Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation: a randomized phase 2 trial.

OBJECTIVE: NGM282 is an analog of fibroblast growth factor 19 (FGF19), a potent inhibitor of bile acid (BA) synthesis in animals and humans. In phase 2 trials in type 2 diabetes and primary biliary cholangitis, NGM282 was associated with dose-related abdominal cramping and diarrhea. We aimed to examine effects of NGM282 on colonic transit, stool frequency and consistency, hepatic BA synthesis (fasting serum C4), fecal fat, and BA in functional constipation (FC). METHODS: Two-dose NGM282 (1 and 6 mg, subcutaneously daily), parallel-group, randomized, placebo-controlled, 14-day study in patients with FC (Rome III criteria) and baseline colonic transit 24 h geometric center (GC) <3.0. We explored treatment interaction with SNPs in genes KLB, FGFR4, and TGR5 (GPBAR1). STATISTICAL ANALYSIS: overall ANCOVA at α = 0.025 (baseline as covariate where available), with three pairwise comparisons among the three groups (α = 0.008). RESULTS: Overall, NGM282 altered bowel function (number of bowel movements, looser stool form, and increased ease of passage) and significantly accelerated gastric and colonic transit. Dose-related effects were seen with GC 24 h, but not with gastric emptying (GE) and GC 48 h. There were no differences in fecal fat or weight, but there was reduced fecal total BA excretion with NGM282. The most common adverse events were increased appetite (n = 0 with placebo, 2 with 1 mg, 9 with 6 mg), injection site reaction (n = 2 placebo, 4 with 1 mg, 8 with 6 mg), and diarrhea (n = 1 with 1 mg and 4 with 6 mg NGM282). There was treatment interaction with KLB SNP, with greater increase in colonic transit in participants with the minor A allele (p = 0.056). CONCLUSION: NGM282 significantly impacts GE and colonic transit, consistent with the observed clinical symptoms. The specific mechanism of prokinetic activity requires further research.

Effects of NK1 receptors on gastric motor functions and satiation in healthy humans: results from a controlled trial with the NK1 antagonist aprepitant.

Aprepitant, an NK1 receptor antagonist, is approved for the treatment of chemotherapy-induced or postoperative emesis by blocking NK1 receptors in the brain stem vomiting center. The effects of NK1 receptors on gastric functions and postprandial symptoms in humans are unclear; a single, crossover study did not show a significant effect of aprepitant on gastrointestinal transit. Our aim was to compare, in a randomized, double-blind, placebo-controlled, parallel-group study (12 healthy volunteers per group), the effects of aprepitant vs. placebo on gastric emptying of solids (by scintigraphy) with a 320-kcal meal, gastric volumes (GVs; fasting and accommodation by single photon emission-computed tomography ), satiation [maximum tolerated volume (MTV)], and symptoms after a dyspeptogenic meal of Ensure. Aprepitant (125 mg on day 1, followed by 80 mg on days 2-5) or placebo, one tablet daily, was administered for 5 consecutive days. Statistical analysis was by unpaired rank sum test, adjusted for sex difference and body mass index. To assess treatment effects on symptoms, we incorporated MTV in the model. Aprepitant increased fasting, postprandial, and accommodation GV and tended to increase volume to fullness and MTV by ~200 kcal. However, aprepitant increased aggregate symptoms, nausea, and pain scores after ingestion the MTV of Ensure. There was no significant effect of aprepitant on gastric half-emptying time of solids. We conclude that NK1 receptors are involved in the control of GV and in determining postprandial satiation and symptoms. Further studies of the pharmacodynamics and therapeutic role of NK1 receptor antagonists in patients with gastroparesis and dyspepsia are warranted.NEW & NOTEWORTHY Aprepitant increases fasting, postprandial, and accommodation gastric volumes. Aprepitant increases volume to fullness and maximum tolerated volume during a nutrient drink test. NK1 receptors are involved in the control of gastric volume and in determining postprandial satiation and symptoms.

Relationship of gastric emptying or accommodation with satiation, satiety, and postprandial symptoms in health.

The contributions of gastric emptying (GE) and gastric accommodation (GA) to satiation, satiety, and postprandial symptoms remain unclear. We aimed to evaluate the relationships between GA or GE with satiation, satiety, and postprandial symptoms in healthy overweight or obese volunteers (total n = 285, 73% women, mean BMI 33.5 kg/m2): 26 prospectively studied obese, otherwise healthy participants and 259 healthy subjects with previous similar GI testing. We assessed GE of solids, gastric volumes, calorie intake at buffet meal, and satiation by measuring volume to comfortable fullness (VTF) and maximum tolerated volume (MTV) by using Ensure nutrient drink test (30 ml/min) and symptoms 30 min after MTV. Relationships between GE or GA with satiety, satiation, and symptoms were analyzed using Spearman rank (rs ) and Pearson (R) linear correlation coefficients. We found a higher VTF during satiation test correlated with a higher calorie intake at ad libitum buffet meal (rs = 0.535, P < 0.001). There was a significant inverse correlation between gastric half-emptying time (GE T1/2) and VTF (rs = -0.317, P < 0.001) and the calorie intake at buffet meal (rs = -0.329, P < 0.001), and an inverse correlation between GE Tlag and GE25% emptied with VTF (rs = -0.273, P < 0.001 and rs = -0.248, P < 0.001, respectively). GE T1/2 was significantly associated with satiation (MTV, R = -0.234, P < 0.0001), nausea (R = 0.145, P = 0.023), pain (R = 0.149, P = 0.012), and higher aggregate symptom score (R = 0.132, P = 0.026). There was no significant correlation between GA and satiation, satiety, postprandial symptoms, or GE. We concluded that GE of solids, rather than GA, is associated with postprandial symptoms, satiation, and satiety in healthy participants.NEW & NOTEWORTHY A higher volume to comfortable fullness postprandially correlated with a higher calorie intake at ad libitum buffet meal. Gastric emptying of solids is correlated to satiation (volume to fullness and maximum tolerated volume) and satiety (the calorie intake at buffet meal) and symptoms of nausea, pain, and aggregate symptom score after a fully satiating meal. There was no significant correlation between gastric accommodation and either satiation or satiety indices, postprandial symptoms, or gastric emptying.

Bile acid disease: the emerging epidemic.

PURPOSE OF REVIEW: Our objective was to review advances in bile acids in health and disease published in the last 2 years. Bile acid diarrhea (BAD) is recognized as a common cause of chronic diarrhea, and its recognition has been facilitated by development of new screening tests. RECENT FINDINGS: Primary BAD can account for 30% of cases of chronic diarrhea. The mechanisms leading to BAD include inadequate feedback regulation by fibroblast growth factor 19 (FGF-19) from ileal enterocytes, abnormalities in synthesis or degradation of proteins involved in FGF-19 regulation in hepatocytes and variations as a function of the bile acid receptor, TGR5 (GPBAR1). SeHCAT is the most widely used test for diagnosis of BAD. There has been significant validation of fasting serum FGF-19 and 7 α-hydroxy-cholesten-3-one (C4), a surrogate measure of bile acid synthesis. Bile acid sequestrants are the primary treatments for BAD; the farnesoid X-receptor-FGF-19 pathway provides alternative therapeutic targets for BAD. Bile acid-stimulated intestinal mechanisms contribute to the beneficial effects of bariatric surgery on obesity, glycemic control and the treatment of recurrent Clostridium difficile infection. SUMMARY: Renewed interest in the role of bile acids is leading to novel management of diverse diseases besides BAD.

Chemical and molecular factors in irritable bowel syndrome: current knowledge, challenges, and unanswered questions.

Several chemical and molecular factors in the intestine are reported to be altered and to have a potentially significant role in irritable bowel syndrome (IBS), particularly in IBS with diarrhea. These include bile acids; short-chain fatty acids; mucosal barrier proteins; mast cell products such as histamine, proteases, and tryptase; enteroendocrine cell products; and mucosal mRNAs, proteins, and microRNAs. This article reviews the current knowledge and unanswered questions in the pathobiology of the chemical and molecular factors in IBS. Evidence continues to point to significant roles in pathogenesis of these chemical and molecular mechanisms, which may therefore constitute potential targets for future research and therapy. However, it is still necessary to address the interaction between these factors in the gut and to appraise how they may influence hypervigilance in the central nervous system in patients with IBS.

Choledochal or pancreatic cyst? Role of endoscopic ultrasound as an adjunct for diagnosis: a case series.

BACKGROUND: Choledochal cysts (CC) are a cystic dilation of the intra- or extrahepatic biliary tree. They are rare, and are associated with a risk of malignant transformation. Due to the close proximity to the pancreas, Type II CC, in which a diverticular outpouching is connected to the extrahepatic bile duct via a narrow stalk, can be difficult to differentiate from pancreatic cysts. The aim of this study was to determine the role of endoscopic ultrasound (EUS) in the diagnosis of Type II CC. METHODS: A retrospective review of all patients seen in the Multidisciplinary Pancreatic Cyst Clinic at Johns Hopkins Hospital from November 2010 to March 2014 was performed to identify patients classified as having Type II CC on computed tomography (CT) or magnetic resonance imaging (MRI) who also underwent EUS. Patient demographics, clinical presentation, imaging, and follow-up were recorded. RESULTS: Four female patients with median age of 52 years, three of whom were identified as having Type II CC and one as equivocal for CC on MRI, and two as having Type II CC, one equivocal for CC and one as branch-duct intraductal papillary mucinous neoplasm on CT. On EUS, no communication was seen in any cases between the CC and common bile duct. EUS-guided fluid aspiration from each cyst demonstrated clear fluid with undetectable bilirubin and either elevated CEA or amylase confirming the diagnosis of pancreatic cyst. CONCLUSIONS: EUS is a useful tool for the differentiation of equivocal cases of CC. It can show a very small separation as little as 1 mm between two structures, and cyst fluid analysis can be performed and used to further differentiate between biliary cysts and other cystic structures.

Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea.

BACKGROUND: In primary bile acid diarrhoea, feedback by farnesoid X receptor (FXR) and fibroblast growth hormone 19 (FGF19) on hepatic bile acid production is impaired. AIMS: To evaluate the safety, mechanisms and efficacy of negative feedback by FXR activation with tropifexor, a non-bile acid FXR agonist, in patients with primary bile acid diarrhoea. METHODS: In this double-blind, multicentre, randomised, cross-over study, patients received tropifexor 60 µg or placebo once daily for 14 days in each of two treatment periods. Primary objectives included tropifexor safety and tolerability, and on stool frequency and form. Other assessments included pharmacokinetic and pharmacodynamic measures, biochemical markers and gastrointestinal transit. RESULTS: Twenty patients (tropifexor 60 µg/placebo [N = 10]; placebo/tropifexor 60 µg [N = 10]) were enrolled. Adverse event rates were lower with tropifexor vs placebo (52.9% vs 73.7%). No patient had pruritus during tropifexor intake. There were no significant differences in stool frequency, stool form or loperamide use between treatments. Tropifexor increased FGF19 and decreased 7α-hydroxy-4-cholesten-3-one (C4) levels for up to 8 h. Plasma tropifexor concentrations peaked at 5 hours post-dose on days 1 and 12. At day 12, tropifexor caused reduction in peak total bile acid concentration (33%, P = 0.032) and exposure (36%, P = 0.005). Moreover, tropifexor showed a significant increase in ascending colon half-emptying time (P = 0.036). CONCLUSIONS: Tropifexor 60 µg once daily had acceptable safety and tolerability. Changes in FGF19 and C4 showed effective target engagement; however, higher doses may be required to observe stool frequency changes. Slowing of ascending colon emptying suggests therapeutic potential of tropifexor in patients with primary bile acid diarrhoea. ClinicalTrials.gov number: NCT02713243.

Biomarkers as a diagnostic tool for irritable bowel syndrome: where are we?

INTRODUCTION: Irritable bowel syndrome (IBS) is a common condition in clinical practice. There are currently no objective tests to rule in the disease, but rather tests to rule out other diseases. Biomarkers in IBS may provide the tools needed for diagnosis, prognosis and therapy. These include identification of differences in microbial composition, immune activation, bile acid composition, colonic transit, and alteration in sensation in subgroups of IBS patients. Areas covered: Studies included in our review were chosen based on a PubMed search for 'biomarkers' and 'IBS'. We have reviewed the literature on biomarkers to appraise their accuracy, validity and whether they are actionable. We have not covered genetic associations as biomarkers in this review. Expert commentary: There is significant promise in the usefulness of biomarkers for IBS. The most promising actionable biomarkers are markers of changes in bile acid balance, such as elevated bile acid in the stool, and altered colonic transit. However, there is also potential for microbial studies and mucosal proteases as future actionable biomarkers.

Does Provider Self-Reporting of Etiquette Behaviors Improve Patient Experience? A Randomized Controlled Trial.

BACKGROUND: There is a glaring lack of published evidence-based strategies to improve the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) patient experience scores on the physician domain. Strategies that have been used are resource intensive and difficult to sustain. OBJECTIVE: We hypothesized that prompting providers to assess their own etiquette-based practices every 2 weeks over the course of 1 year would improve patient experience on the physician domain. DESIGN: Randomized controlled trial. SETTING: 4 acute care hospitals. PARTICIPANTS: Hospitalists. INTERVENTION: Hospitalists were randomized to the study or the control arm. The study arm was prompted every 2 weeks for 12 months to report how frequently they engaged in 7 best-practice bedside etiquette behaviors. Control arm participants received similarly worded questions on quality improvement behaviors. MEASUREMENT: Provider experience scores were calculated from the physician HCAHPS and Press Ganey survey provider items. RESULTS: Physicians reported high rates of etiquette-based behavior at baseline, and this changed modestly over the study period. Self-reported etiquette behaviors were not associated with experience scores. The difference in difference analysis of the baseline and postintervention physician experience scores between the intervention arm and the control arm was not statistically significant (P = 0.71). CONCLUSION: In this 12-month study, biweekly reflection and reporting of best-practice bedside etiquette behaviors did not result in significant improvement on physician domain experience scores. It is likely that hospitalists' self-assessment of their bedside etiquette may not reflect patient perception of these behaviors. Furthermore, hospitalists may be resistant to improvement in this area since they rate themselves highly at baseline. Journal of Hospital Medicine 2017;12:402-406.

Association of self-reported hospital discharge handoffs with 30-day readmissions.

IMPORTANCE: Poor health care provider communication across health care settings may lead to adverse outcomes. OBJECTIVE: To determine the frequency with which inpatient providers report communicating directly with outpatient providers and whether direct communication was associated with 30-day readmissions. DESIGN: We conducted a single-center prospective study of self-reported communication patterns by discharging health care providers on inpatient medical services from September 2010 to December 2011 at The Johns Hopkins Hospital. SETTING: A 1000-bed urban, academic center. PARTICIPANTS: There were 13 954 hospitalizations in this time period. Of those, 9719 were for initial visits. After additional exclusions, including patients whose outpatient health care provider was the inpatient attending physician, those who had planned or routine admissions, those without outpatient health care providers, those who died in the hospital, and those discharged to other healthcare facilities, we were left with 6635 hospitalizations for analysis. INTERVENTIONS: Self-reported communication was captured from a mandatory electronic discharge worksheet field. Thirty-day readmissions, length of stay (LOS), and demographics were obtained from administrative databases. DATA EXTRACTION: We used multivariable logistic regression models to examine, first, the association between direct communication and patient age, sex, LOS, race, payer, expected 30-day readmission rate based on diagnosis and illness severity, and physician type and, second, the association between 30-day readmission and direct communication, adjusting for patient and physician-level factors. RESULTS: Of 6635 included hospitalizations, successful direct communication occurred in 2438 (36.7%). The most frequently reported reason for lack of direct communication was the health care provider's perception that the discharge summary was adequate. Predictors of direct communication, adjusting for all other variables, included patients cared for by hospitalists without house staff (odds ratio [OR], 1.81 [95% CI, 1.59-2.08]), high expected 30-day readmission rate (OR, 1.18 [95% CI, 1.10-1.28] per 10%), and insurance by Medicare (OR, 1.35 [95% CI, 1.16-1.56]) and private insurance companies (OR, 1.35 [95% CI, 1.18-1.56]) compared with Medicaid. Direct communication with the outpatient health care provider was not associated with readmissions (OR, 1.08 [95% CI, 0.92-1.26]) in adjusted analysis. CONCLUSIONS AND RELEVANCE: Self-reported direct communication between inpatient and outpatient providers occurred at a low rate but was not associated with readmissions. This suggests that enhancing interprovider communication at hospital discharge may not, in isolation, prevent readmissions.