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      Environmental Determinants of Type 1 Diabetes: From Association to Proving Causality

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          Abstract

          The rising incidence of type 1 diabetes (T1D) cannot be ascribed to genetics alone, and causative environmental triggers and drivers must also be contributing. The prospective TEDDY study has provided the greatest contributions in modern time, by addressing misconceptions and refining the search strategy for the future. This review outlines the evidence to date to support the pathways from association to causality, across all stages of T1D (seroconversion to beta cell failure). We focus on infections and vaccinations; infant growth and childhood obesity; the gut microbiome and the lifestyle factors which cultivate it. Of these, the environmental determinants which have the most supporting evidence are enterovirus infection, rapid weight gain in early life, and the microbiome. We provide an infographic illustrating the key environmental determinants in T1D and their likelihood of effect. The next steps are to investigate these environmental triggers, ideally though gold-standard randomised controlled trials and further prospective studies, to help explore public health prevention strategies.

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          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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            Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013.

            In 2010, overweight and obesity were estimated to cause 3·4 million deaths, 3·9% of years of life lost, and 3·8% of disability-adjusted life-years (DALYs) worldwide. The rise in obesity has led to widespread calls for regular monitoring of changes in overweight and obesity prevalence in all populations. Comparable, up-to-date information about levels and trends is essential to quantify population health effects and to prompt decision makers to prioritise action. We estimate the global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013. We systematically identified surveys, reports, and published studies (n=1769) that included data for height and weight, both through physical measurements and self-reports. We used mixed effects linear regression to correct for bias in self-reports. We obtained data for prevalence of obesity and overweight by age, sex, country, and year (n=19,244) with a spatiotemporal Gaussian process regression model to estimate prevalence with 95% uncertainty intervals (UIs). Worldwide, the proportion of adults with a body-mass index (BMI) of 25 kg/m(2) or greater increased between 1980 and 2013 from 28·8% (95% UI 28·4-29·3) to 36·9% (36·3-37·4) in men, and from 29·8% (29·3-30·2) to 38·0% (37·5-38·5) in women. Prevalence has increased substantially in children and adolescents in developed countries; 23·8% (22·9-24·7) of boys and 22·6% (21·7-23·6) of girls were overweight or obese in 2013. The prevalence of overweight and obesity has also increased in children and adolescents in developing countries, from 8·1% (7·7-8·6) to 12·9% (12·3-13·5) in 2013 for boys and from 8·4% (8·1-8·8) to 13·4% (13·0-13·9) in girls. In adults, estimated prevalence of obesity exceeded 50% in men in Tonga and in women in Kuwait, Kiribati, Federated States of Micronesia, Libya, Qatar, Tonga, and Samoa. Since 2006, the increase in adult obesity in developed countries has slowed down. Because of the established health risks and substantial increases in prevalence, obesity has become a major global health challenge. Not only is obesity increasing, but no national success stories have been reported in the past 33 years. Urgent global action and leadership is needed to help countries to more effectively intervene. Bill & Melinda Gates Foundation. Copyright © 2014 Elsevier Ltd. All rights reserved.
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              WITHDRAWN: Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition

              To provide global estimates of diabetes prevalence for 2019 and projections for 2030 and 2045.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                01 October 2021
                2021
                01 October 2021
                : 12
                : 737964
                Affiliations
                [1] 1 Institute of Immunology and Immunotherapy, Research College of Medical and Dental Sciences, University of Birmingham , Birmingham, United Kingdom
                [2] 2 Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University , Cardiff, United Kingdom
                [3] 3 Department of Diabetes, University Hospitals of Birmingham NHS Foundation Trust , Birmingham, United Kingdom
                Author notes

                Edited by: Antonio Toniolo, University of Insubria, Italy

                Reviewed by: Magdalena Zoledziewska, Institute of Genetic and Biomedical Research (CNR), Italy; Hasan Alghetaa, University of Baghdad, Iraq

                *Correspondence: Lauren M. Quinn, l.quinn.1@ 123456bham.ac.uk

                This article was submitted to Immunological Tolerance and Regulation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2021.737964
                8518604
                34659229
                7de5f594-95e7-46d8-b12c-4be618cfa811
                Copyright © 2021 Quinn, Wong and Narendran

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 08 July 2021
                : 08 September 2021
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 193, Pages: 15, Words: 7443
                Categories
                Immunology
                Review

                Immunology
                type 1 diabetes (t1d),seroconversion,auto-antibodies,autoimmunity,environmental factors,gut micro biome,obesity,infection - immunology

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