Preterm birth is associated with smaller body dimensions at birth. The impact on body size in later life, measured by body mass index (BMI) and height, remains unclear. A prospective register-based ...cohort study with 62,625 singletons from the Danish National Birth Cohort born 1996-2003 for whom information on gestational age (GA) at birth, length or weight at birth, and at least two growth measurements scheduled at the ages of 5 and 12 months, and 7, 11 and 18 years were available. Linear mixed effects with splines, stratified by sex, and adjusted for confounders were used to estimate standardised BMI and height. GA was positively associated with BMI in infancy, but differences between preterm and term children declined with age. By age 7, preterm children had slightly lower BMI than term children, whereas no difference was observed by adolescence (mean difference in BMI z-score - 0.28 to 0.15). GA was strongly associated with height in infancy, but mean differences between individuals born preterm and term declined during childhood. By adolescence, the most preterm individuals remained shorter than their term peers (mean difference in height z-score from - 1.00 to - 0.28). The lower BMI in preterm infants relative to term infants equalizes during childhood, such that by adolescence there is no clear difference. Height is strongly positively associated with GA in early childhood, whilst by end of adolescence individuals born preterm remain slightly shorter than term peers.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Non-small cell lung cancer (NSCLC) is one of the deadliest cancers worldwide. In search for new NSCLC treatment options, we screened a cationic amphiphilic drug (CAD) library for cytotoxicity against ...NSCLC cells and identified several CAD antihistamines as inducers of lysosomal cell death. We then performed a cohort study on the effect of CAD antihistamine use on mortality of patients diagnosed with non-localized cancer in Denmark between 1995 and 2011. The use of the most commonly prescribed CAD antihistamine, loratadine, was associated with significantly reduced all-cause mortality among patients with non-localized NSCLC or any non-localized cancer when compared with use of non-CAD antihistamines and adjusted for potential confounders. Of the less frequently described CAD antihistamines, astemizole showed a similar significant association with reduced mortality as loratadine among patients with any non-localized cancer, and ebastine use showed a similar tendency. The association between CAD antihistamine use and reduced mortality was stronger among patients with records of concurrent chemotherapy than among those without such records. In line with this, sub-micromolar concentrations of loratadine, astemizole and ebastine sensitized NSCLC cells to chemotherapy and reverted multidrug resistance in NSCLC, breast and prostate cancer cells. Thus, CAD antihistamines may improve the efficacy of cancer chemotherapy.
•Use of cationic amphiphilic antihistamines is associated with reduced mortality among patients with non-localized cancer.•Clinically relevant concentrations of cationic amphiphilic antihistamines sensitize cancer cells to chemotherapy.•Clinically relevant concentrations of cationic amphiphilic antihistamines revert multidrug resistance.Research Context Cationic amphiphilic drugs (CADs) induce lysosomal membrane permeabilization and cell death preferentially in cancer cells. Here, we show that antihistamines with CAD structure, i.e. astemizole, ebastine and loratadine, sensitize cancer cells to chemotherapy and revert multidrug resistance even at low, clinically relevant concentrations. The significance of these experimental findings is supported by an association between CAD antihistamine use and reduced mortality among patients diagnosed with non-localized cancer, especially among those receiving concurrent chemotherapy. These findings are immediately translatable to clinical trials, as loratadine and ebastine, are safe, inexpensive and approved for clinical use.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Summary Background Survivors of childhood cancer are known to be at risk for long-term physical and mental effects. However, little is known about how cancers can affect mental health in the siblings ...of these patients. We aimed to assess the long-term risks of mental disorders in survivors of childhood cancer and their siblings. Methods Hospital contact for mental disorders was assessed in a population-based cohort of 7085 Danish children treated for cancer by contemporary protocols between 1975 and 2010 and in their 13 105 siblings by use of data from the Danish Psychiatric Central Research Registry. Hazard ratios (HRs) for first hospital contact were calculated using a Cox proportional hazards model. We compared these sibling and survivor cohorts with two population-based cohorts who were not childhood cancer survivors or siblings of survivors. Findings Survivors of childhood cancer were at increased risk of hospital contact for mental disorders, with HRs of 1·50 (95% CI 1·32–1·69) for males and 1·26 (1·10–1·44) for females. Children younger than 10 years at diagnosis had the highest risk, and increased risks were seen in survivors of CNS tumours, haematological malignancies, and solid tumours. Survivors had higher risk of neurodevelopmental, emotional, and behavioural disorders than population-based comparisons and siblings, and male survivors had higher risk for unipolar depression. Overall, siblings had no excess risk for mental disorders. However, our data suggest that siblings who were young at the time of cancer diagnosis of the survivor were at increased risk for mental disorders, whereas those older than 15 years at diagnosis were at a lower risk than the general population. Interpretation Childhood cancer survivors should be followed up for mental late effects, especially those diagnosed in young age. Further, clinicians should also be aware that siblings who were young at the time of cancer diagnosis might be at increased risk for mental health disorders. Funding Danish Childhood Cancer Foundation, Danish Agency for Science, Technology and Innovation, Danish Cancer Society, Gangsted Rasmussen Foundation, Rosalie Petersen Foundation, University Hospital Rigshospitalet's Fund for Cancer Rehabilitation, and the Otto Christensen Foundation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
The multivariate method PCA is an exploratory tool often used to get an overview of multivariate data, such as the quantified spot volumes of digitized 2-DE gels. PCA can reveal hidden structures ...present in the data, and thus enables identification of potential outliers and clustering. Based on PCA, we here present an approach for identification of protein spots causing 2-DE gels to become outliers. The approach can potentially obviate analytical exclusion of entire 2-DE gels.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Psoriasis is a chronic skin disease associated with lower quality of life and higher risk of anxiety and depression in adults. We investigate whether adolescents with psoriasis also experience poorer ...mental health than their peers.
In this cross-sectional study, we included questionnaire data on psoriasis and mental health from the 18-year follow-up of the Danish National Birth Cohort. We estimated odds ratios (OR) and 95 % confidence intervals (CI) using a logistic regression with inverse probability weighting to account for potential selection bias, adjusted for potential confounders identified a priori. We estimated associations between self-reported psoriasis and multiple aspects of mental health (self-rated health, life satisfaction, mental well-being, loneliness, overall and internalizing behavioral difficulties, depressive symptoms, and anxiety symptoms). In sensitivity analyses, we examined doctor-diagnosed psoriasis and psoriasis with and without joint pain.
Of the 44,838 included in this study, 1147 (2.6 %) reported psoriasis. Adolescents with psoriasis had a higher risk of nearly all outcomes, including depressive symptoms (OR 1.38; 1.19–1.58) and panic/agoraphobia among both males (OR 1.72; 1.33–2.19) and females (OR 1.60; 1.33–1.92). Associations attenuated when restricted to doctor-diagnosed psoriasis. Associations with poor mental health were mainly observed for adolescents with psoriasis also reporting joint pain.
We could not establish temporality and lacked data on joint pain in referents.
Psoriasis is associated with poor mental health in adolescents. This appears to be driven by adolescents with psoriasis also reporting joint pain and is less evident in those with a doctor-confirmed diagnosis.
•Psoriasis is associated with poor mental health in adolescents.•Even milder forms of psoriasis can impact young people's mental health.•Joint pain has a negative impact on the mental health of adolescents with psoriasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Background
Preterm birth is one of the most important contributors to neonatal mortality and morbidity. Experiencing stress during pregnancy may increase the risk of adverse birth outcomes, including ...preterm birth. This association has been observed in previous studies, but differences in measures used limit comparability.
Objective
The objective of the study was to investigate the association between two measures of maternal stress during pregnancy, life stress and emotional distress, and gestation duration.
Methods
Women recruited in the Danish National Birth Cohort from 1996 to 2002, who provided information on their stress level during pregnancy and expecting a singleton baby, were included in the study. We assessed the associations between the level of life stress and emotional distress in quartiles, both collected at 31 weeks of pregnancy on average, and the rate of giving birth using Cox regression within intervals of the gestational period.
Results
A total of 80,991 pregnancies were included. Women reporting moderate or high levels of life stress vs no stress had a higher rate of giving birth earlier within all intervals of gestational age (e.g. high level: 27–33 weeks: hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.04, 1.84; 34–36 weeks: 1.10, 95% CI 0.97, 1.25; 37–38 weeks: 1.21, 95% CI 1.15, 1.28). These associations between life stress and preterm birth were mainly driven by pregnancy worries. For emotional distress, a high level of distress was associated with shorter length of gestation in the preterm (27–33 weeks: 1.38, 95% CI 1.02, 1.86; 34–36 weeks: 1.05, 95% CI 0.91, 1.19) and early term (1.11, 95% CI 1.04, 1.17) intervals.
Conclusions
Emotional distress and life stress were shown to be associated with gestational age at birth, with pregnancy‐related stress being the single stressor driving the association. This suggests that reverse causality may, at least in parts, explain the earlier findings of stress as a risk factor for preterm birth.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
SUMMARY
We propose to model the cause-specific cumulative incidence function of multivariate competing risks data using a random effects model that allows for within-cluster dependence of both risk ...and timing. The model contains parameters that makes it possible to assess how the two are connected, e.g. if high-risk is related to early onset. Under the proposed model, the cumulative incidences of all failure causes are modeled and all cause-specific and cross-cause associations specified. Consequently, left-truncation and right-censoring are easily dealt with. The proposed model is assessed using simulation studies and applied in analysis of Danish register-based family data on breast cancer.
Background
Childhood cancer survivors have an increased risk of cardiovascular disease (CVD) and diabetes mellitus. Because diabetes is a potentially modifiable risk factor for CVD in the general ...population, it is important to understand how diabetes affects the risk of CVD among childhood cancer survivors.
Methods
This study examined the risk of CVD among survivors with diabetes and 142,742 population comparison subjects. From the national cancer registries of the 5 Nordic countries, 29,324 one‐year survivors of cancer diagnosed before the age of 20 years between 1968 and 2008 were identified. Study subjects were linked to the national hospital registers. The cumulative incidence of CVD was determined with competing risk methods. A Cox proportional hazards model was used to estimate the effects of diabetes and cancer on the hazard of CVD. The interaction between diabetes and cancer was analyzed.
Results
Diabetes was diagnosed in 324 of the 29,324 one‐year survivors, and CVD was diagnosed in 2108. The hazard of diabetes was 1.7 times higher among survivors than comparison subjects (hazard ratio HR, 1.7; 95% confidence interval CI, 1.5‐1.9), whereas the HR of CVD was 3.6 (95% CI, 3.3‐3.8) 1 to 15 years after the cancer diagnosis and 1.9 (95% CI, 1.8‐2.0) after more than 15 years. Individuals with diabetes had a 2.4 times higher hazard of CVD (95% CI, 2.1‐2.8) among both survivors and comparison subjects in comparison with individuals without diabetes.
Conclusions
Childhood cancer survivors with diabetes have a markedly increased risk of CVD in comparison with survivors without diabetes. However, diabetes does not increase the risk of CVD more in survivors than the general population.
Childhood cancer survivors with diabetes mellitus have a markedly increased risk of cardiovascular disease in comparison with survivors without diabetes mellitus. However, diabetes mellitus does not increase the risk of cardiovascular disease more in survivors than the general population.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BackgroundPreterm birth is the leading cause of perinatal morbidity and mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk ...factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence.Methods and findingsWe conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother-child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child's birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and adolescence (>14.0 to 19.0 years). GA was positively associated with BMI in the first decade of life, with the greatest increase in mean BMI z-score during early infancy (0.02, 95% confidence interval (CI): 0.00; 0.05, p < 0.05) per week of increase in GA, while in adolescence, preterm individuals reached similar levels of BMI (0.00, 95% CI: -0.01; 0.01, p 0.9) as term counterparts. The association between GA and overweight revealed a similar pattern of association with an increase in odds ratio (OR) of overweight from late infancy through mid-childhood (OR 1.01 to 1.02) per week increase in GA. By adolescence, however, GA was slightly negatively associated with the risk of overweight (OR 0.98 95% CI: 0.97; 1.00, p 0.1) per week of increase in GA. Although based on only four cohorts (n = 32,089) that reached the age of adolescence, data suggest that individuals born very preterm may be at increased odds of overweight (OR 1.46 95% CI: 1.03; 2.08, p < 0.05) compared with term counterparts. Findings were consistent across cohorts and sensitivity analyses despite considerable heterogeneity in cohort characteristics. However, residual confounding may be a limitation in this study, while findings may be less generalisable to settings in low- and middle-income countries.ConclusionsThis study based on data from infancy through adolescence from 16 cohort studies found that GA may be important for body size in infancy, but the strength of association attenuates consistently with age. By adolescence, preterm individuals have on average a similar mean BMI to peers born at term.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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