Examining Clinical Presentation and Workup of Veterans with Irritable Bowel Syndrome in a Single Medical Centre: A Case Series.

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.

Meeting Report: WHO Workshop on modelling global mortality and aetiology estimates of enteric pathogens in children under five. Cape Town, 28-29th November 2018.

Investment in vaccine product development should be guided by up-to-date and transparent global burden of disease estimates, which are also fundamental to policy recommendation and vaccine introduction decisions. For low- and middle-income countries (LMICs), vaccine prioritization is primarily driven by the number of deaths caused by different pathogens. Enteric diseases are known to be a major cause of death in LMICs. The two main modelling groups providing mortality estimates for enteric diseases are the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle and the Maternal Child Epidemiology Estimation (MCEE) group, led by Johns Hopkins Bloomberg School of Public Health. Whilst previous global diarrhoea mortality estimates for under five-year-olds from these two groups were closely aligned, more recent estimates for 2016 have diverged, particularly with respect to numbers of deaths attributable to different enteric pathogens. This has impacted prioritization and investment decisions for vaccines in the development pipeline. The mission of the Product Development for Vaccines Advisory Committee (PDVAC) at the World Health Organisation (WHO) is to accelerate product development of vaccines and technologies that are urgently needed and ensure they are appropriately targeted for use in LMICs. At their 2018 meeting, PDVAC recommended the formation of an independent working group of subject matter experts to explore the reasons for the difference between the IHME and MCEE estimates, and to assess the respective strengths and limitations of the estimation approaches adopted, including a review of the data on which the estimates are based. Here, we report on the proceedings and recommendations from a consultation with the working group of experts, the IHME and MCEE modelling groups, and other key stakeholders. We briefly review the methodological approaches of both groups and provide a series of proposals for investigating the drivers for the differences in enteric disease burden estimates.

Oral delivery of Hyperimmune bovine serum antibodies against CS6-expressing enterotoxigenic Escherichia coli as a prophylactic against diarrhea.

BACKGROUND: . Oral administration of bovine antibodies active against enterotoxigenic Escherichia coli (ETEC) have demonstrated safety and efficacy against diarrhea in human challenge trials. The efficacy of bovine serum immunoglobulins (BSIgG) against recombinant colonization factor CS6 or whole cell ETEC strain B7A was assessed against challenge with the CS6-expressing B7A. METHODS: . This was a randomized, double-blind, placebo-controlled trial in which healthy adults received oral hyperimmune BSIgG anti-CS6, anti-B7A whole cell killed or non-hyperimmune BSIgG (placebo) in a 1:1:1 ratio then challenged with ETEC B7A. Two days pre-challenge, volunteers began a thrice daily, seven day course of immunoprophylaxis. On day 3, subjects received 1 × 1010 CFUs of B7A. Subjects were observed for safety and the primary endpoint of moderate-severe diarrhea (MSD). RESULTS: . A total of 59 volunteers received product and underwent ETEC challenge. The BSIgG products were well-tolerated across all subjects. Upon challenge, 14/20 (70%) placebo recipients developed MSD, compared to 12/19 (63%; p = .74) receiving anti-CS6 BSIgG and 7/20 (35%; p = .06) receiving anti-B7A BSIgG. Immune responses to the ETEC infection were modest across all groups. CONCLUSIONS: . Bovine-derived serum antibodies appear safe and well tolerated. Antibodies derived from cattle immunized with whole cell B7A provided 50% protection against MSD following B7A challenge; however, no protection was observed in subjects receiving serum antibodies targeting CS6. The lack of observed efficacy in this group may be due to low CS6 surface expression on B7A, the high dose challenge inoculum and/or the use of serum derived antibodies versus colostrum-derived antibodies.

Update on vaccines for enteric pathogens.

BACKGROUND: Acute diarrhoeal disease caused by viral, bacterial and parasitic infections is a major global health problem; in low- and middle-income countries (LMICs) it is associated with substantial mortality and morbidity in children under 5. Some of these infections also impact large segments of populations in high-income countries (HICs), as well as individuals who travel overseas for work, business or pleasure. AIMS: The aim of this review is to describe the current landscape of licensed enteric vaccines, potential new vaccines on the horizon, and the challenges of development and utilization of vaccines against enteric pathogens. SOURCES: Relevant data from the literature, as well as clinical trials described in European and US registries, were examined in the conduct of this review. CONTENT: The review involves discussion of current licensed vaccines against rotavirus, cholera and typhoid, as well as potential second- and third-generation vaccines against these pathogens currently in the development pipeline. In addition, novel vaccines against enterotoxigenic Escherichia coli, shigellosis and norovirus in advanced development are described. Challenges to the development and utilization of global vaccines are discussed. IMPLICATIONS: Despite advances in population health, food security, improved sanitation and water quality, and the reduction in poverty, acute enteric infections continue to plague global populations. Advancing utilization of current enteric vaccines is of critical public health importance, as is the development of new vaccines, particularly for enteric pathogens where none currently exist.

Epidemiology of inflammatory bowel disease among participants of the Millennium Cohort: incidence, deployment-related risk factors, and antecedent episodes of infectious gastroenteritis.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are two pathotypes of inflammatory bowel disease (IBD) with unique pathology, risk factors and significant morbidity. AIM: To estimate incidence and identify IBD risk factors in a US military population, a healthy subset of the US population, using information from the Millennium Cohort Study. METHODS: Incident IBD was identified from medical encounters from 2001 to 2009 or by self-report. Our primary risk factor of interest, infectious gastroenteritis, was identified from medical encounters and self-reported post-deployment health assessments. Other potential risk factors were assessed using self-reported survey responses and military personnel files. Hazard ratios were estimated using Cox proportional hazards analysis. RESULTS: We estimated 23.2 and 21.9 diagnoses per 100 000 person-years, respectively, for CD and UC. For CD, significant risk factors included [adjusted hazard ratio (aHR), 95% confidence interval]: current smoking (aHR: 2.7, 1.4-5.1), two life stressors (aHR: 2.8, 1.4-5.6) and prior irritable bowel syndrome (aHR: 4.7, 1.5-15.2). There was no significant association with prior infectious gastroenteritis. There was an apparent dose-response relationship between UC risk and an increasing number of life stressors. In addition, antecedent infectious gastroenteritis was associated with almost a three-fold increase in UC risk (aHR: 2.9, 1.4-6.0). Moderate alcohol consumption (aHR: 0.4, 0.2-0.6) was associated with lower UC risk. CONCLUSIONS: Stressful conditions and the high risk of infectious gastroenteritis in deployment operations may play a role in the development of IBD in military populations. However, observed differences in risk factors for UC and CD warrant further investigation.

Serologic microbial associated markers can predict Crohn's disease behaviour years before disease diagnosis.

BACKGROUND: Patients with Crohn's disease (CD) have serologic responses to various microbial antigens. Serologic markers are associated with aggressive forms of disease and can be detected before onset of symptoms. Their utility in pre-clinical disease or prediction of complicated disease course before diagnosis is unclear. AIM: To evaluate the pattern of serologic anti-microbial antibodies long prior to diagnosis and the subsequent risk of complicated Crohn's disease at diagnosis. METHODS: Sera from 100 US military personnel with Crohn's disease were obtained from the Department of Defense Serum Repository. For each patient, four samples were obtained at different time points before and around diagnosis, and were tested for 6 microbiota-directed antibodies (ASCA-IgA, ASCA-IgG, anti-OmpC, anti-CBir1, anti-A4-Fla2 and anti-FlaX). Associations between the presence and accumulation of Crohn's disease anti-microbial antibodies before diagnosis and with the later development of complications were evaluated. RESULTS: Overall, 65 patients were positive for at least one Crohn's disease associated anti-microbial antibody in the earliest available sample, at a median of 6 years before Crohn's disease diagnosis (interquartile range, 5.6-8.2). The number of positive anti-microbial antibodies increased up to the time of Crohn's disease diagnosis. Complicated disease developed around the time of diagnosis in 24 patients. The proportion of positive antimicrobial antibodies before diagnosis was higher in patients with complicated vs. noncomplicated Crohn's disease. There was an inverse relationship between the time to first complication and the magnitude of serologic response before diagnosis. CONCLUSION: The presence and accumulation of circulating anti-microbial antibodies years before Crohn's disease diagnosis was associated with complicated Crohn's disease at or shortly after diagnosis.

Diarrhea burden due to natural infection with enterotoxigenic Escherichia coli in a birth cohort in a rural Egyptian community.

Enterotoxigenic Escherichia coli (ETEC) is commonly associated with diarrhea in Egyptian children. Children less than 3 years old in Abu Homos, Egypt, had approximately five diarrheal episodes per child every year, and at least one of these episodes was due to ETEC. The epidemiology of ETEC diarrhea among children living in a rural Egyptian community was further evaluated in this study. Between January 2004 and April 2007, 348 neonates were enrolled and followed for 2 years. Children were visited twice weekly, and a stool sample was obtained every 2 weeks regardless of symptomatology. A stool sample was obtained whenever a child had diarrhea. From the routine stool culture, five E. coli-like colonies were selected and screened for heat-labile and heat-stable toxins by GM1 enzyme-linked immunosorbent assay (ELISA) and further typed for colonization factor antigens by dot blot assay. Incidence of ETEC infection was estimated among children with diarrhea (symptomatic) and without diarrhea (asymptomatic). Incidence of diarrhea and ETEC-associated diarrhea was 7.8 and 1.48 per child-year, respectively. High risk of repeated ETEC diarrhea was associated with being over 6 months of age, warm season, male gender, and crowded sleeping conditions. Exclusive breast-feeding was protective for repeated ETEC infection. ETEC-associated diarrhea remains common among children living in the Nile Delta. The protective role of breast-feeding demonstrates the importance of promoting exclusive breast-feeding during, at least, the first 6 months of life.

Enteric disease on Operation HERRICK.

BACKGROUND: It is increasingly recognised that diarrhoeal disease is an important contributor to disease non-battle injury (DNBI) rates on operations. Current data collection methods (J97/EPINATO) rely on self-presentation of patients to medical care, which is likely to under-record the true incidence of diarrhoea in theatre. Along with this, the data recording itself is less than adequate, with acknowledged issues in classification of diarrhoeal disease within J97/EPINATO categories. METHODS: Two post-tour diarrhoeal disease questionnaire surveillance exercises were carried out at the end of Operation HERRICK 6 (H6) and 10 (H10), respectively. RESULTS: Crude diarrhoeal disease attack rates were similar across the two surveillance periods with approximately 40% of troops questioned reporting at least one diarrhoeal illness episode. The severity of illness increased from H6 to H10 as measured by disease-related symptomatology and days ill and/or off work. Mission burden was substantial and increased in H10 compared with H6. CONCLUSIONS: Diarrhoeal disease is a significant cause of DNBI on operations. Current data collection methodologies underestimate its incidence and true operational burden.

Modifiable diarrhoea risk factors in Egyptian children aged <5 years.

By conducting a case-control study in two university hospitals, we explored the association between modifiable risk behaviours and diarrhoea. Children aged <5 years attending outpatient clinics for diarrhoea were matched by age and sex with controls. Data were collected on family demographics, socioeconomic indicators, and risk behaviour practices. Two rectal swabs and a stool specimen were collected from cases and controls. Samples were cultured for bacterial pathogens using standard techniques and tested by ELISA to detect rotavirus and Cryptosporidium spp. Four hundred cases and controls were enrolled between 2007 and 2009. The strongest independent risk factors for diarrhoea were: presence of another household member with diarrhoea [matched odds ratio (mOR) 4.9, 95% CI 2.8-8.4] in the week preceding the survey, introduction to a new kind of food (mOR 3, 95% CI 1.7-5.4), and the child being cared for outside home (mOR 2.6, 95% CI 1.3-5.2). While these risk factors are not identifiable, in some age groups more easily modifiable risk factors were identified including: having no soap for handwashing (mOR 6.3, 95% CI 1.2-33.9) for children aged 7-12 months, and pacifier use (mOR 1.9, 95% CI 1.0-3.5) in children aged 0-6 months. In total, the findings of this study suggest that community-based interventions to improve practices related to sanitation and hygiene, handwashing and food could be utilized to reduce the burden of diarrhoea in Egyptian children aged <5 years.

The Shigella human challenge model.

Shigella is an important bacterial cause of infectious diarrhoea globally. The Shigella human challenge model has been used since 1946 for a variety of objectives including understanding disease pathogenesis, human immune responses and allowing for an early assessment of vaccine efficacy. A systematic review of the literature regarding experimental shigellosis in human subjects was conducted. Summative estimates were calculated by strain and dose. While a total of 19 studies evaluating nine strains at doses ranging from 10 to 1 × 1010 colony-forming units were identified, most studies utilized the S. sonnei strain 53G and the S. flexneri strain 2457T. Inoculum solution and pre-inoculation buffering has varied over time although diarrhoea attack rates do not appear to increase above 75-80%, and dysentery rates remain fairly constant, highlighting the need for additional dose-ranging studies. Expansion of the model to include additional strains from different serotypes will elucidate serotype and strain-specific outcome variability.

Determinants of incident chronic kidney disease and progression in a cohort of HIV-infected persons with unrestricted access to health care.

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 m(2) 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 m(2) [interquartile range (IQR) 85.3-110.1 mL/min/1.73 m(2)]. 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.

A systematic review of ETEC epidemiology focusing on colonization factor and toxin expression.

INTRODUCTION: Vaccine development for enterotoxigenic Escherichia coli (ETEC) is dependent on in-depth understanding of toxin and colonization factor (CF) distribution. We sought to describe ETEC epidemiology across regions and populations, focusing on CF and toxin prevalence. METHODS: We conducted a systematic review of the published literature, including studies reporting data on ETEC CF and toxin distributions among those with ETEC infection. Point estimates and confidence intervals were calculated using random effects models. RESULTS: Data on 17,205 ETEC isolates were abstracted from 136 included studies. Approximately half of the studies (49%) involved endemic populations, and an additional 17% involved only travel populations. Globally, 60% of isolates expressed LT either alone (27%) or in combination with ST (33%). CFA/I-expressing strains were common in all regions (17%), as were ETEC expressing CFA/II (9%) and IV (18%). Marked variation in toxins and CFs across regions and populations was observed. DISCUSSION/CONCLUSIONS: These results demonstrate the relative importance of specific CFs in achieving target product profiles for a future ETEC vaccine. However, heterogeneity across time, population, and region, confounded by variability in CF and toxin detection methodologies, obfuscates rational estimates for valency requirements.

Case series study of traveler's diarrhea in U.S. military personnel at Incirlik Air Base, Turkey.

Military personnel with traveler's diarrhea (n=202) while deployed to Incirlik Air Base, Turkey, from June to September 2002 were evaluated for pathogen-specific immune responses. Serologic and fecal immunoglobulin A (IgA) titers to enterotoxigenic Escherichia coli antigens (CS6, CS3, and LT) were quite low. In contrast, subjects with Campylobacter infections had high serologic and fecal IgA responses.

Serological evidence of arboviral infection and self-reported febrile illness among U.S. troops deployed to Al Asad, Iraq.

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.

Epidemiology and genetic characterization of Shigella flexneri strains isolated from three paediatric populations in Egypt (2000-2004).

Ninety-seven isolates of Shigella flexneri from children seeking medical care from three sites in Egypt were characterized. Overall, 46.4% of children (median age 17 months) were febrile or reported blood in their stools, 25.8% were dehydrated and 16.5% were admitted to hospital. Serotypes 2a (37.1%), 1b (18.6%), 1c (17.5%), and 6 (15.5%) comprised over 88.7% of the total isolates. We observed marked resistance to ampicillin (87.6%), tetracycline (84.5%) and trimethoprim-sulfamethoxazole (63.9%). Pulsed-field electrophoresis grouped the majority of isolates within a serotype together, separately from isolates of an alternative serotype. The set gene was present in all serogroup 2a isolates, however, the sen gene was detected in every isolate. Our results show S. flexneri 1c has emerged as a dominant S. flexneri serotype in Egypt. Development and application of a Shigella vaccine should consider the diversity of Shigella serotypes within a geographical region prior to administration.

Antimicrobial susceptibility trends among Escherichia coli and Shigella spp. isolated from rural Egyptian paediatric populations with diarrhoea between 1995 and 2000.

Antimicrobial susceptibility testing was performed on 3,627 isolates of Escherichia coli and 180 isolates of Shigella spp. collected in rural locations from 875 Egyptian children with diarrhoea between 1995 and 2000. The cumulative rates of resistance for E. coli and Shigella spp. were high (respectively, 68.2% and 54.8% for ampicillin, 24.2% and 23.5% for ampicillin-sulbactam, 57.2% and 42.5% for trimethoprim-sulphamethoxazole, and 50.9% and 75.4% for tetracycline). Non-enterotoxigenic E. coli (NETEC) isolates had a consistently higher level of antimicrobial resistance than did enterotoxigenic E. coli (ETEC) isolates. Trend testing showed significant decreases in resistance to ampicillin, ampicillin-sulbactam and tetracycline among all E. coli isolates. Increasing rates of resistance were observed for trimethoprim-sulphamethoxazole in ETEC isolates and Shigella spp., but not in NETEC isolates. Low levels of resistance were observed for all other antimicrobial agents tested. Overall, high levels, but decreasing trends, of resistance to commonly used antimicrobial agents were detected among isolates of E. coli and Shigella spp. from children in rural Egypt.

Time course for exercise-induced alterations in insulin action and glucose tolerance in middle-aged people.

The purposes of this study were 1) to investigate glucose tolerance and insulin action immediately after exercise and 2) to determine how long the improved glucose homeostatic mechanisms observed 12-16 h after exercise persist. Nine (seven men, two women) moderately trained middle-aged (51 +/- 3 yr) subjects performed 45 min of exercise at 73 +/- 2% of peak O2 uptake for 5 days, followed by 7 days of inactivity. Oral glucose tolerance tests (OGTT; 75 g) were performed immediately postexercise (IPE; approximately 30 min) after the final exercise bout and 1, 3, 5, and 7 days after exercise. The incremental area under the plasma glucose curve was markedly higher IPE (355 +/- 82 mM.min) compared with those on days 1 (136 +/- 57 mM.min; P < 0.05) and 3 (173 +/- 62 mM.min; P < 0.05). The glucose area was significantly higher on days 5 (213 +/- 80 mM.min) and 7 (225 +/- 84 mM.min) compared with those on days 1 and 3 (P < 0.05). The incremental insulin area IPE (3,729 +/- 1,104 microU.ml-1.min) was 43% higher compared with that on day 1 (2,603 +/- 635 microU.ml-1.min; P < 0.05) and 66% higher compared with that on day 3 (2,240 +/- 517 microU.ml-1.min; P < 0.05). The insulin area increased to 3,616 +/- 617 microU.ml-1.min after 5 days of inactivity (P < 0.05). An additional 48 h of inactivity did not result in any further increase in the plasma insulin response.(ABSTRACT TRUNCATED AT 250 WORDS)