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BACKGROUND: Bystander-initiated basic life support (BLS) plays an important role in improving survival after out-of-hospital cardiac arrest. In 2009, laws mandating BLS course participation when acquiring a driver's licence were implemented in Denmark. The aim of this study was to characterise Danish BLS course participants.METHODS: This study is a Danish, registry-based, follow-up study that examined all Danish BLS course participants from 2016 to 2019. Data concerning BLS course participation were supplied by the major Danish BLS course providers. Socio-economic and healthcare data on all Danish inhabitants were assessed using national registers from Statistics Denmark.RESULTS: Between January 1, 2016, and January 1, 2020, 3.6% of the entire adult population of Denmark attended certified BLS courses annually. Since the implementation of a law mandating BLS course participation when acquiring a driver licence in 2009, approximately 44% of the adult population has participated in a BLS course. BLS course participants were commonly younger and healthier than the general population (mean 31.3 years old vs. 51.3 years old, P < 0.001). Furthermore, law-mandated BLS course participants had a lower disposable income (adjusted OR: 0.23; 95% CI: 0.23-0.23; P < 0.001) and were more likely to live in rural areas (adjusted OR: 0.57; 95% CI: 0.57-0.58; P < 0.001).CONCLUSION: In Denmark, 3.6% of the entire adult population attend certified courses annually. BLS participants are commonly male, younger, healthier, less likely to have small children in the household, and more likely to live in rural areas. Law-mandated BLS course participation prior to acquiring a driver's licence has been successful in reaching segments of the society that are known to have limited participation.

BackgroundDuring the COVID-19 pandemic, decreasing rates of hospitalisations for cardiovascular disease raised concerns for undertreatment, particularly for vulnerable groups. We investigated how the initial COVID-19 public lockdown, impacted the risk of being hospitalised with a major cardiovascular event (MCE: myocardial infarction/stroke/heart failure) according to educational level.MethodsWe grouped all Danish residents according to educational attainment level (low, medium, high) and age (40–59, 60–69, ≥70 years). In each group, we calculated the age-standardised and sex standardised risk of MCE hospitalisation in the initial COVID-19 lockdown-period (13 March 2020–3 May 2020) and in the corresponding calendar period in 2019. We calculated age-standardised and sex-standardised risks to investigate whether the COVID-19 lockdown had a differential effect on MCE incidence according to educational level.ResultsIn the period in 2019, 2700 Danish residents were hospitalised with MCE, compared with only 2290 during the lockdown. During lockdown, the risk of hospitalisation for MCE decreased among residents aged ≥70 with low education (risk difference (RD) −46.2 (−73.2; −19.2) per 100,000) or medium education (RD −23.2 (−50.8; 4.3) per 100 000), but not among residents with high education (RD 5.1 (−32.3; 42.5), per 100 000). The risk of hospitalisation for MCE did not decrease significantly for the younger age groups.ConclusionsThe COVID-19 lockdown is associated with a reduced incidence for MCE, especially among low educated, elderly residents. This raises concern for undertreatment that without clinical awareness and action may widen the educational gap in cardiovascular morbidity and mortality.

Denmark implemented early widespread social distancing to reduce pressure on the healthcare system from the coronavirus disease 2019 (COVID-19) pandemic, with the aims to reduce mortality. Unintended consequences might be delays in treatment for other diseases and subsequent mortality. We examined national all-cause mortality comparing weeks 1–27 in 2020 and 2015–2019. This registry-based study used Danish national registry data until 5 July 2020. We examined all-cause mortality rates among all deaths recorded from 2015 to 2020 and among chronic conditions (cardiovascular (cardiac & circulatory), chronic pulmonary, chronic kidney disease, cancer, and diabetes), comparing each week in 2020 to weeks in 2015–2019. In 2020, there were 28,363 deaths in weeks 1–27 (30 December 2019–5 July 2020), the mean deaths in 2015–2019 were 28,630 deaths (standard deviation 784). Compared to previous years, the mortality rate in weeks 3–10 of 2020 was low, peaking in week 14 (17.6 per 100,000 persons in week 9, 19.9 per 100,000 in week 14). Comorbidity prevalence among deceased individuals was similar in 2020 and 2015–2019: 71.1% of all deceased had a prior cardiovascular diagnosis, 30.0% of all deceased had a prior cardiac diagnosis. There were 493 deaths with COVID-19 in weeks 11–27, (59.8% male), and 75.1% had a prior cardiovascular diagnosis. Weekly mortality rates for pre-existing chronic conditions peaked in week 14, and then declined. During the COVID-19 pandemic, due to timely lockdown measures, the mortality rate in Denmark has not increased compared to the mortality rates in the same period during 2015–2019. Electronic supplementary material The online version of this article (10.1007/s10654-020-00680-x) contains supplementary material, which is available to authorized users.

INTRODUCTION: Family socioeconomic status influences pupils' academic achievements, and studies have established positive associations between physical fitness and academic achievements. However, whether physical fitness mediates the relationship remains unknown.OBJECTIVE: We investigated if pupils' physical fitness mediates the pathway between family socioeconomic status and academic achievement using causal inference-based mediation analysis.METHODS: This study included 527 girls and 552 boys between 13 and 15 years of age from the Danish municipality of Aalborg. Physical fitness was measured through VO2max tests in 2010 and demographic data were obtained from nationwide registers. Family socioeconomic status was classified into four levels ranging from 1 to 4, where level 1 represents the lowest and level 4 the highest based on either family income or education.RESULTS: Controlling for sex, ethnicity, age, and parents' cohabitation status, all total effects display higher academic achievement with increased family socioeconomic status. Splitting the effects, the direct effects reveal the existence of other pathways not involving physical fitness. The indirect effects established physical fitness as a mediator showing that pupils from family socioeconomic status levels one, three, and four changes grade by - 0.13 [95% confidence interval (CI) - 0.26, - 0.01], 0.07 (95% CI 0.00, 0.14), and 0.24 (95% CI 0.14, 0.34), respectively, compared to socioeconomic status level two. The corresponding proportions mediated are 18% (95% CI 1, 57), 6% (95 CI 0, 13), and 12% (95% CI 7, 18) when family socioeconomic status is based on education. Classifying family socioeconomic status on income, pupils from family socioeconomic status levels one, three, and four show grade changes of - 0.07 (95% CI - 0.16, 0.02), 0.22 (95% CI 0.13, 0.32), and 0.26 (95% CI 0.15, 0.37), respectively, compared to socioeconomic status level two. The corresponding proportions mediated are 12% (95% CI - 6, 41), 30% (95% CI 16, 54), and 20% (95% CI 12, 32).CONCLUSION: In conclusion, pupils' physical fitness partially mediated the pathway between family socioeconomic status and academic achievement.

Objective: Psychiatric disorders have been associated with unfavourable outcome following respiratory infections. Whether this also applies to coronavirus disease 2019 (COVID-19) has been scarcely investigated. Methods: Using the Danish administrative databases, we identified all patients with a positive real-time reverse transcription-polymerase chain reaction test for COVID-19 in Denmark up to and including 2 January 2021. Multivariable cox regression was used to calculate 30-day absolute risk and average risk ratio (ARR) for the composite end point of death from any cause and severe COVID-19 associated with psychiatric disorders, defined using both hospital diagnoses and redemption of psychotropic drugs. Results: We included 144,321 patients with COVID-19. Compared with patients without psychiatric disorders, the standardized ARR of the composite outcome was significantly increased for patients with severe mental illness including schizophrenia spectrum disorders 2.43 (95% confidence interval [CI], 1.79–3.07), bipolar disorder 2.11 (95% CI, 1.25–2.97), unipolar depression 1.70 (95% CI, 1.38–2.02), and for patients who redeemed psychotropic drugs 1.70 (95% CI, 1.48–1.92). No association was found for patients with other psychiatric disorders 1.13 (95% CI, 0.86–1.38). Similar results were seen with the outcomes of death or severe COVID-19. Among the different psychiatric subgroups, patients with schizophrenia spectrum disorders had the highest 30-day absolute risk for the composite outcome 3.1% (95% CI, 2.3–3.9%), death 1.2% (95% CI, 0.4–2.0%) and severe COVID-19 2.7% (95% CI, 1.9–3.6%). Conclusion: Schizophrenia spectrum disorders, bipolar disorder, unipolar depression and psychotropic drug redemption are associated with unfavourable outcomes in patients with COVID-19.

Aims To examine socioeconomic differences in care and outcomes in a 1-year period beginning 30 days after hospital discharge for first-time atrial fibrillation or flutter (AF) hospitalization. Methods and results This nationwide register-based follow-up cohort study investigated AF 30-day discharge survivors in Denmark during 2005–2014 and examined associations between patient’s socioeconomic status (SES) and selected outcomes during a 1-year follow-up period beginning 30 days post-discharge after first-time hospitalization for AF. Patient SES was defined in four groups (lowest, second lowest, second highest, and highest) according to each patient’s equivalized income. SES of the included 150 544 patients was: 27.7% lowest (n = 41 648), 28.1% second lowest (n = 42 321), 23.7% second highest (n = 35 656), and 20.5% highest (n = 30 919). Patients of lowest SES were older and more often women. Within 1-year follow-up, patients of lowest SES were less often rehospitalized or seen in outpatient clinics due to AF, or treated with cardioversion or ablation and were slightly more often diagnosed with stroke and heart failure (HF) and significantly more likely to die (16.1% vs. 14.9%, 11.3% and 8.1%). Hazard ratios for all-cause mortality were 0.64 (95% confidence interval 0.61–0.68) for highest vs. lowest SES, adjusted for CHA2DS2-VASc score, chronic obstructive pulmonary disease, rate- and rhythm-controlling drugs, and cohabitation status. Conclusion In 30-day survivors of first-time hospitalization due to AF, lowest SES is associated with increased 1-year all-cause and cardiovascular mortality and fewer cardioversions, ablations, readmissions, and outpatient contacts due to AF. Our findings indicate a need for socially differentiated rehabilitation following hospital discharge for first-time AF.

Background On 13 March 2020, the Danish authorities imposed extensive nationwide lockdown measures to prevent the spread of the coronavirus disease 2019 (COVID-19) and reallocated limited healthcare resources. We investigated mortality rates, overall and according to location, in patients with established cardiovascular disease before, during, and after these lockdown measures. Methods and results Using Danish nationwide registries, we identified a dynamic cohort comprising all Danish citizens with cardiovascular disease (i.e. a history of ischaemic heart disease, ischaemic stroke, heart failure, atrial fibrillation, or peripheral artery disease) alive on 2 January 2019 and 2020. The cohort was followed from 2 January 2019/2020 until death or 16/15 October 2019/2020. The cohort comprised 340 392 and 347 136 patients with cardiovascular disease in 2019 and 2020, respectively. The overall, in-hospital, and out-of-hospital mortality rate in 2020 before lockdown was significantly lower compared with the same period in 2019 [adjusted incidence rate ratio (IRR) 0.91, 95% confidence interval (CI) CI 0.87–0.95; IRR 0.95, 95% CI 0.89–1.02; and IRR 0.87, 95% CI 0.83–0.93, respectively]. The overall mortality rate during and after lockdown was not significantly different compared with the same period in 2019 (IRR 0.99, 95% CI 0.97–1.02). However, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during and after lockdown compared with the same period in 2019 (in-hospital, IRR 0.92, 95% CI 0.88–0.96; out-of-hospital, IRR 1.04, 95% CI1.01–1.08). These trends were consistent irrespective of sex and age. Conclusions Among patients with established cardiovascular disease, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during lockdown compared with the same period in the preceding year, irrespective of age and sex.

Observational evidence suggests that mask wearing mitigates SARS-CoV-2 transmission. It is uncertain if this observed association arises through protection of uninfected wearers (protective effect), via reduced transmission from infected mask wearers (source control), or both. This randomized controlled trial investigates whether recommending surgical mask use when outside the home reduces wearers' risk for SARS-CoV-2 infection in a setting where masks were uncommon and not among recommended public health measures., Visual Abstract. Effectiveness of Mask Recommendation for Preventing SARS-CoV-2 Infection Observational evidence suggests that mask wearing mitigates SARS-CoV-2 transmission. It is uncertain if this observed association arises through protection of uninfected wearers (protective effect), via reduced transmission from infected mask wearers (source control), or both. This randomized controlled trial investigates whether recommending surgical mask use when outside the home reduces wearers' risk for SARS-CoV-2 infection in a setting where masks were uncommon and not among recommended public health measures. Visual Abstract. Effectiveness of Mask Recommendation for Preventing SARS-CoV-2 Infection Observational evidence suggests that mask wearing mitigates SARS-CoV-2 transmission. It is uncertain if this observed association arises through protection of uninfected wearers (protective effect), via reduced transmission from infected mask wearers (source control), or both. This randomized controlled trial investigates whether recommending surgical mask use when outside the home reduces wearers' risk for SARS-CoV-2 infection in a setting where masks were uncommon and not among recommended public health measures., Background: Observational evidence suggests that mask wearing mitigates transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is uncertain if this observed association arises through protection of uninfected wearers (protective effect), via reduced transmission from infected mask wearers (source control), or both. Objective: To assess whether recommending surgical mask use outside the home reduces wearers' risk for SARS-CoV-2 infection in a setting where masks were uncommon and not among recommended public health measures. Design: Randomized controlled trial (DANMASK-19 [Danish Study to Assess Face Masks for the Protection Against COVID-19 Infection]). (ClinicalTrials.gov: NCT04337541) Setting: Denmark, April and May 2020. Participants: Adults spending more than 3 hours per day outside the home without occupational mask use. Intervention: Encouragement to follow social distancing measures for coronavirus disease 2019, plus either no mask recommendation or a recommendation to wear a mask when outside the home among other persons together with a supply of 50 surgical masks and instructions for proper use. Measurements: The primary outcome was SARS-CoV-2 infection in the mask wearer at 1 month by antibody testing, polymerase chain reaction (PCR), or hospital diagnosis. The secondary outcome was PCR positivity for other respiratory viruses. Results: A total of 3030 participants were randomly assigned to the recommendation to wear masks, and 2994 were assigned to control; 4862 completed the study. Infection with SARS-CoV-2 occurred in 42 participants recommended masks (1.8%) and 53 control participants (2.1%). The between-group difference was −0.3 percentage point (95% CI, −1.2 to 0.4 percentage point; P = 0.38) (odds ratio, 0.82 [CI, 0.54 to 1.23]; P = 0.33). Multiple imputation accounting for loss to follow-up yielded similar results. Although the difference observed was not statistically significant, the 95% CIs are compatible with a 46% reduction to a 23% increase in infection. Limitation: Inconclusive results, missing data, variable adherence, patient-reported findings on home tests, no blinding, and no assessment of whether masks could decrease disease transmission from mask wearers to others. Conclusion: The recommendation to wear surgical masks to supplement other public health measures did not reduce the SARS-CoV-2 infection rate among wearers by more than 50% in a community with modest infection rates, some degree of social distancing, and uncommon general mask use. The data were compatible with lesser degrees of self-protection. Primary Funding Source: The Salling Foundations.

Aims To investigate whether incident atrial fibrillation or flutter (AF) diagnosis increases the risk of psychiatric outcomes compared with the general population. Methods and results First-time AF patients and population controls naive to psychiatric disease or filled prescriptions for psychotropic drugs were identified in Danish nationwide registries during 2005–14. AF patients were matched 1:2 with exposure density matching. Patients and controls were compared for 1-year cumulative incidences of depression, anxiety, and stress disorders, and for filled drug prescriptions for antidepressant, anxiolytic, selected antipsychotics, and hypnotics. Lastly, we examined 1-year cumulative incidences of a composite endpoint of the above-mentioned diagnoses or drug redemptions. We included 146 377 AF patients and 292 754 matched controls, 55% men and median age 74 (25–75% 65–82) years. AF patients had significantly higher cumulative incidences of composite endpoints. Furthermore, filled prescriptions for anxiolytics and hypnotics were significantly higher for AF patients compared with healthy population controls. The cumulative incidence of the composite endpoint was significantly higher in AF patients relative to controls 11.1% vs. 8.3%. For the composite endpoint, a significantly higher risk was apparent both in unadjusted (HR: 2.76, 95% CI: 2.67–2.85) and adjusted (HR: 2.51, 95% CI: 2.43–2.60) models for AF patients vs. controls in the first 3 months after study inclusion. Conclusion First-time AF patients were significantly more likely to have psychiatric outpatient or hospital contacts and to fill prescriptions for psychotropic drugs compared with healthy population controls. The risk was significantly elevated only during the first 3 months after AF diagnosis.

Aims Pre-existing cardiovascular diseases (CVDs) have been proposed to identify patients at higher risk of adverse coronavirus disease 2019 (COVID-19) outcomes, but existing evidence is conflicting. Thus, it is unclear whether pre-existing CVDs are independently important predictors for severe COVID-19.Methods and results In a nationwide Danish cohort of hospital-screened COVID-19 patients aged ≥40, we investigated if pre-existing CVDs predict the 30-day risk of (i) composite outcome of severe COVID-19 and (ii) all-cause mortality. We estimated 30-day risks using a Cox regression model including age, sex, each CVD comorbidity, chronic obstructive pulmonary disease-asthma, diabetes, and chronic kidney disease. To illustrate CVD comorbidities’ importance, we evaluated the predicted risks of death and severe infection, for each sex, along ages 40–85. In total, 4090 COVID-19 hospital-screened patients were observed as of 26 August 2020; 22.1% had ≥1 CVD, 23.7% had severe infection within 30 days and 12.6% died. Predicted risks of both outcomes at age 75 among men with single CVD comorbidities did not differ in clinically meaningful amounts compared with men with no comorbidities risks for the composite outcome of severe infection; women with heart failure (28.2%; 95% CI 21.1–37.0%) or atrial fibrillation (30.0%; 95% CI: 24.2–36.9%) showed modest increases compared with women with no comorbidities (24.0%; 95% CI: 21.4–26.9%).Conclusions The results showing only modest effects of CVDs on increased risks of poor COVID-19 outcomes are important in allowing public health authorities and clinicians to provide more tailored guidance to cardiovascular patients, who have heretofore been grouped together as high risk due to their disease status.

Recommendations regarding ibuprofen use in relation to coronavirus disease 2019 (COVID-19) have been conflicting. We examined the risk of severe COVID-19 between ibuprofen-prescribed and non-ibuprofen patients with COVID-19 in a nationwide register-based study of patients with COVID-19 in Denmark between the end of February 2020 and May 16, 2020. Patients with heart failure (n = 208), 14 days before COVID-19 vs. ≤ 14 days of COVID-19 were 17.1% (95% CI 12.3–22.0) vs. 14.3% (95% CI 7.1–23.1). In conclusion, in this nationwide study, there was no significant association between ibuprofen prescription claims and severe COVID-19.

It remains unknown how Coronavirus disease-2019 (COVID-19) prevention measures implemented on March 12, 2020, have affected the rate of pediatric infection-related hospitalizations in Denmark. Therefore, we investigated the rate of pediatric infection–related hospitalizations during the COVID-19 pandemic. We used a retrospective cohort design and included all Danish children < 18 years. Infection-related hospitalizations were assessed during study periods in 2020 vs. 2018/2019, and we computed incidence rate ratios (IRRs) with 95% confidence intervals (CIs) using Poisson regression. In the 2020 study period, 3093 children were hospitalized with an infection, while the corresponding figures for 2018 and 2019 study periods were 4824 and 3830, respectively. When comparing the 2020 to the 2018/2019 study period prior to nationwide lockdown, we observed a decline in infection-related hospitalizations (12.68 (95% CI, 12.22–13.16) vs. 15.49 (95% CI, 15.12–15.86) per 1000 person-years). We further observed decreased IRRs, especially during the lockdown period (week 11: 0.64 (95% CI, 0.55–0.75); week 12: 0.26 (95% CI, 0.21–0.33); week 13: 0.13 (95% CI, 0.10–0.19)). Conclusion: The rate of pediatric infection-related hospitalizations in Denmark declined during the COVID-19 pandemic in 2020 compared to that in 2018/2019, with a 36% decline during initiation of the nationwide lockdown period.What is Known:• Due to the COVID-19 pandemic, several countries have implemented mitigation strategies such as lockdown of non-critical business functions. Most of these strategies have previously been proven effective on interruption of infection transmission.• It remains unclear how the mitigation strategies have affected the rate of pediatric infection–related hospitalizations.What is New:• Insight on how COVID-19 prevention measures have affected the frequency of infection-related hospitalization.• Valuable knowledge on how to act in potential future pandemics. Supplementary Information The online version contains supplementary material available at 10.1007/s00431-021-03934-2.

Background and Objectives Male sex has been associated with severe coronavirus disease 2019 (COVID-19) infection. We examined the association between male sex and severe COVID-19 infection and if an increased risk remains after adjustment for age and comorbidities. Methods Nationwide register-based follow-up study of COVID-19 patients in Denmark until 16 May 2020. Average risk ratio comparing 30-day composite outcome of all-cause death, severe COVID-19 diagnosis or intensive care unit (ICU) admission for men versus women standardized to the age and comorbidity distribution of all patients were derived from multivariable Cox regression. Included covariates were age, hypertension, diagnoses including obesity, alcohol, sleep apnea, diabetes, chronic obstructive pulmonary disease, previous myocardial infarction (MI), ischemic heart disease (IHD), heart failure (HF), atrial fibrillation (AF), stroke, peripheral artery disease, cancer, liver, rheumatic, and chronic kidney disease (CKD). Results Of 4842 COVID-19 patients, 2281 (47.1%) were men. Median age was 57 [25%–75% 43–73] for men versus 52 [38–71] for women (P < .001); however, octogenarians had equal sex distribution. Alcohol diagnosis, diabetes, hypertension, sleep apnea, prior MI and IHD (all P < .001) as well as AF, stroke, and HF (all P = .01) were more often seen in men, and so was CKD (P = .03). Obesity diagnosis (P < .001) were more often seen in women. Other comorbidity differences were insignificant (P > .05). The fully adjusted average risk ratio was 1.63 [95% CI, 1.44–1.84]. Conclusions Men with COVID-19 infection have >50% higher risk of all-cause death, severe COVID-19 infection, or ICU admission than women. The excess risk was not explained by age and comorbidities.

Background: Initially, the World Health Organization (WHO) and national health boards issued a warning against NSAID use in corona virus disease 2019 (COVID-19) patients and recommended that paracetamol or acetaminophen instead should be administered. However, later and current WHO and European Medicine Agency recommendations do not call for avoidance of ibuprofen in COVID-19 patients. Given the current uncertainty of drug safety for NSAID use in patients with COVID-19, we performed a nationwide register-based study on the association of recent ibuprofen exposure and COVID-19 severity. Methods: Using national administrative databases, we identified COVID-19 patients in Denmark between end of February 2020 and April 2, 2020. Patients Results: Among 1,872 patients, 46 (2.5%) were exposed to ibuprofen prior to COVID-19 infection. Patients with recent ibuprofen exposure tended to be older and more likely to have hypertension, diabetes, myocardial infarction, chronic obstructive pulmonary disease, and cancer, though all insignificant (P>0.05). When adjusting for these covariates, odds ratio was 1.57 [95% CI 0.72-3.38], with 12 ibuprofen-exposed patients meeting the endpoint (26.1% [95% CI 13.4-38.8%]) versus 272 unexposed patients (14.9% [95% CI 13.4-16.4%]), P=0.15. Conclusion: The association between ibuprofen and severe COVID-19 was insignificant, although with a trend towards increased disease severity risk.

ObjectivesIn utero exposure to antiepileptic drugs has previously been associated with adverse outcome among offspring, but evidence on longer term milestone development remains limited. We investigated the association between in utero exposure to antiepileptic drugs and learning disabilities in the first year of compulsory education among offspring and assessed which antiepileptic drugs carried the highest risk.MethodsThis population-based case–cohort study used Danish nationwide register data from 2005 to 2008. Cases were offspring exposed to antiepileptic drugs in utero, and controls were unexposed offspring of mothers previously redeeming antiepileptic drug prescriptions. Offspring were followed from birth until the first year of compulsory education from 2011 to 2015. Learning disabilities were defined as mental retardation, specific developmental disorders, autism spectrum disorders, emotional/behavioural disorders or having special educational needs. Logistic regression was used to compute ORs with 95% CIs adjusted for potential confounding.ResultsOf 117 475 incident singleton births, 636 cases and 434 controls were included (median age: 6.1 years, males: 55.7%). Learning disabilities were identified among 7.1% cases compared with 3.7% for controls. During any trimester, the adjusted OR of the association between in utero exposure to antiepileptic drugs and learning disabilities was 2.20 (95% CI 1.16 to 4.17). Among cases not exposed to polytherapy (n=556), in utero exposure to lamotrigine compared with another antiepileptic drug was associated with the lowest adjusted risk (OR 0.42, 95% CI 0.19 to 0.92), and valproate carried a higher risk (OR 4.67, 95% CI 1.73 to 12.59).ConclusionIn utero exposure to antiepileptic drugs was significantly associated with learning disabilities among offspring. Lamotrigine should preferentially be considered over, for example, valproate if clinically feasible.

Aims To compare the hazard of all-cause, chronic obstructive pulmonary disease (COPD) and heart failure (HF) hospitalization in carvedilol vs. metoprolol/bisoprolol/nebivolol users with COPD and concurrent HF from 2009 to 2012, and to evaluate the use and persistence in treatment of these β-blockers, their impact on the risk of COPD-related hospitalization, and the factors important for their selection. Methods and results Cox and logistic regression were used for both unadjusted and adjusted analyses. Carvedilol users had a higher hazard of being hospitalized for HF compared with metoprolol/bisoprolol/nebivolol users in both the unadjusted [hazard ratio (HR) 1.74; 95% confidence interval (CI) 1.65-1.83] and adjusted (HR 1.61; 95% CI 1.52-1.70) analyses. No significant differences were found for all-cause and COPD hospitalization between the two groups. Carvedilol users had a significant lower restricted mean persistence time than metoprolol/bisoprolol/nebivolol users. Patients exposed to carvedilol had an odds ratio (OR) of 1.38 (95% CI 1.23-1.56) for being hospitalized due to COPD within 60 days after redeeming the first carvedilol prescription, which was similar to that observed in metoprolol/bisoprolol/nebivolol users (OR 1.37; 95% CI 1.27-1.48). Patients with concurrent chronic kidney disease had a higher probability of receiving carvedilol (OR 1.16; 95% CI 1.04-1.29). Conclusion Carvedilol prescription carried an increased hazard of HF hospitalization and lower restricted mean persistence time among patients with COPD and concurrent HF. Additionally, we found a widespread phenomenon of carvedilol prescription at variance with the European Society of Cardiology guidelines and potential for improving the proportion of patients treated with β-blockers.

Rationale: Gender-related differences in asthma prevalence, pathophysiology and clinical features induced by sex steroids have been investigated, however, how gender influences response to asthma treatments in routine clinical practice have not yet been elucidated fully. This aspect is crucial for montelukast considering the jeopardization of asthmatic patients that benefit from this treatment and the existence of evidence of gender differences in leukotriene levels. Therefore, to fulfill this medical need, we investigated the role of gender on a set of montelukast' effectiveness surrogates in adults and pediatric patients with asthma. Methods: The study settings were Napoli 2 Local Health Unit (southern Italy) and the entire Danish territory. The study population was composed of adult and pediatric patients with asthma. Cumulative incidence curves, unadjusted and adjusted Cox regression were used as statistical models to compare aforementioned outcomes between genders. Results: Adult Italian male users of montelukast had a statistically lower persistence in montelukast treatment compared to female users. In the adjusted analyses, they had a higher hazard of montelukast' withdrawal (Hazard Ratio [HR] 1.07; 95% Confidence Interval [CI] 1.01-1.14), add-on/switch to a long-term treatment for asthma following montelukast withdrawal (HR 1.72; 95%CI 1.39-2.12), and rescue therapy with short-acting β2 agonist (HR 1.24; 95%CI 1.04-1.47). In the adult Danish cohort, we also found that male users had higher a hazard of rescue therapy with oral corticosteroids (HR 1.10; 95%CI 1.04-1.16). In the pediatric cohorts, no statistically significant differences were observed between genders for aforementioned outcomes. Conclusions: In adults, male gender was associated with increased hazards of montelukast discontinuation, add-on/switch to a long-term treatment for asthma following montelukast withdrawal, and rescue therapy with oral corticosteroids or short-acting β2 agonist when compared to the female gender. As expected, these associations were reversed or absent in pediatric patients. © 2018 Sessa, Mascolo, D'Agostino, Casciotta, D'Agostino, Michele, Polverino, Spaziano, Andersen, Kragholm, Rossi, Torp-Pedersen and Capuano. Rationale: Gender-related differences in asthma prevalence, pathophysiology and clinical features induced by sex steroids have been investigated, however, how gender influences response to asthma treatments in routine clinical practice have not yet been elucidated fully. This aspect is crucial for montelukast considering the jeopardization of asthmatic patients that benefit from this treatment and the existence of evidence of gender differences in leukotriene levels. Therefore, to fulfill this medical need, we investigated the role of gender on a set of montelukast' effectiveness surrogates in adults and pediatric patients with asthma. Methods: The study settings were Napoli 2 Local Health Unit (southern Italy) and the entire Danish territory. The study population was composed of adult and pediatric patients with asthma. Cumulative incidence curves, unadjusted and adjusted Cox regression were used as statistical models to compare aforementioned outcomes between genders. Results: Adult Italian male users of montelukast had a statistically lower persistence in montelukast treatment compared to female users. In the adjusted analyses, they had a higher hazard of montelukast' withdrawal (Hazard Ratio [HR] 1.07; 95% Confidence Interval [CI] 1.01-1.14), add-on/switch to a long-term treatment for asthma following montelukast withdrawal (HR 1.72; 95%CI 1.39-2.12), and rescue therapy with short-acting β2 agonist (HR 1.24; 95%CI 1.04-1.47). In the adult Danish cohort, we also found that male users had higher a hazard of rescue therapy with oral corticosteroids (HR 1.10; 95%CI 1.04-1.16). In the pediatric cohorts, no statistically significant differences were observed between genders for aforementioned outcomes. Conclusions: In adults, male gender was associated with increased hazards of montelukast discontinuation, add-on/switch to a long-term treatment for asthma following montelukast withdrawal, and rescue therapy with oral corticosteroids or short-acting β2 agonist when compared to the female gender. As expected, these associations were reversed or absent in pediatric patients.

OBJECTIVE: Data on special education in offspring exposed to selective serotonin reuptake inhibitors (SSRIs) in utero are lacking. We examined associations of in utero SSRI exposure with special education needs and delayed elementary school start.METHODS: A population-based case-cohort study using Danish nationwide birth and prescription registry data from 2005 to 2008. Follow-up ends during 2011-2015 to capture special education needs during and delayed entry to the first elementary school year. Cases were in utero SSRI-exposed offspring. Cohort-controls were SSRI-unexposed offspring of mothers previously on SSRIs. We reported odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for relevant potential confounders.RESULTS: Of 117 475 first-incident non-multiple pregnancy births, 3314 were SSRI-exposed, and 3536 were unexposed. Among SSRI-exposed offspring, 3.2% (n = 98) had special school needs vs. 2.4% (n = 77) in unexposed offspring, P-value=0.048. Correspondingly, 12.3% (n = 383) among SSRI-exposed children had delayed school entry vs. 9.4% (n = 308) in unexposed offspring, P-value < 0.001. Adjusted OR for the association with special school needs was 1.12 (95% CI 0.82-1.55; P-value = 0.48) and 1.38 (95% CI 0.90-2.13; P-value = 0.14) for exposure in all three trimesters. The corresponding adjusted ORs for delayed school entry were 1.17 (95% CI 0.99-1.38; P-value = 0.073) and 1.40 (95% CI 1.11-1.76; P-value = 0.004).CONCLUSION: In utero SSRI exposure in all three trimesters was associated with delayed elementary school start but not special education needs.

Background Some studies have found positive associations between physical fitness and academic achievements. Pupils’ academic achievements should indicate scholastic abilities to commence a post-compulsory education. However, the effect magnitude of physical fitness and academic achievements on commencement in post-compulsory education is unknown. We examined the pathways between physical fitness and academic achievement on pupils’ commencement in post-compulsory education. Methods This historical cohort study followed 530 girls and 554 boys from the Danish municipality of Aalborg in the period 2008–2014, 13 to 15 years old in 2010. Physical fitness was assessed through a watt-max cycle ergometer test represented as VO2max (mL·kg−1·min−1). Academic achievement, commencement status and information on covariates were obtained from Danish nationwide registers. Causal inference based mediation analysis was used to investigate the indirect and direct pathways by separating the total effect of physical fitness on post-compulsory education commencement. Results Adjusting for sex, age, ethnicity and socioeconomic status, the overall mediation analysis showed an odds ratio (OR) of 1.87 (95% confidence interval (CI): 1.30; 2.73) for the total effect, corresponding to an increase in odds of post-compulsory education commencement when the physical fitness was increased by 10 units of VO2max. The separated total effect showed a natural direct OR of 1.36 (95% CI: 0.93; 1.98) and a natural indirect (i.e., through academic achievement) OR of 1.37 (95% CI: 1.20; 1.57). Thus, 51% (95% CI: 27%; 122%) of the effect of physical fitness on post-compulsory education commencement was mediated through academic achievement. Conclusion Physical fitness had a positive effect on post-compulsory education commencement. A substantial part of this effect was mediated through academic achievement.

Background: Some studies have found positive associations between physical fitness and academic achievements. Pupils' academic achievements should indicate scholastic abilities to commence a post-compulsory education. However, the effect magnitude of physical fitness and academic achievements on commencement in post-compulsory education is unknown. We examined the pathways between physical fitness and academic achievement on pupils' commencement in post-compulsory education. Methods: This historical cohort study followed 530 girls and 554 boys from the Danish municipality of Aalborg in the period 2008-2014, 13 to 15 years old in 2010. Physical fitness was assessed through a watt-max cycle ergometer test represented as VO2max (mL·kg-1·min-1). Academic achievement, commencement status and information on covariates were obtained from Danish nationwide registers. Causal inference based mediation analysis was used to investigate the indirect and direct pathways by separating the total effect of physical fitness on post-compulsory education commencement. Results: Adjusting for sex, age, ethnicity and socioeconomic status, the overall mediation analysis showed an odds ratio (OR) of 1.87 (95% confidence interval (CI): 1.30; 2.73) for the total effect, corresponding to an increase in odds of post-compulsory education commencement when the physical fitness was increased by 10 units of VO2max. The separated total effect showed a natural direct OR of 1.36 (95% CI: 0.93; 1.98) and a natural indirect (i.e., through academic achievement) OR of 1.37 (95% CI: 1.20; 1.57). Thus, 51% (95% CI: 27%; 122%) of the effect of physical fitness on post-compulsory education commencement was mediated through academic achievement. Conclusion: Physical fitness had a positive effect on post-compulsory education commencement. A substantial part of this effect was mediated through academic achievement.

We thank Dr. Goto for his editorial in the Journal of Emergency and Critical Care Medicine entitled “Bystander Interventions for Out-of-Hospital Cardiac Arrests: Substantiated Critical Components of the Chain of Survival” (1), commenting on the recent New England Journal of Medicine manuscript “Bystander Efforts and 1-Year Outcomes in Out-of-Hospital Cardiac Arrest” conducted by our research group (2). Dr. Goto’s outline of the nationwide initiatives taken in Denmark during the last ten to fifteen years to increase rates of early resuscitative efforts by bystanders is extensively and accurately described. These initiatives include widespread voluntary and mandatory courses in basic life support, introduction and implementation of dispatch-assisted CPR, widespread automated external defibrillator (AED) dissemination and formation of an AED registry and linkage to emergency dispatch centers, enabling healthcare professionals to guide bystanders to the nearest AED (1-4). Bystander CPR and 30-day survival rates have more than tripled since the beginning of the past decade, where the Danish Cardiac Arrest Registry was established (5). In addition to the increased survival rates, Dr. Goto also highlighted from our recent New England Journal of Medicine manuscript that 30-day survivors were significantly less likely to be diagnosed with anoxic brain damage or admitted to a nursing home during the first year after out-of-hospital cardiac arrest (OHCA) had they received bystander CPR or bystander defibrillation relative to no bystander resuscitation (1,2).

Aims To compare the hazard of all-cause, chronic obstructive pulmonary disease (COPD) and heart failure (HF) hospitalization in carvedilol vs. metoprolol/bisoprolol/nebivolol users with COPD and concurrent HF from 2009 to 2012, and to evaluate the use and persistence in treatment of these β-blockers, their impact on the risk of COPD-related hospitalization, and the factors important for their selection. Methods and results Cox and logistic regression were used for both unadjusted and adjusted analyses. Carvedilol users had a higher hazard of being hospitalized for HF compared with metoprolol/bisoprolol/nebivolol users in both the unadjusted [hazard ratio (HR) 1.74; 95% confidence interval (CI) 1.65-1.83] and adjusted (HR 1.61; 95% CI 1.52-1.70) analyses. No significant differences were found for all-cause and COPD hospitalization between the two groups. Carvedilol users had a significant lower restricted mean persistence time than metoprolol/bisoprolol/nebivolol users. Patients exposed to carvedilol had an odds ratio (OR) of 1.38 (95% CI 1.23-1.56) for being hospitalized due to COPD within 60 days after redeeming the first carvedilol prescription, which was similar to that observed in metoprolol/bisoprolol/nebivolol users (OR 1.37; 95% CI 1.27-1.48). Patients with concurrent chronic kidney disease had a higher probability of receiving carvedilol (OR 1.16; 95% CI 1.04-1.29). Conclusion Carvedilol prescription carried an increased hazard of HF hospitalization and lower restricted mean persistence time among patients with COPD and concurrent HF. Additionally, we found a widespread phenomenon of carvedilol prescription at variance with the European Society of Cardiology guidelines and potential for improving the proportion of patients treated with β-blockers.