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AimsBetween 1985 and 1996, Sweden experienced an "epidemic" of celiac disease with a fourfold increase in incidence in young children. Timing and amount of gluten introduced during infancy have been thought to explain this "epidemic". We aimed to study whether the cumulative incidence of type 1 diabetes differs between children born during the "epidemic" compared to children born after.MethodsThis is a national register study in Sweden comparing the cumulative incidence of type 1 diabetes in two birth cohorts of 240 844 children 0-17 years old born 1992-1993, during the "epidemic", and 179 530 children born 1997-1998, after the "epidemic". Children diagnosed with type 1 diabetes were identified using three national registers.ResultsThe cumulative incidence of type 1 diabetes by the age of 17 was statistically significantly higher in those born after the "epidemic" 0.77% than in those born during the "epidemic" 0.68% (p < 0.001).ConclusionThe incidence of type 1 diabetes is higher in those born after the epidemic compared to those born during the epidemic, which does not support the hypothesis that gluten introduction increases the incidence of T1D. Changes in gluten introduction did not halt the increased incidence of type 1 diabetes in Sweden., Funding Agencies|Lund University; Swedish state under the Swedish government; country councils; ALF agreement 2018/2022; "The Swedish Diabetes Foundation" (Svenska diabetesstiftelsen)

This study has followed a birth cohort for over 20 years to find factors associated with neurodevelopmental disorder (ND) diagnosis. Detailed, early -life longitudinal questionnaires captured infection and antibiotic events, stress, prenatal factors, family history, and more. Biomarkers including cord serum metabolome and lipidome, human leukocyte antigen (HLA) genotype, infant microbiota, and stool metabolome were assessed. Among the 16,440 Swedish children followed across time, 1,197 developed an ND. Significant associations emerged for future ND diagnosis in general and for specific ND subtypes, spanning intellectual disability, speech disorder, attention-deficit/hyperactivity disorder, and autism. This investigation revealed microbiome connections to future diagnosis as well as early emerging mood and gastrointestinal problems. The findings suggest links to immunodysregulation and metabolism, compounded by stress, early -life infection, and antibiotics. The convergence of infant biomarkers and risk factors in this prospective, longitudinal study on a large-scale population establishes a foundation for early -life prediction and intervention in neurodevelopment., Funding Agencies|Barndiabetesfonden (Swedish Child Diabetes Foundation); Swedish Council for Working Life and Social Research [FAS2004-1775]; Swedish Research Council [K2005-72X-11242-11A, K2008-69X-20826-01-4]; ostgota Brandstodsbolag; Medical Research Council of Southeast Sweden (FORSS); JDRF Wallenberg Foundation [K98-99D-12813-01A]; Region ostergotland; Linkoping University, Sweden; Joanna Cocozza Foundation; JDRF [1-INO-2018-637-A-N]; "Inflammation in human early life: targeting impacts on life-course health" (INITIALISE) consortium - Horizon Europe Program of the European Union [101094099]

Objective To examine the association between early-life atopic manifestations and later risk of inflammatory bowel disease (IBD), for which prospective data are scarce. Study design The population-based All Babies in Southeast Sweden (ABIS) and Norwegian Mother, Father, and Child (MoBa) cohorts follow children from birth (ABIS 1997-1999; MoBa 2000-2009) to the end of 2021. Based on validated questionnaires, parents prospectively reported information on asthma, food-related allergic symptoms, atopic dermatitis, and allergic rhinitis by age 3. IBD was defined by 3 2 diagnostic records in the national health registries. Cox regression estimated hazard ratios adjusted (aHRs) for parental IBD, atopy, education level, smoking habits, and national origin. Cohort-specific estimates were pooled using a random-effects model. Results We compiled data on 83 311 children (ABIS, n = 9041; MoBa, n = 74270). In over 1 174 756 person-years of follow-up, 301 participants were diagnosed with IBD. Children with atopic dermatitis at age 3 had an increased risk of IBD (pooled aHR = 1.46 [95% CI = 1.13-1.88]), Crohn's disease (pooled aHR = 1.53 [95%CI = 1.04-2.26]), and ulcerative colitis (pooled aHR = 1.78 [95%CI = 1.15-2.75]). Conversely, any atopic manifestation by age 3 was not associated with IBD (pooled aHR = 1.20 [95%CI = 0.95-1.52]), nor were analyses specifically focused on early-life food-related allergic symptoms, asthma, and allergic rhinitis. Conclusion While atopic manifestations in early childhood were overall not associated with IBD, children with atopic dermatitis specifically were at increased risk of developing IBD, suggesting shared etiologic traits; these findings might be useful in identifying at-risk individuals for IBD. (J Pediatr 2024;270:114027) ., Funding Agencies|Norwegian Ministry of Health and Care Services; Ministry of Education and Research

Objective To examine the associations between maternal education and household income during early childhood with asthma-related outcomes in children aged 9-12 years in the UK, the Netherlands, Sweden, Australia, the USA and Canada.Methods Data on 31 210 children were obtained from 7 prospective birth cohort studies across six countries. Asthma-related outcomes included ever asthma, wheezing/asthma attacks and medication control for asthma. Relative social inequalities were estimated using pooled risk ratios (RRs) adjusted for potential confounders (child age, sex, mother ethnic background and maternal age) for maternal education and household income. The Slope Index of Inequality (SII) was calculated for each cohort to evaluate absolute social inequalities.Results Ever asthma prevalence ranged from 8.3% (Netherlands) to 29.1% (Australia). Wheezing/asthma attacks prevalence ranged from 3.9% (Quebec) to 16.8% (USA). Pooled RRs for low (vs high) maternal education and low (vs high) household income were: ever asthma (education 1.24, 95% CI 1.13 to 1.37; income 1.28, 95% CI 1.15 to 1.43), wheezing/asthma attacks (education 1.14, 95% CI 0.97 to 1.35; income 1.22, 95% CI 1.03 to 1.44) and asthma with medication control (education 1.16, 95% CI 0.97 to 1.40; income 1.25, 95% CI 1.01 to 1.55). SIIs supported the lower risk for children with more highly educated mothers and those from higher-income households in most cohorts, with few exceptions.Conclusions Social inequalities by household income on the risk of ever asthma, wheezing/asthma attacks, and medication control for asthma were evident; the associations were attenuated for maternal education. These findings support the need for prevention policies to address the relatively high risks of respiratory morbidity in children in families with low socioeconomic status., Funding Agencies|Canadian Institutes of Health Research [OCO-79897, MOP-89886, MSH-95353, ROG-110537]

Maturity Onset Diabetes of the Young (MODY) is a young-onset, monogenic form of diabetes without needing insulin treatment. Diagnostic testing is expensive. To aid decisions on who to test, we aimed to develop a MODY probability calculator for paediatric cases at the time of diabetes diagnosis, when the existing "MODY calculator" cannot be used. Firth logistic regression models were developed on data from 3541 paediatric patients from the Swedish 'Better Diabetes Diagnosis' (BDD) population study (n = 46 (1.3%) MODY (HNF1A, HNF4A, GCK)). Model performance was compared to using islet autoantibody testing. HbA1c, parent with diabetes, and absence of polyuria were significant independent predictors of MODY. The model showed excellent discrimination (c-statistic = 0.963) and calibrated well (Brier score = 0.01). MODY probability > 1.3% (ie. above background prevalence) had similar performance to being negative for all 3 antibodies (positive predictive value (PPV) = 10% v 11% respectively i.e. similar to 1 in 10 positive test rate). Probability > 1.3% and negative for 3 islet autoantibodies narrowed down to 4% of the cohort, and detected 96% of MODY cases (PPV = 31%). This MODY calculator for paediatric patients at time of diabetes diagnosis will help target genetic testing to those most likely to benefit, to get the right diagnosis., Funding Agencies|Linkoeping University

Background Prenatal exposure to environmental contaminants is a significant health concern because it has the potential to interfere with host metabolism, leading to adverse health effects in early childhood and later in life. Growing evidence suggests that genetic and environmental factors, as well as their interactions, play a significant role in the development of autoimmune diseases.Objective In this study, we hypothesized that prenatal exposure to environmental contaminants impacts cord serum metabolome and contributes to the development of autoimmune diseases.Methods We selected cord serum samples from All Babies in Southeast Sweden (ABIS) general population cohort, from infants who later developed one or more autoimmune-mediated and inflammatory diseases: celiac disease (CD), Crohn's disease (IBD), hypothyroidism (HT), juvenile idiopathic arthritis (JIA), and type 1 diabetes (T1D) (all cases, N = 62), along with matched controls (N = 268). Using integrated exposomics and metabolomics mass spectrometry (MS) based platforms, we determined the levels of environmental contaminants and metabolites.Results Differences in exposure levels were found between the controls and those who later developed various diseases. High contaminant exposure levels were associated with changes in metabolome, including amino acids and free fatty acids. Specifically, we identified marked associations between metabolite profiles and exposure levels of deoxynivalenol (DON), bisphenol S (BPS), and specific per- and polyfluorinated substances (PFAS).Impact statement Abnormal metabolism is a common feature preceding several autoimmune and inflammatory diseases. However, few studies compared common and specific metabolic patterns preceding these diseases. Here we hypothesized that exposure to environmental contaminants impacts cord serum metabolome, which may contribute to the development of autoimmune diseases. We found differences in exposure levels between the controls and those who late, Funding Agencies|Swedish Research Council [202003674, K2005-72 x-11242-11A, K2008-69 x-20826-01-4]; Formas [2019-00869]; European Union [101094099]; Barndiabetesfonden (Swedish Child Diabetes Foundation); Swedish Council for Working Life and Social Research [FAS2004-1775]; Ostgota Brandstodsbolag; Medical Research Council of Southeast Sweden(FORSS); JDRF Wallenberg Foundation [K 98-99D-12813-01A]; Joanna Cocozza Foundation; ALF-and LfoU grants from Region Ostergot-land and Linkoping University, Sweden; Orebro University

Introduction To study the HbA1c trajectory from the time of diagnosis to examine if patients at the greatest risk for severe microangiopathy can be identified early allowing clinicians to intervene as soon as possible to avoid complications. Research design and methods In a population-based observational study, 447 patients diagnosed with type 1 diabetes before 35 years of age, 1983-1987, were followed from diagnosis until 2019. Mean HbA1c was calculated each year for each patient. Severe diabetic microangiopathy was defined as proliferative diabetic retinopathy (PDR) or macroalbuminuria (nephropathy). Results After 32 years, 27% had developed PDR and 8% macroalbuminuria. Patients with weighted HbA1c (wHbA1c); <57 mmol/mol; <7.4% did not develop PDR or macroalbuminuria. The HbA1c trajectories for patients developing PDR and macroalbuminuria follow separate courses early on and stay separated for 32 years during the follow-up. Patients without severe complications show an initial dip, after which HbA1c slowly increases. HbA1c in patients with severe complications directly rises to a high level within a few years. Mean HbA1c calculated for the period 5-8 years after diabetes onset strongly predicts the development of severe complications. Females with childhood-onset diabetes exhibit a high peak in HbA1c during adolescence associated with higher wHbA1c and higher prevalence of PDR. Conclusions The HbA1c trajectory from diabetes onset shows that mean HbA1c for the period 5-8 years after diagnosis strongly predicts severe microangiopathy. Females with childhood-onset diabetes exhibit a high peak in HbA1c during adolescence associated with higher wHbA1c and a higher prevalence of PDR., Funding Agencies|Barndiabetesfonden (The Swedish Child Diabetes Foundation); Region Ostergoetlands Stiftelsefonder [RO-760091]

Purpose: Elucidate the prevalence of myopia among young adults from a birth cohort of Swedish children and its relationship to possible risk factors during their childhood. Methods: Five thousand two hundred young adults, mean 23.4 years and 58% females, participating in the prospective birth cohort All Babies in Southeast Sweden (ABIS) answered a questionnaire including questions regarding health and physical activity, spectacle use, myopia and age at first optical correction. Questionnaires at previous follow-ups at ages 2-3, 5-6 and 8 years included information on type of housing, time outdoors, screen time and hours of reading. Myopia prevalence and associations with potential risk factors were analysed in univariate and multivariate regression models with Bonferroni's correction of p-values. Results: In the ABIS Swedish birth cohort of young adults, the prevalence of myopia was 29%. A univariate logistic regression showed a higher odds ratio for myopia with female gender (OR 1.59; p < 0.05) and a completed and started university education (OR 1.52; p < 0.05). Significantly lower odds ratios were found for hours spent outdoors at 8 years of age (OR 0.82; p < 0.05). Multivariate logistic regression showed a higher odds ratio for myopia in females (OR 1.52-1.57; p < 0.05) and completed and started university education (OR 1.34-1.49; p < 0.05) in all models. In a model including accommodative effort, measured in diopter hours at 8 years of age, hours spent outdoors were associated with a lower odds ratio for myopia (OR 0.86; p < 0.05). No association could be detected between myopia and the type of housing or near work. Conclusion: The prevalence of myopia among young adults in a Swedish birth cohort was lower or unchanged compared to previous data. Female gender, higher education and less time spent outdoors in childhood were associated with an increased risk of developing myopia. Recommendations from child health services, Funding Agencies|Juvenile Diabetes Research Foundation

Background Psoriasis is a genetically determined systemic skin disease, although environmental trigger factors are required for disease manifestation. Some of these triggers, such as stress, infections and drug exposure, have been identified. Objectives To explore the role of early nutrition as a risk factor for the development of psoriasis. Methods Parents in the All Babies in Southeast Sweden (ABIS) prospective birth cohort (n = 16 415) answered questionnaires at birth and when their children were aged 1 and 3 years. A diagnosis of psoriasis was determined from the Swedish National Patient Register and National Drug Prescription Register. Statistical analyses were conducted using custom-written R scripts. Results Individuals breastfed for < 4 months and who received infant formula before 4 months of age had a higher risk of psoriasis [odds ratio (OR) 1.84 (P = 0.02) and OR 1.88 (P = 0.02), respectively]. At the 3-year follow-up, the increased consumption of fish, especially from the Baltic Sea, increased the risk of psoriasis (OR 9.61; P = 0.003). In addition, the risk of psoriasis increased following the consumption of a large volume of milk (OR 2.53; P = 0.04). Conclusions Our study underscores, for the first time, the impact of very early nutrition on the manifestation of psoriasis through early adulthood. Exclusive breastfeeding for 4 months appears to be protective., Funding Agencies|Barndiabetesfonden (Swedish Child Diabetes Foundation); Swedish Council for Working Life and Social Research [FAS2004-1775]; Swedish Research Council [K2005-72X-11242-11A, K2008-69X-20826-01-4]; Ostgota Brandstodsbolag; Medical Research Council of Southeast Sweden (FORSS); JDRF Wallenberg Foundation [K98-99D-12813-01A]; Region Ostergotland; Linkoping University, Sweden; Joanna Cocozza Foundation

Introduction The rate of progression to complete insulin deficiency varies greatly in type 1 diabetes. This constitutes a challenge, especially when randomizing patients in intervention trials aiming to preserve beta cell function. This study aimed to identify biomarkers predictive of either a rapid or slow disease progression in children with new-onset type 1 diabetes. Research design and methods A retrospective, longitudinal cohort study of children (<18 years) with type 1 diabetes (N=46) was included at diagnosis and followed until complete insulinopenia (C-peptide <0.03 nmol/L). Children were grouped into rapid progressors (n=20, loss within 30 months) and slow progressors (n=26). A sex-matched control group of healthy children (N=45) of similar age was included for comparison. Multiple biomarkers were assessed by proximity extension assay (PEA) at baseline and follow-up. Results At baseline, rapid progressors had lower C-peptide and higher autoantibody levels than slow. Three biomarkers were higher in the rapid group: carbonic anhydrase 9, corticosteroid 11-beta-dehydrogenase isozyme 1, and tumor necrosis factor receptor superfamily member 21. In a linear mixed model, 25 proteins changed over time, irrespective of group. One protein, a coxsackievirus B-adenovirus receptor (CAR) increased over time in rapid progressors. Eighty-one proteins differed between type 1 diabetes and healthy controls. Principal component analysis could not distinguish between rapid, slow, and healthy controls. Conclusions Despite differences in individual proteins, the combination of multiple biomarkers analyzed by PEA could not distinguish the rate of progression in children with new-onset type 1 diabetes. Only one marker was altered significantly when considering both time and group effects, namely CAR, which increased significantly over time in the rapid group. Nevertheless, we did find some markers that may be useful in predicting the decline of the C-peptide. Moreover, Funding Agencies|Barndiabetesfonden; Olink Proteomics AB in Uppsala, Sweden

Funding Agencies|Kommunfullmktige, Stockholms Stad Clinical research position for Martina Persson

Objective We assessed whether early-life diet quality and food intake frequencies were associated with subsequent IBD. Design Prospectively recorded 1-year and 3-year questionnaires in children from the All Babies in Southeast Sweden and The Norwegian Mother, Father and Child Cohort Study were used to assess diet quality using a Healthy Eating Index and intake frequency of food groups. IBD was defined as >2 diagnoses in national patient registers. Cox regression yielded HRs adjusted (aHRs) for child's sex, parental IBD, origin, education level and maternal comorbidities. Cohort-specific results were pooled using a random-effects model. Results During 1 304 433 person-years of follow-up, we followed 81 280 participants from birth through childhood and adolescence, whereof 307 were diagnosed with IBD. Compared with low diet quality, medium and high diet quality at 1 year of age were associated with a reduced risk of IBD (pooled aHR 0.75 (95% CI=0.58 to 0.98) and 0.75 (95% CI=0.56 to 1.00)). The pooled aHR per increase of category was 0.86 (0.74 to 0.99). Pooled aHR for children 1 year old with high versus low fish intake was 0.70 (95% CI=0.49 to 1.00) for IBD, and showed association with reduced risk of UC (pooled aHR=0.46; 95% CI=0.21, 0.99). Higher vegetable intake at 1 year was associated with a risk reduction in IBD. Intake of sugar-sweetened beverages was associated with an increased risk of IBD. Diet quality at 3 years was not associated with IBD. Conclusion In this Scandinavian birth cohort, high diet quality and fish intake in early life were associated with a reduced risk of IBD., Funding Agencies|Barndiabetes fonden (Swedish Child Diabetes Foundation) [0000]; Swedish Council for Working Life and Social Research [FAS2004-1775]; Swedish Research Council [K2005-72X-11242-11A, K2008-69X-20826-01-4, 2020-01980]; Medical Research Council of Southeast Sweden (FORSS) [0000]; JDRF Wallenberg Foundation [K 98-99D-12813-01A]; Region OEstergoetland; Linkoping University, Sweden; Joanna Cocozza Foundation; Norwegian Ministry of Health and Care Services; Ministry of Education and Research; Swedish Society for Medical Research [S20-0007, TG-23-0002]; ALF [ALFGBG- 915661]; Henning and Johan Throne- Holst Foundation

The composition of human breast milk (HBM) exhibits significant variability both between individuals and within the same individual. While environmental factors are believed to play a role in this variation, their influence on breast milk composition remains inadequately understood. Herein, we investigate the impact of environmental factors on HBM lipid composition in a general population cohort. The study included mothers (All Babies In Southeast Sweden study) whose children later progressed to one or more immune-mediated diseases later in life: type 1 diabetes (n = 9), celiac disease (n = 24), juvenile idiopathic arthritis (n = 9), inflammatory bowel disease (n = 7), hypothyroidism (n = 6), and matched controls (n = 173). Lipidome of HBM was characterized by liquid chromatography combined with high-resolution mass spectrometry. We observed that maternal age, body mass index, diet, and exposure to perfluorinated alkyl substances (PFASs) had a marked impact on breast milk lipidome, with larger changes observed in the milk of those mothers whose children later developed autoimmune diseases. We also observed differences in breast milk lipid composition in those mothers whose offspring later developed autoimmune diseases. Our study suggests that breast milk lipid composition is modified by a complex interaction between genetic and environmental factors, and, importantly, this impact was significantly more pronounced in those mothers whose offspring later developed autoimmune/inflammatory diseases. Our findings also suggest that merely assessing PFAS concentration may not capture the full extent of the impact of chemical exposures; thus, the more comprehensive exposome approach is essential for accurately assessing the impact of PFAS exposure on HBM and, consequently, on the health outcomes of the offspring., Funding Agencies|Forskningsr?det f?r Arbetsliv och Socialvetenskap [K2005-72X-11242-11A, K2008-69X-20826-01-4]; Swedish Research Council [2019-00869]; Formas [NNF20OC0063971, NNF21OC0070309]; Novo Nordisk Foundation; Barndiabetesfonden (Swedish Child Diabetes Foundation) [FAS2004-1775]; Swedish Council for Working Life and Social Research; Medical Research Council of Southeast Sweden (FORSS) [K 98-99D-12813-01A]; Wallenberg Foundation; Region Ostergotland and Linkoping university, Sweden; Joanna Cocozza Foundation

Objectives To examine the association between early-life smoking exposure and later risk of inflammatory bowel disease [IBD].Methods We followed 115663 participants from the Norwegian Mother, Father and Child [MoBa] and All Babies in Southeast Sweden [ABIS] cohorts from birth [1997-2009] through 2021. IBD was identified through national patient registers. Validated questionnaire data defined maternal smoking during pregnancy, maternal environmental tobacco smoke [ETS] exposure during pregnancy, and child ETS exposure by ages 12 and 36 months. Cox regression was used to estimate adjusted hazard ratios [aHRs] for sex, maternal age, education level, parental IBD, and origin. Cohort-specific estimates were pooled using a random-effects model.Results During 1 987 430 person-years of follow-up, 444 participants developed IBD [ABIS, 112; MoBa, 332]. Any vs no maternal smoking during pregnancy yielded a pooled aHR of 1.30 [95% CI = 0.97-1.74] for offspring IBD. Higher level of maternal smoking during pregnancy (compared with no smoking, average >= 6 cigarettes/day: pooled aHR = 1.60 [95% CI = 1.08-2.38]) was associated with offspring IBD, whereas a lower smoking level was not (average 1-5 cigarettes/day: pooled aHR = 1.09 [95% CI = 0.73-1.64]). Child ETS exposure in the first year of life was associated with later IBD (any vs no ETS, pooled aHR = 1.32 [95% CI = 1.03-1.69]). Estimates observed for child ETS exposure by 36 months were similar but not statistically significant.Conclusions In this prospective Scandinavian cohort study, children exposed to higher levels of maternal smoking during pregnancy or ETS during the first year of life were at increased risk of later IBD., Funding Agencies|Swedish Child Diabetes Foundation; Norwegian Ministry of Health and Care Services; Ministry of Education and Research

The type 1 diabetes community is coalescing around the benefits and advantages of early screening for disease risk. To be accepted by healthcare providers, regulatory authorities and payers, screening programmes need to show that the testing variables allow accurate risk prediction and that individualised risk-informed monitoring plans are established, as well as operational feasibility, cost-effectiveness and acceptance at population level. Artificial intelligence (AI) has the potential to contribute to solving these issues, starting with the identification and stratification of at-risk individuals. ASSET (AI for Sustainable Prevention of Autoimmunity in the Society; www.asset.healthcare) is a public/private consortium that was established to contribute to research around screening for type 1 diabetes and particularly to how AI can drive the implementation of a precision medicine approach to disease prevention. ASSET will additionally focus on issues pertaining to operational implementation of screening. The authors of this article, researchers and clinicians active in the field of type 1 diabetes, met in an open forum to independently debate key issues around screening for type 1 diabetes and to advise ASSET. The potential use of AI in the analysis of longitudinal data from observational cohort studies to inform the design of improved, more individualised screening programmes was also discussed. A key issue was whether AI would allow the research community and industry to capitalise on large publicly available data repositories to design screening programmes that allow the early detection of individuals at high risk and enable clinical evaluation of preventive therapies. Overall, AI has the potential to revolutionise type 1 diabetes screening, in particular to help identify individuals who are at increased risk of disease and aid in the design of appropriate follow-up plans. We hope that this initiative will stimulate further research on this very timely topic., Funding Agencies|VINNOVA

Aims/hypothesisType 1 diabetes is an autoimmune disorder that is characterised by destruction of pancreatic beta cells by autoreactive T lymphocytes. Although islet autoantibodies (AAb) are an indicator of disease progression, specific immune biomarkers that can be used as target molecules to halt development of type 1 diabetes have not been discovered. Soluble immune checkpoint molecules (sICM) play a pivotal role in counteracting excessive lymphocyte responses, but their role in type 1 diabetes is unexplored. In this longitudinal study, we measured sICM levels in AAb-positive (AAb+) children to identify molecules related to type 1 diabetes progression.MethodsWe measured the levels of 14 sICM in the sera of AAb+ children (n=57) compared to those with recent-onset type 1 diabetes (n=79) and healthy children (n=44), obtained from two cohorts. AAb+ children were followed up and divided based on their progression to type 1 diabetes (AAbP) or not (AAbNP) (if they lost islet autoimmunity and did not develop disease in subsequent years). sICM were also measured in the sample taken at the visit closest to disease onset in AAbP children.ResultsWe found that AAb+ children had a distinct sICM profile compared with healthy children and those with recent-onset type 1 diabetes. In addition, AAb+ children who progressed to type 1 diabetes (AAbP) had higher sICM concentrations than non-progressors (AAbNP). Further, sICM levels decreased in AAbP children close to disease onset. Application of Cox regression models highlighted that high concentrations of soluble programmed cell death protein 1 (sPD-1) are associated with type 1 diabetes progression (HR 1.71; 95% CI 1.16, 2.51; p=0.007).Conclusions/interpretationThis study reveals an sICM profile that is dysregulated during the preclinical stage of type 1 diabetes, and identifies sPD-1 as a pathophysiologically-relevant molecule that is associated with disease progression, offering a potential target for early interventions in autoim, Funding Agencies|Ministero dell'Universit e della Ricerca

AimEating disorders have a serious impact on quality of life, especially when combined with Type 1 diabetes. We investigated eating disorders in relation to factors early in life with some focus on Type 1 diabetes.MethodsOut of 21,700 children born 1st of Oct 1997-1st of Oct 1999 17,055 (78.6%) were included in ABIS (All Babies in southeast Sweden) and 16,415 had adequate questionnaires. ICD-10 diagnosis from The National Patient Register was merged with the ABIS data.ResultsIn total 247 individuals, 19 boys (7.7%) and 219 girls (92.3%) out of 16,415 (1.5%) developed eating disorders (EDs), 167 (1.0%) Type 1 diabetes of whom 7 (4.2%) also got eating disorders (ED) (OR 3.25 (1.47-7.28); p = 0.04), all of them years after diagnosis of Type 1 diabetes. EDs was associated with high parental education especially in fathers (OR 1.65 (1.09-2.50); p = 0.02) and to at birth anxiety, and depression among mothers. There was no association with the duration of breastfeeding.ConclusionsEating disorders are common in girls, with increased risk in high-educated but psychologically vulnerable families. Prevalence is increased in type 1 diabetes. Even modern diabetes treatment needs to be completed with psychological support.Level of evidenceLevel III: Evidence obtained from well-designed cohort or case-control analytic studies., Funding Agencies|Barndiabetesfonden ( The Swedish Child Diabetes Foundation)

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Previous studies showed a low-grade enterovirus infection in the pancreatic islets of patients with newly diagnosed type 1 diabetes (T1D). In the Diabetes Virus Detection (DiViD) Intervention, a phase 2, placebo-controlled, randomized, parallel group, double-blind trial, 96 children and adolescents (aged 6-15 years) with new-onset T1D received antiviral treatment with pleconaril and ribavirin (n = 47) or placebo (n = 49) for 6 months, with the aim of preserving beta cell function. The primary endpoint was the mean stimulated C-peptide area under the curve (AUC) 12 months after the initiation of treatment (less than 3 weeks after diagnosis) using a mixed linear model. The model used longitudinal log-transformed serum C-peptide AUCs at baseline, at 3 months, 6 months and 1 year. The primary endpoint was met with the serum C-peptide AUC being higher in the pleconaril and ribavirin treatment group compared to the placebo group at 12 months (average marginal effect = 0.057 in the linear mixed model; 95% confidence interval = 0.004-0.11, P = 0.037). The treatment was well tolerated. The results show that antiviral treatment may preserve residual insulin production in children and adolescent with new-onset T1D. This provides a rationale for further evaluating antiviral strategies in the prevention and treatment of T1D. European Union Drug Regulating Authorities Clinical Trials identifier: 2015-003350-41. Results from the DiViD Intervention, a phase 2 randomized, placebo-controlled trial, showed that antiviral treatment with pleconaril and ribavirin for 6 months resulted in higher endogenous insulin production in children and adolescents with new-onset type 1 diabetes., Funding Agencies|Health Region South East, Norway [2016119]; Juvenile Diabetes Research Foundation [2-SRA-2019-810-M-B]; European Union - IMI2-JU [115797, 948268]; Unions Horizon 2020 research and innovation program; EFPIA; JDRF; Leona M. and Harry B. Helmsley Charitable Trust

Background Ecological observations suggest a negative relationship between childhood socioeconomic status (SES) and inflammatory bowel disease (IBD) risk. Individual-level analyses have been inconsistent and mostly lacked refined assessments of SES. We aimed to comprehensively study the association between early-life SES and later IBD.Methods This study included 117 493 participants from the Norwegian Mother, Father and Child cohort and Swedish All Babies in Southeast Sweden cohorts. Participants were followed from birth (1997-2009) through 2021. IBD was identified through national patient registers. Questionnaire and register data were used to define parental educational level, employment, and household income level. Cox regression estimated adjusted hazard ratios (aHRs), accounting for other SES exposures and covariates (eg, parental IBD). Cohort-specific estimates were pooled using a random-effects model.Results During 2 024 299 person-years of follow-up, 451 participants were diagnosed with IBD (All Babies in Southeast Sweden cohort, n = 113 and Norwegian Mother, Father and Child cohort, n = 338). Early-life maternal, but not paternal, educational level was associated with later IBD (low vs high educational level; pooled aHR, 1.81; 95% confidence interval [CI], 1.16-2.82; and pooled aHR, 1.20; 95% CI, 0.80-1.80; respectively). Having a nonworking mother or father was not significantly associated with IBD (pooled aHR, 0.69; 95% CI, 0.47-1.02; pooled aHR, 0.79; 95% CI, 0.45-1.37). High vs low household income level yielded a pooled aHR of 1.33 (95% CI, 0.94-1.89). Overall, results were largely consistent across cohorts.Conclusions In this prospective Scandinavian cohort study, low maternal educational level was, independent of other SES and covariates, significantly associated with later IBD in her child. Further research is needed to elucidate factors that may mediate this relationship. In this Scandinavian birth cohort study with & GE;117 000 participants, w, Funding Agencies|The authors thank all the families of ABIS and MoBa for their participation. MoBa is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research and conducted by the Norwegian Institute of Public; Norwegian Ministry of Health and Care Services; Ministry of Education and Research

Aims: To test, for the first time in latent autoimmune diabetes in adults (LADA), the effects of autoantigen-specific immunotherapy by intralymphatic administration of aluminium-formulated recombinant human glutamic acid decarboxylase 65 (GAD-alum); specifically, to test if this treatment is safe, to test whether it induces a strong immunological response akin to a similar protocol in type 1 diabetes and to look for associations with preserved beta-cell function. Materials and Methods: Three GAD-alum injections, 4 mu g each, were administered 1 month apart into an inguinal lymph node in 14 people with newly diagnosed LADA (age 30-62 years) presenting with high levels of antibodies against glutamic acid decarboxylase (GADA). Adverse effects, immunological variables and beta-cell function were monitored, with detailed measurements at 5 and 12 months from baseline. Results: Clinical adverse effects were minor and transient and measured laboratory variables were unaffected. All participants completed the study. Treatment raised levels of GADA, elicited strong effects on reactivity of peripheral blood mononuclear cells to GAD and raised cytokine/chemokine levels. Beta-cell function appeared stable preferentially in the seven participants carrying human leukocyte antigen (HLA) haplotypes DR3DQ2, as assessed by C-peptide glucagon tests (P < 0.05 vs. seven non-carriers). Conclusion: Intralymphatic treatment with GAD-alum in LADA is without clinical or other safety concerns over a 12-month period. As in a similar protocol used in type 1 diabetes, treatment exerts a strong immunological impact and is compatible with protection of beta-cell function preferentially in HLA-DR3DQ2 LADA patients. These findings pave the way for a randomized controlled trial in this important subgroup of LADA patients., Funding Agencies|St Olavs hospital, Trondheim university hospital (Trondheim, Norway); Central Norway Regional Health Authority (Trondheim,Norway); Norwegian Diabetes Association(Oslo, Norway); Central Norway Regional Health Authority (Trondheim, Norway); Norwegian Diabetes Association (Oslo,Norway); St Olavs Hospital, Trondheim University Hospital(Trondheim, Norway)

Background The etiology of juvenile idiopathic arthritis (JIA) is poorly understood. This study investigated genetic and environmental factors and infant gut microbiota in a prospective birth cohort to assess disease risk.Methods Data was collected from the All Babies in Southeast Sweden (ABIS) population-based cohort (n = 17,055), 111 of whom later acquired JIA (ABISJIA). Stool samples were collected at one year of age for 10.4%. To determine disease association, 16S rRNA gene sequences were analyzed, with and without confound adjustment. Genetic and environmental risks were assessed.Findings ABISJIA had higher abundance of Acidaminococcales, Prevotella 9, and Veillonella parvula and lower abun-dance of Coprococcus, Subdoligranulum, Phascolarctobacterium, Dialister spp., Bifidobacterium breve, Fusicatenibacter saccharivorans, Roseburia intestinalis, and Akkermansia muciniphila (qs < 0.05). Parabacteroides distasonis greatly increased the odds of later contracting JIA (OR = 6.7; 1.81-24.84, p = 0.0045). Shorter breastfeeding duration and increased antibiotic exposure compounded risk in a dose-dependent manner, especially in those with genetic predisposition.Interpretation Microbial dysregulation in infancy may trigger or accelerate JIA development. Environmental risk factors have a stronger impact on genetically predisposed children. This study is the first to implicate microbial dysregulation in JIA at such an early age, with many bacterial taxa associated with risk factors. These findings provide opportunities for intervention or early screening and offer new insights into JIA pathogenesis., Funding Agencies|Barndiabetesfonden; Swedish Council for Working Life and Social Research; Swedish Research Council; Ostgota Brandstodsbolag; Medical Research Council of Southeast Sweden; JDRF-Wallenberg Foundation; Linkoping

The objective of this paper was to investigate if socioeconomic status (SES), measured by maternal education and household income, influenced the risk of developing autoimmune disease (Type 1 Diabetes, Celiac disease, Juvenile Idiopathic Arthritis, Crohns disease, Ulcerative colitis, and autoimmune thyroid disease), or age at diagnosis, and to analyse pathways between SES and autoimmune disease. We used data from the All Babies in Southeast Sweden (ABIS) study, a population-based prospective birth cohort, which included children born 1997-1999. Diagnoses of autoimmune disease was collected from the Swedish National Patient Register Dec 2020. In 16,365 individuals, low maternal education, but not household income, was associated with increased risk of Type 1 Diabetes; middle education RR 1.54, 95% CI 1.06, 2.23; P 0.02, low education RR 1.81, 95% CI 1.04, 3.18; P 0.04. Maternal education and household income was not associated with any other autoimmune disease and did not influence the age at diagnosis. Part of the increased risk of Type 1 Diabetes by lower maternal education was mediated by the indirect pathway of higher BMI and higher risk of Serious Life Events (SLE) at 5 years of age. The risk of developing Type 1 Diabetes associated to low maternal education might be reduced by decreasing BMI and SLE during childhood., Funding Agencies|Linkoeping University; County Council of Ostergot-land, Forskningsradet i Sydoestra Sverige, Vetenskapsradet [K2005-72X-11242-11A]; Knut och Alice Wallenbergs Stiftelse [K 98-99D-12813-01A]; Forskningsradet foer Arbetsliv och Socialvetenskap [FAS20041775]; Barndiabetesfonden; Juvenile Diabetes Research Foundation International; Ostgota Brandstodsbolag

BackgroundBirth cohort studies with linked register-based data on inflammatory bowel disease (IBD) provide opportunities to prospectively study early-life determinants of the disease. However, register-based data often lack information on clinical characteristics and rely on diagnostic algorithms. Within the All Babies in Southeast Sweden (ABIS) cohort, we examined the validity of a register-based definition of IBD, its incidence, and clinical and therapeutic characteristics at diagnosis.MethodsWe followed 16,223 children from birth (1997-1999) until the end of 2020 for the diagnosis of IBD as defined by a minimum of two diagnostic codes for IBD in the Swedish National Patient Register (NPR). We described the incidence and cumulative incidence of IBD. Through a medical record review of cases diagnosed by the end of 2017, we examined the positive predictive value (PPV) for IBD and described its clinical characteristics and treatment.ResultsBy 2020, at an average age of 22.2 years, 113 participants (0.74%, 95% confidence interval [CI] = 0.61-0.89) had a register-based diagnosis of IBD, corresponding to an incidence of 31.3 per 100,000 person-years of follow-up; the incidence for Crohns disease (CD) was 11.1 per 100,000 person-years and 15.8 for ulcerative colitis (UC). Of 77 participants with a register-based definition of IBD by the end of 2017, medical records were identified for 61 participants, of whom 57 had true IBD (PPV = 93%; 95%CI = 0.87-1.00). While oral 5-aminosalicylic acid treatment was equally common in newly diagnosed CD and UC patients, biologics were more often used for newly diagnosed CD. The median faecal calprotectin levels were 1206 mg/kg at diagnosis and 93 mg/kg at the last follow-up (P < 0.001).ConclusionsIn this population-based sample of Swedish children and young adults the cumulative IBD incidence was 0.74. The validity of register-based definition of IBD was high and supports using such data to identify IBD patients in cohort studie

OBJECTIVE Type 2 diabetes is an established risk factor for hospitalization and death in COVID-19 infection, while findings with respect to type 1 diabetes have been diverging. RESEARCH DESIGN AND METHODS Using nationwide health registries, we identified all patients aged >= 18 years with type 1 and type 2 diabetes in Sweden. Odds ratios (ORs) describe the general and age-specific risk of being hospitalized, need for intensive care, or dying, adjusted for age, socioeconomic factors, and coexisting conditions, compared with individuals without diabetes. Machine learning models were used to find predictors of outcomes among individuals with diabetes positive for COVID-19. RESULTS Until 30 June 2021, we identified 365 (0.71%) and 11,684 (2.31%) hospitalizations in 51,402 and 504,337 patients with type 1 and 2 diabetes, respectively, with 67 (0.13%) and 2,848 (0.56%) requiring intensive care unit (ICU) care and 68 (0.13%) and 4,020 (0.80%) dying (vs 7,824,181 individuals without diabetes [41,810 hospitalizations (0.53%), 8,753 (0.11%) needing ICU care, and 10,160 (0.13%) deaths). Although those with type 1 diabetes had moderately raised odds of being hospitalized (multiple-adjusted OR 1.38 [95% CI 1.24-1.53]), there was no independent effect on ICU care or death (OR of 1.21 [95% CI 0.94-1.52] and 1.13 [95% CI 0.88-1.48], respectively). Age and socioeconomic factors were the dominating features for predicting hospitalization and death in both types of diabetes. CONCLUSIONS Type 2 diabetes was associated with increased odds for all outcomes, whereas patients with type 1 diabetes had moderately increased odds of hospitalization but not ICU care and death., Funding Agencies|Swedish state under an agreement concerning research and education of doctors [ALFGBG-966211]; Swedish Heart and Lung Foundation [2021-0345]; Swedish Research Council [2018-02527, 2020-05792, 2021-06525]

Previous prospective studies suggest that progression to autoimmune diseases is preceded by metabolic dysregulation, but it is not clear which metabolic changes are disease-specific and which are common across multiple immune-mediated diseases. Here we investigated metabolic profiles in cord serum in a general population cohort (All Babies In Southeast Sweden; ABIS), comprising infants who progressed to one or more immune-mediated diseases later in life: type 1 diabetes (n = 12), celiac disease (n = 28), juvenile idiopathic arthritis (n = 9), inflammatory bowel disease (n = 7), and hypothyroidism (n = 6); and matched controls (n = 270). We observed elevated levels of multiple triacylglycerols (TGs) an alteration in several gut microbiota related metabolites in the autoimmune groups. The most distinct differences were observed in those infants who later developed HT. The specific similarities observed in metabolic profiles across autoimmune diseases suggest that they share specific common metabolic phenotypes at birth that contrast with those of healthy controls., Funding Agencies|Swedish Research Council [2020-03674]; Formas [2019-00869]; Barndiabetesfonden (Swedish Child Diabetes Foundation); Swedish Council for Working Life and Social Research [FAS2004-1775]; Swed-ish Research Council [K2005-72 x -11242-11A, K2008-69 x -20826-01-4]; Medical Research Council of Southeast Sweden (FORSS); JDRF; Wallenberg Foundation; Ostgota Brandstodsbolag; ALF-and LfoU grants from Region Ostergotland; Linkoping University, Sweden; [K 98-99D-12813-01A]

Background We aimed to investigate whether early-life hygiene-related factors influenced the risk of inflammatory bowel disease (IBD) in a Scandinavian population and test the associations consistency across cohorts.Methods This study followed 117 493 participants in the All Babies in Southeast Sweden study and the Norwegian Mother, Father, and Child Cohort Study. IBD diagnoses were defined by national registers. Comprehensive data on hygiene-related exposures, such as having pets, rural living, daycare attendance, and siblings, were retrieved from questionnaires administered from pregnancy until childs age of 36 months. A multivariable Cox regression model yielded adjusted hazard ratios (aHRs) for IBD accounting for socioeconomic status and perinatal factors. Cohort-specific estimates were pooled using a random-effects model.Results In over 2 024 299 person-years of follow-up 451 participants developed IBD. In pooled estimates children attending daycare up to 36 months of life vs not attending daycare were less likely to develop Crohns disease (aHR, 0.60; 95% confidence interval [CI], 0.37- 0.98). Children having 1 or more siblings had a modestly increased risk of IBD (aHR, 1.17; 95% CI, 0.96-1.42; aHR for each sibling, 1.12; 95% CI, 1.01-1.24). The other hygiene factors were not significantly linked to later IBD. In the Norwegian Mother, Father, and Child Cohort Study cohort, bed sharing was associated with an increased risk of IBD, most notably for ulcerative colitis (aHR, 1.67; 95% CI, 1.01-2.78).Conclusions In this birth cohort study from 2 high-income Scandinavian countries, some early-life hygiene-related exposures were associated with IBD risk. The generalizability of these results to countries of other socioeconomic level is unknown. Exposure to some hygiene factors during early childhood seems to be associated with the risk of later inflammatory bowel disease. The direction and magnitude of the associations need to be further studied before any clinical im, Funding Agencies|The authors are grateful to all the families in Sweden and Norway who participated in these ongoing cohort studies. In addition, they acknowledge Leslie Shaps, PhD, at Proofreading, Editing amp; Translation Global Services for language editing.

Combining and comparing microbiome data from distinct infant cohorts has been challenging because such data are inherently multidimensional and complex. Here, we used an ensemble of machine-learning (ML) models and studied 16S rRNA amplicon sequencing data from 4,099 gut microbiome samples representing 12 prospectively collected infant cohorts. We chose the childbirth delivery mode as a starting point for such analysis because it has previously been associated with alterations in the gut microbiome in infants. In cross-study ensemble models, Bacteroides was the most important feature in all machine-learning models. The predictive capacity by taxonomy varied with age. At the age of 1-2 months, gut microbiome data were able to predict delivery mode with an area under the curve of 0.72 to 0.83. In contrast, ML models trained on taxa were not able to differentiate between the modes of delivery, in any of the cohorts, when the infants were between 3 and 12 months of age. Moreover, no ML model, alternately trained on the functional pathways of the infant gut microbiome, could consistently predict mode of delivery at any infant age. This study shows that infant gut microbiome data sets can be effectively combined with the application of ML analysis across different study populations.IMPORTANCEThere are challenges in merging microbiome data from diverse research groups due to the intricate and multifaceted nature of such data. To address this, we utilized a combination of machine-learning (ML) models to analyze 16S sequencing data from a substantial set of gut microbiome samples, sourced from 12 distinct infant cohorts that were gathered prospectively. Our initial focus was on the mode of delivery due to its prior association with changes in infant gut microbiomes. Through ML analysis, we demonstrated the effective merging and comparison of various gut microbiome data sets, facilitating the identification of robust microbiome biomarkers applicable across varied study popula, Funding Agencies|All authors declare no conflict of interest relevant to this article.

Background: Rotavirus infection is a potential trigger of type 1 diabetes (T1D) and rotavirus vaccination is hypothesized to decrease the incidence of T1D. In Sweden, rotavirus vaccination was introduced in 2014 in two regions and from 2019, nationwide. This study aims to investigate the association between rotavirus vaccination and incidence of T1D in Swedish children and whether rotavirus vaccination is associated with a change in clinical manifestation at diabetes onset.Methods: A nationwide register-based study with all Swedish children <15 years of age, diagnosed with T1D 2009-2019 was conducted. 7893 children were retrieved. Nationwide vaccine coverage was collected from Child Health Services. Three vaccine groups were created: I: Vaccination start 2014; II: Gradual vaccination start 2016-2018; III: No vaccination. Incidence rates of T1D before (2009-2014) and after (2014-2019) introduction of rotavirus vaccine were compared.Findings: The mean incidence of T1D in children <15 years was 4261 per 100000 during the observed period. When comparing the years before and after2014 the incidence rate ratio (IRR) for children <5 years was 086 in group I(p=010), 085 (p=005) in group II and 087 (p=006) in group III. A similar IRRreduction was also seen among older children who received no vaccine.Children developing or not developing T1D were vaccinated to the sameextent. No differences regarding clinical manifestation at onset associated withrotavirus vaccination were seen.Interpretation: There is no association between rotavirus vaccination in children and incidence or clinical manifestation of T1D., Funding Agencies|The National Diabetes Register (former SWEDIABKIDS) has been generously supported by Barndiabetesfonden (The Swedish Child Diabetes Foundation). This study has been generously supported by The Joanna Cocozza Foundation for Research in Children

Human leukocyte antigen (HLA) genes are associated with more diseases than any other region of the genome. Highly polymorphic HLA genes produce variable haplotypes that are specifically correlated with pathogenically different autoimmunities. Despite differing etiologies, however, many autoimmune disorders share the same risk-associated HLA haplotypes often resulting in comorbidity. This shared risk remains an unanswered question in the field. Yet, several groups have revealed links between gut microbial community composition and autoimmune diseases. Autoimmunity is frequently associated with dysbiosis, resulting in loss of barrier function and permeability of tight junctions, which increases HLA class II expression levels and thus further influences the composition of the gut microbiome. However, autoimmune-risk-associated HLA haplotypes are connected to gut dysbiosis long before autoimmunity even begins. This review evaluates current research on the HLA-microbiome-autoimmunity triplex and proposes that pre-autoimmune bacterial dysbiosis in the gut is an important determinant between autoimmune comorbidities with systemic inflammation as a common denominator. Graphical representation of central hypothesis., Funding Agencies|Barndiabetesfonden (Swedish Child Diabetes Foundation) [FAS2004-1775]; Swedish Council for Working Life and Social Research [K2005-72X-11242-11A, K2008-69X-20826-01-4]; Swedish Research Council; Medical Research Council of Southeast Sweden (FORSS) [K 98-99D-12813-01A]; JDRF Wallenberg Foundation; Region stergtland and Linkping University, Sweden

Background and Objective: Retrospective data have linked adult physical activity (PA) to reduced risk of inflammatory bowel disease (IBD). We aimed to prospectively examine the association of PA and screen time (ST) in childhood with later risk of IBD, for which data are scarce.Methods: Using two population-based birth cohorts (All Babies in Southeast Sweden [ABIS] and Norwegian Mother, Father, and Child Cohort Study [MoBa]), we retrieved parent-reported data on PA and ST degree at ages 3 and 8 years. Data were modelled as binary (high vs. low) and numerical (hours/day) exposures. Inflammatory bowel disease was defined as >= 2 diagnostic records in national health registers. Cox regression estimated hazard ratios adjusted for potential confounding from parental IBD, country of origin, education, and smoking habits (Adjusted hazard ratio (aHR)). Our 8-year analyses included a 2-year lag period to reduce the risk of reverse causation. Cohort-specific estimates were pooled using random-effects model.Result: Among 65,978 participants from ABIS (n = 8810) and MoBa (n = 57,168) with available data, 266 developed IBD. At 3 years, children with high versus low PA had an aHR of 1.12 for IBD (95%CI = 0.87-1.43); high versus low ST showed an aHR of 0.91 (95%CI = 0.71-1.17). Conversely, at 8 years, high versus low ST was associated with increased risk of later IBD (aHR = 1.51; 95%CI = 1.02-2.25), but PA at 8 years, was not linked to IBD (aHR = 1.19; 95%CI = 0.80-1.76). Subtype-specific analyses for Crohns disease and ulcerative colitis did not differ appreciably.Conclusion: Acknowledging possible confounding variables, children with high versus low ST at 8 years were at increased risk of IBD. In contrast, PA degree was not linked to IBD at any age category., Funding Agencies|Forskningsradet i Sydoestra Sverige; Region Ostergotland; Linkoping university; JDRF Wallenberg Foundation; Birgitta och Goran Karlssons Stiftelse [K 98-99D-12813-01A]; Forskningsradet for Arbetsliv och Socialvetenskap [FAS2004-1775]; Swedish Research Council; Joanna Cocozza Foundation [K2005-72X-11242-11A, K2008-69X-20826-01-4]; Svenska Sallskapet foer Medicinsk Forskning; Barndiabetesfonden

GAD-alum given into lymph nodes to Type 1 diabetes (T1D) patients participating in a multicenter, randomized, placebo-controlled double-blind study seemed to have a positive effect for patients with DR3DQ2 haplotype, who showed better preservation of C-peptide than the placebo group. Here we compared the immunomodulatory effect of GAD-alum administered into lymph nodes of patients with T1D versus placebo with focus on patients with DR3DQ2 haplotype. MethodsGAD autoantibodies, GADA subclasses, GAD(65)-induced cytokine secretion (Luminex panel) and proliferation of peripheral mononuclear cells were analyzed in T1D patients (n=109) who received either three intra-lymphatic injections (one month apart) with 4 mu g GAD-alum and oral vitamin D supplementation (2000 IE daily for 120 days), or placebo. ResultsHigher GADA, GADA subclasses, GAD(65)-induced proliferation and cytokine secretion was observed in actively treated patients after the second injection of GAD-alum compared to the placebo group. Following the second injection of GAD-alum, actively treated subjects with DR3DQ2 haplotype had higher GAD(65)-induced secretion of several cytokine (IL4, IL5, IL7, IL10, IL13, IFN gamma, GM-CSF and MIP1 beta) and proliferation compared to treated individuals without DR3DQ2. Stratification of samples from GAD-alum treated patients according to C-peptide preservation at 15 months revealed that "good responder" individuals with better preservation of C-peptide secretion, independently of the HLA haplotype, had increased GAD(65)-induced proliferation and IL13 secretion at 3 months, and a 2,5-fold increase of IL5 and IL10 as compared to "poor responders". The second dose of GAD-alum also induced a more pronounced cytokine secretion in "good responders" with DR3DQ2, compared to few "good responders" without DR3DQ2 haplotype. ConclusionPatients with DR3DQ2 haplotype had a distinct early cellular immune response to GAD-alum injections into the lymph node, and predominant GAD(65)-induc

Aims/hypothesis Antibodies specific to oxidative post-translational modifications (oxPTM) of insulin (oxPTM-INS) are present in most individuals with type 1 diabetes, even before the clinical onset. However, the antigenic determinants of such response are still unknown. In this study, we investigated the antibody response to oxPTM-INS neoepitope peptides (oxPTM-INSPs) and evaluated their ability to stimulate humoral and T cell responses in type 1 diabetes. We also assessed the concordance between antibody and T cell responses to the oxPTM-INS neoantigenic peptides. Methods oxPTM-INS was generated by exposing insulin to various reactive oxidants. The insulin fragments resulting from oxPTM were fractionated by size-exclusion chromatography further to ELISA and LC-MS/MS analysis to identify the oxidised peptide neoepitopes. Immunogenic peptide candidates were produced and then modified in house or designed to incorporate in silico-oxidised amino acids during synthesis. Autoantibodies to the oxPTM-INSPs were tested by ELISA using sera from 63 participants with new-onset type 1 diabetes and 30 control participants. An additional 18 fresh blood samples from participants with recently diagnosed type 1 diabetes, five with established disease, and from 11 control participants were used to evaluate, in parallel, CD4(+) and CD8(+) T cell activation by oxPTM-INSPs. Results We observed antibody and T cell responses to three out of six LC-MS/MS-identified insulin peptide candidates: A:12-21 (SLYQLENYCN, native insulin peptide 3 [Nt-INSP-3]), B:11-30 (LVEALYLVCGERGFFYTPKT, Nt-INSP-4) and B:21-30 (ERGFFYTPKT, Nt-INSP-6). For Nt-INSP-4 and Nt-INSP-6, serum antibody binding was stronger in type 1 diabetes compared with healthy control participants (p <= 0.02), with oxidised forms of ERGFFYTPKT, oxPTM-INSP-6 conferring the highest antibody binding (83% binders to peptide modified in house by hydroxyl radical [(OH)-O-?] and >88% to in silico-oxidised peptide; p <=, Funding Agencies|JDRF [1-SRA-2017-512-Q-R]; European Foundation for the Study of Diabetes Future Leaders Mentorship Programme for Clinical Diabetologists 2018; Italian Ministry of Health [GR-201812365982]; AstraZeneca; Ordine dei Medici ed Odontoiatri di Salerno (OMCeO Salerno); European Foundation for the Study of Diabetes/Novo Nordisk Programme for Diabetes Research in Europe 2020; Fondazione Italiana Sclerosi Multipla [2020/R/13]; Progetti di Rilevante Interesse Nazionale [202077EYN7]

Objectives To identify factors affecting early childhood sleep, and investigate the relationship between sleep and overweight/obesity in childhood. Study Design Data were collected using parental-completed questionnaires from N = 10.840 one-year-old children in the prospective ABIS-study (All Babies in Southeast Sweden), followed up until 8 years of age. Chi-squared test and Pearson Correlation were used to assess the relationship between covariates affecting the childrens sleep. Subsequently, longitudinal mixed model analyses were used to predict the effect of different sleep dimensions (bedtime, sleep duration, sleep quality, and the number of awakenings) on BMI Z-scores. Results Children to parents born in Sweden, parents with higher education, non-single parents, non-smoking mothers during pregnancy, and children with fewer siblings, were more likely to have appropriate sleep habits at 1 year age. A greater number of awakenings and nocturnal feeds, and particularly later bedtime (beta = -0.544, p < 0.0001) were linked to shorter sleep duration. Sleep duration early in life was negatively associated with BMI Z-scores (adjusted effect estimate [95% CI]: beta = -0.09, [(-0.15) - (-0.03)], p = 0.005) later. In addition, higher birth weight, small size for gestational age, unhealthy food habits, children of mothers who smoked during pregnancy, and higher parental BMI resulted in higher BMI Z-scores. Conclusion The childs BMI Z-score increases by 0.09 units with every hour shorter sleep duration, indicating that short sleep duration might increase the risk of overweight and obesity in children. Parental educational interventions advising appropriate sleeping patterns should be considered when implementing strategies to combat the development of childhood obesity., Funding Agencies|ALF Region Ostergotland [0000]; Barndiabetesfonden (The Swedish Child Diabetes Foundation); Swedish Council for Working Life and Social Research [FAS2004-1775]; Medical Research Council of Southeast Sweden; JDRF Wallenberg Foundation [K98-99D-12813-01A]; Swedish Research Council [K2008-69X-20826-01-4, K2005-72X-11242-11A]

Background Celiac disease (CD) is an autoimmune disorder triggered by gluten consumption. Almost all CD patients possess human leukocyte antigen (HLA) DQ2/DQ8 haplotypes; however, only a small subset of individuals carrying these alleles develop CD, indicating the role of environmental factors in CD pathogenesis. The main objective of this study was to determine the contributory role of gut microbiota and microbial metabolites in CD onset. To this end, we obtained fecal samples from a prospective cohort study (ABIS) at ages 2.5 and 5 years. Samples were collected from children who developed CD after the final sample collection (CD progressors) and healthy children matched by age, HLA genotype, breastfeeding duration, and gluten-exposure time (n=15-16). We first used 16S sequencing and immunoglobulin-A sequencing (IgA-seq) using fecal samples obtained from the same children (i) 16 controls and 15 CD progressors at age 2.5 and (ii) 13 controls and 9 CD progressors at age 5. We completed the cytokine profiling, and plasma metabolomics using plasma samples obtained at age 5 (n=7-9). We also determined the effects of one microbiota-derived metabolite, taurodeoxycholic acid (TDCA), on the small intestines and immune cell composition in vivo.Results CD progressors have a distinct gut microbiota composition, an increased IgA response, and unique IgA targets compared to healthy subjects. Notably, 26 plasma metabolites, five cytokines, and one chemokine were significantly altered in CD progressors at age 5. Among 26 metabolites, we identified a 2-fold increase in TDCA. TDCA treatment alone caused villous atrophy, increased CD4+ T cells, Natural Killer cells, and two important immunoregulatory proteins, Qa-1 and NKG2D expression on T cells while decreasing T-regulatory cells in intraepithelial lymphocytes (IELs) in C57BL/6J mice.Conclusions Pediatric CD progressors have a distinct gut microbiota composition, plasma metabolome, and cytokine profile before diagnosis. Furthermore, Funding Agencies|G. Harold and Leila Y. Mathers Foundation [MF-2006-00926, MF-1905-00311]; Swedish 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 Research [FAS2004-1775]; Ostgota Brandstodsbolag

IntroductionIn several of the Low and Middle Income countries , many patients with Type 1 diabetes (T1D) are most probably not diagnosed at all which may contribute to their low incidence. As an example of a country with low income and poor resources, we have chosen to study T1D in children/young people in Tanzania. MethodsAnalyses of casebooks and statistics at several Tanzanian hospitals treating young patients with insulin dependent diabetes, usually Type 1 diabetes, and collection of information from different organisations such a Tanzanian Diabetes Association, Life for a Child, Changing Diabetes in Children and World Diabetes Foundation. ResultsThe incidence in several areas is low. However, a lot of data are often missing at studied clinics and therefore the incidence might be higher, and with increased awareness in recent years the number of patients has increased many-folds. Most patients present with typical symptoms and signs of T1D, and a high proportion with plausible ketoacidosis , although this proportion has decreased from about 90% to about 40% in recent decades. Many patients have poor blood glucose control, and complications often develop already after short diabetes duration. In recent years resources have increased, awareness has increased and diabetes clinics started where staff has got training. ConclusionsThere are problems with diabetes care in Tanzania but several facts give hope for the future.

AimsThe aim of this study was to investigate the association between estimated glucose disposal rate (eGDR), a proxy for insulin resistance, and retinopathy or kidney disease, i.e. micro-, or macroalbuminuria, in young individuals with type 1 diabetes (T1D).Material and MethodsUsing data from the Swedish pediatric registry for diabetes (SweDiabKids) and the registry for adults (NDR), all individuals with T1D with a duration of diabetes of less than 10 years between 1998 and 2017 were included. We calculated the crude incidence rates with 95% confidence intervals (CIs) and used multivariable Cox regression to estimate crude and adjusted hazard ratios (HRs) for two cohorts: retinopathy cohort or kidney disease cohort, stratified by eGDR categories: < 4, 4 to 5.99, 6 to 7.99, and >= 8 mg/kg/min (reference).ResultsA total of 22 146 (10 289 retinopathy cohort, and 11 857 kidney disease cohort with an overlapping of 9575) children and adults with T1D (median age 21 years, female 42% and diabetes duration of 6 and 7 years, respectively for the cohorts) were studied. During a median follow-up of 4.8 years (IQR 2.6-7.7) there were 5040 (24.7%), 1909 (48.1%), 504 (52.3%) and 179 (57.6%) events for retinopathy in individuals with an eGDR >= 8, 7.99 to 6, 5.99 to 4, and < 4 mg/kg/min, respectively. Corresponding numbers for kidney disease was 1321 (6.5%), 526 (13.3%), 255 (26.8%) and 145 (46.6%). After multiple adjustments for different covariates, individuals with an eGDR 7.99 to 6, 5.99 to 4 and < 4 mg/kg/min, had an increased risk of retinopathy compared to those with an eGDR >= 8 mg/kg/min (adjusted HRs, 95% CIs) 1.29 (1.20 to 1.40); 1.50 (1.31 to 1.71) and 1.74 (1.41 to 2.14). Corresponding numbers for kidney disease was (adjusted HRs, 95% CIs) 1.30 (1.11 to 1.52); 1.58 (1.25 to 1.99) and 1.33 (0.95 to 1.86), respectively.ConclusionseGDR, a proxy for insulin resistance, is associated with retinopathy and kidney disease in young adu

Heavy metals are known to be able to cross the placental and blood brain barriers to affect critical neurodevelopmental processes in the fetus. We measured metal levels (Al, Cd, Hg, Li, Pb and Zn) in the cord blood of newborns and in the serum of the same children at 5 years of age, and compared between individuals with or without (controls) autism spectrum disorder (ASD) diagnosis. The samples were from a biobank associated with the All Babies in Southeast Sweden (ABIS) registry. We proposed a Bayesian multivariate log-normal model for partially censored values to identify potentially relevant metals for the etiology of ASD. Our results in cord blood suggest prenatal Al levels could be indicative of later ASD incidence, which could also be related to an increased possibility of a high, potentially toxic, exposure to Al and Li during pregnancy. In addition, a larger possibility of a high, potentially beneficial, exposure to Zn could occur during pregnancy in controls. Finally, we found decisive evidence for an average increase of Hg in 5-year-old ASD children compared to only weak evidence for controls. This is concordant with previous research showing an impaired ability for eliminating Hg in the ASD group., Funding: Faculty of Arts and Sciences at Linkouml;ping University, Sweden; Escher Fund for Autism; Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS); Barndiabetesfonden (Swedish Child Diabetes Foundation); Swedish Council for Working Life and Social Research [FAS20041775, K2005-72X-11242-11A]; Swedish Research Council [K2008-69X-20826-01-4, K 98-99D-12813-01A]; Medical Research Council of Southeast Sweden (FORSS); JDRF Wallenberg Foundation [2018-01074]; OEstgoeta Brandstodsbolag; Region OEstergoetland; Linkoeping university, Sweden; Joanna Cocozza Foundation; Linkoeping University; [FAS2004-1775]

During the COVID-19 pandemic, Sweden was among the few countries that did not enforce strict lockdown measures but instead relied more on voluntary and sustainable mitigation recommendations. While supported by the majority of Swedes, this approach faced rapid and continuous criticism. Unfortunately, the respectful debate centered around scientific evidence often gave way to mudslinging. However, the available data on excess all-cause mortality rates indicate that Sweden experienced fewer deaths per population unit during the pandemic (2020-2022) than most high-income countries and was comparable to neighboring Nordic countries through the pandemic. An open, objective scientific dialogue is essential for learning and preparing for future outbreaks.

Aims/hypothesis While autoantibodies are traditional markers for type 1 diabetes development, we identified gut microbial biomarkers in 1-year-old infants associated with future type 1 diabetes up to 20 years before diagnosis. Methods Infants enrolled in the longitudinal general population cohort All Babies In Southeast Sweden (ABIS) provided a stool sample at a mean age of 12.5 months. Samples (future type 1 diabetes, n=16; healthy controls, n=268) were subjected to 16S ribosomal RNA (rRNA) sequencing and quantitative PCR. Microbial differences at the taxonomic and core microbiome levels were assessed. PICRUSt was used to predict functional content from the 16S rRNA amplicons. Sixteen infants, with a future diagnosis of type 1 diabetes at a mean age of 13.3 +/- 5.4 years, and one hundred iterations of 32 matched control infants, who remained healthy up to 20 years of age, were analysed. Results Parasutterella and Eubacterium were more abundant in healthy control infants, while Porphyromonas was differentially more abundant in infants with future type 1 diabetes diagnosis. Ruminococcus was a strong determinant in differentiating both control infants and those with future type 1 diabetes using random forest analysis and had differing trends of abundance when comparing control infants and those with future type 1 diabetes. Flavonifractor and UBA1819 were the strongest factors for differentiating control infants, showing higher abundance in control infants compared with those with future type 1 diabetes. Alternatively, Alistipes (more abundant in control infants) and Fusicatenibacter (mixed abundance patterns when comparing case and control infants) were the strongest factors for differentiating future type 1 diabetes. Predicted gene content regarding butyrate production and pyruvate fermentation was differentially observed to be higher in healthy control infants. Conclusions/interpretation This investigation suggests that microbial biomarkers for type 1 diabetes may b, Funding Agencies|Barndiabetesfonden (Swedish Child Diabetes Foundation); Swedish Council for Working Life and Social Research [FAS2004-1775]; Swedish Research Council [K2005-72X-11242-11A, K2008-69X-20826-01-4]; Medical Research Council of Southeast Sweden (FORSS); JDRF Wallenberg Foundation [K 98-99D-12813-01A]; Region Ostergotland and Linkoping University, Sweden; JDRF [1-INO-2018-637-A-N]; Ostgota Brandstodsbolag

This letter aims to increase interest in better classification of type 2 diabetes. This can be done in a simple and cheap way via determination of autoantibodies. Autoantibody analysis can be used to detect the 7-12% of people with diabetes that is phenotypic of type 2 diabetes but is, in fact, latent autoimmune diabetes in adults (LADA), which may be regarded as a variant of type 1 diabetes. This may help to explain why some individuals with type 2 diabetes do not go into remission after reducing their weight, while others do, and why remission sometimes ends earlier than expected. Improved classification of diabetes may play an important role in determining adequate therapy.

Objective: To examine sex differences in children with newly diagnosed type 1 diabetes (T1D) with respect to age at diagnosis, presence of autoantibodies (GAD antibody [GADA], insulinoma-associated protein 2 [IA-2A], insulin autoantibody [IAA], and zinc transporter 8 autoantibody), and HLA risk. Research design and methods: A population-based nationwide sample of 3,645 Swedish children at T1D diagnosis was used. Results: Girls were younger at T1D diagnosis (9.53 vs. 10.23 years; P < 0.001), more likely to be autoantibody-positive (94.7% vs. 92.0%; P = 0.002), more often positive for multiple autoantibodies (P < 0.001), more likely to be positive for GADA (64.9% vs. 49.0%; P < 0.001), and less likely to be positive for IAA (32.3% vs. 33.8%; P = 0.016). Small sex differences in HLA risk were found in children <9 years of age. Conclusions: The disease mechanisms leading to T1D may influence the immune system differently in girls and boys., Funding: Barndiabetesfonden10.13039/501100004973; Barndiabetesfonden (the Swedish Child Diabetes Foundation)

Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8+, whilst proinsulin-specific clones were both CD8+ and CD4+. Proinsulin-specific CD8+ clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained in situ for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response is divided between targeting the gold core and the antigenic cargo, this offers a route to improving resident memory T-cells formation in response to vaccines. In addition, our scRNAseq data indicate that focusing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans., Funding Agencies|European Commission under the Health Cooperation Work Programme of the 7th Framework Programme [305305]

Background Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are childhood-onset disorders associated with functional and psychosocial impairments that may persist into adulthood, leading to serious personal and societal costs.Objective This study aimed to examine the socio-economic difficulties, physical and mental comorbidities, and psycho-social vulnerabilities associated with ADHD, ASD, and their co-occurrence among young adults.Methods 16 365 families with children born 1997-1999, were involved in the prospective population-based ABIS study (All Babies in Southeast Sweden). A total of 6 233 ABIS young adults answered the questionnaire at the 17-19-year follow-up and were included in this case-control study. Diagnoses of ADHD and ASD from birth up to 17 years of age were obtained from the Swedish National Diagnosis Register. N=182 individuals received a single diagnosis of ADHD, n=78 of ASD, and n=51 received both diagnoses and were considered the co-occurrence group. Multiple multinomial logistic regression analyses were performed.Results In the univariate analyses all three conditions were significantly associated with concentration difficulties, worse health quality, lower socio-economic status, lower faith in the future, less control over life, and lower social support. In the adjusted analyses, individuals with ADHD were almost three-times more likely to have less money compared with their friends (aOR 2.86; p < .001), experienced worse sleep quality (aOR 1.50; p = .043) and concentration difficulties (aOR 1.96; p < .001). ASD group were two-fold more likely to experience concentration difficulties (aOR 2.35; p = .002) and tended not to have faith in the future (aOR .63; p = .055), however, showed lesser risk-taking bahaviours (aOR .40; p < .001). Finally, the co-occurrence was significantly associated with unemployment (aOR 2.64; p = .007) and tended to have a higher risk of autoimmune disorders (aOR 2., Funding Agencies|Linkoping University; County Council of Ostergotland; Swedish Research Council [K2005-72X-11242-11A, K2008-69X-20826-01-4]; Swedish Child Diabetes Foundation (Barndiabetesfonden); Juvenile Diabetes Research Foundation; Wallenberg Foundation [K 98-99D-12813-01A]; Medical Research Council of Southeast Sweden (FORSS); Swedish Council for Working Life and Social Research [FAS2004-1775]; OEstgoeta Brandstodsbolag; Joanna Cocozza Foundation

Aim To evaluate the long-term effect of intra-lymphatic administration of GAD-alum and a booster dose 2.5 years after the first intervention (DIAGNODE Extension study) in patients with recent-onset type 1 diabetes. Methods DIAGNODE-1: Samples were collected from 12 patients after 30 months who had received 3 injections of 4 mu g GAD-alum into a lymph node with one-month interval. DIAGNODE Extension study: First in human, a fourth booster dose of autoantigen (GAD-alum) was given to 3 patients at 31.5 months, who were followed for another 12 months. C-peptide was measured during mixed meal tolerance tests (MMTTs). GADA, IA-2A, GADA subclasses, GAD(65)-induced cytokines, PBMCs proliferation and T cells markers were analyzed. Results After 30-month treatment, efficacy was still seen in 8/12 patients (good responders, GR). Partial remission (IDAA1c < 9) had decreased compared to 15 months, but did not differ from baseline, and HbA1c remained stable. GAD(65)-specific immune responses induced by the treatment started to wane after 30 months, and most changes observed at 15 months were undetectable. GADA subclasses IgG2, IgG3 and IgG4 were predominant in the GR along with IgG1. A fourth intra-lymphatic GAD-alum dose to three patients after 31.5 months gave no adverse events. In all three patients, C-peptide seemed to increase the first 6 months, and thereafter, C-peptide, HbA1c, insulin requirement and IDAA1c remained stable. Conclusion The effect of intra-lymphatic injections of GAD-alum had decreased after 30 months. Good responders showed a specific immune response. Administration of a fourth booster dose after 31.5 months was safe, and there was no decline in C-peptide observed during the 12-month follow-up., Funding Agencies|Linkoping University; Barndiabetesfonden (Swedish Child Diabetes Foundation); Diabetesfonden (the Swedish Diabetes foundation); Diamyd Medical

In this new study the Authors demonstrated that the IGFBP3/TMEM219 pathway is a physiological regulator of pancreatic beta cell homeostasis and it is dysregulated in diabetes. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes. Loss of pancreatic beta cells is a central feature of type 1 (T1D) and type 2 (T2D) diabetes, but a therapeutic strategy to preserve beta cell mass remains to be established. Here we show that the death receptor TMEM219 is expressed on pancreatic beta cells and that signaling through its ligand insulin-like growth factor binding protein 3 (IGFBP3) leads to beta cell loss and dysfunction. Increased peripheral IGFBP3 was observed in established and at-risk T1D/T2D patients and was confirmed in T1D/T2D preclinical models, suggesting that dysfunctional IGFBP3/TMEM219 signaling is associated with abnormalities in beta cells homeostasis. In vitro and in vivo short-term IGFBP3/TMEM219 inhibition and TMEM219 genetic ablation preserved beta cells and prevented/delayed diabetes onset, while long-term IGFBP3/TMEM219 blockade allowed for beta cell expansion. Interestingly, in several patients cohorts restoration of appropriate IGFBP3 levels was associated with improved beta cell function. The IGFBP3/TMEM219 pathway is thus shown to be a physiological regulator of beta cell homeostasis and is also demonstrated to be disrupted in T1D/T2D. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes., Funding Agencies|SID Lombardia Grant; EFSD/JDRF/Lilly Programme on Type 1 Diabetes Research; Italian Ministry of HealthMinistry of Health, Italy [RF-2016-02362512]; Universita di Milano; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DK104155]; Juvenile Diabetes Research FoundationJuvenile Diabetes Research Foundation; Enthera S.r.l.

ObjectiveThis study aimed to examine social gradients in ADHD during late childhood (age 9-11 years) using absolute and relative relationships with socioeconomic status exposure (household income, maternal education) during early childhood (<5 years) in seven cohorts from six industrialised countries (UK, Australia, Canada, The Netherlands, USA, Sweden). MethodsSecondary analyses were conducted for each birth cohort. Risk ratios, pooled risk estimates, and absolute inequality, measured by the Slope Index of Inequality (SII), were estimated to quantify social gradients in ADHD during late childhood by household income and maternal education measured during early childhood. Estimates were adjusted for child sex, mother age at birth, mother ethnicity, and multiple births. FindingsAll cohorts demonstrated social gradients by household income and maternal education in early childhood, except for maternal education in Quebec. Pooled risk estimates, relating to 44,925 children, yielded expected gradients (income: low 1.83(CI 1.38,2.41), middle 1.42(1.13,1.79), high (reference); maternal education: low 2.13(1.39,3.25), middle 1.42(1.13,1.79)). Estimates of absolute inequality using SII showed that the largest differences in ADHD prevalence between the highest and lowest levels of maternal education were observed in Australia (4% lower) and Sweden (3% lower); for household income, the largest differences were observed in Quebec (6% lower) and Canada (all provinces: 5% lower). ConclusionFindings indicate that children in families with high household income or maternal education are less likely to have ADHD at age 9-11. Absolute inequality, in combination with relative inequality, provides a more complete account of the socioeconomic status and ADHD relationship in different high-income countries. While the study design precludes causal inference, the linear relation between early childhood social circumstances and later ADHD suggests a potential role for policies that, Funding Agencies|Canadian Institutes of Health Research [OCO-79897, MOP-89886, MSH-95353, ROG-110537, MOP-123079, HDF70335]; County Council of Ostergotland; Swedish Research Council [K2005-72X-11242-11A, K2008-69X-2082601-4]; Swedish Child Diabetes Foundation (Barndiabetesfonden); Juvenile Diabetes Research Foundation; Wallenberg Foundation [K 98-99D12813-01A]; Medical Research Council of Southeast Sweden(FORSS); Swedish Council for Working Life and Social Research [FAS20041775]; Ostgota Brandstodsbolag; Australian Government Department of Social Services; Australian Institute of Family Studies (AIFS); Australian Bureau of Statistics (ABS); Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; Netherlands Organisation for Health Research and Development (ZonMw) [ZonMw 907.00303, 916.10159]; Netherlands Organisation for Scientific Research (NWO); Ministry of Health, Welfare and Sport; Ministry of Youth and Families; lInstitut de la statistique du Quebec; Fondation Lucie et Andre Chagnon; Ministere de leducation et de lEnseignement superieur; Ministere de la Sante et des Services sociaux; Ministere de la Famille; GRIP Research Unit on Childrens Psychosocial Maladjustment; QUALITY Cohort Collaborative Group; Centre hospitalier universitaire SainteJustine; Institut de recherche Robert-Sauve en sante et en securite au travail; lInstitut de recherche en sante publique de lUniversite de Montreal; Centre de recherche du Centre hospitalier de lUniversite de Montreal (CRCHUM); Fonds de recherche du Quebec Sante (FRQS); Fonds de recherche du Quebec Socie te et culture (FRQSC); Social Sciences and Humanities Research Council (SSHRC); Human Resources and Skills Development Canada (HRSDC); Canadian Institute for Health Research (CIHR); Canadian Foundation for Innovation (CFI); Statistics Canada; Economic and Social Research Council; Office of National Statistics; U.S. Bureau of Labor Statistics; National Institute for Child Health and Human Development

Background Historically, the incidence of cardiovascular disease and mortality in persons with Type I diabetes (TID) has been increased compared to the general population. Contemporary studies on time trends of mortality and cardiovascular disease are sparse. Methods In this observational study, TID persons were identified in the Swedish National Diabetes Registry (n=45,575) and compared with matched controls from the general population (n=220,141). Incidence rates from 2002 to 2019 were estimated with respect to mortality and cardiovascular disease in persons with TID overall and when stratified for prevalent cardiovascular and renal disease relative to controls. Findings Mean age in persons with TID was 32.4 years and 44.9% (20,446/45,575) were women. Age- and sex-adjusted mortality rates declined over time in both groups but remained significantly higher in those with TID compared to controls during 2017-2019, 7.62 (95% CI 7.16; 8.08) vs. 2.23 (95% CI 2.13; 2.33) deaths per 1,000 person years. Myocardial infarction, heart failure and stroke decreased over time in both groups, with persistent excess risks in the range of 3.4 -5.0 times from 2017 to 2019 in those with TID. TID persons >= 45 years without previous renal or cardiovascular complications had standardized mortality rates similar or even lower than controls 5.55 (4.51; 6.60) vs.7.08 (6.75; 7.40) respectively in the last time period. Interpretation Excess mortality persisted over time in persons with TID, largely in patients with cardiorenal complications. Improved secondary prevention with a focus on individualized treatment is needed to dose the gap in mortality for individuals with TID. Copyright (C) 2022 The Authors. Published by Elsevier Ltd., Funding Agencies|ALF-agreement; Novo Nordisk Foundation; Swedish Heart and Lung Foundation