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      Exposure to the Danish Mandatory Vitamin D Fortification Policy in Prenatal Life and the Risk of Developing Coeliac Disease—The Importance of Season: A Semi Ecological Study

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          Abstract

          Few studies have examined the role of maternal diet in relation to development of coeliac disease (CD). In Denmark, cancellation of mandatory vitamin D fortification of margarine in June 1985 provided this opportunity. This study examined if season of birth or prenatal exposure to extra vitamin D from food fortification were associated with developing CD later in life. A strength of this study is the distinctly longer follow-up of patients (30 years). This register-based study has a semi-ecological design. Logistic regression analysis was used to estimate odds ratios and to calculate 95% confidence intervals. The odds ratio for developing CD was 0.81 (95% CI 0.66; 1.00 p = 0.054), comparing those with fetal exposure to mandatory vitamin D fortification policy of margarine to those without after adjusting for gender and season of birth. There was a statistically significant season effect particularly for children born in autumn (OR 1.6 95% CI 1.16; 2.21) and born in summer (OR 1.5 95% CI 1.1; 2.1) when compared to children born in winter. Although this study did not find evidence to support the premise that prenatal exposure to small extra amounts of vitamin D from a mandatory food fortification policy lowered risk of developing CD, the small number of CD cases and observed association between season of birth and CD suggest that environmental exposure ought to be further explored.

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          Most cited references35

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          Coeliac disease

          Coeliac disease occurs in about 1% of people in most populations. Diagnosis rates are increasing, and this seems to be due to a true rise in incidence rather than increased awareness and detection. Coeliac disease develops in genetically susceptible individuals who, in response to unknown environmental factors, develop an immune response that is subsequently triggered by the ingestion of gluten. The disease has many clinical manifestations, ranging from severe malabsorption to minimally symptomatic or non-symptomatic presentations. Diagnosis requires the presence of duodenal villous atrophy, and most patients have circulating antibodies against tissue transglutaminase; in children, European guidelines allow a diagnosis without a duodenal biopsy provided that strict symptomatic and serological criteria are met. Although a gluten-free diet is an effective treatment in most individuals, a substantial minority develop persistent or recurrent symptoms. Difficulties adhering to a gluten-free diet have led to the development of non-dietary therapies, several of which are undergoing trials in human beings.
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            Celiac disease: a comprehensive current review

            Background Celiac disease remains a challenging condition because of a steady increase in knowledge tackling its pathophysiology, diagnosis, management, and possible therapeutic options. Main body A major milestone in the history of celiac disease was the identification of tissue transglutaminase as the autoantigen, thereby confirming the autoimmune nature of this disorder. A genetic background (HLA-DQ2/DQ8 positivity and non-HLA genes) is a mandatory determinant of the development of the disease, which occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota). Its prevalence in the general population is of approximately 1%, with female predominance. The disease can occur at any age, with a variety of symptoms/manifestations. This multifaceted clinical presentation leads to several phenotypes, i.e., gastrointestinal, extraintestinal, subclinical, potential, seronegative, non-responsive, and refractory. Although small intestinal biopsy remains the diagnostic ‘gold standard’, highly sensitive and specific serological tests, such as tissue transglutaminase, endomysial and deamidated gliadin peptide antibodies, have become gradually more important in the diagnostic work-up of celiac disease. Currently, the only treatment for celiac disease is a life-long, strict gluten-free diet leading to improvement in quality of life, ameliorating symptoms, and preventing the occurrence of refractory celiac disease, ulcerative jejunoileitis, and small intestinal adenocarcinoma and lymphoma. Conclusions The present review is timely and provides a thorough appraisal of various aspects characterizing celiac disease. Remaining challenges include obtaining a better understanding of still-unclear phenotypes such as slow-responsive, potential (minimal lesions) and seronegative celiac disease. The identification of alternative or complementary treatments to the gluten-free diet brings hope for patients unavoidably burdened by diet restrictions.
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              Ecologic studies in epidemiology: concepts, principles, and methods.

              An ecologic study focuses on the comparison of groups, rather than individuals; thus, individual-level data are missing on the joint distribution of variables within groups. Variables in an ecologic analysis may be aggregate measures, environmental measures, or global measures. The purpose of an ecologic analysis may be to make biologic inferences about effects on individual risks or to make ecologic inferences about effects on group rates. Ecologic study designs may be classified on two dimensions: (a) whether the primary group is measured (exploratory vs analytic study); and (b) whether subjects are grouped by place (multiple-group study), by time (time-trend study), or by place and time (mixed study). Despite several practical advantages of ecologic studies, there are many methodologic problems that severely limit causal inference, including ecologic and cross-level bias, problems of confounder control, within-group misclassification, lack of adequate data, temporal ambiguity, collinearity, and migration across groups.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                27 April 2020
                May 2020
                : 12
                : 5
                : 1243
                Affiliations
                [1 ]Focused Research Unit for Molecular Diagnostic and Clinical Research, Institute of Regional Health Research, University Hospital of Southern Denmark, 6200 Aabenraa, Denmark; katrinesideniusduus@ 123456gmail.com (K.S.D.); va@ 123456rsyd.dk (V.A.)
                [2 ]Research Unit for Dietary Studies at The Parker Institute, Bispebjerg and Frederiksberg Hospital, Part of the Copenhagen University Hospital, 2000 Frederiksberg, Denmark; eek@ 123456garp.dk (P.F.); Berit.lilienthal.heitmann@ 123456regionh.dk (B.L.H.)
                [3 ]The Department of Public Health, Section for General Practice, University of Copenhagen, 1017 Copenhagen, Denmark
                [4 ]Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
                Author notes
                [* ]Correspondence: caroline.moos@ 123456rsyd.dk ; Tel.: +45-22-77-30-37
                [†]

                Joint senior authors.

                Author information
                https://orcid.org/0000-0003-4997-4319
                https://orcid.org/0000-0002-1630-3132
                https://orcid.org/0000-0002-6809-4504
                https://orcid.org/0000-0002-0127-2863
                Article
                nutrients-12-01243
                10.3390/nu12051243
                7281975
                32349457
                f3ba0814-d7fb-42af-8fc5-cb40e61eb072
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 02 March 2020
                : 24 April 2020
                Categories
                Article

                Nutrition & Dietetics
                vitamin d,coeliac disease,fetal programming,season of birth,prenatal exposure,fortification,d-tect,social experiment,public health epidemiology,ecological study

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