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BACKGROUND: Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking. Our objective was to examine if children with early-life respiratory tract infections had increased risks of lower lung function and asthma at school age.METHODS: We used individual participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow at 75% of FVC (FEF75%) and asthma at a median (range) age of 7 (4-15) years.RESULTS: Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV1, FEV1/FVC and FEF75% (z-score range: -0.09 (95% CI -0.14- -0.04) to -0.30 (95% CI -0.36- -0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR range: 2.10 (95% CI 1.98-2.22) to 6.30 (95% CI 5.64-7.04) and 1.25 (95% CI 1.18-1.32) to 1.55 (95% CI 1.47-1.65), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as a proxy for early-life asthma.CONCLUSIONS: Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower respiratory tract infections.

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

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BackgroundLatent Autoimmune Diabetes in Adults (LADA) constitutes around 10% of all diabetes. Many LADA patients gradually lose their insulin secretion and progress to insulin dependency. In a recent trial BALAD (Behandling Av LADa) early insulin treatment compared with sitagliptin failed to preserve insulin secretion, which deteriorated in individuals displaying high levels of antibodies to GAD (GADA). These findings prompted us to evaluate a treatment that directly affects autoimmunity. Intra-lymphatic GAD-alum treatment has shown encouraging results in Type 1 diabetes patients. We therefore tested the feasibility of such therapy in LADA-patients (the GADinLADA pilot study). Material and MethodsFourteen GADA-positive (>190 RU/ml), insulin-independent patients 30-70 years old, with LADA diagnosed within < 36 months were included in an open-label feasibility trial. They received an intra-nodal injection of 4 mu g GAD-alum at Day 1, 30 and 60 plus oral Vitamin D 2000 U/d from screening 30 days before (Day -30) for 4 months if the vitamin D serum levels were below 100 nmol/L (40 ng/ml). Primary objective is to evaluate safety and feasibility. Mixed Meal Tolerance Test and i.v. Glucagon Stimulation Test at baseline and after 5 and 12 months are used for estimation of beta cell function. Results will be compared with those of the recent BALAD study with comparable patient population. Immunological response is followed. ResultsPreliminary results show feasibility and safety, with almost stable beta cell function and metabolic control during follow-up so far (5 months). ConclusionsIntra-lymphatic GAD-alum treatment is an option to preserve beta cell function in LADA-patients. An ongoing trial in 14 LADA-patients show feasibility and safety. Clinical and immunological responses will determine how to proceed with future trials.

Background/objectives This study analysed the relationship between early childhood socioeconomic status (SES) measured by maternal education and household income and the subsequent development of childhood overweight and obesity. Subjects/methods Data from seven population-representative prospective child cohorts in six high-income countries: United Kingdom, Australia, the Netherlands, Canada (one national cohort and one from the province of Quebec), USA, Sweden. Children were included at birth or within the first 2 years of life. Pooled estimates relate to a total of N = 26,565 included children. Overweight and obesity were defined using International Obesity Task Force (IOTF) cut-offs and measured in late childhood (8-11 years). Risk ratios (RRs) and pooled risk estimates were adjusted for potential confounders (maternal age, ethnicity, child sex). Slope Indexes of Inequality (SII) were estimated to quantify absolute inequality for maternal education and household income. Results Prevalence ranged from 15.0% overweight and 2.4% obese in the Swedish cohort to 37.6% overweight and 15.8% obese in the US cohort. Overall, across cohorts, social gradients were observed for risk of obesity for both low maternal education (pooled RR: 2.99, 95% CI: 2.07, 4.31) and low household income (pooled RR: 2.69, 95% CI: 1.68, 4.30); between-cohort heterogeneity ranged from negligible to moderate (p: 0.300 to < 0.001). The association between RRs of obesity by income was lowest in Sweden than in other cohorts. Conclusions There was a social gradient by maternal education on the risk of childhood obesity in all included cohorts. The SES associations measured by income were more heterogeneous and differed between Sweden versus the other national cohorts; these findings may be attributable to policy differences, including preschool policies, maternity leave, a ban on advertising to children, and universal free school meals., Funding Agencies|Canadian Institutes of Health Research [OCO-79897, MOP-89886, MSH-95353, ROG-110537]; Linkoping University

Although gut microbiome dysbiosis has been illustrated in celiac disease (CD), there are disagreements about what constitutes these microbial signatures and the timeline by which they precede diagnosis is largely unknown. The study of high-genetic-risk patients or those already with CD limits our knowledge of dysbiosis that may occur early in life in a generalized population. To explore early gut microbial imbalances correlated with future celiac disease (fCD), we analyzed the stool of 1478 infants aged one year, 26 of whom later acquired CD, with a mean age of diagnosis of 10.96 +/- 5.6 years. With a novel iterative control-matching algorithm using the prospective general population cohort, All Babies In Southeast Sweden, we found nine core microbes with prevalence differences and seven differentially abundant bacteria between fCD infants and controls. The differences were validated using 100 separate, iterative permutations of matched controls, which suggests the bacterial signatures are significant in fCD even when accounting for the inherent variability in a general population. This work is the first to our knowledge to demonstrate that gut microbial differences in prevalence and abundance exist in infants aged one year up to 19 years before a diagnosis of CD in a general population., Funding Agencies|Barndiabetesfonden (Swedish Child Diabetes Foundation); Swedish Council for Working Life and Social Research [FAS2004-1775]; Swedish Research Council [K2005-72 x -11242-11A, K2008-69 x -2082601-4, K2008-69 x -20826-01-4]; Medical Research Council of Southeast Sweden (FORSS); JDRF Wallenberg Foundation [K 9899D-12813-01A]; Region Ostergotland and Linkoping University, Sweden; Joanna Cocozza Foundation; Ostgota Brandstodsbolag

Aims Albuminuria is strongly associated with risk of renal dysfunction, cardiovascular disease and mortality. However, clinical guidelines diverge, and evidence is sparse on what risk factor levels regarding blood pressure, blood lipids and BMI are needed to prevent albuminuria in adolescents and young adults with type 1 diabetes. Methods A total of 9347 children and adults with type 1 diabetes [mean age 15.3 years and mean diabetes duration 1.4 years at start of follow-up] from The Swedish National Diabetes Registry were followed from first registration until end of 2017. Levels for risk factors for a risk increase in nephropathy were evaluated, and the gradient of risk per 1 SD (standard deviation) was estimated to compare the impact of each risk factor. Results During the follow-up period, 8610 (92.1%) remained normoalbuminuric, 737 (7.9%) individuals developed micro- or macroalbuminuria at any time period of whom 132 (17.9% of 737) individuals developed macroalbuminuria. Blood pressure >= 140/80 mmHg was associated with increased risk of albuminuria (p <= 0.0001), as were triglycerides >= 1.0 mmol/L (p = 0.039), total cholesterol >= 5.0 mmol/L (p = 0.0003), HDL < 1.0 mmol/L (p = 0.013), LDL 3.5- < 4.0 mmol/L (p = 0.020), and BMI >= 30 kg/m(2) (p = 0.033). HbA1c was the strongest risk factor for any albuminuria estimated by the measure gradient of risk per 1 SD, followed by diastolic blood pressure, triglycerides, systolic blood pressure, cholesterol and LDL. In patients with HbA1c > 65 mmol/mol (> 8.1%), blood pressure > 140/70 mmHg was associated with increased risk of albuminuria. Conclusions Preventing renal complications in adolescents and young adults with type 1 diabetes need avoidance at relatively high levels of blood pressure, blood lipids and BMI, whereas very tight control is not associated with further risk reduction. For patients with long-term poor glycaemic control, stricter blo, Funding Agencies|University of Gothenburg; Swedish government; Novo Nordisk FoundationNovo Nordisk FoundationNovocure Limited

Antigen-specific immunotherapy is an appealing strategy to preserve beta-cell function in type 1 diabetes, although the approach has yet to meet its therapeutic endpoint. Direct administration of autoantigen into lymph nodes has emerged as an alternative administration route that can improve the efficacy of the treatment. In the first open-label clinical trial in humans, injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) into an inguinal lymph node led to the promising preservation of C-peptide in patients with recent-onset type 1 diabetes. The treatment induced a distinct immunomodulatory effect, but the response at the cell level has not been fully characterized. Here we used mass cytometry to profile the immune landscape in peripheral blood mononuclear cells from 12 participants of the study before and after 15 months of treatment. The immunomodulatory effect of the therapy included reduction of naive and unswitched memory B cells, increase in follicular helper T cells and expansion of PD-1+ CD69+ cells in both CD8+ and double negative T cells. In vitro stimulation with GAD(65) only affected effector CD8+ T cells in samples collected before the treatment. However, the recall response to antigen after 15 months included induction of CXCR3+ and CD11c+Tbet+ B cells, PD-1+ follicular helper T cells and exhausted-like CD8+ T cells. This study provides a deeper insight into the immunological changes associated with GAD-alum administration directly into the lymph nodes., Funding Agencies|Barndiabetesfonden (Swedish Child Diabetes Foundation); Swedish Diabetes research foundation; Diamyd Medical

Aims: Immunomodulation with autoantigens potentially constitutes a specific and safe treatment for type 1 diabetes (T1D). Studies with GAD-alum administrated subcutaneously have shown to be safe, but its efficacy has been inconclusive. Administration of GAD-alum into the lymph nodes, aimed to optimise antigen presentation, has shown promising results in an open-label clinical trial. Herein, we compared the immune response of the individuals included in the trial with a group who received GAD-alum subcutaneously in a previous study. Materials and methods: Samples from T1D individuals collected 15 months after administration of either three doses 1 month apart of 4 mu g GAD-alum into lymph nodes (LN, n = 12) or two doses 1 month apart of 20 mu g subcutaneously (SC, n = 12) were studied. GADA, GADA subclasses, GAD(65)-induced cytokines, peripheral blood mononuclear cell proliferation, and T cells markers were analysed. Results: Low doses of GAD-alum into the lymph nodes induced higher GADA levels than higher doses administrated subcutaneously. Immune response in the LN group was characterised by changes in GADA subclasses, with a relative reduction of IgG1 and enhanced IgG2, IgG3, and IgG4 proportion, higher GAD(65)-induced secretion of IL-5, IL-10, and TNF-alpha, and reduction of cell proliferation and CD8(+) T cells. These changes were not observed after subcutaneous (SC) injections of GAD-alum. Conclusions: GAD-specific immune responses 15 months after lymph node injections of GAD-alum differed from the ones induced by SC administration of the same autoantigen., Funding Agencies: Swedish Diabetes Research Foundation; Swedish Child Diabetes Foundation; Diamyd Medical

Introduction: The progression to insulin deficiency in type 1 diabetes is heterogenous. This study aimed to identify early characteristics associated with rapid or slow decline of beta-cell function and how it affects the clinical course. Research design and methods: Stimulated C-peptide was assessed by mixed meal tolerance test in 50 children (<18 years) during 2004-2017, at regular intervals for 6 years from type 1 diabetes diagnosis. 40% of the children had a rapid decline of stimulated C-peptide defined as no measurable C-peptide (<0.03 nmol/L) 30 months after diagnosis. Results: At diagnosis, higher frequencies of detectable glutamic acid decarboxylase antibodies (GADA) and IA-2A (p=0.027) were associated with rapid loss of beta-cell function. C-peptide was predicted positively by age at 18 months (p=0.017) and 30 months duration (p=0.038). BMI SD scores (BMISDS) at diagnosis predicted higher C-peptide at diagnosis (p=0.006), 3 months (p=0.002), 9 months (p=0.005), 30 months (p=0.022), 3 years (p=0.009), 4 years (p=0.016) and 6 years (p=0.026), whereas high HbA1c and blood glucose at diagnosis predicted a lower C-peptide at diagnosis (p=<0.001) for both comparisons. Both GADA and IA-2A were negative predictors of C-peptide at 9 months (p=0.011), 18 months (p=0.008) and 30 months (p<0.001). Ten children had 22 events of severe hypoglycemia, and they had lower mean C-peptide at 18 months (p=0.025), 30 months (p=0.008) and 6 years (p=0.018) compared with others. Seven of them had a rapid decline of C-peptide (p=0.030), and the odds to experience a severe hypoglycemia were nearly fivefold increased (OR=4.846, p=0.04). Conclusions: Low age and presence of multiple autoantibodies at diagnosis predicts a rapid loss of beta-cell function in children with type 1 diabetes. Low C-peptide is associated with an increased risk of severe hypoglycemia and higher Hemoglobin A1C. A high BMISDS at diagnosis is predictive of remaining beta-cell function during the 6 ye

Child dental caries (i.e., cavities) are a major preventable health problem in most high-income countries. The aim of this study was to compare the extent of inequalities in child dental caries across four high-income countries alongside their child oral health policies. Coordinated analyses of data were conducted across four prospective population-based birth cohorts (Australia, n = 4085, born 2004; Quebec, Canada, n = 1253, born 1997; Rotterdam, the Netherlands, n = 6690, born 2002; Southeast Sweden, n = 7445, born 1997), which enabled a high degree of harmonization. Risk ratios (adjusted) and slope indexes of inequality were estimated to quantify social gradients in child dental caries according to maternal education and household income. Children in the least advantaged quintile for income were at greater risk of caries, compared to the most advantaged quintile: Australia: AdjRR = 1.18, 95%CI = 1.04-1.34; Quebec: AdjRR = 1.69, 95%CI = 1.36-2.10; Rotterdam: AdjRR = 1.67, 95%CI = 1.36-2.04; Southeast Sweden: AdjRR = 1.37, 95%CI = 1.10-1.71). There was a higher risk of caries for children of mothers with the lowest level of education, compared to the highest: Australia: AdjRR = 1.18, 95%CI= 1.01-1.38; Southeast Sweden: AdjRR = 2.31, 95%CI = 1.81-2.96; Rotterdam: AdjRR = 1.98, 95%CI = 1.71-2.30; Quebec: AdjRR = 1.16, 95%CI = 0.98-1.37. The extent of inequalities varied in line with jurisdictional policies for provision of child oral health services and preventive public health measures. Clear gradients of social inequalities in child dental caries are evident in high-income countries. Policy related mechanisms may contribute to the differences in the extent of these inequalities. Lesser gradients in settings with combinations of universal dental coverage and/or fluoridation suggest these provisions may ameliorate inequalities through additional benefits for socio-economically disadvantaged groups of children., Funding Agencies|Canadian Institutes of Health Research [MOP-123079, HDF70335, OCO-79897, MOP-89886, MSH-95353, ROG-110537]; Australian Government Department of Social Services; Australian Bureau of Statistics (ABS); Australian Institute of Family Studies (AIFS); Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; Netherlands Organisation for Health Research and Development (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 Santeet des Services sociaux; Ministere de la Famille; GRIP Research Unit on Childrens Psychosocial Maladjustment; QUALITY Cohort Collaborative Group; le Centre hospitalier universitaire SainteJustine; Institut de recherche Robert-Sauveen santeet en securiteau travail; lInstitut de recherche en santepublique 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); County Council of Ostergotland; Swedish Research Council [K200572X-11242-11A, K2008-69X-20826-01-4]; 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 National Health and Medical Research Council (NHMRC) Practitioner Fellowship [1155290]; NHMRC Career Development Fellowship [1111160]; Victorian Governments Operational Infrastructure Program

To exemplify autoimmune-associated genetic influence on the colonization of bacteria frequently used in probiotics, microbial composition of stool from 1326 one-year-old infants was analyzed in a prospective general-population cohort, All Babies In Southeast Sweden (ABIS). We show that an individual's HLA haplotype composition has a significant impact on which common Bifidobacterium strains thrive in colonizing the gut. The effect HLA has on the gut microbiome can be more clearly observed when considered in terms of allelic dosage. HLA DR1-DQ5 showed the most significant and most prominent effect on increased Bifidobacterium relative abundance. Therefore, HLA DR1-DQ5 is proposed to act as a protective haplotype in many individuals. Protection-associated HLA haplotypes are more likely to influence the promotion of specific bifidobacteria. In addition, strain-level differences are correlated with colonization proficiency in the gut depending on HLA haplotype makeup. These results demonstrate that HLA genetics should be considered when designing effective probiotics, particularly for those at high genetic risk for autoimmune diseases., Funding: 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]; Ostg ota Brandstodsbolag; Region Osterg otland; Link oping university, Sweden; Joanna Cocozza Foundation; JDRF [1-INO-2018-637-A-N]

OBJECTIVE To evaluate HbA(1c) followed from diagnosis, as a predictor of severe microvascular complications (i.e., proliferative diabetic retinopathy [PDR] and nephropathy [macroalbuminuria]). RESEARCH DESIGN AND METHODS In a population-based observational study, 447 patients diagnosed with type 1 diabetes before 35 years of age from 1983 to 1987 in southeast Sweden were followed from diagnosis until 2019. Long-term weighted mean HbA(1c) (wHbA(1c)) was calculated by integrating the area under all HbA(1c) values. Complications were analyzed in relation to wHbA(1c) categorized into five levels. RESULTS After 32 years, 9% had no retinopathy, 64% non-PDR, and 27% PDR, and 83% had no microalbuminuria, 9% microalbuminuria, and 8% macroalbuminuria. Patients with near-normal wHbA(1c) did not develop PDR or macroalbuminuria. The lowest wHbA(1c) values associated with development of PDR and nephropathy (macroalbuminuria) were 7.3% (56 mmol/mol) and 8.1% (65 mmol/mol), respectively. The prevalence of PDR and macroalbuminuria increased with increasing wHbA(1c), being 74% and 44% in the highest category, wHbA(1c) >9.5% (>80 mmol/mol). In comparison with the follow-up done after 20-24 years duration, the prevalence of PDR had increased from 14 to 27% and macroalbuminuria from 4 to 8%, and both appeared at lower wHbA(1c) values. CONCLUSIONS wHbA(1c) followed from diagnosis is a very strong biomarker for PDR and nephropathy, the prevalence of both still increasing 32 years after diagnosis. To avoid PDR and macroalbuminuria in patients with type 1 diabetes, an HbA(1c) <7.0% (53 mmol/mol) and as normal as possible should be recommended when achievable without severe hypoglycemia and with good quality of life., Funding Agencies|Barndiabetesfonden (The Swedish Child Diabetes Foundation); Region ostergotlands Stiftelsefonder [Ro-760091]

Introduction Type 1 diabetes (T1D) is an autoimmune disease leading to the destruction of the insulin-producing beta cells resulting in insulin deficiency and hyperglycaemic. Today, no approved therapy exists to halt this detrimental immunologic process. In a recent phase 2b study, intralymphatic administration of recombinant human glutamic acid decarboxylase 65 kDa (rhGAD65) adsorbed to Alhydrogel adjuvant to individuals recently diagnosed with T1D and carrying the HLA DR3-DQ2 haplotype showed promising results in preserving endogenous insulin secretion, confirming the results of a large meta-analysis of three randomised placebo-controlled trials of subcutaneous rhGAD65. The aim of the current precision medicine phase 3 study is to determine whether intralymphatic administration of rhGAD65 preserves insulin secretion and improves glycaemic control in presumed responder individuals with recently diagnosed T1D carrying HLA DR3-DQ2. Methods and analysis Individuals >= 12 and <29 years recently diagnosed with T1D (<6 months) will be screened for the HLA DR3-DQ2 haplotype, endogenous insulin production estimated by fasting C-peptide and presence of GAD65 antibodies. 330 patients are planned to be randomised to 3 monthly intralymphatic injections of rhGAD65 or placebo (both accompanied by oral vitamin D supplementation), followed by 22 months of follow-up. The study is powered to detect a treatment effect in the two coprimary endpoints; change from baseline in AUC((0-120min)) C-peptide levels during a mixed meal tolerance test, and change from baseline in glycaemic control estimated by haemoglobin A1c at 24 months. Secondary endpoints include effects on glucose patterns collected by masked continuous glucose monitoring, proportion of patients in partial remission and number of episodes of severe hypoglycaemia and/or diabetic ketoacidosis. Ethics and dissemination The trial is approved by Ethics Committees in Poland (124/2021), the Netherlands (R21.08

Background Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking. Our objective was to examine if children with early-life respiratory tract infections had increased risks of lower lung function and asthma at school age. Methods We used individual participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow at 75% of FVC (FEF75%) and asthma at a median (range) age of 7 (4-15) years. Results Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV1, FEV1/FVC and FEF75% (z-score range: -0.09 (95% CI -0.14- -0.04) to -0.30 (95% CI -0.36- -0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR range: 2.10 (95% CI 1.98-2.22) to 6.30 (95% CI 5.64-7.04) and 1.25 (95% CI 1.18-1.32) to 1.55 (95% CI 1.47-1.65), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as a proxy for early-life asthma. Conclusions Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower respiratory tract infections., Funding Agencies|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; UK Medical Research Council; Wellcome [217065/Z/19/Z]; University of Bristol; Swedish Heart Lung Foundation; ALF Region Stockholm; SFO Epidemiology Karolinska Institutet; European Research Council [757919, ERC-2014-CoG-648916]; Programme Grants for Applied Research funding scheme [RP-PG-0407-10044]; Wellcome Trust [WT101597MA]; Swiss National Science Foundation [320030_163311, SNF: 320030-182628, 320030-162820, 3233-069348, 3200-069349]; Italian Ministry of Health; Lundbeck Foundation [R16-A1694, 195/04, R100-A9193, R264-2017-3099]; Ministry of Health [903516]; Danish Council for Strategic Research [0603-00280B]; Capital Region Research Foundation; Danish National Research Foundation; Danish Regional Committees; Egmont Foundation; March of Dimes Birth Defects Foundation; Novo Nordisk Foundation; Danish Medical Research Council [SSVF 0646, 271-08-0839/06-066023, O602-01042B, 0602-02738B]; Innovation Fund Denmark [0603-00294B (09-067124)]; Nordea Foundation [02-2013-2014]; University of Copenhagen; Danish Council for Independent Research [DFF-4183-00594, DFF-4183-00152]; Foundation for Medical Research (FRM); National Institute for Research in Public health; French Ministry of Health (DGS); French Ministry of Research; INSERM Bone and Joint Diseases National Research (PRO-A) and Human Nutrition National Research Programs; French National Institute for Health Education (INPES); European Union [733206]; Diabetes National Research Program; Mutuelle Generale de lEducation Nationale complementary health insurance (MGEN); French national agency for food security; European Community [261357]; Erasmus MC Rotterdam; Erasmus University Rotte

BACKGROUND: Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking.OBJECTIVE: To examine if children with early-life respiratory tract infections had increased risks of lower lung function and asthma at school-age.METHODS: We used individual-participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow at 75% of FVC (FEF75), and asthma at a median age of 7 (range 4 to 15) years.RESULTS: Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV1, FEV1/FVC and FEF75 (Z-score (95% CI): ranging from -0.09 (-0.14, -0.04) to -0.30 (-0.36, -0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR (95%CI): ranging from 2.10 (1.98, 2.22) to 6.30 (5.64, 7.04)), and from 1.25 (1.18, 1.32) to 1.55 (1.47, 1.65)), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as proxy for early-life asthma.CONCLUSION: Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower upper respiratory tract infections.

Aims Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM). Methods DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 mu g GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values. Results We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR. Conclusions Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2., Funding Agencies|Diamyd Medical AB; Barndiabetesfonden (Swedish Child Diabetes Foundation); Diabetesfonden (Swedish Diabetes Association)

Background We examined absolute and relative relationships between household income and maternal education during early childhood (<5 years) with activity-limiting chronic health conditions (ALCHC) during later childhood in six longitudinal, prospective cohorts from high-income countries (UK, Australia, Canada, Sweden, Netherlands, USA). Methods Relative inequality (risk ratios, RR) and absolute inequality (Slope Index of Inequality) were estimated for ALCHC during later childhood by maternal education categories and household income quintiles in early childhood. Estimates were adjusted for mother ethnicity, maternal age at birth, child sex and multiple births, and were pooled using meta-regression. Results Pooled estimates, with over 42 000 children, demonstrated social gradients in ALCHC for high maternal education versus low (RR 1.54, 95% CI 1.28 to 1.85) and middle education (RR 1.24, 95% CI 1.11 to 1.38); as well as for high household income versus lowest (RR 1.90, 95% CI 1.66 to 2.18) and middle quintiles (RR 1.34, 95% CI 1.17 to 1.54). Absolute inequality showed decreasing ALCHC in all cohorts from low to high education (range: -2.85% Sweden, -13.36% Canada) and income (range: -1.8% Sweden, -19.35% Netherlands). Conclusion We found graded relative risk of ALCHC during later childhood by maternal education and household income during early childhood in all cohorts. Absolute differences in ALCHC were consistently observed between the highest and lowest maternal education and household income levels across cohort populations. Our results support a potential role for generous, universal financial and childcare policies for families during early childhood in reducing the prevalence of activity limiting chronic conditions in later childhood., Funding Agencies|Canadian Institutes of Health Research [OCO-79897, MOP-89886, MSH-95353, ROG-110537]; 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]; Ostgota Brandstodsbolag; Australian Government Department of Social Services; partner organisations 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); Netherlands Organisation for Scientific Research (NWO); Ministry of Health, Welfare and Sport; Ministry of Youth and Families; Human Resources and Skills Development Canada (HRSDC); Social Sciences and Humanities Research Council (SSHRC); Canadian Institute for Health Research (CIHR); Canadian Foundation for Innovation (CFI); Statistics Canada; Economic and Social Research Council; Office of National Statistics; various government departments; US Bureau of Labor Statistics; National Institute for Child Health and Human Development; [907.00303]; [916.10159]

Aim Previous studies have reported an association between month of birth and incidence of type 1 diabetes. Using population-based data, including almost all newly diagnosed children with type 1 diabetes in Sweden, we tested whether month of birth influences the risk of type 1 diabetes. Methods For 8761 children diagnosed with type 1 diabetes between May 2005 and December 2016 in the Better Diabetes Diagnosis study, month of birth, sex and age were compared. Human leucocyte antigen (HLA) genotype and autoantibodies at diagnosis were analysed for a subset of the cohort (n = 3647). Comparisons with the general population used data from Statistics Sweden. Results We found no association between month of birth or season and the incidence of type 1 diabetes in the cohort as a whole. However, boys diagnosed before 5 years were more often born in May (p = 0.004). We found no correlation between month of birth and HLA or antibodies. Conclusion In this large nationwide study, the impact of month of birth on type 1 diabetes diagnosis was weak, except for boys diagnosed before 5 years of age, who were more likely born in May. This may suggest different triggers for different subgroups of patients with type 1 diabetes., Funding Agencies: Barndiabetesfonden (Swedish Child Diabetes Foundation); Region Skånes research and development fund

Background/objectives: This study analysed the relationship between early childhood socioeconomic status (SES) measured by maternal education and household income and the subsequent development of childhood overweight and obesity. Subjects/methods: Data from seven population-representative prospective child cohorts in six high-income countries: United Kingdom, Australia, the Netherlands, Canada (one national cohort and one from the province of Quebec), USA, Sweden. Children were included at birth or within the first 2 years of life. Pooled estimates relate to a total of N = 26,565 included children. Overweight and obesity were defined using International Obesity Task Force (IOTF) cut-offs and measured in late childhood (8–11 years). Risk ratios (RRs) and pooled risk estimates were adjusted for potential confounders (maternal age, ethnicity, child sex). Slope Indexes of Inequality (SII) were estimated to quantify absolute inequality for maternal education and household income. Results: Prevalence ranged from 15.0% overweight and 2.4% obese in the Swedish cohort to 37.6% overweight and 15.8% obese in the US cohort. Overall, across cohorts, social gradients were observed for risk of obesity for both low maternal education (pooled RR: 2.99, 95% CI: 2.07, 4.31) and low household income (pooled RR: 2.69, 95% CI: 1.68, 4.30); between-cohort heterogeneity ranged from negligible to moderate (p: 0.300 to < 0.001). The association between RRs of obesity by income was lowest in Sweden than in other cohorts. Conclusions: There was a social gradient by maternal education on the risk of childhood obesity in all included cohorts. The SES associations measured by income were more heterogeneous and differed between Sweden versus the other national cohorts; these findings may be attributable to policy differences, including preschool policies, maternity leave, a ban on advertising to children, and universal free school meals.

Child dental caries (i.e., cavities) are a major preventable health problem in most highincome countries. The aim of this study was to compare the extent of inequalities in child dental caries across four high-income countries alongside their child oral health policies. Coordinated analyses of data were conducted across four prospective population-based birth cohorts (Australia, n = 4085, born 2004; Québec, Canada, n = 1253, born 1997; Rotterdam, the Netherlands, n = 6690, born 2002; Southeast Sweden, n = 7445, born 1997), which enabled a high degree of harmonization. Risk ratios (adjusted) and slope indexes of inequality were estimated to quantify social gradients in child dental caries according to maternal education and household income. Children in the least advantaged quintile for income were at greater risk of caries, compared to the most advantaged quintile: Australia: AdjRR = 1.18, 95%CI = 1.04-1.34; Québec: AdjRR = 1.69, 95%CI = 1.36-2.10; Rotterdam: AdjRR = 1.67, 95%CI = 1.36-2.04; Southeast Sweden: AdjRR = 1.37, 95%CI = 1.10-1.71). There was a higher risk of caries for children of mothers with the lowest level of education, compared to the highest: Australia: AdjRR = 1.18, 95%CI = 1.01-1.38; Southeast Sweden: AdjRR = 2.31, 95%CI = 1.81-2.96; Rotterdam: AdjRR = 1.98, 95%CI = 1.71-2.30; Québec: AdjRR = 1.16, 95%CI = 0.98-1.37. The extent of inequalities varied in line with jurisdictional policies for provision of child oral health services and preventive public health measures. Clear gradients of social inequalities in child dental caries are evident in high-income countries. Policy related mechanisms may contribute to the differences in the extent of these inequalities. Lesser gradients in settings with combinations of universal dental coverage and/or fluoridation suggest these provisions may ameliorate inequalities through additional benefits for socio-economically disadvantaged groups of children.