EoE CONNECT, the European registry of clinical, environmental, and genetic determinants in eosinophilic esophagitis: rationale, design, and study protocol of a large-scale epidemiological study in Europe

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si lo hubiere, y los autores pertenecientes a la UAMThe 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 EuropeThe authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The establishment and design of the EoE CONNECT registry was developed with a grant from the United European Gastroenterology through the National Societies Link Award program. The maintenance of the database is financed by EUREOS (European Society of Eosinophilic Oesophagitis). Funding agencies had no role in the study design, in the writing of this manuscript, or the decision to submit for publicatio

EoE CONNECT, the European Registry of Clinical, Environmental, and Genetic Determinants in Eosinophilic Esophagitis: rationale, design, and study protocol of a large-scale epidemiological study in Europe

Best practice analysis; Clinical practice patterns; Eosinophilic esophagitisAnálisis de las mejores prácticas; Patrones de práctica clínica; Esofagitis eosinofílicaAnàlisi de les millors pràctiques; Patrons de pràctica clínica; Esofagitis eosinofílicaBackground: 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.The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The establishment and design of the EoE CONNECT registry was developed with a grant from the United European Gastroenterology through the National Societies Link Award program. The maintenance of the database is financed by EUREOS (European Society of Eosinophilic Oesophagitis). Funding agencies had no role in the study design, in the writing of this manuscript, or the decision to submit for publication

Molecular analysis of pancreatic cystic neoplasm in routine clinical practice

BACKGROUND Cystic pancreatic lesions consist of a wide variety of lesions that are becoming increasingly diagnosed with the growing use of imaging techniques. Of these, mucinous cysts are especially relevant due to their risk of malignancy. However, morphological findings are often suboptimal for their differentiation. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) with molecular analysis has been suggested to improve the diagnosis of pancreatic cysts. AIM To determine the impact of molecular analysis on the detection of mucinous cysts and malignancy. METHODS An 18-month prospective observational study of consecutive patients with pancreatic cystic lesions and an indication for EUS-FNA following European clinical practice guidelines was conducted. These cysts included those > 15 mm with unclear diagnosis, and a change in follow-up or with concerning features in which results might change clinical management. EUS-FNA with cytological, biochemical and glucose and molecular analyses with next-generation sequencing were performed in 36 pancreatic cysts. The cysts were classified as mucinous and non-mucinous by the combination of morphological, cytological and biochemical analyses when surgery was not performed. Malignancy was defined as cytology positive for malignancy, high-grade dysplasia or invasive carcinoma on surgical specimen, clinical or morphological progression, metastasis or death related to neoplastic complications during the 6-mo follow-up period. Next-generation sequencing results were compared for cyst type and malignancy. RESULTS Of the 36 lesions included, 28 (82.4%) were classified as mucinous and 6 (17.6%) as non-mucinous. Furthermore, 5 (13.9%) lesions were classified as malignant. The amount of deoxyribonucleic acid obtained was sufficient for molecular analysis in 25 (69.4%) pancreatic cysts. The amount of intracystic deoxyribonucleic acid was not statistically related to the cyst fluid volume obtained from the lesions. Analysis of KRAS and/or GNAS showed 83.33% [95% confidence interval (CI): 63.34-100] sensitivity, 60% (95%CI: 7.06-100) specificity, 88.24% (95%CI: 69.98-100) positive predictive value and 50% (95%CI: 1.66-98.34) negative predictive value (P = 0.086) for the diagnosis of mucinous cystic lesions. Mutations in KRAS and GNAS were found in 2/5 (40%) of the lesions classified as non-mucinous, thus recategorizing those lesions as mucinous neoplasms, which would have led to a modification of the follow-up plan in 8% of the cysts in which molecular analysis was successfully performed. All 4 (100%) malignant cysts in which molecular analysis could be performed had mutations in KRAS and/or GNAS, although they were not related to malignancy (P > 0.05). None of the other mutations analyzed could detect mucinous or malignant cysts with statistical significance (P > 0.05). CONCLUSION Molecular analysis can improve the classification of pancreatic cysts as mucinous or non-mucinous. Mutations were not able to detect malignant lesion

APLICACIÓN DE GESTIÓN POR PROCESOS PARA LA PLANTA ENSAMBLADORA DE JEANS DE HUEJUTLA, MÉXICO

En esta investigación se expone una metodología para la mejora de procesos en una ensambladora de pantalones tipo vaquero, la cual tiene su punto de partida en la búsqueda del compromiso de la dirección y el personal operativo. Para esto fue necesaria la obtención de la factibilidad de aplicación e importancia de herramientas de mejora para tener aumento de la productividad y la disminución de los costos de producción. Como punto de partida se identificaron las insuficiencias de la planta y se determinaron las oportunidades, lo que se tomó como base para el diseño de los procesos para la aplicación de mejora continua. Esto se logró con la implementación de la gestión por procesos, la cual se detalla en tres fases de aplicación: análisis, diseño e implementación de la mejora de procesos, así como la aplicación de herramientas de mejora continua. Los resultados de esta investigación permitieron obtener una regulación de los procesos de la ensambladora para mejorar y satisfacer las expectativas del cliente. PALABRAS CLAVE: Gestión por procesos; productividad; disminución de costos. APPLICATION OF MANAGEMENT BY PROCESS FOR THE ASSEMBLING PLANT OF JEANS DE HUEJUTLA, MEXICOABSTRACTIn this research, a methodology for the improvement of processes in a cowboy jeans jointer is exposed, the study has its starting point in the search of the commitment of the management and the operative personnel. To achieve this, it was necessary to obtain the feasibility of applying improvement tools and the importance of its application to achieve an increase in productivity and decrease in production costs. The starting point was the identification of the insufficiencies of the plant and the opportunities were determined, which was taken as a basis for the design of the processes for the application of continuous improvement. This was achieved with the implementation of process management, which is detailed in three phases of application: analysis, design and implementation of process improvement, as well as the application of continuous improvement tools. The results of this investigation allowed obtaining a regulation of the assembling processes to improve and satisfy the expectations of the client. KEYWORDS: Management by processes; productivity; cost reduction

Immunomodulatory effect of gut microbiota-derived bioactive peptides on human immune system from healthy controls and patients with inflammatory bowel disease

Bioactive peptides secreted by probiotic Bifidobacterium longum (peptide B7) and opportunistic pathogen Bacteroides fragilis (peptide B12) modulate the intestinal cytokine milieu in health. Here, we characterized their capacity to modulate both the mucosal cytokine production and the phenotype of circulating antigen presenting cells (APCs) in active inflammatory bowel disease (IBD). The IBD mucosa produced higher levels of pro-inflammatory cytokines referred to healthy controls (HCs). Peptides B7 and B12, however, did not ameliorate the mucosal cytokine milieu in IBD. Human circulating APCs (B-cells, monocytes, plasmacytoid dendritic cells (pDCs), and conventional dendritic cells (cDCs)) were characterized by flow cytometry in presence/absence of the peptides. Circulating B-cells, monocytes, and cDCs from IBD patients were more activated than those from HCs. Peptide B7, but not B12, decreased CCR2 expression on all APC subsets from HC, but not IBD patients. Moreover, both peptides tend to further increase their pro-inflammatory profile in IBD. In summary, IBD patients display mucosal and circulating APC pro-inflammatory properties. Peptide B7 immunomodulatory capacity elicited over circulating APCs from HC, but not IBD patients, suggests the presence of disrupted modulatory mechanisms for this peptide in IBD. Future studies should address the effect of bacteria-derived immunomodulatory peptides in non-inflamed (quiescent) IBD patientsThis work was supported by the Spanish Ministry of Economy (SAF2014-56642-JIN), the Spanish Ministry of Health (PIE13/00041), GETECCU (Grupo Español de Trabajo en Enfermedad Crohn y Colitis Ulcerosa), and the Community of Madrid (Consejería de Educación, Juventud y Deporte, Programa de Garantía Juvenil 2015 and 2016)

Differential effects of Anti-TNFα and Anti-α4β7 drugs on circulating dendritic cells migratory capacity in inflammatory bowel disease

Inflammatory bowel disease (IBD) is an idiopathic and chronic disorder that includes ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases show an uncontrolled intestinal immune response that generates tissue inflammation. Dendritic cells (DCs) are antigen-presenting cells that play a key role in tolerance maintenance in the gastrointestinal mucosa. Although it has been reported that DC recruitment by the intestinal mucosa is more prominent in IBD patients, the specific mechanisms governing this migration are currently unknown. In this study, the expression of several homing markers and the migratory profile of circulating DC subsets towards intestinal chemo-attractants were evaluated and the effect of biological drugs with different mechanisms of action, such as anti-TNFα or anti-integrin α4β7 (vedolizumab), on this mechanism in healthy controls (HCs) and IBD patients was also assessed. Our results revealed that type 2 conventional DCs (cDC2) express differential homing marker profiles in UC and CD patients compared to HCs. Indeed, integrin β7 was differentially modulated by vedolizumab in CD and UC. Additionally, although CCL2 displayed a chemo-attractant effect over cDC2, while biological therapies did not modulate the expression of the homing markers, we paradoxically found that anti-TNF-treated cDC2 increased their migratory capacity towards CCL2 in HCs and IBD. Our results therefore suggest a key role for cDC2 migration towards the intestinal mucosa in IBD, something that could be explored in order to develop novel diagnostic biomarkers or to unravel new immunomodulatory targets in IBD.This study has been funded through the Instituto de Salud Carlos III (Sara Borrell fellowships, CD17/00014; CD21/00014), Asociación Española de Gastroenterología (Beca del Grupo Joven), Programa Estratégico Instituto de Biología y Genética Molecular (IBGM Junta de Castilla y León. Ref. CCVC8485), Plan Nacional (PID2019-104218RB-I00) from the Spanish Government, Janssen and MSD

Lunasin Peptide is a Modulator of the Immune Response in the Human Gastrointestinal Tract

[Introduction]: Lunasin is a soybean bioactive peptide with a variety of beneficial properties against chronic disorders. However, its effect in human primary intestinal cells remains unknown. Hence, this study aims to characterize its ex vivo biological activity in the human intestinal mucosa. [Methods and Results]: Human intestinal biopsies, obtained from healthy controls, are ex vivo conditioned with lunasin both in the presence/absence of lipopolysaccharide (LPS). Peptide maintains its stability during biopsy culture by HPLC-MS/MS analysis. Lunasin is bioactive in the human mucosa, as it induces IL-1β, TNF-α, IL-17A, CCL2, and PGE2/COX-2 gene expression together with an increased expression of tolerogenic IL-10 and TGFβ, while it also downregulates the expression of iNOS and subunit p65 from NF-κB. Indeed, lunasin also abrogates the LPS-induced pro-inflammatory response, downregulating IL-17A, IFNγ, and IL-8 expression, and inducing IL-10 and TGFβ expression. These results are also mirrored in the cell-free culture supernatants at the protein level by Multiplex. Moreover, lunasin further induces a regulatory phenotype and function on human intestinal conventional dendritic cell and macrophage subsets as assessed by flow cytometry. [Conclusions]: We hereby have characterized lunasin as an immunomodulatory peptide with potential capacity to prevent immune and inflammatory-mediated disorders in the human gastrointestinal tract.This work was supported by the Spanish Ministry of Economy (SAF2014-56642-JIN), the Spanish Ministry of Health (PIE13/00041), the Spanish Ministry of Science, Innovation and Universities (AGL2015-66886-R, PID2019-104218RB-I00), and the Community of Madrid (Consejería de Educación, Juventud y Deporte, Programa de Garantía Juvenil 2015 and 2016). S.F.T. is currently funded by the Instituto de Salud Carlos III (Sara Borrell fellowship CD17/00014). L.O.M. is funded by the Community of Madrid (BMD-5800). D.B. is funded by the Spanish Ministry of Science (RYC-2017-21606)

Budesonide orodispersible tablets for induction of remission in patients with active eosinophilic oesophagitis: A 6-week open-label trial of the EOS-2 Programme

BACKGROUND A novel budesonide orodispersible tablet (BOT) has been proven effective in adult patients with active eosinophilic oesophagitis (EoE) in a 6-week placebo-controlled trial (EOS-1). AIMS To report the efficacy of an open-label induction treatment with BOT in a large prospective cohort of EoE patients within the EOS-2 study. METHODS Patients with clinico-histological active EoE were treated with BOT 1 mg BID for 6 weeks. The primary endpoint was clinico-histological remission (≤2 points on numerical rating scales [0-10] each for dysphagia and odynophagia, and peak eosinophil count <16 eos/mm$^{2}$ hpf (corresponds to <5 eos/hpf)). Further study endpoints included clinical and histological remission rates, change in the EEsAI-PRO score, change in peak eosinophil counts, and deep endoscopic remission using a modified Endoscopic Reference Score. RESULTS Among 181 patients enrolled, 126 (69.6%) achieved clinico-histological remission (histological remission 90.1%, clinical remission 75.1%). The mean peak eosinophil counts decreased by 283 eos/mm$^{2}$ hpf (i.e., by 89.0%). Mean EEsAI-PRO score decreased from baseline by 29 points and deep endoscopic remission was achieved in 97 (53.6%) patients. The majority of patients judged tolerability as good or very good (85.6%) and compliance was high (96.5%). Local candidiasis was suspected in 8.3% of patients; all were of mild severity, resolved with treatment and none led to premature withdrawal from the study. CONCLUSIONS In this large prospective trial, a 6-week open-label treatment with BOT 1 mg BID was highly effective and safe in achieving clinico-histological remission of active EoE and confirmed the results of the placebo-controlled EOS-1 trial

Poor sensitivity of fecal gluten immunogenic peptides and serum antibodies to detect duodenal mucosal damage in celiac disease monitoring

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.This research was funded by a grant from Asociación Castellana de Aparato Digestivo (year 2018) to A.J.L

Long non-coding RNA signatures in the Ileum and Colon of Crohn’s disease patients and effect of Anti-TNF-α treatment on their modulation

Biological therapies only benefit one-third of patients with Crohn’s disease (CD). For this reason, a deeper understanding of the mechanisms by which biologics elicit their effect on intestinal mucosa is needed. Increasing evidence points toward the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of CD, although their role remains poorly studied. We aimed to characterize lncRNA profiles in the ileum and colon from CD patients and evaluate the effect of anti-TNF-α treatment on their transcription. Terminal ileum and left colon samples from 30 patients (active CD = 10, quiescent CD = 10, and healthy controls (HCs) = 10) were collected for RNA-seq. The patients were classified according to endoscopic activity. Furthermore, biopsies were cultured with infliximab, and their transcriptome was determined by Illumina gene expression array. A total of 678 differentially expressed lncRNAs between the terminal ileum and left colon were identified in HCs, 438 in patients with quiescent CD, and 468 in patients with active CD. Additionally, we identified three new lncRNAs in the ileum associated with CD activity. No differences were observed when comparing the effect of infliximab according to intestinal location, presence of disease (CD vs. HC), and activity (active vs. quiescent). The expression profiles of lncRNAs are associated with the location of intestinal tissue, being very different in the ileum and colon. The presence of CD and disease activity are associated with the differential expression of lncRNAs. No modulatory effect of infliximab has been observed in the lncRNA transcriptom