Human Challenge Studies for Cholera.

The human challenge model permits an estimate of the vaccine protection against moderate and severe cholera. It eliminates the difficulty in setting up a vaccine study in endemic area including uncertainties about the incidence of cholera and the logistic arrangements for capturing those who do/do not become ill. Valuable information from small groups of subjects can be obtained in a short period. Under proper precautions and study design, the challenge model is safe and efficient. Although the model has evolved since it was introduced over 50 years ago, it has been used extensively to test vaccine efficacy. Vaccine licensure has resulted from data obtained using the human challenge model. In addition, the model has been used to: (1) Establish and validate a standardized inoculum, (2) Identify immune markers and immune responses, (3) Determine natural immunity (in re-challenge studies), (4) Identify the role of the gastric acid barrier in preventing cholera infection, (5) Show homologous and heterologous infection-derived immunity, and (6) Test the efficacy of anti-diarrheal/anti-secretory small molecules. The aim of this chapter is to present an overview on the state of the art for human challenge models used to study cholera and new medical interventions against it.

Improving Bowel Management in Children With Spina Bifida.

OBJECTIVES: In individuals with spina bifida (SB), bowel incontinence is associated with lower quality of life and lower likelihood of employment. In an effort to maximize bowel continence in children and adolescents, we created a bowel management assessment and follow-up protocol in a multidisciplinary clinic. Here we report the results of this protocol using quality-improvement methodology. METHODS: Continence was defined as no unplanned bowel movements. Our protocol involved: (1) a standardized 4-item questionnaire about bowel continence and consistency; (2) if the patient was not achieving continence, an intervention starting with oral medication (stimulant and/or osmotic laxatives), and/or suppositories (glycerin or bisacodyl) followed by an escalation to trans-anal irrigation, or continence surgery; and (3) follow-up phone calls at regular intervals to monitor progress and make changes as needed. Results are summarized with descriptive statistics. RESULTS: We screened 178 eligible patients in the SB clinic. Eighty-eight agreed to participate in the bowel management program. Of those who did not participate, the majority (68/90, 76%) were already achieving continence with their bowel regimen. Of children in the program, most (68/88, 77%) had a diagnosis of meningomyelocoele. At 1 year, the proportion of patients who were bowel accident free improved to 46% (vs 22% initially, P = 0.0007). CONCLUSIONS: A standardized bowel management protocol, primarily the use of suppositories and trans-anal irrigation to achieve social continence, as well as frequent telephone follow-up, can reduce bowel incontinence in children and adolescents with SB.

Intestinal Guanylate Cyclase-C mRNA Expression in Duodenum and Colon of Children.

OBJECTIVES: Guanylate cyclase-C (GC-C) agonists, which increase intestinal secretion and accelerate transit, are used to treat chronic constipation and constipation-predominant irritable bowel syndrome and are being evaluated for pediatric use. Prior studies suggest GC-C receptor density may be higher in young children, potentially amplifying GC-C agonism with treatment implications. We aimed to quantitate duodenal and colonic GC-C mRNA expression in children. METHODS: Mucosal biopsies were obtained from subjects aged 6 months to 18 years during clinically indicated upper, that is, esophago-gastro-duodenal, and/or colonic endoscopy. Tissue samples without histologic abnormalities were grouped by subject age (<24 months, 24 months to <6 years, 6 to <12 years, and 12 to <18 years) and analyzed for GC-C mRNA expression by qPCR. The relationship between GC-C mRNA levels and age was modeled using regression analyses. RESULTS: Ninety-nine subjects underwent upper endoscopy/colonoscopy; 93 had evaluable samples. Mean relative GC-C mRNA expression was 2.36 (range 2.21-2.46) for duodenal samples and 1.56 (range 1.22-1.91) for colonic samples. Predicted and observed normalized GC-C mRNA expression in each region were comparable among age groups. Pooled expression by region demonstrated lower expression in colonic versus duodenal samples. CONCLUSIONS: Uniform levels of GC-C mRNA expression were detected in children aged >6 months in the duodenum and >12 months in the colon. Higher expression was observed in all age groups in duodenal versus colonic samples, indicating regional variability in GC-C receptor density. These data are reassuring for further studies of GC-C agonists in children.

Universal Recommendations for the Management of Acute Diarrhea in Nonmalnourished Children.

OBJECTIVE: Despite a substantial consistency in recommendations for the management of children with acute gastroenteritis (AGE), a high variability in clinical practice and a high rate of inappropriate medical interventions persist in both developing and developed countries.The aim of this study was to develop a set of clinical recommendations for the management of nonseverely malnourished children with AGE to be applied worldwide. METHODS: The Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition (FISPGHAN) Working Group (WG) selected care protocols on the management of acute diarrhea in infants and children aged between 1 month and 18 years. The WG used a 3-step approach consisting of: systematic review and comparison of published guidelines, agreement on draft recommendations using Delphi methodology, and external peer-review and validation of recommendations. RESULTS: A core of recommendations including definition, diagnosis, nutritional management, and active treatment of AGE was developed with an overall agreement of 91% (range 80%-96%). A total of 28 world experts in pediatric gastroenterology and emergency medicine successively validated the set of 23 recommendations with an agreement of 87% (range 83%-95%). Recommendations on the use of antidiarrheal drugs and antiemetics received the lowest level of agreement and need to be tailored at local level. Oral rehydration and probiotics were the only treatments recommended. CONCLUSIONS: Universal recommendations to assist health care practitioners in managing children with AGE may improve practitioners' compliance with guidelines, reduce inappropriate interventions, and significantly impact clinical outcome and health care-associated costs.

Risk Categorization Predicts Disability in Pain-associated Functional Gastrointestinal Disorders After 6 Months.

INTRODUCTION: For a large portion of youth, pain-associated functional gastrointestinal disorders (FGIDs) are associated with significant impairment over time. Clinically feasible methods to categorize youth with FGIDs at greatest risk for persistent pain-related impairment have not yet been identified. METHODS: Measures of functional disability, pain intensity, and anxiety were collected on 99 patients with FGIDs (ages 8-18) during a visit to a pediatric gastroenterology office to assess for the presence of risk. Follow-up data were obtained on a subset of this sample (n = 64) after 6 months, either in person or via mail. The present study examined whether a greater number of risk factors at baseline predicted greater pain-related disability at follow-up. RESULTS: Patients were divided into 4 groups based on number of risk factors present at the initial assessment: 0 (18.2%), 1 (24.2%), 2 (26.3%), and 3 (31.3%). The presence of 2 or 3 risk factors significantly predicted greater disability at follow-up compared to those with 0 risk factors (R = 0.311) and those with just 1 risk factor (Cohen's d values of -1.07 and -1.44, respectively). DISCUSSION: A simple approach to risk categorization can identify youth with FGIDs who are most likely to report increased levels of pain-related impairment over time. These findings have important clinical implications that support the utility of a brief screening process during medical care to inform referral for targeted treatment approaches to FGIDs.

Single-dose Live Oral Cholera Vaccine CVD 103-HgR Protects Against Human Experimental Infection With Vibrio cholerae O1 El Tor.

BACKGROUND: No licensed cholera vaccine is presently available in the United States. Cholera vaccines available in other countries require 2 spaced doses. A single-dose cholera vaccine that can rapidly protect short-notice travelers to high-risk areas and help control explosive outbreaks where logistics render 2-dose immunization regimens impractical would be a major advance.PXVX0200, based on live attenuated Vibrio cholerae O1 classical Inaba vaccine strain CVD 103-HgR, elicits seroconversion of vibriocidal antibodies (a correlate of protection) within 10 days of a single oral dose. We investigated the protection conferred by this vaccine in a human cholera challenge model. METHODS: Consenting healthy adult volunteers, 18-45 years old, were randomly allocated 1:1 to receive 1 oral dose of vaccine (approximately 5 × 10(8) colony-forming units [CFU]) or placebo in double-blind fashion. Volunteers ingested approximately 1 × 10(5) CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961 10 days or 3 months after vaccination and were observed on an inpatient research ward for stool output measurement and management of hydration. RESULTS: The vaccine was well tolerated, with no difference in adverse event frequency among 95 vaccinees vs 102 placebo recipients. The primary endpoint, moderate (≥3.0 L) to severe (≥5.0 L) diarrheal purge, occurred in 39 of 66 (59.1%) placebo controls but only 2 of 35 (5.7%) vaccinees at 10 days (vaccine efficacy, 90.3%; P < .0001) and 4 of 33 (12.1%) vaccinees at 3 months (vaccine efficacy, 79.5%; P < .0001). CONCLUSIONS: The significant vaccine efficacy documented 10 days and 3 months after 1 oral dose of PXVX0200 supports further development as a single-dose cholera vaccine. CLINICAL TRIALS REGISTRATION: NCT01895855.

Comparison of Recommendations in Clinical Practice Guidelines for Acute Gastroenteritis in Children.

OBJECTIVE: Acute gastroenteritis (AGE) is a major cause of child mortality and morbidity. This study aimed at systematically reviewing clinical practice guidelines (CPGs) on AGE to compare recommendations and provide the basis for developing single universal guidelines. METHODS: CPGs were identified by searching MEDLINE, Cochrane-Library, National Guideline Clearinghouse and Web sites of relevant societies/organizations producing and/or endorsing CPGs. RESULTS: The definition of AGE varies among the 15 CPGs identified. The parameters most frequently recommended to assess dehydration are skin turgor and sunken eyes (11/15, 73.3%), general appearance (11/15, 66.6%), capillary refill time, and mucous membranes appearance (9/15, 60%). Oral rehydration solution is universally recognized as first-line treatment. The majority of CPGs recommend hypo-osmolar (Na 45-60 mmol/L, 11/15, 66.6 %) or low-osmolality (Na 75 mmol/L, 9/15, 60%) solutions. In children who fail oral rehydration, most CPGs suggest intravenous rehydration (66.6%). However, nasogastric tube insertion for fluid administration is preferred according by 5/15 CPGs (33.3%). Changes in diet and withdrawal of food are discouraged by all CPGs, and early refeeding is strongly recommended in 13 of 15 (86.7%). Zinc is recommended as an adjunct to ORS by 10 of 15 (66.6%) CPGs, most of them from low-income countries. Probiotics are considered by 9 of 15 (60%) CPGs, 5 from high-income countries. Antiemetics are not recommended in 9 of 15 (60%) CPGs. Routine use of antibiotics is discouraged. CONCLUSIONS: Key recommendations for the management of AGE in children are similar in CPGs. Together with accurate review of evidence-base this may represent a starting point for developing universal recommendations for the management of children with AGE worldwide.

Required and Elective Experiences During the 4th Year: An Analysis of ACGME Accredited Psychiatry Residency Program Websites.

OBJECTIVE: The objective of this study was to assess and describe required and elective components of the 4th post-graduate year (PGY4) in psychiatry residency programs. METHODS: We reviewed the websites of all 193 2014-2015 ACGME accredited psychiatry residency programs for content describing the specific components of the PGY4 year. RESULTS: Nearly all residency programs (99 %) had some form of required experiences during the PGY4 year. Ninety-four percent had clinical requirements for PGY4 residents, with longitudinal outpatient clinic being the most common (77 %). All programs offered some elective time during PGY4, but the amount of time ranged from 2 months to 100 %. CONCLUSION: Virtually all residency programs include some requirements in the 4th year (most commonly didactics and outpatient clinic) in addition to a broad array of elective experiences. Although 3 years may suffice for residents to complete ACGME requirements, a variety of factors may motivate programs to include required 4th year curricula. Future studies should explore the rationales for and possible benefits of programmatic requirements throughout 4 versus only 3 years of psychiatric training.

CNS, lung, and lymph node involvement in Gaucher disease type 3 after 11 years of therapy: clinical, histopathologic, and biochemical findings.

A Caucasian male with Gaucher disease type 3, treated with continuous enzyme therapy (ET) for 11 years, experienced progressive mesenteric and retroperitoneal lymphadenopathy, lung disease, and neurological involvement leading to death at an age of 12.5 years. Autopsy showed significant pathology of the brain, lymph nodes, and lungs. Liver and spleen glucosylceramide (GluCer) and glucosylsphingosine (GluS) levels were nearly normal and storage cells were cleared. Clusters of macrophages and very elevated GluCer and GluS levels were in the lungs, and brain parenchymal and perivascular regions. Compared to normal brain GluCer (GC 18:0), GluCer species with long fatty acid acyl chains were increased in the patient's brain. This profile was similar to that in the patient's lungs, suggesting that these lipids were present in brain perivascular macrophages. In the patient's brain, generalized astrogliosis, and enhanced LC3, ubiquitin, and Tau signals were identified in the regions surrounding macrophage clusters, indicating proinflammation, altered autophagy, and neurodegeneration. These findings highlight the altered phenotypes resulting from increased longevity due to ET, as well as those in poorly accessible compartments of brain and lung, which manifested progressive disease involvement despite ET.

Current Issues in Transitioning from Pediatric to Adult-Based Care for Youth with Chronic Health Care Needs.

For over 25 years, with medical advances increasing the lifespan of YYASHCN, we have been aware of the need to improve health care transition to adult-based care services. Barriers to health care transition have been identified and in a number of settings, recognition of the problem and preliminary success has been achieved for pilot programs. Evidence-based solutions to improve health care transition for YYASHCN are needed. There are barriers at the patient, family, pediatric, and adult provider, and insurance system levels that must be overcome.

Concordant parent-child reports of anxiety predict impairment in youth with functional abdominal pain.

BACKGROUND: Functional abdominal pain (FAP) is associated with significant anxiety and impairment. Prior investigations of child anxiety in youth with FAP are generally limited by small sample sizes, based on child report, and use lengthy diagnostic tools. It is unknown whether a brief anxiety-screening tool is feasible, whether parent and child reports of anxiety are congruent, and whether parent and child agreement of child anxiety corresponds to increased impairment. The purpose of this investigation was to examine anxiety characteristics in youth with FAP using parent and child reports. Parent-child agreement of child anxiety symptoms was examined in relation to pain and disability. METHODS: One hundred patients with FAP (8-18 years of age) recruited from pediatric gastroenterology clinics completed measures of pain intensity (Numeric Rating Scale) and disability (Functional Disability Inventory). Patients and caregivers both completed a measure of child anxiety characteristics (Screen for Child Anxiety and Related Disorders). RESULTS: Clinically significant anxiety symptoms were more commonly reported by youth (54%) than their parents (30%). Panic/somatic symptoms, generalized anxiety, and separation anxiety were most commonly endorsed by patients, whereas generalized anxiety, separation anxiety, and school avoidance were most commonly reported by parents. The majority (65%) of parents and children agreed on the presence (26%) or absence (39%) of clinically significant anxiety. Parent-child agreement of clinically significant anxiety was related to increased impairment. CONCLUSIONS: A brief screening instrument of parent and child reports of anxiety can provide clinically relevant information for comprehensive treatment planning in children with FAP.

Impact of the information age on residency training: communication, access to public information, and clinical care.

Access to technology in practice helps physicians manage information, communicate, and research topics; however, those in training receive almost no formal preparation for integrating web-based technologies into practice. One reason for this is that many faculty-aside from junior faculty or those in recent generations-did not grow up using Internet communication, may use it minimally, if at all, in their own practices, and may know little about its forms and varieties. This report presents a case to illustrate how these disparities may play out in the supervisory situation and makes suggestions about helping supervisors integrate technology-awareness into their teaching.

Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate.

BACKGROUND & AIMS: Linaclotide is a minimally absorbed agonist of guanylate cyclase-C (GUCY2C or GC-C) that reduces symptoms associated with irritable bowel syndrome with constipation (IBS-C). Little is known about the mechanism by which linaclotide reduces abdominal pain in patients with IBS-C. METHODS: We determined the effects of linaclotide on colonic sensory afferents in healthy mice and those with chronic visceral hypersensitivity. We assessed pain transmission by measuring activation of dorsal horn neurons in the spinal cord in response to noxious colorectal distention. Levels of Gucy2c messenger RNA were measured in tissues from mice using quantitative reverse transcription polymerase chain reaction and in situ hybridization. We used human intestinal cell lines to measure release of cyclic guanosine-3',5'-monophosphate (cGMP) by linaclotide. We performed a post-hoc analysis of data from a phase III, double-blind, parallel-group study in which 805 patients with IBS-C were randomly assigned to groups given an oral placebo or 290 µg linaclotide once daily for 26 weeks. We quantified changes in IBS-C symptoms, including abdominal pain. RESULTS: In mice, linaclotide inhibited colonic nociceptors with greater efficacy during chronic visceral hypersensitivity. Intra-colonic administration of linaclotide reduced signaling of noxious colorectal distention to the spinal cord. The colonic mucosa, but not neurons, was found to express linaclotide's target, GC-C. The downstream effector of GC-C, cGMP, was released after administration of linaclotide and also inhibited nociceptors. The effects of linaclotide were lost in Gucy2c(-/-) mice and prevented by inhibiting cGMP transporters or removing the mucosa. During 26 weeks of linaclotide administration, a significantly greater percentage of patients (70%) had at least a 30% reduction in abdominal pain compared with patients given placebo (50%). CONCLUSIONS: We have identified an analgesic mechanism of linaclotide: it activates GC-C expressed on mucosal epithelial cells, resulting in the production and release of cGMP. This extracellular cGMP acts on and inhibits nociceptors, thereby reducing nociception. We also found that linaclotide reduces chronic abdominal pain in patients with IBS-C.

Fecal microbiota transplantation for Clostridium difficile infection: benefits and barriers.

PURPOSE OF REVIEW: The incidence and severity of Clostridium difficile infection (CDI) have increased worldwide in the past two decades. A principal function of the gut microbiota is to protect the intestine against colonization by exogenous pathogens. Increasingly, the gut microbiota have been shown to influence susceptibility to other genetic and environmentally acquired conditions. Transplantation of healthy donor fecal material in patients with CDI may re-establish the normal composition of the gut microbiota and has been shown to be effective in recurrent CDI. We intend to review the most recent data on fecal microbiota transplantation (FMT) and critically discuss potential advantages and handicaps of this new therapeutic approach. RECENT FINDINGS: Evidence from case series and only one randomized clinical trial suggests that FMT is able to restore the wide diversity of microflora, improve C. difficile-related symptoms and prevent CDI recurrence. SUMMARY: FMT is a promising treatment option for serious and recurrent CDI, and current evidence (although weak) demonstrates consistent and excellent efficacy in clinical outcomes. However, many questions should be answered before it may be recommended as routine standard treatment. Mechanisms of action need to be better understood. Long-term follow-up studies are needed to determine long-lasting effects (including the association with autoimmune diseases).