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Role of Synbiotics Containing d-Allulose in the Alteration of Body Fat and Hepatic Lipids in Diet-Induced Obese Mice
The Relationship between Body Composition and a Gluten Free Diet in Children with Celiac Disease
Effects of High vs. Low Glycemic Index of Post-Exercise Meals on Sleep and Exercise Performance: A Randomized, Double-Blind, Counterbalanced Polysomnographic Study
Descriptive Study of the Different Tools Used to Evaluate the Adherence to a Gluten-Free Diet in Celiac Disease Patients
Itzlinger, A.
Branchi, F.
Elli, L.
Schumann, M.
Gluten-Free Diet in Celiac Disease—Forever and for All?
Alice Itzlinger
Federica Branchi
Luca Elli
Michael Schumann
1,*
Division of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, 12203 Berlin, Germany
Center for the Prevention and Diagnosis of Celiac Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
Nutrients 2018, 10(11), 1796; https://doi.org/10.3390/nu10111796
Received: 16 October 2018 / Revised: 4 November 2018 / Accepted: 15 November 2018 / Published: 18 November 2018
(This article belongs to the Special Issue Gluten-Free Diet)
The gluten-free diet is the only effective treatment available for celiac disease. However, it is difficult to adhere to and a closer look on the diet's implementation and indications reveals several ambiguities: Not only is there controversy on the threshold of gluten that can be tolerated in the frame of a strict gluten-free diet, but it is also unclear whether the gluten-free diet is an appropriate treatment in patient subgroups with asymptomatic or potential celiac disease. Reports from a number of research groups suggest that a certain proportion of patients may effectively develop tolerance to gluten and thus become suitable for gluten reintroduction over time. In this review, we set out to create an overview about the current state of research as regards the definition of a strict gluten-free diet in terms of the gluten thresholds considered tolerable and the indication for a gluten-free diet in the absence of histological abnormalities or symptoms. Furthermore, we discuss the concept that a gluten-free diet must be followed for life by all patients.
gluten; adherence; serology; villous atrophy; mucosal recovery; threshold
Celiac disease (CD) is an autoimmune disorder triggered by the ingestion of gluten. As a consequence of dietary exposure to gluten, genetically susceptible individuals develop autoimmune reactions resulting in histological changes in the small intestine. These are characterized by duodenal villous atrophy and intraepithelial lymphocytosis (IEL), leading to malabsorption and gastrointestinal as well as extraintestinal symptoms [1]. The clinical presentation of CD is diverse, with a considerable number of patients being asymptomatic. The classical form of CD is characterized by an overt malabsorption syndrome that features chronic diarrhea, steatorrhea, weight loss, and failure to thrive in children. Gastrointestinal symptoms as well as extraintestinal symptoms such as fatigue, osteopenia, iron deficiency, anemia and neurological/psychological disorders such as depression may be present [1,2]. On the other hand, in the non-classical form of CD patients present only one or few gastrointestinal or extraintestinal symptoms [2]. Table 1 shows the characteristics of different clinical presentations.
A lifelong gluten-free diet (GFD) has long been considered the only effective treatment for CD. Strict adherence to a GFD has been shown to lead to partial—if not complete—healing of the duodenal mucosa along with resolution of symptoms and signs of malabsorption [2]. It has been observed that mucosal recovery takes more time and is more frequently incomplete in adults than in children [3,4]. There remain, however, open issues regarding not only the tolerable threshold of gluten ingestion but also the appropriateness of a lifelong indication to GFD, particularly in patients with subclinical and potential CD. Considering the impact on the patients' quality of life posed by a restrictive GFD [5,6], its necessity should be reviewed carefully when prescribing it.
First of all, the natural course of CD is not as clearly understood as one might think. It is still unclear if a strict GFD needs to be followed throughout the whole life in all patients or if tolerance may develop in certain patients. While the GFD generally leads to clinical improvement, mucosal abnormalities may persist, but do not add up to functional malabsorption as clinical symptoms decline. Rubio-Tapia et al. observed mucosal recovery in about 35% two years after starting a GFD and in about 66% after five years; however, 82% improved clinically. In line with these findings, clinical improvement of symptoms was not a reliable marker of mucosal recovery (p = 0.7) [7]. On the other hand, cases of patients who—in many cases on their own—interrupt the GFD and remain symptom-free have been reported in some studies [8].
Furthermore, while there are strong data supporting the benefits of a GFD in patients with symptomatic CD or CD irrespective of symptomatology, the outcome of GFD within the subgroups of asymptomatic and potential CD is mostly unclear. In these patients, the response to GFD can neither be measured in terms of symptom relief—nor in terms of mucosal healing for potential CD. For this reason, the issue of the actual role of the GFD in the prevention of CD-related complications (e.g., refractory disease, intestinal lymphoma) and other immune disorders should be addressed. In view of the scattered data on the risk of CD-related complications in these patient groups, the prescription of a GFD needs to be critically debated.
The aim of this article is to critically review existing literature data on the therapeutic and prognostic role of the GFD in CD in order to give an overview about the current clinical indications for the GFD and future perspectives for celiac patients.
A comprehensive literature search was carried out on PubMed to identify peer-reviewed articles on GFD in CD published until August 2018. Search strategies included the following key words: celiac disease, gluten-free diet, adherence, autoimmune disorders, gluten re-challenge, gluten tolerance, gluten contamination, celiac disease complications, lymphoproliferative disorders, and enteropathy-associated T-cell lymphoma. A manual search was also carried out on the bibliographies of the identified articles. The most relevant original research articles in the English language, including randomized controlled trials and observational studies (prospective and retrospective) were selected by the authors and are discussed in the following sections.
3. Gluten-Free Diet: How Strict Should It Be?
Current guidelines suggest that the GFD should be strict, with complete avoidance of gluten containing products and attention to cross-contaminations [2].
Gluten contamination, even within the frame of a strict GFD, cannot be entirely avoided: Plenty of products contain hidden gluten, such as sausages, soups, soy sauce and ice cream. But even in gluten-free-labeled products there are traces of gluten. This is mostly due to cross-contamination with gluten-containing products that are processed or stored in the same place [9]. The term "gluten-free" thus generally refers to an amount of gluten that is thought to be harmless and does not imply total absence of gluten. In fact, the amount of gluten deriving solely from cross-contamination in a supposedly GFD may range from 5 to 50 mg per day [10,11]. The level of gluten content in food products is expressed as parts per million (ppm, corresponding to mg/kg). Gibert et al., collected consumption data of gluten-free products by CD patients in order to estimate the average gluten exposure of celiac patients who follow a GFD. Taking into account different dietary habits in European countries (Norway, Germany, Italy, Spain) they concluded that a limit of 20 ppm for products naturally gluten-free and 100 ppm for products rendered gluten-free would be acceptable [12]. According to the current guidelines of the European Commission a commercially sold product may be called "gluten-free" if it contains less than 20 ppm gluten (20mg/kg) [13].
Several studies have tried to establish a safe threshold of daily gluten intake, as summarized in Table 2. A prospective, multicenter, placebo-controlled, double-blind, randomized gluten challenge trial by Catassi et al., found that the chronic ingestion of small amounts of gliadin leads to a dose-dependent relapse in symptoms: children diagnosed with CD who had followed a GFD for at least three months were given small amounts of gluten for a period of four weeks [14]. Patients who had received 100 mg gliadin/day (= about 200 mg of gluten or the equivalent of 2–5 g wheat flour) displayed minimal morphometric changes in the jejunal histology. Patients who had ingested 500 mg gliadin per day showed significantly more histological abnormalities. Additionally, some patients became positive to antibodies again and experienced a symptom relapse. These results support the findings of a previous study by Ciclitira et al., who found no changes in mucosal histology after the infusion of 10 mg gliadin, minimal changes after 100 mg of gliadin and significant changes after an additional 500 mg of gliadin [15].
A further prospective, double blind, placebo-controlled trial by Catassi et al., analyzed the effects of daily ingestion of 0, 10, or 50 mg gluten for 90 days [9]. While the villous height to crypt depth ratio of the placebo group raised by 9%, no difference was found in the 10 mg group and a −20% was found in the group receiving 50 mg gluten/day. The IEL count did not differ significantly between the three groups. Catassi et al., concluded that the ingestion of contaminating gluten should be kept lower than 50 mg/day in the treatment of CD [9,16].
Two systematic reviews aimed to determine the safe maximum gluten intake. Hischenhuber et al., suggested that the maximum daily gluten intake should lie between 10 and 100 mg [11]. Akobeng and Thomas included thirteen studies and similarly found that the amount of tolerable gluten varied widely between the studies, ranging from patients who tolerated an average of 34–36 mg gluten per day to others who developed symptoms and/or histological abnormalities when consuming 10 mg gluten per day [17]. The results of these systematic reviews show that there is no single definitive threshold for gluten intake but that a daily intake of <10 mg is unlikely to cause mucosal abnormalities (see also Table 2).
More Than A Strict Gluten-Free Diet
Several research groups have observed that in a considerable portion of patients complying to a presumed strict GFD, complete mucosal recovery and/or resolution of symptom do not occur [5,19,20,21,22]. These results led to questions regarding the efficacy of the GFD in obtaining histological remission.
The first step in patients with signs of non-responsive CD should be the evaluation of the GFD by a trained dietitian to unveil possible unwitting intake of gluten. However, current methods and questionnaires still rely on the patients' subjective assertions and not able to accurately measure dietary compliance [23]. A relatively new method to monitor GFD compliance is the detection of gluten immunogenic peptides that can be found in the urine and feces after gluten consumption. This offers an objective method to assess the dietary adherence and has shown to be very sensitive [24,25,26].
While most patients tolerate trace gluten under the 20 ppm threshold, a subgroup might react even more sensitively. It has therefore been suggested that a more-than-strict GFD regimen has the potential to induce mucosal recovery in these patients [27]. The Gluten Contamination Elimination Diet (GCED) is a diet that was developed to remove even minute amount of gluten from the diet, consisting of a more restrictive dietary regimen focusing on the use of naturally gluten-free products rather than processed gluten-free food [27,28,29].
Hollon et al., identified 17 patients not responsive to GFD. Before starting the GCED, all subjects were assessed by a dietitian who excluded hidden gluten ingestion. After completing the GCED for 3–6 months, 82% responded to the GCED and became asymptomatic [28].
Zanini et al., investigated if complete mucosal recovery can be achieved by adopting this restrictive diet or, alternatively, after a prolonged time of GFD [29]. In this small study, after three months of GCED, no changes in villous height and crypt depth were observed as compared to two years of GFD. Only a slight, though significant decrease in IELs and T-cells with a distinctive T-cell receptor (TCR) on their surface, so called TCRγδ+ cells, was found. The study suggested that the intraepithelial lymphocytosis persisting in CD patients during GFD cannot completely be eliminated even on a GCED and is furthermore independent of the duration of adherence to a standard GFD. Whether gluten contamination is unavoidable despite GCED, or a three-month period of GCED was too short, could not be clarified by the study, possibly also due to the small sample size [29]. Given the scarce data, there is insufficient evidence to recommend a gluten contamination elimination diet on a routine basis in patients with CD. However, it should be considered in patients who are not responsive to traditional GFD.
4. Does the Gluten-free Diet Prevent the Development of Autoimmune Diseases and of Celiac Disease Complications?
4.1. Diet and Autoimmune Diseases
Patients with CD are at increased risk for various autoimmune disorders, particularly diabetes mellitus type I and autoimmune thyroiditis but also autoimmune hepatitis, rheumatoid arthritis and Sjögren's syndrome among others [30,31,32]. The same applies vice versa: Patients with autoimmune diseases have a significantly higher prevalence of CD than the healthy population—a Norwegian study found that around 5% patients with type 1 diabetes also have celiac disease [30]. The association between CD and other autoimmune conditions is presumably caused by a common genetic background (the presence of predisposing human leucocyte antigen (HLA) class II haplotypes), but the direct role of gluten exposure in the development of associated autoimmune conditions is still a matter of debate [33].
There are a number of contradictory studies concerning the association between the development of an additional autoimmune disorder and the duration of gluten exposure. Initially, it was hypothesized that strict adherence to GFD could prevent the development of further autoimmune diseases in patients with celiac disease. A cross-sectional study by Ventura et al., in 1999 showed an association between the prevalence of autoimmune disorders in CD patients and the age at diagnosis of CD, suggesting that duration of exposure to gluten might be a predictor of the development of other autoimmune conditions [34]. However, more recent studies tend to argue against a connection: A study by Sategna et al., found no correlation between the duration of exposure to gluten and the prevalence of autoimmune diseases [35]. Similar results were shown in a Finnish study in 2005 [31] as well as by a follow-up study by the same group [36].
All in all, current data allow for the assumption that the GFD has no definite role in the prevention of development of other autoimmune conditions.
4.2. Diet and Celiac Disease Complications
In children, early detection and treatment of celiac disease are of utmost importance to prevent complications such as poor growth, decreased bone mineral density, and enamel defects which can be irreversible [37,38]. But even for adults, a diagnostic delay is associated with decreased quality of life, more days of sickness, and frequent use of medicines and health care services [39]. The GFD is an effective tool against gastrointestinal and extraintestinal manifestations as well as complications such as malabsorption and osteoporosis [39,40,41].
Another complication is refractory CD which is defined as the persistence of clinical signs of CD, as well as villous atrophy, despite adherence to a strict GFD for at least 12 months [1]. Of the two subtypes of refractory CD, type II is associated with a worse prognosis in view of the high risk of development of malignancy. The enteropathy-associated T-cell lymphoma (EATL) is a lymphoproliferative disorder that typically develops in the setting of refractory CD. This is a rare type of T-cell lymphoma that arises from intraepithelial T-cells in the small intestine. A higher risk for developing other malignancies, including small bowel adenocarcinoma, has been reported in the setting of CD, but the underlying pathogenesis is still unclear [42,43,44,45,46].
Given the poor prognosis and limited therapeutic options available for type II refractory CD and EATL, research focused on both early diagnosis and identification of risk factors. The role of the GFD for the prevention of EATL development is controversial. From a pathophysiological point of view, EATL develops from aberrant intestinal lymphocytes that proliferate clonally independently of gluten exposure—a longer exposure to gluten, and thus a prolonged immune activation in the intestinal mucosa, may in fact contribute to create a favorable environment to the development and proliferation of aberrant lymphocytes [47]. However, the natural history of CD and the actual prognostic effect of the GFD are difficult to investigate and mainly based on retrospective data analysis.
Observational studies investigating the association between undiagnosed CD and mortality risk showed contradicting results, possibly also due to difficulty of differentiating between undiagnosed asymptomatic CD from mono-/oligosymptomatic or symptomatic CD based on medical record and patients reports. Rubio-Tapia et al., reported an up to 4-fold increased mortality rate in undiagnosed CD during 45 years of follow up, suggesting both a possible role of gluten exposure in the development of malignancies and the necessity of very long follow-ups in order to investigate this area [42]. Similarly, a German study showed an excess in mortality, particularly due to cancer, in patients with elevated transglutaminase antibody levels [43]. On the other hand, population-based study like that by Lohi et al., could not find an excess of mortality in unrecognized CD, though reporting a tendency to die from lymphoproliferative disorders, stroke and respiratory diseases [48]. In a case-control study published in 2011, Olén et al., assessed the characteristics of CD patients with particular attention to their diet compliance and compared it with the risk of developing malignant lymphoma [49]. They could not find an association between the development of lymphoma and non-compliance to GFD even though they could not entirely exclude a moderate effect. A study by Biagi et al., suggested the amount of exposure to gluten to be a relevant risk factor for developing malignancies such as EATL [50]. This hypothesis was based on an indirect link: the authors observed that reported mortality rates in CD patients were higher in Southern than in Northern Europe and correlated with the gluten content of the typical diet of each country. Hence, it was presumed that the amount of dietary gluten ingested (before and after diagnosis) was responsible for a higher incidence of complications and higher mortality.
Given the ambiguity that exists, we cannot exclude a causal association between duration and amount of gluten consumption and the development of refractory celiac disease (RCD) and malignancies. It therefore remains essential to advise and stress the importance of a strict GFD to patients with celiac disease. Further research and in particular prospective studies about the aforementioned linkage are needed in order to clarify the role of gluten exposure in this setting.
5. Gluten-Free Diet in Potential Celiac Disease
Potential CD is characterized by positive endomysium and/or anti-transglutaminase antibodies and a normal intestinal histology [1]. It is important to emphasize the distinct difference between potential and asymptomatic celiac disease. While all other forms of celiac disease are characterized by intestinal mucosal abnormalities, patients with potential celiac disease do, by definition, not display any histological abnormalities. Individuals with potential CD are often identified as a result of screening or incidental findings on routine examinations (e.g., screening of first-degree relatives or after diagnosis of related autoimmune diseases). The question arises whether individuals with potential CD benefit from a GFD or if the GFD results in a social and economic burden and a risk of malnutrition devoid of health benefits for this subgroup of patients.
First of all, it must be pointed out that individuals with potential CD may not always be completely asymptomatic and a GFD could be of benefit even in the absence of histologically evident mucosal changes [51,52]. Moreover, the adequacy of histology sampling has to be reviewed before classifying a patient with positive serology as potential CD, since at least four duodenal biopsies (according to some guidelines even six biopsies) are required to ensure an adequate diagnosis and some subjects may show histological changes only in the duodenal bulb [2,53,54]. It is a matter of debate if a reference pathologist should be consulted in contradictory cases. This claim is substantiated by data revealing a high interobserver variability in histopathology [55,56,57].
Kurppa et al., studied the effects of a GFD in screening-detected asymptomatic patients with CD [51]. They included also 40 patients positive to IgA-anti-endomysium antibodies that were at risk for CD (potential CD), who were randomized to either group A following a GFD or group B continuing a normal diet for a year. Despite the fact that all subjects prior to the study described themselves as "asymptomatic", only group A improved significantly on the Gastrointestinal Symptoms Rating Scale. However, social functioning was impaired by the GFD. The authors concluded that even apparently asymptomatic patients with positive antibodies benefit from a GFD.
In another study, Mandile et al., evaluated the effect of GFD on clinical symptoms and mucosal histology in children with potential CD [58]. After one year on GFD no significant differences were observed in terms of Marsh grade, lamina propria CD25+ cells, CD3+ and γδ+ intraepithelial lymphocytes density and intestinal anti-TG2 deposits. However, about half of the patients reported improved clinical symptoms. A similar result was observed by Volta et al. [52]. Patients with potential CD that showed symptoms improved clinically by following a GFD.
On the other hand, it is interesting to assess the question how many patients with positive CD serology and normal histology will eventually develop CD characteristic celiac histology. Biagi et al., found only 35% to have developed a flat mucosa in the course of their disease. However, 29% of those with a normal histology decided to switch onto a GFD early on in the course, making it impossible to judge on their further natural course [59]. Interestingly, a reversal of CD serology has also been observed, especially in children [60]. Auricchio et al., studied 210 children with potential CD of which 175 were left on a gluten-containing diet [61]. Antibodies and clinical symptoms were checked twice a year and a small bowel biopsy was taken every second year. They found that 37% of the subjects showed fluctuation and 20% normalization of antibody production over the years, most of them (67%) without ever displaying mucosal damage during 9 years of follow-up. They concluded that a GFD might not always be necessary for individuals with potential CD. Volta et al., after collecting data from 77 adult patients from CD, proposed to prescribe a GFD only to clinically symptomatic patients with potential CD due to the observed improvement of symptoms after gluten withdrawal [52]. In asymptomatic patients who remained on a gluten-containing diet, progression to overt CD could merely be observed in 1 of 16 patients during a 5-years follow up. A possible rational approach in view of available data is shown in Figure 1.
6. Is There A Way Towards Gluten Reintroduction in Celiac Disease?
In recent years, there has been active debate on whether the GFD should be continued lifelong in all celiac patients. Data on the natural history of CD suggest that an excess of mortality, possibly derived from lymphoproliferative disorders, may be subsequent to higher/longer exposure to dietary gluten [7,33,51,62]: On this basis, the GFD should be continued indefinitely not only to prevent clinical relapse and malabsorption, but also to prevent complications.
Nevertheless, there are a number of studies published during the last 30 years that showed proof for the existence of a "latent" form of CD, where symptoms and histologic changes disappear in the course of disease despite consumption of a GFD. As early as 1989, a Finnish study tried to evaluate the possibility of development of gluten tolerance in children: 38 post pubertal children with CD were rebiopsied before a gluten challenge was carried out [63]. Eleven percent did not relapse (clinically and histologically) after 2 years, indicating a possible recovery from CD in this small subgroup.
Matysiak-Budnik et al., in 2007 conducted a retrospective analysis of clinical symptoms, mucosal recovery and laboratory findings of patients diagnosed with CD in childhood who, despite diagnosis, did not follow a GFD but resumed a normal diet and remained clinically silent [64]. They found that about a fifth of CD patients developed long-term latency (normal duodenal histology) after gluten reintroduction. Patients who remained clinically silent but displayed histological abnormalities were at increased risk for osteoporosis. The authors therefore concluded that a GFD is advisable in patients with asymptomatic CD, but that a subgroup of celiac patients may actually become gluten tolerant over time. However, tolerance could be transient and therefore demands regular follow-up. In fact, two "gluten-tolerant" patients actually showed clinical and mucosal relapse during the follow up.
Hopman et al., performed a follow-up with 77 patients who had been diagnosed with CD for over ten years [65]. Gluten consumption, symptoms, bone mineral density and antibodies were examined. Two thirds adhered to GFD, 15% were partially compliant and 23% followed a regular gluten-containing diet. Interestingly, biopsies revealed a normal mucosal histology in four of eight patients on gluten-containing diet and in all patients who were partially compliant. The authors concluded that development of tolerance to gluten was possible in some patients with CD. They suggest a regular follow-up to determine if this tolerance is permanent or not.
Although poor adherence to the GFD is the major predictor of persistence of mucosal lesions at follow-up histology, a recent study by Norsa et al., showed no excess in mortality among celiac patients with a long history of CD with poor or no adherence to the GFD, also reporting a proportion of patients of almost 30% with no relapse of villous atrophy despite chronic voluntary gluten ingestion [8].
Who Could Benefit Most from Gluten Reintroduction?
Screening-detected CD patients are a subgroup of patients that experience more difficulty accepting the diagnosis and permanent dietary restriction since its justification, in the absence of symptoms, is less evident than in symptomatic patients that experience immediate improvement in health when adhering to GFD [66]. They report a decreased perception of health on a GFD [6] and may feel less motivated to adhere to the diet than symptomatic patients [67]. Accordingly, a recent study published in August 2018 studied the long-term health and treatment outcomes in screening-detected CD patients [66]. At a median of 18.5 years after diagnosis, 236 patients completed follow-up questionnaires. With regard to clinical symptoms and quality of life, the screening-detected subgroup showed more anxiety and lower general well-being than CD patients that had been diagnosed due to clinical suspicion. In this group of patients, the GFD is recommended in order to avoid long-term consequences of malabsorption. Moreover, epidemiological data on the excess mortality of CD complications linked to gluten exposure have been questioned [8,48].
In other words, considering the reported proportion—20–30% of CD patients able to develop a gluten tolerance over time and the limited risk of developing osteoporosis and complications over a short time of histological relapse of villous atrophy—it needs to be questioned whether a gluten reintroduction (or "re-challenge") under careful follow-up could be a rational therapeutic option in patients with asymptomatic celiac disease. As follow-up, lifelong assessments including histology would be needed, in order to detect a possible relapse and worsening of mucosal histology. More research is needed before this option can be implemented into the clinical routine, however.
7. Conclusions and Future Perspectives
In patients affected by CD, the GFD ensures improvement of clinical symptoms and signs of malabsorption in the vast majority of cases. Despite extensive research aimed at developing alternative therapies for CD, the GFD remains the only effective treatment available to date [68]. However, it is not easy to follow and may result in a psychological and social burden for patients [5,6]. For this reason, the GFD should be prescribed only once CD diagnosis has been established by means of serology and duodenal histology.
In potential CD, the diet should be reserved to subjects reporting symptoms, while those asymptomatic can be maintained on a gluten-containing diet but should be followed up on a regular basis.
In patients with symptomatic CD, the diet should be followed strictly in view of the risk for complications such as osteoporosis and other consequences of malabsorption. Gluten exposure neither appears to be linked to the onset of other autoimmune disorders nor has an increased risk for malignancies been shown in asymptomatic CD so far. The current literature available, however, does not provide enough evidence to safely recommend a gluten-containing regimen in asymptomatic CD. More research on this topic is needed before introducing a gluten re-challenge for asymptomatic CD patients into the clinical routine.
The natural history of CD on a gluten-containing diet is still far from understood: It is unclear whether the large group of patients with mild or asymptomatic CD is indeed at risk of developing long-term-complications such as EATL. Further studies aimed at investigating the effects of gluten reintroduction in CD are required to identify the subgroup of patients that may develop gluten tolerance over time, without increasing the risk for CD related complications.
Conceptualization, F.B., A.I., M.S. and L.E.; Methodology, A.I. and F.B.; Software, A.I.; Validation, A.I., F.B., M.S. and L.E.; Formal Analysis, A.I., F.B. and M.S.; Investigation, A.I. and F.B.; Resources, A.I., F.B., M.S. and L.E.; Data Curation, A.I. and F.B.; Writing—Original Draft Preparation, A.I. and F.B.; Writing—Review & Editing, A.I, F.B, M.S and L.E.; Visualization, A.I. and F.B.; Supervision, M.S.; Project Administration, F.B., M.S. and L.E.
FB received funding from the ECCO (European Crohn´s and Colitis Organization) fellowship program. MS was funded by the Clinical Scientist program and received funding by the DFG GRK 2318 and DFG TRR241 collaborative research center.
Ludvigsson, J.F.; Leffler, D.A.; Bai, J.C.; Biagi, F.; Fasano, A.; Green, P.H.R.; Hadjivassiliou, M.; Kaukinen, K.; Kelly, C.P.; Leonard, J.N.; et al. The Oslo definitions for coeliac disease and related terms. Gut 2013, 62, 43–52. [Google Scholar] [CrossRef] [PubMed]
Ludvigsson, J.F.; Bai, J.C.; Biagi, F.; Card, T.R.; Ciacci, C.; Ciclitira, P.J.; Green, P.H.R.; Hadjivassiliou, M.; Holdoway, A.; van Heel, D.A.; et al. Diagnosis and management of adult coeliac disease: Guidelines from the British Society of Gastroenterology. Gut 2014. [Google Scholar] [CrossRef] [PubMed][Green Version]
Husby, S.; Koletzko, S.; Korponay-Szabó, I.R.; Mearin, M.L.; Phillips, A.; Shamir, R.; Troncone, R.; Giersiepen, K.; Branski, D.; Catassi, C.; et al. ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J. Pediatr. Gastroenterol. Nutr. 2012, 54, 136–160. [Google Scholar] [CrossRef] [PubMed]
Ciccocioppo, R.; Kruzliak, P.; Cangemi, G.C.; Pohanka, M.; Betti, E.; Lauret, E.; Rodrigo, L. The Spectrum of Differences between Childhood and Adulthood Celiac Disease. Nutrients 2015, 7, 8733–8751. [Google Scholar] [CrossRef] [PubMed][Green Version]
Barratt, S.M.; Leeds, J.S.; Sanders, D.S. Quality of life in Coeliac Disease is determined by perceived degree of difficulty adhering to a gluten-free diet, not the level of dietary adherence ultimately achieved. J. Gastrointest. Liver Dis. 2011, 20, 241–245. [Google Scholar]
Ukkola, A.; Mäki, M.; Kurppa, K.; Collin, P.; Huhtala, H.; Kekkonen, L.; Kaukinen, K. Diet improves perception of health and well-being in symptomatic, but not asymptomatic, patients with celiac disease. Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc. 2011, 9, 118–123. [Google Scholar] [CrossRef] [PubMed]
Rubio-Tapia, A.; Rahim, M.W.; See, J.A.; Lahr, B.D.; Wu, T.-T.; Murray, J.A. Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet. Am. J. Gastroenterol. 2010, 105, 1412–1420. [Google Scholar] [CrossRef] [PubMed]
Norsa, L.; Branchi, F.; Bravo, M.; Ferretti, F.; Roncoroni, L.; Somalvico, F.; Conte, D.; Bardella, M.T.; Fabiano, S.; Barigelletti, G.; et al. Celiac Disease 30 Years After Diagnosis: Struggling With Gluten-free Adherence or Gaining Gluten Tolerance? J. Pediatr. Gastroenterol. Nutr. 2018, 67, 361–366. [Google Scholar] [CrossRef] [PubMed]
Catassi, C.; Fabiani, E.; Iacono, G.; D'Agate, C.; Francavilla, R.; Biagi, F.; Volta, U.; Accomando, S.; Picarelli, A.; De Vitis, I.; et al. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am. J. Clin. Nutr. 2007, 85, 160–166. [Google Scholar] [CrossRef] [PubMed]
Collin, P.; Thorell, L.; Kaukinen, K.; Mäki, M. The safe threshold for gluten contamination in gluten-free products. Can trace amounts be accepted in the treatment of coeliac disease? Aliment. Pharmacol. Ther. 2004, 19, 1277–1283. [Google Scholar] [CrossRef] [PubMed][Green Version]
Hischenhuber, C.; Crevel, R.; Jarry, B.; Mäki, M.; Moneret-Vautrin, D.A.; Romano, A.; Troncone, R.; Ward, R. Review article: Safe amounts of gluten for patients with wheat allergy or coeliac disease. Aliment. Pharmacol. Ther. 2006, 23, 559–575. [Google Scholar] [CrossRef] [PubMed]
Gibert, A.; Espadaler, M.; Angel Canela, M.; Sánchez, A.; Vaqué, C.; Rafecas, M. Consumption of gluten-free products: Should the threshold value for trace amounts of gluten be at 20, 100 or 200 p.p.m.? Eur. J. Gastroenterol. Hepatol. 2006, 18, 1187–1195. [Google Scholar] [CrossRef] [PubMed]
Commission Implementing Regulation (EU) No 828/2014 of 30 July 2014 on the Requirements for the Provision of Information to Consumers on the Absence or Reduced Presence of Gluten in Food Text with EEA Relevance. Available online: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32014R0828 (accessed on 16 October 2018).
Catassi, C.; Rossini, M.; Rätsch, I.M.; Bearzi, I.; Santinelli, A.; Castagnani, R.; Pisani, E.; Coppa, G.V.; Giorgi, P.L. Dose dependent effects of protracted ingestion of small amounts of gliadin in coeliac disease children: A clinical and jejunal morphometric study. Gut 1993, 34, 1515–1519. [Google Scholar] [CrossRef] [PubMed]
Ciclitira, P.J.; Evans, D.J.; Fagg, N.L.; Lennox, E.S.; Dowling, R.H. Clinical testing of gliadin fractions in coeliac patients. Clin. Sci. 1984, 66, 357–364. [Google Scholar] [CrossRef] [PubMed]
Collin, P.; Mäki, M.; Kaukinen, K. Safe gluten threshold for patients with celiac disease: Some patients are more tolerant than others. Am. J. Clin. Nutr. 2007, 86, 260. [Google Scholar] [CrossRef] [PubMed]
Akobeng, A.K.; Thomas, A.G. Systematic review: Tolerable amount of gluten for people with coeliac disease. Aliment. Pharmacol. Ther. 2008, 27, 1044–1052. [Google Scholar] [CrossRef] [PubMed]
Peräaho, M.; Kaukinen, K.; Paasikivi, K.; Sievänen, H.; Lohiniemi, S.; Mäki, M.; Collin, P. Wheat-starch-based gluten-free products in the treatment of newly detected coeliac disease: Prospective and randomized study. Aliment. Pharmacol. Ther. 2003, 17, 587–594. [Google Scholar] [CrossRef] [PubMed]
Lohiniemi, S.; Mäki, M.; Kaukinen, K.; Laippala, P.; Collin, P. Gastrointestinal symptoms rating scale in coeliac disease patients on wheat starch-based gluten-free diets. Scand. J. Gastroenterol. 2000, 35, 947–949. [Google Scholar] [PubMed]
Selby, W.S.; Painter, D.; Collins, A.; Faulkner-Hogg, K.B.; Loblay, R.H. Persistent mucosal abnormalities in coeliac disease are not related to the ingestion of trace amounts of gluten. Scand. J. Gastroenterol. 1999, 34, 909–914. [Google Scholar] [PubMed]
Ciacci, C.; Cirillo, M.; Cavallaro, R.; Mazzacca, G. Long-term follow-up of celiac adults on gluten-free diet: Prevalence and correlates of intestinal damage. Digestion 2002, 66, 178–185. [Google Scholar] [CrossRef] [PubMed]
Mahadev, S.; Murray, J.A.; Wu, T.-T.; Chandan, V.S.; Torbenson, M.S.; Kelly, C.P.; Maki, M.; Green, P.H.R.; Adelman, D.; Lebwohl, B. Factors associated with villus atrophy in symptomatic coeliac disease patients on a gluten-free diet. Aliment. Pharmacol. Ther. 2017, 45, 1084–1093. [Google Scholar] [CrossRef] [PubMed]
Biagi, F.; Andrealli, A.; Bianchi, P.I.; Marchese, A.; Klersy, C.; Corazza, G.R. A gluten-free diet score to evaluate dietary compliance in patients with coeliac disease. Br. J. Nutr. 2009, 102, 882–887. [Google Scholar] [CrossRef] [PubMed]
De Lourdes Moreno, M.; Cebolla, Á.; Muñoz-Suano, A.; Carrillo-Carrion, C.; Comino, I.; Pizarro, Á.; León, F.; Rodríguez-Herrera, A.; Sousa, C. Detection of gluten immunogenic peptides in the urine of patients with coeliac disease reveals transgressions in the gluten-free diet and incomplete mucosal healing. Gut 2017, 66, 250–257. [Google Scholar] [CrossRef] [PubMed]
Moreno Amador, M.L.; Rodríguez-Herrera, A.; Sousa, C.; Comino, I. Biomarkers to Monitor Gluten-Free Diet Compliance in Celiac Patients. Nutrients 2017, 9. [Google Scholar] [CrossRef] [PubMed]
Comino, I.; Fernández-Bañares, F.; Esteve, M.; Ortigosa, L.; Castillejo, G.; Fambuena, B.; Ribes-Koninckx, C.; Sierra, C.; Rodríguez-Herrera, A.; Salazar, J.C.; et al. Fecal Gluten Peptides Reveal Limitations of Serological Tests and Food Questionnaires for Monitoring Gluten-Free Diet in Celiac Disease Patients. Am. J. Gastroenterol. 2016, 111, 1456–1465. [Google Scholar] [CrossRef] [PubMed][Green Version]
Leonard, M.M.; Cureton, P.; Fasano, A. Indications and Use of the Gluten Contamination Elimination Diet for Patients with Non-Responsive Celiac Disease. Nutrients 2017, 9. [Google Scholar] [CrossRef] [PubMed]
Hollon, J.R.; Cureton, P.A.; Martin, M.L.; Puppa, E.L.L.; Fasano, A. Trace gluten contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-responsive celiac disease patients. BMC Gastroenterol. 2013, 13, 40. [Google Scholar] [CrossRef] [PubMed]
Zanini, B.; Marullo, M.; Villanacci, V.; Salemme, M.; Lanzarotto, F.; Ricci, C.; Lanzini, A. Persistent Intraepithelial Lymphocytosis in Celiac Patients Adhering to Gluten-Free Diet Is Not Abolished Despite a Gluten Contamination Elimination Diet. Nutrients 2016, 8. [Google Scholar] [CrossRef] [PubMed]
Elfström, P.; Sundström, J.; Ludvigsson, J.F. Systematic review with meta-analysis: Associations between coeliac disease and type 1 diabetes. Aliment. Pharmacol. Ther. 2014, 40, 1123–1132. [Google Scholar] [CrossRef] [PubMed]
Viljamaa, M.; Kaukinen, K.; Huhtala, H.; Kyrönpalo, S.; Rasmussen, M.; Collin, P. Coeliac disease, autoimmune diseases and gluten exposure. Scand. J. Gastroenterol. 2005, 40, 437–443. [Google Scholar] [CrossRef] [PubMed]
Hadithi, M.; de Boer, H.; Meijer, J.W.R.; Willekens, F.; Kerckhaert, J.A.; Heijmans, R.; Peña, A.S.; Stehouwer, C.D.A.; Mulder, C.J.J. Coeliac disease in Dutch patients with Hashimoto's thyroiditis and vice versa. World J. Gastroenterol. 2007, 13, 1715–1722. [Google Scholar] [CrossRef] [PubMed]
Diamanti, A.; Capriati, T.; Bizzarri, C.; Ferretti, F.; Ancinelli, M.; Romano, F.; Perilli, A.; Laureti, F.; Locatelli, M. Autoimmune diseases and celiac disease which came first: Genotype or gluten? Expert Rev. Clin. Immunol. 2016, 12, 67–77. [Google Scholar] [CrossRef] [PubMed]
Ventura, A.; Magazzù, G.; Greco, L. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease. SIGEP Study Group for Autoimmune Disorders in Celiac Disease. Gastroenterology 1999, 117, 297–303. [Google Scholar] [CrossRef] [PubMed]
Sategna Guidetti, C.; Solerio, E.; Scaglione, N.; Aimo, G.; Mengozzi, G. Duration of gluten exposure in adult coeliac disease does not correlate with the risk for autoimmune disorders. Gut 2001, 49, 502–505. [Google Scholar] [CrossRef] [PubMed][Green Version]
Metso, S.; Hyytiä-Ilmonen, H.; Kaukinen, K.; Huhtala, H.; Jaatinen, P.; Salmi, J.; Taurio, J.; Collin, P. Gluten-free diet and autoimmune thyroiditis in patients with celiac disease. A prospective controlled study. Scand. J. Gastroenterol. 2012, 47, 43–48. [Google Scholar] [CrossRef] [PubMed]
Mustalahti, K.; Collin, P.; Sievänen, H.; Salmi, J.; Mäki, M. Osteopenia in patients with clinically silent coeliac disease warrants screening. Lancet Lond. Engl. 1999, 354, 744–745. [Google Scholar] [CrossRef]
Majorana, A.; Bardellini, E.; Ravelli, A.; Plebani, A.; Polimeni, A.; Campus, G. Implications of gluten exposure period, CD clinical forms, and HLA typing in the association between celiac disease and dental enamel defects in children. A case-control study. Int. J. Paediatr. Dent. 2010, 20, 119–124. [Google Scholar] [CrossRef] [PubMed]
Fuchs, V.; Kurppa, K.; Huhtala, H.; Mäki, M.; Kekkonen, L.; Kaukinen, K. Delayed celiac disease diagnosis predisposes to reduced quality of life and incremental use of health care services and medicines: A prospective nationwide study. United Eur. Gastroenterol. J. 2018, 6, 567–575. [Google Scholar] [CrossRef] [PubMed][Green Version]
Pantaleoni, S.; Luchino, M.; Adriani, A.; Pellicano, R.; Stradella, D.; Ribaldone, D.G.; Sapone, N.; Isaia, G.C.; Di Stefano, M.; Astegiano, M. Bone mineral density at diagnosis of celiac disease and after 1 year of gluten-free diet. Sci. World J. 2014, 2014, 173082. [Google Scholar] [CrossRef] [PubMed]
Laurikka, P.; Salmi, T.; Collin, P.; Huhtala, H.; Mäki, M.; Kaukinen, K.; Kurppa, K. Gastrointestinal Symptoms in Celiac Disease Patients on a Long-Term Gluten-Free Diet. Nutrients 2016, 8. [Google Scholar] [CrossRef] [PubMed]
Rubio-Tapia, A.; Kyle, R.A.; Kaplan, E.L.; Johnson, D.R.; Page, W.; Erdtmann, F.; Brantner, T.L.; Kim, W.R.; Phelps, T.K.; Lahr, B.D.; et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology 2009, 137, 88–93. [Google Scholar] [CrossRef] [PubMed]
Metzger, M.-H.; Heier, M.; Mäki, M.; Bravi, E.; Schneider, A.; Löwel, H.; Illig, T.; Schuppan, D.; Wichmann, H.-E. Mortality excess in individuals with elevated IgA anti-transglutaminase antibodies: The KORA/MONICA Augsburg cohort study 1989-1998. Eur. J. Epidemiol. 2006, 21, 359–365. [Google Scholar] [CrossRef] [PubMed]
Catassi, C.; Fabiani, E.; Corrao, G.; Barbato, M.; De Renzo, A.; Carella, A.M.; Gabrielli, A.; Leoni, P.; Carroccio, A.; Baldassarre, M.; et al. Italian Working Group on Coeliac Disease and Non-Hodgkin's-Lymphoma Risk of non-Hodgkin lymphoma in celiac disease. JAMA 2002, 287, 1413–1419. [Google Scholar] [CrossRef] [PubMed]
Logan, R.F.; Rifkind, E.A.; Turner, I.D.; Ferguson, A. Mortality in celiac disease. Gastroenterology 1989, 97, 265–271. [Google Scholar] [CrossRef]
West, J.; Logan, R.F.A.; Smith, C.J.; Hubbard, R.B.; Card, T.R. Malignancy and mortality in people with coeliac disease: Population based cohort study. BMJ 2004, 329, 716–719. [Google Scholar] [CrossRef] [PubMed]
Chander, U.; Leeman-Neill, R.J.; Bhagat, G. Pathogenesis of Enteropathy-Associated T Cell Lymphoma. Curr. Hematol. Malig. Rep. 2018, 13, 308–317. [Google Scholar] [CrossRef] [PubMed]
Lohi, S.; Mäki, M.; Rissanen, H.; Knekt, P.; Reunanen, A.; Kaukinen, K. Prognosis of unrecognized coeliac disease as regards mortality: A population-based cohort study. Ann. Med. 2009, 41, 508–515. [Google Scholar] [CrossRef] [PubMed]
Olén, O.; Askling, J.; Ludvigsson, J.F.; Hildebrand, H.; Ekbom, A.; Smedby, K.E. Coeliac disease characteristics, compliance to a gluten free diet and risk of lymphoma by subtype. Dig. Liver Dis. 2011, 43, 862–868. [Google Scholar] [CrossRef] [PubMed]
Biagi, F.; Corazza, G.R. Mortality in celiac disease. Nat. Rev. Gastroenterol. Hepatol. 2010, 7, 158–162. [Google Scholar] [CrossRef] [PubMed]
Kurppa, K.; Paavola, A.; Collin, P.; Sievänen, H.; Laurila, K.; Huhtala, H.; Saavalainen, P.; Mäki, M.; Kaukinen, K. Benefits of a gluten-free diet for asymptomatic patients with serologic markers of celiac disease. Gastroenterology 2014, 147, 610–617. [Google Scholar] [CrossRef] [PubMed]
Volta, U.; Caio, G.; Giancola, F.; Rhoden, K.J.; Ruggeri, E.; Boschetti, E.; Stanghellini, V.; Giorgio, R.D. Features and Progression of Potential Celiac Disease in Adults. Clin. Gastroenterol. Hepatol. 2016, 14, 686–693. [Google Scholar] [CrossRef] [PubMed]
Lebwohl, B.; Kapel, R.C.; Neugut, A.I.; Green, P.H.R.; Genta, R.M. Adherence to biopsy guidelines increases celiac disease diagnosis. Gastrointest. Endosc. 2011, 74, 103–109. [Google Scholar] [CrossRef] [PubMed]
Gonzalez, S.; Gupta, A.; Cheng, J.; Tennyson, C.; Lewis, S.K.; Bhagat, G.; Green, P.H.R. Prospective study of the role of duodenal bulb biopsies in the diagnosis of celiac disease. Gastrointest. Endosc. 2010, 72, 758–765. [Google Scholar] [CrossRef] [PubMed]
Villanacci, V.; Lorenzi, L.; Donato, F.; Auricchio, R.; Dziechciarz, P.; Gyimesi, J.; Koletzko, S.; Mišak, Z.; Laguna, V.M.; Polanco, I.; et al. Histopathological evaluation of duodenal biopsy in the PreventCD project. An observational interobserver agreement study. APMIS Acta Pathol. Microbiol. Immunol. Scand. 2018, 126, 208–214. [Google Scholar] [CrossRef] [PubMed]
Corazza, G.R.; Villanacci, V.; Zambelli, C.; Milione, M.; Luinetti, O.; Vindigni, C.; Chioda, C.; Albarello, L.; Bartolini, D.; Donato, F. Comparison of the interobserver reproducibility with different histologic criteria used in celiac disease. Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc. 2007, 5, 838–843. [Google Scholar] [CrossRef] [PubMed]
Taavela, J.; Koskinen, O.; Huhtala, H.; Lähdeaho, M.-L.; Popp, A.; Laurila, K.; Collin, P.; Kaukinen, K.; Kurppa, K.; Mäki, M. Validation of morphometric analyses of small-intestinal biopsy readouts in celiac disease. PLoS ONE 2013, 8, e76163. [Google Scholar] [CrossRef] [PubMed]
Mandile, R.; Discepolo, V.; Scapaticci, S.; Del Vecchio, M.R.; Maglio, M.A.; Greco, L.; Troncone, R.; Auricchio, R. The Effect of Gluten-free Diet on Clinical Symptoms and the Intestinal Mucosa of Patients With Potential Celiac Disease. J. Pediatr. Gastroenterol. Nutr. 2018, 66, 654–656. [Google Scholar] [CrossRef] [PubMed]
Biagi, F.; Trotta, L.; Alfano, C.; Balduzzi, D.; Staffieri, V.; Bianchi, P.I.; Marchese, A.; Vattiato, C.; Zilli, A.; Luinetti, O.; et al. Prevalence and natural history of potential celiac disease in adult patients. Scand. J. Gastroenterol. 2013, 48, 537–542. [Google Scholar] [CrossRef] [PubMed]
Lionetti, E.; Castellaneta, S.; Pulvirenti, A.; Tonutti, E.; Francavilla, R.; Fasano, A.; Catassi, C. Italian Working Group of Weaning and Celiac Disease Risk Prevalence and natural history of potential celiac disease in at-family-risk infants prospectively investigated from birth. J. Pediatr. 2012, 161, 908–914. [Google Scholar] [CrossRef] [PubMed]
Auricchio, R.; Tosco, A.; Piccolo, E.; Galatola, M.; Izzo, V.; Maglio, M.; Paparo, F.; Troncone, R.; Greco, L. Potential celiac children: 9-year follow-up on a gluten-containing diet. Am. J. Gastroenterol. 2014, 109, 913–921. [Google Scholar] [CrossRef] [PubMed]
Elli, L.; Discepolo, V.; Bardella, M.T.; Guandalini, S. Does gluten intake influence the development of celiac disease-associated complications? J. Clin. Gastroenterol. 2014, 48, 13–20. [Google Scholar] [CrossRef] [PubMed]
Mäki, M.; Lähdeaho, M.L.; Hällström, O.; Viander, M.; Visakorpi, J.K. Postpubertal gluten challenge in coeliac disease. Arch. Dis. Child. 1989, 64, 1604–1607. [Google Scholar] [CrossRef] [PubMed]
Matysiak-Budnik, T.; Malamut, G.; de Serre, N.P.-M.; Grosdidier, E.; Seguier, S.; Brousse, N.; Caillat-Zucman, S.; Cerf-Bensussan, N.; Schmitz, J.; Cellier, C. Long-term follow-up of 61 coeliac patients diagnosed in childhood: Evolution toward latency is possible on a normal diet. Gut 2007, 56, 1379–1386. [Google Scholar] [CrossRef] [PubMed]
Hopman, E.G.D.; von Blomberg, M.E.; Batstra, M.R.; Morreau, H.; Dekker, F.W.; Koning, F.; Lamers, C.B.H.W.; Mearin, M.L. Gluten tolerance in adult patients with celiac disease 20 years after diagnosis? Eur. J. Gastroenterol. Hepatol. 2008, 20, 423–429. [Google Scholar] [CrossRef] [PubMed]
Kivelä, L.; Popp, A.; Arvola, T.; Huhtala, H.; Kaukinen, K.; Kurppa, K. Long-term health and treatment outcomes in adult coeliac disease patients diagnosed by screening in childhood. United Eur. Gastroenterol. J. 2018, 6, 1022–1031. [Google Scholar] [CrossRef] [PubMed]
O'Leary, C.; Wieneke, P.; Healy, M.; Cronin, C.; O'Regan, P.; Shanahan, F. Celiac disease and the transition from childhood to adulthood: A 28-year follow-up. Am. J. Gastroenterol. 2004, 99, 2437–2441. [Google Scholar] [CrossRef] [PubMed]
Wungjiranirun, M.; Kelly, C.P.; Leffler, D.A. Current Status of Celiac Disease Drug Development. Am. J. Gastroenterol. 2016, 111, 779–786. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Rational approach to patients with potential CD.
Table 1. The spectrum of clinical presentations of celiac disease.
Classical Non-Classical Asymptomatic Potential
Malabsorption syndrome
diarrhea, steatorrhea, weight loss/growth failure, with or without anemia + − − −
Gastrointestinal symptoms
abdominal pain, bloating, constipation +/− +/− − −
Extraintestinal manifestations
fatigue, osteopenia/osteoporosis, iron deficiency, neurological disorders +/− +/− − −
Serology (tTG/EMA) + + + +
Histological alterations (Marsh) + + + −
tTG, anti-transglutaminase antibodies; EMA, anti-endomysial antibodies.
Table 2. Relevant original studies evaluating the safe daily gluten threshold for celiac disease patients (adapted from Akobeng et al. [17]). CD: celiac disease; GFD: gluten-free diet; IEL: intraepithelial lymphocytosis; RCT: Randomized Controlled Trial.
Aim of the Study
Results/Conclusion
Catassi 2007 [9] RCT from Italy 39 adults with CD on GFD for >2 years 90 days,
50 mg gluten/day (n = 13)
50 mg placebo/day (n = 13)
To evaluate the safe threshold of ingestion of contaminating gluten Ingestion of contaminating gluten should be lower than 50 mg/day
Collin 2004 [10] Cross-sectional study from Finland 76 adults, 16 children with CD on GFD for 1–10 years Median 2 years
naturally GFD (n = 28)
wheat starch-based GFD (n = 64)
To establish a limit for residual gluten in gluten-free products Threshold should be lower than 100 mg/day
Peräaho 2003 [18] RCT from Finland 57 adults with newly diagnosed, untreated CD 1 year
wheat-starch-based-GFD (n = 28)
natural GFD (n = 29)
To evaluate the difference between a wheat starch-based GFD and natural GFD No histological/clinical differences between the two groups
Lohiniemi 2000 [19] Cross-sectional study from Finland 58 adults with CD, 110 healthy controls Patients on wheat starch-based GFD To evaluate the effect of wheat-starch based GFD on clinical symptoms Wheat starch-based gluten-free products are suitable for CD patients
Selby 1999 [20] Cross-sectional study from Australia 89 adults with CD
Codex GFD (<500 ppm) (n = 39)
GFD < 30 mg (n = 50)
To evaluate the effect of gluten traces in GFD No histological differences between the groups
Catassi 1993 [14] Randomized controlled trial from Italy 20 children with CD on GFD 4 weeks
100 mg gliadin/day ≈ 200 mg gluten/day (n = 10)
500 mg gliadin/day ≈ 1 g gluten/day (n = 10)
To evaluate the effects of chronic ingestion of gliadin Histological deterioration and increase in IEL count in both groups, clinical relapse in 30% of 1 g-group
Itzlinger, A.; Branchi, F.; Elli, L.; Schumann, M. Gluten-Free Diet in Celiac Disease—Forever and for All? Nutrients 2018, 10, 1796. https://doi.org/10.3390/nu10111796
Itzlinger A, Branchi F, Elli L, Schumann M. Gluten-Free Diet in Celiac Disease—Forever and for All? Nutrients. 2018; 10(11):1796. https://doi.org/10.3390/nu10111796
Itzlinger, Alice, Federica Branchi, Luca Elli, and Michael Schumann. 2018. "Gluten-Free Diet in Celiac Disease—Forever and for All?" Nutrients 10, no. 11: 1796. https://doi.org/10.3390/nu10111796

redpajama_set_name: RedPajamaCommonCrawl


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Laurent Combalbert, né le  à Toulouse, est un conférencier et négociateur.

Officier de police, il intègre le Raid en 1998, pour lequel il devient négociateur jusqu'en 2004. Il fonde la branche négociation de l'unité d'élite de la police nationale française et contribue à développer le métier de négociateur.

Il se reconvertit dans le conseil aux entreprises et la négociation pour des groupes, en France et à l'étranger.

Il est auteur de plusieurs ouvrages relatifs à la gestion de crise, la négociation, l'anticipation des risques et le management des équipes.

Biographie

Fondateur de la branche négociation du Raid
Laurent Combalbert naît à Toulouse en 1971. Après un diplôme en droit et criminologie, Laurent Combalbert rejoint les bancs de l'université Toulouse-Capitole pour une maîtrise de droit et une maîtrise de sciences politiques, avant d'intégrer l'École nationale supérieure des officiers de police de Cannes Écluses. Là, il exerce des fonctions de commandement au sein des sections de protection et d'intervention des CRS.

Laurent Combalbert intègre le Raid en 1998. Michel Marie, premier négociateur du Raid, lui propose de monter la première équipe de négociateurs.

Il part au Royaume-Uni à Londres pour se former à Scotland Yard. En 2000, Laurent Combalbert se spécialise et part aux États-Unis pour suivre la formation "Crisis Negotiator" au sein de l'Académie du FBI de Quantico, en Virginie, il obtient un dîplome de négociateur de crise.

À son retour, il participe à la fondation de la branche négociation du Raid.

En 2001 et 2002,Il contribue à la création d'un module de formation des négociateurs de crise dispensé par le Raid autour du monde. Il anime les premières formations des négociateurs de crise du Commandement des opérations spéciales.

Il intervient dans la libération d'otages, les kidnappings, la reddition de forcenés. En 2001 il intervient lors de la prise d'otage et la tentative d'évasion à la prison de Fresnes.

En 2003, il est détaché et intègre pendant un an Civipol Conseil, société de conseil du ministère de l'Intérieur. Il parcourt le monde pour former des négociateurs, accompagne les groupes français dans le cadre de leur développement en zone à risques et les aide à s'installer.

Après six ans passés au Raid, il quitte l'unité d'élite de la police française en 2004 pour se réorienter dans le privé.

Il démissionne définitivement de la fonction publique en 2014.

La négociation appliquée aux entreprises
En , il devient directeur associé chez Geos, un groupe international de gestion des risques spécialisé dans la négociation.

Il conseille aussi les comités de direction et les institutions dans le recrutement de leurs équipes et la mise en œuvre de politique de prévention des risques. Il intervient notamment en 2008 dans le Golfe d'Aden pour le compte d'une compagnie d'assurances.
En  Laurent Combalbert quitte le groupe  pour créer sa société de conseil Ulysceo.

L'Agence des Négociateurs
En , Laurent Combalbert s'associe avec Marwan Mery. Ils fondent et dirigent l'Agence des négociateurs, ADN Group. ADN intervient dans les cas de kidnapping, prises d'otages, comportements suicidaires, extorsions, grèves de la faim, ransomware, négociations commerciales, diplomatiques ou thérapeutiques, plans sociaux, séquestrations.

En 2018, l'agence crée ADN Kids, qui forme gratuitement les enfants dans les écoles pour lutter contre la violence et le harcèlement, et leur apprendre à résoudre les conflits sans violence. L'agence met aussi en place des formations destinées aux femmes via ADN Women.

En 2020, Laurent Combalbert quitte la présidence d'ADN pour créer « TTA – The Trusted Agency, l'agence de Confiance(s) ».

Ransom
Laurent Combalbert et Marwan Mery inspirent les studios de cinéma américains. Laurent Combalbert rencontre en 2014 la productrice Valérie Pechels qui imagine une série. En 2016, la chaîne américaine CBS commande une série, Ransom, sur les deux fondateurs d'ADN, qui participent à sa réalisation en tant que conseillers techniques.

En 2019, l'agence de presse française CAPA produit la première série documentaire « Les négociateurs », dans laquelle Laurent Combalbert et Marwan Mery livrent un décryptage et une analyse des plus grandes prises d'otages contemporaines.

Publications
 2005 : Le management des situations de crise, ESF éditeurs
 2006 : Négociation de crise et communication d'influence, ESF
 2007 : Guide de survie du manager, Dunod
 2008 : Entreprises : halte aux prédateurs, Dunod
 2009 : Le négociateur, Presses de la Cité
 2010 : Le leadership de l'incertitude, avec Éric Delbecque, Vuibert
 2011 : Constituer une équipe efficace, avec Éric Delbecque, ESF
 2012 : La gestion de crise avec Eric Delbecque, PUF
 2012 : Négocier en situations complexes, ESF
 2013 : Manuel de négociation complexe avec Marwan Mery, Eyrolles
 2013 : Devenez meilleur négociateur que vos enfants, ESF
2014 : Devenez meilleur négociateur que votre (ex) conjoint ! De la séduction à la séparation, tout est négociation !, ESF
 2015 : Comment neutraliser les profils complexes avec Marwan Mery, Eyrolles
 2015 : Le spectacle de la peur, avec Eric Delbecque, Jacques Marie Laffont, Les Presses du Management
 2016 : Les cinq leviers de la confiance, avec Marwan Mery, Eyrolles
 2017 : Dans la peau de deux négociateurs d'élite, avec Marwan Mery, Eyrolles
2018 : Négocier dans son couple (sans en avoir l'air) : Tous les conseils d'un pro de la négo, avec Jean-Louis Cornalba, ESF
2018 : Le management des situations de crise : anticiper les risques et gérer les crises, ESF
2018 : La gestion de crise, avec Eric Delbecque, PUF
2019 : Négociator, la référence de toutes les négociations, avec Marwan Mery, Dunod
2019 : Rise ! Tout dépend de vous, avec Marwan Mery, Dunod
2020 : Non merci Docteur, avec Marwan Mery et Stéphanie Furtos, Dunod
2021 : Négo, thriller, Calmann-Lévy
2023 : L'Organisation, Calmann-Lévy

Expert et conférencier
Il intervient comme expert auprès de médias français ou internationaux pour commenter les situations de conflit et de négociation.

Il enseigne à l'École supérieure de commerce de Paris et à HEC.

Conférencier auprès de chefs d'entreprises et cadres dirigeants, il réalise à l'instar de très nombreux « gourous » entre 3 et 4 conférences par semaine, qui sont .

Le 10 novembre 2016, il donne une conférence à l'IESEG Paris.

Notes et références

Annexes

Article connexe
 Gestion de crise

Liens externes
 Laurent Combalbert
 The Trusted Agency

Policier français
Auteur en management
Homme d'affaires français
Naissance en février 1971
Naissance à Toulouse
Écrivain policier

redpajama_set_name: RedPajamaWikipedia


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Jill Zarin Likely to Make a Comeback in The Real Housewives Of New York Season 8, Quick Recap of Episode 11, Synopsis for Next Episode Revealed!
The Real Housewives of New York City is an American reality television series that made its debut on Bravo back in 2008. The show that brings the personal and professional lives of several women of New York City into the highlight is currently in its eighth season.
Some rumors pertaining to the show are doing rounds on the internet and they suggest that fans might be witnessing the return of Jill Zarin on The Real Housewives of New York Season 8. Jill was a former participant of the show and she left it back in 2011. She has not made any appearance on the show since her exit.
It is often seen that former housewives occasionally make surprise returns to The Real Housewives of New York for cameos. However, that has not been the case with Jill Zarin who has abstained from making any kind of appearance since she left in 2011.
Jill was quite popular among viewers during her days on the show. Initially fans liked her, however, their feelings for her gradually changed and at point of time she was one of the most hated housewives on the reality series.
She used to pick up fights with everyone and seemed always eager to create drama and thus fans started disliking her. It seems that fans are excited by the prospect of her coming back. However, one of the cast members of season 8- Bethenny Frankel is not party to the idea. She stated that she has nothing but staunch dislike for Jill.
It is known that she has some kind of influence over the producers of the show and thus it won't be easy for Jill to return to the show. However, if indeed she is brought back, fans can expect her to do well since she is already experienced at the whole thing.
Luann de Lesseps stated that she would be very happy if Jill makes a comeback. She was introduced to the show by Jill herself.
Episode 11 of season 8 of The Real Housewives of New York has just come to an end and the synopsis for the next episode has already been released by the showrunners. The episode is titled- Always the B****, Never the Bride.
In the synopsis it was stated that Ramona and Sonja will be seen becoming friends once again. They will be seen plotting to get Sonja back in Bethenny's good graces. Bethenny will be having a health issue on the episode.
It was also stated that Jules will be sharing some kind of a secret business project with Michael who will be impressed by it. Fans will also be witnessing everyone attending the wedding of a dog.
As for the previous episode, it was titled- Invitation Interrupted. A trip to Mexico was planned by the gang and it was seen that Luann de Lesseps was not invited by the others for the trip. Apparently, Bethenny wanted to head over to Mexico in the hunt for the best tequila.
Among the invitees for the trip were- Carole, Ramona, Jules and Dorinda. However, Carole did not want Luann to come along with them. She stated that she will not take the trip if Luann came with them. Eventually, Luann was the one to be left out.
Bethenny was also seen sharing some of her secrets about her boyfriend with Carole. She went on a vacation with him in the recent past. She stated- It's nice to date someone really smart and passionate, and who's busy. I don't want him living my life in my apartment with my money. I want a partner"
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Tag Archives: seekers
Mexican Nationals Now Comprise Majority of Asylum Seekers on Southern Border
The number of Mexican nationals seeking asylum in the U.S. has risen dramatically over the last year as the number of Central American asylum seekers has fallen as a result of Trump administration policies designed to stem the flow of migrants.A study released last month by researchers at the University of Texas and UC San Diego found that over half of all asylum seekers on the southern border are now Mexicans, predominantly coming from the states of Guerrero, Chiapas, Oaxaca, Michoacán, Zacatecas, and Veracruz.Speaking with the Los Angeles Times, many pointed to cartel violence as the primary reason to seek asylum. Others referenced the Central American caravans that made headlines for passing through Mexico on the way to the U.S. border.Since Mexicans are exempt from the "Remain in Mexico" policy that constrains the number of central American asylum seekers, U.S. authorities have adopted a policy known as "metering" which admits only a relatively small number of of Mexican asylum seekers each day. Last week, Ken Cuccinelli, acting deputy secretary of the Department of Homeland Security, announced that Mexican nationals seeking asylum in the United States could be moved to Guatemala rather than being allowed to wait in the United States for their asylum claims to be adjudicated.The White House has been locked in a ongoing court battle over policies to limit the amount of asylum seekers, including requiring that migrants first apply for refugee status in Mexico, or whatever country they enter after leaving home, before seeking asylum in the U.S. The remain in Mexico policy has also been met with legal challenges. The Ninth Circuit is currently hearing arguments regarding the constitutionality of the orders, after the Supreme Court ruled in September that the remain in Mexico policy can remain in effect as legal challenges progress.More than 300,000 Central Americans entered Mexico illegally last year, 80 percent of whom were headed for the U.S. border, according to Mexico's interior minister, Olga Sánchez Cordero. The southern border has been overwhelmed this year with asylum applicants though numbers have waned in recent months following highs in the spring.Former acting DHS secretary Kevin McAleenan said in August that border crossings declined over the summer, with apprehensions dropping 43 percent since May, when arrests between ports of entry at the southern border increased for the fourth straight month to 132,887.
U.S. seeks to charge asylum seekers for immigration
The Trump administration rolled out a proposal Friday to hike application fees for immigrants seeking to remain in the U.S. including a first-ever charge for those seeking refuge. It's the administration's latest move to restrict pathways for obtaining asylum and immigration benefits like U.S. citizenship.
U.S. seeks to charge asylum seekers and hike fees for immigration
November 9, 2019 Sexual Health
For the first time in U.S. history, the Trump administration is looking to impose an application fee for those seeking protection from persecution
Stranded Asylum Seekers Ask Appeals Court to Let Them In
(Bloomberg) — Central Americans seeking asylum in the U.S. said they've waited long enough in Mexico for their applications to be assessed under a Trump administration policy they call unlawful.On Tuesday, their advocates asked the federal appeals court in San Francisco to rule that the policy is illegal. Such a ruling would open the border gates to about 45,000 people, according to the American Civil Liberties Union.The three-judge panel didn't decide whether to uphold a judge's ruling to block the "forced return" policy, as the ACLU asked, but it expressed concern why the government doesn't ask immigrants whether they had any fears about being sent back to Mexico. It's standard practice for asylum seekers to be asked if they are fearful of returning to their home countries.The appeals court previously has allowed the policy to remain in effect during the litigation — which the ACLU says is endangering the tens of thousands of people."Individuals returned to Mexico are sent to areas with some of the highest murder rates in the world," the ACLU said in a court filing. "They face extreme dangers — killings, kidnappings, sexual assault, robbery, and other forms of violence — from cartels, the gangs they fled their home countries to escape, corrupt government officials, and an anti-migrant sentiment."The lawsuit is one of the many fronts on which immigrant rights' advocates have been battling the administration's efforts to block entry to the swelling number of migrants from Central American countries.The government also is trying to stop people from applying for asylum in the U.S. if they didn't make such an application in another country on their way to the U.S. — so a person from El Salvador should have applied for asylum in Guatemala, or Mexico, according to the U.S.In another case the appeals court heard Tuesday, the U.S. is seeking to overturn a judge's decision that found it was illegal to require asylum seekers to apply only at official border crossings.An appeals panel in December rejected the government's request to put the judge's ruling on hold while the case was tried. The panel said it was likely the rule was "arbitrary and capricious."The cases are: East Bay Sanctuary Covenant v. Trump, 18-17274, and Innovation Law Lab v. McAleenan, 19-15716, U.S. Court of Appeals for the Ninth District (San Francisco).(Updates with hearing in second paragraph.)To contact the reporter on this story: Edvard Pettersson in Los Angeles at epettersson@bloomberg.netTo contact the editors responsible for this story: David Glovin at dglovin@bloomberg.net, Peter Blumberg, Steve StrothFor more articles like this, please visit us at bloomberg.com©2019 Bloomberg L.P.
Asylum seekers I meet flee something even worse than Trump's unethical immigration agenda
September 25, 2019 Sexual Health
Our immigration policies seek to discourage border crossings by making life difficult for migrants. But almost nothing could be worse than going home.
Tent courts set to open on border for US asylum seekers
The Trump administration is ready to open a tent court on the border to help handle tens of thousands of cases of asylum seekers forced to wait in Mexico, with hearings held entirely by videoconference. The administration introduced its "Remain in Mexico" policy in San Diego in January and later expanded it to El Paso, but hearings there are conducted inside large buildings with normal courtrooms, and the judge usually appears in person. The policy, assailed by critics for making families and young children wait in violent Mexico border cities, has become a key piece of the U.S. response to a large increase in asylum-seeking families, especially from Central America.
900 asylum seekers returned to wait in Mexican border city
August 4, 2019 Sexual Health
The United States government has sent about 900 mostly Central American and Cuban migrants back to this northern Mexico border city since expanding its controversial "remain in Mexico" program to the easternmost point on the shared border two weeks ago, Mexican authorities say. Under the program, migrants who turn themselves over to U.S. authorities and, in most cases, request asylum, are returned to Mexico after being given a court date.
Trump signs 'cruel and illegal' deal with Guatemala to stop asylum seekers getting to US
The Trump administration has struck a highly controversial deal with Guatemala, which will prevent some migrants fleeing their home countries from submitting asylum applications to the US.Refugees travelling to the US who enter Guatemala, including Salvadorans and Hondurans, will now be required to apply for asylum protection from the Central American nation instead of at the US border.Under the deal Guatemala has been declared a so-called "safe third country".The Central American nation and the US have been negotiating the deal for months.Donald Trump earlier threatened to place trade tariffs on Guatemala if an agreement wasn't reached."We'll either do tariffs or we'll do something. We're looking at something very severe with respect to Guatemala," the US president said on Wednesday.Jimmy Morales, Guatemala's president, said the agreement would allow the country to avoid "drastic sanctions … many of them designed to strongly punish our economy, such as taxes on remittances that our brothers send daily, as well as the imposition of tariffs on our export goods and migratory restrictions." As part of the agreement the US will increase access to the the H-2A visa program for temporary agricultural workers from Guatemala. The country's government said its labour ministry would, in the coming days, "start issuing work visas in the agriculture industry, which will allow Guatemalans to travel legally to the United States, to avoid being victims of criminal organisations, to work temporarily and then return to Guatemala, which will strengthen family unity.""We have long been working with Guatemala and now we can do it the right way." Mr Trump said."This landmark agreement will put the coyotes and smugglers out of business."Despite the president's optimism it remains unclear how the agreement will take effect. Guatemala's constitutional court has granted three injunctions preventing its government from entering into a deal without approval of the country's congress and Mr Morales himself has questioned the concept of a "safe third country", which forms the basis of the agreement."Where does that term exist?" he asked reporters on Friday, hours before the deal was struck."It does not exist, it is a colloquial term. No agreement exists that is called 'safe third country."Rights groups have condemned the deal, with multiple experts questioning its legality.Jordan Rodas, a human rights prosecutor, said his team was studying the agreement and whether Enrique Degenhart, Guatemala's interior minister, had the authority to sign it.Amnesty International condemned the deal, saying "any attempts to force families and individuals fleeing their home countries to seek safety in Guatemala are outrageous."Rights groups and student organisations rallied against the agreement in Guatemala City, gathering in front of the constitutional court.Many believe the nation, which is mired in poverty and unemployment, has no capacity to take in refugees.The problems of homelessness, severe drought, gang violence and unemployment which are endemic in El Salvador and Honduras are also present in Guatemala.Eliot Engel, a Democrat who chairs the House Committee on Foreign Affairs said Mr Trump's decision to sign the agreement was "cruel and immoral."''It is also illegal," he added. "Simply put, Guatemala is not a safe country for refugees and asylum seekers, as the law requires."The president was asked on Friday if he expected to reach similar agreements with Honduras and El Salvador.He replied, "I do indeed." Additional reporting by agencies
The U.S. government on Friday expanded its requirement that asylum seekers wait outside the country to a part of the Texas Rio Grande Valley across from one of Mexico's most dangerous cities. The Department of Homeland Security said that it would implement its Migrant Protection Protocols in Brownsville, Texas, across the border from Matamoros, Mexico. DHS says it anticipates the first asylum seekers will be sent back to Mexico starting Friday.


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Meet Norfolk artist Nigel Wallace
PUBLISHED: 10:58 22 August 2017
Dominic Castle
White One Sugar/Nigel Wallace
Nigel Wallace loves creating beautiful artworks of Norfolk scenes, but his career started out in a rather different direction
ARTIST Nigel Wallace, who produced the beautiful cover image on this month's issue, learned the nuts and bolts of drawing by drawing... nuts and bolts.
He spent 20 years working as a technical illustrator for an aerospace company, drawing highly detailed pieces such as exploded engines. He had found his way into the studio after, in his words, he "drifted through school and ended up at art college, where all drifters end up, studying technical graphics."
But within that environment were a number of artists who encouraged him to pick up his brush and paint. "I was always interested in art and in what other people were doing. I learned a lot from them and spent a lot of spare time painting."
A pivotal moment came when he did a painting of his house. "A friend saw it and said 'can you do me one?' So I did and I spent ten years painting part-time. It built up and then I took early retirement and went for it."
Nigel's style, seen on the cover and in the works on these pages, was inspired by the beautiful classic travel posters which were popular, particularly with the railway companies, between the 20s and the 60s. "I like to visit a place and get the atmosphere, take some photographs and do some sketches. Then its back to the computer to create the artwork."
His business, White One Sugar, is very much a family affair; daughter Karen (whose tea preference is the inspiration for the business name) is a photographer and artist, son Neil draws and wife Tina left a teaching career to help out with administration and other vital tasks to keep things running smoothly. As well as his poster art Nigel is a skilled illustrator, with a large collection of drawings, and a photographer as well.
He fell for Norfolk when the family had a holiday in the county and he produced some of his work which he sold through an art shop at Creake Abbey. His favourite spot is Holkham.
"We love going to Holkham in September, we love the diversity of the place, the wildlife and birds; we're introducing the grandkids to it all!"
He has plans to expand his coverage of the coast, through Burnham Overy Staithe to Cromer and Happisburgh's iconic lighthouse.
You can see more of Nigel's work, and buy copies of his prints and canvases, at www.whiteonesugar.co.uk
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