BACKGROUND:Defining immune dysregulation during the asymptomatic prodrome of immune-mediated diseases offers opportunities for early disease detection and interception. In inflammatory bowel disease (IBD), prodromal immune changes remain poorly characterised. OBJECTIVE:To define preclinical immunological alterations by characterising longitudinal serum antibody repertoires using high-throughput phage-display immunoprecipitation sequencing (PhIP-Seq). DESIGN:We applied PhIP-Seq to profile antibody responses in 2000 longitudinal serum samples from 200 individuals who developed Crohn's disease (CD), 200 who developed ulcerative colitis (UC) and 100 matched healthy controls within the US military Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects cohort, collected up to 10 years before diagnosis. Antibody repertoires were profiled against 357 000 microbial-associated, viral-associated, food-associated and immune-associated peptides. RESULTS:Antibody repertoire variability was increased up to ~4 years prediagnosis in pre-CD and pre-UC individuals. Differential analyses revealed elevated herpesvirus-directed responses (notably Epstein-Barr virus) and anti-flagellin antibodies up to 10 years prediagnosis in CD, particularly in individuals who later developed complicated or ileal disease. In contrast, responses to encapsulated bacteria (eg, Streptococcus pneumoniae, Haemophilus, Neisseria) progressively declined towards diagnosis. Pre-UC was characterised by combined antimicrobial, antiviral and autoantibody signatures, including antibodies against the MAP kinase-activating death domain protein. CONCLUSIONS:Large-scale serological profiling of archived prediagnostic samples identified disease-specific immune trajectories years before IBD onset, providing novel insights into disease pathogenesis in its prodromal phase.

The gram-negative bacterium Shigella is a leading cause of diarrheal morbidity and mortality in children in low- and middle-income countries. Several promising vaccine candidates are in late stages of clinical development against this increasingly antibiotic-resistant pathogen. However, considering the increasingly crowded and costly paediatric immunization schedule, and likely advent of other important new vaccines, it is unclear whether introduction of a Shigella vaccine would represent a high priority for international agencies or health ministries in low- and middle-income countries. To determine whether there is a compelling public health value proposition for a Shigella vaccine, we used the World Health Organization's Full Value of Vaccine Assessment analytic framework and formulated five broad scientific, policy, economic and commercial-related propositions regarding the development of a Shigella vaccine. We also explored the current regulatory, clinical, policy and commercial challenges to a Shigella-containing combination vaccine development and adoption. Through a series of literature reviews, expert consultations, social science field studies and model-based analyses, we addressed each of these propositions. As described in a series of separate publications that are synthesized here, we concluded that the economic and public health value of a Shigella vaccine may be greater than previously recognized, particularly if it is found to also be effective against less severe forms of diarrheal disease and childhood stunting. The decision by pharmaceutical companies to develop a standalone vaccine or a multipathogen combination will be a key factor in determining its relative prioritization by various stakeholders in low- and middle-income countries.

Background. Enterotoxigenic E. coli (ETEC) is a principal cause of diarrhea in travelers, deployed military personnel, and children living in low to middle-income countries. ETEC expresses a variety of virulence factors including colonization factors (CF) that facilitate adherence to the intestinal mucosa. We assessed the protective efficacy of a tip-localized subunit of CF antigen I (CFA/I), CfaE, delivered intradermally with the mutant E. coli heat-labile enterotoxin, LTR192G, in a controlled human infection model (CHIM). Methods. Three cohorts of healthy adult subjects were enrolled and given three doses of 25 μg CfaE + 100 ng LTR192G vaccine intradermally at 3-week intervals. Approximately 28 days after the last vaccination, vaccinated and unvaccinated subjects were admitted as inpatients and challenged with approximately 2 × 107 cfu of CFA/I+ ETEC strain H10407 following an overnight fast. Subjects were assessed for moderate-to-severe diarrhea for 5 days post-challenge. Results. A total of 52 volunteers received all three vaccinations; 41 vaccinated and 43 unvaccinated subjects were challenged and assessed for moderate-to-severe diarrhea. Naïve attack rates varied from 45.5% to 64.7% across the cohorts yielding an overall efficacy estimate of 27.8% (95% confidence intervals: −7.5–51.6%). In addition to reducing moderate–severe diarrhea rates, the vaccine significantly reduced loose stool output and overall ETEC disease severity. Conclusions. This is the first study to demonstrate protection against ETEC challenge after intradermal vaccination with an ETEC adhesin. Further examination of the challenge methodology is necessary to address the variability in naïve attack rate observed among the three cohorts in the present study.

Background: Medication nonadherence is a problem that impacts both the patient and the health system. Objective: The objective of this study was to evaluate the impact of a novel smartphone app with patient-response-directed clinical intervention on medication adherence and blood glucose control in noninsulin-dependent patients with type 2 diabetes mellitus (T2DM). Methods: We enrolled 50 participants with T2DM not on insulin with smartphones from a rural health care center in Northern Nevada for participation in this case-crossover study. Participants underwent a standard of care arm and an intervention arm. Each study arm was 3 months long, for a total of 6 months of follow-up. Participants had a hemoglobin A(1c) (HbA(1c)) lab draw at enrollment, 3 months, and 6 months. Participants had monthly "medication adherence scores" (MAS) and "Self-Efficacy for Appropriate Medication Use Scale" (SEAMS) questionnaires completed at baseline and monthly for the duration of the study. Our primary outcomes of interest were the changes in HbA(1c) between study arms. Secondary outcomes included the evaluation of the difference in the proportion of participants achieving a clinically meaningful reduction in HbA(1c) and the difference in the number of participants requiring diabetes therapy escalation between study arms. Exploratory outcomes included the analysis of the variation in medication possession ratio (MPR), MAS, and SEAMS during each study arm. Results: A total of 30 participants completed both study arms and were included in the analysis. Dropouts were higher in participants enrolled in the standard of care arm first (9/25, 36% vs 4/25, 16%). Participants had a median HbA(1c) of 9.1%, had been living with T2DM for 6 years, had a median age of 66 years, and had a median of 8.5 medications. HbA(1c) reduction was 0.69% in the intervention arm versus 0.35% in the standard of care arm (P=.30). A total of 70% (21/30) of participants achieved a clinically meaningful reduction in HbA(1c) of 0.5% in the app intervention arm versus 40% (12/30) in the standard of care arm (odds ratio 2.29, 95% CI 0.94-5.6; P=.09). Participants had higher odds of a therapy escalation while in the standard of care arm (18/30, 60% vs 5/30, 16.7%, odds ratio 4.3, 95% CI 1.2-15.2; P=.02). The median MPR prior to enrollment was 109%, 112% during the study's intervention arm, and 102% during the standard of care arm. The median real-time MAS was 93.2%. The change in MAS (1 vs -0.1; P=.02) and SEAMS (1.9 vs -0.2; P<.001) from baseline to month 3 was higher in the intervention arm compared to standard of care. Conclusions: A novel smartphone app with patient-response-directed provider intervention holds promise in the ability to improve blood glucose control in complex non-insulin-dependent T2DM and is worthy of additional study.

Shigellosis causes considerable public health burden, leading to excess deaths as well as acute and chronic consequences, particularly among children living in low-income and middle-income countries (LMICs). Several Shigella vaccine candidates are advancing in clinical trials and offer promise. Although multiple target populations might benefit from a Shigella vaccine, the primary strategic goal of WHO is to accelerate the development and accessibility of safe, effective, and affordable Shigella vaccines that reduce mortality and morbidity in children younger than 5 years living in LMICs. WHO consulted with regulators and policy makers at national, regional, and global levels to evaluate pathways that could accelerate regulatory approval in this priority population. Special consideration was given to surrogate efficacy biomarkers, the role of controlled human infection models, and the establishment of correlates of protection. A field efficacy study in children younger than 5 years in LMICs is needed to ensure introduction in this priority population.

ABSTRACTInternational travelers are frequently afflicted by acute infectious diarrhea, commonly referred to as travelers’ diarrhea (TD). Antibiotics are often prescribed as treatment or prophylaxis for TD; however, little is known about the impacts of these regimens on travelers’ gut microbiomes and carriage of antibiotic resistance genes (ARGs). Here, we analyzed two cohorts totaling 153 US and UK servicemembers deployed to Honduras or Kenya. These subjects either experienced TD during deployment and received a single dose of one of three antibiotics [Trial Evaluating Ambulatory Therapy of Travelers’ Diarrhea (TrEAT TD) cohort] or took once-daily rifaximin (RIF), twice-daily RIF, or placebo as prophylaxis to prevent TD [Trial Evaluating Chemoprophylaxis Against Travelers’ Diarrhea (PREVENT TD) cohort]. We applied metagenomic sequencing on 340 longitudinally collected stool samples and whole-genome sequencing on 54 Escherichia coli isolates. We found that gut microbiome taxonomic diversity remained stable across the length of study for most treatment groups, but twice-daily RIF prophylaxis significantly decreased microbiome richness post-travel. Similarly, ARG diversity and abundance were generally stable, with the exception of a significant increase for the twice-daily RIF prophylaxis group. We also did not identify significant differences between the ARG abundance of E. coli isolates from the TrEAT TD cohort collected from different treatment groups or timepoints. Overall, we found no significant worsening of gut microbiome diversity or an increase in ARG abundance following single-dose treatment for TD, underscoring that these can be effective with low risk of impact on the microbiome and resistome, and identified the relative microbiome risks and benefits associated with the three regimens for preventing TD.IMPORTANCEThe travelers’ gut microbiome is potentially assaulted by acute and chronic perturbations (e.g., diarrhea, antibiotic use, and different environments). Prior studies of the impact of travel and travelers’ diarrhea (TD) on the microbiome have not directly compared antibiotic regimens, and studies of different antibiotic regimens have not considered travelers’ microbiomes. This gap is important to be addressed as the use of antibiotics to treat or prevent TD—even in moderate to severe cases or in regions with high infectious disease burden—is controversial based on the concerns for unintended consequences to the gut microbiome and antimicrobial resistance (AMR) emergence. Our study addresses this by evaluating the impact of defined antibiotic regimens (single-dose treatment or daily prophylaxis) on the gut microbiome and resistomes of deployed servicemembers, using samples collected during clinical trials. Our findings indicate that the antibiotic treatment regimens that were studied generally do not lead to adverse effects on the gut microbiome and resistome and identify the relative risks associated with prophylaxis. These results can be used to inform therapeutic guidelines for the prevention and treatment of TD and make progress toward using microbiome information in personalized medical care.

Shigella species cause severe disease among travelers to, and children living in, endemic countries. Although significant efforts have been made to improve sanitation, increased antibiotic resistance and other factors suggest an effective vaccine is a critical need. Artificial Invaplex (InvaplexAR) is a subunit vaccine approach complexing Shigella LPS with invasion plasmid antigens. In pre-clinical studies, the InvaplexAR vaccine demonstrated increased immunogenicity as compared to the first generation product and was subsequently manufactured under cGMP for clinical testing in a first-in-human Phase 1 study. The primary objective of this study was the safety of S. flexneri 2a InvaplexAR given by intranasal (IN) immunization (without adjuvant) in a single-center, open-label, dose-escalating Phase 1 trial and secondarily to assess immunogenicity to identify a dose of InvaplexAR for subsequent clinical evaluations. Subjects received three IN immunizations of InvaplexAR, two weeks apart, in increasing dose cohorts (10 µg, 50 µg, 250 µg, and 500 μg). Adverse events were monitored using symptom surveillance, memory aids, and targeted physical exams. Samples were collected throughout the study to investigate vaccine-induced systemic and mucosal immune responses. There were no adverse events that met vaccination-stopping criteria. The majority (96%) of vaccine-related adverse events were mild in severity (most commonly nasal congestion, rhinorrhea, and post-nasal drip). Vaccination with InvaplexAR induced anti-LPS serum IgG responses and anti-Invaplex IgA and IgG antibody secreting cell (ASC) responses at vaccine doses ≥250 µg. Additionally, mucosal immune responses and functional antibody responses were seen from the serum bactericidal assay measurements. Notably, the responder rates and the kinetics of ASCs and antibody lymphocyte secretion (ALS) were similar, suggesting that either assay may be employed to identify IgG and IgA secreting cells. Further studies with InvaplexAR will evaluate alternative immunization routes, vaccination schedules and formulations to further optimize immunogenicity. (Clinical Trial Registry Number NCT02445963).

Introduction: Irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction with a heightened prevalence in Veterans (35%), compared to the general population (13%). Little is known about the current diagnostic and management strategies of Veterans with IBS within the Veteran Affairs (VA) health care system. Through a retrospective cohort study, we examined the relationship between clinical practices and Veteran gender and IBS subtype at a VA medical center. Methods: Veterans were selected if they had a new IBS diagnostic code entered in their chart for at least 2 clinic visits separated by a period of ≥ 6 months. They were further classified by gender and subtype; IBS-C, IBS-D, IBS-M, and IBS-Other. Via chart review, testing and recommendations were recorded with the standard of care being the American College of Gastroenterology IBS clinical guidelines. Accuracy was validated with a 10% check and statistical analysis for categorical variables (Chi-squared test) and continuous variables (Student’s T-test or Kruskal Wallis) was done. Results: Chart review of 136 eligible Veterans (32 female) with IBS was done. Subtype breakdown was IBS-C (14), IBS-D (60), IBS-M (22), and IBS-O (40). Avoiding antispasmodics was observed more often in females than males (84.4% vs 67.3%, P=0.075). Providers were less likely to recommend probiotics for IBS-C compared to IBS-D, IBS-M, and IBS-O (21.4% vs 50.0%, 50.0%, 52.5%, respectively) and less likely for females than males (37.5% vs 51.0%, P=0.266). The likelihood of recommending fiber was relatively similar for IBS-C, IBS-D, IBS-M, and IBS-O (42.9%, 46.7%, 54.5% and 45.0%, respectively). Fiber was recommended to females and males at essentially equal rates (46.9% vs 47.1%, P=1.00). A low FODMAP diet was more likely to be utilized in patients with IBS-D and IBS-M (20.0% and 18.2%) than with IBS-C and IBS-O (7.1% and 7.5%), and more likely to be recommended to females than males (21.9% vs 12.5%, P=0.190) (Table 1). Conclusion: Diagnostic and management strategies of Veterans with IBS were analyzed based on IBS subtype and gender. Fiber was not recommended in the majority of patients, but nearly twice as likely to be recommended to females than males. Other gender-based differences were appreciated, namely with respect to medications for IBS-D and dietary recommendations for IBS-C. Further research is warranted to understand healthcare utilization for Veterans of all genders and IBS subtypes. Table 1. - Diagnosis and management utilization among eligible cohort study subjects by IBS-subtype and gender IBS-C IBS-D IBS-M IBS-Other Guideline Followed F (N=8) M (N=6) P-value F (N=10) M (N=50) P-value F (N=6) M (N=16) P-value F (N=8) M (N=32) P-value IBS Generic Colonoscopy 6 (75%) 6 (100%) 0.47 10 (100%) 40 (80%) 0.19 5 (83%) 14 (88%) 1.00 8 (100%) 24 (75%) 0.17 Enteric Pathogen Stool Testing 7 (88%) 6 (100%) 1.00 6 (60%) 39 (78%) 0.25 6 (100%) 10 (63%) 0.13 6 (75%) 31 (97%) 0.096 Food Allergy Testing 8 (100%) 6 (100%) N/A 10 (100%) 50 (100%) N/A 6 (100%) 15 (94%) 1.00 8 (100%) 32 (100%) 0 Fiber 3 (38%) 3 (50%) 1.00 6 (60%) 22 (44%) 0.49 4 (67%) 8 (50%) 0.65 2 (25%) 16 (50%) 0.26 TCA 0 (0%) 3 (50%) .06 4 (40%) 15 (30%) 0.71 3 (50%) 3 (19%) 0.28 0 (0%) 1 (3%) 1.00 TCA Contraindication 3 (30%) 13 (26%) 1.00 3 (50%) 3 (19%) 0.28 Antispasmodics 7 (88%) 2 (33%) 0.091 8 (80%) 32 (64%) 0.47 4 (67%) 11 (69%) 1.00 8 (100%) 25 (78%) 0.31 Peppermint oil 0 (0%) 0 (0%) N/A 0 (0%) 1 (2%) 1.00 0 (0%) 0 (0%) N/A 0 (0%) 0 (0%) 0 Probiotics 6 (75%) 5 (83%) 1.00 4 (44%) 26 (52%) 0.73 5 (83%) 6 (38%) 0.15 5 (63%) 14 (44%) 0.44 Low FODMAP diet 1 (17%) 0 (0%) 1.00 2 (20%) 10 (20%) 1.00 4 (67%) 0 (0%) 0.002 0 (0%) 3 (9%) 1.00 IBS-C Specific Guanylate cyclase 6 (75%) 0 (0%) 0.01 Chloride channel activators 2 (25%) 0 (0%) 0.47 Tegaserod 5 (63%) 0 (0%) < 0.001 Tegaserod N/A 0 (0%) 6 (100%) N/A Polyethylene glycol 5 (63%) 4 (67%) 1.00 IBS-D Specific CeD Testing 3 (30%) 14 (29%) 1.00 3 (50%) 3 (19%) 0.28 Fecal Calprotectin 2 (20%) 7 (14%) 0.64 0 (0%) 2 (13%) 1.00 CRP 0 (0%) 7 (14%) 0.59 1 (17%) 1 (6%) 0.48 Rifaximin 0 (0%) 5 (10%) 0.58 0 (0%) 2 (13%) 1.00 Opioids 0 (0%) 0 (0%) N/A 0 (0%) 1 (6%) 1.00 Alosetron 9 (90%) 50 (100%) 0.17 5 (83%) 16 (100%) 0.27 Bile acid sequestrants 9 (90%) 47 (96%) 0.43 6 (100%) 15 (94%) 1.00 F: female, M: male, FODMAP: fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, TCA: tricyclic antidepressant, CeD: celiac disease, CRP: c-reactive protein.

Journal Article Accepted manuscript Advances on the forefront of travelers' diarrhea Get access Mark S Riddle, MD, DrPH, FISTM, Mark S Riddle, MD, DrPH, FISTM Reno School of Medicine, University of Nevada, Reno, NV, USA To whom correspondence should be addressed. Email: mriddle@unr.edu Search for other works by this author on: Oxford Academic PubMed Google Scholar Charles D Ericsson, MD, DFISTM, Charles D Ericsson, MD, DFISTM McGovern Medical School, University of Texas, Houston, TX,, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Robert Steffen, MD, DFISTM Robert Steffen, MD, DFISTM Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, CHDepartment of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston TX, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Journal of Travel Medicine, taad123, https://doi.org/10.1093/jtm/taad123 Published: 23 October 2023 Article history Received: 28 August 2023 Revision received: 10 September 2023 Accepted: 17 September 2023 Published: 23 October 2023

Background Biomarkers for predicting the development of Ulcerative Colitis (UC) and disease-related complications are lacking. Anti-integrin αvβ6 IgG autoantibodies (anti-αvβ6) have been recently described in patients diagnosed with UC. Here, we sought to determine if anti-αvβ6 autoantibodies predate UC development and to study associations between anti-αvβ6 and disease outcomes in newly diagnosed UC patients. Methods In a unique pre-clinical IBD cohort from the PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects (PREDICTS), anti-αvβ6 were measured in longitudinal pre-diagnosis serum samples from 82 subjects who later developed UC as well as in 82 matched subjects that did not develop IBD (HC). Sample A was at the time of UC diagnosis, Sample B was at a median of 2 years before Sample A, Sample C was at a median of 4 years before Sample A and Sample D was at a median of 10 years before Sample A. In a distinct, external validation cohort (the Crohn’s and Colitis Canada Genetics Environment Microbial (GEM) Project), we tested samples from 12 subjects who later developed UC and compared those with 49 matched subjects who remained asymptomatic. Further, anti-αvβ6 were measured in 2 incident IBD cohorts (COMPASS, n=55 and OSCCAR, n=104 UC subjects) and associations between anti-αvβ6 and adverse UC-outcomes were defined using Cox proportional-hazards model. Results Anti-αvβ6 were significantly higher in the PREDICTS cohort among individuals who developed UC compared to HC up to 10 years prior to diagnosis (Figure 1A). The anti-αvβ6 seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 timepoints. Additionally, the predictive performance of anti-αvβ6 autoantibodies as assessed via area under the receiver operator curves (AUROC) with 10-fold cross validation was at least 0.8 up to 10 years before diagnosis (Figure 1B). Elevated levels of anti-αvβ6 in pre-clinical UC samples were further validated in the GEM cohort (Figure 1C). Finally, high anti-αvβ6 were associated with a composite of adverse UC-outcomes including hospitalization, disease extension, colectomy, systemic steroid use and/or escalation to biologic therapy in both incident cohorts (Figure 1D). Conclusion Anti-integrin αvβ6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.

Background and Aims Better biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin αvβ6 autoantibodies (anti-αvβ6) have been described in UC patients. Here, we tested for the presence of anti-αvβ6 antibodies in the pre-clinical phase of UC and studied their association with disease-related outcomes after diagnosis. Methods Anti-αvβ6 were measured in 4 longitudinal serum samples collected from 82 subjects who later developed UC and 82 matched controls from a Department of Defense pre-clinical cohort (PREDICTS). In a distinct, external validation cohort (GEM), we tested 12 pre-UC subjects and 49 matched controls. Further, anti-αvβ6 were measured in 2 incident UC cohorts (COMPASS n=55 and OSCCAR n=104) and associations between anti-αvβ6 and UC-related outcomes were defined using Cox proportional-hazards model. Results Anti-αvβ6 were significantly higher among individuals who developed UC compared to controls up to 10 years before diagnosis in PREDICTS. The anti-αvβ6 seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 timepoints. Anti-αvβ6 predicted UC development with an AUC of at least 0.8 up to 10 years before diagnosis. The presence of anti-αvβ6 in pre-clinical UC samples was validated in the GEM cohort. Finally, high anti-αvβ6 was associated with a composite of adverse UC-outcomes including hospitalization, disease extension, colectomy, systemic steroid use and/or escalation to biologic therapy in recently diagnosed UC. Conclusion Anti-integrin αvβ6 auto-antibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.

The gram-negative bacterium Shigella is an enteric pathogen responsible for significant morbidity and mortality due primarily to severe diarrhea and dysentery, mainly among children younger than five years of age living in low- and middle-income countries (LMICs). Long considered a priority target for vaccine development, recent scientific advances have led to a number of promising Shigella vaccine candidates now entering advanced stages of clinical testing. Yet, there is no guarantee that even a highly efficacious Shigella vaccine will be recommended, prioritized, purchased, and widely adopted-especially if it requires additional doses in the immunization schedule and/or visits within the immunization program. This uncertainty is due to a variety of factors, including continuing declines in Shigella-specific and overall diarrheal disease mortality rates, the increasing complexity and cost of infant immunization programs in LMICs, and the recent availability of other high-priority vaccines. Since combining a Shigella vaccine with an existing infant vaccine would conceivably increase its attractiveness, there is a need to systematically consider the challenges determining the public health value, clinical development, manufacturing, licensure, policy recommendations, and financing for a Shigella-containing combination vaccine. The international non-governmental health organization PATH convened an independent panel of 34 subject matter experts across academic, industry, philanthropic, and global health sectors to discuss hypothetical combinations of a notional parenteral Shigella vaccine with three existing vaccines in order to begin exploring the challenges associated with their development. The resulting insights and recommendations from this meeting contribute to PATH's broader effort to evaluate the public health value of potential Shigella vaccines. They may also help guide future combination vaccine development efforts more broadly.

BACKGROUND: At diagnosis, up to one-third of patients with Crohn's disease (CD) have a complicated phenotype with stricturing (B2) or penetrating (B3) behavior or require early surgery. We evaluated protein biomarkers and antimicrobial antibodies in serum archived years before CD diagnosis to assess whether complicated diagnoses were associated with a specific serological signature.METHODS: Prediagnosis serum was obtained from 201 patients with CD and 201 healthy controls. Samples were evaluated with a comprehensive panel of 1129 proteomic markers (SomaLogic) and antimicrobial antibodies. CD diagnosis and complications were defined by the International Classification of Diseases-Ninth Revision and Current Procedural Terminology codes. Cox regression models were utilized to assess the association between markers and the subsequent risk of being diagnosed with complicated CD. In addition, biological pathway and network analyses were performed.RESULTS: Forty-seven CD subjects (24%) had a B2 (n = 36) or B3 (n = 9) phenotype or CD-related surgery (n = 2) at diagnosis. Subjects presenting with complicated CD at diagnosis had higher levels of antimicrobial antibodies six years before diagnosis as compared with those diagnosed with noncomplicated CD. Twenty-two protein biomarkers (reflecting inflammatory, fibrosis, and tissue protection markers) were found to be associated with complicated CD. Pathway analysis of the altered protein biomarkers identified higher activation of the innate immune system and complement or coagulation cascades up to six years before diagnosis in complicated CD.CONCLUSIONS: Proteins and antimicrobial antibodies associated with dysregulated innate immunity, excessive adaptive response to microbial antigens, and fibrosis precede and predict a complicated phenotype at the time of diagnosis in CD patients.

Antibodies reactive with the SARS-CoV-2 receptor-binding domain (RBD) of the spike protein are associated with viral neutralization, however low antibody titers, specifically against SARS-CoV-2 variants, may result in reduced viral immunity post naturally acquired infection. A cohort study comprised of 121 convalescent individuals from northern Nevada was conducted looking at anti-RBD antibody levels by enzyme-linked immunosorbent assay. Serum was collected from volunteers by staff at the University of Nevada, Reno School of Medicine Clinical Research Center and assessed for antibodies reactive to various SARS-CoV-2 RBD domains relevant to the time of the study (2020-2021). A nonpaired group of vaccinated individuals were assessed in parallel. The goal of the study was to identify antibody levels against the RBD subunit in convalescent and vaccinated individuals from northern Nevada.

BACKGROUND & AIMS: Better biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin avfi6 (anti-avfi6) autoantibodies have been described in patients with UC. We tested for the presence of anti-avfi6 antibodies in the preclinical phase of UC and studied their association with disease-related outcomes after diagnosis. METHODS: Anti-avfi6 autoantibodies were measured in 4 longitudinal serum samples collected from 82 subjects who later developed UC and 82 matched controls from a Department of Defense preclinical cohort (PREDICTS [Prote-omic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects]). In a distinct, external validation cohort (Crohn's and Colitis Canada Genetic Environmental Microbial project cohort), we tested 12 pre-UC subjects and 49 matched controls. Furthermore, anti-avfi6 autoantibodies were measured in 2 incident UC cohorts (COMPASS [Comprehensive Care for the Recently Diagnosed IBD Patients], n = 55 and OSCCAR [Ocean State Crohn's and Colitis Area Registry], n = 104) and associations between anti-av/56 autoantibodies and UC-related outcomes were defined using Cox proportional hazards model. RESULTS: Anti-av/56 autoantibodies were significantly higher among individuals who developed UC compared with controls up to 10 years before diagnosis in PREDICTS. The anti-av/56 auto -antibody seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 time points. Anti-av/56 autoantibodies predicted UC development with an area under the curve of at least 0.8 up to 10 years before diagnosis. The presence of anti-av/56 autoantibodies in preclinical UC samples was validated in the GEM cohort. Finally, high anti-av/56 autoantibodies was associated with a composite of adverse UC outcomes, including hospitalization, disease extension, colec-tomy, systemic steroid use, and/or escalation to biologic therapy in recently diagnosed UC. CONCLUSIONS: Anti-integrin av/56 au-toantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.

Introduction: Irritable bowel syndrome (IBS) is a complex disorder of the gut-brain interaction, which affects 11% of people worldwide. Little is known about the current clinical management of Veterans with IBS within the Veterans Affairs (VA) health system, so we worked to retrospectively analyze the prior diagnostic workup and treatment of Veterans with IBS in multiple care settings in a large VA network. Methods: A retrospective single center chart review study was conducted to identify practice patterns of IBS management in Veterans and areas to focus quality improvement initiatives. Subjects were included if they had at least 2 visits at the VA Sierra Nevada Health Care System with an IBS diagnostic code separated by at least 6 months. Subjects were excluded if they were previously diagnosed with IBS, had protected medical records, or had diagnostic codes of other gastrointestinal disease. IBS-subtype, provider specialty, and utilization of the guidelines from the American College of Gastroenterology were evaluated. Results: The eligible cohort included 136 veterans, separated by subtype: IBS-diarrhea (48.9%), IBS-other (24.1%), IBS-mixed (18.0%), and IBS-constipation (9.0%). GI providers were more likely to recommend fiber and low FODMAP than primary care/non-GI providers (63.0% vs 28.6%, P< 0.0001 and 21.9% vs 6.4%, P=0.0141 respectively). Regarding IBS-D specific treatments, both GI and primary care/non-GI providers frequently followed recommendations related to alosetron use and avoidance of bile acid sequestrants, but they both had low practice utilization for rifaximin and mixed opioid agonist/antagonists. Lastly, GI providers were more likely to order a colonoscopy against recommendations than primary care/non-GI providers (26.0% vs 6.35%, P=0.0025). Conclusion: Differences in practice were noted in our study. GI trended more towards recommending soluble fiber among all IBS patients. In IBS-D, GI had better guideline-based practices for testing for celiac disease, fecal calprotectin and CRP. Additionally, GI specialists were more likely than PC to order a colonoscopy against recommendations. Additional cross-specialty studies may be justified to better understand diagnostic and management practices within the VA (Table 1). Table 1. - Diagnosis and management utilization among eligible cohort study subjects by IBS-subtype IBS-C IBS-D IBS-M IBS-Other Guideline Followed GIN=11 PCN=3 P-value GIN=32 PCN=28 P-value GIN=10 Non-GIN=12 P-value GIN=20 Non-GIN=20 P-value IBS Generic Colonoscopy 9 (82%) 3 (100%) 1.00 24 (75%) 26 (93%) 0.088 7 (70%) 12 (100%) 0.078 14 (70%) 18 (90%) 32 (80%) Enteric Pathogen Stool Testing 10 (91%) 3 (100%) 1.00 21 (66%) 24 (86%) 0.084 6 (60%) 9 (75%) 0.35 17 (85%) 20 (100%) 37 (93%) Food Allergy Testing 11 (100%) 3 (100%) N/A 32 (100%) 28 (100%) N/A 9 (90%) 12 (100%) 0.45 20 (100%) 20 (100%) 40 (100%) Fiber 6 (55%) 0 (0%) 0.21 21 (66%) 7 (25%) 0.002 8 (80%) 4 (33%) 0.043 11 (55%) 7 (35%) 18 (45%) TCA 1 (9%) 2 (67%) .09 10 (31%) 9 (32%) 1.00 2 (20%) 4 (33%) 0.65 2 (10%) 6 (30%) 0.24 TCA Contraindication 9 (28%) 7 (25%) 1.00 2 (20%) 4 (33%) 0.65 Antispasmodics 9 (82%) 0 (0%) 0.027 20 (63%) 20 (71%) 0.59 8 (80%) 7 (58%) 0.38 19 (95%) 14 (70%) 33 (83%) Peppermint oil 0 (0%) 0 (0%) N/A 0 (0%) 1 (4%) 0.47 0 (0%) 0 (0%) N/A 0 (0%) 0 (0%) 0 (0%) Probiotics 8 (73%) 3 (100%) 1.00 8 (25%) 22 (79%) < 0.001 3 (30%) 8 (66%) 0.20 7 (35%) 12 (60%) 19 (48%) Low FODMAP diet 1 (9%) 0 (0%) 1.00 9 (28%) 3 (11%) 0.12 3 (30%) 1 (8%) 0.29 3 (15%) 0 (0%) 3 (8%) IBS-C Specific Guanylate cyclase activators 6 (55%) 0 (0%) 0.21 Chloride channel activators 2 (18%) 0 (0%) 1.00 Tegaserod 5 (45%) 0 (0%) 0.18 Tegaserod N/A 3 (27%) 3 (100%) N/A Polyethylene glycol 6 (55%) 3 (100%) 0.26 IBS-D Specific CeD Testing 14 (44%) 3 (11%) 0.004 3 (30%) 3 (25%) 1.00 Fecal Calprotectin 7 (22%) 2 (7%) 0.15 0 (0%) 2 (17%) 0.48 CRP 5 (16%) 2 (4%) 0.43 1 (10%) 1 (8%) 1.00 Rifaximin 5 (16%) 0 (0%) 0.055 1 (10%) 1 (8%) 1.00 Opioids 0 (0%) 0 (0%) N/A 0 (0%) 1 (8%) 1.00 Alosetron 31 (97%) 28 (100%) 1.00 9 (90%) 12 (100%) 0.45 Bile acid sequestrants 29 (91%) 27 (96%) 0.24 10 (100%) 11 (92%) 1.00 F: female, M: male, FODMAP: fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, CeD: celiac disease, CRP: c-reactive protein, TCA: tricyclic antidepressant, GI: gastroenterology, PC: primary care.

Advancing new O-antigen-based Shigella vaccines is critically dependent on development of an international standard serum and harmonized ELISA, demonstration of field efficacy in young children in low- and middle-income countries, and early engagement with regulators and policy makers.