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An unresolved issue in autoimmunity is the lack of surrogate biomarkers of immunological self-tolerance for disease monitoring. Here, we show that peripheral frequency of a regulatory T cell population, characterized by the co-expression of CD3 and CD56 molecules (TR3-56), is reduced in subjects with new-onset type 1 diabetes (T1D). In three independent T1D cohorts, we find that low frequency of circulating TR3-56 cells is associated with reduced β-cell function and with the presence of diabetic ketoacidosis. As autoreactive CD8+ T cells mediate disruption of insulin-producing β-cells1-3, we demonstrate that TR3-56 cells can suppress CD8+ T cell functions in vitro by reducing levels of intracellular reactive oxygen species. The suppressive function, phenotype and transcriptional signature of TR3-56 cells are also altered in T1D children. Together, our findings indicate that TR3-56 cells constitute a regulatory cell population that controls CD8+ effector functions, whose peripheral frequency may represent a traceable biomarker for monitoring immunological self-tolerance in T1D., Funding agencies: Juvenile Diabetes ResearchFoundation (JDRF n. 2-SRA-2018-479-S-B to M.G.; JDRF n. 1-SRA-2018-477-S-B to P.d.C); the EuropeanFoundation for the Study of Diabetes (EFSD/JDRF/Lilly Programme 2016 to M.G.); the National MultipleSclerosis Society (NMSS n. PP-1804-30725 to M.G.); Fondazione Italiana Sclerosi Multipla (FISM n. 2016/R/18 toG.M.; FISM n. 2018/R/4 to V.D.R.); by Ministero della Salute (n. GR-2016-02363725 to V.D.R); Università degliStudi di Napoli “Federico II” (STAR Program Linea 1 - 2018 to V.D.R.); European Research Council Grant (ERC"menTORingTregs" n. 310496 to G.M.); Telethon (n. GGP 17086 to G.M.); Italian Ministry of Health GiovaniRicercatori (n. GR-2016-02363749 to C.Pr.).

Background Following the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma published in 1983, this technology has received continued use and further recognition for additional earlier as well as refractory forms. After the publication of the first guidelines for this technology in the JEADV in 2014, this technology has maintained additional promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. It has confirmed recognition in well-known documented conditions such as graft-versus-host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection including lung, heart and liver and to a lesser extent inflammatory bowel disease. Materials and methods In order to further provide recognized expert practical guidelines for the use of this technology for all indications, the European Dermatology Forum (EDF) again proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. All authors had the opportunity to review each contribution as it was added. Results and conclusion These updated 2020 guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion. The guidelines are divided in two parts: PART I covers cutaneous T-cell lymphoma, chronic graft-versus-host disease and acute graft-versus-host disease while PART II will cover scleroderma, solid organ transplantation, Crohns disease, use of ECP in paediatrics practice, atopic dermatitis, type 1 diabetes, pemphigus, epidermolysis bullosa acquisita and erosive oral lichen planus.

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Background/Objective Is exposure to maternal infections and use of antibiotics in the prenatal period associated with increased risk of T1D, regardless of genetic risk? Methods Data on infections and use of antibiotics during pregnancy were collected from questionnaires at birth from parents to 16 292 children in the All Babies in Southeast Sweden (ABIS) cohort and validated against national diagnosis registers. As of November 2017, 137 ABIS children had developed T1D, 72 boys and 65 girls (0.8% of the original cohort). Results More cases were born in spring and summer than fall and winter. However, onset of T1D appeared to be more common in either summer or winter. In univariate analyses, respiratory tract infection in the first trimester (P= .002) and gastroenteritis during pregnancy (P= .04) were associated with later risk of T1D in the offspring. Other types of infection or antibiotic treatment were not associated with an increased risk. In a multiple logistic regression model, a mother with an autoimmune disease (P < .001), father with T1D (P < .001) and respiratory tract infection during the first trimester (P= .005) remained as risk factors for T1D in the offspring. In children with neutral HLA alleles antibiotic treatment may increase the risk of T1D (P= .01, OR 3.46, 95% CI 1.25-9.55). Conclusions In the general population there seems to be an association between seasonal maternal respiratory tract infection in the first trimester of pregnancy and later risk of T1D in the offspring. HLA may play a role for the effect of exposure to infections and antibiotics., Funding Agencies|Forskningsrdet fr Arbetsliv och Socialvetenskap [FAS2004-1775]; Forskningsrdet i Sydstra Sverige; JDRF Wallenberg Foundation [K98-99D-12813-01A]; stgta Brandstodsbolag; Swedish Child Diabetes Foundation; Vetenskapsrdet [K2005-72X-11242-11A, K2008-69X-20826-01-4]

Objectives To investigate if socioeconomic status (SES) is predictive of cardiovascular risk factors among Swedish adolescents. Identify the most important SES variable for the development of each cardiovascular risk factor. Investigate at what age SES inequality in overweight and obesity occurs. Design Longitudinal follow-up of a prospective birth cohort. Setting All Babies in Southeast Sweden (ABIS) study includes data from children born between October 1997 and October 1999 in five counties of south east Sweden. Participants A regional ABIS-study subsample from three major cities of the region n=298 adolescents aged 16-18 years, and prospective data from the whole ABIS cohort for overweight and obesity status at the ages 2, 5, 8 and 12 years (n=2998-7925). Outcome measures Blood pressure above the hypertension limit, overweight/obesity according to the International Obesity Task Force definition, low high-density lipoproteins (HDL) or borderline-high low-density lipoproteins according to National Cholesterol Education Program expert panel on cholesterol levels in children. Results For three out of four cardiovascular risk outcomes (elevated blood pressure, low HDL and overweight/obesity), there were increased risk in one or more of the low SES groups (p<0.05). The best predictor was parental occupational class (Swedish socioeconomic classification index) for elevated blood pressure (area under the receiver operating characteristic (ROC) curve 0.623), maternal educational level for overweight (area under the ROC curve 0.641) and blue-collar city of residence for low HDL (area under the ROC curve 0.641). SES-related differences in overweight/obesity were found at age 2, 5 and 12 and for obesity at age 2, 5, 8 and 12 years (all p<0.05). Conclusions Even in a welfare state like Sweden, SES inequalities in cardiovascular risks are evident already in childhood and adolescence. Intervention programmes to reduce cardiovascular risk based on social inequalit, Funding Agencies|Swedish Research CouncilSwedish Research Council [K2005-72X-11242-11A, K2008-69X-20826-01-4]; Swedish Child Diabetes Foundation (Barndiabetesfonden); JDRF Wallenberg Foundation [K 98-99D-12813-01A]; Medical Research Council of Southeast Sweden (FORSS); Swedish Council for Working Life and Social ResearchSwedish Research CouncilSwedish Research Council for Health Working Life & Welfare (Forte) [FAS2004-1775]; Ostgota Brandstodsbolag; Research and PhD studies Committee (FUN), Linkoping University, Sweden (LiU-)

Type 1 Diabetes (T1D) is regarded as an autoimmune disease characterized by insulin deficiency resulting from destruction of pancreatic beta-cells. The incidence rates of T1D have increased worldwide. Over the past decades, progress has been made in understanding the complexity of the immune response and its role in T1D pathogenesis, however, the trigger of T1D autoimmunity remains unclear. The increasing incidence rates, immigrant studies, and twin studies suggest that environmental factors play an important role and the trigger cannot simply be explained by genetic predisposition. Several research initiatives have identified environmental factors that potentially contribute to the onset of T1D autoimmunity and the progression of disease in children/young adults. More recently, the interplay between gut microbiota and the immune system has been implicated as an important factor in T1D pathogenesis. Although results often vary between studies, broad compositional and diversity patterns have emerged from both longitudinal and cross-sectional human studies. T1D patients have a less diverse gut microbiota, an increased prevalence of Bacteriodetes taxa and an aberrant metabolomic profile compared to healthy controls. In this comprehensive review, we present the data obtained from both animal and human studies focusing on the large longitudinal human studies. These studies are particularly valuable in elucidating the environmental factors that lead to aberrant gut microbiota composition and potentially contribute to T1D. We also discuss how environmental factors, such as birth mode, diet, and antibiotic use modulate gut microbiota and how this potentially contributes to T1D. In the final section, we focus on existing recent literature on microbiota-produced metabolites, proteins, and gut virome function as potential protectants or triggers of T1D onset. Overall, current results indicate that higher levels of diversity along with the presence of beneficial microbes and th, Funding Agencies|NIH NIDDKUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [1K01DK117967-01]; G. Harold & Leila Y. Mathers Foundation

Background: A relationship between overweight and obesity early in life and adolescence has been reported. The aim of this study was to track changes in overweight/obesity in children and to assess risk factors related to the persistence of overweight/obesity between 2.5 and 8 years. Study design: Children who participated in all three follow-ups at 2.5, 5 and 8 years in the prospective cohort All Children in Southeast Sweden (ABIS) (N = 2245, 52.1% boys and 47.9% girls) were classified as underweight, normal, overweight or with obesity, and changes within categories with age were related to risk factors for development of obesity in a multivariate analysis. Results: The prevalence of overweight and obesity between 2.5 and 8 years was 11%-12% and 2%-3%, respectively. Children with normal weight remained in the same category over the years, 86% between 2.5 to 5 years and 87% between 5 and 8 years. Overweight and obesity at 5 and 8 years were positively related to each other (p < 0.0001 for both). High level of TV watching at 8 years and high maternal body mass index (BMI) when the child was 5 years were related to lower probability to a normalized ISO-BMI between 5 and 8 years of age (p < 0.05 for both). Conclusion: Children with ISO-BMI 18.5 to 24.9 remain in that range during the first 8 years of life. Children with overweight early in life gain weight and develop obesity, and children with obesity tend to remain with obesity up to 8 years of age. TV watching and high maternal BMI were related to lower probability to weight normalization between 5 and 8 years of age. A multidisciplinary approach to promote dietary and physical activity changes in the entire family should be used for the treatment and prevention of overweight and obesity in early childhood., Funding agencies: Region Östergötland ALF/LuA; JDRFWallenberg Foundation, Grant/A wardNumber: K 98-99D-12813-01A; MedicalResearch Council of Southeast Sweden; Östgöta Brandstodsbolag; Swedish ResearchCouncil, Grant/Award Numbers: K2005-72X-11242-11A, K2008-69X-20826-01-4; SwedishCouncil for Working Life and Social Research,Grant/Award Number: FAS2004–1775; Barndiabetesfonden

Background: In the Swedish welfare system, the prescription and price of antibiotics is regulated. Even so, socioeconomic circumstances might affect the consumption of antibiotics for children. Aim: This study aimed to investigate if socioeconomic differences in antibiotic prescriptions could be found for children aged 2–14 years, and to find predictors of antibiotic consumption in children, especially if morbidity or socioeconomic status in childhood may function as predictors. Design & setting: Participants were from All Babies In Southeast Sweden (ABIS), a prospectively followed birth cohort (N = 17 055), born 1997-1999. Pharmaceutical data for a 10-year period, from 2005–2014 were used (the cohort were aged from 5–7, up to 14–16 years). Participation at the 5-year follow-up was 7443 children. All prescriptions from inpatient, outpatient, and primary care were included. National registries and parent reports were used to define socioeconomic data for all participants. Most children’s infections were treated in primary healthcare centres. Method: Parents of included children completed questionnaires about child morbidity at birth and at intervals up to 12 years. Their answers, combined with public records and national registries, were entered into the ABIS database and analysed. The primary outcome measure was the number of antibiotic prescriptions for each participant during a follow-up period between 2005–2014. Results: The most important predictor for antibiotic prescription in later childhood was parent-reported number of antibiotic-treated infections at age 2–5 years (odds ratio (OR) range 1.21 to 2.23, depending on income quintile; P<0.001). In the multivariate analysis, lower income and lower paternal education level were also significantly related to higher antibiotic prescription. Conclusion: Parent-reported antibiotic-treated infection at age 2–5 years predicted antibiotic consumption in later childhood. Swedish doctors are supposed to treat all p, Funding agencies: County Council of Östergötland (grant number: LIO603511). ABIS has been supported by the Swedish Research Council (reference numbers: K2005-72X-11242-11A and K2008-69X-20826-01-4), the Swedish Child Diabetes Foundation (Barndiabetesfonden), the JDRF Wallenberg Foundation (reference number: K 98-99D-12813-01A), the Medical Research Council of Southeast Sweden (FORSS), the Swedish Council for Working Life and Social Research (reference number: FAS2004–1775), and Östgöta Brandstodsbolag.

HLA-DQA1 and -DQB1 genes have significant and potentially causal associations with autoimmune type 1 diabetes (T1D). To follow up on the earlier analysis on high-risk HLA-DQ2.5 and DQ8.1, the current analysis uncovers seven residues (alpha a1, alpha 157, alpha 196, beta 9, beta 30, beta 57, and beta 70) that are resistant to T1D among subjects with DQ4-, 5-, 6-, and7-resistant DQ haplotypes. These 7 residues form 13 common motifs: 6 motifs are significantly resistant, 6 motifs have modest or no associations (Pvalues >0.05), and 1 motif has 7 copies observed among control subjects only. The motifs "DAAFYDG," "DAAYHDG," and "DAAYYDR" have significant resistance to T1D (odds ratios [ORs] 0.03, 0.25, and 0.18;P= 6.11 x 10(-24), 3.54 x 10(-15), and 1.03 x 10(-21), respectively). Remarkably, a change of a single residue from the motif "DAAYHDG" to "DAAYHSG" (D to S at beta 57) alters the resistance potential, from resistant motif (OR 0.15;P= 3.54 x 10(-15)) to a neutral motif (P= 0.183), the change of which was significant (FisherPvalue = 0.0065). The extended set of linked residues associated with T1D resistance and unique to each cluster of HLA-DQ haplotypes represents facets of all known features and functions of these molecules: antigenic peptide binding, peptide-MHC class II complex stability, beta 167-169 RGD loop, T-cell receptor binding, formation of homodimer of alpha-beta heterodimers, and cholesterol binding in the cell membrane rafts. Identification of these residues is a novel understanding of resistant DQ associations with T1D. Our analyses endow potential molecular approaches to identify immunological mechanisms that control disease susceptibility or resistance to provide novel targets for immunotherapeutic strategies., Funding Agencies|National Institutes of Health/National Institute of Diabetes and Digestive and Kidney DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [1R56 DK117276, DK63861, DK26190]; European Foundation for the Study of Diabetes Clinical Research Grants Programme 2013; Swedish Child Diabetes Foundation (Barndiabetesfonden); Swedish Research CouncilSwedish Research Council; Linne grant; Skane County Council for Research and Development; Swedish Association of Local Authorities and Regions

The negative consequencies of diabetes treatment are traditionally regarded as caused by a disastrous treatment rather than adverse events of the insulin preparations. However, hypoglycemia, changes at the injection site (lipatrophy, lipoma), insulin allergy, obesity and increased risk of certain forms of cancer can easily be regarded as adverse events of the drug, and needle -phobia, psychological problems, increased risk of suicide are adverse events related to insulin and its administration. Also macroongiopathy and even microangiopathy to some extent can be regarded as adverse events as the most crucial part of the treatment of Type 1 diabetes is the insulin treatment. There is still room for improvments of insulin as a drug. We need insulins with more predictable absorption and kinetics, leading to more stable near-normal blood glucose, less risk of hypoglycemia, less effect in periphery and more effect on the liver, and less risk of vascular complications, obesity, cancer.

HLA-DQA1 and -DQB1 are strongly associated with type 1 diabetes (T1D), and DQ8.1 and DQ2.5 are major risk haplotypes. Next-generation targeted sequencing of HLA-DQA1 and -DQB1 in Swedish newly diagnosed 1- to 18 year-old patients (n= 962) and control subjects (n= 636) was used to construct abbreviated DQ haplotypes, converted into amino acid (AA) residues, and assessed for their associations with T1D. A hierarchically organized haplotype (HOH) association analysis allowed 45 unique DQ haplotypes to be categorized into seven clusters. The DQ8/9 cluster included two DQ8.1 risk and the DQ9 resistant haplotypes, and the DQ2 cluster included the DQ2.5 risk and DQ2.2 resistant haplotypes. Within each cluster, HOH found residues alpha 44Q (odds ratio [OR] 3.29,P= 2.38 * 10(-85)) and beta 57A (OR 3.44,P= 3.80 * 10(-84)) to be associated with T1D in the DQ8/9 cluster representing all ten residues (alpha 22, alpha 23, alpha 44, alpha 49, alpha 51, alpha 53, alpha 54, alpha 73, alpha 184, beta 57) due to complete linkage disequilibrium (LD) of alpha 44 with eight such residues. Within the DQ2 cluster and due to LD, HOH analysis found alpha 44C and beta 135D to share the risk for T1D (OR 2.10,P= 1.96 * 10(-20)). The motif "QAD" of alpha 44, beta 57, and beta 135 captured the T1D risk association of DQ8.1 (OR 3.44,P= 3.80 * 10(-84)), and the corresponding motif "CAD" captured the risk association of DQ2.5 (OR 2.10,P= 1.96 * 10(-20)). Two risk associations were related to GAD65 autoantibody (GADA) and IA-2 autoantibody (IA-2A) but in opposite directions. CAD was positively associated with GADA (OR 1.56,P= 6.35 * 10(-8)) but negatively with IA-2A (OR 0.59,P= 6.55 * 10(-11)). QAD was negatively associated with GADA (OR 0.88;P= 3.70 * 10(-3)) but positively with IA-2A (OR 1.64;P= 2.40 * 10(-14)), despite a single difference at alpha 44. The residues are found in and around anchor pockets 1 and 9, as potential T-cell receptor contacts, in the areas for CD4 binding and putative homodi, Funding Agencies|National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [1R01DK117276]; European Foundation for the Study of Diabetes; Swedish Child Diabetes Foundation (Barndiabetesfonden); NIDDK, National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [DK63861, DK26190]; Swedish Research CouncilSwedish Research Council; Skane County Council for Research and Development; Swedish Association of Local Authorities and Regions (SKL)

OBJECTIVE Identifying maturity-onset diabetes of the young (MODY) in pediatric populations close to diabetes diagnosis is difficult. Misdiagnosis and unnecessary insulin treatment are common. We aimed to identify the discriminatory clinical features at diabetes diagnosis of patients with glucokinase (GCK), hepatocyte nuclear factor-1A (HNF1A), and HNF4A MODY in the pediatric population. RESEARCH DESIGN AND METHODS Swedish patients (n = 3,933) aged 1–18 years, diagnosed with diabetes May 2005 to December 2010, were recruited from the national consecutive prospective cohort Better Diabetes Diagnosis. Clinical data, islet autoantibodies (GAD insulinoma antigen-2, zinc transporter 8, and insulin autoantibodies), HLA type, and C-peptide were collected at diagnosis. MODY was identified by sequencing GCK, HNF1A, and HNF4A, through either routine clinical or research testing. RESULTS The minimal prevalence of MODY was 1.2%. Discriminatory factors for MODY at diagnosis included four islet autoantibody negativity (100% vs. 11% not-known MODY; P = 2 × 10−44), HbA1c (7.0% vs. 10.7% [53 vs. 93 mmol/mol]; P = 1 × 10−20), plasma glucose (11.7 vs. 26.7 mmol/L; P = 3 × 10−19), parental diabetes (63% vs. 12%; P = 1 × 10−15), and diabetic ketoacidosis (0% vs. 15%; P = 0.001). Testing 303 autoantibody-negative patients identified 46 patients with MODY (detection rate 15%). Limiting testing to the 73 islet autoantibody-negative patients with HbA1c <7.5% (58 mmol/mol) at diagnosis identified 36 out of 46 (78%) patients with MODY (detection rate 49%). On follow-up, the 46 patients with MODY had excellent glycemic control, with an HbA1c of 6.4% (47 mmol/mol), with 42 out of 46 (91%) patients not on insulin treatment. CONCLUSIONS At diagnosis of pediatric diabetes, absence of all islet autoantibodies and modest hyperglycemia (HbA1c <7.5% [58 mmol/mol]) should result in testing for GCK, HNF1A, and HNF4A MODY. Testing all 12% patients negative for four isl, Funding Agencies|Swedish Child Diabetes Foundation; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DK-063861]; National Institute for Health Research (U.K.)National Institute for Health Research (NIHR); Wellcome TrustWellcome Trust; Wellcome TrustWellcome Trust [098395/Z/12/Z]

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BACKGROUND amp; AIMS: Functional gastrointestinal disorders are highly prevalent, cause significant suffering, and are costly to society. Pain is a central feature of 2 of the most common functional gastrointestinal disorders: irritable bowel syndrome and functional dyspepsia. Although these disorders have been well studied in adults, their etiology is poorly understood. We sought to identify early life factors associated with the development of abdominal pain in children (age, 2-12 y). METHODS: We collected data from the All Babies in Southeast Sweden study of 1781 children, born from October 1, 1997, through October 31, 1999, whose families answered questions about abdominal pain and risk factors at birth, 1 year, 2.5 years, 5 years, 8 years, and 10 to 12 years. We used latent growth curve models to evaluate risk factors for development of abdominal pain. The primary outcomes were prevalence of abdominal pain and associated factors. RESULTS: The prevalence of abdominal pain increased linearly with age in the study cohort, increasing by approximately 6% per year. Psychosocial variables associated with slope of the growth curve included lower emotional control at age 2 years (P = .005), parental concern for the child at age 2 years (P = .02), and measures of parental stress (P = .004). Nonvaginal birth was associated with a reduced slope of the growth curve (P = .03). CONCLUSIONS: In a study of children in Sweden, we found early psychosocial environment and mode of delivery at birth was associated with development of childhood abdominal pain. Factors associated with development of the early immune system, identified in previous recall-based research, were not supported by data from this study. These findings have important implications for the prevention of abdominal pain in children and later in life., Funding Agencies|Swedish Research CouncilSwedish Research Council [K2005-72X-11242-11A, K2008-69X-20826-01-4]; Swedish Child Diabetes Foundation (Barndiabetesfonden); Juvenile Diabetes Research Foundation (JDRF) Wallenberg Foundation [K 98-99D-12813-01A]; Medical Research Council of Southeast Sweden (FORSS); Swedish Council for Working Life and Social ResearchSwedish Research CouncilSwedish Research Council for Health Working Life & Welfare (Forte) [FAS2004-1775]; Ostgota Brandstodsbolag