Diet management in congenital diarrheas and enteropathies - general concepts and disease-specific approach, a narrative review.

Congenital diarrheas and enteropathies (CODE) are a group of rare, heterogenous, monogenic disorders that lead to chronic diarrhea in infancy. Definitive treatment is rarely available, and supportive treatment is the mainstay. Nutritional management in the form of either specialized formulas, restrictive diet, or parenteral nutrition support in CODE with poor enteral tolerance is the cornerstone of CODE treatment and long-term growth. The evidence to support the use of specific diet regimens and nutritional approaches in most CODE disorders is limited due to the rarity of these diseases and the scant published clinical experience. The goal of this review was to create a comprehensive guide for nutritional management in CODE, based on the currently available literature, disease mechanism, and the PediCODE group experience. Enteral diet management in CODE can be divided into 3 distinct conceptual frameworks: nutrient elimination, nutrient supplementation, and generalized nutrient restriction. Response to nutrient elimination or supplementation can lead to resolution or significant improvement in the chronic diarrhea of CODE and resumption of normal growth. This pattern can be seen in CODE due to carbohydrate malabsorption, defects in fat absorption, and occasionally in electrolyte transport defects. In contrast, general diet restriction is mainly supportive. However, occasionally it allows parenteral nutrition weaning or reduction over time, mainly in enteroendocrine defects and rarely in epithelial trafficking and polarity defects. Further research is required to better elucidate the role of diet in the treatment of CODE and the appropriate diet management for each disease.

Effects of Anterior Fundoplication on Postoperative Dysphagia and Reflux After Laparoscopic Esophagocardiomyotomy for Pediatric Achalasia.

Introduction: Achalasia among children often fails endoscopic management (e.g., dilation, botulinum toxin). Laparoscopic esophagocardiomyotomy (L-ECM) is a standard intervention to relieve obstruction but can induce gastroesophageal reflux (GER). Concurrent anterior fundoplication (A-fundo) has been evaluated in randomized trials among adults, demonstrating mixed results on controlling postoperative GER without exacerbating dysphagia. Furthermore, evidence for the best approach among children remains sparse. We hypothesized that, among children undergoing L-ECM without mucosal violation, routine A-fundo would not improve postoperative GER control while exacerbating dysphagia. Materials and Methods: Observational data of 47 consecutive achalasia patients ≤18 years who received L-ECM (2002-2023) at a single academic institution were collected. Patient records were culled for demographics, achalasia characteristics, and outcomes. Two L-ECM groups were identified: with or without A-fundo. Patients were screened for postoperative dysphagia (additional procedures) and GER (new antireflux medications). Univariate independence testing was conducted to identify statistically significant variables. Results: Among 47 patients undergoing L-ECM, 28 (59.6%) received concurrent A-fundo. Compared with patients undergoing L-ECM alone, patients with L-ECM/A-fundo had significantly longer hospital stays (P < .01) without statistically different rates of postoperative dysphagia (P = .81) or GER (P = .51). Five children (10.6%) experienced mucosal injury with L-ECM: 4 recognized intraoperatively received A-Fundo without subsequent leak; 1 mucosal injury was missed and did not receive A-Fundo, which subsequently leaked. Conclusion: In this largest observation of pediatric achalasia patients, A-fundo appeared clinically insignificant when determining contributors to control GER or exacerbate postoperative dysphagia. A-fundo should not be routinely adopted in children having L-ECM for achalasia without further multicenter analysis but appears beneficial in cases having inadvertent mucosal violation.

A human milk oligosaccharide prevents intestinal inflammation in adulthood via modulating gut microbial metabolism.

Observational evidence suggests that human milk oligosaccharides (HMOs) promote the growth of commensal bacteria in early life and adulthood. However, the mechanisms by which HMOs benefit health through modulation of gut microbial homeostasis remain largely unknown. 2'-fucosyllactose (2'-FL) is the most abundant oligosaccharide in human milk and contributes to the essential health benefits associated with human milk consumption. Here, we investigated how 2'-FL prevents colitis in adulthood through its effects on the gut microbial community. We found that the gut microbiota from adult mice that consumed 2'-FL exhibited an increase in abundance of several health-associated genera, including Bifidobacterium and Lactobacillus. The 2'-FL-modulated gut microbial community exerted preventive effects on colitis in adult mice. By using Bifidobacterium infantis as a 2'-FL-consuming bacterial model, exploratory metabolomics revealed novel 2'-FL-enriched secretory metabolites by Bifidobacterium infantis, including pantothenol. Importantly, pantothenate significantly protected the intestinal barrier against oxidative stress and mitigated colitis in adult mice. Furthermore, microbial metabolic pathway analysis identified 26 dysregulated metabolic pathways in fecal microbiota from patients with ulcerative colitis, which were significantly regulated by 2'-FL treatment in adult mice, indicating that 2'-FL has the potential to rectify dysregulated microbial metabolism in colitis. These findings support the contribution of the 2'-FL-shaped gut microbial community and bacterial metabolite production to the protection of intestinal integrity and prevention of intestinal inflammation in adulthood.IMPORTANCEAt present, neither basic research nor clinical studies have revealed the exact biological functions or mechanisms of action of individual oligosaccharides during development or in adulthood. Thus, it remains largely unknown whether human milk oligosaccharides could serve as effective therapeutics for gastrointestinal-related diseases. Results from the present study uncover 2'-FL-driven alterations in bacterial metabolism and identify novel B. infantis-secreted metabolites following the consumption of 2'-FL, including pantothenol. This work further demonstrates a previously unrecognized role of pantothenate in significantly protecting the intestinal barrier against oxidative stress and mitigating colitis in adult mice. Remarkably, 2'-FL-enhanced bacterial metabolic pathways are found to be dysregulated in the fecal microbiota of ulcerative colitis patients. These novel metabolic pathways underlying the bioactivities of 2'-FL may lay a foundation for applying individual oligosaccharides for prophylactic intervention for diseases associated with impaired intestinal homeostasis.

Impact of maternal depression on malnutrition treatment outcomes in older children with sickle cell anemia.

BACKGROUND: Malnutrition and sickle cell anemia (SCA) result in high childhood mortality rates. Although maternal depression is an established risk factor for malnutrition in younger children, little is known about its impact on treatment response in children with malnutrition. We aimed to determine the relationship, if any, between maternal depression scores and malnutrition treatment outcomes in older children with SCA. METHODS: We conducted a planned ancillary study to our randomized controlled feasibility trial for managing severe acute malnutrition in children aged 5-12 with SCA in northern Nigeria (NCT03634488). Mothers of participants completed a depression screen using the Patient Health Questionnaire (PHQ-9).We used a multivariable linear regression model to describe the relationship between the baseline maternal PHQ-9 score and the trial participant's final body mass index (BMI) z-score. RESULTS: Out of 108 mother-child dyads, 101 with maternal baseline PHQ-9 scores were eligible for inclusion in this analysis. At baseline, 25.7% of mothers (26 of 101) screened positive for at least mild depression (PHQ-9 score of 5 or above). The baseline maternal PHQ-9 score was negatively associated with the child's BMI z-score after 12 weeks of malnutrition treatment (ß=-0.045, p = 0.041). CONCLUSIONS: Maternal depressive symptoms has an impact on malnutrition treatment outcomes. Treatment of malnutrition in older children with sickle cell anemia should include screening for maternal depression and, if indicated, appropriate maternal referral for depression evaluation and treatment. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov (#NCT03634488) on January 30, 2018, https://clinicaltrials.gov/study/NCT03634488 .

Identification of a functional peptide of a probiotic bacterium-derived protein for the sustained effect on preventing colitis.

Several probiotic-derived factors have been identified as effectors of probiotics for exerting beneficial effects on the host. However, there is a paucity of studies to elucidate mechanisms of their functions. p40, a secretory protein, is originally isolated from a probiotic bacterium, Lactobacillus rhamnosus GG. Thus, this study aimed to apply structure-functional analysis to define the functional peptide of p40 that modulates the epigenetic program in intestinal epithelial cells for sustained prevention of colitis. In silico analysis revealed that p40 is composed of a signal peptide (1-28 residues) followed by a coiled-coil domain with uncharacterized function on the N-terminus, a linker region, and a ß-sheet domain with high homology to CHAP on the C-terminus. Based on the p40 three-dimensional structure model, two recombinant p40 peptides were generated, p40N120 (28-120 residues) and p40N180 (28-180 residues) that contain first two and first three coiled coils, respectively. Compared to full-length p40 (p40F) and p40N180, p40N120 showed similar or higher effects on up-regulating expression of Setd1b (encoding a methyltransferase), promoting mono- and trimethylation of histone 3 on lysine 4 (H3K4me1/3), and enhancing Tgfb gene expression and protein production that leads to SMAD2 phosphorylation in human colonoids and a mouse colonic epithelial cell line. Furthermore, supplementation with p40F and p40N120 in early life increased H3K4me1, Tgfb expression and differentiation of regulatory T cells (Tregs) in the colon, and mitigated disruption of epithelial barrier and inflammation induced by DSS in adult mice. This study reveals the structural feature of p40 and identifies a functional peptide of p40 that could maintain intestinal homeostasis.

Epidemiology of Maternal Nutritional Status and Risk of Adverse Birth Outcomes in Undernourished Mothers with Sickle Cell Disease: A Systematic Review and Meta-Analysis Protocol.

In pregnancies complicated by sickle cell disease (SCD), the maternal-fetal dyad is at high risk for mortality and morbidity. In healthy pregnancies, maternal nutritional status is a critical factor for the healthy growth and development of the fetus. However, there are no reviews of the current research on the nutritional status of pregnant women with SCD and pregnancy outcomes. First, we aim to assess the burden of malnutrition in pregnant women with SCD. Next, we aim to systematically evaluate if pregnant women with SCD who have poor nutritional status are at increased risk for adverse birth outcomes compared to pregnant women with sickle cell disease and normal nutritional status. We will systematically search multiple electronic databases. Our exposure is pregnant women with SCD and poor nutritional status. The primary outcomes of interest include low birth weight (categorical) and birth weight z-scores (continuous). We will also evaluate maternal and perinatal outcomes as secondary outcomes. We will evaluate the risk of bias and overall certainty of evidence with Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I), and the overall evidence will be assessed using Grading of Recommendation Assessment, Development, and Evaluation (GRADE) criteria. We will pool findings with a meta-analysis if sufficient homogeneity exists among studies. Findings will be published in a peer-reviewed journal and disseminated to SCD advocacy groups. PROSPERO registration number: 429412.

Risk factors in underweight older children with sickle cell anemia: a comparison of low- to high-income countries.

Previously, we demonstrated that older children with sickle cell anemia (SCA) living in Nigeria are at increased risk of death if they are underweight (weight-for-age z score < -1). We now conducted a cross-sectional study in low- and high-income settings to determine the risk factors for being underweight a in children aged 5 to 12 years with SCA. The children from low- and high-income settings were eligible participants for the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria (SPRING; N = 928) and the Silent Cerebral Infarct (SIT, North America/Europe; N = 1093) trials, respectively. The median age in the SPRING and SIT cohorts was 8.1 and 8.5 years, respectively (P < .001). A total of 87.9% (n = 816) of participants in the SPRING trial (low-income) met the study criteria for being underweight (weight-for-age z score < -1), and 22.7% (n = 211) for severely underweight (weight-for-age z score < -3), significantly higher than the SIT (high-income) cohort at 25.7% underweight (n = 281) and 0.7% severely underweight (n = 8; P < .001 for both comparisons). In the combined cohort, older age (odds ratio [OR], 1.24; P < .001) and lower hemoglobin level (OR, 0.67; P < .001) were associated with being underweight. Age and hemoglobin level remained statistically significant in separate models for the SPRING and SIT cohorts. Older age and lower hemoglobin levels in children aged 5 to 12 years with SCA are associated with being underweight in low- and high-income settings.

Pediatric Aerodigestive Medicine: Advancing Collaborative Care for Children With Oropharyngeal Dysphagia.

OBJECTIVES: Aerodigestive disorders encompass various pathological conditions affecting the lungs, upper airway, and gastrointestinal tract in children. While advanced care has primarily occurred in specialty centers, many children first present to general pediatric gastroenterologists with aerodigestive symptoms necessitating awareness of these conditions. At the 2021 Annual North American Society for Pediatric Gastroenterology, Hepatology and Nutrition meeting, the aerodigestive Special Interest Group held a full-day symposium entitled, Pediatric Aerodigestive Medicine: Advancing Collaborative Care of Children with Aerodigestive Disorders. The symposium aimed to underline the significance of a multidisciplinary approach to achieve better outcomes for these complex patients. METHODS: The symposium brought together leading experts to highlight the growing aerodigestive field, promote new scientific and therapeutic strategies, share the structure and benefits of a multidisciplinary approach in diagnosing common and rare aerodigestive disorders, and foster multidisciplinary discussion of complex cases while highlighting the range of therapeutic and diagnostic options. In this article, we showcase the diagnostic and therapeutic approach to oropharyngeal dysphagia (OPD), one of the most common aerodigestive conditions, emphasizing the role of a collaborative model. CONCLUSIONS: The aerodigestive field has made significant progress and continues to grow due to a unique multidisciplinary, collaborative model of care for these conditions. Despite diagnostic and therapeutic challenges, the multidisciplinary approach has enabled and greatly improved efficient, high-quality, and evidence-based care for patients, including those with OPD.

Feasibility trial for the management of severe acute malnutrition in older children with sickle cell anemia in Nigeria.

Children with sickle cell anemia (SCA) living in Nigeria are at an increased risk of malnutrition, which contributes to increased morbidity and mortality. However, evidence-based guidelines for managing malnutrition in children with SCA are lacking. To address this gap, we conducted a multicenter, randomized controlled feasibility trial to assess the feasibility and safety of treating children with SCA aged from 5 to 12 years and having uncomplicated severe acute malnutrition (body mass index z score of <-3.0). Children with SCA and uncomplicated severe acute malnutrition were randomly allocated to receive supplemental ready-to-use therapeutic food (RUTF) with or without moderate-dose hydroxyurea therapy (20 mg/kg per day). Over a 6-month enrollment period, 3190 children aged from 5 to 12 years with SCA were evaluated for eligibility, and 110 of 111 children who were eligible were enrolled. During the 12-week trial, no participants withdrew or missed visits. One participant died of unrelated causes. Adherence was high for hydroxyurea (94%, based on pill counts) and RUTF (100%, based on the number of empty sachets returned). No refeeding syndrome event or hydroxyurea-related myelosuppression occurred. At the end of the trial, the mean change in body mass index z score was 0.49 (standard deviation = 0.53), and 39% of participants improved their body mass index z score to ≥-3.0. Our findings demonstrate the feasibility, safety, and potential of outpatient treatment for uncomplicated severe acute malnutrition in children with SCA aged from 5 to 12 years in a low-resource setting. However, RUTF sharing with household and community members potentially confounded the response to malnutrition treatment. This trial was registered at clinicaltrials.gov as #NCT03634488.

Fecal transplantation for treatment of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic, relapsing disease of the gastrointestinal (GI) tract that is thought to be associated with a complex interplay between the immune system, the GI tract lining, the environment, and the gut microbiome, leading to an abnormal inflammatory response in genetically susceptible individuals. An altered composition of the gut's native microbiota, known as dysbiosis, may have a major role in the pathogenesis of ulcerative colitis (UC) and Crohn disease (CD), two subtypes of IBD. There is growing interest in the correction of this underlying dysbiosis using fecal microbiota transplantation (FMT). OBJECTIVES: To evaluate the benefits and safety profile of FMT for treatment of IBD in adults and children versus autologous FMT, placebo, standard medication, or no intervention. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, two clinical trial registries, and the reference sections of published trials through 22 December 2022. SELECTION CRITERIA: We included randomized controlled trials that studied adults and children with UC or CD. Eligible intervention arms used FMT, defined as the delivery of healthy donor stool containing gut microbiota to a recipient's GI tract, to treat UC or CD. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion. Our primary outcomes were: 1. induction of clinical remission, 2. maintenance of clinical remission, and 3. serious adverse events. Our secondary outcomes were: 4. any adverse events, 5. endoscopic remission, 6. quality of life, 7. clinical response, 8. endoscopic response, 9. withdrawals, 10. inflammatory markers, and 11. microbiome outcomes. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 12 studies with 550 participants. Three studies were conducted in Australia; two in Canada; and one in each of the following: China, the Czech Republic, France, India, the Netherlands, and the USA. One study was conducted in both Israel and Italy. FMT was administered in the form of capsules or suspensions and delivered by mouth, nasoduodenal tube, enema, or colonoscopy. One study delivered FMT by both oral capsules and colonoscopy. Six studies were at overall low risk of bias, while the others had either unclear or high risk of bias. Ten studies with 468 participants, of which nine studies focused on adults and one focused on children, reported induction of clinical remission in people with UC at longest follow-up (range 6 to 12 weeks) and showed that FMT may increase rates of induction of clinical remission in UC compared to control (risk ratio (RR) 1.79, 95% confidence interval (CI) 1.13 to 2.84; low-certainty evidence). Five studies showed that FMT may increase rates of induction of endoscopic remission in UC at longest follow-up (range 8 to 12 weeks); however, the CIs around the summary estimate were wide and included a possible null effect (RR 1.45, 95% CI 0.64 to 3.29; low-certainty evidence). Nine studies with 417 participants showed that FMT may result in little to no difference in rates of any adverse events (RR 0.99, 95% CI 0.85 to 1.16; low-certainty evidence). The evidence was very uncertain about the risk of serious adverse events (RR 1.77, 95% CI 0.88 to 3.55; very low-certainty evidence) and improvement in quality of life (mean difference (MD) 15.34, 95% CI -3.84 to 34.52; very low-certainty evidence) when FMT was used to induce remission in UC. Two studies, of which one also contributed data for induction of remission in active UC, assessed maintenance of remission in people with controlled UC at longest follow-up (range 48 to 56 weeks). The evidence was very uncertain about the use of FMT for maintenance of clinical remission (RR 2.97, 95% CI 0.26 to 34.42; very low-certainty evidence) and endoscopic remission (RR 3.28, 95% CI 0.73 to 14.74; very low-certainty evidence). The evidence was also very uncertain about the risk of serious adverse events, risk of any adverse events, and improvement in quality of life when FMT was used to maintain remission in UC. None of the included studies assessed use of FMT for induction of remission in people with CD. One study with 21 participants reported data on FMT for maintenance of remission in people with CD. The evidence was very uncertain about the use of FMT for maintenance of clinical remission in CD at 24 weeks (RR 1.21, 95% CI 0.36 to 4.14; very low-certainty evidence). The evidence was also very uncertain about the risk of serious or any adverse events when FMT was used to maintain remission in CD. None of the studies reported data on use of FMT for maintenance of endoscopic remission or improvement in quality of life in people with CD. AUTHORS' CONCLUSIONS: FMT may increase the proportion of people with active UC who achieve clinical and endoscopic remission. The evidence was very uncertain about whether use of FMT in people with active UC impacted the risk of serious adverse events or improvement in quality of life. The evidence was also very uncertain about the use of FMT for maintenance of remission in people with UC, as well as induction and maintenance of remission in people with CD, and no conclusive statements could be made in this regard. Further studies are needed to address the beneficial effects and safety profile of FMT in adults and children with active UC and CD, as well as its potential to promote longer-term maintenance of remission in UC and CD.

Fecal microbiota transplantation for the treatment of recurrent Clostridioides difficile (Clostridium difficile).

BACKGROUND: Clostridioides difficile (formerly known as Clostridium difficile) is a bacterium that can cause potentially life-threatening diarrheal illness in individuals with an unhealthy mixture of gut bacteria, known as dysbiosis, and can cause recurrent infections in nearly a third of infected individuals. The traditional treatment of recurrent C difficile infection (rCDI) includes antibiotics, which may further exacerbate dysbiosis. There is growing interest in correcting the underlying dysbiosis in rCDI using of fecal microbiota transplantation (FMT); and there is a need to establish the benefits and harms of FMT for the treatment of rCDI based on data from randomized controlled trials. OBJECTIVES: To evaluate the benefits and harms of donor-based fecal microbiota transplantation for the treatment of recurrent Clostridioides difficile infection in immunocompetent people. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 31 March 2022. SELECTION CRITERIA: We considered randomized trials of adults or children with rCDI for inclusion. Eligible interventions must have met the definition of FMT, which is the administration of fecal material containing distal gut microbiota from a healthy donor to the gastrointestinal tract of a person with rCDI. The comparison group included participants who did not receive FMT and were given placebo, autologous FMT, no intervention, or antibiotics with activity against C difficile. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. proportion of participants with resolution of rCDI and 2. serious adverse events. Our secondary outcomes were 3. treatment failure, 4. all-cause mortality, 5. withdrawal from study, 6. rate of new CDI infection after a successful FMT, 7. any adverse event, 8. quality of life, and 9. colectomy. We used the GRADE criteria to assess certainty of evidence for each outcome. MAIN RESULTS: We included six studies with 320 participants. Two studies were conducted in Denmark, and one each in the Netherlands, Canada, Italy, and the US. Four were single-center and two were multicenter studies. All studies included only adults. Five studies excluded people who were severely immunocompromised, with only one study including 10 participants who were receiving immunosuppressive therapy out of the 64 enrolled; these were similarly distributed between the FMT arm (4/24 or 17%) and comparison arms (6/40 or 15%). The route of administration was the upper gastrointestinal tract via a nasoduodenal tube in one study, two studies used enema only, two used colonoscopic only delivery, and one used either nasojejunal or colonoscopic delivery, depending on a clinical determination of whether the recipient could tolerate a colonoscopy. Five studies had at least one comparison group that received vancomycin. The risk of bias (RoB 2) assessments did not find an overall high risk of bias for any outcome. All six studies assessed the efficacy and safety of FMT for the treatment of rCDI. Pooled results from six studies showed that the use of FMT in immunocompetent participants with rCDI likely leads to a large increase in resolution of rCDI in the FMT group compared to control (risk ratio (RR) 1.92, 95% confidence interval (CI) 1.36 to 2.71; P = 0.02, I2 = 63%; 6 studies, 320 participants; number needed to treat for an additional beneficial outcome (NNTB) 3; moderate-certainty evidence). Fecal microbiota transplantation probably results in a slight reduction in serious adverse events; however, the CIs around the summary estimate were wide (RR 0.73, 95% CI 0.38 to 1.41; P = 0.24, I² = 26%; 6 studies, 320 participants; NNTB 12; moderate-certainty evidence). Fecal microbiota transplantation may result in a reduction in all-cause mortality; however, the number of events was small, and the CIs of the summary estimate were wide (RR 0.57, 95% CI 0.22 to 1.45; P = 0.48, I2 = 0%; 6 studies, 320 participants; NNTB 20; low-certainty evidence). None of the included studies reported colectomy rates. AUTHORS' CONCLUSIONS: In immunocompetent adults with rCDI, FMT likely leads to a large increase in the resolution of recurrent Clostridioides difficile infection compared to alternative treatments such as antibiotics. There was no conclusive evidence regarding the safety of FMT for the treatment of rCDI as the number of events was small for serious adverse events and all-cause mortality. Additional data from large national registry databases might be required to assess any short-term or long-term risks with using FMT for the treatment of rCDI. Elimination of the single study that included some immunocompromised people did not alter these conclusions. Due to the low number of immunocompromised participants enrolled, conclusions cannot be drawn about the risks or benefits of FMT for rCDI in the immunocompromised population.

Underweight children older than 5 years with sickle cell anemia are at risk for early mortality in a low-resource setting.

Undernutrition is a risk factor for under-5 mortality and is also postulated to be a risk factor for mortality in older children and adults with sickle cell anemia (SCA). We tested the hypothesis that underweight is associated with mortality in children aged 5 to 12 years with SCA. We performed a secondary analysis of participants in the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria trial, a double-blind, parallel-group randomized controlled trial for low-dose or moderate-dose hydroxyurea in children with abnormal transcranial Doppler velocities and a comparison group of participants with nonelevated transcranial Doppler velocities in northern Nigeria. Nutritional status was classified as underweight (weight-for-age z score), stunting (height-for-age z score), and wasting (body mass index z score) using the World Health Organization growth reference. The mean weight-for-age z score was lower in children who died during the study than in those who survived. Otherwise, the baseline characteristics of children who died during the study were not significantly different from those of the children who survived. A pooled analysis of participants demonstrated that a lower weight-for-age z score was associated with an increased hazard of death. Underweight participants (weight-for-age z score <-1) had a greater probability of death during follow-up than those who were not underweight. Underweight status in school-aged children with SCA is a previously unrecognized risk factor for early mortality in Nigeria and can be easily applied to screen children at risk for death. This trial was registered at www.clinicaltrials.gov as #NCT02560935.

Multichannel magnetogastrogram: a clinical marker for pediatric chronic nausea.

Chronic nausea is a widespread functional disease in children with numerous comorbidities. High-resolution electrogastrogram (HR-EGG) has shown sufficient sensitivity as a noninvasive clinical marker to objectively detect distinct gastric slow wave properties in children with functional nausea. We hypothesized that the increased precision of magnetogastrogram (MGG) slow wave recordings could provide supplementary information not evident on HR-EGG. We evaluated simultaneous pre- and postprandial MGG and HR-EGG recordings in pediatric patients with chronic nausea and healthy asymptomatic subjects, while also measuring nausea intensity and nausea severity. We found significant reductions in postprandial dominant frequency and normogastric power, and higher levels of postprandial bradygastric power in patients with nausea in both MGG and HR-EGG. MGG also detected significantly lower preprandial normogastric power in patients. A significant difference in the mean preprandial gastric slow wave propagation direction was observed in patients as compared with controls in both MGG (control: 180 ± 61°, patient: 34 ±72°; P < 0.05) and HR-EGG (control: 240 ± 39°, patient: 180 ± 46°; P < 0.05). Patients also showed a significant change in the mean slow wave direction between pre- and postprandial periods in MGG (P < 0.05). No statistical differences were observed in propagation speed between healthy subjects and patients in either MGG or HR-EGG pre/postprandial periods. The use of MGG and/or HR-EGG represents an opportunity to assess noninvasively the effects of chronic nausea on gastric slow wave activity. MGG data may offer the opportunity for further refinement of the more portable and economical HR-EGG in future machine-learning approaches for functional nausea.NEW & NOTEWORTHY Pediatric chronic nausea is a difficult-to-measure subjective complaint that requires objective diagnosis, clinical assessment, and individualized treatment plans. Our study demonstrates that multichannel MGG used in conjunction with custom HR-EGG detects key pathological signatures of functional nausea in children. This quantifiable measure may allow more personalized diagnosis and treatment in addition to minimizing the cost and potential radiation associated with current diagnostic approaches.

Sex Moderates the Relationship Between Nausea Severity and Heart Rate Variability in Adolescents and Young Adults.

BACKGROUND: Nausea is a common complaint among children and is particularly prevalent in children with functional abdominal pain (FAP), with nearly half of children with FAP also endorsing nausea. Dysfunction of the autonomic nervous system, which can be indexed by heart rate variability (HRV), leads to abnormalities in gastric electrical activity that are associated with GI symptoms. AIMS: To evaluate that relationship between nausea severity and HRV in adolescents and young adults with a history of FAP and to assess for sex differences. METHODS: Participants were pediatric patients with a diagnosis of FAP who were recruited from a pediatric GI clinic between 1993 and 2007 for a prospective study of the course of FAP. Study analyses focused on the cross-sectional relationship between HRV, indexed by standard deviation of the R-R interval (SDRRI) and high-frequency (HF) power, and nausea severity collected during a follow-up visit in late adolescence and young adulthood. RESULTS: Controlling for age and BMI, a significant nausea by sex interaction emerged for both SDRRI and HF power. Tests of conditional effects of nausea by sex showed that the inverse relation between nausea severity and both SDRRI and HF was significant for females but not for males. CONCLUSIONS: This is the first study to evaluate the relationship between nausea severity and HRV. Greater nausea severity was associated with lower HRV in females but not in males. Further validation of these results may provide insight into novel treatment approaches for females with nausea that target vagal tone.

Automated Machine Learning Pipeline Framework for Classification of Pediatric Functional Nausea Using High-Resolution Electrogastrogram.

OBJECTIVE: Pediatric functional nausea is challenging for patients to manage and for clinicians to treat since it lacks objective diagnosis and assessment. A data-driven non-invasive diagnostic screening tool that distinguishes the electro-pathophysiology of pediatric functional nausea from healthy controls would be an invaluable aid to support clinical decision-making in diagnosis and management of patient treatment methodology. The purpose of this paper is to present an innovative approach for objectively classifying pediatric functional nausea using cutaneous high-resolution electrogastrogram data. METHODS: We present an Automated Electrogastrogram Data Analytics Pipeline framework and demonstrate its use in a 3x8 factorial design to identify an optimal classification model according to a defined objective function. Low-fidelity synthetic high-resolution electrogastrogram data were generated to validate outputs and determine SOBI-ICA noise reduction effectiveness. RESULTS: A 10 parameter support vector machine binary classifier with a radial basis function kernel was selected as the overall top-performing model from a pool of over 1000 alternatives via maximization of an objective function. This resulted in a 91.6% test ROC AUC score. CONCLUSION: Using an automated machine learning pipeline approach to process high-resolution electrogastrogram data allows for clinically significant objective classification of pediatric functional nausea. SIGNIFICANCE: To our knowledge, this is the first study to demonstrate clinically significant performance in the objective classification of pediatric nausea patients from healthy control subjects using experimental high-resolution electrogastrogram data. These results indicate a promising potential for high-resolution electrogastrography to serve as a data-driven screening tool for the objective diagnosis of pediatric functional nausea.

Development and Validation of Web-Based Tool to Predict Lamina Propria Fibrosis in Eosinophilic Esophagitis.

INTRODUCTION: Approximately half of esophageal biopsies from patients with eosinophilic esophagitis (EoE) contain inadequate lamina propria, making it impossible to determine the lamina propria fibrosis (LPF). This study aimed to develop and validate a web-based tool to predict LPF in esophageal biopsies with inadequate lamina propria. METHODS: Prospectively collected demographic and clinical data and scores for 7 relevant EoE histology scoring system epithelial features from patients with EoE participating in the Consortium of Eosinophilic Gastrointestinal Disease Researchers observational study were used to build the models. Using the least absolute shrinkage and selection operator method, variables strongly associated with LPF were identified. Logistic regression was used to develop models to predict grade and stage of LPF. The grade model was validated using an independent data set. RESULTS: Of 284 patients in the discovery data set, median age (quartiles) was 16 (8-31) years, 68.7% were male patients, and 93.4% were White. Age of the patient, basal zone hyperplasia, dyskeratotic epithelial cells, and surface epithelial alteration were associated with presence of LPF. The area under the receiver operating characteristic curve for the grade model was 0.84 (95% confidence interval: 0.80-0.89) and for stage model was 0.79 (95% confidence interval: 0.74-0.84). Our grade model had 82% accuracy in predicting the presence of LPF in an external validation data set. DISCUSSION: We developed parsimonious models (grade and stage) to predict presence of LPF in esophageal biopsies with inadequate lamina propria and validated our grade model. Our predictive models can be easily used in the clinical setting to include LPF in clinical decisions and determine its effect on treatment outcomes.

Clinical Hypnosis in Pediatric Crohn's Disease: A Randomized Controlled Pilot Study.

OBJECTIVE: The aim of this study was to implement clinical hypnosis (CH) as an adjunctive therapy for adolescents with Crohn's disease (CD) and to assess the impact of CH on quality of life (QoL), abdominal pain, psychosocial measures, and disease activity compared with standard care. METHODS: Forty adolescents with CD were randomized to a hypnosis intervention (HI) or waitlist control (WC) group. The intervention consisted of 1 in-person CH session, self-hypnosis education, and recordings for home practice. Data was collected at baseline, after the 8-week intervention, and at week 16. The primary outcome was patient- and parent-reported QoL; secondary outcomes were patient-reported abdominal pain, depression, anxiety, and sleep; school absences; and disease activity by Pediatric Crohn's Disease Activity Index. Paired and independent t-tests were used to compare differences from baseline to postintervention within and between groups. RESULTS: Forty patients (50% girls, mean 15.8 years) were enrolled from February to May 2019. Seventy-eight percent had inactive disease, and 55% had abdominal pain. Post intervention, significant improvements were noted in HI parent-reported QoL compared with WC in total score (P = 0.05), social functioning (P = 0.01), and school functioning (P = 0.04) but patient-reported QoL was unchanged. Abdominal pain severity significantly improved in HI compared with WC (P = 0.03). School absences decreased in significantly more intervention than control patients (P = 0.01). Patients who practiced self-hypnosis consistently showed a trend toward greater QoL improvement than those who did not (P = 0.1). CONCLUSIONS: CH is an acceptable and feasible adjunct in CD and may improve psychosocial QoL and abdominal pain. Further research is warranted.

Exposure to p40 in Early Life Prevents Intestinal Inflammation in Adulthood Through Inducing a Long-Lasting Epigenetic Imprint on TGFß.

BACKGROUND & AIMS: Colonization by gut microbiota in early life confers beneficial effects on immunity throughout the host's lifespan. We sought to elucidate the mechanisms whereby neonatal supplementation with p40, a probiotic functional factor, reprograms intestinal epithelial cells for protection against adult-onset intestinal inflammation. METHODS: p40 was used to treat young adult mouse colonic (YAMC) epithelial cells with and without deletion of a methyltransferase, su(var)3-9, enhancer-of-zeste and trithorax domain-containing 1ß (Setd1ß), and mice in early life or in adulthood. Anti-transforming growth factor ß (TGFß)-neutralizing antibodies were administered to adult mice with and without colitis induced by 2,4,6-trinitrobenzenesulfonic acid or dextran sulfate sodium. We examined Setd1b and Tgfb gene expression, TGFß production, monomethylation and trimethylation of histone H3 on the lysine 4 residue (H3K4me1/3), H3K4me3 enrichment in Tgfb promoter, differentiation of regulatory T cells (Tregs), and the inflammatory status. RESULTS: p40 up-regulated expression of Setd1b in YAMC cells. Accordingly, p40 enhanced H3K4me1/3 in YAMC cells in a Setd1ß-dependent manner. p40-regulated Setd1ß mediated programming the TGFß locus into a transcriptionally permissive chromatin state and promoting TGFß production in YAMC. Furthermore, transient exposure to p40 during the neonatal period and in adulthood resulted in the immediate increase in Tgfb gene expression. However, only neonatal p40 supplementation induced the sustained H3K4me1/3 and Tgfb gene expression that persisted into adulthood. Interfering with TGFß function by neutralizing antibodies diminished the long-lasting effects of neonatal p40 supplementation on differentiation of Tregs and protection against colitis in adult mice. CONCLUSIONS: Exposure to p40 in early life enables an epigenetic imprint on TGFß, leading to long-lasting production of TGFß by intestinal epithelial cells to expand Tregs and protect the gut against inflammation.