Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

BACKGROUND: Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab). METHODS: We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. RESULTS: Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 µg/mL [P = .49]; adalimumab: 11.1 vs 10.5 µg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 µg/mL [P < .01]; adalimumab: 9.1 vs 12.3 µg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). CONCLUSIONS: LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

For children with Crohn's disease treated with biologic medications, with and without low-dose methotrexate, the role of drug levels on treatment failure in a recent prospective trial is unclear. These data suggest patients on infliximab with therapeutic drug levels are more likely to continue any therapy, and the effect on patients treated with adalimumab requires more investigation.

HLA DQA1*05 and risk of anti-TNF treatment failure and anti-drug antibody development in children with Crohn's Disease: HLA DQA1*05 and Pediatric Crohn's Disease.

OBJECTIVES: HLA DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. METHODS: We analyzed banked serum from patients with CD < 21 years of age enrolled in COMBINE, a multi-center, prospective randomized trial of anti-TNF monotherapy vs. combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development. RESULTS: A trend towards increased treatment failure among HLA DQA1*05 positive participants was not significant (HR 1.58, 95% CI 0.95-2.62; p=0.08). After stratification by HLA DQA1*05 and by methotrexate vs. placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05 positive patients on placebo (HR 0.31, 95% CI 0.13-0.70; p=0.005).A trend toward increased ADA development among HLA DQA1*05 positive participants was not significant (odds ratio [OR] 1.96, 95% CI 0.90-4.31, p=0.09). After further stratification, HLA DQA1*05 negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05 positive patients on placebo (OR 0.12, 95% CI 0.03-0.55; p=0.008). CONCLUSIONS: In a randomized trial of children with CD initiating anti-TNF, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

Outcomes of a Comprehensive Mobile Vaping Cessation Program in Adults Who Vape Daily: Cohort Study.

BACKGROUND: In the United States, e-cigarettes, or vapes, are the second most commonly used tobacco product. Despite abundant smartphone app-based cigarette cessation programs, there are few such programs for vaping and even fewer supporting data. OBJECTIVE: This exploratory, prospective, single-arm, remote cohort study of the Pivot vaping cessation program assessed enrollment and questionnaire completion rates, participant engagement and retention, changes in attitudes toward quitting vaping, changes in vaping behavior, and participant feedback. We aimed to establish early data to inform program improvements and future study design. METHODS: American adults aged ≥21 years who vaped daily, reported ≥5 vape sessions per day, and planned to quit vaping within 6 months were recruited on the web. Data were self-reported via app- and web-based questionnaires. Outcomes included engagement and retention (ie, weeks in the program, number of Pivot app openings, and number of messages sent to the coach), vaping attitudes (ie, success in quitting and difficulty staying quit), vaping behavior (ie, quit attempts, Penn State Electronic Cigarette Dependence Index, 7- and 30-day point-prevalence abstinence [PPA], and continuous abstinence [defined as ≥7-day PPA at 12 weeks+30-day PPA at 26 weeks+0 vaping sessions since 12 weeks]), and participant feedback. RESULTS: In total, 73 participants onboarded (intention-to-treat sample); 68 (93%) completed the 12- and 26-week questionnaires (completer samples). On average, participants were active in Pivot for 13.8 (SD 7.3) weeks, had 87.3 (SD 99.9) app sessions, and sent 37.6 (SD 42.3) messages to their coach over 26 weeks. Mean success in quitting and difficulty staying quit (scale of 1-10) improved from baseline to 12 weeks-4.9 (SD 2.9) to 7.0 (SD 3.0) and 4.0 (SD 2.8) to 6.2 (SD 3.1), respectively (P<.001 in both cases). Most participants (64/73, 88%) made ≥1 quit attempt. At 26 weeks, intention-to-treat 7-day PPA, 30-day PPA, and continuous abstinence rates were 48% (35/73), 45% (33/73), and 30% (22/73), respectively. In total, 45% (33/73) of the participants did not achieve 7-day PPA at 26 weeks; their mean Penn State Electronic Cigarette Dependence Index score decreased from baseline (13.9, SD 3.1) to 26 weeks (10.8, SD 4.5; mean change -3.2, SD 3.9; P<.001); 48% (16/33) of these participants improved in the e-cigarette dependence category. At 2 weeks, 72% (51/71) of respondents reported that using Pivot increased their motivation to quit vaping; at 4 weeks, 79% (55/70) reported using Pivot decreased the amount they vaped per day. CONCLUSIONS: In this first evaluation of Pivot in adult daily vapers, questionnaire completion rates were >90%, average program engagement duration was approximately 14 weeks, and most participants reported increased motivation to quit vaping. These and early cessation outcomes herein suggest a role for Pivot in vaping cessation and will inform associated future study and program improvements.

High Body Mass Index and Response to Anti-Tumor Necrosis Factor Therapy in Pediatric Crohn's Disease.

INTRODUCTION: Obesity is common among patients with pediatric Crohn's disease (PCD). Some adult studies suggest obese patients respond less well to anti-tumor necrosis factor (TNF) treatment. This study sought compares anti-TNF response and anti-TNF levels between pediatric patients with normal and high body mass index (BMI). METHODS: The COMBINE trial compared anti-TNF monotherapy with combination therapy with methotrexate in patients with PCD. In this secondary analysis, a comparison of time-to-treatment failure among patients with normal BMI vs BMI Z -score >1, adjusting for prescribed anti-TNF (infliximab [IFX] or adalimumab [ADA]), trial treatment assignment (combination vs monotherapy), and relevant covariates. Median anti-TNF levels across BMI category was also examined. RESULTS: Of 224 participants (162 IFX initiators and 62 ADA initiators), 111 (81%) had a normal BMI and 43 (19%) had a high BMI. High BMI was associated with treatment failure among ADA initiators (7/10 [70%] vs 12/52 [23%], hazard ratio 0.29, P = 0.007) but not IFX initiators. In addition, ADA-treated patients with a high BMI had lower ADA levels compared with those with normal BMI (median 5.8 vs 12.8 µg/mL, P = 0.02). IFX trough levels did not differ between BMI groups. DISCUSSION: Overweight and obese patients with PCD are more likely to experience ADA treatment failure than those with normal BMI. Higher BMI was associated with lower drug trough levels. Standard ADA dosing may be insufficient for overweight children with PCD. Among IFX initiators, there was no observed difference in clinical outcomes or drug levels, perhaps due to weight-based dosing and/or greater use of proactive drug monitoring.

Long-Term Outcomes of a Comprehensive Mobile Smoking Cessation Program With Nicotine Replacement Therapy in Adult Smokers: Pilot Randomized Controlled Trial.

BACKGROUND: Increased smartphone ownership has led to the development of mobile smoking cessation programs. Although the related body of evidence, gathered through the conduct of randomized controlled trials (RCTs), has grown in quality and rigor, there is a need for longer-term data to assess associated smoking cessation durability. OBJECTIVE: The primary aim was to compare smoking cessation outcomes at 52 weeks in adult smokers randomized to a mobile smoking cessation program, Pivot (intervention), versus QuitGuide (control). The secondary aims included comparison of other smoking-related behaviors, outcomes and participant feedback, and exploratory analyses of baseline factors associated with smoking cessation. METHODS: In this remote pilot RCT, cigarette smokers in the United States were recruited on the web. Participants were offered 12 weeks of free nicotine replacement therapy (NRT). Data were self-reported via a web-based questionnaire with videoconference biovalidation in participants who reported 7-day point-prevalence abstinence (PPA). Outcomes focused on cessation rates with additional assessment of quit attempts, cigarettes per day (CPD), self-efficacy via the Smoking Abstinence Self-Efficacy Questionnaire, NRT use, and participant feedback. Cessation outcomes included self-reported 7- and 30-day PPA, abstinence from all tobacco products, and continuous abstinence. PPA and continuous abstinence were biovalidated using witnessed breath carbon monoxide samples. Exploratory post hoc regression analyses were performed to identify baseline variables associated with smoking cessation. RESULTS: Participants comprised 188 smokers (n=94, 50% in the Pivot group and n=94, 50% in the QuitGuide group; mean age 46.4, SD 9.2 years; n=104, 55.3% women; n=128, 68.1% White individuals; mean CPD 17.6, SD 9.0). Several cessation rates were higher in the Pivot group (intention to treat): self-reported continuous abstinence was 20% (19/94) versus 9% (8/94; P=.03) for QuitGuide, biochemically confirmed abstinence was 31% (29/94) versus 18% (17/94; P=.04) for QuitGuide, and biochemically confirmed continuous abstinence was 19% (18/94) versus 9% (8/94; P=.046) for QuitGuide. More Pivot participants (93/94, 99% vs 80/94, 85% in the QuitGuide group; P<.001) placed NRT orders (mean 3.3, SD 2.0 vs 1.8, SD 1.6 for QuitGuide; P<.001). Pivot participants had increased self-efficacy via the Smoking Abstinence Self-Efficacy Questionnaire (mean point increase 3.2, SD 7.8, P<.001 vs 1.0, SD 8.5, P=.26 for QuitGuide). QuitGuide participants made more mean quit attempts (7.0, SD 6.3 for Pivot vs 9.5, SD 7.5 for QuitGuide; P=.01). Among those who did not achieve abstinence, QuitGuide participants reported greater CPD reduction (mean -34.6%, SD 35.5% for Pivot vs -46.1%, SD 32.3% for QuitGuide; P=.04). Among those who reported abstinence, 90% (35/39) of Pivot participants and 90% (26/29) of QuitGuide participants indicated that their cessation program helped them quit. CONCLUSIONS: This pilot RCT supports the long-term effectiveness of the Pivot mobile smoking cessation program, with abstinence rates durable to 52 weeks. TRIAL REGISTRATION: ClinicalTrials.gov NCT04955639; https://clinicaltrials.gov/ct2/show/NCT04955639.

Spontaneous episodic inflammation in the intestines of mice lacking HNF4A is driven by microbiota and associated with early life microbiota alterations.

The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals who mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. Whereas IBD clinical presentation is well described, how interactions between microbiota and host genotype impact early subclinical stages of the disease remains unclear. The transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) has been associated with human IBD, and deletion of Hnf4a in intestinal epithelial cells (IECs) in mice (Hnf4aΔIEC) leads to spontaneous colonic inflammation by 6-12 mo of age. Here, we tested if pathology in Hnf4aΔIEC mice begins earlier in life and if microbiota contribute to that process. Longitudinal analysis revealed that Hnf4aΔIEC mice reared in specific pathogen-free (SPF) conditions develop episodic elevated fecal lipocalin 2 (Lcn2) and loose stools beginning by 4-5 wk of age. Lifetime cumulative Lcn2 levels correlated with histopathological features of colitis at 12 mo. Antibiotic and gnotobiotic tests showed that these phenotypes in Hnf4aΔIEC mice were dependent on microbiota. Fecal 16S rRNA gene sequencing in SPF Hnf4aΔIEC and control mice disclosed that genotype significantly contributed to differences in microbiota composition by 12 mo, and longitudinal analysis of the Hnf4aΔIEC mice with the highest lifetime cumulative Lcn2 revealed that microbial community differences emerged early in life when elevated fecal Lcn2 was first detected. These microbiota differences included enrichment of a novel phylogroup of Akkermansia muciniphila in Hnf4aΔIEC mice. We conclude that HNF4A functions in IEC to shape composition of the gut microbiota and protect against episodic inflammation induced by microbiota throughout the lifespan. IMPORTANCE The inflammatory bowel diseases (IBD), characterized by chronic inflammation of the intestine, affect millions of people around the world. Although significant advances have been made in the clinical management of IBD, the early subclinical stages of IBD are not well defined and are difficult to study in humans. This work explores the subclinical stages of disease in mice lacking the IBD-associated transcription factor HNF4A in the intestinal epithelium. Whereas these mice do not develop overt disease until late in adulthood, we find that they display episodic intestinal inflammation, loose stools, and microbiota changes beginning in very early life stages. Using germ-free and antibiotic-treatment experiments, we reveal that intestinal inflammation in these mice was dependent on the presence of microbiota. These results suggest that interactions between host genotype and microbiota can drive early subclinical pathologies that precede the overt onset of IBD and describe a mouse model to explore those important processes.

Mepolizumab for treatment of adolescents and adults with eosinophilic oesophagitis: a multicentre, randomised, double-blind, placebo-controlled clinical trial.

OBJECTIVE: We aimed to determine whether mepolizumab, an anti-IL-5 antibody, was more effective than placebo for improving dysphagia symptoms and decreasing oesophageal eosinophil counts in eosinophilic oesophagitis (EoE). METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled, trial. In the first part, patients aged 16-75 with EoE and dysphagia symptoms (per EoE Symptom Activity Index (EEsAI)) were randomised 1:1 to 3 months of mepolizumab 300 mg monthly or placebo. Primary outcome was change in EEsAI from baseline to month 3 (M3). Secondary outcomes included histological, endoscopic and safety metrics. In part 2, patients initially randomised to mepolizumab continued 300 mg monthly for 3 additional months (mepo/mepo), placebo patients started mepolizumab 100 mg monthly (pbo/mepo), and outcomes were reassessed at month 6 (M6). RESULTS: Of 66 patients randomised, 64 completed M3, and 56 completed M6. At M3, EEsAI decreased 15.4±18.1 with mepolizumab and 8.3±18.0 with placebo (p=0.14). Peak eosinophil counts decreased more with mepolizumab (113±77 to 36±43) than placebo (146±94 to 160±133) (p<0.001). With mepolizumab, 42% and 34% achieved histological responses of <15 and ≤6 eos/hpf compared with 3% and 3% with placebo (p<0.001 and 0.02). The change in EoE Endoscopic Reference Score at M3 was also larger with mepolizumab. At M6, EEsAI decreased 18.3±18.1 points for mepo/mepo and 18.6±19.2 for pbo/mepo (p=0.85). The most common adverse events were injection-site reactions. CONCLUSIONS: Mepolizumab did not achieve the primary endpoint of improving dysphagia symptoms compared with placebo. While eosinophil counts and endoscopic severity improved with mepolizumab at 3 months, longer treatment did not yield additional improvement. TRIAL REGISTRATION NUMBER: NCT03656380.

Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.

Outcomes of a Comprehensive Mobile Smoking Cessation Program With Nicotine Replacement Therapy in Adult Smokers: Pilot Randomized Controlled Trial.

BACKGROUND: Cigarette smoking remains the leading cause of preventable illness and death, underscoring ongoing need for evidence-based solutions. Pivot, a US Clinical Practice Guideline-based mobile smoking cessation program, comprises a personal carbon monoxide breath sensor; a smartphone app; in-app, text-based human-provided coaching; nicotine replacement therapy; and a moderated web-based community. Promising Pivot cohort studies have established the foundation for comparative assessment. OBJECTIVE: This study aimed to compare engagement, retention, attitudes toward quitting smoking, smoking behavior, and participant feedback between Pivot and QuitGuide, a US Clinical Practice Guideline-based smoking cessation smartphone app from the National Cancer Institute. METHODS: In this remote pilot randomized controlled trial, cigarette smokers in the United States were recruited on the web and randomized to Pivot or QuitGuide. Participants were offered 12 weeks of free nicotine replacement therapy. Data were self-reported via weekly web-based questionnaires for 12 weeks and at 26 weeks. Outcomes included engagement and retention, attitudes toward quitting smoking, smoking behavior, and participant feedback. The primary outcome was self-reported app openings at 12 weeks. Cessation outcomes included self-reported 7- and 30-day point prevalence abstinence (PPA), abstinence from all tobacco products, and continuous abstinence at 12 and 26 weeks. PPA and continuous abstinence were biovalidated via breath carbon monoxide samples. RESULTS: Participants comprised 188 smokers (94 Pivot and 94 QuitGuide): mean age 46.4 (SD 9.2) years, 104 (55.3%) women, 128 (68.1%) White individuals, and mean cigarettes per day 17.6 (SD 9.0). Engagement via mean "total app openings through 12 weeks" (primary outcome) was Pivot, 157.9 (SD 210.6) versus QuitGuide, 86.5 (SD 66.3; P<.001). Self-reported 7-day PPA at 12 and 26 weeks was Pivot, 35% (33/94) versus QuitGuide, 28% (26/94; intention to treat [ITT]: P=.28) and Pivot, 36% (34/94) versus QuitGuide, 27% (25/94; ITT: P=.12), respectively. Self-reported 30-day PPA at 12 and 26 weeks was Pivot, 29% (27/94) versus QuitGuide, 22% (21/94; ITT: P=.32) and Pivot, 32% (30/94) versus QuitGuide, 22% (21/94; ITT: P=.12), respectively. The biovalidated abstinence rate at 12 weeks was Pivot, 29% (27/94) versus QuitGuide, 13% (12/94; ITT: P=.008). Biovalidated continuous abstinence at 26 weeks was Pivot, 21% (20/94) versus QuitGuide, 10% (9/94; ITT: P=.03). Participant feedback, including ease of setup, impact on smoking, and likelihood of program recommendation were favorable for Pivot. CONCLUSIONS: In this randomized controlled trial comparing the app-based smoking cessation programs Pivot and QuitGuide, Pivot participants had higher engagement and biovalidated cessation rates and more favorable user feedback at 12 and 26 weeks. These findings support Pivot as an effective, durable mobile smoking cessation program. TRIAL REGISTRATION: ClinicalTrials.gov NCT04955639; https://clinicaltrials.gov/ct2/show/NCT04955639.

Colonic Diverticulosis Is Not Associated With Painful Abdominal Symptoms in a US Population.

BACKGROUND AND AIMS: Symptomatic uncomplicated diverticular disease is a controversial diagnosis defined as chronic gastrointestinal symptoms in patients with diverticulosis. We assessed whether individuals with diverticulosis had an increased risk of abdominal pain, irritable bowel syndrome, or altered bowel habits. METHODS: We performed a prospective cohort study of participants who had a first-time screening colonoscopy at the University of North Carolina between 2013 and 2015. The colonoscopy included a detailed assessment for diverticulosis. Participants completed a follow-up interview between 2019 and 2020 to measure bowel habits and gastrointestinal symptoms. Poisson regression was used to estimate relative risk and 95% confidence intervals (CIs). RESULTS: Among the 310 participants, 128 (41%) had diverticulosis at baseline. Follow-up interviews were performed a mean of 6.8 years after the baseline colonoscopy. After adjustment for confounders, there was no association between diverticulosis and abdominal pain lasting >24 hours (relative risk [RR], 0.40; 95% CI, 0.05-3.45) or symptoms of irritable bowel syndrome (RR, 1.30; 95% CI, 0.69-2.42) at the time of follow-up. Compared to those with no diverticulosis, participants with diverticulosis were more likely to have more frequent bowel movements per day (RR, 1.60; 95% CI, 1.05-2.44). The association was stronger in participants with >10 diverticula (RR, 2.03; 95% CI, 1.19-3.48). Diverticulosis was not associated with altered stool consistency. CONCLUSION: These findings suggest that diverticulosis is associated with more frequent bowel movements contrary to the widespread belief that patients with diverticulosis are constipated. Diverticulosis was not associated with abdominal pain or symptoms of irritable bowel syndrome. The diagnosis of symptomatic uncomplicated diverticular disease must be reconsidered.

Obesity is associated with decreased risk of microscopic colitis in women.

BACKGROUND: Microscopic colitis is a leading cause of diarrhea in the older adults. There is limited information about risk factors. We hypothesized that obesity would be associated with microscopic colitis. AIM: To examine the association between obesity and microscopic colitis in men and women undergoing colonoscopy. METHODS: We conducted a case-control study at the University of North Carolina Hospitals. We identified and enrolled men and women referred for elective, outpatient colonoscopy for chronic diarrhea. We excluded patients with a past diagnosis of Crohn's disease or ulcerative colitis. A research pathologist reviewed biopsies on every patient and classified them as microscopic colitis cases or non-microscopic colitis controls. Patients provided information on body weight, height and exposure to medications via structured interviews or Internet based forms. The analysis included 110 patients with microscopic colitis (cases) and 252 non-microscopic colitis controls. Multivariable analyses were performed using logistic regression to estimate odds ratios and 95% confidence intervals. RESULTS: Cases were older and more likely than controls to be white race. Study subjects were well educated, but cases were better educated than controls. Cases with microscopic colitis had lower body mass index than controls and reported more weight loss after the onset of diarrhea. Compared to patients who were normal or under-weight, obese (BMI > 30 kg/m2) patients were substantially less likely to have microscopic colitis after adjusting for age and education, adjusted OR (aOR) 0.35, 95% confidence interval (CI) 0.18-0.66). When stratified by sex, the association was limited to obese women, aOR 0.21, 95%CI: 0.10-0.45. Patients with microscopic colitis were more likely to report weight loss after the onset of diarrhea. After stratifying by weight loss, there remained a strong inverse association between obesity and microscopic colitis, aOR 0.33, 95%CI: 0.10 - 1.11 among the patients who did not lose weight. Ever use of birth control pills was associated with lower risk of microscopic colitis after adjusting for age, education and BMI, aOR 0.38, 95%CI: 0.17-0.84. CONCLUSION: Compared to controls also seen for diarrhea, microscopic colitis cases were less likely to be obese. Mechanisms are unknown but could involve hormonal effects of obesity or the gut microbiome.

Intraepithelial and Lamina Propria Lymphocytes Do Not Correlate With Symptoms or Exposures in Microscopic Colitis.

INTRODUCTION: Microscopic colitis, a common cause of diarrhea, is characterized by a largely normal appearance of the mucosa but increased numbers of lymphocytes in the epithelium and lamina propria on microscopy. We sought to determine whether T-cell percentage was associated with exposures or symptoms. METHODS: We conducted a case-control study that enrolled patients referred for colonoscopy for diarrhea. Patients were classified as microscopic colitis cases or controls by an experienced pathologist. Participants provided information on symptoms and exposures during a telephone or internet survey. Research biopsies from the ascending colon and descending colon were examined using immunofluorescence stains for CD3, CD8, and FOXP3 to determine percent T cells per total epithelial or lamina propria cells. Digital images were analyzed by regions of interest using Tissue Studio. RESULTS: There were 97 microscopic colitis cases and 165 diarrhea controls. There was no association between demographic factors and percentage of intraepithelial or lamina propria T cells. In cases, the mean percent T cells were similar in the right colon and left colon. There was no association between mean percent T cells and stool frequency or consistency. There was no association with irritable bowel syndrome, abdominal pain, or medications purported to cause microscopic colitis. DISCUSSION: The lack of association between the density of T cells and medications raises further doubts about their role in disease etiology. Loose and frequent stools in patients with microscopic colitis are not correlated with T-cell density.

Aberrant Expression and Subcellular Localization of ECT2 Drives Colorectal Cancer Progression and Growth.

ECT2 is an activator of RHO GTPases that is essential for cytokinesis. In addition, ECT2 was identified as an oncoprotein when expressed ectopically in NIH/3T3 fibroblasts. However, oncogenic activation of ECT2 resulted from N-terminal truncation, and such truncated ECT2 proteins have not been found in patients with cancer. In this study, we observed elevated expression of full-length ECT2 protein in preneoplastic colon adenomas, driven by increased ECT2 mRNA abundance and associated with APC tumor-suppressor loss. Elevated ECT2 levels were detected in the cytoplasm and nucleus of colorectal cancer tissue, suggesting cytoplasmic mislocalization as one mechanism of early oncogenic ECT2 activation. Importantly, elevated nuclear ECT2 correlated with poorly differentiated tumors, and a low cytoplasmic:nuclear ratio of ECT2 protein correlated with poor patient survival, suggesting that nuclear and cytoplasmic ECT2 play distinct roles in colorectal cancer. Depletion of ECT2 reduced anchorage-independent cancer cell growth and invasion independent of its function in cytokinesis, and loss of Ect2 extended survival in a Kras G12D Apc-null colon cancer mouse model. Expression of ECT2 variants with impaired nuclear localization or guanine nucleotide exchange catalytic activity failed to restore cancer cell growth or invasion, indicating that active, nuclear ECT2 is required to support tumor progression. Nuclear ECT2 promoted ribosomal DNA transcription and ribosome biogenesis in colorectal cancer. These results support a driver role for both cytoplasmic and nuclear ECT2 overexpression in colorectal cancer and emphasize the critical role of precise subcellular localization in dictating ECT2 function in neoplastic cells. SIGNIFICANCE: ECT2 overexpression and mislocalization support its role as a driver in colon cancer that is independent from its function in normal cell cytokinesis.

Medication use and microscopic colitis.

BACKGROUND: Microscopic colitis is an increasingly common cause of watery diarrhoea. Several classes of medications have been associated with microscopic colitis in prior studies. AIMS: To determine the association between the use of previously implicated medications and microscopic colitis. METHODS: This was a case-control study of patients referred for elective, outpatient colonoscopy for diarrhoea. Patients were excluded for inflammatory bowel disease, C difficile, or other infectious diarrhoea. Colon biopsies were reviewed by the study pathologist and patients were classified as microscopic colitis cases or non-microscopic colitis controls. RESULTS: The study population included 110 microscopic colitis cases and 252 controls. The cases were older, better educated and more likely to be female. Cases reported a greater number of loose, watery, or liquid stools, nocturnal stools, more urgency and weight loss compared to controls. There was no association with proton pump inhibitors (PPIs), adjusted OR (aOR) 0.66, 95% CI 0.38-1.13 or nonsteroidal anti-inflammatory drugs, aOR 0.68, 95% CI 0.40-1.17. Cholecystectomy was less common in cases, aOR 0.33, 95% CI 0.17-0.64, but microscopic colitis cases had more frequent bowel movements following cholecystectomy. CONCLUSION: Compared to similar patients with diarrhoea, cases with microscopic colitis were not more likely to have taken previously implicated medications. They had more diarrhoea following cholecystectomy, suggesting that bile may play a role in symptoms or aetiology. We conclude that the appropriate choice of controls is crucial to understanding risk factors for microscopic colitis.

Obesity Increases the Risk of Hospital Readmission Following Intestinal Surgery for Children With Crohn Disease.

OBJECTIVES: Obese habitus can lead to adverse outcomes for colorectal surgeries due to technical challenges and pro-inflammatory immune mediators associated with excess adipose tissue. Surgical planning, pre-operative risk stratification, and patient counseling of pediatric Crohn disease (CD) patients are limited by the scarcity of data on this topic. We sought to determine the association between obesity and hospital readmission in children with CD undergoing intestinal resection. METHODS: We used the National Surgical Quality Improvement Program-Pediatric (NSQIP-P) database to identify pediatric CD patients undergoing intestinal resection between 2012 and 2018. We calculated age- and sex-adjusted body mass index (BMI) z scores using CDC population statistics. We used logistic regression to evaluate the association between obesity and readmission compared to average-BMI patients adjusting for age, race, sex, steroid exposure, disease activity, and surgery type. RESULTS: We evaluated 1258 pediatric CD intestinal resections occurring between 2012 and 2018. Patients were predominantly adolescent (91%), white (84%), and male (56%). Those with average BMI comprised 50% of the cohort, 31% were underweight, 11% overweight, and 8% obese. The overall 30-day hospital readmission rate was 8.8%. Compared to those with average BMI, obese children had a 2-fold (adjusted odds ratio 1.9, 95% confidence interval 1.0-3.8) increase in risk of hospital readmission. CONCLUSIONS: Obese patients undergoing intestinal resection face a higher risk of 30-day hospital readmission compared to average-BMI patients. These results can inform pre-surgical risk counseling and underscore the need for long-term weight management strategies to aid in risk reduction for obese children with CD at risk of future surgery.

Durability of Abstinence After Completing a Comprehensive Digital Smoking Cessation Program Incorporating a Mobile App, Breath Sensor, and Coaching: Cohort Study.

BACKGROUND: Despite decreasing prevalence over the last several decades, cigarette smoking remains the leading cause of preventable death and disease, underscoring the need for innovative, effective solutions. Pivot is a novel, inclusive smoking cessation program designed for smokers along the entire spectrum of readiness to quit. Pivot leverages proven methods and technological advancements, including a personal portable breath carbon monoxide sensor, smartphone app, and in-app text-based coaching. We previously reported outcomes from the end of active Pivot program participation in 319 adult smokers. Herein, we report longer-term follow up in this cohort. OBJECTIVE: The aim of this study was to assess and report participant outcomes 3 months after completion of Pivot, including smoking behavior, quit rates, continuous abstinence rates and durability, and predictors of abstinence. METHODS: This prospective remote cohort study included US-based cigarette smokers aged 18 to 65 years who smoked ≥5 cigarettes per day (CPD). Three months after completion of active participation in Pivot, final follow-up data were collected via an online questionnaire. Outcomes included smoking behavior (CPD and quit attempts), self-reported quit rates (7- and 30-day point prevalence abstinence [PPA]), and continuous abstinence rates (proportion who achieved uninterrupted abstinence) and duration. Exploratory regression analyses were performed to identify baseline characteristics associated with achievement of 7-day PPA, 30-day PPA, and continuous abstinence. RESULTS: A total of 319 participants completed onboarding (intention-to-treat [ITT]); 288/319 participants (90.3%) completed follow up (completers) at a mean of 7.2 (SD 1.2) months after onboarding. At final follow up, CPD were reduced by 52.6% (SE 2.1; P<.001) among all 319 participants, and most completers (152/288, 52.8%) reduced their CPD by at least 50%. Overall, most completers (232/288, 80.6%) made at least one quit attempt. Quit rates increased after the end of Pivot; using ITT analyses, 35.4% (113/319) achieved 7-day PPA and 31.3% (100/319) achieved 30-day PPA at final follow up compared with 32.0% (102/319) and 27.6% (88/319), respectively, at the end of the Pivot program. Continuous abstinence was achieved in about a quarter of those who onboarded (76/319, 23.8%) and in most who reported 30-day PPA at the end of Pivot (76/88, 86.4%), with a mean abstinence duration of 5.8 (SD 0.6) months. In exploratory regression analyses, lower baseline CPD, more positive baseline attitudes reflecting higher self-efficacy (higher confidence to quit and lower perceived difficulty of quitting), and higher education were associated with achieving abstinence. CONCLUSIONS: This study provides the first longer-term outcomes of the Pivot smoking cessation program. At final follow up, quit rates increased and continuous abstinence was favorable; the majority who achieved abstinence at the end of Pivot sustained abstinence throughout follow up. Decreases in CPD persisted and most participants made a quit attempt. Overall, final follow-up outcomes were stable or improved when compared to previous outcomes from the end of the program. These findings validate earlier results, and suggest that Pivot is an effective and durable solution for smoking cessation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03295643; https://clinicaltrials.gov/ct2/show/NCT03295643.

Creation of a Case-Finding Definition for Identifying Patients With Acute Pouchitis in Administrative Claims Data.

Acute pouchitis is the most common complication after a restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis, affecting 40% of patients within the first year after surgery.1 Although up to 80% of patients can develop pouchitis symptoms,2,3 substantial gaps remain in our understanding of the epidemiology and burden of pouchitis. Administrative claims have been used to advance the knowledge of other areas of inflammatory bowel disease4-6; however, a prerequisite to conducting such studies in pouchitis is a valid, reliable case-finding algorithm. Given concerns that the International Classification of Diseases (ICD) code for pouchitis may not be reliably used by clinicians (resulting in a low sensitivity), the objectives of the study were to (1) develop a series of case-finding definitions for acute pouchitis and (2) compare the performance of these case-finding definitions to that of a single ICD code for pouchitis.

Total Abdominal Colectomies With Proctectomy Are Associated With Higher 30-Day Readmission Rates in Children With Ulcerative Colitis.

BACKGROUND: Hospital readmissions are a burden on patients and families and place financial strain on the health care system. Thirty-day readmission rates for adult patients undergoing colectomy are as high as 30%, and inflammatory bowel disease is a risk factor for readmission. We used a multicenter pediatric surgical database to determine the 30-day readmission rate for pediatric patients with ulcerative colitis (UC) undergoing total abdominal colectomy (TAC) and to identify risk factors for 30-day hospital readmission. METHODS: We used the National Surgical Quality Improvement Program-Pediatrics database to identify pediatric patients with UC undergoing a TAC between 2012 and 2017. We identified patient and procedural data from the index hospitalization and used logistic regression to identify risk factors for 30-day readmission rates, adjusting for confounding factors. RESULTS: We identified 489 pediatric UC TAC hospitalizations between 2012 and 2017, and 19.4% were readmitted within 30 days of surgical discharge. Patient demographics and preoperative laboratory values were not associated with risk of readmission. The TAC procedures that included a proctectomy were at a 2-fold (odds ratio = 2.4; 95% confidence interval, 1.1-5.2) higher risk of 30-day readmission than TAC alone after adjusted analysis. CONCLUSIONS: Nearly 20% of annual pediatric UC hospitalizations involving a colectomy resulted in a 30-day hospital readmission. Notably, TAC procedures that included a proctectomy had significantly higher readmission rates compared to TAC alone. These results can inform risk management strategies aimed at reducing morbidity and hospital readmissions for children with UC.

Natural History of Very Early Onset Inflammatory Bowel Disease in North America: A Retrospective Cohort Study.

BACKGROUND: The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described. METHODS: We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years. RESULTS: The study population included 269 children (105 [39%] Crohn's disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9-5.2). Most (94%) Crohn's disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn's disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis. CONCLUSIONS: Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%-15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population.

Co-morbid risk factors and NSAID use among white and black Americans that predicts overall survival from diagnosed colon cancer.

Black Americans (BA) have higher incidence and higher mortality rates for colorectal cancers (CRC) as compared to White Americans (WA). While there are several identified risk factors associated with the development of CRC and evidence that high levels of adequate screening can reduce differences in incidence for CRC between BA and WA, there remains little data regarding patient co-morbid contributions towards survival once an individual has CRC. Here we set out to identify patient risk factors that influenced overall survival in a cohort of 293 BA and 348 WA with colon cancer. Amid our cohort, we found that patients' age, tobacco usage, and pre-diagnosed medical conditions such as hypertension and diabetes were associated with shorter overall survival (OS) from colon cancer. We identified pre-diagnosed hypertension and diabetes among BA were responsible for one-third of the colon cancer mortality disparity compared with WA. We also identified long-term regular use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, was associated with shorter OS from colon cancer among WA >65 years of age, but not younger WA patients or any aged BA patients. Our results raise the importance of not only treating the colon cancer itself, but also taking into consideration co-morbid medical conditions and NSAID usage to enhance patient OS. Further evaluation regarding adequate treatment of co-morbidities and timing of NSAID continuance after cancer therapy will need to be studied.