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In this cohort study involving 6403 children at increased risk for celiac disease on the basis of HLA haplotype, the risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 26% and 12%, respectively, in those who were homozygous for the DR3–DQ2 haplotype. Patients with celiac disease or type 1 diabetes often carry at least one copy of HLA haplotype DR3–DQ2.5 cis (DRB1*03-DQA1*05:01-DQB1*02:01) or DR4–DQ8 (DRB1*04-DQA1*03-DQB1*03:02). The DR3–DQ2.5 cis haplotype (characterized by the cis arrangement of DQA1*05:01 and DQB1*02:01 on the same copy of chromosome 6) is present in more than 90% of patients with celiac disease. The remainder of patients with this disease carry either the aforementioned HLA haplotype DR4–DQ8 or the DQ2.5 risk alleles but in trans on the genotype DR7–DQ2.2 (DR7-DQA1*02:01-DQB1*02:02)/DR5–DQ3.5 (DR5-DQA1*05:01-DQB1*03:01). The identification of one of these haplotypes is not, by itself, sufficient for the diagnosis of celiac disease, . . .

The Environmental Determinants of Diabetes in the Young study follows an HLA risk selected birth cohort for celiac disease (CD) development using a uniform protocol. Children under investigation come from 6 different regions within Europe and the United States. Our aim was to identify regional differences in CD autoimmunity and CD cumulative incidence for children born between 2004 and 2010. Children (n = 6,628) with DQ2.5 and/or DQ8.1 were enrolled prospectively from birth in Georgia, Washington, Colorado, Finland, Germany, and Sweden. Children underwent periodic study screening for tissue transglutaminase antibodies and then CD evaluation per clinical care. Population-specific estimates were calculated by weighting the study-specific cumulative incidence with the population-specific haplogenotype frequencies obtained from large stem cell registries from each site. Individual haplogenotype risks for CD autoimmunity and CD varied by region and affected the cumulative incidence within that region. The CD incidence by age 10 years was highest in Swedish children at 3%. Within the United States, the incidence by age 10 years in Colorado was 2.4%. In the model adjusted for HLA, sex, and family history, Colorado children had a 2.5-fold higher risk of CD compared to Washington. Likewise, Swedish children had a 1.4-fold and 1.8-fold higher risk of CD compared with those in Finland and Germany, respectively. There is high regional variability in cumulative incidence of CD, which suggests differential environmental, genetic, and epigenetic influences even within the United States. The overall high incidence warrants a low threshold for screening and further research on region-specific CD triggers.

Background: The longitudinal RisCoin study investigated risk factors for COVID-19 vaccination failure among healthcare workers (HCWs) and patients with inflammatory bowel disease (IBD) at a University Hospital in Germany. Since the hospital served as the study sponsor and employer of the HCW, we implemented a custom mobile application. We aimed to evaluate the implementation, adherence, benefits, and limitations of this study’s app. Methods: The app allowed secure data collection through questionnaires, disseminated serological results, and managed bidirectional communication. Access was double-pseudonymized and irreversibly anonymized six months after enrollment. Download frequency, login events, and questionnaire submissions between October 2021 and December 2022 were analyzed. Multivariable logistic regression identified factors associated with app adherence. Results: Of the 3979 participants with app access, 3622 (91%) used the app; out of these, 1016 (28%) were “adherent users” (≥12 submitted questionnaires). App adherence significantly increased with age. Among HCW, adherent users were more likely to be non-smokers (p < 0.001), working as administrators or nursing staff vs. physicians (p < 0.001), vaccinated against influenza (p < 0.001), and had not travelled abroad in the past year (p < 0.001). IBD patients exposed to SARS-CoV-2 (p = 0.0133) and those with adverse events following the second COVID-19 vaccination (p = 0.0171) were more likely adherent app users. Despite technical issues causing dropout or non-adherence, the app served as a secure solution for cohort management and longitudinal data collection. Discussion: App-based cohort management enabled continuous data acquisition and individualized care while providing flexibility and anonymity for the study team and participants. App usability, technical issues, and cohort characteristics need to be thoroughly considered prior to implementation to optimize usage and adherence in clinical research.

To develop an international consensus on the definition of gastroesophageal reflux disease (GERD) in the pediatric population. Using the Delphi process, a set of statements was developed and voted on by an international panel of eight pediatric gastroenterologists. Statements were based on systematic literature searches using Medline, EMBASE, and CINAHL. Voting was conducted using a six-point scale, with consensus defined, a priori, as agreed by 75% of the group. The strength of each statement was assessed using the GRADE system. There were four rounds of voting. In the final vote, consensus was reached on 98% of the 59 statements. In this vote, 95% of the statements were accepted by seven of eight voters. Consensus items of particular note were: (i) GERD is present when reflux of gastric contents causes troublesome symptoms and/or complications, but this definition is complicated by unreliable reporting of symptoms in children under the age of approximately 8 years; (ii) histology has limited use in establishing or excluding a diagnosis of GERD; its primary role is to exclude other conditions; (iii) Barrett's esophagus should be defined as esophageal metaplasia that is intestinal metaplasia positive or negative; and (iv) extraesophageal conditions may be associated with GERD, but for most of these conditions causality remains to be established. The consensus statements that comprise the Definition of GERD in the Pediatric Population were developed through a rigorous process. These statements are intended to be used for the development of future clinical practice guidelines and as a basis for clinical trials.

Background According to Ulrich’s psychoevolutionary theory, contact with green environments mitigates stress by activating the parasympathetic system, (specifically, by decreasing blood pressure (BP)). Experimental studies have confirmed this biological effect. However, greenness effects on BP have not yet been explored using an observational study design. We assessed whether surrounding residential greenness is associated with BP in 10 year-old German children. Methods Systolic and diastolic BPs were assessed in 10 year-old children residing in the Munich and Wesel study areas of the German GINIplus and LISAplus birth cohorts. Complete exposure, outcome and covariate data were available for 2,078 children. Residential surrounding greenness was defined as the mean of Normalized Difference Vegetation Index (NDVI) values, derived from Landsat 5 TM satellite images, in circular 500-m buffers around current home addresses of participants. Generalized additive models assessed pooled and area-specific associations between BP and residential greenness categorized into area-specific tertiles. Results In the pooled adjusted model, the systolic BP of children living at residences with low and moderate greenness was 0.90 ± 0.50 mmHg (p-value = 0.073) and 1.23 ± 0.50 mmHg (p-value = 0.014) higher, respectively, than the systolic BP of children living in areas of high greenness. Similarly, the diastolic BP of children living in areas with low and moderate greenness was 0.80 ± 0.38 mmHg (p-value = 0.033) and 0.96 ± 0.38 mmHg (p-value = 0.011) higher, respectively, than children living in areas with high greenness. These associations were not influenced by environmental stressors (temperature, air pollution, noise annoyance, altitude and urbanisation level). When stratified by study area, associations were significant among children residing in the urbanised Munich area but null for those in the rural Wesel area. Conclusions Lower residential greenness was positively associated with higher BP in 10 year-old children living in an urbanised area. Further studies varying in participants’ age, geographical area and urbanisation level are required.

Background/Objectives: The SARS-CoV-2 pandemic challenged patients with inflammatory bowel disease (IBD) under immunosuppressive therapies. We used data from the RisCoin cohort to investigate factors associated with a poor immune response to mRNA vaccination in these patients. Methods: From 4115 RisCoin participants, we matched 110 IBD patients by age and time interval since the second mRNA vaccination with 306 healthcare workers (HCW) without comorbidities (HCW-healthy) and 292 with medical conditions (HCW-plus); all were SARS-CoV-2 infection naïve. Basic questionnaires collected data on medication, COVID-19 vaccinations and side-effects, dietary patterns, lifestyle factors, and self-perceived stress. Main outcomes included anti-spike immunoglobulin levels and antibody-mediated live-virus neutralization immunity (NT) to the Omicron BA.1 variant (threshold NT ≥ 10 defined as IC50 values ≥1:10 serum dilution) after the second (baseline) and third vaccinations. Results: At baseline, IBD patients treated with anti-TNF but not those under vedolizumab or ustekinumab therapy had lower anti-spike levels compared to HCW-healthy and HCW-plus (166 versus 1384 and 1258 BAU/mL, respectively; p < 0.0001). Anti-TNF compared to vedolizumab/ustekinumab-treated patients reached NT titers above threshold in 17% versus 64%, respectively, and HCW-subgroups in 73% and 79% (all p < 0.0001). Current smokers showed a four to five times increased risk for non-neutralizing immunity compared to non-smokers. After the third vaccination, NT titers did not reach threshold in 15% anti-TNF compared to 5% vedolizumab/ustekinumab-treated patients and none of HCW (p < 0.01). Patients with IBD reported fewer clinical symptoms after vaccination. Perceived stress was not increased. Conclusions: Our findings support individualized schedules for mRNA-based vaccines in IBD patients with different immunosuppressive therapies and enforcement of non-smoking.

NOD2 polymorphisms may affect sensing of the bacterial muramyl dipeptide (MDP) and trigger perturbed inflammatory responses. Genetic screening of a patient with immunodeficiency and enteropathy revealed a rare homozygous missense mutation in the first CARD domain of NOD2 (ENST00000300589; c.160G > A, p.E54K). Biochemical assays confirmed impaired NOD2-dependent signaling and proinflammatory cytokine production in patient’s cells and heterologous cellular models with overexpression of the NOD2 mutant. Immunoprecipitation-coupled mass spectrometry unveiled the ATPase valosin-containing protein (VCP) as novel interaction partner of wildtype NOD2, while the binding to the NOD2 variant p.E54K was abrogated. Knockdown of VCP in coloncarcinoma cells led to impaired NF-κB activity and IL8 expression upon MDP stimulation. In contrast, tunicamycin-induced ER stress resulted in increased IL8, CXCL1, and CXCL2 production in cells with knockdown of VCP, while enhanced expression of these proinflammatory molecules was abolished upon knockout of NOD2. Taken together, these data suggest that VCP-mediated inflammatory responses upon ER stress are NOD2-dependent.

The array of tests that can be used for diagnosis of Helicobacter pylori infection is large, and it can be confusing to define which test to use particularly in children where results may not be comparable to those obtained in adult patients. Using PubMed, we reviewed the English literature from January 1999 to May 2009 to identify articles that determined sensitivity and specificity of H. pylori invasive and non-invasive diagnostic tests in children. We excluded articles that presented a review of the literature, abstracts, case reports, or series where children’s results could not be separated from adult populations. Of the tissue based methods, rapid urease tests have better sensitivity than histology to detect presence of H. pylori ; however, histology can detect the pathology associated with disease including gastritis, intestinal metaplasia, and other conditions that could be the cause of the child’s symptoms. Culture of gastric tissues or stool has 100% specificity but sensitivity is low. Of the serologic tests, immunoblot has the best sensitivity. The urea breath tests have >75% sensitivity for detection of H. pylori before and after treatment. Immunoassays in stool using monoclonal antibodies have >95% sensitivity for detection of H. pylori before and after treatment. PCR testing can be performed in tissue and stool samples and can detect genes associated to antibiotic resistance. In summary, the current commercial non-invasive tests have adequate sensitivity and specificity for detecting the presence of H. pylori ; however, endoscopy with histopathology is the only method that can detect H. pylori and lesions associated with the infection.

In vitro studies, animal experiments, and human exposure studies have shown how ambient air pollution increases the risk of atopic diseases. However, results derived from observational studies are inconsistent. To assess the relationship between individual-based exposure to traffic-related air pollutants and allergic disease outcomes in a prospective birth cohort study during the first 6 years of life. We studied 2,860 children at the age of 4 years and 3,061 at the age of 6 years to investigate atopic diseases and allergic sensitization. Long-term exposure to particulate matter (PM(2.5)), PM(2.5) absorbance, and long-term exposure to nitrogen dioxide (NO(2)) was assessed at residential addresses using geographic information systems based regression models and air pollution measurements. The distance to the nearest main road was used as a surrogate for traffic-related air pollutants. Strong positive associations were found between the distance to the nearest main road and asthmatic bronchitis, hay fever, eczema, and sensitization. A distance-dependent relationship could be identified, with the highest odds ratios (ORs) for children living less than 50 m from busy streets. For PM(2.5) absorbance, statistically significant effects were found for asthmatic bronchitis (OR, 1.56; 95% confidence interval [CI], 1.03-2.37), hay fever (OR, 1.59; 95% CI, 1.11-2.27), and allergic sensitization to pollen (OR, 1.40; 95% CI, 1.20-1.64). NO(2) exposure was associated with eczema, whereas no association was found for allergic sensitization. This study provides strong evidence for increased risk of atopic diseases and allergic sensitization when children are exposed to ambient particulate matter.

Owing to advances in genomics that enable differentiation of molecular aetiologies, patients with monogenic inflammatory bowel disease (mIBD) potentially have access to genotype-guided precision medicine. In this Expert Recommendation, we review the therapeutic research landscape of mIBD, the reported response to therapies, the medication-related risks and systematic bias in reporting. The mIBD field is characterized by the absence of randomized controlled trials and is dominated by retrospective observational data based on case series and case reports. More than 25 off-label therapeutics (including small-molecule inhibitors and biologics) as well as cellular therapies (including haematopoietic stem cell transplantation and gene therapy) have been reported. Heterogeneous reporting of outcomes impedes the generation of robust therapeutic evidence as the basis for clinical decision making in mIBD. We discuss therapeutic goals in mIBD and recommend standardized reporting (mIBD REPORT (monogenic Inflammatory Bowel Disease Report Extended Phenotype and Outcome of Treatments) standards) to stratify patients according to a genetic diagnosis and phenotype, to assess treatment effects and to record safety signals. Implementation of these pragmatic standards should help clinicians to assess the therapy responses of individual patients in clinical practice and improve comparability between observational retrospective studies and controlled prospective trials, supporting future meta-analysis.In this Expert Recommendation, Uhlig and colleagues review the therapeutic landscape for monogenic inflammatory bowel disease and propose recommendations for standardized reporting of clinical outcomes.