Assuntos
Enterite , Esofagite Eosinofílica , Gastrite , Humanos , Esofagite Eosinofílica/terapia , DietaRESUMO
BACKGROUND: Eosinophilic oesophagitis (EoE) is an increasingly common cause of dysphagia in both children and adults, as well as one of the most prevalent oesophageal diseases with a significant impact on physical health and quality of life. We have provided a single comprehensive guideline for both paediatric and adult gastroenterologists on current best practice for the evaluation and management of EoE. METHODS: The Oesophageal Section of the British Society of Gastroenterology was commissioned by the Clinical Standards Service Committee to develop these guidelines. The Guideline Development Group included adult and paediatric gastroenterologists, surgeons, dietitians, allergists, pathologists and patient representatives. The Population, Intervention, Comparator and Outcomes process was used to generate questions for a systematic review of the evidence. Published evidence was reviewed and updated to June 2021. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system was used to assess the evidence and make recommendations. Two rounds of voting were held to assess the level of agreement and the strength of recommendations, with 80% consensus required for acceptance. RESULTS: Fifty-seven statements on EoE presentation, diagnosis, investigation, management and complications were produced with further statements created on areas for future research. CONCLUSIONS: These comprehensive adult and paediatric guidelines of the British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition are based on evidence and expert consensus from a multidisciplinary group of healthcare professionals, including patient advocates and patient support groups, to help clinicians with the management patients with EoE and its complications.
Assuntos
Esofagite Eosinofílica , Gastroenterologia , Adulto , Criança , Consenso , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/terapia , Humanos , Qualidade de Vida , Sociedades MédicasRESUMO
BACKGROUND & AIMS: Substantial heterogeneity in terminology used for eosinophilic gastrointestinal diseases (EGIDs), particularly the catchall term "eosinophilic gastroenteritis," limits clinical and research advances. We aimed to achieve an international consensus for standardized EGID nomenclature. METHODS: This consensus process utilized Delphi methodology. An initial naming framework was proposed and refined in iterative fashion, then assessed in a first round of Delphi voting. Results were discussed in 2 consensus meetings, and the framework was updated and reassessed in a second Delphi vote, with a 70% threshold set for agreement. RESULTS: Of 91 experts participating, 85 (93%) completed the first and 82 (90%) completed the second Delphi surveys. Consensus was reached on all but 2 statements. "EGID" was the preferred umbrella term for disorders of gastrointestinal (GI) tract eosinophilic inflammation in the absence of secondary causes (100% agreement). Involved GI tract segments will be named specifically and use an "Eo" abbreviation convention: eosinophilic gastritis (now abbreviated EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). The term "eosinophilic gastroenteritis" is no longer preferred as the overall name (96% agreement). When >2 GI tract areas are involved, the name should reflect all of the involved areas. CONCLUSIONS: This international process resulted in consensus for updated EGID nomenclature for both clinical and research use. EGID will be the umbrella term, rather than "eosinophilic gastroenteritis," and specific naming conventions by location of GI tract involvement are recommended. As more data are developed, this framework can be updated to reflect best practices and the underlying science.
Assuntos
Enterite , Eosinofilia , Esofagite Eosinofílica , Gastrite , Humanos , Consenso , Enterite/diagnóstico , Enterite/complicações , Gastrite/diagnóstico , Gastrite/complicações , Eosinofilia/diagnóstico , Eosinofilia/complicações , Esofagite Eosinofílica/complicaçõesRESUMO
OBJECTIVE: Antireflux surgery can be proposed in patients with GORD, especially when proton pump inhibitor (PPI) use leads to incomplete symptom improvement. However, to date, international consensus guidelines on the clinical criteria and additional technical examinations used in patient selection for antireflux surgery are lacking. We aimed at generating key recommendations in the selection of patients for antireflux surgery. DESIGN: We included 35 international experts (gastroenterologists, surgeons and physiologists) in a Delphi process and developed 37 statements that were revised by the Consensus Group, to start the Delphi process. Three voting rounds followed where each statement was presented with the evidence summary. The panel indicated the degree of agreement for the statement. When 80% of the Consensus Group agreed (A+/A) with a statement, this was defined as consensus. All votes were mutually anonymous. RESULTS: Patients with heartburn with a satisfactory response to PPIs, patients with a hiatal hernia (HH), patients with oesophagitis Los Angeles (LA) grade B or higher and patients with Barrett's oesophagus are good candidates for antireflux surgery. An endoscopy prior to antireflux surgery is mandatory and a barium swallow should be performed in patients with suspicion of a HH or short oesophagus. Oesophageal manometry is mandatory to rule out major motility disorders. Finally, oesophageal pH (±impedance) monitoring of PPI is mandatory to select patients for antireflux surgery, if endoscopy is negative for unequivocal reflux oesophagitis. CONCLUSION: With the ICARUS guidelines, we generated key recommendations for selection of patients for antireflux surgery.
Assuntos
Refluxo Gastroesofágico/cirurgia , Seleção de Pacientes , Adulto , Atitude do Pessoal de Saúde , Consenso , Técnica Delphi , Endoscopia , Monitoramento do pH Esofágico , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/patologia , Humanos , Manometria , Guias de Prática Clínica como Assunto , Padrões de Prática MédicaRESUMO
Eosinophilic oesophagitis is a disease that has been recognized in the past 30 years. It causes dysphagia and other symptoms of oesophageal dysfunction. Eosinophilic oesophagitis presents either with a chronic feeling of difficulty swallowing, with food moving slowly through the oesophagus, or as an acute food bolus obstruction requiring emergency attention. Patients may also experience chest pain at this time. It is an inflammatory disorder, thought to be driven by food or environmental antigens, where the most distinctive cell type is eosinophils. Eosinophilic oesophagitis is mediated through a local IgG4 mechanism and does not manifest as a systemic disease. It is diagnosed only on endoscopy and biopsy - there are characteristic endoscopic appearances with oedema, rings, furrows and strictures but the golden rule in its diagnosis is to perform multiple biopsies from multiple sites in the oesophagus in all patients with dysphagia or other oesophageal dysfunction. Finding a peak concentration of >15 eosinophils per high power field in this situation is diagnostic of eosinophilic oesophagitis. Eosinophilic oesophagitis is not usually related to gastro-oesophageal reflux disease, but the two conditions may co-exist. Current therapies include topical steroids (oro-dispersible formulation of budesonide), proton pump inhibitors and dietary exclusions. Therapeutic oesophageal dilatation is reserved for refractory symptoms or tight strictures.
Assuntos
Transtornos de Deglutição/fisiopatologia , Esofagite Eosinofílica/fisiopatologia , Qualidade de Vida , Administração Tópica , Biópsia , Budesonida/uso terapêutico , Dietoterapia/métodos , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/patologia , Esofagite Eosinofílica/terapia , Eosinófilos/patologia , Perfuração Esofágica , Estenose Esofágica , Esofagoscopia , Esôfago/patologia , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulina G , Inibidores da Bomba de Prótons/uso terapêuticoRESUMO
BACKGROUND & AIMS: Over the last decade, clinical experiences and research studies raised concerns regarding use of proton pump inhibitors (PPIs) as part of the diagnostic strategy for eosinophilic esophagitis (EoE). We aimed to clarify the use of PPIs in the evaluation and treatment of children and adults with suspected EoE to develop updated international consensus criteria for EoE diagnosis. METHODS: A consensus conference was convened to address the issue of PPI use for esophageal eosinophilia using a process consistent with standards described in the Appraisal of Guidelines for Research and Evaluation II. Pediatric and adult physicians and researchers from gastroenterology, allergy, and pathology subspecialties representing 14 countries used online communications, teleconferences, and a face-to-face meeting to review the literature and clinical experiences. RESULTS: Substantial evidence documented that PPIs reduce esophageal eosinophilia in children, adolescents, and adults, with several mechanisms potentially explaining the treatment effect. Based on these findings, an updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement. CONCLUSIONS: EoE should be diagnosed when there are symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (or approximately 60 eosinophils per mm2) on esophageal biopsy and after a comprehensive assessment of non-EoE disorders that could cause or potentially contribute to esophageal eosinophilia. The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change.
Assuntos
Técnicas de Diagnóstico do Sistema Digestório/normas , Esofagite Eosinofílica/diagnóstico , Gastroenterologia/normas , Inibidores da Bomba de Prótons/administração & dosagem , Algoritmos , Consenso , Esofagite Eosinofílica/tratamento farmacológico , Humanos , Valor Preditivo dos Testes , Prognóstico , Inibidores da Bomba de Prótons/efeitos adversosRESUMO
These are updated guidelines which supersede the original version published in 2004. This work has been endorsed by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG) under the auspices of the oesophageal section of the BSG. The original guidelines have undergone extensive revision by the 16 members of the Guideline Development Group with representation from individuals across all relevant disciplines, including the Heartburn Cancer UK charity, a nursing representative and a patient representative. The methodological rigour and transparency of the guideline development processes were appraised using the revised Appraisal of Guidelines for Research and Evaluation (AGREE II) tool.Dilatation of the oesophagus is a relatively high-risk intervention, and is required by an increasing range of disease states. Moreover, there is scarcity of evidence in the literature to guide clinicians on how to safely perform this procedure. These guidelines deal specifically with the dilatation procedure using balloon or bougie devices as a primary treatment strategy for non-malignant narrowing of the oesophagus. The use of stents is outside the remit of this paper; however, for cases of dilatation failure, alternative techniques-including stents-will be listed. The guideline is divided into the following subheadings: (1) patient preparation; (2) the dilatation procedure; (3) aftercare and (4) disease-specific considerations. A systematic literature search was performed. The Grading of Recommendations Assessment, Develop-ment and Evaluation (GRADE) tool was used to evaluate the quality of evidence and decide on the strength of recommendations made.
Assuntos
Dilatação/métodos , Endoscopia/métodos , Estenose Esofágica/cirurgia , Esôfago/cirurgia , Dilatação/efeitos adversos , Esôfago/patologia , Humanos , Reino UnidoRESUMO
INTRODUCTION: Eosinophilic esophagitis (EoE) is one of the most prevalent esophageal diseases and the leading cause of dysphagia and food impaction in children and young adults. This underlines the importance of optimizing diagnosys and treatment of the condition, especially after the increasing amount of knowledge on EoE recently published. Therefore, the UEG, EAACI ESPGHAN, and EUREOS deemed it necessary to update the current guidelines regarding conceptual and epidemiological aspects, diagnosis, and treatment of EoE. METHODS: General methodology according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used in order to comply with current standards of evidence assessment in formulation of recommendations. An extensive literature search was conducted up to August 2015 and periodically updated. The working group consisted of gastroenterologists, allergists, pediatricians, otolaryngologists, pathologists, and epidemiologists. Systematic evidence-based reviews were performed based upon relevant clinical questions with respect to patient-important outcomes. RESULTS: The guidelines include updated concept of EoE, evaluated information on disease epidemiology, risk factors, associated conditions, and natural history of EoE in children and adults. Diagnostic conditions and criteria, the yield of diagnostic and disease monitoring procedures, and evidence-based statements and recommendation on the utility of the several treatment options for patients EoE are provided. Recommendations on how to choose and implement treatment and long-term management are provided based on expert opinion and best clinical practice. CONCLUSION: Evidence-based recommendations for EoE diagnosis, treatment modalities, and patients' follow up are proposed in the guideline.
RESUMO
AIMS: Reflux symptoms are highly prevalent and non-specific; hence, in the absence of alarm symptoms, endoscopy referral decisions are challenging. This study evaluated whether a non-endoscopic Cytosponge could detect benign oesophageal pathologies and thus have future potential in triaging patients with persistent symptoms. METHODS AND RESULTS: Two complementary cohorts were recruited: (i) patients with reflux symptoms and no prior endoscopy (n = 409), and (ii) patients with reflux symptoms referred for endoscopy (n = 411). All patients were investigated using the Cytosponge and endoscopy. Significant epithelial inflammation was present in 130 (16%) Cytosponge samples, 32 of which had ulcer slough. Candida and significant inflammation was detected in a further 22 (2.3%) cases; epithelial infiltration with >15 eosinophils/high-power field reflecting possible eosinophilic oesophagitis (EOE) in five (0.6%); and viral inclusions suggestive of herpes oesophagitis in one (0.1%). No significant pathology was detected in the majority, 662 (81%), of Cytosponge samples. Cytosponge and endoscopy findings were in agreement in 574 (70%) cases, in 165 (67%) of the discordant cases one investigation showed mild inflammation while the other was negative, with an additional 22 (8.9%) differing on the extent of inflammation. Eighteen cases with severe inflammation, six with candida and two with EOE were detected only at endoscopy, while 18 with candida and significant inflammation, 13 with ulcer slough, one probable EOE and one viral oesophagitis were identified on the Cytosponge only. CONCLUSIONS: The Cytosponge detects a range of benign oesophageal pathologies, and therefore has potential clinical utility in the triaging of patients with troublesome reflux symptoms. This warrants further investigation.
Assuntos
Citodiagnóstico/instrumentação , Citodiagnóstico/métodos , Refluxo Gastroesofágico/diagnóstico , Adulto , Idoso , Esôfago/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Endoscopic therapy has revolutionized the treatment of Barrett's esophagus with high-grade dysplasia (HGD) or intramucosal adenocarcinoma by allowing preservation of the esophagus in many patients who would previously have had an esophagectomy. This paradigm shift initially occurred at high-volume centers in North America and Europe but now is becoming mainstream therapy. There is a lack of uniform guidelines and algorithms for the management of these patients. Our aim was to review important concepts and pitfalls in the endoscopic management of superficial esophageal adenocarcinoma. METHODS: A small group colloquium consisting of gastroenterologists, surgeons, and pathologists reviewed published data and discussed personal and institutional experiences with endotherapy for HGD and superficial esophageal adenocarcinoma. RESULTS: The group reviewed data and provided recommendations and management algorithms for seven areas pertaining to endoscopic therapy for Barrett's HGD and superficial adenocarcinoma: (1) patient selection and evaluation; (2) imaging and biopsy techniques; (3) devices; (4) indications for resection versus ablation; (5) ER specimen handling, processing, and pathologic evaluation; (6) patient care and follow-up after endoscopic therapy; and (7) complications of endoscopic therapy and treatment options. CONCLUSIONS: Endoscopic therapy is preferred over esophagectomy for most patients with HGD or intramucosal adenocarcinoma, and may be applicable to select patients with submucosal tumors. Clear guidelines and management algorithms will aid physicians and centers embarking on endoscopic therapy and enable a standardized approach to the management of these patients that is applicable internationally.
Assuntos
Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Esôfago de Barrett/patologia , Esôfago de Barrett/cirurgia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Esofagoscopia/métodos , Esofagoscopia/efeitos adversos , Esofagoscopia/instrumentação , Humanos , Seleção de Pacientes , Cuidados Pós-Operatórios , Manejo de EspécimesRESUMO
BACKGROUND & AIMS: We compared the ability of laparoscopic antireflux surgery (LARS) and esomeprazole to control esophageal acid exposure, over a 5-year period, in patients with chronic gastroesophageal reflux disease (GERD). We also studied whether intraesophageal and intragastric pH parameters off and on therapy were associated with long-term outcomes. METHODS: We analyzed data from a prospective, randomized, open-label trial comparing the efficacy and safety of LARS vs esomeprazole (20 or 40 mg/d) over 5 years in patients with chronic GERD. Ambulatory intraesophageal and intragastric 24-hour pH monitoring data were compared between groups before LARS or the start of esomeprazole treatment, and 6 months and 5 years afterward. A secondary aim was to evaluate the association between baseline and 6-month pH parameters and esomeprazole dose escalation, reappearance of GERD symptoms, and treatment failure over 5 years in patients receiving LARS or esomeprazole. RESULTS: In the LARS group (n = 116), the median 24-hour esophageal acid exposure was 8.6% at baseline and 0.7% after 6 months and 5 years (P < .001 vs baseline). In the esomeprazole group (n = 151), the median 24-hour esophageal acid exposure was 8.8% at baseline, 2.1% after 6 months, and 1.9% after 5 years (P < .001, therapy vs baseline, and LARS vs esomeprazole). Gastric acidity was stable in both groups. Patients who required a dose increase to 40 mg/d had more severe supine reflux at baseline, and decreased esophageal acid exposure (P < .02) and gastric acidity after dose escalation. Esophageal and intragastric pH parameters, off and on therapy, did not predict long-term symptom breakthrough. CONCLUSIONS: In a prospective study of patients with chronic GERD, esophageal acid reflux was reduced greatly by LARS or esomeprazole therapy. However, patients receiving LARS had significantly greater reductions in 24-hour esophageal acid exposure after 6 months and 5 years. Esophageal and gastric pH, off and on therapy, did not predict long-term outcomes of patients. Abnormal supine acid exposure predicted esomeprazole dose escalation. ClinicalTrials.Gov identifier: NCT00251927 (available: http://clinicaltrials.gov/ct2/show/NCT00251927).
Assuntos
Esomeprazol/uso terapêutico , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/cirurgia , Inibidores da Bomba de Prótons/uso terapêutico , Adolescente , Adulto , Idoso , Monitoramento do pH Esofágico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To assess the long-term effect on symptoms and quality of life of esomeprazole 20 mg once daily, a recommended dose for maintenance therapy of gastroesophageal reflux disease (GERD). RESEARCH DESIGN AND METHODS: This is a post hoc analysis of 5 year data from patients in the LOTUS trial (ClinicalTrials.gov identifier: NCT00251927) who were randomized to esomeprazole 20 mg once daily. All participants had chronic, symptomatic GERD responsive to treatment. Gastrointestinal symptoms were assessed by physicians and by using patient-reported outcome instruments. Investigations included gastrointestinal endoscopy (with biopsy sampling), 24 hour esophageal pH monitoring and laboratory measurements. RESULTS: In total, 157 of 256 patients randomized to esomeprazole 20 mg once daily remained on this dose until the end of follow-up or study discontinuation, whereas 99 patients had their dose increased because of inadequate symptom control (of these, 29 subsequently returned to the allocated dose). On logistic regression, a long objectively defined GERD history, smoking, female sex, absence of Helicobacter pylori infection and high supine baseline acid reflux into the esophagus were associated with an increased likelihood of requiring dose escalation to esomeprazole 40 mg daily (all p < 0.05). Symptoms were fairly stable and quality of life was normal throughout follow-up in patients remaining on esomeprazole 20 mg once daily, with no more than mild symptom severity, and mean (standard deviation) percentage time with intraesophageal pH <4 was reduced from 10.7 (10.7) pre-randomization to 6.3 (10.2) at 6 months and 4.9 (7.3) at 5 years. The number of serious adverse events was low (0.079 per patient per year). LIMITATIONS: Post hoc analysis with no control group. CONCLUSIONS: Esomeprazole at a maintenance dose of 20 mg once daily offers effective long-term treatment for chronic GERD in patients initially responsive to the medication, with durable symptom control and sustained reductions in intraesophageal acid exposure.
Assuntos
Esomeprazol/uso terapêutico , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Endoscopia Gastrointestinal , Monitoramento do pH Esofágico , Feminino , Seguimentos , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do TratamentoRESUMO
Initial case series describing children and adults with symptoms related to esophageal dysfunction and dense esophageal eosinophilia lead to recognition of a "new" disease, eosinophilic esophagitis (EoE). Clinical, basic, and translational studies have provided a deeper understanding of this somewhat enigmatic disease that mechanistically is defined as an antigen-driven condition limited to the esophagus. This article summarizes many of the key historical features of EoE and provides a glimpse of potential future developments.
Assuntos
Esofagite Eosinofílica/história , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/terapia , História do Século XX , História do Século XXI , HumanosRESUMO
INTRODUCTION: Day-case laparoscopic Nissen fundoplication has been described; however, its achievability and limitations in the setting of a busy Foundation Trust hospital are unclear. SUBJECTS AND METHODS: A retrospective cohort study of all cases undergoing laparoscopic Nissen fundoplication between January 1, 2009 and December 31, 2010 at three hospitals in the largest and the least densely populated Trust in the United Kingdom was undertaken. Primary end points of planned and achieved day-case surgery were compared with logistic regression analysis. Secondary end points were unplanned re-admission and complications. RESULTS: During the study period 126 consecutive patients underwent laparoscopic Nissen fundoplication. There were 64 female patients and 62 male patients. Primary surgery was undertaken in 115 patients and revisional surgery in 11. The age range was 21-73 years. Patients had traveled up to 52.3 miles or 80.2 minutes for their surgery. The median length of stay was 0 days in the planned day-case cohort and 1 day in the inpatient cohort. Day-case surgery was planned in 85 (68.55%). Successful day-case discharge was achieved in 71 cases (83.5%). There was no difference in age, geographical remoteness, surgeon volume, or length of surgery between planned and achieved day-case surgery. Patients were more likely to need unplanned admission if their American Society of Anesthesiologists grade was 2, when undergoing revisional surgery, and if the operation was completed after 1300 hours (1 p.m.). After multivariate regression analysis only operation completion time remained significant (P≤.05). The rate of unplanned re-admission related to surgery was 3/126 (2.38%). CONCLUSIONS: Day-case laparoscopic Nissen fundoplication can be achieved in the majority of patients. Unplanned admission is to be expected in approximately 15% of planned cases and cannot be predicted.
Assuntos
Procedimentos Cirúrgicos Ambulatórios , Fundoplicatura/métodos , Refluxo Gastroesofágico/cirurgia , Laparoscopia/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente/estatística & dados numéricos , Reoperação , Estudos Retrospectivos , Resultado do Tratamento , Reino UnidoRESUMO
The natural history of Barrett's esophagus (BE) is difficult to quantify because, by definition, it should describe the course of the condition if left untreated. Pragmatically, we assume that patients with BE will receive symptomatic treatment with acid suppression, usually a proton pump inhibitor, to treat their heartburn. This paper describes the development of complications of stricture, ulcer, dysplasia and adenocarcinoma from this standpoint. Controversies over the definition of BE and its implications in clinical practice are presented. The presence of intestinal metaplasia and its relevance to cancer risk is discussed, and the need to measure the extent of the Barrett's epithelium (long and short segments) using the Prague guidelines is emphasized. Guidelines and international consensus over the diagnosis and management of BE are being regularly updated. The need for expert consensus is important due to the lack of randomized trials in this area. After searching the literature, we have tried to collate the important studies regarding progression of Barrett's to dysplasia and adenocarcinoma. No therapeutic studies yet reported show a clear reduction in the development of cancer in BE. The effect of pharmacological and surgical intervention on the natural history of Barrett's is a subject of ongoing research, including the Barrett's Oesophagus Surveillance Study and the aspirin and esomeprazole cancer chemoprevention trial with interesting results. The geographical variation and the wide range of outcomes highlight the difficulty of providing an individualized risk profile to patients with BE. Future studies on the interaction of genome wide abnormalities in Barrett's and their interaction with environmental factors may allow individualization of the risk of cancer developing in BE.