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A causal association of air pollution with mental diseases is an intriguing possibility raised in a Short Report just published in PLOS Biology. Despite analyses involving large data sets, the available evidence has substantial shortcomings, and a long series of potential biases may invalidate the observed associations. Only bipolar disorder shows consistent results, with similar effects across United States and Denmark data sets, but the effect has modest magnitude, appropriate temporality is not fully secured, and biological gradient, plausibility, coherence, and analogy offer weak support. The signal seems to persist in some robustness analyses, but more analyses by multiple investigators, including contrarians, are necessary. Broader public sharing of data sets would also enhance transparency. [ABSTRACT FROM AUTHOR]

Background: Tuberculous lymphadenitis (TBLA) is the most common extrapulmonary manifestation of tuberculosis (TB), often claimed to be reactivation. We aimed to describe the epidemiology of TBLA in Denmark, as it has not previously been investigated specifically although extrapulmonary TB has been associated with an increased long-term mortality and delays in the diagnosis. Methods: Register-based study of all patients notified with TBLA in Denmark from 2007 through 2016 utilizing six different nationwide registers. Patients were identified through the national TB surveillance register, and the diagnosis evaluated based on microbiology, pathology and/or clinical assessment. Results: In total, 13.5% (n = 489) of all TB patients in Denmark had TBLA with annual proportions from 9.4 to 15.7%. Most patients were immigrants between 25–44 years. Incidence rates ranged from as high as 1,014/100,000 for Nepalese citizens to as a low as 0.06/100,000 for Danes. Danes had a significant higher median age and significant more risk factors and comorbidities, as well as an increased overall mortality, compared with immigrants (p<0.05). A significant and much higher proportion of unique MIRU-VNTR genotypes were seen among TBLA patients compared to other TB manifestations. Conclusion: In Denmark, TBLA is a common manifestation of TB, especially in young immigrants from high-incidence countries. In Danes, it is a rare disease manifestation and associated with higher morbidity and mortality. To our knowledge, this is the first study suggesting that TBLA is predominantly associated with reactivation of latent TB infection based on genotyping although this remains to be clarified. [ABSTRACT FROM AUTHOR]

Background: People with multimorbidity have reduced functional capacity, lower quality of life, higher mortality rates and use healthcare resources more intensively than healthy people or those with a single chronic condition. Multimorbidity was defined as the coexistence of two or more chronic conditions in the same person. The aim of this study was to explore associations between multimorbidity and use of healthcare services and the impact of socioeconomic status on utilization of hospitalizations and bed days. Methods: The study population included all individuals aged 16 years and older who lived in the Capital Region of Denmark on January 1st, 2012. Data on chronic conditions, use of healthcare services and demographics were obtained from Danish national administrative and health registries. Zero-inflated models were used to calculate anticipated annual use of hospitalizations and bed days. Findings: The study population comprised 1,397,173 individuals; the prevalence of multimorbidity was 22%. Prevalence was inversely related to educational attainment. For people with multimorbidity, utilization of hospitalizations and bed days increased approximately linearly with the number of chronic conditions. However, a steep increase in utilization of bed days was observed between five and six or more chronic conditions. An educational gradient in hospitalization rates and use of bed days was observed regardless of the number of chronic conditions. Educational attainment was strongly associated with healthcare utilization. Conclusion: Multimorbidity was associated with a significant increase in utilization of all healthcare services in Denmark. In addition, a socioeconomic gradient was observed in utilization of hospitalizations and bed days. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection is prevalent among people in prison and prisons could therefore represent a unique opportunity to test risk groups for HCV. The aim of this sero-epidemiological study was to determine the incidence and prevalence of HCV infection and the corresponding risk factors in Danish prisons. Participants, recruited from eight Danish prisons, were tested for HCV using dried blood spots and filled out a questionaire with demographic data and risk factors for HCV infection. In total, 76.9% (801/1041) of all eligible prisoners consented to participate. The prevalence of HCV RNA positive prisoners was 4.2% (34/801) and the in-prison incidence rate was 0.7–1.0 per 100PY overall and 18-24/100PY among PWIDs. Infected prisoners were older than the overall population with a mean age of 42 years and only 17.6% (6/34) were younger than 35 years. The prevalence of PWID was 8.5% (68/801) and only 3% (2/68) of PWID were younger than 25 years. Among the PWID, 85.3% (58/68) had ever received opioid substitution therapy (OST) and 47.1% (32/68) were currently receiving OST. Risk factors associated with HCV infection were intravenous drug use, age ≥ 40 years, and being incarcerated ≥ 10 years. In conclusion, the prevalence of PWID in Danish prisons is low, possibly reflecting a decrease in injecting among the younger generation. This together with OST coverage could explain the low prevalence of HCV infection. However among PWIDs in prison the incidence remains high, suggesting a need for improved HCV prevention in prison. [ABSTRACT FROM AUTHOR]

Exploiting nation-wide data from the Danish National Birth Cohort, we show that children’s emotional and behavioral problems measured by the Strengths and Difficulties Questionnaire (SDQ) are closely related to their performance in standardized academic tests for reading and mathematics in sixth grade. The relationship is remarkably linear across the entire distribution for both the total difficulties score and subscale scores of the SDQ; higher scores on the SDQ (more problems) are related to worse performance in academic tests. We assess the similarity across respondent type; parent (child age 7 and 11), teacher (child age 11) and self-reported scores (child age 11), and find that teacher and parent reported scores have very similar slopes in the SDQ–test score relationship, while the child reported SDQ in relation to the academic test performance has a flatter slope. [ABSTRACT FROM AUTHOR]

Objective: Traumatic brain injury (TBI) is common and associated with a marked increased risk of developing epilepsy. Animal studies indicate that treatment with selective serotonin reuptake inhibitors (SSRIs) may increase the risk of epilepsy after TBI. The aim of this study was to investigate whether use of SSRIs modifies the risk of epilepsy after TBI. Methods: This was a cohort study of 205,715 persons, who suffered a TBI in Denmark from 1996 to 2013. For each person with TBI, we matched 10 reference persons (N = 2,057,150) who were alive on the day of TBI and who had the same age and gender but had no history of TBI. We used a stratified Cox regression to calculate the relative risk of epilepsy after TBI for persons exposed to TBI, SSRI or both after adjustment for income, civil status, medical and neurological comorbidities, severe mental disease, and substance abuse. Results: The risk of epilepsy was 5.61 times higher for persons who used SSRI at time of TBI (adjusted Hazard Ratio (aHR): 5.61 (95% CI: 4.88; 6.45)), 3.23 times higher for persons who had a TBI but did not use SSRI at time of TBI (aHR: 3.23 (95% CI: 3.12;3.35)), and 1.31 times higher for persons who used SSRI but had no TBI (aHR: 1.31 (95% CI: 1.18; 1.45)) compared to persons unexposed to both TBI and SSRI. Conclusions: This large population based cohort study showed that people using SSRI at the time of a TBI had higher risk of developing epilepsy compared to people not using SSRI at the time of TBI. The results are in line with those of animal studies and calls for further studies to evaluate whether the association is due to SSRIs or to the underlying disease (e.g. depression or anxiety). [ABSTRACT FROM AUTHOR]

Background: Despite improvements in treatment for rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (axSpA), several key unmet needs remain, such as fatigue. The objective of this study was to describe the severity of fatigue, disease characteristics and socioeconomic factors in people with RA, PsA and axSpA. Methods: The study was designed as a cross-sectional survey collecting patient characteristics such as disease characteristics, socioeconomic factors and fatigue in people with RA, PsA and axSpA in Denmark. Respondents were consecutively recruited for the study over a six-month period in 2018 via routine visits to outpatient rheumatology clinics. Study nurses collected information on diagnosis, current disease-related treatment and disease activity from medical journals. People were invited to complete a questionnaire related to socioeconomic factors and containing the FACIT-Fatigue subscale. Descriptive statistics were analyzed using SAS. Results: We invited 633 people to participate, and 488 (77%) completed the questionnaire. Women constituted 62% of respondents, and the mean age was 53.5 years. Respondents had on average been diagnosed between 11 and 15 years ago. Overall, 79% had no changes to their disease-related treatment during the past year, and the average disease activity as indicated by DAS28 for RA and PsA was 2.48 and 2.36, respectively, and BASDAI for axSpA was 28.40. Fatigue was present in all three diagnoses (mean: 34.31). The mean fatigue score varied from respondents answering that they suffered from no or little fatigue (mean: 45.48) to extreme fatigue (mean: 10.11). Analyses demonstrated that the respondents were not considerably different from nonrespondents, and the study population is considered representative compared with Danish RA and axSpA patients in the Danish National Rheumatology Registry, the DANBIO database. Conclusion: We found that the majority of the study population were fatigued (61%). They had low disease activity and few disease-related treatment changes. [ABSTRACT FROM AUTHOR]

Understanding predictors and trajectories of increased potassium may inform testing and treatment of hyperkalemia. We examined predictors for repeated hyperkalemia among patients after first-time renin angiotensin system inhibitor (RASi) prescription, chronic kidney disease (CKD), or chronic heart failure (CHF); and we also examined potassium trajectories in these patients after their first hyperkalemia event. We used Danish population-based registries to identify all patients with first-time RASi prescription, incident CKD, or incident CHF (2000–2012). For patients with a first hyperkalemia event, potassium trajectories over the following 6 months were examined. The predictors associated with repeated hyperkalemia were assessed, with repeated hyperkalemia defined as a potassium test >5.0 mmol/L after the first event within 6 months. Overall 262,375 first-time RASi users, 157,283 incident CKD patients, and 14,600 incident CHF patients were included. Of patients with a first hyperkalemia event, repeated hyperkalemia within 6 months occurred in 37% of RASi users, 40% with CKD, and 49% of patients with CHF. Predictors included severe hyperkalemia, low eGFR, diabetes, and spironolactone use. In all cohorts, the median potassium levels declined over 2–4 weeks after a hyperkalemia event for the first time, but reverted to levels higher than before the initial hyperkalemia event in those who had repeated hyperkalemia. Following hyperkalemia, discontinuation of RASi and spironolactone was common in the RASi and CHF cohorts. Repeated hyperkalemia was common among the explored cohorts. The first hyperkalemia event was an indicator of increased median potassium levels. Predictors may identify patients likely to benefit from intensified monitoring and intervention. [ABSTRACT FROM AUTHOR]

Background: Socioeconomic disparities in infant mortality have persisted for decades in high-income countries and may have become stronger in some populations. Therefore, new understandings of the mechanisms that underlie socioeconomic differences in infant deaths are essential for creating and implementing health initiatives to reduce these deaths. We aimed to explore whether and the extent to which preterm birth (PTB) and small for gestational age (SGA) at birth mediate the association between maternal education and infant mortality.Methods and Findings: We developed a population-based cohort study to include all 1,994,618 live singletons born in Denmark in 1981-2015. Infants were followed from birth until death, emigration, or the day before the first birthday, whichever came first. Maternal education at childbirth was categorized as low, medium, or high. An inverse probability weighting of marginal structural models was used to estimate the controlled direct effect (CDE) of maternal education on offspring infant mortality, further split into neonatal (0-27 days) and postneonatal (28-364 days) deaths, and portion eliminated (PE) by eliminating mediation by PTB and SGA. The proportion eliminated by eliminating mediation by PTB and SGA was reported if the mortality rate ratios (MRRs) of CDE and PE were in the same direction. The MRRs between maternal education and infant mortality were 1.63 (95% CI 1.48-1.80, P < 0.001) and 1.19 (95% CI 1.08-1.31, P < 0.001) for low and medium versus high education, respectively. The estimated proportions of these total associations eliminated by reducing PTB and SGA together were 55% (MRRPE = 1.27, 95% CI 1.15-1.40, P < 0.001) for low and 60% (MRRPE = 1.11, 95% CI 1.01-1.22, P = 0.037) for medium versus high education. The proportions eliminated by eliminating PTB and SGA separately were, respectively, 46% and 11% for low education (versus high education) and 48% and 13% for medium education (versus high education). PTB and SGA together contributed more to the association of maternal educational disparities with neonatal mortality (proportion eliminated: 75%-81%) than with postneonatal mortality (proportion eliminated: 21%-23%). Limitations of the study include the untestable assumption of no unmeasured confounders for the causal mediation analysis, and the limited generalizability of the findings to other countries with varying disparities in access and quality of perinatal healthcare.Conclusions: PTB and SGA may play substantial roles in the relationship between low maternal education and infant mortality, especially for neonatal mortality. The mediating role of PTB appeared to be much stronger than that of SGA. Public health strategies aimed at reducing neonatal mortality in high-income countries may need to address socially related prenatal risk factors of PTB and impaired fetal growth. The substantial association of maternal education with postneonatal mortality not accounted for by PTB or SGA could reflect unaddressed educational disparities in infant care or other factors. [ABSTRACT FROM AUTHOR]

We evaluate a bridging intervention for a group of young people aged 18–29, with no formal educational qualifications, who are not in employment, education or training. The bridging intervention consisted of classroom training, educational internships and mentoring. Based on Danish register data with a large number of control variables, a propensity score matching estimator was applied to assess the effectiveness of the bridging intervention. The results show that the bridging intervention was effective in increasing educational enrollment and completion for all participants. The effects of the intervention were particularly large for participants assessed to be ‘not ready for education’ and those diagnosed with psychiatric disorders suggesting that the bridging intervention may be especially beneficial for these subgroups. [ABSTRACT FROM AUTHOR]

Background: Suicide accounts for more than 800,000 annual deaths worldwide. Some of these deaths may be preventable by timely identification of individuals at risk and effective intervention. General practitioners (GPs) may have the potential to play an important role in this process. Aim: The present study aimed to assess the frequency of primary health care utilization in the year preceding suicide. Methods: Using Danish national registers, we identified all persons who died by suicide in Denmark from 1997 through 2013 and assessed the frequency of their primary care utilization and compared it with that of an age- and sex-matched reference group sampled from the background population. Results: We identified 11,191 persons who died by suicide (males: 8,095, females: 3,096). Compared with the reference group (N = 55,955), a greater proportion attended general practice in the year before index date (83% vs. 76%). In the last month before index date, these figures were 32.0% and 19.4%, respectively, corresponding to a difference of 12.0 95% CI: (11.1; 12.9) percentage points after adjustment for demographic characteristics and physical comorbidity. Suicide cases had a higher GP attendance in every week in the year before suicide, but the difference increased specifically in the last four months. Conclusion: More than 30% attended the GP in the month before the suicide. This indicates that general practice could be a possible place to identify suicide cases and offer intervention. However, although this proportion represents a markedly higher GP attendance than seen in the reference group, almost 70% of those who died by suicide did not attend primary care in the month before the suicide. Our study suggests that it is important that the GPs have easy access to effective suicide prevention programs for patients at risk of suicide, and that persons with suicidal thoughts are encouraged to contact their GP. [ABSTRACT FROM AUTHOR]

Objective: Breathing difficulties and respiratory diseases have been under-reported in Emergency Medical Services research, despite these conditions being prevalent with substantial mortality. Our aim was two-fold; 1) to investigate the diagnostic pattern and mortality among EMS patients to whom an ambulance was dispatched due to difficulty breathing, and 2) to investigate the initial symptoms and mortality for EMS patients diagnosed with respiratory diseases in hospital. Methods: Population-based historic cohort study in the North Denmark Region 2012–2015. We included two patient groups; 1) patients calling the emergency number with breathing difficulty as main symptom, and 2) patients diagnosed with respiratory diseases in hospital following an emergency call. Main outcome was estimated 1- and 30-day mortality rates. Results: There were 3803 patients with the symptom breathing difficulty, nearly half were diagnosed with respiratory diseases 47.3%, followed by circulatory diseases 13.4%, and symptoms and signs 12.0%. The 1-day mortality rate was highest for circulatory diseases, then respiratory diseases and other factors. Over-all 30-day mortality was 13.2%, and the highest rate was for circulatory diseases (17.7%) then respiratory diseases and other factors. A total of 4014 patients were diagnosed with respiratory diseases, 44.8% had the symptom breathing difficulty, 13.4% unclear problems and 11.3%. chest pain/heart disease. 1-day mortality rates were highest for decreased consciousness, then breathing difficulties and unclear problem. Over-all 30-day mortality rates were 12.5%, the highest with symptoms of decreased consciousness (19.1%), then unclear problem and breathing difficulty. There was an overlap of 1797 patients between the two groups. Conclusions: The over-all mortality rates alongside the distribution of symptoms and diagnoses, suggest the breathing difficulty patient group is complex and has severe health problems. These findings may be able to raise awareness towards the patient group, and thereby increase focus on diagnostics and treatment to improve the patient outcome. [ABSTRACT FROM AUTHOR]

We present a questionnaire-based measure of four animal ethics orientations. The orientations, which were developed in light of existing empirical studies of attitudes to animal use and ethical theory, are: animal rights, anthropocentrism, lay utilitarianism, and animal protection. The two latter orientations can be viewed as variants of animal welfarism. Three studies were conducted in Denmark in order to identify the hypothesised orientations, evaluate their concurrent validity, and report their prevalence and relevance in animal-related opinion formation and behaviour. Explorative factor analysis (Study 1) and confirmative factor analysis (Study 2) successfully identified the four orientations. Study 2 revealed good measurement invariance, as there was none or very modest differential item functioning across age, gender, living area, and contrasting population segments. Evaluation of concurrent validity in Study 2 found that the orientations are associated with different kinds of behaviour and opinion when the human use of animals is involved in the hypothesised directions. In Study 3, a representative population study, the animal protection orientation proved to be most prevalent in the Danish population, and as in study 2 the four orientations were associated with different behaviours and opinions. Remarkably, the animal protection orientation does not lead to increased animal welfare-friendly meat consumption, the main reason for this being non-concern about the current welfare status of farm animals. We argue that the developed measure covers a wide range of diversity in animal ethics orientations that is likely to exist in a modern society such as Denmark and can be used in future studies to track changes in the orientations and to understand and test hypotheses about the sources and justifications of people’s animal-related opinions and behaviours. [ABSTRACT FROM AUTHOR]

Background: In Denmark, the cesarean section rate has increased by 49% between 1998 and 2015 and accounts for 21% of all births. Cesarean sections may cause short- as well as long-term consequences for both the mother and the child and impose further risks in future pregnancies. Delaying pregnancy until advanced maternal age at childbirth has been suggested as contributing to the increase. The proportion of women giving birth at 35 years or above increased from 15% (1998) to 21% (2015). Advanced maternal age at childbirth has been found to be related to increased pre-pregnancy morbidity and associated risk factors that may contribute to an increased risk of cesarean section. The aim of this study was to examine the association between advanced maternal age and cesarean section in a Danish population and the influence of demographic, anthropometric, health, and obstetric factors on this association. Methods: This study draws on a national population-based cohort study of all Danish births between 1998 and 2015 (N = 1,122,964). Maternal age less than 30 years serves as reference with the following age categories: (30–34 years); (35–39 years), and (40 years and above). The primary outcome was a cesarean section. Multivariate regression models with adjustment for demographic, health, pregnancy, fetal, and obstetric characteristics were performed with the results further stratified by parity. Results: In general, a positive association between advanced maternal age and cesarean section was found. Only minor changes in the risk estimate occurred after adjustment for relevant confounders. In comparison with the reference category, nulliparous women aged 35-39- years had twice the risk for cesarean section (adjusted odds ratio (AOR) 2.18, 95% confidence interval (CI) [2.11–2.26]) whereas for women of 40 years or above, the risk was more than tripled (AOR 3.64, 95% CI [3.41–3.90]). For multiparous women aged 35-39-years the risk was more moderate, but still with an AOR of 1.56, 95% CI [1.53–1.60], and for those 40 years and above, the AOR was 2.02, 95% CI [1.92–2.09]. Conclusions: Overall, cesarean section increased with increasing maternal age. Adjustment for maternal and obstetric risk factors had only a minor influence on the association. The association was stronger in nulliparous women compared to multiparous women. Given the lack of impact of demographic and health risks on the relationship between maternal age and cesarean section, the authors suggest obstetric culture could be added to the list of risk factors for a cesarean. Future research on obstetric culture is recommended as are studies on a possible age-related decrease in the ability to maintain the progression of labor. Trial registration: The study uses depersonalized register data and has been approved by the Danish Data Protection Agency (2015-41-4168). [ABSTRACT FROM AUTHOR]

As dog bite injuries are a considerable problem in modern society, in order to reduce such injuries, breed-specific legislation has been introduced in a number of countries. Whilst many studies have shown a lack of effect with such legislation, the commonly used methodology is known to be flawed. Therefore, the aim of this study is to investigate the effect of the Danish breed-specific legislation on the number of dog bite injuries using more credible methods. A time series intervention method was used on a detailed dataset from Odense University Hospital, Denmark, regarding dog bite injuries presented to the emergency department. The results indicate that banning certain breeds has a highly limited effect on the overall levels of dog bite injuries, and that an enforcement of the usage of muzzle and leash in public places for these breeds also has a limited effect. Despite using more credible and sound methods, this study supports previous studies showing that breed-specific legislation seems to have no effect on dog bite injuries. In order to minimise dog bite injuries in the future, it would seem that other interventions or non-breed-specific legislation should be considered as the primary option. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) haplogroups (hgs) are evolutionarily conserved sets of mtDNA SNP-haplotypes with characteristic geographical distribution. Associations of hgs with disease and physiological characteristics have been reported, but have frequently not been reproducible. Using 418 mtDNA SNPs on the PsychChip (Illumina), we assessed the spatio-temporal distribution of mtDNA hgs in Denmark from DNA isolated from 24,642 geographically un-biased dried blood spots (DBS), collected from 1981 to 2005 through the Danish National Neonatal Screening program. ADMIXTURE was used to establish the genomic ancestry of all samples using a reference of 100K+ autosomal SNPs in 2,248 individuals from nine populations. Median-joining analysis determined that the hgs were highly variable, despite being typically Northern European in origin, suggesting multiple founder events. Furthermore, considerable heterogeneity and variation in nuclear genomic ancestry was observed. Thus, individuals with hg H exhibited 95%, and U hgs 38.2% - 92.5%, Danish ancestry. Significant clines between geographical regions and rural and metropolitan populations were found. Over 25 years, macro-hg L increased from 0.2% to 1.2% (p = 1.1*E-10), and M from 1% to 2.4% (p = 3.7*E-8). Hg U increased among the R macro-hg from 14.1% to 16.5% (p = 1.9*E-3). Genomic ancestry, geographical skewedness, and sub-hg distribution suggested that the L, M and U increases are due to immigration. The complex spatio-temporal dynamics and genomic ancestry of mtDNA in the Danish population reflect repeated migratory events and, in later years, net immigration. Such complexity may explain the often contradictory and population-specific reports of mito-genomic association with disease. [ABSTRACT FROM AUTHOR]

Fatty acids in adipose tissue share dietary sources and metabolic pathways and therefore occur in patterns. The aim of the present study was to investigate the association between adipose tissue fatty acid patterns identified by the data-driven dimension-reducing method treelet transform and the risk of atrial fibrillation. A total of 57,053 Danish men and women aged 50–64 years participating in the Diet, Cancer and Health cohort had an adipose tissue biopsy taken at baseline. During a median follow-up of 14.6 years, a total of 4,710 participants developed atrial fibrillation or atrial flutter. Adipose tissue biopsies were analysed for fatty acid content by gas chromatography for all cases of atrial fibrillation and for a randomly drawn subcohort (n = 3,500) representative for the entire cohort. Hazard ratios with 95% confidence intervals for atrial fibrillation according to quintiles of factor scores were determined by weighted Cox proportional hazards regression analyses for men and women separately. From the 32 fatty acids measured, 7 major factors/patterns of fatty acids were identified using treelet transform. We found that a pattern consisting of n-6 polyunsaturated fatty acids (PUFA) (except linoleic acid) was associated with a lower hazard of atrial fibrillation. Patterns consisting of marine n-3 PUFA and containing n-9 fatty acids were associated with a lower hazard of atrial fibrillation in women. In conclusion, patterns of fatty acids in adipose tissue identified by treelet transform may be differentially associated with the risk of atrial fibrillation. [ABSTRACT FROM AUTHOR]

Mitochondria play a significant role in human diseases. However, disease associations with mitochondrial DNA (mtDNA) SNPs have proven difficult to replicate. An analysis of eight schizophrenia-associated mtDNA SNPs, in 23,743 Danes without a psychiatric diagnosis and 2,538 schizophrenia patients, revealed marked inter-allelic differences in mitochondrial haplogroup affiliation and nuclear ancestry. This bi-genomic dependence could entail population stratification. Only two mitochondrial SNPs, m.15043A and m.15218G, were significantly associated with schizophrenia. However, these associations disappeared when corrected for haplogroup affiliation and nuclear ancestry. The extensive bi-genomic dependence documented here is a major concern when interpreting historic, as well as designing future, mtDNA association studies. [ABSTRACT FROM AUTHOR]

The Parental Stress Scale (PSS) was developed as a short measure of perceived stress resulting from being a parent. The current study examined the psychometric properties of the Danish version in a sample of 1110 mothers of children aged 0 to 12 months using Rasch models. Emphasis was placed on the issues of uni-dimensionality and absence of differential item functioning relative to the age and educational level of the mothers. Results showed that no adequate fit could be established for the full PSS scale with 18 dichotomized items. Further analyses showed that items 2 and 11 had to be eliminated from the scale, and that the remaining items did not make up a unidimensional PSS scale, but two subscales measuring different aspect of parental stress: a 9-item scale measuring parental stress and a 7-item scale measuring lack of parental satisfaction. Fit to the Rasch model could not be established for any of the two subscales. For the parental stress subscale, we found evidence of local dependence for four item pairs (3 and 4, 9 and 10, 10 and 16, 12 and 16), as well as evidence of two items functioning differentially: item 16 relative to level of education, and item 3 relative to both age and educational level. For the lack of parental satisfaction subscale, we found evidence of local dependence between some two pairs (1 and 17, 17 and 18), but no evidence of differential item functioning. Both subscales fit graphical loglinear Rasch models adjusting for local dependence and differential item functioning. Plotting the adjusted subscale scores against one another showed that the two-scale solution provides additional information, as some mothers are stressed but not lacking in parental satisfaction. [ABSTRACT FROM AUTHOR]

Background: Consumption of meat prepared by barbecuing is associated with risk of cancer due to formation of carcinogenic compounds including benzo[a]pyrene (BaP). Assessment of a population’s risk of disease and people’s individual probability of disease given specific consumer attributes may direct food safety strategies to where impact on public health is largest. The aim of this study was to propose a model that estimates the risk of cancer caused by exposure to BaP from barbecued meat in Denmark, and to estimate the probability of developing cancer in subgroups of the population given different barbecuing frequencies. Methods: We developed probabilistic models applying two dimensional Monte Carlo simulation to take into account the variation in exposure given age and sex and in the individuals’ sensitivity to develop cancer after exposure to BaP, and the uncertainty in the dose response model. We used the Danish dietary consumption survey, monitoring data of chemical concentrations, data on consumer behavior of frequency of barbecuing, and animal dose response data. Findings: We estimated an average extra lifetime risk of cancer due to BaP from barbecued meat of 6.8 × 10−5 (95% uncertainty interval 2.6 × 10−7 − 7.0 × 10−4) in the Danish population. This corresponds to approximately one to 4,074 extra cancer cases over a lifetime, reflecting wide uncertainty. The impact per barbecuing event on the risk of cancer for men and women of low body weight was higher compared to higher bodyweight. However, the difference due to sex and bodyweight between subgroups are dwarfed by the uncertainty. Interpretation: This study proposes a model that can be applied to other substances and routes of exposure, and allows for deriving the change in risk following a specific change in behaviour. The presented methodology can serve as a valuable tool for risk management, allowing for the formulation of behaviour advice targeted to specific sub-groups in the population. [ABSTRACT FROM AUTHOR]

We provide an estimate of the effect of refugees’ length of waiting time in the Danish asylum system on their subsequent employment using administrative data. In contrast to previous studies, we take into account that refugees’ labor market integration is delayed since their labor market access is restricted during the asylum-seeking phase. We find that an additional year of waiting time decreases subsequent employment by 3.2 percentage points on average. This effect is mostly driven by the delay in the labor market engagement among refugees. Waiting time may have an effect on subsequent employment that is additional to the delay effect, and this could be either positive or negative depending on the nature of the conditions under which asylum seekers live while waiting for their cases to be processed. We find that this additional effect is positive and statistically significant until observable individual characteristics are included, at which point it becomes small in magnitude and no longer significant. [ABSTRACT FROM AUTHOR]

Background: Neutropenia increases the risk of infection, but it is unknown if this also applies to lymphopenia. We therefore tested the hypotheses that lymphopenia is associated with increased risk of infection and infection-related death in the general population.Methods and Findings: Of the invited 220,424 individuals, 99,191 attended examination. We analyzed 98,344 individuals from the Copenhagen General Population Study (Denmark), examined from November 25, 2003, to July 9, 2013, and with available blood lymphocyte count at date of examination. During a median of 6 years of follow-up, they developed 8,401 infections and experienced 1,045 infection-related deaths. Due to the completeness of the Danish civil and health registries, none of the 98,344 individuals were lost to follow-up, and those emigrating (n = 385) or dying (n = 5,636) had their follow-up truncated at the day of emigration or death. At date of examination, mean age was 58 years, and 44,181 (44.9%) were men. Individuals with lymphopenia (lymphocyte count < 1.1 × 109/l, n = 2,352) compared to those with lymphocytes in the reference range (1.1-3.7 × 109/l, n = 93,538) had multivariable-adjusted hazard ratios of 1.41 (95% CI 1.28-1.56) for any infection, 1.31 (1.14-1.52) for pneumonia, 1.44 (1.15-1.79) for skin infection, 1.26 (1.02-1.56) for urinary tract infection, 1.51 (1.21-1.89) for sepsis, 1.38 (1.01-1.88) for diarrheal disease, 2.15 (1.16-3.98) for endocarditis, and 2.26 (1.21-4.24) for other infections. The corresponding hazard ratio for infection-related death was 1.70 (95% CI 1.37-2.10). Analyses were adjusted for age, sex, smoking status, cumulative smoking, alcohol intake, body mass index, plasma C-reactive protein, blood neutrophil count, recent infection, Charlson comorbidity index, autoimmune diseases, medication use, and immunodeficiency/hematologic disease. The findings were robust in all stratified analyses and also when including only events later than 2 years after first examination. However, due to the observational design, the study cannot address questions of causality, and our analyses might theoretically have been affected by residual confounding and reverse causation. In principle, fluctuating lymphocyte counts over time might also have influenced analyses, but lymphocyte counts in 5,181 individuals measured 10 years after first examination showed a regression dilution ratio of 0.68.Conclusions: Lymphopenia was associated with increased risk of hospitalization with infection and increased risk of infection-related death in the general population. Notably, causality cannot be deduced from our data. [ABSTRACT FROM AUTHOR]

Introduction: Intervening effectively to prevent students’ harmful use of alcohol remains a challenge. Harmful alcohol use has been noted as the most dominant public health problem facing universities today. This study sought to investigate the diversity in staff and student perceptions of the contribution alcohol makes to student life in a Danish university setting. Increasing understanding of staff and students’ perceptions of how alcohol fits into student life is required to amend future public health intervention for this population. Materials and methods: This Q methodology study included 38 staff members and 105 students from Aarhus University, Denmark. Participants used online Q sorting software, to rank 40 statements about the contribution alcohol makes to the university student experience from strongly agree to disagree. To support the interpretation of the factors, self-reported alcohol consumption and demographic data were collected. In addition qualitative data was collected on the participant’s reasons for the ranking of the items they most strongly agreed or disagreed with. Results and discussion: Using principal components analysis, five statistically independent viewpoints for students and four for staff were identified. The findings provide evidence to inform approaches to prevent harmful alcohol use. Some viewpoints suggest a need for tailored secondary and tertiary prevention and intervention that focusses on individuals and/or sub-groups who are at risk of consuming alcohol at harmful levels. Other viewpoints suggest the need for primary universal prevention to support the maintenance of healthy norms which can prevent harmful alcohol behaviour. Public health campaigns need to ensure that interventions targeting harmful alcohol use at universities challenge problematic perceptions and attitudes while also bolstering exposure to positive norms. [ABSTRACT FROM AUTHOR]

Background and purpose: National dietary guidelines are intended to promote primary prevention of lifestyle-related diseases, but little is known about their effectiveness in prevention of stroke. Methods: We used the Danish cohort Diet, Cancer and Health (n = 57 053) to investigate whether adherence to the Danish food-based dietary guidelines was associated with risk of stroke. Adherence was assessed by the Danish Dietary Guidelines Index, score 0 [no adherence] to 6 [complete adherence]. Cox proportional hazards models were used to estimate adjusted hazard ratios and 95% confidence intervals for stroke and subtypes of stroke in men and women separately. Results: Incident stroke was determined in 1357 men and 900 women during follow-up (median 12.5 years and 13.0 years, respectively). A higher Danish Dietary Guidelines Index score was inversely associated with total stroke in men but not in women. In men, a high Index score (≥4) was also inversely associated with total ischemic stroke (hazard ratio 0.75, 95% confidence interval 0.65–0.86), large-artery atherosclerosis (hazard ratio 0.63, 95% confidence interval 0.44–0.92) and small artery occlusion (hazard ratio 0.68, 95% confidence interval 0.54–0.84) compared to a low Index score (<4). In women, inverse associations were found for total ischemic stroke (hazard ratio 0.84, 95% confidence interval 0.72–0.98) and intracerebral hemorrhage (hazard ratio 0.64, 95% confidence interval 0.43–0.96). Conclusions: Our findings suggest that adherence to the Danish Dietary Guidelines is associated with a lower rate of stroke, and thus may be useful in primary prevention of disease. [ABSTRACT FROM AUTHOR]

Purpose: To describe the use of antimuscarinic drugs to treat overactive bladder (OAB) in Denmark, Sweden, and the United Kingdom (UK). Methods: We identified new users of darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium aged 18 years or older from the Danish National Registers (2004–2012), the Swedish National Registers (2006–2012), and UK Clinical Practice Research Datalink (2004–2012). Users were followed until disenrollment, cancer diagnosis, death, or study end. Treatment episodes, identified by linking consecutive prescriptions, were described with respect to duration, drug switch, and drug add-on. Results: Mean age of OAB drug users was 66 years in Denmark (n = 72,917) and Sweden (n = 130,944), and 62 years in the UK (n = 119,912); 60% of Danish and Swedish patients and 70% of UK patients were female. In Denmark, of 224,680 treatment episodes, 39% were with solifenacin, and 35% with tolterodine; 2% were with oxybutynin. In Sweden, of 240,141 therapy episodes, 37% were with tolterodine and 35% with solifenacin; 5% were with oxybutynin. In the UK, of 245,800 treatment episodes, 28% were with oxybutynin, 27% with solifenacin, and 26% with tolterodine. In the three countries, 49%-52% of treatment episodes comprised one prescription and over 80% of episodes ended because of no refill; less than 20% ended because of a switch to another antimuscarinic. During the study years, we observed a change in OAB treatment preference from tolterodine to solifenacin. Conclusions: In these cohorts, persistence with antimuscarinic drugs was low. By 2012, the preferred drug was solifenacin; oxybutynin use was marginal in Nordic countries compared with the UK. [ABSTRACT FROM AUTHOR]

Background: Previous studies have investigated physical and psychosocial job exposures separately in relation to foetal growth. We therefore investigated if occupational lifting and psychosocial job strain interact to affect foetal growth and gestational length. We hypothesised that heavy lifting and high job strain would increase the risk of impacted foetal growth (small or large for gestational age) and preterm birth. Methods: The cohort included 47,582 pregnancies from the Danish National Birth Cohort (1996–2002), where the woman was pregnant at 22 gestational weeks (GW), expected one child and worked ≥30 hours/week. Information on occupational lifting and psychosocial job strain was derived from an interview (16±3.0 GW). Data to calculate small and large for gestational age (SGA/LGA) and gestational length was retrieved from the Medical Birth Register. Interaction between lifting and job strain (Karasek’s model) was analysed by multinomial logistic regression. Results: Overall, the adjusted regression analysis showed statistically significant interaction between lifting and job strain for SGA and LGA. For each additional 250 kg lifted/day, high strain women (high Demand/low Control) had increased odds of giving birth to a LGA-child (OR = 1.15; 95% CI 1.06–1.26), whereas women in the active group (high Demand/high Control) had increased odds of giving birth to a SGA child (OR = 1.12; 95% CI 1.03–1.23). When women lifting ≤1000 kg/day were excluded in the sensitivity analyses the interaction between lifting and job strain became insignificant. No interaction of lifting and job strain was found for gestational length. Conclusions: The main findings may give some support to our hypothesis, as lifting in combination high with job strain increased the risk of giving birth to a LGA child. This finding was, however, not supported in the sensitivity analysis and no association of the interaction was found relative to gestational length. [ABSTRACT FROM AUTHOR]

It is unknown whether urban versus rural residency affects pancreatic cancer survival in a universal tax-financed healthcare system. We conducted a nationwide, population-based cohort study of all patients diagnosed with pancreatic cancer in Denmark from 2004–2015. We used nationwide registries to collect information on characteristics, comorbidity, cancer-directed treatment, and vital status. We followed the patients from pancreatic cancer diagnosis until death, emigration, or 1 October 2017, whichever occurred first. We truncated at five years of follow up. We stratified patients into calendar periods according to year of diagnosis (2004–2007, 2008–2011, and 2012–2015). We used Cox proportional hazards model to compute hazard ratios (HRs) with associated 95% confidence intervals (CIs) of death, comparing patients in urban and rural areas. HRs were adjusted for age, sex, comorbidity, tumor stage, and localization. In a sub-analysis, we also adjusted for cancer-directed treatment. We included 10,594 patients diagnosed with pancreatic cancer. Median age was 71 years (inter-quartile range: 63–78 years), and half were men. The majority (61.7%) lived in an urban area at the time of diagnosis. When adjusting for potential confounders, we observed a better survival rate among pancreatic cancer patients residing in urban areas compared with rural areas (adjusted HR: 0.92; 95% CI: 0.87–0.98). When taking treatment into account, the association was unclear (adjusted HR: 0.96; 95% CI: 0.88–1.04). Pancreatic cancer patients residing in urban areas had a slightly better survival rate compared with patients in rural areas. [ABSTRACT FROM AUTHOR]

Background: Cerebral palsy (CP) is the most common physical developmental disability in childhood with a prevalence of 2 to 3 per 1000 live births. β2-adrenoreceptor agonist (β2AA) are widely used for the treatment of asthma. Maternal use of β2AAs may increase the risk of adverse neuro-psychiatric health outcomes in the offspring. No study, however, has evaluated the effect of prenatal exposure to β2AAs on the risk of CP. Objective: To examine the association between prenatal exposure to β2AAs and the risk of childhood cerebral palsy. Methods: This population-based cohort study included all live singleton births in Denmark from January 1, 1997 to December 31, 2003. The information on outpatient prescriptions of β2AAs was extracted from Danish National Prescription Registry. Children born to mothers who used β2AAs from 30 days before pregnancy until delivery were categorized as the exposed. To differentiate the effect of β2AAs from the underlying indications, the exposure window was further extended to 2 years before pregnancy and the exposed groups were re-defined to represent different periods of exposure to maternal use of β2AAs (use only before pregnancy, use only during pregnancy, and use both before and during pregnancy). Cases of CP were identified from the Danish Cerebral Palsy Register. Logistic regression was used to estimate incidence odds ratio (OR) of CP. Results: Among all the 442,278 singletons, 19,616 (4.44%) were exposed to β2AAs in utero (from 30 days before pregnancy until delivery). The risk of childhood CP was 0.21% in exposed and 0.19% in unexposed group, yielding an adjusted OR (aOR) 1.12 (95% confidence interval (CI): 0.82, 1.53). When extending the exposure time window to 2 years prior to pregnancy, no overall significant association was observed regardless of the exposure period. However, an increased risk of CP (aOR = 1.41, 95%CI: 0.92, 2.18) for maternal β2AAs use during pregnancy was observed in female offspring, especially in those born at term (aOR = 1.65, 95%CI: 1.02, 2.67). This increase was mainly attributed to an increased risk in those born to mothers who used β2AAs both before and during pregnancy (aOR = 1.81, 95%CI: 0.99, 3.33). Conclusions: We observed an association between maternal β2AAs use during pregnancy and an increased risk of CP in female offspring, but we could not rule out confounding by the underlying indications for β2AAs. [ABSTRACT FROM AUTHOR]

Patient registry data are commonly collected as annual snapshots that need to be amalgamated to understand the longitudinal progress of each patient. However, patient identifiers can either change or may not be available for legal reasons when longitudinal data are collated from patients living in different countries. Here, we apply astronomical statistical matching techniques to link individual patient records that can be used where identifiers are absent or to validate uncertain identifiers. We adopt a Bayesian model framework used for probabilistically linking records in astronomy. We adapt this and validate it across blinded, annually collected data. This is a high-quality (Danish) sub-set of data held in the European Cystic Fibrosis Society Patient Registry (ECFSPR). Our initial experiments achieved a precision of 0.990 at a recall value of 0.987. However, detailed investigation of the discrepancies uncovered typing errors in 27 of the identifiers in the original Danish sub-set. After fixing these errors to create a new gold standard our algorithm correctly linked individual records across years achieving a precision of 0.997 at a recall value of 0.987 without recourse to identifiers. Our Bayesian framework provides the probability of whether a pair of records belong to the same patient. Unlike other record linkage approaches, our algorithm can also use physical models, such as body mass index curves, as prior information for record linkage. We have shown our framework can create longitudinal samples where none existed and validate pre-existing patient identifiers. We have demonstrated that in this specific case this automated approach is better than the existing identifiers. [ABSTRACT FROM AUTHOR]

Objectives: Several studies suggest a relationship between gestational age at birth and risk of school difficulties. Our study aimed to investigate the association between the entire range of gestational ages and significant school difficulties measured as 1) More than nine hours per week special educational support and 2) Failing to complete compulsory school. Methods: A population-based register study including all children attending the Danish compulsory school in 2015/2016 and all live-born infants born in Denmark from 1992 to 1997. Data were collected and linked using multiple registers held by Statistic Denmark. Multiple logistic regression analyses were used to estimate the association between gestational age and significant school difficulties, adjusted for explanatory variables. Results: For measurement 1) “Special educational support” 615,789 children entered the analyses after exclusion of those with missing neonatal data. The risk of special educational support increased gradually across the entire range of gestation from 40 to ≤24 weeks: The adjusted odds ratio was 1.07 (95% confidence interval 1.03–1.12) at 39 weeks of gestational and 6.18 (95% confidence interval 5.17–7.39) at gestational ages < 28 weeks. For measurement 2) “Failing to complete compulsory school” the cohort consisted of 374,798 children after exclusion of those who died, had emigrated and/or had missing neonatal data. The risk of failing to complete compulsory school increased across the entire range of gestational ages: The adjusted odds ratio was 1.07 (95% confidence interval 1.04–1.10) at 39 weeks of gestation and 2.99 (95% confidence interval 2.41–3.71) at gestational ages < 28 weeks. In both sets of analyses GA = 40 weeks was used as reference. Conclusions: We confirm a clear association between the degree of prematurity and significant school difficulties across the entire range of gestational ages from ≤ 24 to 40 weeks. [ABSTRACT FROM AUTHOR]

Background and aim: Long standing vitamin D deficiency in children causes rickets with growth impairment. We investigated whether sub-ischial leg length (SLL) is shorter, and cephalo-caudal length:length (CCL:L) ratio and sitting height:height (SH:H) ratio larger, with lower cord s-25-hydroxyvitamin D (25OHD) in the population-based prospective Odense Child Cohort, Denmark. Methods: We included healthy singletons born to term with available measures of cord 25OHD and anthropometrics up to three years’ age. Linear regression was stratified by sex a priori and adjusted for maternal ethnicity, pre-pregnancy body mass index and smoking during pregnancy, season of blood sampling and child age. Results: Median (IQR) cord 25OHD was 48.0 (34.0–62.4) nmol/L. At mean age 19.1 months, n = 504, mean (SD) SLL was 31.7 (1.7) cm; CCL:L-ratio 0.62 (0.01). At 36.3 months, n = 956, mean SLL was 42.9 (2.0) cm; SH:H-ratio 0.56 (0.01). No participants had rickets. In adjusted analyses, 19-months-old boys had 0.1 cm shorter SLL (p = 0.009) and 0.1% higher CCL:L-ratio (p = 0.04) with every 10 nmol/L increase in cord 25OHD. Similar findings were seen for late pregnancy 25OHD. In the highest cord 25OHD quartile (>60.7 nmol/L), SLL was 0.8 cm shorter (95% C.I.: 1.36;-0.29, linear trend, p = 0.004), and CCL:L-ratio 0.8% higher (95% C.I. 8.0x10-05;0.01, linear trend, p = 0.01), compared to lowest quartile (<30.7 nmol/L). Similar associations with cord 25OHD were observed in 3-year-old boys. No consistent associations between 25OHD and anthropometrics were seen in girls at either age. Conclusion: No leg shortening was found with decreasing cord s-25OHD in a healthy population of infants. A small, yet significant inverse association between cord 25OHD and SLL in boys 1½-3 years warrants further investigations. [ABSTRACT FROM AUTHOR]

Preeclampsia is a major cause of maternal and perinatal deaths. The aetiology of preeclampsia is largely unknown but a polygenetic component is assumed. To explore this hypothesis, we performed an in-depth whole-exome sequencing study in women with (cases, N = 50) and without (controls, N = 50) preeclampsia. The women were identified in an unselected cohort of 2,545 pregnant women based on data from the Danish National Patient Registry and the Medical Birth Registry. Matching DNA was obtained from a biobank containing excess blood from routine antenatal care visits. Novogene performed the whole-exome sequencing blinded to preeclampsia status. Variants for comparison between cases and controls were filtered in the Ingenuity Variant Analysis software. We applied two different strategies; a disease association panel approach, which included variants in single genes associated with established clinical risk factors for preeclampsia, and a gene panel approach, which included biological pathways harbouring genes previously reported to be associated with preeclampsia. Variant variability was compared in cases and controls at the level of biological processes, signalling pathways, and in single genes. Regardless of the applied strategy and the level of variability examined, we consistently found positive correlations between variant numbers in cases and controls (all R2s>0.88). Contrary to what was expected, cases carried fewer variants in biological processes and signalling pathways than controls (all p-values ≤0.02). In conclusion, our findings challenge the hypothesis of a polygenetic aetiology for preeclampsia with a common network of susceptibility genes. The greater genetic diversity among controls may suggest a protective role of genetic diversity against the development of preeclampsia. [ABSTRACT FROM AUTHOR]

Background: Metformin constitutes first-line treatment of type 2 diabetes mellitus. It is presumed to have lactic acidosis as a dangerous, but rare, side effect. Objectives: To estimate the incidence rate of lactic acidosis in patients with type 2 diabetes mellitus as well as to estimate the relative risk of lactic acidosis associated with metformin treatment. Methods: This is a population-based combined cohort and case-control study among patients with type 2 diabetes mellitus who were acutely admitted with lactic acidosis at Odense University Hospital, Denmark; in the period from 1st June 2009 to 1st October 2013. The patients included as cases were all acutely hospitalized with lactic acidosis (pH <7.35 and lactate ≥2.0 mmol/l). For each case, we identified 24 age- and sex-matched controls sampled from the same cohort with type 2 diabetes mellitus. The use of metformin identified by using a prescription database. Analyses included multivariable logistic regression and adjusting for predefined confounding: renal function, HbA1c, comorbidity and diabetes duration. Results: Our cohort included 10,652 patients with type 2 diabetes mellitus with a median age of 74 years, and 51.5% were male. During follow-up, 163 individuals were hospitalized with lactic acidosis, corresponding to an incidence rate of 391/100,000 person years. Use of metformin was not associated with lactic acidosis: adjusted odds ratio was 0.79 (95%CI 0.54–1.17). Conclusion: Among patients with type 2 diabetes mellitus, the incidence rate of acute hospitalization with lactic acidosis was 391/100,000 person years. Use of metformin did not increase the risk of lactic acidosis. However, comorbidity seems to be an important risk factor. [ABSTRACT FROM AUTHOR]

Genetic biomarkers are sought to personalize treatment of patients with rheumatoid arthritis (RA), given their variable response to TNF inhibitors (TNFi). However, no genetic biomaker is yet sufficiently validated. Here, we report a validation study of 18 previously reported genetic biomarkers, including 11 from GWAS of response to TNFi. The validation was attempted in 581 patients with RA that had not been treated with biologic antirheumatic drugs previously. Their response to TNFi was evaluated at 3, 6 and 12 months in two ways: change in the DAS28 measure of disease activity, and according to the EULAR criteria for response to antirheumatic drugs. Association of these parameters with the genotypes, obtained by PCR amplification followed by single-base extension, was tested with regression analysis. These analyses were adjusted for baseline DAS28, sex, and the specific TNFi. However, none of the proposed biomarkers was validated, as none showed association with response to TNFi in our study, even at the time of assessment and with the outcome that showed the most significant result in previous studies. These negative results are notable because this was the first independent validation study for 12 of the biomarkers, and because they indicate that prudence is needed in the interpretation of the proposed biomarkers of response to TNFi even when they are supported by very low p values. The results also emphasize the requirement of independent replication for validation, and the need to search protocols that could increase reproducibility of the biomarkers of response to TNFi. [ABSTRACT FROM AUTHOR]

Aim: To quantify the contribution of changes in different risk factors population levels and treatment uptake on the decline in CHD mortality in Denmark from 1991 to 2007 in different socioeconomic groups. Design: We used IMPACTSEC, a previously validated policy model using data from different population registries. Participants: All adults aged 25–84 years living in Denmark in 1991 and 2007. Main outcome measure: Deaths prevented or postponed (DPP). Results: There were approximately 11,000 fewer CHD deaths in Denmark in 2007 than would be expected if the 1991 mortality rates had persisted. Higher mortality rates were observed in the lowest socioeconomic quintile. The highest absolute reduction in CHD mortality was seen in this group but the highest relative reduction was in the most affluent socioeconomic quintile. Overall, the IMPACTSEC model explained nearly two thirds of the decline in. Improved treatments accounted for approximately 25% with the least relative mortality reduction in the most deprived quintile. Risk factor improvements accounted for approximately 40% of the mortality decrease with similar gains across all socio-economic groups. The 36% gap in explaining all DPPs may reflect inaccurate data or risk factors not quantified in the current model. Conclusions: According to the IMPACTSEC model, the largest contribution to the CHD mortality decline in Denmark from 1991 to 2007 was from improvements in risk factors, with similar gains across all socio-economic groups. However, we found a clear socioeconomic trend for the treatment contribution favouring the most affluent groups. [ABSTRACT FROM AUTHOR]

Background: Data are sparse on the range of BMI among patients acutely admitted to general hospitals. We investigated BMI values and associated patient characteristics, reasons for hospital admission, and mortality in Denmark. Methods: We identified all persons with an acute inpatient admission 2011–2014 in Central Denmark Region and assessed BMI measurements recorded in the Clinical Information System. We used cross-sectional and cohort analyses to examine the BMI distribution and its association with demographic characteristics, comorbidities, medication use, tobacco smoking, reasons for admission, and 30-day mortality. Results: Among 92,027 acutely admitted patients (median age 62 years, 49% female) with a BMI measurement, 4% had a BMI (kg/m2) <18.5, 42% a BMI between 18.5 and 25, 34% a BMI between 25 and 30, and 20% a BMI ≥30. Compared with normal-weight patients, 30-day mortality was high among patients with BMI <18.5 (7.5% vs. 2.8%, age- and smoking-adjusted odds ratio (aOR) 2.4; 95% confidence interval (CI): 2.0–2.9, whereas patients with overweight (aOR 0.7; 95% CI: 0.6–0.8) and obesity class I (aOR 0.8; 95% CI: 0.6–0.9)). Compared with the total population, patients with BMI <18.5 were older (68 years median); more were female (73%); more had comorbidities (Charlson Comorbidity Index score >0 in 42% vs. 33% overall), more were current smokers (45% vs. 27% overall), and acute admissions due to respiratory diseases or femoral fractures were frequent. In contrast, patients with BMI ≥30 were relatively young (59 years median), fewer smoked (24%): type 2 diabetes, sleep disorders, cholelithiasis, and heart failure were frequent diagnoses. Prevalence of therapies for metabolic syndrome, pain, and psychiatric disorders increased with higher BMI, while patients with BMI <18.5 frequently used asthma medications, glucocorticoids, and antibiotics. Conclusion: In patients acutely admitted to general hospitals, reasons for hospital admission and associated clinical characteristics differ substantially according to BMI range. BMI <18.5 is a clinical predictor of high short-term mortality. [ABSTRACT FROM AUTHOR]

Objective: Illness Management and Recovery (IMR) is a psychosocial intervention with a recovery-oriented approach. The program has been evaluated in different settings; however evidence for the effects of IMR is still deficient. The aim of this trial was to investigate the benefits and harms of the IMR program compared with treatment as usual in Danish patients with schizophrenia or bipolar disorder. Method: The trial was designed as a randomized, assessor-blinded, multi-center, clinical trial investigating the IMR program compared with usual treatment. 198 people diagnosed with schizophrenia or bipolar disorder participated. The primary outcome was the Global Assessment of Functioning (GAF-F) at the end of intervention and the secondary and explorative outcomes included severity of symptoms and service utilization. Results: IMR had no significant effect on functioning, symptoms, substance use or service utilization. Conclusion: This randomized trial contributes to the evidence base of IMR by providing a methodological solid base for its conclusions; however the trial has some important limitations. More research is needed to get a firm answer on the effectiveness of the IMR. [ABSTRACT FROM AUTHOR]

Background: The management of patients with non-valvular atrial fibrillation (NVAF) with rate-lowering or anti-arrhythmic drugs has markedly changed over the last decade, but it is unknown how these changes have affected patients with NVAF with a permanent pacemaker (PPM). Methods: Through Danish nationwide registries, patients with NVAF and a PPM were identified from 2001 to 2012. Changes in concomitant pharmacotherapy and comorbidities were tested using the Cochran–Armitage trend test and linear regression. Patients with NVAF were identified to calculate the proportional amount of PPM implants. Results: A total of 12,231 NVAF patients with a PPM were included in the study, 55.6% of which were men. Median age was 78 years (interquartile range 70–84). From 2001 to 2012, the number of NVAF patients with a PPM increased from 850 to 1344, while the number of NVAF patients increased from 67,478 to 127,261. Thus, the proportional amount of NVAF patients with a PPM decreased from 1.3% to 1.1% (p = 0.015). Overall 45.9% had atrial fibrillation (AF) duration less than one year and the proportion declined from 55.5% to 42.4% (p <0.001). Diabetes mellitus increased from 7.2% to 16.8% (p <0.001). Heart failure (HF) decreased from 36.7% to 29.3% (p = 0.010) and ischemic heart disease (IHD) decreased from 32.4% to 26.1% (p <0.001). Beta-blocker use increased from 38.1% to 58.0% (p <0.001), while digoxin and anti-arrhythmic drug use decreased over time. Conclusion: From 2001 to 2012, the absolute number of NVAF patients with a PPM increased while the proportional amount decreased. The number of NVAF patients receiving a PPM within one year of AF diagnosis decreased. The prevalence of DM increased, while the prevalence of HF and IHD was high but decreasing. The use of beta-blockers increased markedly, while use of digoxin and anti-arrhythmic drugs decreased over time. [ABSTRACT FROM AUTHOR]

Aim: Warfarin is a cornerstone for the prevention of thromboembolism in atrial fibrillation (AF), and several efforts have been taken to increase its usage and safety, including risk stratification schemes. Our aim was to investigate the temporal trends in initiation of warfarin and its effects on incidence of bleeding and thromboembolism in patients with new-onset atrial fibrillation 1996–2011. Methods: All patients with a first-time diagnosis of non-valvular atrial fibrillation were identified from nationwide administrative registries. Trends were determined by linear regression. Results: In total 153,682 patients were included. Initiation of warfarin increased from 14% to 41% (p<0.0001). Events of thromboembolism decreased from 3.9% to 2.6% annually (p<0.0001). The greatest decline in thromboembolic events was observed for patients with a CHA2DS2VASc score >1, where the annual decline was -0.12% (95%CI: -0.161; -0.084)) for those treated with warfarin and -0.073% (95%CI: -0.116;-0.030)) for those not treated with warfarin. Bleeding increased from 3.3% to 3.9% (p = 0.043). For those with a CHA2DS2VASc score >1 annual bleeding rates increased by 0.095% (95%CI: -0.025; -0.165) in warfarin treated and by 0.056% (95%CI: -0.013; -0.100) in patients not treated with warfarin. Conclusion: Warfarin use increased by nearly a 3-fold between 1996 and 2011. During the same period, thromboembolic events declined by a third and bleeding increased by a fifth, suggesting a beneficial effect associated with higher warfarin use. Notably, a small decline in thromboembolic events and increase in bleeding events was observed for the untreated population, suggesting a changing risk profile of AF patients. [ABSTRACT FROM AUTHOR]

The objective was to examine the effect of Expressive Writing Intervention (EWI) on self-reported physical symptoms and healthcare utilization in a nationwide randomized controlled trial with Danish women treated for primary breast cancer, and to explore participant characteristics related to emotion regulation as possible moderators of the effect. Women who had recently completed treatment for primary breast cancer (n = 507) were randomly assigned to three 20 min. home-based writing exercises, one week apart, focusing on emotional disclosure (EWI) of a distressing experience (their cancer or a non-cancer topic) or a non-disclosing topic (control). Outcomes were self-reported physical symptoms and healthcare utilization (visits and telephone contacts with GP) 3 and 9 months post-intervention. Potential moderators were repressive coping, alexithymia, rumination, social constraints, and writing topic. Results revealed no group by time interaction effects for any outcomes. Moderation analyses showed that 1) low alexithymic women in the EWI group showed larger decreases in GP telephone calls over time than both high alexithymic women and controls and 2) women in the EWI group writing about their own cancer, but not women writing about other topics, showed a larger decrease than controls. The results from this large randomized trial are concordant with previous findings showing that EWI is unlikely to be a generally applicable intervention to improve health-related outcomes in cancer patients and cancer survivors. However, written disclosure might have a beneficial impact for individuals who write about their own cancer, as well as for those low in alexithymia. [ABSTRACT FROM AUTHOR]

Background: An interrelationship between hypothyroidism and glaucoma, due to a shared autoimmune background or based on deposition of mucopolysaccharides in the trabecular meshwork in the eye, has been suggested but is at present unsubstantiated. Therefore, our objective was to investigate, at a nationwide and population-based level, whether there is such an association. Subjects and methods: Observational cohort study using record-linkage data from nationwide Danish health registers. 121,799 individuals diagnosed with a first episode of hypothyroidism were identified and were matched with 4 non-hypothyroid controls according to age and sex. Prevalence of glaucoma was recorded and cases and controls were followed over a mean of 7.1 years (range 0–17). Logistic and Cox regression models were used to assess the risk of glaucoma before and after the diagnosis of hypothyroidism, respectively. Results: Overall, we found a higher prevalence of glaucoma in subjects with hypothyroidism as compared to controls (4.6% vs. 4.3%, p < 0.001). Prior to the diagnosis of hypothyroidism, the odds ratio (OR) was significantly increased for glaucoma [1.09; 95% confidence interval (CI): 1.04–1.13]. Based on the Cox regression model, there was no increased risk of glaucoma after the diagnosis of hypothyroidism [hazard ratio (HR) 1.00; 95% CI: 0.96–1.06], and the HR decreased further after adjusting for pre-existing co-morbidity (0.88; 95% CI: 0.84–0.93). Conclusions: There was an increased risk of glaucoma before but not after the diagnosis of hypothyroidism, suggesting that screening for glaucoma in hypothyroid individuals is unwarranted. [ABSTRACT FROM AUTHOR]

Background: Psoriasis (PsO) is a chronic inflammatory disease with predominantly cutaneous manifestations. Approximately one third of patients with PsO develop psoriatic arthritis (PsA), whereas the remaining proportion of patients has isolated cutaneous psoriasis (PsC). These two phenotypes share common immunology, but with different heredity that might in part be explained by genetic variables. Methods: Using a candidate gene approach, we studied 53 single nucleotide polymorphisms (SNPs) in 37 genes that regulate inflammation. In total, we assessed 480 patients with PsO from DERMBIO, of whom 151 had PsC for 10 years or more (PsC10), 459 patients with PsA from DANBIO, and 795 healthy controls. Using logistic regression analysis, crude and adjusted for age and gender, we assessed associations between genetic variants and PsO, PsC10, and PsA, as well as associations between genetic variants and development of PsA in PsO. Results: Eleven polymorphisms in 10 genes were nominally associated with PsO and/or PsC and/or PsA (P < 0.05). After correction for multiple testing with a false discovery rate of 5%, two SNPs remained significant: TNF (rs361525) was associated with PsO, PsC10, and PsA; and IL12B (rs6887695) was associated with PsO. Conclusion: Among a cohort of Danish patients with moderate-to-severe psoriasis, two SNPs in the IL12B and TNF genes were associated with susceptibility of psoriasis. None of the SNPs were specifically associated with isolated cutaneous psoriasis or psoriatic arthritis. [ABSTRACT FROM AUTHOR]

The objective of the study was to examine if exposure to extra vitamin D from food fortification was associated with a decrease in the risk of preeclampsia. The study was based on a natural experiment exploring the effect of the abolition of the Danish mandatory vitamin D fortification of margarine in 1985. The effect of the extra vitamin D (1.25μg vitamin D/100 g margarine) was examined by comparing preeclampsia risk in women who have been exposed or unexposed to extra vitamin D from the fortified margarine during pregnancy, and who gave birth in the period from June 1983 to August 1988. The Danish National Patient Registry allowed the identification of pregnancies complicated by preeclampsia. The study included 73,237 women who gave birth during 1983–1988. We found no association between exposure to vitamin D fortification during pregnancy and the risk of any of the pregnancy related hypertensive disorders, including preeclampsia: Odds ratios (OR, 95%) for all hypertensive pregnancy related disorders among exposed vs. unexposed women was (OR 1.04, 95%CI: 0.98,1.10). In conclusion, the extra vitamin D from the mandatory vitamin D fortification did not influence the risk of preeclampsia. [ABSTRACT FROM AUTHOR]

Background: Crohn’s disease (CD) has traditionally been associated with weight loss and low BMI, yet paradoxically obesity has recently been suggested as a risk factor for CD, but not for ulcerative colitis (UC). We therefore hypothesized that the relation between BMI and CD is U shaped. Aim: To conduct a large population-based prospective cohort study of BMI and later risk of IBD, taking age at IBD diagnosis into account. Methods: A cohort of 74,512 women from the Danish National Birth Cohort, with BMI measured pre-pregnancy and 18 months after delivery, was followed for 1,022,250 person-years for development of IBD, according to the Danish National Patient Register. Associations were tested by Cox regression. Results: Overweight subjects (25≤BMI<30 kg/m2) had the lowest risk of CD, whereas obesity (BMI≥30kg/m2) increased the risk of CD at all ages, and low BMI (BMI<18.5kg/m2) associated with CD diagnosed at age 18-<40 years. Hence, using normal weight subjects as the reference, adjusted HRs for risk of developing CD (at age 18-<40 years) were 1.8(95%CI, 0.9–3.7) for underweight, 0.6(0.3–1.2) for overweight, and 1.5(0.8–2.7) for obese individuals (pre-pregnancy BMI). HRs were greater for BMI determined 18 months after delivery. Splines for CD risk according to waist:height ratio confirmed a U-shaped relationship with CD occurring <40 years, and a linear relationship with CD diagnosed at age 40+. There was no relationship between BMI and risk of UC. Conclusion: For the first time, we demonstrate that both high BMI and low BMI are risk factors for CD. Underweight may be a pre-clinical manifestation of disease being present many years before onset with obesity being a true risk factor. This raises the question as to whether there may be two distinct forms of CD. [ABSTRACT FROM AUTHOR]

Objective: To describe the distribution of specific mitochondrial DNA (mtDNA) haplogroups (hgs) in a cohort of patients with rheumatoid arthritis (RA). Methods: Two-hundred nineteen consecutive patients with RA had mtDNA isolated from their blood, sequenced and haplotyped. Patients were diagnosed according to the American College of Rheumatology (ACR)/European league against Rheumatism (EULAR) criteria. Demographic and clinical data were retrieved from the Danish nationwide database (DANBIO). Logistic regression analyses were performed to test for associations. Results: One-hundred eighty-four patients were eligible for analysis. Haplogroup frequencies were: H (n = 88; 47.8%), U (n = 37; 20.1%), T (n = 22; 12.0%), J (n = 16; 8.7%), K (n = 11; 5.9%), HV (n = 6; 3.3%) and V (n = 4; 2.2%). The distribution of individual hgs was identical to the background population. Radiographic erosions were significantly associated with hg clusters JT (OR = 2.37, 95% confidence interval (CI): 1.07–5.53, p = 0.038). Significantly fewer patients from hg cluster JT received biological treatment (OR = 0.17, 95% CI: 0.03–0.87, p = 0.038). Albeit, none of these associations were significant when corrected for multiple tests. Conclusion: There was no significant association between mtDNA hgs and presence of RA or disease manifestations. There was an, albeit insignificant, overrepresentation of patients with hg JT among patients with erosive disease; however, slightly fewer patients in the JT group were treated with biological drugs. [ABSTRACT FROM AUTHOR]

Immunoparesis (hypogammaglobulinemia) is associated to an unfavorable prognosis in newly diagnosed Multiple myeloma (MM) patients. However, this finding has not been validated in an unselected population-based cohort. We analyzed 2558 newly diagnosed MM patients in the Danish Multiple Myeloma Registry representing the entire MM population in Denmark from 2005–2013. Two-thousand two hundred and fifty three patients (90%) presented with reduction below lower normal levels of at least one uninvolved immunoglobulin. Using multivariable Cox regression we found that high age, high ISS score, high LDH and IgA MM were associated to both shorter overall survival and progression free survival. Furthermore, bone marrow plasma cell % was associated to short progression free survival. Immunoparesis had no independent significant effect on OS (HR 0.9 (95%CI: 0.7;1.0; p = 0.12)). Likewise, the number of suppressed immunoglobulins or the relative degree of suppressed uninvolved immunoglobulins from lower normal level (quantitative immunoparesis) was not associated to OS in the multivariable analysis. However, quantitative immunoparesis with at least 25% reduction (from lower normal level) of uninvolved immunoglobulins was associated to shorter PFS for the entire population. The impact of quantitative immunoparesis on PFS was present irrespective of calendar periods 2005–2008 and 2009–2013. Our population-based study does not confirm that immunoparesis at diagnosis is an independent prognostic factor regarding OS. However, quantitative immunoparesis is associated to a shorter PFS. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the general contextual effect (GCE) of the hospital department on one-year mortality in Swedish and Danish patients with heart failure (HF) by applying a multilevel analysis of individual heterogeneity. Methods: Using the Swedish patient register, we obtained data on 36,943 patients who were 45–80 years old and admitted for HF to the hospital between 2007 and 2009. From the Danish Heart Failure Database (DHFD), we obtained data on 12,001 patients with incident HF who were 18 years or older and treated at hospitals between June 2010 and June2013. For each year, we applied two-step single and multilevel logistic regression models. We evaluated the general effects of the department by quantifying the intra-class correlation coefficient (ICC) and the increment in the area under the receiver operating characteristic curve (AUC) obtained by adding the random effects of the department in a multilevel logistic regression analysis. Results: One-year mortality for Danish incident HF patients was low in the three audit years (around 11.1% -13.1%) and departments performed homogeneously (ICC ≈1.5% - 3.5%). The discriminatory accuracy of a model including age and gender was rather high (AUC≈ 0.71–0.73) but the increment in AUC after adding the department random effects into these models was only about 0.011–0.022 units in the three years. One-year mortality in Swedish patients with first hospitalization for heart failure, was relatively higher for 2007–2009 (≈21.3% - 22%) and departments performed homogeneously (ICC ≈ 1.5% - 3%). The discriminatory accuracy of a model including age, gender and patient risk score was rather high (AUC≈ 0.726–0.728) but the increment in AUC after adding the department random effects was only about 0.010–0.017 units in the three years. Conclusion: Using the DHFD standard benchmark for one-year mortality, Danish departments had a good, homogeneous performance. In reference to literature, Swedish departments had a homogeneous performance and the mortality rates for patients with first hospitalization for heart failure were similar to those reported since 2000. Considering this, if health authorities decide to further reduce mortality rates, a comprehensive quality strategy should focus on all Swedish hospitals. Yet, a complementary assessment for the period after the study period is required to confirm whether department performance is still homogeneous or not to determine the most appropriate action. [ABSTRACT FROM AUTHOR]

Everyday, we are bombarded with periodic, exogenous appeals and instructions on how to behave. How do these appeals and instructions affect subsequent coordination? Using experimental methods, we investigate how a one-time exogenous instruction affects subsequent coordination among individuals in a lab. Participants play a minimum effort game repeated 5 times under fixed matching with a one-time behavioral instruction in either the first or second round. Since coordination behavior may vary across countries, we run experiments in Denmark, Spain and Ghana, and map cross-country rankings in coordination with known national measures of fractualization, uncertainty avoidance and long-term orientation. Our results show that exogenous interventions increase subsequent coordination, with earlier interventions yielding better coordination than later interventions. We also find that cross-country rankings in coordination map with published national measures of fractualization, uncertainty avoidance, and long-term orientation. [ABSTRACT FROM AUTHOR]