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Background and Aims: Patient-reported outcomes (PROs) are vital in assessing disease activity and treatment outcomes in inflammatory bowel disease (IBD). However, manual extraction of these PROs from the free-text of clinical notes is burdensome. We aimed to improve data curation from free-text information in the electronic health record, making it more available for research and quality improvement. This study aimed to compare traditional natural language processing (tNLP) and large language models (LLMs) in extracting 3 IBD PROs (abdominal pain, diarrhea, fecal blood) from clinical notes across 2 institutions. Methods: Clinic notes were annotated for each PRO using preset protocols. Models were developed and internally tested at the University of California, San Francisco, and then externally validated at Stanford University. We compared tNLP and LLM-based models on accuracy, sensitivity, specificity, positive, and negative predictive value. In addition, we conducted fairness and error assessments. Results: Interrater reliability between annotators was >90%. On the University of California, San Francisco test set (n = 50), the top-performing tNLP models showcased accuracies of 92% (abdominal pain), 82% (diarrhea) and 80% (fecal blood), comparable to GPT-4, which was 96%, 88%, and 90% accurate, respectively. On external validation at Stanford (n = 250), tNLP models failed to generalize (61%–62% accuracy) while GPT-4 maintained accuracies >90%. Pathways Language Model-2 and Generative Pre-trained Transformer-4 showed similar performance. No biases were detected based on demographics or diagnosis. Conclusion: LLMs are accurate and generalizable methods for extracting PROs. They maintain excellent accuracy across institutions, despite heterogeneity in note templates and authors. Widespread adoption of such tools has the potential to enhance IBD research and patient care.

Objective:. We aimed to determine whether n-butyl-2-cyanoacrylate (NB2C) adhesive is a safe and effective mechanism for nonpenetrating mesh and peritoneal fixation during laparoscopic groin hernia repair. Background:. Chronic pain after laparoscopic groin hernia repair has been associated with penetrating fixation, but there had been no US Food and Drug Administration–approved devices for nonpenetrating fixation in this context. Methods:. Patients undergoing laparoscopic transabdominal preperitoneal (TAP) or totally extraperitoneal (TEP) groin hernia repair with mesh at 1 of 5 academic medical centers were randomized to mesh (TAP/TEP) and peritoneal (TAP) fixation with NB2C adhesive or absorbable tacks. The primary outcome was improvement in pain (visual analog scale [VAS]) at 6 months. The noninferiority margin was 0.9 (α = 0.025; β = 80%). Recurrence, successful use of the device, quality of life, and rates of adverse events (AEs) were secondary outcomes. Results:. From 2019 to 2021, 284 patients were randomized to either NB2C adhesive or absorbable tacks (n = 142/142). Patient and hernia characteristics were comparable, and 65% were repaired using a TAP approach. The difference in VAS improvement at 6 months with NB2C adhesive was not inferior to absorbable tacks in intention-to-treat and per-protocol analyses, respectively (0.25 [95% CI, −0.33 to 0.82]; P = 0.013; 0.22 [95% CI, −0.36 to 0.80], noninferiority P = 0.011). There were no differences in secondary outcomes including recurrence, successful use of each device to fixate the mesh and peritoneum, quality of life, and additional VAS pain scores. Rates of adverse and serious AEs were also comparable. Conclusions:. NB2C adhesive is safe and effective for mesh fixation and peritoneal closure during laparoscopic groin hernia repair.

Abstract Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged—the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context—and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.

Background & Aims: Deep crypt secretory (DCS) cells are a critical component of the colonic stem cell niche. However, the regulatory mechanisms controlling DCS cell numbers and function are not well understood. Sprouty2 is an inflammation-responsive regulator of intracellular signaling that influences colonic secretory cell numbers in colitis via an epithelial–stromal interleukin (IL)33/IL13 signaling loop. Here, we tested the hypothesis that IL13, induced by epithelial Sprouty2 down-regulation, promotes DCS cell differentiation and function. Methods: Distal colons from mice with an intestinal epithelial-specific Sprouty2 deletion (Spry2ΔIE) and littermate controls were analyzed by in situ hybridization for Reg4+ DCS cells. Single-cell RNA sequencing and immunostaining were used to identify DCS cell–derived host defense peptides (HDPs) and localization of IL13 and IL13 receptor; bulk RNA sequencing and quantitative polymerase chain reaction were used to quantify changes in expression of identified HDPs. Cytokine-treated colonoids were assessed for DCS cells. A requirement for an IL33/IL13 signaling loop in the regulation of DCS cells was assessed in vivo using IL13 null mice. Results: Reg4+ DCS cell numbers were increased 2-fold in distal colons of Spry2ΔIE mice with a concomitant overall increase in DCS cell marker expression (Reg4, Spink4, and Agr2). Single-cell transcriptomics showed the HDP Retnlb/Resistin Like Beta (RELMβ) is highly enriched in DCS cells. Retnlb/RELMβ expression was increased in Spry2ΔIE colons. IL13, but not IL33, induced Reg4 and Retnlb expression in colonic epithelial organoids, and IL33-mediated expansion of the DCS cell population in vivo was dependent on IL13, which was expressed predominantly by type II innate lymphoid cells in the colonic mucosa. Conclusions: Sprouty2 limits colonic DCS cell differentiation through suppression of IL13 signaling. At homeostasis, DCS cells are marked by high levels of the HDP RELMβ. Loss of epithelial Sprouty2 activates type II innate lymphoid cells to release IL13, promoting expansion of the DCS cell population and increased colonic RELMβ levels.

Background: The classic operation for medically refractory Crohn's pancolitis is colectomy with end ileostomy. Ileorectal anastomosis (IRA) in this setting has not been well studied in children. In this study, we review our experience and outcomes with IRA in children with severe Crohn's Disease (CD). Methods: A single-center retrospective study was performed by reviewing the patient charts between 2017 and 2022. Before colectomy, disease severity was assessed by poor response to biologic medication and corticosteroids, the presence of serious comorbidities and history of C. difficile infection (CDI). Proctoscopy was done before IRA, and rectal histopathology at the time of IRA was reviewed. Postoperative complications, time from colectomy to anastomosis, and number of bowel movements were recorded. Results: 6 patients with pancolitis underwent laparoscopic total colectomy with end ileostomy and subsequent IRA. All patients were refractory to biologics and/or steroids. 4 patients had history of CDI. Mean age at the time of surgery was 16 ± 1 years. Postoperative course was complicated by AKI in 1 patient, pancreatitis in 1 patient, and rectal bleeding in 2 patients. A mean 274±130 days elapsed between colectomy and IRA. There were no complications or recurrent flares after IRA over the mean 356 ± 227 days follow-up. Patients had a mean of 5 bowel movements/day after IRA. Conclusion: IRA should be considered after colectomy for medically refractory CD in selected patients. A larger prospective study is necessary before recommendation for IRA as standard treatment. Level of Evidence: N/A

BackgroundPermanent synthetic meshes such as polypropylene (PP) have been utilized for hernia repair for decades, but concerns remain regarding potential long-term, mesh-related complications. A resorbable polymer such as poly-4-hydroxybutyrate (P4HB) represents an alternative with high initial strength, that gradually resorbs, leaving an abdominal wall that is at least as strong as it would be in its native state. We aimed to compare early wound morbidity and clinical outcomes associated with P4HB to traditional, permanent PP in umbilical and small to medium, routine ventral hernias using data from the Abdominal Core Health Quality Collaborative (ACHQC).MethodsInclusion criteria for the umbilical cohort included: all Centers for Disease Control and Prevention (CDC) wound classes, all Ventral Hernia Working Group (VHWG) hernia grades, and hernia defects

Ulcerative colitis (UC), Crohn’s disease (CD), and celiac disease are prevalent intestinal inflammatory disorders with nonsatisfactory therapeutic interventions. Analyzing patient data-driven cohorts can highlight disease pathways and new targets for interventions. Long noncoding RNAs (lncRNAs) are attractive candidates, since they are readily targetable by RNA therapeutics, show relative cell-specific expression, and play key cellular functions. Uniformly analyzing gut mucosal transcriptomics from 696 subjects, we have highlighted lncRNA expression along the gastrointestinal (GI) tract, demonstrating that, in control samples, lncRNAs have a more location-specific expression in comparison with protein-coding genes. We defined dysregulation of lncRNAs in treatment-naive UC, CD, and celiac diseases using independent test and validation cohorts. Using the Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT) inception UC cohort, we defined and prioritized lncRNA linked with UC severity and prospective outcomes, and we highlighted lncRNAs linked with gut microbes previously implicated in mucosal homeostasis. HNF1A-AS1 lncRNA was reduced in all 3 conditions and was further reduced in more severe UC form. Similarly, the reduction of HNF1A-AS1 ortholog in mice gut epithelia showed higher sensitivity to dextran sodium sulfate–induced colitis, which was coupled with alteration in the gut microbial community. These analyses highlight prioritized dysregulated lncRNAs that can guide future preclinical studies for testing them as potential targets.

Abstract Background Parastomal hernia, common after stoma creation, negatively impacts patient quality of life. For patients with a permanent stoma, durable parastomal hernia repair remains a challenge, with few high-quality studies for guidance. An alternative to open retromuscular parastomal hernia repair with retromuscular “keyhole” mesh is the recent Sugarbaker modification. We aim to compare these two techniques in a head-to-head prospective study. Methods This is a registry-based randomized controlled trial designed to investigate whether the retromuscular Sugarbaker technique is superior to the retromuscular keyhole technique for parastomal hernia repair. The primary study endpoint is parastomal hernia recurrence at 2 years. Secondary endpoints include hospital length-of-stay, readmission, wound morbidity, mesh-related complications, re-operation, all 30-day morbidity, and patient-reported outcomes, including hernia-related quality of life, stoma-specific quality of life, pain, and decision regret. Discussion Based on the post hoc analysis of a recent randomized controlled trial, we hypothesize that the retromuscular Sugarbaker technique will reduce parastomal hernia recurrence by 20% at 2 years compared to the retromuscular keyhole mesh technique. The results of this study may provide evidence-based guidance for surgeons repairing parastomal hernias. Trial registration ClinicalTrials.gov NCT03972553. Registered on 3 June 2019

Abstract Low‐dose methotrexate (MTX) is an immunosuppressant used to treat inflammatory bowel disease (IBD). SLCO1B1 genetic variation has been associated with delayed MTX clearance and increased toxicity. The purpose of this study was to evaluate the association between SLCO1B1 genetic variation and MTX‐induced nausea in children with IBD. We performed a single center retrospective chart analysis of 278 patients who were prescribed MTX for IBD. Two hundred two patients had banked DNA and were genotyped for three SLCO1B1 single nucleotide polymorphisms (SNPs; rs4149056, rs2306283, and rs11045819). Diplotypes were determined by combining the SNPs into *1, *4, *5, *14, *15, and *37 alleles. Incidence of nausea was abstracted from clinician notes. Prescriptions and demographics were extracted from the medical record. The cohort was 69.8% boys, 89.1% White, and 87.6% had a diagnosis of Crohn’s disease with a mean age of 16.0 (± 3.8) years. MTX‐induced nausea was noted in 34% of the cohort. MTX‐induced nausea was associated with the number of reduced‐function *15 alleles (p = 0.034) and occurred 2.26 times more often in patients with at least one *15 allele who did not initiate MTX treatment with concomitant ondansetron (p = 0.034). MTX‐induced nausea was significantly independently associated with SLCO1B1 diplotype (p = 0.006) after controlling for MTX dose group and concomitant ondansetron. Our data demonstrate that the SLCO1B1 *15 allele is associated with MTX‐induced nausea in pediatric patients with IBD. Additionally, *15 allele carriers could benefit from a dose reduction of MTX to reduce exposure and treatment initiation with concomitant ondansetron to reduce nausea.

Abstract IL-33 is upregulated in ulcerative colitis and has a protective role in chemically-induced acute murine colitis. We aimed to determine whether IL-33 influences Il10 −/− chronic colitis and its cellular source in health and during colitis. Il10 −/− Il33 −/− and Il10 −/− Il33 +/+ littermates developed colitis of similar severity. Colon Il33 was induced in WT and Il10 −/− mice exposed to DSS, but not in unchallenged Il10 −/− mice with colitis. Il33-citrine reporter mice showed that Il33-citrine colocalized with α-smooth muscle actin+ myofibroblasts and vimentin+ fibroblasts in WT mice. Citrine+CD74+CD90hi inflammatory fibroblasts were increased with DSS treatment. IL-1β induced Il33 expression in colon myofibroblasts, but colon Il33 expression did not differ between DSS-treated WT and Il1r1 −/− mice. In conclusion, deficiency of IL-33 does not alter the severity of chronic colitis in Il10 −/− mice. Induction of Il33 upon DSS exposure in WT and Il10 −/− mice, but not in unchallenged Il10 −/− mice, suggests epithelial injury induces colon IL-33. Fibroblasts are the primary colonic source of IL-33 and IL-33-expressing CD90hiCD74+ fibroblasts are increased during DSS-induced colitis. IL-1β induces Il33 in colon myofibroblasts in vitro, but signaling through the IL-1R1 is not necessary for induction of IL-33 in DSS-induced colitis.

Dynamic regulation of colonic secretory cell numbers is a critical component of the response to intestinal injury and inflammation. Here, the authors show that loss of the intracellular signalling regulator Sprouty2 in the intestinal epithelial cells is a protective response to injury that leads to increased secretory cell numbers, thus limiting colitis severity.

Background & Aims: CD4+ T cells are regulated by activating and inhibitory cues, and dysregulation of these proper regulatory inputs predisposes these cells to aberrant inflammation and exacerbation of disease. We investigated the role of the inhibitory receptor paired immunoglobulin-like receptor B (PIR-B) in the regulation of the CD4+ T-cell inflammatory response and exacerbation of the colitic phenotype. Methods: We used Il10-/- spontaneous and CD4+CD45RBhi T-cell transfer models of colitis with PIR-B-deficient (Pirb-/-) mice. Flow cytometry, Western blot, and RNA sequencing analysis was performed on wild-type and Pirb-/- CD4+ T cells. In silico analyses were performed on RNA sequencing data set of ileal biopsy samples from pediatric CD and non–inflammatory bowel disease patients and sorted human memory CD4+ T cells. Results: We identified PIR-B expression on memory CD4+ interleukin (IL)17a+ cells. We show that PIR-B regulates CD4+ T-helper 17 cell (Th17)-dependent chronic intestinal inflammatory responses and the development of colitis. Mechanistically, we show that the PIR-B– Src-homology region 2 domain-containing phosphatase-1/2 axis tempers mammalian target of rapamycin complex 1 signaling and mammalian target of rapamycin complex 1–dependent caspase-3/7 apoptosis, resulting in CD4+ IL17a+ cell survival. In silico analyses showed enrichment of transcriptional signatures for Th17 cells (RORC, RORA, and IL17A) and tissue resident memory (HOBIT, IL7R, and BLIMP1) networks in PIR-B+ murine CD4+ T cells and human CD4+ T cells that express the human homologue leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3). High levels of LILRB3 expression were associated strongly with mucosal injury and a proinflammatory Th17 signature, and this signature was restricted to a treatment-naïve, severe pediatric CD population. Conclusions: Our findings show an intrinsic role for PIR-B/LILRB3 in the regulation of CD4+ IL17a+ T-cell pathogenic memory responses.

Objective:. To determine the effectiveness of a clinical call center in performing focused long-term patient reported outcome (PRO)-based follow-up for ventral hernia patients in routine practice. Background:. Long-term follow-up remains the mainstay of assessing quality of care in hernia management. Achieving acceptable rates of long-term follow-up outside of clinical trials in the routine care of patients has been very difficult to achieve. Methods:. A prospective quality improvement intervention using a clinical call center in 1000 random patients eligible for long-term (1 year or greater) follow-up after ventral hernia repair in the Abdominal Core Health Quality Collaborative was performed. The primary outcome measure was the proportion of patients with successfully completed PRO-based long-term follow-up. Results:. Between 2013 and 2017, the baseline long-term follow-up PRO completion rate was 2167/13,950 (15.5%). For the Focus on Follow-Up initiative, 890 patients were eligible for contact; a completion rate of 450/890 (50.6%, P < 0.001) was achieved. Conclusions:. Clinical call center-based patient contact can greatly facilitate the completion of PROs utilized for long-term follow-up in ventral hernia repair. This has important implications for quality improvement programs and postmarket device surveillance.

Ulcerative colitis (UC) is a disabling disease, characterized by chronic inflammation of the colon, with a rising prevalence worldwide in the pediatric age group. Although UC presents in children with varying severity, disease extent, and comorbidities, initial treatment is essentially uniform, consisting of 5-aminosalicylate drugs with corticosteroid induction for those with moderately to severely active disease. With the advent of anti-tumor necrosis factor (TNF) biologic therapy and several new biologics and small-molecule drugs for UC, precision medicine approaches to treatment are needed to more rapidly achieve sustained remission, restore quality of life, normalize development, and limit exposure to toxic corticosteroids in children with UC. Here, we review available data on clinical, biochemical, histopathologic, and molecular predictors of treatment response in UC. We also address known predictors and special treatment considerations in specific relevant scenarios such as very-early-onset UC, acute severe UC, ileal pouch anal anastomosis, and UC with concomitant primary sclerosing cholangitis. The review concludes with a prediction of how machine learning will integrate multimodal patient data to bring precision medicine to the bedside of children with UC in the future.

The severity of ulcerative colitis, and response to treatment, is highly variable. Here, the authors examine rectal gene expression signatures and faecal microbiomes of children and adults with the disease and provide new insights in to pathogenesis.

BACKGROUND:Chorioamnionitis has been linked to spontaneous preterm labor and complications such as neonatal sepsis. We hypothesized that microbial cell-free (cf) DNA would be detectable in maternal plasma in patients with chorioamnionitis and could be the basis for a non-invasive method to detect fetal exposure to microorganisms. OBJECTIVE:The purpose of this study was to determine whether next generation sequencing could detect microbial cfDNA in maternal plasma in patients with chorioamnionitis. STUDY DESIGN:Maternal plasma (n = 94) and umbilical cord plasma (n = 120) were collected during delivery at gestational age 28-41 weeks. cfDNA was extracted and sequenced. Umbilical cord plasma samples with evidence of contamination were excluded. The prevalence of microorganisms previously implicated in choriomanionitis, neonatal sepsis and intra-amniotic infections, as described in the literature, were examined to determine if there was enrichment of these microorganisms in this cohort. Specific microbial cfDNA associated with chorioamnionitis was first detected in umbilical cord plasma and confirmed in the matched maternal plasma samples (n = 77 matched pairs) among 14 cases of histologically confirmed chorioamnionitis and one case of clinical chorioamnionitis; 63 paired samples were used as controls. A correlation of rank of a given microorganism across maternal plasma and matched umbilical cord plasma was used to assess whether signals found in umbilical cord plasma were also present in maternal plasma. RESULTS:Microbial DNA sequences associated with clinical and/or histological chorioamnionitis were enriched in maternal plasma in cases with suspected chorioamnionitis when compared to controls (12/14 microorganisms, p = 0.02). Analysis of the microbial cfDNA in umbilical cord plasma among the 1,251 microorganisms detectable with this assay identified Streptococcus mitis, Ureaplasma spp., and Mycoplasma spp. in cases of suspected chorioamnionitis. This assay also detected cfDNA from Lactobacillus spp. in controls. Comparison between maternal plasma and umbilical cord plasma confirmed these signatures were also present in maternal plasma. Unbiased analysis of microorganisms with significantly correlated signal between matched maternal plasma and umbilical cord plasma identified the above listed 3 microorganisms, all of which have previously been implicated in patients with chorioamnionitis (Mycoplasma hominis p = 0.0001; Ureaplasma parvum p = 0.002; Streptococcus mitis p = 0.007). These data show that the pathogen signal relevant for chorioamnionitis can be identified in both maternal and umbilical cord plasma. CONCLUSION:This is the first report showing the detection of relevant microbial cell-free cfDNA in maternal plasma and umbilical cord plasma in patients with clinical and/or histological chorioamnionitis. These results may lead to the development of a specific assay to detect perinatal infections for targeted therapy to reduce early neonatal sepsis complications.