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Purpose Selective IgA deficiency (IgAD) is the most common primary immunodeficiency and may be associated with autoimmune diseases such as celiac disease (CeD). Although IgAD is thought to precede CeD and autoimmunity, the association between the two conditions has not been clarified. Methods Routine techniques were used to measure serum IgA and TG2-IgA and for immunohistochemistry. Results We report two childhood cases of IgA deficiency that evolved after the diagnosis of CeD and the start of a gluten-free diet. Histology showed persistence of IgA in the intestinal mucosa. Conclusion Both children with CeD showed IgA deficiency that developed after the initiation of a gluten-free diet. This supports IgA deficiency as being an autoimmune process that develops gradually and occurs due to specific defects in immunoregulation.

Context Human exposure to perfluoroalkyl substances (PFAS) has been associated with reduced duration of breastfeeding, although not consistently so, and mechanisms by which PFAS might affect breastfeeding are unknown. Objective To examine the association between early pregnancy serum-PFAS concentrations and breastfeeding termination and to elucidate the potential role of serum-prolactin concentrations in pregnancy. Materials and Methods Pregnant women from the Odense Child Cohort provided blood samples for analysis of 5 major PFAS (n = 1300) and prolactin concentrations (n = 924). They subsequently provided information about the duration of breastfeeding in questionnaires at 3 and 18 months postpartum, and a subgroup also provided breastfeeding information via weekly cell phone text messages. Associations between serum-PFAS concentrations and breastfeeding termination were analyzed using Cox regressions, while linear regression was used to assess associations between serum-PFAS and prolactin concentrations. Results Increased serum concentrations of perfluorooctane sulfonic acid, perfluorooctanoic acid, perfluorononanoic acid, and ∑PFAS were associated with a 16% (95% CI: 4%-30%), 14% (95% CI: 2%-26%), 14% (95% CI: 3%-27%), and 20% (95% CI: 6%-36%), respectively, increased risk of terminating breastfeeding at any given time after childbirth. Serum-PFAS concentrations were not associated with serum-prolactin concentrations. Conclusions These findings are of public health importance due to the global exposures to PFAS. Because breastfeeding is crucial to promote both child health and maternal health, adverse PFAS effects on the ability to breastfeed may have long-term health consequences.

Purpose It is controversial whether a higher intake of n-3 long-chain polyunsaturated fatty acids (n-3 LC PUFA) through breastfeeding is associated or not to a lower blood pressure (BP) during childhood. We aimed to clarify this point by undertaking a meta-analysis involving the data from seven European birth cohorts. Methods We searched https://www.birthcohort.net for studies that had collected breast milk samples, and had at least one BP measurement in childhood. Principal investigators were contacted, and all agreed to share data. One additional study was identified by contacts with the principal investigators. For each cohort, we analyzed the association of breast milk n-3 LC PUFAs with systolic and diastolic BP with linear mixed effects models or linear regression, and pooled the estimates with a random effects model. We also investigated age-specific and sex-specific associations. Results A total of 2188 participants from 7 cohorts were included. Overall, no associations between breast milk n-3 LC PUFAs and BP were observed. In the pooled analysis, each 0.1 wt% increment in breast milk docosahexaenoic acid (DHA) was associated with a 1.19 (95% CI − 3.31, 0.94) mmHg lower systolic BP. Associations were similar for boys and girls and at different ages. Conclusion In this individual participant meta-analysis, we found no evidence for an association between breast milk n-3 LC PUFAs and BP.

Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae are the principal causes of bacterial meningitis. It is unexplained why only occasional individuals develop invasive infection, while the vast majority remain healthy and develop immunity when encountering these pathogens. A capsular polysaccharide and an IgA1 protease are common to these pathogens. We tested the hypothesis that patients are primed to susceptibility to invasive infection by other bacteria that express the same capsular polysaccharide but no IgA1 protease. Thereby, the subsequently colonizing pathogen may protect its surface with IgA1 protease-generated Fab fragments of IgA1 devoid of Fc-mediated effector functions. Military recruits who remained healthy when acquiring meningococci showed a significant response of inhibitory antibodies against the IgA1 protease of the colonizing clone concurrent with serum antibodies against its capsular polysaccharide. At hospitalization, 70.8% of meningitis patients carried fecal bacteria cross-reactive with the capsule of the actual pathogen, in contrast to 6% of controls (P, 0.0001). These were Escherichia coli K100, K1, and K92 in patients with infection caused by H. influenzae type b and N. meningitidis groups B and C, respectively. This concurred with a significant IgA1 response to the capsule but not to the IgA1 protease of the pathogen. The demonstrated multitude of relationships between capsular types and distinct IgA1 proteases in pneumococci suggests an alternative route of immunological priming associated with recombining bacteria. The findings support the model and offer an explanation for the rare occurrence of invasive diseases in spite of the comprehensive occurrence of the pathogens.

INTRODUCTION: Bisphenol A (BPA) is frequently used in the production of plastics. It is an endocrine disruptor, and BPA exposure in mice has been associated with reduced offspring growth due to insufficient milk production. However, human studies of associations between BPA exposure and duration of breastfeeding are sparse.METHODS: Pregnant women from the Odense Child Cohort (n = 725) donated a third trimester morning urine sample, which was analyzed for BPA by LC-MS/MS. Information about duration of exclusive and any breastfeeding was obtained through questionnaires three and 18 months postpartum, and a subgroup of women responded to weekly text messages about breastfeeding. Associations between pregnancy BPA exposure and duration of breastfeeding were analyzed using Cox regression adjusting for potential confounders.RESULTS: The median urine BPA concentration was 1.29 ng/mL. Compared to women within the lowest tertile of BPA exposure, women in the second and third tertile were slightly more likely to terminate breastfeeding at any given time; HRs (95% CI) were 1.05 (0.87; 1.26) and 1.06 (0.89; 1.27), respectively, and to terminate exclusive breastfeeding at any time up to 20 weeks after birth, HRs (95% CI) were 1.07 (0.88; 1.28) and 1.06 (0.88; 1.27), respectively. However, confidence intervals were also compatible with no effect or even a protective effect.DISCUSSION: This study indicated that high BPA exposure in pregnancy was associated with shorter duration of breastfeeding. Although our findings were not statistically significant, all estimates were above one suggesting increased risk of early breastfeeding termination with high exposure. Using a single spot morning urine sample to measure BPA has likely caused imprecision as it might not adequately reflect long term exposure. Future studies should consider measuring BPA more than once, including other timepoints during pregnancy and after birth.

OBJECTIVES: The objective of this study was to establish an unselected cohort of Danish adolescents and estimate the prevalence of undiagnosed celiac disease (CeD).METHODS: The Glutenfunen cohort participants were recruited from an unselected subsample of the Danish National Birth Cohort, defined as participants living in the Island of Funen, Denmark. We invited all 7431 eligible participants in the age range of 15 to 21 years to a clinical visit. CeD diagnosis was based on screening with IgA transglutaminase antibodies (TG2-IgA) and if positive, was followed by duodenal biopsies compatible with CeD (Marsh 2-3). We calculated the prevalence of CeD in the Glutenfunen cohort as the number of CeD cases diagnosed before and during the study divided by the number of participants in the Glutenfunen cohort.RESULTS: We included 1266 participants in the Glutenfunen cohort (17%, 1266/7431). 1.1% (14 of 1266 participants) had CeD diagnosed before entering the cohort and based on the Danish National Patient Register, 0.2% of the nonparticipants (14 of 6165) had a diagnosis of CeD. In total, 2.6% (33 participants) had TG2 IgA above the upper limit of normal. Nineteen participants had duodenal biopsies compatible with CeD. The prevalence of CeD in the Glutenfunen cohort was 2.6% [(14 + 19)/1266].CONCLUSIONS: Our study suggests that CeD is much more common than expected among Danish adolescents, comparable to other European countries, and that the majority were asymptomatic or oligosymptomatic and were only found because of the screening procedure.

Background In neonates, rhesus D alloimmunization despite anti-D immunoglobulin prophylaxis is rare and often unexplained. Rhesus D alloimmunization can lead to hemolytic disease of the newborn with anemia and unconjugated hyperbilirubinemia. In past reports, transient congenital hyperinsulinism has been described as a rare complication of rhesus D alloimmunization. Our case report illustrates that rhesus D alloimmunization can result in a pseudosyndrome with severe congenital hyperinsulinism, anemia, and conjugated hyperbilirubinemia, despite correctly administered anti-D immunoglobulin prophylaxis. Case presentation We report of a 36-year-old, Caucasian gravida 1, para 1 mother with A RhD negative blood type who received routine antenatal anti-D immunoglobulin prophylaxis. Her full term newborn boy presented with severe congenital hyperinsulinism, anemia, and conjugated hyperbilirubinemia up to 295 µmol/L (ref. . The child went into clinical remission after 5.5 months. Conclusion Our case demonstrates that rhesus D alloimmunization may present as a pseudosyndrome with transient congenital hyperinsulinism, anemia, and inspissated bile syndrome with conjugated hyperbilirubinaemia, despite anti-D immunoglobulin prophylaxis, possibly due to late fetomaternal hemorrhage.

Background: The popularity of the gluten-free diet and sales of gluten-free products have increased immensely. Aims: To investigate whether gluten induces gastrointestinal symptoms, measured by self-reported questionnaires, as well as mental health symptoms in adolescents from a population-based cohort. Methods: The eligible participants (n = 273) were recruited from a population-based cohort of 1266 adolescents and had at least four different gastrointestinal symptoms. Phase one (n = 54) was a run-in phase where the participants lived gluten-free for 2 weeks. If they improved they continued to phase 2 (n = 33), a blinded randomised cross-over trial. Participants were blindly randomised either to start with 7 days of gluten, eating two granola bars containing 10 g of gluten or to 7 days on placebo, eating two granola bars without gluten, followed by the reverse and separated by a 7-day washout period. The effects of the intervention on gastrointestinal symptoms and mental health symptoms were assessed. Results: In total, 54/273 participants entered the run-in phase and 35 were eligible for randomization. A total of 33 were randomised and 32 completed the trial. The median age was 20.3 (IQR 19.2–20.9) and 32/33 participants were females. Compared with a placebo, gluten did not induce gastrointestinal symptoms. The difference in the average VAS was −0.01 (95% confidence interval −2.07 to 2.05). Nor did we find a difference in the outcomes measuring mental health. Conclusion: Compared with placebo, adding gluten to the diet did not induce gastrointestinal symptoms or worsened mental health in adolescents recruited from a population-based cohort. The trial registration number is NCT04639921.

Currently, the only effective treatment for celiac disease is complete removal of gluten from the diet. However, patients need to follow a strict gluten-free diet that results in symptomatic, serologic, and histologic remission in most patients. Histologic remission is usually complete in children, but recovery is slower and more frequently incomplete in adults. When remission has been achieved, yearly follow-up is recommended for adults, children, and adolescents. This article deals with conventional strategies used in order to follow-up patients on treatment and aiming to obtain the best clinical outcome.

Purpose The purpose of this clinical practice update is to define key modalities in the diagnosis and monitoring of celiac disease (CD) in adults as well as in children and adolescents. Methods The recommendations outlined in this expert review are based on available published evidence, including cohort and case-control studies of the diagnostic process as well as controlled and descriptive studies of disease management. Best Practice Advice 1 : Serology is a crucial component of the detection and diagnosis of CD, particularly tissue transglutaminase–immunoglobulin A (TG2-IgA), IgA testing, and less frequently, endomysial IgA testing. Best Practice Advice 2 : Thorough histological analysis of duodenal biopsies with Marsh classification, counting of lymphocytes per high-power field, and morphometry is important for diagnosis as well as for differential diagnosis. Best Practice Advice 2a : TG2-IgA, at high levels (> ×10 upper normal limit) is a reliable and accurate test for diagnosing active CD. When such a strongly positive TG2-IgA is combined with a positive endomysial antibody in a second blood sample, the positive predictive value for CD is virtually 100%. In adults, esophagogastroduodenoscopy (EGD) and duodenal biopsies may then be performed for purposes of differential diagnosis. Best Practice Advice 3 : IgA deficiency is an infrequent but important explanation for why patients with CD may be negative on IgA isotype testing despite strong suspicion. Measuring total IgA levels, IgG deamidated gliadin antibody tests, and TG2-IgG testing in that circumstance is recommended. Best Practice Advice 4 : IgG isotype testing for TG2 antibody is not specific in the absence of IgA deficiency. Best Practice Advice 5 : In patients found to have CD first by intestinal biopsies, celiac-specific serology should be undertaken as a confirmatory test before initiation of a gluten-free diet (GFD). Best Practice Advice 6 : In patients in whom CD is strongly suspected in the face of negative biopsies, TG2-IgA should still be performed and, if positive, repeat biopsies might be considered either at that time or sometime in the future. Best Practice Advice 7 : Reduction or avoidance of gluten before diagnostic testing is discouraged, as it may reduce the sensitivity of both serology and biopsy testing. Best Practice Advice 8 : When patients have already started on a GFD before diagnosis, we suggest that the patient go back on a normal diet with 3 slices of wheat bread daily preferably for 1 to 3 months before repeat determination of TG2-IgA. Best Practice Advice 9 : Determination of HLA-DQ2/DQ8 has a limited role in the diagnosis of CD. Its value is largely related to its negative predictive value to rule out CD in patients who are seronegative in the face of histologic changes, in patients who did not have serologic confirmation at the time of diagnosis, and in those patients with a historic diagnosis of CD; especially as very young children before the introduction of celiac-specific serology. Management Best Practice Advice 10 : Celiac serology has a guarded role in the detection of continued intestinal injury, in particular as to sensitivity, as negative serology in a treated patient does not guarantee that the intestinal mucosa has healed. Persistently positive serology usually indicates ongoing intestinal damage and gluten exposure. Follow-up serology should be performed 6 and 12 months after diagnosis, and yearly thereafter. Best Practice Advice 11 : Patients with persistent or relapsing symptoms, without other obvious explanations for those symptoms, should undergo endoscopic biopsies to determine healing even in the presence of negative TG2-IgA.

BackgroundInflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract. Surfactant protein D (SP-D) is expressed in the intestinal epithelium and is essential for innate host defense and regulation of inflammatory responses. Genetic variations of SP-D are associated with IBD, but the effects of SP-D in clinical disease development have not been clarified. We hypothesized that colonic epithelial SP-D expression is increased in parallel with intestinal inflammation with the capacity to dampen deleterious effects.MethodsSurgical specimens from IBD patients including Crohn’s disease (n = 9) and ulcerative colitis (n = 18) were scored for expression of SP-D and inflammatory activity. Cohoused Sftpd+/+ and Sftpd-/- mouse littermates were subjected to dextran sodium sulfate (DSS) for 7 days to induce colitis. Colonic tissue was scored for histologic damage and analyzed for inflammatory markers and expression of SP-D.ResultsSurgical specimens from IBD patients showed a strong positive correlation between immunoscore for SP-D and inflammatory activity (R2 = 0.78, P < 0.0001). In mice, colonic epithelial SP-D expression was very low, and DSS-induced colitis was unaffected by SP-D deficiency, although DSS induced transcription of colonic SP-D to a mild degree.ConclusionsA strong positive correlation between inflammatory activity and epithelial expression of SP-D was observed in surgical specimens from IBD patients supporting a role for SP-D in clinical disease. The in vivo study was inconclusive due to very low intestinal SP-D expression in the mouse. Further studies are warranted to support that increased SP-D expression in the human colonic epithelium is protective against intestinal inflammation.

Purpose Bone turnover markers (BTM) are gaining ground in clinical practice but to fully use their potential there is a need for establishing valid reference intervals (RI). Consequently, the purpose of the study was to establish general RI as well as suggested clinical RI for carboxy-terminal cross-linked telopeptide of type I collagen (β-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP) in children and adolescents. Method BTM were measured on Danish children and adolescents participating in the CHAMPS-study DK. A total of 762 participants were included (8–18 years, 50.4% girls) contributing a total of 1410 study visits. The RI was calculated based on 2-years age spans. Participants with biochemical signs of metabolic bone disease were excluded. Results The differences in RI between age groups clearly reflect changes in growth with an initial increase in BTM, greatest in boys, and a subsequent decrease most pronounced in girls. β-CTX and PINP are markers most affected by these changes, compared to OC and bone ALP. The suggested clinical 95% RI included participants with vitamin D insufficiency but no biochemical signs of metabolic bone disease which did not markedly alter the RI. Conclusion RI for β-CTX, PINP, OC and bone ALP varies with age and sex. β-CTX and PINP which reflect bone resorption and formation processes are mostly affected by these changes. We suggest a set of clinically applicable 95% RI for the four BTM to heighten the usefulness and generalizability of the RI.

INTRODUCTION: The immunosuppressive properties of PFASs are widely recognized. Early-life exposure to PFAS has been linked to reduced immune response to childhood vaccinations and increased rates of common infectious diseases, but implications for hospitalizations are unclear.OBJECTIVES: To investigate the association between maternal serum concentrations of five PFASs during pregnancy and the child's rate of hospitalization due to common infectious diseases between birth and 4 years of age.METHODS: Serum samples from first trimester pregnant women from the Odense Child Cohort (OCC) collected in 2010-2012 were analyzed for concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and three other PFASs. Data on child hospitalizations with an ICD-10 code for infectious disease was obtained from the Danish National Patient Register. The following were identified: upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), gastrointestinal infections (GI), and other infections. The Andersen-Gill Cox proportional hazard model for recurrent events was used to investigate the association between PFAS exposure and hospitalizations. The resulting estimates were hazard ratios (HRs), which express the relative change in the instantaneous risk of hospitalization with a doubling in maternal PFAS concentration.RESULTS: A total of 1,503 mother-child pairs were included, and 26% of the children were hospitalized at least once for infectious disease. A doubling in maternal PFOS concentration was associated with a 23% increase in the risk of hospitalization due to any infection (HR: 1.23 (95% CI: 1.05, 1.44). There was indication of an interaction between child sex and PFOS (p = 0.07) and PFDA (p = 0.06), although in opposite directions. Further, every doubling of PFOA or PFOS increased the risk of LRTI by 27% (HR: 1.27 (1.01, 1.59)) and 54% (HR: 1.54 (1.11, 2.15)), respectively. Similar tendencies were seen for URTI and the group of other infections. For GIs, the opposite pattern of association was seen as HR's were consistently below 1 (PFOA, HR: 0.55 (0.32, 0.95)).DISCUSSION: We found an association between PFOS and the overall risk of infectious disease, and between PFOS and PFOA exposures and the risk of LRTI's. These results are in agreement with previous findings from the OCC, in which maternal PFOS and PFOA concentrations were positively associated with the number of days that the children experienced fever, thereby suggesting that PFOS and PFOA may affect the prevalence of both mild and more severe infectious diseases even in a rather low-exposed population.

Surveillance Epidemiology Under Research Exclusion for Celiac Disease (SECURE-CELIAC) is an international, de-identified adult and pediatric database created to monitor and report on the severity of coronavirus disease 2019 (COVID-19) outcomes in patients with celiac disease (CD).

BACKGROUND: Studies on the association between breastfeeding and infections in children beyond the first year of life reveal conflicting results. In a population-based birth cohort, we investigated whether the duration of breastfeeding was associated with the number of hospitalizations due to infection and symptoms of infection at home. METHODS: In the Odense Child Cohort, text message questionnaires were used to register information on breastfeeding (weekly until end of weaning) and symptoms of infection (biweekly; 12–36 months of age). Hospitalization data were obtained from the Danish National Patient Registry. RESULTS: Of the 1087 invited, 815 mother-infant pairs were included. The median duration of any breastfeeding was 7.6 (interquartile range: 3.5–10.4) months and of exclusive breastfeeding was 2.1 (interquartile range: 0.7–4.4) months. Hospitalization due to infection was seen in 207 (25.4%) infants during the first 3 years of life. The adjusted incidence rate ratio (IRR) for hospitalization due to any infection decreased with a longer duration of any breastfeeding (adjusted IRR: 0.96; 95% confidence interval 0.93–0.99; P < .001). The strongest associations between the duration of any breastfeeding and hospitalizations due to infection were found within the first year of life, for lower respiratory tract infections, and other infections (P ≤ .05). For infants exclusively breastfed, the adjusted IRR for hospitalization was 0.88 (95% confidence interval: 0.80–0.96; P = .006). No protective associations were present between breastfeeding and infection symptoms registered at home from ages 12 to 36 months. CONCLUSIONS: The results suggest that increased duration of breastfeeding, especially exclusive breastfeeding, protects against infections requiring hospitalization in the first year of life but not hospitalizations or symptoms of infection at home beyond the first year.

Introduction Many aspects of the management of esophageal atresia (EA) and tracheoesophageal fistula (TEF) are controversial and the evidence for decision making is limited. Members of the European Reference Network for Rare Inherited Congenital Anomalies (ERNICA) conducted a consensus conference on the surgical management of EA/TEF based on expert opinions referring to the latest literature. Materials and Methods Nineteen ERNICA representatives from nine European countries participated in the conference. The conference was prepared by item generation, item prioritization by online survey, formulation of a final list containing the domains diagnostics, preoperative, operative, and postoperative management, and literature review. The 2-day conference was held in Berlin in October 2018. Anonymous voting was conducted via an internet-based system. Consensus was defined when 75% of the votes scored 6 to 9. Results Fifty-two items were generated with 116 relevant articles of which five studies (4.3%) were assigned as level-1evidence. Complete consensus (100%) was achieved on 20 items (38%), such as TEF closure by transfixing suture, esophageal anastomosis by interrupted sutures, and initiation of feeding 24 hours postoperatively. Consensus ≥75% was achieved on 37 items (71%), such as routine insertion of transanastomotic tube or maximum duration of thoracoscopy of 3 hours. Thirteen items (25%) were controversial (range of scores, 1–9). Eight of these (62%) did not reach consensus. Conclusion Participants of the conference reached significant consensus on the management of patients with EA/TEF. The consensus may facilitate standardization and development of generally accepted guidelines. The conference methodology may serve as a blueprint for further conferences on the management of congenital malformations in pediatric surgery.

Background Prenatal phthalate exposure has been suggested to alter immune responses and increase the risk of asthma, eczema and rhinitis. However, few studies have examined the effects in prospective cohorts and only one examined rhinitis. We therefore studied associations between maternal urinary concentrations of phthalate metabolites and asthma, eczema and rhinitis in offspring aged 5 years. Methods From 552 pregnant women in the Odense Child Cohort, we quantified urinary concentrations of 12 phthalate metabolites in third trimester. We assessed asthma, rhinitis and eczema in their offspring at age 5 years with a questionnaire based on the International Study of Asthma and Allergies in Childhood (ISAAC), and conducted logistic regression adjusting for relevant confounders. Results 7.4% of the children had asthma, 11.7% eczema and 9.2% rhinitis. Phthalate exposure was low compared to previous cohorts. No significant associations between prenatal phthalate exposure and asthma were found. Odds ratios (ORs) of child rhinitis with a doubling in ΣDiNPm and di-2-ethylhexyl phthalate metabolite (ΣDEHPm) concentrations were, respectively, 1.15 (95% confidence interval (CI) 0.97,1.36) and 1.21 (CI 0.93,1.58). The OR of eczema when doubling ΣDiNPm was 1.24 (CI 1.00,1.55), whereas the OR of using medicine against eczema when doubling a di-ethyl phthalate (DEP) metabolite was 0.81 (CI 0.68,0.96). Conclusion The lack of association between maternal phthalate exposure and asthma in the offspring may be due to low exposure and difficulties in determining asthma in 5-year-olds. The higher odds of rhinitis may raise public concern but further research in larger cohorts of older children is warranted.

BACKGROUND: The toxic effect of chemotherapy on the gastrointestinal tract may lead to mucositis and is associated with the pathogenesis of other treatment-related complications. We hypothesized that nutrition supplementation with bovine colostrum, rich in bioactive factors, would ameliorate gastrointestinal toxicity and reduce the incidence of fever and infectious complications during induction treatment for childhood acute lymphoblastic leukemia (ALL).METHODS: Children with newly diagnosed ALL were included in a 2-center, randomized, double-blind, placebo-controlled clinical trial. Patients were randomized to receive a daily colostrum or placebo supplement during 4 weeks of induction treatment. Data on fever, bacteremia, need for antibiotics, and mucosal toxicity were prospectively collected. (Trial registration: www.clinicaltrials.gov NCT01766804).RESULTS: Sixty-two patients were included. No differences were found for the primary outcome (number of days with fever). No difference was observed for neutropenic fever, intravenous antibiotics, or incidence of bacteremia. Peak severity of oral mucositis was significantly reduced by colostrum (7/29 patients, 24% mild; 6/29, 21% moderate; 1/29, 3% severe) compared with placebo (12/31, 39% mild; 1/31, 3% moderate; 7/31, 23% severe) (P = 0.02). Among patients receiving at least 1 dose of supplement (colostrum: n = 22; placebo: n = 30), the peak weekly self-reported oral mucositis score was overall significantly less severe in the colostrum group (P = 0.009).CONCLUSION: The use of prophylactic bovine colostrum showed no effect on fever, infectious morbidity, or inflammatory responses. Nevertheless, these data may suggest protective effects on the oral mucosa during induction therapy in childhood ALL, encouraging additional studies confirming these findings.

Coeliac disease (CD) is a chronic immune-mediated disease in genetically susceptible individuals, induced by ingested gluten. The treatment for CD is a lifelong gluten-free diet (GFD). The GFD involves restrictions in diet that may impact on a person's Health-Related Quality of Life (HRQoL).AIM: The aim of the present study was to develop the Coeliac Disease Quality of Life questionnaire (CDQL): a comprehensive CD-specific HRQoL measure that can be completed by children, adolescents, and adults or by proxy.METHODS: The questionnaire was developed in three phases. In phase 1, focus group methods and qualitative analysis of verbatim transcripts generated CD-specific items for a prototype instrument to sensitively captured patient concerns. In phase 2, CD patients completed the prototype CDQL. The questionnaire was refined through analysis of data and cognitive interviewing. In phase 3, the final version of the CDQL was answered by Danish respondents. The psychometric properties of the CDQL were assessed, and the HRQoL data were analyzed.RESULTS: The CDQL was completed by 422 respondents. The CDQL has 12 patient background items, 2 generic HRQoL items, and 30 CD-specific HRQoL item. The CD-specific HRQoL items were distributed on eight scales with acceptable to excellent reliability. Comprehensiveness and understandability was shown by feedback from cognitive interviewing from children, adolescents, and adults. Content validity was ensured by involving patients and clinicians in the development of the questionnaire. Sensitivity of the questionnaire was demonstrated in differences found between children, adolescents, and adult's perception of their HRQoL in relation to having CD.CONCLUSIONS: The CDQL comprehensively measures HRQoL in CD, and is psychometrically robust. The questionnaire may prove useful in tracking HRQoL in CD across age groups.

BACKGROUND: The season in which a child is born may affect the immune system development and thereby influence the risk of infections. In this study, we examined the associations between birth season and the risk of hospital admission or symptoms associated with a wide range of infections.METHODS: This study is a prospective cohort study of 2434 children with an average follow-up of 3.5 years. Admission data were obtained from the Danish National Patient Registry. Via short message service (SMS) questionnaires, 1279 families reported symptoms of infections in a 1-year period.RESULTS: Of the 2434 children, 639 (26.3%) were admitted to the hospital, and the children experienced on average 64.4 days with symptoms of infection within 1 year. There was no association between birth season and hospital admissions due to all infectious causes [incidence rate ratio (IRR) = 0.89; 95% confidence interval (CI), 0.65-1.22; P = 0.471]. However, children born in the fall had a higher IRR for admission due to all infectious causes when excluding admissions within the first year of life. Winter- and spring-born children had lower IRRs for admission due to gastrointestinal infections than summer-born children, but this association was alone present when admissions within the first year of life were included. The short message service-survey showed significantly lower IRRs for any symptom of infection among winter-born (IRR = 0.85; 95% CI, 0.75-0.96; P = 0.009) and fall-born children (IRR = 0.88; 95% CI, 0.78-0.99; P = 0.033) in comparison with summer-born children.CONCLUSIONS: Birth season was not associated with hospital admission due to all infectious causes within the first 5 years of age; however, fall-birth was associated with a higher IRR for admissions due to all infectious causes after the first year of life. The association between birth season and admissions due to gastrointestinal infections was only seen when including children admitted under the age of one. Being born in fall or winter was associated with a decreased IRR for number of days with any symptom of infection registered at home.

Fe deficiency (ID) defined as plasma ferritin 10 mg/l, twin birth or prematurity. Associations with ID were analysed by logistic regression, adjusting for sex, maternal education, duration of partial breast-feeding and current intake of milk, fish and meat. Overall, fifty-six children had ID (15·1 %). Factors associated with increased risk were exclusive breast-feeding beyond 4 months (OR 5·97; 95 % CI 1·63, 21·86) and no intake of oral Fe supplements from 6 to 12 months (OR 3·99, 95 % CI 1·33, 11·97. Duration of partial breast-feeding and current diet was not associated with ID. In conclusion, the ID prevalence was 15·1 %, and both exclusive breast-feeding beyond 4 months and no intake of oral Fe supplements from 6 to 12 months were associated with increased risk of ID in 18-month-old children.

Purpose: The treatment for coeliac disease (CD) is a gluten-free diet (GFD), which impacts the health-related quality of life (HRQoL). The aim of the study was to develop the Gluten-Free Diet Perceived Competence Scale (GFD-PCS): a short and precise CD-specific patient-reported outcome measure. Methods: The GFD-PCS was developed from the scales ‘Perceived Competence (Maintaining a Healthy Diet)’ and ‘Perceived Competence for Diabetes’. The scale was then programmed into a web-based questionnaire and distributed together with generic quality of life (WHO-5) and CD-specific HRQoL (CDQL) questionnaires. Results: There were 931 respondents. The 831 who reported ‘diagnosed CD’ were retained. The average age was 37.6 years (SD = 16.5). There was no statistically significant difference between males (M = 5.9, SD = 1.6) and females (M = 6.2, SD = 1.4) in GFD-PCS score. Respondents younger than 18 years (n = 104) scored lower (M = 5.8, SD = 1.4) than adults (M = 6.2, SD = 1.4). The psychometric properties of the GFD-PCS showed excellent internal reliability (α =.96) and satisfied construct and criterion validity. Conclusion: The GFD-PCS measures patient-perceived dietary competence for maintaining a GFD. The scale is psychometrically robust and provides a useful tool in assessing patients’ difficulties with a GFD.

Purpose: Insulin resistance may exert a negative influence on bone mass in childhood and adolescence. The objective was to assess the association between insulin resistance and total body less head (TBLH) bone mineral content (BMC) and to investigate whether body composition, physical activity or osteocalcin levels may influence this association.Methods: A longitudinal study with follow-up over >6 years was performed and included 562 apparently healthy participants with a mean age of 9.6 years at baseline. Participants underwent DXA scanning at baseline. At the two follow-ups, participants had performed another DXA scanning, had blood samples taken for fasting insulin, glucose and osteocalcin and had physical activity measured with an accelerometer. HOMA-IR was calculated as an index of insulin resistance.Results: HOMA-IR was negatively associated with TBLH BMC in boys at follow-ups (β = -31.4, p Conclusion: Insulin resistance may be detrimental for bone development through puberty in boys independent of body composition and the level of physical activity.

Introduction: Perfluorinated alkylated substances (PFAS) are persistent industrial chemicals that have resulted in global environmental exposures. Previous epidemiological studies have reported possible effects on the immune system after developmental PFAS exposure, but the possible impact on childhood infectious disease is unclear. Objectives: To investigate the association between prenatal exposure to PFAS and symptoms of infections at age 1–4 years. Methods: The Odense Child Cohort is an on-going prospective study on children's health, where serum concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorodecanoic acid (PFDA) and perfluorononanoic acid (PFNA) were measured in 649 pregnant women before gestational week 16. Of these women, 359 reported on symptoms of infection in their child every two weeks for a one-year period. The association between prenatal exposure to PFAS and the symptoms was estimated using a logistic regression model and a negative binomial regression model. For the latter, the outcome was reported as an incidence rate-ratio (IRR), and all models were adjusted for maternal age, educational level, parity and child age. Results: On average, the children experienced symptoms of infection 23% of the time during one year. PFOS exposure in the high tertile compared to the low tertile was associated with a statistically significant increased proportion of days with fever (IRR: 1.65 (95% CI: 1.24, 2.18), P-trend

Background: Phthalates comprise a large class of chemicals used in a variety of consumer products. Several have anti-androgenic properties, and in rodents prenatal exposure has been associated with reduced anogenital distance (AGD)—the distance from the anus to the genitals in male offspring. Few human studies have been conducted, but associations between the anti-androgenic phthalates and male AGD have been reported. Objective: We aimed to study the association between phthalate exposure in late pregnancy in Danish women pregnant in 2010–2012 and AGD in their male infants at 3 months of age (n = 273). Methods: In the Odense child cohort study, urinary concentrations of 12 phthalate metabolites of diethyl, di-n-butyl, diisobutyl, di(2-ethylhexyl), butylbenzyl, and diisononyl phthalate (DEP, DnBP, DiBP, DEHP, BBzP, and DiNP, respectively) were measured among 245 mothers of boys at approximately gestational week 28 (range, 20.4–30.4) and adjusted for osmolality. AGD, penile width, and weight were measured 3 months after the expected date of birth. Associations between prenatal phthalate and AGD and penile width were estimated using multivariable linear regression adjusting for age and weight-for-age standard deviation score. Results: Phthalate levels were lower in this population than in a recent Swedish study in which phthalates were measured in the first trimester. No consistent associations were seen between any prenatal phthalate and AGD or penile width. Most associations were negative for exposures above the first quartile, and for ln-transformed exposures modeled as continuous variables, but there were no consistent dose–response patterns, and associations were not statistically significant (p > 0.05). Conclusion: We found no significant trends towards shorter AGD in boys with higher phthalates exposures in this low exposed Danish population. Citation: Jensen TK, Frederiksen H, Kyhl HB, Lassen TH, Swan SH, Bornehag CG, Skakkebaek NE, Main KM, Lind DV, Husby S, Andersson AM. 2016. Prenatal exposure to phthalates and anogenital distance in male infants from a low-exposed Danish cohort (2010–2012). Environ Health Perspect 124:1107–1113; http://dx.doi.org/10.1289/ehp.1509870

BACKGROUND: Only few studies have quantitated the frequencies of immune cells in the small bowel mucosa and submucosa during gestation. The aims of this study were to describe the frequencies of T and B cells, eosinophils and mast cells in the normal small bowel mucosa and submucosa (NSB) in relation to gestational age (GA) and in the uninvolved small bowel (USB) of premature newborns with necrotizing enterocolitis (NEC).METHODS: We obtained 36 NSB specimens (GA 12-41 weeks) and 8 NEC-USB specimens (GA 24-32 weeks) from autopsies and surgeries and performed immunostaining for CD3, CD79a, BMK-13 and tryptase as well as the histochemical stains giemsa and toluidine blue. Qualitative histological evaluation and two different quantitative cell-samplings were performed using digital imaging analysis with both TissuemorphDP® and newCAST® software. Linear regression analysis was performed with cell frequency as the dependent variable and GA and USB as the independent variables.RESULTS: In the NSB specimens, we found significant linear correlations between cell frequencies and GA for all examined cell types, though B cell frequencies reached a plateau midway through gestation. In the USB cases, submucosal mast cell frequencies were higher than in the NSB specimens, while T cell frequencies were lower. In USB of NEC patients, we found a significant increase of mast cells and a significant decrease of T cells compared to NSB.CONCLUSION: Throughout gestation, we found an increase of all examined immune cell types in the normal small bowel, while the number of B cells came to a standstill at midway. Future studies should examine subtypes of T cells and also include histiocytes. A larger amount of small bowel specimens, covering the full gestational age, would be of great value.

Introduction Improvements in care of patients with esophageal atresia (EA) and tracheoesophageal fistula (TEF) have shifted the focus from mortality to morbidity and quality-of-life. Long-term follow-up is essential, but evidence is limited and standardized protocols are scarce. Nineteen representatives of the European Reference Network for Rare Inherited Congenital Anomalies (ERNICA) from nine European countries conducted a consensus conference on the surgical management of EA/TEF. Materials and Methods The conference was prepared by item generation (including items of surgical relevance from the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN)-The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) guidelines on follow-up after EA repair), item prioritization, formulation of a final list containing the domains Follow-up and Framework, and literature review. Anonymous voting was conducted via an internet-based system. Consensus was defined as ≥75% of those voting with scores of 6 to 9. Results Twenty-five items were generated in the domain Follow-up of which 17 (68%) matched with corresponding ESPGHAN-NASPGHAN statements. Complete consensus (100%) was achieved on seven items (28%), such as the necessity of an interdisciplinary follow-up program. Consensus ≥75% was achieved on 18 items (72%), such as potential indications for fundoplication. There was an 82% concordance with the ESPGHAN-NASPGHAN recommendations. Four items were generated in the domain Framework, and complete consensus was achieved on all these items. Conclusion Participants of the first ERNICA conference reached significant consensus on the follow-up of patients with EA/TEF who undergo primary anastomosis. Fundamental statements regarding centralization, multidisciplinary approach, and involvement of patient organizations were formulated. These consensus statements will provide the cornerstone for uniform treatment protocols and resultant optimized patient care.

Blood pressure (BP) and blood lipid profile (BLP) have been shown to track from childhood into adulthood, and n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) in breast milk have been suggested as mediators of the beneficial long-term effect of breastfeeding on BP and BLP. We aimed to investigate associations between n-3 LC-PUFA content in breast milk at 4 months postpartum and offspring BP and BLP in early life. BP and BLP were measured at 4, 18, and 36 months. Statistical analyses were sex-stratified and adjusted for gestational age, maternal pre-pregnancy body mass index (BMI), and maternal educational level. Based on 336 mother-child dyads, high n-3 LC-PUFA in breast milk was inversely associated with systolic and diastolic BP in boys at 4 months (&beta, = &minus, 20.0 (95% CI = &minus, 33.4, &minus, 6.7), p = 0.004 and &beta, 10.2 (95% CI = &minus, 19.8, &minus, 0.5), p = 0.039, respectively), inversely associated with HDL cholesterol, and directly associated with triglyceride in girls at 4 months (&beta, 0.7 (95% CI = &minus, 1.1, &minus, 0.3), p = 0.001 and &beta, = 3.1 (95% CI = 1.0, 5.2), p = 0.005, respectively). Associations observed at the later time points were non-significant. Furthermore, we observed sex-specific changes over time in both size and direction of the associations. Our results indicate that early intake of n-3 LC-PUFA can affect early development in cardiometabolic factors such as BP and BLP in a sex-specific manner. Follow-up and further investigation in later childhood is planned.

Summary: Bone mass in childhood is highly influenced by puberty. At the same age, bone mass was higher for pubertal than pre-pubertal children. A high level of tracking during 7 years from childhood through puberty was shown, indicating that early levels of bone mass may be important for later bone health. Introduction: Bone mass development in childhood varies by sex and age, but also by pubertal stage. The objectives of this study were to (1) describe bone mass development in childhood as it relates to pubertal onset and to (2) determine the degree of tracking from childhood to adolescence. Methods: A longitudinal study with 7 years of follow-up was initiated in 2008 to include 831 children (407 boys) aged 8 to 17 years. Participants underwent whole body dual-energy X-ray absorptiometry (DXA) scanning, blood collection to quantify luteinizing hormone levels, and Tanner stage self-assessment three times during the 7-year follow-up. Total body less head bone mineral content, areal bone mineral density, and bone area were used to describe development in bone accrual and to examine tracking over 7 years. Results: Bone mass in pubertal children is higher than that of pre-pubertal children at the same age. Analysing tracking with quintiles of bone mass Z-scores in 2008 and 2015 showed that more than 80% of participants remained in the same or neighbouring quintile over the study period. Tracking was confirmed by correlation coefficients between Z-scores at baseline and 7-year follow-up (range, 0.80–0.84). Conclusions: Bone mass is highly influenced by pubertal onset, and pubertal stage should be considered when examining children’s bone health. Because bone mass indices track from childhood into puberty, children with low bone mass may be at risk of developing osteoporosis later in life.

Background & Aims: The intestinal microbiota is believed to be involved in the pathogenesis of celiac disease, in addition to genetic variants and dietary gluten. The gut microbiota is strongly influenced by systemic antibiotics—especially in early life. We explored the association between exposure to a systemic antibiotic in the first year of life and risk of diagnosed celiac disease. Methods: We performed an observational nationwide register-based cohort study. We included all children born in Denmark from 1995 through 2012 or Norway from 2004 through 2012. Children born in Denmark were followed until May 8, 2015 (age at end of follow-up was 2.3–20.3 years) and children born in Norway were followed until December 31, 2013 (age at end of follow-up was 1–10 years). We collected medical information from more than 1.7 million children, including 3346 with a diagnosis of celiac disease. Exposure to systemic antibiotics was defined as a dispensed systemic antibiotic in the first year of life. Results: Exposure to systemic antibiotics in the first year of life was positively associated with diagnosed celiac disease in the Danish and Norwegian cohorts (pooled odds ratio 1.26, 95% confidence interval 1.16–1.36). We found a dose-dependent relation between an increasing number of dispensed antibiotics and the risk of celiac disease (pooled odds ratio for each additional dispensed antibiotic 1.08, 95% confidence interval 1.05–1.11). No specific type of antibiotic or age period within the first year of life was prominent. Adjustment for hospital admissions with an infectious disease in the first year of life did not change the estimates; adjustment for the number of maternally reported infections in the child in 2 large sub-cohorts decreased the association slightly (pooled odds ratio 1.18, 95% confidence interval 0.98–1.39). Conclusion: In a nationwide study of children in Denmark and Norway, we found exposure to systemic antibiotics in the first year of life to be associated with a later diagnosis of celiac disease. These findings indicate that childhood exposure to systemic antibiotics could be a risk factor for celiac disease.

Objectives: Osteopontin (OPN) is a multifunctional protein expressed in many cell types, tissues and body fluids with the highest concentrations found in milk; significantly higher in human than in bovine milk. Intervention studies have indicated beneficial effects of supplementing infant formula with bovine OPN. In this multicenter study, we determined the OPN content in human milk samples from 629 Chinese, Danish, Japanese and Korean mothers. Methods: At each study site, milk samples were collected and analyzed for OPN and protein concentration using ELISA and infrared spectroscopy, respectively. Results: A total of 829 milk samples from 629 women were included. When delivering the first sample, mean maternal age was 31.4 years (SD 4.0), and median infant age was 13.4 weeks (interquartile range 4.6-17.9). The median OPN concentration varied across sites; from 99.7 mg/L in Danish, 185.0 mg/L in Japanese, 216.2 mg/L in Korean to 266.2 mg/L in Chinese mothers (P < 0.001), corresponding to 1.3%, 2.4%, 1.8% and 2.7% of the total protein content (OPN/ protein%) (P < 0.05), respectively. Based on 75 Chinese and 33 Japanese mothers delivering more than 1 sample, multilevel (mixed model) linear regression analysis showed a decrease in OPN concentration with infant age (b ¼ (11.3), 95% confidence interval (CI) ¼ (13.9) to (8.8) and b ¼ (2.1), 95% CI ¼ (3.2) to (0.9), respectively). Conclusions: In this large multicenter study, we observed statistically significant differences in the OPN concentration and the OPN/protein% in human milk samples between countries. Based on mothers delivering more than 1 sample, a significant decrease within the lactation period was observed.

OBJECTIVE: To evaluate the effect of two intervention modalities concerning overweight and obesity among children in general practice.DESIGN: Prospective randomized controlled trial.SETTING: A total of 60 general practices in the former County of Funen, Denmark.SUBJECTS: Overweight children, identified by International Obesity Task Force criteria, aged 5-9 years.INTERVENTION: Model 1 with health consultations in general practice during a two-year period or Model 2, an educational programme for the children and their families in addition to the health consultations.MAIN OUTCOME MEASURES: Change in body mass index (BMI) z-score in order to compare the results, independent of gender- and age-related changes over time.RESULTS: A total of 80 children were recruited with 35 and 45 children allocated to Model 1 and Model 2, respectively. No significant differences were found in the change in BMI z-score (SDS) between the two groups. A decrease in the mean BMI z-score from baseline to study end of -0.20 (95%CI -0.38 to -0.01) in Model 1 and -0.26 (95%CI -0.44 to -0.09) in Model 2, respectively, was detected. The majority of the participants (2/3) continued in the study for more than one year in both models, with a mean of 12 consultations in general practice.CONCLUSION: In this particular setting the two intervention strategies against overweight and obesity did not differ significantly with regard to change in BMI z-scores.

Regulation of appetite and food intake is partly regulated by N-acylethanolamine lipids oleoylethanolamide (OEA), stearoylethanolamide (SEA), and palmitoylethanolamide (PEA), which induce satiety through endogenous formation in the small intestine upon feeding, but also when orally or systemic administered. OEA, SEA, and PEA are present in human milk, and we hypothesized that the content of OEA, SEA, and PEA in mother&rsquo, s milk differed for infants being heavy (high weight-for-age Z-score (WAZ)) or light (low WAZ) at time of milk sample collection. Ultra-high performance liquid chromatography-mass spectrometry was used to determine the concentration of OEA, SEA, and PEA in milk samples collected four months postpartum from mothers to high (n = 50) or low (n = 50) WAZ infants. Associations between OEA, SEA, and PEA concentration and infant anthropometry at four months of age as well as growth from birth were investigated using linear and logistic regression analyses, adjusted for birth weight, early infant formula supplementation, and maternal pre-pregnancy body mass index. Mean OEA, SEA, and PEA concentrations were lower in the high compared to the low WAZ group (all p &lt, 0.02), and a higher concentration of SEA was associated with lower anthropometric measures, e.g., triceps skinfold thickness (mm) (&beta, = &minus, 2.235, 95% CI = &minus, 4.04, &minus, 0.43, p = 0.016), and weight gain per day since birth (g) (&beta, 8.169, 95% CI = &minus, 15.26, &minus, 1.08, p = 0.024). This raises the possibility, that the content of satiety factors OEA, SEA, and PEA in human milk may affect infant growth.

Coeliac disease is increasingly recognized as a global problem in both children and adults. Traditionally, the findings of characteristic changes of villous atrophy and increased intraepithelial lymphocytosis identified in duodenal biopsy samples taken during upper gastrointestinal endoscopy have been required for diagnosis. Although biopsies remain advised as necessary for the diagnosis of coeliac disease in adults, European guidelines for children provide a biopsy-sparing diagnostic pathway. This approach has been enabled by the high specificity and sensitivity of serological testing. However, these guidelines are not universally accepted. In this Perspective, we discuss the pros and cons of a biopsy-avoiding pathway for the diagnosis of coeliac disease, especially in this current era of the call for more biopsies, even from the duodenal bulb, in the diagnosis of coeliac disease. In addition, a contrast between paediatric and adult guidelines is presented.

BACKGROUND & AIMS: Hypovitaminosis D, defined as serum 25-hydroxyvitamin D (s-25(OH)D) METHODS: Women enrolled in Odense Child Cohort, a Danish observational prospective population-based cohort, who gave birth to singletons and donated a blood sample for s-25(OH)D measurements were included (n = 2082).RESULTS: The prevalence of cord vitamin D deficiency was 16.7% and 41.0% for insufficiency. White skin, winter season at birth, maternal supplementation dose of 60 nmol/L.CONCLUSION: Cord hypovitaminosis D was present in 57.7%. Multipara was identified as a novel risk factor of non-adherence to vitamin D supplementation recommendations; and a maternal supplementation dose

Background & Aims The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. Methods We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. Results Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61–99.99); the PPV was 100.00 (95% CI, 98.68–100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67–99.96) to 100.00 (95% CI, 99.23–100.00). Conclusions Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.

BACKGROUND: Studies on prevalence and effects of breastfeeding call for reliable and precise data collection to optimize infant nutrition, growth, and health. Data on breastfeeding and infant nutrition are at risk of, for example, recall bias or social desirability bias.OBJECTIVE: The aim of the present analysis was to compare data on infant nutrition, that is, breastfeeding, use of infant formula, and introduction to complementary foods, obtained by four different methods. We assumed that weekly short message service (SMS) questions were the most reliable method, to which the other methods were compared.DESIGN: The study population was part of the Odense Child Cohort. The four methods used were: (a) self-administered questionnaire 3 months postpartum, (b) self-administered questionnaire 18 months postpartum, (c) registrations from health visitors visiting the families several times within the first year of life, and (d) weekly SMS questions introduced shortly after birth.RESULTS: In total, 639 singleton mothers with data from all four methods were included. The proportion of mothers initiating breastfeeding varied from 86% to 97%, the mean duration of exclusive breastfeeding from 12 to 19 weeks, and the mean age when introduced to complementary foods from 19 to 21 weeks. The mean duration of any breastfeeding was 33 weeks across methods.CONCLUSIONS: Compared with the weekly SMS questions, the self-administered questionnaires and the health visitors' reports resulted in a greater proportion of mothers with an unknown breastfeeding status, a longer duration of exclusive breastfeeding and later introduction to complementary foods, while the duration of any breastfeeding did not differ.

PURPOSE: Celiac disease, an immunological response triggered by gluten, affects ~1 % of the Western population. Information concerning gluten intake in the general population is scarce. We determined intake of gluten from wheat, barley, rye and oat in the Danish National Survey of Diet and Physical Activity 2005-2008. The study population comprised a random cross-sectional sample of 1494 adults 20-75 years, selected from the Danish Civil Registration System.METHODS: Protein content in wheat, rye, barley and oat was determined from the National Danish Food Composition Table and multiplied with the amount of cereal used in recipes. Amount of gluten was calculated as amount of cereal protein ×0.80 for wheat and oat, ×0.65 for rye and ×0.50 for barley. Dietary intake was recorded daily during seven consecutive days in pre-coded food diaries with open-answer possibilities.RESULTS: Mean total gluten intake was 10.4 ± 4.4 g/day (10th-90th percentiles; 5.4-16.2 g/day), in men 12.0 ± 4.6 g/day and 9.0 ± 3.4 g/day in women. It was higher among men than among women in all age groups (20-75 years; P < 0.0001); however, this difference was eliminated when adjusting for energy intake. Intake of different gluten sources tended to be higher in men than in women with the exception of gluten from barley. Total gluten intake decreased with increasing age (P < 0.0001) as did gluten intake from wheat (P < 0.0001), whereas intake of gluten from rye (P < 0.0001) and barley (P = 0.001) increased with increasing age, also when adjusted for energy intake or body weight.CONCLUSION: This study presents representative population-based data on gluten intake in Danish adults. Total gluten intake decreased with increasing age.

Overweight, physical inactivity and sedentary behaviour have become increasing problems during the past decade. Increased sedentary behaviour may change the body composition (BC) by increasing the fat mass relative to the lean mass (LM). These changes may influence bone health to describe how anthropometry and BC predict the development of the bone accruement. The longitudinal study is a part of The CHAMPS study-DK. Children were DXA scanned at baseline and at 2-year follow-up. BC (LM, BF %) and BMC, BMD and BA were measured. The relationship between bone traits, anthropometry and BC was analysed by multilevel regression analyses. Of the invited children, 742/800 (93 %) accepted to participate. Of these, 682/742 (92 %) participated at follow-up. Mean (range) of age at baseline was 9.5 years (7.7-12.1). Height, BMI, LM and BF % predicted bone mineral accrual and bone size positively and independently. Height and BMI are both positive predictors of bone accruement. LM is a more precise predictor of bone traits than BF % in both genders. The effects of height and BMI and LM on bone accruement are nearly identical in the two genders, while changes in BF % have different but positive effects on bone accretion in both boys and girls.

INTRODUCTION: Parenteral nutrition-associated cholestasis (PNAC) is a complication of long-term parenteral nutrition (PN). Removal of lipids may reverse PNAC but compromises the energy to ensure infant growth. The purpose of this study was to test whether a low-fat, high-carbohydrate PN regimen, which prevents and reverses PNAC in adults, could do the same in infants. This regimen could potentially avoid the problem of diminished energy input after removing nutritional lipids.METHODS: Infants developing PNAC over a 2-year period were started on a low-fat PN regimen with calories primarily from carbohydrates. The fat-free PN, containing 314 kJ/ml, was provided 5-6 times a week and fat, including essential fatty acids and fat-soluble vitamins, 1-2 times a week. Enteral feeding was continued according to individual tolerance.RESULTS: The study included 10 infants with short bowel syndrome (six with intestinal failure due to necrotizing enterocolitis, one with gastroschisis, one with complications due to unrecognized anal atresia and two with midgut volvulus). Median duration of PN with fat before initiating the low-fat regime was 69 days (25-75 % percentile: 41-75 days), and mean s-bilirubin was 139 µmol/l (range 87-323 µmol/l). Median duration with low-fat regimen was 69 days (25-75 % percentile: 18-123 days). Bilirubin reversed to normal (CONCLUSIONS: A low-fat, high-carbohydrate PN regimen together with enteral feeding is well tolerated and may be used in reversing liver disease in PN-dependent infants without compromising growth.

Celiac disease (CD) is characterized by an inappropriate immunological reaction against gluten driven by gluten-specific CD4+ T cells. We screened 25 proteases and tested 10 for their potential to degrade gluten in vitro. Five proteases were further tested for their ability to prevent the proliferative response by a gluten-specific CD4+ T cell clone and seven gluten-reactive T cell lines to protease-digested gluten peptides. A proline-specific endo-peptidase from Aspergillus niger (AnP2), was particularly efficient at diminishing proliferation after stimulation with cleaved antigen, and could completely block the response against both native and deamidated gluten peptides. We found that AnP2 was efficient down to a 1:64 protease:substrate ratio (w:w). When AnP2 was tested in assays using seven gluten-reactive T cell lines from individual CD patients (three adults and four children), the response to gluten was diminished in all cases. Our study indicates a therapeutic benefit of AnP2 to CD patients.

Several non-persistent industrial chemicals have shown endocrine disrupting effects in animal studies and are suspected to be involved in human reproductive disorders. Among the non-persistent chemicals that have been discussed intensively during the past years are phthalates, bisphenol A (BPA), triclosan (TCS), and parabens because of their anti-androgenic and/or estrogenic effects. Phthalates are plasticizers used in numerous industrial products. Bisphenol A is the main component of polycarbonate plastics and epoxy resins. Parabens and TCS are antimicrobial preservatives and other phenols such as benzophenone-3 (BP-3) act as a UV-screener, while chlorophenols and phenyl phenols are used as pesticides and fungicides in agriculture. In spite of the widespread use of industrial chemicals, knowledge of exposure sources and human biomonitoring studies among different segments of the population is very limited. In Denmark, we have no survey programs for non-persistent environmental chemicals, unlike some countries such as the USA (NHANES) and Germany (GerES). However, we have analyzed the excretion of seven parabens, nine phenols, and the metabolites of eight different phthalates in urine samples collected over the past 6 years from four Danish cohorts. Here, we present biomonitoring data on more than 3600 Danish children, adolescents, young men, and pregnant women from the general population. Our study shows that nearly all Danes were exposed to the six most common phthalates, to BPA, TCS, and BP-3, and to at least two of the parabens. The exposure to other non-persistent chemicals was also widespread. Our data indicate decreasing excretion of two common phthalates (di-n-butyl phthalate and di-(2-ethylhexyl) phthalate) over time.

Purpose: Celiac disease (CD) is a chronic inflammatory disease requiring constant management with a gluten-free diet (GFD). Little is known about how CD impacts on health-related quality of life (HRQOL) in children and adolescents, and how they feel about and cope with CD and GFD. This qualitative study explores the impact of CD and GFD on HRQOL in everyday living of children and adolescents. Methods: In focus group interviews, we investigated HRQOL in children and adolescents with CD in order to identify patient concerns in living with CD and on a GFD. Seven focus groups were formed with 23 children/adolescents and 3 parents. Interviews were transcribed verbatim. Grounded theory approach was applied to analyse the interviews. Results: CD had varying impact on the children and adolescents HRQOL. Two major categories emerged with importance for HRQOL in children and adolescents with CD, having CD (constructed from the six subcategories: symptoms, the diagnosis-process, self-perception, awareness of CD, social and emotional impact of CD, and thoughts about the future) and coping with CD (constructed from the two subcategories: coping with food and coping with social situations). The complexity of coping with CD in social situations that involve food is presented in a flowchart. Conclusions: Children and adolescents showed large diversity in how much impact CD has on their HRQOL. Different ways of coping with CD and GFD were identified. Findings will be used to generate a patient-driven disease-specific questionnaire to measure HRQOL in children and adolescents with CD.

Polybrominated diphenyl ethers (PBDEs), a group of flame retardants, and perfluoroalkyl substances (PFASs) were analysed in serum samples of pregnant women from Denmark to provide information about their exposure and to study indications of common exposure pathways. The main BDE congener was the fully brominated BDE-209 with a median value of 7.5 ng/g lipid (46 pg/mL; 9.8 pmol/g lipid). Other BDE congeners decreased in the order BDE-47>BDE-99>BDE-153. The summed concentration of tri- to hepta-BDEs was 7.7 ng/g lipid, i.e. in the higher end of previously reported concentrations from Europe, including plasma samples of pregnant Danish women. Total lipid contents were relatively low, on average 5.9 g/L (9.0 mmol/L). The main PFAS compound was perfluorooctane sulfonate with a median concentration of 8.4 ng/mL. Other PFASs decreased in the order perfluorooctanoic acid > perfluorononanoic acid > perfluorodecanoic acid > perfluorohexane sulfonate and resulted in ΣPFAS of 12 ng/mL. Within each group, compounds were highly intercorrelated with the exception of BDE-209, which was not correlated with any of the other compounds. No correlations were found either between PFASs and PBDEs suggesting different sources of exposure and/or pharmacokinetic and metabolisation processes. PBDE and PFAS concentrations were in the range associated with adverse effects in some epidemiological studies.

Purpose Esophageal atresia (EA) is one of the most frequent congenital alimentary tract anomalies with a considerable morbidity throughout childhood. This study evaluates the gastroesophageal problems in 5–15year old children with EA and aims to identify factors predisposing to esophagitis in EA. Material and methods Fifty-nine patients primarily operated at Odense University Hospital, Denmark, during 1993–2005 were included in this follow-up study. The patients underwent the following examinations: Interview, upper endoscopy, endoscopic ultrasonography, high-resolution esophageal manometry (HREM), and pH- and multichannel intraluminal impedance (MII) measurements. Twenty-five patients with suspected gastro-esophageal reflux disease (GERD) underwent the same investigations and served as controls. Results Median age was 10.2years (7.1–13.3). Thirty-three (55.9%) presented with GERD symptoms, 41 (69.5%) with dysphagia, and 33 (55.9%) with respiratory symptoms. Twenty-nine (49.2%) had endoscopic esophagitis, and 26 (44.1%) histological esophagitis. Median reflux index (RI) was 8.3 (4.8–14.9). In 32 (55.2%) RI was above 7. Ten percent had eosinophilic inflammation. HREM showed dysmotility in the esophagus in all EA patients, 83.3% had no propagating swallows. No predictive factors predisposing the development of endoscopic esophagitis were identified. Conclusions Gastroesophageal problems in children born with EA are common. Routine follow-up with endoscopy and pH-metry in EA patients is warranted.

The presence of unique carbohydrate structures in the glycocalyx/mucous layer of the intestine may be involved in a susceptibility to celiac disease (CD) by serving as attachment sites for bacteria. This host-microbiota interaction may influence the development of CD and possibly other diseases with autoimmune components. We examined duodenal biopsies from a total of 30 children, of which 10 had both celiac disease (CD) and type 1 diabetes (T1D), 10 had CD alone, and 10 were suspected of having gastrointestinal disease, but had normal duodenal histology (non-CD controls). Patients with both CD and T1D were examined before and after remission following a gluten-free diet. We performed lectin histochemistry using peanut agglutinin (PNA) and Ulex europaeus agglutinin (UEA) staining for Gal-β(1,3)-GalNAc and Fucα1-2Gal-R, respectively, of the glycocalyx/mucous layer. The staining was scored based on dissemination of stained structures on a scale from 0 to 3. Evaluation of the scores revealed no difference between biopsies obtained before and after remission in the group of children with both CD and T1D. A comparison of this pre-remission group with the children who had CD alone or the non-CD controls also showed no significant differences. Based on our material, we found no indication that the presence of Gal-β(1,3)-GalNAc or Fucα1-2Gal-R is involved in the susceptibility to CD, or that the disease process affects the expression of these carbohydrates.

One of the hallmarks of Celiac disease (CD) is intraepithelial lymphocytosis in the small intestine. Until now, investigations to characterize the T cell subpopulations within the epithelial layer have not discriminated between the heterodimeric co-receptor molecule, CD8αβ, and the possibly immunoregulatory CD8αα homodimer molecule. Besides TCRαβ+ CD4+ cells, no other phenotypes have been shown to be gluten-reactive. Using flow cytometry on lymphocytes from duodenal biopsies, we determined that the number of B cells (CD3- CD19 +) and the number of CD3+ CD4- CD8- double-negative (DN) T cells were elevated 6-7 fold in children with CD. We next isolated and quantified intraepithelial lymphocytes (IELs) from biopsies obtained from patients (both children and adults) with CD, potential CD and non-CD controls. Flow cytometric analysis of the duodenal T cell subpopulations was performed including the markers TCRαβ, TCRγδ, CD4, CD8α and CD8β. Proportions of γδ T cells and CD8αβ+ cells among IELs were increased in CD patients, whereas proportions of CD4+ CD8αα+ and CD4+ single-positive T cells were decreased. Additionally, two gluten-reactive T cell lines (TCLs) derived from CD biopsies were analyzed for changes in proportions of T cell subsets before and after gluten stimulation. In a proliferation assay, dividing cells were tracked with carboxyfluorescein succinimidyl ester (CFSE), and both αβ and γδ T cells proliferated in response to gluten. Changes in duodenal T cell subpopulations in potential CD patients followed the same pattern as for CD patients, but with less pronounced effect.

Alcohol exposure during pregnancy can cause adverse effects to the fetus, because it interferes with fetal development, leading to later physical and mental impairment. The most common clinical tool to determine fetal alcohol exposure is maternal self-reporting. However, a more objective and useful method is based on the use of biomarkers in biological specimens alone or in combination with maternal self-reporting. This review reports on clinically relevant biomarkers for detection of prenatal alcohol exposure (PAE). A systematic search was performed to ensure a proper overview in existing literature. Studies were selected to give an overview on clinically relevant neonatal and maternal biomarkers. The direct biomarkers fatty acid ethyl esters (FAEEs), ethyl glucuronide (EtG), ethyl sulfate, and phosphatidylethanol (PEth) were found to be the most appropriate biomarkers in relation to detection of PAE. To review each biomarker in a clinical context, we have compared the advantages and disadvantages of each biomarker, in relation to its window of detectability, ease of collection, and the ease and cost of analysis of each biomarker. The biomarkers PEth, FAEEs, and EtG were found to be applicable for detection of even low levels of alcohol exposure. Meconium is an accessible matrix for determination of FAEEs and EtG, and blood an accessible matrix for determination of PEth.