Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950.

Background: Prucalopride is a selective and specific 5‐hydroxytryptamine4 receptor agonist that is known to increase stool frequency and to accelerate colonic transit. Aim: To investigate the effect of prucalopride on high‐amplitude propagated contractions and segmental pressure waves in healthy volunteers. Methods: After 1 week of dosing (prucalopride or placebo in a double‐blind, randomized, crossover fashion), colonic pressures were recorded in 10 healthy subjects using a solid‐state pressure catheter with six sensors spaced 10 cm apart. Subjects kept diary records of their bowel habits (frequency, consistency and straining). High‐amplitude propagated contractions were analysed visually, comparing their total numbers and using 10‐min time windows. Segmental pressure waves were analysed using computer algorithms, quantifying the incidence, amplitude, duration and area under the curve of all detected peaks. Results: When taking prucalopride, stool frequency increased, consistency decreased and subjects strained less. Prucalopride just failed to increase the total number of high‐amplitude propagated contractions (P=0.055). The number of 10‐min time windows containing high‐amplitude propagated contractions was increased by prucalopride (P=0.019). Prucalopride increased the area under the curve per 24 h (P=0.026). Conclusions: The 5‐hydroxytryptamine4 receptor agonist prucalopride stimulates high‐amplitude propagated contractions and increases segmental contractions, which is likely to be the underlying mechanism of its effect on bowel habits in healthy volunteers.

In the present study, the gastrocolonic response after ingestion of a standardized liquid meal and the response to a local chemical stimulus were investigated in 10 healthy volunteers and 10 patients with slow-transit constipation (as determined by marker studies). Colonic pressures were recorded while fasting, after ingestion of a standardized meal and after intracolonic bisacodyl infusion, using a 12-channel water-perfused catheter. Pressure waves propagating over at least 20 cm (HAPPW) were identified visually and automated analysis was carried out on remaining segmental motility. Increases of motility after a meal and bisacodyl were seen in healthy subjects, whereas patients did not show these responses. The time until occurrence of the first HAPPW after bisacodyl infusion tended to be prolonged (4.3 +/- 1.4 vs 36.1 +/- 15.3; P = 0.053) and the number of HAPPWs in the first 30 min. after infusion was lower compared to healthy subjects (2.1 +/- 0.2 vs 5.4 +/- 0.3; P < 0.01). The percentage of HAPPWs that were experienced as urge or cramp was significantly lower in constipated patients (53 +/- 3% vs 95 +/- 1%; P < 0.005). In conclusion, this study shows that in patients with slow-transit constipation, the colonic motor response to a meal and to bisacodyl, as well as the perception of bisacodyl-induced propagated pressure waves is decreased.

The aims of this study were to explore all characteristics of high-amplitude propagated contractions (HAPCs) that would allow them to be distinguished from nonHAPC colonic pressure waves, and to develop computer algorithms for automated HAPC detection. Colonic manometry recordings obtained from 24 healthy volunteers were used. Automated analysis was performed to detect propagated pressure waves and to determine their amplitude, duration and area under the curve (AUC). For each of these variables distribution plots were made. Automated HAPC counts were compared to visual counts by experienced investigators. Distribution plots of 141093 colonic pressure waves lacked a bimodal pattern, as was also the case for propagated contractions (n = 8758). With increasing high-amplitude thresholds for HAPC detection, a gradual decrease in the automatically detected HAPC number was observed. These findings precluded determination of a threshold. Taking visually detected HAPCs as reference, amplitude thresholds of 100 mmHg in two channels, and 80 mmHg in one channel yielded the highest sensitivity (92%). In conclusion, objective criteria to distinguish HAPCs from other propagated pressure waves on the basis of their amplitude, duration or AUC do not exist. Automated detection of HAPCs using empirically derived criteria leads to an acceptable degree of correlation with visually detected HAPCs.

The purpose of this study was to develop a computer program for fully automated analysis of all presently known motor patterns in human colonic motility recordings. Colonic pressure recordings obtained from 24 healthy volunteers were used. Algorithms were developed for the detection and numerical analysis of five types of pressure waves: antegrade, retrograde, simultaneous, high-amplitude and isolated pressure waves. Furthermore, periodical motor activity was quantified. Validation was performed by comparison with visual analysis by two experienced observers. Patterns recorded during day- and night-time were compared using multiple-factor analysis of variance with Bonferroni correction. Automated analysis correlated well with visual peak detection (r = 0.98, P <0.01) and detection of antegrade pressure waves (r = 0.98, P <0.01). Most motor patterns showed a diurnal variation. During the night, prevalences of antegrade (938 vs 455; P <0.05), retrograde (112 vs 81; P <0.05), high-amplitude (12.9 vs 1.3; P <0.05), isolated pressure waves (1114 vs 765; P <0.05), and periodic motor activity were decreased (7.33 vs 4.47%; P <0.05). However, when expressed as percentage of absolute numbers of pressure waves, prevalences remained constant. In conclusion, fully automated analysis of all hitherto described colonic motility patterns is feasible. During the night, overall wave prevalences markedly decreased, but the distribution over the various motor patterns was preserved.

BACKGROUND & AIMS: It is currently unclear whether reported changes in the gut microbiome are cause or consequence of inflammatory bowel disease (IBD). Therefore, we studied the gut microbiome of IBD-discordant and -concordant twin pairs, which offers the unique opportunity to assess individuals at increased risk of developing IBD, namely healthy cotwins from IBDdiscordant twin pairs. METHODS: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex-, and body mass index-matched controls, and 99 unrelated patients with IBD. Whole-genome metagenomic shotgun sequencing was performed. Taxonomic and functional (pathways) composition was compared among healthy cotwins, IBD-twins, unrelated patients with IBD, and healthy controls with multivariable (ie, adjusted for potential confounding) generalized linear models.RESULTS: No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins (false discovery rate <0.10). Compared with healthy controls, 13, 19, and 18 species, and 78, 105, and 153 pathways were found to be differentially abundant in healthy cotwins, IBD-twins, and unrelated patients with IBD, respectively (false discovery rate <0.10). Of these, 8 (42.1%) of 19 and 1 (5.6%) of 18 species, and 37 (35.2%) of 105 and 30 (19.6%) of 153 pathways overlapped between healthy cotwins and IBDtwins, and healthy cotwins and unrelated patients with IBD, respectively. Many of the shared species and pathways have previously been associated with IBD. The shared pathways include potentially inflammation-related pathways, for example, an increase in propionate degradation and L-arginine degradation

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