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INTRODUCTION: The population-based Inter99 cohort has contributed extensively to our understanding of effects of a systematic screening and lifestyle intervention, as well as the multifactorial aetiology of type 2 diabetes (T2D) and cardiovascular disease. To understand causes, trajectories and patterns of early and overt cardiometabolic disease manifestations, we will perform a combined clinical deep phenotyping and registry follow-up study of the now 50-80 years old Inter99 participants.METHODS AND ANALYSIS: The Inter99 cohort comprises individuals aged 30-60 years, who lived in a representative geographical area of greater Copenhagen, Denmark, in 1999. Age-stratified and sex-stratified random subgroups were invited to participate in either a lifestyle intervention (N=13 016) or questionnaires (N=5264), while the rest served as a reference population (N=43 021). Of the 13 016 individuals assigned to the lifestyle intervention group, 6784 (52%) accepted participation in a baseline health examination in 1999, including screening for cardiovascular risk factors and prediabetic conditions. In total, 6004 eligible participants, who participated in the baseline examination, will be invited to participate in the deep phenotyping 20-year follow-up clinical examination including measurements of anthropometry, blood pressure, arterial stiffness, cardiometabolic biomarkers, coronary artery calcification, heart rate variability, heart rhythm, liver stiffness, fundus characteristics, muscle strength and mass, as well as health and lifestyle questionnaires. In a subsample, 10-day monitoring of diet, physical activity and continuous glucose measurements will be performed. Fasting blood, urine and faecal samples to be stored in a biobank. The established database will form the basis of multiple analyses. A main purpose is to investigate whether low birth weight independent of genetics, lifestyle and glucose tolerance predicts later common T2D cardiometabolic comorbiditi

Background: Diabetes and its cardiovascular complications are a growing concern worldwide. Recently, some studies have demonstrated that relative risk of heart failure (HF) is higher in women with type 1 diabetes (T1DM) than in men. This study aims to validate these findings in cohorts representing five countries across Europe. Methods: This study includes 88,559 (51.8% women) participants, 3,281 (46.3% women) of whom had diabetes at baseline. Survival analysis was performed with the outcomes of interest being death and HF with a follow-up time of 12 years. Sub-group analysis according to sex and type of diabetes was also performed for the HF outcome. Results: 6,460 deaths were recorded, of which 567 were amongst those with diabetes. Additionally, HF was diagnosed in 2,772 individuals (446 with diabetes). A multivariable Cox proportional hazard analysis showed that there was an increased risk of death and HF (hazard ratio (HR) of 1.73 [1.58–1.89] and 2.12 [1.91–2.36], respectively) when comparing those with diabetes and those without. The HR for HF was 6.72 [2.75–16.41] for women with T1DM vs. 5.80 [2.72–12.37] for men with T1DM, but the interaction term for sex differences was insignificant (p for interaction 0.45). There was no significant difference in the relative risk of HF between men and women when both types of diabetes were combined (HR 2.22 [1.93–2.54] vs. 1.99 [1.67–2.38] respectively, p for interaction 0.80). Conclusion: Diabetes is associated with increased risks of death and heart failure, and there was no difference in relative risk according to sex.

Celiac disease (CD) is an autoimmune disease caused by an abnormal immune response triggered by ingestion of gluten. Treatment of CD is a lifelong gluten-free diet. Both diagnosed and undiagnosed CD has been found to be associated with reduced bone mineral density, which can lead to an increased risk of fractures. We therefore aimed to investigate the association of CD and the risk of fractures and osteoporosis in Denmark in a nationwide registry-based study. We identified all patients with CD (ICD-10 code K90.0) between 2000 and 2018 and included those with at least two contacts with a CD diagnosis. In total, 9397 CD patients and 93,964 randomly selected age- and sex-matched (1:10) references from the general population were identified. The overall hazard ratio (HR) of developing osteoporosis in CD patients compared with matches was 5.39 (95 % confidence interval (CI): 4.89, 5.95), however when excluding events of osteoporosis occurring within 12 months from the date of diagnosis the overall HR was reduced to 3.87 (95 % CI: 3.44, 4.33). The HR for major osteoporotic fractures was 1.37 (95 % CI: 1.25, 1.51) and for any fractures 1.27 (95 % CI: 1.18, 1.36). For osteoporosis, major osteoporotic fractures, and any fracture prior to diagnosis of CD the odds ratios comparing CD patients with matches were 4.32 (95 % CI: 3.64, 4.68), 1.29 (95 % CI: 1.21, 1.37) and 1.34 (95 % CI: 1.27, 1.41), respectively. Thus, this study showed an increased risk of osteoporosis and bone fractures among individuals with CD, both before and after diagnosis of CD. These results underline that the risk of osteoporosis should be considered in the clinical management of patients with CD and that early diagnosis and treatment could be important., Celiac disease (CD) is an autoimmune disease caused by an abnormal immune response triggered by ingestion of gluten. Treatment of CD is a lifelong gluten-free diet. Both diagnosed and undiagnosed CD has been found to be associated with reduced bone mineral density, which can lead to an increased risk of fractures. We therefore aimed to investigate the association of CD and the risk of fractures and osteoporosis in Denmark in a nationwide registry-based study. We identified all patients with CD (ICD-10 code K90.0) between 2000 and 2018 and included those with at least two contacts with a CD diagnosis. In total, 9397 CD patients and 93,964 randomly selected age- and sex-matched (1:10) references from the general population were identified. The overall hazard ratio (HR) of developing osteoporosis in CD patients compared with matches was 5.39 (95 % confidence interval (CI): 4.89, 5.95), however when excluding events of osteoporosis occurring within 12 months from the date of diagnosis the overall HR was reduced to 3.87 (95 % CI: 3.44, 4.33). The HR for major osteoporotic fractures was 1.37 (95 % CI: 1.25, 1.51) and for any fractures 1.27 (95 % CI: 1.18, 1.36). For osteoporosis, major osteoporotic fractures, and any fracture prior to diagnosis of CD the odds ratios comparing CD patients with matches were 4.32 (95 % CI: 3.64, 4.68), 1.29 (95 % CI: 1.21, 1.37) and 1.34 (95 % CI: 1.27, 1.41), respectively. Thus, this study showed an increased risk of osteoporosis and bone fractures among individuals with CD, both before and after diagnosis of CD. These results underline that the risk of osteoporosis should be considered in the clinical management of patients with CD and that early diagnosis and treatment could be important.

Introduction Previous studies have indicated that patients with celiac disease (CD) may have an increased risk of developing neuropsychiatric disorders. However, large-scale epidemiologic studies on the topic are still scarce. We aimed to examine the association between CD and development of neuropsychiatric disorders during an 18-year follow-up period. Methods We conducted a prospective cohort study. All Danish patients with an incident diagnosis of CD (ICD-10 K90.0) from 2000 to 2018 were identified in nationwide registries and compared with birthdate- and sex-matched controls (variable 1:10 ratio) for the development of a neuropsychiatric disease. Individual neuropsychiatric diseases were also examined. The absolute risk was calculated by the cumulative incidence, and the relative risk was estimated in Cox regression models. Results We identified a cohort of 6329 patients with CD diagnosed from 2000 to 2018 and 63,287 matches at risk for developing incident neuropsychiatric disorders. The cumulative incidence of development of any neuropsychiatric disorder was 3.9%, 14.9%, 24.8%, 35.9% after 1, 5, 10, and 15 years of follow-up, respectively, in patients with CD compared with 1.8%, 9.3%, 18.3%, and 27.0% in controls. Gray's test for equality p < 0.001. The relative risk was HR = 1.58 (95% confidence interval: 1.49–1.68) in CD patients compared with matches. For the individual outcomes, CD was associated with an increased relative risk of developing anxiety, depression, eating disorders, epilepsy, migraine, and stress. We also found indications of an increased relative risk of ADHD, alcoholism, bipolar disorders, and drug abuse, although the associations were less clear. No associations were found between CD and dementia, Parkinson's disease, and schizophrenia. Conclusions In this nationwide study including more than 6000 patients with CD, we found an increased risk of development of a neuropsychiatric disorder compared, Introduction: Previous studies have indicated that patients with celiac disease (CD) may have an increased risk of developing neuropsychiatric disorders. However, large-scale epidemiologic studies on the topic are still scarce. We aimed to examine the association between CD and development of neuropsychiatric disorders during an 18-year follow-up period. Methods: We conducted a prospective cohort study. All Danish patients with an incident diagnosis of CD (ICD-10 K90.0) from 2000 to 2018 were identified in nationwide registries and compared with birthdate- and sex-matched controls (variable 1:10 ratio) for the development of a neuropsychiatric disease. Individual neuropsychiatric diseases were also examined. The absolute risk was calculated by the cumulative incidence, and the relative risk was estimated in Cox regression models. Results: We identified a cohort of 6329 patients with CD diagnosed from 2000 to 2018 and 63,287 matches at risk for developing incident neuropsychiatric disorders. The cumulative incidence of development of any neuropsychiatric disorder was 3.9%, 14.9%, 24.8%, 35.9% after 1, 5, 10, and 15 years of follow-up, respectively, in patients with CD compared with 1.8%, 9.3%, 18.3%, and 27.0% in controls. Gray's test for equality p < 0.001. The relative risk was HR = 1.58 (95% confidence interval: 1.49–1.68) in CD patients compared with matches. For the individual outcomes, CD was associated with an increased relative risk of developing anxiety, depression, eating disorders, epilepsy, migraine, and stress. We also found indications of an increased relative risk of ADHD, alcoholism, bipolar disorders, and drug abuse, although the associations were less clear. No associations were found between CD and dementia, Parkinson's disease, and schizophrenia. Conclusions: In this nationwide study including more than 6000 patients with CD, we found an increased risk of development of a neuropsychiatric disorder compared with age- and sex-matched controls.

Aim: To explore pituitary–gonadal hormone concentrations and assess their association with inflammation, severe respiratory failure, and mortality in hospitalized men and women with COVID-19, and compare these to hormone concentrations in hospitalized patients with bacterial community-acquired pneumonia (CAP) and influenza virus CAP and to concentrations in a reference group of healthy individuals. Methods: Serum concentrations of testosterone, estrone sulfate, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and interleukin-6 (IL-6) were measured within 4 days of admission. Associations were assessed by logistic regression analysis in patients with COVID-19, and results were reported as odds ratio with 95% CI per two-fold reduction after adjustment for age, comorbidities, days to sample collection, and IL-6 concentrations. Results: In total, 278 patients with COVID-19, 21 with influenza virus CAP, and 76 with bacterial CAP were included. Testosterone concentrations were suppressed in men hospitalized with COVID-19, bacterial and influenza virus CAP, and moderately suppressed in women. Reductions in testosterone (OR: 3.43 (1.14–10.30), P = 0.028) and LH (OR: 2.51 (1.28–4.92), P = 0.008) were associated with higher odds of mehanical ventilation (MV) in men with COVID-19. In women with COVID-19, reductions in LH (OR: 3.34 (1.02–10-90), P = 0.046) and FSH (OR: 2.52 (1.01–6.27), P = 0.047) were associated with higher odds of MV. Conclusion: Low testosterone and LH concentrations were predictive of severe respiratory failure in men with COVID-19, whereas low concentrations of LH and FSH were predictive of severe respiratory failure in women with COVID-19.

Context: Supraphysiological serum insulin-like growth-factor-I (IGF-I) concentrations have been a matter of concern in children treated with growth hormone (GH) because high IGF-I levels were associated with risk of later disease in former epidemiological studies. Objective: To determine whether a single IGF-I measurement reliably reflects lifetime IGF-I exposure we evaluated intraindividual longitudinal tracking of IGF-I and IGF-binding-protein-3 (IGFBP-3) levels and we estimated cumulative lifetime exposure to IGF-I in healthy and GH-treated individuals. Methods: We included 6,459 healthy participants (cross-sectional = 5,326; longitudinal = 1,133) aged 0----76 years (9,963 serum samples) and nine patients born small-for-gestational-age (SGA) with 238 serum samples during GH treatment.Intraindividual tracking of IGF-I and IGFBP-3 (SDS) was determined by intraclass correlation coefficients (ICC). Cumulative lifetime IGF-I exposure was estimated by area under the curve of the predicted SDS-trajectory from 0-76 years. Results: For IGF-I (SDS), ICCs were 0.50 (95% CI: 0.47-0.53) for male and 0.53 (0.50-0.56) for female participants. Lifetime IGF-I exposure was significantly higher in female (mean 12,723 ± 3,691 SD) than in male participants (12,563 ± 3,393); p = 0.02. In SGA children, treatment with GH increased the lifetime exposure to IGF-I from 9,512 ± 1,889 to 11,271 ± 1,689, corresponding to an increase in lifetime IGF-I trajectory from -0.89 SD ± 0.57 to -0.35 SD ± 0.49. Conclusion: Since IGF-I and IGFBP-3 levels track throughout life, a single measurement reliably reflects lifetime exposure. GH therapy increased the lifetime exposure to IGF-I only slightly and it remained below the average lifetime exposure in the reference population. Keywords: GH treatment; IGF-I; IGFBP-3; SGA; short stature, CONTEXT: Supraphysiological serum insulin-like growth-factor-I (IGF-I) concentrations have been a matter of concern in children treated with growth hormone (GH) because high IGF-I levels were associated with risk of later disease in former epidemiological studies.OBJECTIVE: To determine whether a single IGF-I measurement reliably reflects lifetime IGF-I exposure we evaluated intraindividual longitudinal tracking of IGF-I and IGF-binding-protein-3 (IGFBP-3) levels and we estimated cumulative lifetime exposure to IGF-I in healthy and GH-treated individuals.METHODS: We included 6,459 healthy participants (cross-sectional = 5,326; longitudinal = 1,133) aged 0----76 years (9,963 serum samples) and nine patients born small-for-gestational-age (SGA) with 238 serum samples during GH treatment.Intraindividual tracking of IGF-I and IGFBP-3 (SDS) was determined by intraclass correlation coefficients (ICC). Cumulative lifetime IGF-I exposure was estimated by area under the curve of the predicted SDS-trajectory from 0-76 years.RESULTS: For IGF-I (SDS), ICCs were 0.50 (95% CI: 0.47-0.53) for male and 0.53 (0.50-0.56) for female participants. Lifetime IGF-I exposure was significantly higher in female (mean 12,723 ± 3,691 SD) than in male participants (12,563 ± 3,393); p = 0.02. In SGA children, treatment with GH increased the lifetime exposure to IGF-I from 9,512 ± 1,889 to 11,271 ± 1,689, corresponding to an increase in lifetime IGF-I trajectory from -0.89 SD ± 0.57 to -0.35 SD ± 0.49.CONCLUSION: Since IGF-I and IGFBP-3 levels track throughout life, a single measurement reliably reflects lifetime exposure. GH therapy increased the lifetime exposure to IGF-I only slightly and it remained below the average lifetime exposure in the reference population.

Background: Diabetes and its cardiovascular complications are a growing concern worldwide. Recently, some studies have demonstrated that relative risk of heart failure (HF) is higher in women with type 1 diabetes (T1DM) than in men. This study aims to validate these findings in cohorts representing five countries across Europe. Methods: This study includes 88,559 (51.8% women) participants, 3,281 (46.3% women) of whom had diabetes at baseline. Survival analysis was performed with the outcomes of interest being death and HF with a follow-up time of 12 years. Sub-group analysis according to sex and type of diabetes was also performed for the HF outcome. Results: 6,460 deaths were recorded, of which 567 were amongst those with diabetes. Additionally, HF was diagnosed in 2,772 individuals (446 with diabetes). A multivariable Cox proportional hazard analysis showed that there was an increased risk of death and HF (hazard ratio (HR) of 1.73 [1.58–1.89] and 2.12 [1.91–2.36], respectively) when comparing those with diabetes and those without. The HR for HF was 6.72 [2.75–16.41] for women with T1DM vs. 5.80 [2.72–12.37] for men with T1DM, but the interaction term for sex differences was insignificant (p for interaction 0.45). There was no significant difference in the relative risk of HF between men and women when both types of diabetes were combined (HR 2.22 [1.93–2.54] vs. 1.99 [1.67–2.38] respectively, p for interaction 0.80). Conclusion: Diabetes is associated with increased risks of death and heart failure, and there was no difference in relative risk according to sex.

OBJECTIVES: It has been suggested that infections can trigger functional somatic disorders (FSD). However, current evidence is limited by inconsistent findings in smaller studies conducted in clinical settings within selected populations and short follow-up times. We aimed to test the hypothesis that former infections are associated with FSD using data from nationwide registries and a large population-based cohort study, the Danish Study of Functional Disorders study.DESIGN: FSD cases were identified in a cross-sectional population-based cohort and linked retrospectively to former hospital contacts with infections identified in the Danish National Patient Registry. The associations between FSD and former infections within 17 years were analysed using logistic regressions to calculate ORs and 95% CIs adjusted for age, sex and subjective social status.SETTING: A population-based cohort in Denmark examined between 2011 and 2015.PARTICIPANTS: A total of 9656 men and women aged 18-76 years.MAIN OUTCOME MEASURES: FSD measured by various delimitations, including bodily distress syndrome (BDS), irritable bowel (IB), chronic fatigue (CF), chronic widespread pain (CWP), and multiple chemical sensitivity (MCS).RESULTS: Overall, infections were associated with increased risk of all delimitations of FSD. The associations were more pronounced for multisystemic FSD. The number of prior infections increased the risk in a dose-response manner (p<0.0001). Bacterial but not viral infections were significantly associated with BDS (OR 1.69 (95% CI 1.46 to 1.96)), IB (OR 1.41 (95% CI 1.06 to 1.88)), CWP (OR 1.47 (95% CI 1.13 to 1.90)) and CF (OR 1.62 (95% CI 1.34 to 1.96)), but not MCS.CONCLUSION: Former infections leading to hospital contacts were associated with a higher risk of having FSD. These associations were more pronounced for bacterial than viral infections, and more infections increased the risk in a dose-response manner. These r

It has been suggested that infections can trigger functional somatic disorders (FSD). However, current evidence is limited by inconsistent findings in smaller studies conducted in clinical settings within selected populations and short follow-up times. We aimed to test the hypothesis that former infections are associated with FSD using data from nationwide registries and a large population-based cohort study, the Danish Study of Functional Disorders study. FSD cases were identified in a cross-sectional population-based cohort and linked retrospectively to former hospital contacts with infections identified in the Danish National Patient Registry. The associations between FSD and former infections within 17 years were analysed using logistic regressions to calculate ORs and 95% CIs adjusted for age, sex and subjective social status. A population-based cohort in Denmark examined between 2011 and 2015. A total of 9656 men and women aged 18-76 years. FSD measured by various delimitations, including bodily distress syndrome (BDS), irritable bowel (IB), chronic fatigue (CF), chronic widespread pain (CWP), and multiple chemical sensitivity (MCS). Overall, infections were associated with increased risk of all delimitations of FSD. The associations were more pronounced for multisystemic FSD. The number of prior infections increased the risk in a dose-response manner (p

Objective: The incidence of hypothyroidism is not expected to differ by socioeconomic factors. However, the decision to test and initiate treatment may differ. We aimed to examine whether educational level influences the probability of thyroid stimulation hormone (TSH)-measurement and initiation of levothyroxine treatment. Design: Citizens in the greater Copenhagen Area during 2001-2015 were included. Individual-level data on educational level, diagnoses, GP-contact, TSH-measurement and medication were derived from administrative and healthcare registers. The relative risks (RR) between educational levels of annual TSH-measurement and treatment initiation following a TSH-measurement were analysed in Poisson regression models with generalized estimation equations. Results: A TSH-measurement was performed in 19% of 9,390,052 person years. The probability of TSH-measurement was higher with short (RR 1.16 [95% CI 1.15–1.16]) and medium (RR 1.11 [95% CI 1.06–1.12]) compared with long education. Treatment was initiated after 0.8% of 2,049,888 TSH-measurements. For TSH < 5 mIU/L, RR for treatment initiation ranged between 0.47 (95%CI 0.39–0.57) and 0.78 (95%CI 0.67–0.91) for short and medium compared with long education. For TSH 5–10 mIU/L, there was no statistically significant difference. For TSH > 10 mIU/L, RR was 1.07 (95% CI 1.02–1.12) for short and 1.08 (95% CI 1.03–1.13) for medium compared with long education. Conclusion: The probability of TSH-measurement was higher with shorter education, and the probability of treatment initiation with TSH > 10 mIU/L was marginally higher with short-medium education compared with long education. However, the probability of treatment initiation with TSH < 5 mIU/L, that is treatment incongruous with guidelines, was substantially higher in persons with long education.

AIMS: To use the rs1229984 variant associated with alcohol consumption as an instrument for alcohol consumption to test the causality of the association of alcohol consumption with hay fever, asthma, allergic sensitization and serum total immunoglobulin (Ig)E.DESIGN: Observational and Mendelian randomization analyses using genetic variants as unbiased markers of exposure to estimate causal effects, subject to certain assumptions.SETTING: Europe.PARTICIPANTS: We included a total of 466 434 people aged 15-82 years from 17 population-based studies conducted from 1997 to 2015.MEASUREMENTS: The rs1229984 (ADH1B) was genotyped; alcohol consumption, hay fever and asthma were self-reported. Specific and total IgE were measured from serum samples.FINDINGS: Observational analyses showed that ever-drinking versus non-drinking, but not amount of alcohol intake, was positively associated with hay fever and inversely associated with asthma but not with allergic sensitization or serum total immunoglobulin (Ig)E. However, Mendelian randomization analyses did not suggest that the observational associations are causal. The causal odds ratio (OR) per genetically assessed unit of alcohol/week was an OR = 0.907 [95% confidence interval (CI) = 0.806, 1.019; P = 0.101] for hay fever, an OR = 0.897 (95% CI = 0.790, 1.019; P = 0.095) for asthma, an OR = 0.971 (95% CI = 0.804, 1.174; P = 0.763) for allergic sensitization and a 4.7% change (95% CI = -5.5%, 14.9%; P = 0.366) for total IgE.CONCLUSIONS: In observational analyses, ever-drinking versus not drinking was positively associated with hay fever and negatively associated with asthma. However, the Mendelian randomization results were not consistent with these associations being causal.

Background: The relationship between allergy and celiac disease (CD) is not clear. Objective: The objective of this article is to investigate the association of CD and CD antibody positivity with hay fever, asthma and immunoglobulin (Ig)E sensitization in a general adult population. Methods: A total of 2297 individuals were screened for CD antibodies and underwent allergy testing. CD antibody-positive participants were invited to undergo clinical evaluation including biopsies. Additionally, biobank blood samples from four population-based studies (6423, 973, 1718 and 1101 participants) with data on IgE sensitization to inhalant allergens were screened for CD antibodies. CD antibody-positive participants were screened for serum IgE against food allergens in three biobank studies. CD-antibody positivity was defined as IgA or IgG tissue transglutaminase ≥7 U/ml and/or IgG deamidated gliadin peptide ≥10 U/ml. Results: The nine participants (0.4%) diagnosed with CD had significantly higher prevalence of IgE sensitization to wheat and dust mites. The prevalence of CD antibody positivity was 0.8% (18/2297), and these participants had a significantly higher prevalence of IgE sensitization to food allergens (Fx5), egg, dust mites and mugwort. In the biobank studies, the prevalence of CD antibody positivity was 0.8% to 1.2%. One study showed a positive association between CD antibody positivity and IgE sensitization for dog, horse and food allergens. Conclusion: We found a possible association of CD and IgE sensitization to some food and inhalant allergens in the Health2006 study. In further studies, however, we could not consistently replicate these associations.