Anti-infliximab antibodies and low infliximab levels correlate with drug discontinuation in pediatric inflammatory bowel disease.

BACKGROUND: Infliximab (IFX) use is limited by loss of response often due to the development of anti-IFX antibodies and low drug levels. METHODS: We performed a single center prospective observational cohort study of pediatric and young adult subjects with inflammatory bowel disease (IBD) on IFX with over 3 years of follow-up. Infliximab levels (IFXL) and antibodies to infliximab (ATI) were measured throughout the study. Subjects were followed until IFX was discontinued. RESULTS: We enrolled 219 subjects with IBD (184: Crohn's disease; 33: Ulcerative colitis; and 2 Indeterminant colitis; 84 female, median age 14.4 years, 37% on concomitant immunomodulator). Nine hundred and nineteen serum samples (mean 4.2 ± 2.1 per patient) were tested for IFXL and ATI. During the study, 31 (14%) subjects discontinued IFX. Sixty patients had ATI. Twenty-two of those 60 patients with ATI discontinued IFX; 14 of 31 patients who discontinued IFX had detectable ATI at study onset. The combination of ATI and IFXL < 5 µg/mL at study entry was associated with the highest risk of drug discontinuation (hazard ratios [HR] ATI 4.27 [p < 0.001] and IFXL < 5 µg/mL [HR]: 3.2 p = 0.001). Patients with IFXL 5-10 µg/mL had the lowest rate of discontinuation (6%). IFX dose escalation eliminated ATI in 21 of 60 subjects. CONCLUSIONS: ATI is a strong predictor of needing to stop IFX use and inversely correlates with IFXL. Detection of ATI during therapeutic drug monitoring postinduction but also periodically during maintenance therapy identifies individuals who may benefit from IFX dose escalation and/or the addition of an immunomodulator, as these interventions may reduce or eliminate ATI.

Comparing Gastrointestinal Endoscopy Findings in Children with Autism, Developmental Delay, or Typical Development.

OBJECTIVE: To compare endoscopic and histologic upper endoscopy (esophagogastroduodenoscopy [EGD]) findings in children with autism spectrum disorders (ASD) to age- and gender-matched controls with developmental delay (DD) or with typical development (TD). METHODS: Retrospective, cross-sectional study of children undergoing EGD, identifying those diagnosed with ASD, and matching on age and gender to children with DD or TD in ratio of 1:1:2. Rates of EGD findings were compared between the 3 groups using χ² or Fisher exact test. Multivariable linear regression was performed to identify predictors of abnormal histology. RESULTS: A total of 2104 patients were included (526 ASD; 526 DD; 1052 TD). Children with ASD had higher rates of abnormal esophageal histology (ASD 38.4%; DD 33.4%; TD 30.4%, P = .008), particularly esophagitis. In multivariable modeling, ASD diagnosis was an independent predictor of abnormal esophageal histology (OR [95% CI] 1.38 [1.09, 1.76]) compared with TD. Stomach findings did not differ among the groups. In the duodenum, histologic abnormalities were observed with lower frequency in ASD (ASD 17.0%; DD 20.1%; TD 24.2%, P = .005). In multivariable analysis, ASD diagnosis was not a significant predictor (OR 0.78 [0.56, 1.09]) of abnormal duodenal histology. CONCLUSIONS: Children with ASD have higher rates of histologic esophagitis compared with age- and gender-matched DD and TD controls. ASD was a significant independent predictor of abnormal esophageal, but not, duodenal, histology. These results underscore the importance of EGD in children with ASD.

Efficacy and Safety of Anti-Tumor Necrosis Factor Alpha in Very Early Onset Inflammatory Bowel Disease.

BACKGROUND: Very early onset inflammatory bowel disease (VEOIBD) is defined as disease onset in patients younger than 6 years. Challenges in treatment of VEOIBD include lack of approved therapies and increased incidence of monogenic immunodeficiencies. We report on patterns of anti-TNF use, efficacy, and safety in a large cohort of patients with VEOIBD. METHODS: Very early onset inflammatory bowel disease patients receiving care at a single center were prospectively enrolled in a data registry and biorepository starting in 2012. Whole exome sequencing was available to all patients. Clinical data including IBD medication use and response were extracted from the medical record. We examined antitumor necrosis factor (anti-TNF) cumulative exposure and time to failure and evaluated the effect of covariates on anti-TNF failure using Cox proportional hazard regression. RESULTS: In this cohort of 216 VEOIBD patients with median 5.8-year follow-up, 116 (53.7%) were TNF-exposed. Sixty-two TNF-exposed patients (53.4%) received their first dose at younger than 6 years. Cumulative exposure to anti-TNF was 23.6% at 1 year, 38.4% at 3 years, and 43.4% at 5 years after diagnosis. Cumulative exposure was greater in patients with Crohn's disease (P = .0004) and in those diagnosed in 2012 or later (P < .0001). Tumor necrosis factor failure occurred in 50.9% of those exposed. Features predictive of anti-TNF failure included ulcerative colitis/IBD-unclassified (hazard ratio, 1.94; P = .03), stricturing (hazard ratio, 2.20; P = .04), and younger age at diagnosis (hazard ratio, 1.25; P = .01). Adverse events occurred in 22.6% of infliximab-exposed and 14.3% of adalimumab-exposed. CONCLUSIONS: Efficacy and safety of anti-TNFs in VEOIBD is comparable to what has previously been reported in older patients.

Half of VEOIBD patients followed for a median 5.8 years used anti-TNF. Anti-TNF failure occurred in half of those exposed. Stricturing, UC/IBD-U, and younger age at diagnosis were predictors of failure. Adverse events were similar to those reported in older patients.

Virtual 3D femur model to assess femoral version: comparison to the 2D axial slice approach.

BACKGROUND: Quantifying femoral version is crucial in diagnosing femoral version abnormalities and for accurate pre-surgical planning. There are numerous methods for measuring femoral version, however, reliability studies for most of these methods excluded children with hip deformities. OBJECTIVE: To propose a method of measuring femoral version based on a virtual 3D femur model, and systematically compare its reliability to the widely used Murphy's 2D axial slice technique. MATERIALS AND METHODS: We searched our imaging database to identify hip/femur CTs performed on children (<18 years old) with a clinical indication of femoral version measurement (September 2021-August 2022). Exclusion criteria were prior hip surgery, and inadequate image quality or field-of-view. Two blinded radiologists independently measured femoral version using the virtual 3D femur model and Murphy's 2D axial slice method. To assess intrareader variability, we randomly selected 20% of the study sample for re-measurements by the two radiologists >2 weeks later. We analyzed the reliability and correlation of these techniques via intraclass correlation coefficient (ICC), Bland-Altman analysis, and deformity subgroup analysis. RESULTS: Our study sample consisted of 142 femurs from 71 patients (10.6±4.4 years, male=31). Intra- and inter-reader correlations for both techniques were excellent (ICC≥0.91). However, Bland-Altman analysis revealed that the standard deviation (SD) of the absolute difference between the two radiologists for the Murphy method (mean 13.7°) was larger than that of the 3D femur model technique (mean 4.8°), indicating higher reader variability. In femurs with hip flexion deformity, the SD of the absolute difference for the Murphy technique was 17°, compared to 6.5° for the 3D femur model technique. In femurs with apparent coxa valga deformity, the SD of the absolute difference for the Murphy technique was 10.4°, compared to 5.2° for the 3D femur model technique. CONCLUSION: The 3D femur model technique is more reliable than the Murphy's 2D axial slice technique in measuring femoral version, especially in children with hip flexion and apparent coxa valga deformities.

Risk factors for inadequate and excessive gestational weight gain in 25 low- and middle-income countries: An individual-level participant meta-analysis.

BACKGROUND: Many women experience suboptimal gestational weight gain (GWG) in low- and middle-income countries (LMICs), but our understanding of risk factors associated with GWG in these settings is limited. We investigated the relationships between demographic, anthropometric, lifestyle, and clinical factors and GWG in prospectively collected data from LMICs. METHODS AND FINDINGS: We conducted an individual participant-level meta-analysis of risk factors for GWG outcomes among 138,286 pregnant women with singleton pregnancies in 55 studies (27 randomized controlled trials and 28 prospective cohorts from 25 LMICs). Data sources were identified through PubMed, Embase, and Web of Science searches for articles published from January 2000 to March 2019. Titles and abstracts of articles identified in all databases were independently screened by 2 team members according to the following eligibility criteria: following inclusion criteria: (1) GWG data collection took place in an LMIC; (2) the study was a prospective cohort or randomized trial; (3) study participants were pregnant; and (4) the study was not conducted exclusively among human immunodeficiency virus (HIV)-infected women or women with other health conditions that could limit the generalizability of the results. The Institute of Medicine (IOM) body mass index (BMI)-specific guidelines were used to determine the adequacy of GWG, which we calculated as the ratio of the total observed weight gain over the mean recommended weight gain. Study outcomes included severely inadequate GWG (percent adequacy of GWG <70), inadequate GWG (percent adequacy of GWG <90, inclusive of severely inadequate), and excessive GWG (percent adequacy of GWG >125). Multivariable estimates from each study were pooled using fixed-effects meta-analysis. Study-specific regression models for each risk factor included all other demographic risk factors measured in a particular study as potential confounders, as well as BMI, maternal height, pre-pregnancy smoking, and chronic hypertension. Risk factors occurring during pregnancy were further adjusted for receipt of study intervention (if any) and 3-month calendar period. The INTERGROWTH-21st standard was used to define high and low GWG among normal weight women in a sensitivity analysis. The prevalence of inadequate GWG was 54%, while the prevalence of excessive weight gain was 22%. In multivariable models, factors that were associated with a higher risk of inadequate GWG included short maternal stature (<145 cm), tobacco smoking, and HIV infection. A mid-upper arm circumference (MUAC) of ≥28.1 cm was associated with the largest increase in risk for excessive GWG (risk ratio (RR) 3.02, 95% confidence interval (CI) [2.86, 3.19]). The estimated pooled difference in absolute risk between those with MUAC of ≥28.1 cm compared to those with a MUAC of 24 to 28.09 cm was 5.8% (95% CI 3.1% to 8.4%). Higher levels of education and age <20 years were also associated with an increased risk of excessive GWG. Results using the INTERGROWTH-21st standard among normal weight women were similar but attenuated compared to the results using the IOM guidelines among normal weight women. Limitations of the study's methodology include differences in the availability of risk factors and potential confounders measured in each individual dataset; not all risk factors or potential confounders of interest were available across datasets and data on potential confounders collected across studies. CONCLUSIONS: Inadequate GWG is a significant public health concern in LMICs. We identified diverse nutritional, behavioral, and clinical risk factors for inadequate GWG, highlighting the need for integrated approaches to optimizing GWG in LMICs. The prevalence of excessive GWG suggests that attention to the emerging burden of excessive GWG in LMICs is also warranted.

Gastric Intestinal Metaplasia in Children: Natural History and Clinicopathological Correlation.

INTRODUCTION: Gastric intestinal metaplasia (GIM) is defined as the replacement of the normal gastric epithelium by intestinal-type epithelium. GIM is considered a preneoplastic lesion for gastric adenocarcinoma in adults and is found in 25% of Helicobacter pylori ( H pylori ) exposed adults. However, the significance of GIM in pediatric gastric biopsies is still unknown. METHODS: We conducted a retrospective study of children with GIM on gastric biopsies at Boston Children's Hospital between January 2013 and July 2019. Demographic, clinical, endoscopic, and histologic data were collected and compared to age and sex-matched cohort without GIM. Gastric biopsies were reviewed by the study pathologist. GIM was classified as complete/incomplete based on Paneth cell presence or absence and limited/extensive based on its distribution in the antrum or both antrum and corpus. RESULTS: Of 38 patients with GIM, 18 were male (47%), mean age of detection was 12.5 ± 5.05 years (range, 1-18 years). The most common histologic was chronic gastritis (47%). Complete GIM was present in 50% (19/38) and limited GIM was present in 92% (22/24). H pylori was positive in 2 patients. Two patients had persistent GIM on repeat esophagogastroduodenoscopy (2/12). No dysplasia or carcinoma was identified. Proton-pump inhibitor use and chronic gastritis were more common in GIM patients compared to control ( P = 0.02). CONCLUSION: Most children with GIM had low-risk histologic subtype (complete/limited) for gastric cancer; GIM was rarely associated with H pylori gastritis in our cohort. Larger multicenter studies are needed to better understand outcomes and risk factors in children with GIM.

Oral iron supplementation and anaemia in children according to schedule, duration, dose and cosupplementation: a systematic review and meta-analysis of 129 randomised trials.

INTRODUCTION: WHO guidelines on iron supplementation among children call for further research to identify the optimal schedule, duration, dose and cosupplementation regimen. METHODS: A systematic review and meta-analysis of randomised controlled trials was undertaken. Randomised controlled trials providing ≥30 days of oral iron supplementation versus placebo or control to children and adolescents aged <20 years were eligible. Random-effects meta-analysis was used to summarise the potential benefits and harms of iron supplementation. Meta-regression was used to estimate iron effect heterogeneity. RESULTS: 129 trials with 201 intervention arms randomised 34 564 children. Frequent (3-7/week) and intermittent (1-2/week) iron regimens were similarly effective at decreasing anaemia, iron deficiency and iron deficiency anaemia (p heterogeneity >0.05), although serum ferritin levels and (after adjustment for baseline anaemia) haemoglobin levels increased more with frequent supplementation. Shorter (1-3 months) versus longer (7+ months) durations of supplementation generally showed similar benefits after controlling for baseline anaemia status, except for ferritin which increased more with longer duration of supplementation (p=0.04). Moderate-dose and high-dose supplements were more effective than low-dose supplements at improving haemoglobin (p=0.004), ferritin (p=0.008) and iron deficiency anaemia (p=0.02), but had similar effects to low-dose supplements for overall anaemia. Iron supplementation provided similar benefits when administered alone or in combination with zinc or vitamin A, except for an attenuated effect on overall anaemia when iron was cosupplemented with zinc (p=0.048). CONCLUSIONS: Weekly and shorter duration iron supplementation at moderate or high doses might be optimal approaches for children and adolescents at risk of deficiency. TRIAL REGISTRATION NUMBER: CRD42016039948.

Gastrointestinal factors associated with risk of bronchiectasis in children.

OBJECTIVE: To evaluate gastrointestinal (GI) risk factors for bronchiectasis in children. We hypothesized that upper GI tract dysmotility would be associated with increased risk of bronchiectasis. STUDY DESIGN: Subjects in this retrospective cohort study included those evaluated for persistent pulmonary symptoms in the Aerodigestive Center at Boston Children's Hospital who underwent chest computed tomography (CT) between 2002 and 2019. To determine gastrointestinal predictors of bronchiectasis, baseline characteristics, comorbidities, enteral tube status, medications received, gastroesophageal reflux burden, adequacy of swallow function, esophageal dysmotility, gastric dysmotility, and neutrophil count on bronchoalveolar lavage (BAL) were compared between patients with and without bronchiectasis. Proportions were compared with Fisher's exact test and binary logistic regression with stepwise selection was used for multivariate analysis. ROC analyses were utilized to compare BAL neutrophils and bronchiectasis. RESULTS: Of 192 subjects, 24% were found to have evidence of bronchiectasis on chest CT at age 7.9 ± 0.5 years. Enteral tubes (OR 5.77, 95% CI 2.25-14.83, p < 0.001) and increased BAL neutrophil count (OR 5.79, 95% CI 1.87-17.94, p = 0.002) were associated with increased risk while neurologic comorbidities were associated with decreased risk (OR 0.24, 95% CI 0.09-0.66, p = 0.006). Gastroesophageal reflux was not found to be a significant risk factor. Neutrophil counts >10% had 72% sensitivity and 60% specificity for identifying bronchiectasis. CONCLUSIONS: Enteral tubes were associated with significantly increased risk of bronchiectasis but gastroesophageal reflux was not. Providers should consider obtaining chest CT to evaluate for bronchiectasis in children found to have unexplained elevated BAL neutrophil count.

Clinical Phenotypes and Outcomes in Monogenic Versus Non-monogenic Very Early Onset Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Over 80 monogenic causes of very early onset inflammatory bowel disease [VEOIBD] have been identified. Prior reports of the natural history of VEOIBD have not considered monogenic disease status. The objective of this study is to describe clinical phenotypes and outcomes in a large single-centre cohort of patients with VEOIBD and universal access to whole exome sequencing [WES]. METHODS: Patients receiving IBD care at a single centre were prospectively enrolled in a longitudinal data repository starting in 2012. WES was offered with enrollment. Enrolled patients were filtered by age of diagnosis <6 years to comprise a VEOIBD cohort. Monogenic disease was identified by filtering proband variants for rare, loss-of-function, or missense variants in known VEOIBD genes inherited according to standard Mendelian inheritance patterns. RESULTS: This analysis included 216 VEOIBD patients, followed for a median of 5.8 years. Seventeen patients [7.9%] had monogenic disease. Patients with monogenic IBD were younger at diagnosis and were more likely to have Crohn's disease phenotype with higher rates of stricturing and penetrating disease and extraintestinal manifestations. Patients with monogenic disease were also more likely to experience outcomes of intensive care unit [ICU] hospitalisation, gastrostomy tube, total parenteral nutrition use, stunting at 3-year follow-up, haematopoietic stem cell transplant, and death. A total of 41 patients [19.0%] had infantile-onset disease. After controlling for monogenic disease, patients with infantile-onset IBD did not have increased risk for most severity outcomes. CONCLUSIONS: Monogenic disease is an important driver of disease severity in VEOIBD. WES is a valuable tool in prognostication and management of VEOIBD.

The interferon landscape along the respiratory tract impacts the severity of COVID-19.

Severe coronavirus disease 2019 (COVID-19) is characterized by overproduction of immune mediators, but the role of interferons (IFNs) of the type I (IFN-I) or type III (IFN-III) families remains debated. We scrutinized the production of IFNs along the respiratory tract of COVID-19 patients and found that high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity. Production of specific IFN-III, but not IFN-I, members denotes patients with a mild pathology and efficiently drives the transcription of genes that protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In contrast, compared to subjects with other infectious or noninfectious lung pathologies, IFNs are overrepresented in the lower airways of patients with severe COVID-19 that exhibit gene pathways associated with increased apoptosis and decreased proliferation. Our data demonstrate a dynamic production of IFNs in SARS-CoV-2-infected patients and show IFNs play opposing roles at distinct anatomical sites.

Acid Suppression Does Not Improve Laryngomalacia Outcomes but Treatment for Oropharyngeal Dysphagia Might Be Protective.

OBJECTIVE: To determine whether the use of acid suppression and thickened feeds impact laryngomalacia outcomes in infants, including supraglottoplasty risk, time to supraglottoplasty, and hospitalization risk. STUDY DESIGN: We performed a retrospective cohort study to compare risk and time with supraglottoplasty and frequency and duration of hospitalizations for infants diagnosed with laryngomalacia at Boston Children's Hospital between January 1 and December 31, 2017. The primary outcomes were supraglottoplasty requirement, time to supraglottoplasty, and hospitalization risk. Multivariate analyses were performed to determine predictors of supraglottoplasty and hospitalization risk after adjusting for laryngomalacia severity and comorbidities in addition to propensity score adjustment. Kaplan-Meier curves were created to determine the impact of acid suppression use on time to supraglottoplasty. RESULTS: In total, 236 subjects with mean age 62.6 ± 4 days were included in the analysis; 55% were treated with acid suppression. Subjects treated with acid suppression had a greater risk of supraglottoplasty (hazard ratio 3.36, 95% CI 1.36-8.29, P = .009), shorter time to supraglottoplasty (5.64 ± 0.92 vs 7.98 ± 1.92 months, P = .006), and increased respiratory hospitalization risk (relative risk 1.97, 95% CI 1.01-3.85, 0.047), even after adjustment for covariates. Subjects receiving thickening had fewer respiratory hospitalization nights and longer time to supraglottoplasty (9.3 ± 1.7 vs 4.56 ± 0.73 months, P = .004), even after adjustment. CONCLUSIONS: Acid suppression use does not reduce the frequency of supraglottoplasty and related hospitalizations compared with untreated subjects. However, patients treated with thickening have decreased hospitalization and longer time to supraglottoplasty, suggesting that thickening of feeds may be a preferred intervention over acid suppression.

Predictors of Bilateral Disease in Pediatric Differentiated Thyroid Cancer.

CONTEXT: Total thyroidectomy is recommended for children with papillary thyroid carcinoma, partly because of a high prevalence of bilateral disease. Identifying characteristics that predict bilateral disease might identify candidates for more limited surgery. OBJECTIVE: Investigate associations of preoperative or histopathological characteristics with bilateral disease in children with differentiated thyroid cancer. METHODS: Retrospective cohort study (1998-2020) at 2 academic hospitals. Patients <19 years who underwent total thyroidectomy for differentiated thyroid cancer were included. Clinical, sonographic, and histopathological characteristics were evaluated. The presence of bilateral disease on histopathology was assessed by univariable analysis and multivariable logistic regression. RESULTS: One hundred and fifteen subjects were analyzed (90% with papillary carcinoma). Median (range) age at diagnosis was 15.0 (8.1-18.9) years. Bilateral disease was present in 47/115 subjects (41%). Bilateral disease was associated with solid parenchyma, calcifications, irregular margins, and abnormal lymph nodes detected by ultrasound, Bethesda class V/VI cytology, papillary histology, tumor multifocality in the primary lobe, extrathyroidal extension, lymphovascular invasion, and nodal metastases. In multivariable analysis, only multifocality in the primary lobe was independently associated with bilateral disease (OR 7.61, 95% CI 2.44-23.8, P < .001). Among clinically node-negative subjects with papillary carcinoma who did not have tumor multifocality in the primary lobe, bilateral disease was present in 5/32 (16%). CONCLUSIONS: In children with differentiated thyroid cancer, tumor multifocality in the primary lobe is associated with bilateral disease and should prompt consideration of completion thyroidectomy after initial lobectomy. Clinically node-negative children with tumors that are unifocal in the primary lobe have a low likelihood of contralateral disease.

Natural History of Thyroid Disease in Children with PTEN Hamartoma Tumor Syndrome.

CONTEXT: Thyroid ultrasound screening is recommended in children with PTEN hamartoma tumor syndrome (PHTS) due to increased risk of thyroid neoplasia, but the natural history of thyroid disease in children with PHTS is unclear. OBJECTIVE: Determine the prevalence and natural history of thyroid disease in children with PHTS. METHODS: Retrospective cohort study (1998-2019) in an academic pediatric hospital of individuals with genetically confirmed PHTS diagnosed before age 19 years. Clinical, thyroid ultrasound, and laboratory characteristics are described. Primary outcomes were the prevalence of thyroid nodules ≥10 mm diameter and time course and risk factors for nodule development assessed by Cox regression analysis. Secondary outcomes included thyroid nodule requiring biopsy, other ultrasound findings, and prevalence of autoimmune thyroid disease. RESULTS: Among 64 subjects with PHTS, 50 underwent thyroid ultrasound. A thyroid nodule ≥10 mm was diagnosed in 22/50 (44%) subjects at median (range) age 13.3 (7.0-22.9) years. Nodules were diagnosed earlier in females than in males (10.8 [7.0-17.9] vs 14.2 [9.9-22.9] years, P = .009). In multivariate analysis, risk of thyroid nodules was significantly associated with female sex (hazard ratio 2.90, 95% CI 1.16-7.27, P = .02) and inversely associated with the presence of neurologic findings of PHTS (HR 0.27, 95% CI 0.10-0.69, P = .007). Abnormal-appearing lymph nodes with echogenic foci were observed by ultrasound in 20% of subjects, but these were not associated with malignancy. Autoimmune thyroid disease was present in 10/33 (30.3%) of subjects in whom it was assessed. CONCLUSION: Thyroid disease is common in children with PHTS. This study supports current consensus recommendations for ultrasound screening.

Portal Venous Metabolite Profiling After RYGB in Male Rats Highlights Changes in Gut-Liver Axis.

After Roux-en-Y gastric bypass (RYGB) surgery, the intestine undergoes structural and metabolic reprogramming and appears to enhance use of energetic fuels including glucose and amino acids (AAs), changes that may be related to the surgery's remarkable metabolic effects. Consistently, RYGB alters serum levels of AAs and other metabolites, perhaps reflecting mechanisms for metabolic improvement. To home in on the intestinal contribution, we performed metabolomic profiling in portal venous (PV) blood from lean, Long Evans rats after RYGB vs sham surgery. We found that one-carbon metabolism (OCM), nitrogen metabolism, and arginine and proline metabolism were significantly enriched in PV blood. Nitrogen, OCM, and sphingolipid metabolism as well as ubiquinone biosynthesis were also overrepresented among metabolites uniquely affected in PV vs peripheral blood in RYGB-operated but not sham-operated animals. Peripheral blood demonstrated changes in AA metabolism, OCM, sphingolipid metabolism, and glycerophospholipid metabolism. Despite enrichment for many of the same pathways, the overall metabolite fingerprint of the 2 compartments did not correlate, highlighting a unique role for PV metabolomic profiling as a window into gut metabolism. AA metabolism and OCM were enriched in peripheral blood both from humans and lean rats after RYGB, demonstrating that these conserved pathways might represent mechanisms for clinical improvement elicited by the surgery in patients. Together, our data provide novel insight into RYGB's effects on the gut-liver axis and highlight a role for OCM as a key metabolic pathway affected by RYGB.

Natural history of children with mild Crohn's disease.

BACKGROUND: There is a small and poorly studied population of patients with mild and limited Crohn's disease (CD), who either spontaneously enter remission and can discontinue therapy, or be maintained on milder anti-inflammatory treatment. AIM: To identify a group of children with mild CD who were not escalated to immunomodulators (azathioprine, mercaptopurine, or methotrexate) or biologics (infliximab or adalimumab) within the first two years after their Crohn's diagnosis and outline the natural history and phenotypic features of these patients. METHODS: In a retrospective chart review of the inflammatory bowel disease database at Boston Children's Hospital we reviewed all the mild CD patient's clinic visits, laboratory studies, and procedures for the duration of time they were followed at the center. Patients were included if they had clear diagnosis of Crohn's disease, and they were not escalated to immunosuppressive therapies for at least 2 years after the date of diagnosis. These mild CD patients were compared to controls diagnosed at a similar time, that were treated with immunomodulators or biologics. Data that was abstracted included: Age at diagnosis, sex, disease location utilizing the Paris classification, medical treatment, surgical treatment, endoscopic findings, histology, and hospitalizations. We also analyzed differences in the phenotypic features between those with mild CD and those with moderate to severe disease. RESULTS: Out of 1205 patients with CD diagnosed between 1990 and 2013, we identified 29 patients that met the inclusion criteria, and they were matched with 58 controls. There were no significant differences between the disease behaviors at presentation, with approximately 90% of patients in each group having inflammatory disease. However, patients with mild disease were more likely to have disease limited to the colon (31% vs 12%, P = 0.03). In contrast, patients with moderate to severe disease (aka control group) were more likely to have ileocolonic disease (70% vs 45% in the mild group, P = 0.02). Of the 29 patients, only 8 required medication escalation to immunomodulators during the period of follow-up. The primary indication for escalation to immune suppressive therapies was corticosteroid dependence. We also found that patients treated without immunomodulators or biologics for mild CD continue to exhibit histologic intestinal inflammation. Of the 29 patients, three developed significant complications of ileal disease, though only one required surgical intervention during the period of follow-up. CONCLUSION: We identified a cohort of children with mild CD, who were able to avoid the institution of immune suppressive therapies for several years, and generally had good outcomes during the period of follow-up. While a subset of these patients will eventually require either immunosuppression or surgery, the majority of them have a good quality of life despite having low-grade intestinal inflammation. Importantly, this subset of patients has managed to avoid the potential toxicities of immune suppression for several years. The majority of these patients have either colonic disease with minimal small bowel involvement or limited ileal disease.

Dietary iron and calcium intakes during pregnancy are associated with lower risk of prematurity, stillbirth and neonatal mortality among women in Tanzania.

OBJECTIVE: Prematurity, stillbirth and other adverse birth outcomes remain major concerns in resource-limited settings. Poor dietary intake of micronutrients during pregnancy has been associated with increased risk of adverse outcomes. We determined the relationships between dietary Fe and Ca intakes during pregnancy and risks of adverse birth outcomes among HIV-negative women. DESIGN: Women's diet was assessed through repeated 24 h diet recalls in pregnancy. Mean intakes of total Fe, Fe from animal sources and Ca during pregnancy were examined in relation to adverse birth outcomes and neonatal mortality. Women were prescribed daily Fe supplements as per standard perinatal care. SETTING: Dar es Salaam, Tanzania. SUBJECTS: A cohort of 7634 pregnant women. RESULTS: Median (interquartile range) daily dietary intake of total Fe, animal Fe and Ca was 11·9 (9·3-14·7), 0·5 (0-1·1) and 383·9 (187·4-741·2) mg, respectively. Total Fe intake was significantly associated with reduced risk of stillbirth (trend over quartiles, P=0·010). Animal Fe intake was significantly associated with reduced risk of preterm birth and extreme preterm birth. Animal Fe intake was inversely related to neonatal mortality risk; compared with women in the lowest intake quartile, those in the top quartile were 0·51 times as likely to have neonatal death (95 % CI 0·33, 0·77). Higher Ca intake was associated with reduced risk of preterm birth (relative risk; 95 % CI: 0·76; 0·65, 0·88) and extreme preterm birth (0·63; 0·47, 0·86). Women in the highest Ca intake quartile had reduced risk of neonatal mortality (0·59; 0·37, 0·92). CONCLUSIONS: Daily dietary Fe and Ca intakes among pregnant women are very low. Improvement of women's diet quality during gestation is likely to improve the risks of adverse birth outcomes.

Prevalence and risk factors of cervical squamous intraepithelial lesions among HIV-infected women in Dar es Salaam, Tanzania.

To determine the prevalence and predictors of cervical squamous intraepithelial lesions (SIL) among HIV-infected women in Tanzania, a cross-sectional study was conducted among HIV-infected women at HIV care and treatment clinics. A Papanicolaou (Pap) smear was used as a screening tool for detection of cervical SIL. From December 2006 to August 2009, 1365 HIV-infected women received cervical screening. The median age was 35 (interquartile range [IQR]: 30-42) years, and the median CD4 + cell count was 164 (IQR: 80-257) cells/mm(3). The prevalence of cervical SIL was 8.7% (119/1365). In multivariate analysis, older age (≥50 versus 30-<40 years: prevalence ratio [PR], 2.36; 95% confidence interval [CI], 1.45-3.84, p for trend = 0.001), lower CD4 + cell counts (<100 versus ≥200 cells/mm(3): PR, 1.55; 95% CI, 1.01-2.36, p for trend = 0.03) and cervical inflammation (PR, 1.73; 95% CI, 1.16-2.60, p = 0.008) were associated with an increased risk of cervical SIL. Women with advanced WHO HIV disease stage (IV versus I/II: PR, 3.45; 95% CI, 1.35-8.85, p for trend = 0.01) had an increased risk for high-grade SIL. In resource-limited settings where it is not feasible to provide cervical cancer prevention services to all HIV-infected women, greater efforts should focus on scaling-up services among those who are older than 50 years, with lower CD4 cell counts and advanced HIV disease stage.

Medical history and the risk of biliary tract cancers in Shanghai, China: implications for a role of inflammation.

Several lines of evidence suggest that inflammation may play a role in the etiology of biliary tract cancers. To examine further the role of inflammation, we evaluated the associations between self-reported inflammatory-related medical conditions and the risk of biliary tract cancers in a population-based case-control study in Shanghai, China. Our analysis included 368 gallbladder cancer cases, 191 bile duct cancer cases, 68 ampulla of Vater cancer cases, and 959 healthy subjects. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for biliary tract cancers in relation to six inflammation-related conditions. Gallbladder cancer was significantly associated with cholecystitis occurring at least 5 years prior to interview (OR = 1.7, 95% CI 1.1-2.9). Even though biliary stones did not significantly modify the associations between cholecystitis and gallbladder cancer, 90% of the gallbladder cancer cases with cholecystitis also had biliary stones, indicating that stones likely play an important role in the link between cholecystitis and gallbladder cancer. Among subjects who smoked and drank alcohol, a history of gastric (OR = 4.3, 95% CI 1.2-15.0) or duodenal ulcers (OR = 3.7, 1.2-12.0) was associated with an excess risk of gallbladder cancer. Although the mechanisms are unclear, our results further support the role for inflammation in the etiology of biliary tract cancers.

Predicted 25-hydroxyvitamin D score and incident type 2 diabetes in the Framingham Offspring Study.

BACKGROUND: Accumulating evidence suggests that vitamin D is involved in the development of type 2 diabetes (T2D). OBJECTIVE: Our objective was to examine the relation between vitamin D status and incidence of T2D. DESIGN: We used a subsample of 1972 Framingham Offspring Study participants to develop a regression model to predict plasma 25-hydroxyvitamin D [25(OH)D] concentrations from age, sex, body mass index, month of blood sampling, total vitamin D intake, smoking status, and total energy intake. Using this model, we calculated the predicted 25(OH)D score for each nondiabetic participant at the cohort's fifth examination to assess the association between the predicted 25(OH)D score and incidence of T2D by using Cox proportional hazards models. RESULTS: A total of 133 T2D cases were identified over a 7-y average follow-up. In comparison with individuals in the lowest tertile of the predicted 25(OH)D score at baseline, those in the highest tertile had a 40% lower incidence of T2D after adjustment for age, sex, waist circumference, parental history of T2D, hypertension, low HDL cholesterol, elevated triglycerides, impaired fasting glucose, and Dietary Guidelines for Americans Adherence Index score (hazard ratio: 0.60; 95% CI: 0.37, 0.97; P for trend = 0.03). CONCLUSIONS: Our findings suggest that higher vitamin D status is associated with decreased risk of T2D. Maintaining optimal 25(OH)D status may be a strategy to prevent the development of T2D.

Gender-related differences in the prevalence of cardiovascular disease risk factors and their correlates in urban Tanzania.

BACKGROUND: Urban areas in Africa suffer a serious problem with dual burden of infectious diseases and emerging chronic diseases such as cardiovascular diseases (CVD) and diabetes which pose a serious threat to population health and health care resources. However in East Africa, there is limited literature in this research area. The objective of this study was to examine the prevalence of cardiovascular disease risk factors and their correlates among adults in Temeke, Dar es Salaam, Tanzania. Results of this study will help inform future research and potential preventive and therapeutic interventions against such chronic diseases. METHODS: The study design was a cross sectional epidemiological study. A total of 209 participants aged between 44 and 66 years were included in the study. A structured questionnaire was used to evaluate socioeconomic and lifestyle characteristics. Blood samples were collected and analyzed to measure lipid profile and fasting glucose levels. Cardiovascular risk factors were defined using World Health Organization criteria. RESULTS: The age-adjusted prevalence of obesity (BMI > or = 30) was 13% and 35%, among men and women (p = 0.0003), respectively. The prevalence of abdominal obesity was 11% and 58% (p < 0.0001), and high WHR (men: >0.9, women: >0.85) was 51% and 73% (p = 0.002) for men and women respectively. Women had 4.3 times greater odds of obesity (95% CI: 1.9-10.1), 14.2-fold increased odds for abdominal adiposity (95% CI: 5.8-34.6), and 2.8 times greater odds of high waist-hip-ratio (95% CI: 1.4-5.7), compared to men. Women had more than three-fold greater odds of having metabolic syndrome (p = 0.001) compared to male counterparts, including abdominal obesity, low HDL-cholesterol, and high fasting blood glucose components. In contrast, female participants had 50% lower odds of having hypertension, compared to men (95%CI: 0.3-1.0). Among men, BMI and waist circumference were significantly correlated with blood pressure, triglycerides, total, LDL-, and HDL-cholesterol (BMI only), and fasting glucose; in contrast, only blood pressure was positively associated with BMI and waist circumference in women. CONCLUSION: The prevalence of CVD risk factors was high in this population, particularly among women. Health promotion, primary prevention, and health screening strategies are needed to reduce the burden of cardiovascular disease in Tanzania.