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Spencer D Dorn, Holly O Cirri, Audrey O Chang, Seth D Crockett, Joseph A Galanko, John A Baron Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA Purpose: Managing and communicating colonoscopy-generated pathology results and appropriate follow-up recommendations can be challenging. To improve this process, we developed and implemented a standardized electronic health record-based intervention with built-in decision support.Methods: Fourteen attending endoscopists performed enough colonoscopies to qualify for the study. For each, we randomly sampled and abstracted data from 35 colonoscopies that met prespecified inclusion criteria during both the pre-intervention and also post-intervention periods. Follow-up recommendations were compared to guidelines. We used the Wilcoxon Signed Rank Test to assess the change in the proportion of cases with guideline-concordant results, the proportion with a documented follow-up result letter, and the median time to letter completion. A brief survey assessed endoscopists’ satisfaction with the intervention.Results: In total, 1,947 colonoscopies were extracted, of which 968 met inclusion criteria. The proportion of follow-up recommendations that were guideline concordant increased from a median of 82.9% pre-intervention to 85.7% post-intervention (P=0.72). The proportion of observations with a documented follow-up result letter increased from a median of 88.9% pre-intervention to 97.1% post-intervention (P=0.07). The number of calendar days between the date of the colonoscopy and the date the letter was sent decreased from a median of 7.7 days pre-intervention to 6.8 days post-intervention (P=0.79). Eighty-six percentage of endoscopists were either “very satisfied” or “satisfied” with the overall process.Conclusion: The intervention was not associated with a statistically significant increase in guideline-concordant recommendations or efficiency measures, perhaps due to high baseline performance. The intervention was well received by endoscopists and captured data necessary for important downstream processes. Keywords: colonoscopy, pathology, quality, electronic health record, systems

Background Associations between inflammatory bowel diseases (IBDs) and other immune-mediated diseases have been described in adult populations. Whether such associations exist in childhood-onset disease remains unknown. Objectives The authors sought to evaluate whether paediatric IBD is associated with the occurrence of other immune-mediated diseases. Study design The authors identified cases of Crohn's disease (CD) and ulcerative colitis (UC), <=20 years of age, using administrative data from 87 health plans. Each case was matched to three controls, on the basis of age, gender, and geographical region. The authors used logistic regression to compare the prevalence of various immune-mediated diseases (identified by International Classification of Diseases, ninth revision codes) in cases versus controls. Results The study included 737 children with CD (1997 controls) and 488 with UC (1310 controls). CD was associated with a higher prevalence of rheumatoid arthritis (OR 15.7, 95% CI 4.6 to 53.7), lupus (OR 41.0, 95% CI 2.3 to 719.1) and hypothyroidism (OR 2.9, 95% CI 1.4 to 6.1), with a trend toward an increased prevalence of asthma, eczema, allergic rhinitis and diabetes. UC was associated with a higher prevalence of diabetes (OR 2.7, 95% CI 1.1 to 6.6), with a trend towards increased prevalence of asthma, eczema, allergic rhinitis, hypothyroidism, rheumatoid arthritis and lupus. Discussion Children with IBD, particularly CD, have an elevated risk for immune-mediated conditions. This comorbidity adds to the burden of paediatric IBD, and suggests common aetiologic mechanisms. [ABSTRACT FROM AUTHOR]

Objective: To examine associations of various psychosocial factors with fruit and vegetable intake in African-American adults.Methods: A cross-sectional survey of a population-based sample of 658 African-Americans, aged 18-70 years, in North Carolina. Information was collected on diet-related psychosocial (predisposing, reinforcing and enabling) factors based on the PRECEDE (Predisposing, Reinforcing, and Enabling Constructs in Educational Diagnosis and Evaluation) planning framework; demographic, lifestyle and behavioural characteristics, and fruit and vegetable intake.Results: The mean participant age was 43.9 years (standard deviation 11.6), 57% were female and 76% were overweight/obese. Participants expressed healthy beliefs regarding many of, but not all, the psychosocial factors. For example, although half of the respondents believed it is important to eat a diet high in fruits/vegetables, only 26% knew that >or=5 daily servings are recommended. The strongest associations of the psychosocial factors with fruit/vegetable intake were for predisposing factors (e.g. belief in the importance of a high fruit/vegetable diet and knowledge of fruit/vegetable recommendations) and one reinforcing factor (social support), with differences between the healthiest and least healthy responses of 0.5-1.0 servings per day. There was evidence of effect modification by gender in associations between psychosocial factors and fruit/vegetable consumption (e.g. self-efficacy was only significant in women), with higher intakes and generally healthier responses to the psychosocial variables in women than men.Conclusions: Interventions to increase fruit/vegetable intake in African-Americans may be more effective if they focus primarily on predisposing factors, such as knowledge, self-efficacy and attitudes, but not to the exclusion of reinforcing and enabling factors. The psychosocial factors that are targeted may also need to be somewhat different for African-American men and women. [ABSTRACT FROM AUTHOR]

Objective: To examine associations of the frequency of eating at fast-food restaurants with demographic, behavioural and psychosocial factors and dietary intake in African American adults.Methods: Self-reported data from a population-based cross-sectional survey of 658 African Americans, aged 20-70 years, in North Carolina. An 11-page questionnaire assessed eating at fast-food restaurants, demographic, behavioural and diet-related psychosocial factors, and dietary intake (fruit, vegetable, total fat and saturated fat intakes, and fat-related dietary behaviours).Results: The participants were aged 43.9+/-11.6 years (mean+/-standard deviation), 41% were male, 37% were college graduates and 75% were overweight or obese. Seventy-six per cent reported eating at fast-food restaurants during the previous 3 months: 4% usually, 22% often and 50% sometimes. Frequency of eating at fast-food restaurants was positively associated with total fat and saturated fat intakes and fat-related dietary behaviours (P<0.0001) and inversely associated with vegetable intake (P<0.05). For example, mean daily fat intake was 39.0 g for usually/often respondents and 28.3 g for those reporting rare/never eating at fast-food restaurants. Participants who reported usual/often eating at fast-food restaurants were younger, never married, obese, physically inactive and multivitamin non-users (all P<0.01). Frequency of eating at fast-food restaurants was positively associated with fair/poor self-rated health, weak belief in a diet-cancer relationship, low self-efficacy for healthy eating, weight dissatisfaction, and perceived difficulties of preparing healthy meals and ordering healthy foods in restaurants (all P<0.05). Frequency of eating at fast-food restaurants did not differ significantly by sex, education, smoking, ability to purchase healthy foods or knowledge of the Food Guide Pyramid.Conclusions: Eating at fast-food restaurants is associated with higher fat and lower vegetable intakes in African Americans. Interventions to reduce fast-food consumption and obesity in African Americans should consider demographic and behavioural characteristics and address attitudes about diet-disease relationships and convenience barriers to healthy eating. [ABSTRACT FROM AUTHOR]

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., (©Jennifer D Marler, Craig A Fujii, MacKenzie T Utley, Daniel J Balbierz, Joseph A Galanko, David S Utley. Originally published in JMIR Formative Research (https://formative.jmir.org), 28.10.2024.)

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., (Copyright © 2024 by The American College of Gastroenterology.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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., (Copyright © 2024 by The American College of Gastroenterology.)

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., Competing Interests: Competing interests: ESD has received research funding from Adare/Ellodi, Allakos, Arena, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Shire/Takeda; consulting fees from Abbott, Abbvie, Adare/ Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Landos, LucidDx, Morphic, Nexstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio; and educational grants from Allakos, Holoclara, Invea. IH has received research funding from Adare/Ellodi, Allakos, Arena, AstraZeneca, Meritage, Celgene/Receptos/BMS, Regeneron, Shire/Takeda; consulting fees from Adare/ Ellodi, Allakos, Amgen, Arena/Pfizer, Aslan, AstraZeneca, Celgene/Receptos/BMS, Celldex, EsoCap, Gossamer Bio, Nexstone Immunology, Parexel/Calyx, Phathom, Regeneron, Sanofi, Shire/Takeda. KAP has received research funding from AstraZeneca, Allakos, Adare, Regeneron-Sanofi, Revolo,; Speaker: AGA, Regeneron, Peerview, Takeda, Allakos, WebMD; unrestricted grant support from Allakos, Chobani; consulting or advisory board fees from AGA, Alladapt, AstraZeneca, Allakos, Bristol Meyers Squibb, Ellodi, Invea, Lucid, Nexstone, WebMD, Peerview, Regeneron, Revolo, Takeda, WebMD; and has equity in Nexeos Bio. The other authors report no relevant disclosures., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (©Jennifer D Marler, Craig A Fujii, MacKenzie T Utley, Daniel J Balbierz, Joseph A Galanko, David S Utley. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 18.09.2023.)

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 ( Hnf4a ΔIEC ) leads to spontaneous colonic inflammation by 6-12 mo of age. Here, we tested if pathology in Hnf4a ΔIEC mice begins earlier in life and if microbiota contribute to that process. Longitudinal analysis revealed that Hnf4a ΔIEC 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 Hnf4a ΔIEC mice were dependent on microbiota. Fecal 16S rRNA gene sequencing in SPF Hnf4a ΔIEC and control mice disclosed that genotype significantly contributed to differences in microbiota composition by 12 mo, and longitudinal analysis of the Hnf4a ΔIEC 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 Hnf4a ΔIEC 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., Competing Interests: The authors declare no conflict of interest.

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., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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., (©Jennifer D Marler, Craig A Fujii, MacKenzie T Utley, Daniel J Balbierz, Joseph A Galanko, David S Utley. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 24.11.2022.)

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/m 2 ) 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., Competing Interests: Conflict-of-interest statement: Disclosures: None of the authors have financial, professional or personal conflicts of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

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., Competing Interests: Conflicts of Interest: The authors disclose no conflicts.

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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

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., (©2021 American Association for Cancer Research.)

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., (© 2021 John Wiley & Sons Ltd.)

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

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 disease 4-6 ; 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., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (©Jennifer D Marler, Craig A Fujii, Joseph A Galanko, Daniel J Balbierz, David S Utley. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 15.02.2021.)

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., Competing Interests: The authors have declared that no competing interests exist.

Background: Tobacco use is the leading cause of preventable morbidity and mortality. Existing evidence-based treatments are underutilized and have seen little recent innovation. The success of personal biofeedback interventions in other disease states portends a similar opportunity in smoking cessation. The Pivot Breath Sensor is a personal interactive FDA-cleared (over-the-counter) device that measures carbon monoxide (CO) in exhaled breath, enabling users to link their smoking behavior and CO values, and track their progress in reducing or quitting smoking., Objective: The objective of this study is to assess the Pivot Breath Sensor in people who smoke cigarettes, evaluating changes in attitudes toward quitting smoking, changes in smoking behavior, and use experience., Methods: US adults (18-80 years of age, ≥10 cigarettes per day [CPD]) were recruited online for this remote 12-week study. Participants completed a screening call, informed consent, and baseline questionnaire, and then were mailed their sensor. Participants were asked to submit 4 or more breath samples per day and complete questionnaires at 1-4, 8, and 12 weeks. Outcomes included attitudes toward quitting smoking (Stage of Change, success to quit, and perceived difficulty of quitting), smoking behavior (quit attempts, CPD reduction, and 7-, 30-day point prevalence abstinence [PPA]), and use experience (impact and learning)., Results: Participants comprised 234 smokers, mean age 39.9 (SD 11.3) years, 52.6% (123/234) female, mean CPD 20.3 (SD 8.0). The 4- and 12-week questionnaires were completed by 92.3% (216/234) and 91.9% (215/234) of participants, respectively. Concerning attitude outcomes, at baseline, 15.4% (36/234) were seriously thinking of quitting in the next 30 days, increasing to 38.9% (84/216) at 4 weeks and 47.9% (103/215) at 12 weeks (both P<.001). At 12 weeks, motivation to quit was increased in 39.1% (84/215), unchanged in 54.9% (118/215), and decreased in 6.0% (13/215; P<.001). Additional attitudes toward quitting improved from baseline to 12 weeks: success to quit 3.3 versus 5.0 (P<.001) and difficulty of quitting 2.8 versus 4.3 (P<.001). Regarding smoking behavior, at 4 weeks, 28.2% (66/234) had made 1 or more quit attempts (≥1 day of abstinence), increasing to 48.3% (113/234) at 12 weeks. At 4 weeks, 23.1% (54/234) had reduced CPD by 50% or more, increasing to 38.5% (90/234) at 12 weeks. At 12 weeks, CPD decreased by 41.1% from baseline (P<.001), and 7- and 30-day PPA were 12.0% (28/234) and 6.0% (14/234), respectively. Concerning use experience, 75.3% (171/227) reported the sensor increased their motivation to quit. More than 90% (>196/214) indicated the sensor taught them about their CO levels and smoking behavior, and 73.1% (166/227) reported that seeing their CO values made them want to quit smoking., Conclusions: Use of the Pivot Breath Sensor resulted in a significant increase in motivation to quit, a reduction in CPD, and favorable quit attempt rates. These outcomes confer increased likelihood of quitting smoking. Accordingly, the results support a role for biofeedback via personal CO breath sampling in smoking cessation., Trial Registration: ClinicalTrials.gov NCT04133064; https://clinicaltrials.gov/ct2/show/NCT04133064., (©Jennifer D Marler, Craig A Fujii, Kristine S Wong, Joseph A Galanko, Daniel J Balbierz, David S Utley. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 02.10.2020.)

Fusobacterium nucleatum ( Fn ) is frequently found in colorectal cancers (CRCs). High loads of Fn DNA are detected in CRC tissues with microsatellite instability-high (MSI-H), or with the CpG island hypermethylation phenotype (CIMP). Fn infection is also associated with the inflammatory tumor microenvironment of CRC. A subtype of CRC exhibits inflammation-associated microsatellite alterations (IAMA), which are characterized by microsatellite instability-low (MSI-L) and/or an elevated level of microsatellite alterations at selected tetra-nucleotide repeats (EMAST). Here we describe two independent CRC cohorts in which heavy or moderate loads of Fn DNA are associated with MSI-H and L/E CRC respectively. We also show evidence that Fn produces factors that induce γ-H2AX, a hallmark of DNA double strand breaks (DSBs), in the infected cells., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background & Aims: The prevalence of diverticulosis differs with demographic features of patients, but evidence is limited. Well-defined demographic studies are necessary to understand diverticulosis biology. We estimated the prevalence of diverticulosis among patients of different ages, sexes, and races and ethnicities and calculated odds ratios., Design: Using data from an endoscopic database, we identified 271,181 colonoscopy procedures performed from 2000 through 2012 at 107 sites in the United States. Our analysis included individuals 40 years and older who underwent colonoscopy examination for average-risk screening. The outcome was any reported diverticulosis on colonoscopy. Multivariate analyses were performed using logistic regression to estimate odds ratios (ORs) and 95% CI values, adjusting for confounding variables., Results: The prevalence of diverticulosis increased with age in men and women of all races and ethnicities. Women 40-49 years old had significantly lower odds of any diverticulosis (OR, 0.71; 95% CI, 0.63-0.80) compared with men 40-49 years old, after adjustment. The strength of this association decreased with age. Compared with non-Hispanic white individuals, non-Hispanic black individuals (OR, 0.80; 95% CI, 0.77-0.83) and Asian/Pacific Islanders (OR, 0.38; 95% CI, 0.35-0.41) had lower odds of any diverticulosis. However, non-Hispanic black individuals (OR, 1.53, 95% CI, 1.44-1.62) had increased odds of any proximal diverticulosis, whereas Asian/Pacific Islanders (OR, 3.12; 95% CI, 2.67-3.66) had increased odds of only proximal diverticulosis., Conclusions: In an analysis of data from 271,181 colonoscopy procedures, diverticulosis was less prevalent in women compared with men in the same age groups, indicating that sex hormones might affect pathogenesis. Differences in the odds of diverticulosis by race and ethnicity indicate a genetic contribution to risk., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Eosinophilic esophagitis (EoE) is chronic and recurs if treatment is discontinued. We aimed to determine rates of recurrence, and whether initial treatment with oral viscous budesonide (OVB) resulted in less recurrence than fluticasone from a multidose inhaler (MDI)., Methods: This was the observation phase of a randomized, double-blind, double-dummy trial comparing OVB with MDI for initial EoE treatment. Subjects with a histologic response (<15 eosinophils/high-power field) in the trial entered an observation phase in which treatment was discontinued and symptoms were monitored. Patients underwent an endoscopy or a biopsy when symptoms recurred or at 1 year. We analyzed time to symptom recurrence and assessed endoscopic severity and histologic relapse (≥15 eosinophils/high-power field) at follow-up endoscopy., Results: Thirty-three of the 58 subjects (57%) had symptom recurrence before 1 year. The overall median time to symptom recurrence was 244 days. There was no difference in the rate of symptom recurrence for subjects treated with OVB vs MDI (hazard ratio, 1.04; 95% CI, 0.52-2.08). At symptom recurrence, 78% of patients had histologic relapse. The patients had significant increases in mean Dysphagia Symptom Questionnaire score (3.8 vs 8.7; P < .001), and the EoE Endoscopic Reference Score (1.3 vs 4.6; P < .001) compared with end of treatment., Conclusions: EoE disease activity recurred rapidly after initial histologic response to topical steroids (either OVB or MDI). Because most subjects had recurrent endoscopic and histologic signs not reliably detected by symptoms, maintenance therapy should be recommended in EoE patients achieving histologic response to topical steroids. Clinicaltrials.gov no: NCT02019758., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Weekend surgical admissions to the hospital are associated with worse clinical outcomes when compared with weekday admissions. We aimed to evaluate the association of weekend admission and in-hospital complications for pediatric inflammatory bowel disease (IBD) hospitalizations requiring urgent abdominal surgery., Methods: We performed a cross-sectional analysis of pediatric (18 years old and younger) IBD hospitalizations between 1997 and 2016 using the Kids' Inpatient Database (KID), a nationally representative database of pediatric hospitalizations. We included discharges with a diagnosis code for Crohn's disease (CD) or ulcerative colitis (UC) undergoing a surgical procedure within 48 hours of admission. We used logistic regression to evaluate the association of weekend admission and complications, controlling for confounding factors., Results: Our study included a total of 3255 urgent surgical hospitalizations, representing 4950 hospitalizations nationwide. The risk difference for weekend CD surgical hospitalizations involving a complication vs weekday hospitalizations was 4%. Adjusted analysis demonstrated a 30% increased risk for complications associated with weekend CD hospitalizations compared with weekday hospitalizations (OR 1.3, 95% CI, 1.0-1.7). The risk difference for weekend UC hospitalizations involving a complication compared with the weekday hospitalizations was 7%. Adjusted analysis demonstrated a 70% increased risk of complication for UC weekend surgical hospitalizations compared with weekday hospitalizations (OR 1.7, 95% CI, 1.2-2.3)., Conclusion: Pediatric IBD hospitalizations involving urgent surgical procedures have higher rates of complications when admitted on the weekend vs the weekday. The outcome disparity requires further health services research and quality improvement initiatives to identify contributing factors and improve surgical outcomes., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: Obesity has been associated with an increased risk of colonic diverticulosis. Evidence for this association is limited. We assessed whether anthropometric measures of obesity were associated with colonic diverticulosis., Methods: We analyzed data from a prospective study of 623 patients undergoing screening colonoscopies from 2013 through 2015; colonoscopies included examinations for diverticulosis. Body measurements were made the day of the procedure. Multivariate analyses were performed using modified Poisson regression to estimate prevalence ratios (PRs) and 95% CIs while adjusting for confounding variables. All analyses were stratified by sex., Results: Among men, there was no association between any measure of obesity and diverticulosis. After adjustment, women with an obese body mass index (BMI ≥ 30) had an increased risk of any diverticulosis (PR, 1.48; 95% CI, 1.08-2.04) compared with women with a normal body mass index (BMI 18.5-24.9). The strength of this association was greater for more than 5 diverticula (PR, 2.05; 95% CI, 1.23-3.40). There was no significant association between measures of central obesity and diverticulosis in women. Stratified by sex, colonic diverticulosis was significantly less prevalent in women compared with men before the age of 51 years (29% vs 45%, P = .06). The prevalence of diverticulosis did not differ by sex in older age groups., Conclusions: In an analysis of data from 623 patients undergoing screening colonoscopies, we found that obesity (BMI ≥30) significantly increased the risk of colonic diverticulosis in women but not men. Colonic diverticulosis was less prevalent in premenopausal-age women compared with similar-age men. These findings suggest that sex hormones may influence the development of diverticulosis., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Adults with ulcerative colitis (UC) who undergo colectomy at high-volume centers have better outcomes and fewer complications than those at low-volume centers. We aimed to evaluate the hospital volume of total abdominal colectomy (TAC) for pediatric patients with UC and explore time trends in the proportion of colectomies performed at high-volume centers. We then evaluated the association between hospital colectomy volume and complications., Methods: We performed a cross-sectional analysis of pediatric patients (age, ≤18 y) hospitalized for UC using the Kids' Inpatient Database, a nationally representative database of pediatric hospitalizations. We identified UC hospitalizations with a procedural code (International Classification of Diseases, 9th or 10th revision) for TAC from 1997 through 2016. We defined complications using diagnosis codes adapted from published algorithms. We defined high-volume as hospitals that performed 10 or more TACs annually. We used multivariate statistics to evaluate the association between hospital volume and in-hospital complications., Results: A total of 1453 hospitalizations of children with UC included a TAC (2306 colectomies nationwide). A total of 766 hospitals performed 1 or more annual colectomies and only 36 (4.7%) were high-volume hospitals, accounting for 21% of colectomies. The proportion of colectomies at high-volume hospitals decreased over time. The absolute risk of complication was 16% at high-volume centers compared with 22% at low-volume centers (adjusted odds ratio, 0.7; 95% CI, 0.5-0.9). The effect of annual TAC volume on complication risk was not statistically significant for nonemergent admissions., Conclusions: Pediatric patients with UC who undergo colectomy at high-volume centers have fewer complications. However, only a small proportion of pediatric colectomies (<5%) are performed at high-volume centers., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Topical steroid treatments for eosinophilic esophagitis (EoE) include swallowed fluticasone from a multi-dose inhaler (MDI) or oral viscous budesonide (OVB) slurry, but the 2 have never been compared. We assessed whether OVB was more effective than MDI for initial treatment of patients with EoE., Methods: In a double-blind, double-dummy trial, patients with a new diagnosis of EoE were randomly assigned to groups given 8 weeks of either OVB (1 mg/4 mL) twice daily plus a placebo inhaler (n = 56) or fluticasone MDI (880 μg) twice daily plus a placebo slurry (n = 55). Primary outcomes were post-treatment maximum eosinophil counts per high-power field (eos/hpf) and a validated dysphagia score (dysphagia symptom questionnaire [DSQ]) at week 8. Secondary outcomes included endoscopic severity (validated EoE endoscopic reference score), histologic response (<15 eos/hpf), and safety., Results: In a modified intention-to-treat analysis, the subjects had baseline peak eosinophil counts of 73 and 77 eos/hpf in the OVB and MDI groups, respectively, and DSQ scores of 11 and 8. Post-treatment eosinophil counts were 15 and 21 in the OVB and MDI groups, respectively (P = .31), with 71% and 64% achieving histologic response (P = .38). DSQ scores were 5 and 4 in the OVB and MDI groups (P = .70). Similar trends were noted for post-treatment total EoE endoscopic reference scores (2 vs 3; P = .06). Esophageal candidiasis developed in 12% of patients receiving OVB and 16% receiving MDI; oral thrush was observed in 3% and 2%, respectively., Conclusions: In a randomized clinical trial, initial treatment of EoE with either OVB or fluticasone MDI produced a significant decrease in esophageal eosinophil counts and improved dysphagia and endoscopic features. However, OVB was not superior to MDI, so either is an acceptable treatment for EoE. ClinicalTrials.gov ID NCT02019758., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Malnutrition is common in inflammatory bowel disease (IBD), requiring timely and sufficient nutritional supplementation. In patients hospitalized for active disease, symptoms and/or altered intestinal function hinder enteral nutrition feasibility. In this scenario, parenteral nutrition (PN) is used. We aimed (1) to assess the frequency of PN use between 1997 and 2012 among hospitalized pediatric patients with IBD, (2) to determine the risk of in-hospital thrombus and infection associated with PN, and (3) to identify predictors of thrombus and infection in pediatric IBD hospitalizations utilizing PN., Methods: We performed a cross-sectional analysis of pediatric patients hospitalized between 1997 and 2012. We used the Kids' Inpatient Database (KID) to identify pediatric patients (≤18 years of age) with Crohn's disease (CD) or ulcerative colitis (UC), PN exposure, and primary outcomes including thrombus and infection. We used multivariable regression to identify risk factors for outcomes of interest., Results: Parenteral nutrition was utilized in 3732 (12%) of 30,914 IBD hospitalizations. Three percent of PN patients experienced a thrombotic complication, and 5.5% experienced an infectious complication. Multivariate analysis showed PN as an independent risk factor for thrombus (odds ratio [OR], 4.3; 95% confidence interval [CI], 3.2-5.6) and infection (OR, 3.8; 95% CI, 3.1-4.6). Surgery was an independent risk factor for thrombus (OR, 2.0; 95% CI, 1.4-2.7) and infection (OR, 2.5; 95% CI, 2.0-3.1) in hospitalizations exposed to PN., Conclusions: Hospitalized pediatric IBD patients, particularly surgical, receiving PN are at increased risk for thrombosis and infection. Clinicians must balance these risks with the benefits of PN., (© 2018 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Macrophages (MΦs) are heterogeneous and metabolically flexible, with metabolism strongly affecting immune activation. A classic response to proinflammatory activation is increased flux through glycolysis with a downregulation of oxidative metabolism, whereas alternative activation is primarily oxidative, which begs the question of whether targeting glucose metabolism is a viable approach to control MΦ activation. We created a murine model of myeloid-specific glucose transporter GLUT1 ( Slc2a1 ) deletion. Bone marrow-derived MΦs (BMDM) from Slc2a1 M-/- mice failed to uptake glucose and demonstrated reduced glycolysis and pentose phosphate pathway activity. Activated BMDMs displayed elevated metabolism of oleate and glutamine, yet maximal respiratory capacity was blunted in MΦ lacking GLUT1, demonstrating an incomplete metabolic reprogramming. Slc2a1 M-/- BMDMs displayed a mixed inflammatory phenotype with reductions of the classically activated pro- and anti-inflammatory markers, yet less oxidative stress. Slc2a1 M-/- BMDMs had reduced proinflammatory metabolites, whereas metabolites indicative of alternative activation-such as ornithine and polyamines-were greatly elevated in the absence of GLUT1. Adipose tissue MΦs of lean Slc2a1 M-/- mice had increased alternative M2-like activation marker mannose receptor CD206, yet lack of GLUT1 was not a critical mediator in the development of obesity-associated metabolic dysregulation. However, Ldlr -/- mice lacking myeloid GLUT1 developed unstable atherosclerotic lesions. Defective phagocytic capacity in Slc2a1 M-/- BMDMs may have contributed to unstable atheroma formation. Together, our findings suggest that although lack of GLUT1 blunted glycolysis and the pentose phosphate pathway, MΦ were metabolically flexible enough that inflammatory cytokine release was not dramatically regulated, yet phagocytic defects hindered MΦ function in chronic diseases., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Background: Cigarette smoking is the leading cause of preventable morbidity and mortality, excess health care expenditure, and lost work productivity. Otherwise effective evidence-based treatments have had limited success owing to challenges with access, engagement, and scale. Pivot is a comprehensive digital smoking cessation program that incorporates a Food and Drug Administration-cleared carbon monoxide breath sensor, smartphone app, and text-based human coaching., Objective: This initial evaluation of Pivot aimed to assess participant engagement, changes in attitudes toward quitting, and changes in smoking behavior., Methods: US cigarette smokers aged 18 to 65 years who smoked ≥5 cigarettes per day (CPD) were recruited online. Participants completed a screening call, electronic informed consent, registration, and onboarding before beginning Pivot. Pivot includes 5 sequential stages (Explore, Build, Mobilize, Quit, and Secure), taking 14.5 to 18.5 weeks to complete. Data were collected via app and online questionnaires. Outcomes included engagement and retention (ie, weeks of active engagement and Pivot stage progression); attitudes toward quitting (ie, quit readiness, quit confidence, and expected difficulty maintaining quit); and smoking behavior (ie, quit attempts, cigarette reduction, and abstinence (7- and 30-day point prevalence abstinence [PPA])., Results: A total of 319 participants completed onboarding (intention-to-treat [ITT] sample); 272/319 participants (85.3%) completed the end-of-Pivot questionnaire (study completer sample). Most (212/319, 66.5%) were not ready to quit in the next 30 days at baseline. On average, participants actively engaged in the program for a mean 12.4 (SD 7.1) weeks. Pivot stage completion rates were Explore: 88.7% (283/319), Build: 57.4% (183/319), Mobilize: 43.6% (139/319), Quit: 41.1% (131/319), and Secure: 39.5% (126/319). Repeated measures linear mixed model analyses demonstrated positive changes in attitudes from baseline to Mobilize (pre-Quit): increased confidence to quit (4.2 to 7.4, P<.001) and decreased expected difficulty maintaining quit (3.1 to 6.8, P<.001). The quit attempt rate (ie, those making ≥1 quit attempt lasting ≥1 day) was 79.4% (216/272, completer). At the end of Pivot, 7-day PPA rates were 32.0% (102/319, ITT) and 37.5% (102/272, completer); 30-day PPA rates were 27.6% (88/319, ITT) and 32.4% (88/272, completer). Moreover, 30-day PPA rates were comparable among those ready and not ready to quit in the next 30 days at baseline. Of those not achieving abstinence, 25.9% (44/170, completer) achieved ≥50% reduction in CPD by study end., Conclusions: This study evaluated Pivot's initial performance with comparable quit rates among those ready and not ready to quit in the next 30 days at entry. The present data, considered with the program's accessibility, innovation, evidence-based foundation, and design for all smokers, suggest Pivot has the potential to address limitations of reach and scale and thereby advance smoking cessation efforts., Trial Registration: ClinicalTrials.gov NCT03295643; https://clinicaltrials.gov/ct2/show/NCT03295643 (Archived by WebCite at http://www.webcitation.org/75TiNe6BE)., (©Jennifer D Marler, Craig A Fujii, David S Utley, Lydia J Tesfamariam, Joseph A Galanko, Heather Patrick. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 04.02.2019.)

Differences in tumor characteristics might partially account for mortality disparities between African American (AA) and European American (EA) colorectal cancer patients. We evaluated effect modification by race for exposure and patient-outcomes associations with colorectal tumor methylation among 218 AA and 267 EA colorectal cancer cases from the population-based North Carolina Colon Cancer Study. Tumor methylation was assessed in CACNA1G, MLH1, NEUROG1, RUNX3, and SOCS1. We used logistic regression to assess whether associations between several lifestyle factors-intake of fruits, vegetables, folate, and non-steroidal anti-inflammatory drugs-and tumor methylation were modified by race. Proportional hazards models were used to evaluate whether race modified associations between tumor methylation and time to all-cause mortality. Greater fruit consumption was associated with greater odds of high NEUROG1 methylation among EA at methylation cut points of 15-35% (maximum OR 3.44, 95% CI 1.66, 7.13) but not among AA. Higher folate intake was associated with lower odds of high CACNA1G methylation among EAs but not AAs. Tumor methylation was not associated with all-cause mortality for either group. Race might modify associations between lifestyle factors and colorectal tumor methylation, but in this sample did not appear to modify associations between tumor methylation and all-cause mortality.

Background & Aims: Colonic diverticulosis has been reported to be associated with low-grade mucosal inflammation, possibly leading to chronic gastrointestinal symptoms. However, there is poor evidence for this association. We aimed to determine mucosal inflammation and whether diverticula are associated with chronic gastrointestinal symptoms. We explored whether inflammation was present among symptomatic participants with and without diverticula., Methods: We analyzed data from a prospective study of 619 patients undergoing a screening colonoscopy from 2013 through 2015 at the University of North Carolina Hospital in Chapel Hill, North Carolina. Among our participants, 255 (41%) had colonic diverticula. Colonic mucosal biopsy specimens were analyzed for levels of interleukin 6 (IL6), IL10, and tumor necrosis factor messenger RNAs by quantitative reverse-transcriptase polymerase chain reaction, and numbers of immune cells (CD4+, CD8+, CD57+, and mast cell tryptase) by immunohistochemistry. Gastrointestinal symptoms were assessed using Rome III criteria. Proportional odds models were used to estimate odds ratios (ORs) and 95% confidence interval (CIs)., Results: After adjustment for potential confounders, there was no association between diverticulosis and tumor necrosis factor (OR, 0.85; 95% CI, 0.63-1.16), and no association with CD4+ cells (OR, 1.18; 95% CI, 0.87-1.60), CD8+ cells (OR, 0.97; 95% CI, 0.71-1.32), or CD57+ cells (OR, 0.80; 95% CI, 0.59-1.09). Compared with controls without diverticulosis, biopsy specimens from individuals with diverticulosis were less likely to express the inflammatory cytokine IL6 (OR, 0.59; 95% CI, 0.36-0.96). There was no association between diverticulosis and irritable bowel syndrome (OR, 0.53; 95% CI, 0.26-1.05) or chronic abdominal pain (OR, 0.68; 95% CI, 0.38-1.23). There was no evidence for inflammation in patients with symptoms when patients with vs without diverticulosis were compared., Conclusions: We found no evidence that colonic diverticulosis is associated with mucosal inflammation or gastrointestinal symptoms. Among patients with symptoms and diverticula, we found no mucosal inflammation., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Despite evidence that most nonmalignant colorectal polyps can be managed endoscopically, a substantial proportion of patients with a nonmalignant colorectal polyp are still sent to surgery. Risks associated with this surgery are not well characterized. We describe 30-day postoperative morbidity and mortality and explore risk factors for adverse events in patients undergoing surgical resection for nonmalignant colorectal polyps., Methods: We analyzed data collected prospectively as part of the National Surgical Quality Improvement Program. Our analysis included 12,732 patients who underwent elective surgery for a nonmalignant colorectal polyp from 2011 through 2014. We report adverse events within 30 days of the index surgery. Modified Poisson regression was used to estimate risk ratios and 95% confidence intervals., Results: Thirty-day mortality was .7%. The risk of a major postoperative adverse event was 14%. Within 30 days of resection, 7.8% of patients were readmitted and 3.6% of patients had a second major surgery. The index surgery resulted in a colostomy in 1.8% and ileostomy in .4% of patients. Patients who had surgical resection of a nonmalignant polyp in the rectum or anal canal compared with the colon had a risk ratio of 1.58 (95% confidence interval, 1.09-2.28) for surgical site infection and 6.51 (95% confidence interval, 4.97-8.52) for ostomy., Conclusions: Surgery for a nonmalignant colorectal polyp is associated with significant morbidity and mortality. A better understanding of the risks and benefits associated with surgical management of nonmalignant colorectal polyps will better inform discussions regarding the relative merits of management strategies., (Copyright © 2018 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Pretransplant renal failure is commonly reported to be a poor prognostic indicator affecting survival after liver transplantation (LT). However, whether the impact of renal failure on patient outcome varies according to the aetiology of the underlying liver disease is largely unknown., Methods: We investigated the association between renal failure at the time of LT and patient outcome in patients with alcoholic liver disease (ALD) (n = 6920), non-alcoholic steatohepatitis (NASH) (n = 2956) and hepatitis C (HCV) (n = 14 922) using the United Network for Organ Sharing (UNOS) database between February 2002 and December 2013. A total of 24 798 transplant recipients were included., Results: The presence of renal failure was more frequently seen in patients with ALD (23.95%) and NASH (23.27%) compared to patients with HCV (19.38%) (P < 0.001). In multivariate analysis, renal failure was an independent predictor of poor survival. Renal failure showed detrimental effect on patient survival in the overall series (HR = 1.466, P < 0.0001). Importantly, the impact of renal failure was less marked in patients with ALD (HR = 1.31, P < 0.0001) than in patients with NASH (HR = 1.73, P < 0.0001) or HCV (HR = 1.52, P < 0.0001). Despite a higher model for end-stage liver disease (MELD) score at the time of LT, ALD patients with renal failure had better long-term prognosis than non-ALD patients., Conclusions: Renal failure at the time of LT conferred a lower patient and graft survival post-LT. However, renal failure has less impact on the outcome of patients with ALD than that of patients with non-alcoholic liver disease after LT., Competing Interests: The authors disclose no conflicts., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Arsenic (+3 oxidation state) methyltransferase (As3mt) is the key enzyme in the pathway for methylation of inorganic arsenic (iAs). Altered As3mt expression and AS3MT polymorphism have been linked to changes in iAs metabolism and in susceptibility to iAs toxicity in laboratory models and in humans. As3mt-knockout mice have been used to study the association between iAs metabolism and adverse effects of iAs exposure. However, little is known about systemic changes in metabolism of these mice and how these changes lead to their increased susceptibility to iAs toxicity. Here, we compared plasma and urinary metabolomes of male and female wild-type (WT) and As3mt-KO (KO) C57BL/6 mice and examined metabolomic shifts associated with iAs exposure in drinking water. Surprisingly, exposure to 1 ppm As elicited only small changes in the metabolite profiles of either WT or KO mice. In contrast, comparisons of KO mice with WT mice revealed significant differences in plasma and urinary metabolites associated with lipid (phosphatidylcholines, cytidine, acyl-carnitine), amino acid (hippuric acid, acetylglycine, urea), and carbohydrate (L-sorbose, galactonic acid, gluconic acid) metabolism. Notably, most of these differences were sex specific. Sex-specific differences were also found between WT and KO mice in plasma triglyceride and lipoprotein cholesterol levels. Some of the differentially changed metabolites (phosphatidylcholines, carnosine, and sarcosine) are substrates or products of reactions catalyzed by other methyltransferases. These results suggest that As3mt KO alters major metabolic pathways in a sex-specific manner, independent of iAs treatment, and that As3mt may be involved in other cellular processes beyond iAs methylation.

Background & Aims: Colonic diverticula are the most common finding from colonoscopy examinations. Little is known about the distribution of colonic diverticula, which are responsible for symptomatic and costly diverticular disease. We aimed to assess the number, location, and characteristics of colonic diverticula in a large US screening population., Methods: We analyzed data from a prospective study of 624 patients (mean age, 54 years) undergoing screening colonoscopy at the University of North Carolina Hospital from 2013 through 2015. The examination included a detailed assessment of colonic diverticula. To assess the association between participant characteristics and diverticula, we used logistic regression to estimate odds ratios and 95% confidence intervals., Results: Of our population, 260 patients (42%) had 1 or more diverticula (mean number, 14; range, 1-158). Participants with diverticula were more likely to be older, male, and have a higher body mass index than those without diverticula. The distribution of diverticula differed significantly by race. Among white persons, 75% of diverticula were in the sigmoid colon, 11% in the descending splenic flexure, 6% in the transverse colon, and 8% were in the ascending colon or hepatic flexure. In black persons 64% of diverticula were in the sigmoid colon, 8% in the descending colon or splenic flexure, 7% in the transverse colon, and 20% in the ascending colon or hepatic flexure (P = .0008). The proportion of patients with diverticula increased with age: 35% were 50 years or younger, 40% were 51-60 years, and 58% were older than 60 years. The proportion of patients with more than 10 diverticula increased with age: 8% were 50 years or younger, 15% were 51-60 years, and 30% were older than 60 years., Conclusions: Older individuals not only have a higher prevalence of diverticula than younger individuals, but also a greater density, indicating that this is a progressive disease. Black persons have a greater percentage of their diverticula in the proximal colon and fewer in the distal colon compared with white persons. Understanding the distribution and determinants of diverticula is the first step in preventing diverticulosis and its complications., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Looping is a common problem during colonoscopy that prolongs procedure time. We aimed to determine the efficacy and safety of ColoWrap, an external abdominal compression device, with respect to insertion time and other procedural outcomes., Methods: We performed a prospective study of outpatients undergoing elective colonoscopy (40-80 years old; mean age, 60.5 years) at endoscopy facilities in the University of North Carolina Hospitals from April 2013 through March 2014. Subjects were randomly assigned to groups that received either ColoWrap (n = 175) or a sham device (control, n = 175) during colonoscopy. Colonoscopists and staff were blinded to the application. The primary outcome was cecal intubation time (CIT). Secondary outcomes included use of manual pressure and position change., Results: The mean CIT was similar for the control and ColoWrap groups (6.69 vs 6.67 minutes; P = .98). There were no statistical differences in the frequency of manual pressure (45% for controls vs 37% for ColoWrap group, P = .13) or position changes (4% for controls vs 2% for ColoWrap group, P = .36). Among patients with body mass index between 30 and 40 kg/m(2) (n = 78), CIT was significantly lower for patients in the ColoWrap group (4.69 minutes) than controls (6.10 minutes) (P = .03). Adverse events were similar between groups., Conclusions: In patients undergoing elective colonoscopy, application of an external abdominal compression device did not improve CIT or affect the frequency of ancillary maneuvers. A possible benefit was observed in patients with body mass index between 30 and 40 kg/m(2), but further studies are needed. ClinicalTrials.gov number: NCT02025504., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: A novel approach to regulate obesity-associated adipose inflammation may be through metabolic reprogramming of macrophages (MΦs). Broadly speaking, MΦs dependent on glucose are pro-inflammatory, classically activated MΦs (CAM), which contribute to adipose inflammation and insulin resistance. In contrast, MΦs that primarily metabolize fatty acids are alternatively activated MΦs (AAM) and maintain tissue insulin sensitivity. In actuality, there is much flexibility and overlap in the CAM-AAM spectrum in vivo dependent upon various stimuli in the microenvironment. We hypothesized that specific lipid trafficking proteins, e.g. fatty acid transport protein 1 (FATP1), would direct MΦ fatty acid transport and metabolism to limit inflammation and contribute to the maintenance of adipose tissue homeostasis., Methods: Bone marrow derived MΦs (BMDMs) from Fatp1 (-/-) and Fatp1 (+/+) mice were used to investigate FATP1-dependent substrate metabolism, bioenergetics, metabolomics, and inflammatory responses. We also generated C57BL/6J chimeric mice by bone marrow transplant specifically lacking hematopoetic FATP1 (Fatp1 (B-/-)) and controls Fatp1 (B+/+). Mice were challenged by high fat diet (HFD) or low fat diet (LFD) and analyses including MRI, glucose and insulin tolerance tests, flow cytometric, histologic, and protein quantification assays were conducted. Finally, an FATP1-overexpressing RAW 264.7 MΦ cell line (FATP1-OE) and empty vector control (FATP1-EV) were developed as a gain of function model to test effects on substrate metabolism, bioenergetics, metabolomics, and inflammatory responses., Results: Fatp1 is downregulated with pro-inflammatory stimulation of MΦs. Fatp1 (-/-) BMDMs and FATP1-OE RAW 264.7 MΦs demonstrated that FATP1 reciprocally controled metabolic flexibility, i.e. lipid and glucose metabolism, which was associated with inflammatory response. Supporting our previous work demonstrating the positive relationship between glucose metabolism and inflammation, loss of FATP1 enhanced glucose metabolism and exaggerated the pro-inflammatory CAM phenotype. Fatp1 (B-/-) chimeras fed a HFD gained more epididymal white adipose mass, which was inflamed and oxidatively stressed, compared to HFD-fed Fatp1 (B+/+) controls. Adipose tissue macrophages displayed a CAM-like phenotype in the absence of Fatp1. Conversely, functional overexpression of FATP1 decreased many aspects of glucose metabolism and diminished CAM-stimulated inflammation in vitro. FATP1 displayed acyl-CoA synthetase activity for long chain fatty acids in MΦs and modulated lipid mediator metabolism in MΦs., Conclusion: Our findings provide evidence that FATP1 is a novel regulator of MΦ activation through control of substrate metabolism. Absence of FATP1 exacerbated pro-inflammatory activation in vitro and increased local and systemic components of the metabolic syndrome in HFD-fed Fatp1 (B-/-) mice. In contrast, gain of FATP1 activity in MΦs suggested that Fatp1-mediated activation of fatty acids, substrate switch to glucose, oxidative stress, and lipid mediator synthesis are potential mechanisms. We demonstrate for the first time that FATP1 provides a unique mechanism by which the inflammatory tone of adipose and systemic metabolism may be regulated.

Background: Obesity is associated with an aggressive subtype of breast cancer called basal-like breast cancer (BBC). BBC has no targeted therapies, making the need for mechanistic insight urgent. Reducing adiposity in adulthood can lower incidence of BBC in humans. Thus, this study investigated whether a dietary intervention to reduce adiposity prior to tumor onset would reverse HFD-induced BBC., Methods: Adult C3(1)-Tag mice were fed a low or high fat diet (LFD, HFD), and an obese group initially exposed to HFD was then switched to LFD to induce weight loss. A subset of mice was sacrificed prior to average tumor latency to examine unaffected mammary gland. Latency, tumor burden and progression was evaluated for effect of diet exposure. Physiologic, histology and proteomic analysis was undertaken to determine mechanisms regulating obesity and weight loss in BBC risk. Statistical analysis included Kaplan-Meier and log rank analysis to investigate latency. Student's t tests or ANOVA compared variables., Results: Mice that lost weight displayed significantly delayed latency compared to mice fed HFD, with latency matching those on LFD. Plasma leptin concentrations significantly increased with adiposity, were reduced to control levels with weight loss, and negatively correlated with tumor latency. HFD increased atypical ductal hyperplasia and ductal carcinoma in situ in mammary gland isolated prior to mean latency-a phenomenon that was lost in mice induced to lose weight. Importantly, kinome analysis revealed that weight loss reversed HFD-upregulated activity of PKC-α, PKD1, PKA, and MEK3 and increased AMPKα activity in unaffected mammary glands isolated prior to tumor latency., Conclusions: Weight loss prior to tumor onset protected against the effects of HFD on latency and pre-neoplastic lesions including atypical ductal hyperplasia and DCIS. Using innovative kinomics, multiple kinases upstream of MAPK/P38α were demonstrated to be activated by HFD-induced weight gain and reversed with weight loss, providing novel targets in obesity-associated BBC. Thus, the HFD-exposed microenvironment that promoted early tumor onset was reprogrammed by weight loss and the restoration of a lean phenotype. Our work contributes to an understanding of underlying mechanisms associated with tumor and normal mammary changes that occur with weight loss.

Unlabelled: Epidemiologic studies have associated obesity with increased risk of the aggressive basal-like breast cancer (BBC) subtype. Hepatocyte growth factor (HGF) signaling through its receptor, cMET, is elevated in obesity and is a pro-tumorigenic pathway strongly associated with BBC. We previously reported that high fat diet (HFD) elevated HGF, cMET, and phospho-cMET in normal mammary gland, with accelerated tumor development, compared to low fat diet (LFD)-fed lean controls in a murine model of BBC. We also showed that weight loss resulted in a significant reversal of HFD-induced effects on latency and elevation of HGF/cMET signaling in normal mammary and cMET in normal mammary and tumors. Here, we sought to inhibit BBC tumor progression in LFD- and HFD-fed C3(1)-Tag BBC mice using a small molecule cMET inhibitor, and began crizotinib treatment (50 mg/kg body weight by oral gavage) upon identification of the first palpable tumor. We next investigated if administering crizotinib in a window prior to tumor development would inhibit or delay BBC tumorigenesis., Treatment: Crizotinib significantly reduced mean tumor burden by 27.96 and 37.29 %, and mean tumor vascularity by 35.04 and 33.52 %, in our LFD- and HFD-fed C3(1)-Tag BBC mice, respectively., Prevention: Crizotinib significantly accelerated primary tumor progression in both diet groups but had no effect on total tumor progression or total tumor burden. In sum, cMET inhibition by crizotinib limited tumor development and microvascular density in basal-like tumor-bearing mice but did not appear to be an effective preventive agent for BBC.

Background: Constipation, a low fiber diet, sedentary lifestyle and gravidity are commonly assumed to increase the risk of hemorrhoids. However, evidence regarding these factors is limited. We examined the association between commonly cited risk factors and the prevalence of hemorrhoids., Methods: We performed a cross sectional study of participants who underwent a colonoscopy in a colorectal adenoma prevention trial and who had a detailed assessment of bowel habits, diet and activity. The presence of hemorrhoids was extracted from the subjects' colonoscopy reports. We used logistic regression to estimate odds ratios and 95% confidence intervals while adjusting for age and sex., Results: The study included 2,813 participants. Of these, 1,074 had hemorrhoids recorded. Constipation was associated with an increased prevalence of hemorrhoids (OR 1.43, 95% CI 1.11, 1.86). Of the fiber subtypes, high grain fiber intake was associated with a reduced risk (OR for quartile 4 versus quartile 1 = 0.78, 95% CI 0.62, 0.98). We found no association when comparing gravid and nulligravida women (OR 0.93, 95% CI 0.62-1.40). Sedentary behavior was associated with a reduced risk (OR 0.80, 95% CI 0.65-0.98), but not physical activity (OR 0.83, 95% CI 0.66-1.03). Neither being overweight nor obese was associated with the presence of hemorrhoids (OR 0.89, 95% CI 0.72-1.09 and OR 0.86, 95% CI 0.70-1.06)., Conclusions: Constipation is associated with an increased risk of hemorrhoids. Gravidity and physical activity do not appear to be associated. High grain fiber intake and sedentary behavior are associated with a decreased risk of hemorrhoids.

Objectives: Dysbiosis leading to abnormal intestinal fermentation has been suggested as a possible etiological mechanism in irritable bowel syndrome (IBS). We aimed to investigate the location and magnitude of altered intestinal bacterial fermentation in IBS and its clinical subtypes., Methods: IBS patients who satisfied the Rome III criteria (114) and 33 healthy controls (HC) were investigated. Intestinal fermentation was assessed using two surrogate measures: intestinal intraluminal pH and fecal short-chain fatty acids (SCFAs). Intraluminal pH and intestinal transit times were measured in the small and large bowel using a wireless motility capsule (SmartPill) in 47 IBS and 10 HC. Fecal SCFAs including acetate, propionate, butyrate, and lactate were analyzed by capillary gas chromatography in all enrolled subjects. Correlations between intestinal pH, fecal SCFAs, intestinal transit time, and IBS symptom scores were analyzed., Results: Colonic intraluminal pH levels were significantly lower in IBS patients compared with HC (total colonic pH, 6.8 for IBS vs. 7.3 for HC, P=0.042). There were no differences in total and segmental pH levels in the small bowel between IBS patients and HC (6.8 vs. 6.8, P=not significant). The intraluminal colonic pH differences were consistent in all IBS subtypes. Total SCFA level was significantly lower in C-IBS patients than in D-IBS and M-IBS patients and HC. The total SCFA level in all IBS subjects was similar with that of HC. Colonic pH levels correlated positively with colon transit time (CTT) and IBS symptoms severity. Total fecal SCFAs levels correlated negatively with CTT and positively with stool frequency., Conclusions: Colonic intraluminal pH is decreased, suggesting higher colonic fermentation, in IBS patients compared with HC. Fecal SCFAs are not a sensitive marker to estimate intraluminal bacterial fermentation.