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The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. Although the molecular and cellular mechanisms that regulate mucin production and movement are beginning to be understood, the upstream epithelial signals that contribute to mucin regulation remain unclear. Here, we report that the inflammatory cytokine tumor necrosis factor (TNF), generated by the epithelium, contributes to mucin homeostasis by regulating both cell differentiation and cystic fibrosis transmembrane conductance regulator (CFTR) activity. We used genetic mouse models and noninflamed samples from patients with inflammatory bowel disease (IBD) undergoing anti-TNF therapy to assess the effect of in vivo perturbation of TNF. We found that inhibition of epithelial TNF promotes the differentiation of secretory progenitor cells into mucus-producing goblet cells. Furthermore, TNF treatment and CFTR inhibition in intestinal organoids demonstrated that TNF promotes ion transport and luminal flow via CFTR. The absence of TNF led to slower gut transit times, which we propose results from increased mucus accumulation coupled with decreased luminal fluid pumping. These findings point to a TNF/CFTR signaling axis in the adult intestine and identify epithelial cell-derived TNF as an upstream regulator of mucin homeostasis.

T-cells specifically bind antigens to induce adaptive immune responses using highly specific molecular recognition, and a diverse T-cell repertoire with expansion of antigen-specific clones can indicate robust immune responses after infection or vaccination. For patients with inflammatory bowel disease (IBD), a spectrum of chronic intestinal inflammatory diseases usually requiring immunomodulatory treatment, the T-cell response has not been well characterized. Understanding the patient factors that result in strong vaccination responses is critical to guiding vaccination schedules and identifying mechanisms of T-cell responses in IBD and other immune-mediated conditions. Here we used T-cell receptor sequencing to show that T-cell responses in an IBD cohort were influenced by demographic and immune factors, relative to a control cohort of health care workers (HCWs). Subjects were sampled at the time of SARS-CoV-2 vaccination, and longitudinally afterwards; TCR Vβ gene repertoires were sequenced and analyzed for COVID-19-specific clones. We observed significant differences in the overall strength of the T-cell response by age and vaccine type. We further stratified the T-cell response into Class-I- and Class-II-specific responses, showing that Ad26.COV2.S vector vaccine induced Class-I-biased T-cell responses, whereas mRNA vaccine types led to different responses, with mRNA-1273 vaccine inducing a more Class-I-deficient T-cell response compared to BNT162b2. Finally, we showed that these T-cell patterns were consistent with antibody levels from the same patients. Our results account for the surprising success of vaccination in nominally immuno-compromised IBD patients, while suggesting that a subset of IBD patients prone to deficiencies in T-cell response may warrant enhanced booster protocols.

Background Multimodal analgesia protocols are becoming a common part of enhanced recovery pathways after colorectal surgery. However, few protocols include a robust intraoperative component in addition to pre-operative and post-operative analgesics. Method A prospective cohort study was performed in an urban teaching hospital in patients undergoing minimally invasive colorectal surgery before and after implementation of a multimodal analgesia protocol consisting of pre-operative (gabapentin, acetaminophen, celecoxib), intraoperative (lidocaine and magnesium infusions, ketorolac, transversus abdominis plane block), and post-operative (gabapentin, acetaminophen, celecoxib) opioid-sparing elements. The main outcome measure was use of morphine equivalents in the first 24-h post-operative period. Results The study cohort ( n  = 71) included 41 patients before and 30 patients after implementation of a multimodal analgesia protocol. Mean age of the entire study cohort was 47 ± 19.7 years and 46% were male. Patients undergoing surgery post-multimodal analgesia vs. pre-multimodal analgesia had significantly lower use of IV morphine equivalents in first 24-h post-operative period (5.8 ± 6.4 mg vs. 22.8 ± 21.3 mg; p  = 0.005) and first 48-h post-operative period (7.6 ± 9.4 mg vs. 42 ± 52.9 mg; p  = 0.0008). This reduction in IV morphine equivalent use post-multimodal analgesia was coupled with improved pain scores in the post-operative period. Post-operative hospital length of stay, post-operative ileus, and overall complications were not significantly different between groups. Conclusions Multimodal analgesia incorporating pre-operative, intraoperative, and post-operative opioid-sparing agents is an effective method for reducing perioperative opioid utilization and pain after minimally invasive colorectal surgery.

Definitive draining seton (DDS) alone is an accepted treatment for complex refractory anal fistulas in Crohn’s disease (CD). We evaluated the long-term success of DDS in CD patients. DDS was defined as draining seton placed definitively for at least 12 months. Primary end point was clinical response (CR) defined as a lack of induration, pain, swelling, abscess recurrence, or unintended dislodgement. The study cohort of 23 patients had a median age of 29 (range; 9-61) years and included 14 males (61%). Reasons for DDS included anal stenosis (n = 9; 39%), active proctitis (n = 9; 39%), and/or anal canal ulceration (n = 9; 39%). Median number of setons was 2 (range; 1-6) and 65% had multiple fistula tracts. Almost all patients (n = 22; 96%) were on a biologic postoperatively. At 12-month follow-up, only 39% (n = 9) had a CR. The remaining 14 patients failed due to new abscess formation (n = 6; 26%), new fistula formation (n = 6; 26%), and seton dislodgement (n = 2; 9%). Six (26%) patients required fecal diversion. No patients required proctectomy. DDS for complex CD fistula results in a mediocre CR with many patients developing recurrent abscess/fistula or requiring diversion despite biologic therapy.