Development of a Simple, Point-of-Care Device to Test Anorectal Function in Patients with Constipation: Randomized Clinical Trial.

Functional constipation (FC) is one of the most frequently encountered gastrointestinal conditions in practice.1 Practice guidelines universally recommend that patients with typical constipation symptoms and no alarm features be treated empirically with dietary/lifestyle interventions and laxative therapy.2,3 Unfortunately, by the time a patient reaches a gastroenterologist, these treatments frequently have already been tried. Anorectal function testing (anorectal manometry [ARM] and balloon expulsion test [BET]) is the next best step in management guidelines in this all-too-common scenario, because treatment can then be targeted toward pelvic floor dysfunction or colon transit abnormalities. Unfortunately, more than 95% of patients continue to take only over-the-counter laxatives and receive empirical dietary advice, whereas fewer than 2% undergo physiologic evaluation to ascertain the cause of their symptoms.4 Indeed, more than 90% of patients desire more effective treatment options. These observations call into question the wisdom of a management strategy that fails to recognize the intrinsic diversity of the constipation universe and reinforces the misguided "one size fits all" empirical treatment strategy.

Can a Defecation Posture Modifying Device Correct an Abnormal Balloon Expulsion Test in Chronically Constipated Patients?

Evacuation disorders are common among chronically constipated (CC) patients who fail to respond to laxatives and are typically diagnosed by anorectal manometry (ARM) and/or balloon expulsion testing (BET).1,2 Recently, there has been emerging interest in the use of defecation posture-modifying devices (DPMDs) to improve constipation symptoms, presumably by replicating the physiologic benefits of squatting on stool evacuation, such as straightening of the anorectal angle and relaxing the pelvic floor. However, the ability of DPMDs to normalize anorectal function in adult patients with CC has not been studied.

An Office-Based, Point-of-Care Test Predicts Treatment Outcomes With Community-Based Pelvic Floor Physical Therapy in Patients With Chronic Constipation.

BACKGROUND & AIMS: Rectal evacuation disorders are common among constipated patients. We aimed to evaluate the accuracy of an investigational point-of-care test (rectal expulsion device [RED]) to predict outcomes with community-based pelvic floor physical therapy. METHODS: We enrolled patients meeting Rome IV criteria for functional constipation failing fiber/laxatives for more than 2 weeks. RED was inserted and self-inflated, and then time-to-expel was measured in a left lateral position. All patients underwent empiric community-based pelvic floor physical therapy in routine care with outcomes measured at 12 weeks. The primary end point was global clinical response (Patient Assessment of Constipation Symptoms score reduction, >0.75 vs baseline). Secondary end points included improvement in health-related quality-of-life (Patient Assessment of Constipation Quality of Life score reduction, >1.0) and complete spontaneous bowel movement frequency (Food and Drug Administration complete spontaneous bowel movement responder definition). RESULTS: Thirty-nine patients enrolled in a feasibility phase to develop the use-case protocol. Sixty patients enrolled in a blinded validation phase; 52 patients (mean, 46.9 y; 94.2% women) were included in the intention-to-treat analysis. In the left lateral position, RED predicted global clinical response (generalized area under the curve [gAUC], 0.67; 95% CI, 0.58-0.76]), health-related quality-of-life response (gAUC, 0.67; 95% CI, 0.58-0.77; P < .001), and complete spontaneous bowel movement response (gAUC, 0.63; 95% CI, 0.57-0.71; P < .001). As a screening test, a normal RED effectively rules out evacuation disorders (expected clinical response, 8.9%; P = .042). Abnormal RED in the left lateral position (defined as expulsion within 5 seconds or >120 seconds) predicted 48.9% clinical response to physical therapy. A seated maneuver enhanced the likelihood of clinical response (71.1% response with seated RED retained >13 seconds) but likely is unnecessary in most settings. CONCLUSIONS: RED offers an opportunity to disrupt the paradigm by offering a personalized approach to managing chronic constipation in the community (Clinicaltrials.gov: NCT04159350).

Utility of Anorectal Testing to Predict Outcomes With Pelvic Floor Physical Therapy in Chronic Constipation: Pragmatic Trial.

BACKGROUND & AIMS: We performed a clinical trial that aimed to inform the clinical utility of anorectal manometry (ARM) and balloon expulsion time (BET) as up-front tests to predict outcomes with community-based pelvic floor physical therapy as the next best step to address chronic constipation after failing an empiric trial of soluble fiber supplementation or osmotic laxatives. METHODS: We enrolled 60 treatment-naïve patients with Rome IV functional constipation failing 2 weeks of soluble fiber supplementation or osmotic laxatives. All patients underwent ARM/BET (London protocol) followed by community-based pelvic floor physical therapy. Outcomes were assessed at baseline and 12 weeks. The primary end point was clinical response (Patient Assessment of Constipation-Symptoms instrument). RESULTS: Fifty-three patients completed pelvic rehabilitation and the post-treatment questionnaire. Contemporary frameworks define dyssynergia on balloon expulsion time and dyssynergic patterns (ARM), but these parameters did not inform clinical outcomes (area under the curve [AUC], <0.6). Squeeze pressure (>192.5 mm Hg on at least 1 of 3 attempts; sensitivity, 47.6%; specificity, 83.9%) and limited squeeze duration (inability to sustain 50% of squeeze pressure for >20 seconds; sensitivity, 71.4%; specificity, 58.1%) were the strongest predictors of clinical outcomes. Combining BET with squeeze duration (BET greater than 6.5 seconds and limited squeeze duration) improved predictive accuracy (AUC, 0.75; 95% CI, 0.59-0.90). BET poorly predicted outcomes as a single test (AUC, 0.54; 95% CI, 0.38-0.69). CONCLUSIONS: Using ARM to evaluate squeeze profiles, rather than dyssynergia, appears useful to screen patients with chronic constipation for up-front pelvic floor physical therapy based on likelihood of response. BET appears noninformative as a single screening test (ClinicalTrials.gov: NCT04159350).

Optimizing the Utility of Anorectal Manometry for Diagnosis and Therapy: A Roundtable Review and Recommendations.

BACKGROUND & AIMS: Anorectal manometry (ARM) is a comprehensive diagnostic tool for evaluating patients with constipation, fecal incontinence, or anorectal pain; however, it is not widely utilized for reasons that remain unclear. The aim of this roundtable discussion was to critically examine the current clinical practices of ARM and biofeedback therapy by physicians and surgeons in both academic and community settings. METHODS: Leaders in medical and surgical gastroenterology and physical therapy with interest in anorectal disorders were surveyed regarding practice patterns and utilization of these technologies. Subsequently, a roundtable was held to discuss survey results, explore current diagnostic and therapeutic challenges with these technologies, review the literature, and generate consensus-based recommendations. RESULTS: ARM identifies key pathophysiological abnormalities such as dyssynergic defecation, anal sphincter weakness, or rectal sensory dysfunction, and is a critical component of biofeedback therapy, an evidence-based treatment for patients with dyssynergic defecation and fecal incontinence. Additionally, ARM has the potential to enhance health-related quality of life and reduce healthcare costs. However, it has significant barriers that include a lack of education and training of healthcare providers regarding the utility and availability of ARM and biofeedback procedures, as well as challenges with condition-specific testing protocols and interpretation. Additional barriers include understanding when to perform, where to refer, and how to use these technologies, and confusion over billing practices. CONCLUSIONS: Overcoming these challenges with appropriate education, training, collaborative research, and evidence-based guidelines for ARM testing and biofeedback therapy could significantly enhance patient care of anorectal disorders.

Age- and Gender-Based Differences in Anorectal Function, Gastrointestinal Symptoms, and Constipation-Specific Quality of Life in Patients with Chronic Constipation.

BACKGROUND: The effect of age and gender differences on anorectal function, symptoms severity, and quality of life (QoL) in patients with chronic constipation (CC) is not well studied. This study examines the impact of age and gender on anorectal function testing (AFT) characteristics, symptoms burden, and QoL in patients with CC. METHODS: This is a retrospective analysis of prospectively collected data from 2550 adults with CC who completed AFT. Collected data include demographics, sphincter response to simulated defecation during anorectal manometry (ARM), balloon expulsion testing (BET), and validated surveys assessing constipation symptoms and QoL. DD was defined as both the inability to relax the anal sphincter during simulated defecation and an abnormal BET. RESULTS: 2550 subjects were included in the analysis (mean age = 48.6 years). Most patients were female (81.6%) and Caucasian (82%). 73% were < 60 years old (mean = 41) vs. 27% ≥ 60 years old (mean = 69). The prevalence of impaired anal sphincter relaxation on ARM, abnormal BET, and DD in patients with CC was 48%, 42.1%, and 22.9%, respectively. Patients who were older and male were significantly more frequently diagnosed with DD and more frequently had impaired anal sphincter relaxation on ARM, compared to patients who were younger and female (p < 0.05). Conversely, CC patients who were younger and female reported greater constipation symptoms severity and more impaired QoL (p ≤ 0.004). CONCLUSION: Among patients with CC referred for anorectal function testing, men and those older than 60 are more likely to have dyssynergic defecation, but women and patients younger than 60 experience worse constipation symptoms and QoL.

Video-Based Deep Learning to Detect Dyssynergic Defecation with 3D High-Definition Anorectal Manometry.

BACKGROUND: We developed a deep learning algorithm to evaluate defecatory patterns to identify dyssynergic defecation using 3-dimensional high definition anal manometry (3D-HDAM). AIMS: We developed a 3D-HDAM deep learning algorithm to evaluate for dyssynergia. METHODS: Spatial-temporal data were extracted from consecutive 3D-HDAM studies performed between 2018 and 2020 at Dartmouth-Hitchcock Health. The technical procedure and gold standard definition of dyssynergia were based on the London consensus, adapted to the needs of 3D-HDAM technology. Three machine learning models were generated: (1) traditional machine learning informed by conventional anorectal function metrics, (2) deep learning, and (3) a hybrid approach. Diagnostic accuracy was evaluated using bootstrap sampling to calculate area-under-the-curve (AUC). To evaluate overfitting, models were validated by adding 502 simulated defecation maneuvers with diagnostic ambiguity. RESULTS: 302 3D-HDAM studies representing 1208 simulated defecation maneuvers were included (average age 55.2 years; 80.5% women). The deep learning model had comparable diagnostic accuracy [AUC 0.91 (95% confidence interval 0.89-0.93)] to traditional [AUC 0.93(0.92-0.95)] and hybrid [AUC 0.96(0.94-0.97)] predictive models in training cohorts. However, the deep learning model handled ambiguous tests more cautiously than other models; the deep learning model was more likely to designate an ambiguous test as inconclusive [odds ratio 4.21(2.78-6.38)] versus traditional/hybrid approaches. CONCLUSIONS: Deep learning is capable of considering complex spatial-temporal information on 3D-HDAM technology. Future studies are needed to evaluate the clinical context of these preliminary findings.

Utilization of Dietitians in the Management of Irritable Bowel Syndrome by Members of the American College of Gastroenterology.

INTRODUCTION: The aim of this study was to identify benefits and barriers to using a gastroenterology (GI) dietitian for irritable bowel syndrome (IBS) care. METHODS: A 25-question survey was electronically distributed to the members of the American College of Gastroenterology. Information pertaining to demographics, barriers, and values to using a GI dietitian for IBS patient care was collected. RESULTS: Two hundred seventy-nine survey responses were collected. Although 56% of the GI providers feel they are trained to provide nutrition education, almost half (46%) sometimes, rarely, or never provided information to aid menu planning, label reading, or grocery shopping, and 77% spent ≤10 minutes for nutrition counseling. Of those with access to a local dietitian, 91% strongly agreed or agreed that having access to a GI dietitian would help them manage their IBS patient care more effectively, but 42% lack access to a local GI dietitian. DISCUSSION: Our survey identified gaps in nutrition-based interventions for IBS care.

Organizing and Developing a GI Motility Lab in Community Practice: Challenges and Rewards.

PURPOSE OF REVIEW: Neurogastroenterology and motility is a rapidly evolving subspecialty that encompasses over 33% of gastroenterological disorders, and up to 50% of referrals to gastroenterology practice. It includes common problems such as dysphagia, gastroesophageal reflux disease, irritable bowel syndrome, chronic constipation, gastroparesis, functional dyspepsia, gas/bloating, small intestinal bacterial overgrowth, food intolerance and fecal incontinence Standard diagnostic tests such as endoscopy or imaging are normal in these conditions. To define the underlying mechanism(s)/etiology of these disorders, diagnostic motility tests are often required. These are best performed by well-trained personnel in a dedicated motility laboratory. Our purpose is to provide an up-to-date overview on how to organize and develop a motility laboratory based on our collective experiences in setting up such facilities in academia and community practice. RECENT FINDINGS: A lack of knowledge, training and facilities for providing diagnostic motility tests has led to suboptimal patient care. A motility laboratory is the hub for diagnostic and therapeutic motility procedures. Common procedures include esophageal function tests such as esophageal manometry and pH monitoring, anorectal function tests suchlike anorectal manometry, neurophysiology and balloon expulsion, dysbiosis and food intolerance tests such as hydrogen/methane breath tests, and gastrointestinal transit assessment. These tests provide an accurate diagnosis and guide clinical management including use of medications, biofeedback therapy, neuromodulation, behavioral therapies, evidence-based dietary interventions and endoscopic or surgical procedures. Further, there have been recent developments in billing and coding of motility procedures and training requirements that are not well known. This review provides a stepwise approach on how to set-up a motility laboratory in the community or academic practice and includes the rationale, infrastructure, staffing needs, commonly performed motility tests and their clinical utility, billing and coding strategies, training needs and economic considerations for setting up this service.

Phenotyping patients with borderline elevated esophageal acid exposure.

Acid exposure time (AET) <4% on ambulatory reflux monitoring definitively rules out pathologic gastroesophageal acid reflux, while AET >6% indicates pathologic reflux per the Lyon Consensus, leaving AET of 4-6% as borderline. We aimed to elucidate the borderline AET population and identify metrics that could help differentiate this group. A total of 50 subjects in each group, AET <4, 4-6, and >6% on pH-impedance monitoring between 2015 and 2019, were retrospectively reviewed. In addition to demographic and clinical information, the extracted data included mean nocturnal baseline impedance (MNBI) on reflux study and high-resolution manometry (HRM) parameters and diagnosis. After excluding patients with prior foregut surgery, major esophageal motility disorder, or unreliable impedance testing, a total of 89 subjects were included in the analysis (25 with normal AET < 4%, 38 with borderline 4-6%, 26 with abnormal >6%). MNBI in borderline AET patients was significantly lower compared to normal AET (1607.7 vs. 2524.0 ohms, P < 0.01), and higher than abnormal AET (951.5 ohms, P < 0.01). Borderline subjects had a greater frequency of ineffective esophageal motility (IEM) diagnosis per Chicago classification v3.0 (42.1 vs. 8.0%, P = 0.01), but did not demonstrate any differences compared to abnormal subjects (34.6%, P = 0.56). Patients with borderline AET had an average MNBI that was in between normal AET and abnormal AET. Borderline AET patients also commonly demonstrate IEM on HRM, similar to those with abnormal AET. Our findings can be potentially useful in assigning higher clinical significance for patients found to have borderline AET with concomitant low MNBI and IEM on manometry.

Diffusion of an innovation: growth in video capsule endoscopy in the U.S. Medicare population from 2003 to 2019.

BACKGROUND: Video capsule endoscopy (VCE), approved by the U.S. Food and Drug Administration (FDA) in 2001, represented a disruptive technology that transformed evaluation of the small intestine. Adoption of this technology over time and current use within the U.S. clinical population has not been well described. METHODS: To assess the growth of capsule endoscopy within the U.S. Medicare provider population (absolute growth and on a population-adjusted basis), characterize the providers performing VCE, and describe potential regional differences in use. Medicare summary data from 2003 to 2019 were used to retrospectively analyze capsule endoscopy use in a multiple cross-sectional design. In addition, detailed provider summary files were used from 2012 to 2018 to characterize provider demographics. RESULTS: VCE use grew rapidly from 2003 to 2008 followed by a plateau from 2008 to 2019. There was significant variation in use of VCE between states, with up to 10-fold variation between states (14.6 to 156.1 per 100,000 enrollees in 2018). During this time, the adjusted VCE use on a population-adjusted basis declined, reflecting saturation of growth. CONCLUSIONS: Growth of VCE use over time follows an S-shaped diffusion of innovation curve demonstrating a successful diffusion of innovation within gastroenterology. The lack of additional growth since 2008 suggests that current levels of use are well matched to overall population need within the constraints of reimbursement. Future studies should examine whether this lack of growth has implications for access and healthcare inequities.

How the North American Consensus Protocol Affects the Performance of Glucose Breath Testing for Bacterial Overgrowth Versus a Traditional Method.

INTRODUCTION: The North American Consensus guidelines for glucose breath testing (GBT) for small intestinal bacterial overgrowth (SIBO) incorporated changes in glucose dosing and diagnostic cutoffs. We compared GBT positivity based on hydrogen and methane excretion and quantified symptoms during performance of the North American vs older modified Rome Consensus protocols. METHODS: GBT was performed using the North American protocol (75 g glucose, cutoffs >20 parts per million [ppm] hydrogen increase after glucose and >10 ppm methane anytime) in 3,102 patients vs modified Rome protocol (50 g glucose, >12 ppm hydrogen and methane increases after glucose) in 3,193 patients with suspected SIBO. RESULTS: Positive GBT were more common with the North American vs modified Rome protocol (39.5% vs 29.7%, P < 0.001). Overall percentages with GBT positivity using methane criteria were greater and hydrogen criteria lower with the North American protocol (P < 0.001). Peak methane levels were higher for the North American protocol (P < 0.001). Times to peak hydrogen and methane production were not different between protocols. With the North American protocol, gastrointestinal and extraintestinal symptoms were more prevalent after glucose with both positive and negative GBT (P < 0.04) and greater numbers of symptoms (P < 0.001) were reported. DISCUSSION: GBT performed using the North American Consensus protocol was more often positive for SIBO vs the modified Rome protocol because of more prevalent positive methane excretion. Symptoms during testing were greater with the North American protocol. Implications of these observations on determining breath test positivity and antibiotic decisions for SIBO await future prospective testing.

Provider Variability in the Management Patterns of Increased Nonacid Reflux.

INTRODUCTION: Increased nonacid reflux is diagnosed in a subgroup of patients with gastroesophageal reflux disease who often present with reflux symptoms refractory to proton-pump inhibitor therapy. Despite the prevalence of this condition, the management approach for patients with increased nonacid reflux can often be varied and unclear. AIMS: Our primary aim was to investigate physician management patterns for patients who had received a diagnosis of increased nonacid reflux on impedance-pH studies. METHODS: Reflux studies in patients with increased nonacid reflux per Lyon Consensus criteria and management approaches were retrospectively reviewed. Reflux symptom survey, manometry findings, reflux symptom association (RSA) on reflux testing, immediate posttesting management information, and managing provider information were assessed. RESULTS: A total of 43 subjects in total were analyzed. Management plan after a diagnosis of increased nonacid reflux was decided by a gastroenterologist in over 95% of cases and varied greatly with no changes being the most common. Even among subjects with + RSA on reflux monitoring, no change in management was the most common action, although this occurred much less frequently compared to subjects with - RSA (28.6% vs. 78.6%, p < 0.01). When change in therapy occurred, medical treatment with baclofen was the most common choice (21.4%). Other management changes included medications for visceral hypersensitivity and antireflux surgery, although these changes occurred rarely. CONCLUSIONS: Abnormally increased nonacid reflux is frequently encountered on impedance-pH studies; however, management decisions vary significantly among gastroenterologists. When treatment change is implemented, they are variable and can include lifestyle modifications, medication trials, or antireflux surgery. Future development of standardized management algorithms for increased nonacid reflux is needed.

American Neurogastroenterology and Motility Society Task Force Recommendations for Resumption of Motility Laboratory Operations During the COVID-19 Pandemic.

The American Neurogastroenterology and Motility Society Task Force recommends that gastrointestinal motility procedures should be performed in motility laboratories adhering to the strict recommendations and personal protective equipment (PPE) measures to protect patients, ancillary staff, and motility allied health professionals. When available and within constraints of institutional guidelines, it is preferable for patients scheduled for motility procedures to complete a coronavirus disease 2019 (COVID-19) test within 48 hours before their procedure, similar to the recommendations before endoscopy made by gastroenterology societies. COVID-19 test results must be documented before performing procedures. If procedures are to be performed without a COVID-19 test, full PPE use is recommended, along with all social distancing and infection control measures. Because patients with suspected motility disorders may require multiple procedures, sequential scheduling of procedures should be considered to minimize need for repeat COVID-19 testing. The strategies for and timing of procedure(s) should be adapted, taking into consideration local institutional standards, with the provision for screening without testing in low prevalence areas. If tested positive for COVID-19, subsequent negative testing may be required before scheduling a motility procedure (timing is variable). Specific recommendations for each motility procedure including triaging, indications, PPE use, and alternatives to motility procedures are detailed in the document. These recommendations may evolve as understanding of virus transmission and prevalence of COVID-19 infection in the community changes over the upcoming months.

Small Intestinal Bacterial Overgrowth Is Common in Chronic Pancreatitis and Associates With Diabetes, Chronic Pancreatitis Severity, Low Zinc Levels, and Opiate Use.

OBJECTIVES: Small intestinal bacterial overgrowth (SIBO) is often present in patients with chronic pancreatitis (CP) with persistent steatorrhea, despite pancreatic enzyme replacement therapy. Overall prevalence of SIBO, diagnosed by glucose breath test (GBT), varies between 0% and 40% but 0%-21% in those without upper gastrointestinal (GI) surgery. We investigated the prevalence and nonsurgical independent predictors of SIBO in CP without upper GI surgery. METHODS: Two hundred seventy-three patients ≥18 years old had a presumptive diagnosis of CP and a GBT between 1989 and 2017. We defined CP by Mayo score (0-16) ≥4 and a positive GBT for SIBO by Rome consensus criteria and retrospectively collected data for 5 a priori variables (age, opiates, alcohol use, diabetes mellitus (DM), gastroparesis) and 41 investigational variables (demographics, GI symptoms, comorbidities, CP etiologies and cofactors, CP symptom duration, Mayo score and nondiabetes components, and biochemical variables). RESULTS: Ninety-eight of 273 patients had definite CP and 40.8% had SIBO. Five of 46 variables predicted SIBO: opiates, P = 0.005; DM, P = 0.04; total Mayo score, P < 0.05; zinc, P = 0.005; and albumin, P < 0.05). Multivariable analysis of 3 noncorrelated variables identified zinc level (odds ratio = 0.0001; P = 0.03) as the sole independent predictor of SIBO (model C-statistic = 0.89; P < 0.001). DISCUSSION: SIBO, diagnosed by GBT, occurs in 40.8% of patients with CP without upper GI surgery. In patients with CP, markers of more severe CP (low zinc level, DM and increased Mayo score) and opiate use should raise clinical suspicion for SIBO, particularly in patients with persistent steatorrhea or weight loss despite pancreatic enzyme replacement therapy.

High-Resolution Manometry Diagnosis of Ineffective Esophageal Motility Is Associated with Higher Reflux Burden.

INTRODUCTION: Ineffective esophageal motility (IEM) is the most commonly diagnosed abnormality on high-resolution manometry (HRM). However, the clinical significance of IEM and associated reflux burden remains unclear. AIM: Our primary aim was to compare reflux patterns between IEM versus normal motility on HRM. METHODS: HRM and reflux studies in patients with IEM and normal motility were retrospectively reviewed. Esophageal pressure topography parameters, reflux variables, and patient-reported outcome questionnaires were explored. RESULTS: A total of 239 patients with IEM were explored. Of these, 146 underwent reflux monitoring. Additionally, 100 patients with normal HRM all of whom had undergone reflux monitoring were included. IEM patients were more likely to have an abnormal number of reflux events compared to normal (22.7% vs. 9.0%, p < 0.01). Including only off-proton pump inhibitor (PPI) testing, IEM patients had higher mean total acid exposure time (AET) and total reflux events compared to normal motility (p = 0.02). Within IEM patients, higher AET modestly correlated with increased percentage of impaired swallows. Increased reflux events modestly correlated with higher impaired swallows and decreased lower esophageal sphincter (LES) resting pressure. Reflux burden increased with higher esophagogastric junction (EGJ) subtype, driven mostly by subtype III, although there was no difference in the distribution of EGJ subtypes between the IEM and normal HRM cohorts. CONCLUSIONS: Patients with HRM diagnosis of IEM may be more prone to acid reflux while off-PPI and non-acid reflux while on-PPI. Reflux burden appears to be worse in IEM patients who have lower resting LES pressure, higher EGJ subtype, or higher percentage of impaired swallows.

Examining Balloon Expulsion Testing as an Office-Based, Screening Test for Dyssynergic Defecation: A Systematic Review and Meta-Analysis.

OBJECTIVES: Balloon expulsion testing (BET) is recommended to evaluate for dyssynergic defecation in patients with chronic constipation (CC). However, it remains poorly standardized and is limited to specialized centers. Our goal was to assess the clinical utility of balloon expulsion as an initial test for dyssynergic defecation and to determine appropriate testing parameters. METHODS: We performed a literature search to identify cohort studies of unselected subjects with CC and case-control studies of subjects with/without dyssynergic defecation. We defined dyssynergic defecation by constipation symptoms and a positive reference test (anorectal manometry [ARM], defecography, or electromyography [EMG]). We performed a meta-analysis using a bivariate mixed-effects regression model to assess summary sensitivity, specificity, and area under the curve (AUC) with 95% confidence intervals (CI). We conducted a meta-regression to investigate individual test parameters and demographic variables. RESULTS: We identified 15 eligible studies comprising 2090 individual assessments of BET. Among cohort studies, the AUC was 0.80 (95% CI: 0.61-0.91) with 70% sensitivity (95% CI: 52-83%) and 77% specificity (95% CI: 70-82%). In pooling cohort and case-control studies, the AUC was 0.84 (95% CI: 0.68-0.93) with 70% sensitivity (95% CI: 53-82%) and 81% specificity (95% CI: 75-86%). Subject positioning (seated vs. left lateral decubitus) did not significantly affect test performance in cohort (p = 0.82) or case-control (p = 0.43) analysis. Most studies evaluated 50-60 mL water insufflation. Test performance was not significantly affected by varying the maximum allowed expulsion time between 1 to 5 min. Age and gender likely accounted for significant study heterogeneity between studies. Choice of reference test, continent of study, and year of study did not significantly affect test performance. DISCUSSION: We report an optimized BET protocol. The performance characteristics of BET could support its use as a point of service test to screen for dyssynergic defecation in chronically constipated subjects.

Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans-Part 1: Fasted State Conditions.

The goal of this project was to explore and to statistically evaluate the responsible gastrointestinal (GI) factors that are significant factors in explaining the systemic exposure of ibuprofen, between and within human subjects. In a previous study, we determined the solution and total concentrations of ibuprofen as a function of time in aspirated GI fluids, after oral administration of an 800 mg IR tablet (reference standard) of ibuprofen to 20 healthy volunteers in fasted state conditions. In addition, we determined luminal pH and motility pressure recordings that were simultaneously monitored along the GI tract. Blood samples were taken to determine ibuprofen plasma levels. In this work, an in-depth statistical and pharmacokinetic analysis was performed to explain which underlying GI variables are determining the systemic concentrations of ibuprofen between (inter-) and within (intra-) subjects. In addition, the obtained plasma profiles were deconvoluted to link the fraction absorbed with the fraction dissolved. Multiple linear regressions were performed to explain and quantitatively express the impact of underlying GI physiology on systemic exposure of the drug (in terms of plasma Cmax/AUC and plasma Tmax). The exploratory analysis of the correlation between plasma Cmax/AUC and the time to the first phase III contractions postdose (TMMC-III) explains ∼40% of the variability in plasma Cmax for all fasted state subjects. We have experimentally shown that the in vivo intestinal dissolution of ibuprofen is dependent upon physiological variables like, in this case, pH and postdose phase III contractions. For the first time, this work presents a thorough statistical analysis explaining how the GI behavior of an ionized drug can explain the systemic exposure of the drug based on the individual profiles of participating subjects. This creates a scientifically based and rational framework that emphasizes the importance of including pH and motility in a predictive in vivo dissolution methodology to forecast the in vivo performance of a drug product. Moreover, as no extensive first-pass metabolism is considered for ibuprofen, this study demonstrates how intraluminal drug behavior is reflecting the systemic exposure of a drug.

Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans-Part 2: Fed State.

Exploring the intraluminal behavior of an oral drug product in the human gastrointestinal (GI) tract remains challenging. Many in vivo techniques are available to investigate the impact of GI physiology on oral drug behavior in fasting state conditions. However, little is known about the intraluminal behavior of a drug in postprandial conditions. In a previous report, we described the mean solution and total concentrations of ibuprofen after oral administration of an immediate-release (IR) tablet in fed state conditions. In parallel, blood samples were taken to assess systemic concentrations. The purpose of this work was to statistically evaluate the impact of GI physiology (e.g., pH, contractile events) within and between individuals (intra and intersubject variability) for a total of 17 healthy subjects. In addition, a pharmacokinetic (PK) analysis was performed by noncompartmental analysis, and PK parameters were correlated with underlying physiological factors (pH, time to phase III contractions postdose) and study parameters (e.g., ingested amount of calories, coadministered water). Moreover, individual plasma profiles were deconvoluted to assess the fraction absorbed as a function of time, demonstrating the link between intraluminal and systemic behavior of the drug. The results demonstrated that the in vivo dissolution of ibuprofen depends on the present gastric pH and motility events at the time of administration. Both intraluminal factors were responsible for explaining 63% of plasma Cmax variability among all individuals. For the first time, an in-depth analysis was performed on a large data set derived from an aspiration/motility study, quantifying the impact of physiology on systemic behavior of an orally administered drug product in fed state conditions. The data obtained from this study will help us to develop an in vitro biorelevant dissolution approach and optimize in silico tools in order to predict the in vivo performance of orally administered drug products, especially in fed state conditions.

Family history in colonoscopy patients: feasibility and performance of electronic and paper-based surveys for colorectal cancer risk assessment in the outpatient setting.

BACKGROUND AND AIMS: Family history is crucial in stratifying patients' risk for colorectal cancer (CRC). Previous risk assessment tools developed for use in clinic or endoscopy settings have demonstrated suboptimal specificity for identifying patients with hereditary cancer syndromes. Our aim was to test the feasibility and performance of 2 family history surveys (paper and electronic) in individuals presenting for outpatient colonoscopy. METHODS: Patients presenting for outpatient colonoscopy at a tertiary care center were asked to complete a 5-question paper risk assessment survey (short paper survey) either alone or in conjunction with a second, comprehensive electronic family risk assessment survey (comprehensive tablet survey). Each subject's survey results, along with the electronic medical record, were reviewed, and 10 high-risk criteria and PREMM1,2,6 model scores (a predictive model for carrying a Lynch syndrome-associated gene mutation) were used to identify patients warranting genetic evaluation for suspected hereditary cancer syndromes. RESULTS: Six hundred patients completed the short paper survey (cohort 1), with an additional 100 patients completing both the short paper and comprehensive tablet survey (cohort 2). Using 10 high-risk criteria and/or a PREMM1,2,6 score ≥5%, we identified 10% and 9% of patients as high risk for CRC in cohorts 1 and 2, respectively. Of the 69 high-risk subjects, 23 (33%) underwent genetic evaluations and 7 (10%) carried germline mutations associated with cancer predisposition. Both patients and endoscopists reported the tools were user-friendly and helpful for CRC risk stratification. CONCLUSIONS: Systematic assessment of family history in colonoscopy patients is feasible and can help endoscopists identify high-risk patients who would benefit from genetic evaluation.