Impact of COVID-19 Treatment on Real-World Outcomes in Inflammatory Bowel Disease.

BACKGROUND: While there are multiple safe and effective agents for COVID-19 treatment, their impact in inflammatory bowel disease (IBD) remains uncertain. AIMS: Our objective was to assess the effects of these therapies on both IBD and COVID outcomes. METHODS: A single-center retrospective study of adult patients with IBD who contracted COVID-19 between 12/2020 and 11/2022 was performed. Patients were stratified by COVID-19 treatment (antivirals and/or intravenous antibodies) vs no therapy. The primary outcome was the development of severe COVID-19 infection, defined by need for supplemental oxygen, corticosteroids and/or antibiotics, or hospitalization. Secondary outcomes included rates of withholding advanced IBD therapy (defined as biologic agents or small molecules) and of post-COVID-19 IBD flare. RESULTS: Of 127 patients with COVID-19 infection, 70% were on advanced therapies, 35% received COVID-19 treatment, and 15% developed severe COVID-19. Those treated for COVID-19 were more likely to be on corticosteroids [odds ratio (OR) 4.61, 95% confidence interval (CI) 1.72-12.39, p = 0.002] or advanced IBD therapies (OR 2.78, 95% CI 1.04-7.43, p = 0.041). After adjusting for age, race, sex, corticosteroid use, obesity, COVID-19 vaccination status, and severe COVID-19 infection, those treated for COVID-19 were more likely to have IBD therapy held (OR 6.95, 95% CI 1.72-28.15, p = 0.007). There was no significant difference in rates of post-COVID-19 IBD flares or severe COVID-19 infection. There were no COVID-related deaths. CONCLUSIONS: Patients with IBD on advanced therapies were frequently treated for acute COVID-19. Although COVID-19 treatment was associated with temporary withholding of IBD therapy, it did not result in increased IBD flares.

Probabilistic risk assessment of residential exposure to electric arc furnace steel slag using Bayesian model of relative bioavailability and PBPK modeling of manganese.

Electric arc furnace (EAF) slag is a coproduct of steel production used primarily for construction purposes. Some applications of EAF slag result in residential exposures by incidental ingestion and inhalation of airborne dust. To evaluate potential health risks, an EAF slag characterization program was conducted to measure concentrations of metals and leaching potential (including oral bioaccessibility) in 38 EAF slag samples. Arsenic, hexavalent chromium, iron, vanadium, and manganese (Mn) were identified as constituents of interest (COIs). Using a probabilistic risk assessment (PRA) approach, estimated distributions of dose for COIs were assessed, and increased cancer risks and noncancer hazard quotients (HQs) at the 50th and 95th percentiles were calculated. For the residents near slag-covered roads, cancer risk and noncancer HQs were <1E - 6 and 1, respectively. For residential driveway or landscape exposure, at the 95th percentile, cancer risks were 1E - 6 and 7E - 07 based on oral exposure to arsenic and hexavalent chromium, respectively. HQs ranged from 0.07 to 2 with the upper bound due to ingestion of Mn among children. To expand the analysis, a previously published physiologically based pharmacokinetic (PBPK) model was used to estimate Mn levels in the globus pallidus for both exposure scenarios and further evaluate the potential for Mn neurotoxicity. The PBPK model estimated slightly increased Mn in the globus pallidus at the 95th percentile of exposure, but concentrations did not exceed no-observed-adverse-effect levels for neurological effects. Overall, the assessment found that the application of EAF slag in residential areas is unlikely to pose a health hazard or increased cancer risk.

Use of physiologically based pharmacokinetic modeling to support development of an acute (24-hour) health-based inhalation guideline for manganese.

The toxicokinetics of manganese (Mn) are controlled through homeostasis because Mn is an essential element. However, at elevated doses, Mn is also neurotoxic and has been associated with respiratory, reproductive, and developmental effects. While health-based criteria have been developed for chronic inhalation exposure to ambient Mn, guidelines for short-term (24-h) environmental exposure are also needed. We reviewed US state, federal, and international health-based inhalation toxicity criteria, and conducted a literature search of recent publications. The studies deemed most appropriate to derive a 24-h guideline have a LOAEL of 1500 µg/m3 for inflammatory airway changes and biochemical measures of oxidative stress in the brain following 90 total hours of exposure in monkeys. We applied a cumulative uncertainty factor of 300 to this point of departure, resulting in a 24-h guideline of 5 µg/m3. To address uncertainty regarding potential neurotoxicity, we used a previously published physiologically based pharmacokinetic model for Mn to predict levels of Mn in the brain target tissue (i.e., globus pallidus) for exposure at 5 µg/m3 for two short-term human exposure scenarios. The PBPK model predictions support a short-term guideline of 5 µg/m3 as protective of both respiratory effects and neurotoxicity, including exposures of infants and children.

AGA Technical Review on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn's Disease.

The incidence and prevalence of Crohn's disease (CD) is rising globally. Patients with moderate to severe CD are at high risk for needing surgery and hospitalization and for developing disease-related complications, corticosteroid dependence, and serious infections. Optimal management of outpatients with moderate to severe luminal and/or fistulizing (including perianal) CD often requires the use of immunomodulator (thiopurines, methotrexate) and/or biologic therapies, including tumor necrosis factor-α antagonists, vedolizumab, or ustekinumab, either as monotherapy or in combination (with immunomodulators) to mitigate these risks. Decisions about optimal drug therapy in moderate to severe CD are complex, with limited guidance on comparative efficacy and safety of different treatments, leading to considerable practice variability. Since the last iteration of these guidelines published in 2013, significant advances have been made in the field, including the regulatory approval of 2 new biologic agents, vedolizumab and ustekinumab. Therefore, the American Gastroenterological Association prioritized updating clinical guidelines on this topic. To inform the clinical guidelines, this technical review was completed in accordance with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. The review addressed the following focused questions (in adult outpatients with moderate to severe luminal CD): overall and comparative efficacy of different medications for induction and maintenance of remission in patients with or without prior exposure to tumor necrosis factor-α antagonists, comparative efficacy and safety of biologic monotherapy vs combination therapy with immunomodulators, comparative efficacy of a top-down (upfront use of biologics and/or immunomodulator therapy) vs step-up treatment strategy (acceleration to biologic and/or immunomodulator therapy only after failure of mesalamine), and the role of corticosteroids and mesalamine for induction and/or maintenance of remission. Finally, in adult outpatients with moderate to severe fistulizing CD, this review addressed the efficacy of pharmacologic interventions for achieving fistula and the role of adjunctive antibiotics without clear evidence of active infection.

The emerging role of Janus kinase inhibitors in the treatment of autoimmune and inflammatory diseases.

Autoimmune and inflammatory diseases are common and diverse, and they can affect nearly any organ system. Much of the pathogenesis of these diseases is related to dysregulated cytokine activity. Historically, autoimmune and inflammatory diseases have been treated with medications that nonspecifically suppress the immune system. mAbs that block the action of pathogenic cytokines emerged 2 decades ago and have become widely useful. More recently, agents that simultaneously block multiple pathogenic cytokines via inhibition of the downstream Janus kinase (JAK)-signal transducer and activator of transcription pathway have emerged and are becoming increasingly important. These small-molecule inhibitors, collectively termed JAK inhibitors, are US Food and Drug Administration-approved in a few autoimmune/inflammatory disorders and are being evaluated in many others. Here, we review the biology of the JAK-signal transducer and activator of transcription pathway and the use of JAK inhibitors to treat autoimmune and inflammatory diseases across medical subspecialties.

Sleep Characteristics and Rest-Activity Rhythms Are Associated with Gastrointestinal Symptoms Among Adults with Inflammatory Bowel Disease.

BACKGROUND: Sleep disturbance is common in inflammatory bowel disease (IBD) and is associated with poorer quality of life and increased disease activity; however, sleep is a multidimensional process, and little is known about specific sleep characteristics and rest-activity rhythms (RARs) in this population. AIMS: The purposes were to (1) describe sleep characteristics and RARs; (2) compare sleep characteristics and RARs and GI symptoms by disease activity; and (3) describe associations between sleep characteristics, RARs, and GI symptoms among adults with IBD. METHODS: We conducted a cross-sectional study of adults with IBD. We measured sleep characteristics and RARs (continuous wrist actigraphy); GI symptoms (PROMIS-GI); and disease activity (physicians' global assessment). We conducted cosinor and nonparametric analyses to compute RAR variables and bivariate analyses to address the aims. RESULTS: The sample included 37 participants [age M = 38 years (SD = 13.8) and 21 (56.8%) female], of whom 23 (60.6%) were in remission. Sleep efficiency [M = 82.91% (SD 5.35)] and wake after sleep onset (WASO) [M = 42.26 min (SD 18.57)] were not associated with disease activity. Inter-daily stability of the RAR was associated with heartburn/reflux (r = - .491, p = .005) and gas/bloating (r = - .469, p = .008). Intra-daily variability of the RAR was associated with heartburn/reflux (r = .421, p = .018). CONCLUSIONS: People with IBD may have disrupted RARs, which are associated with GI symptoms. Research is needed to improve understanding of these associations and to develop interventions to improve these characteristics in adults with IBD.

Inhalation cancer risk assessment for environmental exposure to hexavalent chromium: Comparison of margin-of-exposure and linear extrapolation approaches.

Hexavalent chromium [Cr(VI)] exists in the ambient air at low concentrations (average upperbound ~0.1 ng/m3) yet airborne concentrations typically exceed EPA's Regional Screening Level for residential exposure (0.012 ng/m3) and other similar benchmarks, which assume a mutagenic mode of action (MOA) and use low-dose linear risk assessment models. We reviewed Cr(VI) inhalation unit risk estimates developed by researchers and regulatory agencies for environmental and occupational exposures and the underlying epidemiologic data, updated a previously published MOA analysis, and conducted dose-response modeling of rodent carcinogenicity data to evaluate the need for alternative exposure-response data and risk assessment approaches. Current research supports the role of non-mutagenic key events in the MOA, with growing evidence for epigenetic modifiers. Animal data show a weak carcinogenic response, even at cytotoxic exposures, and highlight the uncertainties associated with the current epidemiological data used in risk assessment. Points of departure from occupational and animal studies were used to determine margins of exposure (MOEs). MOEs range from 1.5 E+3 to 3.3 E+6 with a median of 5 E+5, indicating that current environmental exposures to Cr(VI) in ambient air should be considered of low concern. In this comprehensive review, the divergent results from default linear and MOE assessments support the need for more relevant and robust epidemiologic data, additional mechanistic studies, and refined risk assessment strategies.

An adverse outcome pathway for small intestinal tumors in mice involving chronic cytotoxicity and regenerative hyperplasia: a case study with hexavalent chromium, captan, and folpet.

Small intestinal (SI) tumors are relatively uncommon outcomes in rodent cancer bioassays, and limited information regarding chemical-induced SI tumorigenesis has been reported in the published literature. Herein, we propose a cytotoxicity-mediated adverse outcome pathway (AOP) for SI tumors by leveraging extensive target species- and site-specific molecular, cellular, and histological mode of action (MOA) research for three reference chemicals, the fungicides captan and folpet and the transition metal hexavalent chromium (Cr(VI)). The gut barrier functions through highly efficient homeostatic regulation of SI epithelial cell sloughing, regenerative proliferation, and repair, which involves the replacement of up to 1011 cells per day. This dynamic turnover in the SI provides a unique local environment for a cytotoxicity mediated AOP/MOA. Upon entering the duodenum, cytotoxicity to the villous epithelium is the molecular initiating event, as indicated by crypt elongation, villous atrophy/blunting, and other morphologic changes. Over time, the regenerative capacity of the gut epithelium to compensate declines as epithelial loss accelerates, especially at higher exposures. The first key event (KE), sustained regenerative crypt proliferation/hyperplasia, requires sufficient durations, likely exceeding 6 or 12 months, due to extensive repair capacity, to create more opportunities for the second KE, spontaneous mutation/transformation, ultimately leading to proximal SI tumors. Per OECD guidance, biological plausibility, essentiality, and empirical support were assessed using modified Bradford Hill considerations. The weight-of-evidence also included a lack of induced mutations in the duodenum after up to 90 days of Cr(VI) or captan exposure. The extensive evidence for this AOP, along with the knowledge that human exposures are orders of magnitude below those associated with KEs in this AOP, supports its use for regulatory applications, including hazard identification and risk assessment.

Exposure to environmentally-relevant concentrations of hexavalent chromium does not induce ovarian toxicity in mice.

Exposure to high concentrations of hexavalent chromium [Cr(VI)] in drinking water (≥250 ppm) is reported to decrease ovarian follicle counts and increase follicular atresia in mice. To assess effects at lower concentrations, herein we exposed B6C3F1 mice to 0.1-150 ppm Cr(VI) in drinking water for 90 days in a GLP-compliant study. Ovarian follicular counts, differentiation, and degeneration were assessed from every 10th serial section (up to 14 sections per ovary). Ovarian follicular counts, differentiation, and rate of atresia were not altered in any exposure group. Gross and microscopic changes were not apparent in any of the evaluated reproductive or glandular organs. The no observable adverse effect level (NOAEL) for follicular effects was 150 ppm. In addition to these findings, published Cr(VI) studies examining follicles were scored using two methods for assessing study quality for use in risk assessment-including the Toxic Substance Control Act (TSCA) scoring method. Both methods revealed that studies reporting adverse effects on follicles generally received low scores. Overall, the current study indicates no/low potential for Cr(VI) to induce follicular toxicity in mice below 150 ppm Cr(VI) in drinking water (17.7 mg/kg bodyweight).

Hexavalent chromium and stomach cancer: a systematic review and meta-analysis.

Hexavalent chromium [Cr(VI)] is known to cause lung cancer in workers of certain industries, but an association with stomach cancer is uncertain and widely debated. Systematic review and meta-analyses were conducted to assess the risk of stomach cancer mortality/morbidity in humans and experimental animals exposed to Cr(VI). In accordance with the protocol (PROSPERO #CRD4201605162), searches in PubMed and Embase®, and reviews of secondary literature bibliographies, were used to identify eligible studies. Critical appraisal of internal validity and qualitative integration were carried out using the National Toxicology Program's Office of Health Assessment and Translation (OHAT) approach; meta-analyses were conducted based on the occupational data (the only data suitable for quantitative assessment). Forty-seven publications (3 animal, 44 occupational, 0 non-occupational) met the eligibility criteria. Stomach cancer was only observed in one high risk of bias animal study, and in the low risk of bias studies no stomach cancer was observed. Thus, confidence in this evidence base is high. Environmental epidemiology studies did not meet eligibility criteria because exposure and outcome were not measured at the individual level. Meta-analyses of human data resulted in overall meta relative risks of 1.08 (95% CI: 0.96-1.21) including all studies and 1.03 (95%CI: 0.84-1.26) excluding studies associated with the highest risk of bias. Because most occupational studies have high risk of bias for confounding and exposure domains, the overall confidence in this evidence base is low to moderate. Combining the streams of evidence per the OHAT approach, Cr(VI) does not pose a stomach cancer hazard in humans.

JAK2 Disease-Risk Variants Are Gain of Function and JAK Signaling Threshold Determines Innate Receptor-Induced Proinflammatory Cytokine Secretion in Macrophages.

JAK2 genetic variants are associated with inflammatory bowel disease (IBD) and JAK inhibitors are being evaluated for therapy targeting immune-mediated diseases, including IBD. As JAK pathway-mediated cytokine regulation varies across cell types and stimulation conditions, we examined how JAK signaling and IBD-associated JAK2 variants regulate distinct acute and chronic microbial product exposure outcomes in human myeloid cells, consistent with the conditions of initial entry and ongoing intestinal tissue residence, respectively. Macrophages from controls and ulcerative colitis patients carrying the IBD-risk rs10758669 CC genotype showed increased JAK2 expression and nucleotide-binding oligomerization domain 2-induced JAK2 phosphorylation relative to AA carriers. Interestingly, the threshold of JAK2 expression and signaling determined pattern-recognition receptor (PRR)-induced outcomes; whereas anti-inflammatory cytokines progressively decreased with lower JAK2 expression, proinflammatory cytokines switched from decreased to increased secretion below a certain JAK2 expression threshold. Low JAK2-expressing rs10758669 AA macrophages were above this threshold; consequently, both PRR-induced pro- and anti-inflammatory cytokines were decreased. However, relative to rs10758669 CC risk carriers, AA carrier macrophages switched to increased nucleotide-binding oligomerization domain 2-induced proinflammatory cytokines at lower therapeutically used JAK inhibitor doses. Importantly, JAK inhibitors increased proinflammatory cytokines secreted by peripheral macrophages following chronic PRR stimulation and by human intestinal myeloid cells following exposure to intestinal pathogens. Mechanistically, the decreased response to and secretion of autocrine/paracrine IL-10, IL-4, IL-22 and thymic stromal lymphopoietin regulated these JAK-dependent outcomes in myeloid cells. Taken together, the JAK signaling threshold determines whether PRR-induced pro- and anti-inflammatory cytokines are reciprocally regulated in myeloid cells; consideration of JAK2 genotype and targeting of specific cell types might improve JAK-targeted therapy in immune-mediated diseases.

Knowledge Gaps in the Management of Postoperative Crohn's Disease: A US National Survey.

BACKGROUND: Postoperative recurrence (POR) of Crohn's disease (CD) is common. Guidelines on POR management have recently been issued, but clinical practice may vary. AIMS: To examine the current clinical practice of POR management in the USA METHODS: A web-based survey was sent to all members of the American Gastroenterological Association and the American College of Gastroenterology. The survey consisted of multiple-choice questions with clinical scenarios to assess how participants manage POR. RESULTS: A total of 189 responses were received from practices in 34 states. 44% of participants were from academic settings. The median number of CD patients seen each month was 20-30 patients per participant. The majority of participants considered smoking, prior intestinal surgery, penetrating disease, perianal fistula, early disease onset, and long extent of disease as high-risk factors for POR. To diagnose and grade endoscopic recurrence, 57% of participants used an endoscopic scoring system; 86% defined clinical recurrence using a combination of symptoms and endoscopic findings; and 79% of participants routinely performed colonoscopy after surgery. In high-risk patients, 65% offered medical prophylaxis-most often biologics and/or immunomodulators-immediately after surgery, while 34% offered medical prophylaxis regardless of the patient's risk of POR. 64% of participants never stopped medical prophylaxis once initiated. CONCLUSIONS: Most gastroenterologists routinely perform colonoscopy to guide POR management. The majority of these providers continue medical prophylaxis indefinitely regardless of subsequent endoscopic findings. Further research is needed to determine the risks and benefits of continuing versus deescalating therapy in patients with potentially surgically induced remission.

An Adverse Outcome Pathway (AOP) for forestomach tumors induced by non-genotoxic initiating events.

The utility of rodent forestomach tumor data for hazard and risk assessment has been examined for decades because humans do not have a forestomach, and these tumors occur by varying modes of action (MOAs). We have used the MOA for ethyl acrylate (EA) to develop an Adverse Outcome Pathway (AOP) for forestomach tumors caused by non-genotoxic initiating events. These tumors occur secondary to site of contact induced epithelial cytotoxicity and regenerative repair-driven proliferation. For EA, the critical initiating event (IE) is epithelial cytotoxicity, and supporting key events (KEs) at the cellular and tissue level are increased cell proliferation (KE1) resulting in sustained hyperplasia (KE2), with the adverse outcome of forestomach papillomas and carcinomas. For EA, a pre-molecular initiating event (pre-MIE) of sustained glutathione depletion is probable. Supporting data from butylated hydroxyanisole (BHA) are also reviewed. Although there may be some variability in the pre-MIEs and IEs for BHA and EA, they share the same KEs, and evidence for BHA confers support for the AOP. Evolved Bradford Hill considerations of biological plausibility, essentiality, and empirical support were evaluated per OECD guidance. Although an MIE is not specifically described, overall confidence in the AOP is high due to well-developed and accepted evidence streams, and the AOP can be used for regulatory applications including hazard identification and risk assessment for chemicals that act by this AOP.

Assessment of the mode of action underlying development of forestomach tumors in rodents following oral exposure to ethyl acrylate and relevance to humans.

Chronic repeated gavage dosing of high concentrations of ethyl acrylate (EA) causes forestomach tumors in rats and mice. For two decades, there has been general consensus that these tumors are unique to rodents because of: i) lack of carcinogenicity in other organs, ii) specificity to the forestomach (an organ unique to rodents which humans do not possess), iii) lack of carcinogenicity by other routes of exposure, and iv) obvious site of contact toxicity at carcinogenic doses. In 1986, EA was classified as possibly carcinogenic to humans by the International Agency for Research on Cancer (IARC). However, by applying a MOA analyses and human relevance framework assessment, the weight-of-evidence supports a cytotoxic MOA with the following key events: i) bolus delivery of EA to forestomach lumen and subsequent absorption, ii) cytotoxicity likely due to saturation of enzymatic detoxification, iii) chronic regenerative hyperplasia, and iv) spontaneous mutation due to increased cell replication and cell population. Clonal expansion of initiated cells thus results in late onset tumorigenesis. The key events in this 'wound and healing' MOA provide high confidence in the MOA as assessed by evolved Bradford-Hill Criteria. The weight-of-evidence supported by the proposed MOA, combined with a unique tissue that does not exist in humans, indicates that EA is highly unlikely to pose a human cancer hazard.

Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin-of-exposure values for hexavalent chromium.

The current US Environmental Protection Agency (EPA) reference dose (RfD) for oral exposure to chromium, 0.003 mg kg-1  day-1 , is based on a no-observable-adverse-effect-level from a 1958 bioassay of rats exposed to ≤25 ppm hexavalent chromium [Cr(VI)] in drinking water. EPA characterizes the confidence in this RfD as "low." A more recent cancer bioassay indicates that Cr(VI) in drinking water is carcinogenic to mice at ≥30 ppm. To assess whether the existing RfD is health protective, neoplastic and non-neoplastic lesions from the 2 year cancer bioassay were modeled in a three-step process. First, a rodent physiological-based pharmacokinetic (PBPK) model was used to estimate internal dose metrics relevant to each lesion. Second, benchmark dose modeling was conducted on each lesion using the internal dose metrics. Third, a human PBPK model was used to estimate the daily mg kg-1 dose that would produce the same internal dose metric in both normal and susceptible humans. Mechanistic research into the mode of action for Cr(VI)-induced intestinal tumors in mice supports a threshold mechanism involving intestinal wounding and chronic regenerative hyperplasia. As such, an RfD was developed using incidence data for the precursor lesion diffuse epithelial hyperplasia. This RfD was compared to RfDs for other non-cancer endpoints; all RfD values ranged 0.003-0.02 mg kg-1  day-1 . The lowest of these values is identical to EPA's existing RfD value. Although the RfD value remains 0.003 mg kg-1  day-1 , the confidence is greatly improved due to the use of a 2-year bioassay, mechanistic data, PBPK models and benchmark dose modeling.

Longitudinal Changes in Symptom Cluster Membership in Inflammatory Bowel Disease.

PURPOSE: To describe changes in symptom cluster membership over 1 year and to examine which demographic and clinical factors predict changes in symptom cluster membership among adults with inflammatory bowel disease. DESIGN: A retrospective longitudinal study of the Crohn's & Colitis Foundation of America Partners Cohort from 2012 to 2015. METHODS: We measured symptoms of pain interference, fatigue, sleep disturbance, depression, and anxiety. We used latent transition analysis to describe changes in symptom cluster membership (baseline, 6 months, and 12 months) and multinomial regressions to examine factors associated with symptom cluster membership transition. FINDINGS: Four groups were identified (N = 5,296): high symptom burden (32.3%-35.3%), low symptom burden (24.2%-27.1%), physical symptoms (19.0%-20.9%; pain, fatigue, sleep disturbance), and psychological symptoms (20.0%-21.5%; depression, anxiety). The probability of staying in the same group was .814 to .905. Moving from active disease into remission was associated with moving from the high burden to low burden and psychological symptom groups. CONCLUSIONS: Symptom cluster membership was quite stable over 1 year. Research is needed to understand the underlying etiology of symptom clusters better and to develop interventions to reduce symptom burden in this vulnerable population. CLINICAL RELEVANCE: Careful consideration of symptom management options should be done with patients to select options that are effective and potentially target multiple symptoms.

Appendectomy does not decrease the risk of future colectomy in UC: results from a large cohort and meta-analysis.

OBJECTIVES: Early appendectomy is inversely associated with the development of UC. However, the impact of appendectomy on the clinical course of UC is controversial, generally favouring a milder disease course. We aim to describe the effect appendectomy has on the disease course of UC with focus on the timing of appendectomy in relation to UC diagnosis. DESIGN: Using the National Institute of Diabetes and Digestive and Kidney Diseases Inflammatory Bowel Disease Genetics Consortium database of patients with UC, the risk of colectomy was compared between patients who did and did not undergo appendectomy. In addition, we performed a meta-analysis of studies that examined the association between appendectomy and colectomy. RESULTS: 2980 patients with UC were initially included. 111 (4.4%) patients with UC had an appendectomy; of which 63 were performed prior to UC diagnosis and 48 after diagnosis. In multivariable analysis, appendectomy performed at any time was an independent risk factor for colectomy (OR 1.9, 95% CI 1.1 to 3.1), with appendectomy performed after UC diagnosis most strongly associated with colectomy (OR 2.2, 95% CI 1.1 to 4.5). An updated meta-analysis showed appendectomy performed either prior to or after UC diagnosis had no effect on colectomy rates. CONCLUSIONS: Appendectomy performed at any time in relation to UC diagnosis was not associated with a decrease in severity of disease. In fact, appendectomy after UC diagnosis may be associated with a higher risk of colectomy. These findings question the proposed use of appendectomy as treatment for UC.

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition.

BACKGROUND & AIMS: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). METHODS: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. RESULTS: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)). CONCLUSIONS: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

Assessment of the mutagenic potential of hexavalent chromium in the duodenum of big blue® rats.

A cancer bioassay on hexavalent chromium Cr(VI) in drinking water reported increased incidences of duodenal tumors in B6C3F1 mice at exposures of 30-180ppm, and oral cavity tumors in F344 rats at 180ppm. A subsequent transgenic rodent (TGR) in vivo mutation assay in Big Blue® TgF344 rats found that exposure to 180ppm Cr(VI) in drinking water for 28days did not increase cII transgene mutant frequency (MF) in the oral cavity (Thompson et al., 2015). Herein, we extend our analysis to the duodenum of these same TgF344 rats. At study termination, duodenum chromium levels were below either the limit of detection or quantification in control rats, but were 24.6±3.8µg/g in Cr(VI)-treated rats. The MF in control (23.2×10-6) and Cr(VI)-treated rats (22.7×10-6) were nearly identical. In contrast, the MF in the duodenum of rats exposed to 1-ethyl-1-nitrosourea for six days (study days 1, 2, 3, 12, 19, 26) increased 24-fold to 557×10-6. These findings indicate that mutagenicity is unlikely an early initiating event in Cr(VI)-induced intestinal carcinogenesis.

Comparison of Toxicity and Recovery in the Duodenum of B6C3F1 Mice Following Treatment with Intestinal Carcinogens Captan, Folpet, and Hexavalent Chromium.

High concentrations of hexavalent chromium (Cr(VI)), captan, and folpet induce duodenal tumors in mice. Using standardized tissue collection procedures and diagnostic criteria, we compared the duodenal histopathology in B6C3F1 mice following exposure to these 3 carcinogens to determine whether they share similar histopathological characteristics. B6C3F1 mice ( n = 20 per group) were exposed to 180 ppm Cr(VI) in drinking water, 12,000 ppm captan in feed, or 16,000 ppm folpet in feed for 28 days. After 28 days of exposure, villous enterocyte hypertrophy and mild crypt epithelial hyperplasia were observed in all exposed mice. In a subset of mice allowed to recover for 28 days, duodenal samples were generally indistinguishable from those of unexposed mice. Changes in the villi and lack of observable damage to the crypt compartment suggest that toxicity was mediated in the villi, which is consistent with earlier studies on each chemical. These findings indicate that structurally diverse agents can induce similar (and reversible) phenotypic changes in the duodenum. These intestinal carcinogens likely converge on common pathways involving irritation and wounding of the villi leading to crypt regenerative hyperplasia that, under protracted high-dose exposure scenarios, increases the risk of spontaneous mutation and tumorigenesis.