thresholds (0: n = 2,154 [74.9%]; 1: n = 327 [11.4%]; 2: n = 209 [7.3%]; and 3: n = 186 [6.5%]). A linear relationship existed between increasing number of elevated sensory thresholds and constipation severity (Cleveland Clinic constipation score: mean difference per threshold [95% confidence interval] 0.69 [0.48-0.90]; P < 0.001). Several symptoms were significantly (P < 0.05) associated with RH including: infrequent defecation (odds ratio 1.29 [1.17-1.42]), painful evacuation (1.15 [1.05-1.27]), prolonged toileting (1.14 [1.05-1.24]), and digitation or enema use (1.18 [1.08-1.30]). On defecography, a "functional" evacuation disorder was also associated with RH (1.37 [1.25-1.50], P < 0.001), as was megarectum (2.52 [2.08-3.05], P < 0.001). DISCUSSION RH occurs in 25% of patients with refractory functional constipation. Increased number of elevated sensory thresholds is associated with more severe constipation phenotype. These data, in the largest study to date, provide for the first time evidence to show that RH is a major pathophysiologic mechanism in constipation, with recognized clinical impact (http://links.lww.com/AJG/B765).(Equation is included in full-text article.).
Published: 2020
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23. Recommendations for the Protocol of functional examination of the anorectal zone and disorders classification: the International Anorectal Physiology Working Group consensus and Russian real-world practice

Author: O. M. Biryukov, Yury A. Kucheryavyy, A S Rumiantsev, D A Morozov, E. D. Fedorov, E.S. Pimenova, H Knowles, Dmitrii N. Andreev, D. B. Nikityuk, M G Biryukova, Vasily Isakov, Y. A. Shelygin, L H Indeykina, M Y Gvozdev, S. V. Belousova, S. I. Achkasov, A S Shkoda, O.A. Storonova, V. N. Kashnikov, O.Y. Fomenko, Sergey Morozov, Dmitry S. Bordin, S Scott, A.S. Trukhmanov, and Igor V. Maev
Subjects: Protocol (science), History, medicine.medical_specialty, business.industry, Endocrinology, Diabetes and Metabolism, Anorectal manometry, MEDLINE, Rectum, General Medicine, Anal canal, Terminology, Test (assessment), Dyssynergia, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Physical therapy, Medicine, 030211 gastroenterology & hepatology, Family Practice, business
Abstract: This manuscript summarizes consensus reached by the International Anorectal Physiology Working Group (IAPWG) for the performance, terminology used, and interpretation of anorectal function testing including anorectal manometry (focused on high-resolution manometry), the rectal sensory test, and the balloon expulsion test. Based on these measurements, a classification system for disorders of anorectal function is proposed. Aim to provide information about methods of diagnosis and new classification of functional anorectal disorders to a wide range of specialists general practitioners, therapists, gastroenterologists, coloproctologists all who face the manifestations of these diseases in everyday practice and determine the diagnostic and therapeutic algorithm. Current paper provides agreed statements of IAPWG Consensus and comments (in italics) of Russian experts on real-world practice, mainly on methodology of examination. These comments in no way intended to detract from the provisions agreed by the international group of experts. We hope that these comments will help to improve the quality of examination based on the systematization of local experience with the use of the methods discussed and the results obtained. Key recommendations: the International Anorectal Physiology Working Group protocol for the performance of anorectal function testing recommends a standardized sequence of maneuvers to test rectoanal reflexes, anal tone and contractility, rectoanal coordination, and rectal sensation. Major findings not seen in healthy controls defined by the classification are as follows: rectoanal areflexia, anal hypotension and hypocontractility, rectal hyposensitivity, and hypersensitivity. Minor and inconclusive findings that can be present in health and require additional information prior to diagnosis include anal hypertension and dyssynergia.
Published: 2020

24. Position statement by the Pelvic Floor Society on behalf of the Association of Coloproctology of Great Britain and Ireland on the use of mesh in ventral mesh rectopexy

Author: Charles H. Knowles, Andrew Williams, Steven R Brown, and M. Mercer-Jones
Subjects: Position statement, medicine.medical_specialty, Mesh rectopexy, Swine, Association (object-oriented programming), education, 030230 surgery, Pelvic Organ Prolapse, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, Clinical governance, Pelvic floor, business.industry, General surgery, Consensus Statement, Gastroenterology, Pelvic Floor, Rectal Prolapse, Surgical Mesh, medicine.disease, United Kingdom, Surgery, Rectal prolapse, Treatment Outcome, medicine.anatomical_structure, Laparoscopy, 030211 gastroenterology & hepatology, business, Regular Articles
Abstract: The following position statement forms part of a response to the current concerns regarding use of mesh to perform rectal prolapse surgery. It highlights the actions being pursued by the Pelvic Floor Society (TPFS) regarding clinical governance in relation to ventral mesh rectopexy (VMR). The following are summary recommendations. Available evidence suggests that mesh morbidity for VMR is far lower than that seen in transvaginal procedures (the main subject of current concern) and lower than that observed following other abdomino‐pelvic procedures for urogenital prolapse, e.g. laparoscopic sacrocolpopexy.VMR should be performed by adequately trained surgeons who work within a multidisciplinary team (MDT) framework. Within this, it is mandatory to discuss all patients considered for surgery at an MDT meeting.Clinical outcomes of surgery and any complications resulting from surgery should be recorded in the TPFS‐hosted national database (registry) available for this purpose; in addition, all patients should be considered for entry into ongoing and planned UK/European randomized studies where this is feasible.A move towards accreditation of UK units performing VMR will improve performance and outcomes in the long term.An enhanced programme of training including staged porcine, cadaveric and preceptorship sessions will ensure the competence of surgeons undertaking VMR.Enhanced consent forms and patient information booklets are being developed, and these will help both surgeons and patients.There is weak observational evidence that technical aspects of the procedure can be optimized to reduce morbidity rates. Suture material choice may contribute towards morbidity. The available evidence is insufficient to support the use of one mesh over another (biologic vs synthetic); however, the use of polyester mesh is associated with increased morbidity.
Published: 2020
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25. Risk of obstetric anal sphincter injuries (OASIS) and anal incontinence: A meta-analysis

Author: John Hanrahan, Swati Jha, Javier Zamora, Ranee Thakar, Michail Sideris, Charles H. Knowles, David Arroyo-Manzano, Tristan McCaughey, Charlotte Chaliha, and Shakila Thangaratinam
Subjects: medicine.medical_specialty, Vaginal delivery, business.industry, Obstetrics, Anal Canal, Obstetrics and Gynecology, Reproductive age, Delivery, Obstetric, Perineum, Obstetric Labor Complications, Primary repair, medicine.anatomical_structure, Reproductive Medicine, Pregnancy, Meta-analysis, Relative risk, Endoanal ultrasound, Humans, Medicine, Sphincter, Female, Anal sphincter, business, Fecal Incontinence
Abstract: Background Obstetric anal sphincter injuries (OASIS) are the commonest cause of anal incontinence in women of reproductive age. We determined the risk of anal sphincter defects diagnosed by ultrasound, and the risk of anal incontinence in (i) all women who deliver vaginally, (ii) in women without clinical suspicion of OASIS, and (iii) after primary repair of sphincter injury, by systematic review. Methods We searched major databases until June 2018, without language restrictions. Random effects meta-analysis was used to obtain pooled estimates of ultrasound diagnosed OASIS and risk of anal incontinence symptoms at various time points after delivery, and of persistent sphincter defects after primary repair. We reported the association between ultrasound diagnosed OASIS and anal incontinence symptoms using relative risk (RR) with 95 % CI. Results We included 103 studies involving 16,110 women. Of all women who delivered vaginally, OASIS were diagnosed on ultrasound in 26 % (95 %CI, 21–30, I2 = 91 %), and 19 % experienced anal incontinence (95 %CI, 14–25, I2 = 92 %). In women without clinical suspicion of OASIS (n = 3688), sphincter defects were observed in 13 % (10–17, I2 = 89 %) and anal incontinence experienced by 14 % (95 % CI: 6–24, I2 = 95 %). Following primary repair of OASIS, 55 % (46–63, I2 = 98 %) of 7549 women had persistent sphincter defect with 38 % experiencing anal incontinence (33–43, I2 = 92 %). There was a significant association between ultrasound diagnosed OASIS and anal incontinence (RR 3.74, 2.17−6.45, I2 = 98 %). Interpretation Women and clinicians should be aware of the high risk for sphincter defects following vaginal delivery even when clinically unsuspected. This underlines the need of careful and systematic perineal assessment after birth to mitigate the risk of missing OASIS. We also noted a high rate of persistent defects and symptoms following primary repair of OASIS. This dictates the need for provision of robust training for clinicians to achieve proficiency and sustain competency in repairing OASIS.
Published: 2020
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26. Epidemiological trends in surgery for rectal prolapse in England 2001–2012: an adult hospital population‐based study

Author: Y. El-Dhuwaib, Anand Pandyan, and Charles H. Knowles
Subjects: Adult, Male, Reoperation, Laparoscopic surgery, medicine.medical_specialty, medicine.medical_treatment, Population, Q1, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Recurrence, RA0421, Interquartile range, Open Resection, Epidemiology, medicine, Humans, education, Aged, Aged, 80 and over, education.field_of_study, business.industry, Mortality rate, Gastroenterology, R735, Rectal Prolapse, Middle Aged, medicine.disease, R1, Hospitals, Surgery, Rectal prolapse, Treatment Outcome, 030220 oncology & carcinogenesis, Female, Laparoscopy, 030211 gastroenterology & hepatology, business, RA, RD, Cohort study
Abstract: Aim\ud To analyse trends in admission and surgery for rectal prolapse in adults in England between 2001 and 2012 as well as prolapse reoperation rates.\ud \ud Method\ud Analysis of data derived from a comparative longitudinal population‐based cohort study using Hospital Episode Statistics (HES).\ud \ud Results\ud During the study period, a total of 25 238 adults, of median age 73 [interquartile range (IQR: 58–83] years, underwent a total of 29 379 operations for rectal prolapse (mean: 2662 per annum). The female to male ratio of this group of patients was 7:1. Median length of hospital stay was 3 (IQR: 1–7) days with an overall in‐hospital mortality rate of 0.9%. Total number of admissions (4950 in 2001/2002 vs 8927 in 2011/2012) and of patients undergoing prolapse surgery (2230 in 2001/2002 vs 2808 in 2011/2012) significantly increased over the study period (P < 0.001 for trends). The overall increase in prolapse surgery (of 33% overall and of 44% for elective procedures) was dwarfed by an increase in popularity of laparoscopic surgery (of 15‐fold). Overall prolapse reoperation rate was 12.7%. The lowest recurrence rate was observed for elective open resection (9.1%) but this had the highest mortality (1.9%). Laparoscopic and perineal fixations were also associated with low reoperation rates (< 11%) and the lowest mortality rates, of 0.3%, when these procedures were elective. These data refute a trend towards subspecialization (by surgeon or hospital) during the study period.\ud \ud Conclusion\ud Admissions for rectal prolapse increased in England between 2001 and 2012, together with increases in rectal prolapse surgery. Surgical decision making has changed over this period and may be reflected in outcome.
Published: 2020
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27. New Technologies and Applications in Sacral Neuromodulation: An Update

Author: Philip Van Kerrebroeck, Dean Elterman, Stefan Engelberg, Paul A. Lehur, Stefan De Wachter, Michael J. Kennelly, Klaus E. Matzel, Charles H. Knowles, RS: MHeNs - R3 - Neuroscience, MUMC+: MA Urologie (9), and Urologie
Subjects: Adult, Male, STIMULATION, Sacrum, 030213 general clinical medicine, medicine.medical_specialty, Emerging technologies, Urology, MULTICENTER, Guidelines as Topic, system, 03 medical and health sciences, 0302 clinical medicine, Magnetic resonance imaging, Inventions, follow-up, Humans, Medicine, Pharmacology (medical), Medical physics, Aged, Aged, 80 and over, medicine.diagnostic_test, Health professionals, Urinary Bladder, Overactive, business.industry, Therapies, Investigational, Pharmacology. Therapy, Overactive bladder, Sacral neuromodulation, Rechargeable battery, Prostheses and Implants, General Medicine, Middle Aged, Stimulator, fecal incontinence, modulation, Sacral nerve stimulation, 030220 oncology & carcinogenesis, Transcutaneous Electric Nerve Stimulation, Commentary, Female, Human medicine, business
Abstract: Recently rechargeable devices have been introduced for sacral neuromodulation (SNM) with conditional safety for full-body magnetic resonance imaging (MRI). Currently a recharge-free SNM device represents the standard implant; however, it is only approved for MRI head scans. As further new technologies with broader MRI capabilities are emerging, the advantages as well as disadvantages of both rechargeable versus recharge-free devices will be briefly discussed in this commentary from the perspective of patients, healthcare professionals, and providers.
Published: 2020
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28. Trials with repeated cross sections: alternatives to parallel group designs in surgery trials

Author: Charles H Knowles
Subjects: Gastroenterology, Surgery
Published: 2022
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29. Validation of the OAKS prognostic model for acute kidney injury after gastrointestinal surgery

Author: R Ahmed, W U, Bhatia, S, A McLean, K, Khaw, R, Baker, D, K Kamarajah, S, Bell, S, Nepogodiev, D, M Harrison, E, C Glasbey, J, Borakati, A, Burke, J, M Drake, T, F Bath, M, A Claireaux, H, Gundogan, B, Mohan, M, Deekonda, P, Kong, C, Joyce, H, Mcnamee, L, Woin, E, Khatri, C, E Fitzgerald, J, Bhangu, A, Arulkumaran, N, Duthie, F, Hughes, J, D Pinkney, T, Prowle, J, Richards, T, Thomas, M, Blanco-Colino, R, J Chapman, S, Pata, F, Pellino, G, Sgrò, A, Soares, A, van Elst, T, Van Straten, S, H Knowles, C, Dynes, K, Patel, M, Patel, P, Wigley, C, Suresh, R, Shaw, A, Klimach, S, Jull, P, Evans, D, Preece, R, Ibrahim, I, Manikavasagar, V, Smith, R, S Brown, F, Teo, R, Y Sim, D P, E Logan, A, Barai, I, Amin, H, Suresh, S, Sethi, R, Gul, W, Bolton, W, Corbridge, O, Horne, L, Attalla, M, Morley, R, Robinson, C, Hoskins, T, Mcallister, R, Lee, S, Dennis, Y, Nixon, G, Heywood, E, Wilson, H, Ng, L, Samaraweera, S, Mills, A, Doherty, C, Belchos, J, Phan, V, Lim, M, A Miller, F, Chouari, T, Gardner, T, Goergen, N, B Hayes, J D, S MacLeod, C, Mccormack, R, Mckinley, A, Mckinstry, S, Milligan, W, Ooi, L, M Rafiq, N, Sammut, T, Sinclair, E, Smith, M, Wong, J, D Ablett, A, Tie-Gill, T, Ramsay, G, De Paola, L, Mcguckin, S, Alshakhs, A, Ahmeidat, A, A Francis, A, Baker, C, R Boulton, A P, Collins, J, C Copley, H, Fearnhead, N, Fox, H, Mah, T, Mckenna, J, Naruka, V, Nigam, N, Nourallah, B, Perera, S, Qureshi, A, Saggar, S, Sun, L, Wang, X, D Yang, D, Ali, Z, Mullarkey, L, Walshe, R, Lewis, E, Berry, B, Moneim, J, Mookerjee, S, Al-Hadithi, A, Caroll, P, Doyle, C, Elangovan, S, Falamarzi, A, Gascon Perai, K, Greenan, E, Jain, D, Lang-Orsini, M, Lim, S, O'Byrne, L, Ridgway, P, Van der Laan, S, Arthur, J, Barclay, J, Bradley, P, Edwin, C, Finch, E, Hayashi, E, Hopkins, M, Kelly, D, Kelly, M, Mccartan, N, Ormrod, A, Pakenham, A, Christy, S, Hayward, J, Hitchen, C, Kishore, A, Martins, T, Philomen, J, Rao, R, Rickards, C, Burns, N, Copeland, M, Durand, C, Dyal, A, Ghaffar, A, Gidwani, A, Grant, M, Gribbon, C, Gruhn, A, Leer, M, Ojofeitimi, O, Carroll, L, Hylands, A, P Delaugere, L, Reveendran, D, Ahmad, K, Beattie, G, Beatty, M, Campbell, G, Donaldson, G, Graham, S, Holmes, D, Kanabar, S, Liu, H, Mccann, C, Stewart, R, Vara, S, Coulter, C, Ralston, C, Laverty, L, Gallagher, P, Ajibola-Taylor, O, E Andah, E J, Ani, C, O Cabdi, N M, Ito, G, Jones, M, Komoriyama, A, Titu, L, Ahmed, A, Q Yeo, Y, Elliott, D, Bennett, J, Mcnamara, M, Sivarajah, S, Dunmore, C, Basra, M, Gallogly, P, Harinath, G, H Leong, S, Pradhan, A, Siddiqui, I, Zaat, S, Ali, A, Galea, M, L Looi, W, K Ng, J C, H Farhan-Alanie, M M, Aitken, G, Nair, M, H Aly, M, Buari, M, Atkin, G, Azizi, A, Cargill, Z, China, Z, Elliot, J, Jebakumar, R, Lam, J, Mudalige, G, Onyerindu, C, Renju, M, Shankar Babu, V, Ahmed, K, Sheikh, Z, Monks, M, Lehmann, J, Rotimi, O, Hussain, M, Joji, N, Lovett, B, Mownah, H, Dwyer-Hemmings, L, Busuttil, A, Powell, J, Hensher, C, Vivian, F, Ali, B, Cresswell, B, K Dhillon, A, S Dupaguntla, Y, Hungwe, C, D Lowe-Zinola, J, H Tsang, J C, Wcislo, K, Bevan, K, Cardus, C, Duggal, A, Hossain, S, Mchugh, M, Scott, M, Millar, Z, Hirosue, S, Ogunmwonyi, I, Nakakande, D, Chan, F, Evans, R, Gurung, E, Haughey, B, Jacob-Ramsdale, B, Kerr, M, Lee, J, Mccann, E, O'Boyle, K, Reid, N, Kwek, I, Gaze, H, Nirmalanantha, A, A Bin Amran, M, Foulkes, A, Jones, N, F Lau, I S, Hayat, F, Hodgson, S, Johnston, R, Jones, W, Khan, M, Linn, T, Long, S, Seetharam, P, Shaman, S, Smart, B, Pillai, S, Khoury, G, Powell, T, Maleyko, I, Sangheli, A, Ransome, M, Isse, M, Aromolaran, O, Bholah, H, Anilkumar, A, Davies, J, Griffith, J, Hughes, B, Islam, Y, Kidanu, D, Mushaini, N, Qamar, I, Robinson, H, Schramm, M, Yan Tan, C, Murray, V, Theocharidou, L, Malik, T, Janmohamed, I, Carhart, B, Khan, A, Apperley, H, Billyard, C, M Blazeby, J, P Cannon, S, Carse, S, Göpfert, A, Loizidou, A, Parkin, J, Sanders, E, Sharma, S, Slade, G, Telfer, R, Whybrow Huppatz, I, Worley, E, Asif, A, Hullait, R, Quinn, P, Rylance, A, Butt, S, Leathes, J, Chandramoorthy, L, Friend, C, Harris, L, Jain, P, J Karim, M, Killington, K, Mcgillicuddy, J, Rafferty, C, Rahunathan, N, Rayne, T, Varathan, Y, Verma, N, Zanichelli, D, Arneill, M, Brown, F, Campbell, B, Crozier, L, Henry, J, Mccusker, C, Prabakaran, P, Wilson, R, Karelia, S, M Clements, J, Rainey, M, Asif, U, Connor, M, Dindyal, S, Math, N, Pagarkar, A, Saleem, H, Seth, I, Standfield, N, Swartbol, T, Adamson, R, E Choi, J, El Tokhy, O, Ho, W, R Javaid, N, S Mehdi, A, Menon, D, Plumptre, I, Sturrock, S, Turner, J, Warren, O, Joshi, N, Rahman, A, Gallagher, M, Crane, E, Ferris, B, Gadsby, C, Smallwood, J, Vipond, M, Wilson, V, Amarnath, T, Doshi, A, Gregory, C, Kandiah, K, Powell, B, Spoor, H, Toh, C, Vizor, R, Rebuffa, N, Abdelgalil, R, Siaw Yen Lai, R, Smith, E, Common, M, Dunleavy, K, Harris, S, Luo, C, Mesbah, Z, Prem Kumar, A, Redmond, A, Skulsky, S, Walsh, T, Daly, D, Deery, L, Epanomeritakis, E, Harty, M, Kane, D, Khan, K, Mackey, R, Mcconville, J, Mcginnity, K, L Wong, H, Ang, A, Y Kee, J, Leung, E, Norman, S, V Palaniappan, S, Partha Sarathy, P, Yeoh, T, Frost, J, Hazeldine, P, Jones, L, Karbowiak, M, Macdonald, C, Mutarambirwa, A, Omotade, A, Runkel, M, Ryan, G, Sawers, N, Searle, C, Vig, S, Hlukha, L, Pike, G, Kamel, F, Thakkar, R, Mcauliffe, O, Ahmad, A, Mcgartland, R, Sim, R, Song, A, Wayman, J, Brown, R, H Chang, L, Concannon, K, Crilly, C, J Arnold, T, Burgin, A, Cadden, F, H Choy, C, Coleman, M, Lim, D, Luk, J, Mahankali-Rao, P, J Prudence-Taylor, A, Ramakrishnan, D, Russell, J, Fawole, A, Gohil, J, Green, B, Hussain, A, Mcmenamin, L, Tang, M, Azmi, F, Benchetrit, S, Cope, T, Haque, A, Harlinska, A, Holdsworth, R, Ivo, T, Martin, J, Nisar, T, Patel, A, Sasapu, K, Trevett, J, Vernet, G, Aamir, A, Bird, C, Durham-Hall, A, Gibson, W, Hartley, J, May, N, Maynard, V, Goble, M, Downs, E, Wheldon, L, Baggus, E, Mandal, A, Nayeem, A, Ahmed, S, Fradley, W, Johnson, S, McDonald Wood, C, O'Brien, M, Orbell, J, D Stringfellow, T, Tenters, F, Tresidder, S, Wilson, C, Gallagher, S, Criswell, T, Ward, J, Mukkavilli, A, Stubbs, B, Fordyce, W, Cheung, W, Grant, A, Tod, N, Yi Tew, Z, Suchdev, N, Wei Lim, S, Bews-Hair, M, H Lim, Z, W Lim, S, Vella-Baldacchino, M, Auckburally, S, Chopada, A, Easdon, S, Goodson, R, Mccurdie, F, Narouz, M, Radford, A, Rea, E, Taylor, O, Yu, T, R Sookramanien, S, Chan, A, Bointas, G, Alfa-Wali, M, Amani, L, Auluck, I, Bruce, P, Emberton, J, Kumar, R, Lagzouli, N, Mehta, A, Murtaza, A, Raja, M, S Dennahy, I, Frew, K, Given, A, Y He, Y, A Karim, M, Macdonald, E, Mcdonald, E, Mcvinnie, D, K Ng, S, Pettit, A, D Berthaume-Hawkins, S, Charnley, R, Fenton, K, Jones, D, Murphy, C, Q Ng, J, Reehal, R, S Seraj, S, Shang, E, Tonks, A, White, P, Yeo, A, Paul, M, L Ward, K, Bagnall, M, Chong, P, Gabriel, R, Patel, N, Richardson, E, Symons, L, Aubrey-Jones, D, Dawood, S, Dobrzynska, M, Faulkner, S, Griffiths, H, Mahmood, F, Perry, M, Power, A, Simpson, R, A Pherwani, S, Wang, K, 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Pham, H D, Harris, M, Salibasic, M, Pavlov, V, Paycheva, T, Lyulenina, E, Kolev, N, Boev, B, Nguen, D, Mitkov, Y, Mitkov, E, Vladova, P, Dimitrov, V, Gabarski, A, Feradova, H, Mladenov, T, Pös, M, Adel, A, Sotona, O, Bartoš, M, Amjad, T, Malý, O, Berec, S, Hanušová, M, Hurný, M, Örhalmi, J, S Sørensen, J, Chanut, F, Magnin, J, Schöning, L, Cs Simon, S, Galata, C, Karampinis, I, Thäwel, T, M Seckler, A, Kerem, C, Durdevic, S, Herrle, F, Artioli, E, Giaccari, S, Nevoso, V, Schimera, A, Marino, S, Resta, G, Ongaro, D, Baronio, G, Raimondo, S, Casiraghi, S, Salvadori, R, Armellini, A, Vulcano, I, Bertilone, E, Pintabona, G, Viscosi, F, Mazzeo, C, Olivieri, M, Belluco, C, D Antona, A, Basso, S, Frattalone, M, Marino, F, Carbone, F, Incollingo, P, M Romano, F, Anania, M, Pulighe, F, Cruccu, A, L Murru, M, Massaiu, C, Balestra, F, Pazzona, M, De Nisco, C, P Gusai, G, Giannella, A, Santangelo, M, Frangella, F, Magagnano, D, Liberatore, P, Rondelli, F, Castagnoli, G, Bartoli, A, Bellochi, R, Spaziani, A, Conti, D, Poponesi, V, Trippetti, M, Amicucci, S, Tazza, G, Procacci, P, Giovannini, F, Basile, E, Moschetta, G, Cosmi, F, Romeo, G, Gasparrini, M, Virgilio, E, Sparta, C, A Mura, F, Barmina, M, Lorettu, A, Rettaroli, C, Mastino, G, V Ruggiu, G, A Mura, G, A Perrone, B, De Angelis, M, Mereu, A, Adamo, V, Bianco, C, Ricciardiello, M, Campanaro, C, Panaccio, P, M Esposito, L, F Di Mola, F, D'Ascanio, F, Pietroletti, R, Di Marco, F, Amico, A, Schembari, E, Puglisi, S, Tuminello, F, Figà, F, Caiazzo, A, Selvaggi, L, Capozzolo, A, Braccio, B, Truškovs, A, Bartnick, A, Malcevs, E, J Machatschek, M, Alm, J, Lapsa, S, Delorme, M, Zeynalov, F, Larnovskis, J, Sauka, J, Bodrov, D, Gailumsis, R, M Wiemann, A, L Müller, N, Jelovskis, I, Deksnis, D, Bauermeister Potts, O, Slimbajevs, T, Ancans, G, Dulskas, A, Kuliavas, J, Kavaliauskas, P, Kavaliauskaite, R, Te Molder, L, Tromp, J, Matthee, E, M Tissen, Y, Brinkhuis, E, S de Vries, H, 't Hart, E, Beckers, K, Bekker, Y, Kakar, S, C van Smaalen, T, C Veen, O, A Dingemans, S, C van den Brink, L, J Vijgen, G H E, F van de Voort, E M, van der Pool, A, C van Rest, K L, Haak, T, C Gordinou de Gouberville, M, Saleh, S, A Mens, M, M Hoeks, E, Nieuwenhuizen, S, M Brandsma, A, M van Praag, E, Westerduin, E, M Smit, M P C, J van der Lely, S, de Ruiter, A, Ribbers, T, M Aarts, C A, S Tulek, M, de Jonge, J, Kocak, S, J Alqethami, H, Constansia, R, C van Elst, P, W Tissink, M, Azzahhafi, J, Bofarid, S, Kip, M, Saleh, W, Franssen, S, L Boon, C, M Franssen, R J, Romaen, I, F Jense, M T, D'Souza, J, Pascoe, R, Scott, A, Stark, E, Mulholland, K, K Lau, W, Smith, B, B Adams, S I, Shah, N, Ling, E, Young, J, Hawkins, R, Jacobson, A, Macfater, H, Stanfield, B, Henderson, N, Chuang, A, Maskill, L, Ker, H, Mouldey, K, Hu, R, Matthews, C, Aitken, E, Walker, M, Winstanley, J, Miguel, I, Martins, J, F Cunha, M, Melo, J, N Veiga, D, Rachadell, J, Amorim, E, Vareda, R, Roseira, J, Americano, M, Correia, D, Capella, V, Moinhos, T, Costa, F, Gil, I, Morgado, J, Varghese, S, Boyle, E, Aljohmani, L, Alexander, J, Graziadei, V, Mccaughey, C, Jain, A, B O'Connor, D, Ramanayake, H, Sabnani, R, F Colon, L, Bansal, N, Stephens, I, Tan, R, Hoo, M, Doherty, G, Fenn, S, Mulhare, E, Walsh, M, Leavey, C, Costigan, O, Griffin, S, Dockry, É, Khogali, E, K Aly, A, Mcphedran, R, O'Gorman, D, Vermeulen, D, Gopaul, A, R Pentony, A, L Piong, C, Nossier, R, Hanna, J, Sabir, K, Y Eow, S, Ladak, N, Boersma, D, J Kamath, P, W Soh, T B, H Dyer, A, Y Chee, S, H Tan, I X, Kelliher, A, Scanlon, K, Adeusi, L, Howarth, N, Mccawley, N, O'Neill, A, R Jones, M, Saleh, R, Singh, A, O'Dwyer, N, C Mana, O, Gomez, H, Riba, L, Perez, J, Centeno, A, Ortega, C, E Ossola, M, Camarero, E, Martínez Illán, M, Aranda García, L, Lázaro Cardona, M, Montalvo Olmedo, C, Izquierdo Moreno, A, Cuenca Ramírez, A, Margarida, A, Pando, B, Liquete Marín, L, Pérez Calle, M, J Ramos Cordero, M, Sagredo Cuartango, A, Sánchez, E, Marcos Rodrigo, A, Fernandez, A, Curtis, C, Bosch, M, Triguero, D, Bosch Ramírez, M, De La Llave Serralvo, A, J Sánchez, M, Martín-Borregón, P, Quevedo, A, Martínez, J, M Marín, J, Rodríguez, P, Esteban Avendaño, I, Jiménez Relimpio, C, Lancho Lavilla, P, Blanco Bartolomé, I, Gómez Cano, I, Blasco Andrés, C, Abad-Motos, A, Marínez-Hurtado, E, Salvachua-Fernández, R, Muniesa, C, Avelino, L, Cholewa, H, Sancho-Muriel, J, Navasquillo, M, Navío, A, Abelló, D, De Jesus, M, Alvarez, E, Kefleyesus, A, Bugmann, A, M Piotet, L, Meijers, L, Tonchev, P, Tamosiunas, A, J Rottier, S, Negoi, I, R Bernado, I, Eftychiou, S, and L Lorenzon (ORCID:0000-0001-6736-0383)
Abstract: Background: Postoperative acute kidney injury (AKI) is a common complication of major gastrointestinal surgery with an impact on short- and long-term survival. No validated system for risk stratification exists for this patient group. This study aimed to validate externally a prognostic model for AKI after major gastrointestinal surgery in two multicentre cohort studies. Methods: The Outcomes After Kidney injury in Surgery (OAKS) prognostic model was developed to predict risk of AKI in the 7 days after surgery using six routine datapoints (age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker). Validation was performed within two independent cohorts: a prospective multicentre, international study ('IMAGINE') of patients undergoing elective colorectal surgery (2018); and a retrospective regional cohort study ('Tayside') in major abdominal surgery (2011-2015). Multivariable logistic regression was used to predict risk of AKI, with multiple imputation used to account for data missing at random. Prognostic accuracy was assessed for patients at high risk (greater than 20 per cent) of postoperative AKI. Results: In the validation cohorts, 12.9 per cent of patients (661 of 5106) in IMAGINE and 14.7 per cent (106 of 719 patients) in Tayside developed 7-day postoperative AKI. Using the OAKS model, 558 patients (9.6 per cent) were classified as high risk. Less than 10 per cent of patients classified as low-risk developed AKI in either cohort (negative predictive value greater than 0.9). Upon external validation, the OAKS model retained an area under the receiver operating characteristic (AUC) curve of range 0.655-0.681 (Tayside 95 per cent c.i. 0.596 to 0.714; IMAGINE 95 per cent c.i. 0.659 to 0.703), sensitivity values range 0.323-0.352 (IMAGINE 95 per cent c.i. 0.281 to 0.368; Tayside 95 per cent c.i. 0.253 to 0.461), and specif
Published: 2022

30. Caecal volvulus on a background of recurrent caecocolic torsion

Author: Charles H. Knowles and JA Walker
Subjects: Adult, Male, medicine.medical_specialty, 030230 surgery, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Intestinal Volvulus, Internal medicine, Abdomen, parasitic diseases, Cecal Diseases, Humans, Medicine, Colectomy, Ileostomy, business.industry, digestive, oral, and skin physiology, Torsion (gastropod), General Medicine, Abdominal Pain, Surgery, Presentation (obstetrics), Caecal volvulus, business, Intestinal Obstruction
Abstract: Caecal volvulus is an uncommon cause of intestinal obstruction. Diagnosis may be challenging due to lack of clinical familiarity, variable clinical presentation and misinterpretation of diagnostic imaging and procedures. This case report describes a 29-year-old male with acute intestinal obstruction secondary to caecal volvulus, on a background of recurrent caecocolic torsion. Diagnosis required repeat axial imaging and endoscopy when initial imaging studies were misinterpreted.
Published: 2021
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31. Systematic review and meta-analysis of anal motor and rectal sensory dysfunction in male and female patients undergoing anorectal manometry for symptoms of faecal incontinence

Author: Annika M. P. Rasijeff, Karla García‐Zermeño, Gian‐Luca Di Tanna, José Remes‐Troche, Charles H. Knowles, and Mark S. Scott
Subjects: Male, Manometry, Gastroenterology, Rectum, Anal Canal, Humans, Muscle Hypotonia, Female, Fecal Incontinence
Abstract: Manometry is the best established technique to assess anorectal function in faecal incontinence. By systematic review, pooled prevalences of anal hypotonia/hypocontractility and rectal hypersensitivity/hyposensitivity in male and female patients were determined in controlled studies using anorectal manometry.Searches of MEDLINE and Embase were completed. Screening, data extraction and bias assessment were performed by two reviewers. Meta-analysis was performed based on a random effects model with heterogeneity evaluated by IOf 2116 identified records, only 13 studies (2981 faecal incontinence patients; 1028 controls) met the inclusion criteria. Anal tone was evaluated in 10 studies and contractility in 11; rectal sensitivity in five. Only three studies had low risk of bias. Pooled prevalence of anal hypotonia was 44% (95% CI 32-56, IThe number of appropriately controlled studies of anorectal manometry is small with fewer still at low risk of bias. Results were subject to gender differences, wide confidence intervals and high heterogeneity indicating the need for international collective effort to harmonize practice and reporting to improve certainty of diagnosis.
Published: 2021

32. PWE-61 An early evaluation of participant recruitment and compliance following the virtualisation of RELIEVE IBS-D trial

Author: Carol Howell, Charles H. Knowles, Anu Kemppinen, John McLaughlin, H Forsyth, Yan Yiannakou, G Richell, E Markaryan, and Cho Ee Ng
Subjects: medicine.medical_specialty, business.industry, Physical therapy, Medicine, business, Compliance (psychology)
Published: 2021
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33. Double-blind randomised controlled trial of percutaneous tibial nerve stimulation versus sham electrical stimulation in the treatment of faecal incontinence: CONtrol of Faecal Incontinence using Distal NeuromodulaTion (the CONFIDeNT trial)

Author: Emma J Horrocks, Stephen A Bremner, Natasha Stevens, Christine Norton, Deborah Gilbert, P Ronan O’Connell, Sandra Eldridge, and Charles H Knowles
Subjects: faecal incontinence, bowel incontinence, tibial nerve stimulation, neuromodulation, Medical technology, R855-855.5
Abstract: Background: Faecal incontinence (FI) is a common condition which is often under-reported. It is distressing for those suffering from it, impacting heavily on their quality of life. When conservative strategies fail, treatment options are limited. Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive outpatient treatment, shown in preliminary case series to have significant effectiveness; however, no randomised controlled trial has been conducted. Objectives: To assess the effectiveness of PTNS compared with sham electrical stimulation in the treatment of patients with FI in whom initial conservative strategies have failed. Design: Multicentre, parallel-arm, double-blind randomised (1 : 1) controlled trial. Setting: Eighteen UK centres providing specialist nurse-led (or equivalent) treatment for pelvic floor disorders. Participants: Participants aged > 18 years with FI who have failed conservative treatments and whose symptoms are sufficiently severe to merit further intervention. Interventions: PTNS was delivered via the Urgent® PC device (Uroplasty Limited, Manchester, UK), a hand-held pulse generator unit, with single-use leads and fine-needle electrodes. The needle was inserted near the tibial nerve on the right leg adhering to the manufacturer’s protocol (and specialist training). Treatment was for 30 minutes weekly for a duration of 12 treatments. Validated sham stimulation involved insertion of the Urgent PC needle subcutaneously at the same site with electrical stimulation delivered to the distal foot using transcutaneous electrical nerve stimulation. Main outcome measures: Outcome measures were assessed at baseline and 2 weeks following treatment. Clinical outcomes were derived from bowel diaries and validated, investigator-administered questionnaires. The primary outcome classified patients as responders or non-responders, with a responder defined as someone having achieved ≥ 50% reduction in weekly faecal incontinence episodes (FIEs). Results: In total, 227 patients were randomised from 373 screened: 115 received PTNS and 112 received sham stimulation. There were 12 trial withdrawals: seven from the PTNS arm and five from the sham arm. Missing data were multiply imputed. For the primary outcome, the proportion of patients achieving a ≥ 50% reduction in weekly FIEs was similar in both arms: 39 in the PTNS arm (38%) compared with 32 in the sham arm (31%) [odds ratio 1.28, 95% confidence interval (CI) 0.72 to 2.28; p = 0.396]. For the secondary outcomes, significantly greater decreases in weekly FIEs were observed in the PTNS arm than in the sham arm (beta –2.3, 95% CI –4.2 to –0.3; p = 0.02), comprising a reduction in urge FIEs (p = 0.02) rather than passive FIEs (p = 0.23). No significant differences were found in the St Mark’s Continence Score or any quality-of-life measures. No serious adverse events related to treatment were reported. Conclusions: PTNS did not show significant clinical benefit over sham electrical stimulation in the treatment of FI based on number of patients who received at least a 50% reduction in weekly FIE. It would be difficult to recommend this therapy for the patient population studied. Further research will concentrate on particular subgroups of patients, for example those with pure urge FI. Trial registration: Current Controlled Trials ISRCTN88559475. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 77. See the NIHR Journals Library website for further project information.
Published: 2015
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34. Electrophysiological Responses in the Human S3 Nerve During Sacral Neuromodulation for Fecal Incontinence

Author: John L. Parker, Rosana Santos Escapa, Dave Mugan, Charles H. Knowles, Paul F. Vollebregt, Eleanor McAlees, Marjolein E G Thijssen, and Gerrit Gmel
Subjects: Pelvic floor, myoelectric activity, business.industry, General Neuroscience, sacral nerve, Neurosciences. Biological psychiatry. Neuropsychiatry, Stimulation, electrophysiology, Nerve conduction velocity, sacral neuromodulation, Electrophysiology, medicine.anatomical_structure, Sacral nerve stimulation, Anesthesia, Sensation, Sacral nerve, Medicine, Fecal incontinence, medicine.symptom, business, evoked compound action potential (ECAP), fecal incontinence (FI), RC321-571, Neuroscience, Original Research
Abstract: Intra-operative electrode placement for sacral neuromodulation (SNM) relies on visual observation of motor contractions alone, lacking complete information on neural activation from stimulation. This study aimed to determine whether electrophysiological responses can be recorded directly from the S3 sacral nerve during therapeutic SNM in patients with fecal incontinence, and to characterize such responses in order to better understand the mechanism of action (MOA) and whether stimulation is subject to changes in posture. Eleven patients undergoing SNM were prospectively recruited. A bespoke stimulating and recording system was connected (both intraoperatively and postoperatively) to externalized SNM leads, and electrophysiological responses to monopolar current sweeps on each electrode were recorded and analyzed. The nature and thresholds of muscle contractions (intraoperatively) and patient-reported stimulation perception were recorded. We identified both neural responses (evoked compound action potentials) as well as myoelectric responses (far-field potentials from muscle activation). We identified large myelinated fibers (conduction velocity: 36–60 m/s) in 5/11 patients, correlating with patient-reported stimulation perception, and smaller myelinated fibers (conduction velocity
Published: 2021

35. Comparison of cytokine and phosphoprotein profiles in idiopathic and Crohn’s disease-related perianal fistula

Author: Thomas T. MacDonald, Charles H. Knowles, Omar Musbahi, and James B Haddow
Subjects: Crohn’s disease, Anal fistula, medicine.medical_specialty, Crohn's disease, business.industry, medicine.medical_treatment, Observational Study, Pathogenesis, Phosphoproteins, medicine.disease, Gastroenterology, digestive system diseases, 03 medical and health sciences, 0302 clinical medicine, Cytokine, Perianal fistula, 030220 oncology & carcinogenesis, Internal medicine, Phosphoprotein, Cytokines, Medicine, 030211 gastroenterology & hepatology, business
Abstract: BACKGROUND Perianal fistulae are either primary (idiopathic) or secondary [commonly associated with Crohn’s disease, (CD)]. It is assumed, although not proven, that the pathophysiology differs. AIM To systematically compare the clinical phenotypes, cytokine and phosphoprotein profiles of idiopathic and CD-related perianal fistulae. METHODS Sixty-one patients undergoing surgery for perianal fistula were prospectively recruited (48 idiopathic, 13 CD) into a cohort study. Clinical data, including the Perineal Disease Activity Index (PDAI) and EQ-5D-5L were collected. Biopsies of the fistula tract, granulation tissue, internal opening mucosa and rectal mucosa were obtained at surgery. Concentrations of 30 cytokines and 39 phosphoproteins were measured in each biopsy using a magnetic bead multiplexing instrument and a chemiluminescent antibody array respectively. Over 12000 clinical and 23500 laboratory measurements were made. RESULTS The PDAI was significantly higher (indicating more active disease) in the CD group with a mean difference of 2.40 (95%CI: 0.52-4.28, P = 0.01). Complex pathoanatomy was more prevalent in the CD group, namely more multiple fistulae, supralevator extensions, collections and rectal thickening. The IL-12p70 concentration at the internal opening specimen site was significantly higher (median difference 19.7 pg/mL, 99%CI: 0.2-40.4, P = 0.008) and the IL-1RA/IL-1β ratio was significantly lower in the CD group at the internal opening specimen site (median difference 15.0, 99%CI = 0.4-50.5, P = 0.008). However in the remaining 27 cytokines and all 39 of the phosphoproteins across the four biopsy sites, no significant differences were found between the groups. CONCLUSION CD-related perianal fistulae are more clinically severe and anatomically complex than idiopathic perianal fistulae. However, overall there are no major differences in cytokine and phosphoprotein profiles.
Published: 2019
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36. A randomized double-blinded sham-controlled cross-over trial of tined-lead sacral nerve stimulation testing for chronic constipation

Author: Rebecca Maier, Mark Mercer-Jones, Helen Close, SM Plusa, Susan E. Green, Adetayo Kasim, Jeremy Cundall, Charles H. Knowles, KJ Etherson, James Mason, and Yan Yiannakou
Subjects: Adult, Male, animal structures, Adolescent, Double blinded, Lumbosacral Plexus, Electric Stimulation Therapy, Stimulation, law.invention, Prosthesis Implantation, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, Symptom relief, law, Humans, Surgical Wound Infection, Medicine, Lead (electronics), Aged, Chronic constipation, Cross-Over Studies, Hepatology, business.industry, Gastroenterology, Middle Aged, Prognosis, Crossover study, Electrodes, Implanted, Treatment Outcome, Sacral nerve stimulation, 030220 oncology & carcinogenesis, Anesthesia, Chronic Disease, Early Termination of Clinical Trials, Female, Root Cause Analysis, 030211 gastroenterology & hepatology, business, Constipation
Abstract: Objectives\ud Sacral nerve stimulation (SNS) may provide long-term symptom relief to patients suffering from chronic constipation. Patients are currently selected for SNS using a 2-week peripheral nerve evaluation (PNE) comprising stimulation by temporary leads. However, only 40% of test responders receive long-term benefit from treatment meaning that healthcare costs per successfully treated patient are too high. The primary objective was to assess tined-lead testing to predict benefit from SNS for chronic constipation.\ud Patients and methods\ud A randomized double-blind sham-controlled cross-over design evaluated enhanced PNE (ePNE) using tined quadripolar electrode leads over 6 weeks. The design differentiated between patients with discriminate and indiscriminate responses to testing. A score improvement of 25% or more was considered to be a positive response within a stimulation period. The primary outcome was the proportion of patients showing a reduction of at least 0.5 in constipation symptom score at 6 months.\ud Results\ud A total of 45 patients were randomized, of whom 29 (64.4%) were test-phase responders. Of these, 27 were implanted providing permanent SNS. During ePNE, seven (18%) were discriminate responders, 22 (56%) were indiscriminate responders and 10 (26%) were nonresponders. Six patients were withdrawn during the test phase because of infection or noncompliance. At 6 months, there was no significant difference in primary outcome between discriminate and indiscriminate responders (60 vs. 57%, P=0.76). The study was terminated prematurely because of a persistent infection rate of 10 (22%) during ePNE of which nine (20%) were severe.\ud Conclusion\ud ePNE is a poor predictor of treatment response at 6 months. This suggests a strong and persistent placebo response during both SNS PNE and treatment. An extended 6-week PNE poses a high risk of infection.
Published: 2019
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37. Chronic constipation in adults: Contemporary perspectives and clinical challenges. 2: Conservative, behavioural, medical and surgical treatment

Author: Ugo Grossi, Thomas Dudding, Pasquale Giordano, Robin C. Spiller, Charles H. Knowles, Magnus Simren, Maura Corsetti, P. Ronan O’Connell, Kevin Whelan, Mark A. Fox, S. Mark Scott, Anton Emmanuel, Alexander C. Ford, Eirini Dimidi, Giuseppe Chiarioni, Andrew Williams, Eamonn Martin Quigley, William E. Whitehead, Michelle Henderson, Steven R Brown, University of Zurich, and Corsetti, Maura
Subjects: Adult, Male, medicine.medical_specialty, Constipation, Physiology, 610 Medicine & health, Decision Support Techniques, 03 medical and health sciences, 0302 clinical medicine, Quality of life (healthcare), Epidemiology, medicine, Humans, 2715 Gastroenterology, Surgical treatment, Intensive care medicine, algorithm, constipation, IBS-C, treatment, Female, Chronic constipation, Endocrine and Autonomic Systems, business.industry, Gastroenterology, 1314 Physiology, Neurogastroenterology, Management algorithm, Clinical Practice, 2807 Endocrine and Autonomic Systems, 10219 Clinic for Gastroenterology and Hepatology, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, medicine.symptom, business
Abstract: BACKGROUND Chronic constipation is a prevalent disorder that affects quality of life of patients and consumes resources in healthcare systems worldwide. In clinical practice, it is still considered a challenge as clinicians frequently are unsure as to which treatments to use and when. Over a decade ago, a Neurogastroenterology and Motility journal supplement devoted to the investigation and management of constipation was published (Neurogastroenterol Motil 2009;21(Suppl 2):1). In October 2018, the 3rd London Masterclass, entitled "Contemporary management of constipation" was held. The faculty members of this symposium were invited to write two reviews to present a collective synthesis of talks presented and discussions held during this meeting. The first review addresses epidemiology, diagnosis, clinical associations, pathophysiology, and investigation. PURPOSE The present is the second of these reviews, providing contemporary perspectives and clinical challenges regarding behavioral, conservative, medical, and surgical treatments for patients presenting with constipation. It includes a management algorithm to guide clinical practice.
Published: 2021
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38. Understanding the physiology of human defaecation and disorders of continence and evacuation

Author: Paul T, Heitmann, Paul F, Vollebregt, Charles H, Knowles, Peter J, Lunniss, Phil G, Dinning, and S Mark, Scott
Subjects: Colon, Manometry, Rectum, Anal Canal, Magnetic Resonance Imaging, Cine, Pelvic Floor, Magnetic Resonance Imaging, Diet, Humans, Intestine, Large, Defecation, Gastrointestinal Motility, Gastrointestinal Transit, Constipation, Fecal Incontinence, Defecography
Abstract: The act of defaecation, although a ubiquitous human experience, requires the coordinated actions of the anorectum and colon, pelvic floor musculature, and the enteric, peripheral and central nervous systems. Defaecation is best appreciated through the description of four phases, which are, temporally and physiologically, reasonably discrete. However, given the complexity of this process, it is unsurprising that disorders of defaecation are both common and problematic; almost everyone will experience constipation at some time in their life and many will develop faecal incontinence. A detailed understanding of the normal physiology of defaecation and continence is critical to inform management of disorders of defaecation. During the past decade, there have been major advances in the investigative tools used to assess colonic and anorectal function. This Review details the current understanding of defaecation and continence. This includes an overview of the relevant anatomy and physiology, a description of the four phases of defaecation, and factors influencing defaecation (demographics, stool frequency/consistency, psychobehavioural factors, posture, circadian rhythm, dietary intake and medications). A summary of the known pathophysiology of defaecation disorders including constipation, faecal incontinence and irritable bowel syndrome is also included, as well as considerations for further research in this field.
Published: 2021

39. ESCP Safe Anastomosis ProGramme in CoLorectal SurgEry (EAGLE): Study protocol for an international cluster randomised trial of a quality improvement intervention to reduce anastomotic leak following right colectomy

Author: António Sampaio Soares, Tatiana, Garmanova, Gianpiero, Gravante, Edward, Bywater, Michala, Pettitt, Mary, L Venn, James, C Glasbey, Dmitri, Nepogodiev, Elizabeth, Li, Ana, Minaya-Bravo, Ionut, Negoi, Matteo, Frasson, Richard, L Hooper, Charles, H Knowles, Dion Gregory Morton, Aneel, Bhangu, Brett, E Dawson, James, Keatley, Laura, Magill, Rita, Perry, Thomas, Pinkney, Mark, A Potter, Jonathan, P Evans, Sivesh, Kamarajah, Siobhan, C McKay, Daniel, Osei-Bordom, Sanjay, Chaudhri, Luis, Sánchez-Guillén, Jasper, Stijns, Yu Ting Van Loon, Dieter, Hahnloser, David D, E Zimmerman, Nicolas, C Buchs, Liam, Cato, Miguel, Cunha, Charlotte, El-Sayed, David, Finch, Gallo, G, Ruben, Martins, Peter Mark Neary, Pata, Francesco, Tomas, Poskus, April, C Roslani, Elgun, Samadov, Mohammed, Sbaih, Mostafa, Shalaby, Joana, Simões, Aaditya Prakash Sinha, Emre, Sivrikoz, Armen, Vardanyan, Antonino, Spinelli, David, J Beard, Marion, Campbell, Omar, Omar, Aaditya, Sinha, and Surgery
Subjects: Relative risk reduction, dog-leg cluster randomised, medicine.medical_specialty, Colectomies, Leak, Anastomotic Leak, Anastomosis, Dogs, medicine, Animals, Humans, Colectomy, Randomized Controlled Trials as Topic, business.industry, General surgery, Anastomosis, Surgical, Gastroenterology, Absolute risk reduction, randomised trial, Quality Improvement, Colorectal surgery, Cohort, Right Colectomy, quality improvement study, business, anastomotic leak, colorectal surgery, right hemicolectomy, Colorectal Surgery
Abstract: Aim Cohort data suggest that anastomotic leak occurs after 8% of right colectomies causing significant morbidity and mortality. Patient selection, intra-operative factors, and technical variation all contribute to risk of leak. The EAGLE study will assess whether implementation of the European Society of Coloproctology (ESCP) Safe Anastomosis Intervention reduces anastomotic leak following right colectomy. Methods An international, multi-centre, cluster randomised trial will be undertaken with hospitals as clusters. Hospitals will be recruited in a number of distinct phases, with each phase following the same research plan, in which clusters are randomised to one of three, staggered (dog-leg) schedules for implementation of the Safe Anastomosis Intervention. Results Results from different phases will be meta-analysed. The intervention is a three-component behavioural change programme for surgeons, anaesthetists and operating room staff, supported by an online learning environment. All colorectal surgical units around the world will be eligible. Adults undergoing elective or emergency right colectomy or ileocaecal resection, by any approach and for any indication will be included. The primary outcome is 30-day anastomotic leak rate, defined as clinical or radiologically-detected leak or intra-abdominal or pelvic collection. Assuming hospitals provide data for an average of 10 patients per two month recruitment period, 333 clusters (4440 patients in total) will allow for detection of an absolute risk reduction of anastomotic leak from 8.1% to 5.6% (relative risk reduction 30%). This protocol adheres to Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT). Discussion The protocol describes the methods for an evaluation of a hospital-level, education-based quality improvement intervention targeted to reduce the life-threatening surgical complication of anastomotic leak.
Published: 2021

40. Clinician administered and self-report survey both effective for identifying fecal incontinence in patients with Inflammatory Bowel Disease

Author: Christine Norton, Lesley Dibley, Vichithranie W. Madurasinghe, Mandy Fader, Azmina Verjee, Ailsa Hart, Charles H. Knowles, Sally Kerry, Tiffany Wade, Julie Duncan, Doris Lanz, and Helen Terry
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Physiology, Disease, Inflammatory bowel disease, Bowel control, Young Adult, Self-report study, Internal medicine, Surveys and Questionnaires, medicine, Fecal incontinence, Humans, In patient, Aged, Aged, 80 and over, Physician-Patient Relations, business.industry, Gastroenterology, Hepatology, Middle Aged, medicine.disease, Inflammatory Bowel Diseases, Ulcerative colitis, R1, digestive system diseases, Cross-Sectional Studies, Female, Self Report, medicine.symptom, business, Fecal Incontinence
Abstract: Objectives To test two methods for reporting of fecal incontinence (FI) in people with inflammatory bowel disease. Methods Consecutive patients from IBD clinics in six UK hospitals completed a short three-item case-finding survey about FI; they either completed the survey themselves or were asked the same questions face to face by a clinician. Results Of 1336 eligible patients with complete data (48% male; mean 43 years; 55% Crohn’s disease, 41% ulcerative colitis), 772 were asked about FI face to face, and 564 self-completed the survey: FI was reported in 63% and 56%, respectively (p = 0.012). In regression analyses, those aged 51–60, having Crohn’s disease and higher disease activity, were more likely to report FI. Of all respondents, 38.7% were interested in receiving help for their incontinence. Conclusions Fecal incontinence affects the majority of people with IBD. Although more patients reported fecal incontinence when asked face to face than self-reported, routine screening by either method in clinical practice is recommended. Over one-third of patients with IBD want help for bowel control problems.
Published: 2021

41. Chronic constipation in adults:Contemporary perspectives and clinical challenges. 1: Epidemiology, diagnosis, clinical associations, pathophysiology and investigation

Author: Adam D. Farmer, Charles H. Knowles, Asma Fikree, Mark A. Fox, Klaus Krogh, Rebecca E. Burgell, Alexander C. Ford, Karen Nugent, S. Mark Scott, Emma V. Carrington, Maura Corsetti, José María Remes-Troche, Eirini Dimidi, Marc A. Benninga, Kevin Whelan, Caroline L. Hoad, Philip G. Dinning, and Magnus Simren
Subjects: Adult, medicine.medical_specialty, Constipation, Physiology, diagnosis, chronic constipation, Quality of life (healthcare), Epidemiology, Prevalence, medicine, Humans, pathophysiology, Chronic constipation, investigation, Endocrine and Autonomic Systems, business.industry, Research, Gastroenterology, Disease Management, Clinical Practice, Hot topics, Family medicine, IBS-C, Chronic Disease, Quality of Life, epidemiology, medicine.symptom, business, Healthcare system
Abstract: BACKGROUND: Chronic constipation is a prevalent disorder that affects patients' quality of life and consumes resources in healthcare systems worldwide. In clinical practice, it is still considered a challenge as clinicians frequently are unsure as to which treatments to use and when. Over a decade ago, a Neurogastroenterology & Motility journal supplement devoted to the investigation and management of constipation was published (2009; 21 (Suppl.2)). This included seven articles, disseminating all themes covered during a preceding 2-day meeting held in London, entitled “Current perspectives in chronic constipation: a scientific and clinical symposium.” In October 2018, the 3rd London Masterclass, entitled “Contemporary management of constipation” was held, again over 2 days. All faculty members were invited to author two new review articles, which represent a collective synthesis of talks presented and discussions held during this meeting. PURPOSE: This article represents the first of these reviews, addressing epidemiology, diagnosis, clinical associations, pathophysiology, and investigation. Clearly, not all aspects of the condition can be covered in adequate detail; hence, there is a focus on particular “hot topics” and themes that are of contemporary interest. The second review addresses management of chronic constipation, covering behavioral, conservative, medical, and surgical therapies.
Published: 2021
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42. Reprogramming Sacral Neuromodulation for Sub-Optimal Outcomes: Evidence and Recommendations for Clinical Practice

Author: Stefan De Wachter, Karel Everaert, Stefan Engelberg, Lilli Lundby, Arantxa Muñoz-Duyos, Philip Van Kerrebroeck, Michael Sørensen, Emmanuel Chartier-Kastler, Klaus E. Matzel, Thomas C Dudding, Charles H. Knowles, Maria Paola Bertapelle, Mona Rydningen, Paul A. Lehur, University Hospital Southampton NHS Foundation Trust, Ospedale Regionale di Lugano, Copenhagen University Hospital Hvidovre [Hvidovre, Danemark], University of Copenhagen = Københavns Universitet (KU), Medtronic SNT, Medtronic, Service d'Urologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ghent University Hospital, Maastricht University [Maastricht], Queen Mary University of London (QMUL), Aarhus University Hospital, Universitätsklinikum Erlangen [Erlangen], Universitat de Barcelona (UB), University Hospital of North Norway [Tromsø] (UNN), Universiteit Antwerpen [Antwerpen], RS: MHeNs - R3 - Neuroscience, and Urologie
Subjects: medicine.medical_specialty, Sacrum, Lumbosacral Plexus, MULTICENTER, 030232 urology & nephrology, Urinary incontinence, Electric Stimulation Therapy, Troubleshooting, sacral neuromodulation, 03 medical and health sciences, 0302 clinical medicine, Patient satisfaction, Multidisciplinary approach, Fecal incontinence, medicine, Humans, MULTIPLE-SCLEROSIS PATIENTS, Adverse effect, Intensive care medicine, NERVE-STIMULATION, urinary incontinence, business.industry, troubleshooting, reprogramming, General Medicine, OVERACTIVE BLADDER SYMPTOMS, EFFICACY, 3. Good health, Anesthesiology and Pain Medicine, Systematic review, Treatment Outcome, Neurology, Patient Satisfaction, VOIDING DYSFUNCTION, 030220 oncology & carcinogenesis, Human medicine, Neurology (clinical), medicine.symptom, FOLLOW-UP, business, CONSTANT-CURRENT, Reprogramming, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Fecal Incontinence, SINGLE-CENTER
Abstract: International audience; ObjectivesIn some patients treated for urinary or fecal incontinence with sacral neuromodulation (SNM) persistence of symptoms, a reduction in efficacy or adverse effects of stimulation can occur. In such situations, further programming of the SNM device can help resolve problems. Infrequently hardware failure is detected. This article aims to provide practical guidance to solve sub-optimal outcomes (troubleshooting) occurring in the course of SNM therapy.Materials and MethodsA systematic literature review was performed. Collective clinical experience from an expert multidisciplinary group was used to form opinion where evidence was lacking.ResultsCircumstances in which reprogramming is required are described. Actions to undertake include changes of electrode configuration, stimulation amplitude, pulse frequency, and pulse width. Guidance in case of loss of efficacy and adverse effects of stimulation, developed by a group of European experts, is presented. In addition, various hardware failure scenarios and their management are described.ConclusionsReprogramming aims to further improve patient symptoms or ensure a comfortable delivery of the therapy. Initial changes of electrode configuration and adjustment of stimulation parameters can be performed at home to avoid unnecessary hospital visits. A logical and stepwise approach to reprogramming can improve the outcome of therapy and restore patient satisfaction.
Published: 2021
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43. Slow-transit constipation and criteria for colectomy: a cross-sectional study of 1568 patients

Author: S Z Y Tee, Paul F. Vollebregt, Charles H. Knowles, Stephen Scott, and P. Chaichanavichkij
Subjects: Adult, medicine.medical_specialty, Abdominal pain, Constipation, AcademicSubjects/MED00910, Cross-sectional study, medicine.medical_treatment, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Fecal incontinence, Gastrointestinal Transit, Contraindication, Colectomy, Irritable bowel syndrome, Retrospective Studies, Chronic constipation, business.industry, General surgery, General Medicine, medicine.disease, Cross-Sectional Studies, Treatment Outcome, 030220 oncology & carcinogenesis, Original Article, 030211 gastroenterology & hepatology, medicine.symptom, AcademicSubjects/MED00010, business
Abstract: Background Colectomy remains a treatment option for a minority of patients with slow-transit constipation (STC) refractory to conservative treatment. However careful patient selection is essential to maximize benefits and minimize risk of adverse outcome. This study determined the proportion of patients with chronic constipation that would meet criteria for colectomy based on recent European graded practice recommendations derived by expert consensus. Methods Retrospective application of graded practice recommendations was undertaken on a prospectively maintained data set of consecutive adult patients with chronic constipation who underwent whole-gut transit studies using radio-opaque markers. Primary analysis applied contraindications achieving high level of expert consensus (normal whole-gut transit as an absolute contraindication and faecal incontinence as a relative contraindication for colectomy). Secondary analysis applied contraindications with less certain consensus. Results Primary analysis of 1568 patients undergoing a whole-gut transit study between January 2004 and March 2016 found 208 (13.3 per cent) met published criteria to be selected for colectomy, with 974 excluded for normal whole-gut transit and 386 for faecal incontinence. Secondary analysis demonstrated high prevalence of other relative contraindications to colectomy: 165 concomitant upper gastrointestinal symptoms, 216 abdominal pain (including 126 irritable bowel syndrome), and 446 evacuation disorder. The majority of patients (416 of 594) had two or more relative contraindications. If these patients were excluded, only 26 (1.7 per cent) chronically constipated patients retrospectively met selection criteria for colectomy. Conclusions The retrospective application of selection criteria is a limitation. However, the data highlight the high prevalence of factors associated with poor postoperative outcome and provide further caution to surgeons undertaking colectomy for STC.
Published: 2021
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44. Lack of anti-TNF drugs levels in fistula tissue - a reason for nonresponse in Crohn's perianal fistulating disease?

Author: James B Haddow, Ailsa Hart, R. K. S. Phillips, Elaine Holmes, Janindra Warusavitarne, Kapil Sahnan, Charles H. Knowles, Samuel O Adegbola, Omar Faiz, Alexandros Pechlivanis, Phil Tozer, and Magali Sarafian
Subjects: Proteomics, medicine.medical_specialty, Fistula, Pilot Projects, Disease, Gastroenterology, Crohn Disease, Internal medicine, medicine, Adalimumab, Humans, Rectal Fistula, Hepatology, business.industry, Tumor Necrosis Factor-alpha, Drugs levels, medicine.disease, Penetrance, Infliximab, Treatment Outcome, Biomarker (medicine), Tumor necrosis factor alpha, Tumor Necrosis Factor Inhibitors, business, medicine.drug
Abstract: Introduction Anti-TNF therapy is recommended as treatment for patients with Crohn´s perianal fistulas. However, a significant proportion of patients have a sub-optimal response to anti-TNF therapy. Higher serum levels of anti-TNF agents have been associated with improved outcomes in perianal Crohn's disease. Currently, it is unknown whether anti-TNF agent levels can be detected in tissue from fistula tracts themselves and whether this is associated with response. Aims and methods We undertook a pilot study to measure fistula tissue levels of anti-TNF medication (infliximab and adalimumab). We used a previously validated targeted proteomic technique, employing ultraperformance liquid chromatography-mass spectrometry, to detect/quantify anti-TNF drugs. Biopsies were obtained from fistula tracts of patients with Crohn's disease on maintenance treatment; with idiopathic (cryptoglandular) fistula tissues used as negative controls as well as positive controls (by spiking the latter tissues with anti-TNF drugs). Results Tissue was sampled from the fistula tracts of seven patients with Crohn's perianal disease (five patients were on adalimumab and two patients were on infliximab). The anti-TNF drugs, infliximab and adalimumab, were not detected in fistula samples from any of the Crohn's patients despite detection in 'spiked' positive control samples. Conclusion Absence of detection of the anti-TNF drugs in fistula tissue raises the question on the role of tissue penetrance of anti-TNF drugs in response to therapy. Further work is required in a larger number of patients to validate the findings observed and investigate if any correlation exists between tissue and serum levels of anti-TNF and clinical outcome. Summary Predicting response in Crohn's fistula patients on biologic therapy is difficult with no reliable biomarkers. This pilot study uses targeted proteomics to investigate the potential role of tissue drug levels in acting as a biomarker of treatment response.
Published: 2021

45. Integration of a Class of Transcendental Liouvillian Functions with Error-Functions, Part II.

Author: Paul H. Knowles
Published: 1993
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46. Megarectum: systematic histopathological evaluation of 35 patients and new common pathways in chronic rectal dilatation

Author: Milly West, Stewart Cleeve, Charles H. Knowles, William R. English, Sara Peroos, Vinayata Sheshappanavar, Joanne E. Martin, and John V Kendall
Subjects: 0301 basic medicine, medicine.medical_specialty, Neuromuscular disease, business.industry, Megarectum, Rectum, General Medicine, Disease, Neuropathology, medicine.disease, Gastroenterology, Pathology and Forensic Medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Internal medicine, medicine, Etiology, medicine.symptom, Myopathy, business, Pathological
Abstract: AimsMegarectum is well described in the surgical literature but few contemporary pathological studies have been undertaken. There is uncertainty whether ‘idiopathic’ megarectum is a primary neuromuscular disorder or whether chronic dilatation leads to previously reported and unreported pathological changes. We sought to answer this question.MethodsSystematic histopathological evaluation (in accord with international guidance) of 35 consecutive patients undergoing rectal excision surgery for megarectum (primary: n=24) or megarectum following surgical correction of anorectal malformation (secondary: n=11) in a UK university hospital with adult/paediatric surgical and gastrointestinal neuropathology expertise.ResultsWe confirmed some previously reported observations, notably hypertrophy of the muscularis propria (27 of 35, 77.1% of patients) and extensive fibrosis (30 of 35, 85.7% of patients). We also observed unique and previously unreported features including elastosis (19 of 33, 57.6%) and the presence of polyglucosan bodies (15 of 32, 46.9% of patients). In contrast to previous literature, few patients had any strong evidence of specific forms of visceral neuropathy (5 of 35, including 3 plexus duplications) or myopathy (6 of 35, including 3 muscle duplications). All major pathological findings were common to both primary and secondary forms of the disease, implying that these may be a response to chronic rectal distension rather than of primary aetiology.ConclusionsIn the largest case series reported to date, we challenge the current perception of idiopathic megarectum as a primary neuromuscular disease and propose a cellular pathway model for the features present. The severe morphological changes account for some of the irreversibility of the condition and reinforce the need to prevent ongoing rectal distension when first identified.
Published: 2021

47. Integration of a Class of Transcendental Liouvillian Functions with Error-Functions, Part I.

Author: Paul H. Knowles
Published: 1992
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48. Redundancy in the International Anorectal Physiology Working Group Manometry Protocol: A Diagnostic Accuracy Study in Fecal Incontinence

Author: Daphne, Ang, Paul, Vollebregt, Emma V, Carrington, Charles H, Knowles, and S Mark, Scott
Subjects: Manometry, Rest, Rectum, Anal Canal, Humans, Middle Aged, Fecal Incontinence, Retrospective Studies
Abstract: Anorectal manometry (ARM) is essential for identifying sphincteric dysfunction. The International Anorectal Physiology Working Group (IAPWG) protocol and London Classification provide a standardized format for performing and interpreting ARM. However, there is scant evidence to support timing and number of constituent maneuvers.To assess the impact of protocol modification on diagnostic accuracy in patients with fecal incontinence.Retrospective analysis of high-resolution ARM recordings from consecutive patients based on the current IAPWG protocol and modifications thereof: (1) baseline rest period (60 vs. 30 vs. 10 s); (2) number of abnormal short squeezes (SS) out of 3 (SS1/SS2/SS3) based on maximal incremental squeeze pressures over 5 s; (3) resting anal pressures (reflecting recovery) at 25-30 versus 15-20 s after SS1.One hundred patients (86 F, median age 55 [IQR: 39-65]; median St. Mark's incontinence score 14 [10-17]) were studied. 26% and 8% had anal hypotonia and hypertonia, respectively. Compared with 60-s resting pressure, measurements had perfect correlation (κ = 1.0) over 30 s, and substantial correlation (κ = 0.85) over 10 s. After SS1, SS2, and SS3, 43%, 49%, and 46% had anal hypocontractility, respectively. Correlation was substantial between SS1 and SS2 (κ = 0.799) and almost perfect between SS2 and SS3 (κ = 0.9). Compared to resting pressure of 5 s before SS1, pressure recordings at 25-30 and 15-20 s after SS1 were significantly correlated.A 30-s resting anal pressure, analysis of 2 short-squeezes with a 20-s between-maneuver recovery optimizes study duration without compromising diagnostic accuracy. These findings indicate the IAPWG protocol has redundancy.
Published: 2020

49. Species differences in the cerebellar distribution of six members of the Kv1 channel subfamily

Author: Joanne E. Martin, Olimpia E. Curran, Andrew W. Hubball, Charles H. Knowles, and Philip D. Minor
Subjects: Subfamily, urogenital system, Purkinje cell, Biology, Gerbil, complex mixtures, Molecular biology, Staining, medicine.anatomical_structure, nervous system, Basket cell, Polyclonal antibodies, medicine, Hepatic stellate cell, biology.protein, Immunohistochemistry, natural sciences, biological phenomena, cell phenomena, and immunity
Abstract: Comprehensive studies on the distribution of the Kv1 subfamily have been performed in rat (Chung et al., 2001) and gerbil (Chung et al., 2005), but not in mouse or human. We hypothesized that species differences may exist in the localization of these proteins. Two sets of polyclonal antibodies to Kv1.1-6 were used. Immunohistochemistry was performed on archived, formalin-fixed tissue from disease-free human, monkey and mouse cerebellum. Mouse staining corresponded to that described in rat and gerbil, with strong Kv1.1 and Kv1.2 immunoreactivities in the basket cell pinceau at the base of Purkinje cells. Kv1.3, Kv1.4, Kv1.5 and Kv1.6 were predominantly expressed in Purkinje cells. Human and monkey samples showed a similar pattern to mouse for Kv1.1, Kv1.2, Kv1.3 and Kv1.5. However, little or no Purkinje cell staining was seen in the primates with Kv1.4 and Kv1.6, and strong stellate cell expression was noted. All staining was abolished by cognate peptide blocking. Similar distributions were seen with both sets of antibodies. We conclude that there are marked species differences in the distribution of Kv1.4 and Kv1.6 between primates and rodents. Choosing appropriate animal models for studying physiological and disease processes may prove vital for translating research outcomes into clinical applications.
Published: 2020
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50. Coexistent faecal incontinence and constipation: A cross-sectional study of 4027 adults undergoing specialist assessment

Author: Charles H. Knowles, S. Mark Scott, Paul F. Vollebregt, Phil G. Dinning, and Lukasz Wiklendt
Subjects: Pediatrics, medicine.medical_specialty, Constipation, Cross-sectional study, 01 natural sciences, Anorectal physiology, Pelvic floor dysfunction, Mixed incontinence, 03 medical and health sciences, 0302 clinical medicine, medicine, In patient, 030212 general & internal medicine, 0101 mathematics, Medical diagnosis, lcsh:R5-920, business.industry, 010102 general mathematics, Faecal incontinence, General Medicine, medicine.disease, Concomitant, Functional constipation, medicine.symptom, lcsh:Medicine (General), business, Research Paper
Abstract: Background In contrast to paediatric and geriatric populations, faecal incontinence and constipation in adults are generally considered separate entities. This may be incorrect. Methods Cross-sectional study of consecutive patients (18–80 years) referred to a tertiary unit (2004–2016) for investigation of refractory faecal incontinence and/or constipation and meeting Rome IV core criteria (applied post-hoc) for self-reported symptoms. We sought to determine how frequently both diagnoses coexisted, how frequently coexistent diagnoses were recognised by the referring clinician and to evaluate differences in clinical characteristics between patients with single or both diagnoses. Findings Study sample consisted of 4,027 patients (3,370 females [83·7%]). According to Rome IV criteria, 807 (20·0%) patients self-reported faecal incontinence in isolation, 1,569 (39·0%) patients had functional constipation in isolation, and 1,651 (41·0%) met criteria for both diagnoses (coexistent symptoms). In contrast, only 331 (8·2%) patients were referred for coexistent symptoms. Of the 1,651 patients with self-reported coexistent symptoms, only 225 (13·6%) were recognised by the referrer i.e. 86·4% were missed. Coexistent symptoms were most often missed in patients referred for faecal incontinence in isolation. In this group of 1,640 patients, 765 (46·7%) had concomitant symptoms of functional constipation. Opioid usage, comorbidities, childhood bowel problems, mixed incontinence symptoms, prolapse symptoms and structural abnormalities on defaecography were associated with reclassification. Interpretation Over 40% of adults referred for anorectal physiological investigation had coexistent diagnoses of faecal incontinence and functional constipation, based on validated criteria. This overlap is overlooked by referrers, poorly documented in current literature, and may impact management.
Published: 2020

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