Clinical and Psychological Factors Predict Outcome in Patients With Functional Dyspepsia: A Prospective Study.

BACKGROUND & AIMS: Symptoms of functional dyspepsia (FD) fluctuate over time but there are limited data on the impact of factors on change in dyspepsia symptom severity over time. We aimed to evaluate the demographic, clinical, and psychological factors associated with change in dyspepsia symptom severity. METHODS: Consecutive patients with FD presenting to a tertiary care center completed questionnaires assessing clinical and psychological symptoms at the time of the initial visit (baseline) and 3- to 6-month follow-up evaluations. FD and irritable bowel syndrome (IBS) were diagnosed using Rome IV criteria. FD severity was measured using patient assessment of gastrointestinal symptom severity. Patient-reported outcome measures information scales were used to assess the severity of anxiety, depression, and sleep disturbance. RESULTS: Of 128 FD patients, 64 (50%) also met Rome IV criteria for IBS. In the final multivariable model, lower baseline sleep disturbance, improvement in anxiety scores, absence of IBS, and a lower number of medications taken for gastrointestinal symptoms were associated with improvement in dyspepsia scores (P < .05 for all). Conversely, higher baseline dyspepsia severity was associated with greater improvement in dyspepsia severity at follow-up evaluation (P < .001). CONCLUSIONS: Improvement in FD symptom severity over 3 to 6 months was associated with improvement of anxiety, lower sleep disturbance at baseline, absence of IBS, and higher baseline dyspepsia severity.

Peppermint Oil Treatment for Irritable Bowel Syndrome: A Randomized Placebo-Controlled Trial.

INTRODUCTION: Peppermint oil is often used to treat irritable bowel syndrome (IBS); however, the overall quality of previous studies is low, and findings have been heterogeneous. This study aimed to compare the effects of peppermint oil vs placebo in relieving IBS symptoms. METHODS: In a 6-week, randomized, double-blind, placebo-controlled trial at a single academic center in the United States, individuals diagnosed with IBS (Rome IV criteria), with moderate to severe symptoms based on the IBS Severity Scoring System (IBS-SSS score ≥175), were randomized to enteric-coated peppermint oil 180 mg 3 times daily vs placebo in a 1:2 ratio. The primary outcome was mean change in IBS-SSS scores from baseline to 6-week endpoint. RESULTS: A modified intent-to-treat analysis revealed that there were substantial mean improvements from baseline to 6-week endpoint in the main outcome measure (IBS-SSS) for both peppermint oil (90.8, SD = 75.3) and placebo (100.3, SD = 99.6). Although the peppermint oil group reported numerically lower improvement than the placebo group, the effect size was small (d = -0.11), and the difference between the groups was not statistically significant (P = 0.97). Similarly, both groups reported substantial improvements on the secondary endpoints; but again, there were no statistically significant differences between the groups on any of the secondary measures. Sensitivity analyses using multiple imputation to replace missing data produced similar results and revealed no significant differences between peppermint oil and placebo on any outcome measure. DISCUSSION: Peppermint oil and placebo both showed clinically meaningful improvement in IBS symptoms. However, there were no significant differences between the groups. Further large, rigorous trials are needed to evaluate the role of peppermint oil for the treatment of IBS.

Symptom Severity, Mood, and Healthcare Use Are Associated With Satisfaction in Patients With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Patient satisfaction is an important, but largely overlooked, component of management of functional gastrointestinal disorders. We aimed to identify demographic, clinical, psychosocial, and health-care use factors associated with satisfaction of patients with irritable bowel syndrome (IBS). METHODS: We collected data from consecutive patients at an outpatient gastroenterology clinic of a tertiary care center from 2017 through 2019; the patients completed an electronic symptom survey at their initial visit and 3-6 months later. Patients were included in the study if they met Rome IV criteria for IBS with no organic cause for their symptoms. Patient satisfaction was measured using the irritable bowel syndrome satisfaction with care scale. We collected demographic, clinical, psychosocial, and healthcare use information from survey responses and review of medical records. RESULTS: Of the 137 patients who completed the study, most were satisfied a great deal (34.9%) or completely (18.6%), whereas 6.2% were not satisfied at all and 14.7% were a little satisfied. Among the 5 satisfaction subscales, the highest proportion of patients were satisfied with connection with their provider (93.4%). The subscale benefits of the visit had the lowest satisfaction rate (70.8%). Factors associated with overall satisfaction scores in the 3-6 months after initial consultation included decreased severity of IBS, higher number of follow-up gastroenterology visits, higher number of diagnostic tests during the follow-up period, and higher number of recommendations made at initial visit. Additionally, lower depression score at initial visit associated with higher satisfaction after 3-6 months. CONCLUSIONS: Based on a survey of 137 patients with IBS, factors associated with satisfaction 3-6 months after establishing care with a gastroenterologist include reduced IBS severity, lower depression score at initial visit, higher number of recommendations, and higher number of follow-up gastroenterology visits.

Similarities in Clinical and Psychosocial Characteristics of Functional Diarrhea and Irritable Bowel Syndrome With Diarrhea.

BACKGROUND & AIMS: There have been few published studies of clinical and psychological characteristics of patients with functional diarrhea (FDr). We studied the clinical and psychological characteristics of patients with FDr presenting to a tertiary care clinic, and compared symptom profiles of FDr with those of IBS-diarrhea (IBS-D). METHODS: Consecutive patients with a diagnosis of FDr (n = 48) or IBS-D (n = 49), per Rome IV criteria, completed a detailed symptom survey from October 2017 through July 2018. Abdominal pain and diarrhea severity were assessed using patient-reported outcomes measurement information system (PROMIS) questionnaires. Patients with anxiety, depression, or sleep disturbances were identified based on PROMIS T-score of 60 or more. Mean and proportions were compared using the Student t test and chi-square analyses, respectively. RESULTS: A significantly lower proportion of patients with FDr reported abdominal pain (77.1%) than patients with IBS-D (100%, P < .001). The proportion of patients reporting abdominal bloating and level of severity did not differ significantly between groups. Proportions of bowel movements with diarrhea did not differ significantly between groups (P = .54), but the mean diarrhea PROMIS T-score was significantly higher among patients with IBS-D (P = .03). This difference resulted from the significantly higher levels of fecal urgency-related distress reported by patients with IBS-D (P = .007). Proportions of patients with anxiety, depression, or sleep disturbance, and their severities, did not differ significantly between groups. CONCLUSIONS: In an analysis of about 100 patients with FDr or IBS-D, we found overlap in gastrointestinal and psychosomatic symptoms. These 2 entities appear to be a continuum.

Breath Methane Does Not Correlate With Constipation Severity or Bloating in Patients With Constipation.

GOALS: We aimed to study (1) if the breath methane level on glucose breath testing (GBT) was associated with constipation severity and (2) compare methane levels between patients with constipation and diarrhea. BACKGROUND: The breath methane level has been associated with constipation and its severity. However, a few recent studies have questioned these associations. STUDY: Patients presenting consecutively to a tertiary care gastroenterology motility laboratory for GBT were included. GBT was performed using 75-g glucose load following a standard, institutional protocol. Constipation and irritable bowel syndrome (IBS) severity was measured using Patient Assessment of Constipation Symptoms (PAC-SYM) and IBS-symptom severity scale (IBS-SSS). RESULTS: In the cohort of 79 constipated patients, there was no significant correlation between baseline or maximum methane levels with total PAC-SYM score. IBS-SSS or bloating severity also did not correlate with baseline or maximum methane levels. The baseline or maximum methane levels of ≥3 and 5 ppm were equally distributed among those with constipation (n=79) and diarrhea (n=122). Only baseline methane levels of ≥10 and ≥20 ppm significantly correlated with constipation (P<0.001 for both). CONCLUSIONS: We found that constipation and bloating severity did not correlate with methane levels on GBT. In addition, only higher baseline methane levels (≥10 and ≥20 ppm) significantly correlated with constipation as baseline methane levels up to 5 ppm were equally common in patients with diarrhea and constipation. Baseline methane levels had better correlation with constipation compared with maximum levels of methane achieved.

Brief Behavioral Therapy for Insomnia in Patients with Irritable Bowel Syndrome: A Pilot Study.

BACKGROUND: Up to 60% of patients with irritable bowel syndrome (IBS) report fatigue and 50% meet criteria for clinical insomnia. Recent studies have demonstrated a relationship between poor sleep and next-day IBS symptoms. However, no study to-date has evaluated behavioral therapy to treat poor sleep in IBS. AIMS: The aim of the current pilot study is to test feasibility of behavioral therapy for insomnia among patients with IBS and poor sleep. METHODS: This randomized controlled pilot study tested the feasibility of administering brief behavioral therapy for insomnia (BBT-I) to patients with IBS who report poor sleep. Participants were randomized to BBT-I or self-monitoring control. Exploratory analyses evaluated group differences after 4 weeks of treatment. RESULTS: A total of 25 participants were randomized to the study, 13 to BBT-I and 12 to the control group. Three participants dropped out of the treatment group. Satisfaction with treatment was high. At follow-up, there were significant differences between groups in measures of sleep quality and insomnia severity. There were trends toward significance in IBS severity score, with 40% of the BBT-I sample reporting clinically meaningful drop in symptoms compared to 17% of the control group. Similar trends were observed with belly pain and global improvement scores. CONCLUSIONS: This pilot study demonstrates feasibility/acceptability of a brief behavioral therapy for patients with IBS and poor sleep. Additionally, this study provides preliminary evidence to suggest that treatment of sleep difficulties in patients with IBS may improve IBS symptom outcomes. Future, larger randomized controlled studies are needed.

Chronic Diarrhea and Constipation Are More Common in Depressed Individuals.

BACKGROUND AND AIMS: Depression is a major health issue in the United States and is highly comorbid with gastrointestinal conditions. We collected data from the National Health and Nutrition Examination Survey (NHANES), a representative sample of the US population, to study the relationship between depression and bowel habits. METHODS: Using data from the NHANES (2009-2010), we identified 495 depressed and 4709 non-depressed adults who filled out the Bowel Health Questionnaire. Depression was defined according to a validated questionnaire. We used multivariable analysis, controlling for clinical and demographic variables, to evaluate the relationship between mood and bowel habits. RESULTS: In our weighed sample, 24.6% of depressed individuals and 12.6% of non-depressed individuals reported disordered bowel habits. Chronic diarrhea was significantly more prevalent in depressed individuals (15.53%; 95% CI, 11.34%-20.90%) than non-depressed individuals (6.05%; 95% CI, 5.24%-6.98%; P = .0001). Chronic constipation was also more common in depressed individuals (9.10%; 95% CI, 7.02%-11.69%) than non-depressed individuals (6.55%; 95% CI, 5.55%-7.70% CI; P = .003). Mean depression scores in patients with chronic diarrhea (4.9 ± 5.8) and with chronic constipation (4.4 ± 4.93) were significantly higher than mean depression scores for individuals with normal bowel habits (3.2 ± 4.6) (P < .001). Moderate and severe depression were significantly associated with chronic diarrhea but not chronic constipation. Only mild depression was significantly associated with chronic constipation. CONCLUSIONS: In an analysis of the NHANES database, we found a higher proportion of depressed individuals to have chronic diarrhea and constipation than non-depressed individuals; chronic diarrhea was more strongly associated with depression. Our findings provide support for the relationship between mood and specific bowel habits, accounting for multiple co-variables in a large sample of the general US population.

Effects of Irritable Bowel Syndrome on Daily Activities Vary Among Subtypes Based on Results From the IBS in America Survey.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is associated with significant disease burden and decreased quality of life (QOL). We investigated the effects of IBS on different areas of daily function and compared these among disease subtypes. METHODS: The Life with IBS survey was conducted by Gfk Public Affairs & Corporate Communications from September through October 2015. Respondents met Rome III criteria for constipation-predominant or diarrhea-predominant IBS (IBS-C and IBS-D, respectively). Data were collected from 3254 individuals (mean age, 47 years; 81% female; and 90% Caucasian) who met IBS criteria. RESULTS: Respondents who were employed or in school (n = 1885) reported that IBS symptoms affected their productivity an average of 8.0 days out of the month and they missed approximately 1.5 days of work/school per month because of IBS. More than half the individuals reported that their symptoms were very bothersome. Individuals with IBS-C were more likely than with IBS-D to report avoiding sex, difficulty concentrating, and feeling self-conscious. Individuals with IBS-D reported more avoidance of places without bathrooms, difficulty making plans, avoiding leaving the house, and reluctance to travel. These differences remained when controlling for symptom bothersomeness, age, sex, and employment status. In exchange for 1 month of relief from IBS, more than half of the sample reported they would be willing to give up caffeine or alcohol, 40% would give up sex, 24.5% would give up cell phones, and 21.5% would give up the internet for 1 month. CONCLUSIONS: Although the perceived effects of IBS symptoms on productivity are similar among its subtypes, patients with IBS-C and IBS-D report differences in specific areas of daily function.

Placebo Response in Chronic Idiopathic Constipation: A Systematic Review and Meta-Analysis.

OBJECTIVES: Chronic idiopathic constipation (CIC), like other functional gastrointestinal disorders, has been associated with a high placebo response rate. However, the placebo response in randomized controlled trials has not been described. METHODS: We conducted a search of the medical literature following the protocol outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement using MEDLINE, EMBASE and EMBASE Classic, Web of Science, and the Cochrane Central Register of Controlled Trials for all drugs used for the treatment of CIC. Two independent reviewers performed eligibility assessment and data extraction. The mean response rate was examined for the following 2 responder endpoints: (i) greater than or equal to 3 complete spontaneous bowel movements (CSBMs)/wk (≥3 CSBMs/wk responders) and (ii) mean increase of ≥1 CSBM/wk compared with baseline (increase in ≥1 CSBM/wk responders). RESULTS: A total of 23 placebo-controlled trials met our inclusion criteria and were included in this meta-analysis. The placebo response in CIC trials ranged from 4% to 44%. The magnitude of the placebo response was 13% (95% confidence interval 11%-16%) with the ≥3 CSBM/wk responder endpoint and 28% (95% confidence interval 21%-30%) with the increase of ≥1 in the CSBM responder endpoint. Higher baseline CSBM, older age, and trials with more male participants were significantly associated with a stronger placebo response for both the ≥3 CSBMs/wk endpoint and increase in the ≥1 CSBM/wk endpoint. Trial characteristics such as location (Europe vs Asia/United States) and laxative class (prokinetic vs secretagogue) revealed key differences in the placebo response for both endpoints. The placebo response was not significantly affected by the number of study visits, study duration, year of publication, number of drop outs, or likelihood of receiving active drug. DISCUSSION: The placebo response in CIC trials ranges from 4% to 44% depending on the endpoint. Modifying factors of the placebo response include multiple subject and trial characteristics.

Prevalence of Chronic Constipation and Chronic Diarrhea in Diabetic Individuals in the United States.

INTRODUCTION: Diabetic individuals commonly report disordered bowel habits. This study aims to report the prevalence and associated factors of chronic diarrhea (CD) and chronic constipation (CC) in diabetics using a nationally representative sample of US adults. METHODS: Analyses were performed using data from subjects in the 2009-2010 National Health and Nutrition Examination Survey (NHANES) dataset who completed the Bowel Health Questionnaire. The NHANES dataset provides medical comorbidities, demographics, and dietary habits of a nationally representative group of adult survey participants in the United States. CC and CD were defined by Bristol Stool Form Scale (BSFS) Types 1 & 2 and BSFS Types 6 & 7 as the "usual or most common stool type," respectively, and frequent laxative users were also defined as having CC. Co-variables for all subjects included demographic and lifestyle factors, and co-variables evaluated only in diabetics included treatment and severity markers for diabetes. RESULTS: We identified 661 diabetic subjects and 4488 non-diabetic subjects. Diabetic subjects (25.8%) reported disordered bowel habits. In unadjusted analysis, CD was more prevalent in diabetics than in non-diabetics (11.2% vs. 6.0%; p < 0.0001); however, the prevalence of CC was not significantly different between groups (14.6% vs. 11.2%; p = 0.126). When adjusting for covariates (e.g., BMI, gender, age, race/ethnicity, education level, etc.), diabetes itself remained associated with CD. Diabetic individuals with CD more frequently used drugs to lower blood sugar, and diabetic subjects with CC more frequently had poor kidney function. CONCLUSIONS: CD is significantly more prevalent in diabetics than in non-diabetics, whereas CC is not, and the association between CD and diabetes remains significant when adjusting for covariates. Use of medications that lower blood sugar is associated with CD in diabetic individuals, whereas poor kidney function is associated with CC in diabetics.

Significant Morbidity and Mortality Associated with Fecal Impaction in Patients Who Present to the Emergency Department.

BACKGROUND: Fecal impaction (FI) is defined as a large mass of stool in the rectum and/or colon that is unable to be evacuated. No study to date details demographics and outcomes in a sizeable sample of FI patients in the USA. AIMS: The present study aims to develop knowledge of FI by reporting descriptive measures and outcomes of patients presenting to a US emergency department (ED) with FI. METHODS: Medical charts coded with FI at Beth Israel Deaconess Medical Center from 2016 or 2017 were identified retrospectively. Patients diagnosed with FI in the ED or subsequent to direct hospital admission from the ED were included. Patient-specific demographics, visit-specific details, medical and medication histories, and hospital treatment and outcome measures were included in a database and analyzed. RESULTS: Thirty-two patients (mean age of 72.9 years, 62.5% female) had a total of 42 ED visits with FI. Patients had an average of 8.7 diagnoses and 11.2 medications listed in their charts. 54.8% of patients were taking at least one commonly prescribed constipating medication. The median total length of stay for admitted patients was 3 days, with nearly 90% of the ED visits with FI requiring hospital admission. 40.6% of patients experienced serious FI-related morbidities, and 21.9% of patients with FI died in the hospital. CONCLUSION: Patients presenting with FI had high risk of morbidity and mortality, complex medical histories, and large numbers of active treatment regimens. Patients with FI should receive immediate treatment and close monitoring for morbidities and complications.

Prevalence and determinants of postprandial diarrhea in a tertiary care center.

BACKGROUND AND AIMS: Postprandial diarrhea (PPD) is commonly seen in patients with disorders of gut-brain interaction (DGBI), but the factors associated with it have not been well studied. In this study, we aim to study the burden, impact, and predictors of PPD using a clinical cohort of DGBI patients. METHODS: This study included patients with chronic diarrhea fulfilling ROME IV criteria for irritable bowel syndrome (IBS) or functional diarrhea (FDiarr). PPD was defined as patients reporting mushy/watery stools following meals ≥30% of the time in the last 3 months using a ROME IV question on PPD. Age, sex, and BMI, the severity of diarrhea, abdominal pain, depression, anxiety, somatization, and quality of life were assessed using validated measures. Person's chi-square test and Student's t-test were used to compare variables. A multiple linear regression model with backward elimination was done to determine predictors of PPD severity. KEY RESULTS: Of 213 eligible patients, more than three-fourth of patients (75.6%) had PPD. Women (79.0%, p = 0.037), patients with ROME IV diagnosis of IBS-D (90.5%, p = 0.002), and functional dyspepsia (83.2%, p = 0.014), and those with a history of cholecystectomy (CCY) (95.5%, p = 0.022) were more likely to report PPD. PPD patients experienced more severe abdominal pain, diarrhea, and decreased quality of life (QoL) but showed no significant difference in BMI, anxiety, depression, sleep, or somatization. In our regression model, female sex and history of CCY were independent predictors of PPD. CONCLUSIONS AND INFERENCES: PPD is frequently reported among chronic diarrhea patients and is associated with more severe GI symptoms and decreased QoL. Female sex and CCY predict PPD, while psychological factors do not.

Improvement in constipation and diarrhea is associated with improved abdominal pain in patients with functional bowel disorders.

BACKGROUND: Abdominal pain is a bothersome and lifestyle limiting symptom in patients with functional bowel disorders. It is associated with decreased quality of life in affected individuals, as well as significant annual healthcare expenditure. Knowledge of specific factors that predict improvement in abdominal pain in those with functional bowel disorders is thus far limited. METHODS: Consecutive patients presenting for outpatient care at a major academic medical center between October 2017 and March 2020 completed an electronic symptom survey prior to initial clinic visit, and again after 3 months. The Rome IV questionnaires for functional dyspepsia, irritable bowel syndrome, functional constipation, and functional diarrhea were all included. Additionally, all subjects completed the Patient Reported Outcomes Measurement Information System Anxiety, Depression, and sleep disturbance questionnaires. Patients with a diagnosis of a Rome IV functional gastrointestinal disorder without any organic cause for symptoms were identified based on both chart review as well as survey response data. Univariable and multivariable analysis was used to assess predictors of improved abdominal pain after 3 months. KEY RESULTS: 180 patients with a mean age of 45.3 years were included in the final analysis. 78.3% of patients were female, and 77.2% met Rome IV criteria for irritable bowel syndrome. On multivariable analysis, improvement in constipation and diarrhea were both independent predictors of improved abdominal pain after 3 months. CONCLUSIONS AND INFERENCES: Improvement in constipation and diarrhea both predicted improvement in abdominal pain, suggesting that addressing these factors is central to the management of abdominal pain in functional gastrointestinal disorders.

Open-label placebo vs double-blind placebo for irritable bowel syndrome: a randomized clinical trial.

ABSTRACT: It is commonly believed that blinding to treatment assignment is necessary for placebos to have an effect. However, placebos administered without concealment (ie, open-label placebos [OLPs]) have recently been shown to be effective in some conditions. This study had 2 objectives: first, to determine whether OLP treatment is superior to no-pill control (NPC) in irritable bowel syndrome (IBS) and, second, to compare the efficacy of OLP against double-blind placebo (DBP). In a 6-week, 3-arm, randomized clinical trial, participants were randomized in equal proportions to 3 arms: OLP, DBP, or NPC. Two hundred sixty-two adults (72.9% women), with a mean age of 42.0 (SD = 18.1) years, participated in the primary study. The mean improvement on the IBS Severity Scoring System from baseline to the 6-week end point was significantly greater in OLP compared with that in NPC (90.6 vs 52.3, P = 0.038). Open-label placebo and DBP did not differ significantly on IBS Severity Scoring System improvement (100.3 vs 90.6, P = 0.485). Standardized effect sizes were moderate for OLP vs NPC (d = 0.43) and small for OLP vs DBP (d = 0.10). Participants treated with OLP reported clinically meaningful improvements in IBS symptoms that were significantly greater than those on NPC. Open-label placebo and DBP had similar effects that did not differ significantly, suggesting that blinding may not be necessary for placebos to be effective and that OLP could play a role in the management of patients with refractory IBS.

Revealing the structure of pharmacobehavioral space through motion sequencing.

Understanding how genes, drugs and neural circuits influence behavior requires the ability to effectively organize information about similarities and differences within complex behavioral datasets. Motion Sequencing (MoSeq) is an ethologically inspired behavioral analysis method that identifies modular components of three-dimensional mouse body language called 'syllables'. Here, we show that MoSeq effectively parses behavioral differences and captures similarities elicited by a panel of neuroactive and psychoactive drugs administered to a cohort of nearly 700 mice. MoSeq identifies syllables that are characteristic of individual drugs, a finding we leverage to reveal specific on- and off-target effects of both established and candidate therapeutics in a mouse model of autism spectrum disorder. These results demonstrate that MoSeq can meaningfully organize large-scale behavioral data, illustrate the power of a fundamentally modular description of behavior and suggest that behavioral syllables represent a new class of druggable target.

Author Correction: Intragenic antagonistic roles of protein and circRNA in tumorigenesis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Randomized Clinical Trial: Crofelemer Treatment in Women With Diarrhea-Predominant Irritable Bowel Syndrome.

INTRODUCTION: Crofelemer, the active compound purified from latex of Croton lechleri, has been shown to improve HIV and traveler's diarrhea and improve pain in women with irritable bowel syndrome-diarrhea (IBS-D). This trial evaluated the effect of crofelemer on abdominal pain in women with IBS-D. METHODS: Women with IBS-D were randomized to crofelemer (125 mg) or placebo twice daily for 12 weeks. The primary efficacy endpoint was overall change in percentage of abdominal pain/discomfort-free days. Post hoc analysis for Food and Drug Administration (FDA) monthly responders was performed for stool consistency, abdominal pain, and combined stool consistency and abdominal pain. RESULTS: A total of 240 women were enrolled. There was no significant difference in overall percentage of pain/discomfort-free day between the groups. In post hoc analysis, FDA abdominal pain monthly responders were significantly more likely during months 1 through 2 (58.3% vs 45.0%, P = 0.030) as well as during the entire 3 months (54.2% vs 42.5%, P = 0.037) in the crofelemer group when compared with placebo. However, there was no significant difference in the percentage of FDA stool consistency monthly responders or combined stool consistency and pain monthly responders between the groups. Crofelemer had a safety profile similar to placebo. DISCUSSION: Crofelemer did not significantly improve abdominal pain over placebo by the primary endpoint. However, it did based on the FDA abdominal pain monthly responder endpoint. This suggests that crofelemer may have a role in the treatment of abdominal pain associated with IBS-D. Further studies are warranted to evaluate the potential of crofelemer as a visceral analgesic.

Emergency department visits for depression in the United States from 2006 to 2014.

BACKGROUND: Patients with depression frequently seek care in the emergency department (ED), especially in the context of suicidal ideation (SI) and self-harm (SH). However, the prevalence and trends in the United States (US) of ED visits for depression have not yet been characterized using a nationally representative sample. This study evaluates ED trends for depression in the US from 2006 to 2014. METHODS: Data was obtained from the Nationwide Emergency Department Sample (NEDS) in 2006 and 2014 using a primary ICD-9 diagnosis of depression or a primary diagnosis of suicidal ideation (SI) and a secondary diagnosis of depression. RESULTS: Between 2006 and 2014, there was a 25.9% increase in visits to the ED for depression, which was higher than the 14.8% increase in total ED visits during this time period. The mean inflation adjusted charges associated with depression-related ED visits increased by 107.7%, which was higher than the increase in mean charges for all ED visits in the same time period (40.47%). Visit rates were bimodally distributed with respect to age, with peaks in adolescence and middle age. Notably there was a 61.3% increase in ED visits for depression in individuals younger than 20 between 2006 and 2014. Over half of patients were admitted for inpatient care with a mean length of stay of 5.6 days in both years. Inpatient charges increased 71.8% between 2006 and 2014. CONCLUSIONS: ED visits for depression in the United States rose 25.9% between 2006 and 2014, which was higher than the 14.8% increase in total ED visits during this time period. Over half of ED depression visits were admitted to inpatient stay (mean 5.6 days both years).

Fecal urgency is common in constipated patients and is associated with anxiety.

BACKGROUND: Fecal urgency is a symptom generally associated with diarrhea but is also reported by patients with constipation. Our aim was to (a) assess the prevalence and burden of fecal urgency in constipated patients (b) evaluate gastrointestinal and psychiatric predictors of moderate to severe fecal urgency in these patients. METHODS: Patients presenting consecutively to a tertiary outpatient gastroenterology clinic with constipation were included. Patients were considered to have moderate to severe fecal urgency if ≥50% of bowel movements (BMs) in the past 3 months were associated with fecal urgency. Anxiety, depression, and sleep disturbance were diagnosed using a Patient-Reported Outcomes Measurement Information System (PROMIS) t-score of ≥60. Abdominal pain and constipation severity were also assessed using PROMIS questionnaires. Univariable and stepwise logistic regression were used to identify predictors of moderate to severe fecal urgency. KEY RESULTS: Of 139 constipated patients, 70.8% reported experiencing fecal urgency in the past 3 months and 25.8% reported being significantly bothered by it. Moderate to severe fecal urgency was reported by 27% of 139 patients. Frequency of loose stools (OR 1.5, 95% CI 1.1, 2.0) and presence of anxiety (OR 2.3, 95% CI 1.1, 5.0) were independent predictors of moderate to severe fecal urgency. CONCLUSIONS AND INFERENCES: Fecal urgency is common in patients with constipation and is frequently bothersome to many patients. We identified clinical and psychiatric factors associated with moderate to severe fecal urgency in constipated patients with potential therapeutic implications if validated in future studies.

PTEN Methylation by NSD2 Controls Cellular Sensitivity to DNA Damage.

The function of PTEN in the cytoplasm largely depends on its lipid-phosphatase activity, though which it antagonizes the PI3K-AKT oncogenic pathway. However, molecular mechanisms underlying the role of PTEN in the nucleus remain largely elusive. Here, we report that DNA double-strand breaks (DSB) promote PTEN interaction with MDC1 upon ATM-dependent phosphorylation of T/S398-PTEN. Importantly, DNA DSBs enhance NSD2 (MMSET/WHSC1)-mediated dimethylation of PTEN at K349, which is recognized by the tudor domain of 53BP1 to recruit PTEN to DNA-damage sites, governing efficient repair of DSBs partly through dephosphorylation of γH2AX. Of note, inhibiting NSD2-mediated methylation of PTEN, either through expressing methylation-deficient PTEN mutants or through inhibiting NSD2, sensitizes cancer cells to combinatorial treatment with a PI3K inhibitor and DNA-damaging agents in both cell culture and in vivo xenograft models. Therefore, our study provides a novel molecular mechanism for PTEN regulation of DSB repair in a methylation- and protein phosphatase-dependent manner. SIGNIFICANCE: NSD2-mediated dimethylation of PTEN is recognized by the 53BP1 tudor domain to facilitate PTEN recruitment into DNA-damage sites, governing efficient repair of DNA DSBs. Importantly, inhibiting PTEN methylation sensitizes cancer cells to combinatorial treatment with a PI3K inhibitor combined with DNA-damaging agents in both cell culture and in vivo xenograft models.This article is highlighted in the In This Issue feature, p. 1143.