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Objectives As socioeconomic factors may impact the risk of chronic kidney disease ( CKD), we evaluated the incidence and risk factors of incident CKD among an HIV-infected cohort with universal access to health care and minimal injecting drug use ( IDU). Methods Incident CKD was defined as an estimated glomerular filteration rate (eGFR) <60 ml/min/1.73 m2 for ≥ 90 days. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration ( CKD-EPI) equation. Rates were calculated per 1000 person-years ( PY). Associations with outcomes were assessed using two separate Cox proportional hazard models, adjusting for baseline and time-updated covariates. Results Among 3360 participants [median age 29 years; 92% male; 44% African American ( AA)] contributing 23 091 PY of follow-up, 116 developed incident CKD [5.0/1000 PY; 95% confidence interval ( CI) 4.2-6.0/1000 PY]. The median first eGFR value was 97.0 mL/min/1.73 m2 [interquartile range ( IQR) 85.3-110.1 mL/min/1.73 m2]. Baseline factors associated with CKD included older age, lower CD4 count at HIV diagnosis [compared with CD4 count ≥ 500 cells/μL, hazard ratio ( HR) 2.1 (95% CI 1.2-3.8) for CD4 count 350-499 cells/μL; HR 3.6 (95% CI 2.0-6.3) for CD4 count 201-349 cells/μL; HR 4.3 (95% CI 2.0-9.4) for CD4 count ≤ 200 cells/μL], and HIV diagnosis in the pre-highly active antiretroviral therapy ( HAART) era. In the time-updated model, low nadir CD4 counts, diabetes, hepatitis B, hypertension and less HAART use were also associated with CKD. AA ethnicity was not associated with incident CKD in either model. Conclusions The low incidence of CKD and the lack of association with ethnicity observed in this study may in part be attributable to unique features of our cohort such as younger age, early HIV diagnosis, minimal IDU, and unrestricted access to care. Lower baseline CD4 counts were significantly associated with incident CKD, suggesting early HIV diagnosis and timely introduction of HAART may reduce the burden of CKD. [ABSTRACT FROM AUTHOR]

Understanding the epidemiology of current health threats to deployed U.S. troops is important for medical assessment and planning. As part of a 2004 study among U.S. military personnel deployed to Al Asad Air Base, in the western Anbar Province of Iraq, over 500 subjects were enrolled, provided a blood specimen, and completed a questionnaire regarding history of febrile illness during this deployment (average approximately 4 months in country). This mid-deployment serum was compared to pre-deployment samples (collected approximately 3 months prior to deployment) and evaluated for seroconversion to a select panel of regional arboviral pathogens. At least one episode of febrile illness was reported in 84/504 (17%) of the troops surveyed. Seroconversion was documented in nine (2%) of deployed forces tested, with no association to febrile illness. Self-reported febrile illness was uncommon although often debilitating, and the risk of illness due to arbovirus infections was relatively low. [ABSTRACT FROM AUTHOR]

Much has been written about injury, diarrhea, and respiratory cases but less is known about other threats, specifically snake, scorpion, and spider encounters. To examine the risk from local fauna, a cross-sectional study using an anonymous survey was conducted among U.S. troops in Southwest Asia between January 2005 and May 2006. Among 3,265 troops, 9 cases (0.3%) of snakebites and 85 cases (2.6%) of spider stings and scorpion bites were reported, equating to an incidence of 46.1 per 10,000 person-months for scorpion/spider encounters and 4.9 per 10,000 person-months for snakebites. There was a significant association with service branch and toileting facilities for snakebites. Season, deployment location, rank, and toileting facilities were associated with differential risk of scorpion/spider encounters. Troops are at risk for local fauna encounters while deployed in the current operational environment. The potential morbidity, mortality, and operational impact of these health hazards need to be considered. [ABSTRACT FROM AUTHOR]

To evaluate the relationship between medical knowledge and clinical practice, a survey on travelers' diarrhea was administered to military health care providers attending a professional development and trauma management conference. The survey was administered at the beginning of the conference and 58 of the 76 attendees participated by completing a questionnaire. Respondents were aware of the standard definition of travelers' diarrhea; however, their knowledge about the epidemiology and management of travelers' diarrhea was low. Less than one-third correctly answered questions on etiology and more than two-thirds made incorrect management choices in treatment of mild to moderate watery diarrhea and dysentery. Important knowledge gaps about gastroenteritis were identified and should serve as a basis to develop military-specific clinical guidelines and training programs. [ABSTRACT FROM AUTHOR]

Disease nonbattle injury (DNBI) surveillance is a critical component of U.S. military force health protection and has been aggressively implemented by the U.S. Central Command. This study presents a multivariate analysis of factors associated with DNBI incidence rates as well as a description of morbidity measures associated with DNBI from U.S. Navy ships deployed to the Middle East from October 2000 through September 2001. Weekly DNBI reports (N = 331) from a total of 44 individual units representing six different classes of U.S. Navy ships were included in the analysis. There were statistically significant differences in summary and categorical DNBI rates associated with ship class, season, and presence of female sailors embarked. The top three DNBI categories associated with the most lost workdays because of sick in quarters and hospitalization were other medical/surgical (36%), infectious gastrointestinal (23%), and all types of nonbattle injury combined (17%). [ABSTRACT FROM AUTHOR]

The Current Topics in Military Tropical Medicine series provides focused reviews addressing specific questions faced by operational military medical personnel. This issue in the series explores the diagnosis and management of persistent diarrhea in deployed service members. [ABSTRACT FROM AUTHOR]

(n = 150) Nonbattle injury (NBI) continues to be a leading cause of morbidity among troops currently deployed to Iraq and Afghanistan. To assess NBI incidence, impact, and risk factors, a survey was given to soldiers during mid- or postdeployment from Iraq, Afghanistan, and surrounding region, from January 2005 through May 2006. Among 3,367 troops completing a survey, 19.5% reported at least one NBI, and 85% sought care at least once for their symptoms. Service component, rank, and unit type were among factors associated with differential NBI risk. Twenty percent stated that NBI resulted in back-up personnel being called or shift change to cover impacted duties, and among those reported having been grounded from flight status, a third were the result of NBI. NBI continues to be a problem in recent deployments, and given the findings on individual and potential operational impact indicators, NBI should be viewed as a primary force health protection problem. [ABSTRACT FROM AUTHOR]

Background and Methods: Vector-borne diseases are known threats to deployed troops. We performed a cross-sectional study of troops deployed to Southwest Asia between January 2005 and February 2007 to evaluate practices of personal protective measures and their relationship to self-report of Old World cutaneous leishmaniasis (CL), a marker of vector-borne disease threat.Results: Regular or always N, N-diethyl-m-toluamide (DEET) use was low (2-5%). Associations for DEET use were command emphasis, branch of service, uniform treatment with permethrin, and duty station. Uniform treatment with permethrin was associated with branch of service, command emphasis, and use of DEET. We identified 22 cases of CL (incidence density of 1.8-3.7 per 100 person-years) with increased risk among Reserve/National Guard components, Air Force and Marine personnel.Conclusions: Commanders can influence the use of the military insect repellent system. Unit-based treatment of uniforms improves prevalence. CL incidence may be higher than previously reported. [ABSTRACT FROM AUTHOR]

Background: Background incidence rates (IRs) of health outcomes in Lyme disease endemic regions are useful to contextualize events reported during Lyme disease vaccine clinical trials or post-marketing. The objective of this study was to estimate and compare IRs of health outcomes in Lyme disease endemic versus non-endemic regions in the US during pre-COVID and COVID era timeframes., Methods: IQVIA PharMetrics® Plus commercial claims database was used to estimate IRs of 64 outcomes relevant to vaccine safety monitoring in the US during January 1, 2017-December 31, 2019 and January 1, 2020-December 31, 2021. Analyses included all individuals aged ≥ 2 years with ≥ 1 year of continuous enrollment. Outcomes were defined by International Classification of Diseases Clinical Modification, 10th Revision (ICD-10-CM) diagnosis codes. IRs and 95 % confidence intervals (CIs) were calculated for each outcome and compared between endemic vs. non-endemic regions, and pre-COVID vs. COVID era using IR ratios (IRR)., Results: The study population included 8.7 million (M) in endemic and 27.8 M in non-endemic regions. Mean age and sex were similar in endemic and non-endemic regions. In both study periods, the IRs were statistically higher in endemic regions for anaphylaxis, meningoencephalitis, myocarditis/pericarditis, and rash (including erythema migrans) as compared with non-endemic regions. Conversely, significantly lower IRs were observed in endemic regions for acute kidney injury, disseminated intravascular coagulation, heart failure, myelitis, myopathies, and systemic lupus erythematosus in both study periods. Most outcomes were statistically less frequent during the COVID-era., Conclusion: This study identified potential differences between Lyme endemic and non-endemic regions of the US in background IRs of health conditions during pre-COVID and COVID era timeframes to inform Lyme disease vaccine safety monitoring. These regional and temporal differences in background IRs should be considered when contextualizing possible safety signals in clinical trials and post-marketing of a vaccine targeted at Lyme disease prevention., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JD, JHS, MZ, MSR, JDM, QJ, CI, and SB were employees and shareholders at Pfizer, Inc. at the time of this study. MDK, SM, CB, BC, RF, JNT and HK were consultants to Pfizer through their employment at IQVIA at the time of the study., (Copyright © 2024 Pfizer, Inc. Published by Elsevier Ltd.. All rights reserved.)

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 × 10 7 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.

Importance: The 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., Competing Interests: The authors declare no conflict of interest.

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., ((c) 2024 The authors; licensee World Health Organization.)

Norovirus is attributed to nearly 1 out of every 5 episodes of diarrheal disease globally and is estimated to cause approximately 200,000 deaths annually worldwide, with 70,000 or more among children in developing countries. Noroviruses remain a leading cause of sporadic disease and outbreaks of acute gastroenteritis even in industrialized settings, highlighting that improved hygiene and sanitation alone may not be fully effective in controlling norovirus. Strengths in global progress towards a Norovirus vaccine include a diverse though not deep pipeline which includes multiple approaches, including some with proven technology platforms (e.g., VLP-based HPV vaccines). However, several gaps in knowledge persist, including a fulsome mechanistic understanding of how the virus attaches to human host cells, internalizes, and induces disease., Competing Interests: Declaration of Competing Interest BAL reports personal fees from Epidemiological Research and Methods, LLC. MO acknowledges financial support from ANID PIA/PUENTE AFB220003 and reports receiving grants and research support from Janssen Vaccines & Prevention B.V., Bharat Biotech International Limited, and HilleVax Inc. CFL declares that he receives research grant funding to his Institute from Takeda Vaccines Inc. and HilleVax Inc. for norovirus epidemiology and a norovirus vaccine phase II trial, respectively. All other authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Introduction: Enterotoxigenic E. coli (ETEC) is a leading cause of diarrhea in travelers as well as for children living in low- to middle-income countries. ETEC adhere to intestinal epithelium via colonization factors (CFs). CFA/I, a common CF, is composed of a polymeric stalk and a tip-localized minor adhesive subunit, CfaE. Vaccine delivery by the transcutaneous immunization of dscCfaE was safe but was poorly immunogenic in a phase 1 trial when administered to volunteers with LTR(192G) and mLT. To potentially enhance the immunogenicity of CfaE while still delivering via a cutaneous route, we evaluated the safety and immunogenicity of two CfaE constructs administered intradermally (ID) with or without mLT., Methods: CfaE was evaluated as a donor strand-complemented construct (dscCfaE) and as a chimeric construct (Chimera) in which dscCfaE replaces the A1 domain of the cholera toxin A subunit and assembles non-covalently with the pentamer of heat-labile toxin B (LTB). Subjects received three ID vaccinations three weeks apart with either dscCfaE (1, 5, and 25 µg) or Chimera (2.6 and 12.9 µg) with and without 0.1 µg of mLT. Subjects were monitored for local and systemic adverse events. Immunogenicity was evaluated by serum and antibody-secreting cell (ASC) responses., Results: The vaccine was well-tolerated with predominantly mild and moderate local vaccine site reactions characterized by erythema, induration and post-inflammatory hyperpigmentation. High rates of serologic and ASC responses were seen across study groups with the most robust responses observed in subjects receiving 25 µg of dscCfaE with 0.1 mcg of LT(R192G)., Conclusion: Both ETEC adhesin vaccine prototypes were safe and immunogenic when co-administered with mLT by the ID route. The observed immune responses induced with the high dose of dscCfaE and mLT warrant further assessment in a controlled human infection model.

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., Competing Interests: Declaration of interests NB provides regulatory advice to the regulated industry. PBP receives funding from the Bill & Melinda Gates Foundation for Enterics for Global Health Shigella surveillance. DCK received funding from the Bill & Melinda Gates Foundation while at PATH, and chaired the WHO Product Development for Vaccines Advisory Committee until 2022. MSR consulted for Emergent Biosolutions and Limmatech Biologics while at the University of Nevada. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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 (Invaplex AR ) is a subunit vaccine approach complexing Shigella LPS with invasion plasmid antigens. In pre-clinical studies, the Invaplex AR 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 Invaplex AR 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 Invaplex AR for subsequent clinical evaluations. Subjects received three IN immunizations of Invaplex AR , 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 Invaplex AR 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 Invaplex AR will evaluate alternative immunization routes, vaccination schedules and formulations to further optimize immunogenicity. (Clinical Trial Registry Number NCT02445963)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

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., (Copyright © 2023 AGA Institute. All rights reserved.)

Background & Aims: Better biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin αvβ6 (anti-αvβ6) autoantibodies have been described in patients with UC. We tested for the presence of anti-αvβ6 antibodies in the preclinical phase of UC and studied their association with disease-related outcomes after diagnosis., Methods: Anti-αvβ6 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 [Proteomic 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-αvβ6 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-αvβ6 autoantibodies and UC-related outcomes were defined using Cox proportional hazards model., Results: Anti-αvβ6 autoantibodies were significantly higher among individuals who developed UC compared with controls up to 10 years before diagnosis in PREDICTS. The anti-αvβ6 autoantibody 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-αvβ6 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-αvβ6 autoantibodies in preclinical UC samples was validated in the GEM cohort. Finally, high anti-αvβ6 autoantibodies 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., Conclusions: Anti-integrin αvβ6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction (DGBI) that affects about 10% of the adult population in the United States. IBS pathoetiology understanding has evolved and clinical management improved despite the underdevelopment of diagnostics. Within the Veterans Affairs (VA) system, the prevalence and impact of DGBIs are high. Yet there is a paucity of information on the patient demographic features. Our team examined the history and workup of patients referred to an IBS clinic within the VA's gastroenterology service through a systematic case series study to begin a quality improvement initiative.

Objective: To identify a panel of serum biomarkers that could specifically identify imminent cases of rheumatoid arthritis (RA) before diagnosis., Methods: Serum samples were collected at 4 time points from active component US military personnel, including 157 anti-citrullinated protein antibody (ACPA)-seropositive and 50 ACPA-seronegative RA subjects, 100 reactive arthritis (ReA) subjects, and 76 healthy controls. The cohorts were split into 2 phases, with samples tested on independent proteomic platforms for each phase. Classification models of RA diagnosis based on samples obtained within 6 months prior to diagnosis were developed both in univariate analyses and by multivariate random forest modeling of training sample sets and testing sample sets from each phase., Results: Increases in serum analytes, including C-reactive protein levels, serum amyloid A, and soluble programmed cell death 1 (PD-1), were observed in seropositive RA subjects at the time point closest to diagnosis, up to several years before diagnosis. Only a small fraction of RA subjects had levels above the 95th percentile of healthy control levels until the time period within 6 months of diagnosis. For classification of RA diagnosis using samples obtained within 6 months prior to diagnosis, soluble PD-1 provided superior specificity compared to ReA cases (>89%), with a sensitivity of 48% for RA classification. An 8-analyte model provided superior sensitivity (69%), with comparable specificity relative to ReA (>82%)., Conclusion: Our findings demonstrate that imminent RA diagnosis could be classified with high specificity, relative to healthy controls and ReA cases, using a panel of cytokines measured in serum samples collected within 6 months before actual diagnosis., (© 2022 American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background & Aims: Anti-granulocyte macrophage-colony stimulating factor autoantibodies (aGMAbs) are detected in patients with ileal Crohn's disease (CD). Their induction and mode of action during or before disease are not well understood. We aimed to investigate the underlying mechanisms associated with aGMAb induction, from functional orientation to recognized epitopes, for their impact on intestinal immune homeostasis and use as a predictive biomarker for complicated CD., Methods: We characterized using enzyme-linked immunosorbent assay naturally occurring aGMAbs in longitudinal serum samples from patients archived before the diagnosis of CD (n = 220) as well as from 400 healthy individuals (matched controls) as part of the US Defense Medical Surveillance System. We used biochemical, cellular, and transcriptional analysis to uncover a mechanism that governs the impaired immune balance in CD mucosa after diagnosis., Results: Neutralizing aGMAbs were found to be specific for post-translational glycosylation on granulocyte macrophage-colony stimulating factor (GM-CSF), detectable years before diagnosis, and associated with complicated CD at presentation. Glycosylation of GM-CSF was altered in patients with CD, and aGMAb affected myeloid homeostasis and promoted group 1 innate lymphoid cells. Perturbations in immune homeostasis preceded the diagnosis in the serum of patients with CD presenting with aGMAb and were detectable in the noninflamed CD mucosa., Conclusions: Anti-GMAbs predict the diagnosis of complicated CD long before the diagnosis of disease, recognize uniquely glycosylated epitopes, and impair myeloid cell and innate lymphoid cell balance associated with altered intestinal immune homeostasis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

In this study, we aimed to examine the association between gastrointestinal (GI) symptom presence during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the prevalence of GI symptoms and the development of post-infectious irritable bowel syndrome (PI-IBS). We used data from a prospective cohort and logistic regression to examine the association between GI symptom status during confirmed SARS-CoV-2 infection and prevalence of persistent GI symptoms at ≥45 days. We also report the incidence of PI-IBS following SARS-CoV-2 infection. Of the 1475 participants in this study, 33.8% ( n = 499) had GI symptoms during acute infection. Cases with acute GI symptoms had an odds of persisting GI symptoms 4 times higher than cases without acute GI symptoms (odds ratio (OR) 4.29, 95% confidence interval (CI) 2.45-7.53); symptoms lasted on average 8 months following infection. Of those with persisting GI symptoms, 67% sought care for their symptoms and incident PI-IBS occurred in 3.0% ( n = 15) of participants. Those with acute GI symptoms after SARS-CoV-2 infection are likely to have similar persistent symptoms 45 days and greater. These data indicate that attention to a potential increase in related healthcare needs is warranted.

Background: It is unclear if state laws supporting breastfeeding are associated with exclusive breastfeeding (EBF) practice among low-income mothers participating in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). The main objectives of our study were to assess the relationship between such laws and EBF among WIC-participating mothers and to assess whether this association varied by employment status. We also assessed how mother's exposure to WIC breastfeeding consultation was associated with EBF., Methods: A cross-sectional study was conducted across seven WIC program locations (i.e., Georgia, Massachusetts, Nevada, Pennsylvania, Wisconsin, Wyoming, Chickasaw Nation) between July-August 2020. Data were collected using convenient sampling from each program location and surveys were administered electronically or on paper to WIC-participating mothers. We restricted our analysis to data from 1161 WIC-participating mothers with infants aged zero to five months old. Multivariable mixed models were used to estimate the relationship between our exposures of interest (i.e., number of laws supporting breastfeeding, employment-related breastfeeding laws, WIC breastfeeding consultation) and EBF, while controlling for potential confounders and accounting for clustering by program location. Effect modification by employment status was assessed on the additive and multiplicative scales., Results: Among WIC-participating mothers living in program locations with no employment-related breastfeeding laws, EBF was 26% less prevalent for employed mothers compared to unemployed mothers (adjusted prevalence ratios [aPR]: 0.74, 95% CI: 0.67,0.83). Among all mothers, a one-unit increase in laws supporting breastfeeding was not associated with EBF (aPR: 0.88, 95% CI: 0.71,1.10). However, among employed mothers, living in areas with more employment-related laws was associated with a higher prevalence of EBF (aPR: 1.43, 95% CI: 0.83, 2.44). Infants whose mothers received a WIC breastfeeding consultation had 33% higher prevalence of being exclusively breastfed compared to infants whose mothers did not receive a WIC breastfeeding consultation (aPR: 1.33, 95% CI: 1.05,1.70)., Conclusions: Infants whose WIC-participating mothers were employed, were less likely to be exclusively breastfed, but our effect modification analyses showed that laws supporting breastfeeding at the workplace may promote EBF among employed women. EBF was more prevalent among mothers who received a WIC breastfeeding consultation compared to those who did not receive such a consultation., (© 2022. The Author(s).)

We are at an exciting moment in time with the advancement of many vaccines, including a shigella vaccine for the world. It is instructive to look at the long road that some vaccines have traveled to recognize the remarkable accomplishments of those who were pioneers, appreciate the evolution of scientific and applied technology, and inform the future history of a vaccine that would have great potential for global health. To achieve this valuable retrospective, a narrative historical literature review was undertaken utilizing PubMed and Embase databases with relevant search terms. Retrieved articles were reviewed and information was organized into historical themes, landmark discoveries, and important vaccine development parallels. The literature reviewed was synthesized into major eras of shigella vaccine development from pathogen discovery and first attempts to empirical approaches of killed whole-cell and live-attenuated approaches, and a modern era that applied recombinant DNA engineering and structural vaccinology. The history of shigella vaccine development has largely followed the evolutionary path of vaccine development over the last 120 years, but with important lessons learned that should be considered as we embark on the future chapters of bringing to the world a safe and effective vaccine for global health.

The Deployment and Travel Medicine Knowledge, Attitude, Practice and Outcomes Study investigates the various clinician and traveler contributions to medical outcomes within the U.S. Military Health System. Travelers' diarrhea is among the most common travel-related illnesses, making travelers' diarrhea self-treatment (TDST) important for traveler health. A cohort of 80,214 adult travelers receiving malaria chemoprophylaxis for less than 6 weeks of travel were identified within the U.S. Department of Defense Military Health System Data Repository. Associated prescriptions for TDST medications within 2 weeks of chemoprophylaxis prescriptions were identified. Prescription patterns were compared by service member versus beneficiary status and site of care, military facility versus civilian facility. At military facilities, medical provider demographics were analyzed by clinical specialty and categorized as travel medicine specialists versus nonspecialists. Overall, there was low prescribing of TDST, particularly among civilian providers and military nonspecialists, despite guidelines recommending self-treatment of moderate to severe travelers' diarrhea. This practice gap was largest among service member travelers, but also existed for beneficiaries. Compared with nonspecialists, military travel medicine specialists were more likely to prescribe a combination of an antibiotic and antimotility agent to beneficiaries, more likely to provide any form of TDST to service members, and more likely to prescribe azithromycin than quinolones when using antibiotics. Our study suggests that enhancing provider knowledge and use of travelers' diarrhea treatment recommendations combined with improved access to formal travel medicine services may be important to increase the quality of care.

Objectives: proving causality between an exposure and outcome can be difficult in humans. Here, we utilize the Bradford Hill (BH) criteria to summarize the causal relationship between Campylobacter infection and the development of Irritable Bowel Syndrome (IBS)., Methods: we utilized the BH criteria to assess the strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy of the current evidence linking Campylobacter to IBS. Through a consensus amongst all authors, the confidence of each criterion was graded as high, moderate, low, or very low., Results: a total of four criteria (strength, temporality, plausibility, and analogy) were graded as high; four criteria (consistency, biological gradient, coherence, and experiment) were graded as moderate; and one criterion (specificity) was graded as low. Large-scale epidemiological studies report a risk ratio of 2.7-5.6 for developing IBS after campylobacter. In rodent models, Campylobacter jejuni 81-176 can cause loose stool months after the infection is cleared and share common pathophysiology as IBS patients such as elevated intestinal TLR-4 and IL-8, antibodies to CdtB and vinculin, increased intraepithelial lymphocytes, and small intestinal bacterial overgrowth., Conclusions: Campylobacter infection appear to cause IBS in a subset of patients. This may hold implication in risk factor identification, public health policy, and possibly treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of FEMS.)

Background: Travellers' diarrhoea (TD) is the most common clinical syndrome affecting travellers. This narrative review summarizes key discoveries reported in the last two years related to TD and suggests areas for future research., Methods: A PubMed literature search was conducted for novel data in TD research published between 12 January 2018 and 12 January 2020. Inclusion was based on contribution to epidemiology, aetiology, diagnostics, management and long-term consequences and relevance to public health, discovery and clinical practice., Results: The initial literature search yielded 118 articles. We retrieved 72 and reviewed 31 articles for inclusion. The findings support our understanding that TD incidence varies by traveller group and environment with students and military-travel remaining moderately high risk, and control of food and water in mass gathering events remain an important goal. The growth of culture-independent testing has led to a continued detection of previously known pathogens, but also an increased detection frequency of norovirus. Another consequence is the increase in multi-pathogen infections, which require consideration of clinical, epidemiological and diagnostic data. Fluoroquinolone resistant rates continue to rise. New data on non-absorbable antibiotics continue to emerge, offering a potential alternative to current recommendations (azithromycin and fluoroquinolones), but are not recommended for febrile diarrhoea or dysentery or regions/itineraries where invasive pathogens are likely to cause illness. Recent studies investigated the interaction of the microbiome in TD prevention and consequences, and while discriminating features were identified, much uncertainty remains. The prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) acquisition and carriage is increasing. Finally, continued research documents the post-infectious consequences, whereas mechanisms of reactive arthritis and post-infectious IBS necessitate further investigation., Conclusions: Globally, TD remains an important travel health issue and advances in our understanding continue. More research is needed to mitigate risk factors where possible and develop risk-based management strategies to reduce antibiotic usage and its attendant consequences., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Travellers' diarrhoea (TD) is the most common travel-related illness with an estimated 10 million people afflicted annually. Outcome measures to assess the efficacy of primary and secondary TD interventions were historically based on diarrhoea frequency with ≥1 associated gastrointestinal symptom. Furthermore, efficacy determination is often made on the presence or absence of TD, rather than on TD illness severity. Current severity classifications are based on subjective consideration of impact of illness on activity. We sought to develop a standardized scoring system to characterize TD severity to potentially apply as a secondary outcome in future field studies., Methods: Data on multiple signs and symptoms were obtained from a previously published multisite TD treatment trial conducted by the US Department of Defense (TrEAT TD). Correlation, regression and multiple correspondence analyses were performed to assess impact on activity and a TD severity score was established., Results: Numerous signs and symptoms were associated with impaired function, with malaise and nausea most strongly associated [odds ratio (OR) 5.9-44.3, P < 0.0001 and OR 2.8-37.1, P < 0.0001, respectively). Based on co-varying symptomatology, a TD severity score accounting for diarrhoea frequency in addition to several signs and symptoms was a better predictor of negative impact on function than any single sign/symptom (X2 = 127.16, P < 0.001). Additionally, there was a significant difference (P < 0.0001) in the mean TD severity score between those with acute watery diarrhoea (3.9 ± 1.9) and those with dysentery or acute febrile illness (6.2 ± 2.0)., Conclusions: The newly developed disease severity score better predicted a negative impact on activity due to TD than did any single sign or symptom. Incorporating multiple parameters into the TD severity score better captures illness severity and moves the field towards current recommendations for TD management by considering symptoms with high functional impact. Further validation of this score is needed in non-military travellers and other settings., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We assessed the compliance with self-collection of stool smears on Whatman® FTA® Elute Card (FTA Card) and detection of travellers' diarrhoea (TD)-associated pathogens by using a quantitative Polymerase Chain Reaction (PCR) assay [customized TaqMan® array card (TAC)] in a prospective, observational cohort of travellers., Methods: Enrolled travellers documented symptoms on a travel diary and collected an FTA Card during a diarrhoeal episode, or at the end of travel if they remained asymptomatic. TAC testing was performed on FTA Cards from TD cases and 1:1 matched asymptomatic controls and 1:1 matched loose stool cases that did not meet TD criteria. Odds ratios were used to determine the association between detected pathogens and TD., Results: Of 2456 travellers, 484 (19.7%) completed an illness diary and met TD criteria, and 257 (53.1%) collected an FTA Card during the TD episode. FTA Cards were stored for a median of 2 years at room temperature (IQR: 1-4 years) before extraction and testing. The overall TAC detection rate in TD cases was 58.8% (95% CI: 52.5-64.8). Enterotoxigenic Escherichia coli was the most common pathogen in TD cases (26.8%), and 3.5% of samples were positive for norovirus. The odds of detecting TD-associated pathogens in 231 matched cases and asymptomatic controls were 5.4 (95% CI: 3.6-8.1) and 2.0 (95% CI: 1.1-3.7) in 121 matched TD and loose stool cases (P < 0.05). Enteroaggregative E. coli was the most common pathogen detected in asymptomatic controls and loose stool cases. Detection of diarrhoeagenic E. coli, Shigella/enteroinvasive E. coli and Campylobacter spp. was significantly associated with TD., Conclusion: FTA Cards are a useful adjunct to traditional stool collection methods for evaluating the pathogen-specific epidemiology of TD in austere environments. Qualitative detection of pathogens was associated with TD. Measures to improve compliance and quality of FTA Card collection with decreased storage duration may further optimize detection., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society of Travel Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Enterotoxigenic Escherichia coli (ETEC) is a common cause of infectious diarrhoea and a leading cause of morbidity and mortality in children living in resource-limited settings. It is also the leading cause of travellers' diarrhoea among civilian and military travellers. Its dual importance in global public health and travel medicine highlights the need for an effective vaccine. ETEC express colonization factors (CFs) that mediate adherence to the small intestine. An epidemiologically prevalent CF is coli surface antigen 6 (CS6). We assessed the safety and immunogenicity of a CS6-targeted candidate vaccine, CssBA, co-administered intramuscularly with the double-mutant heat-labile enterotoxin, dmLT [LT(R192G/L211A)]., Methods: This was an open-label trial. Fifty subjects received three intramuscular injections (Days 1, 22 and 43) of CssBA alone (5 µg), dmLT alone (0.1 µg) or CssBA (5, 15, 45 µg) + dmLT (0.1 and 0.5 µg). Subjects were actively monitored for adverse events for 28 days following the third vaccination. Antibody responses (IgG and IgA) were characterized in the serum and from lymphocyte supernatants (ALS) to CS6 and the native ETEC heat labile enterotoxin, LT., Results: Across all dose cohorts, the vaccine was safe and well-tolerated with no vaccine-related severe or serious adverse events. Among vaccine-related adverse events, a majority (98%) were mild with 79% being short-lived vaccine site reactions. Robust antibody responses were induced in a dose-dependent manner with a clear dmLT adjuvant effect. Response rates in subjects receiving 45 µg CssBA and 0.5 µg dmLT ranged from 50 to 100% across assays., Conclusion: This is the first study to demonstrate the safety and immunogenicity of CssBA and/or dmLT administered intramuscularly. Co-administration of the two components induced robust immune responses to CS6 and LT, paving the way for future studies to evaluate the efficacy of this vaccine target and development of a multivalent, subunit ETEC vaccine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Travelers' diarrhea (TD) is one of the most common illnesses affecting modern-day travelers, including military personnel. Previous work has shown that afflicted travelers may alter their itineraries and be confined to bed rest due to symptoms, and military personnel may become incapable of completing operational requirements. Examination of signs, symptoms, and severity of diarrheagenic pathogens can inform clinical diagnosis and prioritization of future surveillance and research activities., Methods: Utilizing a global laboratory network, culture and molecular testing were performed in parallel at each site on a group of core pathogens, and definitions for acute diarrhea (AD), severe AD, acute gastroenteritis (AGE), and severe AGE were determined using data elements in the modified Vesikari scale. We included 210 cases of TD reporting all variables of interest in our severity assessment analysis., Results: Out of all cases, 156/210 (74%) met criteria for severe AD and 35/210 (17%) for severe AGE. Examination of severity by pathogen revealed that, at non-military sites, 17/19 (89%) of enteropathogenic Escherichia coli (E. coli) (EPEC) infections, 28/32 (88%) of enterotoxigenic E. coli (ETEC) infections, and 13/15 (87%) of Shigella/enteroinvasive E. coli (EIEC) infections resulted in severe AD cases. At the military site, all infections of ETEC (6/6), Shigella-EIEC (4/4), and enteroaggregative E. coli (EAEC) resulted in AD. Norovirus infections at non-military and military sites resulted in 27% (14/51) and 33% (3/9) severe AGE cases, respectively., Conclusions: This study found a high percentage of participants enrolled at both military and non-military sites experienced severe AD with concerning numbers of severe cases at non-military sites reporting hospitalization and reductions in performance. Since travelers with mild TD symptoms are less likely to present to health care workers than those with more severe TD, there is a potential selection bias in this study that may have overestimated the proportion of more severe outcomes among all individuals who could have participated in the GTD study. Future research should examine other covariates among pathogen and host, such as treatment and comorbid conditions, that may contribute to the presence of signs and symptoms and their severity., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Multiple factors contribute to variation in disease burden, including the type and quality of data, and inherent properties of the models used. Understanding how these factors affect mortality estimates is crucial, especially in the context of public health decision making. We examine how the quality of the studies selected to provide mortality data, influence estimates of burden and provide recommendations about the inclusion of studies and datasets to calculate mortality estimates., Methods: To determine how mortality estimates are affected by the data used to generate model outputs, we compared the studies used by The Institute of Health Metrics and Evaluation (IHME) and Maternal and Child Epidemiology Estimation (MCEE) modelling groups to generate enterotoxigenic Escherichia coli (ETEC) and Shigella-associated mortality estimates for 2016. Guided by an expert WHO Working Group, we applied a modified Newcastle-Ottawa Scale (NOS) to evaluate the quality of studies used by both modelling groups., Results: IHME and MCEE used different sets of ETEC and Shigella studies in their models and the majority of studies were high quality. The distribution of the NOS scores was similar between the two modelling groups. We observed an overrepresentation of studies from some countries in SEAR, AFR and WPR compared to other WHO regions., Conclusion: We identified key differences in study inclusion and exclusion criteria used by IHME and MCEE and discuss their impact on datasets used to generate diarrhoea-associated mortality estimates. Based on these observations, we provide a set of recommendations for future estimates of mortality associated with enteric diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)