Randomized controlled trial of linaclotide in children aged 6-17 years with functional constipation.

OBJECTIVES: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for treatment of children 6-17 years old with functional constipation (FC). This study evaluated the safety and efficacy of several linaclotide doses in children 6-17 years old with FC. METHODS: In this multicenter, randomized, double-blind, placebo-controlled phase 2 study, 173 children with FC (based on Rome III criteria) were randomized to once-daily linaclotide (A: 9 or 18 µg, B: 18 or 36 µg, or C: 36 or 72 µg) or placebo in a 1:1:1:1 ratio for 6- to 11-year-olds (dosage determined by weight: 18 to <35 or ≥35 kg) and linaclotide (18, 36, 72, or 145 µg) or placebo in a 1:1:1:1:1 ratio for 12- to 17-year-olds. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency throughout the 4-week treatment period. Adverse events (AE), clinical laboratory values, and electrocardiograms were monitored. RESULTS: Efficacy and safety were assessed in 173 patients (52.0% aged 6-11 years; 48.0% aged 12-17 years); 162 (93.6%) completed the treatment period. A numerical improvement in mean SBM frequency was observed with increasing linaclotide doses (1.90 in 6- to 11-year-olds [36 or 72 µg] and 2.86 in 12- to 17-year-olds [72 µg]). The most reported treatment-emergent AE was diarrhea, with most cases being mild; none were severe. CONCLUSIONS: Linaclotide was well tolerated in this pediatric population, with a trend toward efficacy in the higher doses, warranting further evaluation.

Linaclotide Reduced Response Time for Irritable Bowel Syndrome With Constipation Symptoms: Analysis of 4 Randomized Controlled Trials.

INTRODUCTION: These post hoc analyses provide clinically relevant data concerning time to response for individual irritable bowel syndrome with constipation (IBS-C) symptoms after linaclotide use. METHODS: Time-to-response data were pooled from 4 randomized controlled trials. Response time for abdominal symptoms (pain, discomfort, and bloating) and complete spontaneous bowel movements (CSBMs) were analyzed using the Kaplan-Meier method; patients were categorized as early responders (≤4 weeks), late responders (>4-12 weeks), or nonresponders. RESULTS: Among 2,350 patients (1,172 placebo and 1,178 linaclotide 290 µg), >50% of patients with IBS-C who initiated linaclotide treatment experienced a decrease of ≥30% in abdominal pain, discomfort, or bloating within 3-4 weeks (median). The median time to achieving ≥3 CSBMs was 4 weeks. Although not all linaclotide-treated patients responded within 12 weeks, a late response occurred between 4 and 12 weeks in 1 in 6 patients for abdominal pain and in approximately 1 in 10 patients for CSBM frequency. Comparisons of early responders, late responders, and nonresponders for both response definitions indicated that women, Whites, and patients with less severe baseline abdominal symptoms were more likely to respond early. DISCUSSION: Although treatment responses with linaclotide occurred in >50% of patients with IBS-C within 4 weeks of treatment initiation, benefits for individual abdominal symptoms and/or CSBM frequency can still occur between 4 and 12 weeks. A lack of improvement in one symptom does not negate the possibility of response for others, highlighting the importance of discussing all symptoms with patients and not assuming treatment futility at 4 weeks.

The pharmacokinetics of oral trazpiroben (TAK-906) after organic anion transporting polypeptide 1B1/1B3 inhibition: A phase I, randomized study.

Trazpiroben is a dopamine D2 /D3 receptor antagonist under development for the treatment of gastroparesis. This phase I, open-label, randomized, two-way crossover study (NCT04121078) evaluated the effect of single-dose intravenous rifampin, a potent inhibitor of the organic anion transporting polypeptides (OATPs) 1B1 and 1B3, on the pharmacokinetics and safety of trazpiroben in healthy adults. The utility of coproporphyrin (CP) I and CPIII as biomarkers of OATP inhibition was also assessed. Overall, 12 participants were enrolled and randomized (1:1) into one of two treatment sequences (AB and BA). Participants received either a single oral dose of trazpiroben 25 mg (treatment A) or a single oral dose of trazpiroben 25 mg immediately after a single 30-min intravenous infusion of rifampin 600 mg (treatment B). After a washout period of at least 7 days, participants received the other treatment. Geometric mean area under the curve from time 0 extrapolated to infinity (AUC∞ ) and maximum serum concentration (Cmax ) of plasma trazpiroben were higher in participants receiving treatment B than those receiving treatment A (AUC∞ , 168.5 vs. 32.68 ng*h/ml; Cmax , 89.62 vs. 14.37 ng/ml); corresponding geometric mean ratios (90% confidence interval) showed 5.16 (4.25-6.25) and 6.24 (4.62-8.42)-fold increases in these parameters, respectively. In this study, trazpiroben was confirmed as a substrate of OATP1B1/1B3, and therefore co-administration of trazpiroben with moderate to strong inhibitors of OATP1B1/1B3 is not recommended. This is also the first assessment of the utility of CPI and CPIII as endogenous biomarkers of OATP1B1/1B3 inhibition after a single intravenous dose of rifampin.

Evaluation of the Pharmacokinetics of Felcisetrag (TAK-954), a 5-HT4 Receptor Agonist, in the Presence and Absence of Itraconazole, a Potent CYP3A4 Inhibitor.

The 5-hydroxytryptamine type-4 receptor agonist felcisetrag (TAK-954) is being investigated for improving gastrointestinal motility in postoperative gastrointestinal dysfunction. Polypharmacy often occurs in this setting, and as in vitro data indicate, felcisetrag is primarily metabolized by cytochrome P450 (CYP) 3A4, its CYP3A4-mediated drug-drug interaction potential requires consideration. This phase 1, fixed-sequence, open-label, crossover trial (ClinicalTrials.gov identifier NCT03173170) investigated the effect of itraconazole, a potent CYP3A4 inhibitor, on felcisetrag pharmacokinetics in healthy adults. Over 2 study periods (period 1, 6 days; period 2, 9 days), participants received a single felcisetrag 0.2-mg intravenous dose (day 1, period 1; and day 4, period 2), and once-daily oral itraconazole 200-mg doses (days 1-8, period 2). For felcisetrag alone, felcisetrag total systemic exposure was lower than with itraconazole coadministration. The geometric mean ratio for area under the plasma concentration-time curve from time 0 to infinity of felcisetrag plus itraconazole: felcisetrag alone was 1.49 (90% confidence interval, 1.39-1.60). Peak exposure was similar between regimens (geometric mean ratio, 1.06; 90% confidence interval, 0.96-1.18), and both treatments were well tolerated. These data suggest limited CYP3A4-mediated drug-drug interaction inhibition for felcisetrag.

Epidemiology, Etiology, and Treatment of Gastroparesis: Real-World Evidence From a Large US National Claims Database.

BACKGROUND & AIMS: Although gastroparesis carries a considerable health care and patient burden, associated epidemiological data are limited. To provide new real-world evidence for gastroparesis, we estimated disease prevalence, and investigated patient demographics and disease etiology in a large US claims database. METHODS: This retrospective, cross-sectional analysis used de-identified, longitudinal patient-level enrollment and billing data for adults from the Optum Clinformatics Data Mart database, a large US national administrative health insurance claims database. Prevalence was age-, sex-, and geographical region-standardized using the 2018 US census. Descriptive analyses of demographic and clinical variables and underlying disease etiologies were performed. RESULTS: The overall standardized prevalence of gastroparesis was 267.7 (95% confidence interval [CI] 264.8-270.7) per 100,000 US adults, whereas prevalence of "definite" gastroparesis (individuals diagnosed within 3 months of gastric emptying scintigraphy testing with persistent symptoms for more than 3 months) was 21.5 (95% CI 20.6-22.4) per 100,000 persons. Patients with gastroparesis had an overall Charlson Comorbidity Index score of 4.2, indicating substantial comorbidity burden. The most frequently documented comorbidities were chronic pulmonary disease (46.4%), diabetes with chronic complication (37.3%), and peripheral vascular disease (30.4%). Patients most commonly had a diabetic etiology (57.4%; type 1, 5.7% and type 2, 51.7%), followed by postsurgical (15.0%), drug-induced (11.8%), and idiopathic (11.3%) etiologies. CONCLUSIONS: New evidence is provided regarding the prevalence, patient demographics, and etiology of gastroparesis in the US general population. Wider availability of reliable objective gastric emptying measures and further education of medical professionals in recognizing and diagnosing gastroparesis would benefit future studies and improve understanding of disease epidemiology.

Evaluation of the Pharmacokinetics of Trazpiroben (TAK-906), a Peripherally Selective D2/D3 Dopamine Receptor Antagonist, in the Presence and Absence of Itraconazole, a Potent CYP 3A4 Inhibitor.

PURPOSE: Treatment options for gastroparesis, such as metoclopramide and domperidone, are limited because of safety concerns, which may be exacerbated in the presence of inhibitors of drug metabolism. This study evaluated the effect of itraconazole on the pharmacokinetics, safety, and tolerability of trazpiroben (previously TAK-906), a novel, peripherally selective D2/D3 dopamine receptor antagonist. METHODS: This was a phase 1, two-period, crossover trial in healthy participants (NCT03161405). On day 1, period 1 (days 1-3), participants received a single oral dose of trazpiroben 25 mg. During period 2 (days 4-9), participants received oral itraconazole 200 mg once daily (days 1-5) and one oral dose of trazpiroben 25 mg post itraconazole on day 4. Trazpiroben pharmacokinetics were assessed. Safety assessments included triplicate electrocardiograms. RESULTS: Twelve healthy males (24-45 years old) were studied. Co-administration of itraconazole increased trazpiroben area under the concentration-time curve from time 0 to infinity by 1.28-fold (90% confidence interval: 1.10, 1.49) and maximum plasma concentration (Cmax) by 1.98-fold (1.64, 2.39) versus trazpiroben alone. Placebo-corrected, change from baseline in corrected QT interval at the observed geometric mean Cmax for trazpiroben alone (9.53 ng/mL) and with itraconazole (18.00 ng/mL) was estimated at 1.31 ms (-0.39, 3.01) and 1.54 ms (-0.15, 3.24), respectively. There were no clinically relevant abnormalities in any safety parameters. CONCLUSION: These results indicate that TAK­906 is relatively insensitive to inhibition of cytochrome P450 3A4, and cardiovascular safety concerns associated with domperidone are unlikely to be elicited by trazpiroben under similar conditions.

Randomised study: effects of the 5-HT4 receptor agonist felcisetrag vs placebo on gut transit in patients with gastroparesis.

BACKGROUND: Gastroparesis is defined by delayed gastric emptying with associated symptoms in the absence of mechanical obstruction. AIM: To evaluate pharmacokinetics and pharmacodynamics of felcisetrag, a highly selective 5-HT4 receptor agonist, on total gut transit in patients with documented delayed gastric emptying of solids. METHODS: Single-centre, placebo-controlled study of 36 participants receiving placebo, 0.1mg, 0.3mg or 1.0mg of felcisetrag I.V. infusion, daily, for 3 days. At baseline, each participant completed a 4h, 99m Tc-egg meal (300 kcal, 30% fat) gastric emptying test. Following infusion (Day 2), gastric, small bowel and colonic transit of solids were measured over 48h (same meal plus 111 In-charcoal delivered in methacrylate-coated capsule). Samples were collected for pharmacokinetics. The primary endpoint was gastric emptying T1/2 . Statistical analysis used baseline parameters as covariates (ANCOVA). RESULTS: Patients (22 idiopathic, 14 diabetic gastroparesis) were randomised to felcisetrag (0.1 mg, n = 10; 0.3 mg, n = 9; 1.0 mg, n = 7) or placebo (n = 10). Compared to placebo, felcisetrag significantly accelerated gastric emptying T1/2 , colonic filling at 6h, and 10% small bowel transit time (overall P < 0.01; all three doses individually Bonferroni corrected P < 0.05) for all three measurements. Ascending colon emptying (T1/2 ) was significantly accelerated (all doses), and colonic transit at 48 hours was accelerated with 0.1 mg and 0.3 mg felcisetrag compared to placebo. Pharmacokinetic results were dose proportional. Felcisetrag was well tolerated with no clinically significant findings from clinical laboratory, vital signs or ECG. CONCLUSION: I.V. felcisetrag significantly accelerated gastric, small bowel and colonic transit in patients with gastroparesis, and should be further evaluated for short-term treatment of gastric and intestinal motility disorders. ClinicalTrials.gov #NCT03281577.

Epidemiology and outcomes of gastroparesis, as documented in general practice records, in the United Kingdom.

OBJECTIVE: To generate real-world evidence for the epidemiology of gastroparesis in the UK, we evaluated the prevalence, incidence, patient characteristics and outcomes of gastroparesis in the Clinical Practice Research Datalink (CPRD) database. DESIGN: This was a retrospective, cross-sectional study. Prevalence and incidence of gastroparesis were evaluated in the CPRD database, with linkage to Hospital Episodes Statistics Admitted Patient Care and Office for National Statistics mortality data. Prevalence and incidence were age and sex standardised to mid-2017 UK population estimates. Descriptive analyses of demographics, aetiologies, pharmacological therapies and mortality were conducted. RESULTS: Standardised prevalence of gastroparesis, as documented in general practice records, was 13.8 (95% CI 12.6 to 15.1) per 100 000 persons in 2016, and standardised incidence of gastroparesis rose from 1.5 (95% CI 1.1 to 1.8) per 100 000 person-years in 2004 to 1.9 (95% CI 1.4 to 2.3) per 100 000 person-years in 2016. The most common disease aetiologies were idiopathic (39.4%) and diabetic gastroparesis (37.5%), with a similar distribution of type 1 and type 2 diabetes among the 90% who had type of diabetes documented. Patients with diabetic gastroparesis had a significantly higher risk of mortality than those with idiopathic gastroparesis after diagnosis (adjusted HR 1.9, 95% CI 1.2 to 3.0). Of those with gastroparesis, 31.6% were not offered any recognised pharmacological therapy after diagnosis. CONCLUSION: This is, to our knowledge, the first population-based study providing data on epidemiology and outcomes of gastroparesis in Europe. Further research is required to fully understand the factors influencing outcomes and survival of patients with gastroparesis.

Blinded, Double-Dummy, Parallel-Group, Phase 2a Randomized Clinical Trial to Evaluate the Efficacy and Safety of a Highly Selective 5-Hydroxytryptamine Type 4 Receptor Agonist in Critically Ill Patients With Enteral Feeding Intolerance.

BACKGROUND: Delayed gastric emptying is the leading cause of enteral feeding intolerance (EFI) in critical illness. This phase 2a study compared TAK-954, a selective agonist of 5-hydroxytryptamine type 4 receptors, with metoclopramide in critically ill patients with EFI (NCT01953081). METHODS: A blinded, double-dummy trial was conducted in mechanically ventilated patients with EFI (>200 mL gastric residual volume within 24 hours before randomization). Patients were randomized to receive either 0.5 mg intravenous TAK-954 over 1 hour then 0.9% saline injection 4 times/d (sham metoclopramide) or the active comparator 10 mg intravenous metoclopramide 4 times/d and a 1-hour 0.9% saline infusion. After initial dosing, participants received a radiolabeled meal of liquid nutrient (Ensure; 106 kcal), and gastric emptying was measured (scintigraphy). Adverse events (AEs) were recorded from the time of consent through to day 5; serious AEs were collected to day 30. RESULTS: Thirteen patients (TAK-954, n = 7; metoclopramide, n = 6) participated. Five patients in the TAK-954 group and 4 in the metoclopramide group experienced AEs (2 and 3, respectively, were serious). All AEs except 1 (diarrhea in the metoclopramide group) were considered unrelated to study drug. Following treatment, a greater proportion of patients receiving TAK-954 had normal gastric retention (<13% retention at 180 minutes) than those receiving metoclopramide (6/7 vs 3/6 patients, respectively). CONCLUSION: A single dose of 0.5 mg intravenous TAK-954 appears to have at least similar efficacy in accelerating gastric emptying to multiple doses of 10 mg metoclopramide and was not associated with increased AEs.

Incidence, Risk Factors, and Clinical Consequence of Enteral Feeding Intolerance in the Mechanically Ventilated Critically Ill: An Analysis of a Multicenter, Multiyear Database.

OBJECTIVES: To determine the incidence of enteral feed intolerance, identify factors associated with enteral feed intolerance, and assess the relationship between enteral feed intolerance and key nutritional and clinical outcomes in critically ill patients. DESIGN: Analysis of International Nutrition Survey database collected prospectively from 2007 to 2014. SETTING: Seven-hundred eighty-five ICUs from around the world. PATIENTS: Mechanically ventilated adults with ICU stay greater than or equal to 72 hours and received enteral nutrition during the first 12 ICU days. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: We defined enteral feed intolerance as interrupted feeding due to one of the following reasons: high gastric residual volumes, increased abdominal girth, distension, subjective discomfort, emesis, or diarrhea. The current analysis included 15,918 patients. Of these, 4,036 (24%) had at least one episode of enteral feed intolerance. The enteral feed intolerance rate increased from 1% on day 1 to 6% on days 4 and 5 and declined daily thereafter. After controlling for site and patient covariates, burn (odds ratio 1.46; 95% CIs, 1.07-1.99), gastrointestinal (odds ratio 1.45; 95% CI, 1.27-1.66), and sepsis (odds ratio 1.34; 95% CI, 1.17-1.54) admission diagnoses were more likely to develop enteral feed intolerance, as compared to patients with respiratory-related admission diagnosis. enteral feed intolerance patients received about 10% less enteral nutrition intake, as compared to patients without enteral feed intolerance after controlling for important covariates including severity of illness. Enteral feed intolerance patients had fewer ventilator-free days and longer ICU length of stay time to discharge alive (all p < 0.0001). The daily mortality hazard rate increased by a factor of 1.5 (1.4-1.6; p < 0.0001) once enteral feed intolerance occurred. CONCLUSIONS: Enteral feed intolerance occurs frequently during enteral nutrition delivery in the critically ill. Burn and gastrointestinal patients had the highest risk of developing enteral feed intolerance. Enteral feed intolerance is associated with lower enteral nutrition delivery and worse clinical outcomes. Identification, prevention, and optimal management of enteral feed intolerance may improve nutrition delivery and clinical outcomes in important "at risk" populations.

Prokaryotic and viral community of the sulfate-rich crust from Peñahueca ephemeral lake, an astrobiology analogue.

Peñahueca is an athalassohaline hypersaline inland ephemeral lake originated under semiarid conditions in the central Iberian Peninsula (Spain). Its chemical composition makes it extreme for microbial life as well as a terrestrial analogue of other planetary environments. To investigate the persistence of microbial life associated with sulfate-rich crusts, we applied cultivation-independent methods (optical and electron microscopy, 16S rRNA gene profiling and metagenomics) to describe the prokaryotic community and its associated viruses. The diversity for Bacteria was very low and was vastly dominated by endospore formers related to Pontibacillus marinus of the Firmicutes phylum. The archaeal assemblage was more diverse and included taxa related to those normally found in hypersaline environments. Several 'metagenome assembled genomes' were recovered, corresponding to new species of Pontibacillus, several species from the Halobacteria and one new member of the Nanohaloarchaeota. The viral assemblage, although composed of the morphotypes typical of high salt systems, showed little similarity to previously isolated/reconstructed halophages. Several putative prophages of Pontibacillus and haloarchaeal hosts were identified. Remarkably, the Peñahueca sulfate-rich metagenome contained CRISPR-associated proteins and repetitions which were over 10-fold higher than in most hypersaline systems analysed so far.

The American neurogastroenterology and motility society gastroparesis cardinal symptom index-daily diary (ANMS GCSI-DD): Psychometric evaluation in patients with idiopathic or diabetic gastroparesis.

BACKGROUND: The purpose of this study was to evaluate the measurement properties of the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary, a patient-reported outcome instrument developed to meet US FDA recommendations for a symptom-based clinical trial endpoint in gastroparesis. The ANMS GCSI-DD assesses nausea, early satiety, postprandial fullness, and upper abdominal pain on a severity score from none (0) to very severe (4) and number of vomiting episodes during the past 24 hours. The composite score includes the first four symptoms, the core symptom score includes all five symptoms. METHODS: Seventy-one patients diagnosed with idiopathic or diabetic gastroparesis were recruited for a four-week observational study. Patients completed the ANMS GCSI-DD at home between Baseline and Week 4. Statistical analyses included confirmatory factor analysis, item response theory analysis, internal consistency, test-retest reliability, and construct and known-groups validity. KEY RESULTS: Unidimensionality for the composite and core symptom scores was supported, and items exhibited good fit. Internal consistency (Cronbach's alpha =0.85 and 0.83) and test-retest reliability were 0.89 and 0.88, for composite and core symptom scores, respectively. Convergent validity was supported by strong correlations with patient-reported and clinician measures. Baseline and Week 4 scores differed for three measures used to define disease severity status (P < 0.0001), supporting known-groups validity. CONCLUSIONS & INFERENCES: The ANMS GCSI-DD has excellent reliability and validity, supporting its use to assess symptom-based endpoints in gastroparesis clinical studies. Further analyses will be conducted using clinical trial data to ascertain treatment responsiveness and define a responder.

Prokaryotic and viral community structure in the singular chaotropic salt lake Salar de Uyuni.

Salar de Uyuni (SdU) is the largest hypersaline salt flat and the highest lithium reservoir on Earth. In addition to extreme temperatures and high UV irradiance, SdU has high concentrations of chaotropic salts which can be important factors in controlling microbial diversity. Here, for the first time we characterize the viral diversity of this hypersaline environment during the two seasons, as well as the physicochemical characteristics and the prokaryotic communities of the analysed samples. Most of the selected samples showed a peculiar physicochemical composition and prokaryotic diversity, mostly different from each other even for samples from locations in close proximity or the same season. In contrast to most hypersaline systems Bacteria frequently outnumbered Archaea. Furthermore, an outstanding percentage of members of Salinibacter sp., likely a species different from the cosmopolitan Salinibacter ruber, was obtained in most of the samples. Viral communities displayed the morphologies normally found in hypersaline environments. Two seasonal samples were chosen for a detailed metagenomic analysis of the viral assemblage. Both viral communities shared common sequences but were dominated by sample-specific viruses, mirroring the differences also observed in physicochemical and prokaryotic community composition. These metaviromes were distinct from those detected in other hypersaline systems analysed to date.

Unilateral Versus Bilateral Lung Transplantation: Do Different Esophageal Risk Factors Predict Chronic Allograft Failure?

GOALS: To assess the effect of unilateral versus bilateral lung transplantation (LTx) on esophageal motility and gastroesophageal reflux, and the association with the development of obstructive chronic lung allograft dysfunction (o-CLAD). BACKGROUND: We have shown that esophagogastric junction outflow obstruction, incomplete bolus transit, and proximal reflux are all independent risk factors for the development of chronic allograft failure. However, it remains unclear whether these factors are influenced by the type of surgery and how this relates to allograft failure. STUDY: Patients post-LTx (n=48, 24 female; aged 20 to 73 y) completed high-resolution impedance manometry and 24-hour pH/impedance. RESULTS: Patients who had undergone unilateral LTx were more likely to exhibit esophagogastric junction outflow obstruction (47% vs. 18%; P=0.046) and less likely to exhibit hypocontractility (0% vs. 21%; P=0.058) than those who had undergone bilateral LTx. Although the proportion of patients exhibiting gastroesophageal reflux was no different between groups (33% vs. 39%; P=0.505), those undergoing bilateral LTx were more likely to exhibit proximal reflux (8% vs. 37%; P=0.067). Univariate Cox proportion hazards regression analysis did not show a difference between unilateral versus bilateral LTx in the development of o-CLAD (hazard ratio=1.17; 95% confidence interval, 0.48-2.85; P=0.723). CONCLUSION: The type of LTx performed seems to lead to different risk factors for the development of o-CLAD. Physicians should be aware of these differences, as they may need to be taken into account when managing patient's post-LTx.

The content validity of the ANMS GCSI-DD in patients with idiopathic or diabetic gastroparesis.

BACKGROUND: The American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary (ANMS GCSI-DD) was developed to meet Food and Drug Administration (FDA) recommendations for patient-reported outcome (PRO) endpoints in gastroparesis studies, including therapeutic trials. The current version of the ANMS GCSI-DD contains five items pertaining to nausea, early satiety, post-prandial fullness, upper abdominal pain, and vomiting. The specific aims of this study were to determine if the appropriate symptoms are included in the ANMS GCSI-DD and to assess the content validity in patients with idiopathic (IG) and diabetic gastroparesis (DG). METHODS: Patients diagnosed with IG or DG were recruited by five clinical sites in the United States for a cross-sectional, qualitative study involving one-on-one in-person concept elicitation and cognitive debriefing interviews. Concept elicitation included open-ended questions to elicit patients' symptoms and impacts of gastroparesis, while cognitive debriefing was designed to assess the comprehensiveness of the ANMS GCSI-DD and clarity of the instructions, items, and response scales. The interviews were audio-recorded and transcribed. Transcripts were analyzed using a content analysis approach with ATLAS.ti. RESULTS: Of 25 patients interviewed, 15 (60%) had IG and 10 (40%) DG. Mean age of the sample was 42.3 years (range: 20-70 years), and most patients were female (n = 19, 76%) and white (n = 19, 76%). During concept elicitation, patients endorsed the following signs and symptoms as relevant and important to their condition: early satiety (n = 25, 100%), post-prandial fullness (n = 25, 100%), nausea (n = 22, 88%), upper abdominal pain (n = 18, 72%), vomiting (n = 15, 60%), and bloating (n = 11, 44%). Many patients (n = 20, 80%) experienced day-to-day symptom change. During cognitive debriefing, patients confirmed the ANMS GCSI-DD content was comprehensive and reflective of their gastroparesis experience. Patients could easily select a response option and describe how they arrived at their answers. Overall, patients found the instrument's instructions, recall period, items, and response options clear and understandable. CONCLUSIONS: The ANMS GCSI-DD was easily understood, found to contain the most important symptoms for patients with IG and DG, and no changes were recommended. Results support the content validity of the ANMS GCSI-DD for clinical trials and clinical care among IG or DG patients.

Impaired Esophageal Motility and Clearance Post-Lung Transplant: Risk For Chronic Allograft Failure.

OBJECTIVES: Gastroesophageal reflux is common in patients post-lung transplantation (LTx) and thus considered a risk factor for aspiration and consequently allograft rejection and the development of chronic allograft failure. However, evidence supporting this remains unclear and often contradictory. Our aim was to examine the role played by esophageal motility on gastroesophageal reflux exposure, along with its clearance and that of boluses swallowed, and the relationship to development of obstructive chronic lung allograft dysfunction (o-CLAD). METHODS: Patients post-LTx (n=50, 26 female; mean age 55 years (range, 20-73 years)) completed high-resolution impedance manometry and 24-h pH/impedance. Esophageal motility abnormalities were classified based upon the Chicago Classification version 3.0. RESULTS: Esophagogastric junction outflow obstruction alone (EGJOOa) (P=0.01), incomplete bolus transit (IBT) (P=0.006) and proximal reflux (P=0.042) increased the risk for o-CLAD. Patients with EGJOOa were most likely to present with o-CLAD (77%); despite being less likely to exhibit abnormal numbers of reflux events (10%) compared with those with normal motility (o-CLAD: 29%, P<0.05; abnormal reflux events: 64%, P<0.05). Patients with EGJOOa had lower total reflux bolus exposure time than those with normal motility (0.6 vs. 1.5%; P<0.05). In addition, poor esophageal clearance documented by abnormal post-reflux swallow-induced peristaltic wave index associated with o-CLAD; inversely correlating with the proportion of reflux events reaching the proximal esophagus (r=-0.251; P=0.052). CONCLUSIONS: These observations support esophageal dysmotility, especially EGJOOa, and impaired clearance of swallowed bolus or refluxed contents, more so than just the presence of gastroesophageal reflux alone, as important risk factors in the development of o-CLAD.

Seasonal dynamics of extremely halophilic microbial communities in three Argentinian salterns.

Seasonal sampling was carried out at three Argentinian salterns, Salitral Negro (SN), Colorada Grande (CG) and Guatraché (G), to analyze abiotic parameters and microbial diversity and dynamics. Microbial assemblages were correlated to environmental factors by statistical analyses. Principal component analysis of the environmental data grouped SN and CG samples separately from G samples owing to G's higher pH values and sulfate concentration. Differences in microbial assemblages were also found. Many archaeal sequences belonged to uncultured members of Haloquadratum and Haloquadratum-related genera, with different environmental optima. Notably, nearly half of the archaeal sequences were affiliated to the recently described 'Candidatus Haloredividus' (phylum Nanohaloarchaeota), not previously detected in salt-saturated environments. Most bacterial sequences belonged to Salinibacter representatives, while sequences affiliated to the recently described genus Spiribacter were also found. Seasonal analysis showed at least 40% of the microbiota from the three salterns was prevalent through the year, indicating they are well adapted to environmental fluctuations. On the other hand, a minority of archaeal and bacterial sequences were found to be seasonally distributed. Five viral morphotypes and also eukaryal predators were detected, suggesting different mechanisms for controlling prokaryotic numbers. Notably, Guatraché was the saltern that harbored the highest virus-to-cell ratios reported to date for hypersaline environments.

Accuracy of in vivo colorectal polyp discrimination by using dual-focus high-definition narrow-band imaging colonoscopy.

BACKGROUND: Discriminating neoplastic from non-neoplastic polyps can significantly reduce the cost of colonoscopy. The American Society for Gastrointestinal Endoscopy (ASGE) recently set threshold levels for optical diagnostic accuracy to be acceptable for clinical use. OBJECTIVE: In this study, we compare a novel colonoscope capable of dual-focus imaging with standard colonoscopy with respect to the ASGE guidelines. SETTING: An academic medical center ambulatory surgical center. PATIENTS AND INTERVENTIONS: Patients at average risk were randomized to standard colonoscopy (Olympus CF-H180 and Exera II 180 colonoscopes, Olympus America, Center Valley, Pa) or dual-focus colonoscopy (Olympus CF-HQ190 and Exera III 190 colonoscopes, Olympus America). All polyps were given an optical diagnosis and compared with histology. RESULTS: A total of 600 patients were consented and 522 completed all aspects of the procedure. A total of 927 polyps were analyzed. Optical diagnostic accuracy was 79% (95% confidence interval, 74%-83%) for the 190 and 77% (95% confidence interval, 73%-81%) for the 180 colonoscope. Adenoma detection rates were also similar between the 2 groups (50% for the 190 vs 52% for the 180 colonoscope). For small distal rectosigmoid polyps with a high confidence diagnosis, the negative predictive value for adenoma was 96% (range 89%-99%) for the 180 in the narrow-band imaging (NBI) mode and 97% (range 88%-99%) for the 190 colonoscope in NBI mode. Agreement of surveillance intervals by using optical diagnosis was 94% to 95% for all modalities (180 and 190 colonoscopes, white light imaging, NBI). LIMITATIONS: Our study evaluated the accuracy of the 180 and 190 colonoscopes at a center with already-established expertise in endoscopic imaging. CONCLUSIONS: Both traditional and new dual-focus colonoscopes provide highly accurate optical polyp discrimination. There was no difference between the 2 systems in terms of discrimination or adenoma detection. Both systems are consistent with ASGE guidelines for optical diagnosis of selected colorectal polyps without histological confirmation.

Development and validation of the Mayo Clinic Bowel Prep Tolerability Questionnaire.

BACKGROUND: Bowel cleansing is paramount for colonoscopy quality. Unfortunately, an adequate bowel preparation is often limited by side effects and/or patient's intolerance to bowel preparation solutions. Comparisons among different preparations are limited by the lack of validated instruments designed to assess patient's tolerability. AIM: To develop and validate a simple, comprehensive instrument to assess bowel preparation tolerability in patients undergoing colonoscopy. METHODS: Development and validation by phases: Phase I (bibliographic search and questionnaire design); Phase II (assessment of content validity and modification of the questionnaire); Phase III (assessment of reproducibility, final validation, and definitive version of the questionnaire). RESULTS: The initial draft of the questionnaire was generated based on a systematic literature review and feedback from a panel of consultants. Content validity was tested in a focus group of 25 patients undergoing colonoscopy. Patients' suggestions were reviewed by the research team and a second draft of the questionnaire was generated. Final validation and reproducibility were successfully tested (agreement: 86-100%, kappa: 0.77-1.00) in a convenience sample of 100 patients undergoing bowel preparation with different cleansing solutions. CONCLUSION: The Mayo Clinic Bowel Prep Tolerability Questionnaire is a simple, comprehensive instrument suitable to evaluate the tolerability of various types of bowel preparations.

Irritable bowel syndrome in middle-aged and elderly Palestinians: its prevalence and effect of location of residence.

OBJECTIVES: The prevalence of irritable bowel syndrome (IBS) around the world is variable, ranging from as little as 1.1 to 45%. Limited studies have been carried out in Arab populations. The aim of this study was to determine the prevalence of IBS and its subtypes in the West Bank, Palestine, and to assess variation by locality of residence. METHODS: We conducted a population-based, cross-sectional study. Participants were randomly selected from all districts of the West Bank, including cities, villages, and refugee camps, and they were at least 50 years of age. Participants completed the Rome III IBS questionnaire along with demographic data. The primary outcome was the effect of location of residence on the prevalence of IBS. A multivariable logistic regression model was used to assess the difference in IBS prevalence based on locality of residence. RESULTS: A total of 1,601 people were approached for interview, of which 1,352 agreed to participate (response rate 84%). Most participants (53%; n=637) lived in urban centers. The overall prevalence of IBS was 30% (28-33%). IBS was more common in refugee camps (34%) and in villages (34%) compared with urban centers (27%) (P<0.05). Mixed IBS (IBS-M) was the most common of IBS subtypes (55%, n=244). In a multivariable logistic regression analysis, living in refugee camps (odds ratio (OR) 1.68 (95% confidence interval (CI) 1.14-2.40), P=0.005) and in villages (OR 1.33 (1.02-1.72), P=0.033) was associated with increased odds of having IBS when compared with residents of urban centers. IBS, IBS with constipation, and IBS-M were more common in women than in men (P<0.05). CONCLUSIONS: The prevalence of IBS among middle-aged and elderly residents of Palestine is high. Residents in refugee camps and rural areas have a higher incidence of IBS than those in urban areas.