Bharucha, Adil E.

The Institute of Medicine and US Food and Drug Administration (FDA) recognize that activating clinical trials in the United States is lengthy and inefficient. Downstream consequences include increased expense, suboptimal accrual, move of clinical trials overseas, and delayed availability of treatments for patients. An in‐tandem processing initiative is here highlighted that transformed the activation of clinical trials (TACT), reduced the activation time by 70%, and offers a paradigm for enhanced translational readiness.

AbstractBackgroundMost measures of fecal incontinence (FI) severity assess the frequency of solid and liquid FI, but may incorporate other features. We compared two scales—the Fecal Incontinence Severity Score (FISS) and Fecal Incontinence Severity Index (FISI)—to determine which questionnaire and which individual questions predict FI Quality of Life (FIQOL).MethodsA national sample of American adults completed a health questionnaire, and 234 with monthly FI were selected. Participants completed assessments of FI severity, FIQOL, and somatization. Stepwise linear regression models evaluated whether FISS and FISI total scores, or individual items on the FISS and FISI predicted FIQOL after adjusting for gender, age, income, and somatization (Brief Symptom Inventory‐18).Key ResultsReliable responses were provided by 186. Age was 49 years, and 52% were women. The mean FISS score was 8.4 (95% confidence interval [CI] 8.0‐8.9, 13 questions) and mean FISI was 29.9 (95% CI 27.4‐32.4, 62 questions), indicating moderate FI severity. The mean FIQOL was 2.6 (95% CI 2.4‐2.7, 5 questions). Lower income, greater somatization, and total FISS and FISI scores explained 69% of FIQOL; and total FISS and FISI scores were independent predictors. On the FISS, frequency, amount, and urgency to defecate were independently associated with FIQOL. After adding somatization, all but amount remained significant. For the FISI scale, solid and liquid FI and gas were significant predictors, but adjusting for somatization excluded solid FI.Conclusions and InferencesFive variables independently explained FIQOL: overall frequency of FI, frequency of liquid and gas leakage, urgency, and somatization.

AbstractBackgroundWhile limited data suggest that the fecal microbiota in healthy people is stable over time, the intraindividual variability of the fecal microbiota in constipated patients is unknown.MethodsThis study evaluated the intraindividual reproducibility of fecal microbiota analyzed with 16S rRNA gene sequencing in two stool samples collected without and after a laxative, respectively, in 25 healthy people and 25 constipated women. Participants completed a food record for 3 d before the stool collection. Colonic transit was measured with scintigraphy.Key ResultsThe constipated patients were older (48±15 vs 39±10 y, P=.02) than healthy participants but had a similar BMI. The total daily caloric intake was less (P=.005) in constipated (1265±350 kcal) than healthy participants (1597±402 kcal). Fourteen patients but only two controls (P<.005), had delayed colonic transit. For most measures of alpha (eg, Observed OTU number, Shannon index) and beta diversity (eg, Bray‐Curtis dissimilarity, UniFrac, phyla level abundance), the ICCs between two stool samples were high, indicating moderate or strong agreement, and similar in healthy people and constipated patients. The ICC for the weighted UniFrac distance, which is weighted by abundance, was lower than its unweighted counterpart, indicating that the unweighted measure is more robust and reproducible.Conclusions and InferencesThe intraindividual reproducibility of fecal microbiota in constipated patients is high and comparable to healthy participants. For most purposes, evaluating the fecal microbiota in a single stool sample should generally suffice in adequately powered studies of healthy and constipated patients.

AbstractIntroduced approximately 10 years ago, high‐resolution manometry catheters have fostered interest in anorectal manometry. This review, which accompanies two articles in this issue of Neurogastroenterology and Motility, reviews the methods, clinical indications, utility, and pitfalls of anorectal manometry and revisits the American Gastroenterological Association (AGA) Medical Position Statement on Anorectal Testing Techniques, which was last published in 1999. High‐resolution manometry provides a refined assessment of the anorectal pressure profile, obviates the need for station pull‐through maneuvers, and minimizes movement artifacts. In selected cases, this refined assessment may be useful for identifying structural abnormalities or anal weakness. However, many manometry patterns that were previously regarded as abnormal are also observed in a majority of healthy patients, which substantially limits the utility of manometry for identifying defecatory disorders. It is our impression that most conclusions of the AGA medical position statement from 1999 remain valid today. High‐resolution techniques have not substantially affected the number of publications on or management of anorectal disorders. The ongoing efforts of an international working group to standardize techniques for anorectal manometry are welcome. Although high‐resolution manometry is more than an expensive hobby, improvements in catheter design and further research to rigorously define and evaluate these techniques are necessary to determine if they are worth every penny.

AbstractBackgroundDifferences in the gut microbiota and breath methane production have been observed in chronic constipation, but the relationship between colonic microbiota, transit, and breath tests remains unclear.MethodsIn 25 healthy and 25 constipated females we evaluated the sigmoid colonic mucosal and fecal microbiota using 16S rRNA gene sequencing, abundance of hydrogenogenic FeFe (FeFe‐hydA) and hydrogenotrophic (methyl coenzyme M reductase A [mrcA] and dissimilatory sulfite reductase A [dsrA]) genes with real‐time qPCR assays, breath hydrogen and methane levels after oral lactulose, and colonic transit with scintigraphy.Key ResultsBreath hydrogen and methane were not correlated with constipation, slow colon transit, or with abundance of corresponding genes. After adjusting for colonic transit, the abundance of FeFehydA, dsrA, and mcrA were greater (P<.005) in colonic mucosa, but not stool, of constipated patients. The abundance of the selected functional gene targets also correlated with that of selected taxa. The colonic mucosal abundance of FeFe‐hydA, but not mcrA, correlated positively (P<.05) with breath methane production, slow colonic transit, and overall microbiome composition. In the colonic mucosa and feces, the abundance of hydrogenogenic and hydrogenotrophic genes were positively correlated (P<.05). Breath methane production was not associated with constipation or colonic transit.Conclusions & InferencesCorroborating our earlier findings with 16S rRNA genes, colonic mucosal but not fecal hydrogenogenic and hydrogenotrophic genes were more abundant in constipated vs. healthy subjects independent of colonic transit. Breath gases do not directly reflect the abundance of target genes contributing to their production.

AbstractBackgroundWhile widely used in clinical practice, the reproducibility of high‐definition anorectal manometry (HD‐ARM) remains unclear. We evaluated the intra‐individual reproducibility of HD‐ARM and compared pressures measured with HD‐ARM and high‐resolution anorectal manometry (HR‐ARM).MethodsThirty‐six women with fecal incontinence had an initial HD‐ARM (HD‐ARM1); on the same day, after randomization, 21 had a second (HD‐ARM2). Sixteen women had a third (HD‐ARM3) 4 weeks later. Twenty‐five had also been evaluated by HR‐ARM previously. Rectoanal pressures were assessed at rest, during squeeze and simulated evacuation. Concordance among pressures was assessed with Lin's concordance correlation coefficient (CCC).Key ResultsAnal resting and squeeze pressures measured with HD‐ARM were reproducible on the same and different days; for average resting pressures of HD‐ARM1 vs HD‐ARM2, CCC = 0.73 (95% confidence interval [CI]: 0.53–0.94), and for HD‐ARM1 vs HD‐ARM3, CCC = 0.60 (95% CI: 0.28–0.93). For maximum squeeze pressures of HD‐ARM1 vs HD‐ARM2, CCC = 0.86 (95% CI: 0.75–0.97), and for HD‐ARM1 vs HD‐ARM3, CCC = 0.56 (95% CI: 0.21–0.91). The rectoanal gradient during evacuation was significantly concordant between HD‐ARM1 and HD‐ARM2 but not HD‐ARM1 and HD‐ARM3. Resting (CCC = 0.38 [95% CI: 0.14–0.62]) and squeeze pressures (CCC = 0.73 [95% CI: 0.57–0.89]) measured with HD‐ARM1 and HR‐ARM were also concordant.Conclusions & InferencesAmong women with fecal incontinence, measurements with HD‐ARM were reproducible on the same (anal resting and squeeze pressures and rectoanal gradient during evacuation) and different days (anal resting and squeeze pressures) and correlated with HR‐ARM measurements. These findings support use of HD‐ARM and HR‐ARM for longitudinal assessments of anal resting and squeeze pressures.

Abstract Background Therapeutic options for management of diabetic gastroparesis are limited. Failure to maintain upregulation of heme oxygenase ( HO 1) leads to loss of interstitial cells of Cajal and delayed gastric emptying ( GE ) in non‐obese diabetic mice. Our hypothesis was that hemin upregulation of HO 1 would restore normal GE in humans with gastroparesis. Aims To compare effects of hemin and placebo infusions on HO 1 activity and protein, GE , autonomic function, and gastrointestinal symptoms in diabetic gastroparesis. Methods In a single‐center, double‐blind, placebo‐controlled, randomized clinical trial, we compared intravenous hemin, prepared in albumin, or albumin alone (placebo) in 20 patients, aged 41 ± 5 ( SEM ) years with diabetic gastroparesis. After infusions on days 1, 3, and 7, weekly infusions were administered for 7 additional weeks. Assessments included blood tests for HO 1 protein and enzyme activity levels, GE with 13 C‐spirulina breath test, autonomic functions (baseline and end), and gastrointestinal symptoms every 2 weeks. Key Results Nine of 11 patients randomized to hemin completed all study procedures. Compared to placebo, hemin increased HO 1 protein on days 3 ( p = 0.0002) and 7 ( p = 0.008) and HO 1 activity on day 3 ( p = 0.0003) but not after. Gastric emptying, autonomic functions, and symptoms did not differ significantly in the hemin group relative to placebo. Conclusions & Inferences Hemin failed to sustain increased HO 1 levels beyond a week and did not improve GE or symptoms in diabetic gastroparesis. Further studies are necessary to ascertain whether more frequent hemin infusions or other drugs would have a more sustained effect on HO 1 and improve GE .