Are Outcomes From an Exercise Therapy and Patient Education Program for Osteoarthritis Associated With Hip and Knee Replacement Within Two Years? A Register-Based Study of 9,339 Patients With Osteoarthritis.

OBJECTIVE: The objective of this study was to determine whether short-term outcomes from exercise therapy and patient education for osteoarthritis (OA) are associated with hip or knee replacement within two years. METHODS: Individual-level data from the Good Life with osteoArthritis in Denmark (GLA:D) Registry were linked to the Danish National Patient Registry and other national registries. Cox proportional hazards models were used to investigate associations between program outcomes (baseline to three-month changes) and time to primary hip or knee replacement. Patients who did not receive joint replacement were censored at two years, time of death, or emigration. RESULTS: A total of 2,304 and 7,035 patients with clinically diagnosed hip and knee OA, respectively, were included. Of these, 30% with hip OA and 10% with knee OA had joint replacement within two years. Postprogram improvements in hip-related quality of life and arthritis self-efficacy (pain subscale) were associated with a reduced hazard of hip replacement (adjusted hazard ratios [HRs] for a 10-unit improvement: 0.74 [95% confidence interval (CI) 0.69-0.80] and 0.90 [95% CI 0.85-0.96], respectively). Improvements in knee pain, knee-related quality of life, and arthritis self-efficacy (pain subscale) were associated with a lower hazard of knee replacement (adjusted HRs for 10-unit improvement: 0.81 [95% CI 0.76-0.86] to 0.90 [95% CI 0.86-0.95], 0.70 [95% CI 0.63-0.78] to 0.79 [95% CI 0.72-0.86], and 0.89 [95% CI 0.83-0.94], respectively). CONCLUSION: The magnitude of improvement in key measures after exercise therapy and education was significantly associated with the likelihood of surgery. Progression to hip replacement was three times higher than progression to knee replacement. This information can guide patient-clinician conversations around anticipated program outcomes.

Cardiovascular risks of continuing vs. initiating NSAIDs after first-time myocardial infarction or heart failure: a nationwide cohort study.

AIMS: It is unknown whether the cardiovascular risks associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) shortly after first-time myocardial infarction (MI) or heart failure (HF) differ between patients continuing and initiating use. METHODS AND RESULTS: Using nationwide health registries, we conducted a cohort study of all patients with first-time MI or HF during 1996-2018 (n = 273 682). NSAID users (n = 97 966) were categorized as continuing (17%) and initiating (83%) users according to prescription fillings < 60 days before index diagnosis. The primary outcome was a composite of new MI, HF admission, and all-cause death. Follow-up started 30 days after the index discharge date. We used Cox regression to compute hazard ratios (HRs) with 95% confidence intervals (CIs) comparing NSAID users vs. non-users. The most commonly filled NSAIDs were ibuprofen (50%), diclofenac (20%), etodolac (8.5%), and naproxen (4.3%). The composite outcome HR of 1.25 (CI: 1.23-1.27) was driven by initiators (HR = 1.39, 1.36-1.41) and not continuing users (HR = 1.03, 1.00-1.07). The lack of association among continuing users was also observed for individual NSAIDs (ibuprofen and naproxen), except diclofenac (HR = 1.11, 95% CI: 1.05-1.18). Among initiators, the HR was 1.63 (CI: 1.57-1.69) for diclofenac, 1.31 (CI: 1.27-1.35) for ibuprofen, and 1.19 (CI: 1.08-1.31) for naproxen. The results were consistent for both MI and HF patients, the individual components of the composite outcome, and various sensitivity analyses. CONCLUSION: NSAID initiators were more susceptible to adverse cardiovascular outcomes after first-time MI or HF than continuing users.

Dicloxacillin-warfarin drug-drug interaction-A register-based study and in vitro investigations in 3D spheroid primary human hepatocytes.

AIMS: Dicloxacillin is used to treat staphylococcal infections and we have previously shown that dicloxacillin is an inducer of cytochrome P450 enzymes (CYPs). Here, we employed a translational approach to investigate the effect of a treatment with dicloxacillin on warfarin efficacy in Danish registries. Furthermore, we assessed dicloxacillin as an inducer of CYPs in vitro. METHODS: We conducted a register-based study and analysed international normalized ratio (INR) levels in chronic warfarin users before and after short- and long-term use of dicloxacillin (n = 1023) and flucloxacillin (n = 123). Induction of CYPs were investigated in a novel liver model of 3D spheroid primary human hepatocytes at the level of mRNA, and protein and enzyme activity. RESULTS: Short- and long-term dicloxacillin treatments decreased INR levels by -0.65 (95% confidence interval [CI]: -0.57 to -0.74) and -0.76 (95% CI: -0.50 to -1.02), respectively. More than 90% of individuals experienced subtherapeutic INR levels (below 2) after long-term dicloxacillin treatment. Flucloxacillin decreased INR levels by -0.37 (95% CI: -0.14 to -0.60). In 3D spheroid primary human hepatocytes, the maximal induction of CYP3A4 mRNA, protein and enzyme activity by dicloxacillin were 4.9-, 2.9- and 2.4-fold, respectively. Dicloxacillin also induced CYP2C9 mRNA by 1.7-fold. CONCLUSION: Dicloxacillin induces CYPs and reduces the clinical efficacy of warfarin in patients. This effect is substantially exacerbated during long-term treatment with dicloxacillin. The in vitro results corroborated this drug-drug interaction and correlated to the clinical findings. Caution is warranted for warfarin patients that initiate dicloxacillin or flucloxacillin, especially for a long-term treatment of endocarditis.

Initiation of glucose-lowering drugs reduces the anticoagulant effect of warfarin-But not through altered drug metabolism in patients with type 2 diabetes.

AIMS: Drug metabolism might be altered in patients with type 2 diabetes. We aimed to evaluate if initiation of glucose-lowering drugs impacts warfarin efficacy and drug metabolism. METHODS: First, we conducted a register-based self-controlled cohort study on Danish and Scottish warfarin users. Warfarin efficacy (international normalized ratio [INR]) was compared before and after initiation of glucose-lowering drugs. Second, we conducted a clinical pharmacokinetic trial comprising treatment-naïve type 2 diabetes patients. Patients ingested probe drugs for drug-metabolizing enzymes (the Basel Cocktail) before initiating glucose-lowering treatment, and after 3 and 12 weeks of treatment. Drug metabolism, glycaemic control, and inflammation were assessed on each visit. RESULTS: In the Danish and Scottish cohorts (n = 982 and n = 44, respectively), initiating glucose-lowering drugs reduced warfarin efficacy. INR decreased from 2.47 to 2.21 in the Danish cohort (mean difference -0.26; 95% CI -0.35; -0.17) and from 2.33 to 2.13 in the Scottish cohort (-0.21; 95% CI -0.52; 0.11) after initiation of glucose-lowering treatment. This impact on INR was more pronounced among individuals with stronger effects of glucose-lowering treatment. In the clinical pharmacokinetic trial (n = 10), initiating metformin did not affect drug metabolism after 3 weeks (geometric mean ratio of CYP3A metabolic ratio: 1.12 [95% CI: 0.95; 1.32]) or 12 weeks of metformin treatment. Glycaemic control improved during treatment, while inflammation remained low and unchanged during treatment. CONCLUSIONS: In conclusion, initiation of glucose-lowering drugs among chronic warfarin users seems associated with a reduction in INR, particularly among individuals with a large decrease in HbA1c . This effect seems unrelated to CYP enzyme activity and warfarin drug metabolism.

Epidemiological Factors Associated with Prescription of Opioids for Chronic Non-Cancer Pain in Adults: A Country-Wide, Registry-Based Study in Denmark Spans 2004-2018.

Purpose: Denmark has a high consumption of prescribed opioids, and many citizens with chronic non-cancer pain (CNCP). Therefore, we aimed to characterize and assess epidemiological risk factors associated with long-term non-cancer opioid use among Danish citizens. Patients and Methods: We conducted a longitudinal, retrospective, observational, register-based study using nationwide databases containing essential medical, healthcare, and socio-economic information. Statistical analysis, including backward stepwise logistic regression analysis, was used to explain long-term opioid use by individuals filling at least one prescription for an opioid product N02AA01-N02AX06 during 01/01/2004-31/12/2017, follow-up until the end of 2018. Results: The analyzed cohort contained N=1,683,713 non-cancer opioid users, of which 979,666 were classified with CNCP diagnosis using ICD-10 codes. Long-term opioid use was predicted by a mean of 1,583.30 and a median of 300 oral morphine equivalent mg (OMEQ) per day during the first year, together with divorced, age group 40-53 years, retirement, receiving social welfare or unemployment ≥6 months. In addition, living in Northern Jutland, co-medications such as beta-blockers, anti-diabetics, anti-rheumatics, and minor surgery ≤90 days before inclusion. Protective variables were an education level of secondary school or higher, children living at home, household income of middle or highest tertile, opioid doses in either the 2nd or 3rd quartile OMEQ, male, the oldest age group, living in the Capital Region or Zealand, co-medication lipid-lowering, one comorbidity, heart failure, surgeries ≤90 days before the index: lips/teeth/jaw/mouth/throat, heart/vessels, elbow/forearm, hip/thigh, knee/lower leg/ankle/foot. Conclusion: Long-term opioid users differ epidemiologically from those using opioids for a shorter period. The study findings are essential for future recommendations revision in Denmark and comparable countries.

Development and Validation of a Nordic Multimorbidity Index Based on Hospital Diagnoses and Filled Prescriptions.

Purpose: To develop the Nordic Multimorbidity Index (NMI), a multimorbidity measure specifically suited to the Nordic health and administrative registry data based on current diagnosis, treatment, and coding practices. Methods: The NMI was developed to predict 5-year mortality in a population-based cohort of randomly sampled Danish residents aged ≥40 years (n = 425,087) followed from 2013 to 2018. Included predictors were selected from hospital diagnoses and filled drug prescriptions based on a combination of subject matter knowledge and a data-driven approach using backwards elimination. The performance of the NMI was assessed in a temporal validation cohort of Danish residents followed from 2007 to 2012 and in six cohorts of new users of selected drugs. The discriminative performance of the NMI, Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) was assessed using the c-statistic from logistic regression models with 5-year mortality as dependent variable and the multimorbidity index score, age, and sex as independent variables. Results: The NMI included 50 predictors. In the temporal validation cohort, the c-statistic of the NMI (0.887, 95% CI 0.883-0.890) exceeded that of the CCI (0.871, 95% CI 0.868-0.874) and ECI (0.866, 95% CI 0.863-0.870). In all new user cohorts, the NMI outperformed the other indices with c-statistics ranging from 0.781 (95% CI 0.779-0.784) to 0.838 (95% CI 0.834-0.842). Conclusion: The NMI predicted 5-year mortality in a general Danish population and six cohorts of new users of selected drugs and was superior to the CCI and ECI. The NMI could be preferred over these indices to quantify the level of multimorbidity for, eg, descriptive purposes or confounding control. The NMI should be validated in other patient populations and other Nordic countries.

Statin Discontinuation and Cardiovascular Events Among Older People in Denmark.

Importance: Statin use is common in older persons. Given uncertainties in ongoing benefit, changes in health status, and shifting goals of care and preferences, statin discontinuation may be considered in some older persons, although there is currently little evidence to guide this decision. Objective: To evaluate the association between statin discontinuation and the rate of major adverse cardiovascular events (MACE) among people aged 75 years or older who receive long-term statin treatment. Design, Setting, and Participants: This cohort study included all persons in Denmark aged 75 years or older who were treated with statins for at least 5 consecutive years as of January 1, 2011. Participants were followed up until December 31, 2016. Data were analyzed from July to November, 2020. Exposure: Statin discontinuation. Main Outcomes and Measures: Rate of occurrence of MACE and its components (myocardial infarction, ischemic stroke or transient ischemic attack, coronary revascularization, and death due to myocardial infarction or ischemic stroke) in persons continuing statins compared with those discontinuing statins. Confounding adjustment was done using inverse probability of treatment weighting. Analyses were conducted separately for primary prevention (no history of cardiovascular disease) and secondary prevention (history of cardiovascular disease). Results: The study included 67 418 long-term statin users, including 27 463 in the primary prevention analysis (median age, 79 years [IQR, 77-83 years]; 18 134 [66%] female) and 39 955 in the secondary prevention analysis (median age, 80 years [IQR, 77-84 years]; 18 717 [47%] female). In both primary and secondary prevention analyses, the rate of MACE was higher among persons who discontinued statins compared with those who continued statins. In the primary prevention cohort, the weighted rate difference was 9 per 1000 person-years (95% CI, 5-12 per 1000 person-years) and the adjusted sub-hazard ratio was 1.32 (95% CI, 1.18-1.48), corresponding to 1 excess MACE per 112 persons who discontinued statins per year. In the secondary prevention cohort, the weighted rate difference was 13 per 1000 person-years (95% CI, 8-17 per 1000 person-years) and the adjusted sub-hazard ratio was 1.28 (95% CI, 1.18-1.39), corresponding to 1 excess MACE per 77 persons who discontinued statins per year. Conclusions and Relevance: In this cohort study, among older adults receiving long-term statin treatment, discontinuation of statins was associated with a higher rate of MACE compared with statin continuation in both the primary and the secondary prevention cohorts. These findings suggest a need for robust evidence from randomized clinical trials.

Prognostic factors of total hip replacement during a 2-year period in participants enrolled in supervised education and exercise therapy: a prognostic study of 3657 participants with hip osteoarthritis.

BACKGROUND: Evidence on prognostic factors associated with progression to total hip replacement (THR) in hip osteoarthritis (OA) is for the most patient- and disease-specific characteristics either conflicting or inconclusive. Therefore, the objectives of this study of participants with hip OA enrolled in a structured program of supervised education and exercise therapy were to describe the rate of THR and to identify prognostic factors for receiving THR within the following 2 years. METHODS: Participants aged ≥ 45 years with hip OA enrolled in Good Life with osteoArthritis in Denmark (GLA:D®) from July 2014 to March 2017 were included. Potential prognostic factors included demographic and disease-specific baseline characteristics and measures of physical activity and quality of life (QoL). Information on THR was retrieved from The Danish National Patient Registry. A multivariable Cox proportional hazards model was developed. RESULTS: Of 3657 included participants, 30% received a THR within 2 years. Of the 100 participants already wait-listed for THR, 60% had the procedure. Of 22 candidate prognostic factors, 14 were statistically significant for receiving THR. Factors associated with a faster rate of THR included being "male" (HR 1.43), having "self-reported radiographic hip OA" (HR 2.32), being "wait-listed for THR" (HR 2.17), and having a higher "pain intensity" (HR 1.01). In contrast, faster "walking speed" (HR 0.64), better "hip-related QoL" (HR 0.98), and having "three or more comorbidities" (HR 0.62) were predictive of a slower rate of THR. CONCLUSION: During the 2-year follow-up period, 30% of the cohort received a THR. Notably, 40% of those wait-listed for THR when entering the program did not receive THR within 2 years. A number of baseline prognostic factors for receiving THR were identified.

Proton Pump Inhibitor Use Is Not Strongly Associated With SARS-CoV-2 Related Outcomes: A Nationwide Study and Meta-analysis.

BACKGROUND & AIMS: Proton pump inhibitor (PPI) use has been associated with increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe outcomes. However, meta-analyses show unclear results, leading to uncertainty regarding the safety of PPI use during the ongoing coronavirus disease 2019 (COVID-19) pandemic. METHODS: We conducted a nationwide observational study including all SARS-CoV-2 cases (n = 83,224) in Denmark as of December 1, 2020. The association of current PPI use with risk of infection was examined in a case-control design. We investigated the risk of severe outcomes, including mechanical ventilation, intensive care unit admission, or death, in current PPI users (n = 4473) compared with never users. Propensity score matching was applied to control for confounding. Finally, we performed an updated meta-analysis on risk of SARS-CoV-2 infection and COVID-19 mortality attributable to PPI use. RESULTS: Current PPI use was associated with increased risk of infection; adjusted odds ratio, 1.08 (95% confidence interval [CI], 1.03-1.13). Among SARS-CoV-2 cases, PPI use was associated with increased risk of hospital admission; adjusted relative risk, 1.13 (1.03-1.24), but not with other severe outcomes. The updated meta-analysis showed no association between PPI use and risk of infection or mortality; pooled odds ratio, 1.00 (95% CI, 0.75-1.32) and relative risk, 1.33 (95% CI, 0.71-2.48). CONCLUSIONS: Current PPI use may be associated with an increased risk of SARS-CoV-2 infection and hospital admission, but these results with minimally elevated estimates are most likely subject to residual confounding. No association was found for severe outcomes. The results from the meta-analysis indicated no impact of current PPI use on COVID-19 outcomes.

Impact of EMA regulatory label changes on hydroxyzine initiation, discontinuation and switching to other medicines in Denmark, Scotland, England and the Netherlands: An interrupted time series regression analysis.

BACKGROUND: Hydroxyzine is indicated for the management of anxiety, skin and sleep disorders. In 2015, the European Medicines Agency (EMA) concluded that hydroxyzine was pro-arrhythmogenic and changes to the product information were implemented in Europe. This study aimed to evaluate their impact in Denmark, Scotland, England and the Netherlands. METHOD: Quarterly time series analyses measuring hydroxyzine initiation, discontinuation, and switching to other antihistamines, benzodiazepines and antidepressants in Denmark, England, Scotland and the Netherlands from 2009 to 2018. Data were analysed using interrupted time series regression. RESULTS: Hydroxyzine initiation in quarter one 2010 in Denmark, Scotland, England and the Netherlands per 100 000 was: 23.5, 91.5, 35.9 and 34.4 respectively. Regulatory action was associated with a significant: immediate fall in hydroxyzine initiation per 100 000 in England (-12.05, 95%CI -18.47 to -5.63) and Scotland (-19.01, 95%CI -26.99 to -11.02); change to a negative trend in hydroxyzine initiation per 100 000/quarter in England (-1.72, 95%CI -2.69 to -0.75) and Scotland (-2.38, 95%CI -3.32 to -1.44). Regulatory action was associated with a significant: immediate rise in hydroxyzine discontinuation per 100 000 in England (3850, 95%CI 440-7240). No consistent changes were observed in the Netherlands or Denmark. Regulatory action was associated with no switching to other antihistamines, benzodiazepines or antidepressants following hydroxyzine discontinuation in any country. CONCLUSION: The 2015 EMA regulatory action was associated with heterogeneous impact with reductions in hydroxyzine initiation varying by country. There was limited impact on discontinuation with no strong evidence suggesting unintended consequences of major switching to other antihistamines, benzodiazepines or antidepressants.

Use of tramadol and other analgesics following media attention and risk minimization actions from regulators: a Danish nationwide drug utilization study.

PURPOSE: To describe the use of tramadol and other analgesics in Denmark focusing on the impact of media attention (June and December 2017) and regulatory actions (September 2017 and January 2018) on the use of tramadol. METHODS: Using nationwide registries, we identified all adults who filled a prescription for tramadol and other analgesics from 2014 to 2019. We described incidence rates, prevalence proportions, and total use of tramadol and other analgesics over time. We also described switching between analgesics, treatment duration, skewness in drug use, and doctor-shopping. RESULTS: From early 2017 until the end of 2019, total tramadol use decreased markedly while the use of morphine and oxycodone decreased slightly. The quarterly prevalence of tramadol use decreased from 32/1000 individuals in 2014 to 18/1000 at the end of 2019, dropping mainly at the time of media attention. Concomitantly, the quarterly prevalence increased for oxycodone (from 5.1 to 8.2) and morphine (from 8.5 to 9.8), mainly due to more short-term and sporadic users, and decreased for codeine (14 to 9.6). From 2014 to mid-2017, the incidence of tramadol use was stable (around 2.2/1000 person-months) but dropped in June 2017 to 1.7/1000, coinciding with the media attention. The incidence of tramadol use continued to decrease (to 1.1/1000 at the end of 2019). CONCLUSION: We identified a decline in tramadol use coinciding with the media attention in 2017 and continuing during regulatory actions. There was generally no evidence of unintended effects on the utilization of opioids related to the media attention and regulatory actions.

Impact of EU regulatory label changes for diclofenac in people with cardiovascular disease in four countries: Interrupted time series regression analysis.

OBJECTIVE: Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations. METHOD: Quarterly interrupted time series regression (ITS) analyses of diclofenac initiation among cohorts with contraindications (congestive cardiac failure [CHF], ischaemic heart disease [IHD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]) and cautions (hypertension, hyperlipidaemia, diabetes) from Denmark, the Netherlands, England and Scotland. RESULTS: The regulatory action was associated with significant immediate absolute reductions in diclofenac initiation in all countries for IHD (Denmark -0.08%, 95%CI -0.13, -0.03; England -0.09%, 95%CI -0.13 to -0.06%; the Netherlands -1.84%, 95%CI -2.51 to -1.17%; Scotland -0.34%, 95%CI -0.38 to -0.30%), PAD and hyperlipidaemia, the Netherlands, England and Scotland for hypertension and diabetes, and England and Scotland for CHF and CVD. Post-intervention there was a significant negative trend in diclofenac initiation in the Netherlands for IHD (-0.12%, 95%CI -0.19 to -0.04), PAD (-0.13%, 95%CI -0.22 to -0.05), hypertension, hyperlipidaemia and diabetes, and in Scotland for CHF (-0.01%, 95%CI -0.02 to -0.007%), IHD (-0.017, 95%CI -0.02, -0.01%), PAD and hypertension. In England, diclofenac initiation rates fell less steeply. In Denmark changes were more strongly associated with the earlier EMA 2012 regulatory action. CONCLUSION: Although significant reductions in diclofenac initiation occurred, patients with contraindications continued to be prescribed diclofenac, the extent of which varied by country and target condition. Understanding reasons for such variation may help to guide the design or dissemination of future safety warnings.

Use of Tic-Suppressing Medication and Other Psychotropic Drugs in Children and Adolescents with Newly Diagnosed Tic Disorders in Denmark.

Objective: Only few psychotropic drugs are approved to treat tic disorders. The aim was to describe use of tic-suppressing medication and other psychotropic drugs in children with tics. Methods: Using nationwide registries, we identified children receiving a tic diagnosis in Denmark during 2006-2017 and extracted data on tic-suppressing medication and other psychotropic drugs. Results: Antipsychotics were used by 12%. Use of tic-suppressing medication increased with age and varied according to sex. Over time less children with tics were medicated (from 44% to 38% in the total use of psychotropic drugs) mainly due to decreased use of antipsychotics (from 18% to 6.4%). In recent years, use of aripiprazole exceeded that of risperidone (38% vs. 35%), although risperidone was most often first choice (34%) followed by aripiprazole (22%). Most children stayed on their initial treatment. Attention-deficit/hyperactivity disorder medication (27%) was the most common additional psychotropic drug class used. Regional variations were found in the treatment of tics. Hospital specialists were mainly responsible for treatment. Conclusions: Most children with tics do not use tic-suppressing or other psychotropic drugs. The use of aripiprazole superseded risperidone, however risperidone remains the most common first-choice treatment. Treatment was mainly handled by specialists, which is reassuring given the lack of national guidelines, however, regional variations merit further attention as do the variation in treatment between young girls and boys.

Characteristics and predictors of hospitalization and death in the first 11 122 cases with a positive RT-PCR test for SARS-CoV-2 in Denmark: a nationwide cohort.

BACKGROUND: Population-level knowledge on individuals at high risk of severe and fatal coronavirus disease 2019 (COVID-19) is urgently needed to inform targeted protection strategies in the general population. METHODS: We examined characteristics and predictors of hospitalization and death in a nationwide cohort of all Danish individuals tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from 27 February 2020 until 19 May 2020. RESULTS: We identified 11 122 SARS-CoV-2 polymerase chain reaction-positive cases of whom 80% were community-managed and 20% were hospitalized. Thirty-day all-cause mortality was 5.2%. Age was strongly associated with fatal disease {odds ratio [OR] 15 [95% confidence interval (CI): 9-26] for 70-79 years, increasing to OR 90 (95% CI: 50-162) for ≥90 years, when compared with cases aged 50-59 years and adjusted for sex and number of co-morbidities}. Similarly, the number of co-morbidities was associated with fatal disease [OR 5.2 (95% CI: 3.4-8.0), for cases with at least four co-morbidities vs no co-morbidities] and 79% of fatal cases had at least two co-morbidities. Most major chronic diseases were associated with hospitalization, with ORs ranging from 1.3-1.4 (e.g. stroke, ischaemic heart disease) to 2.6-3.4 (e.g. heart failure, hospital-diagnosed kidney disease, organ transplantation) and with mortality with ORs ranging from 1.1-1.3 (e.g. ischaemic heart disease, hypertension) to 2.5-3.2 (e.g. major psychiatric disorder, organ transplantation). In the absence of co-morbidities, mortality was <5% in persons aged ≤80 years. CONCLUSIONS: In this nationwide population-based COVID-19 study, increasing age and multimorbidity were strongly associated with hospitalization and death. In the absence of co-morbidities, the mortality was, however, <5% until the age of 80 years.

Existing Data Sources in Clinical Epidemiology: The Danish COVID-19 Cohort.

BACKGROUND: To facilitate research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a prospective cohort of all Danish residents tested for SARS-CoV-2 in Denmark is established. DATA STRUCTURE: All Danish residents tested by reverse transcriptase polymerase chain reactions (RT-PCR) for SARS-CoV-2 in Denmark are included. The cohort is identified using the Danish Microbiology Database. Individual-level record linkage between administrative and health-care registries is facilitated by the Danish Civil Registration System. Information on outcomes related to SARS-CoV-2 infection includes hospital admission, intensive care unit admission, mechanical ventilation, and death and is retrieved from the five administrative Danish regions, the Danish National Patient Registry, and the Danish Register of Causes of Death. The Patient Registry further provides a complete hospital contact history of somatic and psychiatric conditions and procedures. Data on all prescriptions filled at community pharmacies are available from the Danish National Prescription Registry. Health-care authorization status is obtained from the Danish Register of Healthcare Professionals. Finally, selected laboratory values are obtained from the Register of Laboratory Results for Research. The cohort is governed by a steering committee with representatives from the Danish Medicines Agency, Statens Serum Institut, the Danish Health Authority, the Danish Health Data Authority, Danish Patients, the Faculties of Health Sciences at the Danish universities, and Danish regions. The steering committee welcomes suggestions for research studies and collaborations. Research proposals will be prioritized based on timeliness and potential clinical and public health implications. All research protocols assessing specific hypotheses for medicines will be made publicly available using the European Union electronic Register of Post-Authorisation Studies. CONCLUSION: The Danish COVID-19 cohort includes all Danish residents with an RT-PCR test for SARS-CoV-2. Through individual-level linkage with existing Danish health and administrative registries, this is a valuable data source for epidemiological research on SARS-CoV-2.

Impact of EMA regulatory label changes on systemic diclofenac initiation, discontinuation, and switching to other pain medicines in Scotland, England, Denmark, and The Netherlands.

PURPOSE: In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescribing of systemic diclofenac in Denmark, The Netherlands, England, and Scotland. METHODS: Quarterly time series analyses measuring diclofenac prescription initiation, discontinuation and switching to other systemic nonsteroidal anti-inflammatory (NSAIDs), topical NSAIDs, paracetamol, opioids, and other chronic pain medication in those who discontinued diclofenac. Absolute effects were estimated using interrupted time series regression. RESULTS: Overall, diclofenac prescription initiations fell during the observation periods of all countries. Compared with Denmark where there appeared to be a more limited effect, the regulatory action was associated with significant immediate reductions in diclofenac initiation in The Netherlands (-0.42%, 95% CI, -0.66% to -0.18%), England (-0.09%, 95% CI, -0.11% to -0.08%), and Scotland (-0.67%, 95% CI, -0.79% to -0.55%); and falling trends in diclofenac initiation in the Netherlands (-0.03%, 95% CI, -0.06% to -0.01% per quarter) and Scotland (-0.04%, 95% CI, -0.05% to -0.02% per quarter). There was no significant impact on diclofenac discontinuation in any country. The regulatory action was associated with modest differences in switching to other pain medicines following diclofenac discontinuation. CONCLUSIONS: The regulatory action was associated with significant reductions in overall diclofenac initiation which varied by country and type of exposure. There was no impact on discontinuation and variable impact on switching.

Ischemic Stroke and Systemic Embolism in Warfarin Users With Atrial Fibrillation or Heart Valve Replacement Exposed to Dicloxacillin or Flucloxacillin.

The antibiotics dicloxacillin and flucloxacillin induce cytochrome P450-dependent metabolism of warfarin. We explored the influence of these drug-drug interactions on the clinical effectiveness of warfarin therapy due to atrial fibrillation or heart valve replacement. Using the population-based Danish registers, we performed a propensity-score matched cohort study including around 50,000 episodes of dicloxacillin/flucloxacillin matched to phenoxymethylpenicillin and to no antibiotic, respectively. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) by comparing 21-day (days 7-28) risks of ischemic stroke/systemic embolism (SE) following initiation of each exposure. When compared with phenoxymethylpenicillin, dicloxacillin/flucloxacillin was associated with an HR of ischemic stroke/SE of 2.09 (95% CI 1.51-2.90; strongest for dicloxacillin (HR 2.17; 95% CI 1.56-3.02)). Use of an untreated comparator strengthened the association (HR 2.84; 95% CI 1.97-4.09). Dicloxacillin should be used with caution in patients receiving warfarin. This may also apply to flucloxacillin; however, more data on the risks associated with flucloxacillin exposure during warfarin therapy are needed.

Classroom-based physical activity improves children's math achievement - A randomized controlled trial.

This RCT investigated the effect on children of integrating physical activity (PA) into math lessons. The primary outcome was math achievement and the secondary outcomes were executive functions, fitness and body mass index. Twelve Danish schools were randomized to either an intervention group or a control group. A total of 505 children with mean age 7.2 ± 0.3 years were enrolled in the study. Change in math achievement was measured by a 45-minute standardized math test, change in executive function by a modified Eriksen flanker task, aerobic fitness by the Andersen intermittent shuttle-run test, and body mass index by standard procedures. PA during the math lessons and total PA (including time spent outside school) were assessed using accelerometry (ActiGraph, GT3X and GT3X+). Children in the intervention group improved their math score by 1.2 (95% CI 0.3; 2.1) more than the control group (p = 0.011) and had a tendency towards a higher change in physical activity level during math lessons of 120,4 counts/min (95% CI -9.0;249.8.2, p = 0.067). However, the intervention did not affect executive functions, fitness or body mass index. Participation in a 9-month PA intervention (from 2012-2013) improved math achievement among elementary school children. If replicated, these findings would suggest that implementation of physical activity in school settings could lead to higher academic achievement.

Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study.

OBJECTIVE: To perform an expedited assessment of cancer risk associated with exposure to N-nitrosodimethylamine (NDMA) through contaminated valsartan products. DESIGN: Nationwide cohort study. SETTING: Danish health registries on individual level prescription drug use, cancer occurrence, and hospital diagnoses. PARTICIPANTS: 5150 Danish patients with no history of cancer, aged 40 years or older, and using valsartan at 1 January 2012 or initiating use between 1 January 2012 and 30 June 2017. Participants were followed from one year after cohort entry (lag time period) until experiencing a cancer outcome, death, migration, or end of study period (30 June 2018). Each participant's exposure to NDMA (ever exposure and predefined categories of cumulative valsartan exposure) was mapped out as a time varying variable while also applying a one year lag. MAIN OUTCOME MEASURES: Association between NDMA exposure and a primary composite endpoint comprising all cancers except non-melanoma skin cancer, estimated using Cox regression. In supplementary analyses, the risk of individual cancers was determined. RESULTS: The final cohort comprised 5150 people followed for a median of 4.6 years. In total, 3625 cohort participants contributed 7344 person years classified as unexposed to NDMA, and 3450 participants contributed 11 920 person years classified as ever exposed to NDMA. With 104 cancer outcomes among NDMA unexposed participants and 198 among exposed participants, the adjusted hazard ratio for overall cancer was 1.09 (95% confidence interval 0.85 to 1.41), with no evidence of a dose-response relation (P=0.70). For single cancer outcomes, increases in risk were observed for colorectal cancer (hazard ratio 1.46, 95% confidence interval 0.79 to 2.73) and for uterine cancer (1.81, 0.55 to 5.90), although with wide confidence intervals that included the null. CONCLUSIONS: The results do not imply a markedly increased short term overall risk of cancer in users of valsartan contaminated with NDMA. However, uncertainty persists about single cancer outcomes, and studies with longer follow-up are needed to assess long term cancer risk.