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Supplemental material, sj-docx-2-mde-10.1177_23821205221096269 for Fear Not: Utilizing Simulation for Medical Malpractice Education by Kate E. Hughes, Thomas M. Cahir, Diana Nordlund, Samuel M. Keim and Patrick G. Hughes in Journal of Medical Education and Curricular Development

Supplemental material, sj-docx-1-mde-10.1177_23821205221096269 for Fear Not: Utilizing Simulation for Medical Malpractice Education by Kate E. Hughes, Thomas M. Cahir, Diana Nordlund, Samuel M. Keim and Patrick G. Hughes in Journal of Medical Education and Curricular Development

Supplemental material, sj-docx-2-mde-10.1177_23821205221096269 for Fear Not: Utilizing Simulation for Medical Malpractice Education by Kate E. Hughes, Thomas M. Cahir, Diana Nordlund, Samuel M. Keim and Patrick G. Hughes in Journal of Medical Education and Curricular Development

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Ninety years ago next month the deadliest natural disaster in U.S. history killed more Americans than the Chicago Fire, the San Francisco Earthquake, and the Johnstown Flood all put together.

Background: Inflammatory bowel disease (IBD) has a remitting and relapsing disease course; however, relatively little is understood regarding how inflammatory damage in acute colitis influences the microbiota, epithelial barrier, and immune function in subsequent colitis. Methods: Mice were administered trinitrobenzene sulphonic acid (TNBS) via enema, and inflammation was assessed 2 days (d2) or 28 days (d28) later. Colitis was reactivated in some mice by re-treating at 28 days with TNBS and assessing 2 days later (d30). Epithelial responsiveness to secretagogues, microbiota composition, colonic infiltration, and immune activation was compared between all groups Results: At day 28, the distal colon had healed, mucosa was restored, and innate immune response had subsided, but colonic transepithelial transport (P = 0.048), regulatory T-cell (TREG) infiltration (P = 0.014), adherent microbiota composition (P = 0.0081), and responsiveness of stimulated innate immune bone marrow cells (P < 0.0001 for IL-1β) differed relative to health. Two days after subsequent instillation of TNBS (d30 mice), the effects on inflammatory damage (P < 0.0001), paracellular permeability (P < 0.0001), and innate immune infiltration (P < 0.0001 for Ly6C+ Ly6G- macrophages) were reduced relative to d2 colitis. However, TREG infiltration was increased (P < 0.0001), and the responsiveness of stimulated T cells in the mesenteric lymph nodes shifted from pro-inflammatory at d2 to immune-suppressive at d30 (P < 0.0001 for IL-10). These effects were observed despite similar colonic microbiota composition and degradation of the mucosal layer between d2 and d30. Conclusions: Collectively, these results indicate that acute colitis chronically alters epithelial barrier function and both innate and adaptive immune responses. These effects reduce the consequences of a subsequent colitis event, warranting longitudinal studies in human IBD subjects. Refereed/Peer-reviewed

Gastrointestinal inflammation is a hallmark of highly prevalent disorders, including cancer treatment–induced mucositis and ulcerative colitis. These disorders cause debilitating symptoms, have a significant impact on quality of life, and are poorly managed. The activation of toll-like receptor 4 (TLR4) has been proposed to have a major influence on the inflammatory signalling pathways of the intestinal tract. Inhibition of TLR4 has been postulated as an effective way to treat intestinal inflammation. However, there are a limited number of studies looking into the potential of TLR4 antagonism as a therapeutic approach for intestinal inflammation. This review surveyed available literature and reported on the in vitro, ex vivo and in vivo effects of TLR4 antagonism on different models of intestinal inflammation. Of the studies reviewed, evidence suggests that there is indeed potential for TLR4 antagonists to treat inflammation, although only a limited number of studies have investigated treating intestinal inflammation with TLR4 antagonists directly. These results warrant further research into the effect of TLR4 antagonists in the intestinal tract Refereed/Peer-reviewed

Inflammatory bowel disease (IBD) is a chronic relapsing and remitting inflammatory disease of the gastrointestinal tract. The diagnosis and monitoring of IBD are reliant on endoscopy, which is invasive and does not provide information on specific mediators. Symptom flare in IBD is associated with increased activation of innate immune pathways. Immuno-PET approaches have previously demonstrated the ability to detect colitis; however, a direct comparison of antibodies targeted to innate immune mediators and cells has not been done. We aimed to compare immuno-PET of antibodies to IL-1β and CD11b against standard (18)F-FDG and MRI approaches to detect colonic inflammation. Methods: Colonic concentrations of IL-1β and myeloperoxidase were determined by ELISA, and colonic infiltration by CD11b-positive CD3-negative innate immune cells was determined by flow cytometry and compared between healthy and dextran sodium sulphate–treated colitic mice. PET of (89)Zr-lα-IL-1β, (89)Zr-α-CD11b, and (18)F-FDG was compared by volume-of-interest analysis and with MRI by region-of-interest analysis. Imaging results were confirmed by ex vivo biodistribution analysis. Results: Colonic inflammation was associated with impaired colonic epithelial barrier permeability, increased colonic IL-1β and myeloperoxidase concentrations, and increased CD11b-positive CD3-negative innate immune cell infiltration into the colon. (89)Zr-α-IL-1β and (89)Zr-α-CD11b immuno-PET detected colonic inflammation, as did (18)F-FDG, and all PET tracers were more sensitive than MRI. Although (18)F-FDG volumes of interest correlated with colitis severity and a strong trend was observed with (89)Zr-α-IL-1β, no correlation was observed for (89)Zr-α-CD11b or MRI. (89)Zr-α-IL-1β was distributed mainly to the gastrointestinal tract, whereas (89)Zr-α-CD11b was distributed to more tissue types. Conclusion: Immuno-PET using antibodies directed to innate immune markers detected colonic inflammation, with (89)Zr-α-IL-1β providing a more tissue-specific signal than (89)Zr-α-CD11b. Development of these technologies for human subjects will potentially provide a less invasive approach than endoscopy for diagnosing and monitoring IBD.

Background and Aims: Previous studies have shown that antidepressants reduce inflammation in animal models of colitis. The present trial aimed to examine whether fluoxetine added to standard therapy for Crohn’s disease [CD] maintained remission, improved quality of life [QoL] and/or mental health in people with CD as compared to placebo. Methods: A parallel randomized double-blind placebo controlled trial was conducted. Participants with clinically established CD, with quiescent or only mild disease, were randomly assigned to receive either fluoxetine 20 mg daily or placebo, and followed for 12 months. Participants provided blood and stool samples and completed mental health and QoL questionnaires. Immune functions were assessed by stimulated cytokine secretion [CD3/CD28 stimulation] and flow cytometry for cell type. Linear mixed-effects models were used to compare groups. Results: Of the 26 participants, 14 were randomized to receive fluoxetine and 12 to placebo. Overall, 14 [54%] participants were male. The mean age was 37.4 [SD=13.2] years. Fluoxetine had no effect on inflammatory bowel disease activity measured using either the Crohn’s Disease Activity Index [F(3, 27.5)=0.064, p=0.978] or faecal calprotectin [F(3, 32.5)=1.08, p=0.371], but did have modest effects on immune function. There was no effect of fluoxetine on physical, psychological, social or environmental QoL, anxiety or depressive symptoms as compared to placebo [all p>0.05]. Conclusions: In this small pilot clinical trial, fluoxetine was not superior to placebo in maintaining remission or improving QoL. [ID: ACTRN12612001067864.] Refereed/Peer-reviewed