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Aim To assess the association between socioeconomic factors and mortality in Danish children diagnosed with different types of severe chronic disease, including cancer. Methods National cohort study 1994-2020 including Danish children with chronic disease. Inclusion was based on diagnoses in The National Patient Register, socioeconomic information was obtained from Statistics Denmark and mortality was ascertained from the Cause of Death Register. Hazard ratios (HR) with 95% confidence intervals (CIs) were based on Cox regression. The factors were combined in one common risk score and the association with disease-specific mortality was analysed overall and by ethnicity status. Results Overall, non-Danish ethnicity (HR = 1.96 (95% CI 1.69-2.28)) was associated with all-cause mortality in 128 129 children (69 435 male and 58 694 female) with chronic disease. Median age at first diagnosis was 1.42 years (range 0-18 years). Low family income was associated with mortality regardless of ethnicity status, and young maternal age was also a notable risk factor across ethnicities. The socioeconomic association was more pronounced in children with cancer. Conclusion In the high-income setting of Denmark, ethnicity and differences in socioeconomic background were associated with child mortality even among children with severe chronic disease. The pattern was more pronounced in paediatric cancer patients.

Preterm infants have an increased risk of neurodevelopmental disorders. We established a direct quantitative comparison of the association between the degree of prematurity and three different neurodevelopmental disorders.In this cohort study, we combined data from 995,498 children in the Danish Medical Birth Register, from birth years 1997-2013, with information on cerebral palsy, epilepsy, and special educational needs. We estimated the gestational week-specific prevalence and risk for each of the disorders.The risk ratio of cerebral palsy at gestational weeks 21-24, compared to term birth, was more than ten times higher than for the two other disorders. The prevalence of epilepsy and special educational needs declined almost parallel, with 9.2% (4.6%-13.5%) and 12.5% (11.2%-13.7%), respectively, per week of gestation toward term birth. Cerebral palsy did not decline similarly: from gestational weeks 21-24 until week 29 the prevalence declined insignificantly by 0.6% (-11.1%-11.0%) per week; whereas from week 29 until term, the prevalence declined markedly by 36.7% (25.9%-45.9%) per week.The prevalence and risk of cerebral palsy are affected differently by the degree of prematurity compared with epilepsy and special educational needs, possibly reflecting important differences in cerebral pathophysiology.For each week of gestation toward term birth, there was a clear log-linear decline in the prevalence of early childhood epilepsy and special educational needs. In contrast, the risk of cerebral palsy was high at the earliest gestational age, and the prevalence did not decline significantly until gestational week 29, from where it declined notably by nearly 40% for each week of gestation until term birth. Our results indicate important differences in the pathophysiological processes that associate preterm birth with these three neurodevelopmental disorders.

ObjectivesTo estimate the association between childhood vaccination and subsequent morbidity and mortality by adjusting for environmental and host factors. Further, to examine the degree of residual confounding in such observational studies.DesignRegister-based cohort study including 1 122 929 Danish children.ParticipantsAll children born in Denmark in the period 1999–2016 who survived until 16 months of age without prior migration followed from 16 months until the first of the following: event of interest, migration, 5 years of age or 31 December 2016.Main outcome measuresAdjusted HRs (aHRs) and absolute risks were calculated for the three outcomes: mortality, hospitalisation for infection and asthma using register data on deaths, specific hospital contacts and dispensed prescribed medication. The exposure was the combination of the routine vaccines against diphteria–tetanus–pertussis–polio–Haemophilus influenzaetype b and measles–mumps–rubella (DTP and MMR in short) administered in early childhood. Hospitalisation due to accidents was analysed as a negative control outcome to examine residual confounding.ResultsChildren with 3DTP+MMR had a lower hazard of mortality than the reference group with 3DTP, adjusted HR (aHR)=0.45 (95% CI: 0.35 to 0.57), whereas the children with 1 or 2 DTP had higher hazards of dying, aHR=1.55 (95% CI: 1.14 to 2.13) and aHR=1.96 (95% CI: 1.34 to 2.89). The vaccination group 3DTP+MMR was associated with a reduced hazard of asthma aHR=0.94 (95% CI: 0.92 to 0.96). Also, the vaccination group 3DTP+MMR was associated with a reduced hazard of hospitalisation due to accidents, aHR=0.83 (0.80 to 0.85) compared with the reference group with 3 DTP.ConclusionsThe results suggested a beneficial impact of MMR on under-five mortality but did not support the hypothesis that DTP is detrimental, since the group of children with fewer DTP vaccinations experienced increased mortality. The results of the study may to some degree be prone to residual confounding since an unexpected association between MMR vaccination and hospitalisation for accidents was observed.

ObjectivesTo describe the temporal development of mortality and health service utilisation defined as in- and outpatient hospital contacts, contacts with general practitioner and specialists, and prescribed dispensed medication among Danish children 0-5 years of age from 1999 to 2016.DesignRegister-based descriptive study.ParticipantsAll children born in Denmark in the period 1994-2016 followed until 5 years of age.Main outcome measuresAnnual incidence rates of mortality and health service utilisation outcomes, and incidence rate ratios compared to the reference calendar year 1999. The new measure of post-discharge mortality is presented.ResultsPost-discharge mortality decreased from 1999 to 2016, IRR2016 = 0.49 (95% CI: 0.36 to 0.66). Total contacts did not change much over time, IRR2016 = 1.02 (1.02 to 1.03), but increased among neonates, IRR2016 = 3.69 (3.63 to 3.75), and decreased among children with chronic disease IRR2016 = 0.94 (0.93 to 0.94). In- and out-patient hospitalisations increased, IRR2016 = 1.26 (1.24-1.27) resp. IRR2016 = 1.62 (1.60-1.63), contacts with medical specialists increased, IRR2016 = 1.43 (1.42 to 1.43), whilst contacts with general practitioner decreased, IRR2016 = 0.91 (0.91 to 0.91). Medication use decreased, IRR2016 = 0.82 (0.82 to 0.82).ConclusionsOur measure of post-discharge mortality was halved during the study period indicating improved health. Overall health service utilisation did not change much, but the type of utilisation changed, and the development over time differed between subgroups defined by age and chronic disease status. Our findings call for considerations about the benefit of increased specialisation and increased use of health services among 'healthy' children not suffering from chronic disease.

Objectives To study a potential positive association (referred to as 'a match') between the need for health service (expressed by a mortality risk score) and observed health service utilisation among healthy Danish under-fives. Further, municipal differences in the match were examined to motivate focused comparisons between the organisation of regional health services. Design Register-based national cohort study. Participants The population of 1,246,599 Danish children born 1997-2016 who survived until date of first discharge to the home after birth without a diagnosis of severe chronic disease. Main outcome measures Hazard ratios (HR) for a doubling of the mortality rate were calculated for the following health services: Total contacts, inpatient contacts (admission > 1 day), outpatient contacts, general practitioner contacts, specialist contacts, medication use, and vaccinations. Results The use of total contacts, inpatient contacts (> 1 day) and general practitioner contacts as well as medication matched with the mortality risk score, HRs between 1.027 (1.026 to 1.028) and 1.111 (1.108 to 1.113), whereas outpatient and specialist contacts as well as vaccinations did not, HRs between 0.913 (0.912 to 0.915) and 0.991 (0.991 to 0.991). There were some remarkable differences among the 98 Danish municipalities. Conclusions We found some match between need and use for total contacts, inpatient contacts (> 1 day), contacts with general practitioner, and medication use although the associations were relatively weak. For outpatient and specialist contacts, the mismatch may be related to services not addressing potentially fatal disease whereas for vaccination there was a small mismatch. Our results indicate local discrepancies in diagnosis, and a low adjusted utilisation of hospital admissions in Aarhus compared to the other three major cities in Denmark suggests that a comparison of the organisation of services could be useful.

High concentrations of cadmium in brown crab are an issue of food safety, and large variations between different areas have been found. To investigate the relative importance of dietary and aqueous uptake regarding the overall accumulation in brown crab, we used stable isotopes to trace the uptake from both routes simultaneously in the same animals. We demonstrated that the analytical challenges regarding background concentrations of natural isotope distribution and polyatomic interferences in the different matrices can be overcome with an appropriate analytical setup and modern mathematical corrections using a computer software. Cadmium was accumulated via both routes and was found in all measured organs at the end of the exposure phase. The obtained data were used to establish accumulation curves for both uptake routes and estimate accumulation parameters for hepatopancreas, as the most important organ in crab regarding total cadmium body burden. Using the estimated parameters in combination with naturally relevant cadmium concentrations in seawater and diet in a model, allowed us to predict the relative importance of the aqueous and dietary uptake route to the total hepatopancreas burden. According to the prediction, the dietary route is the main route of uptake in brown crab with a minimum of 98% of the accumulated cadmium in hepatopancreas originating from diet. Future studies addressing the source and accumulation of cadmium in crab should therefore focus on the uptake from feed and factors connected to foraging. publishedVersion

Exogenously administered B-type natriuretic peptide (BNP) has been shown to offer cardioprotection through activation of particulate guanylyl cyclase (pGC), protein kinase G (PKG) and KATP channel opening. The current study explores if cardioprotection afforded by short intermittent BNP administration involves PI3K/Akt/p70s6k dependent signaling, and whether this signaling pathway may participate in regulation of BNP mRNA expression at early reperfusion. Isolated Langendorff perfused rat hearts were subjected to 30 min of regional ischemia and 120 min of reperfusion (IR). Applying intermittent 3 × 30 s infusion of BNP peptide in a postconditioning like manner (BNPPost) reduced infarct size by >50% compared to controls (BNPPost 17 ± 2% vs. control 42 ± 4%, p < 0.001). Co-treatment with inhibitors of the PI3K/Akt/p70s6k pathway (wortmannin, SH-6 and rapamycin) completely abolished the infarct-limiting effect of BNP postconditioning (BNPPost + Wi 36 ± 5%, BNPPost + SH-6 41 ± 4%, BNPPost + Rap 37 ± 6% vs. BNPPost 17 ± 2%, p < 0.001). Inhibition of natriuretic peptide receptors (NPR) by isatin also abrogated BNPPost cardioprotection (BNPPost + isatin 46 ± 2% vs. BNPPost 17 ± 2%, p < 0.001). BNPPost also significantly phosphorylated Akt and p70s6k at early reperfusion, and Akt phosphorylation was inhibited by SH-6 and isatin. Myocardial BNP mRNA levels in the area at risk (AA) were significantly elevated at early reperfusion as compared to the non-ischemic area (ANA) (Ctr(AA) 2.7 ± 0.5 vs. Ctr(ANA) 1.2 ± 0.2, p < 0.05) and the ischemic control tissue (Ctr(AA) 2.7 ± 0.5 vs. ischemia 1.0 ± 0.1, p < 0.05). Additional experiments also revealed a significant higher BNP mRNA level in ischemic postconditioned (IPost) hearts as compared to ischemic controls (IPost 6.7 ± 1.3 vs. ischemia 1.0 ± 0.2, p < 0.05), but showed no difference from controls run in parallel (Ctr 5.4 ± 0.8). Akt inhibition by SH-6 completely abrogated this elevation (IPost 6.7 ± 1.3 vs. IPost + SH-6 1.8 ± 0.7, p < 0.05) (Ctr 5.4 ± 0.8 vs. SH-6 1.5 ± 0.9, p < 0.05). In conclusion, Akt dependent signaling is involved in mediating the cardioprotection afforded by intermittent BNP infusion at early reperfusion, and may also participate in regulation of reperfusion induced BNP expression. publishedVersion

Background The incidence of atopic dermatitis, wheezing, asthma and allergic rhinoconjunctivitis have been increasing. Register-based studies are essential for research in subpopulations with specific diseases, and facilitate epidemiological studies to identify causes and evaluate interventions. Algorithms have been developed to identify children with atopic dermatitis, asthma or allergic rhinoconjunctivitis using register information on disease-specific dispensed prescribed medication and hospital contacts, but the validity of the algorithms has not been evaluated. The present study validated the algorithms versus gold standard deep telephone interviews with the caretaker about physician-diagnosed atopic dermatitis, wheezing, asthma, or allergic rhinoconjunctivitis in the child. Methods The algorithms defined each of the three atopic diseases using register-based information on disease specific hospital contacts and/or filled prescriptions of disease specific medication. Confirmative answers to questions about physician-diagnosed atopic disease were used as the gold standard for the comparison with the algorithms, resulting in sensitivities and specificities and 95% confidence intervals. The interviews with the caretaker of the included 454 Danish children born 1997-2003 were carried out May-September 2015; the mean age of the children at the time of the interview being 15.2 years (standard deviation 1.3 years). Results For the algorithm capturing children with atopic dermatitis, the sensitivity was 74.1% (95-% confidence interval: 66.9-80.2%) and the specificity 73.0% (67.3-78.0%). For the algorithm capturing children with asthma, both the sensitivity of 84.1% (78.0-88.8%) and the specificity of 81.6% (76.5-85.8%) were high compared with physician-diagnosed asthmatic bronchitis (recurrent wheezing). The sensitivity remained high when capturing physician-diagnosed asthma: 83.3% (74.3-89.6%), however, the specificity declined to 66.0% (60.9-70.8%). For allergic rhino-conjunctivitis, the sensitivity was 84.4% (78.0-89.2) and the specificity 81.6% (75.0-84.4). Conclusion The algorithms are valid and valuable tools to identify children with atopic dermatitis, wheezing, asthma or allergic rhinoconjunctivitis on a population level using register data. This article is protected by copyright. All rights reserved.

Objectives Estimating associations between somatic and socioeconomic risk factors and post-discharge under-five mortality. Design Register-based national cohort study using multiple Cox regression. Participants The population of 1,263,795 Danish children live-born 1997-2016 who survived until date of first discharge to the home after birth was followed from that date until death, emigration, 5 years of age or 31 December 2016. Main outcome measures (A) Mortality hazard ratios (HRs) among all children, (B) mortality HRs among children without severe chronic disease, and (C) mortality HRs among children without severe chronic disease or asthma. Main results In the total population (1,947 deaths) severe chronic disease was associated with mortality HR = 15.28 (95% CI: 13.77-16.95). In children without severe chronic-disease (719 deaths) other somatic risk factors were immature birth HR = 3.40 (1.92-6.02), maternal smoking HR = 1.84 (1.55-2.18) and low birth weight HR = 1.74 (1.21-2.51). Socioeconomic risk factors for mortality included: maternal age < 25 years HR = 1.91 (1.38-2.64) compared to > 35 years (similar for 30-35 years and 25-29 years), lowest vs. highest family income tertile HR = 1.76 (1.23-2.51), not living with both parents HR = 1.63 (1.25-2.13), maternal unemployment HR = 1.54 (1.12-2.12), presence of siblings HR = 1.44 (1.20-1.71) and secondary vs. tertiary parental education HR = 1.33 (1.07-1.65) for fathers and HR = 1.23 (1.01-1.52) for mothers. Factors not found to be associated with child mortality in this population included presence of asthma HR = 1.29 (0.83-1.98) and non-Danish ethnicity HR = 0.98 (0.70-1.37). Conclusions Childhood death after discharge to the home after birth and before 5 years of age is a very rare event in Denmark. This 'post-discharge' mortality was heavily associated with severe chronic disease. In children without severe chronic disease, immature birth, maternal smoking and certain socioeconomic characteristics were noticeable risk factors. Mortality may possibly be decreased by focusing on vulnerable groups.