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Circulating miRNAs as Potential Biomarkers for Celiac Disease Development.
Tan, IL, Coutinho de Almeida, R, Modderman, R, Stachurska, A, Dekens, J, Barisani, D, Meijer, CR, Roca, M, Martinez-Ojinaga, E, Shamir, R, et al
Frontiers in immunology. 2021;:734763
Abstract
BACKGROUND & AIMS Celiac disease (CeD), an immune-mediated disease with enteropathy triggered by gluten, affects ~1% of the general European population. Currently, there are no biomarkers to predict CeD development. MicroRNAs (miRNAs) are short RNAs involved in post-transcriptional gene regulation, and certain disease- and stage-specific miRNA profiles have been found previously. We aimed to investigate whether circulating miRNAs can predict the development of CeD. METHODS Using next-generation miRNA-sequencing, we determined miRNAs in >200 serum samples from 53 participants of the PreventCD study, of whom 33 developed CeD during follow-up. Following study inclusion at 3 months of age, samples were drawn at predefined ages, diagnosis (first anti-transglutaminase antibody (TGA) positivity or diagnostic biopsy) and after the start of a gluten-free diet (GFD). This allowed identification of circulating miRNAs that are deregulated before TGA positivity. For validation of the biomarkers for CeD and GFD response, two additional cohorts were included in subsequent meta-analyses. Additionally, miRNAs were measured in duodenal biopsies in a case-control cohort. RESULTS 53 circulating miRNAs were increased (27) or decreased (26) in CeD versus controls. We assessed specific trends in these individual miRNAs in the PreventCD cohort by grouping the pre-diagnostic samples of the CeD patients (all had negative TGA) by how close to seroconversion (first sample positive TGA) the samples were taken. 8/53 miRNAs differed significantly between controls and samples taken <1 year before TGA positivity: miR-21-3p, miR-374a-5p, 144-3p, miR-500a-3p, miR-486-3p let-7d-3p, let-7e-5p and miR-3605-3p. 6/26 downregulated miRNAs reconstituted upon GFD, including miR-150-5p/-3p, whereas no upregulated miRNAs were downregulated upon GFD. 15/53 biomarker candidates also differed between CeD biopsies and controls, with a concordant direction, indicating that these circulating miRNAs might originate from the intestine. CONCLUSIONS We identified 53 circulating miRNAs that are potential early biomarkers for CeD, of which several can be detected more than a year before TGA positivity and some start to normalize upon GFD.
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Systematic Review with Meta-Analysis: Lactobacillus reuteri DSM 17938 for Treating Acute Gastroenteritis in Children. An Update.
Patro-Gołąb, B, Szajewska, H
Nutrients. 2019;11(11)
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Acute gastroenteritis (AGE) is a common health problem in children and, globally, diarrhoea is one of the leading causes of death in children younger than the age of 5 years. Probiotics have been extensively studied as a supportive treatment regimen in children with AGE and shown to be effective in reducing both diarrhoea duration and severity, and potentially reducing the duration of hospitalization. The aim of this systematic review and meta-analysis of four randomised controlled trials including 347 children was to provide an update on the research into a particular strain of Lactobacillus reuteri for the treatment of AGE. The meta-analysis showed a significantly reduced duration of illness and hospitalisation, as well as increased cure rate on day 1 and 2, but not 3, 4 or 5. Based on two of the four trials there was no difference in number of watery stools on day 1, 2, 3 or 4. The authors note that the clinical relevance of the findings was limited due to the small effect size and methodological limitations of the included studies.
Abstract
The effectiveness of Lactobacillus reuteri DSM 17938 (L. reuteri) for the management of acute gastroenteritis (AGE) has been recently questioned. We performed a systematic review to update evidence on L. reuteri for treating AGE in children. We searched MEDLINE, EMBASE, the Cochrane Library databases, and additional data sources from January 2016 (end of search for our 2016 systematic review) to August 2019. The primary outcomes were stool volume and duration of diarrhea. Four RCTs were included. None of them evaluated stool volume. Compared with placebo or no treatment, L. reuteri reduced diarrhea duration (four RCTs, n = 347, mean difference, MD -0.87 days, 95% CI [-1.43, -0.31]). L. reuteri use was also associated with a reduced duration of hospitalization (three RCTs, n = 284, MD -0.54 days, 95% CI [-1.09, 0.0]). The small effect sizes of limited clinical relevance and methodological limitations of the included trials should be noted when interpreting these findings.
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Lactobacillus rhamnosus GG in the Primary Prevention of Eczema in Children: A Systematic Review and Meta-Analysis.
Szajewska, H, Horvath, A
Nutrients. 2018;(9)
Abstract
Current guidelines recommend the use of probiotics to reduce the risk of eczema. It remains unclear which strain(s) to use. We systematically evaluated data on the efficacy of Lactobacillus rhamnosus GG (LGG) supplementation prenatally and/or postnatally for the primary prevention of eczema. The Cochrane Library, MEDLINE, and EMBASE databases were searched up to August 2018, with no language restrictions, for systematic reviews of randomized controlled trials (RCTs) and RCTs published afterwards. The primary outcome was eczema. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (CI). A random-effects model was used to pool data. Heterogeneity was explored using the I² statistics. The GRADE criteria were used to assess the overall quality of evidence supporting the primary outcome. Seven publications reporting 5 RCTs (889 participants) were included. High to moderate certainty in the body of evidence suggests that LGG supplementation (regardless of the timing of administration) did not reduce the risk of eczema. There was also no consistent effect on other allergic outcomes. This meta-analysis shows that LGG was ineffective in reducing eczema. It does not support the general recommendation to use probiotics for preventing eczema, unless specific strains would be indicated.
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Systematic review with meta-analysis: early infant feeding and coeliac disease--update 2015.
Szajewska, H, Shamir, R, Chmielewska, A, Pieścik-Lech, M, Auricchio, R, Ivarsson, A, Kolacek, S, Koletzko, S, Korponay-Szabo, I, Mearin, ML, et al
Alimentary pharmacology & therapeutics. 2015;(11):1038-54
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BACKGROUND New evidence emerged on early feeding practices and the risk of coeliac disease. AIM: To systematically update evidence on these practices to find out whether there is a need to revise current recommendations. METHODS MEDLINE, EMBASE and the Cochrane Library were searched from July 2012 (end of last search) to February 2015 for studies of any design that assessed the effect of gluten consumption and breastfeeding on the development of coeliac disease and/or coeliac disease-related autoimmunity. RESULTS We identified 21 publications, including two, new, large, randomised controlled trials performed in high-risk infants. Exclusive or any breastfeeding, as well as breastfeeding at the time of gluten introduction, did not reduce the risk of developing coeliac disease during childhood. For infants at high risk of developing coeliac disease, gluten introduction at 4 months of age in very small amounts, or at 6 or 12 months of age, resulted in similar rates of coeliac disease diagnosis in early childhood. Later gluten introduction was associated with later development of coeliac specific autoimmunity and coeliac disease during childhood, but not total risk reduction. Observational studies indicate that consumption of a higher amount of gluten at weaning may increase the risk for coeliac disease development. CONCLUSIONS Infant feeding practices (breastfeeding, time of gluten introduction) have no effect on the risk of developing coeliac disease during childhood (at least at specific timeframes evaluated in the included studies), necessitating an update of current European recommendations.
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Lactobacillus reuteri DSM 17938 for managing infant colic: protocol for an individual participant data meta-analysis.
Sung, V, Cabana, MD, D'Amico, F, Deshpande, G, Dupont, C, Indrio, F, Mentula, S, Partty, A, Savino, F, Szajewska, H, et al
BMJ open. 2014;(12):e006475
Abstract
INTRODUCTION Infant colic, or excessive crying of unknown cause in infants less than 3 months old, is common and burdensome. Its aetiology is undetermined, and consensus on its management is still lacking. Recent studies suggest a possible link between infant colic and gut microbiota, indicating probiotics to be a promising treatment. However, only a few strains have been tested, and results from randomised controlled trials are conflicting. It is important to clarify whether probiotics are effective for treating infant colic in general, and to identify whether certain subgroups of infants with colic would benefit from particular strains of probiotics. METHODS AND ANALYSIS Through an individual participant data meta-analysis (IPDMA), we aim to identify whether the probiotic Lactobacillus reuteri DSM 17938 is effective in the management of infant colic, and to clarify whether its effects differ according to feeding method (breast vs formula vs combined), proton pump inhibitor exposure, and antibiotic exposure. The primary outcomes are infant crying duration and treatment success (at least 50% reduction in crying time from baseline) at 21 days postintervention. Individual participant data from all studies will be modelled simultaneously in multilevel generalised linear mixed-effects regression models to account for the nesting of participants within studies. Subgroup analyses of participant-level and intervention-level characteristics will be undertaken on the primary outcomes to assess if the intervention effect differs between certain groups of infants. ETHICS AND DISSEMINATION Approved by the Royal Children's Hospital Human Research Ethics Committee (HREC 34081). Results will be reported in a peer-reviewed journal in 2015. TRIAL REGISTRATION NUMBER PROSPERO CRD42014013210.
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The role of meta-analysis in the evaluation of the effects of early nutrition on mental and motor development in children.
Szajewska, H
The American journal of clinical nutrition. 2011;(6 Suppl):1889S-1895S
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Abstract
The role of early nutrition as a cost-effective measure to ensure optimal infant growth, development, and long-term health is gaining attention. In particular, the role of supplementation with nutrients such as n-3 (omega-3) fatty acids, iron, zinc, and B vitamins, which are relevant to brain structure and function, is of interest. However, for all of these nutrients, there is a lack of clarity and no consensus regarding their role in the mental and motor development of children. Systematic reviews with or without a meta-analysis are a well-established means of reviewing existing evidence and of integrating findings from various studies, including those related to infant nutrition. In this article, I provide an overview of the basic principles of systematic review and meta-analysis of randomized controlled trials (RCTs) and summarize such evidence related to the effects of early nutrition on mental and motor development. The inclusion of only RCTs in a systematic review could be considered the major strength. Randomization is the only means to control for unknown and unmeasured differences between comparison groups as well as for those that are known and measured. However, even if only RCTs are included, reviews are not free of potential biases. An understanding of the strengths and limitations of the meta-analytic approach, which I discuss in this article, is needed by everyone involved in decision making regarding interventions assessed by this approach.
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Meta-analysis: Lactobacillus rhamnosus GG for abdominal pain-related functional gastrointestinal disorders in childhood.
Horvath, A, Dziechciarz, P, Szajewska, H
Alimentary pharmacology & therapeutics. 2011;(12):1302-10
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BACKGROUND A lack of reliable treatments for abdominal pain-related functional gastrointestinal disorders prompts interest in new therapies. AIM: To evaluate systematically the effect of Lactobacillus rhamnosus GG (LGG) for treating abdominal pain-related functional gastrointestinal disorders in children. METHODS MEDLINE, EMBASE, CINAHL, the Cochrane Library, trial registries and proceedings of major meetings were searched for randomised controlled trials (RCTs) evaluating LGG supplementation in children with abdominal pain-related functional gastrointestinal disorders based on the Rome II or Rome III criteria. Risk of bias was assessed for generation of the allocation sequence, allocation concealment, blinding and follow-up. RESULTS Compared with placebo, LGG supplementation was associated with a significantly higher rate of treatment responders (defined as no pain or a decrease in pain intensity) in the overall population with abdominal pain-related functional gastrointestinal disorders (three RCTs, n = 290; risk ratio, RR 1.31, 95% CI 1.08-1.59, number needed to treat, NNT 7, 95% CI 4-22) and in the irritable bowel syndrome (IBS) subgroup (three RCTs, n = 167; RR 1.70, 95% CI 1.27-2.27, NNT 4, 95% CI 3-8). However, no difference was found in the rate of treatment responders between children with functional abdominal pain or functional dyspepsia who received placebo or LGG. The intensity of pain was significantly reduced in the overall study population and in the IBS subgroup. The frequency of pain was significantly reduced in the IBS subgroup only. CONCLUSION The use of Lactobacillus rhamnosus GG moderately increases treatment success in children with abdominal pain-related functional gastrointestinal disorders, particularly among children with IBS.
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Meta-analysis: the effects of Saccharomyces boulardii supplementation on Helicobacter pylori eradication rates and side effects during treatment.
Szajewska, H, Horvath, A, Piwowarczyk, A
Alimentary pharmacology & therapeutics. 2010;(9):1069-79
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BACKGROUND Problems with currently recommended Helicobacter pylori eradication therapies include unsatisfactory eradication rates and/or therapy-associated side effects. AIM: To investigate the effects of Saccharomyces boulardii as supplementation to standard triple therapy on H. pylori eradication rates and therapy-associated side effects. METHODS The Cochrane Library, MEDLINE and EMBASE databases were searched in July 2010, with no language restrictions, for randomized controlled trials (RCTs); additional references were obtained from reviewed articles. RESULTS Five RCTs involving a total of 1307 participants (among them only 90 children) met the inclusion criteria. Compared with placebo or no intervention, S. boulardii given along with triple therapy significantly increased the eradication rate [four RCTs, n = 915, relative risk (RR) 1.13, 95% confidence interval (CI) 1.05-1.21] and reduced the risk of overall H. pylori therapy-related adverse effects (five RCTs, n = 1305, RR 0.46, 95% CI 0.3-0.7), particularly of diarrhoea (four RCTs, n = 1215, RR 0.47, 95% CI 0.32-0.69). There were no significant differences between groups in the risk of other adverse effects. CONCLUSION In patients with H. pylori infection, there is evidence to recommend the use of S. boulardii along with standard triple therapy as an option for increasing the eradication rates and decreasing overall therapy-related side effects, particularly diarrhoea.
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Meta-analysis: enteral nutrition in active Crohn's disease in children.
Dziechciarz, P, Horvath, A, Shamir, R, Szajewska, H
Alimentary pharmacology & therapeutics. 2007;(6):795-806
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BACKGROUND Controversy exists surrounding the optimal treatment for inducing remission in active Crohn's disease. AIM: To review and update evidence on the effectiveness of enteral nutrition (EN) in treating active Crohn's disease in children. METHODS MEDLINE, EMBASE and The Cochrane Library (up to February 2007) were searched for randomized controlled trials (RCTs) relevant to Crohn's disease and EN in children. RESULTS We included 11 RCTs (n = 394). Seven RCTs (n = 204) compared EN with corticosteroid therapy. On the basis of pooled results of four RCTs (n = 144), we found no significant difference in the remission rates between groups (relative risk, RR 0.97, 95% CI 0.7-1.4, random effect model). Four RCTs (n = 190) compared two EN regimens. One of the four RCTs (n = 50) revealed a significant increase in the percentage of patients achieving remission in the total EN group compared with the partial EN group (RR 2.7, 95% CI 1-7.4). Because of lack of data, formal pooling of results was not possible for many outcomes (e.g., time until remission, duration of remission, growth data). CONCLUSIONS Limited data suggest similar efficacy for EN and corticosteroids. As the number of patients needed to provide a definite answer is too large, future studies should focus on detailed outcome measurements including growth and quality of life.