Search

Study Question: Is fertility treatment with clomiphene citrate associated with an increased risk of childhood epilepsy, including specific subtypes of epilepsy?Summary Answer: Fertility treatment with clomiphene citrate may be associated with a small increased risk of idiopathic generalized epilepsy and focal epilepsy in childhood.What Is Known Already: Clomiphene citrate is among the most commonly prescribed drugs for fertility treatment. However, concerns have been raised as to whether the treatment may harm the developing fetus.Study Design, Size, Duration: This nationwide cohort study included all pregnancies in Denmark from 1 July 1995 resulting in a live-born singleton child before 31 December 2013. The children were followed until 31 December 2016.Participants/materials, Setting, Methods: Children conceived after fertility treatment with clomiphene citrate were identified from the Danish National Prescription Registry. The primary outcomes were childhood epilepsy, idiopathic generalized epilepsy, and focal epilepsy identified from the Danish National Patient Register and from antiepileptic drug prescriptions in the Danish National Prescription Registry. All analyses were conducted using Cox proportional hazards regression.Main Results and the Role Of Chance: A total of 1 081 291 pregnancies were included; 12 644 children (1.2%) developed epilepsy. Fertility treatment with clomiphene citrate was associated with a small increased risk of childhood epilepsy (hazard ratio [HR]: 1.10; 95% CI: 1.00-1.22), idiopathic generalized epilepsy (HR: 1.41; 95% CI: 1.16-1.72), and focal epilepsy (HR: 1.26; 95% CI: 1.04-1.53).Limitations, Reasons For Caution: The increased risk of idiopathic generalized epilepsy may be due to confounding from time stable parental characteristics related to treatment with clomiphene citrate, since the association was strongest with the lowest administered dosage of clomiphene citrate prior to conception, and the association disappeared in a sibling analysis.Wider Implications Of the Findings: The increased risk of focal epilepsy may be related to the hormonal treatment, since the association tended to increase with increasing cumulative dosage of clomiphene citrate prior to conception, and the association persisted in a sibling analysis. This finding may be of clinical importance, since alternative hormones are available for fertility treatment.Study Funding/competing Interest(s): Financial support from Aarhus University and the Aase and Ejnar Danielsen Foundation. U.S.K. received personal teaching fees from Merck, outside the submitted work.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: Is birth weight for gestational age associated with infertility in adulthood among men and women?Summary Answer: Being born small for gestational age (SGA) was associated with infertility in adulthood among men.What Is Known Already: Fetal growth restriction may affect fertility, but results from previous studies have been inconsistent.Study Design, Size, Duration: In this population-based cohort study, we used data from a Danish birth cohort, including 5594 men and 5342 women born between 1984 and 1987. Information on infertility was obtained from Danish health registers during the period from the participants' 18th birthday and up until 31 December 2017.Participants/materials, Setting, Methods: Participants were men and women born in two Danish municipalities, Aalborg and Odense. Information on birth weight and gestational age was obtained from birth records, and information on infertility diagnoses and fertility treatment was retrieved from the Danish National Patient Registry (NPR) and the Danish In Vitro Fertilisation (IVF) registry. Information on potential maternal confounders was obtained from questionnaires during pregnancy and was included in adjusted analyses. Logistic regression analysis was used to estimate crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for infertility according to birth weight for gestational age.Main Results and the Role Of Chance: Men born SGA had a 55% higher risk of being diagnosed with or treated for infertility compared to men born appropriate for gestational age (AGA) (adjusted OR = 1.55, 95% CI: 1.09-2.21). The association attenuated after exclusion of men born with hypospadias or cryptorchidism (OR = 1.37, 95% CI: 0.93-2.01). No association was found between women's birth weight for gestational age and risk of infertility (adjusted OR = 1.00, 95% CI: 0.73-1.37).Limitations, Reasons For Caution: Estimation of gestational age is associated with some uncertainty and might have caused non-differential misclassification. The study design implicitly assumed similar distribution of reproductive and health-seeking behaviour across the groups that were compared.Wider Implications Of the Findings: Men born SGA had a higher risk of infertility. Genital malformations may account for part of the observed association, but this must be explored further.Study Funding/competing Interest(s): This study was supported by Health, Aarhus University. No competing interests are declared.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Introduction: Prediction models using logistic regression may perform poorly in external patient cohorts. However, there is a need to standardize and validate models for clinical use. The purpose of this project was to describe a method for validation of external NTCP models used for patient selection in the randomized trial of protons versus photons in head and neck cancer radiotherapy, DAHANCA 35. Material and methods: Organs at risk of 588 patients treated primarily with IMRT in the randomized controlled DAHANCA19 trial were retrospectively contoured according to recent international recommendations. Dose metrics were extracted using MatLab and all clinical parameters were retrieved from the DAHANCA database. The model proposed by Christianen et al. to predict physician-rated dysphagia was validated through the closed testing, where change of the model intercept, slope and individual beta's were tested for significant prediction improvements. Results: Six months prevalence of dysphagia in the validation cohort was 33%. The closed testing procedure for physician-rated dysphagia showed that the Christianen et al. model needed an intercept refitting for the best match for the Danish patients. The intercept update increased the risk of dysphagia for the validation cohort by 7.9 ± 2.5% point. For the raw model performance, the Brier score (mean squared residual) was 0.467, which improved significantly with a new intercept to 0.415. Conclusions: The previously published Dutch dysphagia model needed an intercept update to match the Danish patient cohort. The implementation of a closed testing procedure on the current validation cohort allows quick and efficient validation of external NTCP models for patient selection in the future. [ABSTRACT FROM AUTHOR]

Study Question: How does celiac disease (CD) influence women's reproductive life, both prior to and after the diagnosis?Summary Answer: Prior to the diagnosis of CD, an increased risk of adverse pregnancy outcomes was seen, whereas after the diagnosis, no influence on reproductive outcomes was found.What Is Known Already: CD has been associated with several conditions influencing female reproduction and pregnancy outcomes including spontaneous abortion and stillbirth.Study Design, Size, Duration: A nationwide matched cohort study following 6319 women diagnosed with CD and 63166 comparison women and identifying reproductive events between the ages of 15 and 50 years.Participants/materials, Setting, Methods: Through linkage of several Danish national health registers, we identified all women diagnosed with CD between 1977 and 2016. We identified an age- and sex-matched comparison cohort and obtained data on reproductive outcomes for both cohorts. Adjusted stratified Cox and logistic regression models were used to estimate differences in reproductive outcomes between women with and without CD.Main Results and the Role Of Chance: Comparing women with diagnosed CD with the non-CD women, the chance of pregnancy, live birth and risk of stillbirth, molar and ectopic pregnancy, spontaneous abortion and abortion due to foetal disease was the same. However, prior to being diagnosed, CD women had an excess risk of spontaneous abortion equal to 11 extra spontaneous abortions per 1000 pregnancies (adjusted odds ratio (OR) = 1.12, 95% CI: 1.03, 1.22) and 1.62 extra stillbirths per 1000 pregnancies (adjusted OR = 1.57, 95% CI: 1.05, 2.33) compared with the non-CD women. In the period 0-2 years prior to diagnosis fewer pregnancies occurred in the undiagnosed CD group, equal to 25 (95% CI: 20-31) fewer pregnancies per 1000 pregnancies compared to the non-CD group and in addition, fewer undiagnosed CD women initiated ART-treatment in this period, corresponding to 4.8 (95% CI: 0.9, 8.7) fewer per 1000 women compared to non-CD women.Limitations, Reasons For Caution: Validity of the diagnoses in the registers was not confirmed, but reporting to the registers is mandatory for all hospitals in Denmark. Not all spontaneous abortions will come to attention and be registered, whereas live- and stillbirths, ectopic and molar pregnancies and abortion due to foetal disease are unlikely not to be registered. We adjusted for several confounding factors but residual confounding cannot be ruled out.Wider Implications Of the Findings: These findings suggest that undiagnosed CD can affect female reproduction and the focus should be on early detection of CD in risk groups.Study Funding/competing Interest(s): This study was funded by the Health Research Fund of Central Denmark Region and The Hede Nielsens Foundation, Denmark. The authors report no conflicts of interest in this work. [ABSTRACT FROM AUTHOR]

Background Despite extensive research, the aetiology of atopic dermatitis remains largely unknown, but reduced intestinal microbiota diversity in neonates has been linked to subsequent atopic dermatitis. Consequently, postnatal antibiotics have been proposed as a risk factor, but a potential association between prenatal antibiotics and atopic dermatitis is not well studied. Overall, the current evidence suggests a positive association between exposure to prenatal antibiotics and atopic dermatitis. Objective To investigate the association between prenatal antibiotics and atopic dermatitis among 18-month-old children. Methods This study conducted within the Danish National Birth Cohort included 62 560 mother-child pairs. Data on maternal prenatal antibiotics were collected in the 30th gestation week and 6 months post-partum, and offspring atopic dermatitis 18 months post-partum through telephone interviews. Antibiotic use was categorized by the timing of exposure as 1st-2nd trimester (gestation week 0-29), 3rd trimester (gestation week 30-birth), all three trimesters or none. Data were analysed by logistic regression analyses adjusting for potential confounders. Results Exposure to antibiotics prenatally was associated with increased odds of atopic dermatitis among children born by atopic mothers but only when used in both 1st-2nd and 3rd trimester ( ORadj 1.45, 95% CI: 1.19-1.76). The findings were consistent using different definitions of atopic dermatitis. Conclusions and Clinical Relevance Prenatal exposure to antibiotics throughout pregnancy was associated with an increased risk of atopic dermatitis but only within the first 18 months of life among children born by atopic mothers. The clinical usefulness of this finding must rest on corroboration in independent data sources. [ABSTRACT FROM AUTHOR]

Aim To investigate the possible association between vitamin D deficiency and cardiovascular autonomic neuropathy in people with diabetes. Methods A total of 113 people with Type 1 or Type 2 diabetes [mean (interquartile range) diabetes duration 22.0 (12-31) years, mean ( sd) age 56.2 (13.0) years, 58% men] underwent vitamin D (D2 and D3) assessment, and were screened for cardiovascular autonomic neuropathy using three cardiovascular reflex tests [heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio) and to the Valsalva manoeuvre] and assessment of 5-min resting heart rate and heart rate variability indices. Results We found an inverse U-shaped association between serum vitamin D level and E/I ratio, 30/15 ratio and three heart rate variability indices ( P < 0.05). Vitamin D level was non-linearly associated with cardiovascular autonomic neuropathy diagnosis ( P < 0.05 adjusted for age and sex). Linear regression models showed that an increase in vitamin D level from 25 to 50 nmol/l was associated with an increase of 3.9% (95% CI 0.1;7.9) in E/I ratio and 4.8% (95% CI 4.7;9.3) in 30/15 ratio. Conversely, an increase from 125 to 150 nmol/l in vitamin D level was associated with a decrease of 2.6% (95% CI −5.8;0.1) and 4.1% (95% CI −5.8;−0.5) in the respective outcome measures. Conclusions High and low vitamin D levels were associated with cardiovascular autonomic neuropathy in people with diabetes. Future studies should explore this association and the efficacy of treating dysvitaminosis D to prevent cardiovascular autonomic neuropathy. [ABSTRACT FROM AUTHOR]

Aims Cardiovascular autonomic neuropathy and diabetic peripheral neuropathy are common diabetic complications and independent predictors of cardiovascular disease. The glucose metabolite methylglyoxal has been suggested to play a causal role in the pathogeneses of diabetic peripheral neuropathy and possibly diabetic cardiovascular autonomic neuropathy. The aim of this study was to investigate the cross-sectional association between serum methylglyoxal and diabetic peripheral neuropathy and cardiovascular autonomic neuropathy in a subset of patients in the ADDITION-Denmark study with short-term screen-detected Type 2 diabetes (duration ~ 5.8 years). Methods The patients were well controlled with regard to HbA1c, lipids and blood pressure. Cardiovascular autonomic neuropathy was assessed by measures of resting heart rate variability and cardiovascular autonomic reflex tests. Diabetic peripheral neuropathy was assessed by vibration detection threshold ( n = 319), 10 g monofilament ( n = 543) and the Michigan Neuropathy Screening Instrument questionnaire ( n = 966). Painful diabetic neuropathy was assessed using the Brief Pain Inventory short form ( n = 882). Results No associations between methylglyoxal and cardiovascular autonomic reflex tests or any measures of diabetic peripheral neuropathy or painful diabetic neuropathy were observed. However, a positive association between methylglyoxal and several heart rate variability indices was observed, although these associations were not statistically significant when corrected for multiple testing. Conclusion Serum methylglyoxal is not associated with cardiovascular autonomic neuropathy, diabetic peripheral neuropathy or painful diabetic neuropathy in this cohort of well-treated patients with short-term diabetes. [ABSTRACT FROM AUTHOR]

Summary: The study estimates the cost of poor and suboptimal refill compliance by estimating fracture costs and assessing the association between refill compliance with oral bisphosphonates and incident fractures using Danish health registers. Patients with poor and suboptimal refill compliance had more major osteoporotic fractures, and the direct costs related to hospital care, primary care, and pharmaceutical treatment for these excess fractures reached almost 14 M DKK (2.5 M USD) for the study population which compares to a national annual excess cost of around 17 M DKK (3.1 M USD) using 2011 prescription prevalence. Introduction: Adherence to oral anti-osteoporosis treatment has been shown in several studies to be relatively low and the potential impact on fracture burden is high. The aim of the study was to assess the association between refill compliance and all-cause health care costs. Methods: A national dataset was extracted with all treatment-naive patients who began oral bisphosphonate (BP) treatment for osteoporosis in Denmark between 1997 and 2006 ( N = 54,876, 87 % women). Patients who survived for at least 2 years ( N = 47,176) were divided into groups based on Medication Possession Ratio (MPR). Logistic regressions were used to derive difference in the probability of incident fractures between the three MPR groups. Fracture costs (related to medication use, primary care practice, specialists, and hospitals) were derived by comparing cost 12 months before and after fracture. Results: For alendronate, the adjusted risk of major osteoporotic fractures was significantly reduced (OR 0.768; 0.686-0.859), including fractures of the hip (0.718; 0.609-0.846) and humerus (0.54; 0.431-0.677) with MPR ≥ 0.8. The risk reduction was lower with etidronate. Over 2 years, a total of 171 hip fractures and 53 other major osteoporotic fractures were attributed to suboptimal or poor refill compliance, with an excess cost of 13.7 M DKK (2.5 M USD). Conclusions: Poor refill compliance is not unusual in patients on oral bisphosphonates, and we demonstrate that this is accompanied by excess major osteoporotic fractures and health care costs at the societal level. [ABSTRACT FROM AUTHOR]

Summary: In this study of 100,949 new users of oral bisphosphonates age ≥35 years, 'early quitters' were found to differ from others with poor refill compliance in terms of socioeconomic, demographic, and treatment-related characteristics. New risk factors for poor compliance and persistence were identified. Introduction: Poor compliance with anti-osteoporotic therapy is an on-going worldwide challenge. In this study, we hypothesized that 'early quitters' differ in socioeconomics, demographics, co-medications, and comorbid conditions from other patients with low compliance. Methods: The study was a register-based nationwide cohort study of anti-osteoporotic therapy comprising 100,949 men and women. Statistical analysis including backward stepwise logistic regression analysis was used to explain causes of treatment failure and Kaplan-Meier survival analysis to estimate persistence of treatment. Results: It was noted that 56.6 % of the patients were persistent and compliant, 4.7 % of the patients were persistent but 'low compliant' while 38.7 % of the patients were 'early quitters'. 'Early quitters' were found to differ in socioeconomics from 'low compliant' patients. Differences concerning increased risk of 'early quitters' were associated with high household income, subjects' age 71.9-79 years, living in the countryside or village, prior treatment with analgesics and anti-parkinson drugs, and dementia. Differences concerning decreased risk of 'early quitters' were associated with male, living in an apartment, children living at home, living close to a university hospital, anti-osteoporotic therapy other than alendronate, number of drugs especially above three, pulmonary disease, collagen disease. Conclusion: The results suggest a need for improved support for patients to facilitate the interpretation of the disease and the perception of the benefits and risks of treatment-to reduce the risk of 'early quitters'. We were able to identify new risk groups that may be candidates for targeted actions. [ABSTRACT FROM AUTHOR]

Dizygotic twinning rates have changed over time, which has been seen as a sign of a decline in fecundity. Since a woman's birthweight has been shown to be a marker of her fecundity, maternal birthweight may correlate with subsequent twinning rates. In the Danish National Birth Cohort (1996-2002), we examined if maternal birthweight, and whether she was born at term or preterm, correlated with her probability of multiple birth. For 20,719 live born infants, we had self-reported information about maternal birthweight, collected during the first wave of the 7-year follow-up, and information on multiple births from record linkage. The association between maternal birthweight and multiple births was investigated by use of logistic regression and presented as odds ratios (ORs) with 95% confidence intervals (CIs). Compared to women born at term with a birthweight of 3001-4000 g, women with a birthweight > 4500 g appeared to have higher chance of multiple birth while women with a birthweight of 4001-4500 had a lower chance, especially if the analysis was restricted to women with a BMI < 25 (Adjusted ORs 2.3 [1.0-5.4] and 0.4 [0.2-0.9] respectively). Odds ratios for dizygotic twinning were of the same magnitude. In women with a BMI >or= 25, no obvious pattern was present. Our findings do not indicate that twinning is a fecundity indicator. Women with a birthweight that may indicate a pregnancy complicated with gestational diabetes had the highest rate of multiple birth. These findings are new and should be put to a critical test in other data sources. [ABSTRACT FROM AUTHOR]

The article focuses on the reconstruction of the courthouse and prison buildings at the Town Hall of Copenhagen, Denmark. The City Council of Copenhagen appointed Carl Frederik Hansen as the architect for the construction in 1800. He conceptualized the design as comprising two different buildings linked by arched passages. The Gaol was given a forbidden character, having barred windows and rusticated walls.

Background/objectives: For decades, the Mediterranean diet has been in focus regarding healthy eating as it has been associated with reduced risk of non-communicable diseases. Less interest has been given to health benefits of other regional diets. The aim of the present study was to assess whether adherence to a healthy Nordic food index was associated with lower risk of myocardial infarction (MI) among middle-aged Danes.Subjects/methods: Data were obtained from the Danish Diet, Cancer and Health cohort study of 57 053 men and women aged 50-64 years recruited between 1993 and 1997. The healthy Nordic food index comprised healthy Nordic food items selected a priori (fish, cabbage, rye bread, oatmeal, apple and pears and root vegetables). Information on incident MI was ascertained through linkage with national registries. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated from sex-specific Cox proportional hazard models.Results: In total, 1669 men and 653 women developed MI during follow-up (13.6 median years). In adjusted models, those with an index score of 5-6 points (highest scores) had significantly lower MI risk (men: HR=0.77, 95% CI=0.62, 0.97; women: HR=0.55, 95% CI=0.37, 0.82) relative to those scoring 0 points in the index (lowest score). A significantly lower MI risk was found per 1-point increment in the index in both men (HR=0.95, 95% CI=0.92, 0.99) and women (HR=0.93, 95% CI=0.88, 0.98).Conclusions: A healthy Nordic diet is associated with lower MI risk among middle-aged Danes, suggesting that Nordic diets should be considered in recommendations for dietary changes in the promotion of coronary health. [ABSTRACT FROM AUTHOR]

The article discusses on the architectural plans for the reconstruction of the Christiansborg Palace and its chapel in Copenhagen, Denmark. These two structures were ruined by fire in 1794. The plan for their reconstruction was drawn by Carl Frederik Hansen on 1803, as a result of his commitment in other rebuilding projects. Hansen's drawings were presented again on 1810 and were completed in 1822. His designs were based on the position of the earlier chapel.

Background: Strategies to reach out-of-hospital cardiac arrests (called cardiac arrest) in residential areas and reduce disparities in care and outcomes are warranted. This study investigated incidences of cardiac arrests in public housing areas., Methods: This register-based cohort study included cardiac arrest patients from Amsterdam (the Netherlands) from 2016 to 2021, Copenhagen (Denmark) from 2016 to 2021, and Vienna (Austria) from 2018 to 2021. Using Poisson regression adjusted for spatial correlation and city, we compared cardiac arrest incidence rates (number per square kilometer per year and number per 100 000 inhabitants per year) in public housing and other residential areas and examined the proportion of cardiac arrests within public housing and adjacent areas (100-m radius)., Results: Overall, 9152 patients were included of which 3038 (33.2%) cardiac arrests occurred in public housing areas and 2685 (29.3%) in adjacent areas. In Amsterdam, 635/1801 (35.3%) cardiac arrests occurred in public housing areas; in Copenhagen, 1036/3077 (33.7%); and in Vienna, 1367/4274 (32.0%). Public housing areas covered 42.4 (12.6%) of 336.7 km 2 and 1 024 470 (24.6%) of 4 164 700 inhabitants. Across the capitals, we observed a lower probability of 30-day survival in public housing versus other residential areas (244/2803 [8.7%] versus 783/5532 [14.2%]). The incidence rates and rate ratio of cardiac arrest in public housing versus other residential areas were incidence rate, 16.5 versus 4.1 n/km 2 per year; rate ratio, 3.46 (95% CI, 3.31-3.62) and incidence rate, 56.1 versus 36.8 n/100 000 inhabitants per year; rate ratio, 1.48 (95% CI, 1.42-1.55). The incidence rates and rate ratios in public housing versus other residential areas were consistent across the 3 capitals., Conclusions: Across 3 European capitals, one-third of cardiac arrests occurred in public housing areas, with an additional third in adjacent areas. Public housing areas exhibited consistently higher cardiac arrest incidences per square kilometer and 100 000 inhabitants and lower survival than other residential areas. Public housing areas could be a key target to improve cardiac arrest survival in countries with a public housing sector., Competing Interests: Disclosures Dr Juul Grabmayr has received research grants from Trygfonden and Helsefonden. Dr Hansen has received grants from the Independent Research Fund Denmark, TrygFonden, Laerdal Foundation, Helsefonden, and the Capital Region of Denmark Research Fund. Dr Krychtiuk has received speaker fees from Zoll Medical and Daiichi Sankyo and consulting fees from Novartis and Amgen, unrelated to this article’s topic. Christian Torp-Pedersen has received grants from Bayer and Novo Nordisk unrelated to the current study. Dr Tan has received funding from the European Union’s Horizon 2020 research and innovation program under the acronym ESCAPE-NET, registered under grant agreement number 733381, and the COST Action PARQ (grant agreement No. CA19137) supported by COST (European Cooperation in Science and Technology), not related to the current study. Drs Andelius and Kjoelbye were supported by a research grant from TrygFonden, unrelated to the current study. The other authors report no conflicts.

Importance: This study is important because it shows the potential epidemiological silence associated with the use of culture as the primary diagnostic method for the laboratory identification of human campylobacteriosis. Also, we show how polymerase chain reaction methods are associated with a systematic increase in the number of human campylobacteriosis episodes as reported by routine disease surveillance. These findings are operationally relevant and have public health implications because they tell how crucial it is to consider changes in diagnostic methods, e.g., in the epidemiological analysis of historical data and in the interpretation of future data in light of the past. We also believe that this study highlights how the synergy between microbiology and epidemiology is essential for disease surveillance., Competing Interests: The authors declare no conflict of interest.

Background: Since 2015, when the first cystic fibrosis transmembrane conductance regulator (CFTR) modulators were approved for people with cystic fibrosis (CF) homozygous for F508del-CFTR, studies have shown improved lung function after initiation of the treatment and patients experience improved physical capacity. The aim of this study was to investigate change in exercise capacity after initiation of Lumacaftor/Ivacaftor and Tezacaftor/Ivacaftor treatment (LUM/IVA, TEZ/IVA)., Methods: We performed a single group prospective observational cohort study with follow-up at six and 12 months. The study examined change in exercise capacity in people with CF initiating treatment with LUM/IVA and TEZ/IVA, measured by cardio-pulmonary exercise testing (CPET). Inclusion criteria were people with CF homozygous for F508del-CFTR aged 12 years or older eligible for LUM/IVA and TEZ/IVA treatment from June 2017 until June 2019. Primary outcomes were change in VO 2peak and maximal workload. Secondary outcomes were change in muscle strength, muscle power and body composition in a subgroup of the study population., Results: A total of 91 patients were included in the analysis. The mean change in VO 2peak and VO 2peak divided by body weight from baseline to 12-months follow-up was 145.7 (91.2;200.2) ml/min and 1.07 (95% CI 0.19;1.95) ml/min/kg, respectively. The mean change in maximal workload between baseline and 12 months was 14.2 Watt (95% CI 9.1;19.2). All improvements in exercise capacity were statistically significant., Conclusions: Patients in this study improved their exercise capacity by a statistically significant increase in VO 2peak and maximal workload 12 months after initiation of treatment with LUM/IVA and TEZ/IVA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background Little is known about how COVID-19 influenced engagement of citizen responders dispatched to out-of-hospital cardiac arrest (OHCA) by a smartphone application. The objective was to describe and analyze the Danish Citizen Responder Program and bystander interventions (both citizen responders and nondispatched bystanders) during the first COVID-19 lockdown in 2020. Methods and Results All OHCAs from January 1, 2020, to June 30, 2020, with citizen responder activation in 2 regions of Denmark were included. We compared citizen responder engagement for OHCA in the nonlockdown period (January 1, 2020, to March 10, 2020, and April 21, 2020, to June 30, 2020) with the lockdown period (March 11, 2020, to April 20, 2020). Data are displayed in the order lockdown versus nonlockdown period. Bystander cardiopulmonary resuscitation rates did not differ in the 2 periods (99% versus 92%; P =0.07). Bystander defibrillation (9% versus 14%; P =0.4) or return-of-spontaneous circulation (23% versus 23%; P =1.0) also did not differ. A similar amount of citizen responders accepted alarms during the lockdown (6 per alarm; interquartile range, 6) compared with the nonlockdown period (5 per alarm; interquartile range, 5) ( P =0.05). More citizen responders reported performing chest-compression-only cardiopulmonary resuscitation during lockdown compared with nonlockdown (79% versus 59%; P =0.0029), whereas fewer performed standardized cardiopulmonary resuscitation, including ventilations (19% versus 38%; P =0.0061). Finally, during lockdown, more citizen responders reported being not psychologically affected by attending an OHCA compared with nonlockdown period (68% versus 56%; P <0.0001). Likewise, fewer reported being mildly affected during lockdown (26%) compared with nonlockdown (35%) ( P =0.003). Conclusions The COVID-19 lockdown in Denmark was not associated with decreased bystander-initiated resuscitation in OHCAs attended by citizen responders.

Background Citizen responder programs are implemented worldwide to dispatch volunteer citizens to participate in out-of-hospital cardiac arrest resuscitation. However, the risk of injuries in relation to activation is largely unknown. We aimed to assess the risk of physical injury for dispatched citizen responders. Methods and Results Since September 2017, citizen responders have been activated through a smartphone application when located close to a suspected cardiac arrest in the Capital Region of Denmark. A survey was sent to all activated citizen responders, including a specific question about risk of acquiring an injury during activation. We included all surveys from September 1, 2017, to May 15, 2020. From May 15, 2019, to May 15, 2020, we followed up on all survey nonresponders by phone call, e-mail, or text messages to examine if nonresponders were at higher risk of severe or fatal injuries. In 1665 suspected out-of-hospital cardiac arrests, 9574 citizen responders were dispatched and 76.6% (7334) answered the question regarding physical injury. No injury was reported by 99.3% (7281) of the responders. Being at risk of physical injury was reported by 0.3% (24), whereas 0.4% (26) reported an injury (25 minor injuries and 1 severe injury [ankle fracture]). When following up on nonresponders (2472), we reached 99.1% (2449). No one reported acquired injuries, and only 1 reported being at risk of injury. Conclusions We found low risk of physical injury reported by volunteer citizen responders dispatched to out-of-hospital cardiac arrest. Risk of injury should be considered and monitored as a safety measure in citizen responder programs.

Background Little is known about the psychological risks of dispatched citizen responders who have participated in resuscitation attempts. Methods and Results A cross-sectional survey study was performed with 102 citizen responders who participated in a resuscitation attempt from July 23, 2018, to August 22, 2018, in the Capital Region of Denmark. Psychological distress, defined as symptoms of posttraumatic stress disorder, was assessed 3 weeks after the resuscitation attempt and measured with the Impact of Event Scale-Revised. Perceived stress was measured with the Perceived Stress Scale. Individual differences were assessed as the personality traits of agreeableness, conscientiousness, extraversion, neuroticism, and openness to experience with the Big Five Inventory, general self-efficacy, and coping mechanisms (Brief Coping Orientation to Problems Experienced Inventory). Associations between continuous variables were examined with the Pearson correlation. The associations between psychological distress levels and contextual factors and individual differences were analyzed in multivariable linear regression models to determine factors independently associated with psychological distress levels. The mean overall posttraumatic stress disorder score was 0.65 of 12; the mean perceived stress score was 7.61 of 40. The most common coping mechanisms were acceptance and emotional support. Low perceived stress was significantly associated with high general self-efficacy, and high perceived stress was significantly associated with high scores on neuroticism and openness to experience. Non-healthcare professionals were less likely to report symptoms of posttraumatic stress disorder. Conclusions Citizen responders who participated in resuscitation reported low levels of psychological distress. Individual differences were significantly associated with levels of psychological distress and should be considered when engaging citizen responders in resuscitation.

Seroprevalence studies have proven an important tool to monitor the progression of the coronavirus disease 2019 (COVID-19) pandemic. We present results of consecutive population-based seroprevalence surveys performed in Denmark in 2020. In spring, late summer and autumn/winter of 2020, invitation letters including a questionnaire covering symptoms were sent to representative samples of the population above 12 years and to parents of children below 18 years in the sample. Blood samples were analysed for total Ig and seroprevalence estimates per population segment were calculated and compared to other surveillance parameters. Based on 34 081 participants (participation rate 33%), seroprevalence estimates increased from 1.2% (95%CI: 0.3-1.9%) in May to 4.1% (95%CI: 3.1-4.9%) in December 2020. Seroprevalence estimates were roughly three times higher in those aged 12-29 years compared to 65 + and higher in metropolitan municipalities. By December 2020, 1.5% of the population had tested positive by RT-PCR. Infected individuals in older age groups were hospitalised several fold more often than in younger. Amongst seropositives, loss of taste/smell were the more specific symptoms, 32-56% did not report any symptoms. In more than half of seroconverted families, we did not see evidence of transmission between generations. Seroprevalence increased during 2020; adolescents were primarily infected in the autumn/winter. Denmark has a high per capita test rate; roughly one undiagnosed infection of SARS-CoV-2 were estimated to occur for each diagnosed case. Approximately half were asymptomatically infected. The epidemic appears to have progressed relatively modestly during 2020 in Denmark., (© 2021. The Author(s).)

Background: The long-term clinical course of patients with an enterovirus central nervous system infection (ECI) is poorly understood., Methods: We performed a nationwide population-based cohort study of all Danish patients with ECI diagnosed 1997-2016 (n = 1745) and a comparison cohort from the general population individually matched on date of birth and sex (n = 17 450). Outcomes were categorized into mortality and risk of cancer and likely measures of neurological sequelae: neuropsychiatric morbidities, educational landmarks, use of hospital services, employment, receipt of disability pension, income, number of sick leave days, and nursing home residency., Results: Mortality in the first year was higher among patients with ECI (mortality rate ratio [MRR] = 10.0; 95% confidence interval [CI], 4.17-24.1), but thereafter mortality was not higher (MMR = 0.94; 95% CI, 0.47-1.86). Long-term outcomes for patients with ECI were not inferior to those of the comparison cohort for risk of cancer, epilepsy, mental and behavioral disorders, dementia, depression, school start, school marks, high school education, use of hospital services, employment, receipt of disability pension, income, days of sick leave, or nursing home residency., Conclusions: Diagnosis of an ECI had no substantial impact on long-term survival, health, or social/educational functioning., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Dispatching citizen responders through a smartphone application (app) holds the potential to increase bystander cardiopulmonary resuscitation (CPR) and defibrillation in out-of-hospital cardiac arrest (OHCA)., Objectives: This study investigated arrival at the OHCA location of app-dispatched citizen responders before the Emergency Medical Services (EMS) and the association with bystander CPR and bystander defibrillation., Methods: Suspected OHCAs with alerted citizen responders from September 1, 2017, to August 31, 2018, were included. Citizen responders located 1.8 km (1.1 miles) from the OHCA were dispatched to start CPR or retrieve an automated external defibrillator. OHCAs where at least 1 citizen responder arrived before EMS were compared with OHCAs where EMS arrived first. In both groups, random bystanders could be present before the arrival of citizen responders and the EMS. Primary outcomes were bystander CPR and bystander defibrillation, which included CPR and defibrillation by citizen responders and random bystanders., Results: Citizen responders were alerted in 819 suspected OHCAs, of which 438 (53.5%) were confirmed cardiac arrests eligible for inclusion. At least 1 citizen responder arrived before EMS in 42.0% (n = 184) of all included OHCAs. When citizen responders arrived before EMS, the odds for bystander CPR increased (odds ratio: 1.76; 95% confidence interval: 1.07 to 2.91; p = 0.027) and the odds for bystander defibrillation more than tripled (odds ratio: 3.73; 95% confidence interval: 2.04 to 6.84; p < 0.001) compared with OHCAs in which citizen responders arrived after EMS., Conclusions: Arrival of app-dispatched citizen responders before EMS was associated with increased odds for bystander CPR and a more than 3-fold increase in odds for bystander defibrillation. (The HeartRunner Trial; NCT03835403)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Regional variation in incidence and survival after out-of-hospital cardiac arrest (OHCA) may be caused by many factors including differences in definitions and reporting. We examined regional differences in Denmark., Methods: From the Danish Cardiac Arrest Registry we identified adult OHCA patients between 2009-2014 of presumed cardiac cause. Patients were grouped according to the five administrative/geographical regions of Denmark and survival was examined based on all arrest-cases (30-day survival percentage) and number of survivors per 100,000 inhabitants., Results: We included 12,902 OHCAs of which 1550 (12.0 %) were alive 30 days after OHCA. No regional differences were observed in age, sex or comorbidities. Incidence of OHCA ranged from 32.9 to 42.4 per 100,000 inhabitants; 30-day survival percentages ranged from 8.5% to 13.8% and number of survivors per 100,000 inhabitants ranged from 3.5 to 5.9, across the regions. In one of the regions car-manned pre-hospital physicians were discontinued from 2011. Here, the incidence of OHCA per 100,000 inhabitants increased markedly from 37.1 in 2011 to 52.2 in 2014 and 30-day survival percentage decreased from 10.9 % in 2011 to 7.5 % in 2014; while the number of survivors per 100,000 inhabitants stagnated from 4.0 in 2011 to 3.9 in 2014. In comparison, survival increased in the other four regions., Conclusion: Differences in incidence and 30-day survival after OHCA were observed between the five regions of Denmark. Comparisons of survival should not only be based on survival percentages, but also on number of survivors of the background population as inclusion bias can influence survival outcomes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Exposure to exogenous sex hormones with estrogenic or anti-androgen properties may influence intrauterine development of male genitals. This population-based cohort study based on data from 44,408 live-born singleton sons in the Danish National Birth Cohort (DNBC) aimed to investigate whether maternal use of oral contraceptives prior to or during early pregnancy increase the risk of cryptorchidism or hypospadias. We found no consistent association between use of oral contraceptives and cryptorchidism or hypospadias, neither in those exposed any time four months prior to conception [cryptorchidism: adjusted Odds Ratio (aOR): 1.06 (95% CI: 0.91; 1.23), hypospadias: 0.74 (95% CI: 0.53; 1.03)] nor in those exposed any time during the first trimester of pregnancy [cryptorchidism: aOR: 0.93 (95% CI: 0.53; 1.62), hypospadias: 1.02 (95% CI: 0.32; 3.23)]. Despite relatively strong exposure levels from oral contraceptive use in pregnancy, this study revealed no evidence of an increased risk of either two genital malformations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: During basic life support (BLS) training, instructors assess learners' cardiopulmonary resuscitation (CPR) skills and correct errors to ensure high-quality performance. This study aimed to investigate certified BLS instructors' assessments of CPR skills., Methods: Data were collected at BLS courses for medical students at Aarhus University, Aarhus, Denmark. Two certified BLS instructors evaluated each learner with a cardiac arrest test scenario, where learners demonstrated CPR on a resuscitation manikin for 3.5 minutes. Instructors' assessments were compared with manikin data as reference for correct performance. The first 3 CPR cycles were analyzed. Correct chest compressions were defined as 2 or more of 3 CPR cycles with 30 ± 2 chest compressions, 50 to 60 mm depth, and 100 to 120 min rate. Correct rescue breaths were defined as 50% or more efficient breaths with visible, but not excessive manikin chest inflation (for instructors) or 500 to 600mL air (manikin data)., Results: Overall, 90 CPR assessments were performed by 16 instructor pairs. Instructors passed 81 (90%) learners, whereas manikin pass rate was 2%. Instructors identified correct chest compressions with a sensitivity of 0.96 [95% confidence interval (CI) = 0.79-1) and a specificity of 0.05 (95% CI = 0.01-0.14), as well as correct rescue breaths with a sensitivity of 1 (95% CI = 0.40-1) and a specificity of 0.07 (95% CI = 0.03-0.15). Instructors mistakenly failed 1 learner with adequate chest compression depth, while passing 53 (59%) learners with improper depth. Moreover, 80 (89%) improper rescue breath performances were not identified., Conclusions: Certified BLS instructors assess CPR skills poorly. Particularly, improper chest compression depth and rescue breaths are not identified.

Background: The incidence of pediatric neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease have not been reported previously. Our aim was to estimate the incidence of pediatric NMOSD and the occurrence of anti-MOG antibody-associated disease in Denmark during 2008-18, and to evaluate the diagnostic usefulness of antibodies against MOG and aquaporin-4 (AQP4) in children <18 years., Methods: We undertook a nationwide, population-based, multicenter cohort study using data from the Danish National Patient Register, the Danish Multiple Sclerosis Registry, and laboratories providing anti-AQP4 and anti-MOG antibody analyses. Diagnoses were confirmed by review of the medical records, including blinded MRI review in most children with acute disseminated encephalomyelitis (ADEM)., Results: In children with acquired demyelinating syndromes, anti-AQP4 antibodies were detected in 4% and anti-MOG antibodies in 18%, including in the two children with ADEM who relapsed. We identified four children with NMOSD, equivalent to an incidence of 0.031/100,000 (95% confidence interval = 0.011‒0.082). In anti-MOG antibody-positive children, 32% relapsed during follow-up., Conclusions: Pediatric NMOSD and MOG antibody-associated disease are rare, but one-third of anti-MOG-positive children relapsed. In pediatric ADEM, only anti-MOG antibody-positive children relapsed, but the overall risk of relapse after pediatric ADEM was low., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Family studies have established that the heritability of blood pressure is significant and genome-wide association studies (GWAS) have identified numerous susceptibility loci, including one within the non-coding part of Rho GTPase-activating protein 42 gene (ARHGAP42) on chromosome 11q22.1. Arhgap42-deficient mice have significantly elevated blood pressure, but the phenotypic effects of human variants in the coding part of the gene are unknown. In a Danish cohort of carriers with apparently balanced chromosomal rearrangements, we identified a family where a reciprocal translocation t(11;18)(q22.1;q12.2) segregated with hypertension and obesity. Clinical re-examination revealed that four carriers (age 50-77 years) have had hypertension for several years along with an increased body mass index (34-43 kg/m 2 ). A younger carrier (age 23 years) had normal blood pressure and body mass index. Mapping of the chromosomal breakpoints with mate-pair and Sanger sequencing revealed truncation of ARHGAP42. A decreased expression level of ARHGAP42 mRNA in the blood was found in the translocation carriers relative to controls and allele-specific expression analysis showed monoallelic expression in the translocation carriers, confirming that the truncated allele of ARHGAP42 was not expressed. These findings support that haploinsufficiency of ARHGAP42 leads to an age-dependent hypertension. The other breakpoint truncated a regulatory domain of the CUGBP Elav-like family member 4 (CELF4) gene on chromosome 18q12.2 that harbours several GWAS signals for obesity. We thereby provide additional support for an obesity locus in the CELF4 domain.

Study Question: Does female weekly alcohol intake and binge drinking impact the chance of a successful fertility treatment?, Summary Answer: Low-to-moderate weekly alcohol drinking and binge drinking were not associated with the chance of achieving a clinical pregnancy or a live birth among women and couples undergoing medically assisted reproduction (MAR) treatments., What Is Known Already: Alcohol consumption is common among women of reproductive age, even though health authorities advise women trying to conceive to abstain from drinking. A growing number of couples struggle with infertility, but it is unknown whether low-to-moderate levels of alcohol consumption and alcohol binge drinking impair success in fertility treatment., Study Design, Size, Duration: Cohort study with prospectively collected exposure information including 1708 women and potential partners undergoing fertility treatment at the public fertility clinic, Aarhus University Hospital, 1 January 2010 to 31 August 2015. In total, data on 1511 intrauterine insemination (IUI) cycles, 2870 in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles and 1355 frozen embryo transfer cycles., Partticipants/materials, Setting, Methods: Exposure to weekly average alcohol intake was assessed from questionnaires completed by participants before the start of treatment. Outcome measures are the achievement of a clinical pregnancy and live birth in consecutive treatment cycles in the Danish national health registries, enabling complete follow-up. A modified Poisson regression with robust standard errors was used to evaluate associations between a weekly average alcohol intake and MAR outcomes, adjusting for female age, body mass index, cigarette smoking, coffee consumption, chronic diseases, level of education, and cycle number. When evaluating the association between binge drinking in the month prior to baseline and MAR outcomes the analyses were further adjusted for average weekly alcohol consumption., Main Results and the Role of Chance: Low-to-moderate average weekly alcohol intake was not statistically significantly associated with the chance of achieving a clinical pregnancy or a live birth following IUI or IVF/ICSI treatment cycles. Compared to women abstaining from alcohol, the adjusted relative risks for achieving a live birth among those reporting 1-2, 3-7, and >7 drinks per week were 1.00 (95% CI 0.66; 1.53), 1.20 (0.76; 1.91), and 1.48 (0.56; 3.93), respectively, among women initiating IUI treatments. Among those initiating IVF/ICSI treatments, the chance for achieving a live birth among those reporting 1-2, 3-7, and >7 drinks per week were 1.00 (0.83; 1.21), 0.95 (0.75; 1.20), and 0.89 (0.53; 1.51), respectively. The chance of achieving a live birth in the first IUI or IVF/ICSI treatment cycle was unrelated to the number of binge drinking episodes in the month preceding baseline., Limitations, Reasons for Caution: The risk of non-differential exposure misclassification, confounding, or chance cannot be ruled out. In addition, due to the low number of women reporting an intake of >7 drinks/week, the potential effect of high alcohol consumption should be interpreted with caution., Wider Implications of the Findings: Although it remains unsettled if and how alcohol affects female reproduction, our results indicate that is not necessary to abstain from alcohol when striving for a successful outcome following fertility treatment., Study Funding/competing Interest(s): J.L. is supported by a fully financed Ph.D. scholarship from Aarhus University and has received funds from the A.P. Møller foundation. The funding sources had no involvement in the conduct of the article. Dr Kesmodel reports personal fees from MSD and Ferring Pharmaceuticals outside the submitted work. All other authors have no conflicts of interest to declare and all have completed the ICMJE disclosure form., Trial Registration Number: Not relevant., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Adjuvant chemotherapy following curative resection is the standard treatment for pancreatic adenocarcinoma (PC). Randomized clinical trials using gemcitabine have shown a median overall survival (mOS) of 2 years and a 5-year survival rate of 15-20%. However, the effect of gemcitabine outside these trials is less clear. We examined the effect of postoperative gemcitabine on survival in an unselected cohort of patients receiving curative resection for PC in Denmark during a five-year period. Material and methods: From 1 May 2011 to 30 April 2016, 731 patients treated with curative resection were identified in the Danish Pancreatic Cancer Database (DPCD). Thirty patients died within 10 weeks postoperatively; 78 received other regimens or preoperative chemotherapy and were excluded. Of the remaining 623 patients, the chemotherapy (CT) group ( n  = 409, 66%) received gemcitabine within 10 weeks after resection, whereas the non-chemotherapy (NCT) group ( n  = 214, 34%) did not receive CT within 10 weeks. Results: CT patients were slightly younger than NCT patients but did not otherwise differ in baseline characteristics. The CT group showed a mOS of 24 months (95% CI; 21-27) and a 5-year survival rate of 22% (95% CI; 17-27); the NCT group had a mOS of 22 months (95% CI; 16-26, p  = .27) and a 5-year survival rate of 26% (95% CI; 19-34, p  = .66). Most patients (415/623) had lymph node metastases. Of these patients, those in the CT group ( n  = 280) had significantly longer mOS [20 months (95% CI; 18-24)] than those in the NCT group ( n  = 135) [14 months (95% CI; 11-17)]. Conclusions: In this national Danish cohort of PC patients undergoing resection between 2011 and 2016, the survival after postoperative gemcitabine was similar to that reported in previous clinical trials. However, the survival advantage of postoperative gemcitabine was limited to patients with lymph node metastases.

Aims: Optimization of automated external defibrillator (AED) placement and accessibility are warranted. We examined the associations between AED accessibility, at the time of an out-of-hospital cardiac arrest (OHCA), bystander defibrillation, and 30-day survival, as well as AED coverage according to AED locations., Methods: In this registry-based study we identified all OHCAs registered by mobile emergency care units in Copenhagen, Denmark (2008-2016). Information regarding registered AEDs (2007-2016) was retrieved from the nationwide Danish AED Network. We calculated AED coverage (AEDs located ≤200 m route distance from an OHCA) and, according to AED accessibility, the likelihoods of bystander defibrillation and 30-day survival., Results: Of 2500 OHCAs, 22.6% (n = 566) were covered by a registered AED. At the time of OHCA, <50% of these AEDs were accessible (n = 276). OHCAs covered by an accessible AED were nearly three times more likely to receive bystander defibrillation (accessible: 13.8% vs. inaccessible: 4.8%, p < 0.001) and twice as likely to achieve 30-day survival (accessible: 28.8% vs. inaccessible: 16.4%, p < 0.001). Among bystander-witnessed OHCAs with shockable heart rhythms (accessible vs. inaccessible AEDs), bystander defibrillation rates were 39.8% vs. 20.3% (p = 0.01) and 30-day survival rates were 72.7% vs. 44.1% (p < 0.001). Most OHCAs were covered by AEDs at offices (18.6%), schools (13.3%), and sports facilities (12.9%), each with a coverage loss >50%, due to limited AED accessibility., Conclusions: The chance of a bystander defibrillation was tripled, and 30-day survival nearly doubled, when the nearest AED was accessible, compared to inaccessible, at the time of OHCA, underscoring the importance of unhindered AED accessibility., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Study Question: Is maternal age at menarche associated with pubertal development in sons and daughters?, Summary Answer: Maternal age at menarche was associated with pubertal development in both sons and daughters., What Is Known Already: Studies have shown that age at menarche is greatly inherited from mother to daughter, but it remains largely unknown to what extent age at menarche in mothers is associated with timing of puberty in sons., Study Design, Size, Duration: In this population-based study we used data from the Puberty Cohort nested within the Danish National Birth Cohort. Live-born singletons aged 11 were followed from 2012 to 2016., Participants/materials, Setting, Methods: In total, 15 822 children (7697 sons and 8125 daughters) gave half-yearly information on puberty from the age of 11 years until full sexual maturity or 18 years of age through self-administrated questionnaires (participation rate 71%). Information on maternal age at menarche was reported by the mothers during pregnancy. Maternal age at menarche was used both as a continuous and as a categorical variable (earlier, same time or later than peers). A multivariable regression model for interval-censored data was used., Main Results and the Role of Chance: Maternal age at menarche was positively associated with timing of genital development, pubic hair development, first ejaculation of semen, voice break, axillary hair development and acne in sons, and with timing of breast development, pubic hair development, menarche, axillary hair development and acne in daughters. In sons, the associations were of similar strength for all pubertal markers, whereas in daughters, the associations were strongest for breast development and menarche., Limitations, Reasons for Caution: Age at menarche was recalled during pregnancy. However, studies indicate that age at menarche is recalled moderately in adulthood. Information on puberty was self-reported, but inaccuracy of data would probably cause non-differential misclassification., Wider Implications of the Findings: Early maternal age at menarche was associated with earlier pubertal development, and late maternal age at menarche was associated with later pubertal development in both sons and daughters. The largest effect-estimates were for the associations between maternal age at menarche and the daughters' age at menarche and age at breast development., Study Funding/competing Interest(s): The study was funded by the Danish Council for Independent Research (4183-00152). There are no competing interests., Trial Registeration Number: N/A.

Introduction: In-hospital cardiac arrest has a poor prognosis and often occurs in patients lying in a hospital bed. A bed mattress is a soft compressible surface that may decrease cardiopulmonary resuscitation (CPR) quality. Often hospital CPR training is performed with a manikin on the floor., Aim: To study CPR quality following realistic CPR training with a manikin in a bed compared with one on the floor., Methods: We conducted a randomised controlled study. Healthcare professionals were randomised to CPR training with a manikin in a hospital bed or one on the floor. Data on CPR quality was collected from manikins. The primary outcome measure was chest compression depth., Results: In total, 108 healthcare professionals (age: 40years, female: 94%) were included. The mean chest compression depth was 39mm (standard deviation (SD): 10), for the bed group compared with 38mm (SD: 9) for the floor group, p=0.49. A post hoc analysis showed that regardless of the training method, the participants who optimised their working position by jumping onto the bed or lowering the bed had a median chest compression depth of 39mm (25th-75th percentiles: 33-45) compared with 29mm (25th-75th percentiles: 23-41) for participants who did neither, p=0.04., Conclusion: There was no significant difference in chest compression depth between healthcare professionals who trained CPR on a manikin in a hospital bed compared with one on the floor. Chest compression depth was too shallow in both groups. Irrespective of the training method, participants who optimised their working position performed deeper chest compressions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The Integrative Psychiatric Research (iPSYCH) consortium has established a large Danish population-based Case-Cohort sample (iPSYCH2012) aimed at unravelling the genetic and environmental architecture of severe mental disorders. The iPSYCH2012 sample is nested within the entire Danish population born between 1981 and 2005, including 1 472 762 persons. This paper introduces the iPSYCH2012 sample and outlines key future research directions. Cases were identified as persons with schizophrenia (N=3540), autism (N=16 146), attention-deficit/hyperactivity disorder (N=18 726) and affective disorder (N=26 380), of which 1928 had bipolar affective disorder. Controls were randomly sampled individuals (N=30 000). Within the sample of 86 189 individuals, a total of 57 377 individuals had at least one major mental disorder. DNA was extracted from the neonatal dried blood spot samples obtained from the Danish Neonatal Screening Biobank and genotyped using the Illumina PsychChip. Genotyping was successful for 90% of the sample. The assessments of exome sequencing, methylation profiling, metabolome profiling, vitamin-D, inflammatory and neurotrophic factors are in progress. For each individual, the iPSYCH2012 sample also includes longitudinal information on health, prescribed medicine, social and socioeconomic information, and analogous information among relatives. To the best of our knowledge, the iPSYCH2012 sample is the largest and most comprehensive data source for the combined study of genetic and environmental aetiologies of severe mental disorders.

Background: Approximately 30-40% of heart patients develop anxiety and/or depression, which might influence recovery and long-term survival. Research has suggested that support from relatives may decrease anxiety and depression among heart patients; however, the results are inconsistent and often based on small study populations., Aim: The paper aimed to investigate the association between having supportive relatives and the occurrence of anxiety and depression in heart patients., Methods: A population-based cross-sectional study among Danish patients diagnosed with ischemic heart disease, atrial fibrillation, heart failure, or heart valve disease. Presence of supportive relatives was measured as the degree to which the patients felt that they had relatives they could count on, while symptoms of anxiety and depression were measured by the Hospital Anxiety and Depression Scale (HADS). Multiple logistic regression analyses accounting for confounders were used to examine the association between supportive relatives and anxiety/depression., Results: The questionnaire was answered by 2496 heart patients, corresponding to 50% of the invited population. Patients with low or some degree of supportive relatives had a higher odds ratio (OR) of anxiety than patients with a high degree (OR = 2.20, 95% confidence interval (CI): 1.28-2.37; OR = 1.75, 95% CI: 1.57-3.08, respectively). Likewise, patients with low or some degree of supportive relatives had a higher OR of depression than patients with a high degree (OR = 1.96, 95% CI: 1.40-2.66; OR = 1.93, 95% CI: 1.37-2.60, respectively)., Conclusions: The presence of supportive relatives was found to be associated with lower occurrence of anxiety and depression. Health professionals should focus on including relatives in the treatment and rehabilitation of heart patients.

Aims: The aims were to translate, validate and test the reliability of the Practice Environment Scale of the Nursing Work Index in a Danish context; and to compare Danish nurses' ratings of their nurse work environments with the highest rated work environments, USA magnet hospitals., Background: Patient quality and safety are priorities for managers, administrators and policy makers worldwide. A supportive work environment is an important factor to improve quality and safety. The most used scale to measure the nurse work environment is Practice Environment Scale of the Nursing Work Index. There is no Danish translation of the scale or a comparison of nurse work environment between Denmark and other countries., Methods: The translation and cultural adaption followed the steps recommended by the World Health Organization. Content validity was evaluated using cognitive interviewing in-person and through surveys. The reliability was tested using Cronbach's alpha. Finally, Practice Environment Scale of the Nursing Work Index ratings from 127 nurses were compared with results from Magnet and non-Magnet hospitals using t-tests., Findings: The Danish translation of Practice Environment Scale of the Nursing Work Index had a high validity and reliability. Danish nurses rated their nurse work environment more favourable than nurses in non-Magnet hospitals and at the same level as Magnet hospitals. Lowest Danish scores were found in the two hospital-level subscales in items related to staff nurses' involvement in discussions on daily problems, the visibility of the chief nursing officer and importance of up-to-date nursing documentation., Conclusion: Danish nurses report a supportive nurse work environment with overall scores at the same level as Magnet hospitals. Opportunities for improvement were identified in the subscales., Implications for Nursing and Health Policy: A first step to improve patient quality and safety is addressing factors that influence quality and safety. Using the Danish Practice Environment Scale of the Nursing Work Index, interventions to improve specific areas can be planned, implemented and evaluated. Further, Practice Environment Scale of the Nursing Work Index is a nursing quality indicator that can be included in quality databases in Denmark., (© 2015 International Council of Nurses.)

From June 2014 through February 2015, respiratory samples from 130 Danish patients were screened for enterovirus D68 (EV-D68). Fourteen EV-D68 cases were detected, of which 12 presented with respiratory symptoms, and eight had known underlying disease. The median age of EV-D68 cases was three years (interquartile range: 0–30 years). Acute flaccid paralysis (AFP) was not detected although Danish EV-D68 strains showed > 98% nt identity with EV-D68-strains from AFP cases from the United States and France.

Study Question: Is age of menarche (AOM) associated with subfecundity and/or infertility in adulthood?, Study Answer: A late onset of menarche was associated with a slightly increased risk of subfecundity and infertility., What Is Known Already: Abnormal age at onset of menarche is a risk factor for several diseases later in life, but the effect on infertility is unknown., Study Design, Size and Duration: A cohort study of  73 107 pregnant Danish women enrolled in the Danish National Birth Cohort (DNBC) between 1996 and 2002 with self-reported data on AOM and waiting time to pregnancy (TTP)., Participants/materials, Setting and Methods: Information on AOM and TTP was collected through a computer-assisted telephone interview scheduled in pregnancy Week 12. We estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) using multivariate logistic regression with TTP categorized as subfecundity (TTP ≥6 months) and infertility (TTP >12 months). Multiple imputation was performed to account for missing data., Main Results and the Role of Chance: We found trends towards higher odds of subfecundity and infertility with increasing age of menarche, using 13 years as the starting point. Among women reaching menarche at 15 years, the odds for subfecundity were 1.09 (95% CI: 1.03-1.15), and 1.17 (95% CI: 1.09-1.25) for women reaching menarche later than 15 years compared with the reference group of girls reaching menarche at 13 years. Additionally, women reaching menarche older than 15 years had an OR of infertility of 1.18 (95% CI: 1.08-1.29). Women younger than 11 years at menarche had lower odds of subfecundity. The results were generally attenuated when adjusting for women's age of pregnancy, but the significant positive trend of higher OR for subfecundity persisted, as did the higher OR for subfecundity among women experiencing menarche older than 15 years., Limitations, Reasons for Caution: We used retrospectively collected self-reported information on AOM and TTP. Information on male factors was limited in this cohort. We only included pregnant women and have therefore no data on women with untreated and unsuccessfully treated infertility, limiting the generalizability to women who became pregnant., Wider Implication of the Findings: This study indicates that the onset of menarche at 15 years or later is associated with subfecundity and infertility., Study Funding/competing Interests: The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the DNBC. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the DNBC is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Foundation. This specific study was supported by a scholarship from the Ministry of Science and Innovation. No conflict of interest declared., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Study Question: Does moderate alcohol intake affect menstrual cycle characteristics among women in the Danish population?, Summary Answer: Levels of alcohol exposure as seen in this study do not substantially affect the menstrual cycle., What Is Known Already: Animal studies indicate alcohol-induced disruptions of the reproductive system, but previous epidemiological studies addressing the possible association between alcohol intake and the menstrual cycle are sparse., Study Design, Size, Duration: A cross-sectional study with retrospectively collected data including 82 146 pregnant Danish women in the Danish National Birth Cohort (DNBC) enrolled during the years 1996-2002., Participants/materials, Setting, Methods: Information on weekly alcohol consumption and menstrual cycle characteristics before pregnancy was obtained through a computer-assisted telephone interview in pregnancy Week 12-16. The associations between weekly alcohol consumption and menstrual cycle irregularity (≥7 days difference between cycles) and length (short cycle: ≤24 days, long cycle: ≥32 days) were analysed using logistic regression with weekly alcohol intake categorized into abstainers (0 drinks per week), low (0.5-2.0 drinks per week), moderate (2.5-14.0 drinks per week) and high (14.0-86.5 drinks per week). Estimates are given as adjusted odds ratios with 95% confidence intervals., Main Results and the Role of Chance: The overall participation rate was 60% of the women invited. We found that a high weekly alcohol consumption was not associated with menstrual cycle disturbances. We observed higher odds of irregular and short cycles among abstainers when compared with women with a low weekly alcohol consumption, but found no trend of more cycle disturbances with higher alcohol consumption., Limitations, Reasons for Caution: Possible limitations in our study include a risk of selection bias due to the moderate participation rate and the use of retrospective information on alcohol exposure and menstrual cycle characteristics before getting pregnant. The higher odds of irregular and short cycles among abstainers may reflect other health problems in these women rather than an actual effect of alcohol on the menstrual cycle., Wider Implications of the Findings: The generalizability of the study results is restricted to women who manage to conceive and women who do not use oral contraceptives within 2 months before getting pregnant. This study suggests that the menstrual cycle is not substantially affected by higher alcohol consumption among the participating women., Study Funding/competing Interest(s): Supported by a scholarship from Aarhus University Research Foundation. The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the DNBC. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the DNBC is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Foundation. No conflict of interest declared.

Study Question: Does in utero exposure to constituents of cigarette smoke have a programming effect on daughters' age of menarche and markers of long-term reproductive health?, Summary Answer: In utero exposure to constituents of cigarette smoke was associated with earlier age of menarche and--to a lesser extent--changes in the testosterone profile of the young women., What Is Known Already: Studies observe potential effects of in utero exposure to constituents of cigarette smoke on the intrauterine formation of female gonads, but the consequences on long-term reproductive health in daughters remain unclear., Study Design, Size and Duration: A prospective cohort study was designed using data from 965 pregnant women enrolled prior to a routine 30th-week antenatal examination at a midwifery practice in Denmark from 1988 to 1989 and a follow-up of their 19-21-year-old daughters in 2008., Participants/materials, Setting and Methods: The pregnant women provided information on lifestyle factors during pregnancy, including the exact number of cigarettes smoked per day during the first and the second trimesters. A total of 438 eligible daughters were asked to complete a web-based questionnaire on reproductive health and subsequently invited to participate in a clinical examination during 2008. Of the 367 daughters (84%) who answered the questionnaire, 267 (61%) agreed to further examination. Information on menstrual pattern was provided at examination, blood samples were drawn to be analyzed for serum levels of reproductive hormones [FSH, LH, estradiol (E(2)), sex hormone-binding globulin, anti-Müllerian hormone, dehydroepiandrosterone-sulphate (DHEAS), free testosterone and free E(2)] and number of follicles (2-9 mm) were examined by transvaginal ultrasound. The daughters were divided into three exposure groups according to the level of maternal smoking during first trimester [non-exposed (reference), low-exposed (mother smoking >0-9 cigarettes/day) and high-exposed (mother smoking ≥ 10 cigarettes/day)]. Data were analyzed by multiple regression analyses in which we adjusted for potential confounders. Both crude and adjusted test for trend were carried out using maternal smoking during the first trimester as a continuous variable., Main Results and the Role of Chance: We observed an inverse association between in utero exposure to constituents of cigarette smoke and age of menarche (P = 0.001). Daughters exposed to >0-9 cigarettes/day debuted with -2.7 [95% confidence interval (CI) -5.2 to -0.1] percentage earlier age of menarche, whereas daughters exposed to ≥ 10 cigarettes/day had -4.1 (95% CI: -6.6 to -1.5) percentage earlier age of menarche corresponding to 6.5 (95% CI: -10.7 to -2.2) months. There was a non-significant tendency towards lower levels of testosterone and DHEAS with increasing in utero exposure to constituents of cigarette smoke but no associations with follicle number, cycle length or serum levels of the other reproductive hormones were observed., Limitations and Reasons for Caution: We collected information on age of menarche retrospectively but the recall time was relatively short (2-10 years) and the reported values were within the normal range of Caucasians. Analyses of reproductive hormones are presented only for the group of daughters who were non-users of hormonal contraceptives because users were excluded, leaving only a low number of daughters available for the analyses (n = 75), as reflected in the wide CIs. The analyses of hormones were further adjusted for menstrual phase at time of clinical examination (follicular, ovulation and luteal phase) because blood samples were not collected on a specific day of the menstrual cycle., Wider Implications of the Findings: This study supports the limited evidence of an inverse association between maternal smoking during pregnancy and age of menarche and further addresses to what extent reproductive capacity and hormones may be programmed by maternal smoking during pregnancy. A trend toward earlier maturation of females is suggested to have implications on long-term reproductive function., Study Funding/competing Interest(s): Supported by a scholarship from The Lundbeck Foundation (R93-A8476). No conflict of interest declared.

Aim: To investigate whether sons of gardeners and building painters have increased risk of infertility in comparison with sons of bricklayers, carpenters and electricians., Methods: Participants were men born 1965-1984 in Denmark whose fathers the year before birth had worked as gardeners, painters, bricklayers, carpenters or electricians (N=22,978). Cases of infertility were identified by Danish registers, and participants were followed-up for up to 24 years after their 20th birthday., Results: Sons of gardeners did not have increased risk of infertility. Hazard ratios for sons of painters fluctuated around the null in main analyses but were 1.6 (98% CI: 1.0-2.5) and 1.7 (95% CI: 0.9-3.2) in the subset of participants with smallest risk of paternal exposure misclassification., Conclusions: Working as gardener or building painter was not related to increased risk of infertility among the next generation of males in main analyses. However, inherent limitations in data may have attenuated true associations., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The association between last 5 days of alcohol intake, semen quality and reproductive hormones was estimated in this cross-sectional study among 347 men. Conventional semen characteristics, DNA fragmentation index and reproductive hormones (testosterone, estradiol, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and inhibin B) were determined. There was a tendency towards lower semen characteristics at higher intake of alcohol past 5 days, albeit with no statistically significant dose-response association. The ratio between free estradiol and free testosterone was higher at higher alcohol intake during the 5 days preceding semen sampling. In conclusion, alcohol intake was associated with impairment of most semen characteristics but without a coherent dose-response pattern. The study indicates an association between recent alcohol intake and a hormonal shift towards higher estradiol/testosterone ratio. The hormonal changes observed may over time, lead to adverse effects on semen quality, but longitudinal studies are needed to study this., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background/objectives: Follow-up studies have suggested that total intake of trans fatty acids (TFA) is a risk factor for gain in body weight and waist circumference (WC). However, in a cross-sectional study individual TFA isomers in adipose tissue had divergent associations with anthropometry. Our objective was to investigate the association between intake of TFA from ruminant dairy and meat products and subsequent changes in weight and WC. Furthermore, potential effect modification by sex, age, body mass index and WC at baseline was investigated., Subjects/methods: Data on weight, WC, habitual diet and lifestyle were collected at baseline in a Danish cohort of 30,851 men and women aged 50-64 years. Follow-up information on weight and WC was collected 5 years after enrolment. The associations between intake of ruminant TFA (R-TFA) and changes in weight and WC were analysed using multiple linear regression with cubic spline modelling., Results: Intake of R-TFA, both absolute and energy-adjusted intake, was significantly associated with weight change. Inverse associations were observed at lower intakes with a levelling-off at intakes >1.2 g/day and 0.4 energy percentage (E %). Absolute, but not energy-adjusted, intake of R-TFA was significantly associated with WC change. An inverse association was observed at lower intakes with a plateau above an intake of 1.2 g/day., Conclusions: The present study suggests that intake of R-TFA is weakly inversely associated with changes in weight, whereas no substantial association with changes in WC was found.

Modic changes are of increasing interest, however their age and gender prevalence are not well described. To date, the associations between Modic changes and other common vertebral pathologies have only been described in small samples (n < 100). Our aim was, in a large dataset of people with low back pain, to (1) describe the prevalence of a range of spinal pathoanatomies, and (2) examine the association between Modic changes and stages of intervertebral disc (IVD) pathology. Common pathologies were coded from the lumbar spine MRIs from 4,233 consecutive people imaged while attending a publicly-funded secondary care outpatient facility in Denmark. Prevalence data were calculated by pathology and by vertebral level. Prevalence was also calculated by age and gender categories for Modic changes. The association between stages of IVD pathology (degeneration, bulge, herniation) and Modic changes at L4/5 and L5/S1 was expressed using prevalence ratios (PR) and 95% confidence intervals. The prevalence of Modic changes and IVD pathology were greater in L4/5 and L5/S1, compared with the upper lumbar spine. There was no significant gender difference in prevalence of Modic changes (p = 0.11). The prevalence of IVD disc pathology occurring concurrently with Modic changes ranged from 11.5 to 17.5% (Type 1), 8.5 to 12.7% (Type 2) and 17.1 to 25.6% (Type 1 and/or 2) while the prevalence occurring in the absence of Modic changes ranged from 0.5 to 6.3% (Type 1), 0.3 to 4.9 (Type 2), 0.8 to 9.7% (Type 1 and/or 2). The associated PR for IVD pathology occurring concurrently with Modic changes ranged from 1.8 to 29.2 (p < 0.05). The highest PR (29.2) was between degeneration and Modic changes, indicating that it is rare for Modic changes to occur without disc degeneration. Spinal pathoanatomy was common in this population, particularly IVD pathologies, and a consistent trend of a relatively greater prevalence in the lower lumbar spine was identified. Modic changes were more likely to be present among individuals with IVD pathology than without, which may implicate mechanical factors as being one aetiological pathway for Modic changes, although other hypotheses may equally explain this association.

Background: Sex hormones closely regulate development of the male genital organs during fetal life. The hypothesis that xenobiotics may disrupt endogenous hormonal signalling has received considerable scientific attention, but human evidence is scarce., Objectives: We analyse occurrence of hypospadias and cryptorchidism according to maternal and paternal occupational exposure to possible endocrine disrupting chemicals., Methods: We conducted a follow-up study of 45,341 male singleton deliveries in the Danish National Birth Cohort during 1997-2009. Information on work during pregnancy was obtained by telephone interviews around gestational week 16. Parents' job titles were classified according to DISCO-88. A job exposure matrix for endocrine disrupting chemicals (EDCs) was implemented to assess occupational exposures. The Medical Birth and National Hospital Register provided data on congenital anomalies diagnosed at birth or during follow-up, which ended in 2009. Crude and adjusted hazard ratios (HR) were obtained from Cox regression models., Results: Among all pregnancies, 6.3% were classified as possibly or probably exposed to EDCs. The most prevalent occupations conferring possible exposure were cleaners, laboratory technicians, hairdressers and agricultural workers (58% of all potentially exposed). The final cumulative incidence of cryptorchidism in boys was 2.2% (1002 cases), and of hypospadias 0.6% (262 cases). The occurrence of hypospadias increased when mothers were probably [HRa = 1.8 (95% CI 1.0-2.6)] or possibly exposed to one or more EDCs [HRa = 2.6 (95% CI 1.8-3.4). Possible paternal exposure to heavy metals increased the risk of hypospadias [HRa 2.2 (95% CI: 1.0-3.4)] and cryptorchidism [HRa 1.9 (95% CI: 1.1-2.7)]. None of the exposure groups reached statistical significance., Conclusion: The study provides some but limited evidence that occupational exposure to possible endocrine disrupting chemicals during pregnancy increases the risk of hypospadias.

Background: Little is known about the long-term consequences of sickness presence (ie, going to work despite ill-health), although one study suggests an association with coronary heart disease. This study examined the effect of sickness presence on future long-term sickness absence., Methods: Information from a random sample of 11 838 members of the Danish core workforce was collected from questionnaires, containing questions about work, family and attitudes towards sickness absence. Information on prospective sickness absence spells of at least 2 weeks was derived from an official register during a follow-up period of 1.5 years., Results: Sickness presence is associated with long-term sickness absence of at least 2 weeks' duration as well as with spells lasting at least 2 months. Participants who had gone to work ill more than six times in the year prior to baseline had a 74% higher risk of becoming sick-listed for more than 2 months, even when controlling for a wide range of potential confounders as well as baseline health status and previous long-term sickness absence. The association was consistent for most subgroups of employees reporting various symptoms, but either disappeared or became insignificant when analysing subgroups of employees with specific chronic diseases., Conclusions: Going to work ill repeatedly is associated with long-term sickness absence at a later date. For this reason, researchers and policy-makers should consider this phenomenon more carefully when planning future studies of sickness absence or when laying out new policies.