Safety and Efficacy of Iltamiocel Cellular Therapy for the Treatment of Fecal Incontinence. Results of a Phase 1/2 Study.

OBJECTIVE: To examine the safety and efficacy of iltamiocel, an investigational cellular therapy of autologous muscle-derived cells, as a treatment for fecal incontinence (FI) in adults. BACKGROUND: Limited therapeutic options are available for patients with FI refractory to conservative treatments. Cell therapy using autologous muscle-derived cells represents a promising, minimally invasive approach for restoring anal sphincter function. METHODS: In this multicenter, prospective, non-randomized study, 48 participants were treated with a single iltamiocel dose of 250×10 6 cells. The primary outcome was the incidence of product or procedure-related adverse events (AEs) and serious AEs. Secondary outcomes were changes in the number of FI episodes, Cleveland Clinic Incontinence Score, Fecal Incontinence Quality of Life, and anorectal manometry at 3, 6, and 12 months compared to baseline. RESULTS: No serious AEs and only one product-related AE of inflammation at the injection site were reported. At 12 months, there was a reduction in median FI episodes (-6.0; 95% confidence interval (CI): -10.0, -1.0) and days with episodes (-4.0; 95% CI: -8.0, -1.0). A ≥50% reduction in FI episodes was observed in 53.7% of participants, and 24.4% had complete restoration of continence. Symptom severity and quality of life improved with mean Cleveland Clinic Incontinence Score reduction (-2.9; 95% CI: -3.7, -2.1), and Fecal Incontinence Quality of Life increased (2.2; 95% CI:1.4, 2.9). No significant changes were detected in anorectal manometry measurements. A history of episiotomy was significantly associated with treatment response in multivariate analysis. CONCLUSION: The administration of iltamiocel cellular therapy is safe. Iltamiocel shows promise for significantly improving fecal incontinence symptoms and quality of life.

The Clinical Impact of Obesity in Patients With Disorders of Defecation: A Cross-Sectional Study of 1,155 Patients.

INTRODUCTION: Obesity is a global epidemic. Its clinical impact on symptoms of fecal incontinence (FI) and/or constipation and underlying anorectal pathophysiology remains uncertain. METHODS: This is a cross-sectional study of consecutive patients meeting Rome IV criteria for FI and/or functional constipation, with data on body mass index (BMI), attending a tertiary center for investigation between 2017 and 2021. Clinical history, symptoms, and anorectal physiologic test results were analyzed according to BMI categories. RESULTS: A total of 1,155 patients (84% female) were included in the analysis (33.5% normal BMI; 34.8% overweight; and 31.7% obese). Obese patients had higher odds of FI to liquid stools (69.9 vs 47.8%, odds ratio [OR] 1.96 [confidence interval: 1.43-2.70]), use of containment products (54.6% vs 32.6%, OR 1.81 [1.31-2.51]), fecal urgency (74.6% vs 60.7%, OR 1.54 [1.11-2.14]), urge FI (63.4% vs 47.3%, OR 1.68 [1.23-2.29]), and vaginal digitation (18.0% vs 9.7%, OR 2.18 [1.26-3.86]). A higher proportion of obese patients had Rome criteria-based FI or coexistent FI and functional constipation (37.3%, 50.3%) compared with overweight patients (33.8%, 44.8%) and patients with normal BMI (28.9%, 41.1%). There was a positive linear association between BMI and anal resting pressure (ß 0.45, R 2 0.25, P = 0.0003), although the odds of anal hypertension were not significantly higher after Benjamini-Hochberg correction. Obese patients more often had a large clinically significant rectocele (34.4% vs 20.6%, OR 2.62 [1.51-4.55]) compared with patients with normal BMI. DISCUSSION: Obesity affects specific defecatory (mainly FI) and prolapse symptoms and pathophysiologic findings (higher anal resting pressure and significant rectocele). Prospective studies are required to determine whether obesity is a modifiable risk factor of FI and constipation.

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

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

Supported Intervention Versus Intervention Alone for Management of Fecal Incontinence in Patients With Inflammatory Bowel Disease: A Multicenter Mixed-Methods Randomized Controlled Trial.

PURPOSE: The aims of this study were to test a noninvasive self-management intervention supported by specialist nurses versus intervention alone in patients with inflammatory bowel disease (IBD) experiencing fecal incontinence and to conduct a qualitative evaluation of the trial. DESIGN: Multicenter, parallel-group, open-label, mixed-methods randomized controlled trial (RCT). SUBJECTS AND SETTING: The sample comprised patients from a preceding case-finding study who reported fecal incontinence and met study requirements; the RCT was delivered via IBD outpatient clinics in 6 hospitals (5 in major UK cities, 1 rural) between September 2015 and August 2017. Sixteen participants and 11 staff members were interviewed for qualitative evaluation. METHODS: Adults with IBD completed the study activities over a 3-month period following randomization. Each participant received either four 30-minute structured sessions with an IBD clinical nurse specialist and a self-management booklet or the booklet alone. Low retention numbers precluded statistical analysis; individual face-to-face or telephone interviews, recorded digitally and transcribed professionally, were conducted to evaluate the RCT. Transcripts were analyzed thematically using an inductive method. RESULTS: Sixty-seven participants (36%) of the targeted 186 participants were recruited. The groups comprised 32 participants (17% of targeted participants) allocated to the nurse + booklet intervention and 35 (18.8% of targeted participants) allocated to the booklet alone. Less than one-third (n = 21, 31.3%) completed the study. Given the low recruitment and high attrition, statistical analysis of quantitative data was considered futile. Participant interviews were conducted concerning study participation and 4 themes emerged that described experiences of patients and staff. These data provided insights into reasons for low recruitment and high attrition, as well as challenges of delivering resource-heavy studies in busy health service environments. CONCLUSIONS: Alternative approaches to trials of nurse-led interventions in hospital settings are needed as many interfering factors may prevent successful completion.

Double-blinded randomised placebo controlled trial of enterosgel (polymethylsiloxane polyhydrate) for the treatment of IBS with diarrhoea (IBS-D).

OBJECTIVE: Irritable 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. DESIGN: After 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. RESULTS: 440 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%, p<0.0001) abdominal pain (53.3% vs 40.2%, p=0.003), stool frequency (treatment effect -0.32 (-0.62 to -0.02)) and urgency (treatment effect -0.59 (-0.85 to -0.33)). 60% of patients reported adequate relief of symptoms after open-label treatment. Adverse event frequency was similar in both groups, with no serious events attributable to enterosgel. CONCLUSION: Enterosgel is safe and effective in IBS-D, providing an alternative to the limited current treatment options. TRIAL REGISTRATION NUMBER: ISRCTN17149988.

Decoy bypass for appetite suppression in obese adults: role of synergistic nutrient sensing receptors GPR84 and FFAR4 on colonic endocrine cells.

OBJECTIVE: Colonic enteroendocrine cells (EECs) store and release potent anorectic hormones that are key regulators of satiety. EECs express multiple nutrient sensing receptors, particularly for medium-chain fatty acids (MCFAs): GPR84 and FFAR4. Here we show a non-surgical approach with targeted colonic delivery of MCFA, which induces EEC and neuronal activation leading to anorectic effects. DESIGN: A randomised, double-blind, placebo-controlled, cross-over study was performed in obese adults given combined GPR84 and FFAR4 agonists in colonic release capsules before meals. We measured serum hormones, energy intake and appetite perception. Cell type, activation by agonists and hormone/serotonin release were determined in human colonic explants. Mouse colonic afferent nerve responses to nutrients/mediators were recorded electrophysiologically. RESULTS: Subjects receiving GPR84 and FFAR4 agonists had reduced overall calorific intake and increased postprandial levels of PYY versus placebo. Receptors including GPR84 and FFAR4 were coexpressed on human colonic EEC. Activation of GPR84 exclusively induced intracellular pERK, whereas FFAR4 selectively activated pCaMKII. Coactivation of GPR84 and FFAR4 induced both phosphoproteins, and superadditive release of GLP-1 and PYY. Nutrients and hormones convergently activated murine colonic afterent nerves via GLP-1, Y2 and 5-HT3 receptors. CONCLUSIONS: Colonic GPR84 and FFAR4 agonists reduce energy intake and increase postprandial PYY in obese adults. Human colonic EECs coexpress these receptors, which activate cells via parallel intracellular pathways and synergistically evoke hormone release. Further synergism occurs in sensory nerve responses to MCFA and EEC mediators. Thus, synergistic activation of colonic endocrine cells via nutrient receptors is an important target for metabolic regulation. TRAIL REGISTRATION NUMBER: NCT04292236.

Abnormal Perception of Urge to Defecate: An Important Pathophysiological Mechanism in Women With Chronic Constipation.

INTRODUCTION: Although the association of absent or attenuated "call to stool" with constipation is well-recognized, no studies have systematically evaluated the perception of urge to defecate in a well-defined cohort of patients with chronic constipation (CC). METHODS: A prospective study of 43 healthy adult women and 140 consecutive adult women attending a tertiary center for investigation of CC. All participants completed a 5-day viscerosensory questionnaire, and all women with CC also underwent anorectal physiologic investigations. Normal urge perception and abnormal urge perception were defined using a Naive Bayes model trained in healthy women (95% having normal urge). RESULTS: In total, 181 toilet visits in healthy women and 595 in women with CC were analyzed. Abnormal urge perception occurred in 70 (50.0%) women with CC. In this group, the urge to defecate was more often experienced as abdominal sensation (69.3% vs 41.4%; P < 0.0001), and the viscerosensory referral area was 81% larger (median pixels anterior: 1,849 vs 1,022; P < 0.0001) compared to women with CC and normal urge perception. Abnormal (vs normal) urge in women with CC was associated with more severe constipation (Cleveland Clinic constipation score: 19 vs 15 P < 0.0001), irritable bowel syndrome (45.7% vs 22.9% P < 0.0001), and a functional evacuation disorder on defecography (31.3% vs 14.3% P = 0.023). A distinct pattern of abnormal urge was found in women with CC and rectal hyposensitivity. DISCUSSION: Abnormal urge perception was observed in 50% of women with CC and was frequently described as abdominal sensation, supporting the concept that sensory dysfunction makes an important contribution to the pathophysiology of constipation.

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.

AIM: 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. METHODS: 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 I2 . RESULTS: Of 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, I2 = 96.35%) in women and 27% (95% CI 14-40, I2 = 94.12%) in men. The pooled prevalence of anal hypocontractility was 69% (95% CI 57-81; I2 = 98.17%) in women and 36% (95% CI 18-53; I2 = 96.77%) in men. Pooled prevalence of rectal hypersensitivity was 10% (95% CI 4-15; I2 = 80.09%) in women and 4% (95% CI 1-7; I2 = 51.25%) in men, whereas hyposensitivity had a pooled prevalence of 7% (95% CI 5-9; I2 = 0.00%) in women compared to 19% (95% CI 15-23; I2 = 0.00%) in men. CONCLUSIONS: The 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.

Redundancy in the International Anorectal Physiology Working Group Manometry Protocol: A Diagnostic Accuracy Study in Fecal Incontinence.

BACKGROUND: 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. AIMS: To assess the impact of protocol modification on diagnostic accuracy in patients with fecal incontinence. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Clinical Impact of Rectal Hyposensitivity: A Cross-Sectional Study of 2,876 Patients With Refractory Functional Constipation.

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.).

Systematic Characterization of Defecographic Abnormalities in a Consecutive Series of 827 Patients With Chronic Constipation.

BACKGROUND: Barium defecography can assess structural and functional abnormalities in patients with chronic constipation. OBJECTIVE: The purpose of this study was to determine the prevalence of individual and overlapping defecographic findings in this setting. DESIGN: This was a cross-sectional study. SETTINGS: The study was conducted at a university hospital tertiary GI physiology department. PATIENTS: 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. MAIN OUTCOME MEASURES: 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). RESULTS: 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 for >85% of patients. Only 136 patients (16.4%) had a normal defecography (34.3% males vs 13.9% females; p < 0.0001). 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%; p < 0.0001). Expulsion time was longer in females compared with males (110 s (60-120 s) vs 90 s (60-120 s); p = 0.049). LIMITATIONS: The study was limited by its lack of multiorgan opacification. CONCLUSIONS: 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. CARACTERIZACIN SISTEMTICA DE ANOMALAS DEFECOGRFICAS EN UNA SERIE CONSECUTIVA DE PACIENTES CON ESTREIMIENTO CRNICO: 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 representaron >85% de los pacientes.Solo 136 (16,4%) pacientes tuvieron una defecografía normal (34,3% hombres vs. 13,9% mujeres; P < 0,0001). 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%, P < 0,0001). 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.

The science behind programming algorithms for sacral neuromodulation.

AIM: Sacral neuromodulation (SNM) is a widely adopted treatment for overactive bladder, non-obstructive urinary retention and faecal incontinence. In the majority, it provides sustained clinical benefit. However, it is recognized that, even for these patients, stimulation parameters (such as amplitude, electrode configuration, frequency and pulse width) may vary at both initial device programming and at reprogramming, the latter often being required to optimize effectiveness. Although some recommendations exist for SNM programming, the scientific data to support them are understood by few clinicians. METHODS: This is a narrative review of the literature covering some of the science behind stimulating a mixed peripheral nerve and available preclinical data in the field of SNM. It covers electrode configuration, amplitude, frequency, pulse width and cycling considerations. The review is targeted at clinicians with an interest in the field and does not seek to provide exhaustive detail on basic neuroscience. RESULTS AND CONCLUSIONS: Knowledge of the science of neuromodulation provides some guiding principles for programming but these are broad. These principles are not refuted by preclinical data but specific parameters in clinical use are not strongly supported by animal data, even after the limitations of small and large animal models are considered. The review presents a shortlist of programming principles on a theoretical basis but acknowledges that current practice is as much derived from evolved experience as science.

Altered anal slow-wave pressure activity in low anterior resection syndrome: short case series in two independent specialist centres provide new mechanistic insights.

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 < 0.0001). Peaks of the mean spectrum in healthy individuals were concentrated at 16 cpm and 3-4 cpm. CONCLUSION: Over half of the male LARS patients studied had altered anal slow-wave pressure activity based on analysis of HR-ARM recordings. Further studies could investigate the relative contributions of sex, human baseline variance and neoadjuvant/surgical therapies on anal slow waves, and correlate the presence of abnormal activity with symptom severity.

Clinician Administered and Self-Report Survey Both Effective for Identifying Fecal Incontinence in Patients with Inflammatory Bowel Disease.

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.

Reprogramming Sacral Neuromodulation for Sub-Optimal Outcomes: Evidence and Recommendations for Clinical Practice.

OBJECTIVES: In 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 METHODS: A systematic literature review was performed. Collective clinical experience from an expert multidisciplinary group was used to form opinion where evidence was lacking. RESULTS: Circumstances 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. CONCLUSIONS: Reprogramming 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.

Programming Algorithms for Sacral Neuromodulation: Clinical Practice and Evidence-Recommendations for Day-to-Day Practice.

BACKGROUND: In sacral neuromodulation (SNM), stimulation programming plays a key role to achieve success of the therapy. However to date, little attention has been given to the best ways to set and optimize SNM programming during the test and chronic stimulation phases of the procedure. OBJECTIVE: Standardize and make SNM programming easier and more efficient for the several conditions for which SNM is proposed. METHODS: Systematic literature review and collective clinical experience report. RESULTS: The basic principles of SNM programming are described. It covers choice of electrode configuration, stimulation amplitude, pulse frequency and pulse widths, while use of cycling is also briefly discussed. Step-by-step practical flow charts developed by a group of 13 European experts are presented. CONCLUSIONS: Programming of SNM therapy is not complex. There are few programming settings that seem beneficial or significantly impact patient outcomes. Only four basic electrode configurations could be identified according to four different options to define the cathode. In a majority of patients, the proposed stimulation parameters will allow a satisfactory improvement for long periods of time. A regular follow-up is, however, necessary to assess and eventually optimize results, as well as to reassure patients.

Changes in neuromuscular structure and functions of human colon during ageing are region-dependent.

OBJECTIVE: To determine if human colonic neuromuscular functions decline with increasing age. DESIGN: Looking for non-specific changes in neuromuscular function, a standard burst of electrical field stimulation (EFS) was used to evoke neuronally mediated (cholinergic/nitrergic) contractions/relaxations in ex vivomuscle strips of human ascending and descending colon, aged 35-91 years (macroscopically normal tissue; 239 patients undergoing cancer resection). Then, to understand mechanisms of change, numbers and phenotype of myenteric neurons (30 306 neurons stained with different markers), densities of intramuscular nerve fibres (51 patients in total) and pathways involved in functional changes were systematically investigated (by immunohistochemistry and use of pharmacological tools) in elderly (≥70 years) and adult (35-60 years) groups. RESULTS: With increasing age, EFS was more likely to evoke muscle relaxation in ascending colon instead of contraction (linear regression: n=109, slope 0.49%±0.21%/year, 95% CI), generally uninfluenced by comorbidity or use of medications. Similar changes were absent in descending colon. In the elderly, overall numbers of myenteric and neuronal nitric oxide synthase-immunoreactive neurons and intramuscular nerve densities were unchanged in ascending and descending colon, compared with adults. In elderly ascending, not descending, colon numbers of cell bodies exhibiting choline acetyltransferase immunoreactivity increased compared with adults (5.0±0.6 vs 2.4±0.3 neurons/mm myenteric plexus, p=0.04). Cholinergically mediated contractions were smaller in elderly ascending colon compared with adults (2.1±0.4 and 4.1±1.1 g-tension/g-tissue during EFS; n=25/14; p=0.04); there were no changes in nitrergic function or in ability of the muscle to contract/relax. Similar changes were absent in descending colon. CONCLUSION: In ascending not descending colon, ageing impairs cholinergic function.

High-resolution Anorectal Manometry Measures Are More Accurate Than Conventional Measures in Detecting Anal Hypocontractility in Women With Fecal Incontinence.

BACKGROUND & AIMS: Anorectal manometry is a common test of anal tone and contractility. However, existing measures are often criticized for their poor ability to detect functional differences between individuals with presumably normal sphincter function and individuals with fecal incontinence. We investigated whether new measures, derived from high-resolution anal manometry (HR-ARM), more accurately identify incontinent women with abnormal sphincter function than measures from conventional anal manometry (C-ARM). METHODS: We performed a prospective HR-ARM study of 85 healthy female volunteers (median age 41 years; range 18-68 years) and 403 women with fecal incontinence (median age 55; range 18-91 years) from June 2013 through December 2015. We compared the diagnostic accuracy of conventional measurements of contractility (C-ARM squeeze increment) and tone (C-ARM resting pressure) (the reference standards), with HR-ARM measures (HR-ARM squeeze increment, HR-ARM contractile integral, HR-ARM resting average, HR-ARM rest integral). We also investigated associations between symptom severity and structural sphincter integrity. RESULTS: We identified anal hypocontractility in 129 women with fecal incontinence using the C-ARM squeeze increment (32% sensitivity; likelihood ratio, 6.4), in 189 women using the HR-ARM squeeze increment (47% sensitivity; likelihood ratio, 9.4), and in 220 women using the HR-ARM contractile integral (55% sensitivity; likelihood ratio, 11.0). In contrast, HR-ARM measures of anal tone did not particularly outperform conventional measures (31% sensitivity for HR-ARM resting average vs 28% for C-ARM resting pressure). Ninety-eight of the 206 patients with fecal incontinence who were classified as having normal anal function, based on C-ARM measures, were reclassified as having abnormal function based on HR-ARM measures. CONCLUSION: In a prospective study of healthy women and women with fecal incontinence, we demonstrated that the newly developed HR-ARM contractile integral increased the sensitivity of detection of anal hypocontractility, from 32% to 55%, compared with conventional measurements of squeeze.

Ex vivo study of human visceral nociceptors.

OBJECTIVE: The development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible methodology to study visceral nociception in human tissue that could aid future target identification and drug evaluation. DESIGN: Electrophysiological (single unit) responses of visceral afferents to mechanical (von Frey hair (VFH) and stretch) and chemical (bradykinin and ATP) stimuli were examined. Thus, serosal afferents (putative nociceptors) were used to investigate the effect of tegaserod, and transient receptor potential channel, vanilloid 4 (TRPV4) modulation on mechanical responses. RESULTS: Two distinct afferent fibre populations, serosal (n=23) and muscular (n=21), were distinguished based on their differences in sensitivity to VFH probing and tissue stretch. Serosal units displayed sensitivity to key algesic mediators, bradykinin (6/14 units tested) and ATP (4/10), consistent with a role as polymodal nociceptors, while muscular afferents are largely insensitive to bradykinin (0/11) and ATP (1/10). Serosal nociceptor mechanosensitivity was attenuated by tegaserod (-20.8±6.9%, n=6, p<0.05), a treatment for IBS, or application of HC067047 (-34.9±10.0%, n=7, p<0.05), a TRPV4 antagonist, highlighting the utility of the preparation to examine the mechanistic action of existing drugs or novel analgesics. Repeated application of bradykinin or ATP produced consistent afferent responses following desensitisation to the first application, demonstrating their utility as test stimuli to evaluate analgesic activity. CONCLUSIONS: Functionally distinct subpopulations of human visceral afferents can be demonstrated and could provide a platform technology to further study nociception in human tissue.

Paediatric Intestinal Pseudo-obstruction: Evidence and Consensus-based Recommendations From an ESPGHAN-Led Expert Group.

OBJECTIVES: Chronic intestinal pseudo-obstructive (CIPO) conditions are considered the most severe disorders of gut motility. They continue to present significant challenges in clinical care despite considerable recent progress in our understanding of pathophysiology, resulting in unacceptable levels of morbidity and mortality. Major contributors to the disappointing lack of progress in paediatric CIPO include a dearth of clarity and uniformity across all aspects of clinical care from definition and diagnosis to management. In order to assist medical care providers in identifying, evaluating, and managing children with CIPO, experts in this condition within the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition as well as selected external experts, were charged with the task of developing a uniform document of evidence- and consensus-based recommendations. METHODS: Ten clinically relevant questions addressing terminology, diagnostic, therapeutic, and prognostic topics were formulated. A systematic literature search was performed from inception to June 2017 using a number of established electronic databases as well as repositories. The approach of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was applied to evaluate outcome measures for the research questions. Levels of evidence and quality of evidence were assessed using the classification system of the Oxford Centre for Evidence-Based Medicine (diagnosis) and the GRADE system (treatment). Each of the recommendations were discussed, finalized, and voted upon using the nominal voting technique to obtain consensus. RESULTS: This evidence- and consensus-based position paper provides recommendations specifically for chronic intestinal pseudo-obstruction in infants and children. It proposes these be termed paediatric intestinal pseudo-obstructive (PIPO) disorders to distinguish them from adult onset CIPO. The manuscript provides guidance on the diagnosis, evaluation, and treatment of children with PIPO in an effort to standardise the quality of clinical care and improve short- and long-term outcomes. Key recommendations include the development of specific diagnostic criteria for PIPO, red flags to alert clinicians to the diagnosis and guidance on the use of available investigative modalities. The group advocates early collaboration with expert centres where structured diagnosis and management is guided by a multi-disciplinary team, and include targeted nutritional, medical, and surgical interventions as well as transition to adult services. CONCLUSIONS: This document is intended to be used in daily practice from the time of first presentation and definitive diagnosis PIPO through to the complex management and treatment interventions such as intestinal transplantation. Significant challenges remain to be addressed through collaborative clinical and research interactions.