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Background: Eosinophilic esophagitis (EoE) predominantly affects males across all ages; however, little is known about sex differences for other aspects of EoE., Objective: To investigate associations between sex and clinical presentation, endoscopic features, treatment choice and response in EoE patients in real-world practice., Methods: Cross-sectional analysis of the multicenter EoE CONNECT registry. The independent contribution of patients' sex and other relevant variables were statistically assessed by multivariate models., Results: A total of 2976 patients (76% male) were evaluated. Males were diagnosed at a younger age compared to females (32.7 ± 14.8 vs. 34.8 ± 15.6 years, respectively; p = 0.002) with similar diagnostic delay. EoE symptoms varied significantly between sexes, with food impaction predominating in males and dysphagia, heartburn, regurgitation and abdominal and epigastric pain in females. However, female sex contributed to higher symptom severity at diagnosis as measured with Dysphagia Symptom Score (R 2  = 0.57; p = 0.013) and presented higher peak eosinophil count in esophageal biopsies (p = 0.005). Males showed increased risk of stricturing or mixed phenotypes (adjusted OR 1.43, 95%CI:1.05-1.96; p = 0.024). No association was found between patients' sex and first-line treatment modality: proton pump inhibitors (PPI) were preferred over topical corticosteroids in patients with inflammatory phenotypes instead of stricturing or mixed phenotypes, and in patients who did not present food impaction. Both topical corticosteroids and dietary interventions were preferred over PPI in pediatric patients regardless of sex., Conclusions: Sex is associated with clinical and phenotypical presentation of EoE at diagnosis, with more fibrotic findings in males but higher symptom score in females., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Introduction: Genetic variations impact drug response, driving the need for personalised medicine through pre-emptive pharmacogenetic testing. However, the adoption of pre-emptive pharmacogenetic testing for commonly prescribed drugs, such as statins, outside of tertiary hospitals is limited due to a lack of pharmacoeconomic evidence to support widespread implementation by healthcare policy-makers. The Spanish Consortium for the Implementation of Pharmacogenetics (iPHARMGx Consortium) addresses this by developing a clinical trial master protocol that will govern multiple nested adaptive clinical trials that compare genotype-guided treatments to standard care in specific drug-gene-population triads, asses their cost-efficacy and identify novel biomarkers through advanced sequencing techniques. The first of these studies aims to assess whether a pre-emptive statin therapy genotyping scheme reduces the incidence of statin-associated muscle symptoms (SAMS) in a population at risk of cardiovascular disease susceptible of receiving high-intensity or moderate-intensity doses of statins: The PREVESTATGx trial., Methods and Analysis: the PREVESTATGX trial is a multicentre, adaptive randomised controlled pragmatic phase IV clinical trial nested to the iPHARMGx master protocol with two parallel arms, aiming for superiority. Randomisation will be conducted on an individual basis with a centralised approach and stratification by centre. After inclusion in the trial and genotyping has been performed, subjects will be randomly allocated to experimental group (pharmacogenetic genotype-guided statin prescription) or standard-of-care statin prescription (as deemed by attending physician). The main objective is to assess the efficacy of a statin pre-emptive genotyping strategy in reducing the incidence of SAMS. A total of 225 subjects will be recruited among the 10 participating centres if no futility/efficacy boundary is reached in the prespecified interim analyses. Recruitment will be carried out during a 12-month period and subjects will be followed for a 9-month period., Ethics and Dissemination: The PREVESTATGx trial received ethical approval on 24 April 2024. Results will be disseminated via publication in peer-reviewed journals as well as presentation at international conferences. Trial results will be submitted for publication in an open-access peer-reviewed medical speciality-specific publication., Trial Registration Number: EU CT number: 2023-509418-12-00/Clinical trial Identifier (ClinicalTrials.gov): NCT06262685. Protocol version 1.2 12 April 2024 (includes non-substantial modification number 14 June 2024). Trial registration of this study can be located at both the EU Clinical Trials Register available from https:// euclinicaltrials.eu/search-for-clinical-trials/?lang=en and https://clinicaltrials.gov. Registration on both websites was done before the enrolment of the first patient complying with European regulations. EU Clinical Trials Register is a primary registry according to the WHO., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Exhaled breath tests (BTs) are the main diagnostic method for fructose and lactose malabsorption/intolerance (FI and LI, respectively) and for detecting small intestine bacterial or methanogen overgrowth (SIBO/IMO). Although FI/LI-BTs may provide evidence of the presence of SIBO/IMO, there is limited literature evaluating their reliability for this purpose. The objective of this study was to assess the sensitivity and specificity of FI/LI-BTs in detecting SIBO and their concordance with SIBO-BTs in the identification of IMO., Methods: In this retrospective observational study, FI/LI-BTs and SIBO-BTs performed in the same patients within a period of 6 weeks were selected from 652 gas chromatography-based BTs., Results: A total of 146 BTs from 67 eligible adult patients were identified. LI-BTs had higher specificity than FI-BT in detecting SIBO (93.8 % vs. 72.7 %). In contrast, FI-BTs showed higher sensitivity (60.0 % vs. 28.6 %) as FI was more frequently established in SIBO-positive patients (70 % vs. 29 %). With regard to IMO, concordance with LI-BT was 100 %, with a 27 % of false negatives on FI-BTs., Conclusions: Findings suggestive of SIBO or IMO on LI-BTs were highly consistent with those of SIBO-BTs. In contrast, the rate of false positives for SIBO and the rate of false negative for IMO on FI-BTs was 27 % in both cases., Competing Interests: Competing interests: The authors state no conflict of interest., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Background: HLA-DQA1*05 carriage has been associated with an increased risk of immunogenicity in patients with immune-mediated inflammatory diseases treated with tumour necrosis factor-alpha [TNF-a] antagonists. Results have shown an inconsistent association with a loss of response [LOR] in patients with inflammatory bowel disease [IBD], which could be modified when using proactive optimisation and association with immunomodulatory drugs., Aims: To define the association of HLA-DQA1*05 on anti-drug antibody development and loss of response [LOR] to anti-TNF-a in IBD., Methods: We searched MEDLINE, EMBASE, and SCOPUS, for the period up to August 2023, to identify studies reporting the risk of immunogenicity and/or LOR in IBD patients with HLA-DQA1*05 genotype., Results: A total of 24 studies comprising 12 papers, 11 abstracts and one research letter, with a total of 5727 IBD patients, were included. In a meta-analysis of 10 studies [2984 patients; 41.9% with HLA-DQA1*05 genotype], HLA-DQA1*05 carriers had higher risk of immunogenicity compared with non-carriers (risk ratio, 1.54; 95% confidence interval [CI], 1.23 - 1.94; I2 = 62%) [low certainty evidence]. Lack of therapeutic drug monitoring [TDM] increased immunogenicity in the presence of risk human leukocyte antigen [HLA] [risk ratio 1.97; 95% CI, 1.35 - 2.88; I2 = 66%], whereas proactive TDM revoked this association [very low certainty of evidence]. A meta-analysis of six studies [765 patients] found that risk for secondary LOR was higher among HLA-DQA1*05 carriers [hazard ratio 2.21; 95% CI, 1.69 - 2.88; I2 = 0%] [very low certainty evidence], although definition and time to assessment varied widely among studies., Conclusion: HLA-DQA1*05 carriage may be associated with an increased risk of immunogenicity and secondary LOR in IBD patients treated with TNF-a antagonists., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Recently, we have identified a dysregulated protein signature in the esophageal epithelium of eosinophilic esophagitis (EoE) patients including proteins associated with inflammation and epithelial barrier function; however, the effect of proton pump inhibitor (PPI) treatment on this signature is unknown. Herein, we used a proteomic approach to investigate: (1) whether PPI treatment alters the esophageal epithelium protein profile observed in EoE patients and (2) whether the protein signature at baseline predicts PPI response., Methods: We evaluated the protein signature of esophageal biopsies using a cohort of adult EoE (n = 25) patients and healthy controls (C) (n = 10). In EoE patients, esophageal biopsies were taken before (pre) and after (post) an 8-week PPI treatment, determining the histologic response. Eosinophil count PostPPI was used to classify the patients: ≥15 eosinophils/hpf as non-responders (non-responder) and < 15 eosinophils/hpf as responders (R). Protein signature was determined and differentially accumulated proteins were characterized to identify altered biological processes and signaling pathways., Results: Comparative analysis of differentially accumulated proteins between groups revealed common signatures between three groups of patients with inflammation (responder-PrePPI, non-responder-PrePPI, and non-responder-PostPPI) and without inflammation (controls and responder-PostPPI). PPI therapy almost reversed the EoE specific esophageal protein signature, which is enriched in pathways associated with inflammation and epithelial barrier function, in responder-PostPPI. Furthermore, we identified a set of candidate proteins to differentiate responder-PrePPI and non-responder-PrePPI EoE patients before treatment., Conclusion: These findings provide evidence that PPI therapy reverses the alterations in esophageal inflammatory and epithelial proteins characterizing EoE, thereby providing new insights into the mechanism of PPI clinical response. Interestingly, our results also suggest that PPI response could be predicted at baseline in EoE., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

This study compared short-term effectiveness of proton pump inhibitors (PPI), swallowed topical corticosteroids (STC), and dietary therapies in reversing clinical and histological features in pediatric patients with eosinophilic esophagitits (EoE). Determinants for treatment choice and PPI therapy effectiveness were also assessed.  A cross-sectional study analysis of patients under 18 years old recruited onto the multicenter EoE CONNECT registry was performed. Clinico-histological response was defined as symptomatic improvement plus a peak eosinophil count below 15 per high-power field after treatment. Effectiveness of first-line options used in monotherapy was compared. Overall, 393 patients (64% adolescents) receiving PPI, STC, or dietary monotherapy to induce EoE remission were identified. PPI was the preferred option (71.5%), despite STC providing the highest clinico-histological response rates (66%) compared to PPI (44%) and diet (42%). Logistic regression identified fibrotic features and recruitment at Italian sites independently associated to first-line STC treatment; age under 12 associated to dietary therapy over other options. Analysis of 262 patients in whom PPI effectiveness was evaluated after median (IQR) 96 (70-145) days showed that this effectiveness was significantly associated with management at pediatric facilities and use of high PPI doses. Among PPI responders, decrease in rings and structures in endoscopy from baseline was documented, with EREFS fibrotic subscore for rings also decreasing among responders (0.27 ± 0.63 vs. 0.05 ± 0.22, p < 0.001).    Conclusion: Initial therapy choice for EoE depends on endoscopic phenotype, patient's age, and patients' origin. High PPI doses and treatment in pediatric facilities significantly determined effectiveness, and reversed fibrotic endoscopic features among responders. What is Known: • Proton pump inhibitors are widely used to induce and maintain remission in EoE in real practice, despite other first-line alternative therapies possibly providing higher effectiveness. What is New: • Proton pump inhibitors represent up to two-thirds of first-line monotherapies used to induce EoE remission in pediatric and adolescent patients with EoE. The choice of STC as first-line treatment for EoE was significantly associated with fibrotic features at baseline endoscopy and recruitment in Italian centers; age less than 12 years was associated with dietary therapy. • PPI effectiveness was found to be determined by use of high doses, attendance at pediatric facilities, presenting inflammatory instead of fibrotic or mixed phenotypes, and younger age. Among responders, PPI therapy reversed both inflammatory and fibrotic features of EoE after short-term treatment., (© 2024. The Author(s).)

Background: Swallowed topical corticosteroids (tC) are common therapy for patients with eosinophilic esophagitis (EoE). Widely heterogeneous results have occurred due to their active ingredients, formulations and doses., Objective: To assess the effectiveness of topical corticosteroid therapy for EoE in real-world practice., Methods: Cross-sectional study analysis of the multicentre EoE CONNECT registry. Clinical remission was defined as a decrease of ≥50% in dysphagia symptom scores; histological remission was defined as a peak eosinophil count below 15 per high-power field. The effectiveness in achieving clinico-histological remission (CHR) was compared for the main tC formulations., Results: Overall, data on 1456 prescriptions of tC in monotherapy used in 866 individual patients were assessed. Of those, 904 prescriptions with data on formulation were employed for the induction of remission; 234 reduced a previously effective dose for maintenance. Fluticasone propionate formulations dominated the first-line treatment, while budesonide was more common in later therapies. A swallowed nasal drop suspension was the most common formulation of fluticasone propionate. Doses ≥0.8 mg/day provided a 65% CHR rate and were superior to lower doses. Oral viscous solution prepared by a pharmacist was the most common prescription of budesonide; 4 mg/day provided no benefit over 2 mg/day (CHR rated being 72% and 80%, respectively). A multivariate analysis revealed budesonide orodispersible tablets as the most effective therapy (OR 18.9, p < 0.001); use of higher doses (OR 4.3, p = 0.03) and lower symptom scores (OR 0.9, p = 0.01) were also determinants of effectiveness., Conclusion: Reduced symptom severity, use of high doses, and use of budesonide orodispersible tablets particularly were all independent predictors of tC effectiveness., (© 2024 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Competing Interests: Conflicto de intereses: Los autores declaran no tener ningún conflicto de intereses.

Proton-pump inhibitors (PPIs) are the most administered first-line treatment for eosinophilic esophagitis (EoE). However, only around half of EoE patients respond histologically to a double dosage of PPI. In addition, 70% of responders maintain EoE in remission after tapering the PPI dose. In order to avoid endoscopy with biopsies-the only accurate method of assessing PPI response-efforts have been made to identify PPI responder patients. The clinical or endoscopic features and biomarkers evaluated so far, however, have not proven to be sufficient in predicting PPI response. Although new approaches based on omics technologies have uncovered promising biomarkers, the specialized and complex procedures required are difficult to implement in clinical settings. Alternatively, PPI pharmacogenetics based on identifying variations in CYP2C19 and STAT6 genes have shown promising results in EoE, and could easily be performed in most laboratories. Other genetic variations have also been associated with PPI response and may explain those cases not related to CYP2C19 or STAT6 . Here, we provide an overview of PPI treatment in EoE and evidence of how genetic variations in CYP2C19 and other genes could affect PPI effectiveness, and also discuss studies evaluating the role of pharmacogenetics in predicting PPI response in patients with EoE.

Proton pump inhibitors (PPIs) are the first-line drug for eosinophilic esophagitis (EoE), although it is estimated that there is a lack of histological remission in 50% of patients. This research aimed to identify pharmacogenetic biomarkers predictive of PPI effectiveness and to study their association with disease features. Peak eosinophil count (PEC) and the endoscopic reference score (EREFS) were determined before and after an eight-week PPI course in 28 EoE patients. The impact of the signal transducer and activator of transcription 6 ( STAT6 ), CYP2C19 , CYP3A4 , CYP3A5, and ABCB1 genetic variations on baseline PEC and EREFS, their reduction and histological response, and on EoE symptoms and comorbidities was analyzed. PEC reduction was higher in omeprazole-treated patients (92.5%) compared to other PPIs (57.9%, p = 0.003). STAT6 rs12368672 (g.18453G>C) G/G genotype showed higher baseline PEC values compared to G/C and C/C genotypes (83.2 vs. 52.9, p = 0.027). EREFS reduction in STAT6 rs12368672 G/G and G/C genotypes was higher than in the C/C genotype (36.7% vs. -75.0% p = 0.011). However, significance was lost after Bonferroni correction. Heartburn incidence was higher in STAT6 rs167769 (g.27148G>A) G/G patients compared to G/A (54.55% vs. 11.77%, p = 0.030). STAT6 rs12368672G>C and rs167769G>A variants might have a relevant impact on EoE status and PPI response. Further research is warranted to clarify the clinical relevance of these variants.

Eosinophilic esophagitis (EoE) is a chronic, progressive, type 2 inflammatory disease with increasing global prevalence. An eosinophil-predominant inflammation that permeates the epithelium and deeper esophageal layers characterizes the disease. Several cytokines, mainly derived from inflammatory T-helper 2 (Th2) cells and epithelial cells, are involved in perpetuating inflammatory responses by increasing surface permeability and promoting tissue remodeling characterized by epithelial-mesenchymal transition (EMT) and collagen deposition. This leads to esophageal strictures and narrow caliber esophagi, which are proportional a patient's age and untreated disease length. Pathophysiological mechanisms leading to EoE have been described in recent years, and transforming growth factor beta (TGF)-beta have been involved in fibrotic phenomena in EoE. However, evidence on the dependence of these phenomena on TGF-beta is scarce and contradictory. This review provides state-of-the art knowledge on intimate mechanisms of esophageal fibrosis in EoE and its clinical consequences.

Background: Eosinophilic esophagitis (EoE) is a chronic non-IgE-mediated allergic disease of the esophagus. An unbiased proteomics approach was performed to investigate pathophysiological changes in esophageal epithelium. Additionally, an RNAseq-based transcriptomic analysis in paired samples was also carried out., Methods: Total proteins were purified from esophageal endoscopic biopsies in a cohort of adult EoE patients (n = 25) and healthy esophagus controls (n = 10). Differentially accumulated (DA) proteins in EoE patients compared to control tissues were characterized to identify altered biological processes and signaling pathways. Results were also compared with a quantitative proteome dataset of the human esophageal mucosa. Next, results were contrasted with those obtained after RNAseq analysis in paired samples. Finally, we matched up protein expression with two EoE-specific mRNA panels (EDP and Eso-EoE panel)., Results: A total of 1667 proteins were identified, of which 363 were DA in EoE. RNA sequencing in paired samples identified 1993 differentially expressed (DE) genes. Total RNA and protein levels positively correlated, especially in DE mRNA-proteins pairs. Pathway analysis of these proteins in EoE showed alterations in immune and inflammatory responses for the upregulated proteins, and in epithelial differentiation, cornification and keratinization in those downregulated. Interestingly, a set of DA proteins, including eosinophil-related and secreted proteins, were not detected at the mRNA level. Protein expression positively correlated with EDP and Eso-EoE, and corresponded with the most abundant proteins of the human esophageal proteome., Conclusions: We unraveled for the first time key proteomic features involved in EoE pathogenesis. An integrative analysis of transcriptomic and proteomic datasets provides a deeper insight than transcriptomic alone into understanding complex disease mechanisms., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: To predict primary failure of infliximab (IFX) therapy in Crohn's disease (CD) and to identify patients who maintain long-term effectiveness to IFX is currently not feasible. Some genetic variations are proposed as potential biomarkers., Aim: We assessed a set of single nucleotide polymorphisms (SNPs) in genes related to the IFX mechanism of action and the presence of HLA-DQA1 * 05 allele on the primary response and long-term durability in CD patients., Methods: A multi-centre cross-sectional study of IFX-exposed adult patients with CD was undertaken. Treatment persistence and time to failure were co-primary endpoints. DNA from the 131 patients was genotyped. Association between SNPs and clinical variables with IFX persistence was assessed., Results: Failure to IFX was documented in 65 (49.6%) out of 131 patients. IFX persistence was associated either with carrying the TT genotype in ADAM17 rs10929587 (ORa=0.2; 95%CI=0.1-0.8; p = 0.021), or the CC genotype in SLCO1C1 rs3794271 (ORa=0.2; 95%CI=0.1-0.7; p = 0.008), according to multivariate logistic regression. In contrast, previous bowel resection increased the risk of IFX failure (ORa=2.8; 95%CI=1.1-7.3; p = 0.025). Cox regression analysis confirmed these findings and also identified IL23R rs10489629-TT (HRa 0.41; 95%CI=0.22-0.75; p = 0.004) and concomitant immunosuppressants (HRa 0.46; 95%CI=0.27-0.77; p = 0.003) as protection from IFX failure. However, no association between HLA-DQA1 * 05 allele and persistence of IFX therapy was found, with similar failure rates among carriers and non-carriers (52.8% vs. 47.4%, respectively; p = 0.544)., Conclusions: SNPs rs10929587-TT in ADAM17, rs10489629-TT in IL23R and rs3794271-CC in SLCO1C1, together with no previous bowel surgery and concomitant immunosuppression, were identified as protection from failure to IFX., Competing Interests: Conflict of interest statement The authors have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Direct comparisons of childhood- and adulthood-onset eosinophilic esophagitis (EoE) are scarce., Aim: To compare disease characteristics, endoscopic and histological features, allergic concomitances and therapeutic choices across ages., Methods: Cross-sectional analysis of the EoE CONNECT registry., Results: The adulthood-onset cohort (those diagnosed at ≥18y) comprised 1044 patients and the childhood-onset cohort (patients diagnosed at <18 y), 254. Vomiting, nausea, chest and abdominal pain, weight loss, slow eating and food aversion were significantly more frequent in children; dysphagia, food bolus impaction and heartburn predominated in adults. A family history of EoE was present in 16% of pediatric and 8.2% of adult patients (p<0.001). Concomitant atopic diseases did not vary across ages. Median±IQR diagnostic delay (years) from symptom onset was higher in adults (2.7 ± 6.1) than in children (1 ± 2.1; p<0.001). Esophageal strictures and rings predominated in adults (p<0.001), who underwent esophageal dilation more commonly (p = 0.011). Inflammatory EoE phenotypes were more common in children (p = 0.001), who also presented higher eosinophil counts in biopsies (p = 0.015) and EREFS scores (p = 0.017). Despite PPI predominating as initial therapy in all cohorts, dietary therapy and swallowed topical corticosteroids were more frequently prescribed in children (p<0.001)., Conclusions: Childhood-onset EoE has differential characteristics compared with adulthood-onset, but similar response to treatment., Competing Interests: Conflict of Interest AJ Lucendo has served as a speaker, and/or has received research and/or education funding and/or consulting fees from Adare/Ellodi, Dr. Falk Pharma, Regeneron, Dr. Falk Pharma and EsoCap. C. Santander received honoraria as consultant and trainer at Laborie/MMS and Medtronic Covidien AG, and received research funding from AstraZeneca, EsoCap Biotech, Regeneron Pharmaceuticals Inc., Adare Pharmaceuticals Inc., and Dr. Falk Pharma GmbH. J. Alcedo has served as a speaker, consultant and advisory member for or has received research funding from Adare Pharmaceuticals Inc, Abbvie, MSD, Allergan, and Shire Pharmaceuticals. C Gutiérrez-Junquera has received research funding from Dr. Falk Pharma. The remaining authors have no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Eosinophilic esophagitis (EoE) is a chronic, Th2-inflammatory disease of the esophagus that can severely affect food intake. Currently, diagnosis and assessing response to treatment of EoE is highly invasive and requires endoscopy with esophageal biopsies. Finding non-invasive and accurate biomarkers is important for improving patient well-being. Unfortunately, EoE is usually accompanied by other atopies, which make it difficult to identify specific biomarkers. Providing an update of circulating EoE biomarkers and concomitant atopies is therefore timely. This review summarizes the current knowledge in EoE blood biomarkers and two of its most common comorbidities, bronchial asthma (BA) and atopic dermatitis (AD), focusing on dysregulated proteins, metabolites, and RNAs. It also revises the current knowledge on extracellular vesicles (EVs) as non-invasive biomarkers for BA and AD, and concludes with the potential use of EVs as biomarkers in EoE.

The stool antigen test (SAT) represents an attractive alternative for detection of Helicobacter pylori. The aim of this study was to assess the accuracy of a new SAT, the automated LIAISON® Meridian H. pylori SA based on monoclonal antibodies, compared to the defined gold standard 13C-urea breath test (UBT). This prospective multicentre study (nine Spanish centres) enrolled patients ≥18 years of age with clinical indication to perform UBT for the initial diagnosis and for confirmation of bacterial eradication. Two UBT methods were used: mass spectrometry (MS) including citric acid (CA) or infrared spectrophotometry (IRS) without CA. Overall, 307 patients (145 naïve, 162 with confirmation of eradication) were analysed. Using recommended cut-off values (negative SAT < 0.90, positive ≥ 1.10) the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 67%, 97%, 86%, 92% and 91%, respectively, obtaining an area under the receiver operating characteristic (ROC) curve (AUC) of 0.85. Twenty-eight patients, including seven false positives and 21 false negatives, presented a discordant result between SAT and UBT. Among the 21 false negatives, four of six tested with MS and 11 of 15 tested with IRS presented a borderline UBT delta value. In 25 discordant samples, PCR targeting H. pylori DNA was performed to re-assess positivity and SAT accuracy was re-analysed: sensitivity, specificity, positive predictive value, negative predictive value, accuracy and AUC were 94%, 97%, 86%, 99%, 97% and 0.96, respectively. The new LIAISON® Meridian H. pylori SA SAT showed a good accuracy for diagnosis of H. pylori infection.

Background: Poor adherence to clinical practice guidelines for eosinophilic esophagitis (EoE) has been described and the diagnostic delay of the disease continues to be unacceptable in many settings., Objective: To analyze the impact of improved knowledge provided by the successive international clinical practice guidelines on reducing diagnostic delay and improving the diagnostic process for European patients with EoE., Methods: Cross-sectional analysis of the EoE CONNECT registry based on clinical practice. Time periods defined by the publication dates of four major sets of guidelines over 10 years were considered. Patients were grouped per time period according to date of symptom onset., Results: Data from 1,132 patients was analyzed and median (IQR) diagnostic delay in the whole series was 2.1 (0.7-6.2) years. This gradually decreased over time with subsequent release of new guidelines (p < 0.001), from 12.7 years up to 2007 to 0.7 years after 2017. The proportion of patients with stricturing of mixed phenotypes at the point of EoE diagnosis also decreased over time (41.3% vs. 16%; p < 0.001), as did EREFS scores. The fibrotic sub-score decreased from a median (IQR) of 2 (1-2) to 0 (0-1) when patients whose symptoms started up to 2007 and after 2017 were compared (p < 0.001). In parallel, symptoms measured with the Dysphagia Symptoms Score reduced significantly when patients with symptoms starting before 2007 and after 2012 were compared. A reduction in the number of endoscopies patients underwent before the one that achieved an EoE diagnosis, and the use of allergy testing as part of the diagnostic workout of EoE, also reduced significantly over time (p = 0.010 and p < 0.001, respectively)., Conclusion: The diagnostic work-up of EoE patients improved substantially over time at the European sites contributing to EoE CONNECT, with a dramatic reduction in diagnostic delay., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: The growing prevalence of eosinophilic esophagitis (EoE) represents a considerable burden to patients and health care systems. Optimizing cost-effective management and identifying mechanisms for disease onset and progression are required. However, the paucity of large patient cohorts and heterogeneity of practice hinder the defining of optimal management of EoE., Methods: EoE CONNECT is an ongoing, prospective registry study initiated in 2016 and currently managed by EUREOS, the European Consortium for Eosinophilic Diseases of the Gastrointestinal Tract. Patients are managed and treated by their responsible specialists independently. Data recorded using a web-based system include demographic and clinical variables; patient allergies; environmental, intrapartum, and early life exposures; and family background. Symptoms are structurally assessed at every visit; endoscopic features and histological findings are recorded for each examination. Prospective treatment data are registered sequentially, with new sequences created each time a different treatment (active principle, formulation, or dose) is administered to a patient. EoE CONNECT database is actively monitored to ensure the highest data accuracy and the highest scientific and ethical standards., Results: EoE CONNECT is currently being conducted at 39 centers in Europe and enrolls patients of all ages with EoE. In its aim to increase knowledge, to date EoE CONNECT has provided evidence on the effectiveness of first- and second-line therapies for EoE in clinical practice, the ability of proton pump inhibitors to induce disease remission, and factors associated with improved response. Drug effects to reverse fibrous remodeling and endoscopic features of fibrosis in EoE have also been assessed., Conclusion: This prospective registry study will provide important information on the epidemiological and clinical aspects of EoE and evidence as to the real-world and long-term effectiveness and safety of therapy. These data will potentially be a vital benchmark for planning future EoE health care services in Europe., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Alfredo J. Lucendo has served as a speaker, and/or has received research and/or education funding and/or consulting fees from Adare/Ellodi, Dr. Falk Pharma, Regeneron, and EsoCap. Cecilio Santander has received training and consultant fees from Laborie/MMS. The rest of the authors have no conflict of interest., (© The Author(s), 2022.)

Background: Long-standing inflammation leads to esophageal remodeling with stricture formation in patients with eosinophilic esophagitis (EoE). The ability of proton pump inhibitors (PPI) to reverse endoscopic features of fibrosis is still unknown., Objective: To investigate the effect of a short course of PPI treatment in reducing endoscopic findings indicative of esophageal fibrosis in EoE patients., Methods: Cross-sectional analysis of the EoE CONNECT registry. Patients who received PPI to induce EoE remission were evaluated. Endoscopic features were graded using the EoE Endoscopic Reference Score (EREFS), with rings and strictures indicating fibrosis. Results were compared to those from patients treated with swallowed topic corticosteroids (STC)., Results: Clinico-histological remission was achieved in 83/166 adult patients treated with PPI (50%) and in 65/79 (82%) treated with STC; among responders, 60 (36%) and 57 (72%) patients respectively achieved deep histological remission (<5 eosinophils/hpf). At baseline, mean±SD EREFS was lower in patients treated with PPI compared to those who received STC (p < 0.001). Short term treatment significantly reduced EREFS scores in patients treated either with PPI or STC as well as rings and strictures. Among patients treated with PPI, deep histological remission (<5 eosinophils/hpf) provided further reduction in total EREFS score., Conclusion: Effective PPI therapy for EoE significantly reduced endoscopic esophageal fibrosis in the short term., Competing Interests: Conflict of interest None of the authors have any conflict of interest to declare., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Adalimumab (ADL), infliximab (IFX) and their biosimilars are widely used biological drugs. Some patients, however, generate neutralizing antibodies that hamper the effectiveness of these drugs. Evidence shows therapeutic drug monitoring of serum levels ADL/IFX and anti-drug antibodies (ADA) is useful to improve treatment effectiveness. We evaluated a new rapid quantitative method, Quantum Blue (QB), for determining serum anti-ADL and anti-IFX antibodies (Research Use Only labelling) by comparing it with two established ELISA kits, Promonitor (PM) and Lisa-Tracker (LT)., Methods: Eighty samples (40 for each drug type) were analysed. Percentage of agreement and kappa statistic were used to compare positive/negative ADA results. Clinical implications for drug treatment in the patients with discordant results were evaluated. The Chi-square test was used to analyze differences for ADA detection in patients with disease flare and without concomitant immunosuppressant treatment., Results: Agreement exceeded 80 % among anti-ADL methods. Although LT ELISA showed a lower capacity in detecting anti-ADL antibodies, discrepancies were found for levels close to the cut-off concentration, thus having minimal impact on clinical decisions. Conversely, QB anti-IFX displayed low agreement with PM and LT ELISA kits (67.5 % and 50 %, respectively), and was unable to detect high levels of antibodies, therefore having major clinical implications. Agreement between PM and LT ELISA anti-IFX kits was 82.5 % with all discordant results being undetected for PM and slightly positive for LT., Conclusion: QB anti-ADL shows similar performance to ELISA kits while QB anti-IFX needs further improvements to achieve reliable antibody detection., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory esophageal disease triggered by food antigens. Cumulative evidence supports the implication of microbiota and the innate immune system in the pathogenesis of EoE. Changes in the esophageal microbiome were investigated by applying 16S rRNA gene sequencing on esophageal biopsies of adult patients with active EoE at baseline (n = 30), and after achieving remission with either proton pump inhibitors (PPI, n = 10), swallowed topical corticosteroids (STC, n = 10) or food-elimination diets (FED, n = 10). Ten non-EoE biopsies were also characterized as controls. Compared to controls, no differences in alpha (intra-sample) diversity were found in EoE microbiota overall. However, it decreased significantly among patients who underwent FED. As for beta (inter-sample) diversity, non-EoE controls separated from EoE baseline samples. Post-treatment samples from patients treated with PPI and FED had a more similar microbiota composition, while those receiving STC were closer to controls. Differential testing of microbial relative abundance displayed significant changes for Filifactor, Parvimonas and Porphyromonas genera. Analysis of predicted functions indicated alterations in metabolic pathways and abundance of sulphur-cytochrome oxidoreductases. Our findings demonstrate changes in microbiota associated with EoE, as well as a treatment effect on the microbiome.

A lifelong gluten-free diet (GFD) is the only current treatment for celiac disease (CD), but strict compliance is complicated. Duodenal biopsies are the "gold standard" method for diagnosing CD, but they are not generally recommended for disease monitoring. We evaluated the sensitivity and specificity of fecal gluten immunogenic peptides (GIPs) to detect duodenal lesions in CD patients on a GFD and compared them with serum anti-tissue transglutaminase (tTG) IgA antibodies. A prospective study was conducted at two tertiary centers in Spain on a consecutive series of adolescents and adults with CD who maintained a long-lasting GFD. Adherence to a GFD and health-related quality of life were scored with validated questionnaires. Mucosal damage graded according to the Marsh-Oberhüber classification (Marsh 1/2/3) was used as the reference standard. Of the 97 patients included, 27 presented duodenal mucosal damage and 70 had normal biopsies (Marsh 0). The sensitivity (33%) and specificity (81%) of GIPs were similar to those provided by the two assays used to measure anti-tTG antibodies. Scores in questionnaires showed no association with GIP, but an association between GIPs and patients' self-reported gluten consumption was found ( p = 0.003). GIP displayed low sensitivity but acceptable specificity for the detection of mucosal damage in CD.

Background & Aims: Topical steroids, proton pump inhibitors (PPIs), and dietary interventions are recommended first- and second-line therapies for eosinophilic esophagitis (EoE). We investigated differences in their effectiveness in a real-world, clinical practice cohort of patients with EoE., Methods: We collected data on the efficacy of different therapies for EoE (ability to induce clinical and histologic remission) from the multicenter EoE CONNECT database-a database of patients with a confirmed diagnosis of EoE in Europe that began in 2016. We obtained data from 589 patients, treated at 11 centers, on sex, age, time of diagnosis, starting date of any therapy, response to therapy, treatment end dates, alternative treatments, and findings from endoscopy. The baseline endoscopy was used for diagnosis of EoE; second endoscopy was performed to evaluate response to first-line therapies. After changes in treatment, generally because lack of efficacy, a last endoscopy was performed. The time elapsed between endoscopies depended on the criteria of attending physicians. Clinical remission was defined by a decrease of more than 50% in Dysphagia Symptom Score; improvement in symptoms by less than 50% from baseline was considered as clinical response. Histologic remission was defined as a peak eosinophil count below 5 eosinophils/hpf. A peak eosinophil count between 5 and 14 eosinophils/hpf was considered histologic response. We identified factors associated with therapy selection and effectiveness using χ2 and multinomial logistic regression analyses RESULTS: PPIs were the first-line treatment for 76.4% of patients, followed by topical steroids (for 10.5%) and elimination diets (for 7.8%). Topical steroids were most effective in inducing clinical and histologic remission or response (in 67.7% of patients), followed by empiric elimination diets (in 52.0%), and PPIs (in 50.2%). Among the 344 patients who switched to a second-line therapy, dietary interventions were selected for 47.1% of patients, followed by PPIs (for 29.1%) and topical steroids (for 18.6%). Clinical and histologic remission or response was achieved by 80.7% of patients treated with topical steroids, 69.2% of patients given PPIs, and 41.7% of patients on empiric elimination diets. Multivariate analyses found the stricturing phenotype of EoE to be associated with selection of topical steroids over PPIs as the first-line therapy; lack of fibrotic features at initial endoscopy was associated with selection of elimination diets over topical steroids as a second-line therapy. The recruiting center was significantly associated with therapy choice; second-line treatment with topical steroids or PPIs were the only variables associated with clinical and histologic remission., Conclusions: In an analysis of data from a large cohort of patients with EoE in Europe, we found topical steroids to be the most effective at inducing clinical and histologic remission, but PPIs to be the most frequently prescribed. Treatment approaches vary with institution and presence of fibrosis or strictures., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Proton pump inhibitors (PPIs) are the most commonly used first-line therapy for patients with eosinophilic oesophagitis (EoE). However, many aspects related to PPIs in EoE are still unknown., Aims: To assess the effectiveness of PPI therapy for EoE in real-world practice., Methods: This cross-sectional study collected data on PPI efficacy from the multicentre EoE CONNECT database. Clinical remission was defined as a decrease of ≥50% in dysphagia symptom score; histological remission was defined as a peak eosinophil count below 15 eosinophils per high-power field. Factors associated with effectiveness of PPI therapy were identified by binary logistic regression multivariate analyses., Results: Overall, 630 patients (76 children) received PPI as initial therapy (n = 600) or after failure to respond to other therapies (n = 30). PPI therapy achieved eosinophil density below 15 eosinophils per high-power field in 48.8% and a decreased symptom score in 71.0% of patients. More EoE patients with an inflammatory rather than stricturing phenotype accomplished clinico-histological remission after PPI therapy (OR 3.7; 95% CI, 1.4-9.5); as well as those who prolonged treatment length from 8 to 12 weeks (OR 2.7; 95% CI, 1.3-5.3). After achieving clinico-histological remission of EoE, PPI dosage reduction was effectively maintained in 69.9% of patients, but tended to be less effective among those with a stricturing phenotype., Conclusions: Inflammatory EoE phenotype and treatment duration up to 12 weeks correlated with greater chance for inducing remission of EoE. A stricturing phenotype decreased response rates to PPI therapy both initially and in the long term., (© 2020 John Wiley & Sons Ltd.)

Studies of inflammatory bowel disease (IBD) have been inconclusive in relating microbiota with distribution of inflammation. We report microbiota, host transcriptomics, epigenomics and genetics from matched inflamed and non-inflamed colonic mucosa [50 Crohn's disease (CD); 80 ulcerative colitis (UC); 31 controls]. Changes in community-wide and within-patient microbiota are linked with inflammation, but we find no evidence for a distinct microbial diagnostic signature, probably due to heterogeneous host-microbe interactions, and show only marginal microbiota associations with habitual diet. Epithelial DNA methylation improves disease classification and is associated with both inflammation and microbiota composition. Microbiota sub-groups are driven by dominant Enterbacteriaceae and Bacteroides species, representative strains of which are pro-inflammatory in vitro, are also associated with immune-related epigenetic markers. In conclusion, inflamed and non-inflamed colonic segments in both CD and UC differ in microbiota composition and epigenetic profiles.

There is evidence of an increased fragility in the inflamed esophagus of patients with eosinophilic esophagitis (EoE). We performed a systematic review on presentation, management and outcomes of and surgical interventions for esophageal perforation in these patients, by searching in the MEDLINE, Embase and Scopus databases. Of the 599 references identified, 41 full-papers and 9 abstract met the inclusion criteria. Overall, 76 esophageal perforation episodes in 70 individual patients aged between 9 and 65 years were reported. 51 patients had not been diagnosed with EoE at the time of perforation; 14 patients had an untreated disease and the remaining were non responsive to therapy. Acute or progressive pain after long-lasting dysphagia and food impaction was the most common symptom leading to diagnosis in 42 patients who presented with Boerhaave syndrome. Pushing impacted food into the stomach led to perforation in 5 cases. Eight episodes appeared after dilation. CT scans demonstrated perforation in 82.4% of patients. Conservative management (including esophageal stenting) was used in 67.1% patients. The 25 remaining patients underwent surgery. Recovery was uneventful in the vast majority of patients. No death was reported. Active inflammation due to undiagnosed or untreated EoE was present in most cases of esophageal perforation. Conservative treatment of perforation should always be considered in EoE., (Copyright © 2019. Published by Elsevier Ltd.)

Following the publication of this article [1], the authors reported errors in Figs. 1, 2 and 5. Due to a typesetting error the asterisks denoting significance were missing from the published figures.

Background: Shotgun metagenomic sequencing reveals the potential in microbial communities. However, lower-cost 16S ribosomal RNA (rRNA) gene sequencing provides taxonomic, not functional, observations. To remedy this, we previously introduced Piphillin, a software package that predicts functional metagenomic content based on the frequency of detected 16S rRNA gene sequences corresponding to genomes in regularly updated, functionally annotated genome databases. Piphillin (and similar tools) have previously been evaluated on 16S rRNA data processed by the clustering of sequences into operational taxonomic units (OTUs). New techniques such as amplicon sequence variant error correction are in increased use, but it is unknown if these techniques perform better in metagenomic content prediction pipelines, or if they should be treated the same as OTU data in respect to optimal pipeline parameters., Results: To evaluate the effect of 16S rRNA sequence analysis method (clustering sequences into OTUs vs amplicon sequence variant error correction into amplicon sequence variants (ASVs)) on the ability of Piphillin to predict functional metagenomic content, we evaluated Piphillin-predicted functional content from 16S rRNA sequence data processed through OTU clustering and error correction into ASVs compared to corresponding shotgun metagenomic data. We show a strong correlation between metagenomic data and Piphillin-predicted functional content resulting from both 16S rRNA sequence analysis methods. Differential abundance testing with Piphillin-predicted functional content exhibited a low false positive rate (< 0.05) while capturing a large fraction of the differentially abundant features resulting from corresponding metagenomic data. However, Piphillin prediction performance was optimal at different cutoff parameters depending on 16S rRNA sequence analysis method. Using data analyzed with amplicon sequence variant error correction, Piphillin outperformed comparable tools, for instance exhibiting 19% greater balanced accuracy and 54% greater precision compared to PICRUSt2., Conclusions: Our results demonstrate that raw Illumina sequences should be processed for subsequent Piphillin analysis using amplicon sequence variant error correction (with DADA2 or similar methods) and run using a 99% ID cutoff for Piphillin, while sequences generated on platforms other than Illumina should be processed via OTU clustering (e.g., UPARSE) and run using a 96% ID cutoff for Piphillin. Piphillin is publicly available for academic users (Piphillin server. http://piphillin.secondgenome.com/.).

Background Therapeutic drug monitoring (TDM) of adalimumab (ADA) in inflammatory bowel diseases (IBDs) has gained increased attention since several studies showed a correlation between drug levels and mucosal healing. The limitations of routine usage of enzyme-linked immunoabsorbent assay (ELISA) kits for measuring serum ADA concentrations have prompted the development of rapid methods, such as Quantum Blue (QB). We evaluated the interchangeability and agreement between the QB method and two established ELISA kits, Promonitor (PM) and Lisa-Tracker (LT). Methods Fifty samples from patients with IBD were included. Quantitative analysis was performed using the ANOVA test for repeated measures, Deming regression and the Bland-Altman plot. Clinical implications were evaluated by concordance in classifying patients into therapeutic windows according to the proposed cut-off levels for subtherapeutic (either <5 or <7.5 μg/mL) and supratherapeutic (>12 μg/mL) ranges. Results Statistical differences were detected between the QB method and the two ELISA kits, with QB overestimating ADA serum values compared to them. A lack of interchangeability was observed between methods, with greater differences as ADA levels increased. An analysis of a sub-set of samples with ADA values below 9 μg/mL (n = 25) showed that QB fulfilled the criteria to be interchangeable with the LT assay. Concordance for patient classification into ADA therapeutic windows was better for QB vs. LT than for QB vs. PM, with high agreement (>75%) for subtherapeutic levels among the three methods. Conclusions Although quantitative differences existed between the rapid method and ELISA kits that hampered their interchangeability, the agreement for identifying patients with subtherapeutic values of ADA was high.

Introduction: Several factors, such as trough serum anti-TNF levels, have been associated with response to therapy in Crohn's disease. However, this association is observed after initiation of treatment. Identifying DNA variants may prove useful for predicting long-term response or failure to these drugs before initiation of treatment., Objective: To identify genetic variants associated with long-term response to infliximab and trough levels in Crohn's disease., Patients and Methods: An observational, longitudinal study was conducted. We analyzed blood samples from 132 infliximab-treated patients diagnosed with Crohn's disease from 2 hospitals. We genotyped 21 polymorphisms previously related to anti-TNF response in genes involved in the NFkB-mediated inflammatory response, TNFα-signaling and cytokines regulated by NFkB, using real-time PCR. Trough infliximab levels were measured using ELISA. The association between SNPs and time-to-failure (defined as the time from the initiation of induction therapy to the date of treatment withdrawal due to a primary or secondary failure) was analyzed using log-rank test. The association between SNPs and supra-(>7 μg/mL) or infratherapeutic (<3 μg/mL) infliximab trough levels was analyzed using a linear-by-linear association chi-squared test., Results: Two SNPs in TLR2, rs1816702 and rs3804099, and 1 SNP in TNFRSF1B, rs1061624, were associated with long-term response (up to ten years follow-up) to infliximab (HR, 0.13 [95%CI, 0.02-1.00], p < 0.05; HR, 0.39 [95%CI, 0.18-0.88], p < 0.05; and HR, 0.04 [95%CI, 0.18-0.92] p > 0.05, respectively). In addition, IL6 rs10499563 C and IL10 rs1800872 A were associated with supratherapeutic trough infliximab levels; IL10 rs3024505 T was associated with infratherapeutic levels (p < 0.05)., Conclusion: Genotyping of the variants identified in the genes encoding TLR2, TNFRSF1B, IL6 and IL10 reported herein represent a promising tool for the identification and selection of those patients who will benefit most from infliximab., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A growing body of evidence has been published about the usefulness of measuring calprotectin in faecal samples (FCAL) in inflammatory bowel disease (IBD) assessment, including diagnosis, monitoring of disease activity and relapse prediction. Several systematic reviews with meta-analyses compiling studies for each particular clinical setting have been carried out in recent years. Most of these were focused on the use of FCAL in IBD diagnosis and showed a relevant role for this marker in selecting patients with gastrointestinal symptoms who would not need a further examination by endoscopy. Although a lesser number of meta-analyses have been performed on the use of FCAL as a surrogate marker of disease activity, a close correlation between FCAL and endoscopic activity of IBD has been shown. With respect to the predictive capacity of FCAL for IBD relapse, a single meta-analysis published indicates that this role is more limited. Furthermore, FCAL thresholds vary considerably depending on the clinical setting and, what is more concerning, among different commercially available assays due to a lack of FCAL concentration interchangeability. Here, we summarise recent publications about the role and limitations of FCAL in IBD, with a special focus on meta-analyses, and give an overview of alternative faecal biomarkers.

Background: The frequency of eosinophilic oesophagitis (EoE) occurrence is escalating. Current diagnostic criteria recently proposed for the disease, determine that previous estimates of incidence and prevalence are outdated., Aim: To gauge the current incidence and prevalence of EoE by performing a systematic review of population-based studies., Methods: Three electronic databases were searched from their inception dates to September 2018. A total of 2386 documents were screened; 29 studies reported on the prevalence and incidence of EoE in the general population., Results: The pooled prevalence of EoE was 34.4 cases per 100 000 inhabitants (95% CI, 23.1-47.5), and was higher for adults (42.2; 95% CI, 31.1-55) than for children (34; 95% CI, 22.3-49.2). The pooled EoE incidence rates were 6.6/100 000 person-years (95% CI, 3-11.7) in children and 7.7/100 000 (95% CI, 1.8-17.8) in adults. No differences were found between North American and European studies using varied sources of data (insurance and administrative databases compared to hospital-bases case series). Subgroup analysis according to risk of bias did not change results significantly. A steady rise in EoE incidence and prevalence rates was observed over time, comparing studies conducted under subsequent definitions for EoE. No significant publication bias was found., Conclusions: In a systematic review and meta-analysis, we found a sharp increase, higher than previous estimates, in the incidence and prevalence of EoE in population based studies. Results from studies carried out in developed countries show broad consistency and provide evidence of increasing pooled prevalence and incidence of EoE rates over time., (© 2019 John Wiley & Sons Ltd.)

Background and Aims: Alterations in short chain fatty acid metabolism, particularly butyrate, have been reported in inflammatory bowel disease, but results have been conflicting because of small study numbers and failure to distinguish disease type, activity or other variables such as diet. We performed a comparative assessment of the capacity of the microbiota for butyrate synthesis, by quantifying butyryl-CoA:acetate CoA-transferase [BCoAT] gene content in stool from patients with Crohn's disease [CD; n = 71], ulcerative colitis [UC; n = 58] and controls [n = 75], and determined whether it was related to active vs inactive inflammation, microbial diversity, and composition and/or dietary habits., Methods: BCoAT gene content was quantified by quantitative polymerase chain reaction [qPCR]. Disease activity was assessed clinically and faecal calprotectin concentration measured. Microbial composition was determined by sequencing 16S rRNA gene. Dietary data were collected using an established food frequency questionnaire., Results: Reduced butyrate-synthetic capacity was found in patients with active and inactive CD [p < 0.001 and p < 0.01, respectively], but only in active UC [p < 0.05]. In CD, low BCoAT gene content was associated with ileal location, stenotic behaviour, increased inflammation, lower microbial diversity, greater microbiota compositional change, and decreased butyrogenic taxa. Reduced BCoAT gene content in patients with CD was linked with a different regimen characterised by lower dietary fibre., Conclusions: Reduced butyrate-synthetic capacity of the microbiota is more evident in CD than UC and may relate to reduced fibre intake. The results suggest that simple replacement of butyrate per se may be therapeutically inadequate, whereas manipulation of microbial synthesis, perhaps by dietary means, may be more appropriate., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Background: Proton pump inhibitor (PPI) use is associated with an increased risk of Clostridium difficile infection (CDI), though the mechanism is unclear. PPI induced alterations to the gut microbiome may facilitate the emergence of CDI, though the effects of PPIs on gut microbiota are not well characterised. [Correction added on 10 March 2016, after first online publication: microflora has been changed to microbiota throughout the article.], Aim: To compare the faecal microbiomes of long-term PPI users to those with no history of PPI use., Methods: We used a population-based database to identify individuals with ≥5 years of continuous PPI use along with non-PPI using controls. Stool samples were subjected to microbiological analysis, with hierarchical clustering at genus level, along with alpha and beta diversity measures comparing the two groups. Metadata was accounted for using quantile regression to eliminate potential confounding variables in taxonomic abundance comparisons., Results: Sixty-one subjects (32 PPI, 29 controls) were analysed. While no significant differences in alpha diversity were found between the PPI users and controls, a moderate shift of the PPI users away from the non-PPI user cluster in the beta diversity was observed. After controlling for pertinent confounders, we discovered a decrease in Bacteroidetes and an increase in Firmicutes at the phylum level. We also performed species classifications and found Holdemania filiformis and Pseudoflavonifractor capillosus to be increased and decreased in the PPI cohort, respectively., Conclusions: Long-term PPIs use has an effect on the gut microbiome. The alteration in the ratio of Firmicutes to Bacteroidetes may pre-dispose to the development of CDI., (© 2016 John Wiley & Sons Ltd.)

Background and Objective: To analyze the usefulness and ability of procalcitonin (PCT) to predict the presence of bacteremia in patients with community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae (S. pneumoniae) or other bacteria., Patients and Method: This is an observational, prospective and descriptive study involving patients who were diagnosed with CAP in our Emergency Department. Data collected included socio-demographic and comorbidity variables, Charlson index, stage in the Pneumonia Severity Index and criteria of severe NAC, microbiologic studies and biomarker determinations (PCT and C reactive protein). The follow-up was carried out during 30 days to calculate the predictive power and the diagnostic performance for bacteremia caused or not by S. pneumoniae., Results: Four hundred and seventy-four patients were finally included in the study. Blood cultures were positive in 85 individuals (17.9%) and S. pneumoniae was identified as the responsible pathogen in 75 of them (88.4%) (in 5 cases together with another agent). The area under the Receiver Operating Characteristic curve for PCT to predict bacteremia (caused by S. pneumoniae or not) was 0.988 (95% confidence interval 0.908-0.995; P<.001) and, considering a cut-off value≥0.95ng/mL, the negative predictive value and the positive likelihood ratio were>98% and>10, respectively. The most frequently isolated serotypes of S. pneumoniae were 19A, 7F, 1 and 3. The highest mean levels of PCT were found in serotypes 7F, 19A, 3 and 1, which showed statistically significant differences with regard to the others serotypes considered (P=.008). Serotypes associated with the highest percentage of severe sepsis-septic shock, 30-days mortality and multi-lobe or bilateral affection were 3, 1 and 19A; 1, 3 and 19A; and 3, 19A and 6A, respectively., Conclusions: PCT had a remarkable diagnostic ability to discard or suspect bacteremia and to guide the etiology of CAP caused by S. pneumoniae. Serotypes 1, 3, 19A and 7F showed greater frequency, systemic inflammatory response and clinical severity., (Copyright © 2013 Elsevier España, S.L. All rights reserved.)

Objectives: To analyse the usefulness and performance of several biomarkers [C-reactive protein (CRP), mid-regional pro-adrenomedullin (MR-proADM), procalcitonin (PCT)] and lactate in predicting short- and medium-term mortality compared with the prognostic severity scales (PSS) usually employed for community-acquired pneumonia (CAP) and in assessing the aetiological suspicion of infection by Streptococcus pneumoniae and bacteraemia., Methods: Observational, prospective and analytical study was conducted on patients who were diagnosed with CAP in our emergency department (ED). The data collected included socio-demographic and comorbidity variables, Charlson index, priority level according to the Spanish Triage System (STS), stage in the Pneumonia Severity Index (PSI) and in the CURB-65 (confusion, urea, respiratory rate, blood pressure and age ≥65years), criteria of severe CAP, microbiological studies, and biomarkers determinations. The patients were followed-up for 180days to calculate the prognostic power and the diagnostic performance for bacteraemia and aetiology., Results: A total of 127patients were finally enrolled in the study. The 30-day mortality was 10.3% (13), and 22.6% (28) at 180 days. Blood cultures were positive in 29 patients (23%) and S.pneumoniae was identified as the responsible pathogen in 28 cases (22.2%). The area under the ROC curve (AUC-ROC) for lactate and MR-proADM to predict 30-day mortality was 0.898 (95%CI: 0.824-0.973; P<.0001) and 0.892 (95%CI: 0.811-0.974; P<.0001), respectively, and for MR-proADM at 180 days it was 0.921 (95%CI: 0.874-0.968; P<.0001). The AUC-ROC for PCT to predict bacteraemia was 0.952 (95%CI: 0.898-1.000; P<.0001) and, considering a cut-off value ≥0.95ng/ml, the negative predictive value (NPV) and the likelihood ratio (LR+) were 97.8% and 9.03, respectively. Using a PCT cut-off value >0.85ng/ml, the NPV and the LR+ were 96.6% and 5.89%, respectively, to predict a S.pneumoniae infection., Conclusions: MR-proADM and lactate showed a similar or even better performance for 30-day intra-hospital mortality than PSI, CURB-65, STS and CAP severity criteria in patients diagnosed with CAP (P>.05). Furthermore, the MR-proADM capacity to predict 180-day mortality was higher than PSS and the rest of biomarkers (P>.05), and its AUC-ROC increased if it was used in combination with PSI, CURB65 and STS. The determination of PCT has a remarkable diagnostic performance to rule out bacteraemia and to orientate the aetiology towards a S.pneumoniae infection., (Copyright © 2012 Elsevier España, S.L. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.)

Background: Although LDL-C has been traditionally estimated using the Friedewald formula (FF), several direct homogeneous assays have been developed to overcome the limitations of this formula and the complicated manual procedure required in the reference method. However, several differences have been reported between these assays in certain situations., Methods: Two groups of 105 samples with extreme low and high HDL-C concentrations were processed, employing four different instruments and with the reagents for total cholesterol, triglycerides, HDL-C and LDL-C provided by the distinct manufacturers., Results: Statistical tests indicated important differences between HDL-C and LDL-C homogeneous methods. Poor correlation, significant bias and high discrepancy in cardiovascular disease risk classification were observed for LDL-C direct assays in the low HDL-C group, whereas better results were obtained when comparing LDL-C levels estimated with the FF. In contrast, three of the four instruments generated LDL-C direct results with a good agreement in the high HDL-C group, even though an appreciable misclassification percentage in risk categories must be taken into account., Conclusions: Our results indicate that extreme low or high HDL-C levels can represent a non-previously described source of variation between commercially available LDL-C homogeneous assays., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Celiac disease (CD) is an autoimmune disorder caused by an inappropriate immunological response to gluten ingestion in genetically susceptible individuals. IgA anti-tissue transglutaminase (tTG) antibodies have been widely employed as a specific biochemical marker for CD. Recent studies have also shown its usefulness in evaluating patient compliance with a gluten-free diet., Methods: A group of 28 subjects with CD was selected for the study. Each fulfilled the requirement of a gluten-free diet for more than one year. IgA anti-tTG determination was performed every two months for half a year. These data were used to estimate the biological variation (BV) of IgA anti-tTG in celiac patients and to calculate the reference change value (RCV)., Results: The within-subject biological variation (CVI) and between-subject biological variation (CV(G)) were 19.2% and 75.6%, respectively, and the index of individuality was 0.25. The RCV calculated using these data together with our analytical imprecision (5.7%) was 55.5% for a 95% level of significance., Conclusions: We have determined for the first time the BV and the RCV for IgA anti-tTG in a celiac population. This value and the probability curve generated from our data could be a valuable tool for monitoring patients' adherence to dietary treatment., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Biological variation (BV) and reference change values (RCVs) have been widely described for the general population, but the use of these data derived from adults in the elderly population is a controversial issue. We determined the within- and between-subject BV and RCV in both elderly and young people and compared them with previously published analyses., Methods: Samples were collected from 135 volunteers over 80 years of age at weekly intervals over 4 weeks. Eighteen biochemical and eight haematological analytes were measured. The Fraser and Harris methods were used to calculate the components of BV and RCV. To perform a comparative analysis, a reference group of 118 young subjects was studied under the same conditions., Results: The obtained coefficients of BV showed statistical differences in many cases, but in general, both the elderly and young patient data fall within the ranges previously described for the general population. The indexes of individuality for the analytes investigated did not exceed 1.4 in any case and were <0.6 for some analytes. The RCVs derived from elderly subjects were similar to those published in the young population, both in healthy and diseased individuals., Conclusions: The strong individuality observed supports the preferential use of RCVs rather than population-based reference intervals in elderly people. For most of the analytes studied, data from the young population can be applied to elderly people, but the specific elderly coefficients of BV and RCVs are a recommended option.

Objectives: To investigate the effect of extreme levels of high density lipoprotein cholesterol (HDL-C) in the calculation of low density lipoprotein cholesterol (LDL-C) using Friedewald's formula (FF) and other formulas proposed recently., Design and Methods: Lipoprotein profile was performed in 2603 samples with HDL-C ≤ 20 mg/dL and 1953 samples with HDL-C ≥ 100 mg/dL., Results: Wilcoxon's and Student's t-tests showed significant differences (p<0.001) between calculated LDL-C by different formulas and direct determination in the two groups of HDL-C values. Passing-Bablok regression and Bland-Altman plot showed disagreement for the four formulas studied, except for Vujovic formula in the HLD-C ≥ 100 mg/dL group., Conclusions: Our results suggested that none of the formulas under analysis should be used for estimating LDL-C in samples with extreme HDL-C concentrations due to absence of statistical correlation with LDL-C direct measurement., (Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)